Title of Invention	THIOPHENE AMIDINES
Abstract	Disclosed is a method for treating the symptoms of an acute or chronic disorder mediated by the classical pathway of the complement cascade, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula (I) or a solvate. hydrate or pharmaceutically acceptable salt thereof: wherein R1, R2, R3, R4 and R7 are defined in the specification, Z is SO or SO2 and Ar is an aromatic or heteroaromatic group as defined herein.

Title of Invention

THIOPHENE AMIDINES

Abstract

Disclosed is a method for treating the symptoms of an acute or chronic disorder mediated by the classical pathway of the complement cascade, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula (I) or a solvate. hydrate or pharmaceutically acceptable salt thereof: wherein R1, R2, R3, R4 and R7 are defined in the specification, Z is SO or SO2 and Ar is an aromatic or heteroaromatic group as defined herein.

Full Text	Thiophene Amidines Background of the Invention Field of the Invention The present invention is in the field of medicinal chemistry. In particular, the invention is directed to novel heterocyclic amidines and their use for inhibiting the enzyme Cls, a protease in the classical pathway of the complement system; and the use of this inhibition to treat or ameliorate acute or chronic disorders in mammals. Related Art The immune system of the human body is equipped with several defense mechanisms to respond to bacterial, viral, or parasitic infection and injury. One such defense mechanism involves the complement system. Complement consists of a complex series of approximately 30 plasma and membrane protein components, many of which are proteinases. Once activated, this system of enzymes non-specifically complements the imrnunologically specific effects of antibody by modulating the immune response, lysing target cells, stimulating vascular and other smooth muscle cells, facilitating the transport of immune complexes, producing anaphylatoxins which cause degranulation of mast cells and release of histamine, stimulating chemotaxis (migration) of leukocytes toward the area of complement activity, activating B lymphocytes and macrophages, and inducing phagocytosis and lysis of cells (Eisen, H. N., Immunology, Harper & Row Publishers, Inc., Hagerstown, Md., p. 512 (1974); Roitt, I. et al., Immunology, Gower Medical Publishing, London, New York, pp. 7.1-7.14 (1985); U.S. Patent Nos. 5,472,939 and 5,268,363). The complement system functions as a "cascade." The enzyme cascades are initiated when inactive enzyme precursor molecules are activated, through limited proteolysis, by membrane-bound enzymes. A small fragment is lost from the enzyme precursor and a nascent membrane binding site is revealed. The major fragment then binds to the membrane as the next functionally active enzyme of the complement cascade. Since each enzyme is able to activate many enzyme precursors, the system forms an amplifying cascade, resembling the reactions seen in blood clotting and fibrinolysis (Roitt, I. et al., Immunology, Gower Medical Publishing, London, New York, pp. 7.1- 7,14(1985}). The proteins of the complement system form two inter-related enzyme cascades, termed the classical and alternative pathways. The classical pathway is usually initiated by antigen-antibody complexes, while the alternative pathway is activated by specific polysaccharides, often found on bacterial, viral, and parasitic cell surfaces. The classical pathway consists of components C1-C9, while the alternative pathway consists of components C3- C9 (excluding C4) and several factors, such as Factor B, Factor D, and Factor H. The sequence of events comprising the classical complement pathway consists of three stages: recognition, enzymatic activation, and membrane attack leading to cell death. The first phase of complement activation begins with C1. C1 is made up of three distinct proteins: a recognition submit, C1q, and the serine proteinase subcomponents, C1r and C1s, which are bound together in a calcium-dependent tetrameric complex, C1r2S2. An intact C1 complex is necessary for physiological activation of C1 to result. Activation occurs when the intact C1 complex binds to immunoglobulin complexed with antigen. This binding activates C1s which then cleaves both the C4 and C2 proteins to generate C4a and C4b, as well as C2a and C2b. The C4b and C2a fragments combine to form the C3 convertase, which in turn cleaves C3 to form C3a and C3b (Makrides, Pharmacol Rev. 5(9:59-87 (1998); and U.S. Patent No. 5,268,363). Both the classical and alternative pathways are capable of individually inducing the production of the C3 convertase to convert C3 to C3b, the generation of which is the central event of the complement pathway. C3b binds to C3b receptors present on neutrophils, eosinophils, monocytes and macrophages, thereby activating the terminal lytic complement sequence, C5-C9 (Roitt, I. et al.. Immunology, Gower Medical Publishing, London, New York, pp. 7.1-7.14 (1985)). Complement is designed to fight infection and injury; however, this same mechanism, if inappropriately activated, can cause a significant amount of inflammation and tissue damage as a result of the rapid and aggressive enzyme activity. Complement-induced inflammation and tissue damage has been implicated in a number of disease states, including: the intestinal inflammation of Crohn's disease which is characterized by the lymphoid infiltration of mononuclear and polymorphonuclear leukocytes (Ahrenstedt et al., New Engl. J. Med. 322:1345-9 (1990)), thermal injury (burns, frostbite) (Gelfand et al., J. Clin. Invest. 70:1170 (1982); Demling et a!., Surgery 106:52-9(1989)), hemodialysis (Deppisch et al., Kidney fast. 37:696-706 (1990); Kojima et al., Nippon Jenzo Gakkai Shi 31:91-7 (1989)), post pump syndrome in cardiopulmonary bypass (Chenoweth et al., Complement. Injlamm. 5:152-165 (1981); Chenoweth et al., Complement 3:152-165 (1986); Salama et al., N. Engl. J. Med. .318:408-14 (1988)), and ischaemia (Huang et al., Science 285:595 (1999); Naka et al., Transplantation (54:1248 (1997); Pemberton et al., J. Immunol 750:5104 (1993); Chavez-Cartaya et al., Transplantation 59:1047 (1995); Hill et al., J. Immunol. 149:1723 (1992); Weisman et al., Science 249:146 (1990)). Both complement and leukocytes are reported to be implicated in the pathogenesis of adult respiratory distress syndrome (Zilow et al., Clin. Exp. Immunol. 79:151-57 (1990); Langlois et al., Heart Lung 75:71-84 (1989)). Activation of the complement system is suggested to be involved in the development of fatal complications in sepsis (Hack et al., Am. J. Med. 86:20-26 (1989)) and causes tissue injury in animal models of autoimmune diseases such as immune-complex-induced vasculitis (Cochrane, Springer Seminar Immunopathol. 7:263 (1984)), glomerulonephritis (Couser et al., Kidney Inst. 29:879 (1985)), type II collagen-induced arthritis (Watson & Townes,J. Exp. Med. 7(52:1878 (1985)), and experimental allergic neuritis (Feasby et al., Brain Res. 419:91 (1987)). The complement system is also involved in hyperacute allograft and hyperacute xenograft rejection (Knechtle et al., J. Heart Transplant 4(5):54l (1985); Guttman, Transplantation 77:383 (1974); Adachi et al., Trans. Proc. 19(1):1145 (1987)). Complement activation during immunotherapy with recombinant IL-2 appears to cause the severe toxicity and side effects observed from IL-2 treatment (Thijs et al., J. Immunol. 144:2419 (1990)). Complement fragments generated by the classical portion of the complement cascade have been found to be present in the immune complexes formed against indigenous tissue in autoimmune diseases. Such diseases include, but are not limited to: Hashimoto's thyroiditis, glomerulonephritis and cutaneous lesions of systemic lupus erythematosus, other glomerulonephritides, bullous pemphigoid, dermatitis herpetiformis, Goodpasture's syndrome, Graves' disease, myasthenia gravis, insulin resistance, autoimmune hemolyic anemia, autoimmune thrombocytopenic purpura, and rheumatoid arthritis (Biesecker et al. J. Exp. Med. 154: 1779 (1981); Biesecker et al., N. Engl J. Med. 306: 264 (1982); Falk et al.., Clin. Research 32:503A (Abstract) (1984); Falk et al., J. Clin. Invest. 72:560 (1983); Dahl et al., J. Invest. Dennatol 52:132 (1984); Dahl et al., Arch. Dermatol. 121:70 (1985); Sanders et al., Clin. Research 35:388A (Abstract) (1985); and U.S. Patent Nos. 5,268,363 and 4,722,890). Compounds that potently and selectively inhibit complement will have therapeutic applications in several acute and chronic immunological and non- immunological disorders, and a. variety of neurodegenerative diseases. Evidence from both human and animal studies shows that activation of the classical complement pathway is primarily involved in neurodegenerative diseases of the central nervous system (CNS). Autoimmune diseases in which these inhibitors of the complement cascade system will be therapeutically useful include myasthenia gravis (MG), rheumatoid arthritis, and systemic lupus erythematosus. Neurodegenerative diseases in which inhibitors of the complement cascade system, will be therapeutically useful include the demyelinating disorder multiple sclerosis (MS), the neuropathies Guillain- Barre syndrome (GBS) and Miller-Fisher syndrome (MFS), Alzheimer's disease (AID), and prion-related disease (variant Creutzfeld Jacob disease). Other diseases and conditions include hereditary and acquired angioedema (in which a deficiency in complement inhibitory protein leads to an active complement consumption and repeated episodes of life-threatening angiodema), septic shock, paroxysmal nocturnal hemoglobinuria, organ rejection (transplantation), burns (wound healing), brain trauma, soft tissue trauma, asthma, platelet storage, hemodialysis, isehemia-reperfusion injury, and cardiopulmonary bypass equipment (Makrides, Pharmacol. Rev. 50:59-87 (1998); Spiegel et al., Strategies for Inhibition of Complement Activation in the Treatment of Neurodegenerative Diseases in: Nenroinflammation: Mechanisms and Management, Wood (ed.), Humana Press, Inc., Totowa, NJ, Chapter 5, pp. 129-176; and U.S. Patent No. 4,916,219). A number of strategies have been proposed for the inhibition of primarily the classical complement pathway. Efforts to directly inhibit complement activation have focused on chemical compounds that inhibit complement components such as C1r and C1s. Small peptide inhibitors of convertases, such as the C3 and C5 convertases., have also been described (Liszewski and Atkinson, Exp. Opin. Invest. Drugs 7: 323-332 (1998). So far, the best studied 'designer' complement inhibitor for treatment of CNS disorders is soluble recombinant human complement receptor Type 1 (sCR1). sCR1 has proven effective in animal models of CNS diseases and is under investigation for use in man (Fearon, Clin. Exp, Immunol. 86 (Suppl.l):43-46 (1991)). However, there are several drawbacks to the use of sCRl in disorders of the CNS: the agent is expensive, must be administered systemically, and has a short half-life in vivo. The next generation of complement inhibitors are likely to solve many of these drawbacks (Spiegel et al.., Strategies for Inhibition of Complement Activation in the Treatment of Neurodegenerative Diseases in: Nenroinflammation: Mechanisms and Management, Wood (ed.), Humana Press, Inc., Totowa, NJ, Chapter 5, pp. 129-176). A need continues to exist for non-peptidic compounds that are potent inhibitors of complement, specifically C1s, and which possess greater bioavailability and fewer side-effects than currently available C1s inhibitors. Accordingly, novel C1s inhibitors, characterized by potent inhibitory capacity, are potentially valuable therapeutic agents for a variety of conditions. Summary of the Invention The present invention provides a novel class of thienyl amidines. The thienyl amides of Formula I inhibit the enzyme C1s, a protease in the classical pathway of the complement system, and thus, can be used to treat or ameliorate complement-mediated acute or chronic disorders in mammals. Thus, a first aspect of the present invention is directed to novel compounds of Formula I. In a second embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier or diluent. The present invention further provides a method for treating acute and chronic disorders associated with activation of the classical pathway of the complement system by administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I. These acute and chronic conditions are caused either in whole or in part by inflammation and tissue damage that result from aberrant activation of the complement cascade. In one embodiment, compounds of Formula I can be administered to a mammal to treat complement-mediated inflammation and tissue damage. Examples of conditions that can be treated include intestinal inflammation of Crohn's disease, thermal injury (burns, frostbite), post pump syndrome in cardiopulmonary bypass, and ischaemia (stroke, myocardial infarction, ischaemic colitis, hemorrhagic shock, trauma, post-surgical tissue damage and delayed or impaired function of organ or graft following transplant). The complement system is activated in hyperacute allograft and hyperacute xenograft rejection, and in acute humoral rejection mediated by donor-specific antibodies. Thus, in yet another embodiment, compounds of Formula I can be administered to a mammal before, during or after the transplant of an organ or a graft to ameliorate the rejection of such organ or graft by the mammal. Grafts can include an allograft or xenograft. Complement activation during immunotherapy with recombinant IL-2 appears to cause acute vascular leak syndrome that results in the severe toxicity and side effects observed from IL-2 treatment and other conditions such as bone marrow transplantation and acute pancreatitis. In another embodiment of the present invention, a compound of Formula I is administered to a mammal before, during or after treatment of said mammal with IL-2, bone marrow transplantation, or onset of pancreatitis, in an amount effective to reduce the vascular leak syndrome that causes toxicity and side- effects associated with the treatment or disorders. In another embodiment., compounds of Formula I can be administered to a mammal to treat complement-mediated tissue injury associated with autoimmune diseases. Examples of autoimmune diseases that are treatable according to the present invention include Hashimoto's thyroiditis, Addison's disease, glomerulonephritis and cutaneous lesions of systemic lupus erythematosus, other glomerulonephritides, bullous pemphigoid, pemphigus, Goodpasture's syndrome, Graves' disease, immune-complex-induced vasculitis, hemolytic anemia, myasthenia gravis, allergic neuritis, myasthenia gravis, Type I diabetes mellitus, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, type II collagen-induced arthritis, and rheumatoid arthritis. Autoimmune diseases preferred for treatment by inhibitors of the present invention include myasthenia gravis (MG), rheumatoid arthritis, and systemic lupus erythematosus. Another embodiment of the present invention is directed to administering a therapeutically effective amount of a compound of Formula I to a mammal that has been diagnosed with a neurodegenerative disease. Neurodegenerative diseases m winch inhibitors of the complement cascade system will be therapeutically useful include the demyelinating disorder multiple sclerosis (MS), the neuropathies Guillain-Barre syndrome (GBS) and Miller-Fisher syndrome (MFS)., Alzheimer's disease (AD), and variant Creutzfeldt-Jakob disease. In another embodiment, compounds of the present invention can be administered to a mammal to treat complement-mediated complications in sepsis, or symptoms of adult respiratory distress syndrome. Other diseases and conditions that can be treated include hereditary and acquired angioedema, paroxysmal nocturnal hemoglobinuria, brain trauma and other soft tissue trauma, asthma and hemodialysis. Compounds of Formula I can also be employed in vitro for human organ and graft storage as well as platelet storage. Detailed Description of the Preferred Embodiments Compounds useful in the present invention have the general Formula I: or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein: Z is-S(O)-or-S(O2)-; R1 is C1-4 alkyl, halo, amino, C1-6 alkylthio, C2-6 alkenylthio, C1-6 alkoxy, trifluoromethyl, methylsulfonyl, or benzylthio; preferably halo, C1-4 alkylthio or C2-4 alkenylthio; Ar is phenyl, naphthyl, pyridyl, imidazolyl, thiazolyl, furanyl, thienyl, benzothiazolyl, pyrazolyl, pyrimidinyl, benzimidazolyl, benzofuranyl, indolyl, benzothiophenyl or benzo[c]chromenyl, any of which is optionally substituted; R2, R3 and R4 are independently hydrogen, C1-4 alkyl, C6-10 aryl, C1-4 hydroxyalkyl, C1-4 aminoalkyl, mono(C1-4)alkylamino(C2-6)alkyl, di(C1- 4)alkylamino(C2-6)alkyl, carboxy(C1-4)alkyl, cyano, amino, nitro, C1-4 alkoxy, or hydroxy, or -CO2RW, where Rw is hydrogen, hydroxy, C1-4 alkoxy, cyano, C1-4 alkoxycarbonyl, C1-4 alkyl, C3-8 cycloalkyl, phenyl, benzyl, where Rd and Re are independently hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rf is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rg is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, and Rh is C6-10 ar(C1-4)alkyl or C1-6 alkyl; and R7 is hydrogen, chloro, fluoro or amino. A first preferred group of compounds falling within the scope of the present invention include compounds of Formula I wherein Ar is naphthyl or phenyl substituted by one or two of C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, halo, hydroxy, phenyl, phenoxy, amino or phenylamino. Useful values of Ar in this aspect of the invention include 2-phenylphenyl, naphth-2-yl, 2- methoxyphenyl, 4-methoxyphenyl, 4-chlorophenyl, 2-bromophenyl, 3,4- dimethylphenyl, 3-methoxyphenyl, 3-bromophenyl, 4-ethylphenyl, 4- bromophenyl, 4-phenylphenyl, 3,4-dimethoxyphenyl, 2-isopropylphenyl, 3,5- dichlorophenyl, 3-hydroxyphenyl, 2-methyl-5-t-butylphenyl, 4-t-butylphenyl, 3-bromo-5-t-butoxyphenyl., 3-bromo-5-hydroxyphenyl, 3-bromo-5- methoxyphenyl, 3-bromo-5-vinyloxyphenyl, 3-phenoxyphenyl, 5-bromo-3- methylphenyl and 2-aminophenyl. Another group of compounds falling within the scope of the present invention include compounds of Formula I wherein Ar is phenyl substituted by one or two of C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, halo, hydroxy, phenyl, phenoxy, amino, phenylamino, hydroxytetrahydropyranyl, (C1-4 alkoxy)- tetrahydropyranyl, hydroxypiperidinyl, hydroxy-N-(C1-4 alkyl)-piperidinyl, hydroxy-pyridinyl-(C1-4)alkyl or (C1-4 alkoxy)carbonyl(C2-6)alkenyl. Additional useful values of Ar in this aspect of the invention include 4-amino- 3-bromophenyl, 3-(4-hyiroxytetrahydropyran-4-yl)-phenyl, 3-(4-hydroxy- 1-methylpiperidin-4-yl)-phenyl, 3-(4-methoxytetrahydropyran-4-yl)-phenyl, 3-(hydroxy-pyridin-2-yl-methyl)-phenyl, 3-(1-ethoxycarbonyl-propen-2-yl)- phenyl, 3-chloro-4-fluorophenyl and 3-iodophenyl. Another group of compounds falling within the scope of the present invention include compounds of Formula I wherein Ar is pyridyl, imidazolyl, furanyl, thienyl, thiazolyl, benzothiazolyl, benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl or benzo[c]chromenyl, any of which is optionally substituted by one or two of C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, halo, hydroxy, amino, phenyl, phenoxy or tolyl. Useful values of Ar in this aspect of the invention include pyrid-2-yl, pyrid-3-yl, imidazol-2-yl, 1- methylimidazol-2-yl, 2-methylfuran-2-yl, thien-2-yl, thiazol-2-yl, 4- phenylthiazol-2-yl, 5-ethoxybenzothiazol-2-yl, benzimidazol-2-yl, 7-bromo-1- methyl-1H-benzoimidazolyl, 4-bromo-1 -methyl-1H-benzoimidazolyl, 4- bromo-2-methyl-1H-benzoimidazolyl, 4-bromo-1H-benzoimidazolyl, 6- bromo-benzimidazolyl, pyrrol-2-yl, and piperdin-2-yl. An additional useful value of Ar in this aspect of the invention is 6H-benzo[c]chromen-2-yl. Useful values of Ar in this aspect of the invention also include those of Formula LA: wherein: Rx is halo, or phenyl substituted by one or two of C1-6 alkyl or C1-4 alkyl)oxy(C1-4)alkyl wherein one of the C1-4 alkyl portions is optionally substituted by carboxy; Ry is hydrogen, amino, halo, phenoxy or C1-6 alkylamino wherein the alkyl portion is optionally substituted by one of phenyl, pyridyl, tetrahydrofuranyl, imidazolyl, morpholinyl, (C1-4 haloalkyl)-pyridyl, sulfonamidophenyl, hydroxy, (C1-4 alkyl)-thienyl or aminopyrimidinyl; and Rz is hydrogen, halo or C1-4 alkyl. Useful values of Rx include 2-methylphenyl, 2-carboxymethoxymethyl-6-methylphenyl and bromo. Useful values of Ry include hydrogen, chloro, amino, phenoxy, benzylamino, isopropylamino, pyrid-3-ylmethylamino, pyrid- 4-ylmethylamino, pyrid-2-ylmethylamino, tetrahydrofuran-2-ylmethylamino, 3-(imidazol-1-yl)-propylamino, 2-methyl-2-(morpholin-4-yl)-propylamino, 6-trifluoromethyl-pyrid-3-yl]tnethylamino, 2-(3H-imidazol-1-yl)-ethylamino, 4-sulfamoylbenzylamino, 2,2-dimethyl-3-hydroxypropylamino, 3-methylthien-2-ylmethylamino and 4-aminopyrimidin-5-ylmethylamino. Useful values of Rz include hydrogen, methyl or ethyl. Preferred values of Rx include bromo. Preferred values of Ry include optionally-substituted C1-6, alkylamino. Preferred values of Rz include hydrogen. Useful values of Ar in this aspect of the invention also include those of Formula IB: wherein: R13 and R14 are independently hydrogen, halo or C1-4 alkyl; EL15 is hydrogen, halo or tolyl; PL17 is hydrogen or C1-4 alkyl; and one of R16 and R18 is an electron pair and the other is hydrogen, C1-6 alkyl, C2-6 alkenyl, cyclopropylmethyl, phenyl, benzyl, 1-phenylethyl, pyridylmethyl or isoxazolylmethyl optionally substituted with one or two methyl groups, wherein said benzyl is unsubstituted or is substituted with one or two of halo, nitro, amino or (2-carboxyethyl)-sulfanylacetylamino. Useful values of R13 and R14 include hydrogen, methyl and ethyl. Useful values of R15 include hydrogen, bromo, chloro and o-tolyl. Useful values of R17 include hydrogen, methyl and ethyl. Useful values of R16 and R18, other than an electron pair, include hydrogen, methyl, cyclopropylmethyl, allyl, 3-methylbut-2-enyl, pyrid- 2-ylmethyl, 3,5-dimethylisoxazol-4-ylmethyl, phenyl, 1-phenylethyl, benzyl, 2,6-dichlorobenzyl, 2,5-difluorobenzyl, 2.,6-difluorobenzyl, 2-fluoro- 5-nitrobenzyl, 2-fluoro-4-nitrobenzyl, 2-fluoro-5-aminobenzyl and 5-[(2-carboxyethyl)-sulfanylacetylamino]-2-fluorobenzyl. Preferred R13 include hydrogen. Preferred R14 include hydrogen. Preferred R15 include brorno and chloro. More preferred is bromo. Preferred R17 include hydrogen. Preferred R16 and R18 ,other than an electron pair, include hydrogen, phenyl, 1-phenylethyl, benzyl and benzyl substituted with one or two, preferably two, of halo, amino or nitro. More preferred are benzyl and benzyl substituted with two of fluoro, chloro, arnino or nitro. In yet another aspect of the invention, Ar is a substituted phenyl group having a required substituent in the 3-position of the phenyl ring and an optional substituent on one of the remaining positions of the phenyl ring. Thus, this aspect of the invention is directed to compounds of the overall Formula II: or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein: R1, R2, R3, R4,R7 and Z are defined as above, and R5 is phenyl., naphthyl, thienyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, benzothienyl, benzofuranyl, benzimidazolyl, quinolinyl, isoquinolinyl, pyrazinyl, piperidinyl or piperazinyl, any of which is optionally substituted; and. R6 is hydrogen, C1-4 alkyl., hydroxy, C1-4 alkoxy, C2-4 alkenyloxy, phenoxy, benzyloxy, halo, ammo or nitro. In one embodiment R5 is naphthyl, phenyl or phenyl substituted by one to five, preferably one or two groups independently selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxyalkyl, C1-4 haloalkyl, C2-4 alkenyl. (C1-4 alkyl)carbonyl, cyano, amino, mono(C1-4)alkylamino, di(C1-4)alkylamino, formyl, (C1-4 alkoxy)carbonyl, halo(C1-4 alkoxy)carbonyl, phenyl, phenoxy, phenoxyphenyl, biphenyl, halo, C1-4 haloalkoxy, carboxy, nitro, methylenedioxo (-O-CH2-O-), ethylenedioxo, C1-4 alkylsulfonyl, C1-4 alkylsulfinyl, C1-4 alkylthio, hydroxy, aminocarbonyl, mono(C1-4alkyl)aminocarbonyl, di(C1-4alkyl)aminocarbonyl and halogenated C1-4 hydroxyalkyl. Useful values of R5 in this embodiment include phenyl, 2-methoxyphenyl, 2-methylphenyl, 2-vinylphenyl, 2-hydroxymethylphenyl, 2-(l-hydroxyethyl)phenyl, 2-trifluoromethylphenyl, 2-formylphenyl, 2-hydroxyphenyl, 2-chloromethylphenyl, 2-amino, 2-chlorophenyl, 3-methoxyphenyl, 3-methylphenyl, 3-formylphenyl, 3-hydroxymethylphenyl, 3-aminophenyl, 3-isopropylphenyl, 3-ethoxyphenyl, 3-ethoxycarbonylphenyl, 3-methylcarbonylphenyl, 3-ca.rboxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl, 3-dimethylaminocarbonylphenyl, 3-trifluoromethylphenyl, 3-trifluoromethoxycarbonylphenyl, 4-vinylphenyl, 4-trifluoromethoxyphenyl, 4-methoxycarbonylphenyl, 4-methylphenyl, 4-hydroxymethylphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl, 4-ethoxyphenyl, 4-dimethylaminophenyl, biphenyl, 4-phenoxyphenyl, 4-chloromethyl, 4-methylsulfonyl)phenyl, 4-hydroxyphenyl., 4-fluorophenyl, 2,5-dimethylphenyl, 2,2-dichlorophenyl., 2,3-dimethylphenyl, 2,5-dichlorophenyl, 3,,5-dichlorophenyl, 3-hydroxy-4-phenylphenyl, 3,5-bistrifluoromethylphenyl, 2-hydroxy-5-phenylphenyl, 4-methyl-3- nitrophenyl, 3,4-rnethylenedioxophenyl, 3,5-dimethylphenyl, 2,4-dimethoxyphenyl, 2-ethoxy-6-methylphenyl, 3-isopropoxycarbonyl-2- methylphenyl, 3-fluoro-4-phenylphenyl, 4-formylphenyl, 2-carboxy-6- methylphenyl, 3-formyl-2-methylphenyl, 3-hydroxy-6-methylphenyl, 3-formyl-6-methylphenyl, 3-formyl-6-hydroxyphenyl, 3-formyl-6- methoxyphenyl, 2-amino-6-methylphenyl, 3,4-dimethoxyphenyl, 3-[(2,2,2- trifluoro-1 -hydroxy)ethyl]phenyl, 4-nitrophenyl, 2-fluoro-4-phenylphenyl, 2,4-dimethoxyphenyl, 4-hydroxy-3-formylphenyl, 2-tolyl-5- morpholinephenyl, 4-methoxyphenyl, 3-hydroxyaminomethyl phenyl, 4- phenyl-acetamide, 4-benzamide, 2,6-dimethylphenyl, phenoxyphenyl, 2- methyl-6-hydroxym ethyl phenyl, 2-methyl-5-hydroxymethyl phenyl, 2- hydroxy-3-phenylphenyl, naphthyl and 4-ethoxycarbonylphenyl. An additional useful value of R5 is 6-methyl-3,4-methylenedioxophenyl. In another embodiment R5 is phenyl substituted by one to three groups independently selected from the group consisting of C1-4 alkyl, C1-4, alkoxy, C1- 4 hydroxyalkyl, C1-4 haloalkyl, C2-4 alkenyl, (C1-4 alkyl)carbonyl, cyano, amino, mono(C1-4)alkylammo, di(C1-4)alkylamino, formyl, (C1-4 alkoxy)carbonyl, halo(C1-4 alkoxy)carbonyl, phenyl, phenoxy, phenoxyphenyl, biphenyl, halo, C1-4 haloalkoxy, carboxy, nitro, methylenedioxo (-O-CH2-O-), ethylenedioxo, C1-4 alkylsulfonyl, C1-4 alkylsulfinyl, C1-4 alkylthio, hydroxy, aminocarbonyl, mono(C1-4alkyl)aminocarbonyl, di(C1-4alkyl)aminocarbonyl, halogenated C1-4 hydroxyalkyl, carboxy(C1-4)alkoxy(C1-4)alkyl, carboxy(C1-4)aIkoxy, C1-4 alkylthio(C1-4)alkyl wherein the alkyl portion of C1-4 alkylthio is optionally substituted with one or two carboxy groups, phosphono(C2-4)alkenyl, phosphono(C1-4)alkylamino, C1-4 haloalkylsulfonylamino, phosphono(C1-4)alkoxy, C1-4 alkylsulfonylamino, carboxy(C1-4)alkylamino, morpholinyl(C1-4)alkyl, morpholinyl, morphol.inyl(C1-4)alkylaminocarbonyl, piperazinyl(C1-4)alkyl or piperazinyl wherein either of said piperazinyl(C1-4)alkyl or piperazinyl is optionally N-substituted with methyl or ethyl, formylamino, morpholinyl (C1-4)alkylamino, optionally-substituted alkylcarbonylamino, optionally-substituted ureido and optionally-substituted guanidino. Useful optionally-substituted alkylcarbonylamino groups have the formula -N(H)-C(O)-C(H)(W1)-Yla-X1-Ylb-ZI, wherein: W1 is hydrogen or amino; Yla is a direct covalent bond or an a,?-diradical of a C1-10 straight or branched alkane; X1 is O or S, or a. direct covalent bond; Ylb is an a,?-diradical of a C1-10 straight or branched alkane, optionally substituted with a carboxy group or an amino group; and Z1 is carbamoyl, carboxy, C1-6 alkylsulfonyl, (C1-6 alkoxy)carbonyl, C2-6 alkanoylamino, sulfo, phosphono, phenyl, aminosulfonyl, amino, C1-6 haloalkylsulfonylamino, fonnylamino, C1-6 alkylamino, C1-6 alkylaminosulfonyl, C1-6 alkylsulfonylamino or 2-oxo-hexahydro- thieno[3,4-d]imidazol-6-yl-(C1-6 alkyl)carbonylamino; or, W1 is hydrogen and Yla-X1-Y1b-Z1 represents hydrogen, halo, amino or tri-(C1-4 alkyl)ammonio; provided that, if Yla is a direct covalent bond and X is 0 or S, then W1 is hydrogen. Useful optionally-substituted ureido groups have the formula -N(L1)C(O)-N(L2)-Y2a-X2-Y2b-Z2, wherein: L1 and L2 are both hydrogen, or L1 and L2 together represent ethylene or trimethylene; Y2a is a direct covalent bond or an a,?-diradical of a C1-10 straight or branched alkane; X2 is O or S, or a direct covalent bond; Y2b is an a,?-diradical of a C1-10 straight or branched alkane, optionally substituted with a carboxy group; and Z2 is carboxy, (C1-6 alkoxy)carbonyl, phenoxy, carboxyphenoxy, C1-6 alkylsulfonyl, phenyl, benzyloxycarbonylamino, amino, C1-4 alkylamino, halophertyl, indolyl, diphenylmethyl, phenylsulfonylamino, N'-(carboxy(C1-4)alkyl)ureido, tetrazolyl, phosphono or phenylamino; or, Y2a-X2-Y2b-Z2 represents C1-4 alkylsulfonyl or -(CH2CH2-O-)m-(CH2)n-C(O)OR wherein m is an integer from 2 to 6, n is an integer from 2 to 4, and R is hydrogen or C1-4 alkyl. Useful optionally-substituted guanidino groups have the formula -N(L3)-C(=NL4)-N(L5)-Z3, wherein: L3 is hydrogen or C1-4 alkyl; L4 and L5 are both hydrogen, or L4 and L5 together represent ethylene; and Z3 is hydrogen, C1-6 alkyl, phenyl(C1-6)alkyl, carboxy(C1-6)alkyl, C1-4 alkoxy, (C1-4 alkyl)carbonyl or C1-4 alkylsulfonyl(C1-6)alkyl. One group of preferred compounds in this embodiment includes those wherein R5 is phenyl substituted at the 2'-position by methyl and at the 4'-position by optionally-substituted guanidino. A more preferred group of compounds in this embodiment includes those wherein R5 is phenyl substituted at the 2'-position by methyl, at the 4'-position by optionally- substituted guanidino, and at the 6'-position by optionally-substituted alkylcarbonylamino or optionally-substituted ureido. Another group of preferred compounds in this embodiment includes those wherein R5 is phenyl substituted at the 2'-position by methyl and at the 6'-position by optionally- substituted alkylcarbonylamino or optionally-substituted ureido. Within these preferred groups, R1 is preferably methylthio, R2, R3, R4, R6 and R7 are preferably hydrogen, and Z is preferably -SO2-. Useful values of R5 in this embodiment also include those of Formula IIA: wherein: R8 is hydrogen or methyl; R9 is hydrogen, formylamino or carbamoyl; R10 is methoxy, hydroxy, carboxymethoxy, phosphonomethylamino, trifluoromethanesulfonylamino, phosphonomethoxy, carboxymethylamino, amino, chloro, fluoro, 2-(morpholin-4-yl)-ethylamino, carboxy, carbamoyl, (l,2-dicarboxyethyl)-sulfanylacetylamino, carboxymethoxyacetylamino, 4-amino-4-carboxybutyrylainino, 6-[5-(2-oxo-hexahydro- thieno[3,4-d]imidazol-6-yl)--peritanoylamino]-hexanoylamino, bromoacetylamino, 2-amino-4-carboxybutyrylamino, triethylammonioacetylamino, 2-amino-4-methanesulfonylbutyrylamino, aminoacetylamino, carbamoylmethylsulfanylacetylamino, 3-phosphonopropionylamino, ureido, N'-(5-carboxypentyl)-ureido, N'-(5-ethoxycarbonylpentyl)-ureido, N'-(3-methanesulfonylpropyl)-ureido, guanidino, N'-(3-phenylpropyl)-guanidino, N'-(2-phenylethyl)-guanidino, N'-(3-methylbutyl)-guanidino, N'-acetylguanidino, N'-(4-methanesulfonylbutyl)-guamdino, N'-(3-methanesulfonylpropyl)- guanidino, N'-(6-methamesulfonylhexyl)-guanidino, N'-(5-methanesulfonylpentyl)-guanidino, N'-methoxyguanidino, N-methylguanidino, N'-hexylgiaanidino, N'-(5-carboxypentyl)-guanidino or 4,5-dihydro-1H-imidazol -2-ylamino; R11 is hydrogen, 3-(morpholin-4-yl)-propylaminocarbonyl or carboxymethoxymethyl; and R12 is carboxymethoxymethyl, 2-carboxyethoxymethyl, nitro, amino, methyl, (l,2-dicarboxyethyl)-sulfanylmethyl, 2-phosphonovinyl, morpholin- 4-ylmethyl, 4-methylpiperazin-1-ylmethyl, morpholin-4-yl, formylamino, methanesulfonylamino, carboxymethylamino, 3-(morpholin-4-yl)- propylaminocarbonyl, chloro, acetylamino, carbamoylmethylsulfanylacetylamino, (2-carbox}'ethyl)-sulfanylacetylamino, 4-methanesulfonylbutyrylammo, (1,2-dicarboxyethyl)-sulfanylacetylamino, methoxyciirbonylmethoxyacetylamino, carboxymethoxyacetylamino, bromoacetylamino, 4-carboxybutyrylamino, carbamoylmethoxyacetylamino, (2-acetylamino-2-carboxy-l,l-dimethylethyl)-sulfanylacetylamino, (2-sulfoethyl)-sulfanylacetylarnino, (2-methoxycarbonylethyl)- sulfanylacetylamino, (2-acetyliimino-2-carboxyethyl)-sulfanylacetylamino, methanesulfonylacetylamino, 6-methanesulfonylhexanoylamino, 3-methanesulfonylpropionylamino, 2-methanesulfonylpropionylamino, benzylsulfanylacetylamino, 4-aminosulfonylbutyrylamino, 11 -aminoundecanoylamino, 4-trifluoromethanesulfonylaminobutyrylamino, 5-carboxyvalerylamino, carboxyacetylamino, 3-carboxypropionylamino, 11-carboxyundecanoylamino, 5-methoxycarbonylvalerylamino. N'-ethoxycarbonylmethylureido, N'-carboxymethylureido, N'-[5-(4-carboxyphenoxy)-pentyl]-ureido, N'-(2-methanesulfonylethyl)- ureido, N'-(5-carboxypentyl)-ureido, N'-(2-[2- {2-(2-carboxyethoxy)-ethoxy}- ethoxy]-ethoxyethyl)-ureido, N'-methanesulfonylureido, N'-(4-methanesulfonylbutyl)-ureido, N'-(3-phenylpropyl)-ureido, N'-benzyiureido, N'-( 1 -carboxy-2-phenyleth yl)-ureido, N'-(5-benzyloxycarbonylamino-5-carboxypentyl)-ureido, N'-(2-phenylethyl)- ureido, N'-(5-amino-5-carboxypentyl)-ureido, N'-[2-(4-bromophenyl)-ethyl]- ureido, N'-[2-(indol-3-yl)-ethyl]-ureido, N'-(3,3-diphenylpropyl)-ureido, N'-(2-phenylsulfonylaminoethyl)-ureido, N'-(2-methanesulfonylaminoethyl)- ureido, N'-[2-(N'-carboxyinethylureido)-ethyl]-ureido, N-[2-(2H-tetrazol- 5-yl)-ethyl]-ureido, N'-[4-(2H-tetrazol-5-yl)-butyl]-ureido, N'-[5-(2H-tetrazol- 5-yl)-pentyl]-ureido, N'-(5-phosphonopentyl)-ureido, N'-(5-ethoxycarbonylpentyl)-ureido, N'-(3-methanesulfonylpropyl)-ureido, N'-(2-phenylaminoethyl)-ureido or 2-oxo-imidazolidin-1-yl. One preferred group of compounds in this embodiment includes those wherein R8 is methyl, and R9 and R11 are both hydrogen. Another preferred group of compounds in this embodiment includes those wherein R8 is methyl, and R9, R11 and R12 are all hydrogen. Another preferred group of compounds in this embodiment includes those wherein R8 is methyl, and R9, R10 and R11 are all hydrogen. In an additional embodiment, R5 is thienyi, furanyl, imidazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, benzothienyl, benzofuranyl, dibenzofuranyl, benzimidazolyl, qumolinyl, isoquinolinyl, indolyl or pyrazinyl, optionally substituted by one or two groups independently selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxyalkyl, C1-4 haloalkyl, C2-4 alkenyl, formyl, (C1-4 alkoxy)carbonyl, phenyl, C1-4 alkylphenyl, phenoxy, halo, C1-4 haloalkoxy, carboxy, hydroxy, nitro, amino, C1-10 alkylsulfonyl(C1-4 alkyl)ureido, sulfo(C1-4)alkyl, trimethylsilanyl(C1-4)alkoxy(CC1-4)alkyl and C1-4 alkoxy(C1-4)alkyl. Where R5 is a heteroaryl group, useful values include thien-3-yl, quinolin-7-yl, 3,5-dimethylisoxazol-4-yl, 5-chlorothien-2-yl, pyrid-3-yl, pyrimidin-4-yl, quinolin-3-yl, benzothien-2-yl, benzofuran-2-yl, furan-2-yl, furan-3-yl, 4-methylpyrid-3-yl, 3-methyl-pyrid-2-yl, 6-methylbenzimidazol-5- yl, benzimidazol-6-yl, l-rnethyl-4-(2'-methylphenyl)benzimidazol-6-yl, 2- methyl-4-(2'-methylphenyl)benzimidazol-6-yl, dibenzo furan-2-yl, 2- methylirnidazolyl, 6-ethoxy-benzothiazolyl, 6-methyl-pyrid-3-yl, 6-chloro- pyrid-3-yl, and 3-chloro-pyrid-2-yl. Where R5 is a heteroaryl group, useful values also include 3-methyl- 5-nitropyrid-2-yl, 5-amino-3-methylpyrid-2-yl, 4-methylpyrimidin-5-yl, 3-methylpyrid-2-yl, 2-chloropyrid-3-yl, 6-formylpyrid-2-yl, 3-methyl- 5-[N'-(3-methanesulfonylprop-l-yl)]-ureidopyrid-2-yl, 3-methyl-pyrid-4-yl, 3-amino-5-methyl-pyrid-4-yl, 3-chloro-5-trifluoromethylpyrid-2-yl, 1H-benzimidazol-2-yl, 1 -methyl-1H-benzimidazol-2-yl, 3 -methyl- 3H-imidazol-4-yl, 1H-imidazol-2-yl, l-methyl-1H-tmidazol-2-yl, 1-ethyl- 1H-benzimidazol-2-yl, 2,5-dimethyl-1H-irnidazol-4-yl, l-(3-sulfoprop-l-yl)- 1H-benzimidazol-2-yl, 3-methylpyrazin-2-yl, 5-methyl-1-(2-trimethylsilanyl- ethoxymethyl)-1H-benzimidazol-4-yl, 5-methyl-1H-benzimidazol-4-yl, 1-methyl-1H-benzimidazol-5-yl, 2-methoxymethyl-6-methyl- 1H-benzimidazol-5-yl, 2,6-dimei:hyl-iH-benzimidazol-5-yl and 1,6-dimethyl- 1H-benzimidazol-5-yl. In an additional embodiment, R5 is -NRaRb, wherein Ra and Rb are independently C1-6 alkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a ring selected from the group consisting of piperidinyl, pyrroldinyl, piperazinyl, imidazolidinyl, pyrazolidinyl and morpholinyl, wherein said ring is optionally substituted by one or two C1-4 alkyl groups. In this embodiment, useful values of R5 include piperidin-1-yl and 4-methylpiperazin-1-yl. Useful values of R6 include hydrogen, methyl, halo, amino, methoxy, ethoxy, vinyloxy, hydroxy and benzyloxy. For each embodiment above, preferred values of R1 include bromo, methylthio, ethylthio or prop-2-en-l-ylthio, more preferably bromo or methyltbio, most preferably methylthio. One useful value of Z is SO2 An additional value of Z is SO. Preferred values of R2, R3 and R4 are independently hydrogen, C1-6 alkyl, amino, cyano, C1-4 alkoxy or hydroxy, and are preferably all hydrogen. Useful values of R2, R3 and R4 include hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy, methoxy, and ethoxy. Additional preferred values of R2, R3 and R4 in Formula I also include prodrugs such as -CO2RW, where Rw, in each instance, is preferably one of C1-4alkyl, C4-7cycloalkyl or benzyl. Suitable values of R2. R3 and R4 include hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy, methoxy, ethoxy, cyano, -CO2CH3, -CO2CH2CH3 and -CO2CH2CH2CH3. Also suitable at R2, R3 and R4 is the group -CO2RW, where Rw is one of where Rd-Rh are defined as above. When R2, R3 and R4 are -CO2RW, where Rw is one of these moieties, the resulting compounds are prodrugs that possess desirable formulation and bioavailability characteristics. A preferred value for each of Rd, Re and Rg is hydrogen, preferred Rf is methyl, and preferred values for Rh include benzyl and /erf-butyl. Specific compounds for use in the method of the invention include the compounds described in the Examples, such as the following: 4-(4'-hydroxy-[l,l';3',l"]terphenyl-3"-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate, 4-(2'-methoxymethoxy-[ 1,1' :3',1"]terphenyl-3-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate, 3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2- methyl-biphenyl-3-carboxylic acid isopropyl ester trifluoroacetate, 3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6- methyl-biphenyl-2-carboxylic acid trifluoroacetate, 4-(6'-hydroxymethyl-2'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate, 4-(3'-formyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate, 4-(5'-hydroxymethyl-2'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate, 4-(5'-formyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate, 4-[3-(4-methyl-pyridin-3-yl)-benzenesulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate, 4-[3-(2-chloro-pyridm-3-yl)-benzenesulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate, 4-[3-(3-methyl-pyridin-2-yl)-benzenesulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidinebis-trifluoroacetate, 4-(3-allyloxy-5-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene- 2-carboxamidine trifluoroacetate, 4-(3-bromo-5-methoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene- 2-carboxamidine trifluoroacetate, 4-(5-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-tbiophene-2- carboxamidine trifluoroacetate, 4-(5-methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine hydrochloride, 4-(5-allyloxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate., 4-(5-benzyloxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine hydrochloride, 4-(2'-chloro-5-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate, 4-(2'-chloro-5-methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate, 5-bromo-4-(3'-formyl-biphenyl-3-sulfonyl)-thiophene-2- carboxamidine trifluoroacetate, 5-amino-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxamidine trifluoroacetate, 5-chloro-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2- carboxamidine trifluoroacetate, 4-(2'-methyl-bif)henyl-3--sulfonyl)-thiophene-2-carboxamidine trifluoroacetate, 5-bromo-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2- carboxamidine trifluoroacetate, 4-(2'-amino-6'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate, 4-(3'-formyl-4'-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate, {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]- imino-methyl} -carbamic acid tert-butyl ester, 5-methylsulfanyl-4-[3'-(2,2,2-trifluoro-1-hydroxy-ethyl)-biphenyl-3- sulfonyl]-thiophene-2-carboxamidine trifluoroacetate, 5-methylsulfanyl-4-[3'-(2,2,2-trifluoro-acetyl)-biphenyl-3-sulfonyl]- thiophene-2-carboxamidine trifluoroacetate, 4-[3-(6-methyl-3H-benzoimidazol-5-yl)-benzenesulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine bis-trifluoroacetate, N-hydroxy-4-[3-(6-methyl-3H-benzoimidazol-5-yl)-benzenesulfonyl]- 5-methylsulfanyl-thiophene:-2-carboxamidine trifluoroacetate, 4-[2'-(l-hydroxy-ethyl)-biphenyl-3-sulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate, 4-[4'-(l-hydroxy-ethyl)-biphenyl-3-sulfonyl]-5-methylsulfanyl- thiophene-2-carboxarmdinetrifiuoroacetate, 4-(2'-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-(3'-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-biphenyl- 3-carboxylic acid trifluoroacetate, 4-(5'-formyl-2'-methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate, 4-(5'-formyl-2'-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidme trifluoroacetate, N-[3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)- biphenyl-3-yl]-formimidic acid trifluoroacetate, 4-(3'-formylamino-biphenyl-3-sulfonyl)-5-methyl-sulfanyl-thiophene- 2-carboxamidine trifluoroacetate, 4-(4-tert-butyl-benzenesulfonyl)-5-methylsulfanyl-thiophene-2- carboxarnidine trifluoroacetate, 4-(l-methyl-1H-imidazole-2-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-(3,5-dichloro-benzenesulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 5-bromo-4-(2-methoxy-benzenesulfbnyl)-thiophene-2-carboxamidine trifluoroacetate, 5-methylsulfanyl-4-(napb.thalene-2-sulfonyl)-thiophene-2- carboxamidine trifluoroacetate, 4-(2',4'-dimethoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-(4'-methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiopheme-2- carboxatnidine trifluoroacetate, 4-(3',4'-dimethoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-(3'-methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-(2'-methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-tbiophene-2- carboxamidine trifluoroacetate, 4-(3',5'-dicbioro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-(2',5'-dichloro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-(3',5'-bis-trifluoromethyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate, 4-(3-benzofuran-2-yl-benzenesulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-(3-benzo[b]thiophen-2-yl-benzenesulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate, 4-(4'-methyl-3'-nitro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene- 2-carboxamidine trifluoroacetate, 4-(4'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-(4'-chloro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 5-methylsulfanyl-4-(4"-trifluoromethyl-biphenyl-3-sulfonyl)- thiophene-2-carboxamidine trifluoroacetate, 5-methylsulfanyl-4-(4'-trifluoromethoxy-biphenyl -3- sulfonyl)- thiophene-2-carboxamidine trifluoroacetate, 5-methylsulfanyl-4-(4'-phenoxy-biphenyl-3-sulfonyl)-thiophene-2- carboxamidine trifluoroacetate, 5-methylsulfanyl-{imino-[4-(4'-methanesulfonyl-biphenyl-3-sulfonyl)- thiophen-2-yl]-rnethyl}-carbarnic acid tert-butyl ester, 4-(3-benzo[l,3]dioxol-5-yl-benzenesulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine tdfluoroacetate, 5-methylsulfanyl-4-(3-quinolin-7-yl-benzenesulfonyl)-thiophene-2- carboxamidine trifluoroacetate, 4-(3'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxami dine trifluoroacetate, 4-(3'-forniyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-(3'-amino~biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 5 -methylsulfanyl-4-(3'-trifluoromethyl-biphenyl- 3 -sulfonyl)- thiophene-2-carboxamidine trifiuoroacetate, 4-(3'-hydroxymethyl-biphenyl-3-sulfonyl)-5-methylsulfany]- thiophene-2-carboxamidine trifluoroacetate, 5-methylsulfanyl-4-([1,1';3', 1"]terphenyl-3-sulfonyl)-thiophene-2- carboxamidine trifluoroacetate, 4-(3-dibenzofuran-4-yl-benzenesulfonyl)-5-methylsulfanyl-thiophene- 2-carboxamidine trifluoroacetate, 5-methylsulfanyl-4-(2'-trifluoromethyl-biphenyl-3-sulfonyl)- thiophene-2-carboxamidine trifluoroacetate, 4-(2'-hydroxymethyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate, 4-(2'-chloro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 5-methylsulfanyl-4-(3-pyridin-3-yl-benzenesulfonyl)-thiophene-2- carboxamidine trifluoroacetate, 5-methylsulfanyl-4-(3-pyrimidin-5-yl-benzenesulfonyl)-thiophene-2- carboxamidine trifluoroacetate, 4-(3-furan-3-yl-benzenesulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 5-raethylsulfanyl-4-(3-quinolin-3-yl-benzenesulfonyl)-thiophene-2- carboxamidine trifluoroacetate, 3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-biphenyl- 4-carboxylic acid methyl ester, 4-(3',5'-dimethyl-bipheny]-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-(3-furan-2-yl-benzenesulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 5-methylsulfanyl-4-(3-thiophen-3-yl-benzenesulfonyl)-thiophene-2- carboxamidine trifluoroacetate, 5-methylsulfanyl-4-(3'-nitro-biphenyl-3-sulfonyl)-thiophene-2- carboxamidine trifluoroacetate, 4-(4'-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate. 4-(4'-formyl-biphenyl-3-sulfbnyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-(4'-fluoro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-(2'-fluoro-[l,l';4',1"]terphenyl-3"-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate, 4-(4'-hydroxymethyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate, 4-(4'-cyano-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-(4'-acetyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-(4'-dimethylamino-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene- 2-carboxamidine trifluoroacetate, 5-methylsulfanyl-4-2'-vinyl-biphenyl-3-sulfonyl)-thiophene-2- carboxamidine trifluoroacetate, 4-(4'-ethoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-[3-(3,5-dimethyl-isoxazol-4-yl)-benzenesulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate, 4-(2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 5-methylsulfanyl-4-(3-naphthalen-l-yl-benzenesulfonyl)-thiophene-2- carboxamidine trifluoroacetate, 4-[3-(5-chloro-thiophen-2-yl)-benzenesulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate, 4-(2'-formyl-biphenyl--3-sulfbnyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 5-methylsulfanyl-4-(4'-vinyl-biphenyl-3-sulfonyl)-triophene-2- carboxamidine trifluoroacetate, 4-(3'-ethoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-(2',6'-dirnethyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-(3'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-(3'-isopropyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-(2',3'-dimethyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-(2',3'-dichloro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate., 4-(3'-acetyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-biphenyl- 3-carboxylic acid ethyl ester, 3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-biphenyl- 3-carboxylic acid dimethylamide, 3'-(5-carbamimidoy]-2-methylsulfanyl-thiophene-3-sulfonyl)-biphenyl- 3-carboxylic acid amide., N-[3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)- biphenyl-3-yl]-acetamide, 4-(2'-amino-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-[3-(lH-benzoimidazol-5-yl)-benzenesulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate. 4-(7-bromo-3-methyl-3H-benzoimidazole-5-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate, 4-(7-bromo-l-methyl-lH-benzoimidazole-5-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate, 5-methylsulfanyl-4-(3-methyl-7-o-tolyl-3H-benzoimidazole-5- sulfonyl)-thiophene-2-carboxamidine trifluoroacetate, 5-methylsulfanyl-4-(2-methyl-7-o-tolyl-3H-benzoimidazole-5- sulfonyl)-thiophene-2-carboxamidine trifluoroacetate, 5-methylsulfiany]-4-(7-o-tolyl-3H-benzoimidazole-5-sulfonyl)- thiophene-2-carboxamidine trifluoroacetate, 4-(7-bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate, 4-(6-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-(2-methyl-furan-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 5-methylsulfanyl-4-(4-phenyl-thiazole-2-sulfonyl)-thiophene-2- carboxamidine hydrochloride, 4-(6-etlioxy-berizothia:iole-2-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine hydrochlonde, 4-(6-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate, 4-(3-methoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine hydrochlon de, 5-methylsulfanyl-4-(3-phenoxy-benzenesulfonyl)-thiophene-2- carboxamidine hydrochlonde, and 4-(Biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate, as well as pharmaceutically acceptable salts thereof, or a prodrug thereof. Definitions The term "alkyl" as employed herein by itself or as part of another group refers to both straight and branched chain radicals of up to 12 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl. The term "alkenyl" is used herein to mean a straight or branched chain radical of 2-20 carbon atoms, unless the chain length is limited thereto, wherein there is at least one double bond between two of the carbon atoms in the chain, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2- methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Preferably, the alkenyl chain is 2 to 10 carbon atoms in length, more preferably 2 to 8 carbon atoms in length, most preferably 2 to 4 carbon atoms in length. In all instances herein where there is an alkenyl moiety as a substituent group, the unsaturated linkage, i.e., the vinylene linkage, is preferably not directly attached to a nitrogen, oxygen or sulfur moiety. The term "alkylthio" as employed herein by itself or as part of another group refers to a straight or branched chain radical of 1 to 20 carbon atoms, unless the chain length is limited thereto, bonded to a sulfur atom, including, but not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, and the like. Preferably the alkylthio chain is 1 to 10 carbon atoms in length, more preferably 1 to 8 carbon atoms in length. The term "alkoxy" as employed herein by itself or as part of another group refers to a straight or branched chain radical of 1 to 20 carbon atoms, unless the chain length is limited thereto, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like. Preferably the alkoxy chain is 1 to 10 carbon atoms in length, more preferably 1 to 8 carbon atoms in. length. The term "cycloalkyl" as employed herein by itself or as part of another group refers to cycloalkyl groups containing 3 to 9 carbon atoms. Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl. The terms "halogen" or "halo" as employed herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine, with chlorine being preferred. The term "monoalkylamine" as employed herein by itself or as part of another group refers to an amino group which is substituted with one alkyl group having from 1 to 6 carbon atoms. The term "dialkylamine" as employed herein by itself or as part of another group refers to an amino group which is substituted with two alkyl groups, each having from 1 to 6 carbon atoms. The term "aryl" as employed herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 14 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl. The term "aralkyl" or "arylalkyl" as employed herein by itself or as part of another group refers to C1-6alkyl groups as discussed above having an aryl substituent, such as benzyl, phenylethyl or 2-naphthylmethyl. The terms "heterocyclic," "heterocyclo" or "heterocycle" as employed herein by themselves or as part of larger groups refer to a saturated or wholly or partially unsaturated 3-7 membered monocyclic, or 7-10 membered bicyclic ring system, which consists of carbon atoms and from one to four heteroatoms independently selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur heteroatoms; can be optionally oxidized, the nitrogen can be optionally quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, and wherein the heterocyclic ring can be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Especially useful are rings containing one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms. Examples of such heterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazmyl., oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, benzofuranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl. The term "heteroatom" is used herein to mean an oxygen atom ("O"), a sulfur atom ("S") or a nitrogen atom ("N"). It will be recognized that when the heteroatom is nitrogen, it may form an NRyRz moiety, wherein Ry and Rz are, independently from one another, hydrogen or C1 to C8 alkyl, or together with the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6-, or 7-membered ring. The term "heteroaryl" as employed herein refers to groups having 5 to 14 ring atoms; 6, 10 or 14 % electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms (where examples of heteroaryl groups are: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuranyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl., indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, ß-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazlnyl, isoxazolyl, furazanyl and phenoxazinyl groups). The expression "prodrug" denotes a derivative of a known direct acting drug, which derivative has enhanced delivery characteristics and therapeutic value as compared to the drug, and is transformed into the active drug by an enzymatic or chemical process. Useful prodrugs are those where R2, R3 and/or R4 are -CO2RW, where Rw is defined above. See U.S. Patent No. 5,466,811 and Saulnier et al., Bioorg. Med. Chem. Lett. 4:1985-1990 (1994). The term "substituted," as used herein, means that one or more hydrogens of the designated moiety are replaced with a selection from the indicated group, provided that no atom's normal valency is exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., =0), then 2 hydrogens attached to an atom of the moiety are replaced. By "stable compound" or "stable formula" is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent. When any variable occurs more than one time in any constituent or in any Formula, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. Methods of Use The present invention provides a method for treating acute and chronic disorders associated with activation of the classical pathway of the complement system by administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I. These acute and chronic conditions include inflammation and tissue damage that arise as a result of rapid and aggressive enzyme activity of the complement cascade. Complement-mediated inflammation and the resultant tissue damage has been implicated in a number of disease states including: 1) ischaemia reperfusion damage, such as occurs post myocardial infarction, post transplant, post surgery and in hemorrhagic shock; 2) antibody-mediated conditions, such as hyperacute allograft and xenograft rejection, organ transplant rejection and auto-immune diseases; and 3) other disease states, such as thermal injury., trauma, adult respiratory distress syndrome (ARDS), sepsis and prion disease. The compounds of the present invention are believed to inhibit the functioning of the protease activity of C1s. This protease-inhibition activity results in the inhibition or blocking of a variety of complement-mediated immunological functions. Therefore, compounds of Formula I can be used to ameliorate a number of disease states induced by complement-mediated inflammation and tissue damage. The term "treatment of inflammation" or "treating inflammation" is intended to include the administration of compounds of the present invention to a subject for purposes which can include prophylaxis, amelioration, prevention or cure of an inflammatory response. Such treatment need not necessarily completely ameliorate the inflammatory response. Further, such treatment can be used in conjunction with other traditional treatments for reducing the inflammatory condition known to those of skill in the art. By an "efficacious level" of a composition of the invention is meant a level at which some relief is afforded to the patient who is the recipient of the treatment. By an "abnormal" host inflammatory condition is meant a level of inflammation in the subject at a site which exceeds the norm for the healthy medical state of the subject, or exceeds a desired level. By "secondary" tissue damage or toxic effects is meant the tissue damage or toxic effects which occur to otherwise healthy tissues, organs, and the cells therein, due to the presence of an inflammatory response, including as a result of a "primary" inflammatory response elsewhere in the body. The "animals" referred to herein are preferably mammals and most preferably humans, although the invention is not intended to be limited to such. In one embodiment, compounds of Formula I can be administered to a mammal to treat complement-mediated inflammation and tissue damage that is a consequence of ischaemia/reperfusion injury. Thus, the C1s inhibitors of the present invention can be employed to prevent, or at least ameliorate, inflammation and tissue damage: arising from a stroke, myocardial infarction, hemorrhagic shock, and surgery. In particular, compounds of Formula I can be employed to prevent inflammation of transplanted tissue and organs. The compounds of Formula I can also be provided as a "preventive" treatment before detection of an inflammatory state, so as to prevent the same from developing in patients at high risk for the same, such as, for example, transplant patients. The compounds of Formula I can be used to treat chronic or acute inflammation that is the result of an antibody-mediated reaction, such as hyperacute allograft and xenograft rejection, organ transplant rejection and auto-immune diseases, which include arthritis, rheumatoid arthritis, multiple sclerosis (MS), type I diabetes, intestinal inflammation of Crohn's disease, systemic lupus erythematosus (lupus), immune-complex-induced vasculitis, restenosis and psoriasis. The complement system is activated in hyperacute allograft and hyperacute xenograft rejection, and in acute humoral rejection mediated by donor-specific antibodies. In another embodiment, compounds of Formula I can be administered to a mammal before, during or after the transplant of an organ or a graft to ameliorate the rejection of such organ or graft by the mammal. Organ transplant and graft patients undergo concurrent immunotherapy. Complement activation during immunotherapy with recombinant IL-2 appears to cause acute vascular leak syndrome that results in the severe toxicity and side effects observed from IL-2 treatment and other conditions such as bone marrow transplantation and acute pancreatitis. Thus, in a further embodiment of the present invention, a compound of Formula I is administered to a mammal before, during or after treatment of said mammal with IL-2, bone marrow transplantation, or onset of pancreatitis, in an amount effective to reduce the vascular leak syndrome that causes toxicity and side- effects associated with the treatment or disorders. Another embodiment of the present invention is directed to administering a therapeutically effective compound of Formula I to a mammal that has been diagnosed with an autoimmune disease. Autoimmune diseases that are treatable according to the present invention include Addison's disease. Type I diabetes mellitus, Hashimoto's thyroiditis, glomerulonephritis and cutaneous lesions of systemic lupus erythematosus, other glomerulonephritides, bullous pemphigoid, dermatitis herpetiformis, Goodpasture's syndrome, Graves' disease, myasthenia gravis, insulin resistance, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, immune-complex-irtduced vasculitis glomerulonephritis, type II collagen-induced arthritis, rheumatoid arthritis, and allergic neuritis. Autoimmune diseases preferred for treatment by inhibitors of the present invention include myasthenia gravis (MG), rheumatoid arthritis, and systemic lupus erythematosus. Another embodiment of the present invention is directed to administering a therapeutically effective amount, of a compound of Formula I to a mammal that has been diagnosed with a neurodegenerative disease. Neurodegenerative diseases in which inhibitors of the complement cascade system will be therapeutically useful include the demyelinating disorder multiple sclerosis (MS)., the neuropathies Guillain-Barre syndrome (GBS) and Miller-Fisher syndrome (MFS), Alzheimer's disease (AD) and variant Creutzfeldt-Jakob disease (vCJD). In another embodiment, efficacious levels of the C1s inhibitors of the invention are administered so as to provide therapeutic benefits against the secondary harmful inflammatory effects of inflammation. In an additional embodiment, compounds of the present invention can be administered to a mammal suffering from the symptoms of ARDS. ARDS is a complex pulmonary disorder affecting 150,000 people in the U.S. yearly with a 50% mortality rate. Leukocytes, platelets and the proteolytic pathways of coagulation and complement mediate ARDS. ARDS involves activation of the contact activation pathway and depletion of C1 inhibitor and may be induced by either sepsis or trauma. Sepsis-induced ARDS results in more severe Disseminated intravascular coagulation (DIG) and fibrinolysis, more fibrin degradation products and reduced ATIII levels compared to trauma- induced ARDS (Carvalho et al., J. Lab. Clin. Med. 112:270-277 (1988)). In. a further embodiment, compounds of Formula I can be administered to a person in septic shock. Septic shock is the most common cause of death of humans in intensive care units in the United States (Parillo et al., Ann. Int. Med. 113:227-242 (1990); Schmeichel C. J. & McCormick D., BioTechnol. 10 :264-267 (1992)). In recent years aggressive fluid infusion therapy has been accepted as a primary means of treatment for septic shock. The increase in cardiac output and vasodilation in septic shock is attributed to the action of inflammatory mediators. In septic shock, components of the kallikrein-kinin system are depleted, suggesting activation of this system. This is not the case in cardiogenic shock, suggesting that the kallikrein-kinin system is a key player in septic shock (Martinez-Brotons F. et al., Thromb. Haemostas. 55:709-713 (1987)). While the actual events leading to septic shock, DIC and hypotension have not been established, the known interactions among various components of the many physiological systems suggest that activation of the contact pathway may lead to a state of septic shock, multi-organ failure, and death (Bone, R. C, Arch. Intern. Med. 752:1381-1389 (1992); Gorman, R. W., New Engl. J. Med. 32(9:1207-1209 (1989)). The contact activation pathway is also involved in both fibrin deposition and lysis, as well as triggering neutrophil activation, activation of complement and modulation of blood pressure. Inhibition of the complement cascade is expected to lead to downstream utilities associated with the contact system of coagulation and the complement system. This interaction between components of the complement and coagulation systems at the surface of blood platelets and endothelium can generate inflammatory and chemotactic peptides at sites of vascular thrombus formation and may contribute to the altered hemostasis associated with immune disease states. In addition, immune reactions affecting blood platelets and endothelium can lead to platelet aggregation, the secretion of proteolytic enzymes and vasoactive amines from platelet storage granules, and increase adherence of platelets and leukocytes to the endothelial lining of blood vessels. Other diseases and conditions that can be treated with compounds of Formula I include hereditary angioedema, paroxysmal nocturnal hemoglobinuria, wound healing, brain trauma, asthma, hemodialysis, infection, dermatosis, inflammatory bowel disease, osteoporosis, esteoarthritis, thermal injury (burns and frostbite), hemolytic anemia and post pump syndrome in cardiopulmonary bypass. It has been demonstrated that membrane-uptake of C3b and C5b-9 proteins can occur spontaneously during incubation of platelets in citrated plasma. Complement activation can also occur during blood collection as a result of exposure to plastic surfaces supporting the C3-convertase reaction. While the implications of complement activation during blood collection and in vitro storage for transfusion have not been directly addressed, it is nevertheless known that plasma levels of coagulation factors V and VIII rapidly decline in stored platelet concentrates at a rate considerably faster than their decay in cell-free plasma, suggesting consumptive loss. Further, platelet collection and storage is associated with an increase in vesicular plasma membrane microparticles, a product of C5b-9 initiated platelet secretion. These physiological and enzymatic changes greatly reduce the potential shelf life of stored platelets, particularly platelet-rich plasma concentrates used for transfusions, which is generally only 72 hours at best. Furthermore, this interaction of activated C5b-9, platelets, and coagulation factors in stored platelet concentrates will adversely affect the hemostatic effectiveness of these units when infused. In vitro human organ and tissue storage and survival of the transplanted graft is also adversely affected by the spontaneous activation of the complement system, resulting in membrane insertion of the C5b-9 proteins into vascular endothelium. Activation of C5 to C5a and C5b can be catalyzed by plastics and other synthetic membranes required to maintain perfusion of vascular beds during in vitro tissue and organ storage. In addition, membrane deposition of C5b-9 in vivo has been implicated in the acute rejection of transplanted tissue due to immune activation of the recipient's plasma complement system against the endothelial cells within the donor's organ. Platelet and endothelial cell activation by C5b-9 also has ramifications in autoimmune disorders and other disease states. The importance of spontaneous complement activation and the resulting exposure of platelets and endothelium to activated C5b-9 to the evolution of vaso-occlusive disease is underscored by consideration that a) leukocyte infiltration of the subendothelium, which is known to occur in regions of atheromatous degeneration and suggests localized generation of C5a at the vessel wall, is potentially catalyzed by adherent platelets; and b) local intravascular complement activation resulting in membrane deposition of C5b-9 complexes accompanies coronary vessel occlusion and may affect the ultimate extent of myocardial damage associated with infarction. It is therefore an aspect of the present invention to provide a means and method for the modulation and inhibition of complement-mediated platelet and endothelial cell activation in vivo and in vitro. It is a further aspect of the present invention to provide a means and method for increasing the survival and therapeutic efficacy of platelets and tissues or organs collected and stored in vitro. Preferably, the treatment methods of the invention deliver the C1s inhibitor either by contacting cells of the animal with a C1s inhibitor described above or by administering to the animal a C1s inhibitor described above. The inhibitors can be used in vitro or in vivo. They can be administered by any number of known routes, including orally, intravenously, intramuscularly, subcutaneously, intrathecally, topically, transdermally, and by infusion (Platt et al., U.S. Patent No. 4,510,130; Badalamente et al., Proc. Natl. Acad. Sci. U.S.A. 55:5983-5987 (1989); Staubli et al., Brain Research 444:153-158 (1988)) and will generally be administered in combination with a physiologically acceptable carrier (e.g., physiological saline) or diluent. The effective quantity of inhibitor given will be determined empirically and will be based on such considerations as the particular inhibitor used, the condition of the individual, and the size and weight of the individual. It is to be expected that the general end-use application dose range will be about 0.01 to 100 mg per kg per day, preferably 0.1 to 75 mg per kg per day for an effective therapeutic effect. Amounts and regimens for the administration of C1s inhibitors and compositions of the invention can be determined readily by those with ordinary skill in the clinical art of treating inflammation-related disorders such as arthritis, tissue injury and tissue rejection. Generally, the dosage of the composition of the invention will vary depending upon considerations such as: type of pharmaceutical composition employed; age; health; medical conditions being treated; kind of concurrent treatment, if any; frequency of treatment and the nature of the effect desired; extent of tissue damage; gender; duration of the symptoms; and contraindications, if any, and other variables to be adjusted by the individual physician. A desired dosage can be administered in one or more applications to obtain the desired results. Pharmaceutical compositions containing the C1s inhibitors of the invention can be provided in unit dosage forms. la one embodiment, dosing will be by intravenous injection or short- term infusion. In a further embodiment, the C1s inhibitors of the present invention will be administered orally, in the form of a tablet, pill, lozenge, troche or capsule. To achieve optimal therapeutic effect, maintenance dosing may be required. Such maintenance dosing may be given repeatedly during the course of a day by, for instance, repeated individual injections, repeated oral dosing, or by introduction of a continuous drip infusion. Effective dosages can be readily determined by one of ordinary skill in the art through routine trials establishing dose response curves. Pharmaceutical Compositions Pharmaceutical compositions for treating a complement-mediated disease state, comprising a compound of Formula I in an amount effective to inhibit C1s protease function in a mammal and a pharmaceutically acceptable carrier or diluent, are within the scope of the present invention. Pharmaceutical compositions comprising an effective amount of the C1s inhibitors of the invention, in combination with any conventional pharmaceutically acceptable carrier or diluent, are included in the present invention. For medicinal use, the pharmaceutically acceptable acid addition salts, those salts in which the anion does not contribute significantly to toxicity or pharmacological activity of the organic cation, are preferred. The acid addition salts are obtained either by reaction of an organic base of Formula I with an organic or inorganic acid, preferably by contact in solution, or by any of the standard methods detailed in the literature available to any practitioner skilled in the art. Examples of useful organic acids are carboxylic acids such as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid, isethionic acid, succinic acid, cyclamic acid, pivalic acid and the like; useful inorganic acids are hydrohalide acids such as HC1, HBr, and HI; sulfuric acid; phosphoric acid and the like. Preferred acids for forming acid addition salts include HC1 and acetic acid. The pharmaceutical compositions of the invention can be administered to any animal that can experience the beneficial effects of the compounds of the invention. Foremost among such animals are humans, although the invention is not intended to be so limited. The pharmaceutical compositions of the present invention can be administered by any means that achieve their intended purpose. For example, administration can be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, or ocular routes. Alternatively, or concurrently, administration can be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.. In addition to the pharmacologically active compounds, the new pharmaceutical preparations can contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. The pharmaceutical preparations of the present invention are manufactured in a manner that is, itself, known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tncalcium phosphate or calcium hydrogen phosphate, as well as binders, such as, starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents can be added, such as, the above-mentioned starches and also carboxymethyl-starch, cross- linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as, sodium alginate. Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as, magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings that, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol, and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as, acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses. Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as, glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules that may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as, fatty oils or liquid paraffin.. In addition, stabilizers may be added. Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water- soluble salts, alkaline solutions and cyclodextrin inclusion complexes. Especially preferred salts are hydrochloride and acetate salts. One or more modified or unmodified cyclodextrins can be employed to stabilize and increase the water solubility of compounds of the present invention. Useful cyclodextrins for this purpose are disclosed in U.S. Patent Nos. 4,727,064, 4,764,604, and 5,024,998. In addition, suspensions of the active compounds as appropriate oily injection suspensions can be administered. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400). Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers. When employed as thrombin inhibitors, the compounds of the present invention may be administered in an effective amount within the dosage range of about 0.1 to about 500 mg/kg, preferably between about 0.1 and about 10 mg/kg body weight, on a regimen in single or 2-4 divided daily doses. Methods of Making Many synthetic methods used to form compounds of the present invention generally involve the formation of an amidine from a carboxylic acid derivative, such as an ester. In the process a Lewis acid, such as trimethylaluminum, is added to a source of ammonia, such as ammonium chloride, in an aprotic solvent, such as a toluene, under an inert atmosphere (e.g., under an atmosphere of nitrogen or argon gas) at a temperature between -15°C and 5°C, preferably at 0°C. An appropriate carboxylic acid derivative is added to the mixture and the mixture is heated at reflux for a predetermined period of time, preferably between 1 hr. and 24 hrs., and most preferably between 1 hr. and 4 hrs. The resulting solution is allowed to cool to room temperature and the amidine product is isolated by known methods. Scheme 1 illustrates a general approach to compounds of Formula / where X = O or S, and R1 = alkylthio, aralkylthio, arylthio, alkyloxy, aralkyloxy or aryloxy. Starting with the heterocycle where X = O or S appropriately substituted by a leaving group, the leaving groups can be sequentially displaced by an appropriate thiol to produce the 4-substituted heterocycles. In some cases a disulfide and a reducing agent such as triphenylphosphine can be used for the in situ generation of the thiol. Examples of leaving groups include chlorine, bromine or iodine. The resulting sulfide is oxidized, either to the sulfoxide or the sulfone with an appropriate oxidizing agent such as meta-chloroperoxybenzoic acid or hydrogen peroxide in acetic acid. When the 4-substituent is a sulfone, the nitro group can then be displaced by an appropriate; nucleophile (preferably the anion of the group R1 to be substituted) to produce a 5-substituted heterocycle. Preferable nucleophiles include anions of thiols or alcohols having as the counter ion an alkali or alkali earth metal such as sodium, lithium, potassium, magnesium or cesium. Scheme 2 illustrates approaches to providing the amidine ((R3R4N)CNR2) functionality of compounds of Formula / where X = O or S, and R1 = halo, alkyl, alkylthio, aralkylthio, arylthio, alkyloxy, aralkyloxy or aryloxy. Depending on the nature of the group W in 4, several methods may be employed in the transformation of W to (R3R4N)CNR2. When W in 4 is a cyano group (CN), primary amide (CONH2) or ester (CO2R9), direct conversion to an unsubstituted amidine 6 (i.e., Formula / where R2, R3, R4 = H) can be effected by treatment with a reagent consisting of a Lewis acid complexed to ammonia. This complex is produced by treatment of ammonia or an ammonium salt, preferably an ammonium halide and most preferably ammonium chloride or bromide, with an appropriate Lewis acid, preferably a trialkylaluminum and most preferably trimethyl- or triethylaluminum in a solvent inert to the Lewis acid employed. For example, when a trialkylaluminum Lewis acid is employed with an ammonium halide, reaction occurs with loss of one equivalent of alkane to produce the dialkylhaloaluminum complex of ammonia (see, for example, Sidler, D.R., et al., J. Org. Chem., 59:1231 (1994)). Examples of suitable solvents include unsaturated hydrocarbons such as benzene, toluene, xylenes, or mesitylene, preferably toluene, or halogenated hydrocarbons such as dichloroethane, chlorobenzene or dichlorobenzene. The amidination reaction is generally carried out at elevated temperatures, preferably 40-200°C, more preferably 80-140 °C, and most preferably at the reflux temperature of a solvent in the range of 80-120 °C. When W is a cyano group (CN), direct conversion to a mono- or disubstituted amidine 6 is also possible by treatment with a reagent consisting of a Lewis acid, preferably a trialkylaluminum, complexed to a mono- or disubstituted amine H2NR3 or HNR-'R4 (Garigipati, R., Tetrahedron Lett. 31: 1969 (1990)). Alternatively the same addition of a mono- or disubstituted amine may be catalyzed by a copper salt such as Cu(I) chloride (Rousselet, G., et al., Tetrahedron Lett. 34: 6395 (1993)). When W in 4 is a carboxyl group (CO2H), indirect conversion to an unsubstituted amidine 6 can be carried out by initial esterification to 5 by any of a number of well-known dehydrating agents (for example, dicyclohexylcarbodiimide) with an alcohol (R8OH). More preferably 5 can be made by initial formation of an. acid chloride by treatment of 4 with any of a number of anhydrides of HC1 and another acid, such as thionyl chloride, POCl3, PCl3, PCl5, or more preferably oxalyl chloride, with or without an added catalyst such as N,N-dimethylforrnamide (DMF), followed by the alcohol R8OH. Conversion to the unsubstituted amidine 6 (R2, R3, R4 = H) can be carried out by treatment with a. Lewis acid complexed to ammonia. Amidines 6 can also be produced indirectly by conversion of 4 (W = CN) to iminoethers 7 by exposure to a strong acid such as a hydrogen halide, HBF4 or other non-nucleophilic acid, preferably gaseous HCl in the presence of an alcohol R8OH (R8 = alkyl, branched alkyl or cycloalkyl, preferably Me or Et) and most preferably with the alcohol as solvent. Alternatively when W = CONH2, conversion to an iminoether can be carried out by treatment with a trialkyloxonium salt (Meerwein's salts). In either case, treatment of the iminoether with ammonia (R3, R4 = H) or a mono- or disubstituted amine (HNR3R4) provides the corresponding, unsubstituted or substituted amidines 6 (i.e., via classical Pinner synthesis: Pinner, A., Die Iminoaether und ihre Derivate, Verlag R. Oppenheim, Berlin (1892)). Conversion to substituted amidine 6 (R2, R3 = H and, R4 = OH) can be achieved by refluxing in ethanol the unsubstituted amidine 6 (R2, R3, R4 = H), hydroxylamine, and a base, preferably triethylamixie. scheme 3 Scheme 3 illustrates one approach to aryl thiols, which can be used in Scheme 1 when such aryl thiols are not commercially available. Starting with an aryl halide with sufficient stability to strong nucleophiles, the aryl halide can be reacted with an alkali earth metal in an inert ethereal solvent such as diethyl ether under reflux, yielding a reactive organometallic species. Preferred metals include lithium, magnesium, and sodium, while the halide can be an aryl iodide or bromide. Alternatively, the aryl-metal species can be generated through a metal-halogen exchange with another organometallic reagent at low temperature in am ethereal solvent. Useful organometallic reagents include any of the isomeric butyllithiums and isopropylmagnesium bromide or chloride. In this instance, the aryl halide must be an aryl bromide or iodide and stable to strong nucleophiles. The aryl-metal reagent may then be reacted with elemental sulfur to provide a mixture of the aryl thiol (12) and the disulfide oxidation products The disulfide can be reacted with a reducing agent such as sodium borohydride, dithiothreitol, or triphenylphosphine, to give the aryl thiol (12). scheme 4 Scheme 4 illustrates another approach to aryl thiols, which can be used in Scheme 1 when such aryl thiols are not commercially available. An arylamine 13 can be converted to the diazonimn salt and reacted with O- ethylxanthic acid potassium salt (Aldrich Chemical Company) to give an O- ethyl-S-aryl dithiocarbonate. which can subsequently be hydrolyzed to the aryl thiol 15. In some cases hydrolysis can provide a mixture of the aryl thiol (15) and the disulfide oxidation products (14). The disulfide can be reacted with a reducing agent such as sodium borohydride, dithiothreitol, or triphenylphosphine, to give the aryl thiol (15). scheme 5 Scheme 5 illustrates a general approach to compounds of Formula I where X = O or S, and R1 == halo. The nitroheterocycle 3 obtained in the manner described in Scheme 1 is reduced to the aminoheterocycle 16. Appropriate reagents to effect reduction of the nitro functionality include hydrogen gas in the presence of a catalyst such as palladium or platinum metal deposited on carbon or barium sulfate in any number of solvents such as methanol, ethanol, ethyl acetate, DMF, or THF. Tin (II) chloride may be employed as a reductant in a solvent such as methanol or ethanol. Alternatively, metals such as zinc or iron (Stanetty, P. and Kremslehner, M.. Heterocycles 48: 259 (1998)) may also be used. More preferably, titanium (III) chloride in HC1 (see Ho, Wong, Synthesis, 45 (1974)) can be used as the reducing reagent. The aminoheterocycle 16 can then be converted to the halide 17 by diazotization. When X = C1 or Br, this reaction is carried out by treating the aminoheterocycle 16 with t-butyl nitrite and copper (II) chloride or bromide as described in the Sandmeyer reaction (see Doyle; Siegfried; Dellaria, J. Org. Chem. 42: 242(5 (1977)). Scheme 6A Scheme 6a illustrates approaches to providing the biaryl functionality present in compounds of Formula II, where R3 can be a substituted aromatic or heteroaromatic ring (aryl or heteroaryl). Starting with either of two aryl bromides, the methyl carboxylate 18 or the Boc-amidine 20, a transition-metal catalyzed cross-coupling reaction can take place using an appropriately substituted arylboronic acid, arylzincate, or arylstannane under Suzuki (Miyaura, N.; Suzuki, A., Chem. Rev. 95:2457 (1995)), Negishi (Negishi, E. et al., J. Org. Chem. 42:1821 (1977)), or Stille conditions (Stille, J. K. Angew. Chem., Int. Ed. Engl. 25: 50S (1986), and references contained therein), respectively. The Stille-type cross-coupling reaction takes place under inert atmosphere between an arylstannane and an aryl halide mediated by a catalyst such as palladium tetrakis-triphenylphosphine. The reaction is usually performed at temperatures ranging from room temperature to 150 °C in an aprotic solvent of appropriate boiling point such as tetrahydrofuran, toluene, or dimethylformamide. In some; cases, additives such as lithium chloride (Curran, D.P. et al., J. Org. Chem. 61:6480 (1996)) or copper iodide (Liebeskind, L. S.; Fengl, R. W., J. Org. Chem. .55:5359 (1990)) can facilitate the cross-coupling reaction. A more preferable cross-coupling reaction of aryl bromides 18 and 20 takes place under Negishi conditions, utilizing an aryl zinc reagent. The aryl zinc reagent can be prepared by transmetalation of an aryl grignard or aryl lithium reagent with a zinc halide salt, or more preferably, directly prepared from an aryl halide and activated zinc (Reike, R.D., Tetrahedron 53:1925 (1997). The cross-coupling reaction generally takes place at temperatures between 60 and 100 °C in THF or THF/polar aprotic co-solvent mixtures. Palladium tetrakis(triphenylphosphine) is the most widely used catalyst, although new catalysts such as palladium di-tert-butylphosphine (Dai, C; Fu, G.C., J. Am. Chem. Soc. 123:2719 (2001)) can offer enhanced reactivities. The most preferable and widely applicable biaryl-forming reaction conditions for aryl bromides 18 and 20 take place under Suzuki conditions. Many sets of reaction conditions can be employed to promote the Suzuki-type cross-coupling reactions. These include appropriate combinations of anhydrous or water-containing solvents, appropriate bases such as metal carbonates, phosphates, and fluorides, and the transition-metal catalyst. For the synthesis of biarylsulfones 21 and 23, the most universal reaction conditions consisted of reacting aryl bromide 18 or 20 with an arylboronic acid or an aryboronate ester (e.g. pinacolboronate) in a biphasic toluene/ethanol/aqueous sodium carbonate solvent system. Palladium tetrakis- triphenylphosphine is used as the catalyst under these aqueous conditions. Under anhydrous conditions, new catalysts such as palladium di-tert- butylphosphine (Littke, A.F. et al., J. Am. Chem. Soc. 122:4020 (2000)) and bis (o-(dicyclohexylphosphino)biphenyl) palladium (Wolfe, J.P. et al., J. Am. Chem. Soc. 121: 9550 (1999)) can offer enhanced reactivity at lower catalyst loadings. Scheme 6b describes an alternate route to compounds of Formula II where R5 is an aryl, or heteroaryl. Boc-protected amidine 20 is converted to an organoboron or organostannane 66, which is then reacted with a suitable halide or trifiate in the presence of a palladium catalyst to give 21, which is converted to the amidine 22 as described in scheme 6a. The preferred method for the synthesis of 66 when E is a boron or tin species is to first treat 20 with a base such isopropylmagnesium chloride, followed by lithiation with a suitable reagent such as n-butyllithium, followed by reaction with an electrophile such as trimethyl borate or tributyltin chloride. Another approach to introduce heteroaromatics is to prepare 61. This is accomplished by treatment of the organolithium species, prepared as outlined above, with a suitable electrophile such as N,N-dimethylformamide. Conversion of 67 to 21 can then be accomplished using diamine reagents such as 1,2-phenyldiamine to give 2-substituted benzimidazoles or ammonium acetate and glyoxal to give 2-substituted imidazoles, which is converted to the amidine 22 as described in scheme 6a. scheme 6C Scheme 6c describes methods for the introduction of alkyl groups to the phenyl ring of Formula I. Compound 20 is treated with a base such as isopropylmagnesiurn chloride, followed by lithiation with a suitable reagent such as n-butyllithium., followed by reaction with electrophiles such as aldehydes and ketones to give 68 (Wakefield, B.J. The Chemistry of Organolithium Compounds; Pergamon: Oxford, 1974; Wakefield, B.J. Organolithium Methods; Academic: San Diego, 1990), which is converted to the amidine 22 as described in scheme 6a. Scheme 6d describes an approach to compounds of formula I, where the Ar residue is substituted with amines at the meta-position. Transition metal catalyzed coupling of the bromide 69 with amines is used to synthesize arylamine 70. Examples of suitable transition metal catalyst include palladium(0) or palladium(II) compounds such as Pd(II) acetate (Pd(OAc)2), dipalladium tris(dibenzylidineacetone) (Pd2(dba)3), tetrakis(triphenylphosphine) palladium(O) (Ph3P)3Pd), nickel(II) bis( 1,5- cyclooctadiene) (Ni(COD)2), or (l,1'-bis(diphenylphosphino)ferrocenyl nickel dichloride, in the presence or absence of coordinating ligand and in the presence of a suitable base and solvent. Preferred catalyst include Pd(OAc)2 and Pd2(dba)3. Examples of coordinating ligands include tri-t-butylphosphine, 2,2'-bis(diphenylphosphino)-l,1'-binaphthyl (BINAP), 2,2'- bis(ditolylphosphino)-l,l'binaphthyl (tol-BINAP), 1,1'- bis(diphenylphosphino)ferrocene (DPPF), bis(2- diphenylphosphinophenyl)ether(DPEphos), 2-(di-t-butylphosphino)biphenyl (DBPB), 2-(di-cyclohexylphosphino)biphenyl (DCPB), 2- dicyclohexylphosphino-2,-(N,N-dimethylamino)biphenyl (DCDMB). Preferred ligands for palladium-catalyzed reactions include BINAP, DBPB, DCPB, and DCDMB. Preferred ligands for nickel-catalyzed reactions include DPPF or 1,10-phenanthroline. Examples of suitable bases include sodium t- butoxiode, potassium t-butoxide, cesium carbonate, potassium carbonate, potassium phosphate or cesium fluoride, with sodium t-butoxide, potassium phosphate or cesium carbonate preferred depending on the other functionality present in 70 and the amine being coupled. Suitable solvents include aromatic hydrocarbons such as benzene, toluene, or xylenes; ethers such as dimethoxyethane (DME) or 1,4-dioxane; or amides such as N,N- dimethylformamide, N,N-dimiethylacetamide or N-methylpyrrolidinone. Preferred solvents include toluene, DME and 1,4-dioxane. The coupling reaction may be carried out at a temperature of 20-160 C, preferably 20-100 C, and most preferably at the lowest possible temperature that provides reaction times of less than 24 hours. For representative methodologies, catalysts, examples of conditions and reviews of these types of palladium-catalyzed coupling reactions see: J.P. Wolfe, et al., Acc. Chem. Res., 31:805-18(1998), C.G. Frost, et al.., J. Chem. Soc., Perkin Trans 1, 2615-23 (1998) and J.P. Wolfe, J. Org. Chem., 65:1158-74 (1998). For examples of nickel-catalyzed reactions see J.P. Wolfe and S.L. Buchwald, J. Am. Chem. Soc, 119:6054-58 (1997). The nitrile 70 can be converted to the BOC-protected amidine by treating with lithiated tert-butylcarbamate (Aldrich Chemical Company, WI, USA). The amidine 72 is obtained by treating 71 with TFA. After completion of the biaryl species, amidine 22 is completed either through amidination of the methyl carboxylate 23 (Scheme 2), or by deprotection of Boc-amidine 21 with trifluoroacetic acid or hydrochloric acid in an organic solvent such as dioxane. When not commercially available, arylboronic acids of formulas 25 and 26, where Ar is phenyl, naphthyl, or heterocycle, any of which are optionally substituted, can be synthesized by the methods illustrated in Scheme 7. When Y is Br, I, or C1 and Ar is tolerant to strong basic and/or nucleophilic conditions, the preferred method involves lithium/halogen exchange with n-BuLi followed by treatment with trimethyl borate, triisopropyl borate, or triethyl borate to give compounds of formula 26 where R10 is Me, Et, iPr, or H. Alternatively, regioselective metalation of 24 can be directly achieved with n-BuLi or t-BuLi when Y is H and an ortho directing group is present in Ar. La such cases, treatment of the metalated species with trimethyl borate triisopropyl borate, or triethyl borate gives rise to compounds of formula 26 where R10 is Me, Et, iPr or H. Examples of ortho directing groups suitable for this transformation include but are not limited to OCH2OCH3, SO2NR2, CONR2, CONHR, NHCOR, NHCO2R, and CSNHR (Mark, R., et al., J. Org. Chem. 47: 2101 (1982); Townsend, C, et al., Tetrahedron Lett. 3923 (1981)). When Ar contains functional groups that are sensitive to base and/or nucleophiles, conversion of 24, where Y is Br, I, Cl, or OTf to arylboronic acids of formula 25 can be effected using one of several methods involving palladium(O)-mediated boronation of arylhalides (Ishiyama, T., et al., J. Org. Chem. 60: 7508 (1995)). Examples of this transformation include but are not limited to treatment of 24 with: 1) Pd(PPh3)4, (PPh3)2Pda2, or PdCl2(dppf), pinacolborane, and Et3N in dioxane at 100 °C (Murata, M., et al., J. Org. Chem. 65:164 (2000)); 2) Pd(OAc)2, (2'- Dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine, bis(pinacolato)diboron, and K3PO4 in toluene at 95 °C (Old, D.W., et al., J. Am. Chem. Soc. 120:9722 (1998)); 3) PdCl2(dppf), bis(pinacolato)diboron, and KOAc in DMSO (Ishiyama, T., et al., J. Org. Chem. (50:7508 (1995)). Suitable reaction times for this transformation are 12-24 hr. Scheme 8 illustrates an alternate approach to compounds of Formula / where X = O or S, and R1 = halo, alkylthio, aralkylthio, arylthio, alkyloxy, aralkyloxy or aryloxy. A heterocycle 27 appropriately substituted with a leaving group L may be substituted with an anion of R1 to give intermediate 28. When L = halo, the halide can be left alone to give R1 = halo. The amine 29 is then derived from reduction of the nitro group. Appropriate reagents to effect reduction of the nitro functionality include hydrogen gas in the presence of a catalyst such as palladium or platinum metal deposited on carbon or barium sulfate in any number of solvents such as methanol, ethanol, ethyl acetate, DMF, or THF. More preferably, tin (II) chloride may be employed as a reductant in a solvent such as methanol or ethanol. Alternatively, metals such as zinc or iron (Stanetty, P. and Kremslehner, M., Heterocycles 48: 259 (1998)) may also be used. When R1 is halo, titanium (HI) chloride in HC1 (see Eo, Wong, Synthesis 45 (1974)) is the preferred reducing reagent. The amine 29 can then be converted to the sulfonyl chloride 30 by diazotization in the presence of sulfur dioxide and copper (II) chloride (Ramsay, G. C. et al., J. Am. Chem. Soc. 93:1166-1171 (1971), European Patent EP 983982). The sulfonyl chloride 30 can then be treated with sodium sulfite and sodium bicarbonate to afford the sodium sulfinate 31 (Field L. and Clark. R. D., Organic Synthesis Collective Vol. IV, 674-677, John Wiley and Sons, Inc. 1963). The sulfinate 31 can be converted to sulfone 32 by reacting the sulfinate 31 with an alkyl or aryl group appropriately substituted with a leaving group in a solvent such as ethanol (Field L. and Clark. R. D., Organic Synthesis Collective Vol. IV, 674-677, John Wiley and Sons, Inc. 1963). Scheme 9 illustrates a specific example of the method shown in Scheme 8. The sulfinate 33 can be obtained by treating 4-nitro-5-bromo- thiophene-2-carboxylic acid methyl ester (DelPErba, C. and Spinelli, D., Tetrahedron 21: 1061 (1965); Dell'Erba, C. et al., J. Chem. Soc, Perkin Trans 2, 1779 (1989)) according to scheme 8. The sulfinate 33, can be treated with 34 (Hazelton, C. J. et al., Tetrahedron, 51:5591 (1995)) in a solvent such as aqueous ethanol with acetic acid as catalyst to give the sulfone 35. Sulfone 35 is treated with sodium dithionite in aqueous ethanol to afford 36 (Hazelton, C. J. et al., Tetrahedron, 51:5591 (1995)), which can be cross-coupled to an aryl residue using the methods described in Scheme 6 to give compounds of formula 37. Both compound 36 and 37 can be treated with hot formic acid to give compounds 42 and 38 respectively. Benzimidazoles 38 and 42 can then be alkylated to give 39-41 and 43-44 respectively. These esters can be converted to their amidines by the methods described in Scheme 2. Scheme 9b illustrates approaches to 1-alkyl-5-sulfonyl-benzimidazoles of compounds of Formula X, where R = H, halo, alkyl, alkyloxy, and Ri= alkyl or aryl. Appropriately substituted sulfinate can be prepared from the corresponding sulfonyl chloride in a manner similar to that described in scheme 11. Reaction of the appropriately substituted arylsulfinate 74 with the bromo-nitro-thiophene, 1 yields a mixture of mono- and bis-sulfone adducts. Thiomethoxide addition at—78 °C chemoselectively occurs at the 5-position of the thiophene for both adducts, giving the intermediate 75. The aniline 75 is converted to the arylhalide 76 under Sandmeyer diazotization conditions (Doyle, M. P. et al.. J. Org. Chem. 42, 2426 (1977)). Heating this halo- nitroarene with an amine or arylamine at 60-80 °C in the presence of a base (NaOAc or DIEA) yields the substituted aniline 77. Reduction of the nitro group (e.g. Fe/AcOH in ethanol) followed by heating in formic acid gives the benzimidazole 78, which can be converted to the amidine 79 as described in Scheme 2. The synthesis of compounds of formulas 48 and 49, having two meta- substitutions on the phenyl ring with respect to the sulfone are described in Scheme 10. The tert-butyl phenol ether in compound 45 can be deprotected using a strong acid treatment such as TFA or HC1 in DCM or dioxane, respectively. The free phenol as in compound 46 can be alkylated under standard conditions with alkyl halide and a base, preferably CS2CO3 in acetone, to furnish compounds described by formula 47. Examples of alkylating agents (R11) include but are not limited to allyl bromide, benzyl bromide, methyl iodide, 2-bromoacetate, and 2-bromoacetamide. The carboxylic acid ester in formula 47 can be directly converted to the amidine or a masked amidine as described in Scheme 2 to give compounds of formula 48. Alternatively, 47 can be cross-coupled with a variety of arylboronic acids and heterocyclic boronic acids as shown in Scheme 6, followed by amidination as previously described to afford compounds contained in formula 49. Scheme 11 illustrates yet another approach to compounds of Formula I where X = O or S, R1 = halo, alkylthio. aralkylthio, arylthio, alkyloxy, aralkyloxy or aryloxy. A sulfonyl chloride 50, where Ar is aryl or heteroaryl, is treated with sodium sulfite and sodium bicarbonate to afford the sodium sulfinate 51 (Field L. and Clark. R. D., Organic Synthesis Collective Vol. IV, pp. 674-677, John Wiley and Sons, Inc. (1963)). The sulfinate 51 can be converted to sulfone 3 by reacting the sulfinate 51 with 1. The sulfone 3 can then be treated as described in scheme 1 to give intermediate 4, which can be converted to an amidine by the methods described in scheme 2. Scheme 12 illustrates a specific example of the method shown in scheme 11. Pyridylsulfonylchloridie (Aldrich), 52 is converted to the sulfinic acid and reacted with thiophene ester 54 to give the sulfone, 55. The sulfone (55) is then treated as described in scheme 1 to give the intermediate 56. Intermediate 56 can be treated with ammonia or zinc dust in acetic acid (Krutosikova, A.; Sleziak, R. Collect. Czech. Chem. Commun. (1996) 61, 1627-1636) to give compounds 58 or 59 respectively. The amide 58 can be converted to the biaryl compound 60 using methods described in scheme 6. Compounds 56, 58, 59, and 60 can be converted to the corresponding amidines 57, 61, 62, and 63 respectively, as described in scheme 2. Scheme 13 illustrates a general route to compounds of formula I where Ar is substituted 3-pyridyl (when A = N) and compounds of formula II where the phenylsulfone moiety has an amino group at the 4-position (A = N, C). The sulfone 56 is prepared as described in scheme 12 and then treated as described in scheme 1 to give the corresponding amidine, which is BOC- protected to give intermediate 64. The C1 group in intermediate 64 can be displaced with an amine to give a substituted aminopyridine, which upon treatment with trifluoroacetic acid gives compound 65. Intermediate 56 can be treated with Zn dust (Krutosikova, A.; Sleziak, R. Collect. Czech. Chem. Commun. (1996) 61, 1627-1636) to give the dehalogentaed product 59, which can also be converted to the amidine 63. The halogen Y in intermediate 56 (when A = N or C) can also be substituted with ammonia to give 58, which can be converted to the amidine 62. Alternatively, 58 can be converted to the biaryl compound 60 using methods described in scheme 6. Scheme 14 illustrates this general approach to the synthesis of compounds of formula n, where R5 is 2-aminophenyl or 2-amino-4-pyridyl and the amino groups are further substituted. The Biaryl-intermediate 80 can be prepared either by treating 20 with an appropriately substituted arylboronate or boronic acid using conditions similar that described in scheme 6a or by treating 66 with an appropriately substituted arylhalide or triflate using conditions similar to that described in scheme 6b. Intermediate 2 can be converted to the corresponding substituted ureas 81 using conditions such as p-nitrophenylchloroformate in the presence of a base such as pyridine, followed by addition of a substituted amine, followed by treatment with an acid such as trifluoroacetic acid. In an alternative approach intermediate 80 can be treated with reagents such as substituted isocyanates in the presence of a base such as triethylamine, followed by treatment with an acid such as trifluoroacetic acid to give the corresponding substituted ureas 81. The intermediate 2 can also be converted to the corresponding amides 82 using reagents such as substituted acids in the presence of coupling reagents such as EDCI and HOBt, followed by treatment with an acid such as trifluoroacetic acid. The intermediate 80 can also be converted to the corresponding amides or sulfonamides 82 by treating with acid chlorides, sulfonyl chlorides, anhydrides, or activated esters in the presence of a base such as triethylamine, followed by treatment with an acid such as trifluoroacetic acid. Scheme 15 illustrates a general approach to the synthesis of compounds of formula II, where R5 is 2,4-diaininophenyl and the amino groups are further substituted. Intermediate 83 can be synthesized in a manner similar to that described in scheme 14. When R23 is a masked amine such as nitro. or trimethylsilylethyl carbamate (Teoc), the ortho-aniline may be functionalized with a variety of reagents such as acid chlorides, sulfonyl chlorides, activated carboxylic esters, and isocyanates to give compound 84. When R" of compound 84 is a nitro-group it can be reduced to an amino- group under mild conditions using iron powder in ethanolic aqueous ammonium chloride (R1 = NO2) and further reacted with reagents such as acid chlorides, sulfonyl chlorides, activated carboxylic esters, isocyanates, guanidinylating reagents, alkyl halides, and aldehydes (reductive animation) to give compound 86. When R23 is a protected aniline it can be deprotected. For example a Teoc group is removed by treatment with a fluoride anion source such as tetrabutylammonium fluoride in THF to give compound 85. This can be further functionalized in the manner described above. Scheme 16 illustrates approaches to providing the arylguanidine functionality of compounds of Formula II where R5 is a substituted phenyl group with a 4-araino functionality. Depending on the nature of the group R, several methods may be employed in the guandinylation of the aniline 87 to compounds 89, 90 or 92. When R1 is H or alkyl, unsubstituted or N,N'-bis- substituted arylguanidines 90, can be synthesized by the reaction of the aniline with a diprotected S-alkyl isothiourea (e.g. bis-Boc-SMe-isothiourea). This reaction can generally be promoted by either of two reaction conditions; 1) a mercury salt (e.g. HgCl2) with triethylamine at 50 °C [WO-99/206208] or 2) acetic acid in methanol at 40 °C [Tetrahedron Lett., 43, 6563-6566 (2000)]. When R' is a strong electron-withdrawing group (e.g. nitro), or contains other acid-sensitive functionality, the mercury reagent is preferred. When R31 is, or, contains an amino-group, selective guanidinylation at the 4-amino group can be achieved using the acetic acid/methanol conditions. Monosubstituted N'- arylguanidines 89 can be synthesized by reaction of the aniline (R1 =: H, alkyl) with a substituted diprotected S-alkyl isothiourea (e.g. alkylN(Boc)- C(SMe)=NBoc). The acetic acid in methanol reaction condition is the method of choice for this transformation. The monoalkyl isothiourea starting materials can be synthesized via alkylation of the bis-Boc-SMe-isothiourea with a hydride base/alkyl halide [J. Med. Chem., 36, 2956-2963 (1993)] or Mitsunobu reaction [J. Med. Chem., 43, 2362-2370 (2000)}. Alternatively, arylguanidines can be prepared from corresponding thiourea intermediates 91 and 94. Preparation of 91 is achieved by reacting the aniline scaffold with an isothiocyanate. Alternatively, the aniline scaffold may be converted to the isothiocyanate [J. Org. Chem., 51, 2613-2615 (1986)] followed by reaction with an alkylamine, aniline, hydrazide, or alkoxylamine to give 94. The thiourea may then be converted to the guanidine using mercuric oxide in the presence of excess amine (e.g. ammonia, methylamine, etc.) [J. Chem. Soc, 475, 479 (1949)]. Scheme 17 illustrates the general approach to the synthesis of compounds of formula II, represented by examples 213-214. The alcohol 95 can be converted to the corresponding mesyiate 98 in the presence of a methanesulfonyl chloride and a base such as triethylamine, in a solvent such as dichloromethane. Mesyiate 98 can be treated with a variety of substituted nucleophiles in the presence of a base such as triethylamine in a solvent such as dichloromethane, followed by treatment with an acid such as trifluoroacetic acid to give the corresponding product 99. Alternatively, compound 95 can be converted to the corresponding aldehyde 96 in the presence of an oxidizing agent such as manganese dioxide. Aldehyde 96 can then be treated with a variety of phosphorus ylides to give the corresponding olefin, (see Paterson, I., et al., Org. Lett. 5(I):35-38 (2003)), followed by treatment with an acid such as trifluoroacetic acid to give compound 100. For example, aldehyde 96 is treated with (diethoxy-phosphorylmethyl)-phosphonic acid diethyl ester in the presence of a base such as sodium hydride in a solvent such as tetrahydrofuran, followed by treatment with trimethylsilyl iodide and a solvent such as dichloromethane to give compound 91 (see Ruzziconi, R. el al, J Org. Chem. 68(3):736-142 (2003)). The following examples are illustrative, but not limiting, of the method and compositions of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered and obvious to those skilled in the art are within the spirit and scope of the invention. EXAMPLES Example 1 a) 4-Methoxymethoxy-biphenyl To an oven-dried flask containing a stirbar was added 4- hydroxybiphenyl (1.70 g, 10 mmol), toluenesulfonic acid (190 mg, 1.1 mmol), dichloromethane (DCM, 5 mL), and dimethoxypropane (5 mL)- The solution was heated and stirred at 40 °C for 48 h. Solid NaHCO3 (200 mg) was added, followed by EtOAc (100 mL) and NaOH (1N, 20 mL). The layers were separated and the organic layer was further extracted with NaOH (1N, 12 x 20 ml), brine (30 mL), and was dried over sodium sulfate. Removal of the solvents in vacuo yielded the title compound (385 mg, 18%) which was used without further purification. 1H-NMR (CDCl3); d 7.56 (m, 4H), 7.44 (m, 2H), 7.34 (m, 1H), 7.14 (m, 2H), 5.24 (s, 2H), 3.54 (s, 3H). b) 4-Methoxymethoxy-biphenyl-3-yl-boronic acid Butyllithium (2.5M, 1.44 mL, 3.6 mmol) was added over 5 min to a stirred solution of 4-methoxymethoxy-biphenyl (from the previous step 385 mg, 1.8 mmol) in Et2O (18 mL) at 0 °C. The reaction was allowed to warm to rt and stirred for 2 h. The solution was cooled to -78 °C and trimethylborate (1.23 mL, 10.8 mmol) in THF (10 mL) was quickly added. The reaction wanned to rt over 1 h and was stirred 1 h at rt, during which it became cloudy and a gelatin-like residue appeared. EtOAc (70 mL) and water (30 mL) were added along with HC1 (IN, 1 mL). The biphasic solution was stirred for 10 min and the layers were separated. The organic layer was further extracted with HC1 (0.1N, 3 x 20 mL)., brine (60 mL), and was dried over sodium sulfate. Removal of the solvents in vacuo followed by chromatography of the residue (20-40% EtOAc in hexaries) yielded the title compound (135 mg, 29%) as a light-brown solid. The title compound exists as a mixture of boronic acids and anhydrides in CDCl3, therefore the reported NMR signals represent pairs or groups of related signals. 1H-NMR (CDCl3): d 8.07 (d, 1H, J = 2.6 Hz), 7.60 (m, 3H);, 7.42 (m, 2H), 7.31 (m, 1H), 7.19 (d, 1H, J = 8.6 Hz), 6.20 (s, 1H), 5.32 (s, 2,H), 3.77 (s, 1H), 3.53 (s, 3H). c) {Imino-[4-(4'-methoxymethoxy-[1,1';3;1']terphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester A 2-dram vial with a septa-containing screwcap was charged with {[4- (3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}- carbamic acid tert-butyl ester (Example 27 (50 mg, 0.1 mmol)), 4- methoxyrnethoxy-biphenyl-3-yl-boronic acid (from the previous step 103 mg, 0.4 mmol), aqueous Na2CO3 (2M, 0.8 mL, 1.6 mmol), ethanol (0.8 mL) and (1.6 mL). A stirbar was added, the vial was capped, the solution was sparged with argon for 10 min, and Pd(PPh3)4 (29.4 mg, 0.025 mmol) was added. The biphasic solution was vigorously stirred under inert atmosphere at 80 °C for 16 h, then was cooled to rt. EtOAc (20 mL) and water (10 mL) were added and the layers were separated. The organic layer was washed with saturated NaHCO;, (2 x 10 mL), brine (10 mL) and was dried over sodium sulfate. Removal of the solvents in vacuo followed by preparative TLC (25% EtOAc in hexanes) of the residue yielded the title compound (15 mg, 24%) as a light-yellow glass. 1H-NMR (CDCl3): 6 8.27 (t, 1H, J = 1.9), 7.99 (ddd, 1H, J = 1.2, 1.6, 7.9 Hz), 7.96 (s, 1H), 7.84 (dt, 1H, J = 1.4, 7.9 Hz), 7.57 (m, 5H), 7.45 (m, 2H), 7.36 (m, 1H), 7.30 (m, 1H), 5.18 (s, 2H), 3.41 (s, 3H), 2.59 (s, 3H), 1.52 (s, 9H). ESI-MS (m/z): Calcd. for C31H32N2O6S3: 624.8; found: 624.9. d) 4-(4'-Hydroxy-[1,1';3',1 ']terphenyl-3'-sulfonyl)-5-methylsulfonyl- thiophene-2-carboxamidine trifluoroacetate The {imino-[4-(4'-methoxymethoxy-[ 1,1 ';3',1']terphenyl-3-sulfonyl)- 5-methylsulfanyl-thiophen-2-yl}-methyl}-carbamic acid tert-butyl ester ((Example 1: step c) 15 mg, 0.024 mmol) was dissolved in DCM (5 mL), water (3 drops) was added, followed by trifluoroacetic acid (5 mL). The solution was stirred for 2 h at rt and the solvents were removed in vacuo. The residue was purified via HPLC (C18-column, 10-70% CH3CN over 30 min) which yielded the title compound as a white solid (11 mg, 73%). 1H-NMR (CD3OD): d 8.34 (t, 1H, J = 1.6 Hz), 8.32 (s, 1H), 7.98 (m, 2H), 7.66 (t, 1H, J = 7.9 Hz), 7.58 (m, 2H), 7.53 (d, 1H, J = 2.1 Hz), 7.50 (dd, 1H, J = 2.3, 8.4 Hz), 7.41 (m, 2H), 7.29 (m, 1H), 7.02 (d, 1H, J = 8.4 Hz), 2.71 (s, 3H). ESI- MS (m/z): Calcd. for C24H20N2O3S3: 481.6 (M+H); found: 481.3. Example 2 4-(2'-Methoxymethoxy-[1,1';3',1']terphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate a) 2-Methoxym ethoxy-biphenyl The procedure as in Example 1: step a was followed using 2- hydroxybiphenyl (1.70 g, 10 mmol), p-toluenesulfonic acid (190 mg, 1.1 mmol), DCM (5 mL), and dimethoxypropane (5 mL). Analogous aqueous workup yielded the title compound (225 mg, 11%) which was used without further purification. 1H-NMR (CDCl3): d 7.58 (m, 2H), 7.44 (m, 2H), 7.36 (m, 2H), 7.32 (m, 1H), 7.25 (dd, 1H, J = 1.2, 8.1 Hz), 7.12 (dt, 1H, J = 1.2, 7.4 Hz), 5.14 (s,2H), 3.42 (s, 3H). b) 4-Methoxymethoxy-biphenyl-3-yl-boronic acid The procedure used in Example 1: step b was followed using 2- methoxymethoxy-biphenyl ((Example 2: step a) 225 mg, 1.05 mmol), butyllithium (2.5M, 1.44 mL, 3.6 mmol), and trimethylborate (1.23 mL, 10.8 mmol). Analogous aqueous workup and SiO2 flash chromatography yielded the title compound (123 mg, 45%) as a light brown solid. The title compound exists as a mixture of boronic acids and anhydrides in CDCl3; therefore the reported NMR signals represent pairs or groups of related signals. 1H-NMR (CDCl3): d 7.53 (m, 1H), 7.23 (m, 2H), 7.12 (m, 3H), 7.05 (m, 1H), 6.94 (m, 1H), 4.2S (s, 2H), 3.51 (s, 1H), 2.96 (s, 3H). c) {Imino-[4-(2'-methoxymethoxy-[1,l';3',1']terphenyI-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-methyI}-carbamic acid tert-butyl ester The procedure used in Example 1: step c was followed using {[4-(3- bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}- carbamic acid tert-butyl ester (Example 27 (50 mg, 0.1 mmol)), 2- methoxymethoxy-biphenyl-3-yl-boronic acid ((Example 2: step b) 103 mg, 0.4 mmol), Na2CO3 (2M, 0.8 mL, 1.6 mmol), Pd(PPh3)4 (29.4 mg, 0.025 mmol), ethanol (0.8 mL), and toluene (1.6 mL). Analogous aqueous workup and purification of the crude material by preparative TLC (25% EtOAc in hexanes) yielded the title compound (18 mg, 29%) as a light-yellow glass. 1H- NMR (CDCl3): d 8.24 (t, 1H, J = 1.7 Hz), 8.06 (s, 1H), 7.95 (ddd, 1H, J = 1.2, 1.9, 7.9 Hz), 7.86 (dt, 1H, J == 1.4, 7.7 Hz), 7.60 (t, 1H, J - 7.9 Hz), 7.56 (m, 2H), 7.2-7.45 (m, 6H), 4.22 (s, 2H), 2.60 (s, 3H), 2.47 (s, 3H), 1.48 (s, 9H). ESI-MS (m/z): Calcd. for C31H32N2O6S3: 624.8; found: 624.9. d) 4-(2'-Methoxymethoxy-[1,1';3',1']terphenyl-3-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate The procedure used in Example 1: step d was followed using {imino- [4-(2'-methoxymethoxy- [ 1,1'; 3', 1' ]terphenyl-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester ((Example 2: step c) 18 mg, 0.029 mmol). Analogous purification by HPLC yielded the title compound as a white solid (17 mg, 94%). 1H-NMR (CD3OD): d 8.32 (s, 1H), 8.27 (t, 1H, J = 1.7 Hz), 7.99 (ddd, 1H: J = 1.2, 1.9, 7.9 Hz), 7.92 (ddd, 1H, J = 1.2, 1.6, 7.9 Hz), 7.66 (dt, 1H, J = 0.5, 7.9 Hz), 7.52 (m, 2H), 7.45 (m, 2H), 7.36 (m, 2H), 7.26 (ddd, 2H, J = 1.7, 3.5, 7.2 Hz), 7.07 (t, 1H, J = 7.9 Hz), 2.71 (s, 3H). ESI-MS (m/z): Calcd. for C24H20N2O3S3 (M+H): 481.6; found: 481.2. Example 3 3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-methyl- biphenyl-3-carboxylic acid isopropyl ester trifluoroacetate a) 3-Bromo-2-methyl-benzoic acid isopropyl ester Thionyl chloride (6 mL) was added over 1 min to a 0 °C suspension of 3-bromo-2-methyl benzoic acid (2.15 g, 10 mmol) in DCM (10 mL). After 30 min of stirring, THF (5 mL) was added to induce dissolution. The now homogeneous solution was stirred for 24 h at rt and the volatile component were removed in vacuo. A portion of the crude acid chloride was dissolved in dry isopropyl alcohol (10 mL) and pyridine (2 mL) was added. After stirring for 4 h at rt, the volatile components were removed in vacuo. The residue was partitioned between EtOAc (70 mL) and HC1 (1M, 30 mL) and the layers were separated. The organic layer was washed with HC1 (1M, 10 mL), NaHCO3 (3 x 20 mL), water (30 mL), brine (30 mL), and was dried over sodium sulfate. Removal of solvent in vacuo yielded the title compound as a light-yellow oil which was used without further purification. 1H-NMR (CDCl3): d 7.69 (d, 2H, J = 7.7 Hz), 7.11 (t, 1H, J = 7.9 Hz), 5.26 (heptet, 1H, J = 6.3 Hz), 2.63 (s, 3H), 1.39(d,6H,J = 6.3Hz). b) 2-Methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzoic acid isopropyl ester A 2-dram vial with a septa-containing screwcap was charged with a stirbar, 3-bromo-2-methyl-benzoic acid isopropyl ester ((Example 3: step a) 257 mg, 1 mmol), PdCl2(PPh3)2 (42 mg, 0.06 mmol), dioxane (4 mL), and triethylamine (420 µL, 3 mmol). Upon dissolution, 4,4,5,5-tetramethyl- [l,3,2]dioxaborolane (220 µL, 1.5 mmol) was added and the solution was vigorously stirred for 16 h at 100 °C. After cooling to rt. EtOAc (30 mL) and water (10 mL) were added (gas evolution!) and the layers were separated. The organic layer was washed with NaHCO3 (2 x 10 mL), brine (10 mL), and was dried over sodium sulfate. Removal of the solvents in vacuo followed by SiO2 flash chromatography of the residue yielded the title compound (130 mg, 43%) as a light-yellow glass. 1H-NMR (CDCl3): d 7.86 (dd, 1H, J = 1.4, 7.4 Hz), 7.80 (dd; 1H, J = 1.6, 7.7 Hz), 7.23 (t, 1H, J = 7.7 Hz), 5.26 (heptet, 1H, J = 6.3 Hz), 2.75 (s, 3H), 1.37 (m, 18H). c) 3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl- thiophene-3-sulfonyl]-2-methyl-biphenyl-3-carboxylic acid isopropyl ester The procedure used in Example 1: step c was followed using {[4-(3- bromo-berizenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-memyl}- carbamic acid tert-butyl ester (Example 27 (50 mg, 0.1 mmol)), 2-methyl-3- (4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzoic acid isopropyl ester ((Example 3: step b) 92 mg, 0.3 mmol), Na2CO3 (2M, 0.4 mL, 0.8 mmol), Pd(PPh3)4 (29.4 mg, 0.025 mmol), ethanol (0.4 mL) and toluene (0.8 mL). Analogous aqueous workup and purification of the crude material by preparative TLC (25% EtOAc in hexanes) yielded the title compound (29 mg, 49%) as a colorless glass. 1H-NMR (CDCl3): d 7.98 (dt, 1H, J = 1.6, 7.6 Hz), 7.93 (m, 2H), 7.79 (t, 1H, J = 1.7 Hz), 7.58 (t, 1H, J = 7.6 Hz), 7.53 (dt, 1H, J = 1.6, 7.6 Hz), 7.36 (s, 1H), 7.30 (d, 1H, J = 4.5 Hz), 5.27 (heptet, 1H, J = 6.2 Hz), 2.58 (s, 3H), 2.35 (s, 3H), 1.51 (s, 9H), 1.39 (d, 1H, J = 6.2 Hz). ESI-MS (m/z): Calcd. for C28H32N2O6S3: 588.8; found: 588.9. d) 3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfouyl)-2- methyl-biphenyl-3-carboxylic acid isopropyl ester trifluoroacetate The procedure used in Example 1: step d was followed using 3'-[5- (tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3- sulfonyl]-2-methyl-biphenyl-3-carboxylic acid isopropyl ester ((Example 3: step c) 29 mg, 0.049 mmol). Analogous purification by HPLC yielded the title compound (25 mg, S3%) as a white solid. 1H-NMR (CD3OD): d 8.32 (s. 1H), 8.05 (dt, 1H, J = 1.7, 7.7 Hz), 7.95 (t, 1H, J - 1.7 Hz), 7.78 (m. 1H). 7.70 (t, 1H, J = 7.7 Hz), 7.66 (dt, 1H, J = 1.4, 7.7 Hz), 7.36 (s, 1H), 7.35 (d, 1H, J = 1.2 Hz), 5.22 (heptet, 1H, J = 6.3 Hz), 2.71 (s, 3H), 2.31 (s, 3H), 1.38 (d, 1H, J = 6.3 Hz). ESI-MS (m/z): Calcd. for C23H24N2O4S3: 489.7 (M+H); found: 489.2. Example 4 3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyI- biphenyl-2-carboxylic acid trifluoroacetate a) 2-Iodo-3-methyl-benzoic acid tert-butyl ester A 100-mL RB flask was charged with 2-iodo-3-methylbenzoic acid (l.lg, 4.2 mmol), a stirbar, Et2O (15 mL) and DCM (35 mL) and was cooled to —78 °C under an argon atmosphere. Trifluoromethanesulfonic acid (250 µL) was added over 30 sec and isobutylene was bubbled into the solution (until the solution became cloudy) using a 8"/20 gauge steel needle. The reaction was stirred for 6 h between -78 and -20 °C. Solid NaHCO3 (250 mg) was added and the solution was allowed to warm to it with stirring. After 20 min, the solution was poured into an extraction funnel containing DCM (50 mL) and Na2CO3 (2M, 20 mL). The layers were separated and the organic layer was washed with Na2CO3 (2M, 2 x 10 mL), water (20 mL), brine (30 mL) and dried over sodium sulfate. Removal of the solvent in vacuo yielded the title compound (1.05 g, 78%) which was used without further purification. 1H-NMR (CDCl3): d 7.25 (m, 3H), 2.50 (s, 3H), 1.62 (m, 9H). b) 4-Methyl-2'(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid tert-butyl ester The procedure used in Example 3: step b was followed using 2-iodo-3- methyl-benzoic acid tert-butyl ester ((Example 4: step a) 960 mg, 3 mmol), PdCl2(PPh3)2 (126 mg, 0.18 mmol), triethylamine (1.25 mL, 9 mmol), and 4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (660 (µL, 4.5 mmol) in. dioxane (12 mL) at a reaction temperature of 80 °C. Analogous aqueous workup and purification by SiO2 flash chromatography yielded the title compound (618 mg, 64%). 1H-NMR (CDCl3): d 7.67 (m, 1H), 7.25 (m, 2H), 2.43 (s, 3H), 1.57 (m,9H), 1.44 (m, 12H). c) 3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl- thiophene-3-sulfonyl]-6-methyl-biphenyl-2-carboxylic acid tert-butyl ester The procedure used in Example 1: step c was followed using {[4-(3- bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}- carbamic acid tert-butyl ester (Example 27 (50 mg, 0.1 mmol)), 4-methyl-2- (4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzoic acid tert-butyl ester ((Example 4: step b) 127 mg, 0.4 mmol), Na2CO3 (2M, 0.8 mL, 1.6 mmol), Pd(PPh3)4 (29.4 nag, 0.025 mmol), ethanol (0.8 mL) and toluene (1.6 mL). Analogous aqueous workup and purification of the crude material by preparative TLC (25% EtOAc in hexanes) yielded the title compound (35 mg, 58%) as a light-yellow glass. 1H-NMR (CDCl3): d 8.01 (ddd, 1H, J = 1.2, 1.9, 7.9 Hz), 7.92 (s, 1H), 7.83 (t, 1H, J = 1.7 Hz), 7.65 (m, 1H), 7.56 (t, 1H, J = 7.8 Hz), 7.43 (dt, 1H, J = 1.4, 7.7 Hz), 7.36 (m, 2H), 2.58 (s, 3H), 2.00 (s, 3H), 1.51 (s, 9H). ESI-MS (m/z): Calcd. for C29H34N2O6S3: 602.8; found: 602.9. d) 3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6- methyl-biphenyl-2-carboxylic acid trifluoroacetate The procedure used in Example 1: step d was followed using 3'-[5- (tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3- sulfonyl]-6-methyl-biphenyl-2-carboxylic acid tert-butyl ester ((Example 4, step c) 29 mg, 0.048 mmol). Analogous punfication by HPLC yielded the title compound (23 mg, 70%) as a white solid. 1H-NMR (CD3OD): d S.28 (s. 1H). 7.99 (ddd, 1H, J = 1.2, 1.9, 7.9 Hz), 7.83 (m, 1H, J = 0.5, 1.9 Hz), 7.76 (ddd, 1H, J = 0.5, 1.4, 7.7 Hz), 7.63 (dt, 1H, J = 0.5, 7.7 Hz), 7.50 (ddd, 1H, J = 1.2, 1.6, 4.9 Hz), 7.49 (ddd, 1H, J -0.7, 1.4, 7.7 Hz), 7.40 (t, 1H, J = 7.7 Hz), 2.72 (s, 3H), 2.02 (s, 3H). ESI-MS (m/z): Calcd. for C20H18N2O4S3 (M+H): 447.6; found: 447.1. Example 5 4-(6'-Hydroxymethyt-2'-methyl-biphenyl-3-suIfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine a) (2-Iodo-3-methyl-phenyl)-methanol Thionyl chloride (6 miL) was added over 1 min to a 0 °C solution of 2- iodo-3-methyl benzoic acid (3.0 g, 11.4 mmol) in DCM (10 mL). The solution was stirred for 24 h at rt and the volatile components were removed in vacuo. A portion of the crude acid chloride (955 mg) was dissolved in THF (15 mL) and NaBH4 (380 mg, 10 mmol) was added. After stirring for 90 min, multiple spots were evident by TLC analysis. The reaction mixture was cooled to -78 °C and solid LiAlH4, (300 mg, 7.91 mmol) was added. The reaction was stirred for 30 min, after which TLC analysis showed one major spot. The reaction was quenched by addition of EtOAc (10 mL) and was slowly poured into a vigorously stirred solution of HC1 (1M, 30 mL). EtOAc (70 mL) was added, the layers were separated, and the organic layer was washed with NaHCO3 (3 x 15 mL), water (15 mL), brine (40 mL), and was dried over sodium sulfate. Removal of the solvent in vacuo yielded the title compound (752 mg, 89%) as a thick oil which was used without further purification. 1H-NMR (CDCl3): d 7.27 (m, 2H), 7.20 (m, 2H), 4.74 (m, 2H), 2.50 (s, 3H), 2.0 (br s, 1H). b) 7-Methyl-3H-benzo[c][1,2]oxaborol-1-ol Butyllithium (2.5 M, 2.91 mL, 7.3 mmol) was added dropwise to a -78°C solution of aryl halide ((Example 5: step a) 723 mg, 2.91 mmol) in Et2O (12 mL). The solution was stirred at -78°C for 2 h and trimethylborate (3.3 mL, 29.1 mmol) was added in one portion. The solution was warmed to rt over 15 min and stirred for 1 h at rt (appearance of gelatin-like ppt). EtOAc (80 mL) and HC1 (0.1 N, 30 mL) were added and the biphasic solution was stirred for 15 min. The layers were separated and the organic layer was washed with HC1 (0.1N, 2 x 10 mL), water (10 mL), brine (30 mL), and was dried over sodium sulfate. Concentration of the solution in vacuo yielded an oily solid which further solidified upon trituration with hexanes. The crude title compound (contaminated with butylboronate products) was used without further purification, existing as a mixture of the cyclic half-ester and the free boronic acid. 1H-NMR (CDCl3): d 7.1-7.4 (m, 3H), 5.23 (m, 2H), 2.57 (s, 3H). c) {[4-(6'-Hydroxymethyl-2'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-immo-inethyl}-carbamic acid ten-butyl ester The procedure used in Example 1: step c was followed using {[4-(3- bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}- carbamic acid tert-butyl ester (Example 27 (50 mg, 0.1 mmol)), 7-methyl-3H- benzo[c][l,2]oxaborol-1-ol ((Example 5: step b) 59 mg, 0.4 mmol), Na2CO3 (2M, 0.8 mL, 1.6 mmol), Pd(PPh3)4 (29.4 mg, 0.025 mmol), ethanol (0.8 mL) and toluene (1.6 mL). Analogous aqueous workup and purification of the crude material by preparative TLC (40% EtOAc in hexanes) yielded the title compound (21 mg, 40%) as a light-yellow glass. 1H-NMK- (CDCl3): d 7.96 (m, 2H), 7.86 (m, 1H), 7.54 (m, 1H), 7.43 (m, 1H), 7.18-7.38 (m, 3H), 4 53 (d, 1H= 13.3 Hz), 4.45 (d, 1H. J = 13.3 Hz), 2.54 (s, 3H), 1.96 (s, 3H), 1.49 (s, 9H). ESI-MS (m/z): Calcd. for C25H28N2O5S3: 532.7; found: 532.9. d) 4-(6'-Hydroxymethyl-2'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxamidine The procedure used in Example 2: step d was followed using {[4-(6'- hydroxymethyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2- yl]-imino-rnethyl}-carbamic acid tert-butyl ester ((Example 5, step c) 21 mg, 0.039 mmol). Analogous purification by C18-HPLC yielded the title compound (19 mg, 86%) as a white solid. 1H-NMR (CD3OD): d S.33 (s, 1H), 8.04 (ddd, 1H, J = 1.2, 1.9, 7.9 Hz), 7.S8 (m, 1H), 7.71 (dt, 1H, J = 0.5, 7.7 Hz), 7.57 (ddd. 1H, J = 1.2, 1.6, 7.7 Hz), 7,42 (m, 1H), 7.34 (t, 1H, J = 7.7 Hz), 7.26 (m, 1H), 4.20 (s, 2H), 2.72 (s, 3H), 1.99 (s, 3H). ESI-MS (m/z): Calcd. for C20H20N2O3S3 (M+H): 433.6; found: 433.1. Example 6 4-(3'-formyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate a) 3-Bromo-N-methoxy-2,N-dimethyl-benzamide Thionyl chloride (6 mL) was added over 1 min to a 0 °C solution of 2- iodo-3-methyl benzoic acid (3.0 g, 11.4 mmol) in DCM (10 mL). The solution was stirred for 24 h at rt and the volatile components were removed in vacuo. A portion of the crude acid chloride (1.56 g, 6.7 mmol) was dissolved in dry DCM (15 mL). N,O-dimethylhydroxylamine (814 mg, 8.35 mmol) was added followed by triethylamine (2.80 mL, 20.1 mmol). After stirring for 18 h at rt the solvents were removed in vacuo. After partitioning the residue between EtOAc (60 mL) and aqueous HC1 (1N, 20 mL), the organic layer was further extracted with HCl (1N, 10 mL), NaOH (1N, 3 x10 mL), water (10 mL), brine (20 mL), and was dried over sodium sulfate. Removal of the solvent in vacuo yielded the title compound (1.58 g, 92%) which was used in subsequent reactions without further purification. 1H-NMR (CDCl3): d 7.57 (dd, 1H, J = 1.2, 7.9 Hz), 7.21 (d, 1H, J = 7.4 Hz), 7.08 (t, 1H, J = 7.7 Hz), 3.39 (br s, 3H), 3.35 (br s, 3H), 2.36 (s, 3H). b) 3-Bromo-2-methyl-benzaldehyde Lithium aluminum hydride (201 mg, 5.31 mmol) was added in one portion to a -78 °C solution of 3-bromo-N-methoxy-2,N-dirnethyl-benzamide ((Example 6: step b) 1.1 g, 4.24 mmol) in THF (25 mL). After stirring for 1 h at -78 °C, the hydride reagent was quenched with EtOAc (10 mL), and the solution was slowly poured into a vigorously stirred mixture of citric acid (10%, 30 mL) and EtOAc (50 mL). After separating the layers, the organic layer was washed with NaHCO3 (3 x 20 mL), water (20 mL), and brine (30 mL). The solution was dried (sodium sulfate) and the solvent was removed in vacuo, giving the title compound (813 mg, 96%) as a colorless oil which was used without further purification. 1H-NMR (CDCl3): d 10.28 (s, 1H), 7.80 (m, 2H), 7.25 (m, 1H), 2.78 (s, 3H). c) l-Bromo-3-dimethoxymethyl-2-methyl-benzene The 3-bromo-2-methyl-benzaldehyde ((Example 6: step c) 813 mg, 4.08 mmol) was dissolved in dry MeOH (50 mL) and trimethyl orthoformate (8 mL). Toluenesulfonic acid (100 mg) was added and the solution was stirred for 6 h at rt. Solid NaHCO3 (200 mg) was added, the solution was stirred for 30 min, and the volatile components were removed in vacuo. The residue was dissolved in dry EtOAc (10 mL), the solution was filtered (45 micron filter), and the solvent was removed in vacuo. 1H NMR analysis of the crude material (918 mg, 92%) revealed approximately a 90% conversion of the starting material to the title compound, which was used without further purification. 1H-NMR (CDCl3): d 7.47 (dd, 1H, J = 1.2, 8.1 Hz), 7.44 (dd, 1H, J = 0.9, 7.9 Hz), 6.99 (t, 1H, J == 7.9 Hz), 5.37 (s, 1H), 3.25 (s, 6H), 2.37 (s, 3H). d) 2-Formyl-1-methyl-phenylboronic acid The 1-bromo-3-dimethoxymethyl-2-methyl-benzene ((Example 6: step c) 500 mg, 2 mmol), butyllithium (2.5 M, 1 mL, 2.5 mmol), and trimethylborate (2.3 mL, 20 mmol) were reacted as in Example 5: step b. After aqueous workup, the residue was dissolved in acetone (18 mL) and HCl (1N, 2 mL). After standing for 18 h at rt, the volatile components were removed in vacuo and the residue was purified by SiO2 flash chromatography (25-40% EtOAc in hexanes) to give the title compound (126 mg, 38%). The title compound exists as a mixture of boronic acids and anhydrides in CDCl3, therefore the reported NMR signals represent pairs or groups of related signals. 1H-NMR (CDCl3): d 10.44 (s, 1H), 8.38 (dd, 1H, J = 1.4, 7.4 Hz), 7.49 (t, 1H, J = 7.5 Hz), 3.12 (s, 3H). e) [4-(3'-Formyl-2'-methyl-biphenyl-3-sulfonyl)-5-methyIsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester The procedure used in Example 1: step c was followed using {[4-(3- bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}- carbamic acid tert-butyl ester ((Example 27) 50 mg, 0.1 mmol), Pd(PPh3)4 (29.4 mg, 0.025 mmol), 2-formyl-1-methyl-phenylboronic acid ((Example 6: step d) 65 mg, 0.4 mmol), Na2CO3 (2M, 0.8 mL, 1.6 mmol), ethanol (0.8 mL) and toluene (1.6 mL). Analogous aqueous workup and purification of the crude material by preparative TLC (25% EtOAc in hexanes) yielded the title compound (30 mg, 56%) as a light-yellow glass. 1H-NMR (CDCl3): d 10.36 (s, 1H), 8.02 (s, 1H), 7.99 (ddd, 1H, J = 1.4, 1.9, 7.7 Hz), 7.93 (t 1H, J = 1.6 Hz), 7.87 (dd, 1H, J = 3.0, 6.3 Hz), 7.60 (dt, 1H, J = 0.5, 7.7 Hz), 7.54 (dt, 1H, J = 1.5, 7.7 Hz), 7.43 (m, 2H), 2.57 (s, 3H), 2.49 (s, 3H), 1.51 (s, 9H). ES1- MS (m/z): Calcd. for C25H26N2O5S3: 530.7; found: 530.9. f) 4-(3'-Formyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate The procedure used in Example 1: step d was followed using {[4-(3'- formyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]- irnino-methyl}-carbamic acid tert-butyl ester ((Example 6: step e) 30 mg, 0.056 mmol). Analogous purification by HPLC yielded the title compound (22 mg, 73%) as a white solid. The aldehyde is hydrated according to proton NMR analysis. 1H-NMR (CD3OD): d 8.36 (s, 1H), 8.07 (ddd, 1H, J = 1.4, 1.9, 7.7 Hz), 7.98 (t, 1H, J = 1.5 Hz), 7.72 (dt, 1H, J = 0.5, 7.7 Hz), 7.67 (dt, 1H, J = 1.5, 7.9 Hz), 7.63 (dd, 1H, J = 1.4, 7.7 Hz), 7.33 (t, 1H, J = 7.7 Hz), 7.22 (dd, 1H, J = 1.4, 7.4 Hz), 5.56 (s, 1H), 2.76 (s, 3H), 2.22 (s, 3H). ESI-MS (m/z): Calcd. for C20H18N2O3S3: 431.6 (M+H); found: 431.3, 448.2 (M+H2O). Example 7 4-(5'-Hydroxymethyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate a) 3-Hydroxymethyl-2-melhyl-phenylboronic acid Butyllithium (2.5 M, 4 mL, 10 mmol), 3-iodo-4-methyl-benzyl alcohol (1 g, 4 mmol), and trimethylborate (6 mL, 53 mmol) were reacted as in Example 5: step b. Aqueous workup and purification by SiO2 flash chromatography (40-50% EtOAc in hexanes) yielded the title compound (180 mg, 27%). The title compound exists as a mixture of boronic acids and anhydrides in CDCl3, therefore the reported NMR signals represent pairs or groups of related signals. 1H-NMR (CDCl3): d 7.06-7.30 (m, 3H), 4.56 (s, 3H), 4.16 (brs, 1H), 2.32 (s, 3H). b) {[4-(5'-Hydroxymethyl-2'-methyl-biphenyI-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yI]-imino-methyl}-carbamic acid tert-butyl ester The procedure used in Example 1: step c was followed using {[4-(3- bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}- carbamic acid tert-butyl ester (Example 27 (100 mg, 0.2 mmol)), Pd(PPh3)4 (59 mg, 0.05 mmol), 3-hydroxymethyl-2-methyl-phenylboronic acid ((Example 7: step a) 105 mg, 0.63 mmol), Na2CO3 (2M, 0.8 mL, 1.6 mmol), ethanol (0.8 mL) and toluene (1.6 mL). Analogous aqueous workup and purification of the crude material by SiO2 flash chromatography (25-50% EtOAc in hexanes) yielded the title: compound (72 mg, 67%) as a light-yellow glass. 1H-NMR (CDCl3): d 8.00 (s, 1H), 7.96 (dt, 1H, J = 2.1, 4.4 Hz), 7.93 (m, 1H), 7.54 (m, 2H), 7.27 (m, 2H), 7.18 (d, 1H, J = 1.4 Hz), 4.68 (s, 2H), 2.54 (s, 3H), 2.20 (s, 3H), 1.51 (s, 9H). c) 4-(5'-Hydroxymethyl-2'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate The procedure used in Example 1: step d was followed using {[4-(3'- formyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]- imino-methyl}-carbamic acid tert-butyl ester ((Example 7: step b) 15 mg, 0.028 mmol). Analogous purification by HPLC yielded the title compound (12 mg, 80%) as a white solid. 1H-NMR (CD3OD): d 8.32 (s, 1H), 8.02 (m, 1H), 7.99 (m, 1H), 7.68 (m, 2H), 7.29 (d, 2H, J = 1.8 Hz), 7.21 (br s, 1H), 4.61 (s, 2H), 2.72 (s, 3H), 2.22 (s, 3H). ESI-MS (m/z): Calcd. for C20H20N2O3S3 (M+H): 433.6; found: 433.1. Example 8 4-(5'-Formyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiopherte-2- carboxamidine trifluoroacetate a) {[4-(5'-formyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester The {[4-(5'-hydroxymethyl-2'-methyl-biphenyl-3-sulfony])-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbarmic acid tert-butyl ester ((Example 7: step b) 30 mg, 0.056 mmol) was dissolved in a mixture of DMSO (1 mL) and DCM (1 mL) and cooled to 0 °C. Triethylamine (12 µL, 0.084 mmol) and sulfur trioxide-pyridine complex (11 mg, 0.068 mmol) were added and the solution was stilted for 1 h at 0 °C. Partial conversion was evident by TLC. Additional triethylamine (20 µL, 0.14 µL) and sulfur trioxide-pyridine complex (18 mg, 0.11 mmol) were added and the solution was stirred for 3 h at rt. Isopropanol (250 µL) was added, the reaction was stirred for 15 min, and EtOAc (40 mL) was added. The EtOAc solution was extracted with citric acid (2 x 10 mL), NaHCO3 (2 x 10 mL), water (5 x 10 mL), and brine (20 mL), and was dried over sodium sulfate. Removal of the solvent in vacuo yielded the title compound (26 mg, 87%) which was used without further purification. 1H-NMR (CD3OD): d 10.00 (s, 1H), 7.99 (m, 3H), 7.81 (dd, 1H, J = 1.6 7.7 Hz), 7.72 (d, 1H, J = 7.7 Hz), 7.59 (m, 2H), 7.46 (d, 1H, J = 7.7 Hz), 2.58 (s, 3H), 2.30 (s, 3H), 1.51 (s, 9H). b) 4-(5'-Formyl-2'-methyl-biphenyI-3-sulfonyl)-S-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate The procedure used in Example 1: step d was followed using {[4-(5'- formyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]- imino-methyl}-carbamic acid tert-butyl ester ((Example 8: step b) 15 mg). Analogous purification by HPLC yielded the title compound (12 mg, 80%) as a white solid. The aldehyde is apparently 80% hydrated according to proton NMR analysis. 1H-NMR (CD3OD): d 8.33 (s, 1H), 8.03 (m, 1H), 7.9S (m, 1H), 7.68 (m, 2H), 7.35 (m, 2H), 7.26 (d, 1H, J = 1.6 Hz), 5.39 (s, 1H), 2.73 (s, 3H), 2.24 (s, 3H). ESI-MS (m/z): Calcd. for C20H18N2O3S3 (M+H): 431.6; found: 431.2. Example 9 4-[3-(4-Methyl-pyridin-3-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophene- 2-carboxamidine trifluoroacetate a) (Imino-{4-[3-(4-methyl-pyridin-3-yl)-benzenesulfonyl]-5- methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester Butyllithium (2.5 M, 1.88 mL, 4.5 mmol) was added dropwise to a -78°C solution of 3-bromo-4-methylpyridine (645 mg, 3.75 mmol) in Et2O (15 mL). The solution was stirred at -78 °C for 1 h and trimethylborate (5 mL, 44 mmol) was added in one portion. The solution was wanned to rt over 15 min and stirred for 2 h at rt. The volatile components were removed in vacuo and the solid residue was dried under high vacuum for 2 h. A portion of the crude solid (81 mg, 0.4 mmol) was reacted with {[4-(3-bromo-benzenesulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (Example 27 (50 mg, 0.1 mmol)), Pd(PPh3)4 (29 mg, 0.025 mmol), Na2CO3 (2M, 0.8 mL, 1.6 mmol), ethanol (0.8 mL) and toluene (1.6 µL) according to the procedure used in Example 1: step c. Analogous aqueous workup and purification of the crude material by preparative TLC (50% EtOAc in hexanes) yielded the title compound (36 mg, 71%) as a light-yellow glass. 1H- NMR (CDCl3): d 8.50 (d 1H, J = 5.1 Hz), 8.42 (s, 1H), 8.07 (s, 1H), 7.99 (m, 2H), 7.45-7.70 (m, 5H), 7.24 (d, 1H, J = 5.1 Hz), 2.59 (s, 3H), 2.27 (s, 3H), 1.52 (s, 9H). ESI-MS (m/z): Calcd. for C23H25N3O4S3: 503.7; found: 503.8. b) 4-[3-(4-Methyl-pyridin-3-yl)-benzenesulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine bis-trifluoroacetate The procedure used in Example 1: step d was followed using (imino- {4-[3-(4-methyl-pyridin-3-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophen-2- yl}-methyl)-carbamic acid tert-butyl ester ((Example 9: step a) 36 mg, 0.071 mmol). Analogous purification by C18-HPLC (10-40% CH3CN over 30 min) yielded the title compound (22 mg, 49%) as a white solid. 1H-NMR (CD3OD): d 8.74 (br s, 2H), 8.37 (s, 1H), 8.19 (m, 2H), 8.01 (d, 1H, J = 5.6 Hz), 7.85 (m, 2H), 2.74 (s, 3H), 2.55 (s, 3H). ESI-MS (m/z): Calcd. for C18H17N3O2S3 (M+H): 404.5; found: 404.1. Example 10 4-[3-(2-Chloro-pyridin-3-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophene- 2-carboxamidine; bis-trifluoroacetate a) ({4-[3-(2-Chloro-pyridin-3-yl)-benzenesulfonyl]-5-methylsulfanyl- thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester Butyllithium (2.5 M, 1.0 mL, 2.5 mmol) was added dropwise to a -78°C solution of 3-bromo-2-chloropyridine (384 mg, 2.0 mmol) in Et2O (10 mL). The solution was stirred at -78 °C for 1 h and trimethylborate (2.3 mL, 20 mmol) was added in one portion. The solution was warmed to rt over 15 min and stirred for 2 h at rt . The: volatile components were removed and the solid material was dried under high vacuum for 2 h. A portion of the crude solid (105 mg, 0.63 mmol) was reacted with {[4-(3-bromo-benzenesulfonyl)- 5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (Example 27 (50 mg, 0.1 mmol)), Pd(PPh3)4 (29 mg, 0.025 mmol), Na2CO3 (2M, 0.8 mL, 1.6 mmol), ethanol (0.8 mL) and toluene (1.6 mL) according to the procedure used in Example 1: step c. Analogous aqueous workup and purification of the crude material by preparative TLC (50% EtOAc in hexanes) yielded the title compound (31 mg, 58%) as a light-yellow glass. b) 4-[3-(2-Chloro-pyridin-3-yl)-benzenesulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine; bis-trifluoroacetate The procedure used in Example 1: step d was followed using ({4-[3-(2- chloro-pyridin-3-yl)-benzenesulfonyl]-5-methylsulfanyl-miophen-2-yl}- imino-methyl)-carbamic acid tert-butyl ester ((Example 10: step b) 31 mg, 0.0.9 mmol). Analogous purification by C18-HPLC (10-40% CH3CN over 30 min) yielded the title compound (29 mg, 74%) as a white solid. 1H-NMR (CD3OD): d 8.45 (dd, 1H, J = 1.9, 4.9 Hz), 8.36 (s, 1H). 8.16 (t, 1H. 3 = 1.5 Hz), 8.12 (ddd, 1H, J = 1.2, 1.9, 7.7 Hz), 7.90 (dd, 1H, J = 1.9, 7.7 Hz). 7.83 (dt, 1H, J = 1.5, 7.7 Hz), 7.75 (dt, 1H, J = 0.5, 7.7 Hz), 7.53 (dd, 1H, J - 4.9, 7.7 Hz), 2.73 (s, 3H). ESI-MS (m/z): Calcd. for C17H14CIN3O2S3 (M+H): 424.0; found: 424.1. Example 11 4-[3-(3-Methyl-pyridin-2-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophene- 2-carboxamidine bis-trifluoroacetate A 2-dram vial with a septa-containing screwcap was charged with {[4- (3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}- carbamic acid tert-butyl ester (Example 27 (100 mg, 0.2 mmol)) and Pd(PPh3)4 (59 mg, 0.025 mmol). Tetrahydrofuran was added followed by 3- methyl-2-pyridylzinc bromide (Aldrich Chemical Company) (0.5 M in THF, 800 uL, 0.4 mmol). The reaction was heated to 80 °C for 1 h and was worked up as in Example 1:step c Flash chromatography (SiO2) of the crude material (25-50% EtOAc in hexanes) yielded a light-yellow glass (74 mg, 73%) which was treated with trifluoroacetic acid and purified by C18-HPLC (10-40% CH3CN over 30 min) as in Example 1: step d, giving the title compound (46 mg, 61%) as a white solid. 1H-NMR (CD3OD): d 8.59 (dd, 1H, J = 0.9, 5.1 Hz), 8.34 (s, 1H), 8.22 (m, 2H), 8.16 (ddd, 1H, J = 0.7, 1.4, 7.9 Hz), 7.92 (ddd, 1H, J = 0.5, 1.1, 7.7 Hz), 7.82 (dt, 1H, J = 0.7, 7.7 Hz), 7.68 (dd, 1H, J = 5.4, 7.9 Hz), 2.73 (s, 3H), 2.39 (s, 3H). ESI-MS (m/z): Calcd. for C18H17N3O2S3 (M+H): 404.5; found: 404.1. Example 12 4-(3-Allyloxy-5-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine hydrochloride a) l,3-Dibromo-5-tert-butoxy-benzene To a vigorously stirred solution of 1,3-dibromophenylboronic acid (4.5 g, 16.1 mmol) in MeOH (50 mL) and THF (50 mL) was alternately added (dropwise) aqueous hydrogen peroxide (30%, 10 mL) and NaOH (1M, 20 mL) (dropwise), maintaining pH~10. The solution became cloudy and was stirred for 30 min (pH maintained at ~10 using 10 N NaOH). EtOAc (200 mL) and sat'd NaHCO3 (50 mL) were added and the layers were separated. The organic layer was extracted with NaHCO3 (50 mL), water (20 mL), brine (50 mL), and was dried over sodium sulfate. The solvent was removed in vacuo and the residue was dissolved in DCM (80 mL). After cooling to -78°C, isobutylene was added (~20 mL) followed by trifluoromethanesulfonic acid (300 µL). The cloudy solution was stirred for 15 min at -78 °C and for lh at -2,0 to -10°C. Additional amounts of isobutylene (~10 mL) and trifluoromethanesulfonic acid (200 µL) were added and the solution was stirred for 1 h. Solid K2CO3 (1 g) was carefully added, the solution was stirred for 10 min at rt, and NaOH (1N, 30 mL) was added. The layers were separated and the organic layer was further extracted with NaOH (1N, 5 x 10 mL), water (10 mL), and brine (30 mL). After drying and removal of the solvent in vacuo, the residue was purified by SiO2 flash chromatography (2- 5% EtOAc in hexanes) to yield the title compound (3.80 g, 77%). 1H-NMR (CDCl3): d 7.38 (t, 1H. J = 1.6 Hz), 7.09 (d, 2H, J = 1.6 Hz), 1.36 (s. 9H). b) 4-(3-Bromo-5-tert-butoxy-benzenesulfonyl)-5-nitro-thiophene-2- carboxylic acid methyl ester Butyllithium (2.5 M, 3.25 mL, 8.13 mmol) was added dropwise to a -78 °C solution of l,3-dibromo-5-tert-butoxy-benzene ((Example 12: step a) 2.4 g, 7.71 mmol) in Et2O (80 mL). The solution was stirred at -78 °C for 2 h and sulfur (310 mg, 9.69 mmol) was added in one portion. The solution was warmed to rt over 30 min and stirred for 2 h at rt. EtOAc. (50 mL) and citric acid (5%, 30 mL) were added and the layers were separated. The organic layer was washed with NaHCO3 (2 x 30 mL), water (10 mL) and brine (30 mL), and was dried over sodium sulfate. The solvent was removed in vacuo and the residue was redissolved in THF (40 mL). Triphenylphosphine (2.03 g, 7.74 mmol), 4-bromo-5-nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 2.13 g, 8.0 mmol), water (1 mL), and DMAP-resin (7.0 g, 10 mmol) were added and the mixture was stirred for 18 h at rt The solution was filtered, the solids were washed with DCM, and the solvent was removed in vacuo. The residue was partially purified by SiO2 flash chromatography (25% EtOAc in hexanes) to yield a mixture of the title compound and 4-bromo-5-nitro-thiophene-2-carboxylic acid methyl ester starting material. The crude material was redissolved in DCM (60 mL), mCPBA (77%, 6.04 g, 27.1 mmol) was added, and the solution was stirred for 5 h at 40 °C. DCM (50 mL) and aqeous sodium thiosulfate were added (exothermic), and the layers were separated. The organic layer was extracted with Na2CO3 (2M, 6 x 30 mL), brine (50 mL), and was dried over sodium sulfate. Concentration of the solvent in vacuo followed by SiO2 flash chromatography (25-75% DCM in hexanes) yielded the title compound as a colorless glass (2.85 g, 77%). lH-NMR (CDCl3): d 8.28 (d, 1H, J = 0.5 Hz), 7.71 (t, 1H, J = 1.6 Hz), 7.68 (m, 1H), 7.39 (m, 1H), 4.00 (s, 3H), 1.42 (s, 9H). c) 4-(3-Bromo-5-tert-butoxy-benzenesulfonyl)-5-methylsnlfanyl- thiophene-2-carboxylic acid methyl ester Sodium thiomethoxide (1M in EtOH, 4.4 mL, 4.4 mmol) was added dropwise to a -78 °C solution of 4-(3-bromo-5-tert-butoxy-benzenesulfonyl)- 5-nitro-thiophene-2-carboxylic acid methyl ester (1.91 g, 4.0 mmol) in THF (40 mL). The solution was stirred for 30 min at -78 °C and glacial acetic acid (1 mL) was added. The solution was diluted with EtOAc (60 mL), extracted with NaHCO3 (2 x 30 mL), water (2 x 20 mL), brine (30 mL), and was dried over sodium sulfate. Concentration of the solution in vacuo followed by SiO2 flash chromatography of the residue yielded the title compound (1.48 g, 76%). 1H-NMR (CDCl3): d 8.01 (d, 1H, J = 0.5 Hz), 7.74 (m, 1H), 7.66 (m, 1H), 7.37 (m, 1H), 3.99 (s, 3H), 2.48 (s, 3H), 1.41 (s, 9H). d) 4-(3-Bromo-5-hydroxy-benzenesulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester Trifluoroacetic acid (5 mL,) was added to a solution of 4-(3-bromo-5- tert-butoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 12: step c) 240 mg, 0.5 mmol) in DCM (5 mL). The solution was stirred at rt for 2 h and the solvents were removed in vacuo, yielding 214 mg of an oil (quantitative) which was used without further purification. e) 4-(3-Allyloxy-5-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene- 2-carboxylic acid methyl ester Cesium carbonate (33 mg., 0.1 mmol) and allylbromide (30 µL, 0.35 mmol) were added to a solution of 4-(3-bromo-5-hydroxy-benzenesulfonyl)-5- methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 12: step d) 30 mg, 0.71 mmol) dissolved in dry DMF (3 mL). After stirring for 16 h at rt, the solution was poured into a mixture of water (20 mL) and EtOAc (30 mL). The layers were separated and the organic layer was extracted with water (5 x 5 mL), brine (20 mL), and was dried over sodium sulfate. The solvent was removed in vacuo to yield the title compound, which was used without further purification. f) 4-(3-Allyloxy-5-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene- 2-carboxamidine hydrochloride AIM stock solution of dimethylaluminum amide was freshly prepared by careful addition of trimethylalummum (2M in toluene, 10 mL) to a suspension of NH4CI (1.08 g, 11 rnmol) in toluene (10 mL). 4-(3-Allyloxy-5- bromo-benzenesulfonyl)-5-methyli;ulfanyl-thiophene-2-carboxylic acid methyl ester (33 mg, 0.07 mmol) was treated with the dimethylaluminum amide solution (2 mL, 20 mmol) and was heated to 100 °C for 2 h, during which a precipitate formed. The solution was poured into a vigorously stirred mixture of SiO2 (20 g) in CHC13 (70 mL). The flask was rinsed with methanol (10 mL) and the SiO2 mixture was stirred for 10 min. The solution was filtered through a fritted column and the SiO2 was eluted with 15% MeOH in DCM (150 mL). Concentration of the eluent and purification of the residue by preparative TLC (10% MeOH in DCM) yielded the title compound (15 mg, 44%) as a white solid. 1H-NMR (CD3OD): d 8.27 (s, 1H), 7.69 (t, 1H, J = 1.6 Hz), 7.52 (dd, 1H, J = 1.6, 2.3 Hz), 7.44 (dd, 1H, J = 1.6, 2.3 Hz), 6.03 (m, 1H), 5.41 (ddd, 1H, J = 1.6, 3.3, 17.2 Hz), 5.29 (ddd, 1H, J = 1.4, 2.8, 10.5 Hz), 4.64 (dt, 2H, J = 1.6, 5.4 Hz), 2.74 (s, 3H). ESI-MS (m/z): Calcd. for C15H15BrN2O3S3: 447.4; found: 447.1. Example 13 4-(3-Brom o-5-m ethoxy~benzenesulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine hydrochloride Following the procedure for Example 12: step e, 4-(3-bromo-5- hydroxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester ((Example 12: step d) 30 mg, 0.71 mmol) was alkylated using cesium carbonate (33 mg, 0.1 mmol) and methyl iodide (44 µL, 0.71 mmol). After analogous workup, the residue was subjected to amidination conditions as Example 12: step f. Analogous purification procedures yielded the title compound (17 mg, 53%) as a white solid. 1H-NMR (CD3OD): d 8.27 (s, 1H), 7.69 (t, 1H, J = 1.6 Hz), 7.52 (dd, 1H, J = 1.6, 2.3 Hz), 7.37 (dd, 1H, J = 1.6, 2.3 Hz), 3.87 (s, 3H), 2.72 (s, 3H). ESI-MS (m/z): Calcd. for C13H13BrN2O3S3: 421.4; found: 421.1. Example 14 4-(5-Hydroxy-biphenyI-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidin e hydro chloride a) 4-(5-tert-Butoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid ethyl ester The procedure used in Example 1: step d was followed using benzeneboronic acid (42 mg, 0.35 mmol), 4-(3-bromo-5-tert--butoxy- benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 12: step c) (83 mg, 0.17 mmol)), Na2CO3 (2M, 1.4 mL, 2.8 mmol), Pd(PPh3)4 (48 mg, 0.04 mmol), toluene (5.6 mL), and ethanol (2.8 mL). Analogous aqueous workup and SiO2 flash chromatography (20 % EtOAc in hexanes) yielded the title compound (55 mg, 65%). 1H-NMR (CDCl3): d 8.03 (s, 1H), 7.91 (t, 1H, J = 1.6 Hz), 7.63 (t, 1H, J = 2.0 Hz), 7.57 (m, 2H), 7.47 (m, 2H), 7.41 (m, 2H), 4.33 (q, 2H, J = 7.2 Hz), 2.60 (s, 3H), 1.42 (s, 9H), 1.36 (t, 3H,J = 7.2Hz). b) 4-(5-Hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid ethyl ester 4-(5-tert-butoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid ethyl ester (55 mg, 0.11 mmol) was dissolved in 1:1 TFA/DCM (10 mL) and stirring for 1 h. Removal of the solvent in vacuo yielded the title compound (48 mg, 98%), which was used without further purification. c) 4-(5-Hydroxy-biphenyl-3-sulfonyI)-5-methylsulfanyl-thiophene-2- carboxamidine hydrochloride 4-(5-Hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid ethyl ester ((Example 14: step b) 12 mg, 0.02S mmol) was treated with dimethylaluminum amide reagent (2 mL, 2 mmol) as in Example 12: step f. Analogous quench, workup, and purification procedures yielded the title compound (10 mg? 89%) as a white solid. 1H-NMR (CD3OD): d 8.30 (s, 1H), 7.69 (t, 1H, J = 1.6 Hz), 7.59 (m, 2H), 7.47 (m, 2H), 7.40 (m, 2H), 7.32 (m, 1H), 2.74 (s, 3H). ESI-MS (m/z): Calcd. for C13H13BrN2O3S3: 421.36; found: 421.1. Example 15 4-(5-Methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine hydrochloride Following the procedure in Example 12: step e, 4-(5-hydroxy- biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester ((Example 14: step b) 12 mg, 0.028 mmol) was alkylated using cesium carbonate (13.5 mg, 0.041 mmol) and iodomethane (9 µL, 0.138 mmol) in DMF (1.2 mL). After analogous workup, the residue was treated with dimethylaluminum amide reagent (2 mL) following the procedure in Example 12: step f. The title compound was isolated as a white solid (10 mg, 86 %) after preparative TLC purification (15% MeOH in DCM). 1H-NMR (CD3OD): d 8.32 (s,1H), 7.82 (t, 1H, J = 1.6 Hz), 7.65 (m, 1H), 7.63 (m, 1H), 7.53 (dd, 1H, J = 1.6, 2.3 Hz), 7.46-7.50 (m, 3H), 7.41 (m, 1H), 3.93 (s, 3H), 2.7 (s, 3H). ESI-MS (m/z): Calcd. for C13H13BrN2O3S3: 421,4; found: 421.1. Example 16 4-(5-Allyloxy-biphenyI-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine Following the procedure in Example 12: step e, 4-(5-hydroxy- biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester ((Example 14: step b) 12 mg3 0.028 mmol) was alkylated using cesium carbonate (13.5 mg, 0.041 mmol) and allyl bromide (12 µL, 0.138 mmol) in DMF (1.2 mL). After analogous workup, the residue was treated with dimethylaluminum amide reagent (2 mL) following the procedure in Example 12: step f. The title compound was isolated as a white solid (10 mg, 81 %) after preparative TLC purification (15% MeOH in DCM). 1H-NMR (CD3OD): d 8.32 (s, 1H), 7.82 (t, 1H, J = 1.6 Hz), 7.63 (m, 2H), (dd, 1H, J = 1.6, 2.3 Hz), 7.48 (m, 3H), 7.42 (in, 1H), 6.08 (m, 1H), 5.45 (ddd, IH, J = 1.6, 3.3, 17.2 Hz). 5.31 (ddd, 1H, J = 1.4; 2.8, 10.5 Hz), 4.64 (dt, 2H, J = 1.6, 5.1 Hz), 2.75 (s, 3H). Example 17 4-(5-Benzyloxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine hydrochloridc Following the procedure in Example 12: step e, 4-(5-hydroxy- biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester ((Example 14: step b) 12 mg, 0.028 mmol) was alkylated using cesium carbonate (13.5 mg, 0.041 mmol) and benzyl bromide (17 µL, 0.138 mmol) in DMF (2 mL). After analogous workup. the residue was treated with dimethylaluminum amide reagent (2 mL) following the procedure in Example 12: step f. The title compound was isolated as a white solid (9 mg, 66 %) after preparative TLC purification (15% MeOH in DCM). 1H-NMR (CD3OD): d 8.26 (s, 1H), 7.82 (t, 1H, J = 1.6 Hz), 7.62 (m, 2H), 7.54 (m, 2H), 7.30-7.50 (m, 8H), 5.26 (s, 2H), 2.70 (s, 3H). ESI-MS (m/z): Calcd. for C13H13BrN2O3S3: 421.4; found: 421.1. Example 18 4-(2'-Chloro-5-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2~ carboxamidine trifluoroacetate a) {[4-(3-Bromo-5-hydroxy-benzenesulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid teri-butyl ester Following the procedure and workup in Example 14: step f, the 4-(3- bromo-5-tert-butoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid methyl ester ((Example 12: step c) 1.48 g, 3.1 mmol) was converted to the amidine (40 mL of dimethylaluminum amide reagent) with concomitant removal of the tert-butyl ether. A portion of the crude amidine (800 mg) was dissolved in DMF and di-tert-butyl dicarbonate (436 mg, 2 mmol), diisopropylethylamine (350 µL, 2 mmol), and DMAP (50 mg) were added. After stirring for 16 h, the solution was poured into EtOAc (60mL) and citric acid (20 mL). The layers were separated and the organic layer was further extracted with citric acid (10 mL), NaHCO3 (2 x 20 mL), water (5 x 10 mL), and brine (30 mL). After drying over sodium sulfate and removal of solvent in vacuo, the residue was dissolved in MeOH and solid K2CO3 was added. The mixture was stirred overnight, the solution was filtered, and the solvent was removed in vacuo. Purification of the residue by SiO2 flash chromatography yielded the title compound (80 mg, 0.158 mmol). b) {[4-(2'-Chloro-5-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester Following the procedure outlined in Example 1: step c, {[4-(3-bromo- 5-hydroxy-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-y]]-imino-methyl}- carbamic acid tert-butyl ester (80 mg, 0.158 mmol) was reacted with 2- chlorophenylboronic acid (98.6 mg, 0.631 mmol), Na2CO3 (134 rng, 1.26 mmol), and Pd(PPh3)4 (45.5 mg, 0.039 mmol). Aqueous workup followed by SiO2 flash chromatography yielded the title compound (20 mg, 24 %). c) 4-(2'-Chloro-5-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate The procedure used in Example 1: step d was followed using {[4-(2'- chloro-5-methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]- imino-methyl}-carbamic acid tert-butyl ester (10 mg, 0.0185 mmol). Analogous purification by C18-HPLC yielded the title compound (4 mg, 50%) as a white solid. 1H-NMR (CD3OD): d 8.28 (s, 1H), 7.51 (m, 2H), 7.44 (dd, 1H, J = 1.6, 2.3 Hz), 7.40 (m, 2H), 7.38 (m, 3H), 7.13 (dd, 1H, J = 1.6, 2.3 Hz), 2.73 (s, 3H). ESI-MS (m/z): Calcd. for C13H13BrN2O3S3: 421.4; found: 421.1. Example 19 4-(2'-Chloro-5-methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate a) {[4-(2'-Chloro-5-methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester Iodomethane (3 µL, 0.045 mmol) and tetrabutylammonium fluoride (1M in THF, 14 µL, 0.014 mmol) was added to a solution of {[4-(2'-chloro-5- hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-y.l]-imino- methyl}-carbamic acid tert-butyl ester ((Example 19: step b) 5 mg, 0.009 mmol) in THF. After stirring for 2 hours, the solution was diluted with EtOAc (20 mL). The organic layer was washed with water (2 x 4 mL) and brine (5 mL), and was dried over MgSO4. Removal of the solvent in vacuo followed by purification of the residue (preparative TLC; 30% EtOAc in hexanes) afforded the title compound (3.1 mg, 62%). 1H-NMR (CDCl3): d 7.84 (s, 1H), 7.64 (t, 1H, J = 1.6 Hz), 7.53 (dd, 1H, J = 1.6, 2.6 Hz), 7.47 (m, 1H), 7.33 (m, 3H), 7.21 (dd, 1H, J = 1.6, 2.6 Hz), 3.89 (s, 3H), 2.60 (s, 3H), 1.52 (s, 9H). ESI-MS (m/z): Calcd. for C13H13BrN2O3S3: 421.4; found: 421.1. b) 4-(2t-Chloro-5-methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate The procedure used in Example 1: step d was followed using {[4-(2'- chloro-5-me1:hoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]- imino-methyl}-carbamic acid tert-butyl ester (3.1 mg, 0.008 mmol). Analogous purification by C18-HPLC yielded the title compound (1.8 mg, 50) as a white solid. 1H-NMR (CD3OD): d 8.32 (s, 1H), 7.64 (t, 1H, J = 1.6 Hz).. 7.59 (dd, 1H, J = 1.4, 2.6 Hz), 7.55 (m, 1H), 7.42 (m, 3H), 7.13 (dd, 1H, J = 1.4, 2.6 Hz), 3.93 (s, 3H), 2.75 (s, 3H). ESI-MS (m/z): Calcd. for C13H13BrN2O3S3: 421.4; found: 421.1. Example 20 5-Brorno-4-(3'-formyl-biphenyl-3-sulfonyl)-thiophene-2-carboxamidine trifluoroacetate a) 4-(3-Bromo-phenylsulfanyl)-5-nitro-thiophene-2-carboxylic acid methyl ester 4-Bromo-5-nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 1 g, 3.75 mmol) and Et3N (523 µL, 3.75 mmol) were dissolved with THF (10 mL) into a round bottom flask with stir bar. To this 3- bromothiophenol (467 µL., 4.51 mmol) was added with stirring. The reaction became turbid therefore additional THF (12 mL) was added. The reaction was stirred at rt for 12 hours. The reaction mixture was concentrated in vacuo and then dissolved into EtOAc. The organic layer was washed several times with saturated NaHCO3 and brine. The combined organic layers were dried over sodium sulfate. Removal of the solvents in vacuo yielded the title compound (1.40 g, quantitative yield), which was used without further purification. 1H- NMR (CDCl3): d 7.79 (t, 1H, J = 1.8 Hz), 7.67-7.70 (m, 1H), 7.54-7.85 (m, 1H), 7.37-7.41 (t, 1H, J = 7.9 Hz), 6.87 (s, 1H), 3.88 (s, 1H). b) 4-(3-Bromo-benzenesulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester 4-(3-Bromo-phenylsulfanyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (1.40 g, 4 mmol) and m-CPBA (6.1 g, 20 mmol) were dissolved into DCM (25 mL) with heating at 40 °C for 2 hours. The reaction mixture was quenched by the addition of saturated sodium thiosulfate followed by aqueous workup with brine and saturated NaHCO3. The combined organic layers were dried over sodium sulfate. Removal of the solvents in vacuo yielded the title compound (1.60 g, quantitative yield) which was used without further purification. 1H-NMR (CDCl3): d 8.31 (s, 1H), 8.12-8.14 (t, 1H, J= 1.9 Hz), 8.02-8.05 (m, 1H), 7.78-7.82 (m, 1H), 7.44-7.50 (t 1H, J = 7.9 Hz), 4.01 (s, 3H). c) 5-Amino-4-(3-bromo-benzenesulfonyl)-thiophene-2-carboxylic acid methyl ester 4-(3-Bromo-benzenesulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (407 mg, 1.0 mmol, Example 20: step b) was dissolved into EtOH (6mL). To this was added ammonium chloride (535 mg, 10 mmol) dissolved into water (3 mL). This mixture was heated to 50°C with stirring and then iron (277 mg, 5 mmol) was added. The reaction was then heated to 80°C with stirring for 12 hours. The reaction mixture was then filtered through Celite and washed with 10% DCM/MeOH. Removal of the solvents in vacuo yielded the title compound (598 mg, quantitative yield) which was used without further purification. 1H-NMR (CDCl3): d 8.05 (s, 1H), 7.84-7.86 (m, 1H), 7.70-7.75 (m, 1H), 7.56 (s, IH), 7.40 (m, 1H), 6.02 (br s, 2H), 3.85 (s, 3H). ESI-MS (m/z): Calcd. for C12H10BrNO4S2: 375.9 (M+H); found: 376.1. d) 5-Amin o-4-(3'-formyl-biphenyl-3-sulfonyl)-thiophene-2-carboxylic acid methyl ester The procedure as in Example 1: step c was followed using 5-amino-4- (3-bromo-benzenesulfonyl)-thiophene-2-carboxylic acid methyl ester (754.2 mg, 2 mmol, Example 20: step e), 3-formyl phenyl boronic acid (599.7 mg, 4 mmol), Pd(PPh3)4 (462.2 mg, 0.4 mmol), aqueous Na2CO3 (2M, 8 mL, 16 mmol), ethanol (8 mL) and toluene (16 mL). Purification by flash column chromatography (Biotage Flash™ System - 40 M SiO2 column) (25% EtOAc in hexanes) of the residue yielded the title compound (317 mg, 40%) as a brown solid. 1H-NMR (CDCl3): d 10.10 (s, 1H), 8.10-8.17 (m, 2H), 7.92-7.95 (m, 2H), 7.82-7.89 (t, 2H, J = 8.1 Hz), 7.58-7.70 (m, 3H), 6.05 (br s, 2H), 3.80 (s, 3H). e) 5-Bromo-4-(3'-formyl-biphenyl-3-sulfonyl)-thiophene-2-carboxylic acid methyl ester A dry 3-neck flask fitted with addition funnel, condenser and septa cap was purged with argon. To this flask t-butylnitrite (121 µL, 1.58 mmol) and copper (II) bromide (36.8 mg, 1.58 mmol) were dissolved with acetonitrile (2 mL) and heated to 60°C A solution of 5-arnino-4-(3'-forrnyl-biphenyl-3- sulfonyl)-thiophene-2-carboxylic acid methyl ester (317.2 mg, 0.79 mmol, Example 20: step d) in acetonitrile (2 mL) was added dropwise with continued stirring and heat for 1.5 hours. The reaction mixture was dissolved into EtOAc and washed with brine. The organic layer was dried over sodium sulfate. Removal of the solvents in vacuo followed by flash column chromatography (Biotage Flash™ System - 40 M SiO2 column) (25% EtOAc in hexanes) of the residue yielded the title compound (128 mg, 34%) as a brown solid. 1H-NMR (CDCl3): d 10.10 (s, 1H), 8.26-8.28 (m, 1H), 8.08-8.16 (m, 2H) 8.01-8.06 (m, 1H), 7.86-7.89 (m, 3H), 7.64-7.70 (t, 2H, J = 8.1 Hz), 3.90 (s, 3H). f) 5-Bromo-4-(3'-formyl-biphenyl-5-sulfonyl)-thiophene-2- carboxamidine trifluoroacetate A 1M solution of dimethyl aluminum amide was prepared by combining NH4Cl (426 mg, 8 mmol), AlMe3 (2M solution in toluene, 4 mL, 8 mmol) and toluene (4mL). This solution was then heated to 80 °C for 15 and then allowed to cool to it. The 1M solution of dimethyl aluminum amide was then added to a dry flask containing 5-bromo-4-(3'- formyl-biphenyl-3-sulfonyl)-thiophene-2-carboxylic acid methyl ester (128 mg, 0.28 mmol) and the reaction was heated 90 °C for 2 hours. The reaction. was quenched by adding silica (1g) to the solution with stirring followed by filtration and elution with 10% MeOH in DCM. Concentration of the filtrate in vacuo followed by purification by C18-HPLC (10-80% CH3CN over 25 min) yielded the title compound (49 mg, 38%) as an off-white solid. lH- NMR (CD3OD and CD3C1): d: 10.10 (s, 1H), 8.35 (s, 1H), 8.31-8.33 (m, 1H), 8.17-8.18 (t, 1H, J = 1.39 Hz), 8.04-8.10 (m, 2H), 7.96-7.99 (m, 2H), 7.75- 7.77 (m, 2H). ESI-MS (m/z): Calcd. for C13H13BrN2O3S2: 448.9 (M+H) ; found: 449.2. Example 21 5-Amino-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxamidine trifluoroacetate 5-Amino-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxylic acid methyl ester was prepared following the procedure as in Example 1: step c using 5-amino-4-(3-bromo-benzenesulfonyl)-thiophene-2-carboxylic acid methyl ester (598.9 mg, 1.6 mmol) (Example 20: steps a-c), o-tolyl- phenyl boronic acid (435.6 mg, 3.2 rnmol), pd(PPh3),, (366.6 mg, 0.32 mmol), aqueous Na2CO3 (2M, 6.4 mL, 12.8 mmol), etbanol (6.4mL) and toluene (128 mL). Purification by flash column chromatography (Biotage FlashTM System - 40 M SiO2 column) (25% EtOAc in hexanes) of the residue yielded the adduct (137 mg, 23%) as a light brown solid. ESI-MS (m/z): Calcd. for C19H17NO4S2. 387.02; found: 388.3. 5-Ammo-4-(2'-methyl-biphenyl-3- sulfonyl)-thiophene-2-carboxylic acid methyl ester (61 mg, 16 mmol) was then converted to the amidine and purified as described in Example 20: step f to isolate the title compound (6 mg, 10 %) as a light brown solid, !H-NMR (CD3OD): d: 7.96-7.99 (m, 1H), 7.95 (s, 1H), 7.93-7.94 (m, 1H), 7.63-7.69 (m, 3H), 7.18-7.32 (m, 3H), 2.22 (s, 3H). ESI-MS (m/z): Calcd. for C18H17N3O2S2: 372.0 (M+H); found: 372.2. Example 22 5-Chloro-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxamidine trifluoroacetate a) 5-Chloro-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-carhoxylic acid methyl ester The procedure as in Example 20: step e was followed using t- butylnitrite (104 µL, 88 mmol) and copper (II) chloride (118.5 mg, 0.88 mmol), acetonitrile (2 mL) and 5-amino-4-(2'-methyl-biphenyl-3-sulfonyl)- thiophene-2-carboxylic acid methyl ester (170.2 mg, 0.43 mmol, Example 21) in acetonitrile (2mL). Purification by flash column chromatography (Biotage Flash™ System - 12 M SiO2 colunm) (25% EtOAc in hexanes) of the residue yielded the title compound (128 mg, 34%) as a brown solid. 1H-NMR (CDCl3): d 8.26 (1H, s), 7.92-7.98 (3H, m), 7.56-7.60 (2H, m) 7.28-7.32 (3H, m), 3.90 (3H, s), 2.24 (3H, s). b) 5-Chloro-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2- carboxamidine trifluoroacetate 5-Chloro-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxylic acid methyl ester (36 mg, 0.09 rnmol) was then converted to the amidine and purified as described in Example 20: step f to isolate the title compound (7.1 mg, 20 %) as a white solid. 1H-NMR (CD3OD): d: 8.35 (s, 1H), 8.03-8.06 (m, 1H), 7.95-7.97 (m, 1H), 7.71-7.74 (m, 2H), 7.30-7.33 (m, 2H), 7.25-7.30 (m, 1H), 7.19-7.21 (d, 1H, J = 6.74 Hz), 2.24 (s, 3H). ESI-MS (m/z): Calcd. for C18H15CIN2O2S2: 391.0 (M+H); found: 391.2. Example 23 4-(2'-Methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxamidine trifluoroacetate 4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene- 2-carboxylic acid methyl ester (4.0 mg, 0.01 mmol) was isolated as a byproduct from Example 22: step a. The molecule was then converted to the amidine and purified as described in Example 20: step f to isolate the title compound (0.9 mg, 25%). 1H-NMR (CD3OD): d: 8.80 (s, 1H), 8.25-8.26 (d, 1H, J = 1.6 Hz), 8.02-8.05 (m, 1H), 7.95-7.96 (m, 2H), 7.68-7.71 (m, 2H), 7.17-7.21 (m, 1H), 2.24 (s, 3H). ESI- MS (m/z): Calcd. for C18H16N2O2S2: 357.0 (M+H); found: 357.3. Example 24 5-Bromo-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxamidine trifluoroacetate a) 5-Chloro-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxylic acid methyl ester The procedure as in Example 20: step e was followed using t- butylnitrite (10 µL, 0.05 mmol) and copper (II) bromide (11 mg, 0.05 mmol) and 5-amino-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxylic acid methyl ester (9.1 mg, 0.03 mmol, Example 21) in acetonitrile (1 mL). Purification by flash column chromatography (Biotage Flash™ System - 12 M SiO2 column) (25% EtOAc in hexanes) of the residue yielded the title compound (5.1 mg, 42%) as an off-white solid. 1H-NMR (CDCl3): d 8.08 (s, 1H), 7.92-7.98 (m, 2H), 7.59-7.61 (m, 2H) 7.29-7.30 (m, 3H), 7.19-7.21 (m, 1H), 3.90 (s, 3H), 2.24 (s, 3H). b) 5-Bromo-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2- carboxamidine trifluoroacetate 5-Bromo-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxylic acid methyl ester (5.1 mg, 0.01 mmol, Example 24: step a) was then converted to the amidine and purified as described in Example 20: step f to isolate the title compound (1.1 mg, 21%). 1H-NMR (CD3OD): d: 8.33 (s, 1H), S.04-8.07 (m, 1H), 7.98-7.99 (m, 1H) 7.71-7.73 (m, 2H), 7.30-7.32 (m, 3H), 7.25-7.30 (m, 1H), 7.19-7.21 (m, 1H), 2.24 (s, 3H). ESI-MS (m/z): Calcd. for C13H13BrN2O2S2: 434.0 found: 437.1. Example 25 4~(2'-Amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate a) 2-Bromo-3-methyl-phenylamine The procedure as in Example 20: step c was followed using 2-bromo- 1-methyl-3-nitro-benzene (lg, 4.6 mmol dissolved in 12 mL EtOH, Aldrich Chemical Company), ammonium chloride (2.5g, 46 mmol dissolved in 6 mL H2O) and iron (1.3g, 23 mmol). The title compound was obtained (1.0 g, quantitative yield) which was used without further purification, 1H-NMR (CDCl3): d 6.95-7.00 (t, 1H, J = 7.6 Hz), 6.60-6.65 (dd, 2H, J = 8.1, 4.4 Hz), 4.10 (brs,2H), 2.35 (s,3H). b) 3-Methyl-2-(4,4,5,5-tetramethyl-[l,3,2}dioxaborolan-2-yl)- phenylamine The procedure described in Example 3: step b was followed using 2- bromo-3-methyl-phenylamine (185 mg, 1.0 mmol, Example 25: step a), PdCl2(PPh3)2 (70.2 mg, 0.1 mmol), dioxane (3 ml.), and Et3N (729 µL, 6 mmol), 4,4,5,5,-tetramethyl-[l,3,2]-dioxaborolane (453 µL, 3 mmol). Purification by preparative SiO2 TLC (25% EtOAc in hexanes) of the residue yielded the title compound (94 mg. 40%) as a yellow solid. ESI-MS (m/z): Calcd. for C13H20BNO2:234.1 (M+H) found:234.1. c) {[4-(2'-Amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester The procedure described in Example 1: step c was followed using 3- methyl-2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenylamine (95 mg 0.41 mmol. Example 25: step b), {[4-(3-bromo-benzenesulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (100.7 mg, 0.21 mmol, Example 27: step c), Pd(PPh3)4 (47 mg, 0.04 mmol), aqueous Na2CO3 (2M, 0.8 ml,, 1.6 mmol), ethanol (0.8 mL) and toluene (1.6 mL). Purification by preparative SiO2 TLC (33% EtOAc in hexanes) of the residue yielded the title compound (30 mg, 28%) as an off-white solid. ESI- MS (m/z): Calcd. For C24H27N3O4S3: 517.2; found: 517.8. d) 4-(2'-Amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate {[4-(2'-Amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (30 mg, 0.058 mmol, Example 25: step c) was deprotected and purified as in Example 1: step d, yielding the title compound as an off-white solid (28.1 mg, 94%). 1H- NMR (CD3OD): d 8.36 (s, 1H), 8.08-8.12 (m, 1H), 7.96 (t, 1H, J = 1.6 Hz), 7.76-7.80 (t, 1H, J = 7.6 Hz), 7.60-7.64 (dd, 1H, J = 1.6, 7.6 Hz), 7.22-7.25 (t, 1H, J = 7.9 Hz), 6.98-7.03 (m, 2H), 2.73 (s, 3H), 1.97 (s, 3H). ESI-MS (m/z): Calcd. for C19H19N3O2S3: 418.1 (M+l); found: 418.1. Example 26 4-(3'-Formyl-4'-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene- 2-carboxamidine trifluoroacetate a) 4-Bromo-2-dimethoxymethyl-phenol To a solution of 5-bromo-2-hydroxy-benzaldehyde (lg, 4.9 mmol, Aldrich Chemical Company) in MeOH (25 mL) at 0 °C, sodium borohydride (226 mg, 5.9 mmol) was added slowly with stirring. After the addition, the reaction was allowed to warm to rt and stir for an additional hour. Reaction mixture was dissolved into EtOAc and washed with brine (20 mL x 2). The organic layer was dried over sodium sulfate. Removal of the solvents in vacuo gave the title compound (1.2 g, quantitative) a yellow oil which was used with out further purification. lH-NMR (CD3OD): d 7.35 (m, 2H), 6.75-6.77 (d,lH, J - 7.2 Hz), 5.55 (s, 1H), 3.33 (s, 6H). b) {[4-(3'-Dimethoxymethyl-4'-hydroxy-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester 2-Dimethoxymethyl-4-hydroxyl phenylboronic acid (212 mg. 1.0 mmol) was prepared using the procedure described in Example 1: step b using butyllithium (2.5M, 2.8 mL, 7 mmol), trimethylborate (0.812 mL, 5.6 mmol), 4-bromo-2-dimethoxymethyl-phenol (685 mg, 2.8 mmol, Example 26: step a) in THF (5 mL) and was used in the next step without purification. The procedure described in Example 1: step c was followed using {[4-(3-bromo- berizenesulfonyl)-5-rnethylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (100 mg, 0.21 mmol, Example 27: step c), Pd(PPh:,)4 (47 mg, 0.04 mmol), aqueous Na2CO3 (2M, 0.8 mL, 1.6 mmol), ethanol (0.8 mL), toluene (1.6 mL) and 2-diniethoxymethyl-4-hydroxy-phenylboronic acid (212 mg, 1.0 mmol). Purification by preparative SiO2 TLC (33% EtOAc in hexanes) of the residue yielded the title compound (37 mg, 28%) as a white solid. ESI-MS (m/z): Calcd. for C26H30N2O7S3: 579.1 (M+l); found: 579.9. c) 4-(3'-Formyl-4'-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate {[4-(3'-Dimethoxymethyl-4'-hydroxy-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (37 mg) (Example 26: step b) was deprotected and purified as in Example 1: step d, yielding the title compound as an off-white solid (5 mg, 14%). 1H- NMR (CD3OD): d 10.34 (s, 1H), 8.46 (m, 1H), 8.25-8.27 (m, 1H), 7.89-7.94 (m, 3H), 7.72-7.75 (m, 1H), 7.13-7.16 (m, 1H), 2.49 (s, 3H). ESI-MS (m/z): Calcd. for C19H16N2O4S3: 433.0 (M+l); found: 433.2. Example 27 {[4-(3-Bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino- methyl}-carbamic acid tert-butyl ester a) 4-(3-Bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid methyl ester 4-(3-Bromo-benzenesulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (5.9 g, 0.015 mol, Exstmple 20: step b) was dissolved into 40 mL THF and cooled to -78°C. To this was added sodium thiomethoxide (1M, 15 mL, 0.015 mmol, in EtOH) dropwise for an hour. The reaction was quenched with acetic acid (878 µL, 0.015 mol) and the reaction mixture was concentrated in vacuo. The residue was then dissolved into EtOAc and washed with saturated NaHCO3 and brine solutions. The organic layer was dried over sodium sulfate. Removal of the solvents in vacuo followed by flash column chromatography SiO2 (25% EtOAc in hexanes) of the residue yielded the title compound (3.0g, 50%) as a yellow solid. 1H-NMR (CDCl3): d 8.14 (t, 1H, J - 1.8 Hz), 8.02 (s 1H), 7.94-7.96 (m, 1H), 7.72-7.74 (m, 1H), 7.38-7.42 (t, 1H, J = 7.9 Hz), 7.26 (s 1H), 3.88 (s 1H), 2.62 (s 1H). b) 4-(3-Bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate 4-(3-Bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid methyl ester (1.9 g, 0.004 mol) was converted to the amidine and purified as described in Example 20: step f to isolate the title compound (1.9 g, quantitative yield). 1H-NMR (CD3OD): d: 8.31 (s, 1H), 8.16 (t, 1H, J = 1.8 Hz), 8.01-8.04 (m, 1H), 7.86-7.90 (m, 1H), 7.52-7.57 (t, 1H, J = 7.9Hz), 2.74 (s, 3H). c) {[4-(3-Bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]- imino-methyl}-carbamic acid tert-butyl ester 4-(3-Bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine (1.9 g, 0.0048 mol, Example 27: step b) was dissolved into DMF (35 mL) with sonication. To this was added DIEA (1.67 mL, 0.0096 mol) and di-tert-butyl-dicarbonate (1.27 g, 0.0058 mol) and reaction stirred at rt for 16 hours. The reaction mixture was dissolved into EtOAc and washed with 20% citric acid and then brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The remaining residue was triturated with hexane to isolate the title compound (1.84g, 76%). 1H-NMJR. (CDCl3): d: 8.15 (s, 1H), 8.13-8.14 (t, 1H, J - 1.6 Hz), 7.95-7.99 (m, 1H), 7.79-7.84 (m, 1H), 7.72 (s, 1H), 7.48-7.52 (t, 1H, J - 7.9 Hz), 7.19-7.21 (m, 1H), 2.66 (s, 3H), 1.51 (s, 9H). ESI-MS (m/z): Calcd. for C17H19BrN2O4S3: 492.4 (M+l); found: 492.6. Example 28 5-Methylsulfanyl-4-{3'-(2,2,2-trifluoro-l-hydroxy-ethyl)-biphenyl-3- sulfonyl]-thiophene-2-carboxamidine trifluoroacetate a) l-(3-Bromo-phenyl)-2,2,2-trifluoro-ethanone In a dry round bottom flask, 3-bromo-benzoic acid methyl ester (2 g, 9.3 mmol, Aldrich Chemical Company) and trimethyl(trifluoromethyl)silane (1.72 mL, 11.6 mmol, Aldrich Chemical Company) were dissolved in dry toluene (50 mL). Upon cooling the solution to -78 °C, TBAF (232 uL, 0.23 mmol) was added and the reaction was allowed to warm up slowly to it overnight. After stirring for 20 hr, 2N HC1 (50 mL) and EtOAc (100 mL) were added, the layers were separated, and the aqueous layer was extracted with another portion of EtOAc, The combined organic fractions were dried (MgSO4), concentrated in vacua, and resulting crude oil was purified using SiO2 flash chromatography (elution: 5-20% EtOAc in hexanes) to give 1.5 g (65%) the title compound as a light yellow oil. 1H-NMR (CDCl3; 400 MHz) d 8.18 (br s, 1H), 7.98-8.00 (m, 1H), 7.82-7.85 (m, 1H), 7.42-7.46 (m, 1H). 19F-NMR (CDCl3; 400 MHz) 5 -72.06 (s). b) 2,2,2-Trifluoro-l-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- phenyl]-ethanol To an oven-dried round bottom flask fitted with a stir bar and a rubber septum was added l-(3-bromo-phenyl)-2,2,2-trifluoro-ethanone (560 mg, 2.2 mmol, as prepared in Example 28, step a), 4,4,5,5-tetramethyl- [l,3,2]dioxaborolane (0.96 mL, 6.6 mmol, Aldrich Chemical Company), (PPh3)2PdCl2 (93 mg, 0.132 mmol, Streni Chemicals, Inc., Newburyport, MA), and Et3N (1.8 mL, 13.2 mmol). The reaction mixture was evacuated, purged with argon, and then suspended in dioxane (16 mL). After stirring for 18 hr at 95 °C, the reaction was allowed to cool and then filtered through Celite.® The filtrate was concentrated in vacuo and the residue was purified by chromatography (SiCh, flash elution: 5% EtOAc in hexanes) to give 350 mg (53%) of an oil that was used without further purification. c) (Imino-{5-methylsulfanyl-4-[3'-(2,2,2-trifluoro-1-hydroxy-ethyl)- biphenyl-3-sulfonyl]-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester Following the same procedure in Example 1, step c, reaction of 2,2,2- trifluoro-l-[3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-ethanol (123 mg, 416 mmol, as prepared in Example 28, step b), {[4-(3-bromo- benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (100 mg, 0.2 mmol, as prepared in Example 27, step c), tetrakis(triphenylphosphine)palladium(0) (59 mg, 0.05 mmol, Strem Chemicals Inc, Newburyport, MA), Na2CO3 (800 µL, 2M aqueous), and toluene/EtOH mixture (2:1, 2.4 mL) afforded 100 mg (85%) after purification (SiO2, flash elution: 30% EtOAc in hexanes) of the title compound as a white foam. 1H-NMR (CDCl3; 400 MHz) d 8.20 (t, 1H, J = 1.7 Hz), 7.94-7.99 (m, 2H), 7.77-7.81 (m, 1H), 7.67 (br s, 1H), 7.57 (m, 1H), 7.27-7.34 (m, 1H), 7.15-7.21 (m, 2H), 5.11 (q, 1H, J = 6.8 Hz), 2.51 (s, 3H), 1.49 (s, 9H). 19F- NMR (CDCl3; 400 MHz) 5 -78.51 (d, J = 6.9 Hz). ESI-MS (m/z): Calcd. for C25H25F3N2O5S3: 586.7; found: 586.7. d) 5-MethylsuIfanyl-4-[3'-(2,2,2-trifluoro-l-hydroxy-ethyl)-biphenyl-3- sulfonyl]-thiophene-2-carboxamidine trifluoroacetate (Imino-{5-methylsulfanyl-4-[3'-(2,2,2-trifluoro-l-hydrcxy-ethyl)- biphenyl-3-sulfonyl]-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester (25 mg, 0.043 mmol, as prepared in Example 28, step c) was treated with trifluoroacetic acid (50% in DCM) for 1 hr at rt. The reaction mixture was concentrated in vacuo and the residue obtained was purified using C18-HPLC (10-80% CH3CN in H2O (0.1% TFA) over 25 min) to give 18 mg (86%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz) d 8.33 (s, 1H), 8.30 (t, 1H, J = 1.7), 7.97-8.05 (m, 2H), 7.91 (br s, 1H), 7.68-7.74 (m, 2H), 7.53-7.56 (m, 2H), 5.15 (q, 1H, J = 7.0 Hz), 2.74 (s, 3H). 19F-NMR (CD3OD; 400 MHz) 5 -80.09 (d, J = 6.9 Hz). ESI-MS (rn/z): Calcd. for C20H17F3N2O3S3: 487.6 (M+H); found: 487.3. Example 29 5-Methylsulfanyl-4-[3'-(2f2,2-trifluoro-acetyl)-biphenyl-3-sulfonyl]- thiophene-2-carboxamidine trifluoroacetate a) (Imino-{5-methylsulfanyl-4-[3'-(2,2,2-trifluoro-acetyl)-biphenyl-3- sulfonyl]-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester In a reaction vial, (imino-{5-methylsulfanyl-4-[3'-(2,2,2-trifluoro-l- hydroxy-ethyl)-biphenyl-3-sulfonyl]-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester (30 mg, 0.051 mmol, as prepared in Example 28, step c) and l,l,l-triacetoxy-l,l-dihydro-l,2-benziodoxol-3(lH)-one (31 mg, 0.072 mmol. Lancaster Synthesis, Windham, NH) were dissolved in DCM (2 ml,). To that solution, wet DCM (1 mL, 4 µL H2O) was added slowly via a syringe. After 1 hr of stirring at rt, the reaction was evaporated and the residue was partitioned between Et2O (30 mL) and 10% Na2S2O3-saturated NaHCO3 (1:1, 15 mL). The aqueous layer was washed with an additional portion of Et2O. The combined organic washes were dried with MgSQ4 and concentrated in vacuo to give 30 mg (quantitative yield) of the title compound that was used without purification. 1H-NMR (CDCl3; 400 MHz) d 8.28 (br s, 1H), 8.26 (t, 1H, J = 1.7 Hz), 8.0S-S.13 (m, 1H), 7.99-8.04 (m, 1H), 7.96 (s, 1H), 7.91-7.95 (m, 1H), 7.82-7.86 (m, 1H), 7.62-7.71 (m, 2H), 2.59 (s, 3H), 1.51 (s, 9H). 19F- NMR (CDCl3; 400 MHz) 6 -84.93 (s). ESI-MS (m/z): Calcd. for C25H23F3N2O5S3: 487.6 (M+H); found: 487.2. b) 5-Methylsulfanyl-4-[3'-(2,2,2-trifluoro-acetyl)-biphenyl-3-sulfonyl]- thiophene-2-carboxamidine trifluoroacetate (Imino-{5-methylsulfanyl-4-[3'-(2,2,2-trifluoro-acetyl)-biphenyl-3- sulfonyl]-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester (30 mg, 0.051 mmol, as prepared in Example 29, step a) was treated with trifluoroacetic acid (50% in DCM) for 1 hr at rt. The reaction mixture was concentrated in vacuo and the residue obtained was purified using C18-HPLC (20-60% CH3CN in H2O (0.1% TFA) over 25 min) to give 20 mg (80%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz) d 8.35 (s, 1H), 8.33 (t, 1H, J = 1.7 Hz), 7.98-8.07 (m, 2H), 7.90-7.93 (m, 1H), 7.68-7.78 (m, 3H), 7.60 (t, 1H, J = 7.8 Hz), 2.77 (s, 3H). 19F-NMR (CDCl3; 400 MHz) 5 -84.99 (s). ESI-MS (m/z): Calcd. for C20H15F3N2O3S3: 485.5 (M+H); found: 485.3, 503.3 (M+H2O), 517.3 (M+CH3OH). Example 30 4-[3-(6-Methyl-3H-benzoimidazol-5-yl)-benzenesulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine bis-trifluoroacetate a) 5-Chloro-6-methyl-benzoimidazole-1-carboxylic acid tert-butyl ester and 5-Chloro-6-methyl-benzoimidazole-3-carboxylic acid tert-butyl ester 4-Chloro-5-methyl-benzene-l,2-diarnine (560 mg, 3.6 mmol, Maybridge Chemical Co. Ltd., Cornwall, UK) was dissolved in formic acid (10 mL) and the solution was refluxed at 100°C for 18 hr. The reaction was allowed to cool and then evaiporated to dryness in vacuo to give 5-chloro-6- methyl-lH-benzoimidazole as a tan solid (quantitative yield) that was used without further purification. The solid obtained above (410 mg, 2.4 mmol), di- tert-butyl dicarbonate (1.6 g, 7.4 mmol), and DMAP (29 mg, 0.24 mmol) were dissolved in CH3CN (20 mL). To the mixture, DIEA (1.3 mL, 7.4 mmol) was added and the reaction was stirred for 18 hr at rt. The solvents were evaporated in vacuo and the residue partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (75 mL). The aqueous layer was separated and washed with EtOAc (100 mL). The combined organic layers were dried with MgSO4 and concentrated in vacua. The crude residue was purified using flash SiO2 chromatography (20% EtOAc in hexanes) to give 620 mg (97%) of the title compound as a 1:1 mixture of regioisomers that were used without separation. 1H-NMR (CDCl3; 400 MHz, 1:1 mixture of isomers) d 8.35 and 8.36 (s, 1H), 7.89 and 7.99 (s, 1H), 7.62 and 7.75 (s, 1H), 2.48 and 2.50 (s, 3H), 1.698 and 1.700 (s, 9H). ESI-MS (m/z): Calcd. for C13H15ClN2O2: 266.7; found: 266.9, 167.2 (M-Boc). b) 5-Methyl-6-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- benzoimidazole-1-carboxylic acid tert-butyl ester and 5-Methyl-6-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzoimidazole-1-carboxylic acid tert- butyl ester To a dry reaction vial fitted with a stir bar and a Teflon-lined screw cap, a mixture of 5-chloro-6-methyl-benzoimidazole-l-carboxylic acid tert- butyl ester and 5-chloro-6-methyl-benzounidazole--3-carboxylic acid tert-butyl ester (150 mg, 0.56 mmol, as prepared in Example 30, step a), 4,4.5,5,4',4',5',5'-octaraethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (284 mg. 1.12 mmol, Aldrich Chemical Company), (2'-dicyclohexylphosphanyl-biphenyl-2- y3)-dimethyl-amine (17.7 mg, 0.045 mmol, Strem Chemicals Inc, Newburyport, MA), Pd(OAc)2 (6.7 mg, 0.03 mmol. Strem Chemicals Inc, Newburyport, MA), and K3PO4 (238 mg, 1.12, mmol) were added, The vial was capped, purged with argon, and then suspended in toluene (3 mL). After stirring for 18 hr at 95 °C, the reaction was allowed to cool and then filtered through Celite.® The filtrate was concentrated in vacuo and the residue was purified using preparative thin layer chromatography (1:3 EtOAc/hexanes, 2000 µ SiO2 plate) to afford 100 mg (50%) of the title compound (1:1 mixture of regioisomers) as a yellow oil. ES1-MS (m/z): Calcd. for C19H27BN2O4: 358.2; found: 303.2 (M-'Bu), 259.3 (M-Boc), c) 4-[3-(6-Methyl-3H-benzoimidazol-5-yl)-benzenesuIfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine bis-trifluoroacetate Following the same procedure in Example 1, step c, 5-methyl-6- (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-berizomiidazo]e-l -carboxylic acid tert-butyl ester and 5-methyl-6-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan- 2-yl)-benzoitnidazole-l-carboxylic acid tert-butyl ester (90 mg, 0.25 mmol, as prepared in Example 30, step b), {[4-(3-bromo-benzenesulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (62 mg, 0.126 mmol, as prepared in Example 27, step c), tetrakis(triphenylphosphine)palladium(0) (37 mg, 0.032 mmol Strem Chemicals, Inc., Newburyport, MA), Na2CO3 (400 µL, 2M aqueous), and tolueae/EtOH mixture (2:1, 1.2 mL) were reacted to give 170 mg of a tan foam. This crude material was separated using preparative thin layer chromatography (1:2 EtOAc/hexanes, 2000 µ SiO2 plate). From several bands that were isolated and analyzed by ESI-MS, two bands exhibited an observed mass consistent with the di-Boc (7 mg) and mono-Boc (47 mg) products, respectively. Both of these compounds were combined and then treated with trifluoroacetic acid (50% in DCM) for 1 hr at rt. The reaction mixture was concentrated in vacuo and the residue obtained was purified using C18-HPLC (15-35% CH3CN in H2O (0.1% TFA) over 25 min) to give 8 mg (15%) of the title compound as a white solid. 1H-NMR (CD3OD): d 9.34 (s, 1H), 8.34 (s, 1H), 8.04-8.10 (m, 2H). 7.79 (br s, 1H), 7.74-7.75 (m, 2H), 7.67 (br s, 1H), 2.72 (s, 3H), 2.37 (s, 3H). ESI-MS (m/z): Calcd. for C20H18N4O2S3: 443.6 (M+H); found: 443.1, 222.3 (M++). Example 31 N-Hydroxy-4-[5-(6-methyl-3H-benzoimidazol-5-yl)-benzenesulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate a) N-Hydroxy~4-[3-(6-methyl-3H-benzoimidazol-5-yl)-benzenesulfonyl]- 5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate 4-[3-(6-Methyl-3H-benzoimidazol-5-yl)-benzenesulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine bis-trifluoroacetate (5 mg, 7.5 µmol, as prepared in Example 30, step c), hydroxylamine hydrochloride (50 mg, 720 mmol), and Et3N (139 µL, 1 mmol)) were suspended in EtOH (3 mL). The reaction mixture was refluxed for 2 hr at which time thin layer chromatography showed complete disappearance of the starting material. The reaction mixture was concentrated in vacuo and the residue was purified using C18-HPLC (10-50% CH3CN m H2O (0.1% TFA) over 20 mm) to give 4.9 rag (quantitative yield) of the title compound as a hygroscopic white solid. 1H- NMR (CD3OD): 5 9.38 (s, 1H), 8.0S-8.12 (m, 2H), 8.05-8.07 (m, 1H), 7.82 (br s, 1H), 7.73-7.77 (m, 2H), 7.70 (br s, 1H), 2.70 (s, 3H), 2.38 (s, 3H). ESI-MS (m/z): Calcd. for C20Hl8N403S3: 459.6 (M+H); found: 459.2. Example 32 4-[2'-(1-Hydroxy-ethyl)-biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate a) {Imin o-[5-m ethylsulfanyl-4-(2'-vinyl-biphenyl-3-sulfonyl)-thiophen - 2-yl]-methyl}-carbamic acid tert-butyl ester Following the procedure outlined for Examples 41-107, reaction of 2- vinyl-phenylboronic acid (30 mg, 0.20 mmol, Aldrich Chemical Company), {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino- methyl}-carbamic acid tert-butyl ester (SO mg, 0.1 mmol, as prepared in Example 27, step c), tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol Strem Chemicals, Inc., Newburyport, MA), Na2CO3 (400 µL, 2M aqueous), and toluene/EtOH mixture (2:1, 1.2 mL) afforded 25 mg (50%) after purification (1:3 EtOAc/hexanes, 2000 µ SiO2 plate) of the title compound as a white foam. b) 4-[2'-(1-Hydroxy-ethyl)-biphenyl-3-sulfonyl]-5-metltylsulfanyl- thiophene-2-carboxamidine trifluoroacetate {Imino-[5-methylsulfanyl-4-(2'-vinyl-biphenyl-3-sulfonyl)-thiophen-2- yl]-methyl}-carbamic acid tent-butyl ester (25 mg, 0.05 mmol) was treated with trifluoroacetic acid (50% in DCM) for 1 hr at rt. The reaction mixture was concentrated in vacuo and then basified with 1 M NaOH to pH 8 and allowed to stand for 10 min. The solution was then re-acidified with TFA and purified using C18-HPLC (10-80% CH3CN in H2O (0.1% TFA) over 30 mm) to give 7 mg (33%) of the title compound as a white solid (Rt: 12.3 min). 1H- NMR (CD2OD): d 8.32 (s, 1H), 8.01-8.05 (m, 1H), 7.98-8.00 (m, 1H), 7.64- 7.71 (m, 3H), 7.44-7.49 (m, 1H), 7.32-7.36 (m, 1H), 7.16-7.18 (m, 1H), 4.75 (q, 1H, J = 6.5 Hz), 2.72 (s, 3H), 1.28 (d, 3H, J = 6.5 Hz). ESI-MS (m/z): Calcd. for C20H20N2O3S3: 433.6 (M+H); found: 433.1. Example 33 4-[4'-(1-Hydroxy-ethyl)-biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophene-2- carboxamidine Trifluoroacetate a) {Imino-[5-methylsulfanyl-4-(4'-vinyl-biphenyl-3-sulfouyl)-thiophen- 2-yl]-methyl}-carbamic acid tert-butyl ester Following the procedure outlined in Example 1, step c, reaction of 4- vinyl-phenyl-boronic acid (181 mg, 1.22 mmol), {[4-(3-bromo- benzenesulfonyl)-5-methylsulfariyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (300 mg, 0.61 mmol, as prepared in Example 27, step c), tetrakis(triphenylphosphine)palladium(0) (141 mg, 0.122 mmol, Strem Chemicals, Inc., Newburyport, MA), Na2CO3 (2.4 mL, 2M aqueous), and toluene/EtOH mixture (2:1, 7.2 mL) afforded 138 mg (45%) of the title compound as a white glassy solid after SiO2 flash chromatography (1:3 EtOAc/hexanes). 1H-NMR (CDCl3): d 8.21 (t, 1H, 1.7 Hz), 8.00 fbrs, 1H); 7.92-7.95 (m, 1H), 7.79-7.81 (m, 1H), 7.48-7.58 (m, 5H), 6.75 (dd, 1H, J = 17.7, 10.9 Hz), 5.S2 (d, 1H, J = 17.5), 5.31 (d, 1H, J = 10.9 Hz), 2.54 (s, 3H), 1.50 (s,9H). b) 4-[4'-(l-Hydroxy-ethyt)-biphenyl-3-sulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine Trifluoroacetate {Imino-[5-methylsulfaiiyl-4-(4'-vinyl-biphenyl-3-sulfonyl)-thiophen-2- yl]-methyl}-carbamic acid tert-butyl ester (14 mg, 0.027 mmol, as prepared in Example 33, step a) was treated with trifluoroacetic acid (50% in DCM) for 1 hr at rt. The reaction mixture was concentrated in vacuo and then brought to pH 8 with 1 M NaOH and allowed to stand for 10 min. The solution was then re-acidified with TFA and purified using C18-HPLC (10-80% CH3CN in H2O (0.1% TFA) over 30 min) to give 9 mg (81%) of the title compound as a white solid (Rt: 11.8 min). 1H-NMR (CD3OD): d 8.33 (s, 1H), 8.25 (t, 1H, 1.7 Hz), 7.95-8.01 (m, 2H), 7.61-7.71 (m, 3H), 7.49-7.53 (m, 2H), 4.89 (q, 1H, J = 6.5 Hz), 2.73 (s, 3H), 1.47 (d, 3H, J = 6.5 Hz). ESI-MS (m/z): Calcd. for C20H20N2O3S3: 433.6 (M+H); found: 433.2. Example 34 4-(2'-Hydroxy-biphenyl-3-Sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate a) 4-(2'-Methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoracetate Following the procedure outlined in Example 1, step c, reaction of 2- methoxy-phenyl-boronic acid (181 mg, 1.22 mmol), {[4-(3-bromo- benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-rnethyl}-carbamic acid tert-butyl ester (100 mg, 0.2 mmol, as prepared in Example 27, step c), terrakis(triphenylphosphine)palladium(0) (141 mg, 0.122 mmol, Strem Chemicals, Inc., Newburyport, MA), Na2CO3 (800 µL, 2M aqueous), and toluene/EtOH mixture (2:1, 2.4 mL) afforded 100 mg (96%) of a white glassy solid after SiO2 flash chromatography (1:3 EtOAc/hexanes). This material was treated with trifluoroacetic acid (50% in DCM) for 1 hr at rt and the crude product was purified using C18-HPLC to give 65 mg (80%) of the title compound as a white solid. 1H-NMR (CD3OD): d S.29 (s, 1H), 8.12 (brs, 1H), 8.02 (brd, 1H, J = 7.9 Hz), 7.86-7.90 (m, 1H), 7.54 (t, 1H, J = 8.0 Hz), 6.88- 7.36 (m, 4H), 3.30 (s, 3H), 2.73 (s, 3H). ESI-MS (m/z): Calcd. for C19H18N2O3S3: 419.5 (M+H); found: 419.3. b) 4-(2'-Hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate 4-(2'-Methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate (46 mg, 0.086 mmol, as prepared in Example 34, step a) was treated with BBr3 (1 M in DCM) for 18 hr at rt. The reaction was quenched with MeOH at 0°C and then concentrated in vacuo to a solid. Purification of this solid using C18-HPLC (10-80% CH3CN in H2O (0.1% TFA) over 25 min) afforded 34 mg (77%) of the title compound as a white solid. 1H-NMR (CD3OD): d 8.30 (s, 1H), 8.27 (t, 1H, J = 1.9 Hz), 7.89-7.96 (m, 2H), 7.61 (t, 1H, J = 7.9 Hz), 7.26-7.30 (m, 1H), 1.19-1.24 (m, 1H), 6.90- 6.95 (m, 2H), 2.70 (s, 3H). ESI-MS (m/z): Calcd. for C18H16N2O3S3: 405.5 (M+H); found: 405.2. Example 35 4-(3'-Hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate 4-(3'-Methoxy-biphenyl-3-s;ulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate (1.4 mg, 3.3 µmol, as prepared in Example 44) was treated with BBr3 (1 M in DCM) for 18 hr at rt. The reaction was quenched with MeOH at 0 °C and then concentrated in vacuo to a solid. Purification of this solid using C18-HPLC (10-80% CH3CN in H2O (0.1% TFA) over 25 min) afforded 1.0 mg (77%) of the title compound as a white solid. 1H-NMR (CD3OD): d 8.33 (s, 1H), 8.23 (t, 1H, J = 1.6 Hz), 7.98-8.01 (m, 1H), 7.92-7.95 (m, 1H), 7.68 (t, 1H, J = 7.8 Hz), 7.31 (t, 1H, J = 7.8 Hz), 7.05-7.12 (m, 2H), 6.84-6.87 (m, 1H), 2.74 (s, 3H). ESI-MS (m/z): Calcd. for C18H16N2O3S3: 405.5 (M+H); found: 405.2. Example 36 5-Bromo-4-(2-methoxy-benzenesulfonyl)-thiophene-2-carboxamidine triflouroacetate The procedure as in Example 20: step a was followed using 4-bromo- 5-nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 200 mg, 0.75 mmol) and 2-methoxy-benzenethiol (109 µL, 1.25 mmoL Aldrich Chemical Company) to isolate 4-(2-methoxy-phenylsulfanyl)-5-nitro- thiophene-2-carboxylic acid methyl ester. 4-(2-Methoxy-phenylsulfanyl)-5- nitro-thiophene-2-carboxylic acid methyl ester (200 mg, 0.61 mmol) was then treated with TiCl3 (20% aq. HC1 solution, 5 mL, 6.1 mmol) in THF (6mL). The reaction was stirred for 20 minutes at rt. The reaction mixture was concentrated in vacuo and then dissolved into EtOAc. The organic layer was washed several times with saturated NaHCO3. The combined organic layers were dried over sodium sulfate. Removal of the solvents in vacuo yielded 5- amino-4-(2-methoxy-phenylsulfanyl)-thiophene-2-carboxylic acid methyl ester. The procedure as in Example 20: step e was followed using 5-amino-4- (2-methoxy-phenylsulfanyl)-thiophene-2-carboxylic acid methyl ester (160 mg, 0.54 mmol), t-butylnitrite (96 µL, 0.81 mmol), and copper (II) bromide (112.6 mg, 0.65 mmol) resulting in 5-bromo-4-(2-methoxy-phenylsulfanyl)- thiophene-2-carboxylic acid methyl ester. The procedure as in Example 20: step b was followed using 5-brorno-4-(2-methoxy-phenylsulfanyl)-thiophene- 2-carboxylic acid methyl ester (18 mg, 0.05 mmol) and m-CPBA (32 mg, 0.25 mmol) resulting in 5-bromo-4-(2-methoxy-benzenesulfonyl)-thiophene-2- carboxylic acid methyl ester. The procedure as in Example 20: step f was followed using 5-bromo-4-(2-methoxy-benzenesulfonyl)-thiophene-2- carboxylic acid methyl ester (45 mg, 11 mmol) and dimethyl aluminum amide (1M, 0.57 mL, 0.55 mmol) resulting in the title compound 5-bromo-4-(2- methoxy-benzenesulfonyl)-thiophene-2-carboxamidine (4mg, 13%). 1H-NMR (CD3OD): d: 8.30 (s, 1H), 8.12-S.14 (d of d, J = 6.1, 1.8 Hz, 1H), 7.70-7.74 (m, 1H), 7.16-7.24 (m, 2H), 3.79 (s, 3H). Example 3 7 5-Methylsulfanyl-4-(naphthalene-2-sulfonyl)-thiophene-2-carboxamidine triflouroacetate To a suspension of NaH (30 mg, 1.24 mmol) in DMF was slowly added dropwise naphthalene-2-thiol (199 mg, 1.24 mmol, Aldrich Chemical Company) in DMF at rt. This clear solution was then added dropwise to a solution of 4-bromo-5-nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 300 mg, 1.27 mmol) in DMF at rt. Aqueous workup resulted in isolation of 4-(naphthalen-2-ylsulfanyl)-5-nitro-thiophene-2- carboxylic acid methyl ester. The procedure as in Example 20: step b was followed using 4-(naphthalen-2-ylsulfanyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (194 mg. 0.56 mmol) and m-CPBA (354.4 mg, 1.2 mmol) resulting in 4-(naphthalene-2-sulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester. The procedure as in Example 27: step a was followed using 4- (naphthalene-2-sulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (32 mg, 0.085 mmol) sodium thiomethoxide (7.55 mg, 0.94 mmol) resulting in 5- methylsulfanyl-4-(naphthalene-2-sulfonyl)-thiophene-2-carboxylic acid methyl ester. The procedure as in Example 20: step f was followed using 5- methylsulfanyl-4-(naphthalene-2-sulfonyl)-thiophene-2-carboxylic acid methyl ester (29 mg, 0.77 mmol) and dimethyl aluminum amide (0.39 mL, 0.39 mmol) resulting in the title compound 5-methylsulfanyl-4-(naphthalene- 2-sulfonyl)-thiophene-2-carboxamidine triflouroacetate (19 mg, 70%). 1H- NMR (CD3OD): d: 8.67 (m, 1H), 8.37 (s, 1H), 8.05-8.15 (m. 2H), 7.95-8.01 (d, J = 7.21 Hz, 1H), 7.90-7.95 (d of d, J = 6.7, 2.0 Hz), 7.65-7.75 (m, 2H), 2.70 (s, 3H). Example 38 4-(7-Bromo-3H-benzoimidazole-5-sulfonyI)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate a) 4-Chlorosulfonyl-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester To a —5°C solution of 4-amino-5-methylsulfanyl-thiophene-2- carboxylic acid methyl ester (Illig et al.. US 6,291,514, 24 g, 0.12 mol) in methylene chloride:methanol (2:1, 40 mL), CuCl2-2H2O (6.04 g, 0.035 mol), and concentrated HC1 (19.7 mL, 0.24 mol) was added. Excess SO2 was condensed into the reaction mixture. To this mixture, was added t-butyl nitrite (27.6 mL, 0.24 mol) dropwise at -5°C and then stirred at same temperature for 2 hours. The reaction mixture was allowed to warm up to room temperature, and the solvents were removed in vacuo. The residue was diluted in methylene chloride (500 mL), washed with water (100 mL) and brine (50 mL), and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography in 30-50% ethyl acetate in hexanes to afford 4-chlorosulfonyl-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester as a solid (12 g, 35%). b) Sodium salt of 5-methylsulfanyl-4-sulfino-thiophene-2-carboxylic acid methyl ester To a solution of Na2SO3 (7.51 g, 0.06 mol) and NaHCO;, (5.22 g. 0.06 mol) in water (27 mL) at 75°C was added 4-chlorosulfonyl-5-rnethylsulfanyl- thiophene-2-carboxylic acid methyl ester ((Example 38, step a) 12 g, 0.05 mol) portion-wise over 3 hours and then stirred for an additional hour. Water was removed in vacuo, and the residue was dissolved in hot water (10 mL). This solution was cooled in a refrigerator for 1 week at which time the product precipitated out. This solid was filtered, washed with cold water and dried to give 12 g (87 %) of the sodium salt of 5-methylsulfanyl-4-sulfino-thiophene- 2-carboxylic acid methyl ester. 1H-NMR (DMSO-d6): d 7.64 (s, 1H), 3.78 (s, 3H), 2.57 (s, 3H). c) 4-(7-Bromo-spiro[benzoimidazole-2,1'-cyclohex]e-5-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxylic acid methyl ester To a solution of 4,6-dibromo-spiro[benzoimidazole-2,1'-cyclohexane] (200 mg, 0.58 mmol, prepared according to Hazelton et al., Tetrahedron:51:5597 (1995)) in ethanol (15 mL) was added an aqueous solution of the sodium salt of 5-methylsulfanyl-4-sulfino-thiophene-2- carboxylic acid methyl ester ((Example 38, step b) 175 mg, 064 mmol, 15 mL H2O) and acetic acid (40 µL, 0.70 mmol). This mixture was stirred for 2.5 hours at room temperature and poured into an ice-water slurry. The resulting aqueous solution was extracted with methylene chloride (100 mL, 3x). The organic layer was separated, washed with brine (25 mL), and dried over MgSO4. The solvents were removed in vacuo to afford 4-(7-bromo- spiro[benzoimidazole-2,r-cyclohex]e-5-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester as a brown solid (200 mg, 67 %). 1H-NMR (CDCl3): d 8.08 (m, 1H), 8.04 (s, 1H), 7.60 (m, 1H). 3.91 (s. 3H), 2.66 (s, 3H), 2.00-1.24 (m, 10.H). d) 4-(3,4-Diamino-5-bromo-benzenesulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester To a solution of 4-(7-bromo-spiro[benzoimidazole-2-cyclohex]e-5- sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 38, step c) 200 mg, 039 mmol) in 1:1 ethanol:water (30 mL) was added sodium dithionite (159 mg, 0.78 mmol) and heated to 80°C for 45 minutes. The solution was cooled to room temperature and poured into an ice- water slurry. This aqueous mixture was extracted with methylene chloride (50 mL, 3x). The organic layer was separated, washed with brine (25 mL), and dried over MgSO4. The solvents were removed in vacuo to afford 170 mg of 4-(3,4-diamino-5-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid methyl ester as a brown oil. This was used in the next step without further purification. e) 4-(7-Bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester 4-(3,4-Diamino-5-bromc)-benzenesulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester ((Example 38, step d) 170 mg, 0.39 mmol) was dissolved in formic acid (2.5 mL) and heated to 100°C for 2 hours. The resulting solution was cooled to room temperature, poured over ice-water slurry, and basified to pH 8 with NaHCO3 This aqueous solution was extracted with ethyl acetate (75 mL, 3x). The organic layer was separated and washed with water, brine, and dried over MgSO4- Solvents were removed in vacuo to afford 100 mg (57 %) of 4-(7-bromo-3H-benzoimidazole-5- sulfonyl)-5-methylsulfanyl-thiophene-2-carboxyhc acid methyl ester as a brown oil. ESI-MS (m/z): Calcd. for C14H11BrN2O4S3: 447 (M+H); found: 447.1 and 449.1. f) 4-(7-Bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate 1M stock solution of dimethylaluminum amide reagent was made by the addition of AlMe3 solution (2M in toluene, 5 mL, 10 mmol) to a suspension of NH4Cl (0.54 g, 10 mmol) in toluene (5 mL) under inert conditions, and then heated to 80°C for 5 minutes. This solution (2.5 mL, 2.5 mmol) was added to 4-(7-bromo-3H-benzoimidazole-5-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 38, step e) 15 mg, 0.034 mmol) and then heated to 100°C for 2 hrs. The resulting solution was cooled to room temperature and added to a slurry of silica gel in methylene chloride (15 g silica gel in methylene chloride 120 mL). and stirred for 30 minutes. The slurry was filtered and the silica was washed with methanol. The filtrate and methanol fractions were combined and evaporated under vacuum. The residue was purified by HPLC (C18-column, 10-70% CH3CN over 30 min) to afford 3.0 mg (21%) of 4-(7-bromo-3H- benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate as a white solid. 1H-NMR (CD3OD): d S.51 (s, 1H), S.36 (d, 1H, J = 1.6), 8.33 (s, 1H), 8.05 (d, 1H, J = 1.6), 2.72 (s, 3H). ESI-MS (m/z): Calcd. for C13H11BrN4O2S3,: 430.92 (M+H); found 431.2 and 433.1. Examples 39-40 4-(7-Bromo-3-methyl-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate and 4-(7-Bromo-l-methyl-lH- benzoimidazole-5-sulfonyl)~S-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate. a) 4-(7-Bromo-3-tnethyl-3H-benzoimidazole-5-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxylic acid methyl ester and 4-(7-Bromo-l- methyl-lH-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid methyl ester To a solution of 4-(7-bromo-3H-benzoimidazole-5-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxylic acid methyl ester (as prepared in Example 38, step e) (100 mg, 0.22 mmol) in dimethylformamide (2 mL) was added Mel (13.9 µL, 0.22 mmol) and K2CO3 (61.8 mg, 0.45 mmol). then stirred overnight at room temperature. The solvents were removed in vacuo and the residue was diluted with ethyl acetate (100 mL). The ethyl acetate layer was washed with water (15 mL) and biine (25 mL), and dried over MgSO4. The solvent was removed in vacuo to afford 20 mg (19 %) of 4-(7- bromo-3-methyl-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene- 2-carboxylic acid methyl ester and 4-(7-bromo-1-methyl-1H-benzoimidazole- 5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester as a mixtuire. This mixture was used directly in the following step. b) 4-(7-Bromo-3-methyl-3H-benzoimidazole-5-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxamidine triflnoroacetate and 4-(7- Bromo-l-methyl-lH-benzoimidazole-5-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate 1M stock solution of dimethylaluminum amide reagent was made by the addition of AlMe3 solution (2M in toluene, 5 mL, 10 mmol) to a suspension of NH4CI (0.54 g, 10 mmol) in toluene (5 mL) under inert conditions, and then heated to 80°C for 5 minutes. To the mixture from above ((Examples 39-40, step a) 20 mg, 0.043 mmol) was added dimethylaluminum amide reagent (2.5 mL, 2.5 mmol), and then heated to 100°C for 2 hrs. This solution was cooled to room temperature, added to 15 g silica gel and methylene chloride (120 mL) slurry, and stirred for 30 minutes. The slurry was filtered and washed with rnethanol. The solvents were removed in vacuo, and the crude material was purified by HPLC (C18-column, 10-70% CH3CN over 30 min) to afford 4-(7-bromo-3-methyl-3H-benzoimidazole-5-sulfonyl)- 5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate, 39 (4.5 mg) and 4-(7-bromo-1-methyl-1H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate, 40 (2.5 mg). Example 39: 1H-NMR (CD3OD): d 8.48 (s, 1H), 8.34 (s, 1H). 8.33 d, 1H, J = 1.6), 8.06 (d, 1H, J = 1.6), 4.01 (s, 3H), 2.72 (s, 3H). ESI-MS (m/z): Calcd. for C14H13BrN4O2S3: 445 (M+H); found 445.1 and 447.1. Example 40: 1H--NMR (CD3OD): d 8.39 (s, 1H), 8.34 (d, IH, J = 14), 8.33 (s, 1H), 8.07 (d, 1H, J = 1.2), 4.21 (s, 3H), 2.72 (s, 3H). ESI-MS (m/z): Calcd. forC14H13BrN4O2S3: 445 (M+H); found 445.1 and 447.1. Examples 41-107 The compounds in examples 41 to 107 (see table 1) were synthesized in a parallel fashion as follows: To dry 2-dram vials, each fitted with a stir bar and a Teflon®-lined screw cap was added {[4-(3-bromo-benzenesulfonyl)-5- methylsulfanyl-thiophen-2-yr\|-imino-methyl}-carbamic acid tert-butyl ester (0.1 mrnol, as prepared in Example 27, step c), the appropriate boronic acid (0.2 mrnol), and tetrakis(triphenylphosine)palladium(0) (0.025 mmol). Each vial was twice treated with an argon purge/evacuation cycle and then charged with a mixture of toluene/EtOH (2:1, 1.2 mL) and 2 M Na2CO3 (0.4 mL) via a syringe. The vials were placed in an oil bath at 80 °C and stirred overnight. To the cooled reaction mixtures was added EtOAc (4 mL), the organic layer was filtered (1-g silica SPE column), and the filtrate was evaporated in vacuo. The resulting residue was purified using preparative TLC (SiO2) to afford the Boc- protected amidine product. After treatment of this material with trifluoroacetic acid (50% in DCM) for 1 hr at rt, the solvents were removed in vacuo and the residue was purified using C18;-HPLC (typical HPLC method: 10% to 80 % CH3CN in H2O (0.1% TFA) over 25 min) to afford the desired compound. Example 94 was prepared in an identical fashion except for removal of the Boc protecting group which was achieved by treatment with 4 N HCl in dioxane for 1 hr at it. This was found to minimize side reactions involving the vinylic group (see Example 32). Examples 108-110 5-MethylsuIfanyl-4-(3-methyl-7-o-tolyl-3H-benzoimidazole-5-sulfonyl)- thiophene-2-carboxamidine trifluoroacetate, 5-Methylsulfanyl-4-(2-methyl- 7-o-tolyl-3H-benzoimidazole-5-sulfonyl)-thiophene-2-carboxamidine and 5-Methylsulfanyl-4-(7-o-tolyl-3H-benzoimidazole-5-sulfonyl)-thiophene-2- carboxamidin e a) 4-(7-Bromo-l,3-dihydro-spiro[benzoimidazole-2,1'-cyclohex]e-5- sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester 4-(7-Bromo-spiro[benzoimidazole-2,1'-cyclohex]e-5-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 38, step c) 300 mg, 0.58 mmol) in ethanol:water solution (1:1, 60 mL) was treated with sodium dithionite (203 mg, 1.16 mmol) as in Example 38, step d. A brown precipitate formed upon addition of sodium dithionite. This precipitate was filtered and dried under vacuum to give 163.6 mg of 4-(7-bromo- 1,3-dihydro- spiro[benzoimidazole-2,1'-cyclohex]e-5-sulfonyl)-5-methylsulfany]- thiophene-2-carboxylic acid methyl ester as a brown solid. This solid was used in the next step without further purification. b) 5-Methylsulfanyl-4-(7-o-tolyl-l,3-dihydro-spiro[benzoimidazole-2,1'- cyclohex]e-5-sulfonyl)-thiophene-2-carboxylic acid methyl ester and 5- Methylsulfanyl-4-(7-o-tolyl-1,3-dihydro-spiro[benzoimidazole-2,1'- cyclohex]e-5-sulfonyl)-thiophene-2-carboxylic acid ethyl ester To a dried flask was added 4-(7-bromo-l,3-dihydro- spiro[benzoimidazole-2,r-cyclohex]e-5-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester (129 mg, 0.249 mmol) from above step a, o-tolyl boronic acid (136 mg, 0.779 mmol), aqueous Na2CO3 (2M, 1 mL, 43 mmol), ethanol (1 mL)., and toluene (2 mL). The flask was sparged with argon, and Pd(PPh3)4 (72 mg, 0.062 mmol) was added. The reaction mixture was stirred and heated at 80° for 18 hrs, and then cooled to room temperature. The solvents were removed in vacuo. The residue was dissolved in ethyl acetate (150 mL), washed with water (20 mL) and brine (20 mL), and then dried over MgSO4. Ethyl acetate was removed in vacuo and the residue was purified via preparative TLC (20-30% ethyl acetates/hexanes) to afford a mixture of 5-methylsulfanyl-4-(7-o-tolyl-l,3-dihydro-spiro[benzoimidazole- 2,1'-cyclohex]e-5-sulfonyl)-thiophene-2-carboxylic acid methyl ester and 5- methylsulfanyl-4-(7-o-tolyl-l ,3-dihydro-spiro[benzoimidazole-2,1'- cyclohex]e-5-sulfonyl)-thiophene-2-carboxylic acid ethyl ester as a brown oil (130 mg). ESI-MS (m/z): Calcd. for C26H28N2O4S3 and C27H30N2O4S3: 529.12 (M+H); found 529.3 and 543.3. c) 5-Methylsulfanyl~4-(7-o-tolyl-3H-benzoimidazole-5-sulfonyl)- thiophene-2-carboxylic acid methyl and ethyl esters A mixture of 5-methylsulfanyl-4-(7-o-tolyl-l,3-dihydro- spiro[benzoimidazole-2,1'-cyclohex]e-5-sulfonyl)-thiophene-2-carboxylic acid methyl and ethyl esters (130 mg) from above step b was treated with formic acid as in Example 38: step e followed by analogous work up to afford a crude mixture of 5-methylsulfanyl-4-(7-o-tolyl-3H-benzoimidazole-5-sulfonyl)- thiophene-2-carboxylic acid methyl and ethyl esters as a brown oil (100 mg). This mixture was used in the following step without further purification. MS (m/z): Calcd. for C21H18N2O4S3: 459.04 (M+l); found 459.2 and 473.2. d) 5-Methylsulfanyl-4-(3-methyl-7-o-tolyl-3H-benzoimidazole-5- sulfonyl)-thiophene-2-carboxamidine trifluoroacetate, 5-Methylsulfanyl-4- (2-methyl-7-o-tolyl-3H-benzoimidazole-5-sulfonyl)-thiophene-2- carboxamidine trifluoroacetate and 5-Methylsulfanyl-4-(7-o-tolyl-3H- benzoimidazole-5-sulfonyl)-thiophene-2-carboxamidine trifluoroacetate A mixture of 5-rnethylsulfanyl-4-(7-o-tolyl-3H-benzoimidazole-5- sulfonyl)-thiophene-2-carboxylic acid methyl and ethyl esters (100 mg, 0.22 mmol) from above step c was treated with methyl iodide (13.6 µL, 0.22 mmol) and K2CO3 (60.2 mg, 0.44 ;m-mol) in dimethylformamide (2 mL) as in Example 39: step a, followed by analogous work up to afford 40 mg of a crude mixture. This mixture was treated with the dimethyl aluminum amide reagent (5 mL, 5 mmol) as in Example 39: step b. After 1 hour, additional dimethylaluminum amide reagent (5 mL, 5 mmol) was added. After 1.5 hours, the reaction was quenched as in Example 39: step b followed by HPLC (CIS-column, 10-70% CH3CN over 30 min) purification to afford 5- methylsulfanyl-4-(3-methyl-7-o-tolyl-3H-benzoimidazole-5-sulfonyl)- thiophene-2-carboxamidine trifluoroacetate (108), 5-methylsulfanyl-4-(2- methyl-7-o-tolyl-3H-ben2:oimidazole-5-sulfonyl)-thiophene-2-carboxamidine trifluoroacetate (109) and 5-methylsulfanyl-4-(7-o-tolyl-3H-benzoimidazole- 5-sulfonyl)-thiophene-2-carboxamidine trifluoroacetate (110). 108: 1H-NMR (CD3OD): d 8.63 (s, 1H), 8.41 (m, 1H), 8.36 (m, 1H), 7.82 (m, 1H), 7.38-7.26 (m, 4H), 4.08 (s, 3H), 2.72 (s, 3H), 2.09 (s, 3H). 109: 1H-NMR (CD3OD): d S.41 (m, 1H), 8.35 (s, 1H), 7.73 (m, 1H), 7.46-7.28 (m, 4H), 3.32 (s, 3H), 2.70 (s, 3H), 2.02 (s, 3H). 110: 1H-NMR (CD3OD) C: 5 8.56 (s, 1H), 8.41 (m, 1H), 8.36 (m, 1H), 7.78 (m, 1H), 7.44-7.27 (m, 4H), 2.71 (s, 3H), 2.10 (s, 3H). Example 111 4-(2-Methyl-furan-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxamidine hydrochloride a) 4-(2-Methyl-furan-3-ylsulfanyl)-5-nitro-thiophene-2-carboxylic acid methyl ester 4-Bromo-5-nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 532 mg, 2 mmol), 2-methyl-furan-3-thiol (600 mg, 5.26 mmol), and DMAP-polystyrene resin (2 g, 2.86 rnmol) were stirred in THF (10 mL) for 12 h at rt. The resin was filtered and washed with several portions of DCM (100 mL total volume). The filtrate was concentrated in vacuo and the yellow residue (480 mg, 80%) was used without further purification. 1H-NMR (CDCl3): d 7.46 (d, 1H, J - 1.9 Hz), 7.05 (s, 1H), 6.43 (d, 1H, J = 1.9 Hz), 3.90 (s, 3H), 2.38 (s, 3H). b) 4-(2-Methyl-furan-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid methyl ester m-Chloroperbenzoic acid (276 mg, 4 mmol) and 4-(2-methyl-furan-3- ylsulfanyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (117 mg, 0.39 mmol) were dissolved in DCM (15 mL) and stirred for 6 h at 40 °C. DCM (50 mL) and aqueous sodium thiosulfate were added (exothermic), and the layers were separated. The organic layer was extracted with Na2CO3 (2M, 6 x 30 mL), brine (50 mL), and was dried over sodium sulfate. Concentration of the solvent in vacuo followed by SiO2 flash chromatography (25-75% DCM in hexanes) yielded the sulfone compound (85 mg, 66%) which was redissolved THF (5 mL). The procedure in Example 12: step c was followed, using 275 µL (0.275 mmol) of sodium thiomethoxide. Analogous aqueous workup and purification by SiO: flash chromatography yielded the title compound (72 mg, 85%) as a colorless solid. c) 4-(2-Methyl-furan-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine hydrochloride Following the procedure used in Example 12: step f, 4-(2-methyl- furan-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (26 mg, 0.078 mmol) was converted to the amidine using 3 mL of dimethyl aluminum amide reagent. The title compound was isolated as a white solid (16 mg, 58%) after preparative TLC purification (15% MeOH in DCM). 1H-NMR (CD3OD): d 8.26 (s, 1H), 7.49 (d, 1H, J = 2.1 Hz), 6.69 (d, 1H, J = 2.1 Hz), 2.74 (s, 3H), 2.63 (s, 3H). ESI-MS (m/z): Calcd. for C11H12N2O3S3 (M+H): 317.4; found: 317.2. Example 112 5-Methylsulfanyl-4-(4-phenyl-thiazole-2-sulfonyl)-thiophene-2- carboxamidine hydrochloride a) 5-Nitro-4-(4-phenyl-thiazole-2-sulfonyl)-thiophene-2-carboxylic acid methyl ester The procedure in Example 111: step a was followed, using 4-bromo-5- mtro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 532 mg, 2 mmol), 4-phenyl-thiazole-2-thiol (483 mg, 2.5 mmol), and DMAP- polystyrene resin (2 g, 2.86 mmol) in THF (10 mL). Analogous workup yielded the crude sulfide which was treated with m-chloroperoxybenzoic acid (1.38 g, 8 mmol) in DCM (30 mL) as in Example 111: step b. Analogous workup and purification by SiO2 flash chromatography (25-50 % EtOAc in hexanes) yielded the title compound (245 mg, 30%) as a white solid. 1H- NMR (CDCl3): d 8.25 (s, 1H), 7.80 (m, 2H), 7.75 (s, 1H), 7.34-7.44 (m, 3H), 7.05 (s, 1H), 6.43 (d, 1H, J = 1.9 Hz), 3.98 (s, 3H). b) 5-Methylsulfanyl-4-(4-phenyl-thiazole-2-sulfonyl)-thiophene-2- carboxamidine hydrochloride Following the procedure in Example 12: step c, 5-nitro-4-(4-phenyl- thiazole-2-sulfonyl)-thiophene-2-carboxylic acid methyl ester (110 mg, 0.27 mmol) was reacted with sodium thiomethoxide (1M in EtOH, 325 µL, 0.325 mmol) in THF (5 mL). Analogous aqueous workup and purification by SiO2 flash chromatography yielded the thiomethylated intermediate (82 mg, 75%) as a white solid. A portion of the solid (52 mg, 0.126 mmol) was treated with dimethyl aluminum amide reagent (5 mL) as in Example 12: step f. Analogous workup and purification by preparative TLC (15% MeOH in DCM) resulted in the title compound (21 mg, 38%) as a white solid. 1H-NMR (CD3OD): d 8.38 (s, 1H), 8.31 (s, 1H), 7.90 (m, 2H), 7.36-7.46 (m, 3H), 2.76 (s, 3H). ESI-MS (m/z): Calcd. for C15H13N3O2S4 (M+H): 396.6; found: 396.1. Example 113 4-(6-Ethoxy-benzothiazole-2-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine hydrochloride a) 4-(6-Ethoxy-benzothiazole-2-sulfonyl)-5-nitro-thiophene-2- carboxylic acid methyl ester The procedure in Example 111: step a was followed, using 4-bromo-5- nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 266 mg, 1 mmol), 6-ethoxy-benzothiazole-2-thiol (264 mg, 1.25 mmol), and DMAP- polystyrene resin (0.75 g, 1.05 mmol) in THF (6 mL). Analogous workup yielded the crude sulfide, which was treated with m-chloroperoxybenzoic acid (692 mg, 4 mmol) in DCM (30 mL) as in Example 111: step b. Analogous workup and purification by SiO2 flash chromalography (25-50 % EtOAc in hexanes) yielded the title compound (250 mg, 58%) as a colorless glass, 1H- NMR (CDCl3): d 8.40 (s, 1H), 7.94 (d, 1H, J = 9.1 Hz), 7.38 (d, 1H, J = 2.6 Hz), 7.17 (dd, 1H, J-= 2.6, 9.1 Hz), 4.13 (q, 2H, J = 7.0 Hz), 4.00 (s, 3H), 1.47 (t, 3H, J = 7.0 Hz). ESI-MS (m/z): Calcd. for C15H12N2O7S3 (M-H): 429.5; found: 429.1. b) 4-(6-Ethoxy-benzothiazole-2-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine hydrochloride Following the procedure in Example 12: step c, 4-(6-ethoxy- benzothiazole-2-sulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (65 mg, 0.15 mmol) was reacted with sodium thiomethoxide (1M in EtOH, 175 µL 0.175 µmol) in THF (5 mL). Analogous aqueous workup and purification by SiO2 flash chromatography yielded the thiomethyl intermediate (53 mg, 82%) as a colorless glass. A portion of the material (41 mg, 0.10 mmol) was treated with dimethylaluminum amide reagent (3 mL) as in Example 12: step f. Analogous workup and purification by preparative TLC (15% MeOH in DCM) yieded the title compound (18 mg, 42%) as a white solid. 1H-NMR (CD3OD): d 8.37 (s, 1H), 7.96 (d, 1H, J = 9.1 Hz). 7.62 (d, 1H, J = 2.6 Hz), 7.22 (dd, 1H, J = 2.6, 9.1 Hz), 4.14 (q, 2H, J = 7.0 Hz), 2.74 (s, 3H), 1.44 (t, 3H, J = 7 0 Hz). ESI-MS (m/z): Calcd. for C15H15N3O3S4 (M+H): 414.6; found: 414.1. Example 114 4-(3-Methoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine hydrochloride HCl a) 4-Bromothiophene-2-carboxylic acid To a flask equipped with a mechanical stirrer was added 25 g (130 mmol) 4-bromothiophene-2-carbaldehyde (Aldrich Chemical Company), acetonitrile (200 mL), and 4.5 g (37.5 mmol) of sodium dihydrogen phosphate dissolved in 35 mL of water. After cooling this mixture on an ice-salt bath, 15 mL (169 mmol) of 35% hydrogen peroxide and 15.3 g (169 mmol) of sodium chlorite were added, and the mixture was stirred for 1 h. The reaction mixture was then stirred at room temperature for 3 h. The solvent was removed in vacuo, and the solid was suspended in a mixture of water (175 mL) and 1 N hydrochloric acid (4 mL) and stirred for 10 min at rt. The solid was collected on a Buchner funnel and washed with water (2 x 150 mL) to afford 26 g (97%) of 4-bromothiophene-2-carboxylic acid, which was used in the next step without further purification. b) 4-Bromothiophene-2-carboxylic acid Methyl Ester To a dry flask under N2 with a stirbar was added 6 g (29.1 mmol) of 4- bromothiophene-2-carboxylic acid (as prepared in the previous step) and dry methanol (100 mL). The solution was cooled in an ice-salt bath for 15 min and 2.55 mL (34.9 mmol) of thionyl chloride was added over 15 min. keeping the temperature for an additional 15 min, then for 1 h at rt, and finally refluxed for S h under N2. The resulting solution was cooled and concentrated to 6.7 g of pale amber oil. This oil was passed through 150 g of silica with ~600 mL CH2Cl2 (discarded the first 120 mL wliich contained minor impurities and no ester). The solvent was removed in vacuo to afford 6.11 g (95% yield) of the title compound as a colorless solid, which was used in the next step without further purification. c) 4-Bromo-5-nitrothiophene-2-carboxylic acid Methyl Ester The nitrating mixture (HNO3 d =1.42, 2 mL; concentrated H2SO4, 6 mL) was slowly added with stirring, at -5° to -10°C, to 4-Bromothiophene-2- carboxylic acid methyl ester (3 g, 13.57 mmol) dissolved in concentrated H2SO4 (10 mL). After being kept at -5 to -10°C for 30 min. the mixture was poured over crushed ice. The solid precipitate was separated by filtration and washed with water and dried over P2O5 to give 3.7 g of 4-bromo-5- nitrothiophene-2-carboxylic acid methyl ester as a tan solid, which was used in the next step without further purification. d) 4-(3-Methoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid methyl ester To a cooled (ice bath) solution of 4-bromo-5-nitrothiophene-2- * carboxylic acid methyl ester (0.5 g, 1.88 mmol) from above step c, in dimethylformamide (DMF) was added 3-methoxybenzenethiol ( 0.29 g, 2.1 mmol) and Cs2CO3 (0.67 g, 2.1 mmol). The resulting mixture was heated at 50 °C for 3 h. DMF was removed under vacuum and the residue was partitioned between EtOAc and 10 % HC1. The EtOAc layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give an oil. This oil was purified by silica gel column chrormatography (EtOAc:hexane) to give 0.56 g (91 %) of 4- (3-Methoxy-phenylsulfanyl)-5-mtro-thiophene~2-carboxylic acid methyl ester. This ester was dissolved in CH2Cl2 (6 mL) and treated with m- chloroperoxybenzoic acid (MCPBA, 1.1 g) and heated at reflux for 6 h. The resulting mixture was diluted with CH2Cl2 (10 mL) and washed with sat. sodium thiosulfate, IN NaOH and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc:hexane) to give an oil. This oil was dissolved in DMF (5 mL) and cooled in an ice bath. To this solution sodium thiomethoxide (126 mg, Aldrich Chemical Company) was added and the mixture was stirred for 5 h. The reaction was quenched with 10% HC1 and the solvents were removed in vacuo. The residue was dissolved in EtOAc, washed with brine and dried over Na2SO4 The solvent was removed in vacuo and the residue was purified by preparative thin-layer chromatography to give 171 mg of 4-(3-methoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester, which was directly used in the next step. e) 4-(3-Methoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine 4-(3-methoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid methyl ester from above step d (171 mg, 0.48 mmol) was treated with dimethylaluminum amide reagent (2 mL) as in Example 12: step f. Analogous workup and purification by preparative TLC (15% MeOH in DCM) gave the title compound (50 mg, 30%) as a white solid. 1H-NMR (DMSO-de): d 9.24 (broad s, 4H), 8.43 (s, 1H), 7.64-7.51 (m, 2H), 7.44 (s, H), 7.31 (d, 1H, J = 9.3 Hz), 3.83 (s, 3H), 2.70 (s, 3H). ESI-MS (m/z): Calcd. for C13H14N2O3S3 (M+H): 343.0; found: 343.2. Example 115 4-(6-Methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate a) 6-Methyl-biphenyl-3-ylamine To a dried flask was added 3-bromo-4-methyl-phenylamine (1 g, 5.37 mmol), phenyl boronic acid (2.62 g, 21.5 mmol), aqueous Na2CO3 (2M, 21.5 mL, 43 mmol), ethanol (21.5 mL), and toluene (43 mL). The flask was sparged with Ar, and Pd(PPh3)4 (1.55 g, 1.34 mmol) was added. The reaction mixture was stirred and heated at 80° for 18 hrs, then cooled to room temperature. The solvent was removed in vacua and the residue was dissolved in ethyl acetate. The organic layer was washed with water and brine, then dried over MgSO4. The solvent was removed in vacuo and the residue was purified via column chromatography (SiO2, 5% DCM/hexane) to afford a yellow oil (463 mg, 47%). This was directly used in the next step. b) 6-Methyl-biphenyl-3-thiol To a cooled solution of 6-methyl-biphenyl-3-ylamine (463 mg, 2.53 mmol) from above step a, in hydrochloride solution (0.42 mL cone. HC1 in 0.5 mL H2O, 5 mmol) was added dropwise a solution of NaNO2 (Aldrich, 0.18 g in 0.3 mL H2O, 2.6 mmol) at -2°C. The resulting diazonium ion solution was stirred for 20 min and added to a solution of KS2COEt in H2O (0.61 g in 0.8 mL of H2O, 3.81 mmol) with stirring. The resultant mixture was heated to 80°C for a few minutes, then cooled to room temperature and extracted with diethyl ether. Ether was removed in vacuo and the residue was treated with a potassium hydroxide solution (0.5 g in 1.5 mL in ethanol, 8.91 mmol, 3.56 eq) and heated at reflux for 8 h. The reaction mixture was cooled to room temperature, diluted with H2O, and acidified with HC1 to pH~3. This solution was extracted with Et20 and the organic layer was washed with H2O and brine, then dried over MgSO4. The solvent was removed in vacua to afford a yellow oil (510 mg, 100%). This was directly used in the next step. c) 4-(6-Methyl-biphenyl-3-ylsulfanyl) -5-nitro-thiophene-2-carboxylic acid methyl ester To a solution of triphenylphosphine (0.67 g, 2.55 mmol), 4-bromo-5- nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 1 g, 3.76 mmol) and 4-(dimethyl)aminopyridme resin (1 eq) in THF was added 6- methyl-biphenyl-3-thiol from above step b. This mixture was stirred for 3 hrs. The reaction mixture was filtered and the solvents were removed in vacuo. The residue was purified via column chromatography (SiO2, 15% ethyl acetate/hexane) to afford a yellow glass (600 mg, 61%), which was used in the following step. d) 4-(6-Methyl-biphenyl-3-sulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester To a solution of 4-(6-methyl-biphenyl-3-ylsulfanyl)-5-nitro-thiophene- 2-carboxylic acid methyl ester (0.6 g, 1.56 mmol, 1 eq) from above step c, in DCM was added 3-chloroperoxybenzoic acid (1.04 g, 3.42 mmol, 2.2 eq). The reaction mixture was heated to reflux for 2 hrs, then cooled to room temperature. The reaction mixture was quenched with saturated Na2S2O3 solution, then washed with saturated Na2CO3 solution, water, brine, and was dried over MgSO4. The solvent was removed in vacua to afford a yellow solid (170 mg, 26%), which was taken on to the next step. e) 4-(6-Methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid methyl ester To a solution of 4-(6-methyl-biphenyl-3-sulfonyl)-5-nitro-thiophene-2- carboxylic acid methyl ester (170 mg, 0.41 mmol) from above step d, in anhydrous THF at -78°C was added dropwise a 1M solution of NaSMe in ethanol (0.4 rnL, 0.41 mmol). The reaction mixture was stirred for .2 hrs. at -78° C, quenched with acetic acid (23 p.1, 0.41 mmol), and wanned to room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated NaHCO3 solution (2x), water, and brine. The organic layer was dried over MgSO4 and removed in vacuo. The residue was purified via column chromatography (SiO2, 15% DCM/hexane) to afford a yellow glass (130mg,76%). f) 4-(6-Methyl-biphenyl-3-sulfonyl)-5-methylsulfunyl-thiophene-2- carboxamidine trifluoroacetate In a dried flask was suspended NH4Cl (Aldrich, 1.08 g, 20 mmol) in anhydrous toluene (10 mL) under argon. To this suspension was added 2M solution of AlMe3 in toluene (10 mL, 20 mmol). This mixture was heated to 100°C for a few minutes. This dimethylaluminum amide reagent (5 mL, 5 mmol) was added to 4-(6-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- fhiophene-2-carboxylic acid methyl ester (130 mg, 0.31 mmol) from above step e, under Ar. This reaction mixture was heated to reflux for 1.5 h then cooled to room temperature. The reaction mixture was quenched by pouring it into a slurry of silica gel in CHCl3. The slurry was stirred for 30 minutes, and then filtered with 10% MeOH/DCM and MeOH. The solvents were removed in vacuo and the residue was dissolved in 10% MeOH/DCM, and filtered through a syringe filter. The solvent was removed in vacuo and the residue was purified via preparatory HPLC to afford a beige solid (5 mg, 4 %). 1H- NMR (DMSO-d6): d 9.39 (bs, 1H), 8.96 (bs, 2H), 8.41 (s, 1H), 7.88 (dd, 1H), 7.74 (m, 1H), 7.61 (m, 1H), 7.52-7.35 (m, 5H). Calcd. for C19H1SN2O2S3: 402.05; found: 403.2. Example 116 5-Methylsulfanyl-4- (3-phenoxy-benzenesulfonyl)-thiophene-2- carboxamidine hydrochloride salt a) 3-Phenoxy-benzenethiol To a cooled solution of 3-phenoxyainiline (2 g, 0.01 mol) in hydrochloride solution (1.69 mL cone. HC1 in 2 mL H2O, 0.02 mol) was added dropwise a solution of NaNO2 (Aldrich, 0. 8 g in 2 mL H2O, 0.01 mol) at 0-2°C. The resulting diazonlum ion solution was stirred for 20 min and then added to a solution of KS2COEt in H2O (2.6 g in 4 mL of H2O, 0.02 mol) with stirring. This mixture was heated to 80°C for a 20 minutes, then cooled to room temperature, and extracted with diethyl ether. The ether layer was washed with water, brine and dried over Na2SO4. Ether was removed in vacuo and the residue was taken in ethanol and treated with a sodium hydroxide solution (12 N, 0.04 mol, 3.56 eq) and heated at reflux for 8 h. The reaction mixture was cooled to room temperature, diluted with H2O, and acidified with H2SO4 to pH~3. This solution was extracted with Et2O and the organic layer was washed with H2O and brine, and then dried over MgSO4. The solvent was removed in vacuo to afford a yellow oil which was purified by silica gel column chromatography to give a mixture of 3-Phenoxy-benzenethiol and the corresponding disulfide (1.2 g). This was directly used in the next step. h) 5-Nitro-4-(3-phenoxy-phenylsulfanyl)-thiophene-2-carboxylic acid methyl ester The mixture from above step a (171 mg, 0.48 mmol) was treated with triphenylphosphine (1.98 g, 7.52 mmol), 4-bromo-5-nitro-thiophene-2- carboxylic acid methyl ester ((Example 114, step c) 0.5 g, 1.8S mmol) and 4- (dimethyl)ammopyridine resin (1 eq) in THF (25 mL). This mixture was stirred for 18 h. The reaction mixture was filtered and the solvents were removed in vacuo. The residue was purified via silica gel column chromatography to afford a yellow glass (420 mg), which was used in the following step. c) 5-Nitro-4-(3-phenoxy-benzenesuIfonyl)-thiophene-2-carboxylic acid methyl ester To a solution of 5-nitro-4-(3-phenoxy-phenylsulfanyl)-thiophene-2- carboxylic acid methyl ester (42:0 mg, 1.1 mmol) from above step b, in DCM was added 3-chloroperoxybenzoic acid (1.31 g, 4.34 mmol, 4 eq). The reaction mixture was heated to reflux for 18 h, then cooled to room temperature. The reaction mixture was quenched with saturated Na2S2O3 solution, then washed with 1N KaOH solution, brine, and dried over MgSO4. The solvent was removed in vacuo and the residue was taken on to the next step. d) 5-Methylsulfanyl-4-(3-phcmoxy-benzenesulfonyl)-thiophene-2- carboxylic acid methyl ester To a solution of 5-Nitro-4-(3-phenoxy-benzenesulfonyl)-thiophene-2- carboxylic acid methyl ester from above step c, in anhydrous THF at -78° C was added dropwise a 1M solution of NaSMe in ethanol (1.06 mL, 1.08 mmol). The reaction mixture was stirred for 5 h at -78° C, quenched with acetic acid (61 µL, 1.08 mmol). and warmed to room temperature. The reaction mixture was diluted with ethyl acetate, washed with 10% HCl, saturated NaHCO3 solution (2x), water, and brine. The organic layer was dried over Na2SO4 and removed in vacuo. The residue was purified via silica gel column chromatography to afford 250 mg (55 %) of 5-methylsulfanyl-4- (3-phenoxy-benzenesulfonyl)--thiophene-2-carboxylic acid methyl ester. e) 5-Methylsulfanyl-4-(3-phenoxy-benzenesulfonyl) -thiophene-2- carboxamidine hydrochloride salt 5-Methylsulfanyl-4-(3-phenoxy-benzenesulfonyl)-thiophene-2- carboxylic acid methyl ester from above step d (200 mg, 0.48 mmol) was treated with dimethylaluminum amide reagent (2 mL) as in Example 12: step f. Analogous workup and purification by preparative TLC (10% MeOH in DCM) gave the title compound (120 mg, 62 %) as a white solid: 1H-NMR (DMSO-d6): d 9.46 (bs, 2H), 9.20 (bs, 2H), 8.43 (s, 1H), 7.71-7.63 (m, 2H), 7.49-7.43 (m, 3H), 7.35 (d, 1H, J = 7.9 Hz), 7.24 (t, 1H, J = 7.2 and 7.4 Hz), 7.1 (d, 2H, J = 7.7 Hz), 2.68 (s, 3H). Calcd. for C18H15N2O3S3: 405.03 (M+H); found: 405.2. Example 117 4-(Biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate To a dry 2-dram vial, fitted with a stir bar and a Teflon-lined screw cap was added {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2- yl]-imino-methyl}-carbarnic acid tert-butyl ester (100 mg, 0.2 mmol, as prepared in Example 27, step c), phenylboronic acid (0.3 mmol), and tetrakis(triphenylphosine)palladium(0) (0.025 mmol). Each vial was twice treated with an argon purge/evacuation cycle and then charged with a mixture of toluene/EtOH (2:1, 2.4 mL) and 2 M Na2CO3 (0.8 mL) via a syringe. The vials were placed in an oil bath at 80 °C and stirred overnight. To the cooled reaction mixtures was added EtOAc (4 mL), the organic layer was filtered (1-g silica SPE column), and the filtrate was evaporated in vacuo. The resulting residue was purified using preparative TLC (SiO2) to afford the Boc-protected amidine product. After treatment of this material with trifluoroacetic acid (50% in DCM) for 1 hr at rt, the solvents were removed in vacuo and the residue was purified using C18-HPLC (20% to 100 % CH3CN in H2O (0.1% TFA) over 15 min) to afford 10 mg (13 %) 4-(biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate: lH-NMR (DMSO-d6): d 8.32 (s, 1H), 8.25 (m, 2H), 8.02-7.95 (m, 2H), 7.72-7.63 (m, 3H), 7.52-7.47 (m, 2H), 7.44-7.39 (m, 1H), 2.72 (s, 3H). Calcd. for C13H16N2O2S3: 389.04 (M+H); found: 389.2. Example 118 4-(5-Bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine a) 5-Bronio-6-chloro-pyridine-3-sulphenic acid 5-Bromo-6-chloro-pyridine-3-sulfonyl chloride (2.5 g, 8.6 mmol), sodium sulfite (2.0 g, 16.1 mmol), and sodium bicarbonate (1.4 g, 16,9 mmol) were dissolved into water (8 mL) and EtOH (3 mL). The reaction mixture was allowed to stir at RT for 12 hours. TLC analysis showed loss of SM and formation of a very polar new spot. Reaction mixture was concentrated in vacua resulting in a white solid and was used without further purification. ESI-MS (m/z): Calcd. for C5H3BrClNO2S: 255.8 (M+H); found: 256.0. 1H- NMR (CD3OD): d 8.55 (m, 1H), 8.29 (m, IH). b) 4-(5-Bromo-6-chloro-pyridine-3-sulfonyl)-5-nitro-thiophene-2- carboxylic acid methyl ester 4-Bromo-5-nitro-thiophene-2-carboxylic acid methyl ester (5.0 g, 19.9 mmol) was dissolved into DMF (20 mL) and cooled to 0°C. To this was added a solution of 5-bromo--6-chloro-pyridine-3-sulphenic acid (Example 118, step a) (1.8 g, 6.6 mmol) in DMF (20 mL) dropwise for 2 hours. The reaction was then wanned to RT and allowed to continue to stir for an additional 2 hours. The reaction was concentrated in vacuo and purified by SiOi flash column chrornatography (Biotage - 40 M, 25 % EtOAc in hexanes). The product was isolated as a white solid (2.5 g, 48%). ESI-MS (m/z): Calcd. for C11H6BrCIN2O6S2: 440.8 (M+H); found: 441.0. c) 4-(5-Bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester The procedure as in Example 27, a was followed using 4-(5-bromo-6- chloro-pyridine-3-sulfonyl)-5-mtro-thiophene-2-carboxylic acid methyl ester (3.5 g, 8.10 mmol, Example 118, step b) and sodium thiomethoxide (560 mg, 8.10 mmol as 1M solution in EtOH). The reaction was allowed to stir for 2.5 hours and was quenched with acetic acid. The resulting mixture was dissolved into EtOAc, and aqueous work up with brine and saturated NaHCO3 resulted in isolation of a mixture. This mixture was purified by SiO2 flash column chromatography (Biotage - 40 M, 100 % hexanes to 25 % EtOAc in hexanes). The product was isolated as a yellow solid (750 mg, 21 %). ESI-MS (m/z): Calcd. for C12Hl0BrClNO4S3: 441.8 (M+H); found: 442.1. 1H-NMR (CD3OD + CDCl3): 5 8.93 (m, 1H), 8.50 (m, 1H), 8.06 (s, 1H), 3.91 (m, 3H), 2.67 (m, 3H). d) 4-(5-Bromo-6-chloro-pyridine-3-sulfonyl)-5-ntethylsulfanyl- thiophene-2-carboxamidine The procedure as in Example 20, f was followed using 4-(5-bromo-6- chloro-pyridine-3-sulfonyl)-5-raethylsulfanyl-thiophene-2-carboxylic acid methyl ester (14 mg, 0.03 mmol, Example 118, step c) dimethylaluminuim amide (1M, 5 mL). The reaction was stirred for 3 hours at 90 °C and TLC analysis indicated that the reaction was complete. The reaction was quenched with SiCh and filtered. The resulting filtrate was concentrated in vacuo followed by purification by C18-HPLC (10-70% CH3CN over 30 minutes). The title compound was isolated as a white solid (6.4 mg, 46%). ESI-MS (m/z): Calcd. for C11H9BrClN3O2S3: 425.9 (M+H); found: 426.1. 1H-NMR (CD3OD): 6 8.96 (s, 1H), 8.65 (s, 1H), 8.33 (s, 1H), 2.76 (s, 3H). Example 119 4-(6-Amino-5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine a) 4-(6-Amino-5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid amide An ammonia bomb was; used to prepare the title compound. Ammonia gas (5mL) was condensed into the Teflon core of a metal bomb with a stir bar and 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester (321 mg, 0.73 mmol, Example 118, step c). The Teflon® core was kept at -78°C during the addition of reagents. Following the addition of reagents, the bomb was assembled and then sealed tight by hand and then tightened by wrench action. The sealed bomb was checked for leaks by use of pH paper. The bomb was then added to an oil bath and heated to 80°C overnight with a shield in place. The following day the bomb was allowed to cool to rt and then was cooled further to —78°C in an dry ice/acetone bath. The cooled vessel was then opened and remaining ammonia was allowed to evaporate. The: resulting red solid obtained was used without further purification (306 mg, 95%). ESI-MS (m/z): Calcd. for C11H10BrN3O3S3: 407.9 (M+H); found: 408.1. 1H-NMR (CD3OD): d 8.56 (m, 1H), 8.18 (m, 1H), 8.07 (s, 1H), 2.72 (s, 3H). b) 4-(6-Amino-5-bronto-pyridine-3-sulfonyl)-5-methylsulfanyl- th ioph en e-2-carboxam idin e The procedure as in Example 20, /was followed using 4-(6-amino-5- bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid amide (14 mg, 0.03 mmol. Example 119, step a) dimethylaluminuim amide (1M, 5 mL). The reaction was stirred for 3 hours at 90 °C and TLC analysis indicated that the reaction was complete. The reaction was quenched with SiO2 and filtered. The resulting filtrate was concentrated in vacuo followed by purification by C18-HPLC (10-70% CH3CN over 30 minutes). The title compound was isolated as a white solid (4.9 mg, 39%). ESI-MS (m/z): Calcd. for C11H11BrN4O2S3: 406.9 (M+H); found: 407.1. 1H-NMR (CD3OD): d 8.54 (m, 1H), 8.26 (m, 1H), 8.15 (m, 1H), 2.74 (s, 3H). Example 120 4-(5-Bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine a) 4-(5-Bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid methyl ester A flask with 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxylic acid methyl ester (25 mg, 0.06 mrnol, Example 118, step c) and zinc dust (4 mg, 0.06 mmol) was dissolved with mL acetic acid and heated to 50°C for 4 hours. TLC analysis indicated the formation of a new spot. The reaction mixture was concentrated in vacuo and purified by elution through Celite® using 10% MeOH in DCM. The crude product was carried on without further purification. ESI-MS (m/z): Calcd. for C12H10BrNO4S3: 407.9 (M+H); found: 408.1. b) 4-(5-Bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine The procedure as in Example 20, /was followed using 4-(5-bromo- pyridine-3-sulfonyl)-5-melhylsulfanyl-thiophene-2-carboxylic acid methyl ester (5 mg, 0.01 mmol, Example 120, step a) dimethylaluminuim amide (1M, 5 mL). The reaction was stirred for 3 hours at 90 °C and TLC analysis indicated that the reaction was complete. The reaction was quenched with SiO2 and filtered. The resulting filtrate was concentrated in vacuo followed by purification by C18-HPLC (10-70% CH3CN over 30 minutes). The title compound was isolated as a white solid (4.6 mg, 92%). ESI-MS (m/z): Calcd. for C11H10BrN3O2S3: 391.9 (M+H); found: 392.1. 1H-NMR (CD3OD): d 9.14 (m, 1H), 8.97 (m, 1H), 8.55 (m, 1H), 8.34 (s, 1H), 2.76 (m, 3H). *************Example 121 4-(6-Amino-5-o-tolyl-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2- earboxamidine a) 4-(6-Amino-5-o-tolyl-pyridine-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid amide The procedure as in Example 1: step c was followed using 4-(6-amino- 5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid amide (25 mg, 0.06 mmol. Example 120: step a), o-tolyl phenyl boronic acid (33 mg, 0.25 mmol), Pd(PPh3)4 (14 mg, 0.01 mmol), aqueous Na2CO3 (2M, 0.4 mL), ethanol (0.4 mL) and toluene (0.8 mL). Purification by preparative SiO2 chromatography (25% EtOAc in hexanes) of the residue yielded the title compound (7.4 mg, 32%) as a brown solid. ES1-MS (m/z): Calcd. for C18H17N3O3S3: 420.0 (M+H); found: 420.2. b) 4-(6-Amino-5-o-tolyl-pyridine-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine The procedure as in Example 20, f was followed using 4-(6-amino-5-o- tolyl-pyridine-3-sulfonyl)-5--me1:hylsulfanyl-thiophene-2-carboxylic acid amide (7.4 mg, 0.02 mmol, Example 121, step a) dimethylaluminuim amide (1M, 5 mL). The reaction was stirred for 3 hours at 90 °C and TLC analysis indicated that the reaction was complete. The reaction was quenched with S1O2 and filtered. The resulting filtrate was concentrated in vacuo followed by purification by C18-HPLC (10-70% CH3CN over 30 minutes). The title compound was isolated as a white solid (2.6 mg, 35%). ES1-MS (m/z): Calcd, for C18H18N4O2S3: 419.0 (M+H); found: 419.1. 1H-NMR (CD3OD): d S.6 (m, 1H), 8.28 (s, 1H), 7.74 (m, 1H), 7.36 (m, 3H), 7.16 (m, 1H), 2.74 (m, 3H),2.13(m,3H). Example 122 4-(6'-Methyl-2'-morpholin-4-yl-biphenyl-3-sulfonyl)-5-methyisulfanyl- thiophene-2-carboxaniidine trifluoroacetate a) {Imino-[4-(6'-methyl-2'-morpholin-4-yl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester {[4-(2'-Amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (20 mg, 0.04 mmol, Example 25 : step c). K2CO3 (8 mg, 0.06 mmol), 2,6-lutidine (8 mg, 0.08 mmol) and 2-bromoethyl ether (18 mg, 0.08 mmol) were dissolved in acetonitrile (1 mL) and heated to 80 °C with stirring under argon. After 6 hours, Et3N (8 µL, 0.06 mmol) was added and the reaction continued stirring for 20 hours. Purification of the residue by preparative SiO2 TLC (50% EtOAc in hexanes) yielded the title compound (7.5 mg, 32%) as a yellow solid. ESI-MS (m/z): Calcd. for C28H33N3O5S3: 588.2 (M+l); found: 588.0. b) 4-(6'-Methyl-2f-morp}wlin-4-yl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate {Imino-[4-(6'-methyl-2'-morpholm-4-yl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester (7.5 mg, 0.013 mmol, Example 122 : step a) was deprotected and purified as in Example 1: step d, yielding the title compound as a clear glass (2.2 mg, 35%). 1H-NMR (CD3OD): d S.34(s, 1H), 8.02-8.05 (m, 1H), 7.94-7.92 (t, 1H, J= 1.6 Hz), 7.66-7.70 (t, 1H, J= 7.2 Hz), 7.61-7.64 (m, 1H, J= 7.9 Hz), 7.23-7.28 (t, 1H,J= 7.67 Hz), 6.98-7.05 (m, 2H), 3.13-3.27 (m, 4H), 2.71 (s, 3H), 2.63- 2.67 (m, 4H), 2.05 (s, 3H). ESI-MS (m/z): Calcd. for C23H25N3O3S3: 488.1 (M+l); found: 488.3. Example 123 4-(6-Bromo-5-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate a) 6-Bromo-5-chloro-pyridine-3-sodium sulphonate Sodium sulfite (794 mg. 6.3 mmol) and sodium bicarbonate (554 mg, 6.6 mmol) were dissolved into water (4 mL) with heat (70 °C). 6-Bromo-5- chloro-pyridine-3-sulfonyl chloride (1000 mg, 3.4 mmol) was added slowly as a solid over one hour. The reaction was heated at 70 °C for two additional hours followed by standing at RT overnight. The solvents were removed in vacuo resulting in the title compound that was used without further purification or characterization. b) 4-(6-Bromo-5-chloro-pyridine-3-sulfonyl)-5-nitro-thiophene-2- carboxylic acid methyl ester 4-Bromo-5-nitro-thiophene-2-carboxylic acid methyl ester (2.6 g, 10.2 mmol, Example 27: step c) was dissolved into DMF (15 mL) and 6-Bromo--5- chloro-pyridine-3-sodium sulphonate (946 mg, 3.4 mmol, Example 123: step a) was partially dissolved into DMF (15 mL). The solution of 4-Bromo-5- nitro-thiophene-2-carboxylic acid methyl ester was cooled to -20 °C and to this was added the solution of 6-Bromo-5-chloro-pyridine-3-sodium sulphonate, dropwise over one hour. The reaction mixture was maintained at -20 °C with stirring for 3 hours. The solvents were removed in vacuo followed by purification by flash column chromatography (Biotage Flash System - 40 M SiO2 column) (30% EtOAc in hexanes) that yielded the title compound (430 mg, 29%) as a white solid. ESI-MS (m/z): Calcd. for C11H6BrClN2O2S2: 440.9 (M+l); found: 441.1 c) 4-(6-Bromo-5-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester The procedure described in Example 27: step a was followed using 4- (6-Bromo-5-chloro-pyridine-3-sulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (63 mg, 0 14 mmol. Example 123: step b) and sodium thiomethoxide (0.5 M in EtOH, 0.18 mmol, 360 µL). The reaction was quenched with acetic acid (10 uL, 0.18 mol) followed by concentration in vacuo. The residue was then dissolved into EtOAc and washed with saturated NaHCO3 and brine solutions. The organic layers were dried (Na2SO4) and removal of the solvents in vacuo was followed by purification by preparative SiO2 TLC (30% EtOAc in hexanes) that yielded the title compound (14.2 mg, 23%) as a yellow solid. ESI-MS (m/z): Calcd. for C12H9BrClNO4S3: 441.9 (M+l) found: 442.0. d) 4-(6-Bromo-5-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoro acetate 4-(6-Bromo-5-chloro-pyridine-3-sulfonyl)-5-methylsulfany]- thiophene-2-carboxylic acid methyl ester {Example 123: step c) was then converted to the amidine and purified as described in Example 20: step f to isolate the title compound (6.4 mg, 50%). 1H-NMR (CD3OD): d: 8.97 (s, 1H), 8.66 (s, 1H), 8.33 (s, 1H), 2.76 (s, 3H). ESI-MS (m/z): Calcd. for C11H9BrClN3O2S3: 425.9 (M+l) found: 426.1. Example 124 4-(6-Amino-5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate a) 4-(6-Amino-5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester Ammonia gas was condensed with a cold finger into the Teflon core of a stainless steel bomb. Approximately 5 mL of liquid ammonia was collected and maintained at -78 °C. To this was added 4-(6-Bromo-5-chloro-pyridine- 3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (15 mg, 0.034 mmol, Example 123: step c). The reaction vessel was capped, sealed and heated to 80°C overnight protected by shield. The reaction bomb was cooled to RT then to —78°C before opening. The remaining ammonia mixture was allowed to evaporate to dryness in hood resulting in title compound and 4-(6-Amino-5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid amide (14 mg, 98%). ESI-MS (m/z): Calcd. for C12H11BrN2O4S3: 422.9 (M+l) found: 423.0. b) 4-(6-Amino-5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate The mixture of 4-(6-Amino-5-bromo-pyridine-3-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxylic acid methyl ester and 4-(6-Amino-5- bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid amide (Example 124: step a) was then converted to the amidine and purified as described in Example 20: step f to isolate the title compound (4.9 mg, 36%). H-NMR (CD3OD): d: 8.55 (s, 1H), 8.27 (s, 1H), 8.14 (s, 1H), 2.74 (s, 3H). ESI-MS (m/z): Calcd. for C11H11BrClN4O2S3: 406.9 (M+l) found: 407.1. Example 125 4-(6-Amino-5-o-tolyl-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate a) 4-(6-Amino-5-o-toly!-pyridine~3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester The procedure as in Example 1: step c was followed using 4-(6- Amino-5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid methyl ester (2.5 mg, 0.06 mmol, Example 124: step a), 2- methyl phenyl boronic acid (33 mg, 0.25 mmol), Pd(PPh3)4 (14 mg, 0.01 mmol), aqueous Na2CO3 (2M, 400 µL, 0.5 mmol), ethanol (400 uL) and toluene (800 µL). The reaction was heated to 80°C for 12 hours. The residue was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4) and removal of the solvents in vacuo was followed by preparative SiO2 TLC purification (20% MeOH in DCM) that yielded the title compound (7.4 mg, 29%) as a white solid. ESI-MS (m/z): Calcd. for C19H18N2O4S3: 420.0 (M+l) found: 420.2. b) 4-(6-Amino-5-o-tolyl-pyridine-3-sulfonyl)-5-methylsulfanyl- thiophene-2-Carboxamidine trifluoroacetate 4-(6-Amino-5-o-tolyl-pyridine-3-sulfonyl)-5-memylsulfanyl- thiophene-2-carbox.ylic acid methyl ester {Example J25: step a) was then converted to the amidine and purified as described in Example 20: step f to isolate the title compound (2.6 mg, 35%). 1H-NMR (CD3OD): d: 8.60 (s, 1H), 8.28 (s, 1H), S.14 (s, 1H), 7.74-7.73(d, 1H, J = 2.74 Hz) 7.36 (s. IK), 7.32- 7.2S (m, 1H), 7.16-7.14 (d, 1H, J= 8.14 Hz), 2.74 (s, 3H), 2.13 (s, 3H). ESI- MS (m/z): Calcd. for Ci8Hj8N4O2S3: 419.0 (M+l) found: 419.1. Example 126 4-(5-Bromo-6-phenoxy-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate a) 4-(5-Bronto-6-phenoxy-pyridine-3-sulfonyl)-5-methylmlfanyl- thiophene-2-carboxylic acid methyl ester 4-(6-Brorno-5-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxylie acid methyl ester (110 mg, 0.24 mmol, Example 123, step c), cesium carbonate (156 mg, 0.48 mmol), phenol (180 rag. 1.92 mmol), copper (II) trifluoromethanesulfonate benzene complex (4 mg, 0.006 mmol) and EtOAc (1.0 mg, 0.02 mmol) were all dissolved into toluene (10 mL) and heated to 110 °C for 12 hours. The reaction mixture was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4) and removal of the solvents in vacuo was followed by purification by flash column SiO2 (30% EtOAc in hexanes) that yielded the title compound. ESI-MS (m/z): Calcd. for C18H14BrNO5S3: 599.9 (M+l) found: 500.1. b) 4-(5-Bromo-6-phenoxy~pyridine-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoro acetate 4-(5-Bromo-6-phenoxy-pyridine-3-sulfonyl)-5-methylsulfany]- thiophene-2-carboxylic acid methyl ester (Example 126: step a) was then converted to the amidine and purified as described in Example 20: step f to isolate the title compound (1.0 mg). 1H-NMR (CD3OD): d: 8.66-8.65 (m, 1H), 8.59-8.58 (m, 1H), 8.33 (s, 1H), 7.48-7.44(m, 2H), 7.33-7.29 (r.n, 1H), 7.18- 7.15 (m, 2H), 2.76 (s, 3H). ESI-MS (m/z): Calcd. for Ci7HKBrNjO3S3: 483.9 (M+l) found: 484.1. Example 127 4-(5-Bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate a) Di-5-bromo-3-pyridyl dteulfide 2,4-dibromopyridine (2000 mg, 8.4 nimol) was dissolved into ether (1.0 mL) at RT. The reaction mixture was cooled to -78°C and n-butyllithium (2.5M, 3.4 mL, 8.4 mmol) was added dropwise. The reaction was stirred at - 78°C for an hour followed by quenching with sulfur (269 mg, 8.4 mmol). The reaction was allowed to warn to RT over 2 hours. Removal of the solvents in vacuo was followed by purification by flash column SiO2 (30% EtOAc in hexanes). The product was used without further characterization or purification. b) 4-(5-Bromo-pyridin-3-ylsulfanyl)-5-nitro-thiophene-2-carhoxylic acid methyl ester Di-5-bromo-3-pyridyl disulfide (600 mg, 1.6 mmol, Example 127:step a), Et3N (223 uL, 1.6 mmol), triphenylphosphine (419 mg, 1.6 mmol) and 4- Bromo-5-nitro-thiophene-2-carboxylic acid methyl ester (427 mg, 1.6 mmol, Example 114: step c) were dissolved into THF (5 mL) and stirred at RT for 3 days. Removal of the solvents in vacuo was followed by flash column SiO2 purification (25% EtOAc in hexanes) to isolate the title compound (200 mg, 33%). ESI-MS (m/z): Calcd. for C11H7BrN2O4374.9(M+1) found: 377.1. c) 4-(5-Bromo-pyridine-3-sulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester 4-(5-Bromo-pyridin-3--ylsulfanyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (126 mg, 0.33 mmol, Example 127:step b) and m-CPBA (438 mg, 1.67 mmol, 77%) were dissolved into DCM (10 mL) and heated to 38°C with stirring for 2 hours. The reaction was quenched with Na2S2O3, dissolved into DCM and washed with NaHCO3. The organic layers were dried (MgSO4) and the solvents were removed in vacuo followed by flash column SiO2 purificeition (25% EtOAc in hexanes) to isolate the title compound (151 mg, 99%) as a yellow solid. ESI-MS (m/z): Calcd. for C11H7BrN2O6S2: 406.9 (M+l) found: 407.1 d) 4-(5-Brom o-pyridin e-3-sulfonyl)-5-m ethylsulfanyl-th ioph en e-2- carboxylic acid methyl ester The procedure described in Example 27: step a was followed using 4- (5-Bromo-pyridine-3-sulfonyl)-5-mtro-thiophene-2-carboxylic acid methyl ester (151 mg, 0.37 mmol, Example 127: step c) and sodium thiomethoxide (1.0 M in EtOH, 26.3 mg, 0.37 mmol). The reaction was quenched with acetic acid (21 uL, 0.37 mol) and the solvents were removed in vacuo. The residue was then dissolved into EtOAc and washed with saturated NaHCO3 and brine solutions. The organic layer was dried (Na2SO4) and removal of the solvents in vacuo was followed by purification by flash column chromatography SiO2 (30% EtOAc in hexanes) to yield the title compound. ESI-MS (m/z): Calcd. for C12H10BrNO4S3: 407.9 (M+l) found: 408.1. e) 4-(5-Bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate 4-(5-Bromo-p;/ridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid methyl ester {Example 127: step d) was then converted to the amidine and purified as described in Example 20: step f to isolate the title compound (2.7 mg). 1H-NMR (CD3OD): d: 9.15 (m, 1H), 9.00 (m, 1H), 8.58 (m, 1H), S.35(s, 1H), 2.77 (s, 3H). ESI-MS (m/z): Calcd. for C11H10BrN3O2S3: 391.9 (M+l) found: 392.2. Example 128 5-Methylsulfanyl-4-(5-o-tolyl-pyridine-3-sulfonyl)-thiophene-2- Carboxamidine trifluoroacetate a) {[4-(5-Bromo-pyridin e-3-sulfonyl)-5-m ethylsulfanyl-thiophen -2-yl]- imino-methylj-carbamic add tert-butyl ester 4-(5-Bromo-pyridine-3-!3ulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine (300 mg, 0.77 mmol, Example 127:step e) was dissolved mto DMF (10 mL). To this was added DIEA (267 ul mg, 1.53 mmol) and (Boc)2O (201.6, 0.92 mmol). The reaction was stirred at RT for 12 hours. The solvents were removed in vacuo and the residue was dissolved into DCM and washed with 20% citric acid and brine. The organic layers were dried (MgSO/t) and the solvents were removed in vacuo followed by purification by flash column chromatography SiO2 (50% EtOAc in hexanes) that resulted in the title compound. ESI-MS (m/z): Calcd. for C16H18BrN3O4S3: 491.9 (M+l) found: 491.1. b) {Imino-[5-methylsulfanyl-4-(5-o-tolyl-pyridine-3-sulfonyl)-thiophen- 2-yl]-methyl}-carbamic acid tert-bntyl ester The procedure described in Example 1: step c was followed using {[4- (5-Bromo-pyridine-3-sulfonyl)-5-methylsulfany]-thiophen-2-yl]-imino- methyl}-carbamic acid tent-butyl ester (50mg, 0.08 mmol), 2-methyl phenyl boronic acid (23 mg, 0.17 minol), Pd(PPh3)4 (19 mg, 0.02 mmol), aqueous Na2CO3 (2M, 800 µL, 0.4 mmol), ethanol (800 µL) and toluene (1600 µL). The reaction was heated to 80°C for 12 hours. The residue was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4) and removal of the solvents in vacua resulted in a crude mixture of the product that was used without further purification or characterization. c) 5-Methylsulfanyl-4-(5-o-tolyl-pyridine-3-sulfonyl)-thiophene-2- carboxamidine trifluoroacetate {Imino-[5-methylsulfanyl-4-(5-o-tolyl-pyridine-3-sulfonyl)-thiophen- 2-yl]-methyl}-carbamic acid tert-butyl ester (127 mg. Example! 28: step b) was deprotected and purified as in Example 1: step d, yielding the title compound as an off-white solid (8 mg, 8 %). 1H-NjVIR (CD3OD): d 9.15 (s, 1H), 8.84 (s, 1H), 8.37 (rn, 2H), 8.36 (m, 4H), 2.75 (s, 3H), 2.56 (s, 3H). ESI- MS (m/z): Calcd. for C18H17BrN3O2S3: 404.1 (M+l); found: 404.1 EXAMPLE 129 4-(2'-Formylamino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsuifanyl- thiopherie-2-carboxamidine trifluoroacetate {[4-(2'-Amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-immo-methyl}-carbamicacid tert-butyl ester (5S mg, 0.11 mmol, Example 25 : step c) was dissolved into formic acid (3mL, 96%) and heated to 100 ° C for 24 hours. The solvents were removed in vacuo resulting in the desired product with removal of the tert-butyl protection group. The resulting compound was purified as in Example 1: step d, yielding the title compound as an off-white solid (11 mg, 22%). ESI-MS (m/z): Calcd. for C20H19N3O3S3: 446.1 (M+l); found: 446.1. Example 130 [3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl- biphenyl-2-ylamino]-acetic acid {[4-(2'-Ammo-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-immo-methyl}-carbamic acid tert-butyl ester (75 mg, 0.15 mmol, Example 25 : step c), tert-butyl bromoaeetate (43 µL, 0.29 mmol), -potassium carbonate (29 mg, 0.21 mmol) and 2,6-lutidine (33 µL, 0.29 mmol) were dissolved into toluene (2mL). The reaction was stirred and heated to 80 °C for 12 hours. Et3N (41 pL, 0.3 mmol) was added to reaction and heated to 80 °C for another 12 hours. The reaction mixture was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4), the solvents were removed in vacua followed purified by preparative SiO2 TLC purification (20% MeOH in DCM) resulting in {3'-[5-(tert- Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]- 6-methyl-biphenyl-2-ylamino}-acetic acid tert-butyl ester. ESI-MS (m/z): Calcd. for C30H37N3O6S3: 632.2 (M+l) found: 631.9. {3'-[5-(tert- Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]- 6-methyl-biphenyl-2-ylamino} -acetic acid tert-butyl ester was deprotected and purified as Example 1: step d, yielding the title compound as brown solid (1.7 mg). 1H-NMR (CD3OD): d 8.35 (s, 1H), S.08-8.06 (d, 1H, J= 8.83 Hz), 7.77 (t, 1H, .7=7.44 Hz, .7=7.67 Hz), 7.63-7.61 (d, 1H,J= 7.67 Hz), 7.16 (t, 1H,J = 7.91 Hz, J= 7.91 Hz), 7.05-6.68 (d, 2H, 7= 7.67 Hz), 6.52-6.50 (d, 1H, J = 8.14 Hz), 3.81 (s, 1H), 2.72 (s, 3H), 2.17 (s, 3H). ESI-MS (m/z): Calcd. for C21H21N3O4S3: 476.1 (M+l); found: 476.1. Example 131 {2-[5-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfony])-pyridin-3- yl]-3-methyl-benzyIoxy} -acetic acid a) 2-lodo-i-methyl-benzoyl chloride 2-iodo-3-methyl benzoic acid (1310 mg, 5 mmol) and thionyi chloride (730 uL, 10 mmol) were dissolved into THF (10 mL) and stirred at RT for 4 days. The solvents were removed in vacua and the resulting residue was dissolved into EtOAc, washed with brine. The combined organic layers were dried (MgSO4) and the solvents were removed in vacuo resulting in an oil that was used without further purification or characterization. b) (2-Iodo-3-methyl-phenyl)-methanol 2-Iodo-3-methyl-benzoyl chloride (1360 mg, 4.86 mmol. Example 131: a) was dissolved into THF (2 mL) and cooled to -78 °C. To this was slowly added a slurry of lithium aluminum hydride (184.3 mg, 4.86 mmol) that was carefully weighed into a dry flask and cooled to 78 °C, before THF (2 mL) was added. The reaction was warmed to RT slowly and stirred for an hour. The reaction was quenched by cooling back to —78 °C and adding 200 µL water. 200 µL 15% NaOH, 600 µL water and then poured over celite and filtered with THF. The title compound was obtained as a yellow solid. 1H- NMR (CDCl3): d 7.21-7.19 (m, 2H), 7.14-7.11 (m, 1H,), 4.61 (s, 2H), 2.43 (s, 3H). c) (2-Iodo-3-methyl-benzyloxy)-acetic acid tert-butyl ester (2-Iodo-3-methyl-phenyl)-methanol (1608 mg, 6.8 mmol, Example 131: step b) was dissolved into DMF (10 mL). The solution was cooled to 0°C. To this was added sodium hydride in one portion and the reaction continued to stir at 0 °C for 30 minutes. To the cooled solution was added t- butylbromoacetate (1.3 mL, 8.9 mmol) and then the reaction was wanned to RT and then heated to 50 °C for 4 hours. The solvents were removed in vacuo and the resulting residue was dissolved into EtOAc and washed with brine. The combined organic layers were dried (MgSO4) and the solvent was removed in vacuo resulting in the title compound (1.29 g, 53%) that was used with out further purification. 1H-NMR (CDCl3): d 7.28-7.13 (m, 3H), 4.63 (s, 2H), 4.07 (s, 2H), 2.44 (s? 3H), 1.47 (s, 9H). d) [3-Methyl-2-(4,4,S,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- benzyloxy]-acetic acid tert-butyl ester (2-Iodo-3-methyl-benzyloxy)-acetic acid tert-butyl ester (360 mg, 1.46 mmol, Example 131: step c), trans- Dichlorobis(triphenylphosphine)palladium(II) (102 mg, 0.15 mmol) and Et3N (1.2 mL, 8.76 mmol) were dissolved into dioxane (10 mL). To this was slowly added 4.4,4,5,5,5-tetrarnethyldioxaborolane (423 µL, 2.91 mmol) and reaction was heated to 80 °C for 2 hours. Catalytic amounts of 4,4,4,5,5,5- tetramethyldioxaborolane and dichlorobis(triphenylphosphine)palladium(II) were added and the reaction continued heating at 50 °C overnight. The solvents were removed in vacuo and the residue was dissolved into EtOAc followed by washing with brine. The combined organic layers were dried (MgSO4) and the solvents were removed in vacuo. The crude reaction mixture was purified by flash column chromatography (30% EtOAc/hexanes) yielding the title compound (335 mg, 63 %) as a brown oil. 1H-NMR (CDCl3): d 7.23- 7.06 (m, 3H), 4.72 (s, 2H), 4.09 (s, 2H), 2.42 (s, 3H), 1.45 (m, 12H), 1.38 (s, 9H). e) (2-{5-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl- thiophene-3-sulfonyl]-pyridin-3-yl}-3-methyl-benzyloxy)-acetic acid tert- butyl ester The procedure as in Example 1: step c was followed using [3-Methyl- 2-(4,4,5,5-tetramethyl-[l,3.2]dioxaborolan-2-yl)-benzyloxy]-acetic acid tert- butyl ester (252.2 mg, 0.62 mmol, Example]31: step d), {[4-(5-Bromo- pyridine-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}- carbamic acid tert-butyl ester (75.9 mg, 0.15 mmol. Example 128: step a), Pd(PPh3)4 (35 mg, 0.03 mmol), aqueous Na2CO3 (2M, 1 mL), ethanol (1 mL) and toluene (2 mL). The reaction was heated to 80°C for 24 hours. The reaction mixture was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4) and removal of the solvents in vacuo was followed by purification by flash column chromatography (SiO2) (30% EtOAc in hexanes) of the residue yielded the title compound (460 mg) as a brown oil. ESI-MS (ni/z): Calcd. for C30H37N3O7S3: 648.2 (M+l) found: 647.9. j) {2-[5-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)- pyridin-3-yl]-3-methyl-benz.yloxy}-acetic acid (2-{5-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl- thiophene-3-sulfonyl]-pyridin-3-yI} -3-methyl-benzyloxy)-acetic acid tert- butyl ester (127 mg) {Example 11: step e) was deprotected and purified as in Example 1: step d, yielding the title compound as an off-white solid. 1H- NMR (CD3OD): S 9.05 (s, 1H), 8.65 (s, 1H), 8.26 (m, 1H), 8.19 (s, 1H), 7.28- 7.24 (m, 3H), 4.12 (s, 2H), 3.67 (s, 2H ), 2.63 (s, 3H), 1.92 (s, 3H). ESI-MS (m/z): Calcd. for C21H21N3O5S3: 492.1 (M+l); found: 492.1. Example 132 N-[3(-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl- biphenyl-2 -yl] -malonamic acid a) N-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-malonamic acid methyl ester {[4-(2'-Amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-rnethyl}-carbamic acid tert-butyl ester (22 mg, 0.04 mmol, Example 25: step c ) was dissolved into THF (lmL) and to this was added chlorocarbonyl-acetlc acid methyl ester (9 µL, 0.085 mmol). The reaction was heated to 50°C for 5 hours and then allowed to stir at RT for 48 hours. The reaction mixture was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4) and removal of the solvents in vacuo was followed by purification by preparative TLC (SiO2) (30% EtOAc in hexanes) that yielded the title compound. ESI-MS (m/z): Calcd. for C28H31N3O7S3: 618.1 (M+l) found: 617.9. b) N-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3sulfonyl]-6-methyl-biphenyl-2-yl}-malonamic acid N-{3'-[5-(tert-Butoxycarbonylammo-immo-methyl)-2-methylsulfanyl- thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-malonamic acid methyl ester (20 mg, 0.03 mmol, Example 132: step a) and NaOH (1M, 90 µL, 0.09 mmol) were dissolved into MeOH (1.5 mL). The reaction was stirred for 2 hours. LiOH (1.0 mg, 0.05 mmol) was added and the reaction was stirred at RT overnight. The solvents were removed in vacuo and used with out further purification in the next step. ESI-MS (m/z): Calcd. for C27H29N3O7S3: 604.1 (M+l); found: 504.0 (loss of boc). c) N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6- methyl-biphenyl-2-yl]-malonamic acid N-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl- thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-malonamic acid (Example 132: step b) was deprotected and purified as in Example 1: step d, yielding the title compound as a glassy solid. 1H-NMR (CD3OD): d 8.28 (s, 1H), 8.07- 8.05 (m, 1H), 7.85 (s, 1H), 7.72-7.68 (t, 1H, J = 7.67 Hz, J= 7.90 Hz), 7.57- 7.55 (m, 1H), 7.43-7.26 (m, 3H), 2.74 (s, 3H ), 2.07 (s, 3H), 2.05 (s, 2H). ESI- MS (m/z): Calcd. for C22H21N3O5S3: 504.1 (M+l); found: 503.9. Example 133 N-[3'-(5-Carbamiinicloy]-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl- biphenyl-2-yl]-succinamic acid trifluoroacetate a) N-{3'-[5-(tert-Butoxycarbonylamino-immo-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-succinamic acid ethyl ester {[4-(2'-Amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid teit-butyl ester (38.5 mg, 0.07 mmol, Example 25: step c) and 3-chlorocarboriyl-propionic acid ethyl ester (13 µL 0.09 mnioi) were dissolved into THF (1 mL) and heated to 50 °C for one hour. The reaction was dissolved into EtOAc and washed with brine. The combined organic layers were dried, (MgSO4) and the solvents were removed in vacuo. Purification by preparative TLC (30% EtOAc/hexanes) yielded the title compound. ESI-MS (m/z): Calcd. for C30H35N3O7S3: 646.2 (M+l); found: 645.8. b) N{3'-[5-(tert-Butoxycatbonylamino-imino-met/iyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphe}iyl-2-yl}-succinamic acid N-{3'-[5-(tert-Butoxycarbonylammo-immo-methyl)-2-methyl5uifanyl- thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-succinamic acid ethyl ester {Example 133: step a) and LiOH were dissolved into MeOH and stirred at RT for 2 hours. The solvents were removed in vacua yielding the title compound that was used with out further purification or characterization. c) N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6- methyl-biphenyl-2-yl]-maionamic acid triflnoroacetate N-{3'-[5-(tert-Butoxycarbonylamino-imino-met.hyl)-2-methylsulfaiwl- thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-succinamic acid {Example 133: step c) was deprotected and purified as in Example 1: step d, yielding the title compound as a white solid. 1H-NMR (CD3OD): d 8.31 (s, 1H), S.07-8.05 (m, 1H), 7.85 (s, 1H), 7.72-7.68 (t, 1H, J= 7.67 Hz, J= 7.90 Hz), 7.56-7.53 (m, 1H), 7.37-7.35 (t, 1H, J= 7.67 Hz, J= 7.67 Hz), 7.29-7.21 (m, 1H), 3.36 (s, 4H), 2.74 (s, 3H), 2.09 (s, 3H). ESI-MS (m/z): Calcd. for C23H23N3O5S3: 518.1 (M+l); found: 518.1. Example 134 4-(4l-Amino-2'-chloro-6'-me1.hyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate a) {[4-(2'-Chloro-6'-methyl-4'-mtro-bip1ienyl-3-sulfony1)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester 2-Bromo-l-chloro-3-methyl-5-nitro-benzene (45 mg, 0.219 mmol), {[4-(3-Boranyl-dihydroxy-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]- imino-methyl}-carbamic acid tert-butyl ester (50 mg, 0.11 mmol, Example 140: step a) and Pd(PPh3)4 (25 mg, 0.02 mmol) were combined in aqueous Na2CO3 (2M, 500 µL), ethanol (500 µL) and toluene (1 mL). The reaction was heated to S0°C overnight. The resulting residue was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4) and the solvent was removed in vacuo followed by preparative TLC purification (30% EtOAc/hexanes) that yielded the title compound (20mg, 29%). ESI-MS (m/z): Calcd. for C24H24CIN3O6S3: 5S2.1 (M+l); found: 582.1. b) {[4-(4'-Amino-2'-chloro-6'-methyl-biphenyl-3-sulfonyl)-5- nietliylsulfanyl-thiophen-2-yl)-imino-methyl}-carbamic acid tert-butyl ester {[4-(2'-Chloro-61-methyl-4'-nitro-bipheny]-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (20 mg, 0.034 mmol, Example 134: step a) was dissolved into EtOH (2 mL). To this was added ammonium chloride (18 mg, 0.34 mmol) dissolved into water (4 mL). The reaction was heated to 50°C and iron (9.6 mg, 0.34 mmol) was added. The reaction was then heated to 80°C for 12 hours followed by filtration through celite with methanol and EtOAc. The solvents were removed in vacuo resulting in desired product that was used with out further purification or characterization. c) 4-(4'-Amino-2'-chloro-6'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate {[4-(4'-Amino-2'-chloro-6'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester {Example 134: step b) was deprotected and purified as in Example 1: step d, yielding the title compound as a dark yellow solid. 1H-NMR (CD3OD): d 8.33 (s, 1H), 8.03-8.00 (m, 1H), 7.85-7.84 (m, 1H), 7.70-7.66 (t, 1H, J = 7.67 Hz, J= 7.67 Hz), 7.54-7.52 (m, 1H), 6.94 (s, 1H), 6.84 (m, 1H), 2.70 (s, 3H), 1.99 (s, 3H). ESI-MS (m/z): Calcd. for C19H18N3O2S3: 452.0 (M+l); found: 452.1. Example 135 N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-chloro-6- methyl-biphenyl-2-yl]-4-methanesulfonyl-butyramidetrifluoroacetate a) 4-Brom o-3-methyl-5-nitro-phenylamin e (4-Bromo-3-methyl-5-nitro-phenyl)-carbainic acid tert-butyl ester (1000 mg, 2.9 mmol) was dissolved into DCM (10 mL). To this was added TFA (10 mL) and the reaction was stirred at RT for 1 hour. The pH was adjusted to 8 with 1 N NaOH and the solvents were removed in vacuo. The reaction mixture was dissolved into EtOAc and the layers were separated. The organic layers were dried (MgSO4) and the solvents were removed in vacuo resulting in title compound (756 mg, quantitative) as a brown oil. 1H-NMR (CDCl3): d 8.44 (s, 1H), 8.02 (s, 1H), 7.61 (s, 1H), 3.05 (s, 3H). b) 2-Brom o-5-chIoro-l-m ethyl-3-n itro-benzen e A 3-neck flask fitted with septa, addition funnel and condenser was charged with t-butylnitrite (966 µ, 8.12 mmol) and copper (II) chloride (1090 mg, 8.12 mmol) in acetonitrile (10 mL). 4-Bromo-3-methyl-5-nitro- phenylamine (756 mg, 4.06 mmol, Example 135: step a) was dissolved in acetonitrile (6 mL) and added slowly through the addition funnel while heating to 60°C. The reaction was quenched with EtOAc and washed with water. The organic layers were dried (MgSO4) and the solvents were removed in vacuo resulting in the title compound as a brown solid (721 mg, 72%). 1H- NMR (CDCl3): d 7.54 (d, 1H, J= 2.33), 7.44 (d, 1H, J = 2.56 Hz), 2.55 (s, 3H). c) 2-Bromo-5-chloro-3-methyl-pheuylamine 2-Bromo-5-chloro-l-methyJ-3-nitro-benzene (721 mg, 3.5 rrunol, Example 135: step b) was dissolved into EtOH (6 mL). To this was added ammonium chloride (1.9 g, 35 mmol) dissolved into water (10 mL). The reaction was heated to 50°C, iron (9.6 mg, 0.34 mmol) was added and the reaction was then heated to 80°C for 12 hours. The reaction mixture was filtered through celite, washed with methanol and EtOAc and the solvents were removed in vacua. The residue was dissolved into EtOAc and washed with brine to remove salts. The organic layers were dried (MgSO4) and the solvents were removed in vacuo resulting in the title compound (595 mg, 78%) as a brown solid. 1H-NMR (CDCl3): d 6.63-6.61 (m, 2H), 2.33 (s, 3H). d) 5-Chloro-3-methyl-2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- phenylamine 2-Bromo-5-chloro-3-methyl-phenylamine (595 mg, 2.7 mmol, Example 135: step c), Pd(OAc)2 (30.3 mg, 0.14 mmol), 2- (dicyclohexylphosphino)biphenyl (189.2 mg, 0.54 mmol) and Et3N (1.5 mL, 10.8 mmol) were dissolved into dioxane (10 mL). To this was added 4,4,5,5- Tetramethyl-[l,3,2]dioxaborolane (1.2 mL, 8.1 mmol) slowly. The reaction was heated to 80°C overnight. The solvents were removed in vacuo and the resulting residue was dissolved into EtOAc amd washed with brine. The combined organic layers were dried (MgSO4) and removal of the solvents in vacuo resulted in a mixture of the title compound and 3-Methyl-2,5-bis- (4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenylamine were obtained and used with out further purification. e) {[4-(2'-Amino-4'-chloro-6'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester The procedure as in Example 1: step c was followed 5-Chloro-3- methyl-2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenylamine (663 mg, 2.5 mmol, Example 135, step d), {[4-(3-Bromo-benzenesulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (1.2 g, 2.5 mmol, Example 27: step c), Pd(PPh3)4 (577 mg, 0.5 mmol), aqueous Na2CO3 (2M, 10 mL), ethanol (10 mL) and toluene (20 mL). The reaction was heated to 80°C for 24 hours. The reaction mixture was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4) and removal of the solvents in vacuo was followed by purification by flash column chromatography (SiO2) (30% EtOAc in hexanes) that yielded the title compound as a brown oil. ESI-MS (m/z): Calcd. for C24H26CIN3O4S3: 552.1 (M+l) found: 551.7. f) ({4-[4'-Chloro-2'-(4-methanesulfonyl-butyrylamino)-6'-methyl- biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)- carbamic acid tert-butyl ester {[4-(2'-Amino-4'-chloro-6l-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (120 mg, 0.22 mmol, Example 135, e) and Et3N (0.91 µL, 0.65 mmol) were dissolved into DCM (4 mL). To this was added (4-Methanesulfonyl-butyryl chloride (0.144 M, 3.1 mL, 0.44 mmol, Example 209: a) and the reaction was stirred at RT overnight. The solvents were removed in vacuo followed by purification by flash column, chromatography (20% EtOAc/hexanes) that yielded the title compound as an orange solid (124 mg, 81%). ESI-MS (m/z): Calcd. for C29H34CIN3O7S4: 700.1 (M+l) found: 700.1. g) N-[3'-(5-Carbamimidoyl-2-methyhulfanyl-thiophene-3-sulfonyl)-4- chloro-6-methyl-biphenyl-2-y!]-4-methanesulfonyl-butyramide trifluoroacetate ({4-[4'-Chloro-2'-(4-methanesuIfonyl-butvrylamino)-6'-methyl- biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-iinino-methyl)- carbamic acid tert-butyl ester (124mg, 0.18 mmol, Example 135: step/) was deprotected and purified as in Example 1: step d, yielding the title compound as a clear glass (70 mg, 65%). 1H-NMR (CD3OD): d 8.32 (s, 1H), 8.08-8.06 (d, 1H, 7 = 10.00 Hz), 7.87 (m, 1H), 7.71 (t, 1H, J= 7.91 Hz, J= 8.61 Hz), 7.56-7.54 (d, 1H, J= 9.07), 7.33 (m, 2H), 2.92 (s, 3H), 2.85 (t, 2H, J = 7.91 Hz, J= 7.67 Hz), 2.73 (s, 3H), 2.21 (t, 2H, J= 5.35 Hz, J = 7.91 Hz), 2.07 (s, 3H), 1.82-1.73 (m, 2H). ESI-MS (m/z): Calcd. for C24H26CIN3O5S4: 600.1 (M+l); found: 600.1. Example 136 4-[4'-(N'-Hexyl-guanidino)-2'-methyl-biphenyl-3-sulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate a) ({4-/4'-(3-Hexyl-thioureido)-2'-methyl-biphenyl-3-sulfonyl]-5- methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester 4-(4'-Amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine (26 mg, 0.05 mmol, Example 220: step b) was dissolved into EtOH. To this was added hexylisothiocyanate (30µL) and the reaction was heated for 4 hour at S0°C. The solvent was removed in vacuo and the reaction was purified by preparative TLC resulting in the title compound that was used without further purification or characterization. b) ({4-[4'-(N'-Hexyl-guanidino)-2'-methyl-biphenyl-3-sulfonyl]-5- methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester ({4-[4'-(3-Hexyl-thioureido)-2'-methyl-biphenyl-3-sulfonyl]-5- methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbanric acid tert-butyl ester (33 mg, .14 mrnol. Example 136: step a) was dissolved into ammonia in methanol (2.0 M, 4 mL). To this was added mercury (II) oxide (33.9 mg, 0.16 mmol) and the reaction stirred at RT for 2 hours. Additional mercury (II) oxide (154 mg, 0.08 mmol) was added and the reaction was heated to 40°C overnight. The reaction was filtered with 0.2 µM disk and washed with EtOAc followed by removal of solvents in vacua that yielded the title compound which was used without further purification (30 mg). ESI-MS (m/z): Calcd. for C31H41N5O4S3: 644.2 (M+l); found: 644.1. c) 4-[4'-(N'-Hexyl-guanidino)-2'-methyl-biphenyl-3-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate ({4-[4'-(N'-Hexyl-guanidino)-2'-methyl-biphenyl-3-sulfonyl]-5- methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert--butyl ester (30 mg, Example 136: step b) was deprotected and purified as in Example 1: step d, yielding the title compound as a yellow glass (11.5 mg, 43%). H- NMR (CD3OD): d 8.34 (s, 1H), 8.03-8.00 (m, 2H), 7.73-7.67 (m, 2H), 7.33- 7.31 (m, 1H), 7.24-7.18 (m, 2H), 3.63 (m, 2H), 2.72 (s, 3H), 2.27 (s, 3H), 1.69-1.62 (m, 2H), 1.44-1.33 (m, 6H). ESI-MS (m/z): Calcd. for C26H33N5O2S3: 544.2 (M+l); found: 544.1. Example 137 5-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl- biphenyl-2-ylcarbamoyl]-pentanoic acid trifluoroacetate a) 5-{3'-[5-(tert-Butoxycarbonylam in o-im in o-m ethyl)-2-m ethylsulfanyl- thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylcarbamoyl}-pentanoic acid methyl ester {[4-(2'-Amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (100 mg, 0.19 mmol, Example 25 : step c) was dissolved into THF (3 mL). To this was added 5-Chlorocarbonyl-pentanoic acid methyl ester (41.5 mg, 0.23 mmol) and the reaction was stirred at RT for 2 hours. The reaction was dissolved into EtOAc and washed with brine. The combined organic layers were dried (MgSO4) followed by removal of solvents in vacuo resulted in the title compound that was used without further purification. ESI-MS (m/z): Calcd. for C31H37N3O7S3: 660.2 (M+l); found: 660.8. b) 5-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl- thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylcarbantoyl}-pentanoic acid 5-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl- thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylcarbamoyl}-pentanoic acid methyl ester (125 mg, 0.19 mmol, Example 137: step a) and LiOH (12.5 nag, 0.54 mmol) were dissolved into MeOH (3 mL) and heated to 60°C for 12 hours. The reaction was dissolved into EtOAc and washed with 20 % citric acid. The aqueous layers were acidified with acetic acid (pH 3) and extracted with EtOAc. The organic layers were combined and dried (MgSO4) followed by removal of solvents in vacuo. The resulting material was purified by preparative RP -HPLC (0-100% water/acetonitrile - both solvents were free of TFA, 45 minutes, ? = 245 ran). 1H-NMR (CDCl3): d 7.95-7.93 (d, 1H, i = 9.3 Hz), 7.81-7.78 (d, 1H, J - 7.91 Hz), 7.63-7.59 (m, 1H), 7.55-7.53 (t, 1H, J = 8.35, Hz, J = 7.59 Hz), 7.38-7.36 (d, 1H, J = 9.35 Hz), 7.25-7.21 (m, 1H), 7.07-7.05 (d, 1H, J - 7.07 Hz), 6.78 (s, 1H), 3.55 (s, 2H), 2.51 (s, 3H), 2.15- 2.12 (m, 2H), 1.96-1.95 (m, 2H), 1.93 (s, 3H). c) 5-[3'-(5-Carbammimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6' methyl-biphenyl-2-ylcarbamoyl]-pentanoic acid trifluoroacetate 5-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl- thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylcarbamoyl}-pentanoic acid (Example 137: step b) was depirotected and purified as in Example 1: step d, yielding the title compound as a white glass. 1H-NMR (CD3OD): d S.29 (s, 1H), 8.06-8.04 (m, 1H), 7.89 (s, 1H), 7.68 (t, 1H, J = 7.67 Hz, J = S.S4 Hz), 7.54-7.52 (d, 1H, J = 7.91 Hz), 7.38-7.29 (m, 2H), 7.18-7.16 (d, 1H, J = 7.67 Hz), 2.75 (s, 3H), 2.11-2.09 (m, 2H), 2.08 (s, 3H), 2.03 - 1.91 (m, 2H), 1.27- 1.08 (m, 4H). ESI-MS (m/z): Calcd. for C25H27N3O5S3: 546.1 (M+l); found: 546.1. Example 138 4-[3-(3-Methyl-pyridin-4-yl)-benzenesulfbnyl]-5-methylsulfanyl-thiophene-2- carboxamidine trifiuoroacetate a) 4-Bromo-3-methyl-pyridin~l~ol Acetyl bromide (5 mL) was cooled to 0°C. To this was added 4-Nitro- 3-methyl-pyridin-1-ol (1000 mg, 6.48 mmol) portionwise while maintaining temperature. After the addition was complete, the reaction was heated to 50°C and stirred for 2 hours. The reaction was then cooled to 0°C, quenched with ice and neutralized with solid Na2CO3 (pH = 8). The neutral aqueous reaction mixture was extracted into DCM. The organic layer was dried (MgSO4), the solvents were removed in vacuo resulting in the title compound as a yellow solid (1.05 mg, 86%). ESI-MS (m/z): Calcd. for C6H6BrNO: 188.0 (M+l); found: 188.0. b) 4-Bromo-3-methyl-pyridine 4-Bromo-3-methyl-pyridin-l-ol (1050 mg, 5.6 mmol, Example 138: step a) was dissolved into DCM (10 ml.) and cooled to -20°C. To this was slowly added PCl3 and the reaction was stirred at -20°C for 15 minutes. The reaction was then warmed to RT for 15 minutes. The reaction was then quenched with water (5mL) after cooling back to -20°C. The reaction was then warmed to RT and quenched with NaOH (246 mg. 1.1 mmol) in water (5mL). The reaction mixture was separated and the organic layers were washed with brine. The water layer was adjusted with 10N NaOH to pH = 10. The aqueous layer was then extracted with DCM and EtOAc, all organic layers were combined and dried with (MgSO4) and the solvents were removed in vacuo. 1H-NMR (CDCl3): d 8.26 (s, 1H), 8.08-8.06 (d, 1H, J == 5.14 Hz), 7.30-7.29 (d, 1H, J = 5.35 Hz), 2.21 (s, 3H). c) (Imino-{4-[3-(3-m ethyl-pyridin -4-yl)-benzenesulfonyl]-5- methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester 4-Bromo-3-methyl-pyridine (100 mg, 0.219 mmol, Example 138: step b), {[4-(3-Boranyl-dihydroxy-benzenesulfonyl)-5-methylsulfanyl-thiophen-2- yl]-imino-methyl}-carbamic acid tert-butyl ester (266 mg, 0.58 mmol, Example 140: step a) and Pd(PPh3)4 (134 mg, 0.12 mmol) were combined in aqueous Na2CO3 (2M, 2 mL), ethanol (2 mL) and toluene (4 mL) and heated to 80°C overnight. The reaction mixture was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4) and the solvent was removed in vacuo. Purification by flash column chromatography (10% DCM/MeOH) afforded the title compound (120mg, 41%). ESI-MS (m/z): Calcd. for C23H25N3O4S3: 504.1 (M-l); found: 503.7. d) 4-[3-(3-Methyl-pyridin-4-yl)-benzenesulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidin e trifluoroacetate (Imino-{4-[3-(3-methyl-pyridin-4-yl)-benzenesulfonyl]-5- methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester (Example 138 : step c) was deprotected and purified as in Example 1: step d, yielding the title compound as a white glass. 1H-NMR (CD3OD): d 8.85 (s, 1H), 8.78-8.76 (d, 1H, J = 5 78 Hz), 8.38 (s, 1H), 8.24-8.21 (m, 2H), 7.92-7.84 (m, 3H); 2.75 (s, 3H), 2.47 (s, 3H). ESI-MS (m/z): Calcd. for C18H17N3O2S3: 404.1 (M+l); found: 404.1. Example 139 4-[3-(3-Amino-5-methyl-pyridin-4-yl)-benzenesulfonyl]-5-methylsulfanyl- thiophene-2-Carboxamidine trifluoroacetate a) (5-Methyl-pyridin-3-yl)-carbamic acid tert-butyl ester 5-Methyl-nicotinic acid (2g, 14.6 mmol) was dissolved into t-Butanol (59 mL). To this was added N,N-Diisopropylethylamine (7.6 mL, 43.8 mmol) and diphenylphosphoryl azide (3.8 mL, 17.5 nrniol). The reaction was heated to 80°C overnight in a flask fitted with septa and argon gas line. The solvents were evaporated in vacuo arid the resulting residue was dissolved into EtOAc, washed with saturated NaHCO3 and water. The combined organic layers were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash column chromatography (SiO2) (50% EtOAc in hexanes) that yielded the title compound as a white solid (2.03 g, 67%). 1H-NMR (CDCl3): d 8.22 (m, 1H), 8.14 (m, 1H), 7.88 (br s, 1H), 6.58 (br s, 1H), 2.34 (s, 3H), 1.55 (s,9H). b) (4-Iodo-5-methyl-pyridin-3-yl)-carbamic acid tert-butyl ester (5-Methyl-pyridin-3-yl)-earbamic acid tert-butyl ester (255 mg, 1.2 mmol, Example 139: step a) and trimethylethylenediamine (905 µL, 6.0 mmol) v/ere dissolved into THF (4 mL) and cooled to -78 °C. To this was added n-Butyllithium (2.5M, 2.4 mL, 6.0 mmol). The reaction was stirred at - 78°C for 30 minutes and then warmed to RT for 30 minutes. Iodine (L.5 g, 6.0 mmol) was dissolved into THF (4 mL) and added to the reaction mixture at - 78°C slowly. The reaction was wanned to RT for 1 hour and the solvents were removed in vacuo. The residue was dissolved into EtOAc and washed with brine and water. The combined organic layers were dried (MgSO4) and solvents were removed in vacuo followed by purification by flash column chromatography (SiO2) (50% EtOAc in hexanes) that yielded the title compound as a yellow solid (55 mg, 14 %). 1H-NMR (CDCl3): d S.91 (s, 1H), 8.07 (s, 1H), 6.81 (br s, 1H), 2.44 (s, 3H), 1.56 (s, 9H). ESI-MS (m/z): Calcd. for C11H15IN2O2: 335.0 (M+l); found: 334.9. c) ({4-[3-(3-Amino-S-methyl-pyridin-4-yl)-benzenesulfonyl]-5- methylsulfanyl-thiophen-2-yt}-imino-methyl)-carbamic acid tert-butyl ester (4-Iodo-5-methyl-pyridm-3-yl)-carbamic acid tert-butyl ester (106 mg, 0.32 mmol, Example 139: step b), {[4-(3-Boranyl-dihydroxy- benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (145 mg, 0.32 mmol, Example 140: step a) and Pd(PPh3)4 (74 mg, 0.06 mmol) were combined in aqueous Na2CO3 (2M, 1.2 mL), ethanol (1.2 mL) and toluene (2.4 mL) and was heated to 80°C overnight. The reaction mixture was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4) and solvents were removed in vacuo. Purification by flash column chromatography (40% EtOAc/hexanes) afforded the title compound. ESI-MS (m/z): Calcd. for C28H34N4O6S3: 619.2 (M+l); found: 618.8. d) 4-[3-(3-Amino-5-methyl-pyridin-4-yl)-benzenesulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate ({4-[3-(3-Amino-5-methyl-pyridin-4-yl)-benzenesuIfonyl]-5- methylsulfanyl-thiophen-2-yl}-iraino-methyl)-carbamic acid tert-butyl ester (Example 139 : step c) was deprotected and purified as in Example 1: step d, yielding the title compound as a white solid. 1H-NMR (CD3OD): d 8.37 (s, 1H), 8.18-8.16 (d, 1H, J = 8.84 Hz), 8.06 - 8.05(m, 2H), 7.99 (s, 1H), 7.87 (t, 1H, J = 7.67 Hz, J = 7.44 Hz), 7.71-7.68 (d, IH, J - 7.67 Hz), 2.73 (s, 3H), 2.09 (s, 3H). ESI-MS (m/z): Calcd. for C18H18N4O2S3: 419.1 (M+l); found: 419.1 Example 140 4-[3-(2,5-Dimethyl-1H-imidazol-4-yl)-benzenesulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate a) {[4-(3-Dihydroxyboranyl-benzenesulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester. A solution of 2M i-PrMgCl in THF (1.1 mL, 2.2 mmol) was added dropwise at 0 °C to {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.5 g, 1.0 mmol) (Example 27c) in 5.0 mL THF. The solution was stirred for 20 mins at 0 °C, then cooled to -78 °C and a solution of 2.5 M n-BuLi in hexanes (0.6 mL, 1.5 mmol) was added. The mixture was stirred for 5 mins then trimethylborate (0.35 mL, 3.3 mmol) was added at -78 C °C and the mixture allowed to attain RT. The reaction was quenched with sat. NH4Cl (10 mL) and extracted with EtOAc (3 x 20 mL), dried over Na2SO4 and evaporated. The crude solid was purified by elution from a 5 g SPE with 10% MeOH/DCM to give 0.45 g (95%) of the title compound as a yellow solid:: 1H NMR (400 MHz, CD3OD) 5 8.28 (m, 1H), 8.05 (m, 1H), 7.95 (m, 1H), 7.60 (m, 2H), 2.66 (s, 3H), 1.51 (s, 9H). Mass spectrum (ESI, m/z) calcd. for C17H21N3O4S3 456.1, found 456.7 (M+H). General Procedure for Suzuki Coupling: To a flask charged with 0.50 g (1.1 mmol) of {[4-(3-dihydroxyboranyl- benzenesulfonyl)-5-m.ethy[sulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester, 0.22 g (1 mmol) of 5-iodo-2,4-dimethyl-lH-imidazole and 0.006 g of Pd(PPh3)4 (5 mol %) is added S ml of toluene, 4 mL of EtOH, and 4 mL of 2 M Na2CO3. The mixture is backfilled with argon and then heated at SO °C for 4 hrs. The mixture is diluted with water (10 mL) and the product extracted with EtOAc (3 x 10 mL), dried (Na2SO4), filtered and evaporated. The crude product is purified by flash chromatography to give the title compound as a BOC-protected amidine. The BOC-protected amidine is stirred at 25 °C for 1 hr in 2 mL of 50% TFA/DCM, and then the solvents are evaporated and the crude product purified by RP-HPLC, eluting with a linear gradient of 10% CH3CN to 50% CH3CN in 0.1% TFA/H2O over 30 mins to give 0.39 g (75%) of the title compound as a yellow solid: 1H NMR (400 MHz, CD3OD) 5 8.37 (s, 1H), S.25 (m, 1H), 8.14 (m, 2H), 7.88 (m, 1H), 7.63 (s, 1H), 2.74 (s, 3H), 2.68 (s, 3H), 2.49 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C17H1SN4O2S;3 406.1, found 407.1 (M+H). Example 141 4-[3-(3-Methyl-3H-imidazol-4-yl)-benzenesulfonyl]-5-methylsuifanyl- thiophene-2-carboxaraidine trifluoroacetate Prepared according to the general procedure in Example 140 H NMR (400 MHz, CD3OD) 5 9.08 (s, 1H), 8.38 (s, 1H), 8.29 (m, 1H), 8.24 (m, 1H), 7.96 (m, 1H), 7.85 (m, 1H), 7.81 (s, 1H), 3.92 (s, 3H), 2.75 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C16Hi6N4O2S3 392.1, found 393.1 (M+H). Example 142 4-[3-(l-Methyl-lH-imidazol-2-yl)-benzenesulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate Prepared according to the general procedure in Example 140. 1H NMR (400 MHz, CD3OD) 5 8.37 (s, 1H), 8.25 (m, 1H), 8.14 (m, 1H), 7.91 (m, 1H), 7.81 (m, 1H), 2.74 (s, 3H), 2.68 (s, 3H), 2.49 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C23H25N3O4S3 392.1, found 393.1 (M+H). Example 143 4-[3-(l -Methyl-1H-benzoimidazol-2-yl)-benzenesulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate a) {[4-(3-Formyl-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]- imino-methyl}-carbamic acid tert-butyl ester A solution of 2 M i-PrMgCl in THF (1.1 mL. 2.2 mmol) was added dropwise at 0 °C to {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.5 g, 1.0 mmol) (Example 27c) in 5.0 mL THF. The solution was stirred for 20 m:ins at 0 °C, then cooled to -78 °C and a solution of 2.5 M n-BuLi in hexanes (0.6 mL, 1.5 mmol) was added. The mixture was stirred for 5 mins then N,N- dimethylformamide (0.30 mL, 3.8 mmol) was added at -78 °C and the mixture allowed to attain RT. The reaction was quenched with sat. NH4Cl (10 mL) and extracted with EtOAc (3 x 20 mL), dried over Na2SO4 and evaporated. The crude solid was purified by elution from a 20g SPE with 50% EtOAe/hex to give 0.33 g (75%) of the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) 5 10.06 (s, 1H), 8.48 (s, 1H), 8.26 (m, 1H), 8.10 (m, 1H), 8.06 (s, 1H), 7.71 (s, 1H), 2.50 (s, 3H), 1.51 (s, 9H). Mass spectrum (ESI, m/z) calcd. for C18H20N205S3 440.1, found 440.8 (M+H). The above aldehyde (0.026g, 0.06 mmol) and N-methyl-1,2- phenylenediamine (0.014g, 0.12 mmol) in 0.2 mL of ethanol was heated at 80 °C for 12 hours. The solvent was evaporated and the residue taken up in 1 mL of 50% TFA/DCM and stirred for 30 mins at 25 °C. The solvent was evaporated and the crude product purified by RP-HPLC, eluting with a linear gradient of 10% CH3CN in 0,1% TFA/H2O to 50 % CH3CN over 30 mins, to give 0.028 g (87 %) of the title compound as red solid: 1H NMR. (400 MHz, CD3OD) 5 8.62 (m, 1H), 8.45 (m, 1H), 8.41 (s, 1H), 8.28 (m, 1H), 8.03 (m, 1H), 8.00 (m, 1H), 7.90 (m, 1H), 7.75 (m, 2H), 4.13 (s, 3H), 2.76 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C20H18N4O2S3 442.1, found 443.1 (M+H). Example 144 4-[3-(lH-Benzoimidazol-2-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophene- 2-carboxamidine trifluoroacetate This compound was prepared according to Example 143 using 1,2- phenylenediamine. 1H NMR (400 MHz, CD3OD) 5 8.85 (m, 1H), 8.44 (m, 1H), 8.42 (s, 1H), 8.33 (m, 1H), 7.95 (m, 1H), 7.82 (m, 2H), 7.56 (m, 2H), 2.74 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C19H16N4O2S3 428.0, found 429.1 (M+H). Example 145 4-[3-(l-Ethyl-lH-benzoimidazol-2-yl)-benzenesulfonyl]-5-methy].sulfanyl- thiophene-2-earboxamidine trifluoroacetate A mixture containing ({4-[3-(lH-benzoimidazol-2-yl)- benzenesulfonyl]-5-methy]sulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester (prepared in Example 144) (25 mg, 0.05 mmol), K2CO3 (13 mg, 0.10 mmol), and iodoethane (12 mg, 0.08 mmol) in 0.5 mL acetone was heated to 60 °C for 2 hrs. The mixture was filtered then concentrated, and the residue dissolved in 0.5 ml of 50% TFA/DCM and stirred at 25 °C for 30 mins. The solvent was evaporated and the crude product purified by RJP- HPLC, eluting with a linear gradient of 10% CH3CN in 0.1% TFA/H2O to 50 % CH3CN over 30 mins, to give 26 mg (93%) of the title compound as yellow solid: 1H NMR (400 MHz, CD3OD) 5 8.58 (m, 1H), 8.44 (m, 1H), 8.41 (s, 1H), 8.20 (m, 1H), 8.02 (m, 2H), 7.90 (m, 1H), 7.71 (m, 2H), 4.55 (q, 2H), 2.75 (s, 3H), 1.59 (t, 3H). Mass spectrum (ESI, m/z) calcd. for C21H2oN4O2S3 456.1, found 457.1 (M+H). Example 146 3-{2-[3-(5-Carbarnimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-phen}'l]- benzoimidazol-l-yl}-propane-1-sulfonic acid trifluoroacetate This compound was prepared in a similar manner to Example 145 using 1,3- propane sultone in DMF. lH NMR (400 MHz, CD3OD) 8 8.58 (m, 1H), 8.43 (m, 1H), 8.36 (s, 1H), 8.25 (m, 1H), 8., 10 (m, 1H), 8.00 (m, 1H), 7.88 (m, 1H), 7.71 (m, 2H), 4.72 (t, 2H), 2.79 (t, cH), 2.77 (s, 3H), 2.32 (m, 2H). Mass spectnim (ESL m/z) calcd. for C22H22N4O5S4 550.1, found 550.1 (M+H). Example 147 4-[3-(Hydroxy-pyridin-2-yl-]methyl)-benzenesulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate A solution of 2 M i-PrMgCl in THF (0.16 mL 0.36 mmol) was added dropwise at 0 °C to {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.08 g. 0.16 mmol) (Example 27c) in 0.75 mL THF. The solution was stirred for 20 mins at 0 °C, then cooled to -78 °C and a solution of 2-5 M n-BuLi in hexanes (0.084 mL, 0.21 mmol) was added. The mixture was stirred for 5 mins then 2- pyridinecarboxyaldehyde (0.023 mL, 0.24 mmol) was added at -78 °C and the mixture allowed to attain RT. The reaction was quenched with sat. NH4Cl (5 mL) and extracted with EtOAc (3 x 10 mL), dried over Na2SO4 and evaporated. The crude solid was purified by flash chromatography to give the title compound as a BOC-protected amidine, which was deprotected in 2 mL of 50% TFA/DCM (25 °C, 1 hr) to give 0.035 g (40%) of the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) 5 8.79 (m, 1H), 8.53 (m, 1H), 8.33 (s. 1H), 8.24 (m, 1H), 7.97 (m, 3H), 7.86 (m, 1H), 7.67 (m, 1H), 6.32 (s, 1H), 2.50 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C18H17N3O3S3 419.0, found 420.0 (M+H). Example 148 4-[3-(4-Hydroxy-l-methyl-piperidin-4-yl)-benzenesulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate Prepared in a similar manner to Example 147 using l-methyl-4- piperdone. 1H NMR (400 MHz, CD3OD) 5 8.34 (s, 1H), 8.2S (in, 1H), 7.96 (m, 1H), 7.84 (m, 1H), 7.66 (m, 1H), 3.48 (ni, 4H), 2.96 (s, 3H), 2.73 (s, 3H), 2.38 (m, 2H), 1.98 (m, 2H). Mass spectrum (ESI, m/z) calcd. for C18H23N3O3S3 425.1, found 426.1 (M+H). Example 149 4-[3-(4-Hydroxy-tetraliydro-pyran-4-yl)-benzenesulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate Prepared in a similar manner to Example 147 using tetrahydro-4H- pyran-4-one. 1H NMR (400 MHz, CD30D) 5 8.30 (s. 1H), 8.24 (m, 1H), 7.92 (m, 1H), 7.83 (m, 1H), 7.60 (m, 1H), 3.88 (m, 4H), 2.71 (s, 3H), 2 12 (m, 2H), 1.63 (m, 2H). Mass spectrum (ESI, m/z) calcd. for C17H20N2O4S3 412.1, found 413.0 (M+H). Example 150 4-[3-(4-Methoxy-tetratiydro-pyran-4-yl)-benzenesulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate To a solution of the BOC-protected amidine (46 mg, 0.09 mmol) (prepared in example 149) in 0.2 mL of DMF at 25 °C was added NaH (60% oil dispersion, 5.7 mg, 0,14 mmol). The reaction was allowed to stir for 20 mins then iodomethane (6 uL, 0.09 mmol) was added and the reaction stirred for additional 12 hrs. The solvent was evaporated and the crude material purified by flash chromatography to give the title compound as a BOC protected amidine, which was deprotected in 2 mL of 50% TFA/DCM (25 °C, 1 hr) to give the title compound (11.5 mg, 20%) as a yellow solid: 1H NMR (400 MHz, CD3OD) 5 8.34 (s, 1H), 8.14 (m, 1H), 7.92 (m, 1H), 7.80 (m, 1H), 7.66 (m, 1H), 3.89 (m, 4H), 3.00 (s, 3H), 2.74 (s, 3H), 2.02 (m, 4H). Mass spectrum (ESI, m/z) calcd. for C18H22N2O4S3 426.1, found 427.1 (M+H). Example 151 4-(3-Furan-2-yl-benzenesulfonyl)-5-methylsulfanyl-thiophene-2- caiboxamidine trifluoroacetate A solution containing 50 mg (0.10 mmol) of {[4-(3-bromo- benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (prepared in Example 27c), 54 mg (0.15 mmol) of 2- tributylstannylfuran, and 12 mg (10 mol%) of Pd(PPh3)4 in 0.5 mL of THF was healed at 80 °C under Argon for 10 hrs. The reaction was quenched with NH4AC (5 mL), extracted with EtOAc (3 x 5mL), dried over Na2SO4 and concentrated under reduced pressure. The crude material was stirred in 1 mL of 50 % TFA/DCM for 1 hr at 25 °C and then concentrated and purified by RP-HPLC to give 19 mg (50%) of the title compound as a yellow solid: 1H NMR (400 MHz, CD3OD) 5 8.35 (s, 1H), 8.32 (m, 1H), 8.01 (m, 1H), 7.90 (m, 1H), 7.66 (m, 1H), 7.65 (m, 1H), 6.98 (m, 1H), 6.60 (m, 1H), 2.75 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C16H14N2O3S3 378.0, found 379.1 (M+H). Example 152 3-[3-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-phenyl]-but- 2-enoic acid ethyl ester trifluoroacetate a) Imino-[5-methylsulfanyl-4-(3-tributylstannanyl-benzenesulfonyl)- thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester A solution of 2 M i-PrMgCl in THF (1.1 mL, 2.2 mmol) was added dropwise at 0 °C to {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.5 g, 1.0 mmol) (Example 27c) in 5.0 mL THF. The solution was stirred for 20 mins at 0 °C, then cooled to -78 °C and a solution of 2.5 M n-BuLi in hexanes (0.6 mL, 1.5 mmol) was added. The mixture was stirred for 5 mins then tributyltin chloride (0.65 g, 2.0 mmol) was added at —78 °C and the mixture allowed to attain RT. The reaction was quenched with sat. NH4Cl (10 mL) and extracted with EtOAc (3 x 20 mL), dried over Na2SO4 and evaporated. The crude solid was purified by flash chromatography to give 0.35 g (50%) of the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) d 8.14 (m, 1H), 8.00 (s, 1H), 7.S7 (m, 1H), 7.71 (m, 1H), 7.46 (m, 1H), 2.59 (s, 3H), 1.53 (s, 9H), 1.51 (m, 6H), 1.34 (m, 6H), 1.11 (m, 6H), 0.89 (m, 9H). Mass spectrum (ESI m/z) calcd. for C29H46N2O4S3Sn 702.2, found 702.7 (M+H). A mixture containing 42 mg (0.06 mmol) of {imino-[5-methylsulfanyl- 4-(3-tributylstannanyl-benzenesulfonyl)-thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester, 21 mg (0.09 mmol) of ethyl cis-3-iodocrotonate, 3 mg (5 mol%) of Pd(PPh3)4 and 1 mg (10 mol%) of Cul in 0.3 mL of DMF was heated under argon at 100 °C for 12 hrs. The DMF was evaporated and the crude material stirred m 1 mL of 50% TFA/DCM for 1 hr at 25 °C. The solvents were evaporated and the crude product was purified by RP-HPLC to give 7 mg (23%) of the title compound as a yellow solid: 1H NMR (400 MHz, CD3OD) d 8.30 (s, 1H), 8.02 (m, 1H), 7.88 (m, 1H), 7.61 (m, 2H), 6.05 (s, 1H), 3.90 (q, 3H), 2.78 (s, 3H), 2.22 (s, 3H), 1.02 (t, 3H). Mass spectrum (ESI, m/z) calcd. for C18H20N2O4S3 424.1, found 425.1 (M+H). Example 153 4-[3-(lH-Imidazol-2-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate A mixture containing 20 mg (0.04 mmol) of {[4-(3-formyl- benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (Example 143a), 10 uL (0.06 mmol) of 40% aqueous glyoxal, and 65 mg (0.84 mmol) of NH4Ac was heated at 80 °C for 12 hrs in methanol. The solvents were evaporated and the residue stirred in 1 mL of 50% TFA/DCM for 1 hr at 25 °C. The solvents were again evaporated and the crude material purified by RP-HPLC to give 4 mg (18%) of the title compound as a yellow solid: 1H NMR (400 MHz, CD3OD) 5 8.64 (m, 1H), 8.39 (s, 1H), 8.24 (m, 2H), 7.88 (m, 1H), 7.63 (s, 1H), 2.73 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C15H14N4O2S3 378.0, found 379.1 (M+H). Example 154 N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-biphenyl-2- yl]-acetamide trifluoroacetate A solution containing 30 mg (0.06 mmol) of {[4-(2'-amino-biphenyl-3- sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl} -carbamic acid tert- butyl ester (prepared according to the general procedure for Suzuki coupling in Example 140 using 2-aminophenyl boronic acid), 10 mg (0.09 mmol) of 2,6-lutidine, and 7 mg (0.07 mmol) of acetic anhydride was stirred in 2 mL of DCM at 25 °C for 12 hrs. The crude material was purified by flash chromatograpy to give the title compound as a BOC protected amidine which was deprotected by stirring at 25 °C for 1 hr in 1 mL of 50% TFA/DCM. The solvent was evaporated and the crude material purified by RP-HPLC to give 20 mg (60 %) of the title compound as a yellow solid: 1H NMR (400 MHz, CD3OD) 5 8.31 (s, 1H), 8.18 (m, 1H), 8.07 (m, 1H), 7.76 (m, 1H), 7.71 (s, 1H), 7.47 (m, 4H), 2.82 (s, 3H), 2.74 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C20H19N3O3S3 445.1, found 446.1 (M+H). Example 155 4-(2'-Methanesulfonylamino-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate A solution containing 30 mg (0.06 mmol) of {[4-(2'-amino-biphenyl-3- sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert- butyl ester (prepared according to the general procedure for Suzuki coupling in Example 140 using 2-aminophenyl boronic acid), 10 mg (0.09 mmol) of 2,6-lutidine, and 8 mg (0.07 mmol) of methanesulfonyl chloride was stirred in 2 mL of DCM at 25 °C for 12 hrs. The crude material was purified by flash chromatograpy to give the title compound as a BOC protected amidine which was deprotected by stirring at 25 °C for 1 hr in 1 mL of 50% TFA/DCM. The solvent was evaporated and the crude material purified by RP-HPLC to give 25 mg (70 %) of the title compound as a yellow solid: 1H NMR (400 MHz, CD3OD) 5 8.29 (s, 1H), 8.06 (m, 1H), 8.03 (m, 1H), 7.73 (m, 2H), 7.42 (m, 4H), 2.73 (s, 3H), 1.96 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C19H19N3O4S4 481.0, found 482.1 (M+H). Example 156 4-[5-Bromo-6-(3-imidazol-l-yl-propylamino)-pyridine-3-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate a) 4-[5-Bromo-6-(3-imidazol-l-yl-propylamino)-pyridine-3-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxylic acid methyl ester To a vial containing a stirbar was added 4-(5-bromo-6-chloro-pyridine- 3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.050 g, 0.113 mmol), (Example 2:step c), 3-imidazol-l-yl-propylamine (0.018 g, 0.146 mmol), diisopropylethylamine (0.073 g, 0.565 mmol), THF [0.50 mL], DMF [0.50 mL]. The reaction vessel was sealed and the solution was heated to 80 °C for 18 hours. Removal of the solvents in vacuo followed by chromatography (5% MeOH/DCM) yielded the title compound. 1H-NMR (CDCl3): d 8.69 (d, 1H, J=2.1 Hz), 8.10 (d, 1H .7=2.1 Hz), 8.03 (s, 1H), 8.02 (s, 1H), 7.57 (s, 1H), 7.10 (s, 1H), 6.97 (s 1H), 5.70 (t, 1H, J=5.S Hz), 4.06 (t, 2H, 7=6.8 Hz), 3.89 (s, 3H), 3.57 (m, 2H), 2.97 (s, 2H), 2.90 (s, 2H), 2.64 (s, 3H), 2.17 (m, 2H). ESI-MS (m/z): Calcd. For C18H19BrN4O4S3: 532.5 (M+H); found 530.9, 532.9. b) 4-[5-Bromo-6-(3-imidazol-l-yl-propylamino)-pyridine-3-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate Trimethyl aluminum [2M in toluene], (1.12 mL, 2.26 mmol) was added slowly to a flask containing a stirbar and ammonium chlonde (0.120 g, 2.26 mmol). This solution was placed in a 90°C oil bath for 5 minutes under argon. Solution was allowed to cool to room temperature. This solution was then added to 4-[5-Bromo-6-(3-imidazol-l-yl-propylamino)-pyridine-3- sulfonyl]-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (100 mg, 0.22 mmol) which was dissolved in toluene [2 mL]. Reaction was heated at 80 °C for two hours. Reaction was added to a slurry of silica gel in DCM. The slurry was filtered using 15% MeOH/DCM. Removal of the solvents in vacuo followed by reverse-phase HPLC of the residue [acetonitrile/water (0.01 %TFA)] yielded the title compound. 1H-NMR (MeOH): d 8.96 (s, 1H), 8.62 (d, 1H, y=2.0 Hz), 8.26 (s, 1H), 8.12 (d, 1H, J =2.3 Hz), 7.68 (t, 1H,.J =1.7 Hz), 7.56 (t, 1H, .7=1.6 Hz), 4.32 (t, 2H, J =7.2 Hz), 3.60 (t, 2H, J =6.7 Hz), 2.72(s, 3H), 2.24 (m, 2H). ESI-MS (m/z): Calcd. For C17H19BrN6O2S3: 515.47 (M+H); found 515.1, 517.0. Example 157 4-[5-Bromo-6-(2-methyl-2-morpholin-4-yl-propylamino)-pyridine-3- sulfonyl]-5-methylsulfanyl-thiophene-2-carboxamidinetrifluoroacetate a) 4-[5-Bromo-6-(2-methyl-2-morpholin-4-yl-propylainino)-pyridin e-3- sulfonyl]-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester The reaction was conducted following the procedure for Example 156:step a, using 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester (0.050 g, 0.113 mmol), (Example 2:step c), 2-methyl-2-morpholin-4-yl-propylarn.ine (0.023 g, 0.146 mmol), diisopropylethylamine (0.073g, 0.565 mmol), THF [0.5 mL], DMF [0.5 mL]. Chromatography of the residue (25%-50%EtOAc/Hx) yielded the title compound. 1H-NMR (CDCl3): d 8.70(d, 1H, J =2.1 Hz), 8.0S(d, 1H, J =2.1 Hz), 8.02 (s, 1H), 6.82 (t, 1H, J =4.1), 3.90 (s, 3H), 3.76 (t, 4H, J =4.1), 3.37 (d, 2H, J=4.1), 2.64 (s, 3H), 2.57 (t, 4H, J =4.5),1.59 (s, 3H), 1.13 (s, 6H). ESI-MS (m/z): Calcd. For C20H26BrN3O5S3: 565.54 (M+H); found 564.0, 565.9. b) 4~[5-Bromo-6-(2-methyl-2-morpholin-4-yl-propylamino)-pyridine-3- sulfonyl]-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate The reaction was conducted following the procedure for Example 156:step b, using trimethyl aluminum [2M in toluene], (0.194 mL, 0.389 mmol), ammonium chloride (0.021 g, 0.389 mmol), 4-[5-bromo-6-(2-methyl- 2-morpholin-4-yl-propylamino)-pyridine-3-sulfonyl]-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester (0.022 g, 0.039 mmol), toluene [lmL\|. Reverse-phase HPLC yielded title compound. ESI-MS (m/z): Calcd. for C19H26N5O3S3: 549.54 (M+H); found 547.9,549.9. Example 158 4-{5-Bromo-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridine-3- sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate a) 4-{5-Bromo-6-[(6-triflttoromethyl-pyridin-3-ylmethyl)-amino]- pyridine-3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester The reaction was conducted following the procedure for Example 156:step a, using 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester (0.050 g, 0.113 mmol), (Example 2:step c), 3-aminomethyl-6-trifluoromethyl pyridine (0.026 g, 0.146 mmol), diisopropylethylamine (0.073 g. 0.565 mmol), THF [0.5 mL], DMF [0.5 mL]. Chromatography of the residue (25%-50%EtOAc/Hx) yielded the title compound. ESI-MS (m/z): Calcd. For C19H15BrN3O4S3: 583.44 (M+H); found 582.0, 583.9. b.) 4-{5-Bromo-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]- pyridine-3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate The reaction was conducted following the procedure for Example 156:step b, using trimethyl aluminum [2M in toluene], (0.463 mL, 0.927 mmol), ammonium chloride (0.049 g, 0.927 mmol), 4-{5-bromo-6-[(6- trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridine-3-sulfonyl}-5- methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.054 g, 0.093 mmol), toluene [lmL]. Reverse-phase HPLC yielded title compound. ESI- MS (m/z): Calcd. For C18H15BrF3N5O2S3: 567.44 (M+H); found 566.0, 567.9. Example 159 4-{5-Bromo-6-[2-(3H-imidazol-4-yl)-ethylamino]-pyridine-3-sulfonyl}-5- 5 methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate a) 4-{5-Bromo-6-[2-(3H-imidazol-4-yl)-ethylamino]-pyridine-3- sulfonyl}-5-methylsulfanyl~thiophene-2-carboxylic acid methyl ester The reaction was conducted following the procedure for Example 156:step a, using. 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester (0.050 g, 0.113 mmol), (Example 2:step c), 2-(3H-imidazol-4-yl)-ethylamine (0.027 g, 0.146 mmol), diisopropylethylamine (0.073 g, 0.565 mmol), THF [0.5 mL], DMF [0.5 mL]. Chromatography of the residue (0%-6%MeOH/DCM) yielded the title compound. ESI-MS (m/z): Calcd. for C17H17BrN4O4S3: 518.44 (M+H); found 517.0,519. b) 4-{5-Bromo-6-[2-(3H-imidazol-4-yl)-ethyiamino]-pyridine-3- sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate The reaction was conducted following the procedure for Example 156:step b, using trimethyl aluminum [2M in toluene], (0.773 mL, 1.546 mmol), ammonium chloride (0.082 g, 1.546 mmol), 4-{5-bromo-6-[2-(3H- imidazol-4-yl)-ethylamino]-pyridine-3-sulfonyl}-5-methylsulfanyl-thiophene- 2-carboxylic acid methyl ester (0.080 g, 0.155 mmol), toluene [2mL]. HPLC yielded title compound. ESI-MS (m/z): Calcd. for C17H17BrN4O4S3: 501.45 (M+H); found 502.2, 504.2. Example 160 4-[5-Bromo-6-(4-sulfamoyl-benzylamino)-pyndine-3-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate a) 4-[5-Bromo-6-(4-sulfamoyl-benzylamino)-pyridine-3-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxylic acid methyl ester The reaction was conducted following the procedure for Example 156:step a, using. 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester (0.050 g, 0.113 mmol), (Example 2:step c), 4-aminomethyl-benzenesulfonamide (0.033 g, 0.146 mmol), diisopropylethylamine (0.073 g, 0.565 mmol), THF [0.5 mL], DMF [0.5 mL]. Chromatography of the residue (0%-5%MeOH/DCM) yielded the title compound. ESI-MS (m/z): Calcd. for C19H18BrN3O6S4: 592.53 (M+H); found 592.0, 593.9. b) 4-[5-Bromo-6-(4-sulfamoyl-benzylamino)-pyridine-3-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate The reaction was conducted following the procedure for Example 156:step b, using triraethyl aluminum [2M in toluene], (0.773 mL, 1.546 mmol), ammonium chloride (0.082 g, 1.546 itnmol), 4-{5-bromo-6-[2-(3H- imidazol-4-yl)-ethylamino]-pyridine-3-sulfonyl}-5-methylsulfanyl-thiophene- 2-carboxylic acid methyl ester (O.OSO g, 0.155 mmol), toluene [2mL]. Reverse-phase HPLC yielded the title compound. ESI-MS (m/z): Calcd. for C17H17BrN4O4S3: 501.45 (M+H); found 502.2, 504.2. Example 161 4-(6-Benzylamino-5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene- 2-ca.rboxamidine trifluoroacetate a) 4-(6-Benzylamino-5-bromo-pyridine-3-snlfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester To a vial containing a stirbar was added 4-(5-bromo-6-chloro-pyridine- 3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.020 g, 0.045 mmol), (Example 2:step c), benzylamine (0.005 g, 0.407 mmol), MeOH [2.0 mL]. Reaction vessel was sealed and heated to 50°C for 72 hours. Removal of the solvents in vacuo followed by chromatography of the residue (10%-20% EtOAc/Hx) yielded the title compound. ESI-MS (m/zl: Calcd. for C19H17BrN2O4S3: 514.45 (M+H); found 513.2,515.1. b) 4-(6-Benzylamino-5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate The reaction was conducted following the procedure for Example 156:step b, using trimethyl aluminum [2M in toluene], (0.120 mL, 0.253 mmol), ammonium chloride (0.014 g, 0.253 mmol), 4-(6-Benzylamino-5- bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.013 g, 0.0253 mmol), toluene [2mL]. Reverse-phase HPLC yielded title compound. ESI-MS (m/z): Calcd. for C19H18BrN3O2S3: 497.47 (M+H); found 497.3, 499.1. Example 162 4-(5-Bromo-6-isobutylamino-pyridine-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidmetrifluoroacetate a) 4-(5-Bromo-6-isopropylamino-pyridine~3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester To a vial containing a stirbar was added 4-(5-bromo-6-chloro-pyridme- 3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.100 g, 0.226 mmol), (Example 2:step c), isopropylamine (0.012 g, 0.204 mmol), THF [2.0 mL]. Reaction vessel was sealed and heated to 70°C for 72 hours. Removal of the solvents in vacuo followed by chromatography (0%-15% EtOAc/Hx) yielded the title compound. ESI-MS (m/z): Calcd. lor C15H17BrN2O4S3: 466.41 (M+H); found 466.9. b) 4-(5-Bromo-6-isobutylamino-pyridine-3-sulfotiyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate The reaction was conducted following the procedure for Example 156:step b, using trimethyl aluminum [2M in toluene], (0.620 mL, 1.247 mmol), ammonium chloride (0.067 g, 1.247 mmol), 4-(5-bromo-6- isopropy]amino-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.058 g, 0.125 mmol), toluene [2mL]. Reverse-phase HPLC yielded title compound. ESI-MS (m/z): Calcd. for C14H13BrN4O2S3: 450.41 (M+H); found 449.1, 451.0. Example 163 4-{5-Bromo-6-[(pyridin-3-ylmethyl)-amino]-pyridine-3-sulfonyl}-5- methylsulfanyl-thiophaene-2-carboxamidine trifluoroacetate a) 4-{5-Bromo-6-[(pyridm-3-ylmethyl)-amino]-pyridine-3-sulfonyl}-5- methylsulfanyl-thiophene-2-carboxylic acid methyl ester The reaction was conducted following the procedure for Example 162:step a, using 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester (0.100 g, 0.226 mmol). (Example 2:step c), 3-aminomethyl pyridine (0.046 g, 0.430 mmol), THF [4.0 mL]. Chromatography of the residue (25%-50% EtOAc/Hx) yielded the title compound. ESI-MS (m/z): Calcd. for C18H16BrN3O4S3: 515.44 (M+H); found 514.1,516.0. b) 4-{5-Bromo-6-[(pyridin-3-ylmethyl)-amino]-pyridine-3-sulfonyl}-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate The reaction was conducted following the procedure for Example 156:step b, using trimethyl aluminum [2M in toluene], (0.710 mL, 1.439 mmol), ammonium chloride (0.077 g, 1.439 mmol) 4-{5-Bromo-6-[(pyridin-3- ylmethyl)-amino]-pyridine-3-sulfonyl}-5-methylsulfanyl-thiophene-2- carboxylic acid methyl ester (0.074 g, 0.1439 mmol), toluene [2 mL]. Reverse-phase HPLC yielded title compound. ESI-MS (m/z): Calcd. for C17H16BrN5O2S3: 499.44 (M+H); found 499.1, 501.0. Example 164 4-{5-Bromo-6-[(pyridin-4-ylmethyl)-arnino]-pyridine-3-sulfonyl}-5- methylsulfanyl+thiophene-2-carboxamidine trifluoroacetate a) 4-(5-Bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine Trimethyl aluminum [2M in toluene], (0.S50 mL, 1.694 mmol) was added slowly to a flask containing ammonium chloride (0.091 g, 1.694 mmol) and a stir bar. This solution was placed in a 90°C oil bath for 5 minutes under argon. Solution was then allowed to cool to room temperature. This solution was then added 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester (0.075 g, 0.1694 mmol), (Example 2:step c), which was dissolved in toluene [1 mL]. Reaction was heated at 80 °C for two hours. Reaction was added to a slurry of silica gel in DCM. The slurry was filtered using 15% MeOH/DCM. Used crude material in next step. ESI-MS (m/z): Calcd. for C11H9BrClN3O2S3: 427.76 (M+H); found 426.0, 428.0. b) {[4-(5-Broino-6~chloro-pyridine-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester To a flask containing a stir bar was added 4-(5-bromo-6-chloro- pyridine-3-sulfonyl)-ethylsu[fanyl-thiophene-2-carboxamidine (0.96 g, 2.25 mmol), di-tert-butyl dicarbonate (0.74 g, 3.39 mmol), diisopropylamine (1.16 g, 9.03 mmol), DMF (60.0 mL). Solution was stirred at room temperature for 18 hours. Removal of the solvents in vacuo followed by chromatography (10%-15% EtOAc/Hx). Compound contained residual di-tert-butyl dicarbonate. Compound was dissolved in hexane, heated to 40°C for 1 hour. Solution was filtered to yield title compound. ESI-MS (m/z): Calcd. for C11H9BrClN3O3S3: 527.76 (M+H); found 426.0, 428.0. c) [(4-{5~Bromo-6-[(pyridin-4-ylmethyl)-amino]-pyridine-3-sulfonyl}-5- methylsulfanyl-thiophen-2-yl)-imino-methyl]-carbamic acid ten-butyl ester To a vessel containing a stir bar was added {[4-(5-bromo-6-chloro- pyridme-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}- carbamic acid tert-butyl ester (0.035 g, 0.066 mmol), 4-aminomethylpyridine (0.015 g, 0.133 mmol), THF [3 mL]. The reaction vessel was sealed and heated to 70°C for 18 hours, cooled to room temperature and concentrated in vacuo. The crude; residue was dissolved in a solution of chloroform/trifluoroacetic acid (1/1) [2 mL] and was allowed to stir at room temperature for 2 hours. The reaction was concentrated in vacuo followed by reverse-phase HPLC [acetonitrile/water (0.01%TFA)] to give the title compound. ESI-MS (m/z): Calcd. for C17H16BrN5O2S3: 499.44 (M+H); found 498.0, 500.0. Example 165 4-{5-Bromo-6-[(pyridin-2-ylmethyl)-amino]-pyridine-3-sulfonyl}-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate a) 4-{5-Bromo-6-[(pyridin~2-ylmethyl)-amino]-pyridine-3-sulfonyl}~5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate The reaction was conducted following the procedure for Example 164: step c, using {[4-(5-bromo-6-chloro-pyridme-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.035 g, 0.066 mmol), (example 164:step b), 2-aminomethylpyridine (0.014 g, 0.133 mmol), THF [3 mL], followed by chloroform/TFA (1:1) to yield the title compound. ESI-MS (m/z): Calcd. for C17H16BrN5O2S3: 499.44 (M+H); found 499.1, 501.0. Example 166 4-{6-[(4-Amino-pyrimidin-5-y]methyl)-amino]-5-bromo-pyridine-?-sulfonyl}- 5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate The reaction was conducted following the procedure for Example 164:step c, using {[4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.035 g, 0.067 mmol), 4-amino-5-aminomethyl-2-methylpyrimidine (0.018 g, 0.135 mmol), THF [2 mL], followed by DCM/TFA (1:1) and reverse-phase HPLC to yield the title compound. ESI-MS (m/z): Calcd. for C18H19BrN6O2S3: 528.48 (M+H); found 528.0, 529.9. Example 167 4-[5-Bromo-6-(3-hydroxy-2,2-dimethyl-propylamino)-pyridine-3-sulfonyl]-5- methylsulfanyl-thiopbene-2-carboxamidine trifluoroacetate The reaction was conducted following the procedure for Example 164:step c, using {[4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.035 gr 0.066 mmol), 3-amino-2,2-dimethylpropanol (0.013 g, 0.133 mmol), THF [2 mL], followed by DCM/TFA (1:1) and reverse-phase HPLC to yield the title compound. ESI-MS (m/z): Calcd. for C17H22BrN3O3S3: 493.48 (M+H); found 493.1, 495.0. Example 168 4-{5-Brorno-6-[(3-rnethyl-thiophen-2-ylmethyl)-amino]-pyridine-3-sulfonyl}- 5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate To a vessel containing a stir bar was added {[4-(5-bromo-6-chloro- pyridine-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}- carbamic acid tert-butyl ester (0.035 g, 0.066 mmol), 3-methylthiophene-2- methylamine (0.016 g, 0.133 mmol), THF [2 mL]. The reaction vessel was sealed and heated to 70°C for 18 hours, cooled to room temperature and concentrated in vacua. Chromatography of crude material (10%-25% EtOAC/Hx) yielded the intermediate which was dissolved in a solution of chloroform/trifluoroacetic acid (1/1) [2 mL] and was allowed to stir at room temperature for 2 hours. The reaction was concentrated in vacuo followed by reverse-phase HPLC [acetonitrile/water (0.01 %TF A)] to give the title compound. ESI-MS (m/z): Calcd. for C18H18BrN3O2S4: 517.52 (M+H); found 516.9,518.9. Example 169 4-{5-Bromo-6-[(tetrahydro-furan-2-ylmethy])-amino]-pyridine-3-sulfony!}-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate a) 4-{5-Bromo-6-[(tetrahydro-furan-2-ylmethyl)~amino]-pyridine-3- sulfonyl}-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester The reaction was conducted following the procedure for Example 156:step a, using. 4-(5-bromo-6-chloro-pyridine-3-sulfbnyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester (0.050 g, 0.113 mmol), (Example 2:step c), c-(tetrahydro-furan-2-yl)-methylarnine (0.015 g, 0.146 mmol), diisopropylethylamine (0.073 g, 0.565 mmol), THF [0.5 mL], DMF [0.5 mL]. Chromatography of the residue (10%-35% EtOAc/Hx) yielded the title compound. ESI-MS (m/z): Calcd. for C17H19BrN2O5S4: 508.45 (M+H); found 507.1,509.0 b) 4-{5-Bromo-6-[(tetrahydro-furan-2-ylmethyl)-amino]-pyridine-3- sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate The reaction was conducted following the procedure for Example 156:step b, using trimethyl aluminum [2M in toluene], (0.443 mL, 0.867 mmol), ammonium chloride (0.046 g, 0.867 mmol), 4-{5-bromo-6- [(tetrahydro-furan-2-ylmethyl)-aimno]-pyridme-3-sulfonyl}-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester (0.044 g, 0.087 mmol), toluene [lmL]. Reverse-phase HPLC yielded title compound. ESI-MS (m/z): Calcd. For C16H19BrN4O3S3: 492.45 (M+H); found 4911, 493.0. Example 170 4-{4'--[N'-(4-Methanesulfonyl-butyl)-guanidino]-2'-methyl-biphenyl-3- sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate a) 2-methyl-l-(4-methanesulfonyl-butyl)-l,3-bis (carbamic acid-tert- butyl ester)-isothiourea The reaction was conducted following the procedure for Example 171:step b, using 4-methariesulfonyl-butylamine (0.058 g, 0.378 mmol), 2- methyl-l-(3-methanesulfonyl-propyl)-l,3-bis (carbamic acid-tert-butyl ester)- isothiourea (0.100 g, 0.344 tnmol), Triphenylphosphine (0.098 g, 0.378 mmol), THF[ 6 mL]. To this was added Diisopropyl azodicarboxylate (0.076 g, 0.378 mmol). Chromatography of the residue (50% EtOAc/Hx) yielded the title compound. b) [Imino-(4-{4'-[N'-(4-metlianesulfonyl-butyl)-N',N"--(carbamic acid tert-butyl ester)-guanidino]-2'-methyl-biphenyl-3-sulfonyl}-5- methylsulfanyl-thiophen-2-yl)-methyl]-carbamic acid tert-butyl ester The reaction was conducted following the procedure for Example 171-.step c, using {[4-(4'-amino-2'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.025 g, 0.480 mmol), (Example 120:step b), 2-methyl-l-(4-methanesulfonyl- butyl)-l,3-bis (carbamic acid-tert-butyl ester)-isothiourea (0.101 g, 0 240 mmol), MeOH [2 mL], acetic acid (0.029 g, 0.480 mmol). Chromatography (10%-20% EtOAc/Hx). The compound was dissolved in trifluoroacetic acid/dichloromethane (1:1). [4 mL]. Solvent was removed in vacuo followed by reverse-phase HPLC to yield the title compound. ESI-MS (m/z): Calcd. for C25H31N5O4S4: 594.81 (M+H); found 594.1. Example 171 4-{4'-[N'-(3-Methanesulfonyl-propyl)-guanidino]-2'-methyl-biphenyl-3- sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate a) 3-Methatiesulfonyl-propan-l-ol 3-bromo-propan-l-ol was dissolved in EtOH [2 mL], methane sulfinic acid was dissolved in H2O [2 mL]. The two solutions were added together and heated to 50°C for 18 hours. Reaction was cooled to room temperature and the compound was extracted with EtOAc, dried using sodium sulfate, and the solvent was removed in vacuo. Chromatography of the residue (l%-7% MeOH/DCM) yielded the title compound. 1H-NMR (CDCl3): d 3.69 (m, 2H), 3.14 (m, 2H), 2.91 (s, 3H), 2.02 (m, 2H). b) 2-methyl-l-(3-methanesulfonyl-propyl)-l,3-bis (carbamic acid-tert- butyl ester)-isothionrea Under argon, 3-metfaanesulfonyl-propan-l-ol (0.059 g, 0.362mmol), 2- methyl-l-(3-methanesulfonyl-propyl)-l,3-bis (carbamic acid-tert-butyl ester)- isothiourea (0.123 g, 0.329 mmol), Triphenylphosphine (0.112 g, 0.362 mmol), THF [8 mL] was charged to a flask containing a stirbar. To this was added diisopropyl azodicarboxylate (0.095 g, 0.362 mmol). Reaction stired at room temperature for 18 hours. Solvent was removed in vacuo followed by chromatography (0%-25% EtOAc/Hx) to yield title compound (0.089 g). 1H- NMR (CDCl3): d 3.75 (t, 2H, 1=6.7 Hz), 3.14 (m, 2H), 2.94 (s, 3H), 2.42 (s, 3H), 2.20 (m, 2H), 1.52 (s, 9H), 1.50 (s, 9H). c) [Immo-(4-{4'-[N'-(3-methanesulfonyl-propyl)-Nr,N"-(carbamic acid tert-butyl ester)-guanidino)-2'-methyi-biphenyl-3-sulfonyl}-5- methylsulfanyl-thiophen-2-yl)-methyl]-carbamic acid tert-butyl ester 2-methyl-1 -(3-methanesulfonyl-propyl)-1,3-bis (carbamic acid-tert- butyl ester)-isothiourea (0.089 g, 0.217 mmol), {[4-(4'-Amino-2'-methyl- biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}- carbamic acid tert-butyl ester (0.022 g, 0.043 mmol), (Example 1.20:step b), MeOH [2 mL] was added to a flask containing a stirbar. To this was added acetic acid (0.026 g, 0.434 mmol) and the solution was heated to 40°C for 18 hours. Reaction was cooled to room temperature, solvent was removed in vacuo, and residue was chromatographed (10%-20% EtOAc/DCM) giving the title compound (0.026 g, 68%). ESI-MS (rn/z): Calcd. for C39H53N5O10S4: 881.13 (M+H); found 879.8, 880.8. d) 4-{4'-[N'-(3-Methanesulfonyl-propyl)-guanidino]-2'-methyl- biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate [Imino-(4-{4'-[N'-(3--methanesulfonyl-propyl)-N',N"-(carbamic acid tert-butyl ester)-guanidino]-2'-methyl-biphenyl-3-sulfonyl}-5-methylsulfanyl- thiophen-2-yl)-methyl]-carbamic acid tert-butyl ester (0.026 g, 0.029 mmol) was dissolved in 1:1 solution of trifluoroacetic acid: dichloromethane [1.5 mL:1.5mL]. Solution was allowed to stir at room temperature for 2 hours. The reaction was concentrated in vacuo followed by reverse-phase HPLC [acetonitrile/water (0.01 %TFA)] to give the title compound (0.017 g). ESI-MS (m/z): Calcd. for C24H29N5O4S4: 580.78 (M+H); found 580.1. Example 172 4-{4'-[N'-(6-Methanesulfonyl-hexyl)-guanidino]-2'-methyl-biphenyl-3- sulfonyl}-5-methylsulfany]-thiophene-2-carboxamidinetrifluoroacetate a) 6-Methanesulfonyl-hexan-1-ol The reaction was conducted following the procedure for Example 171:step a, using 6-bromo-hexan-l-ol (0.300 g, 1.660 mmol), methane sulfinic acid, (0.844 g, 8.280 mmol), EtOH [2 mL], H2O, [2 mL]. Chromatography of the residue (l%-5% MeOH/DCM) yielded the title compound (0.141 g 48%). 1H-NMR (CDCl3): d 3.67 (t, 2H, J =6.2 Hz), 3.03 (t, 2H, J =8.0 Hz), 2.92 (s, 3H), 1.89 (m, 2H), 1.60 (m, 2H), 1-46 (m, 4H). b) 2-methyl-l-(6-methanesulfonyl-hexyl)-l,3-bis (carbamic acid-tert- butyl ester)-isothiourea The reaction was conducted following the procedure for Example 171:step b, using 6-methanesulfonyl-hexan-l-oi (0.141 g, 0.782 mmol), 2- methyl-l-(3-methanesulfonyl-propyl)-l,3-bis (carbamic acid-tert-butyl ester)- isothiourea (0.206 g, 0.711 mmol), Triphenylphosphine (0.205 g, 0.782 mmol), THF [5 mL]. To this was added Diisopropyl azodicarboxylate (0.158 g, 0.782 mmol). Chromatography of the residue (0%-100%EtOAc/Hx) yielded the title compound (0.213 g, 66%) ESI-MS (m/z): Calcd. for C19H36N2O6S2: 453.63 (M+H); found 253.1. c) [Imino-(4-{4'-[N'-(6-methanesulfonyl-hexyl)-N',N"--(carbamic acid tert-butyl ester)-guanidino]-2'-methyl-biphenyl-3-sulfonyl}-5- methylsulfanyl-thiophen-2-yl)-methyl]-carbamic acid tert-butyl ester The reaction was conducted following the procedure for Example 171:step c, using 2-methyl-l-(6-methanesulfonyl-hexyl)-l,3-bis (carbamic acid-tert-butyl ester-isothiourea (0.213 g, 0.471 mmol), {[4-(4'-amino-2'- methyl-biphenyl-3 -sulfony l)-5 -methylsulfanyl-thiophen-2 -yl] -imino-methyl} - carbamic acid tert-butyl ester (0.081 g, 0.157 mmol), (Example 120:step b), MeOH [4 mL], acetic acid (0.094 g, 1.570 mmol). Chromatography (0%-20% EtOAc/Hx) yielded the title compound. (0.086 g 60%) ESI-MS (m/z): Calcd. for C42H59N5O10S4: 923.21 (M+H); found 921.8. d) 4-{4'-[N'-(6-Methanesulfonyl-hexyl)-guanidino]-2'-methyl-biphenyl- 3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate The reaction was conducted following the procedure for Example 171:step d, using imino-(4-{4'-[N'-(6-methanesulfonyl-hexyl)-N',N"-(carbamic acid tert-butyl ester)-guanidino]-2'-methyl-biphenyl-3-sulfonyl} -5- methylsulfanyl-thiophen-2-yl)-rnethyl]-carbamic acid tert-butyl ester (0.086 g, 0.093 mmol), trifluoroacetic acid [2mL], DCM [2mL]. Reverse-phase HPLC yielded the title compound (0.021 g, 38%). ESI-MS (m/z): Calcd. for C27H35N5O4S4: 622.86 (M+H); found 622.2. Example 173 4-{4'-[N'-(5-Methanesulfonyl-pentyl)-guanidino]-2'-methyl-biphenyl-3- sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidinetrifluoroacetate a) l-Chloro-5-methanesulfonyl-pentane The reaction was conducted following the procedure for Example 171:step a, using l-bromo-5-chloro-pentane (0.400 g, 2.150 mmol), methane sulfmic acid, (1.090 g, 10.75 mmol), EtOH [3 mL], H2O, [3 ml.]. Chromatography of the residue (0%-25% MeOH/DCM) yielded the title compound (0.213 g 53%). 1H-NMR (CDCl3): d 3.55 (t, 2H, J=6.3 Hz), 3.03 (t, 2H, J =8.0 Hz), 2.91 (s, 3H), 1.85 (m, 4H), 1.63 (m, 2H) b) 2-methyl-l-(5-methanesulfonyl-pentyl)-l,3-bis (carbamic acid-tert- butyl ester)-isothiourea l-chloro-5-methanesulfonyl-pentane (0.021 g, 1.153 mmol), sodium iodide (0.086 g, 5.765 mmol), acetone [5mL] were heated to 50°C for 1 hour. Reaction was cooled to room temperature, extracted EtOAc, and concentrated in vacuo. This solid was then taken up in DMF [1 mL] and added to a solution of sodium hydride (0.020 g, 0.865 mmo;) and 2-methyl-l-(3-methanesulfonyl- propyl)-l,3-bis (carbamic acid-tert-butyl ester)-isothiourea (0.016 g, 0.576 mmol) in DMF [3 mL] at 0°C. To this was added sodium iodide (0.864 g, 5.765 mmol) and the reaction was heated at 50°C for 18 hours. The reaction was cooled to room temperature and filtered to give the title compound (0.124 g, 49%). ESI-MS (m/z): Calcd. for C18H34N2O6S4: 439.60 (M+H); found 239.2. c) [Imino-(4-{4'-[N'-(6-methanesulfonyl-hexyl)-N',N"-(carbamic acid tert-butyl ester)-guanidino]-2'-methyl-biphenyl-3-sulfonyl}-5- methylsulfanyl-thiophen-2-yl)-methyl]-carbamic acid tert-bntyl ester The reaction was conducted following the procedure for Example 171:step c, using 2-methyl-l-(5-methanesulfonyl-pentyl)-l,3-bis (carbamic acid-tert-butyl ester)-isothiourea (0.124 g, 0.2S3 mmol), {[4-(4'-amino-2'- methyl-biphenyl-3-sulfonyl)-5-rnethylsulfanyl-thiophen-2-yl]-imino-methyl}- carbamic acid tert-butyl ester (0.048 g, 0.094 mmol), (Example 120:step b), MeOH [4 mL], acetic acid (0.057 g, 0.942 mmol). Chromatography (5%-40% EtOAc/Hx) yielded the title compound (0.049 g 18%). ESI-MS (m/z): Calcd. for C41H57N5O10S4: 909.18 (M+H); found 907.8, 908.9. d) 4-{4'-[N'-(5-Methanesulfonyl-pentyl)-guanidino]-2'-methyl- biphenyl-3-sulfonyl}-5~methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate [Imino-(4-{4'-[N'-(6-methanesulfonyl-hexyl)-N',N"-(carbarnic acid tert-butyl ester)-guanidino]-2'-methyl-biphenyl-3-sulfonyl}-5-methylsulfanyl- thiophen-2-yl)-methyl]-carbamic acid tert-butyl ester (0.049 g, 0.054 mmol) was dissolved in 1:1 solution of trifluoroacetic acid:dichloromethane [3 mL:3 mL]. Solution was allowed to stir at room temperature for 2 hours. The reaction was concentrated in vacuo followed by reverse-phase HPLC [acetomtrile/water (0.01%TFA)] to give the title compound (0.030 g, 92%). ESI-MS (m/z): Calcd. for C26H33N5O4S4: 608.84 (M+H); found 608.2. Example 174 (5-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6- methyl-biphenyl-2-yl]-ureido}-pentyl)-phosphonic acid trifluoroacetate a) [5-(l,3-Dioxo-l,3-dihydro-isoindol-2-yl)-pentyl]-phosphonic acid diethyl ester Added bromophthalamide (0.400 g, 1.351 mmol) and trimethylphosphite (0.900 mL, 5.250 mmol) together in flask containing stirbar. Heat reaction to 80°C for 18 hours. Reaction was cooled to room temperature followed by chrornatography (50%-100% EtOAc/Hx) to yield the title compound (0.300 g, 62%). ESI-MS (m/z): Calcd. for C21H24NO5P: 354.35 (M+H); found 354.1. b) (5-Amino-pentyl)-phosphonic acid diethyl ester [5-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-pentyl]-phosphonic acid diethyl ester (0.300 g, 0.849 mmol) was dissolved in THF [2 mL], IPA [4 mL]. Hydrazine (0.081 g, 2.540 mmol) was added to this solution and stirred at room temperature for 18 hours. The white precipitate was filtered and washed with dichloromethane. Removal of the solvent in vacuo yielded the title compound (0.136 g, 72%) 1H-NMR (CDCl3): d 4.07 (m, 4H), 2.68 (t, 2H, J=6.74 Hz), 1.72 (m, 2H), 1.60 (m, 2H), 1.43 (m, 4H), 1.31 (m, 6H). c) [5-(3-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-ureido)- pentyl]-phosphonic acid {[4-(6'-Amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiopheri-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.100 g, 0.204 mmol), (Example 25:step c), 4-nitrophenyl chloroformate (0.041 g, 0.204 mmol), pyridine (0.018 g, 0.224 mmol), DCM [3 mL] were added to a flask containing a stirbar. This solution was stirred at room temperature for 2.5 hours. To this solution was added (5-Amino-pentyl)-phosphonic acid diethyl ester (0.136 g, 0.611 mmol) and Triethylamine (0.062 g, 0.611 mmol). Solution was stirred at room temperature for 18 hours. Reaction was concentrated in vacuo followed by chromatography (50%-100% EtOAc/Hx) to yield title compound (0.138 g, 88%). ESI-MS (m/z): Calcd. for C34H47N4O8PS3: 767.93 (M+H); found 667.1. d) (5-{3-[3'-(5-Carbaniimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)- 6-methyl-biphenyl-2-yl]-ureido}-pentyl)-phosphonic acid [5-(3-{3'-[5-(teit-Butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-ureido)- pentyl]-phosphonic acid (0.058 g, 0.076 mmol), trimethylsilyl iodide (0.162 g, 0.756 mmol) and DCM [5 mL] were added to a flask and heated to 40°C for 10 minutes. The reaction was removed from the heat bath and allowed to stir at room, temperature for 1 hour. H2O [56 µL] was added to this solution and stirred for 1 hour. The reaction was concentrated in vacuo. MeOH [2 mL] and 20 wt.% HC1 (aq.) [84 µL] were added to the concentrate and allowed to stir at room temperature for 18 hours. Reaction was concentrated in vacuo followed by reverse-phase HPLC [acetonitrile/water (0.01 %TFA)] to yield the title compound. ESI-MS (m/z): Calcd. for C25H31N4O6PS3: 611.71 (M+H); found 611.0. Example 175 N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfony])-6-methyl- biphenyl-2-yl]-4-methanesulfonyl-butyratnidehydrochloride a) (Imino-{4-[6'-(4-methanesulfonyl-butysylamino)-2'-methyl-biphenyl- 3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert- butyl ester {[4-(6'-Amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.500 g, 2.020 mmol), (Example 25:step c), triethylamine (0.153 g, 3.030 mmol), and DCM [30mL] were added to a flask containing a stirbar. 4-Methanesulfonyl-butyryl chloride (0.013 g, 0.611 mmol) was added slowly while monitoring reaction. Reaction was concentrated in vacuo followed by chromatography (50%-80% EtOAc/Hx). Material was dissolved in a solution of trifluoroacetic acid/dichloromethane (1:1), [4mL]. This solution stirred at room temperature for 2 hours. Reaction was concentrated in vacuo followed by reverse-phase HPLC [acetonitrile/water (0.01%TFA)] to yield title compound (0.138 g, 88%). ESI-MS (m/z): Calcd. for C24H27N3O5S4: 566.75; found 566.1. Example 176 {[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-methyl- biphenyl-4-ylamino]-methyl}-phosphonic acid a) ({3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl- thiophetie-3-sulfonyl]-2-methyl-biphenyl-4-ylamino}-methyl)-phosphonic acid diethyl ester To a mixture of {[4-(4'-amino-2'-raethyl-biphenyl-3-sulfonyl)--5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (30 mg, 58.0 µmol), as prepared according to the procedure of step b of Example 120, cesium carbonate (19 mg, 58 µmol), and N,N- dimethylacetamide (0.4 mL) was added a solution of trifluoro- methanesulfonic acid diethoxy-phosphorylmethyl ester (18 mg, 58 µmol) (Xu, Y. et al., J. Org. Chem. 61, 7697 (1996); Phillion, D. et al., Tetrahedron Lett. 27, 1477 (1986)), and heated at 50 °C for 48 h. Additional trifluoro- methanesulfonic acid diethoxy-phosphorylmethyl ester (18 mg, 58 µmol) was added. The mixture was heated at 50 °C for additional 24 h. Solvent was evaporated. The resulting mixture was partitioned between DCM and H2O. Aqueous layer was separated and extracted with DCM. All the DCM layers were combined, washed with H2O and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel column, eluting with EtOAc/DCM (20 and 30 %) to give the title compound (38 mg, 98 % yield) as an orange oil. 1H NMR (CDCl3): d 8.23 (s, 1H), 7.92-7.88 (m, 2H), 7.53-7.46 (m, 2H), 6.98 (d, IH,J= 8.0 Hz), 6.56-6.53 (m, 2H), 4.23-4.15 (m, 4H), 3.56 (d, 2H, J = 12.5 Hz), 2.43 (S, 3H), 2.16 (S, 3H), 1.52 (S, 9H), 1.35 (t, 6H, ./= 7.0 Hz). ESI-MS (m/z): Cald. For C29H39N3O7PS3: 668.2 (M+H); found: 667.8. b) {[3'-(5-Carbamunidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2- methyl-biphenyl-4-ylamino]-methyl}-phosphonic acid To a solution of ({3'-[5-(tert-butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-svilfonyl]-2-methyl-biphenyl-4-ylamino}-methyl) phosphonic acid diethyl ester (38 mg, 0.057 mmol) in DCM (1.2 mL) at 0 °C was added iodotrimethylsilane (25 µL) over 3 minutes period. After 1 h at 0 °C, H2O was added. The mixture was stirred for 30 minutes, and then concentrated to give a brown solid. The solid was dissolved in MeOH (1.32 mL), 20 % HC1 was added, and stirred at ambient temperature for 3h. The mixture was concentrated to give a brown solid. To this solid was added TFA/DCM (1:1, 3 mL) and stirred at ambient temperature for 40 minutes. The reaction mixture was then concentrated and purified by HPLC (C18 column, 10-70 % CH3CN over 30 minutes) to give the title compound (11 mg, 38 % yield) as a white solid. ESI-MS (m/z): Cald. For C20H23N3O5PS3: 512.1 (M+H); found: 512.1. Example 177 5-Methylsulfanyl-4-(2'-methyl-4'-trifluoromethanesulfonylamino-biphenyl-3- sulfonyl)-1:hiophene-2-carboxamidine trifhioroacetate a) {Imino-[5-methylsulfanyl-4-(2'-methyl-4'- trifluoromethanesulfonylamino-biph enyl-3-sulfonyl)-thiophen -2-yl]- methyl]-carbamic acid tert-butyl ester To a solution of {[4-(4'-amino-2'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid ten-butyl ester (34 mg, 66 µmol), as prepared according to the procedure of step b of Example 120, and DIEA (28 µL, 0.16 mmol) in DCM (1.0 mL) in an ice-H2O bath was added trifluoromethanesulfonic anhydride (12 µL, 72 µmol) with stirring. After the ice bath expired, the mixture was continued to stir at ambient temperature for 16 h, and then poured into saturated NaHCO3, and extracted with EtOAc (2 x). The extracts were combined, washed with H2O and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel column, eluting with EtOAc/hexane (20 to 40 %) to give the title compound (9 mg, 21% yield) as an oil. ESI-MS (m/z): Cald. For C15H27F3N3O6S4: 650.1 (M+H); found: 649.6. b) 5-Methylsulfanyl-4-(2'-methyl-4'-trifluoromethanesulfonylainino- biphenyl-3-sulfonyl)-thiophene-2-carboxamidine trifluoroacetaie A mixture of {imino-[5-methylsulfanyl-4-(2'-methyl-4'- trifluoromethanesulfonylamino-biphenyl-3-sulfonyl)-thiophen-2-yl]-methyl}- carbamic acid tert-butyl ester (9 mg, 14 µmol) in TFA/DCM (1:1, 3mL) was stirred at ambient temperature for 40 min. The mixture was concentrated, and flashed chromatographed on silica gel column, eluting with MeOH/DCM (5 to 8%) to give the title compound (5 mg, 54% yield) as a pale yellow solid. 1H KMR (CDCl3): d S.32 (s, 1H), 8.04-8.01 (m, 1H), 7.96-7.95 (m, 1H), 7.68- 7.66 (m, 2H), 7.17 (m, 3H), 2.72 (s, 3H), 2.21 (s, 3H), ESI-MS (m/z): Cald. For C20H19 F3N3O4S4: 550.0 (M+H); found: 550.0. Example 178 3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl- biphenyl-2-ylmethoxy]-propionic acid a) 3-{3'-[5-(tert-Butoxycarbonylamino-imino-inethyl)-2-methylsulfanyl- thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylmethoxy}-propionic acid ethyl ester To a suspension of NaH (2.7 mg, 68 µmol, 60% oil dispersion) in DMF (0.1 mL) was added a solution of {[4-(2'-hydroxymethy[-6'-methyl- biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen--2-yl]-imino-methyl}- carbamie acid tert-butyl ester (30 mg, 56.4 µmol) in DMF (0.1 mL), as prepared according to the procedure of step b of Example 213. The mixture was stirred at ambient temperature for 30 min, and then placed in an ice-water bath. After 20 min, a solution of ethyl 3-bromopropionate (8.6 µL, 67.0 µmol) in DMF (0.05 mL) was added once. Ice-water bath was removed, and the mixture was stirred for 16 h. H2O was added, and the mixture was extracted with EtOAc (3x). The extracts were combined, washed with H2O, dried over Na2SO4, concentrated, and flash chromatographed on silica gel, eluting with EtOAc/DCM (15 %) followed by EtOAc/hexane (40%) to give the title compound (9 mg, 25%) yield) as an oil. 1H NMR (CDCl3): 8 7.99 (d, 1H, J= 7.7 Hz), 7.88 (s, 1H), 7.68 (s, 1H), 7.60- 7.56 (m, 1H), 7.44 (d, 1H, J= 7.6 Hz), 7.38 (d, 1H, .7=7.4 Hz), 7.34-7.30 (m, 1H), 7.23 (d, 1H, J = 7.3 Hz), 4.27-4.09 (m, 4H), 3.78 (bs, 2H), 2 67 (t, 2H, J = 5.9 Hz), 2.57 (s, 3H), 2.02 (s, 3H), 1.47 (s, 9H), 1.28 (t, 3H,J= 7.1 Hz). ESI-MS (m/z): Cald. For C30H37N2O7S3: 633.2 (M+H); found: 632.9. b) 3-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl- thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylmethoxy}-propionic acid To a solution of 3-{3'-[5-(tert-butoxycarbonylammo-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylmethoxy}- propionic acid ethyl ester (7.0 mg, 11 µmol) in THF (0.5 mL) and MeOH (0.25 mL) was added a solution of lithium hydroxide monohydrate (0.56 mg, 13 µmol) in H2O (50 mL). The mixture was microwaved at 80 °C for 150 seconds, acidified with 0.25 N HC1. to ~ pH 3, extracted with EtOAc/DCM (1:1, 3x). The extracts were combined, washed with H2O, dried over Na2SO4, concentrated, and flash chromatographed on silica gel column, eluting with MeOH/DCM (2 to 4%) to give the title compound (5.1 mg, 76% yield) as a white solid. 1H NMR (CDCl3): d 8.03-8.00 (m, 1H), 7.88-7.87 (m, 1H), 7.70 (bs, 1H), 7.57 (t, 1H, J= 7.7 Hz), 7.43-7.40 (m, 1H), 7.36-7.28 (m, 2H), 7.23 (d, 1H, J= 6.9 Hz), 4.28-4.15 (m, 2H), 3.65-3.75 (m, 2H), 2.65 (t, 2H, J =6.0 Hz), 2.58 (s, 3H),2.01 (s, 3H). ESI-MS (m/z): Cald. For C28H33N2O7S3: 605.1 (M+H); found: 604.8. c) 3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6- methyl-biphenyl-2-ylm ethoxy]-propionic acid A mixture of 3-{3'-[5-(tert-butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylmethoxy}- propionic acid (5.1 mg, 8.4 µmol) in TFA/DCM (1:1, 1.5 mL) was stirred at ambient temperature for 1 h. The mixture was concentrated and flash chromatographed on silica gel, eluting with MeOH/DCM (5 to 12 %) to give the title compound (3.0 mg, 69 % yield) as a white solid. 1H NMR (CD3OD): d 8.18 (s, 1H), 8.03-8.00 (m, 1H), 7.88 (t, 1H, 7= 1.6 Hz), 7.68 (t, 1H, J= 7.8 Hz), 7.54-7.52 (m, 1H), 7.41 (d, 1H, J= 7.6 Hz), 7.33 (t, 1H, J= 1.6 Hz), 7.24 (d, 1H, J= 7.4 Hz), 4.23-4.16 (m, 2H), 3.64 (t, 2H, .J= 6.1 Hz), 2.69 (s, 3H), 2.54 (t, 2H,J= 6.0 Hz), 1.99 (s, 3H). ESI-MS (m/z): Cald. for C23H24N2O5S3: 505.1 (M+H); found: 505.1. Example 179 5-Methylsulfanyl-4-(6'-methyl-2'- {3-[4-(2H-tetrazol-5-yl)-butyl]-ureido} - biphenyl-3-sulfonyl)-thiophene-2-carboxamidinetrifluoroacetate a) 5-(l,3-Dioxo-l,3-dihydro-isoindol-2-yl)-pentanenitrile To a solution of 5-bromovaleronitrile (5.12 g, 30.0 mmol) in DMF (40 mL) was added potassium phthalimide (6.00 g, 32.4 mmol). The above suspension was heated at 60 °C for 16 h, concentrated, and partitioned between H2O and DCM. The DCM layer was separated, washed with H2O (3x) and brine, dried over Na2SO4, and concentrated to give the title compound (6.84 g, quantitative yield) as a white solid. lH NMR (CDCl3): 8 7.87-7.80 (m, 2H), 7.76-7.70 (m, 2H), 3.73 (t, 2H, J = 6.1Hz), 2.43 (t, 2H, J= 7.1 Hz), 1.89-1.82 (m, 2H), 1.74-1.67 (m, 2H). ESI-MS (m/z): Cald. For C13H13N2O2: 229.1 (M+H); found: 229.1. b) 2-[4-(2H-Tetrazol-5-yl)-butyl]-isoindole-l,3-dione To a solution of 5-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-pentanenitrile (6.84 g, 30 mmol) and azidotrimethylsilane (14 mL, 108 mmol) in toluene (40 mL) was added dibutyltin oxide (2.1g, 6.0 mmol). The mixture was heated at 100 °C for 48 h, concentrated, and flash chromatographed on silica gel column, eluting with EtOAc/DCM (30 and 60 %) followed by methanol/DCM (2.5 and 5%) to give the title compound (6.72 g, 83 % yield) as a white solid. 1H NMR (DMSO): 6 7.86-7.80 (m, 4H), 3.59 (t, 2H,.J = 6.8 Hz), 2.90 (t, 2H, J = 7.1 Hz), 1.74-1.58 (m,4H). ESI-MS (m/z): Cald. For C13H14N5O2: 272.1 (M+H); found: 272.0. c) 2-[4-(2-Trityl-2H-tetrazol-5-yl)-butyl]-isoindole-l,3-dione To a solution of 2-[4-(2H-tetrazol-5-yl)-butyl]-isoindole-l,3-dione (4.07 g, 15.0 mmol) and diisopropylethylamine (7.8 mL, 45.0 mmol) in DCM (60 mL) was added trityl chloride (5.86 g, 21.0 mmol). The solution was stirred at ambient temperature; for 14 h, and concentrated. The resulting residue was partitioned between EtOAc/DCM (3:1) and H2O. Organic layer was separated, washed, with H2O and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel, eluting with DCM/hexane (40, 80, and 100 %) followed by EtOAc/DCM (1 and 2%) to give the title compound (5.08 g, 66% yield) as a pale yellow solid. 1H NMR (CDCl3): d 7.S7-7.82 (m, 2H), 7.74-7.70 (m, 2H), 7.36-7.31 (m, 9H), 7.12-7.09 (m, 6H), 3.71 (t, 2H, J= 7.1 Hz), 2.99 (t, 2H,./= 7.2 Hz), 1.89-1.71 (m, 4H). d) 4-(2-Trityl-2H-tetrazol-5-yl)-butylamine To a solution of 2-[4-(2-trityl-2H-tetrazol-5-yl)-butyl]-isoindole-l,3- dione (175 mg, 0.313 mmol) in 2-propanol / THF (2:1, 3.0 mL) was added hydrazine (30 mL, 0.939 mmol). The solution was stirred at ambient temperature for 16 h. White solid was filtered off and washed with DCM (5x). The filtrate and the washings were combined, concentrated, dissolved in DCM, washed with H2O (2x) and brine, dried over Na2SO4, and concentrated to give the title compound (131 mg, 97 % yield) as apale yellow oil. 1H NMR (CDCl3): d 7.36-7.28 (m, 9H), 7.12-7.09 (m, 6H), 2.93 (t. 2H, J= 7.6 Hz), 2.69 (t, 2H, J= 7.0 Hz), 1.S4-1.77 (m, 2H), 1.52-1.45 (m, 2H). e) {Imino-[5-methylsulfanyl-4-(6'-methyl-2'-{3-[4-(2-trityl-2H-tetrazol- 5-yl)-butyl]-ureido}-biphenyl-3-sulfonyl)-thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester To a solution of {[4-(2'-ammo-6'-methyl-biphenyl-3-sulfonyl)5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (60 mg, 0.116 mmol), as prepared according to the procedure of step c of Example 25, and pyridine (10 mg, 0.12S mmol) in DCM (1.1 mL) was added 4-nitrophenyl chloroformate (23 mg, 0.116 mmol), and stirred at ambient temperature for 4 h. To the above mixture was added a solution of 4-(2-trityl- 2H-tetrazol-5-yl)-butylamine (65 mg, 0.151 mmol) in DCM (0.65 mL), and stirred for 4S h. The mixture was concentrated and purified on a preparative TLC plate (1000 µm), developing with EtOAc/DCM (5 and 20 %) to give the title compound (15 mg, 14% yield) as a yellow solid. 1H NMR. (CDCl3): d 7.95 (d, 1H, J= 7.93 Hz), 7.88 (t, 1H, J= 1.6 Hz), 7.74 (s, 1H), 7.56 (t, 1H, J= 7.7 Hz), 7.44-7.42 (m, 1H), 7.35-7.28 (m, 13 H), 7.23- 7.19 (m, 1H), 7.11-7.08 (m, 7H), 4.94 (t, 1H, J == 5.5 Hz), 3.26-3.16 (m, 2H), 2.91 (t, 2H, J= 7.3 Hz), 2.62 (s, 3H), 2.10 (s, 3H), 1.80-1.72 (m, 2H), 1.56- 1.44 (m, 1H). ESI-MS (m/z): Cald. For C49H51N8O5S3: 927.3 (M+H); found: 926.8. f) 5-Methylsulfavyl-4-(6'-methyl-2'-{3-[4-(2H-tetrazol-5-yl)-butyl]- ureido}-biphenyl-3-sulfonyl)-thiophene-2-carboxamidine trifluoroacetate A solution of {immo-[5-methylsulfanyl-4-(6'-methyl-2T-{3-[4-(2-trityl- 2H-tetrazol-5-yl)-butyl]-ureido}-biphenyl-3-sulfonyl)-thiophen-2-yl]-methyl}- carbamic acid tert-butyl ester (15 mg, 16 µmol) in TFA/DCM (1:1, 2.0 mL) was stirred at ambient temperature for 1 h. The mixture was concentrated, and flash chromatographed on silica gel column, eluting with MeOH/DCM (3 to 7.5 % containing 0.1 % TFA) to give the title compound (5 mg, 45% yield) as a white solid. 1H NMR (CDCl3): d 8.29 (s, 1H), 8.02-8.00 (m, 1H), 7.88 (t, 1H, J= 1.7 Hz), 7.67 (t, 1H, J= 7.7 Hz), 7.56-7.53 (m, 1H), 7.42 (d, 1H, J= 7.8 Hz), 7.28 (t, 1H, J= 7.7 Hz), 7.12 (d, 1H, J= 7.5 Hz), 3.05 (t, 2H, J= 6.4 Hz), 2.92 (t, 2H, J= 7.5 Hz), 2.70 (s, 3H), 2.92 (s, 3H), 1.73-1.65 (m, 2H), 1.44-1.36 (m, 2H) ESI-MS (rn/z): Cald. For C25H29N8O5S3: 585.1 (M+H); found: 5S5.0. Example ISO 5-Methylsulfanyl-4-(6'-methyl-2'-{3-[5-(2H-tetrazol-5-yl)-pentyl]-ureido}- biphenyl-3-sulfonyl)-thiophene-2-carboxamidine trifluoroacetate The title compound was; prepared from 6-bromohexanenitrile according to the procedures in Example 179. 1H NMR (CD3OD): d 8.30 (s, 1H), 8.05-8.02 (m, 1H), 7.89 (t, 1H, J= 1.6 Hz), 7.69 (t, 1H, J= 7.8 Hz), 7.56-7.54 (m, 1H), 7.42 (d, 1H, J= 7.8 Hz), 7.28 (t, 1H,J= 7.8 Hz), 7.11 (d, 1H, J= 7.5 Hz), 3.00 (t, 2H, J= 6.5 Hz), 2.93 (t, 2H, J= 7.5 Hz), 2.70 (s, 3H), 1.99 (s, 3H), 1.78-1.71 (m, 2H), 1.42-1.34 (m, 2H), 1.30-1.25 (m,2H). ESI-MS (m/z): Cald. For C26H31N8O3S3: 599.2 (M+H); found: 599.0. Example 181 5-Methylsulfanyl-4-(6'-methyl-2'-{3-[2-(2H-tetrazol-5-yl)-ethyl]-ureido}- biphenyl-3-sulfonyl)-thiophene-2-carboxamidine trifluoroacetate a) {Imino-[5-methylsulfanyl-4-(6'-methyl-2'-{3-[2-(2H-tetrazol-5-yl)- ethyl]-ureido}-biphenyl-3-sulfonyl)-thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester A mixture of [(4-{2'-[3-(2-cyano-ethyl)-ureido]-6'-methyl-biphenyl-3- sulfonyl} -5-methylsulfanyl-thiaphen-2-yl)-immo-methyl]-carbamic acid tert- butyl ester (31 mg, 51 µmol), as prepared from {[4-(2'-amino-6'-methyl- biphenyl-3-sulfonyl)-5-methylsulfany]-thiophen-2-yl]-imino-methyl}- carbamic acid tert-butyl ester and 3-aminopropionitrile according to the procedure of step e of Example 179, azidotrimethylsilane (40 µL, 0.30 mmol), dibutyltin oxide (3.5 mg, 10 µmol), and toluene (1.5 mL) was heated at 70 °C for 16 h and 80 °C for 4h. The mixture was concentrated and purified by flash chromatography on silica gel, eluting with EtOAc/DCM (50, 100 %) followed by MeOH/DCM (5, 10 %) to give the title compound (14 mg, 42 % yield) as a colorless oil. 1H NMR (CDCl3): d 8.00 (s, 1H), 7.75-7.71 (m, 2H), 7.34-7.29 (m, 3H), 7.21 (t, 1H, J = 7.8 Hz), 7.10-1.01 (m, 2H), 6.58 (bs, 1H), 6.00 (bs, 1H), 3.60 (bs, 2H), 3.04 (bs, 2H), 2.52 (s, 3H), 1.93 (s, 3H), 1.49 (s, 9H). ESI-MS (m/z): Cald. For C28H33N8O5S3: 657.2 (M+H); found: 656.8. b) S-Methylsulfanyl-4-(6'-methyl-2'-{3-[2-(2H-tetrazol-5-yl)-ethyl]- ureido}-biphenyl-3-sulfonyl)-thiophene-2-carboxamidine trifluoroacetate A solution of {imino-[5-methylsuIfanyl-4-(6'-methyl-2'-{3-[2-(2H- tetrazol-5-yl)-ethyl]-ureido}-biphenyl-3-sulfonyl)-thiophen-2-yl]-methyl}- carbamic acid tert-buryl ester (10 mg, 15.3 fimol) in TFA/DCM (2.0 mL, 1:1) was stirred at ambient temperature for 1.5 h. The reaction mixture was concentrated to dryness, and flash chromatographed on silica gel column, eluting with 10% MeOH/DCM containing 0.1 % TFA to give the title compound (4.7 mg, 46 % yield) as a white solid. 1H NMR (CD3OD): d 8.29 (s, 1H), 8.03-S.01 (m, 1H), 7.86 (t, 1H, J=1.6 Hz), 7.68 (t, 1H, J= 7.8 Hz), 7.52-7.50 (m, 1H), 7.42 (d, 1H, J= 7.9 Hz), 7.2S (1, 1H, J= 7.7 Hz), 7.12 (d, 1H, J- 7.5 Hz), 3.48-3.41 (ra, 2H), 3.00 (t, 2H, .J = 6.7 Hz), 2.70 (s, 3H), 1.99 (s, 3H). ESI-MS (m/z): Cald. For C23H25N8O3S3: 557.1 (M+H); found: 557.0. Example 182 5-Methy]sulfanyl-4-(2'-methyl-4'- {3-[4-(2H-tetrazol-5-yl)-butyl ]-ureido} - biphenyl-3-sulfonyl)-thiophene-2-carboxamidine trifluoroacetate According to the procedures of Example l79, the title compound was synthesized from {[4-(4'-amino-2'-methyl-biphenyl-3-sulfonyr)-5- methylsulfariyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester, which was prepared using the procedure of step b of Example 120. 1H NMR (CD3OD): d 8.32 (s, 1H), 8.00-7.95 (m, 2H), 7.66-7 65 (m, 2H), 7.31-7.27 (m, 2H), 7.10 (d, 1H, J= 8.3 Hz), 3.26 (t, 2H, J= 6.8 Hz), 3.00 (t, 2H, J= 7.5 Hz), 2.72 (s, 3H), 2.20 (s, 3H), 1.90-1.82 (m, 2H), 1.64-1.57 (m, 2H) ESI-MS (m/z): Cald. For C25H29N8O5S3: 585.1 (M+H); found: 585.0. Example 183 4-[4'-(N'-Acetyl-guanidino)-2'-methyl-biphenyl-3-sulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate a) l-Acetyl-l,3-bis-tert-butoxycarbonylimino-2-methyl-isothiourea To a solution of l,3-bis-tert-butoxycarbonylimino-2-methyl- isothiourea (2.33 g, 8.0 mmol) in dichloromethane (DCM) (8.0 mL) was added diisopropylethylamirte (DIEA) (2.79 mL, 16.0 mmol) and acetyl chloride (0.60 mL, 8.4 mmol) and stirred at ambient temperature for 2 hours. Additional DIEA (2.79 mL, 16.0 mmol) and acetyl chloride (0.60 mL, 8.4 mmol) were added. After 1 hour the mixture was concentrated to dryness, partitioned between dichloromethane and saturated NaHCO3. Organic layer was separated, washed with H2O and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel column, eluting with DCM/hexane (40 %, 100 %) to give the title compound (2.60 g, 97% yield) as a yellow oil. 1H NMR (CDCl3): d 2.48 (s, 3H), 2.46 (s, 3H), 1.52 (s, 9H), 1.47 (s, 9H). b) 4-[4'-(N'-Acetyl-guanidino)-2'-methyl-biphenyl-3-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate To a solution of {[4-(4'-amino-2'-rnethyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (60 mg, 0.116 mmol), as synthesized from {[4-(4'-amino-2'-methyl-biphenyl- 3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester using the procedure of step b of Example 120, and 1-acetyl- l,3-bis-tert-butoxycarbonylimino-2-methyl-isothiourea (193 mg, 0.5S mmol) in methanol (4.0 mL) was added acetic acid (66 µL, 1.16 mmol) and heated at 40 °C for 16 h. Triethylamine (0.25 mL) was added. The mixture was concentrated to dryness followed by flash chromatography on silica gel column, eluting with ethylacetate / DCM (5, 10 15%) to deliver the guanidinated product (60 mg) as a yellow solid. This solid was treated with trifluoroacetic acid/DCM (6 mL, 1:1) at ambient temperature for 1 h, and concentrated to dryness. The resulting residue was purified via HPLC (C18- column, 20-65 % CH3CN over 25 min) to give the title compound (33 mg, 49 % yield) as a white solid. 1H NMR (CD3OD): d 8.32 (s, 1H), 8.02-7.98 (m, 1H), 7.96 (s, 1H), 7.67-7.66 (m, 2H), 7.50-7.48 (m, 2H), 7.15 (d, 1H, J = 8.0 Hz), 2.72 (s, 3H), 2.22 (s, 3H),2.14(s, 3H). Example 184 4-{4'-Guanidino-2'-[3-(4-methanesulfonyl-butyl)-ureido]-6'-methyl-biphenyl- 3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxarnidine trifluoroacetate a) [(4-{4'-Amino-2'-[3-(4-methanesulfonyl-butyl)-ureido]-6'-metltyl- biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophen-2-yl)-imino-methyl]- carbamic acid tert-butyl ester To a solution of a) {3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene- 3-sulfonyl)-2-[3-(4-methanesu]fonyl-butyl)-ureido]-6-methyl-biphenyl-4-yli- carbamic acid 2-trimethyl silanyl-ethyl ester (148 mg, 0.173 mmol), as prepared from 4-methanesulfonyl-butylamine (step c of Exampl 202) and [2- ammo-3'-(5-carbamoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl- biphenyl-4-yl]-carbamic acid 2-trimethylsilanyl-ethyl ester (step c of Example 294) using the procedure of step e of Example 179, in THF (5.0 rnL) was added a solution of tetrabutylammonium fluoride in THF (0.87 mL, 0.87 mmol, 1.0 M) over 5 minutes period. The mixture was then heated at 50 °C for 30 minutes, concentrated, and flash chromatographed on silica gel column, eluting with EtOAc followed by methanol/DCM (2.5, 5%) to give the title compound (100 mg, 82% yield) as a yellow solid. 1HNMR (CD3OD): d 8.16 (s, 1H), 7.98-7.95 (m, 1H), 7.85 (t, 1H, J = 1.6 Hz), 7.64 (t, 1H, J = 7.8 Hz), 7.50-7.48 (m, 1H), 6.82 (d, 1H, J = 2.2 Hz), 6.49-6.48 (m, 1H), 3.11-3.02 (m, 4H), 2.94 (s, 3H), 2.65 (s, 3H), 1.90 (s, 3H), 1.73-1.67 (m, 2H), 1.51-1.46 (m, 1H). b) l(4-{4'-(N',N'-Di-tert-tert-butoxycarbonyl-guanidino)-2'-[3-(4- methanesitlfonyl-butyl)~ureido]-6'-methyl-biphenyl-3-sulfonyl}-5- niethylsulfanyl-thiophen-2-yl)-imino-methyl]-carbamic acid tert-butyl ester To a mixture of [(4-{4'-amino-2'-[3-(4-methanesulfonyl-butyl)-ureido]- 6'-methyl-biphenyl-3-sulfonyl}-;i-methylsulfanyl-thiophen-2-yr)-imino- methylj-carbamic acid tert-butyl ester (100 mg, 0.141 mmol), 1,3-bis-tert- butoxycarbonylimino-2-methyl-isothiourea (205 mg, 0.705 mmol), and methanol (5.0 mL) was added acetic acid (0.081 mL, 1.41 mmol), and heated at 40 °C for 16 h. Triethylamine (0.3 mL) was added. The mixture was concentrated, and flash chromatographed on silica gel column, eluting with EtOAc /DCM (0 to 40 %) to afford the title compound (110 mg, S2 % yield) as an off-white solid, 1H NMR (CD3OD): S 8.19 (s, 1H), 8.04-8.02 (m, 1H), 7.S7 (t, 1H, ./= 1.6 Hz), 7.70 (t, 1H, J= 7.9 Hz), 7.63 (bs, 1H), 7.51-7.54 (m, 1H), 7.35 (bs, 1H), 3.11- 3.04 (m, 4H), 2.93 (s, 3H), 2.64 (s, 3H), 1.98 (s, 3H), 1.76-1.68 (m, 2H), 1.58 (bs, 9H), 1.54-1.46 (m, 20 H). c) 4-{4'-Guanidino-2'-[3-(4-methanesulfonyl-butyl)-ureido}-6'-methyl- bipheny1-3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate To a flask charged with [(4-{4'-(N',N"-di-tert-butoxycarbonyl- guanidino)-2'-[3-(4-methanesulfonyl-butyl)-ureido]-6'-methyl-bipiienyl-3- sulfonyl}-5-methylsulfanyl-thiophen-2-yl)-imino-methyl]-carbam]c acid tert- butyl ester (110 mg, 0.116 mmol) was added a solution of trifluoroacetic acid in DCM (3.0 mL, 50 %) and stirred at ambient temperature for 1h. The mixture was concentrated, and purified by HPLC (C18-column, 5-50% CH3CN in H2O over 15 min.) to give the title compound (63 mg, 62 % yield) as a white solid. 1H NMR (CD3OD): d 8.34 (s, 1H), 8.08-8.05 (m, 1H), 7.91 (t, 1H, J= 1.7 Hz), 7.76 (t, 1H, J= 7.9 Hz), 7.57-7.52 (m, 2H), 7.00 (d, 1H, J= 1.7 Hz), 3.13-3.10 (m, 4H), 2.95 (s, 3H), 2.71 (s, 3H), 2.00 (s, 3H), 1.78-1.71 (m, 2H), 1.57-1.50 (m, 2H). ESI-MS (m/z): Cald. For C26H34N7O5S4: 652.1 (M+H); found: 652.1. Examples 185-186 4-[7-Cliloro-3-(2,6-difluoro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidme trifluoroacetate 4-[7-Chloro-l-(2,6-difluoro-benzyl)-lH-benzoimidazole-5-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate a) Sodium salt of5-methyisulfanyl-4-sulfino-thiophene-2-carboxylic acid methyl ester 4,6-Dichloro-spiro[benzoimidazole-2,1'-cyclohexane] 4-(7-Chloro-spiro[benzoimidazole-2,1'-cyclohex]e-5-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxylic acid methyl ester A solution of 4.6-dk:hloro-spiro[benzoimidazole-2,1'-cyclohexane] {{made according to literature preparation: Hazelton, C. J. et al.., Tetrahedron, 51:5597 (1995)) 0.200 g, 0.729 mmol) in absolute ethanol (5 mL) was treated with the sodium salt of 5-methylsulfanyl-4-sulfino-thiophene- 2-carboxylic acid methyl ester {{Example 38: step b) 0.200 g, 0.729 mmol) as a solution in watenethanol (2:1, 3.3 mL). Acetic acid was added and the reaction stirred at room temperature 21.5 h. The reaction mixture was poured over ice water and the ethanol was removed in vacuo. The resulting aqueous mixture was extracted with CH2Cl2 (4 x 25 mL). The combined organic layers were washed with brine and dried over Na2SO4. The solvents were removed in vacuo to afford the product 4-(7-chloro-spiro[benzoimidazole-2,1'- cyclohex]e-5-sulfonyl)-5-rnethylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.307 g, 89%) as a brown oil. 1H NMR (CDCl3): d 3.051 (d, 1H, J= 1.2 Hz), 8.038 (s, 1H), 7.381 (d, 1H, J = 1.2 Hz), 3.908 (s, 3H), 2.662 (s, 3H), 1.964 (m, 1 OH). b) 4-(3,4-Diamino-5-chloro-benzenesulfonyl)-5~methylsulfanyl- thiophene-2-carboxylic acid methyl ester A solution of 4-(7-chloro-spiro[benzoimidazole-2,1'-cyclohex]e-5- sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (from above step a, 0.307 g, 0.652 Mmol) in ethanol:water (1:1, 6.4 mL) was treated with Na2S2O4 and heated to 80 °C 1.5 h. The mixture was cooled, poured over ice water, and extracted with CH2CI2 (4 x 25 mL). The combined organic layers were washed with brine and dried over Na2SO4. The solvents were removed in vacuo to afford the product 4-(3,4-diamino-5-chloro- benzenesuifonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.224 g, 87%) as a brown oil. Formic acid (4.5 mL) was added and the resulting solution was refrigerated for storage overnight due to the instability of the free diamine. c) 4-(7-Chloro-lH-benzoimidazole-5-sulfofiyl)-5-methylsulfanyl- thiophette-2-carboxylic acid methyl ester The refrigerated solution of 4-(3,4-diamino-5-ch[oro-berv2eiiesuIfonyi)~ 5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((from above step b) 0.224 g, 0.570 mmol) in formic acid (4.5 mL) from above was allowed to slowly warm to room temperature and then heated to reflux (110 °C) 5 h. The mixture was cooled to room temperature and poured over ice. The pH was adjusted to pH 8 by carefully adding solid NaHCO3 portionwise with stirring. The aqueous solution was extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed in vacuo to afford the product 4-(7-chloro-lH-benzoimidazole- 5-sulfonyl)-5-methylsulfanyl-1:hiophene-2-carboxylic acid methyl ester (0.201 g, 87%) as a brown foamy solid. The crude material was used directly in the next reaction. d) 4-[7-Chloro-3-(2,6-difluoro-benzyl)-3H-benzoimidazole-5-sulfonyl]- 5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester 4-[7-Chloro-l-(2,6-difluoro-benzyl)-lH-benzoimidazole-5-sulfonyl]- 5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester A solution of 4-(7-chloro-lH-benzoimidazole-5-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((from above step c) 0.201 g, 0.499 mmol) in DMF (4 mL) was treated with a-bromo-2,6- difluorotoluene (0.114 g, 0.549 mmol) and solid K2CO3 (0.152 g, 1.10 mmol). The reaction was stirred at room temperature 17 h, diluted with EtOAc and washed well with water (5 x 150 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. Silica gel chrornatography (2% MeOH with 2 M NH3 in CH2C12) afforded the products 4-[7-chloro-3-(2,6-difluoro- benzyl)-3H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophene-2- carboxylic acid methyl ester and 4-[7-chloro-l-(2,6-difiuoro-benzyl)-IH- benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophene-2-carboxyhc acid methyl ester (0.102 g, 38%). These isomers were not separable by silica gel chromatography, but they were carried on together into the next reaction. e) 4-[7-Chloro-3-(2,6-difluoro-benzyl)-3H-benzoimidazole-5-sulfonyl]- 5-methylsulfanyl-thiophene-2-earboxamidine trifluoroacetate 4-[7-Chloro-l-(2,6~difluoro-benzyl)-lH-benzoimidazole-5sulfonyl]- 5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate A solution of 4-[7-chloro-3-(2,6-difluoro-benzyl)-3H-benzoimidazole- 5-sulfonyl]-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester and 4- [7-chloro-l-(2,6-difluoro-benzyl)-1H-benzoimidazole-5-sulfonyl]-5- methylsulfanyl-thiophene-2--carboxylic acid methyl ester {{from above step d) 0.101 g, 0.191 mmol) in dry toluene (5 mL) was treated with preformed dimethylaluminum amide and heated to 100 CC 2.5 h. The reaction mixture was cooled to room temperature and added portionwise to silica suspended in CH2Cl2. The suspension was stirred 20 min. then was filtered through a fine porosity fritted funnel. The silica was rinsed with 10% MeOH in CH2Cl2 (1000 mL), and the filtrate was concentrated in vacuo. Preparatory HPLC (10- 55% acetonitrile in 1% TFA/water over 30 min.) afforded products 4-[7- chloro-3-(2,6-difluoro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate (0.006 g, 6%) and 4-[7-chloro-l-(2,6-difluoro-benzyl)-1H-benzoimidazole-5-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate (0.007 g, 7%) as white solids. Example 185 4-[7-chloro-3-(2,6-difluoro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate 1H NMR (MeOD): d 8.479 (s, 1H), 8.348 (d, 1H, J= 1.6 Hz), 8.341 (s, 1H), 7.931 (d, 1H, J = 1.6 Hz), 7.460 (m, 1H), 7.049 (t, 2H, J = 8.4 Hz), 6.004 (s, 2H), 2.736 (s, 3H). C20H15CIF2N4O2S3: 513.00 (M+l) found: 513.10. Example 186 447-chloro-l-(2,6-difluoro-benzyl)-lH-benzoimidazole-5-sulfbnyl]-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate 1H NMR (MeOD): d 9.001 (s. 1H), 8.384 (d, 1H, J= 2.0 Hz), 8.372 (s, 1H), 7.984 (d, 1H, J= 1.6 Hz), 7.532 (m, 1H), 7.141 (t, 2H, J= 8.0 Hz), 5.825 (s, 2H), 2.674 (s, 3H). C20H15CIF2N4O2S3: 513.00 (M+l) found: 513.10 Example 187-188 4-[7-Bromo-3-(2-fluoro-5-nitro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5- methylsulfanyl-thLlophene-2-carboxamidme trifluoroacetate 4-[7-Bromo-l-(2-fluoro-5-nitro-benzyl)-lH-benzoimidazole-5-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate a) 4-(7-Bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester 4-(7-Bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine A solution of 4-(7-bromo-3H-benzoimidazole-5-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 38: step e) 2.19 g, 4.90 mmol) in dry toluene (20 mL) was treated with a solution of 2 M AlMe3 (39.0 mL, 78.0 mmol) and NH4Cl (4.21 g, 78.7 mmol) in dry toluene (39 mL) as described in Example 20: step f. The crude material (2.11 g, 100%) was used directly in the next reaction. b) 4-Bromo-6-[5-(tert-butoxycarbonylamino-imino-metltyl)-2~ methylsulfanyl-thiophene-3-sulfonyl]-benzoimidazole-1-carboxylic acid tert- butyl ester A solution of 4-(7-bromo-3H-benzoimidazole-5-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxamidine ((from above step a) 2.11 g, 4.89 mmol) in dry DMF (30 mL) was treated with di-tert-butyl dicarbonate (4.27 g, 19.6 rrµmol) and N,N-diisopropylefhylamine (3.40 rnL, 19.5 nimol). The reaction mixture was stirred at room temperature 2 days, and the solvents were removed in vacuo. Silica gel chromatography (30-50% EtOAc in hexanes raised in 5% increments) afforded the product 4-bromo-6-[5-(tert- butoxycarbonylamino-immo-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]- benzoimidazole-1-carboxylic acid tert-butyl ester (1.30 g, 42%) as a brown oil. 1H NMR (CDCl3): d 8.675 (m, 1H), 8.62 (s, 1H), 8.16 (d, 1H, J = 1.6 Hz), 7.89 (s, 1H), 2.56 (s, 3H), 1.73 (s, 9H), 1.52 (s, 9H). c) {[4-(7-Bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester A solution of 4-bromo-6-[5-(tert-butoxycarbonylamino-imino-methyl)- 2-methylsulfanyl-thiophene-3-sulfonyl]-benzoimidazole-1 -carboxylic acid ten-butyl ester {(from above step b) 1.00 g, 1.58 mmol) in MeOH (10 mL) was treated with aqueous Na2CO3 (0.340 g, 3.17 mmol in 2 mL water). The reaction mixture was stirred at room temperature 30 min., and solvents were removed in vacuo. The residue was taken up in. EtOAc and washed with water (1 x 50 mL) and brine (1 x 50 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to afford the product {[4-(7-bromo-3H- benzoimidazole-5-sulfbnyl)-5-methylsulfanyl-t]iiophen-2-yl]-imino-methyl}- carbamic acid tert-butyl ester (0.755 g, 90%) as a brown solid. 1H NMR (MeOD): d 8.48 (s, 1H), 8.32 (m, 1H), 8.20 (s, 1H), 8.03 (d, 1H, J= 1.6 Hz), 2.63 (s,3H), 1.48 (s, 9H). d) ({4-[7-Bromo-l-(2-fluoro-5-nitro-benzyl)-lH-benzoimidazole-5- sulfonyl]-5-methylsulfanyl-tlriophen-2-yl}-imino-methyl)-carbamic, acid tert- butyl ester {4-[7-Bromo-3-(2-fluoro-5-nitro-benzyl)-3H-benzoimidazole-5- sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyt)-carbamic acid tert- butyl ester A solution of {[4-(7-bromo-3H-benzoimidazole-5-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((from above step c) 0.132 g, 0.248 mmol) in dry DMF (3 mL) was treated with 2-fluoro-5-nitrobenzylbromide (0.087 g, 0.373 mmol) and diisopropylamine (0.070 mL, 0.497 mmol) and heated to 40 °C 24 h. The solution was diluted with EtOAc and washed well with water (4 x 35 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to afford the products ({4-[7-bromo-l -(2-fluoro-5-nitro-benzyl)-1H-benzoimidazole-5- sulfonyl]-5-methylsulfanyl-th:iophen-2-yl} -irnino-methyl)-carbamic acid tert- butyl ester and ({4-[7-bromo-3-(2-fluoro-5-nitro-benzyl)-3H-benzoimidazole- 5-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester (0.015 g, 9%) as a brown solid. C25H23BrFN5O6S3: 684..00 (M+l) found 684.60. e) 4-[7-Bromo-3-(2-fluoro-5-nitro-benzyl)-3H-benzoimidazole-5- sulfonyl]-5-methylsulfanyl~thiophene-2-carboxamidine trifluoroacetate 4-[7-Bromo-l-(2-fluoro-5-nitro-benzyl)-lH-benzoimidazole-5- sulfonyl]-S-methysulfanyl-thiophene-2-carboxamidine trifluoroacetate A solution of ({4-[7-bromo-1-(2-fluoro-5-nitro-henzyl)-1H- benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)- carbamic acid tert-butyl ester and ({4-[7-bromo-3-(2-fluoro-5-nitro-benzyl)- 3H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino- methyl)-carbamic acid tert-butyl ester ((from above step d) 0.015 g, 0.022mmol) in CH2C12 (1 mL) was cooled to 0 °C and treated with 25% trifluoroacetic acid in CH2Cl2 (1.00 mL). The mixture was allowed to warm to room temperature and was stirred 3.2 h. The solvents were removed in vacuo. Preparatory HPLC (10-80% acetonitrile in 1% TFA/water over 30 min.) afforded the products 4-[7-bromo-3-(2-fluoro-5-nitro-benzyl)-3H- benzoimidazole-5-sulfonyl]-5-methylsulfany3-tbiophene-2-carboxamidine trifluoroacetate (0.002 g, 47%) and 4-[7-bromo-l-(2-fluoro-5-nitro-benzyl)- 1H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate (0.002 g, 47%) as white solids. Example 187 4-[7-bromo-3-(2-fluoro-5-nitro-benzyl)-3H-benzoimidazole-5- sulfonyl]-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate 1H NMR (MeOD): d 8.728 (s, 1H), 8.355 (m, 2H), 8.309 (s 1H), 8.286 (d, 1H, J = 1.6 Hz), 8.060 (d, 1H, J = 1.6 Hz), 7.468 (t, 1H, J= 9.6 Hz), 5.832 (s, 2.H), 2.623 (s, 3H). C20H15BrFN504S3: 583.95 (M+l.) found 585.0. Example 188 4-[7-bromo-l-(2-fluoro-5-nitro-benzyl)-1H-benzoimidazole-5- sulfonyl]-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate 1H NMR (MeOD): d 8.636 (s, 1H), 8.455 (d, 1H, J= 1.6 Hz), 8.337 (s. 1H), 8.295 (m, 1H), S.098 (d, 1H, J= 2.0 Hz), 7.610 (dd, 1H, J= 6.4 Hz, J = 2.8 Hz), 7.468 (t, 1H, J= S.8 Hz), 6.054 (s, 2H), 2.722 (s, 3H). C20H15BrFN5O4S3: 583.95 (M+l) found 585.0. Example 189 4-[7-Bromo-3-(2-fluoro-4-nitro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidinetrifluoroacetate a) ({4-[7-Bromo-l-(2-fluoro-4-nitro-benzyl)-lH-benzoimidazole-5- sulfonyl]-5-methylsulfanyl-thiophen-2-yl)-imino0methyl)-carbamic acidtert- butyl ester {4-[7-Bromo-3-(2-fluoro-4-mtro-benzyl)-3H-benzoimidazole-5- sulfonyl]-5-methylsulfanyl-thiophen-2-yl)-imino-methyl)-carbamic acid tert- butyl ester A solution of {[4-(7-bromo-3H-benzoimidazole-5-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 187-188: step c) 0.097 g, 0.183 mmol) in DMF (3 mL) was treated with 2-fluoro-4-nitrobenzylbromide (0.064 g, 0.274 mmol) arid diisopropylamine (0.051 mL, 0.365 mmol) and heated to 40 C 24 h. The solution was diluted with EtOAc and washed well with water (4 x 35 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to afford the products ({4-[7-bromo-l-(2-fluoro-4-nitio-benzyl)-lH-benzoimidazole-5- sulfonyl]-5-methylsulfanyl-thiophen-2-yl)-imino-methyl)-carbamic acid tert- butyl ester and ({4-[7-bromo-3-(2-fluoro-4-nitTo-benzy])-3H-benzoimidazole- 5-sulfonyl]-5-methylsulfanyl-thiophen-2-yl)-imino-methyl)-carbamic acid tert-butyl ester (0.012 g, 10%) as a brown solid. C25H23BrFN5O6S3: 684.00 (M+l) found 684.50. b) 4-[7-Bromo-3-(2-fluoro-4-nitro-benzyl)-3H-benzoimidazole-5- sulfonyl]-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate A solution of ({4-[7-bromo-l-(2-fluoro-4-nitro -benzyl)-1H- benzoirnidazole-5-sulfonyl]-5-methylsulfanyl-thiophen-2-yl)-imino-methyl)- carbamic acid tert-butyl ester and ({4-[7-broino-3-(2-fluoro-4-nitro-benzyl)- 3H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophen-2-yl)-imino- methyl)-carbamic acid tert-butyl ester {(from above step a) 0.005 g, 0.007 mmol) in CH2C12 (1 mL) v/as cooled to 0 °C and treated with 2.5% trifluoroacetic acid in CH2Cl2 (1.00 mL). The mixture was allowed to warm to room temperature and was stirred 3 h. Solvents were removed in vacuo. Preparatory HPLC (10-80% acetonitrile in 1% TFA/water over 30 min.) afforded the product 4-[7-bromo-3-(2-fluoro-4-nitro-benzyl)-3H- benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate (0.002 g, 47%) as a white solid. 1H NMR (MeOD): d 8.714 (s, 1H), S.308 (s, 1H), 8.231 (d, 1H, J= 1.6 Hz), 8.106 (m, 2H), 8.047 (d, 1H, J = 0.8 Hz), 7.556 (t, 1H, J = 8.4 Hz), 5.854 (s, 2H), 2.630 (s, 3H). C20H15BrFN5O4S3: 583.95 (M+l) found 585.05. Example 190 4-[l-(5-Amino-2-fluoro-benzyl)-7-bromo-lH-benzoimidazole-5-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxarnidine trifluoroacetate A solution of ({4-[7-bromo-l-(2-fluoro-5-nitro -benzyl)-1H- benzoimidazole-5-sulfbnyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)- carbamic acid tert-butyl ester {{Example 187-188: step d) 0.030 g, 0.044 mmol) in EtOH (3 mL) was treated with NH4C1 (0.023 g, 0.438 rnmol) as an aqueous solution and heated to 50 °C. Iron powder (0.012 g, 0.219 mmol) was added and the reaction heated to 80 °C for 4 h. The mixture was cooled and filtered through Celite. The filter cake was rinsed with EtOH, and the EtOH was removed in vacuo. The remaining aqueous solution was basified to pH 10 with saturated aqueous NaHCO3 and extracted with EtOAc (2 x 25 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was taken up in CH2Cl2 (3 mL) and treated with tnfluoroacetic acid (0.75 mL). The mixture: was stirred at room temperature 1.5 h, and solvents were removed in vacuo. Preparatory HPLC (10-50% acetonitrile in 1% TFA/water over 30 min.) afforded the product 4-[3-(5-amino-2-fluoro- benzyl)-7-bromo-3H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophene- 2-carboxamidine trifluoroacetate (0.014 g, 49%) as a white solid. 1H NMR (MeOD): d 8.714 (s, 1H), 8.308 (s, 1H), 8.231 (d, IK J= 1.6 Hz), 8.106 (m, 2H), 8.047 (d, 1H, J= 0.8 Hz), 7.556 (t, 1H, J= 8.4 Hz), 5.854 (s, 2H), 2.630 (s, 3H). Example 191 3-({3-[4-Bromo-6-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)- ben2oimidazol-l-ylmethy]]-4-fluoro-phenylcarbamoyl}-methylsulfanyl)- proplonic acid trifluoroacetate a) [(4-{7-Bromo-3-[5-(2-bromo-acetylamino)-2-fluoro-benzyl]-3H- benzoimidazole-5-sulfonyl}-5-methylsulfanyl-thiophen-2-yl)-imino-methyl]- carbamic acid tert-butyl ester A solution of ({4-[3-(5-amino-2-fluoro-benzyl)-7-bromo-3H- benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophen-2-yl)-imino-methyl)- carbamic acid tert-butyl ester ((Example 190) 0.012 g, 0.018 mmol) in CH2C12 (3 mL) was treated with bromoacetylbromide (0.007 g, 0.037 mmol) and triethylamine (0.006 mL, 0.046 mmol) and stirred at room temperature 3 h. The reaction mixture was diluted with CH2Cl2 and washed with water (2 x 10 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to afford the product [(4-{7-bromo-3-[5-(2-bromo-acetylamino)-2-lluoro- benzyl]-3H-benzoimidazole-5-sulfonyl}-5-methylsulfanyl-thiophen-2-yl)- imino-methyl]-carbamic acid tert-butyl ester (0.014 g, 92%) as a tan solid. C27H26Br2FN5O5S3: 773.94 (M+l) found 774.10. b) 3-[(3-{4-Bromo-6-[5-(iert-butoxycarbonylamino-imin o-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-benzoimidazol-l-ylmethyl}-4-fluoro- pheny!carbamoyl)-methylsulfanyl]-propionic acid methyl ester A solution of [(4-{7-bromo-3-[5-(2-bromo-acetylamirio)-2-fluoro- benzyl]-3H-benzoimidazole-5-sulfonyl}-5-methylsuIf;myl-thiophen-2-yl)- imino-methyl]-carbamic acid tert-butyl ester ((Example 191: step a) 0.014 g, 0.017 mmol) in CH.2C12 (2 mL) was treated with methyl 3- mercaptopropionoate (2.50 µL, 0.025 mmol) and stirred at room temperature 30 min. The reaction was diluted with CH2Cl2 and washed with water (1 x 10 mL). The organic layer was dried over MgSO4 and concentrated in vacua to afford the product 3-[(3-{4-bromo-6-[5-(tert-butoxycarbonylammo-imino- methyl)-2-methylsulfanyl- thiopihene-3-sulfonyl]-benzoimidazol-1-ylmethyl} - 4-fluoro-phenylcarbamoyl)-methylsulfanyl]-propionic acid methyl ester (0.011, 85%) as a tan solid. C31H33BrFN5O8S4: 814.04 (M+l) found 814.70. c) 3-({3-[4-Bromo-6-(5-carbamimidoyl-2-metbylsulfanyl-tbiophene-3- sulfonyl)-benzoimidazol-l-ylmethyl]-4-fluoro-phenylcarbamoyl}- methylsulfanyl)-propionic acid trifluoroacetate A solution of 3-[(3-{4-bromo-6-[5-(tert-butoxycarbonylaimno-imino- methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-benzoimidazol-1 -ylmethyl) - 4-fluoro-phenylcarbamoyl)-methylsulfanyl]-propionic acid methyl ester ((Example 191: step b) 0.011 g, 0.014 mmol) in MeOH:H2O (2:1, 3 mL) was treated with LiOH (1.61 mg, 0.070 mmol) and the reaction stirred at room temperature 2 h. The solvents were evaporated in vacuo and the residue taken up in CH2Cl2 (3 mL). Trifluoroacetic acid (0.750 mL) was added and the reaction stirred at room temperature 45 min. Solvents were evaporated in vacuo. Preparatory HPLC (10-50% acetonitnle in 1% TFA/wav.er over 30 min.) afforded the product 3-({3-[4-bromo-6-(5-carbamimidoyl-2- metbylsulfanyl-thiophene-3-sulfonyl)-benzoimidazol-l-ylmethyl]-4~fluoro- phenylcarbamoyl}-methylsulfanyl)-propionic acid trifluoroacetate (0.004 g, 43%) as a white solid. 1H NMR (MeOD): d 8.691 (s, 1H), 8.140 (s, 1H), 8.068 (s, 1H), 8.018 (s, 1H), 7.647 (m, 1H), 7.547 (dd, 1H, J= 6.4 Hz, J= 2.4 Hz), 7.176 (t, 1H. J = 9.6 Hz), 5.692 (s, 2H), 3.498 (quint, 1H, J = 1.6 Hz), 3.148 (quint, 1H, 7= 1.6 Hz), 2.875 (d, 2H, J= 7.2 Hz), 2.651 (d, 2H, J = 7.2 Hz), 2.529 (s, 3H). C25H23BrFN5O5S4: 699.97 (M+l) found 700.90. Example 192 [3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-methoxy-6- methyl-bipheny]-2-ylmethoxy]-acetic acid trifluoroacetate a) 2-Bromo-5-methoxy-l,3-dimethyl-benzene A solution of 4-bromo-3,5-dimethylphenol (1.00 g, 4.97 mmol) in acetone (40 mL) was treated with solid CsCO3 (1.17 g, 4.97 mmol) and methyl iodide (0.310 mL, 4.97 mmol) and heated to 40 °C for 3 h. Additional methyl iodide (0.310 mL, 4.97 mmol) was added over the course of the reaction to replace that lost to evaporation. The acetone was removed in vacuo. The resulting white solid residue was partitioned between water and CH2Cl2. The layers were separated and the aqueous layer was further extracted with CH2Cl2 (2 x 25 mL). The combined organic layers were washed with water (1 x 25 mL) and dried over MgSO4. The solvent was removed in vacuo to afford the product 2-bromo-5-methoxy-l,3-dimethyl-benzene (1.01 g, 94%) as a colorless oil, which slowly solidified upon standing. 1H NMR (CDCl3): d 6.644 (s, 2H), 3.762 (s, 3H), 2.382 (s, 6H). b) 2-Brom o-l -bromom ethyl-5-m eth oxy-3-m ethyl-ben zen e A solution of 2-bromo-5-methoxy-l,3-dimethyl-benzene {{Example 192: step a) 1.01 g, 4.70 mmol) in CC14 (50 mL) was treated with N- bromosuccinamide and AIBN (catalytic amount) and heated to 75 °C 3.5 h. The reaction was diluted with CH2C12 and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the product 2-bromo-l-bromomethyl-5-methoxy-3-mei:hyl-benzene (1.27 g, 92%) as a pale orange solid. 1H NMR (CDCl3): d 6.641 (s, 2H), 4.601 (s, 2H), 3.760 (s, 3H), 2.380 (s, 3H). c) (2-Bromo-5-methoxy-3-methyl-phenyl)-methanol A solution of 2-brorao-l-bromoniethyl-5-methoxy-3-methyl-benzene ({Example 192: step b) 10.8 g, 36.7 mmol) in dioxane:water (1:1, 200 mL) was treated with CaCO3 and heated to reflux (110 °C)18 h. The reaction mixture was cooled to room temperature and filtered by gravity to remove solid salts. The dioxane was removed in vacuo. Dilute HC1 (10 mL) was added, and the mixture was extracted with CH2Cl2 (2 x 150 mL). The combined organic layers were dried over MgSO4. The solvents were removed in vacuo to afford a pale orange oil, which slowly solidified upon standing. Silica gel chromatography (25% EtOAc in hexanes) yielded the product (2- bromo-5-methoxy-3-methyl-phenyl)-methanol (1.03 g, 12%) as a yellow oil. 1H NMR (CDCl3): d 6.905 (d, 1H, J = 3.2 Hz), 6.746 (d, 1H, J = 3.2 Hz), 4.720 (d, 2H, J= 3.6 Hz), 3.798 (s, 3H), 2.390 (s, 3H). d) (2-Bromo-5-methoxy-3-methyl-benzyloxy)-acetic acid tert-butyl ester A solution of (2-bromo-5-methoxy-3-methyl-phenyl)-methanol {{Example 192: step c) 0.800 g, 3.46 mmol) in DMF (10 mL) was cooled to 0 C and treated with NaH (0.100 g of 95% dispersion, 4.15 mmol) and allowed to warm to room temperature 30 min. The mixture was then treated with tert- butyl bromoacetate (0.614 mL, 4.15 mmol) and stirred at room temperature 1 h. The reaction was diluted with water and extracted with EtOAc (2 x 125 mL). The combined organic layers were washed well with water (3 x 300 mL), dried over MgSO4, and concentrated in vacuo to afford the product (2- bromo-5-methoxy-3-methyl-benzyloxy)-acetic acid tert-butyl ester (1.19 g, 98%) as a yellow oil. lH NMR (CDCl3): d 6.967 (d, 1H, J= 2.8 Hz), 6.745 (d, 1H, J= 3.2 Hz), 4.6S3 (s, 2H), 4.086 (s, 2H), 3.794 (s, 3H), 2.3S0 (s, 3H), 1.496 (s,9H). e) [5-Methoxy-3-methyl-2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolait-2- yl)-benzyloxy]-acetic acid tert-butyl ester A solution of (2-brorno-5-methoxy-3-methyl-benzyloxy)-acetic acid tert-butyl ester ((Example 192: step d) 1.19 g, 3.45 mmol) in dioxane (10 mL) was treated with PdCl2(PPh3)2 (0.242 g, 0.345 mmol) and triethylamine (2.38 mL, 20.7 mmol). 4,4;,5,5-Tetramethyl-l,3,2-dioxaborolane (1.00 mL, 6.89 mmol) was added slowly and the mixture heated to 80 °C 15 h. The reaction was diluted with EtOAc and washed with brine (2 x 50 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. Silica gel chromatography (25% EtOAc in hexanes) afforded the product [5-methoxy-3- methyl-2 -(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyloxy]-acetic acid tert-butyl ester (0.793 g, 58%) as a brown oil. The crude material was used directly in the next reaction. f) 3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl- thiophene-3-sulfonyl]-4-methoxy-6-methyl-biphenyl-2-ylmethoxy}-acetic acid tert-butyl ester A solution of [5-methoxy-3-methyl-2-(4,4,5,5-tetramethyl- [l,3,2]dio 192: step e) 0.790 g, 2.01 mmol) in tolutene:EtOH (2:1, 15 mL) was treated with {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino- methyl}-carbamic acid tert-buty! ester ((Example27: step c) 0.247 g, 0.503 mmol), aqueous Na2CO3 (2 M, 2.01 mL, 4.03 mmol), and Pd(PPh3)4 (0.116 g, 0.101 mmol). The mixture was heated to 80 C 16.3 h. The reaction wa:3 diluted with EtOAc and washed with brine (2 x 25 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. Silica gel chromatography (5%-60% EtOAc in hexanes raised in 5% increments) afforded the product 3'- [5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3- sulfonyl]-4-methoxy-6-methyl-biphenyl-2-ylmethoxy} -acetic acid tert-butyl ester (0.107 g, 31%) as an off-white solid. !H NMR (CDCl3): d 8.013 (d, 1H, J = 7.6 Hz), 7.961 (s, 1H), 7.934 (t, 1R J - 1.6 Hz), 7.570 (t, 1H, J = 7.6 Hz), 7.440 (d, 1H, J = 2.0 Hz): 6.896 (d, 1H, J = 2.4 Hz), 6.S32 (d, 1H, J = 2.4 Hz), 4.200 (s, 2H), 3.876 (s, 3H), 3.868 (s, 2H), 2.630 (s, 3H), 2.036 (s. 3H), 1.585 (s, 9H), 1.540 (s, 9H). C32H40N2O8S3: 677.19 (M+l) found 676.90. g) [3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonylj-4- methoxy-6-methyl-biphenyl-2-ylmethoxy]-acetic acid trifluoroacetate A solution of 3'-[5-(tert-butoxyccirbonylamino-iraino-methyl)-2- methylsulfanyl-thiophene-3-suIfonyl]-4-methoxy-6-methyl-biphenyl-2- ylmethoxy}-acetic acid tert-butyl ester {{Example 192: step f) 0.107 g, 0.158 mmol) in CH2Cl2 (10 mL) was treated with 50% trifluoroacetic acid in CH2Cl2 (10 mL) and stirred at room temperature 4 h. Solvents were evaporated in vacuo. Preparatory HPLC (5-50% acetonitrile in 1% TFA/water over 30 min.) afforded the product [3'-(5-carbamimidoyl-2-methylsulfanyl-thjophene-3- sulfonyl)-4-methoxy-6--methyl-biphenyl-2-ylmethoxy]-acetic acid trifluoroacetate (0.080 g, 97%) as a white glassy solid. 1H NMR (MeOD): d 8.345 (s, 1H), 8.047 (d, 1H, J= 8.8 Hz), 7.848 (t, 1H, J= 1.6 Hz), 7.692 (t, 1H, J= 7.6 Hz), 7.554 (d, 1H, J= 7.6 Hz), 6.992 (d, 1H, J = 2.0 Hz), 6.871 (d, 1H, J = 2.0 Hz), 4.202 (d, 2H, J= 5.6 Hz), 3.852 (s, 3H), 3.818 (d, 2H, J= 2.4 Hz), 2.736 (s, 3H), 1.999 (s, 3H). C23H24N2O6S3: 521.08 (M+l) found 521.00. Example 193 a) [3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4- hydroxy-6-methyl-biphenyl-2-ylmethoxy]-acetic acid triflnoroacetate A solution of [3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3- sulfonyl)-4-methoxy-6-metfayl-biphenyl-2-ylmethoxy]-acetic acid {(Example 192: step g) 0.077 g, 0.0148 mmol) in dry CH2C12 (10 mL) was cooled to 0 °C and treated with BBr3 (0.592 mL, 0.592 mmol) dropwise. The reaction stirred at 0 CC for 30 min. then was allowed to warm to room temperature and stir 27 h. The reaction mixture was cooled to 0 °C and quenched with MeOH. Some HBr evolution was seen. All solvents were evaporated in vacuo, and the residue was taken up in EtOAc (100 mL) and washed with water (1 x 75 mL) and brine (2 x 50 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. Preparatory HPLC (5-50% acetonitrile in 1% TFA/water over 30 min.) afforded the product [3'-(5-carba:mimidoyl-2- methylsulfanyl-thiophene-3-sulfonyl)-4-hydroxy-6-methyl-biphenyl-2- ylmethoxy]-acetic acid trifloroacetate (0.039, 52%) as a white glassy solid. 1H NMR (MeOD): d 8.344 (s, 1H), 8.090 (d, 1H, J= 8.0 Hz), 7.877 (t, 1H, J = 2.0 Hz), 7.721 (t, 1H, J= 7 6 Hz), 7.572 (d, 1H, J= 7.6 Hz), 6.778 (d, 1H, J = 2.8 Hz), 6.735 (d, 1H, .7= 2,0 Hz), 2.710 (s, 3H), 2.028 (s, 2H), 1.935 (s, 3H), 1.254 (t,2H,J= 7.6 Hz). Example 194 4-{2'-[3-(2-Benzenesulfonylamino-ethyl)-ureido]-6'-methyl-biphenyl-3- sulfonyl}-5-methylsulfanyl-miophene-2-carboxamidme trifluoroacetate a) (4-{2'-[3-(2-Amino-ethyl)-ureido]-6'-methyl-biphenyl-3-sulfonyl}-5- methylsulfanyl-thiophen-2-yl)-imino-methyl]-carbarnic acid tert-butyl ester A solution of [4-(2'-amino-6'-methyl-biphenyl-3--sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester {{Example 25: step c) 0.150 g, 0.290 mmol) in dry CH2C12 (10 mL) was treated with pyridine (0.026 mL, 0.319 mol) and p-nitrophenyl chloroformate (0.064 g, 0.319 mmol) and stirred 1.7 h. The reaction mixture was treated with ethylene diamine (0.194 mL, 2.90 mmol) and triethylamine (0.485 mL, 3.4S mmol) and stirred at room temperature 16 h. The reaction was diluted with CH2Cl2 and washed with water (3 x 50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the product [(4-{2'-[3-(2-amino-ethyl)-ureido]-6'-methyl-biphenyl-3-sulfonyl}-5- methylsulfanyl-thiophen-2-yl)-imino-methyl]-carbamic acid tert-butyl ester (0.145 g, 82%) as a tan solid. 1H NMR (MeOD): d 8.195 (s, 1H), 8.057 (d, 1H, J= 8.0 Hz), 7.902 (t, 1H, J= 1.6 Hz), 7.718 (t, 1H, J= 8.0 Hz), 7.554 (d, 1H, J= 8.0 Hz), 7.511 (d, 1H, 7= 8.0 Hz), 7.289 (t, 1H, J= 1.6 Hz), 7.119 (d, 1H, J= 1.1 Hz), 3.099 (m, 2H), 2.676 (s, 3H), 2.621 (m, 2H), 2.007 (s, 3H), 1.511 (s, 9H). C27H33N5O5S3: 604.16 (\l+l) found 603.90. b) 4-{2'-[3-(2-Benzenesulfoiiylamino-ethyi)-ureido]-6'-methyl-biphenyl- 3-sulfonyl}-5-inethylsulfanyl-thiopheite-2-carhoxamidine trifluoroacetate A solution of [(4{2'-[3-(2-amino-ethyl)-ureido-6'-melhyl-biphenylo- sulfonyl}-5-methylsulfanyl--thiophen-2-y])-imino-methyl]-carbamic acid tert- butyl ester ((Example 194: step a) 0.060 g, 0.099 mmol) in CH:C12 (10 mL) was treated with phenylsulfonyl chloride (0.015 mL, 0.119 rnmol) and triethylamine (0.033 mL, 0.238 mmol) and stirred 16 h. The reaction mixture was diluted with CH2Cl2 and washed with water (2 x 25 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was taken up in CH2Cl2 (10 mL), treated with trifluoroacetic acid (2 mL), and stirred at room temperature 1.5 h. The solvents were evaporated in vacuo. Preparatory HPLC (10-80% acetonitrile in 1% TFA/water over 30 min.) afforded, the product 4-{2'-[3-(2-benzenesulfonyhimino-ethyl)-ure\do]-6'- methyl-biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate (0.026 g, 41%) as a white glassy solid. 1H NMR (MeOD): d 8.292 (s, 1H), 8.036 (d, 1H, J = 8.0 Hz), 7.878 (t, IK, J = 1.6 Hz), 7.820 (d, 2H, J = 6.8 Hz), 7.534 (t, 1H, J = 1.6 Hz), 7.694 (t, 1H, J = 8.0 Hz), 7.616 (m, 1H), 7.562 (d, 2H, J = 7.6 Hz), 7.438 (d, 1H, J = 7.6 Hz). 7.276 (t, 1H, J = 7.6 Hz), 7.212 (d, 1H, J = 7.2 Hz), 3.075 (q, 2H, J = 4.8 Hz), 2.448 (dt, 2H, J = 6.0 Hz, J = 2.4 Hz), 2.710 (s, 3H), 2.003 (s, 3H). Example 195 a) 4-{2'-[3-(2-Methanesulfonylamino-ethyl)-ureido]-6'-methyl- biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate A solution of [(4-{2'-[3-(2-amino-ethyl)-ureido]-6'-methyl-biphenyl-3- sulfonyl} -5-methylsulfanyl-thiophen-2-yl)-immo-methyl]-carbamic acid tert- butyl ester ((Example 194: step a) 0.050 g, 0.083 mmol) in CH2C12 (10 mL) was treated with methylsulfonylchloride (9.50 µL, 0.099 mmol) and triethylamine (27.7 µL, 0.199 mmol) and stirred at room temperature 7 h. The reaction was diluted with CH2Cl2 and washed with water (1 x 50 mL). The organic layer was dried over MgSO4, concentrated in vacuo, taken up in CH2Cl2 (8 mL), treated with trifluoroacetic acid (0.4 mL) and stirred at room temperature 2 h. Solvents were evaporated in vacuo. Preparatory HPLC (10- 50% acetonitrile in 1% TF A/water over 30 min.) afforded the product 4-{2'- [3-(2-methanesulfonylamino-ethyl)-ureido]-6'-methyl-biphenyl-3-sulfonyl}-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate (0.023 g, 48%) as a white glassy solid. 1H NMR (MeOD): d 8.305 (s, 1H), 8.052 (d 1H, J = 9.2 Hz), 7.887 (t 1H, J - 1.6 Hz), 7.719 (t, 1H, J = 7.6 Hz), 7.571 (d, 1H, J= 7.2 Hz), 7.450 (d, 1H, J= 7.2 Hz), 7.2S4 (t, 1H, J= 8.0 Hz), 7.131 (d, 1H, J= 7.6 Hz), 3.140 (m, 2H), 3.040 (m, 2H), 2.898 (s, 3H), 2.718 (s, 3H), 2.005 (s, 3H). C23H27N5O5S4: 582.09 (M+l) found 582.00. Example 196 [3-(2-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6- methyl-biphenyl-2-yl]-ureido}-ethyl)-ureido]-acetic acid trifluoroacetate a) {3-[2-(3-{3'-[5-(tert-Butoxycarbonylamino-imino-metltyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-ureido)- ethyl]-ureido}-acetic acid methyl ester A solution of [(4-{2'-[3-(2-amino-ethyl)-ureido]-6'-methyl-biphenyl-3- sulfonyl }-5-methylsulfanyl-thiophen-2-yl)-imino-methyl]-carbamic acid tert- butyl ester ((Example 194: step a) 0.030 g, 0.050 rnmol) in CH2C12 (10 mL) was treated with ethyl isocyanatoacetate (6.70 µL, 0.060 mmol) and stirred at room temperature 35 min. The reaction was diluted with CH2Cl2 and washed with water (1 x 15 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to afford the product {3-[2-(3-{3'-[5-(tert- butoxycaLrbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]- 6-methyl-biphenyl-2-yl}-ureido)-efhyl]-ureido}-acetic acid methyl ester (0.031 g, 86%) as an off-white solid. C32H40N6O8S3: 733.21 (M+l) found 732.90. b) {3-[2-(3-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-ureido)- ethyl]-iweido}-acetic acid A solution of {3-[2-(3-{3'-[5-(tert-butoxycarbonylarnino-imino- methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-raethyl-bipheny[-2-yl}- ureido)-ethyl]-ureido}-acetic acid methyl ester ((Example 197: step a) 0.031 g, 0.042 mmol) in MeOH:water (2:1, 15 mL) was treated with NaOH (10 N, 0.042 mL, 0.420 mmoi) and stirred at room temperature 18 h. MeOH was evaporated in vacuo and the remaining aqueous solution was acidified to pH 5 with glacial acetic acid. The solution was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were dried over MgSO4 and evaporated in vacuo to afford the product {3-[2-(3-{3'-[5-(tert-butoxycarbonylamino-imino- methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}- ureido)-ethyl]-ureido}-acetic acid (0.025 g, 83%) as an off-white solid. The crude material was used directly in the next reaction. c) l3-(2-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophen e-3- sulfonyl)-6-methyl-biphenyl-2-yl]-ureido}-ethyl)-ureido]-acetic acid trifluoroacetate A suspension of {3-[2-(3-{3'-[5-(tert-butoxycarbonylamino-imino- methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}- ureido)-ethyl]-ureido}-acetic acid ({Example 196: step b) 0.025 g, 0.035 mmol) in CH2Cl2 (10 mL) was treated with trifluoroacetic acid (1.00 mL) and stirred at room temperature 1.2 h. Solvents were removed in vacuo. Preparatory HPLC (10-80% acetonitrile in 1% TFA/water over 30 min.) afforded the product [3-(2-{3-[3'-(5-caxbamimidoyl-2-rnethylsulfanyl- thiophene-3-sulfonyl)-6-methyl-biphenyl-2-yl]-ureido}-ethyl)-ureido]-acetic acid trifluoroacetate (0.013 g, 60%) as a white glassy solid. 1H NMR. (CD3CN): d 8.099 (s, 1H), 8.048 (d, 1H, J = 9.6 Hz), 7.815 (t, 1H, J = 1.6 Hz), 7.709 (t, 1H, J= 8.0 Hz), 7.575 (d, 1H, J= 7.6 Hz), 7.498 (d, 1H, J = 8.0 Hz), 7.295 (t, 1H, J= 7.6 Hz), 7.161 (d, 1H, J= 8.0 Hz), 3.756 (s, 2H), 2.979 (s br, 4H), 2.681 (s, 3H), 2.079 (s, 3H). Example 197 a) 5-methylsulfanyl-4-[6'-methyl-2'-(N'-methanesulfonyhireido)- biphenyl-3-sulfonyl]-thiophene-2-carboxamidine A solution of [4-(2'-amino-6'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 25: step c) 0.050 g, 0.097 mmol) in CH2C12 (5 mL) was treated with pyridine (8.6 µL, 0.106 mmol) and p-nitrophenylchloroformate (0.021 g, 0.106 mmol) and stirred 2 h. The mixture was treated with methane sulfonamide (0.018 g, 0.193 mrnol) and triethylamine (0.108 mL, 0.773 mmol) and stirred 2 h. The reaction mixture was diluted with CH2Cl2 and washed with water (2 x 25 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was taken up in CH2C12 (5 mL), treated with trifluoroacetic acid (1.00 mL), and stirred 1 h. Solvents were evaporated in vacuo. Preparatory HPLC (10-80% acetonitrile in 1% TFA/water over 30 min.) afforded the title compound (0.015 g, 57%) as a white glassy solid. lH NMR (MeOD): d 8.359 (s, 1H), 8.123 (d, 1H, J = 9.6 Hz), 7.993 (t, 1H J = 1.6 Hz), 7.790 (t, 1H, J = 8.4 Hz), 7.625 (d, 1H, J - 7.6 Hz), 7.370 (t, 1H, J = 8.0 Hz), 7.244 (d, 1H, J = 7.2 Hz), 7.170 (d, 1H, J = 7.2 Hz), 3.008 (s, 3H), 2.722 (s, 3H), 2.003 (s, 3H). C21H22N4O5S4: 539.05 (M+l) found 538.90. Example 198 4-[4'-Methoxy-6'-methyl-2'-(2-oxo-imidazolidin-l-yl)-biphenyl-3-sulfonyl]-5- methylsulfanyl-thiopbene-2-carboxamidme trifluoroacetate a) 2-Bromo-5-methoxy-3-methyl-benzoic acid A solution of (2-bromo-5-methoxy-3-methyl-phenyl)-methanol ((Example 192: step c) 7.85 g, 34.0 mmol) in acetone (300 mL) was heated to 60 °C and treated over 25 min. with KMnO4 (12.6 g, 79.8 mmol) as an aqueous solution (175 mL). The mixture was heated to 60 °C for an additional 35 min. A saturated aqueous solution of NaHSC)3 was added until the solution turned beige in color. Concentrated NH4OH was added to pH 10 and the solids were filtered through a medium porosity fritted funnel. The filtrate was acidified to pH 4 with concentrated HC1, and the solution was extracted with ether (2 x 200 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the product 2-bromo-5-methoxy-3-methyl- benzoic acid (4.15 g, 50%) as a white solid. 1H NMR (MeOD): d 6.968 (d, 1H, J= 2.8 Hz), 6.775 (d, 1H, J= 3.2 Hz), 3.776 (s, 3H), 2.352 (s, 3H). b) (2-Bromo-5-methoxy-3-methyl-phenyl)-carbamic acid tert-butyl ester A solution of 2-bromo-5-methoxy-3-methyl-benzoic acid ({Example 198: step a) 3.39 g, 13.8 mmol) in dry tert-butanol was treated with DPPA (3.58 mL, 16.6 mmol) dropwise and stirred 5 min. The solution was treated with diisopropylethylamine (2.89 mL, 16.6 mmol) and heated to 80 °C 17.5 h. Terc-butanol was removed in vacuo. The residue was taken up in EtOAc and washed with saturated aqueous NaHCO3 (2 x 60 mL) and water (1 x 60 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Silica gel chromatography (10% EtOAc in hexanes) afforded the product (2-bromo-5-methoxy-3-methyl-phenyl)-carbamic acid ten-butyl ester (3.05 g, 70%) as a colorless oil. 1H NMR (CDCl3): d 7.701 (d, 1H, J= 1.6 Hz), 7.146 (s, NH), 6.517 (d, 1H, J= 3.2 Hz), 3.797 (s, 3H), 2.360 (s, 3H), 1.534 (s,9H). c) 2-Bromo-5-methoxy-3-methyl-phenylamine A solution of (2-bromo-5-methoxy-3-methyl-phenyl)-carbamic acid tert-butyl ester ({Example 198: step b) 3.00 g, 9.49 mmol) in CH2C12 (50 mL) was treated with trifluoroacetic acid (7.00 mL) dropwise. The solution was stirred at room temperature 1.3 h. The solvents were evaporated in vacuo to yield the product 2-bromo-5-methoxy-3-methyl-phenylamine (2.04 g, 65%) as a yellow solid trifluoroacetate salt. The crude mixture was used directly in the next reaction. d) 5-Methoxy-3-m ethyl-2-(4,4,5,5-tetram ethyl-[1,3,2]dioxaborolan -2- yl)-phenylamine A solution of 2-bromo-5-methoxy-3-niethyl-phenylamine ((Example 198: step c) 2.04 g, 6.18 mmol) in dry dioxane (100 mL) was treated with triethylamine (5.26 mL, 37.7 mmol), 2-(dicyclohexylphosphino)biphenyl (0.662 g, 1.89 mmol), and Pd(OAc)2 (0.106 g, 0.472 mmol). 4,4,5,5- Tetramethyl-l,3,2-dioxaborolane (4.09 mL, 28.3 mmol) was added slowly and the mixture heated to reflux for 1 h. The dioxane was evaporated in vacuo. The residue was taken up in EtOAc and washed with water (2 x 75 mL). The organic layer was filtered by gravity to remove the palladium residue, dried over MgSO4 and concentrated in vacuo. Silica gel chromatography (10-25% EtOAc in hexanes raised in 5% increments) afforded the product 5-methoxy- 3-methyl-2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenylarnine (1.61 g, 98%) as a light brown solid. 1H NMR (CDCl3): d 7.361 (d, 1H, J = 7.6 Hz), 7.279 (d, 1H,J= 8.0 Hz), 3.815 (s, 3H), 2.46 (s, 3H), 1.356 (s, 12H). e) {[4-(2'-Amino-4'-methoxy-6'-methyl-biphenyl-3-sulfonyl)-5- methylsidfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester A solution of {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 27: step c) 1.50 g, 3.05 mmol) in toluene:EtOH (2:1, 45 raL) was treated with 5- methoxy-3-methyl-2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- phenylamine (((Example 1.98: step d) 1.61 g, 6.11 mmol), aqueous Na2CO3 (2 M, 12.2 mL, 24.4 mmol) and Pd (PPh3)4 (0.706 g, 0.611 mmol). The mixture was heated to 80 °C 4 h. The reaction was cooled to room temperature, diluted with EtOAc, washed with brine (1 x 75 mL) and water (2 x 75 mL), dried over MgSO4 and concentrated in vacuo. Silica gel chromatography (25% then 35% then 50% EtOAc in hexanes) afforded the product {[4-(2'- amino-4'-methoxy-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen- 2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.680 g, 40%) as a yellow- brown solid. 1H NMR (MeOD): 8 8.223 (s, 1H), 8.001 (d, 1H, J = 7.2 Hz), 7.879 (t, 1H, J = 1.6 Hz), 7.698 (t, 1H, J = 8.0 Hz), 7.549 (d, 1H, J = 8.0 Hz), 6.287 (dd, 2H, J = 7.2 Hz, J == 2.4 Hz), 3.770 (s, 3H), 2.669 (s, 3H), 1.900 (s, 3H), 1.510 (s, 9H). C25H29N3O5S3: 548.13 (M+l) found 547.70. f) 4-[4'-Methoxy-6'-methyl-2'-(2-oxo-imidazolidin-l-yl)-biphenyl-3- sulfonyl]-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate A solution of {[4-(2'-amino-4'-methoxy-6'-methyl-biphenyl-3- sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-rnethyl}-carbarnic acid tert- butyl ester {{Example 198: step e) 0.050 g, 0.091 mmol) in dry CH2C12 (10 mL) was treated with bromoethylisocyanate (0.010 mL, 0.110 mmol) and stirred at room temperature 4 h. Additional bromoethylisocyanate (0.010 mL, 0.110 mmol) was added and the reaction stirred at room temperature 15 h. The reaction mixture was washed with water (1x15 mL), dried over MgSO4, and concentrated in vacua. The residue was taken up in CH2Cl2 (10 mL), treated with trifluoroacetic acid (1.00 mL), and stirred at room temperature 1 h. The solvents were evaporated in vacito. Preparatory HPLC (10-80% acetonitrile in 1% TFA/water over 30 min.) afforded the product 4-[4'- methoxy-6'-methyl-2'-(2-oxo-irnidazolidin-l-yl)-biphenyl-3-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate (0.010 g, 21%) as a white glassy solid. 1H NMR (MeOD): d 8.354 (s, 1H), 8.032 (d, 1H, .J = 7.6 Hz), 7.946 (s, 1H), 7.733 (t, 1H, J = 7.6 Hz), 7.574 (d, 1H, J = 8.0 Hz), 7.059 (s, 1H), 6.967 (s, 1H), 3.877 (s, 3H), 2.730 (s, 3H), 2.101 (s, 3H), 3.841 (dt, 4H, J= 8.8 Hz, J= 2.4 Hz). C23H24N4O4S3: 517.10 (M+l) found 517.10. Example 199 N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-methoxy- 6-methyl-biphenyl-2-yl]-4-methanesulfonyl-butyramide trifluoroacetate A solution of {[4-(2'-amino-4"-methoxy-6'-methyl-biphenyl-3- sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl} -carbamic acid tert- butyl ester {{Example 198: step e) 0.050 g, 0.091 mmol) in CH2C12 (10 mL) was treated with triethylamine (38.0 µL, 0.274 mmol) and 4-methanesulfonyl- butyryl chloride ( 0.025 g, 0.137 mmol) as a solution in CH2Cl2 (3 mL) and stirred at room temperature 3 h. The reaction mixture was washed with saturated aqueous NaHCO3 (1 x 15 mL). The organic layer was dried over MgSO4 and trifluoroacetic acid (0.5 mL) was added. The solution stirred at room temperature 1 h and solvents were removed in vacuo. Preparatory HPLC (10-50% acetonitrile in 1% TFA/water over 30 min.) afforded the product N-[3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4- methoxy-6-methyl-biphenyl-2-yl]-4-methanesulfonyl-butyramide trifluoroacetate (0.013 g, 24%) as a white glassy solid. 1H NMR (MeOD): 8 8.309 (s, 1H), 8.032 (d, 1H, J= 8.8 Hz), 7.868 (t, 1H, J= 1.6 Hz), 7.684 (t, 1H, J= 8.0 Hz), 7.543 (d, 1H, J= 8.0 Hz), 6.871 (s, 1H), 6.817 (d: 1H, J= 2.4 Hz), 3.841 (s, 3H), 2.922 (s, 3H), 2.822 (t, 2H, J = 7.6 Hz), 2.742 (s, 3H), 2.202 (t, 2H, J= 6.8 Hz), 2.063 (s, 3H), 1.765 (m, 2H). C25H29N3O6S4: 596.09 (M+l) found 596.10. Example 200 a) 4-{2'-[3-(2-Methanesulfonyl-ethyl)-ureido]-4'-methoxy-6'-methyl- biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate A solution of {[4-(2'-amino-4'-methoxy-6'-methyl-biphenyl-3- sulfonyl)-5-methylsulfanyl-thicphen-2-yl]-imino-methyl} -carbamic acid tert- butyl ester {{Example 198: step e) 0.070 g, 0.128 mmol) in dry CH2C12 (3 mL) was treated with l-isocyanato-2-methanesulfonyl-ethane (0.019 g, 0.128 mmol) as a solution in CH2Cl2 (2 mL) and stirred 20 min. The reaction mixture was washed with saturated aqueous NaHCO3 (1 x 25 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was taken up in CH2Cl2 (10 rnL) and treated with trifluoroacetic acid (2.00 mL), stirring at room temperature 30 min. The solvents were removed in vacuo. Preparatory HPLC (10-80% acetonitrile in 1% TFA/water over 30 min.) afforded the product 4-{2'-[3-(2-methanesulfonyl-ethyl)-ureido]-4'- methoxy-6'-methyl-biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate (0.040 g, 53%) as a white glassy solid. 1H NMR (MeOD): d 8.300 (s, 1H), 8.031 (d, 1H, J= 8.0 Hz), 7.865 (t, 1H, J = 1.6 Hz), 7.688 (t, 1H, 7= 7.6 Hz), 7.568 (d, 1H, J= 8.0 Hz), 7.063 (d, 1H, J = 1.6 Hz), 6.730 (d, 1H, J== 1.6 Hz), 3.818 (s, 3H), 3.507 (t, 2H, J= 6.4 Hz), 3.171 (t, 2H, J = 6.0 Hz), 2.928 (s, 3H), 2.725 (s, 3H), 2.315 (s, 3H). C24H28N4O0S4: 597.09 (M+l) found 597.00. Example 201 4-{2'-[3-(4-Methanesulfonyl-butyl)-ureido]-6'-methyl-biphenyl-3-sulfonyl}-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate a) 2-(4-Methylsulfattyl-butyl)-isoindole-l,3-dione A solution of 2-(4-bromo-butyl)-isoindole-l,3-dione (l.00g, 3.54 mmol) in MeOH (60 mL) was treated with sodium thiomethoxide (0.298 g, 4.25 mmol) and heated to reflux 18 h. The solvent was evaporated in vacuo and the residue partitioned between EtOAc and water. The aqueous layer was further extracted with EtOAc (1 x 75 mL). The organic layers were dried over MgSO4 and concentrated in vacuo to afford the product 2-(4-methylsulfanyl- butyl)-isoindole-l,3-dione (0.803 g, 91%). 1H NMR (MeOD) 7.844 (m, 4H), 3.704 (t, 2H, J = 7.2 Hz), 2.549 (t, 2H, J = 7.2 Hz), 2.063 (s, 3H), 1.792 (quint, 2H, J = 7.2 Hz), 1.731 (quint, 2H, J = 7.2 Hz). b) 2-(4-Methanesulfonyl-butyl)-isoindole-l,3-dione A solution of 2-(4-methylsulfanyl-butyl)-isoindole-l,3-dione ((Example 201: step a) 1.35 g, 5.42 mmol) in CH2Cl2 (50 mL) was treated with 3-chloroperbenzoic acid (mCPBA, 3.03 g, 13.5 mmol) and stirred at room temperature 17 h. The solution was washed with aqueous Na2S2O3 (2 x 40 mL) and water (1 x 40 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to afford the product 2-(4-methanesulfonyl-butyl)- isoindole-l,3-dione (0.866 g, 57%). 1H NMR (MeOD): d 7.S27 (m, 4H), 3.732 (t, 2H, J = 6.4 Hz), 3.193 (t, 2H, J = 7.2 Hz), 2.939 (s, 3H), 1.843 (m, 4H). c) 4-Methanesulfonyl-butylamine A solution of 2-(4-metlianesulfonyl-butyl)-isoindole-l,3-dione ((Example 201: step b) 0.866 g, 3.08 mmol) in EtOH (30 mL) was treated with hydrazine and stirred at room temperature 18 h. The solid precipitate was removed by filtration and the filtrate was concentrated in vacuo. To remove any excess hydrazine, the resulting waxy solid was titrated with toluene and with THF and placed under liigh vacuum overnight to afford the product (0.400 g, 86%) as a waxy, off-white solid. +NMR (MeOD): d 3.153 (dd, 2H, J - 8.8 Hz, J = 0.0 Hz), 2.962 (s, 3H), 2.582 (dd, 2H, J = 7.6 Hz, J = 0.0 Hz), 1.811 (m,2H) 1.747 (m,2H). d) 4-{2'-[3-(4-Methanesulfonyl-butyl)-ureido]-6'-methyl-biphenyl-3- sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate A solution of [4-(2'-arnino-6'-methyl-biphenyl-3-sulfonyl)-5- methylsu]fanyl-thjophen-2-y]]-immo-methy3}-carbamic acid tent-butyl ester ((Example 25: step c) 0.100 g, 0.193 mmol) in CH2C12 (10 mL) was treated with pyridine (0.017 mL, 0.213 mmol) and p-nitrophenylchloroformate (0.043 g, 0.213 mmol) and stirred 2 h. The solution was treated with 4- methanesulfonylbutylaimine (Example 201: step c, 0.035 g, 0.232 mmol) and triethylamine (0.215 mL, 1.54 mmol) and stirred 2 h. The mixture was diluted with CH2Cl2 and washed with water (1 x 50 mL). The organic layer was dried over MgSO4 and filtered. The remaining CH2Cl2 solution was treated with trifluoroacetic acid (1.00 mL) and stirred 1.5 h, The solvents were evaporated in vacuo. Preparatory HPLC (10-50% aeetomtrile in 1% TFA/water over 30 min.) afforded the product 4-{2'-[3-(4-methanesulfonyl-butyl)-ureidoJ-6'- methyl-biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate (0.022 g, 19%) as a white glassy solid. !H NMR (MeOD): d 8.326 (s, 1H), 8.069 (d, 1H, J = 8.0 Hz), 7.917 (t, 1H, J = 1.6 Hz), 7.740 (t, 1H, J = 8.0 Hz), 7.586 (d, 1H, J = 7.6 Hz), 7.441 (d, 1H, J = 7.2 Hz), -7.305 (t, 1H, J = 8.0 Hz), 7.151 (d 1H, J = 8.0 Hz), 3.116 (dd, 2H, J - 8.8 Hz, J = 6.4 Hz), 3.069 (t, 2H, J = 6.8 Hz), 2.962 (s, 3H), 2.739 (s, 3H), 2.025 (s, 3H) 1.732 (quint, 2H, J = 7.6 Hz), 1.506 (quint, 2H, J = 7.6 Hz). C25H30N4O5S4: 595.11 (M+l) found 595.10. Examples 202-208 A solution of [4-(2'-amino-6'-inethyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 25: step c) 1.00 g, 1.93 mmol) in dry CH2C12 (20 mL) was treated with pyridine (0.172 mL, 2.13 mmol) and p-nitrophenylchloroformate (0.428 g, 2.13 mmol). The mixture was stirred at room temperature 2 h. The solution of the resulting carbatnate, {3'-[5-(tert-butoxycarbonylamino-imino-methyl)- 2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-carbamic acid 4-nitro-phenyl ester, was divided into vials and treated with the following amines (1.1 equivalents) and triethylamine (8.0 equivalents). Example 202 2-((4-Bromo-phenyl)-ethylamine) Example 203 (3-Phenyl-propylamine) Example 204 (Berizylamine) Example 205 (2-Aniino-3-phenyl-propionic acid) Example 206 (6-Amino-2-tert-butoxycarbonylamino-hexanoic acid) Example 207 (2-(lH-Indol-3-yl)-ethylamine) Example 208 (3,3-Diphenyl-propylamine) The reaction mixtures stirred at room temperature 4 h. The solutions were washed with water and the organic layers dried over MgSO4 and concentrated in vacuo. The residues were taken up in CH2Cl2 (1 mL) and treated with trifluoroacetic acid (0.25 mL) for 2 h. Solvents were evaporated in vacuo. Preparatory HPLC (10-80% acetonitrile in 1% TFA7water over 30 min.) afforded the products shown in Examples 203-208. All were white glassy solids. Example 202 4-(2'-{3-[2-(4-Bromo-phenyl)-ethyl]-ureido}-6'-methyl-biphenyl-3-sulfonyl)- 5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate 1H NMR (MeOD): d 8.299 (s, 1H), 8.075 (d, 1H, J= S.4 Hz), 7.894 t, 1H, J = 1.6 Hz), 7.708 (t, 1H, J= 8.0 Hz), 7.529 (d, 1H, J= 8.4 Hz), 7.376 (d, 2H, J = 8.4 Hz), 7.834 (t, 1H, J= 8.4 Hz), 7.279 (t, 1H, J= 7.6 Hz), 7.134 (d, 1H, J = 7.6 Hz), 6.957 (d, 2H, J= 7.6 Hz), 3.20 (m, 2H), 2.656 (s, 3H), 2.555 (m, 2H), 1.995 (s,3H). C28H27BrN4O3S3: 643.04 (M+l) found 643.00. Example 203 4-{6'-Methyl-2'-[3-(3-phenyl-propyl)-ureido]-biphenyl-3-sulfonyl}-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate 1H NMR (MeOD): d 8.293 (s, 1H), 8.056 (d, 1H, J= 8.0 Hz), 7.916 (t, 1H, J - 1.6 Hz), 7.715 (t, 1H, J= 7.6 Hz), 7.592 (d, 1H, J= 7.6 Hz), 7.449 (d, 1H, .7 = 7.6 Hz), 7.308 (t, 1H, J = 7.6 Hz), 7.255 (d, 2H, J= 7.2 Hz), 7.166 (t, 2H, J = 7.2 Hz), 7.147 (d, 2H, J = 8.0 Hz), 3.021 (t, 2H, J= 6.4 Hz), 2.697 (s, 3H), 2.515 (t, 2H, J = 7.6 Hz), 2.026 (s, 3H), 1.638 (quint, 2H, J = 7.6 Hz). C29H30N4O3S3: 579.15 (M+l) found 579.10. Example 204 4-[2'-(3-Benzyl-ureido)-6'-methyl-biphenyl-3-sulfonyl]-5-methylsulfanyl- thiophene -2-carboxamidme trifiuoroacetate 1H NMR (MeOD): d 8.243 (s, 1H), 8.073 (d, 1H, J= 9.2 Hz), 7.951 (t, 1H, J = 1.6 Hz), 7.685 (t, 1H, J = 8.0 Hz), 7.558 (d, 1H, J= 7.(5 Hz), 7.406 (d, 1H, J = 8.8 Hz), 7.301 (t, 1H, J= 8.0 Hz), 7.232 (m, 4H), 6.977 (d, 2H, .7= 8.4 Hz), 4.137 (q, 2H, J= 16 Hz), 2.649 (s, 3H), 2.029 (s, 3H). C27H26N4O3S3: 55.12 (M+l) found 551.10. Example 205 2-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl- biphenyl-2-yl]-ureido}-3-phenyl-propionic acid trifluoroacetate 1H NMR (CD3CN): d 10.027 (s br, 1H), 8.083 (s, 1H), 7.875 (s, 1H), 7.807 (s, 1H), 7.729 (t, 1H, y = 7.525 Hz), 7.525 (d, 1H, J= 6.8 Hz), 7.429 (m, 1H), 7.272 (m, 5H), 7.101 (m, 2H), 5.446 (t, 1H, J= 10.4 Hz), 3.077 (m, 2H), 2.674 (s, 3H), 2.018 (s, 3H). C29H28N4O5S3: 609.12 (M+l) found 609.10. Example 206 2-Ammo-6-{3-[3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)- 6-methyl-biphenyl-2-yl]-ureido}-hexanoic acid tnfluoroacetate 1H NMR (CD3CN): d 8.135 (s, 1H), 8.037 (d, 1H, J= 7.6 Hz), 7.839 (s, 1H), 7.702 (t, 1H, J = 7.6 Hz), 7.566 (d, 1H, J= 8.0 Hz), 7.413 (d, 1H, ./= 8.0 Hz), 7.297 (t. 1H, J= 7.6 Hz), 7.186 (d, 1H, J= 7.2 Hz), 3.951 (s br, 1H), 2.939 (t, 2H, 7= 1.6 Hz), 2.674 (s, 3H), 2.043 (s, 3H), 1.854 (m, 2H), 1.311 (m, 4H). C26H31N5O5S3: 590.15 (M+l) found 590.10. Example 207 4-(2'- {3-[2-(lH-Indol-3-yl)-ethyl]-ureido} -6'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxamidine tnfluoroacetate 1H NMR (MeOD): d 8.270 (s, 1H), 8.069 (d, 1H, J= 8.0 Hz), 7.901 (t, 1H, J = 1.6 Hz), 7.661 (t, 1H, J= 7.2 Hz), 7.467 (t, 2H,J= 8.8 Hz), 7.351 (t, 2H, J = 6.8 Hz), 7.296 (t, 1H, J= 7.6 Hz), 7.163 (d, 1H, J= 8.0 Hz), 7.103 (t, 1H, J = 7.2 Hz), 6.991 (t, 1H, J= 6.8), 6.855 (s, 1H), 3.428 (m, 2H), 2.712 (t, 2H,J = 8.8 Hz), 2.575 (s, 3H), 2.028 (s, 3H). C30H29N5O3S3: 604.14 (M+l) found 604.10. Example 208 4-{2'-[3-(3,3-Diphenyl-propyl)-ureido]-6'-methyl-biphenyl-3-sulfonyl}-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate 1H NMR (MeOD): d 8.263 (s, 1H), 8.022 (d, 1H, J= 8.8 Hz), 7.913 (t, 1H, J = 1.6 Hz), 7.679 (t, 1H, J-= 7.6 Hz), 7.585 (d, 1H, J= 7.6 Hz), 7.416 (d, 1H, J = 7.416 Hz), 7.253 (m, 9H), 7.163 (t, 3H, J = 6.8 Hz), 3.878 (t, 1H,./= 7.6 Hz), 2.944 (dt, 2H, J= 6.8 Hz, J= 2.4 Hz), 2.689 (s, 3H), 2.081 (q, 2H, J = 7.6 Hz), 2.032 (s, 3H). C35H34N4O3S3: 655.18 (M+l) found 655.10. Example 209 N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl- biphenyl-2-yl]-4-methanesulfonyl-butyiramide trifluoroacetate a) 4-Methanesulfonyl-butyryl chloride 4-Methylsulfanyl-butyriic acid methyl ester (0.50 g, 3.37 mmol) in dichloromethane [5 mL] was added dropwise to a solution of mCPBA (1.57 g, 9.11/ mmol) in dichloromethane [15 mL] at room temperature and then refluxed for 1 hour.. The solution was then cooled to room temperature and solid sodium sulfite was added. The reaction was filtered, washed with IN NaOH, brine and dried with magnesium sulfate and evaporated. The crude residue was then dissolved in THF/methanol/water [2/1/0.1 mL] and lithium hydroxide (0.18 g, 4.38 mmol) was added. The reaction was heaved to 50°C for 24 hours. The reaction was cooled to room temperature and IN HC1 was added and the product was extracted with ethyl acetate, dried with magnesium sulfate to give the product (0.12 g, 21%). 1H-NMR (CDCl3): d 3.20 (t, 2H, J=7.6 Hz), 2.98 (s, 3H), 2.52 (t, 2H, J=7.2 Hz), 2.09 (m, 2H). The acid was dissolved in dichloromethane [5 mL] and thionyl chloride [5mL] was added. The reaction was stirred at room temperature for 3 hours, evaporated and used directly in the next step. b) (Imino-{4-[2'-(4-methanesulfonyl-butyrylamino)-6'-methyl-biphenyl- 3-sulfonyl]-5-methyhulfanyl-thiophen-2-yl}-methyl)-carbamic acidtert- butyl ester 4-Methanesulfonyl-butyryl chloride (0.333 g, 1.81 mmol) 1 example 209, step a] was added to a solution of {[4-(2'-amino-6'-methyl-biphenyl-3- sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl} -carbamic acid tert- butyl ester (0.468 g, 0.905 mmol) [example 25, step c] and triethylamine (1.S3 g, 18.1 mmol) in dichloromethaxie at room temperature. The reaction was stirred for 24 hours and then evaporated. Column chiomatography (25% EtOAc in hexanes) of the residue yielded the title compound (0.520 g, 78%) as a solid. ESI-MS (m/z): Calcd. for C29H35N3O7S4: 665.14; found: 665.8. c) N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6- methyl-biphenyl-2--yll-4-niethanesulfonyl-butyrami.de trifluoroacetate A solution of dichloromethane/ trifiuoroacetic acid (1/1) [1 mL] was added to (imino- {4-[2'-(4-methcinesulfonyl-butyrylamino)-(5'-methy]-biphenyl- 3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester (0.011 g, 0.017 mmol) [example 209, step b] at room temperature and stirred for 1 hour. The reaction mixture was evaporated and purified via reverse-phase HPLC [acetonitrile/water (0.01 %TFA)] to give the title compound (0.004 g, 36%) as a solid. 1H-NMR (MeOD): 6 8.29 (s, 1H), 8.04 (md, 1H, J=6A Hz), 7.87 (t, 1H, .7=2.0 Hz), 7.69 (t, 1H, .7=7.6 Hz), 7.54 (md, 1H, .7=7.6 Hz), 7.34 (t, 1H, J=7.6 Hz), 7.28 (d, 1H, .7=7.2 Hz), 7.18 (d, 1H, 7=7.2 Hz), 2.91 (s, 3H), 2.78 (t, 2H, J=7.6 Hz), 2.72 (s, 3H), 2.18 (t, 2H, J=7.6 Hz), 2.07 (s, 3H), 1.74 (m, 2H). ESI-MS (m/z): Calcd. for C24H27N3O5S4: 566.1; found: 566.8. Example 210 N-[3l-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl- biphenyl-2-yl]-4-sulfamoyl-butyramide trifluoroacetate a) (Imino-{4-[6'-methyl-2'-(4-siilfamoyl-butyrylamino)-biphenyl-3- sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester {[4-(2'-Amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.013 g, 0.025 mmol) [example 25, step c] was added to a solution of 4-sulfamoyl-butyric acid (0.011 g, 0.068 mmol), EDCI (0.013 g, 0.068 mmol) and HOBt (0.009 g, 0.068 mmol) in DMF [0.5 mL] at room temperature. The reaction was stirred for 24 hours and then evaporated. Column chromatography (25% EtOAc in hexanes) of the residue yielded the title compound (0.010 g, 60%) as a solid. ESI-MS (m/z): Calcd. for C28H34N4O7S4: 666.13; found: 666.8. b) N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6- methy1-biphenyl-2-yl]-4-sulfamoylbntyramide trifluoroacetate A solution of dichloromethane/ trifluoroacetic acid (1/1) [1 mL] was added (irnino-{4-[6'--methyl-2'-(4-sulfamoyl-butyrylarnino)-biphenyl-3- sulfonyl]-5-methylsulfanyl-thiophen-2-yl} -methyl)-carbamic acid tert-butyl ester (0.010 g, 0.015 mmol) [example 210, step a] at room temperature and stirred for 1 hour. The reaction mixture was evaporated and purified via reverse-phase HPLC [acetonitrile/water (0.01%TFA)] to give the title compound (0.005 g, 36 %) as a solid. 1H NMR (MeOD): d 8.30 (s, 1H), 8.04 (md, 1H, 7=7.6 Hz), 7.88 (t, 1H, .7=1.6 Hz), 7.70 (t, 1H, .7=7.6 Hz), 7.54 (md, 1H, .7-7.6 Hz), 7.36 (t, 1H, .7=7.6 Hz), 7.29 (d, 1H, .7=6.8 Hz), 7.19 (d, 1H, .7=8.0 Hz), 2.77-2.72 (m, 5H), 2.16 (t, 2H, .7=7.2 Hz), 2.09 (s, 3H), 1.76 (m, 2H). ESI-MS (m/z): Calcd. for C23H26N4O5S4: 566.08; found: 567.1. Example 211 11-Amino-undecanoic acid [3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene- 3-sulfonyl)-6-methyl-biphenyl-2-yl]-amidebistrifluoroacetate a) (10-{3'-[5-(tert-Butoxycarbonylamino-imino-niethyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl--biphenyl-2-ylcarbamoyl}- decyl)-carbamic acid 9H-fluoren-9-ylmethyl ester Thionyl chloride (0.86 mL, 2.36 mmol) was added to a solution of 11- (9H-fluoren-9-ylmethoxycarbonylamino)-undecanoic acid (0.086 g, 0.194 mmol) in dichloromethane/DMF [1 mL/1 drop] and stirred at room temperature for 3 hours. The reaction mixture was evaporated, dissolved in dichloromethane [5 mL] was added dropwise to a solution of {[4-(2'-amino-6'- methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}- carbamic acid tert-butyl ester (0.050 g, 0.097 mmol) [example 25, step c] and triethylamine (0.03 mL, 0.19 mmol) in dichloromethane [3 mL] at room temperature and stirred for several hours. The crude reaction was evaporated and column chromatography (25% EtOAc in hexanes) of the residue yielded the title compound (0.042 g, 47 %) as a solid. ESI-MS (m/z): Calcd. for C50H58N4O7S3: 922.35; found: 923.0. b) ({4-12'-(ll-Amino-undecanoylamino)-6'-methyl-biphenyl-3- sulfonyl]-5-methylsulfanyl-thiopheii-2-yl}-imino-methyl)-carbamicacidtert- butyl ester A solution of 50% piperidine in DMF [1 mL] was added to (10-{3'-[5- (tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3 - sulfonyl]-6-methyl-biphenyl-2-ylcarbamoyl}-decyl)-carbamic acid 9H- fluoren-9-ylmethyl ester (0.040 g, 0.043 mmol) [example 211, step a] and stirred for 0.5 hours, followed by evaporation. Column chromatography (10% MeOH in dichloromethane) of the residue yielded the title compound (0.024 g, 77 %) as a solid. ESI-MS (m/z): Calcd. for C35H48N4O5S3: 700.28; found: 701.0. c) 11-Amino-undecanoic acid [3'-(5-carbamimidoyl-2-methylsulfanyl- thiophene-3-sulfonyl)- 6-methyl-biphenyl-2-yl]-amide bistrifluoroacetate A solution of dichloromethane/ trifluoroacetic acid (1/1) [1 mL] was added to ({4-[2'-(! l-amino-undecanoylamino)-6'-methyl-biphenyl-3- sulfonyl]-5-methylsulfanyl-miophen-2-yl}-imino-methyl)-carbamic acid tert- butyl ester (0.005 g, 0.007 mmol) [example 211, step b] at room temperature and stirred for 1 hour. The reaction mixture was evaporated and purified via reverse-phase HPLC [acetonitrile/water (0.01%TFA)] to give the title compound (0.003 g, 76 %) as a solid. 1H-NMR (MeOD): d 8.28 (s, 1H), 8.02 (d, 1H, J=7.2 Hz), 7.87 (m, Hi), 7.66 (t, 1H, J=8.0 Hz), 7.53 (d, 1H, 7=8.0 Hz), 7.34 (t, 1H, y=7.6 Hz), 7.27 (d, 1H, J=7.6 Hz), 2.91 (t, 2H, .7=8.0 Hz), 2.71 (s, 3H), 2.03 (s, 3H), 1.96 (q, 2H, .7=7.2 Hz), 1.65 (m, 2H), 1.41-1.12 (m, 14H). ESI-MS (m/z): Calcd. for C30H40N4O3S3: 600.23; found: 601.2. Example 212 N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl- biphenyl-2-yl]-4-trifluoromethanesulfonylamino-butyramide trifluoroacetate a) 4-Trifliioromethanesulfonylamino-biitync acid methyl ester Trifluoromethanesulfonyl chloride (0.23 mL, 2.16 mmol) was added dropwise to a solution of 4-amino-butyric acid methyl ester hydrochloride (0.30 g, 1.96 mmol) and triethylamine (0.68 mL, 4.90 mmol) in dichloromethane and stirred at room temperature for 18 hours. 1N HC1 was added and the product, was extracted with dichloromethane, dried with magnesium sulfate and evaporated to give the title compound (0.42 g, 85 %). 1H-NMR (CDCl3): d 4.89 (s, 1H), 3.12 (t, 2H, J-7.2 Hz), 2.94 (s, 3H), 2.41 (t, 2H, J=7.2 Hz), 1.84 (m, 2H, J=l2 Hz). b) 4-Trifluoromethanesulfonylamino-butyryl chloride 4-Trifluorometbanesulfonylamino-butyrie acid methyl ester (0.42 g, 1.77 mmol) [example 212, step a] was taken up in methanol [2 mL] and 1N NaOH was added [2.66 mL] and stirred for 2 hours. 1N HCl was added and the product was extracted with ethyl acetate, dried with magnesium sulfate and evaporated. The crude product (0.13 g, 0.57 mmol) was dissolved in dichloromethane/DMF [1 mL/1 drop] and thionyl chloride (0.08 mL, 1.14 was added. The reaction was stirred at room temperature for 2 hours and then evaporated and used directly in the next step. c) (Imino-{5-methylsnlfanyl-4-[6'-methyl-2'-(4- trifluoromethanesulfonylaminobutyrylamino)-biphenyl-3-sulfonyl]- thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester A solution of 4-trifluoromethanesulfonylamino-butyryl chloride (0.015 g, 0.058 mmol) [example 212, step b] in dichloromethane [1 mL] was added to a solution of {[4-(2'-amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-iniino-methyl}-carbamic acid tert-butyl ester (0.025 g, 0.049 mmol) [example 25, step c] in dichloromethane [1 mL] at room temperature with vigorous stirring for 0.5 hours. The reaction mixture was evaporated and column chromatography (25% EtOAc in hexanes) of the residue yielded the title compound (0.020 g, 57%) as a solid. ESI-MS (m/z): Calcd. for C29H33F3N4O7S4: 734.12; found: 734.7. d) N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfoityl)-6- methyl-biphenyl-2-yl]-4-trifluoromethanesulfonylamino-butyramide triflnoroacetate A solution of dichloromethane/ trifluoroacetic acid (1/1) [2 mL] was added to (imino-{5-methylsulfanyl-4-[6'-methyl-2'-(4- trifluoromethanesulfonylanunobutyrylamino)-biphenyl-3-sulfonyl]-thiophen- 2-yl}-methyl)-carbamic acid tert-butyl ester (0.020 g, 0.027 mmol) [example 212, step c] at room temperature and stirred for 1 hour. The reaction mixture was evaporated and purified via reverse-phase HPLC [acetonitrile/water (0.01 %TFA)] to give the title compound (0.009 g, 54%) as a solid. 1H-NMR (MeOD): d 8.29 (s, 1H), 8.03 (md, 1H, J=8.4 Hz), 7.87 (m, 1H), 7.68 (t, 1H, .1=7.6 Hz), 7.53 (md, 1H, J=1.6 Hz), 7.34 (t, 1H, 1=1.6 Hz), 7.2S (d, 1H, J=7.2 Hz), 7.19 (d, 1H, J=7.2 Hz), 2.98 (m, 2H), 2.72 (s, 3H), 2.06 (s, 3H), 2.05 (t, 2H, J=7.6 Hz), 1.48 (m, 2H). ESI-MS (m/z): Calcd. for C24H25F3N4O5S4: 634.07; found: 635.1. Example 213 E/Z-{2-[3'-(5-Carbamiraido)d-2-methylsulfanyl-thiophene-3-suifonyl)-6- methyl-biphenyl-2-yl]-vinyl} -phosphonic acid trifluoroacetate a) (2-Iodo-3-methyl-phenyl)-m ethanol Thionyl chloride [5 ml,] was added to 2-iodo-3-methyl-benzoic acid (2.00 g, 7.63 mmol) at room temperature and heated to 50°C for 1 hour. The solution was then cooled and evaporated. The crude residue was dissolved in ethyl acetate, washed with brine and dried with magnesium sulfate. The crude product was then dissolved in THF [5 mL] and a 1M solution of lithium aluminum hydride [10.7 mL] was added at room temperature and stirred for 1 hour. Water [0.1 mL] and 15% NaOH [0.1 mL] were added followed by evaporation. Column chromatography (50% EtOAc in hexanes) of the residue yielded the title compound (0.50 g, 26 %) as a solid. 1H-NMR (CDCl3): d 3.20 (t, 2H, J=7.6 Hz), 2.98 (s, 3H), 2.52 (t, 2H, J=7.2 Hz), 2.09 (m, 2H). b) {[4-(2'-Hydroxymethyl-6'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester n-Butyllithium (2.5.M) [4.03 mL] was added to a solution of (2-iodo-3- methyl-phenyl)-methanol (1.00 g, 4.04 mL) [example 213, step a] in ether [20 mL] at -78°C and stilted for 0.5 hours. Trimethyl borate [1.13 mL, 10.1 mmol) was added and the solution was stirred for 2 hours at room temperature, followed by evaporation. The crude residue was dissolved in ethanol/toluene (1/2) [30 mL] and 2M sodium carbonate [16.2 mL] followed by addition of {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino- methyl}-carbamic acid tert-butyl ester (0.49 g, 1.01 mmol) [example 27, step c]. The solution was bubbled with argon and then tetrakis (triphenylphosphine) palladium (0) (0.18 g, 0.15 mmol) was added. The reaction was refluxed for 3 hours and then cooled to room temperature. Ethyl acetate was added and the crude reaction was washed with brine, dried over magnesium sulfate and evaporated. Column chromatography (50% EtOAc in hexanes) of the residue yielded the title compound (0.40 g, 74 %) as a solid. ESI-MS (m/z): Calcd. for C25H28N2O5S3: 532.12; found: 532.7. c) E/Z-(2-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-vinyl)- phosphonic acid diethylester Manganese dioxide (0.041 g, 0.470 mmol) was added to a solution of ({[4-(2'-hydroxymethyl-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.025 g, 0.047 mmol) [example 213, step b] in dichloromethane [5 mL] and refluxed for 3 hours. The reaction was filtered through Celite and evaporated.. The crude residue was dissolved in anhydrous THF [2 mL] and added to a solution of (diethoxy-phosphorylmethyl)-phosphonic acid diethyl ester (0.011 g, 0.061 mmol) and sodium hydride (0.003 g, 0.056 mmol) in THF [2 mL] at room temperature and stirred for 0.5 hours. A solution of 1N NaOH/MeOH (1/1) [10 mL] was added and the crude product was extracted with ether, dried with magnesium sulfate and evaporated. Column chromatography (50% EtOAc in hexanes) of the residue yielded the title compound (0.019 g, 57%) as a solid. ESI-MS (m/z): Calcd. for C30H37N2O7PS3: 664.15; found: 664.8. d) E/Z-{2-[3'-(5-Carbam im idoyl-2-m ethyhulfanyl-th ioph en e-3- sulfonyl)-6-methyl-biphenyl-2-yl]-vinyl}-phosphonic acid trifluoroacetate Trimethylsilyl iodide (0.058 g, 0.271 mmol) was added dropwise to a solution of E/Z-(2- {3'-[5-(tert-butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene--3-sulfonyl]-6-methyl-biphenyl-2-yl}-vinyl)- phosphonic acid diethylester (0.018 g, 0.027 mmol) [example 213, step c\| in dichloromethane [3 mL] and heated to 45°C for 3 hours. The reaction was quenched with water [0.025 mL], stirred for 0.5 hours and evaporated. The crude residue was the dissolved in methanol and 20% HC1 was added [020 mL], stirred for 1 hour and concentrated. The reaction mixture was purified via reverse-phase HPLC [acetonitrile/water (0.01 %TFA)] to give the title compound (0.005 g, 28%) as a solid. 1H-NMR (MeOD): d 8.28 (s, 1H), 8.04 (t, 1H, .7=7.6 Hz), 7.83 (s, 1H), 7.71 (t, 1H, .7=7.6 Hz), 7.63 (m, 1H), 7.52 (m, 1H), 7.38 (m, 1H), 7.26 (m, 1H), 7.18 (t, 1H, J=7.2 Hz), 6.92 (t. 1H, J=17.6 Hz), 6.34 (t, 1H, J=18.0 Hz), 2.74 (s, 3H), 2.02-1.95 (d, 3H). ESI-MS (m/z): Calcd. for C21H21N2O5PS3: 508.04; found: 509.1. Example 214 2-[3'-(5-Carbaniimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-niethy]- biphenyl-2-ylmethylsulfanyl]-succinic acid trifluoroacetate a) Methanesulfonic acid 3'-[5-(tert-butoxycarbonylamiiw-imino- methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2- ylmethyl ester Methanesulfonyl chloride (0.027 g, 0.241 mmol) was added to a solution of {[4-(2'-hydroxymethyl-6'-methyl-biphenyl-3-suifonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.100 g, 0.188 mmol) [example 213, step b] and triethylamine (0.048 g: 0.470 mmol) in THF [3 mL] at room temperature and stirred for 18 hours. Column chromatography (25% EtOAc in hexanes) of the residue yielded the title compound (0.017 g, 14%). ESI-MS (m/z): Calcd. for C26H30N2O7S4: 610.09; found: 611.8. b) 2-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-suIfonyl)-6- methyl-biphenyl-2-ylmethylsulfanylJ-succinic acid trifluoracetate 2-Mercapto-succinic acid (0.004 g, 0.028 mmol) was added to a solution of methanesulfonic acid 3'-[5-(ter1:-butoxycarbonylarnino-imino- methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2- ylmethyl ester (0.017 g, 0.028 mmol) [example 214, step a] and triethylamme (0.009 g, 0.084 mmol) in dichloromethane [0.5 mL] at 40°C, stirred for 2 hours and then evaporated. The crude reaction was dissolved in a solution of dichloromethane/ trifluoroacetic acid (1/1) [2 mL] and stirred for 1 hour. The reaction mixture was evaporated and purified via reverse-phase HPLC [acetonitrile/water (0.01%TFA)] to give the title compound (0.005 g, 42 %) as a solid. 1H-NMR (MeOD): d 8.31 (s, 1H), 8.06 (t, 1H, J=8.0 Hz), 7.83 (d, 1H, .7=16.8 Hz), 7.70 (q, 1H, .7=6.8 Hz), 7.57 (t, 1H, J=7.2 Hz), 7.29-7.21 (m, 3H), 3.60-3.48 (m, 1H), 3.54 (s, 3H), 3.37-3.34 (m, 1H), 2.70 (s, 3H), 2.68-2.57 (m, 1H), 2.31-2.14 (m, 1H), 1.97 (s, 3H). ESI-MS (m/z): Calcd. for C24H24N2O6S4: 564.05; found: 565.1. Example 215 [3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2,6-dimethyl- biphenyl-4-yloxy]-acetic acid trifluoroacetate a) {3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl- thiophene-3-sulfonyl]-2,6-dimethyl-biphenyl-4-yloxy}-acetic acid tert-butyl ester Bromo-acetic acid tert-butyl ester (0.013 mL, 0.0S5 mmol) was added dropwise to a solution of {[4-(4'-hydroxy-2',6'-dimetriyl-biphenyl-3-sulfonyl)- 5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbarnic acid tert-butyl ester (0.050 g, 0.077 mmol) [example 124, step b] and potassium carbonate (0.021 g, 0.154 mmol) in acetone [1 mL] at room temperature and stirred for 18 hours. The reaction was evaporated and column chromatography (25% EtOAc in hexanes) of the residue yielded the title compound (0.011 g, 28%) as a solid. ESI-MS (m/z): Called, for C31H38N2O7S3: 646.18; found: 646.8. b) [3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2,6- dimethyl-biphenyl-4-yloxy]-acetic acid trifluoroacetate A solution of dichloromethane/ trifluoroacetic acid (1/1) [2 mL] was added to {3'-[5-(tert-bu1:oxycarbonylamino-imino-methyl)-2-methylsulfanyl- thiophene-3-sulfonyl]-2,6-climethyl-biphenyl-4-yloxy}-acetic acid tert-butyl ester (0.020 g, 0.030 mmol) [example 215, step a] at room temperature and stirred for 1 hour. The reaction mixture was evaporated and purified via reverse-phase HPLC [acetonitrile/water (0.01 %TFA)] to give the title compound (0.011 g, 75%) as a solid. 1H-NMR (MeOD): d 8.36 (s, 1H), 8.01 (md, 1H, J=7.6 Hz), 7.81 (m, 1H), 7.72 (m, 1H), 7.51 (d, 1H, J=7.6 Hz), 7.26 (d, 1H, 7=8.0 Hz), 6.74 (s, 2H), 4.67 (s, 2H), 2.73 (s, 3H), 1.96 (s, 6H). ESI- MS (m/z): Calcd. for C22H22N2O5S3: 490.07; found: 491.2. Example 216 4-{4'-Guanidino-6'-methyl-2'-[3-(2-phenylamino-ethyl)-ureido]-biphenyl-3- sulfonyl}-5-methylsulfianyl-thiophene-2-carboxamidine trifluoroacetate a) [(4-{4'-Amino-6'-methyl-2'-[3-(2-phenylamino-ethyl)-ureido]- biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophen-2-yl)-imino-methyl]- carbamic acid tert-butyl ester 4-Nitrophenylchloroformate (0.047 g, 0.232 rnrriol) was added to a solution of {2-arnino-3'-[5-(tert-butoxycairbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3 -sulfonyl]-6-methyl-biphenyl-4-yl} -carbamic acid 2-trimethylsilanyl-ethyl ester (0.150 g, 0.222 mmol) [example 294, step f] and pyridine (0.018 g, 0.232 mmol) in dichloromethane [5 mL] and stirred at room temperature for 1 hour. N-l-Phenyl-ethane-l,2-diamine (0.060 g, 0.444 mmol) was added and the reaction was stirred for an additional hour. The reaction was evaporated and column chrornatography (50% EtOAc in hexanes) of the residue yielded the title compound (0.150 g, 81%) as a solid. This solid was dissolved in THF [1 mL] and tetrabutylammonium fluoride [0.536 mL] was added. The reaction was heated to 50°C and stirred for 2 hours. The reaction was evaporated and column chromatography (50% EtOAc in hexanes) of the residue yielded the title compound (0.079 g, 64%) as a solid. ESI-MS (m/z): Calcd. for C33H38N6O5S3: 694.21; found: 694.9. b) [(4-{4'-(N',N"-di-tert-butoxycarbonyl-guanidino)-6'-methyl-2'-[3-(2- phenylamino-ethyl)-ureido]-biphenyl-3-sulfonyl}-5-methylsulfanyl- thiophen-2-yl)-imin o-methyl]-carbarnic acid tert-butylester l,3-Bis-t-butoxycarbonyl-2-methyl-2-thiopseudourea (0.033 g, 0.114 mmol) was added to a solution of [(4-{4'-amino-6'-methyl-2'-[3-(2- pheny]amino-ethyl)-u;reido]-biphenyl-3-sulfonyl}-5-niethylsulfanyl-thiophen- 2-yl)-i]mino-methyl]-carbainic acid tert-butyl ester [example 216, step a] in methanol [1 mL] and 1 drop of acetic acid. The reaction was stirred at room temperature for 1 hour and evaporated. The reaction was evaporated and column chromatography (25% EtOAc in hexanes) of the residue yielded the title compound (0.072 g, 6S%) as a solid. ESI-MS (m/z): Calcd. for C44H56N8O9S3: 936.33; found: 936.9. c) 4-{4'-Guanidiiio-6'-methyl-2'-[3-(2-phenylamino-ethyl)-ureido]- biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxainidine bistrifluoroacetate A solution of dichioromethane/ trifluoroacetic acid (1/1) [1 mL] was added to [(4-{4'-(N\ N"-di-tert-butoxycarbonyl-guanidino)-6'-methyl-2l-[3-(2- phenylamino-ethyl)-ureido\|-biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophen- 2-yl)-imino-methyl]-carbamic acid tert-butylester (0.007 g, 0.007 mmol) [example 216, step b] at room temperature and stirred for 1 hour. The reaction mixture was evaporated and purified via reverse-phase HPLC [acetonitrile/water (0.01%TFA)] to give the title compound as a solid. 1H- NMR (MeOD): d 8.35 (s, 1H), 8.05 (md, 1H, 7=8.0 Hz), 7.95 (m, 1H), 7.73 (t, 1H, 7=8.0 Hz), 7.57 (m, III), 7.39 (m, 2H), 7.14 (m, 3H), 7.05 (m, 1H), 3.37 (m, 4H), 2.71 (s, 3H), 2.03 (s, 3H). ESI-MS (m/z): Calcd. for C29H32N8O.1S3: 636.18; found: 637.1. Example 217 4-(3'-Formylamino-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate a) {(4-(3'-Amino-biphenyl-3-sulfonyl)-5-metltylsulfanyl-thiophen-2-yl]- imino-methyl]-carbamic acid tert-butyl ester Following the same procedure as in Example 1, step c, reaction of 3- amino-phenyl boronic acid (27 mg, 0.2 mmol), {[4-(3-bromo- benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (50 mg, 0.1 mmol, as prepared in Example 27, step c), tetrakis(triphenylphosine)palladium(0) (29 mg, 0.025 mmol, Strem Chemicals Inc, Newburyport, MA), Na2CO3 (400 \£L, 2M), and toluene/EtOH mixture (2:1, 1.2 mL) afforded 35 ing (70%) after purification (SiO2, flash elution: 30% EtOAc in hexanes) of the title compound as a white foam. ESJ-MS (m/z): Calcd. for C23H25N3O4S;,: 503.6; found: 503.9, 404.1 (M-Boc). b) 4-(3'-Formylamino-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate {[4-(3'-Amino-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]- imino-methyl}-carbamic acid tert-butyl ester (30mg, 0.06 mmol, as prepared in Example 217, step a) was dissolved in formic acid (5 mL) and the reaction mixture was refluxed overnight. The formic acid was removed in vacuo and the residue was treated with trifluoacetic acid (50% in DCM) for 1 h at rt. The mixture v/as concentrated in vacuo and the residue obtained was purified using C18-HPLC (10-80% CH3CN in H2O (0.1% TFA) over 25 min) to give the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): d 8.34 (s, 1H), 8.33 (s, 1H), 8.29 (t, 1H, J= 1.6 Hz), 8.11-8.13 (m, 1H), 7.96-8.03 (m, 2H), 7.70 (t, 1H, J = 7.7 Hz), 7.42-7.50 (m, 3H), 2.75 (s, 3H). ESI-MS (m/z): Calcd. for C19H17N3O3S3: 432.1 (M+H); found: 432.1. Example 218 3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-biphenyl-3- carboxylic acid amide trifluoracetate Following the same procedure as in Example 1: step c, reaction of 3- carbamoyl-phenyl boronic acid (33 mg, 0.2 mrnol), {[4-(3-bromo- benzenesulfonyl)-5-methylsulf£Lnyl-tbiophen-2-yl]-iniino-methyl}-carbamic acid tert-butyl ester (50 mg, 0.1 mmol, as prepared in Example 27, step c), tetrakis(triphenylphosine)palladiurn(0) (29 mg, 0.025 mmol, Strem Chemicals Inc, Newburyport, MA), Na2CO3 (400 µL, 2M), and toluene/EtOH mixture (2:1, 1.2 mL) afforded 38 mg (72%) after purification (SiO2, flash elution: 30% EtOAc in hexanes) of a white foam whose mass was consistent with the Boc protected title intermediate. ESI-MS (m/z): Calcd. for C24H25N3O5S3: 531.7; found: 531.9, 432.1 (M-Boc). Treatment of this intermediate with trifluoacetic acid (50% in DCM) for 1 h at rt and purification using C18-HPLC (10-65% CH3CN in H2O (0.1% TFA) over 30 min) provided the title compound as a white solid (25 mg, 66%). 1H-NMR (CD3OD; 400 MHz): d 8.34 (s, 1H), 8.33 (t, 1H, J= 1.9 Hz), 8.19 (t, 1H, J=l.9 Hz), 8.00-8.05 (m, 2H), 7.85-7.88 (m, 2H), 7.73 (t, 1H, J= 7.8 Hz), 7.62 (t, \R,J= 7.8 Hz), 2.74 (s, 3H). ESI-MS (m/z): Calcd. for C19H17N3O3S3: 432.2 (M+H); found: 432.2. Example 219 4-(4'-Fluoro-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine trifluoroacetate Following the same procedure as in Example 1, step c, reaction of 4- fluoro-2-methyl-phenyl boronic acid (35 mg, 0.2 mmol), {[4-(3-bromo- benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-rnethyl}-carbamic acid tert-butyl ester (50 mg, 0.1 mmol, as prepared in Example 27, step c), tetrakis(triphenylphosme)palladium(0) (29 mg, 0.025 mmol, Strem Chemicals Inc, Nev/buryport, MA), Na2CO3 (400 µL, 2M), and toluene/EtOH mixture (2:1, 1.2 mL) afforded after purification (Preparative TLC, 1:3 EtOAc/hexanes, 2000 µ SiO2 plate) 62 mg of {[4-(4'-fluoro-2'-methyl- biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}- carbamic acid tert-butyl ester as a tan oil. NMR (CDCl3; 400 MHz) 5 8.02 (s, 1H), 7.91-7.97 (m, 2H), 7.51-7.57 (m, 2H), 7.14 (dd, 1H, J = 8.4, 5.8 Hz), 6.92-7.00 (m, 2H), 2.57 (s, 3H), 2.20 (s, 3H), 1.51 (s, 9H). Treatment of this intermediate with trifluoacetic acid (50% in DCM) for 1 h at rt and purification using Cl8-HPLC (20-70% CH3CN in H2O (0.1% TFA) over 30 min) provided the title compound as a white solid (30 mg, 60%). 1H-NMR (CD3OD; 400 MHz) 5 8.32 (s, 1H), 8.03 (dt, 1H, J= 7.0, 1.9 Hz), 7.94-7.96 (m, 1H), 7.64-7.70 (m, 2H), 7.22 (dd, 1H, J= 8.6, 5.8 Hz), 6.98-7.09 (m, 2H), 2.72 (s, 3H), 2.22 (s, 3H). ESI-MS (m/z): Calcd. for C19H17FN2O2S3: 421.2 (M+H); found: 421.2. Example 220 4-(4'-Amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine bis-trifluoroacetate a) 3-Methyl-4-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)- phenylamine To an oven-dried round bottom flask fitted with a stir bar was added 4- bromo-3-methylaniline (5.7 gm, 31 mmol), 4,4,5,5-tetramethyl-l, 3,2- dioxaborolane (13.3 ml., 92 mmol, Aldrich Chemical Company), and PdCl2(PPh3)2 (2.2 gm, 3.1 mmol, Strem Chemicals Inc, Newburyport, MA). The flask was sealed with a rubber septum, purged with Argon, and then charged with dry dioxane (100 mL) and triethylamine (26 mL). The reaction mixture was stirred vigorously at 95 °C for 16 h. After cooling to rt, the dioxane was removed hi vacuo and the residue was partitioned between EtOAc (200 mL) and water (100 mL). The organic layer was washed with saturated NaHCO3 (2 x 75 ml.), brine (50 mL), and was dried over MgSO4. Removal of the solvents in vacuo followed by flash chromatography of the residue yielded the product (3.3 gm, 46%) as a tan oil. 1H-NMR (CDCl3; 400 MHz): d 7.61-7.64 (m, 1H), 6.48-6.58 (m, 2H), 3.60-3.90, (br s, 2H), 2.49 (s, 3H), 1.34 (s, 12H). ESI-MS (m/z): Calcd. for Cl3H2oBN02: 234.1 (M+H); found: 234.2 b) {4-(4'-Amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-yl]-imino-methyl}-carbamic acid tert-butyl ester Following the same procedure as in Example 1, step c, reaction of 3- methyl-4-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-phenylamine (432 mg, 1.86 mmol, as prepared in Example 220, step a), {[4-(3-bromo- benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (610 mg, 1.24 mmol, as prepared in Example 27, step c), tetrakis(triphenylphosirie)palladium(0) (215 mg, 0.186 mmol, Strem Chemicals Inc, Newburyport, MA), Na2CO3 (5 mL, 2M), and toluene/EtOH mixture (2:1, 15 mL) afforded 403 mg (63%) after purification (SiO2, flash elution: 30% to 50% EtOAc in hexanes) of the title compound as a white foam. 1H-NMR (CDCl3, 400 MHz): S 8.00 (s, 1H), 7.87-7.92 (m, 2H), 7.47- 7.55 (m, 2H), 6.98 (d, 1H, J = 7.9 Hz), 6.55-6.61 (m, 2H), 3.65-3.82 (br s, 2H), 2.53 (s, 3H), 2.15 (s, 3H), 1.51 (s, 9H). ESI-MS (m/z): Calcd. for C24H27N3O4S3: 517.7; found: 517.7, 418.1 (M-Boc). c) 4-(4'-Amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine bis-trifluoroacetate {4-(4'-Amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (32 mg, 0.06 mmol, as prepared in Example: 220, step b) was treated with trifluoroacetic (50% in DCM) for 1 h at rt and purified using C18-HPLC (20-70% CH3CN in H2O (0.1% TFA) over 30 niin) affording the title compound as a white solid (20 mg, 55%). 1H-NMR (CD3OD; 400 MHz) 5 8.35 (s, 1H), 7.99-8.05 (m, 2H), 7.67-7.73 (m, 2H), 7.28 (d, 1H, J= 8.1 Hz), 7.10-7.17 (m, 2H), 2.74 (s, 3H), 2.27 (s, 3H). ESI-MS (m/z): Calcd. for C19H19N3O2S3: 418.1 (M+H); found: 418.1. Example 221 4-[2'-Methyl-4'-(2-morpholin-4-yl-ethylamino)-biphenyl-3-sulfonylJ-5- methylsulfanyl-thiophene-2-carboxamidine bis-trifluoroacetate a) (4-Bromo-3-methyl-phenyl)-(2-morpholin-4-yl-ethyl)-amine 4-Bromo-3-methylaniline (0.96 gm, 5.14 mmol), 4-(2-chloro-ethyl)- morpholine (1 gm, 5.4 mmol), K2CO3 (1.5 gm, 10.8 mmol), and Nal (0.81 gm, 5.4 mmol) were suspended in DMSO (10 mL) and the mixture was stirred vigorously at reflux for 12 h. The mixture was; cooled, diluted with EtOAc, and washed with saturated NaHCO3. The organic layer was washed with another portion of NaHCO3, brine (50 mL). arid was dried over MgSO4, Removal of the solvents in vacuo followed by flash chromatography of the residue (Biotage Flash System - 40 M SiO2 column, 10% EtOAc in hexanes to 100% EtOAc) yielded the product (500 mg, 31%) as a tan oil. 1H-NMR (CDCl3; 400 MHz): 8 7.36 (d, 1H, J = 8.6 Hz), 6.61 (d, 1H, J = 2.8 Hz), 6.43 (dd, 1H, d, 8.6, 2.8 Hz), 4.36 (br s, 1H), 3.80 (t, 4H, J = 4.6 Hz), 3.20 (t, 2H, J = 5.8 Hz), 2.69 (t, 2H, J = 6.0 Hz), 2.54 (t, 4H, J = 4.4 Hz), 2.40 (s, 3H). ESI- MS (m/z): Calcd. for C13H19BrN2O: 299.2; found: 299.1, 301.1. b) 4-[2'-Methyl-4'-(2-morpholin-4-yl-ethylamino)-biphenyl-3-sulfonyl]- 5-methylsulfanyl-thiophene-2-carboxamidine Following the same procedure as in Example 220, step a, reaction of (4-bromo-3-methyl-phenyl)-(2-morpholin-4-yl-ethyl)-amine (440 mg, 1.9 mmol, as prepared in Example 221, step a), 4,4,5,5-tetramethyl-l,3,2- dioxaborolane (13.3 mL, 92 mmol, Aldrich Chemical Company), PdCl2(PPh3)2 (2.2 gm, 3.1 mmol, Strem Chemicals Inc, Newburyport, MA), Et3N (1.6 mL, 11.4 mmol), and dioxane (5 mL) afforded 520 mg (79%) after purification (SiO2, flash elution: 30% EtOAc in hexanes) of a tan oil. ESI-MS (m/z): Calcd. for C19H31BN2O3: 347.3 (M+H); found: 347.2. The above boronate ester (520 mg, 1.5 mmol) was reacted according to the procedure used in Example 1, step c, with {[4-(3-bromo-benzenesulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (368 mg, 0.75 mmo 1, as prepared in Example 27, step c), tetrakis(triphenylphosine)palladium(0) (217 mg, 0.19 mmol, Strem Chemicals Inc, Nev/buryport, MA), Na2CO3 (3 mL, 2M), and toluene/EtOH mixture (2:1, 9 mL) to afford 400 mg (85%) of (imino-{4-[2'-methyl-4'-(2-morpholin-4-yl- ethylamino)-biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-methyl)- carbamic acid tert-butyl ester after purification (SiO2, flash elution: EtOAc in hexanes). ESI-MS (m/z): Calcd. for C30H38N4O5S3: 630.8; found: 630.9, 531.1 (M-Boc). Treatment of this intermediate with trifluoroacetic acid and purification using C18-HPLC (as in Example 220, step c) provided 312 mg (78%; of the title compound as a white solid. 1H-NMR (CD3OD, 400 MHz): d 8.31 (s, 1H), 7.90-7.95 (m: 2H), 7.60-7.65 (m, 2H), 7.04 (d, 1H. J= 8.1 Hz), 6.61-6.66 (m, 2H), 3.95 (br s, 4H), 3.61 (t, 2H, J = 6.3 Hz), 3.41 (m, 6H), 2.71 (s, 3H), 2.19 (s, 3H). ESI-MS (m/z): Calcd. for C25H30N4O3S3: 531.2 (M+H); found: 531.1, 266.2 (M2+). Example 222 3'-(5-Carbamimidoyl-2-meth.ylsulfanyl-thiophene-3-sulfonyl)-2-methyl- biphenyl-4-carboxylic acid trifluoroacetate Following the same procedure as in Example 220, step a, reaction of 4- bromo-3-methyl-benzoic acid methyl ester (1.75 gm, 7.6 mmol), 4,4,5,5- tetramethyl-l,3,2-dioxaborolane (3.3 mL, 23 mmol, Aldrich Chemical Company), PdCl2(PPh3)2 (530 mg, 0.76 mmol, Strem Chemicals Inc, Newburyport, MA), Et3N (6.3 mL, 46 mmol), and dioxane (30 mL) afforded 1.2 gm of a clear oil (79%) after purification (SiO2, flash elution: 30% EtOAc in hexanes. The above boronate ester (220 mg, 0.8 mmol) was reacted according to the procedure used in Example 1, step c, with {[4-(3-bromo- benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (100 mg, 0.8 mmo 1, as prepared in Example 27, step c), tetrakis(triphenylphosine)palladiurn(0) (58 mg, 0.05 mmol, Strem Chemicals Inc, Newburyport, MA), Na2CO3 (1.6 mL, 2 M), and toluene/EtOH mixture (2:1, 2.4 mL) to afford 3'-[5-(tert-butoxycarbonylammo-imino-methyl)-2- methylsulfanyl-thiophene-3-su].fonyl]-2-methyl-biphenyl-4-carboxylic acid methyl ester after purification (preparative TLC, 1:3 EtOAc/hexanes, 2000 µ SiO2 plate). ESI-MS (m/z): Calcd. for C26H28N2O6S3: 560.7; found: 461.1 (M- The above methyl benzoate (45 mg. 0.08 mmol) was treated with 1 N NaOH in MeOH (1:1) and stirred at 50 °C overnight. The reaction mixture was neutralized with acetic acid, the solvents were removed in vacuo, and the residue was subjected to TFA treatment followed by C18-HPLC purification as described in Example 220, step c to afford the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz) 5 8.35 (s, 1H), 8.06-8.11 (m, 1H), 8.00-8.03 (m, 2H), 7.95 (m, 1H), 7.72-7.76 (m, 2H), 7.35 (d, 1H, J= 7.9 Hz), 2.75 (s, 3H), 2.30 (s, 3H). ESI-MS (m/z): Calcd. for C20H18N2O4S3: 447.1 (M+H); found: 447.1. Example 223 2-Amino-N-[3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2- methyl-biphenyl-4-yl]-acetamide trifluoroacetate To a solution of {4-(4'-amino-2'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophene-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (80 mg. 0.15 mmol, as prepared in Example 220, step b) in DCM (2.2 mL) was added Boc-gly-N-hydroxysuccinimide ester (126 mg, 0.5nimol), and triethylamine (69 µL, 0.5 mmol). The reaction mixture was stirred at rt overnight (16 h). The reaction mixture was then diluted with EtOAc and extracted with water and saturated NaHCO3. The separated organic layer was dried with MgSO,}, filtered, and concentrated in vacuo to give a residue that was purified using preparative TLC (1:3 EtOAc/hexanes, 1000 µ SiO2 plate) to provide 100 mg (99%) of a tan glassy solid. ESI-MS (m/z): Calcd. for C31H38N4O7S3: 674.8 (M+); found: 674.8, 575.0, 519.0, 475.1. Treatment of this intermediate with trifluoroacetic acid and purification using C18-HPLC (as in Example 220, step c) provided the title compound as a white solid in 78% yield. 1H-NMR (CD3OD, 400 MHz): 6 8.34 (s, 1H), 7.99-8.05 (m, 2H), 7.67- 7.72 (m, 2H), 7.57 (m, 2H), 7.22 (d, 1H, J= 8.1 Hz), 3.90 (s, 2H), 2.74 (s, 3H), 2.25 (s, 3H). ESI-MS (rn/z): Calcd. for C21H22N4O3S3: 475.1 (M+H); found: 475.1. Example 224 4-(4'-Hydroxy-2',6'-dimethyl-biphenyl-3-sulfonyl)-5-methylsulf'anyl- thiophene-2-carboxamidine trifluoroacetate a) 3,5-Dimethyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenol Following the procedure described in Example 220, step a, reaction of 4-bromo-3,5-dirnethy[-phenol (1.5 gm, 7.6 mmol), 4,4,5,5-tetramethyl-1,3,2- dioxaborolane (3.3 mL, 23 mmol, Aldrich Chemical Company), PdCl2(PPh3)2 (530 mg, 0.76 mmol, Strem Chemicals Inc., Newburyport, MA), Et3N (634 p.L, 46 mmol), and dioxane (30 mL) afforded 3.4 gm of a tan glassy solid after chromatography (50 gm, silica SPE column) which was used without further purification. 1H-NMR (CDCl3; 400 MHz): d 6.4 (s, 2H), 2.3 (s, 6H), 1.4 (s, 12H). b) {[4-(4'-Hydroxy-2', 6'-dimethyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester Following the same procedure as in Example 1, step c, reaction of 3,5- dimethyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenol (355 mg, 0.8 mmol, assuming quantitative yield from Example 224. step a), {[4-(3- bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}- carbamic acid tert-butyl ester (100 mg, 0.2 mmol, as prepared in Example 27, step c), tetrakis(triphenylphosme)palladium(0) (58 mg, 0.05 mmol, Strem Chemicals Inc, Newburyport, MA), Na2CO3 (0.8 mL, 2M), and toluene/EtOH mixture (2:1, 2.4 mL) afforded 35 mg (13%) after purification (PTLC) of the title compound as a tan solid. ESI-MS (m/z): Calcd. for C25H28N2O5S3: 532.7; found: 532.8, 477.0, 433.1 (M-Boc). c) 4-(4'-Hydroxy-2',6'-dimethyl-biphenyl-3-snlfonyl)-5-methylsnlfanyl- thiophene-2-carboxamidine trifluoroacetate {[4-(4'-Hydroxy-2',6'-dimethyl-bipheny]-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (15 mg, 0.03 mmol, as prepared in Example 224, step c) was treated with tnfluoroacetic (50% in DCM) for 1 h at rt and purified using C18-HPLC (10-60% CH3CN in H2O (0.1% TFA) over 30 min) affording the title compound as a white solid (8 mg, 53%). !H-NMR (CD30D; 400 MHz) 5 8.35 (s, 1H), 8.00 (m, 1H), 7.80 (t, 1H, 7= 1.6 Hz), 7.68 (t, 1H, J = 7.7 Hz), 7.50 (m, 1H), 6.58 (s, 2H), .67-7.73 (m, 2H), 7.28 (d, 1H, J= 8.1 Hz), 7.10-7.17 (m, 2H), 2.73 (s, 3H), 1.91 (s, 6H). ESI-MS (m/z): Calcd. for C20H20N2O3S3: 433.1 (M+H); found: 433.1. Example 225 3'-(5-Carbamimidoyl-2-rnethylsulfanyl-thiophene-3-sulfonyl)-2-methyl- biphenyl-4-carboxylic acid amide trifluoroacetate Following the same procedure as in Example 220, step a, reaction of 4- bromo-3-methyl-benzamide (200 mg, 0.93 mmol), 4,4,5,5-tetramethyl-l,3,2- dioxaborolane (0.41 mL, 2.8 mmol, Aldrich Chemical Company), PdCl2(PPh3)2 (65 mg, 0.093 mmol, Strem Chemicals Inc, Newburyport, MA), Et3N (700 [iL, 46 mmol), and dioxane (5 mL) afforded 140 mg of a brown oil (58%) after purification (SIO2, flash elution: 30% EtOAc in hexanes. The above boronate ester (140 mg, 0.54 mmol) was reacted according to the procedure used in Example 1, step c, with {[4-(3-bromo-benzenesulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-ca.rbamic acid tert-butyl ester (88 mg, 0.18 mmo 1, as prepared in Example 27, step c), tetrakis(triphenylphosine)palladLum(0) (52 mg, 0.05 mmol, Strem Chemicals Inc, Newburyport, MA), Na2CO3 (0.7 mL, 2 M), and toluene/EtOH mixture (2:1, 2.1 mL) to afford {[4-(4'-Carbamoyl-2'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester after purification (preparative TLC, 1:3 EtOAc/hexanes, 3 x 1000 µ SiO2 plate). ESI-MS (m/z): Calcd. for C25H27N3O5S3: 545.7; found: 446.1 (M-Boc). The above benzamide (44 mg. 0.08 mmol) was subjected to TEA treatment followed by C18-HPLC purification as described in Example 220, step c to afford 26 mg (59%) of the title compound as a white solid. lH-NMIR. (CD3OD; 400 MHz) 5 8.33 (s, 1H), 8.04-8.08 (m, 1H), 7.99-8.01 (m, 1H), 7.85 (m, 1H), 7.78 (m, 1H), 7.70-7..73 (m, 2H), 7.32 (d, 1H, J= 7.9 Hz), 2.72 (s, 3H), 2.29 (s, 3H). ESI-MS (m/z): Calcd. for C20H19N3O3S3: 446.1 (M+H); found: 446.1. Example 226 {2-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-methyl- biphenyl-4-ylcarbamoyl]-ethyl}-phosphonic acid trifluoroacetate Thionyl chloride (1.7 mL, 23.0 mmol) was added dropwise to a suspension of 3-(diethylphosphono)propanoic acid (0.5 gm, 2.3 mmol, Epsilpon Chimie, Brest, France) in DCM (2 mL) at 0 °C. The reaction mixture became clear upon addition of acid chloride. The ice bath was removed and stirring was continued overnight at rt. The solvents were removed in vacuo and the resulting solid was stored under high vacuum before further use. The acid chloride prepared above (53 mg, 0.232 mmol) was transferred to a solution of {4-(4'-amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (40 mg, 0.077 mmol, as prepared in Step 220, step b) and Et3N (900 µL, 0.62 mmol) in DCM (2 mL). The mixture was stirred for 4 h at rt and then another 40 mg of the acid chloride was added. After stirring for ~12 h, the volatiles were removed and the residue was partitioned between EtOAc and water. The organic layer was washed with another portion of water and saturated NaHCO3 dried over MgSO4, and filtered. The crude product was chromatographed (PTLC 1000 µ. plate) to give 33 mg (61%) of the desired (diethylphosphono)propanamide. ESI-MS (m/z): Calcd. for C31H40N3O8PS3: 709.8 (M+); found: 709.8, 610.1 (M-Boc), Using a modification of the procedure reported by Zhang, Z.Y., et al., (J. Med. Chem., 1999, 42:3199-3202), the above (diethylphosphono)propanamide (33 mg, 0.046) in DCM (2 mL) was treated with iodotrimethylsilane (20 µL, 0.14 mmol) at 0 °C for 1 h. Water was added to quench the reaction. After stirring for 20 minutes, 2.0 N HC1 (2 mL) and MeOH (2 mL) were added to the reaction mixture. The reaction mixture became clear following the addition. Stirring was continued for 3 h at rt, solvents were removed in vacuo, and the resulting residue was treated with TFA and purified using C18-HPLC as described in Example 220, step c to afford 12 mg (50%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): d 7.61-7.69 (m, 3H), 6.95-7.27 (m, 4H), 6.55 (d, 1H, J= 8.6 Hz), 2.41-2.50 (m, 2H), 2.19 (s, 3H), 1.76 (s, 3H), 1.58-1.63 (m, 2H). ESI-MS (m/z): Calcd. for C22H24N3O6PS3: 554.1 (M+H); found: 554.1. Example 227 {[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-methyl- biphenyl-4-ylcarbamoyl]-methoxy}-acetic acid trifluoroacetate To a solution of {4-(4'-amino-2'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophene-2-yl]-iniino-methyl}-carbamic acid tert-butyl ester (25 mg, 0.048 mmol, as prepared in Step 220, step b) and Et3N (33 µL, 0.24 mmol) in DCM (1 mL) was added diglycolic anhydride (17mg, 0.144 mmol). The reaction was stirred overnight at rt. The solvents were removed in vacuo and the residue was treated with TFA (as in Example 220, step c). Purification using a C18-HPLC provided 17 mg (68%) of the title compound as a white solid. 1H-NMR (CD3OD, 400 MHz): d 8.32 (s, 1H), 7.96-8.03 (m, 2H), 7.65- 7.70 (m, 2H), 7.57-7.62 (m, 2H), 7.19 (d, 1H, J= 8.6 Hz), 4.31 (s, 2H), 4.24 (s, 2H), 2.72 (s, 3H), 2.23 (s, 3H). ESI-MS (m/z): Calcd. for C23H23N3O6S3: 534.1 (M+H); found: 534.1. Example 228 5-Methylsulfanyl-4-(2'-methy]-4'-ureido-biphenyl-3-sulfonyl)-thiophene-2- carboxamidine trifluoroacetate According to the procedure by Rivier et al.. (J. Med. Chem. 2001, 44, 453-467) trimethylsilyl isocyante (45 \|xL, 0.29 mmol) was added to a solution of {4-(4'-Amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiopherie- 2-yl]-irnino-methyl}-carbarnic acid tert-butyl ester (43 mg, 0.083 mmol, as prepared in Step 220, step b) in DMF (0.2 mL). The reaction was stirred for 3 days at rt. The DMF was removed in vacuo and the residue was treated with TFA (as in Example 220, step c, except 1% w-cresol was added in the deprotection mixture). The crude reaction mixture was concentrated to an oily residue that was triturated with Et2O to remove m-cresol. Purification using C18-HPLC provided 10 mg (25%) of the title compound as a white solid. 1H- NMR (CD3OD, 400 MHz): d 8.34 (s, 1H), 7.96-8.04 (m, 2H), 7.65-7.70 (m, 2H), 7.31.738 (m, 2H), 7.13 (d, 1H, J= 7.9 Hz), 2.74 (s, 3H), 2.22 (s, 3H). ESI-MS (m/z): Calcd. for C20H20N4O3S3: 461.1 (M+H); found: 461.1. Example 229 2-Amino-4-[3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2- methyl-biphenyl"4-ylcarbamoyl]-butyric acid bis-trifluoroace:tate Following the same procedure described for Example 223, but substituting Boc-L-glu(OSu)-OtBu for Boc-gly-N-hydroxysuccinimide ester, provided the title compound as a white solid in 75% yield. 1H-NMR (CD3OD, 400 MHz): d 8.34 (s, 1H), 7.97-8.03 (m, 2H), 7.66-7.71 (m, 2H), 7.52-7.56 (m, 2H), 7.18 (d, 1H, J= 8.1 Hz), 4.12 (t, 1H, J= 6.5 Hz), 2.73 (s, 3H), 2.71- 2.75 (m, 2H), 2.24 (s, 3H), 2.24-2.38 (m, 2H). ES1-MS (m/z): Calcd. for C24H26N4O5S3: 547.1 (M+H); found: 547.1. Example 230 6-[5-(2-Oxo-hexahydro-thieno[3,4-d]imidazol-6-yl)-pentanoylamino]- hexanoic acid [3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)- 2-methyl-biphenyl-4-yl]-amide trifluoroacetate Following the same procedure described for Example 223, but substituting N-(+)-biotmyl-6-aminocaproic acid N-succinimidyl ester for Boc- gly-N-hydroxysuccinimide ester, provided the title compound as a white solid in 11% yield. 1H-NMR (CD3OD, 400 MHz): d 8.33 (s, 1H), 7.99-8.02, (m, 1H), 7.95-7.97 (m, 1H), 7.66-7.69 (m, 2H), 7.49-7.53 (m, 2H), 7.17 (d, 1H, J = 8.4 Hz), 4.47 (dd, 1H, J= 7.9, 4.2 Hz), 4.27 (dd, 1H, J= 7.8, 4.2 Hz), 3.15- 3.22 (m, 4H), 2.91 (dd, lH,J= 12.6, 4.9 Hz), 2.73 (s, 3H), 2.41 (t, 2H, J= 7.6 Hz), 2.23 (s, 3H), 2.19 (t, 2 H,./= 7.4 Hz), 1.35-1.80 (m, 12H). ESI-MS (m/z): Calcd. for C35H44N6O5S4: 757.2 (M+H); found: 757.3 Example 231 4-Ammo-4-[3'-(5-carbamimidoyl-2-methylsulfEinyl-thiophene-3-sulfonyl)-2- methyl-biphenyl-4-ylcarbamoyl]-butyric acid bis-trifluoroacetate Following the same procedure described for Example 223, but substituting Boc-L-glu(OtBu)-OSu for Boc-gly-N-hydroxysuccinimide ester, provided the title compound as a white solid in 64% yield. 1H-NMR (CD3OD, 400 MHz): d 8.34 (s, 1H), 7.99-8.05 (m, 2H), 7.67-7.73 (m, 2H\|, 7.56-7.61 (m, 2H), 7.23 (d, 1H, J= 8.1 Hz), 4.10 (t, 1H, J= 6.0 Hz), 2.74 (s, 3H), 2.58 (t, 2H, J= 7.4 Hz), 2.26 (s, 3H), 2.20-2.35 (m, 2H). ESI-MS (m/z): Calcd. for C24H26N4O5S3: 547.1 (M+H); found: 547.1. Example 232 2-Amino-N-[3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2- methy]-biphenyl-4-yl]-4-methanesulfonyl-butyramide bis-trifluoroacetate In a scintillation vial, Boc-L-methionine sulfone (124 mg, 0.44 mmol, Chem-Impex, International, INC., Wood Dale, IL) was dissolved in DMF (2 mL). To the solution was added HBTU (159 mg, 0.42 mmol), HOBT (60 mg, 0.44 mmol), and D1EA (400 µL, 2.1 mmol). After 10 min of vigorous stirring (solution turned pale yellow), the mixture was transferred to a reaction vial charged with a stir bar and {4-(4'-amino-2'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophene-2-yr]-imino-methyl}-carbamic acid tert-butyl ester (73 mg, 0.14 mmol, as prepared in Step 220, step b). The resulting mixture was stirred overnight at rt. Analogous work up as described for Example 223 followed by TFA treatment and RP-HPLC provided 5S mg (72%) of the title compound as the bis-trifiuoroacetate salt. 1H-NMR (CD3OD, 400 MHz): S 8.33 (s, 1H), 7.97-8.03 (m, 2H), 7.66-7.71 (m, 2H), 7.57-7.62 (m, 2H), 7.23 (d, 1H, J = 8.1 Hz), 4.24 (t, 1H, J = 6.4 Hz), 3.25-3.39 (m, 2H), 3.06 (s, 3H), 2.72 (s, 3H), 2.40-2.56 (iri, 211), 2.25 (s, 3H). ESI-MS (m/z): Calcd. for C24H28N4O5S4: 581.1 (M+H); found: 581.0. Example 233 4-[4'-(4,5 -Dihydro-1H-imidazol-2-ylamino)-2'-methyl-biphenyl-3 -sulfonyl] - 5- methylsulfanyl-thiophene-2-carboxamid:inebis-trifluoroacetate a) 2-Methylsulfanyl-4,5-dihydro-imidazole-l-carboxylic acid tert-butyl ester 4,5-Dihydro-2-methylthioimidazole hydroiodide (3 gm, 12 mmol, Aldrich Chemical Company), di-tert-butyl-dicarbonate (5.4 gm, 24.8 mmol), Et3N (5 mL, 36 mmol), and DMAP (70 mg, 0.57 mmol) were dissolved in DCM (35 mL). The reaction was stirred at rt for 16 h then diluted, with more DCM and washed with water and saturated NaHCO3 The organic layer was dried (MgSC^), filtered, and evaporated in vacuo to give 1 gm (38%) of the title compound as a white crystalline solid. 1H-NMR (CDCl3; 400 MHz): d 3.82-3.86 (m, 4H), 2.39 (s, 3H), 1.51 (s, 9H). ESI-MS (m/z): Calcd. for C9H16N2O2S: 217.1 (M+H); found: 216.8, 161.0, 117.2 (M-Boc). b) 4-[4'-(4,5-Dihydro-lH-imidazol-2-ylamino)-2'-methyl-biphenyl-3- sulfonyl]-5-methylsulfanyl-thiophene-2-carboxainidine bis-trifluoroacetate According to a procedure by Mundla et al.. (Tetrahedron Lett. 2000, 41, 6563-6566), {4-(4I-amino-2'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophene-2-yl]-imino-methyl}-Ci3rbamic acid tert-butyl ester (18 mg, 0.035 mmol., as prepared in Example 220, step b) and 2- methylsulfanyl-4,5-dihydro-irnidazole-l-carboxylic acid tert-butyl ester (23 mg, 0.1 mmol, as prepared in Example 233, step a) were dissolved in a MeOH / Acetic acid mixture (10:1, 1 mL). The reaction mixture was stirred overnight at 55 "C and then concentrated to dryness. The resulting residue was treated with TFA and purified using C18-HPLC as described in Example 220, step c to afford 12 mg (70%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): d 8.00-8.05 (m, 2H), 7.66-7.73 (m, 2H), 7.19-7.33 (m, 3H), 3.84 (s, 4H), 2.72 (s, 3H), 2.27 (s, 3H). ESI-MS (m/z): Calcd. for C22H23N5O2S3: 486.1 (M+H); found: 486.1. Example 234 2-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-methyl- biphenyl-4-ylcarbamoyl]-methylsulfanyl}-acetamide trifluoroacetate a) ({4-[4'-(2-Bromo-acetylamino)-2'-methyl-biphenyl-3-sulfonyl]-5- ntethylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester {4-(4'-Amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-yl]-imino-methyl}-earbamic acid tert-butyl ester (110 mg, 0.21 mmol, as prepared in Example 220, step b), bromoacetyl bromide (19 µL, 0.21 mmol), and Et3N (33 µL, 0.23 mmol) were dissolved in chloroform (2 mL) and the reaction was stirred for 3 h at rt As TLC indicated small amount of aniline remaining in the reaction mixture, 4 µL of bromoacetyl bromide were added and the reaction was stirred for 2 more hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and 20 % citric acid. The organic layer was washed with saturated NaHCO3, water, and brine, then dried (MgSO4), and concentrated in vacuo to give 135 mg (100%) of crude product as a tan solid. Purification of this material using PTLC (1:1 EtOAc/hexanes, 2 x 1500 µ SiO2 plate) provided the title compound in 89 % yield as a pale yellow solid. 1H-NMR (CDCI3, 400 MHz): S 8.24 (s, 1H), S.00 (dt, 1H,J= 7.3, 1.8 Hz), 7.96 (br s, 1H), 7.92 (m, 1H), 7.55-7.62 (m, 2H), 7.41-7.47 (m, 2H), 7.19 (d, 1H, J= 8.1 Hz), 4.09 (s, 2H), 2.52 (s, 3H), 2.25 (s, 3H), 1.54 (s, 9H). ESI-MS (m/z): Calcd. for C24H27N3O4S3: 517.7; found: 517.7,418.1 (M-Boc). b) 2-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2- methyl-biphenyl-4-ylcarbamoyl]-methylsulfanyl}-acetamidetrifluoroacetate To a solution of ({4-[4'-(2-bromo-acetylammo)-2'-methyl-biphenyl-3- sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert- butyl ester (44 mg, 0.069 mmol, as prepared in Example 234, step a) in MeOH (0.6 mL) was added 2-mercapto acetamide (100 u.L of 10% methanolic solution, Maybridge pic) and Et3N (30 µL, 0.21 mmol). The reaction mixture was stirred at rt for 0.5 h and then concentrated in vacuo. The residue was treated with TFA and purified using C18-HPLC as described in Example 220, step c to afford 32 mg (84%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): d 8.32 (s, 1H), 7.99-8.02 (m, 1H), 7.95-7.97 (m, 1H), 7.66-7.68 (m, 2H), 7.51-7.55 (m, 2H), 7.17 (d, 1H, J = 8.1 Hz), 3.48 (s, 2H), 3.37 (s, 2H), 2.72 (s, 3H), 2.23 (s, 3H). ESI-MS (m/z): Calcd. for C24H25N3OSS4: 664.1 (M+H); found: 564.1. Example 235 2-{[3'-(5-Carbamimidoyl-2-raethylsulfanyl-thiophene-3-sulfonyl)-2-methyl- biphenyl-4-ylcarbamoyl]-methylsulfanyl} -succinic acid trifluoroacetate Following the same procedure as described in Example 234, step b, reaction of ({4-[4'-(2-bromo-acetylamino)-2'-methyl-biphenyl-3 -sulfonylj-5- methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester (17 mg. 0.027 mmol, as prepared in Example 234, step a), mercaptosuccinate (6 mg, 0.04 mmol), Et3N (12 pL, 0.08 mmol), a.nd MeOH (3 mL) provided 12 mg (75%) of the title compound as a white solid after RP-HPLC purification. 1H-NMR (CD3OD; 400 MHz): 6 8.34 (s, 1H), 7.99-8.00-8.05 (m, 1H), 7.97- 7.99 (m, 1H), 7.68-7.70 (m, 2H), 7.54-7.58 (m, 2H), 7.19 (d, 1H, .J= 7.9 Hz), 3.85 (dd, 1H, J= 9.5, 5.6 Hz), 3.56 and 3.69 (AB quartet, 2H, J = 15.1 Hz), 2.97 (dd, 1H, J= 17.2, 9.8 Hz), 2.76 (dd, 1H,J= 17.0, 5.6 Hz), 2.74 (s, 3H), 2.25 (s, 3H). ESI-MS (m/z): Calcd. for C25H25N3O7S4: 608.1 (M+H); found: 608.1. Example 236 4-(4'-Guanidino-2'-meth)'l-6'-nitro-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine bis-trifluoroacetate a) {[4-(4'-Amino-2'-methyl-6'-nitro-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acidtert-butyl ester Following the procedure used for Example 295, step h, reaction of 4- bromo-3-methyl-5-nitro-phenylamine (350 mg, 1.5 mmol, as prepared in Example 135, step a), {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (1.0 gm, 2.27 mmol, as prepared in Example 140, step a), tetrakis(triphenylphosine)palladium(0) (433 mg, 0.375 mmol, Strem Chemicals Inc, Newburyport, MA), Na2CO3 (6 mL, 2M), and toluene/EtOH mixture (2:1, 18 mL) at 80 "C for 24 h afforded 250 mg (30%) after purification (SiO2, flash elution: 5% to 50% EtOAc in hexanes) of the title compound as a yellow solid. ESI-MS (m/z): Calcd. for C24H26N4O6S3: 563.1 (M+H); found: 562.8, 463.1 (M-Boc). b) ({4-[4'-(N,N'-Bis-tert-butoxycarbonyl)-guanidino-2'-methyl-6'-tiitro- biphenyl-3-sulfonyl]-5-methyhulfanyl-thiophen-2-yl}-imino-methyl)- carbamic acid tert-butyl ester According to a previously published procedure (Bergerson et al.., J. Org. Chem. 1987, 52, 1700-1703; WO 99/20608), mercury (II) chloride (190 mg, 0.7 mmol) was added in one portion to a stirred mixture of {[4-(4'-amino- 2'-methyl-6'-nitro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]- imino-methyl}-carbamic acid tert-butyl ester (130 ing, 0.23 mmol.. as prepared in Example 236, step a), N,N'-bis(tert-butoxycarbonyl)-S-methylisothiourea (203 mg, 0.7 mmol, Aldrich Chemical Company), and Et3N (173 µL, 1.15 mmol) in DCM (3 mL). The mixture was stirred for 24 h at rt and then purified using flash chromatorgraphy (Biotage Flash System - 40 M SiO2 column, 10% to 30 % EtOAc in hexanes) to afford 145 mg (78%) of the title compound as a clear oil. ESI-MS (m/z): Calcd. for C35H44N6O10S3: 805.2 (M+H); found: 804.7, 704.9, 604.9, 505.1 (M-3xBoc). c) 4-(4'-Guanidino-2'-methyl-6'-nitro-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxamidinebis-trifluoroacetate ({4-[4'-(N,N'-Bis-tert-hutoxycarbonyl)-guanidino-2'-methyl-6'-nitro- biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)- carbamic acid tert-butyl ester (10 mg, 12.4 µmol, as prepared in Example 236, step b) was treated with TFA and purified using C18-HPLC as described in Example 220, step c to afford 1.1 mg (17%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): d 8.34 (s, 1H), 8.04 (ddd, 1H, J= 7.9, 1.9, 1.2 Hz), 7.92-7.94 (m, 1H), 7.72-7.79 (m, 2H), 7.62 (ddd, 1H, J= 7.7, 1.6, 1.2 Hz), 7.60 (dd, 1H, J= 2.1, 0.7 Hz), 2.72 (s, 3H), 2.18 (s, 3H). ESI-MS (m/z): Calcd. for C20H20N6O4S3: 505.1 (M+H); found: 505.1. Example 237 4-(6'-Amino-4'-guan:idino-2'-]tnethyl-biphenyl--3-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidinebis-trifluoroacetate a) {[4-(2',4'-Diamino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-nrethyl}-carbamic acid tert-butyl ester {2-Amino-3'-[5-(teit-butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-4-yl} -carbamic acid 2-trimethylsilanyl-ethyl ester (1000 mg, 1.48 mmol, Example 294, step f) was dissolved into THF (25 rnL). To this was added TB.AJF' (1M, 1.62 mL, 1.62 mmol) and the reaction was wanned to 40°C with stirring for 3 hours. Additional TBAF (1.48 mL, 1.48 mmol) was added and the reaction was stirred at rt overnight. The solvents were removed in vacuo, the residue was dissolved into EtOAc and washed with water several times (5 washes). The combined organic layers v/ere dried (MgSO4) and the solvents were removed in vacuo resulting in the title compound as a yellow solid (800 mg, 100%). 1H- NMR (CDCl3): d: 8.03 (s, 1H), 7.95-7.93 (m, 1H), 7.89-7.88 (m, 1H), 7.59 - 7.53 (m, 2H), 6.08 (m, 1H), 5.99 (m, 1H), 2.55 (s, 3H), 1.85 (s, 3H), 1.52 (s, 9H). b) 4-{4'-[N',N"-Bis(tert-butoxycarbonyl)]-}-{f4-(2'-amino-6'-methyl- biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}- carbamic acid tert-butyl ester {[4-(2',4l-Diamino-6l-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (342 mg, 0.64 mmol, Example 237, step a) was dissolved into MeOH (4 mL) and acetic acid (200 µL). To this was added l,3-bis(tert-butoxycarbonyl)-2-methyl-2- thiopseudourea (203 mg, 0.70 mmol) slowly as a suspension in MeOH and the reaction was stirred ait rt overnight. The solvents were removed in vacuo followed by flash column chromatography purification (SiCb) (40% EtOAc in hexanes) that yielded the title compound (235 mg, 47%) as a white solid. ESI- MS (m/z): Calcd. for C35H46N6O8S3: 775.3 (M+l); found: 774.8. c) 4-(6'-Amino-4'-guanidino-2'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxamidinebis-trifluoroacetate 4- {4'-[N',N"-Bis(tert-butoxycarbonyl)]-} - {[4-(2'-amino-6'-methyl- biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}- carbamic acid tert-butyl ester (10 mg, 12.9 µmol, as prepared in Example 237, step b) was treated with TFA and purified using C18-HPLC as described in Example 220, step c to afford 3 mg (50%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): d 8.35 (s, 1H), 8.04 (ddd, 1H, J= 7.9, 1.9, 1.1 Hz), 7.92-7.95 (m, 1H), 7.75 (t, 1H, J = 7.8 Hz), 7.58 (dt, 1H, J= 7.6, 1.1 Hz), 6.65-6.63 (m, 2H), 2.71 (s, 3H), 1.94 (s, 3H). ESI-MS (m/z): Calcd. for C20H22N6O2S3: 475.1 (M+H); found: 475.1. Example 238 3-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4- guanidino-6-methyl-biphenyl--2-ylcarbamoyl]-methylsulfanyl}-propionic acid methyl ester bis-trifluoroacetate a) ({4-[6'-(2-Hydroxy-acetylamino)-2'-methyl-4'-nitro-biphenyl-3- sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert- butyl ester To a solution of {[4-(6'-amino-2'-methy]-4'-nitro-biphenyl-3-sulfonyl)- 5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (216 mg, 0.384 mmol, as prepared in Example 295, step h) in DCM (2 mL) was added DIEA (212 µL, 1.15 mmol) and acetoxyacetyl chloride (54 mL, 0.5 mmol). The solution was stirred at rt for 3 hr. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to provide 256 mg of a crude: oil that was used without further purification. ESI- MS (m/z): Calcd. for C28H30N4O9S3: 663.1 (M+H); found: 662.7, 563.0 (M- Boc). To a solution of the crude intermediate obtained above in MeOH (2.5 mL) was added 1 N NaOH (2.5 mL) and the mixture was stirred at rt for 45 min at which time TLC was consistent with complete conversion. The reaction mixture was neutralized with acetic acid, concentrated in vacuo, and the residue partitioned between EtOAc and saturated NaHC03. The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to give 220 mg (92%, crude yield over two steps) of the title compound which was used without further purification. ESI-MS (m/z): Calcd. for C26H28N4O8S3: 621.1 (M+H); found: 620.7, 521.0 (M-Boc). b) ({4-[4'-(N,N'-Bis-tert-butoxycarbonyl)-guanidino-6'-(2-hydroxy- acetylamino)-2'-methyl-biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2- yl}-imino-methyl)-carbamic acid tert-butyl ester To a solution of ({4-[6'-(2-hydroxy-acetylamino)-2'-methyl-4'-nitro- biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)- carbamic acid tert-butyl ester (220 mg, .354 mmol, as prepared in Example 237, step a) in EtOH (2.2 mL) was added a solution of NH4Cl (1.1 mL, 3.2 M, 3.54 mrnol). The mixture was stirred vigorously at 50 °C for 30 min. Iron powder (100 mg, 1.77 mmol) was added and the mixture was heated to 80 °C for 3.5 h. The reaction mixture was filtered (0.2 \i , Wheaton syringe filter) and the filtrate was concentrated to a solid that was partitioned between EtOAc and 1 N Na2CO3. The organic layer was washed with another portion of Na2CO3, dried (MgSO4), filtered, and concentrated to give the crude desired product. Purification using PTLC (4 x 1500 p. plate, 5% MeOH in DCM) provided 58 mg of the desired aniline. ESI-MS (m/z): Calcd. for C26H30N4O6S3: 591.1 (M+H); found: 591.0, 491.0 (M-Boc). To a solution of this aniline (55 mg, 0.09 mmol) in MeOH / AcOH (10:1, 5 mL), N,N'-bis(tert- butoxycarbonyl)-S-methylisothiourea (78 mg, 0.27 mmol, Aldrich Chemical Company) was added. The reaction mixture was warmed to 40 °C and stirred for 3 h. The mixture was concentrated in vacuo to a solid that was purified on PTLC (2 x 1000 µ plate, 1:1 EtOAc/hexanes) to give 45 mg (60%) of the title compound as a clear oil. 1H-NMR (CDCl3; 400 MHz): d 11.60 (s, 1H), 10.27 (s, 1H), 8.20 (m, 2H), 8.04 (d, 1H, J= 6.7 Hz), 7.90 (br s, 1H), 7.64 (t, 1H, J = 7.8 Hz), 7.40-7.45 (m, 2H), 4.42 (br s, 1H), 3.84 and 3.99 (AB quartet, 2H, J = 15.4 Hz), 2.55 (s, 3H), 1.93 (s, 3H), 1.57 (s, 9H), 1.53 (s, 9H), 1.48 (s, 9H). ESI-MS (m/z): Calcd. for C17H48N6O10S3: 833.2 (M+H); found: 832.8, 732.8, 632.9,533.1. c) Methanesulfonic acid (3'-[5-(tert-butoxycarbonylamino-imino- methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-4-(N,N'-bis-tert- butoxycarbonyl)-guanidino-6-methyl-biphenyl-2-ylcarbamoyl}-methyl ester To a solution of ({4-[4'-(N,N'-bis-tert-butoxyciirbony])-guanidino-6'- (2-hydroxy-acetylamino)-2'-met:hyl-biphenyl-3-sulfonyl]-5-methylsulfanyl- thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester (40 mg, 48 µmmol, as prepared in Example 238, step b) and diisopropyl ethylamine (100 µL, 192 µmol) in DCM (I mL) at 0 °C was added methanesulfonyl chloride (10 µL, 130 µmol). The solution was stirred at 0 °C for 30 min and then allowed to warm up and stirred at it for 5 h. The reaction mixture was concentrated in vacuo and the residue was chromatographed (PTLC, 1:1 EtOAc/hexanes, 1000 µ SiO2 plate) to afford 40 mg (97%) of the desired title compound as a glassy solid. ESI-MS (m/z): Calcd. for C38H50N6O14S4: 911.2 (M+H); found: 910.7, 810.3, 710.8, 611.1. d) 3-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4- guamdino-6-methyl-biphenyl-2-ylcarbamoyl]-methylsulfanyl}-propionic acid methyl ester bis-trifluoroacelate Methyl 3-mercapto propionate (large molar excess) was added to a solution of (Methanesulfonic acid {3'-[5-(tert-butoxycarbonylamino-imino- methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-4-(N,N'-Bis-tert- butoxycarbonyl)-guanidino-6-methyl-biphenyl-2-ylcarbamoyl}-methyl ester (7 mg, 7.7 µmol, as prepared in Example 238, step c) and Et3N (20 µL) in DCM (200 µL). The solution was; stirred for 1 hr at rt then concentrated in vacuo. The resulting residue was treated with TFA and purified using C18- HPLC as described in Example 220, step c to afford 3 mg (45%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): 6 8.32 (s, 1H), 8.08 (ddd, 1H, .1 = 8.07 2.0, 1.2 Hz), 7.92 (t, 1H, J = 1.6 Hz), 7.74 (t, lH, 3 = 8.0 Hz), 7.57 (dt, 1H, J = 7.6, 1.6 Hz), 7.45 (d, 1H, J = 2.3 Hz), 7.20 (dd, 1H, J = 2.3, 0.7 Hz), 3.67 (s, 3H), 5.05 and 3.10 (AB quartet, 2H, J = 15.5 Rz), 2.73 (s, 3H), 2.40-2.44 (m, 2H), 2.27-2.33 (m, 2H), 2.08 (s, 3H). ESI-MS (m/z): Calcd. for C26H30N6O5S4: 635.1 (M+H); found: 635.1. Example 239 3-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4- guanidino-6-methyl-biphenyl-2-ylcarbamoyl]-methylsulfanyl}-propionic acid bis-trifluoroacetate 3-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4- guanidino-6-methyl-biphenyl-2-ylcarbamoyl]-methylsulfanyl}-propionic acid methyl ester bis-trifluoroacetate (5.7 mg, 6.3 µmol, as prepared in Example 238, step d), dissolved in MeOH (200 µL), was treated with 1 N NaOH (200 µL) at rt for 2 hr. The reaction was acidified with acetic acid and the crude product was purified using C18-HPLC as described in Example 220, step c to provide 4 mg (75%) of the title compound as a white solid. 1H-NMR (CD3CN; 400 MHz): d 9.67 (br s, 1H), 9.44 (br s, 2H), 8.36 (s, 1H), 8.19 (s, 1H), 8.12 (ddd, 1H, J = 8.1, 1.9, 1.1 Hz), 7.88 (t, 1H, J = 1.6 Hz), 7.75-7.81 (m, 3H), 7.55 (dt, 1H, J = 7.7, 1.5 Hz), 7.10 (d, 1H, J = 1.9 Hz), 6.84 (br s, 4H), 3.01 and 3.08 (AB quartet, 2H, J = 16.2 Hz), 2.69 (s, 3H), 2.24-2.36 (m, 4H), 2.04 (s, 3H). ESI-MS (m/z): Calcd. for C25H28N6O5S4: 621.1 (M+H); found: 621.0. Example 240 6-{3-[3"-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl- biphenyl-2-yl]-ureido}-hexanoic acid trifluoroacetate To a solution of {[4-(6'-amino-2'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (23 mg, 0.044 mmol, as prepared in Example 25, step c) and Et3N (50 µL, 0.36 mmol) in DCM (2 mL) v/as added 6-isocyanato-hexanoic acid ethyl ester (40 µL, 0.22 mmol) and the mixture was stirred for 3 h at rt. The reaction mixture was diluted with EtOAc and then washed with water and saturated NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude product was taken up in MeOH (3 mL) and treated with 1 N NaOH (3 mL) at rt for 2 h. The reaction was acidified with acetic acid, concentrated in vacuo, and the residue was subjected to TFA treatment followed by C18-HPLC purification as described in Example 220, step c to afford the title compound as a white solid. 1H--NMR (CD3OD; 400 MHz) 5 8.30 (s, 1H), 8.05 (ddd, 1H, J = 7.9, 1.9, 1.2 Hz), 7.89 (t, 1H, J = 1.6 Hz), 7.71 (t, 1H, J = 7.8 Hz), 7.54-7.58 (m, 1H), 7.43 (d, 1H, J = 7.7 Hz), 7.28 (t, 1H, J = 7.8 Hz), 7.10-7.14 (m, 1H), 2.97 (td, 2H, J = 6.8, 2.2 Hz), 2.72 (s, 3H), 2.26 (t, 2H, J = 7.4 Hz), 2.00 (s, 3H), 1.51-1.59 (m, 2H), 1.19-1.36 (m, 4H). ESI-MS (m/z): Calcd. for C26H30N4O5S3: 575.1 (M+H); found: 575.1. Example 241 3-(2-{2-[2-(2-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3- sulfonyl)-6-methyl-biphenyl-2-yl]-ureido} -ethoxy)-ethoxy]-ethoxy) -ethoxy)- propionic acid trifluoroacetate As described in Example 194, step a, {[4-(6'-amino-2'-methyl- biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-immo-methyl}- carbamic acid tert-butyl ester (75 mg, 0.145 minol, as prepared in Example 25, step c), p-nitrophenyl chloroformate (31 mg, 0.152 mmol), pyridine (40 µL, 0.435 mmol) in DCM (1 niL) were stirred at it for 3 h. To the mixture was added amino-dPEG4-™-t-butyl ester (93 mg, 0.29 mmol, Quanta Biodesign, Powell, Ohio) and the reaction was stirred for another 1(5 h at rt. The mixture was concentrated and the residue was subjected to TFA treatment followed by C18-HPLC purification as described in Example 220, step c to afford 25 mg (24%) of the title compound as a glassy solid. 1H-NMR (CD3OD; 400 MHz) 8 8.31 (s, 1H), 8.07 (ddd, 1H, J= 7.9, 1.9, 1.1 Hz), 7.87-7.90 (m, 1H), 7.72 (t, 1H, J= 7.8 Hz), 7.55-7.58 (m, 1H), 7.45 (d, 1H, J= 8.1 Hz), 7.28, (t, m,J = 7.8 Hz), 7.12 (d, 1H, J= 7.3 Hz), 3.68 (t, 2H, J = 6.3 Hz), 3.50-3.62 (m, 12H), 3.39 (t, 2H, J= 5.2 Hz), 3.16 (t, 2H, J= 5.3 Hz), 2.72 (s, 3H), 2.50 (t, 2H, J = 6.3 Hz), 2.00 (s, 3H). ESI-MS (m/z): Calcd. for C31H40N4O9S3: 709.2 (M+H); found: 709.2. Example 242 4-[2'-Methyl-6'-(3-phene1:hyl-ureido)-biphenyl-3-sulfonyl]-5-methylsulfanyl- thiopheme-2-carboxamidine trifluoroacetate To a solution of {[4-(6'-amino-2'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (30 mg, 0.058 mmol, as prepared in Example 25, step c) and DEEA (100 µL, 0.57 mmol) in DCM (1.5 mL) was added (2-Isocyanato-ethyl)-benzene (100 p.L, 0.68 mmol) and the mixture was stirred for 4 h at rt. The reaction mixture was diluted with EtOAc and then washed with water and saturated NaHCCh. The organic layer was dried over MgSO4 filtered, and concentrated in vacuo. The resulting residue was subjected to TFA treatment followed by C18-HPLC purification as described in Example 220, step c to afford 20 mg (62%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz) 5 8.30 (s, 1H), 8.08 (ddd, 1H, J= 7.9, 1.9, 1.1 Hz), 7.90 (t, 1H, J= 1.6 Hz), 7.71 (t, 1H, J = 7.8 Hz), 7.51-7.55 (m, 1H), 7.36-7.39 (m, 1H), 7.22-7.30 (m, 3H), 7.12-7.19 (m, 2H), 7.02-7.06 (m, 2H), 3.14-3.24 (m, 2H), 2.64 (s, 3H), 2.52-2.62 (m, 2H), 2.00 (s, 3H). ESI-MS (m/z): Calcd. for C28H28N4O3S3: 565.1 (M+H); found: 565.1. Example 243 {3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl- biphenyl-2-yl]-ureido}-acetic acid ethyl ester trifluoroacetate To a solution of {[4-(6'-amino-2'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (15 mg, 0.029 mmol, as prepared in Example 25, step c) and Et3N (20 µL, 0.15 mmol) in DCM (1.0 mL) was added isocyanato-acetic acid ethyl ester (10 µL, 0.087 mmol) and the; mixture was stirred for 4 h at rt. The reaction mixture was diluted with EtOAc and then washed with water and saturated NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude product was split in two equal portions. One portion was subjected to TFA treatment followed by C18-HPLC purification as described in Example 220, step c to afford the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): S 8.31 (s, 1H), 8.07 (ddd, 1H, J= 7.9, 1.9, 1.2 Hz), 7.90 (t, 1H, J = 1.6 Hz), 7.72 (t, 1H, J= 7.S Hz), 7.56-7.60 (m, 1H), 7.46- 7.50 (m, 1H), 7.30 (t, 1H, J= 7.8 Hz), 7.12-7.16 (m, 1H), 4.16 (q, 2H,.J= 7.2 Hz), 3.76 (d, 2H, J= 4.2 Hz), 2.72 (s, 3H), 2.01 (s, 3H), 1.26 (t, 3H, J= 7.2 Hz). ESI-MS (m/z): Calcd. for C24H26N4O5S3: 547.1 (M+H); found: 547.1. Example 244 {3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl- biphenyl-2-yl]-ureido}-acetic acid trifluoroacetate The other portion of the crude ethyl ester obtained in Example 244 was saponified by treatment with a mixture of MeOH/1 N NaOH (l:1, 2 mL) at rt for 4 h. The crude reaction mixture was acidified with acetic acid, concentrated in vacuo, and the residue was subjected to TFA treatment followed by Cis-HPLC purification as described in Example 220, step c to afford the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): d 8.31 (s, 1H), 8.07 (ddd, lH,.J=7.9, 1,9, 1.2 Hz), 7.88 (t, 1H,J= 1.8 Hz), 7.72 (t, 1H, J= 7.8 Hz), 7.56-7.60 (m, 1H), 7.47-7.51 (m, 1H), 7.30 (t, 1H, J= 7.9 Hz), 7.12-7.15 (m, 1H), 3.6S-3.80 (m, 2H), 2.72 (s, 3H), 2.01 (s, 3H). ESI-MS (m/z): Calcd. for C22H22N4O5S3: 519.1 (M+H); found: 519.1. Example 245 {[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl- biphenyl-2-y]carbarnoyl]-methoxy}-acetic acid trifluoroacetate Following the same procedure as in Example 227, reaction of {[4-(6'- amino-2'-methyl-bipheny]-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino- methyl}-carbamic acid tert-butyl ester (28 trig, 0.054 mmol, as prepared in Example 25, step c), Et3N (45 µL, 0.32 mmol), and diglycolic anhydride (20mg, 0.16 mmol) in DCM (2 mL) followed by analogous work up and purification provided the title compound (50% yield over two steps). 1H-NMR (CD3OD; 400 MHz): d 8.28 (s, 1H), 8.0S (ddd, 1H, J= 7.9, 1.9, 1.2 Hz), 7.S5 (t, 1H, J = 1.5 Hz), 7.72 (t, 1H, J= 7.8 Hz), 7.56-7.60 (m, 1H), 7.53 (d, 1H, J = 8.1 Hz), 7.36 (t, 1H, J= 7.8 Hz), 7.26 (d, 1H, J = 7.7 Hz), 3.70-3.91 (in, 4H), 2.72 (s, 3H), 2.08 (s, 3H). ESI-MS (m/z): Calcd. for C23H23N3O6S3: 534.1 (M+H); found: 534.1. Example 246 2-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl- biphenyl-2-ylcarbamoyl]-methylsulfanyl}-acetamide trifluoroacetate a) ({4-[6'-(2-Brom o-acetylamino)-2'-methyl-biphenyl-3-sulfonyl]-5- methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester Following the procedure described for Example 234, step a, reaction of {[4-(6'-i3mino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2- yl]-imino-methyl}-carbamic acid tert-butyl ester (137 mg, 0.265 mmol, as prepared in Example 25, step c), bromoacetyl bromide (28 µL, 0.32 mmol), and DIEA (70 µL, 0.40 mmol) in chloroform (3 mL) afforded 129 mg (76%) of the title compound as a yellow foamy solid after chromatography (PTLC, 10% EtOAc in DCM, 2 x 1500 µ SiO2 plate). 1H-NMR (CDCl3; 400 MHz): d 8.05-8.10 (m, 1H), 7.85-7.95 (m, 2H), 7.65-7.73 (m, 2H), 7.46-7.51 (m, 1H), 7.35 (t, 1H, J= 7.9 Hz), 7.16 (d, 1H, J= 7.7 Hz), 3.64 and 3.74 (AB quartet, 2H, J = 14.0 Hz), 2.60 (s, 3H), 2.03 (s, 3H), 1.52 (s, 9H). ESI-MS (m/z): Calcd. for C26H28BrN3O5S3: 637.0 (M+H); found: 637.8, 639.8, 538.0, 540.0 (M-Boc). b) 2-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6- methyl-biphenyl-2-ylcarbamoyl]-methylsulfanyl}-acetamide trifluoroacetate To a solution of ({4-[6'-(2-bromo-acetylamino)-2'-methy]-biphenyl-3- sulfonyl]-5-methylsulfanyl-thiophen-2-yl} -imino-methyl)-carbamic acid tert- butyl ester (9 mg, 0.014 rnmol, as prepared in Example 246, step a) in MeOH (0.1 mL) was added 2-mercapto acetamide (20 µL of 10% methanolic solution, Maybridge pic) and Et3N (6 µL, 0.042 mmol). The reaction mixture was stirred at rt for 0.5 h and then concentrated in vacuo. The residue was treated with TFA as described in Example 220, step c and then purified using C18-HPLC (10-60% CH3CN in H2O with 0.1% TFA) to afford 8.7 mg (94%) of the title compound as a clear glassy solid. 1H-NMR (CD3OD; 400 MHz): d 8.30 (s, 1H), 8.09 (ddd., 1H, J= 7.9, 1.9, 1.2 Hz), 7.88 (t, 1H, J= 1.6 Hz), 7.72 (t, 1H, J= 7.9 Hz), 7.57-7.60 (m, 1H), 7.35-7.40 (m, 2H), 7.27-7.31 (m, 1H), 3.05 and 3.11 (AB quartet, 2H, J = 14.9 Hz), 2.78 and 2.85 (AB quartet, 2H, J = 14.9 Hz), 2.74 (s, 3H), 2.08 (s, 3H). ESI-MS (m/z): Calcd. for C23H24N4O4S4: 549-1 (M+H); found: 549.1. Example 247 3-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl- biphenyl-2-ylcarbamoyl]-methylsulfanyl}-propionic acid trifluoroacetate Following the same procedure as described in Example 246, step b, reaction of ({4-[6'-(2-bromo-acetylamino)-2'-methyl-biphenyl-3-sulfonyl]-5- methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester (15.2 mg, 0.029 mmol, as prepared in Example 246, step a), 3- mercaptopropionate (8 µL, 0.09 mmol), Et3N (20 µL, 0.12 mmol), in MeOH (1 mL) for 1 h afforded 9 mg (56%) of the title compound as a white solid after TFA treatment and RP-HPLC purification. 1H-NMR (CD3OD; 400 MHz): d 8.28 (s, 1H), 8.06-8.09 (m, 1H), 7.88 (t, 1H,J = 1.9 Hz), 7.70 (t, 1H, J= 7.8 Hz), 7.53-7.57 (m, 1H), 7.33-7.38 (m, 2H), 7.25-7.29 (m, 1H), 2.95 and 3.04 (AB quartet, 2H, J = 15.4 Hz), 2.73 (s, 3H), 2.31-2.36 (m ,2H), 2.16- 2.20 (m ,2H), 2.04 (s, 3H). ESI-MS (m/z): Calcd. for C24H25N3O5S4: 564.1 (M+H); found: 564.1. Example 248 2-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl- biphenyl-2-ylcarbamoyl]-methylsulfanyl}-succinic acid trifluoroacetate Following the same procedure as described in Example 246, step b, reaction of ({4-[6'-(2-bromo-acetylamino)-2'-methyl-biphenyl-3-sulfonyl]-5- methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester (15.3 mg, 0.03 mmol, as prepared in Example 246, step a), mercaptosuccinate (14 mg, 0.09 mmol), Et3N (20 µL, 0.12 mmol), and MeOH (1 mL) for 2 h provided 12 mg (67%) of the: title compound as a white solid after TFA treatment and RP-HPLC purification. 1H-NMR (CD3OD; 400 MHz, (+) and (- ) enantiomers appear as two distinct diastereomers on NMR presumably due to conformational restriction around o-methyl-biphenyl ring system): d 8.27 (s, 1H), 8.04-8.09 (m, 1H), 7.84-7.S8 (m, 1H), 7.66-7.73 (m, 1H), 7.53-7.57 (m, 1H), 7.32-7.44 (m, 2H), 7.27 (t, 1H, J = 6.7 Hz), 3.38-3.42 (m, 0.5H), 3.09-3.29 (m, 2H), 2.62-2.79 (m, 2.5H), 2.75 (s, 3H), 2.44-2.50 (m, 0.5II), 2.22-2.28 (m, 0.5H), 2.06 (s, 3H). ESI-MS (m/z): Calcd. for C25H25N3O7S4: 608.1 (M+H); found: 608.1. Example 249 2-Bromo-N-[3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6- methyl-biphenyl-2-yl]-acetamide trifluoroacetate ({4-[6'-(2-bromo-acetylamino)-2'-methyl-biphenyl-3-sulfonyl]-5- methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester (22 mg, 0.034 mmol, as prepjjred in Example 246, step a) was stirred in a mixture of TFA / DCM (1:1, 4 mL) for 1 h at it. The reaction was concentrated in vacuo and the resulting residue was purified using RP-HPLC (10-50% CH3CN in H2O with 0.1% TFA over 30 min) to afford 15 mg (68%) of the title compound as a clear glassy solid (purity >99.9% by analytical RP- HPLC). ESI-MS (m/z): Calcd. for C21H20BrN3O3S3: 538.0 (M+H); found: 538.0 and 540.0 Example 250 2-Acetylamino-3-{\|[3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3- sulfonyl)-6-methyl-biphenyl-2-ylc arbamoyl]-methylsulfanyl}-3-methyl- butyric acid trifluoroacetate N-Acetyl-penicilla.mine (3.0 mg, 0.0154 mmol, racemic) and DIEA (7 µL, 0.04 mmol) were dissolved in DMSO (223 µL) and then transferred to a solution of 2-bromo-N-[3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3- sulfonyl)-6-methyl-biphenyl-2-yl]-acetamide trifluoroacetate (20 mM in DMSO, 230 µL, 0.0046 mmol, prepared from the title compound described in Example 249). The reaction was mixed on a shaker for 1 h at rt. Bromomethyl wang resin (16 mg, 1.47 mmol/gm) was added to scavenge the excess thiol. After 2 h of shaking, the resin was filtered and the filtrate was directly purified using PP-HPLC as previously described in Example 246, step b, to afford 1.5 mg (50%, single peal: on analytical RP-HPLC) of the title compound as a glassy solid. ESI-MS (m/z): Calcd. for C28H32N4O6S4: 649.1 (M+H); found: 649.1. Example 251 2-Acetylamino-3-{[3'-(5-carbamirnidoyl-2-methylsulfanyl-thiophene-3- sulfonyl)-6-methyl-biphenyl-2-ylcarbamoyl]-methylsulfany]}-propionic acid trifluoroacetate Following the same procedure as described in Example 246, step b, reaction of ({4-[6'-(2-bromo-acetylamino)-2'-methyl-biphenyl-3-sulfonyl]-5- methylsulfanyl-thiophen-2-yl}-]jnino-methyl)-carbamic acid tert-butyl ester (10 mg, 0.016 mmol, as prepared in Example 246, step a), (L)-N- acetylcysteine (22 mg, 0.135 mmol), Et3N (50 µL, 0.12 mmol), and DCM (0.5 mL) for 2 h provided 7 mg (71%) of the title compound as a white solid after TFA treatment and RP-HPLC purification. 1H-NMR (CD3OD; 400 MHz): 6 8.30 (s, 1H), 8.06-8.09 (m, 1H), 7.87 (t, 1H, J= 1.6 Hz), 7.68-7.'73 (m, 1H), 7.54-7.59 (m, 1H), 7.34-7.39 (m, 2H), 7.26-7.30 (m, 1H), 4.41-4.48 (m, 1H), 2,94-3.10 (m, 2H), 2.74 (s, 3H),.2.59-2.64 (m ,1H), 2.43-2.49 (m, 1H), 2,06 (s, 3H). 2.00 (d, 3H, 2.1 J = 2.1 Hz). ESI-MS (m/z): Calcd. for C26H28N4O6S4: 621.1 (M+H); found: 621.1. Example 252 3-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-methoxy- 6-methyl-biphenyl-2-ylcarbamoyl]-methylsulfanyl}-propionic acid trifluoroacetate a) ({4-[6'-(2-Brom o-acetylamino)-4'-m eth oxy-2'-methyl-biphenyl-3- sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert- butyl ester Following the procedure described for Example 234, step a, reaction of {[4-(6'-amino-4'-methoxy-2'-raethyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (204 mg, 0.37 mmol, as prepared in Example 198, step e), bromoacetyl bromide (39 µL, 0.45 mmol), and Et3N (77 µL, 0.56 mmol) in DCM (5 mL) afforded 170 mg (69%) of the title compound as a yellow foamy solid after chromatography (PTLC, 50% EtOAc in hexanes, 4 x 1000 µ SiO2 plate). 1H-NMR (CDCl3; 400 MHz): 8 8.02-8.05 (m, 1H), 7.91 (s, 1.H), 7.87 (t, 1R, J = 1.6 Hz), 7.73 (br s, 1H), 7.63-7.67 (m, 2H), 7.45-7.49 (m, 1H), 6.69 (d, 1H, J= 2.1 Hz), 3.85 (s, 3H), 3.69 and 3.74 (AB quartet, 2H, J = 14.1 Hz), 2.59 (s, 3H), 2.00 (s, 3H), 1.52 (s, 9H). ESI-MS (m/z): Calcd. for C27H30BrN3O6S3: 668.0 (M+H); found: 669.6, 667.6, 570.0, 568.0 (M-Boc). b) 3-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4- methoxy- 6-methyl-biphenyl-2-ylcarbamoyl]-in ethylsulfanyl]-propionic acid trifluoroacetate Following the same procedure as described in Example 246, step b, reaction of ({4-[6'-(2-bromo-acetylamino)-4'-methoxy-2'-methyl-biphenyl-3- sulfonyl]-5-methylsulfanyl-thiophen-2-yl} -imino-methyl)-carbamic acid tert- butyl ester (12 mg, 0.018 rnmol, as prepared in Example 252, step a), 3- mercaptopropionate (8 u.L, 0.09 mmol), Et3N (20 µL, 0.12 mmol), in MeOH (1 mL) for 1 h afforded 9 3 mg (62%) of the title compound as a white solid after TFA treatment and RP-HPLC purification. 1H-NMR (CD3OD; 400 MHz): d 8.29 (s, 1H), 8.07 (ddd, 1H, J= 7.9, 1.9, 1.2 Hz), 7.87 (t, 1H, J= 1.6 Hz), 7.70 (t, 1H, J= 7.8 Hz), 7.53-7.57 (m, 1H), 7.05 (d, 1H, J= 2.5 Hz), 6.84 (d, 1H, J = 2.5 Hz), 3.83 (s, 3H), 2.98 and 3.06 (AB quartet, 2H,.J = 15.4 Hz), 2.73 (s, 3H), 2.32-2.36 (m ,2H), 2.19-2.23 (m ,2H), 2.02 (s, 3H). ESI-MS (m/z): Calcd. for C25H27N3O6S4: 594.1 (M+H); found: 594.0. Example 253 3-{\|'3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyri-4-methoxy- 6-methyl-biphenyl-2-ylcarbamoylj-methylsulfanyl}-propionic acid methyl ester trifluoroacetate Following the same procedure as described in Example 246. step b, reaction of ({4-[6'-(2-bromo-acetylamino)-4'-methoxy-2'-methyl-biphenyl-3- sulfonyl]-5-methylsulfanyl-thiophen-2-yl} -imino-methyl)-carbamic acid tert- butyl ester (22 mg, 0.04 mmol, as prepared in Example 252, step a), methyl 3- mercaptopropionate (10 µL, 0.09 mmol), Et3N (20 µL, 0.12 mmol), in MeOH (1 mL) for 1 h afforded the; title compound as a white solid after TFA treatment and RP-HPLC purification. 1H-NMR (CD3OD; 400 MHz): d 8.31 (s, 1H), 8.07 (ddd, 1H, J= 7.9, 1.9, 1.2 Hz), 7.87 (t, 1H, .J== 1.6 Hz). 7.70 (t, 1H, J = 7.8 Hz), 7.53-7..57 (m, 1H), 7.06 (d, 1H, J = 2.4 Hz), 6.85 (d, 1H, J= 2.4 Hz), 3.84 (s, 3H), 3.68 (s, 3H), 3.00 and 3.07 (AB quartet, 2H, J = 15.4 Hz), 2.74 (s, 3H), 2.39-2.42 (m, 2H), 2.23-2.27 (m, 2H), 2.03 (s, 3H). ESI-MS (m/z): Calcd. for C26H29N3O6S4: 608.1 (M+H); found: 608.1. Example 254 N-[3'-(5-Carbamimidoyl-2-me1:hylsulfanyl-thiophene-3-sulfonyl)-4-methoxy- 6-methyl-biphenyl-2-yl]-2-methanesulfonyl-acetamidetrifluoroacetate Following the same procedure as described in Example 257, reaction of ({4-[6'-(2-bromo-acetylamino)-4'-methoxy-2'-methyl-biphenyl-3-sulfonyl]- 5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester (37 mg, 0.065 mmol, as prepared in Example 252, step a) and sodium methanesulfinate (25 mg, 0.195 mmol, Aldrich Chemical Company) in EtOH/CH3CN (1:1, 2 mL) provided 29 mg (66%) of the title compound as a white solid after TFA treatment and RP-HPLC purification. 1H-NMR (CD3OD; 400 MHz): v 8.30 (s, 1H). 8.03 (ddd, 1H, J= 7.9, 1.9, 1.2 Hz), 7.84 (t, 1H, J= 1.6 Hz), 7.66 (t, 1H, J= 7.8 Hz), 7.51-7.54 (m, 1H), 6.99 (d, 1H, J = 2.6 Hz), 6.84 (d, 1H, J = 2.6 Hz), 3.89 and 3.93 (AB quartet, 2H, J = 14.1 Hz), 3.82 (s, 3H), 2.86 (s, 3H), 2.72 (s, 3H), 2.01 (s, 3H). ESI-MS (m/z): Calcd. for C23H25N3O6S4: 568.1 (M+H); found: 568.0. Example 255 6-Methanesulfonyl-hexanoic acid [3'-(5-carbamimidoyl-2-rnethylsulfanyl- thiophene-3-sulfonyl)-4-methoxy-6-methyl-biphenyl-2-yl]-amide trifluoroacetate Following the procedure described for Example 234, step a, reaction of {[4-(6'-amino-4'-methoxy-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (60 mg, 0.11 mmol, as prepared in Example 198, step e), 6-bromo-hexanoyl chloride (26 µL, 0.17 mmol), and Et3N (79 µL, 0.55 mmol) in DCM (1 mL) afforded the title compound as a crude oil after aqueous work up. ESI-MS (m/z): Calcd. for C31H38BrN3O6S3: 724.1 (M+H); found: 626.1, 624.1 (M-Boc). The crude bromide intermediate obtained above was suspended in a EtOH-water mixture (1:1, 3 mL) and to the mixture was added sodium methanesulfinate (45 mg, 0.33 mmol, Aldrich Chemical Company). The reaction mixture was heated at 50 °C for 48 h and then concentrated in vacua. The residue was treated with TFA as described in Example 220, step c and then purified using Cis-HPLC (10-60% CH3CN in H2O with 0.1% TFA) to afford 12 mg (18% from the aniline) of the title compound as a clear glassy solid. 1H-NMR (CD3OD; 400 MHz): d 8.30 (s, 1H), 8.02 (ddd, 1H,7=7.9, 1.9,1.1 Hz), 7.86 (t, 1H,7 = 1.6 Hz), 7.67 (t, 1H, J= 7.9 Hz), 7.52 (dt, 1H, 7 = 7.7, 1.2 Hz), 6.85 (d, 1H, 7 = 2.5 Hz), 6.77 (d, 1H, 7=2.5 Hz), 3.82 (s, 3H), 2.98-3.04 (m, 2H), 2.96 (s, 3H), 2.72 (s, 3H), 1.99-2.04 (m, 2H), 2.03 (s, 3H), 1.57-1.66 (m, 2H), 1.05-1.25 (m, 4H). ESI-MS (m/z): Calcd. for C27H33N3O6S4: 624.1 (M+H); found: 624.1 Example 256 N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-methoxy- 6-methyl-biphenyl-2-yl]-3-methanesulfonyl-propionamide trifluoroacetate Following the procedure described for Example 234, step a, reaction of {[4-(6'-amino-4'-methoxy--2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-rnethyl}-carbamic acid tert-butyl ester (60 mg, 0.11 mmol, as prepared in Example 198, step e), acryloyl chloride (22 µL, 0.22 mmol), and Et3N (80 µL, 0.55 mmol) in THF (1 mL) afforded the title compound as a crude oil after aqueous work up. ESI-MS (m/z): Calcd. for C28H31N3O6S3: 602.1 (M+H); found: 601.9, 502.1 (M-Boc). The crude acrylamide intermediatte obtained above was suspended in a EtOH-water mixture (1:1, 3 mL) and to the mixture was added sodium metlianesulfmate (45 mg., 0.33 mmol, Aldrich Chemical Company). The reaction mixture was heated at 50 °C for 48 h and then concentrated in vacuo. The residue was treated with TFA as described in Example 220., step c and then purified using C18-HPLC (10-60% CH3CN in H2O with 0.1% TFA) to give 15 mg (23% from the aniline) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): d 8.30 (s, 1H), 8.03 (ddd, 1H, J- 7.9, 1.9, 1.1 Hz), 7.83 (t, lH,J= 1.6 Hz), 7.67 (t, 1H, J= 7.8 Hz), 7.54 (dt, 1H, J= 7.7, 1.3 Hz), 6.84-6.87 (m, 2H), 3.82 (s, 3H), 3.07 (t, 2H, J= 7.8 Hz), 2.86 (s, 3H), 2.73 (s, 3H), 2.44-2.51 (m, 2H), 2.06 (s, 3H). ESI-MS (m/z): Calcd. for C24H27N3O6S4: 582.1 (M+H); found: 582.1. Example 257 N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl- biphenyl-2-yl]-2-methanesuIfonyl-acetarnide trifluoroacstate To a solution of ({4-[6'-(2-bromo-acetylamino)-2'-methyl-biphenyl-3- sulfonyl]-5-methylsulfanyl-thk>pb.en-2-yl} -immo-methyl)-carbam:ic acid tert- butyl ester (8 mg, 0.0125 mmol, as prepared in Example 246, step a) in EtOH (1.0 mL) was added sodium methanesulfinate (13 mg, 0.127 mmol, Aldrich Chemical Company) and the reaction was stirred overnight and monitored by MS and TLC. After ~16 h at n:, the starting material had disappeared and the reaction was concentrated in vacuo to give an oil. Treatment of this intermediate with trifluoroacetic acid for 2 h followed by RP-HPLC purification afforded 5.2 mg (78%) of the title compound as a white solid. 'H- NMR (CD3OD; 400 MHz): 6 8.31 (s, 1H), 8.05 (ddd, lH,J= 7.9, 1.9,1.2 Hz), 7.87 (t, 1H, J= 1.6 Hz), 7.68 (t, 1H, 7= 8.0 Hz), 7.53-7.56 (m, 1H), 7.33-7.37 (m, 2H), 7.26-7.30 (m, 1H), 3.85-3.94 (m, 2H) 2.84 (s, 3H), 2.72 (s, 3H), 2.04 (s, 3H). ESI-MS (m/z): Calcd. for C22H23N3O5S4: 538.0 (M+H); found: 538.0. Example 258 N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl- biphenyl-2-yl]-2-methanesulfonyl-propionamide trifluoroacetate a) ({4-[6'-(2-Bromo-propionylamino)-2'-methyl-biphenyl-3-sulfonyl]-5- methylsulfanyl-thiophen-2-yl}-imitw-methyl)-carbamic acid tert-butyl ester Following the procedure described for Example 234, step a, reaction of {[4-(6'-amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2- yl]-imino-methyl}-carbamic acid tert-butyl ester (65 mg, 0.126 mmol, as prepared in Example 25, step c), racemic 2-bromo-propionyl bromide (19 µL, 0.189 mmol), and Et3N (52 µL, 0.37S mmol) in DCM (2 mL) afforded 55 mg (67%) of the title compound as a glassy solid after chromatography (PTLC, 10% EtOAc in DCM, 2 x 1500 µ SiO2 plate). ESI-MS (m/z): Calcd. for C27H30BrN3O5S3: 652.0 (M+H); found: 653.6, 651.7, 553.9, 552.0 (M-Boc). b) N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6- methyl-biphenyl-2-yl]-2-methanesulfonyl-propionamide trifluoroacetate Following the procedure described for Example 257, reaction of ({4- [6'-(2-bromo-propionylamino)-2'-methyl-biphenyl-3-sulfonyl]-5- methylsulfanyl-thiophen-2-y!}-imino-methyl)-carbamic acid tert-butyl ester (30 mg, 0.046 mmol, as prepared in Example 258, step a) and sodium methanesulfmate (48 mg, 0.46 mmol, Aldrich Chemical Company) in EtOH (1 mL) provided 18 mg (72%) of the title compound as a white solid after TFA treatment and RP-HPLC purification. 1H-NMR (CD3OD; 400 MHz, (+) and (- ) enantiomers appear as two distinct diastereomers on NMR presumably due to conformational restriction around o-methyl-biphenyl ring system): 6 8.32, 8.31 (2 x s, 1H), 8.05-8.08 (m, 1H), 7.87-7.88 (m, 1H), 7.69 (t, 1H, J= 7.8 Hz), 7.52-7.55 (m, 1H), 7.27-7.39 (m, 3H), 3.67-3.74 (m. 1H); 2.78, 2.724, 2.718, 2.16 (4 x s, 6H), 2.06, 2.03 (2 x s, 3H), 1.30, 1.28, 1.17, 1.15 (4 x s, 3H). ESI-MS (m/z): Calcd. for C23H25N3O5S4: 552.1 (M+H); found: 652.0. Example 259 6-{3-[3'-(5-Carbaminiidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4- guanidino-biphenyl-2-yl]-ureido}-hexanoic acid a) 6-{3-[3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-4-(2-trimethylsilanyl- ethoxycarbonylamino)-biphenyl-2-yl]-ureido}-hexanoic acid ethyl ester A solution of {2-amino-3'-[5-(imino-methoxycarbonylamino-methyl)- 2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyi-4-yl}-carbarnic acid 2-trimethylsilanyl-ethyl ester {{Example 294: step f) 0.020 g, 0.030 mmol) in dry CH2Cl2 (3 mL) was treated with 6-isocyanato-hexanoic acid ethyl ester (5.30 µL, 0.030 mmol) and stirred at room temperature 40 min. The reaction mixture was diluted with CH2Cl2 and washed with water (1 x 15 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to afford the product 6-{3-[3'-[5-(tert-butoxycarbonylamino-imino-:rnethyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-4-(2-trimethylsilanyl- ethoxycarbonylamino)-bipheny]-2-yl]-ureido}-hexanoic acid ethyl ester (0.025 g, 98%) as an off-white solid. 1H NMR (CD3OD): d 8.217 (s, 1H), 8.062 (d, 1H, J= 8.0 Hz), 7.920 (t, 1H, J= 1.6 Hz), 7.718 (t, 1H, J= 8.0 Hz), 7.647 (d, 1H, J = 1.6 Hz), 7.556 (d, 1H, J= 7.6 Hz), 7.282 (s, 1H), 4.292 (dd, 2H, J = 8.4 Hz, J= 1.6 Hz), 3.063-3.002 (m, 2H), 2.699 (s, 3H), 2.327 (t, 2H, J= 7.2 Hz), 2.011 (s, 3H), 1.604 (quint, 2H, J= 7.2 Hz), 1.538 (s, 9H), 1.403-1.362 (m, 2H), 1.124 (dd, 2H, J= 7.2 Hz, 7= 1.6 Hz), 1.281 (t, 3H, J = 7.2 Hz). ESI-MS (m/z): Calcd. for C39H55N5O9S3Si (M+H): 862.3; found 861.90. A) 6-{3-[3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-4-(2-trimethylsilanyl- ethoxycarbonylamino)-biphenyl-2-yl]-ureido}-hexanoic acid A solution of 6-{3-[3'-[5-(tert-butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-4-(2-trimethylsilanyl- ethoxycarbonylamino)-biphenyl-2-yl]-ureido}-hexanoic acid ethyl ester ((Example 259: step a) 0.437 g, 0.507 mmol) in THF:water (2:1, 15 mL) was treated with solid LiOH (0.097 g, 4.06 mmol) and stirred at room temperature 18.5 h. The THF was removed in vacuo, and the remaining aqueous solution was acidified to pH 5 with glacial acetic acid. The solution was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (0.4222 g, 99%) as an off-white solid. ESI-MS (m/z): Calcd. for C37H51N5O9S3S1 (M+H): 834.3; 834.2. c) 6-(3-{4-Amino-3'-l5-(tert-butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-1hiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-ureido)- hexanoic acid A solution of 6-{3-[3'-[5-(tert-butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-4-(2-trimethylsilanyl- ethoxycarbonylamino)-biphenyl-2-yl]-ureido}-hexanoic acid {{Example 259: step b) 0.422 g, 0.506 mmol) in dry THF (20 mL) was treated with tetrabutylamrnonium fluoride (1 M in hexanes, 3.39 mL, 3.39 mmol) and stirred at 40 °C 4 h. Solvents; were evaporated in vacuo. The residue was taken up in CH2Cl2 and washed with water (4 x 50 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. Silica gel chromatography (4% MeOH in CH2C12) afforded the product 6-(3-{4-amino-3'-[5-(tert- butoxycarbonylamirio-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]- 6-methyl-biphenyl-2-yl}-ureido)-hexanoic acid (0.200 g, 57%) as an off-white solid. The material was combined with 1,3-bis(tret-butoxycarbonyl)-2- methyl-2-thiopseudourea (0.252 g, 0.870 mmol) and acetic acid (0.5 mL) in MeOH (10 mL) and was stirred at 40 °C 2 h. The solvent was removed in vacuo. Silica gel chromatography (4% MeOH in CH2C12 then 10% MeOH in CH2C12) afforded the title compound (0.215 g, 80%) as a white solid. VH- NMR (CD3OD): d 8.22 (s, 1H), 8.06 (m, 1H), 7.89 (m, 1H), 7.72 (m, 1H), 7.69 (m, 1H), 7.53 (m, 1H), 7.32 (m, 1H), 3.01 (m, 2H), 2.66 (s, 3H), 2.27 (t, 2H, 7.4 Hz), 1.97 (s, 3H), 1.57 (m, 2H), 1.54 (s, 18H), 1.51 (s, 9H), 1.37 (m, 2H), 1.27 (m,2H). d) 6-{3-[3'-(5-Carbainimidoyl-2-methylsulfanyl-thiophetie-3-sulfonyl)- 4-guanidino-biphenyl-2-yl]-ureido}-hexanoic acid bis-trifluoroacetate The reaction conditions used in Example 1: step d were followed using 6-(3-{3'-[5-(tret-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl- thiophene-3-sulfonyl]-4-(N',N"-bis-tret-butoxycarbonyl-guanidino)-6-methyl- biphenyl-2-yl}-ureido)-hexanoic acid ((Example 259: step c) 80 mg, 0.086 mmol). Analogous purification by HPLC yielded the title compound as a white solid (70 mg, 95%). 1H-NMR (CD3CN/D2O): d 8.23 (s, 1H), 8.04 (m, 1H), 7.83 (m, 1H), 7.74 (m, 1H), 7.55 (m, 1H), 7.48 (m, 1H), 6.99 (m, 1H), 2.92 (m, 2H), 2.66 (s, 3H), 2.24 (t, 2H, 7.4 Hz), 1.95 (s, 3H), 1.48 (m, 2H), 1.27 (m, 2H), 1.25 (m, 2H). ESI-MS (m/z): Calcd. for C27H33N7O5S3 (M+H): 632.2; found: 632.1. Example 260 N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-guanidino- 6-methyl-biphenyl-2-yl]-4-methanesulfonyl-butyraniidebis-trifluoroacetate a) ({4-[4'-Amino-6 '-(4-methanesulfonyl-butyrylamino)-2'-methyl- biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)- carbamic acid tert-butyl ester The procedure in Example 261: step b was followed using 4- methanesulfonyl-butyryl chloride {Example 209; step a (53 mg, 0.29)), {[4- (6'-arnino-2'-methyl-4'-nitro-biph.enyl-3-sulfonyl)-5-methylsulfanyl-thiophen- 2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 295: step h) 130 mg, 0.23 mmol), and Et3N (192 µL, 1.38 mmol) in DCM (5 mL). After stirring for 1 h, starting material remained and an additional 20 mg of acid chloride was added. The solution was partitioned between EtOAc (70 mL) and aq NH4Cl (30 mL) and the layers were separated. The organic layer was washed with NaHCO3 (20 mL) and brine (30 mL) and was dried over sodium sulfate. The solution was concentrated and the residue was purified by SiO2 flash column chromatography to yield 126 mg of the amide product. The residue dissolved in EtOH (5 mL). Saturated aqueous NH4Cl (1.5 mL) was added followed by iron powder (110 mg, 2 mmol). The mixture was vigorously stirred at 80 °C for 30 min. The solution was filtered through a 0.22 urn filter and was then partitioned between EtOAc (70 mL) and water (20 mL). The layers were separated, the organic solution was dried over sodium sulfate, and the solution was concentrated to give the crude title compound which was used without further purification. 1H-NMR (CDCl3): 8 7.99 (s, 1H) 7.96 (m, 2H), 7.77 (s, 1H), 7.57 (t, 1H, J= 7.9 Hz), 7.43 (dr., 1H, J= 1.3, 7.7 Hz), 7.10 (br s, 1H), 7.04 (br s, 1H), 6.43 (br s, 1H), 3.85 (br s, 2H), 2.92 (m, 2H), 2.88 (s, 3H), 2.56 (s, 3H), 2.20 (t, 2H, J= 6.7 Hz), 1.98 (m, 2H), 1.90 (s,3H), 1.50 (s, 9H). b) N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4- guanidino-6-methyl-biphenyl-2-yl]-4-methanesulfonyl-butyramidebis- triflnoroacetate Acetic acid (500 µL) was added to a solution of ({4-[4'-amino-6'-(4- methanesulfonyl-butyrylammo)-2'-methyl-biphenyl-3-sulfonyl]-5- methylsulfanyl-thiophen-2-yl}-imino-methy])-carbamic acid ten -butyl ester {{Example 260: step a) 136 mg., 0.2 mmol) and l,3-bis-(tert-butoxycarbonyl)- 2-methyl-2-thiopseudourea (145 mg, 0.5 mmol) in MeOH (10 mL). The solution was stirred for 16 h at 40 °C, then was partitioned between EtOAc (80 mL) and water (40 mL). The layers were separated and the organic layer was washed with aq NaHCO3 (2 x 30 mL) and brine (30 mL) and was dried over sodium sulfate. After concentration, the residue was purified by preparative TLC. The residue was treated with 1:1 TFA/DCM as in Example 1: step d and analogously purified by HPLC to yield the title compound (47 mg, 23%) as a white solid. 1H-NMR (CD;OD): S 8.39 (s, 1H), 8.09 (ddd, 1H, J - 0.9, 1.9, 8.1 Hz), 7.92 (t, 1H, J = 1.6 Hz), 7.74 (t, 1H, J= 7.7 Hz) 7.58 (m, 1H), 7.24 (m, 2H), 2.94 (s, 3H), 2.86 (t> 2H, J- 7.7 Hz), 2.76 (s, 3H), 2.24 (m, 2H), 2.12 (s, 3H), 1.80 (m, 2H). ESI-MS (m/z): Calcd. for C15H10N4O5S4 (M+H): 623.1; found: 623.1. Example 261 5-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-guanidino- 6-methyl-biphenyl-2-ylcarbamoyl]-pentanoic acid bis-trifluoroacetate a) 5-{4-Amino-3'-[5-(tert-butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylcarbamoyl}- pentanoic acid methyl ester To a solution of {[4-(6l-amino-2'-methyl-4'-nitro-biphenyl-3-sulfonyl)- 5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tot-butyl ester {{Example 295: step h) 130 mg, 0.23 nimol), and Et3N (192 yL, 1.38 mmol) in DCM (5 mL) at 0° C was added 5-chlorocarboriyl-pentanoic acid methyl ester (53 mg, 0.29). After stirring for 1 h, the solution was partitioned between EtOAc (70 mL) and aq NH4Cl (30 mL) and the layers were separated. The organic layer was washed with NaHCO3 (20 mL) and brine (30 mL) and was dried over sodium sulfate. The; solution was concentrated and the residue was purified by SiO2 flash column chromatography to yield 36 mg of the amide product. The residue dissolved in EtOH (5 mL). Saturated aqueous NH4C1 (1.5 mL) was added followed by iron powder (110 mg, 2 mmol). The mixture was vigorously stirred at 80 °C for 30 min. The solution was filtered through a 0.22 fim filter and was then partitioned between EtOAc (70 mL,) and water (20 mL). The layers were separated, the organic solution was dried over sodium sulfate, and the solution was concentrated to give the crude title compound which was used without further purification. 1H-NMR (CDCl3): d 8.0 (m, 2H), 7.84 (s, 1H), 7.96 (m, 2H), 7.59 (t, 1H, J= 7.7 Hz), 7.43 (m, 1H), 7.23 (br s, 1H), 6.86 (br s, 1H), 6.45 (br s, 1H), 3.85 (br s, 2H), 3.65 (s, 3E), 2.60 (m, 3H), 2.35 (m, 2H), 2.00 (m, 2H), 1.90 (s, 3H), 1.67 (m, 2H), 1.90 (s,3H), 1.53 (s,9H). b) 5-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4- guanidino-6-methyl-biphenyl-2-ylcarbamoyl]-pentanoic acid bis- trifluoroacetate Acetic acid (500 µL) was added to a solution of 5-{4-amino-3'-[5-(tert- butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]- 6-methyl-biphenyl-2-ylcarbamoyl}-pentanoic acid methyl ester ((Example 260: step b) 136 mg, 0.2 mmol) and l,3-bis-(tert-butoxycarbonyl)-2-methyl-2- thiopseudourea (145 mg, 0.5 mmol) in MeOH (10 mL). The solution was stirred for 16 h at 40 °C, then was partitioned between EtOAc (80 mL) and water (40 mL). The layers were separated and. the organic layer was washed with aq NaHCO3 (2 x 30 mL) and brine (30 mL) and was dried over sodium sulfate. After concentration, the residue was purified by preparative TLC. The residue was dissolved in MeOH (10 mL) and 1N NaOH was added (400 µL, 0.4 mmol). After stirring for 6 h, the solution was neutralized with AcOH (100 µL) and the solvent was removed in vacuo. The residue was treated with 1:1 TFA/DCM as in Example 1: step d and analogously purified by HPLC to yield the title compound (12 mg, 19%) as a white solid. 1H-NMR (CD3OD): S 8.30 (s, 1H), 8.09 (ddd, 1H, J= 1.2, 2.1, 7.9 Hz), 7.88 (t, 1H, J= 1.6 Hz), 7.70 (t, 1H, J= 1.1 Hz) 7.52 (m, 1H), 7.22 (m, 1H), 7.17 (m, 1H), 2.72 (s, 3H), 2.12 (m, 2H), 2.08 (s, 3H), 2,02 (m, 2H), 1.25 (m, 2H). ESI-MS (m/z): Calcd. for C26H30N6O5S3 (M+H): 603.1; found: 603.2. Example 262 4-[2'-Methyl-4'-(N-methyl-guanidino)-biphenyl-3-sulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidinebis-trifluoroacetate a) (4-Brom o-3-m ethyl-ph enyl)-m ethyl-am ine A solution of 4-bromo-3-methylaniline (3.72 g, 20 mmol) in formic acid (15 mL) was heated a.t 100 °C for 8 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc (100 mL) and aq NaHCO3 (50 mL). The layers were separated and the organic layers was dried (Na2SO4) and concentrated. The residue was dissolved in THF (80 mL) and cooled to 0 °C. Lithium aluminum hydride (1.52 g, 40 mmol) was added portionwise over 10 min. The mixture v/as stirred at rt for 8 h and an additional equivalent (750 mg) of LAH was added. After 16 h, the mixture was quenched with EtOAc and MeOH and the solids were filtered. The material was purified by SiO2 flash column chromatography to yield the title compound (2.56 g, 64%) as a colorless oil. 1H-NMR (CDCl3): d 7.29 (d, 1H, J= 8.6 Hz), 6.33 (dd, 1H, J = 2.8 Hz), 7.29 (d, 1H, J= 2,8, 8.6 Hz), 3.66 (s, 2H), 2.81 (d, 1H, J= 5.4 Hz), 2.33 (s, 3H). b) {Imino-[4-(2'-methyl-4'-methylamino-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester The procedure in Example 294: step e was followed using (4-bromo-3- methyl-phenyl)-methyl-amine {{Example 262: step a) 600 mg, 3 mmol), palladium acetate (34 mg, 0.15 mmol), and 2- •(dicyclohexylphosphino)biphenyl (210 mg, 0.6 mmol) in dioxane (20 mL). Analogous workup yielded the crude pinacolboronate ester (720 mg, 98%) which was used without further purification. Following the procedure in Example 294: step /the crude boronate (540 mg, 2.1S mmol) was; reacted with {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino- methyl}-carbarmc acid tert-butyl ester {(Example 27: step c) 715 mg, 1.46 mmol), aq Na2CO3 (2M, 4.4 mL, 8.8 mL), and Pd(PPh3)4 (407 mg, 0.37 mmol) in ethanol (4.4 mL) and toluene (8.8 mL). Analogous workup and SiO2 flash column chromatography yielded the title compound (482 mg, 62%) as a yellow glass. 1H-NMR (CDCl3): d 8.0 (s, 1H), 7.95 (m, 1H), 7.90 (m, 1H), 7.55 (m, 1H), 7.51 (m, 1H), 7.05 (m, 1H), 6.53 (m, 2H), 2.9 (s, 3H), 2.56 (s, 3H), 2.56 (s, 3H), 2.22 (s, 3H), 1.52 (s, 9H). c) 4-[2'-Methyl-4'-(N-methyl-guanidino)-biphenyl-3-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine bis-trifluoroacetate The procedure in Example 314 was followed using {imino-[4-(2'- methyl-4'-methylamino-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]- methyl}-carbamic acid tert-butyl ester ({Example 262: step b) 106 mg, 0.2 mmol), HgCl2 (109 mg, 0.4 mmol), l,3-bis-(ferr-butoxycarbonyl)-2-methyi-2- thiopseudourea (116 mg, 0.4 mmol), and DIEA (350 µL, 2 mmol) in DMF (3 mL) at 50 °C. After analogous workup and purification by SiO2 flash column chromatography, the material was treated with 1:1 TFA/DCM as iin Example 1: step d. Purification by HPLC yielded the title compound as a white solid. 1H-NMR. (CD3OD): ft 8.35 (s, 1H), 8.04 (m, 2H), 7.72 (m, 2H), 7.39 (m, 2H), 7.31 (m, 1H), 3.40 (s, 3H), 2.72 (s, 3H), 2.29 (s, 3H). ESI-MS (m/z): Calcd. for C21H23N5O2S3 (M+H); 474.1; found: 474.1. Example 263 6-{N'-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2- methyl-biphenyl-4-yl]-guanidmo} -hexanoic acid a) l,3-bis-(tert-butoxycarbonyl)-l-(trimethylsilylethyl-6-hexanoate)-2- methyl-2-thiopseudourea Diisopropylcarbodiimide (1.72 mL, 11 mmol) was added dropwise to a 0 °C solution of 6-bromohexanoic acid (1.95 g, 10 mmol), trimethylsilylethanol (2.4 g, 20 mmol), and DMAP (122 mg, 1 mmol) in DCM (20 mL). The mixture warmed to rt over 1 h and was allowed to stir at rt for 16h. The solvent was removed in vacuo, the residue was dissolved in EtOAc (100 mL), and the solution was filtered. The solution was extracted with 5% citric acid (3 x 20 mL), NaHCO3 (3 x 20 mL), and brine (30 mL), then was dried over sodium sulfate. Concentration of the solution in vacuo yielded the TMSE ester as a non-viscous oil (2.25 g, 76%) which was used without further purification. 1H-NMR (CDCl3): d 4.16 (m, 2H), 2.41 (s, 3H), 3.41 (t, 2H, J = 6.75 Hz), 2.30 (t, 2H, J= 6.75 Hz), 1.8S (m, 2H), 1.65 (m, 2H), 1.47 (m, 2H). Sodium hydride was added to a 0 °C solution of l,3-bis-(/er/- butoxycarbonyl)-2-methyl-2-thiopseudourea (581 mg> 2 mmol) in DMF (10 mL). After stirring for 30 min at 0 °C, a solution of 2-trimethylsilyethyl-6- bromohexanoate (738 mg, 2.5 mmol) was added and the reaction was warmed to rt. The reaction was stirred at rt for 2 h, 60 "C for 1 h, then at 80 °C for 18 h. The solution was partitioned between EtOAc (120 mL) and water (50 mL) and the layers were separated. The organic layer was extracted with water (8 x 30 mL) and brine (50 mL), then was dried over sodium sulfate. Concentration of the solution followed by SiO2 flash column chromatography yielded the title compound (526 mg, 52%). 1H-NMR (CDCl3): d 4.13 (m, 2H), 2.41 (s, 3H), 2.30 (t, 2H, J= 7.4 Hz), 1.69 (m, 4H), 1.53 (s, 9H), 1.50 (s, 9H), 1.34 (m, 4H), 1.00 (m, 2H). b) 6-{N'-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)- 2-methyl-biphenyl-4-yl]-guanidino}-hexanoic acid Acetic acid (0.5 ml,) was added to a solution of {[4-(4'-amino-2'- methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}- carbamic acid tert-butyl ester ((Example 220: step b) 130 mg, 0.25 mmol) and 1,3-bis-(tert-butoxycarbonyl)-1 -(trimethylsilylethyl-6-hexanoate)-2-methyl-2- thiopseudourea {{Example 263: step a) 245 mg, 0.5 mmol) in MeOH (10 mL). The solution was heated at 40 °C for 24 h. The solvent was removed in vacuo and the residue was purified by SiO2 flash column chromatography to yield the protected guanidine (112 mg, 46%). A portion of the material (15 mg) was treated with 1:1 TFA/DCM as in Example 1: step d. Purification by HPLC yielded the title compound (9.3 mg, 75%) as a white solid. 1H-NMR (CD3OD): d 8.36 (s, 1H), 8.04 (m, 2H), 7.71 (m, 2H), 7.35 (d, 1H, J= S.I Hz), 7.27 (d, 1H, J = 1.9 Hz), 7.22 (dd, 1H, J= 1.9, 8.1 Hz), 3.34 (m, 2H), 2.74 (s, 3H), 2.36 (t, 2H, J= 7.4 Hz), 2.29 (s, 3H), 1.70 (rn, 4H), 1.48 (m, 2H). ESI- MS (m/z): Calcd. for C26H31N5O4S3 (M+H): 574.2; found: 574.2. a) 4-(4-Amino-3-nitro-benzenesulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid methyl ester Sodium sulfite (1.5. g, 11.9 mmol) and NaHCO3 (1.12 g, 13.3 mmol) were dissolved in water (30 mL) and 4-acetylamino-3-nitro-benzenesulfonyl chloride (1.94 g, 7 mmol) was added. Ethanol (10 mL) and the mixture was stirred for 6 h at rt. Aqueous NaOH (10N, 6 mL, 60 mmol) was added and the reaction was heated to 80 °C for 2 h. The solution was brought to pH-8 with cone. HC1, and the solvent was removed in vacua. DMF (15 mL) was added, the mixture was stirred for 15 rnin, and the inorganic salts were then allowed to settle. The DMF was removed via syringe, the salts were washed with a second portion of DMF (10 mL), and the combined DMF solution was slowly added to a 0 °C solution of 4-bromo-5-nitro-thiophene-2-carboxylic acid methyl ester {{Example 114, step c) 931 mg, 3.5 mmol) in DMF (15 mL). The solution was stirred for 0 "C for 1 h then overnight at rt. The DMF was removed in vacuo and the residue was partitioned between EtOAc (100 mL) and aq NaHCO3 (30 mL). The layers were separated and the organic layer was washed with aq NaHCO3 (2 x 20 mL), water (30 mL), and brine (30 mL), then dried over sodium sulfate. The solution was concentrated and the residue was dissolved in THF (20 mL) and cooled to -78 °C. A solution of sodium methoxide in methanol (1M, 7 mL, 7 mmol) was added dropwise and the reaction was stirred for 30 min. Acetic acid (500 µL) was added followed by EtOAc (100 mL). The solution was washed with NaHCO3 (3 x 30 mL), brine (40 mL), and was dried over sodium sulfate. Concentration and chromatography of the residue yielded the title compound (381 mg, 28%) as a yellow solid. 1H-NMR (CDCl3): d 10.56 (br s, 2H), 9.04 (d, 1H, .J= 8.8 Hz), 8.89 (d, 1H, J= 2.3 Hz), 8.22 (dd, 1H, J= 2.3, 9.1 Hz), 8.04 (s, 1H), 3.90 (s, 3H), 2.64 (s, 3H), 2.35 (s, 3H). b) 4-(4-Bromo-3-nitro-benzenesulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid methyl ester The procedure used in Example 318: part c was followed using 4-(4- amino-3-nitro-benzenesulfonyl)-5-memylsulfanyl-thiophene-2-carboxylic acid methyl ester {{Example 264: step a) 100 mg, 0.26 mmol), CuBr2 (73 mg, 0.31 mmol), and tert-butylnitrite (46 µL, 0.39 mmol) in acetonitrile (8 mL total). The title compound (118 mg, 100%) was used without further purification. 1H-NMR (CDCl3): d 8.46 (m, 1H), 8.03 (m, 2H), 7.94 (d, 1H, J'= 8.4 Hz), 3.90 (s, 3H), 2.65 (s, 3H). c) 5-Methylsulfanyl-4-{3-nitro-4-[(pyridin-2-ylmethyl)-amino]- benzenesulfonyl}-thiophene-2-carboxylic acid methyl ester Pyridin-2-yl-methylamine (60 µL), DIEA (175 µL, 1 mmol), and 4-(4- bromo-3-nitro-benzenesulfbnyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 264: step b) 56 mg, 0.12 mmol) were heated at 60 °C in THF (3 mL) for 30 min. The solvent was removed in vacuo and the residue was purified by SiO2 flash column chromatography to yield the title compound (41 mg, 69%). 1H-NMR (CDCl3): 8 9.46 (m, 1H), 8.90 (m, 1H), 8.64 (m, 1H), 8.01 (d, 1H, J = 2.6 Hz), 7.94 (m, 1H), 8.03 (m, 2H);, 7.71 (dt, 1H, J = 1.9, 7.7 Hz), 7.28 (m, 2H), 6.95 (d, 1H, J = 9.0 Hz), 4.67 (d, 1H, J = 5.1 Hz), 3.87 (s, 3H), 2.60 (s, 3H). d) 5-Methylsulfanyl-4-(l-pyridin-2-ylmethyl-lH-benzoimidazole-5- sulfonyl)-thiophene-2-carboxylic acid methyl ester The procedure in Example 318: part e was followed using 5- methylsulfanyl-4-{3-nitro-4-[(pyridin-2-ylmethyl)-amino]-benzenesulfonyl} - thiophene-2-carboxylic acid methyl ester ((Example 264: step c) 41 mg, 0.08 mmol), iron (110 mg, 2 mmol), and EtOH /aq. AcOH, followed by treatment with formic acid to yield the title compound. 1H-NMR (CD3OD): d 8.50 (m, 1H), 8.42 (s, 1H), 8.08 (m, 1H), 7.97 (d, 1H, J = 2.5 Hz), 7.85 (m, 1H), 7.72 (m, 1H), 7.71 (dt, 1H, J = 1.9, 7.7 Hz), 7.57 (m, 1H), 7.29 (m, 1H), 7.22 (d, 1H J = 7.8 Hz), 6.95 (d, 1H, J = 9.0 Hz), 5.57 (s, 2H), 3.82 (s, 3H), 2.56 (s, 3H). e) 5-Methylsulfanyl-4-(l-pyridin -2-ylm ethyl-1H-benzoimidazole-5- sulfonyl)-thiophene-2-carboxamidine bis-trifnoroacetate The procedure in Example 12: step f was followed using 5- methylsulfanyl-4-(l-pyridin-2-ylmethyl-lH-benzoimidazole-5-sulfonyl)- thiophene-2-carboxylic acid methyl ester ((Example 264: step d) 36 nig) and 5 mL (5 mmol) of dimethylaluminum amide solution. Analogous workup and purification yielded the title compound (13.2 mg, 23%) as a white solid. 'H- NMR (CD3OD): d 8.63 (ddd, 1H, J = 0.9, 1.6, 5.35 Hz), 8.58 (m, 1H), 8.34 (s, 1H), 8.19 (dt, 1H, J = 1.6, 7.8 Hz), 8.08 (dd, 1H, J = 1.6, 8.7 Hz), 7.85 (d, 1H, J = 8.7 Hz), 7.69 (m, 1H), 7.66 (m, 1H), 5.98 (s, 1H), 2.72 (s, 3H). ESI-MS (m/z): Calcd. for C19H17N5O2S3 (M+H): 444.1; found: 444.1. Examples 265-266 4-(3-Benzyl-7-bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate and 4-(l-Benzyl-7-brorao-lH- benzoiraidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate a) 4-(3-Benzyl-7-bromo-3H-benzoimidazole-5-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxylic acid methyl ester and 4-(l-Benzyl-7- bromo-lH-benzoimidazole-5-sulfonyl)-S-methylsulfanyl-thiophene-2- carboxylic acid methyl ester The procedure as in Example 39: step a was followed using 4-(7- bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid methyl ester (20 mg, 44.7 µmol, Example 38: step e), benzyl bromide (5.3 µL, 44.7 µmol), K2CO3 (12.4 mg, 89.4 µmol), and DMF (1.5 mL). Removal of the solvents in vacuo was followed by preparative TLC (2-4 % 2.0 M NH3 in methanol/CH2Cl2) to afford a mixture of 4-(3-benzyl-7- bromo-3 H-benzoimidazole-5-sulfonyl)-5-methylsuifanyl-thiophene-2- carboxylic acid methyl ester and 4-(l-benzyl-7-bromo-lH-benzoimidazole-5- sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester compound as a brown oil (27.7 mg, quantitative). This mixture was used directly in the following step. ESI-MS (m/z): Calcd. for C21H17BrN2O4S3: 536 (M+l); found: 538.9. b) 4-(3-Benzyl-7-bromo-3H-benzoimidazole-5-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate and 4-(l- Benzyl- 7-brom o-lH-ben zoim idazole-5-sulfonyl)-5-m ethylsulfanyl- thiophene-2-carboxamidine trifluoroacetate The mixture from Examples 265-266: step a (27.7 mg, 44.7 µmol) was converted to the amidine and purified as described in Examples 39-40: step a to afford the 2 regioisomers: the 3-benzyl (1.6 mg, beige solid) and the 1-benzyl (2.0 mg, white solid). lH-NMR (CD3OD, 3-benzyl): d 9.08 (s, 1H), 8.27 (s, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 7.35-7.45 (m, 5H), 5.70 (s, 2H), 2.58 (s, 3H). ESI-MS (m/z): Calcd. for C20H17BrN4O2S3: 521.0 (M+l); found: 523.0. 1H-NMR (CD3OD, 1-benzyl): 6 S.73 (s, 1H), 8.44 (s, 1H), 8.32 (s, 1H), 8.10 (s, 1H), 7.27-7.37 (m, 3H), 7.06-7.11 (m, 2H), 5.93 (s, 2H), 2.72 (s, 3H). ESI-MS (m/z): Calcd.. for C20H17BrN4O2S3: 521.0 (M+l); found: 523.0. Example 267-268 4-(3-Allyl-7-bromo-3H-berizoimidazole-5-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate and 4-(l-Allyl-7-bromo-3H- benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate a) 4-(3-Allyl-7-bromo-3H-benzoimidazole-5-sulfonyi)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester and 4-(l-Allyl-7-bromo-lH- benzoiinidazole-S-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester The procedure as in Example 39: step a was followed using 4-(7- bromo-3i^-benzoimida2:ole-5-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid methyl ester (2.0 mg, 44.7 jamol, Example 38: step e), ally! bromide (3.9 jiL, 44.7 jimol), K2CO3 (12.4 mg, 89.4 fimol), and DMF (1.5 mL). The crude was purified by preparative TLC (2-4 % 2.0 M NH3 in methanol/CH2Cl2) to afford a mixture of 4-(3-allyl-7-bromo-3H- benzoim.idazole-5-sulfonyl)-5-methylsulfanyl-thiiophene-2-carboxylic acid methyl ester and 4-(l-allyl-7-bromo-lH-benzoimidazole-5-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxylic acid methyl ester as a brown oil (22.4 mg, quantitative). This mixture was used directly in the following step. ESI- MS (m/z): Calcd. for CnH^BrNsCljSa: 486.9 (M+l); found: 488.9. b) 4-(3-Allyl-7-bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate and 4-(3-Allyl-7-bromo-3H- benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate The mixture from Example 267-268: step a (22.4 mg, 44.7 famoi) was converted to the amidine and purified as described in Example 20; step b to afford the 2 regioisomers: the 3-allyl (1.0 mg, beige solid) and the 1-allyl (2.5 mg, beige solid). 1H-NMR (CD3OD, 3-allyl): d 8.54 (s, 1H), 8.31-8.34 (m, 2H), 8.04-8.05 (m, 1H), 6.05-6.14 (m, 1H), 5.33-5.36 (m, 1H), 5.21-5.26 (m, 1H), 5.05-5.0S (m, 2H), 2.71 (s, 3H). ESI-MS (m/z): Calcd. for Ci6H,5BrN4O2S3: 471.0 (M+l); found: 473.0. !H-NMR (CD3OD. 1-allyl): d 8.31-8.55 (m, 3H), 8.05-8.11 (m, 1H), 6.10-6.22 (m, 1H), 4.92-5.32 (m, 4H), 2.72 (s, 3H). ESI-MS (m/z): Calcd. for CieHisBrN^Sj: 471.0 (M+l); found: 473.0. Example 269 4-(7-Bromo-3-phenyl-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate a) 4-(7-Bronw-3-phenyl-3H-benzoimidazole-5-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxylic acid methyl ester 4-(7-Bromo-3-phenyl-3H-benzoimidazole-5-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxylic acid methyl ester was prepared according to literature (Lam, P. Y. S. et al., Tetrahedron Letters, 42:3415 (2C 01)) using 4-(7-broma-3J7-benzoimidazole-5-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester (20 mg, 44.7 µmol, Example 38: step e), phenylboronic acid (1L4 mg, 93.5 µmol), Cu(OAc)2 (8.5 rag, 46.S µmol), pyridine N-oxide (4.7 mg, 49.2 jamol), triethylamine (13jliL, 93.3 µmol), and CH2Cl2 (1.5 mL) in a loosely-capped, 1-dram vial. The reaction mixture was diluted in CH2Cl2 and washed with water and brine. The organic layer was dried over magnesium sulfate. Removal of solvents in vacuo followed by preparative TLC afforded the title compound as a brown oil (12 mg, 51%). ESI-MS (m/z): Calcd. for C20H15BrN2O4S3: 522.9 (M+l); found: 525.0. b) 4-(7-Bromo-3-phenyl-3H-benzoimidazole-5-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate 4-(7-Bromo-3-phenyl-3H-benzoimidazole-5-suifonyl)-5- methylsulfanyl-thiophene-2-carboxylic acid methyl ester (12 mg, 22.9 µmol) was converted to the amidine and purified as described in Example 20: step f to afford the title compound as a beige solid (1.6 mg, 14 %). 1H.-NMR (CD3OD): d S.80 (s, 1H), S. 13-8.32 (m, 3H), 7.63-7.74 (m, 5H), 2.73 (s, 3H). ESI-MS (m/z): Calcd. for C19H15BrN4O2S3: 507.0 (M+l); found: 509.0. Example 2 70-271 4-(7-Bromo-3-cyclopropylmethyl-3H-benz;oimidazole-5-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxainidine trifluoroacetate and 4-(7-Bromo- l-cyclopropylmethyl-lH-benzoimidazole-5-sulfonyl)-5-methylsulfanyl- thiophene-2-c arboxaniidine tri fluoroacetate a) 4-(7-Bromo-3-cyclopropylmethyl-3H-benzoimidazole-5-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxylic acid ethyl ester The procedure as in Example 39: step a was followed using 4-(7- bromo-3/f-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid ethyl ester (100 mg, 0.217 mmol, Example 38: step e), (bromomethyl)cyclopropane (21 µL, 0.217 mmol), K2CO3 (60 mg, 0.434 mmol), and DMF (3 mL). The crude was purified by preparative TLC (2-4 % 2.0 M NH3 in methanol/CH2Cl2) to afford a mixture of 4-(7-bromo-3- cyclopropylmethyl-3H-beniioimidazole-5-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid ethyl ester and 4-(7-bromo-l-cyclop.ropylmethyl- lH-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester as a brown oil (72 mg, 64 %). This mixture was used directly in the following step. ESI-MS (m/z): Calcd. for C18H17BrN2O4S3: 515 (M+l); found: 516.9. b) 4-(7-Bromo-3-cyclopropylmethyl-3H-benzoimidazole-5-tnilfonyl)-5- methylsulfanyl-thiophene-2-earboxamidine trifliioroacetate and 4-(7- Bromo-l-cyclopropylmethyl-lH-benzoimidazole-S-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxamidine trifluoloacetate The mixture from Examples 270-271: step a (72 mg, 0.14 mmoi) was converted to the amidine and purified as described in Examples 39-40: step b to afford 2 regioisomers: the 3-cyclopropylmethyl (3-CPM) (2.S mg, beige solid) and the 1-cyclopropylmethyl (1-CPM) (3,3 mg, beige solid). 1H-NMR (CD3OD, 3-CPM): d 8.63 (s, 1H), 8.40 (d, 1H, J = 1.40 Hz), 8.35 (s, 1H), 8.05 (d, 1H, J= 1.40 Hz), 4.27 (d, 2H, J= 7.21 Hz), 2.72 (s, 3H), 135-1.42(m, 1H), 0.68-0.73 (m, 2H), 0.5-0.54 (m, 2H). ESI-MS (m/z): Calcd. for C17H17BrN4O2S3: 485.0 (MM); found: 4S7.0. 1H-NMR (CD3OD, 1-CPM): d 8.55 (s, 1H), 8.37-8.38 (m, 1H), 8.34 (s, 1H), 8.10-8.11 (m, 1H)7 4 52 (d, 2H, J= 7.21 Hz), 2.72 (s, 3H), 1.43-1.51 (m, 1H), 0.62-0.67 (m, 2H), 0.47- 0.52 (m, 2H). ESI-MS (m/z): Calcd. for C17H17BrN4O2S3: 485.0 (M+1); found: 487.0. Examples 272-273 4-[7-Bromo-3-(2,6-dichloro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate and 4-[7-Bromo- l-(2,6-dichloro-benzyl)-lH-benzoimidazole-5-sulfonyl]-5-methylsulfanyl- thiophene- 2-carboxamidine tif luoroacetate a) 4-[7-Bromo-3-(2,6-dichloro-benzyl)-3H-benzoimidazole-5-sulfonyl]- 5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester and 4-[7-Bromo-1- (2,6-dichloro-benzyl)-lH-benzoimidazole-5-sulfonyl]-5-methylsulfanyl- thiophene-2-carboxylic acid ethyl ester The procedure as in Example 39: step a was followed using 4-(7- bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid ethyl ester (100 nig, 0.217 minol, Example 38: step e), 2- bromomethyl-l,3-dichloro-benzene (52 mg, 0.217 mmol), K2CO3 (60 mg, 0.434 mmol), and DMF (3 mL). The crude was purified by preparative TLC (2-4 % 2.0 M NH3 in methanoly/CH2Cl2) to afford a mixture of 4-[7-bromo-3- (2,6-dichloro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl- thiophene-2-carboxylic acid ethyl ester and 4-[7-bromo-l-(2.6-dichloro- benzyl)-lH-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophene-2- carboxylic acid ethyl ester as brown oil (70 mg, 52.2 %). This mixture was used directly in the following step. ESI-MS (m/z): Calcd. for C21H,5BrCl2N2O4S3: 618.9 (M+1); found: 620.9. b) 4-[7-Bromo-3-(2,6-dichloro-benzyl)-3H-benzoimidazole-5-snlfonyl]- 5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate and 4-[7- Bromo-l-(2,6-dichloro-benzyl)-lH-benzoimidazole-5-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidiiie tifluoroacetate The mixture from Examples 272-273: step a (70 mg, 0.11 mmol) was converted to the amidine and purified as described in Examples 39-40: step b to afford 2 regioisomers: the 3-(2,6-dichlorobenzyl) (3-DCB) (2.5 mg, beige solid) and the l-(2,6-dichlorobenzyl) (1-DCB) (2.2 mg, beige solid). 1H-NMR (CD3OD, 3-DCB): d 8.58 (s, 1H), 8.30-8.33 (m, 2H), 8.00 (d, 1H, J= 1.63 Hz), 7.55-7.58 (m, 2H), 7.44-7.49 (m, 1H), 5.90 (s, 2H), 2.64 (s, 3H). ESI-MS (m/z): Calcd. for C20H15BrCl2N4O2S3: 588.9 (M+1); found: 590.9. ]H-NMR (CD3OD, 1-DCB): § 8.34-8.40 (m, 2H), 8.16-S.1S (m, 1H), 7.86-7.90 (m, 1H), 7.46-7.60 (m, 3H), 6.22 (s, 2H), 2.64 (s, 3H). ESI-MS (m/z): Calcd. for C20H15BrCl2N4O2S3: 588.9 (M+1); found: 590.9. Examples 274-275 4-[7-Bromo-3-(2,5-difluoro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidme trifluoroacetate and 4-[7-Bromo- l-(2,5-difluoro-benzyl)1H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl- tWophene-2-carboxamidine trifluoroacetate a) 4-[7-Bromo-3-(2,5-difluoro-benzyl)-3H-benzoimidazole-5-sulfonyl]- 5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester and 4-[7-Bromo-l- (2,5-difluoro-benzyl)1H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl- thiophene-2-carboxylic acid ethyl ester The procedure as in Example 39: step a was followed using 4-(7- bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid ethyl ester (100 mg, 0.217 minol, Example 3S: step e), 2- bromomethyl-l,4-difluoro-benzene (28 µL, 0.217 mmol), K2CO3 (60 mg, 0.434 nµmol), and DMF (3 mL). The crude was purified by preparative TLC (2-4 % 2.0 M NH3 in methanol/CH2Cl2) to afford a mixture of 4-[7-bromo-3- (2,5-difluoro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl- thiophene-2-carboxylic acid ethyl ester and 4-[7-bromo-l-(2,5-difluoro- benzyl)1H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophene-2- carboxylic acid ethyl es;ter as a brown oil (70 mg, 55 %).. This mixture was used directly in the next step. ESI-MS (m/z): Calcd. for C21H15BrF2N2O4S3: 586.0 (M+1); found: 588.9. b) 4-[7-Bromo-3-(2,5-diftuoro-benzyl)-3H-benzoimidazole-5-sulfonyl]- 5-methylsulfanyl-thiophene-2-carboxamiditte trifluoroacetate and 4-[7- Bromo-l-(2,5-difluoro-benzyl)1H-benzoimidazole-5-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidwetrifluoroacetate The mixture from Examples 274-275: step a (70 mg, 0.12 mmol) was converted to the amidine and purified as described in Examples 39-40: step b to afford 2 regioisomers: the 3-(2,5-difluorobenzyl) (3-DFB) (3.0 mg, white solid) and the l-(2,5-difluorobenzyl) (1-DFB) (3.2 mg, white solid). 1H-NMR (CD3OD, 3-DFB): d 8.58 (s, 1H), 8.30-S.33 (m, 2H), 8.00 (d, IB., J = 1.63 Hz), 7.55-7.58 (m, 2H), 7.44-7.49 (m, 1H), 5.90 (s, 2H), 2.64 (s, 3H). ESI-MS (m/z): Calcd. for C2oHi5BrCl2N402S3: 588.9 (M+1); found: 590.9. 1H-NMR (CD3OD, 1-DFB): d 8.57 (s, 1H), 8.41-8.45 (m, 1H), 8.32-8.36 (m, 1H), 8.07- S.ll (m, 1H), 7.05-7.27 (m, 2H), 6.43-6.54 (m, 1H), 5.94 (s, 2H), 2.72 (s, 3H). ESI-MS (m/z): Calcd. for C20H15BrCl2N4O2S3: 588.9 (M+1); found: 590.9. Examples 276-277 4-[7-Bromo-3-(2,6-difluoro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5- methylsulfanyl-thiophene-2-cai-boxamidine trifiuoroacetate and 4-[7-Bromo- l-(2,6-difluoro-benzyl)1H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate a) 4-[7-Brom o-3-(2,6-difluoro-benzyl)-3H-benzoimidazole-5-sulfonyl]- 5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester and 4-[7-Bromo- l-(2,6-difluoro-benzyl)1H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester The procedure as in Example 39: step a was followed using 4-(7- bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid methyl ester (50 mg, 0.11 rrµmol, Example 38: step e), 2- bromomethyl-l,3-difluoro-benzene (23 mg, 0.11 mmol), K2CO3 (31 mg, 0.22 mmol), and DMF (1.5 mL). The crude was purified by preparative TLC (2-4 % 2.0 M NH3 in methano]yCH2Cl2) to afford a mixture of 4-[7-bromo-3-(2,6- difluoro-benzyl)-3H-benzoi:tnidazole-5-sulfonyl]-5-methylsulfanyl-thiophene- 2-carboxylic acid methyl ester and 4-[7-bronio-l-(2,6-difluoro-benzyl)1H- benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester as a brown oil (67 mg, quantitative). ESI-MS (m/z): Calcd. for C21H15BrF2N2O4S3: 572.9 (M+1); found: 574.9. b) 4-[7-Bromo-3-(2,6-difluoro-benzyl)-3H-benzoimidazole-5-sulfonyl]- 5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate and 4-[7- Bromo-l-(2,6-difluoro-benzyl)1H-benzoiniidazole-5-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate The mixture from Examples 276-277: step a (67 mg, 0.11 rrunol) was converted to the amidine and purified as described in Example 39-40: step a to afford 2 regioisomers: the 3-(2,6-difluorobenzyl) (3-DFB) (3.5 mg. beige solid) and the l-(2,6-difluorobenzyl) (1-DFB) (1.6 mg? white solid). 1H-NMR (CD3OD, 3-DFB): d 8.64 (s, 1H), 8.31-S.35 (m, 2H), 8.02 (s, 1H). 7.45-7.54 (m, 1H), 7.08-7.14 (m, 2H), 5.74 (s, 2H), 2.65 (s, 3H). ESI-MS (m/'z): Calcd. for C20H15BrF2N402S3: 556.0 (M+1); found: 559.0. 1H-NMR (CD3OD, 1-DFB): d 8.42 (s, 1H), 8.35-S.37 (m, 1H), 8.32 (s, 1H), 7.39-7.4S (m, 1H), 6.99-7.06 (m, 1H), 7.03 (t, 2H, J= 8.34), 6.02 (s, 2H), 2.71 (s, 3H). ESI-MS (m/z): Calcd. for C20H15BrF2N4O2S3: 556.0 (M+1); found: 559.0. Example 278 6-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-(4- carboxy-butyrylamino)-6-methyl-biphenyl-4-yl]-ureido}-hexanoic acid trifluoroacetate a) 6-[3-(4-Bromo-3-methyl-5-nitro-phenyl)-ureido]-hexanoic acid ethyl ester 6-Isocyanato-hexanoic acid ethyl ester (370 p.L, 2.16 mmol) was added to a solution of 4-bromo-3-methyl-5-nitro-phenylamine (250 mg, 1.08 mmol, Example 135: step a) in CH2Cl2 (5 mL, anhydrous) at rt. The reaction mixture was stirred overnight, then diluted in EtOAc and washed with saturated NH4Cl solution, water, and brine. The organic layer was dried over magnesium sulfate. Removal of solvents in vacuo was followed by flash chromatography (50-75% EtOAc/hexanes) to afford the title compound as a brown oil (162 mg, 36%). 1H-NMR (CDCl3): d 7.59 (d, 1H, J = 2.56 Hz), 7.42-7.48 (m, 1H), 4.10-4.17 (m, 2H), 3.20-3.28 (m, 2H), 2.39 (s, 3H), 2.29-2.35 (m, 2H), 1.47- 1.68 (m, 4H), 1.23-1.41 (m, 5H). b) 6-(3-{3'-[5-(tert-Buioxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-2-nitro-biphenyl-4-yl}- ureido)-hexanoic acid ethyl ester A 25 mL round bottom flask was charged with 6-[3-(4-bromo-3- methyl-5-nitro-phenyl)-ureido]-hexanoic acid ethyl ester (110 mg, 0.264 mmol, Example 278: step a), {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5- methylsulfanyl-tbiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (234 mg, 0.529 mmol, Example 140: step a), aqueous Na2CCh (2M, 1.06 mL, 2.12 mmol), ethanol (1.06 mL, anhydrous) and toluene (2.11 mL, anhydrous). A stir bar was added, the solution was degassed for 10 min, and Pd(PPh3 )4 (76 mg, 65.8 µmol) was added. The reaction mixture was stirred under Ar at 80 ° C for 5 hrs, then cooled to rt. The solvents were removed in vacuo. The residue was diluted in EtOAc, washed with brine, and dried over magnesium sulfate. Removal of solvents in vacuo followed by preparative TLC (50-100% EtOAc/hexanes) afforded the title compound as a brown oil (74 mg, 37%). ESI-MS (m/z): Calcd. for C33H41N5O9S3: 748.2 (M+1); found: 747.8. c) 6-(3-{2-Amino-3'-[5-(tert-butoxycarbonylamino-imino-methyl)-2- methylsnlfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-4-yl}-ureido)- hexanoic acid ethyl ester 6-(3- {3'-[5-(/e/t-Butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-2-nitro-biphenyl-4-yl}- ureido)-hexanoic acid ethyl ester (74 mg, 98.9 µmol, Example 278: step b) in EtOH (5 mL) was reduced as in Example 20: step c using Fe (28 mg, 0.50 mmol) and aqueous NH4Cl solution (50 mg, 0.93 mmol, 10 mL). The solvents were removed from the filtrate in vacuo. The crude was diluted in EtOAc and washed with water and brine. The organic layer was dried over magnesium sulfate. The solvents were removed in vacuo to yield the title compound as a brown oil (70.8 mg, quantitative). ESI-MS (m/z): Calcd. for C33H43N5O7S3: 718.2 (M+1); found: 718,1. d) 6-{3-[3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-2-(4-methoxycarbonyl-butyrylamino)- 6-methyl-biphenyl-4-yl]-ureido}-hexanoic acid ethyl ester 4-Chlorocarbonyl-butyric acid methyl ester (20.4 µL, 0.148 mmol) was added to a solution of 6-(3-{2-amino-3'-[5-(re;-r-butoxycarbonylamino-imino- methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-4-yl}- ureido)-hexanoic acid ethyl ester (70.8 mg, 96.4 µmol, Example 278: step c) and triethylamine (41.2 µL, 0.296 nimol) in CH2Cl2 (5 mL, anhydrous) at rt. The reaction mixture was stirred overnight at rt, then diluted in EtOAc, washed with water and brine, and dried over magnesium sulfate. Removal of solvents in vacuo followed by flash chromatography (75-100 % EtOAc/hexanes) yielded the title compound as a brown oil (45.5 mg, 54.5%). ESI-MS (m/z): Calcd. for C39H51N5O10S3: 846.3 (M+1); found: 845.9. e) 6-{3-[3'-[5-(tert-Butoxycarbonylamino-imitw-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-2-(4-carboxy-butyrylamino)-6-methyl- biphenyl-4-yl]-ureidoj-hexanoic acid Lithium hydroxide (53.8 \|U.L, 0.215 mmol. 4N aqueous) was added to a solution of 6-{3-[3'-[5-(tert-butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-2-(4-methoxycarbonyl-butyrylamino)-6- methyl-biphenyl-4-yl]-ureido}-hexanoic acid ethyl ester (45.5 mg, 53.8 µmol, Example 278: step d) in MeOH/H2O (10 mL, 2:1) at 0 °C. The reaction mixture was warmed to rt and stirred overnight. The solvents were removed in vacuo to afford the title compound as a yellow solid (50 mg, quantitative). ESI-MS (m/z): Calcd. for C36H45N5O10S3: 804.2 (M+1); found: 803.9. f) 6-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-$ulfonyl)- 2-(4-carboxy-butyrylamino)-6-inethyl-biphenyl-4-yl]-ureido}-hexanoicacid trifluoroacetate 6-{3-[3'-[5-(te7t-ButoxycarbonylaiTiino-iinino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-2-(4-carboxy-butyrylamino)-6-methyl- biphenyl-4-yl]-ureido}-hexanoic acid (43.2 mg, 53.7 (imol, Example 278: step e) was deprotected and purified as in Example 1: step d to afford the title compound as a white solid (15 mg, 40 %). 1H-NMR (CD3OD): d 8.27 (s, 1H), 8.00-8.04 (m, 1H), 7.87-7.89 (m, 1H), 7.63-7.71 (m, 1H). 7.49-7.54 (m. 1H), 7.32-7.35 (m, 1H), 7.25-7.26 (m, 1H), 3.22 (t, 2H, J= 6.98 Hz), 2.73 (s, 3H), 2.34 (t, 2H, J = 7.44 Hz), 2.05 (s, 3H), 1.88-2.03 (m, 4H). 1.54-1.71 (m, 4H), 1.34-1.48 (m, 4H). ESI-MS (m/z): Calcd. for C31H37N5O8S3: 704.2 (M+1); found: 704.1. Example 279 6-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-(4- methanesulfonyl-butyrylamino)-6-methyl-biphenyl-4-yl]-ureido}-hexanoic acid trifluoroacetate a) 6-{3-[3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-2-(4-methanesulfonyl-butyrylamino)- 6-methyl-biphenyl-4-yl]-ureido}-hexanoic acid ethyl ester The procedure as in Example 278: step d was followed using 6-{3-[3'- [5-(tert-butoxycarbonylamino-imino-rnethyl)-2-rnethylsulfanyl-thiophene-3- sulfonyl]-2-(4-methanesulfonyl-butyrylamino)-6-methyl-biphenyl-4-yl]- ureido}-hexanoic acid ethyl ester (39 mg, 54.3 µmol, Example 278: step b), triethylamine (22.7 µL, 0.163 mmol), 4-methanesulfonyl-butyryl chloride (15 mg, 81.5 µmol, Example 209: step a), and CH2C12 (3 mL, anhydrous). The reaction mixture was diluted in EtOAc, washed with water and brine, and dried over magnesium sulfate. The solvents were removed in vacuo to afford the title compound as a brown oil (48 mg, quantitative). ESl-MS (m/z): Calcd. for C38H51N5O10S4: 866.3 (M+1); found: 865.8. b) 6-{3-[3'-[5-(tert-Butoxycarbonylamwo-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-2-(4-methanesulfonyl-buty}ylanrino)- 6-methyl-biphenyl-4-yl]-ureido}-hexanoic acid The procedure as in Example 278: step e was followed using 6-{3-[3'- [5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3- sulfonyl]-2-(4-methanesulfonyl-butyrylamino)-6-methyl-biphenyl-4-yl]- ureido}-hexanoic acid ethyl ester (48 mg, 54.3 µmol, Example 279: step a) in a MeOH/H2O (2:1) solution and 4N LiOH (54.3 µL, 0.217mmol). The crude was taken on directly to the next step. ESI-MS (m/z): Calcd. for C36H47N5O10S4: 838.2 (M+1); found: 837.8. c) 6-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)- 2-(4-methanesulfonyl-butyrylamino)-6-methyl-biphenyl-4-yl]-ureido}- hexanoic acid trifluoroacetatc 6-{3-[3'-[5-(rer/-Butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-2-(4-methanesulfonyl-butyrylamino)-6- methyl-biphenyl-4-yl]-ureido}-hexanoic acid (45.5 mg, 54,3 µmol, Example 279; step b) was deprotected and purified as in Example 1: step d to afford the title compound as a beige solid (10 mg, 25 %). 1H-NMR (CD3OD): d 8.30 (s, 1H), 8.01-8.05 (m, 1H), 7.86-7.89 (m, 1H), 7.68 (t, 1H, J = 7.91 Hz), 7.52- 7.57 (m, 1H), 7.23-7.37 (m:, 2H), 3.23 (t, 2H, J=- 6.98 Hz), 2.92 (s, 3H), 2.80 (t, 2H, J= 7.68 Hz), 2.74 (s, 3H), 2.34 (t, 2H, J= 7.44 Hz), 2.18 (t, 2H, J = 7.21 Hz), 2.05 (s, 3H), 1.72-1.79 (m, 2H), 1.63-1.71 (m, 2H), 1.54-1.62 (m, 2H), 1.39-1.47 (m, 2H). ESI-MS (m/z): Calcd. for C31H39N5O8S4: 738.2 (M+1); found: 738.1. Example 280 4-{2'-Methy]-4'-[N'-(3-phenyl-propyl)-guanidino]-biphenyl-3-sulfonyl}-5- methylsulfanyl-thiophene-2-carboxamidine bistrifluoroacetate a) l,3-bis(tert-butoxycarbonyl)-3-(3-phenylpropyl)-2-methyl-2- thiopseiidourea Sodium hydride (95.Smg, 2.40 mmol, 60% dispersion in mineral oil) was added to a solution of l,3-bis(tert-butoxycarbonyl)-2-rnethyl-2- thiopseudourea (580 mg, 2.0 mmol) in DMF (4 mL, anhydrous) at 0 °C in 2 portions. The reaction mixture was stirred for 10 rain, at 0 °C, then (3-bromo- propyl)-benzene (607 µL, 3.99 mmol) was added and the reaction mixture was heated to 60 °C for 16 hr". The reaction mixture was cooled to rt, diluted in EtOAc, and washed with water and brine. The organic layer was dried over magnesium sulfate. Removal of solvents in vacuo was followed by preparatory TLC (5-10% EtOAc/hexanes) to afford the title compound as a pale yellow oil (310 mg, 38%). 1H-NMR (CDCl3): d 7.16-7-30 (m, 5H), 3.53- 3.58 (m, 2H), 2.62-2.66 (m, 2H), 2.38 (s, 3H), 1.95-2.05 (m, 2H), 1.5 (s, 9H), 1.46 (s,9H). b) 4-{4'-[N\N' - bis(tert-butoxycarbonyl)-N'-(3-phenyl-propyl)- guanidino]-2'-methyl-biphenyl-3-sulfonyl}-N-methyl-5-methylsulfanyl- thiophene-2-carboxamidine {[4-(4'-Amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (40 mg, 77.3 µmol, Example 220: step b) and l,3-bis(tert-butoxycarbonyl)-3-(3- phenylpropyl)-2-methyl-2-thiopseudourea (63 mg, 0.154 mmol. Example 280: step a) were dissolved in 5 % acetic acid/MeOH (1.5 mL) solution and heated to 40 ° C overnight. The reaction mixture was cooled to it and the solvents were removed in vacuo. The crude was purified by preparative TLC (5-10 % EtOAc/CH2Cl2) to afford the title compound as a red oil (26.9 mg. 40%). ESI- MS (m/z): Calcd. For C44H55N5O8S3: 878.3 (M+1); found: 877.9. c) 4-{2'-Methyl-4'-[N'-(3-phenylpropyl)-guanidino]-biphenyl-3- sulfonyl}-5-methylsulfanyl-thwphene-2-carboxamidinebistrifluoroacetate 4-{4'-[N',N"- bis(toY-Butoxycarbonyl)-N'-(3-phenyl-propyl)- guanidino]-2'-methyl-biphenyl-3-sulfonyl}-N-methyl-5-methylsulfanyl- thiophene-2-carboxamidine (26.9 mg, 30.6 {imol, Example 280: step b) was deprotected and purified as in Example 1: step d to afford the title compound as a white solid (11 mg, 62 %). 1H-NMR (CD3OD): d 8.34 (s, 1H), S.00-8.04 (m, 2H), 7.69-7.73 (m, 2H), 7.17-7.34 (m, 8H), 3.30-3.34 (m, 2H), 2.71-2.76 (m, 5H), 2.27 (s, 3H), 1.93-2.02 (m, 2H). ESI-MS (m/z): Calcd. for C29H3JN5O7S3: 578.2 (M+1); found: 57S.2. Example 281 4-[2'-Methyl-4'-(N'-phenethyl-guanidino)-biphenyl-3-sulfony]]-5- methylsulfanyl-thiophene-2-carboxamidine bistrifluoroacetate a) l,3-bis(tert-butoxycarbonyl)-3-(3-phenylethyl)-2-methyl-2- thiopseudourea The procedure as in Example 280: step a was followed using 1,3- bis(re/'/-butoxycarbonyl)-2-methyl-2-thiopseudourea (580 mg, 2.0 mmol), NaH (95.8mg, 2.40 mmol, 60% dispersion in mineral oil), (2-iodo-ethyl)- benzene (578 yiL, 3.99 mmol), and DMF (4 mL, anhydrous). The reaction mixture was cooled to rt, diluted in EtOAc, and washed with water and brine. The organic layer was dried over magnesium sulfate. Removal of solvents in vacuo was followed by preparatory TLC (5-10% EtOAc/hexanes) to afford the title compound as a pale yellow oil (146 mg, 19%). 1H-NMR (CDCl3): d 7.18-7.33 (m, 5H), 3.71-3.75 (m, 2H), 2.96-3.01 (m, 2H), 2.37 (s, 3H), 1.51 (s,9H), 1.49(s,9H). b) ({4-[4'-(N',N"-bis(tert-butoxycarbonyl)-N'-phenethyl-guanidino)-2'- methyl-biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)- carbamic acid tert-butyl ester The procedure as in Example 280: step b was followed using {[4-(4'- amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino- methyl}-carbamic acid tert-butyl ester (40 mg, 77.3 µmol, Example 220: step b), l,3-bis(tert-butoxycarbonyl)-3-(3-phenylethyl)-2-methyl-2-thiopseudourea (61 mg, 0.155 mmol, Example 281: step a), and 5 % acetic acid/MeOH (1.5 mL) solution. The reaction mixture was cooled to rt, then concentrated in vacuo. The crude was purified by preparative TLC (5-10 % EtOAc/CH:Cl2) to afford the title compound as a red oil (31.5 mg, 47%). ESI-MS (m/z): Calcd. for C13H53N5O8S3: 864.3 (M+1); found: 863.9. c) 4-[2f-Methyl-4'-(N'-phenethyl-guaniduw)-biplienyl-3-sulfonylJ-5- methylsulfanyl-thiophene-2-carboxamidine bistrifluoroacetate ({4-[4'-(N',N"-bis(tert-butoxycarbonyl)-N'-phenethyl-guanidino)-2'- methyl-biphenyl-3-suIfbnyl] -5-rnethy3sulfanyl-thiophen-2-yl} -imino-methyl)- carbamic acid tert-butyl ester (31.5 mg, 36.5 µmol, Example 281: step b) was deprotected and purified as in Example 1: step d to afford the title compound as a white solid (14.2 mg, 68.9 %). 1H-NMR (CD3OD): d 8.34 (s, ] H), 7.99- 8.05 (m, 2H), 7.65-7.72 (m, 2H), 7.24-7.39 (m, 6H), 7.03-7.09 (m, 2H), 3.60 (t, 2H, J= 7.02 Hz), 2.96 (t, 2H, J= 7.02 Hz), 2.72 (s, 3H), 2.23 (s, 3H). ESI- MS (m/z): Calcd. for C28H29N5O2S3: 564.2 (M+1); found: 564.2. Example 282 4-{21-Methy]-4'-[N'-(3-methy]-butyl)-guanidino]-bipheny]-3-sulfonyl]}-5- methylsulfanyl-thiophene-2-carboxamidinebistrifluoroacetate a) l,3-bis(tert-butoxycarbonyl)-3-(3-phetiylethyl)-2-methyl-2- thiopseudonrea The procedure as in Example 280: step a was followed using 1,3- bis(te/t-butoxycarbonyl)-2-methyl-2-thiopseudourea (580 mg, 2.0 mmol), NaH (95.8mg, 2.40 mmol, 60% dispersion in mineral oil), l-iodo-3-methyl- butane (528 \xL, 3.99 mmol), and DMF (4 mL, anhydrous). The reaction mixture was cooled to rt, diluted in EtOAc, and washed with water and brine. The organic layer was dried over magnesium sulfate. Removal of solvents in vacuo was followed by preparatory TLC (5-10% EitOAc/hexanes) to afford the title compound as a pale yellow oil (235 mg, 33%). 1H-NMR (CDCl3): d 3.49-3.56 (m, 2H), 2.39 (s, 3H), 1.52-1.60 (m, 3H), 1.51 (s, 9H), 1.48 (s, 9H), 0.89-0.94 (m, 6H). b) 4-{4 r-[N',N'-bis(tert-butoxycarbonyl)-N'-(3-methyl-butyl)- guamdino]-2'-methyl-biphenyl-3-sulfonyl}-N-tert-butoxycarbonyl-S- m ethylsulfanyl-th ioph en e-2-carboxant idin e The procedure as in Example 280: step b was followed using {[4-(4'- amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino- methyl}-carbamic acid tert-butyl ester (40 mg, 77.3 µmol, Example 220: step b), l,3-bis(tert-butoxycarbonyl)-l-(3-methylbutyl)-2-methyl-2-thiopseudourea (56 mg, 0.155 mmol, Example 282: step a), and 5 % acetic acid/MeOH (1.5 mL) solution. The reaction mixture was cooled to rt, then concentrated in vacuo. The crude was purified by preparative TLC (5-10 % EtOAc/CH:Cl2) to afford the title compound as a red oil (29.2 nig, 46 %). ESI-MS (m/z): Calcd. forC40H55N5O8S3: 830.3 (M+1): found: 829.9. c) 4-{2'-Methyl-4'-[N'-(3-phenyl-propyl)-guanidino]-biphenyl-3- sulfonylf-5-m ethylsulfanyl-thiophene-2-carboxamidine bistrifluoroacetate 4-{4'-[N',N"-bis(/erf-Butoxycarbonyl)-N'-(3-methyl-butyl)-guanidino]- 2'-methyl-biphenyl-3-sulfonyl}-N-te7-r-butoxycarbonyl-5-methylsulfanyl- thiophene-2-carboxamidine (29.2 mg, 35.2 jimol, Example 282: step b) was deprotected and purified as in Example 1: step d to afford the title compound as a white solid (13.6 mg, 73 %). 1H-NMR (CD3OD): d 8.34 (s, 1H), 8.00- 8.05 (m, 2H), 7.67-7.73 (m, 2H), 7.18-7.34 (m, 3H), 3.30-3.34 (m, 2H), 2.72 (s, 3H), 2.27 (s, 3H), 1.66-1.79 (m, 1H), 1.52-1.59 (m, 2H), 0.99 (d, 6H, J = 6.64 Hz). ESI-MS (m/z): Calcd. for C25H31N5O2S3: 530.2 (M+1); found: 530.2. Example 283 4-(5-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfanyl)-4- guanidino-6-methyl-biphenyl-2-yl]-ureido}-pentyloxy)-benzoic acid bistrifluoroacetate a) 4-[5-(l,3-Dioxo-l,3-dihydro-isoindol-2-yl)-petityloxy]-benzoic acid methyl ester A mixture of 4-hydroxy-benzoic acid methyl ester (3.01 g, 19 8 mmol), 2-(5-bromo-pentyl)-isoindole-l,3-dione (3.9 g, 13.2 rnmol), and K1CO3 (1.82 g, 13.2 rnmol) in acetone (150 mL) was heated to reflux for 24 hrs. The reaction mixture was cooled to rt and the solvents were removed in vacuo. The crude was diluted in EtOAc: and washed with 1N NaOH and brine. The organic layer was dried over sodium sulfate. The solvents were removed in vacuo. The crude was recrystallized from EtOAc to afford the title compound as a white solid (4 g, 83%). 1H-NMR (CDCh): d 7.95-7.98 (m, 2H), 7.83- 7.86 (m, 2H), 7.70-7.73 (m, 2H), 6.86-6.89 (m, 2H), 4.00 (t, 2H, J= 6.22 Hz), 3.88 (s, 3H), 3.73 (t, 2H? J = 7.29 Hz), 1.82-1.89 (m, 2H), 1.73-1.81 (m, 2H), 1.50-1.57 (m,2H). b) 4-(5-Amino-pentyfoxy)-benzoic acid methyl ester A suspension of 4-[5-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)- pentyloxy]-benzoic acid methyl ester (1 g, 2.72 mmol, Example 283: step a) and hydrazine (98.4µL, 3.13 rnmol) in MeOH:H2O (10 mL, 4:1) was heated to 65 °C for 2 hrs. Additional hydrazine was added (171 µL, 5.44 mmol) to the reaction mixture at rt. The reaction mixture was heated to 70 °C for 2 hrs then stirred overnight at it. Potassium carbonate (30 mL, IN aqueous) and methylene chloride (200 mL) were added to the reaction. The organic layer was dried over magnesium sulfate. The solvents were removed in vacuo to afford the title compound as a white solid (500 mg, 77%). 1H-NMR (CDCl3): d 7.95-8.00 (m, 2H), 6.88-6.92 (m, 2H), 4.02 (t, 2H, J = 6.43 Hz), 3.88 (s, 3H), 2.71-2.76 (m, 2H), 1.79-1.86 (m, 2H), 1.49-1..56 (m, 411). c) 4-(5-{3-[3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-4-(2-trimethylsilanyl- ethoxycarbonylamino)-biphenyl-2-yl]-ureido}-pentyloxy)-benzoic acid methyl ester 4-Nitrophenyl chloroformate (99.2 mg, 0.49 mmol) was added to a solution of {2-amino-3"-[5-(tert-butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-bi.phenyl-4-yl}-carbamic acid 2-trimethylsilanyl-ethyl ester (303 mg, 0.45 mmol. Example 294: step i) and pyridine (39.8 p.L, 0.49 mmol) in methylene chloride (5 mL) at rt. The reaction mixture was stirred for 2 hrs at rt. 4-(5-Arnino-pentyloxy)-benzoic acid methyl ester (117 mg, 0.49 mmol, Example 283: step b) and triethylamine were added to the reaction mixture and stirred for 2 hrs at rt. The reaction mixture was diluted in EtOAc, washed with water and brine, and dried over magnesium sulfate. Removal of solvents in vacuo was followed by flash chromatography (50-60% EtOAc/hexanes) to afford the title compound as a yellow solid (280 mg, 66.5%). ESI-MS (m/z): Calcd. for C44H57N5O10S3Si: 940.3 (M+1); found: 939.9. d) 4-(5-{3-[3'-[5-(tert-Butoxycarbonylamino-imiuo-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-4-(2-trimethylsilaiiyl- e.thoxycarbonylamino)-biphenyl-2-yl]-ureido}-pentyloxy)-benzoic acid Lithium hydroxide (45.8 mg, 2.08 mmol) was added to a solution of 4- (5-{3-[3'-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl- thiophene-3-sulfonyl]-6-methyl-4-(2-trimethylsilanyl-ethoxycarbonylamino)- biphenyl-2-yl]-ureido}-pentyloxy)-benzoic acid methyl ester (280 mg, 0.298 mmol. Example 283: step c) in l,4-dioxane:water (10 mL, 2:1) over 2 days at rt. The solvents were removed in vacuo. The residue was diluted in water, acidified to pH - 5 with acetic acid, and extracted with EtOAc. The organic layer was washed with brine and dried over magnesium sulfate. The solvents were removed in vacuo to afford the title compound as a yellow solid (276 mg, quantitative). 1H-NMR (CDCI3/CD3OD): d 7.93-7.99 (m, 3H), 7.83-7.S6 (m, 2H), 7.52-7.59 (m, 2H), 7.15-7.20 (m, 2H), 6.85-6.89 (m, 2H), 4.21-4.26 (m, 2H), 3.99 (t, 2H, J = 6.43 Hz), 3.13-3.24 (m, 2H), 2.61 (s; 3H), 2.02 (s, 3H), 1.75-1.83 (m, 2H), 1.43-1.56 (m, 13H), 1.02-1.08 (m, 2H), 0.07 (s, 9H). e) 4-[5-(3-{4-Amino-3'-[5-(tert-butoxycarbonylamitw-imino-methyl)-2- methylsutfanyl-thiophene-3-sidfoityl]-6-methyl-biphenyl-2-yl}-ureido)- pentyloxyj-benzoic acid Tetrabutyl ammonium fluoride solution (2.38 mL, 1M in THF) was added to a solution of 4-(5-{3-[3'-[5-(tert-butoxycarbonylamiiio-imino- methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-4-(2- trimethylsilanyl-ethoxycarbonylaraino)-biphenyl-2-yl]-ureido}-pentyloxy)- benzoic acid (276 mg, 0.298 mmol. Example 283: step d) in THF (10 mL) over 2 days at 35 °C. The solvents were removed in vacuo. The residue was diluted in EtOAc, washed with water and brine, and dried over magnesium sulfate. The solvents were removed in vacuo to afford the title compound as a brown solid (300 mg, quantitative). ESI-MS (m/z): Calcd. for C37H44N5O8S3: 782.2 (M+1); found: 781.8. J) 4-(5-{3-[3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-4-(Nt,N"'bis(tertbutoxycarbonyl)- guanidino)-6-methyl-biphenyl-2-yl]-ureido}-pentyloxy)-benzoic acid l,3-bis(tert-Butoxycarbonyl)- 2-methyl-2-thiopseudourea (433 mg, 1.49 mmol) was added to a solution of 4-[5-(3-{4-amino-3'-[5-(tert- butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]- 6-methyl-biphenyl-2-yl}-ureido)-pentyloxy]-benzoic acid (233 mg, 0.298 mmol, Example 283: step e) in 5% AcOH/MeOH (10 mL) over 2 days at 35 °C. The solvents were removed m vacuo and the residue was purified by flash chromatography (1-6% MeOH/methylene chloride) to afford the title compound as a yellow solid (70 mg, 23%). ESI-MS (m/z): Calcd. for C48H61N7O12S3: 1024.4 (M+1); found: 1024.0. g) 4-(5-{3-[3'-(5-Carbamimidoyl-2-methylsnlfanyl-thiophene-3- sulfonyl)-4-guanidino-6-methyl-biphenyl-2-yl]-ureido}-pentyloxy)-beiiz.oic acid bistrifluoroacetate 4-(5-{3-[3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-4-(N', N"-bis(tert-butoxycarbonyl)- guanidino)-6-methyl-biphenyl-2-yl]-ureido}-pentyloxy)-benzoic acid (15 mg, 14.6 jamol, Example 283: step f) was deprotected and purified as in Example 1: step d to afford the title compound as a white solid (4.2 mg, 39.6%). 1H- NMR (CD3CN/D2O): d 8.19 (s, 1H), 7.98-8.03 (m, 1H), 7.90-7.95 (m, 2H), 7.80-7.83 (m, 1H), 7.69-7.74 (m, 1H). 7.49-7.55 (m, 2H), 6.93-6.97 (m, 3H), 4.01 (t, 2H, J - 6.43 Hz), 2.88-3.03 (m. 2H), 2.64 (s, 3H), 1.94-1.97 (m, 3H), 1.66-1.73 (m, 2H), 1.29-1.37 (m, 4H). ESI-MS (m/z): Calcd. for C33H37N7O6S3: 724.2 (M+1); found: 724.2. Example 284 4-(4-Amino-3-bromo-beozenesuIfonyl)-5-methylsulfanyl-tbJophene-2- carboxamidine The reaction conditions in Example 12: step /were followed using 4- (4-amino-3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid amide {{Example 319: step d) 50 mg, 0.12 mmol) and dimethylaluminum amide reagent (5 mL). Analogous workup and HPLC puriiication yielded the title compound as an off-white solid (26 mg, 34%). 1H-NMR (CD3OD): d 8.23 (s, 1H), 7.96 (d, 1H, J= 2.1 Hz), 7.67 (dd. 1H, J = 2.1, 8.6 Hzi. 6.S5 (d. 1H, J = 8.6 Hz), 2.71 (s, 3H). ES1-MS (m/z): Calcd. for CnH^BrNjChS? (M+H): 405.9; found: 405.9, 407.9 (m+2). Example 285 [3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2,6-dimethyl- biphenyl-4-yloxymethyl]-phosphonicacid To a flask containing {[4-(4'-hydroxy-2',6'-dimethyl-biphenyl-3- sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert- butyl ester ((Example 224: step b) 233 mg, 0.42 mmol), Cs2CO3 (137 mg, 0.42 mmol), DMF (2 mL), and trifluoro-methcinesulfonic acid diethoxy- phosphorylmethyl ester (200 mg, 0.67 mmol, (Xu, Y. et al. J. Org. Chem. 61, 7697 (1996); Phillion, D. et al. Tetrahedron Lett. 27, 1477 (1986)) were added and heated to 50 C. This mixture was heated and stirred for 18 h under an Ar atmosphere. DMF was removed under vacuum and the residue was taken in EtOAc and washed with waiter and saturated NaCl. The EtOAc layer was separated dried over Na2SO4 and evaporated under vacuum to give an oil. This was purified by preparative thin-layer chromatography (EtOAc/Hexane) to give 94 mg (33 %) of {3'-[5--(tert-butoxycarbonylamino-imino-methyl)-2- methylsuIfanyl-thiophene-3-sulfonyl]-2,6-dimethyl-biphenyl-4-yloxymethyl}- phosphonic acid diethyl ester as a white solid. This solid was dissolved in dichloromethane (2 mL), and cooled in an ice bath. To this iodotrimethylsilane (Aldrich Chemical Company, 60 (aL) was added and the mixture was stirred for lh at which time the dicbJoromethane was removed and the residue was taken in MeOH and treated with 6N HC1. This mixture was stirred for 3 h and the solvents were removed under high vacuum. To this residue a 50% solution of TFA in dichloromethane was added and the mixture was stirred for 1 h. TFA and dichloromethane were removed under vacuum and the residue was purified by preparative HPLC (Rev. Phase acetonitrile/water) which yielded the title compound as a white solid (30 me, 33%). 1H-NMR (CD3OD): d 7.8- 7.7 (m, 2H), 7.62 (s, 1H), 7.5-7.3 (m, 2H), 6.7 (s, 2H), 3.77 (d, 2H, J - 9.8 Hz), 2.44 (s, 3H), 1.74 (s, 6 H). ESI-MS (m/z): Calcd. for C21H23N2O6PS3: 527.1 (M+H); found: 527.1. Example 286 5-Methylsulfanyl-4-(3-piperidin-l-yl-benzenesulfonyl)-thiophene-2- carboxamidine a) 4-Brom o-5-nitro-th ioph en e-2-carbaldehyde A solution of potassium nitrate (110 g, 1.09 mol) in H2SO4 (550 mL, cone.) was added to a solution of 4-bromo-thiophene-2-carbaldehyde (207.6 g, 1.08 mol) in H2SO4 (1.1 L, cone.) at CH2C12 (5 mL, anhydrous) at 0 °C over a 45 minute period. The reaction mixture was stirred 0 °C for 2 hrs, then stirred overnight at rt. The reaction mixture was poured over ice, filtered, and washed with water and hexanes. The yellow solid was dried overnight to afford the title compound (251.4 g, 98.6%). 1H-NMR. (DMSO-d6): d 9.90 (s, 1H), 8.56 (s, 1H). b) 4-Bromo-5-nitro-tlii.ophene-2-carbaldehyde oxime Hydroxylamine hydrochloride (85 g, 1.2 mol) was added to a solution of 4-bromo-5-nitro-thiophene-2-carbaldehyde (234 mg, 0.529 mmol, Example 286: step a) in EtOH (7.5 mL 200 proof - anhydrous) :pyndmt: (lOOmL, anhydrous) at rt over 5 min. The reaction mature was heated to reflux overnight, then cooled to rt. The solvents were removed in vacuo resulting in a solid residue that was washed with water and filtered. The solid was dried overnight under high vacuum to afford the title compound as a yellow solid (225 g, SS%). The solid was; used for the next step without further characterization. c) 4-Bromo-5-nitro-thiophene-2-carbonitrile A mixture of 4-bromo-5-nitro-thiophene-2-carbaldehyde oxime (216 g, 0.86 mol, Example 286: step b) and acetic anhydride (1 L, 10.6 mol) was heated to reflux for 4 hrs. The reaction mixture was cooled to rt and the solvents were removed in vacuo. The crude reaction mixture was diluted in methylene chloride and washed with water. The organic layer was dried over magnesium sulfate and concentrated in vacuo resulting in a residue, which was stirred in diethyl ether/hexanes and filtered to afford the title compound as a yellow solid (170.2 g, 85%). 1H-NMR (DMSO-d0): d S.25 (a, 1H). d) 4-(3-Bromo-phenylsulfanyl)-S-nitro-thiophene-2-carbonitrile Triethylamine (104 ml,, 0.7:5 mol) was slowly added to a solution of 4- bromo-5-niiTD-thiophene-2-carbonitrile (165 g, 0.708 mol, Example 286: step c) and 3-bromo-benzenethiol (78 ml, 0.76 mmol) in THF (1.2 L) at rt for 2 days. The solvents were removed in vacuo and the resulting residue was diluted in EtOAc, washed with saturated Na2CO3 solution, and dned over magnesium sulfate. The solvents were removed in vacuo and the residue was stirred in diethyl ether rhexanes (1:5) and filtered to afford the title compound as a yellow solid (232.7 g, 96%). ]H-NMR (DMSO-de): d 7.88-7.92 (m, 1H), 7.65-7.81 (m, 2H), 7.48-7.54 (m, 1H), 7.22 (s, 1H). e) 4-(3-Bromo-benzenesulfonyl)-5-nitro-thiophene-2-carbonitnlc A solution of mCPBA (26.3 g, 11.7 mol, 77%) in 1,2-dichloroethane was added to a solution of 4-(3-bromo-phenylsulfanyl)-5-nitro-thiophene-2- carbonitnle (10 g, 29.3 mmol, Example 286: step d) in 1,2-dichloroethane (200 mL) at rt over 30 min. The reaction mixture was heated to reflux for 2.5 hrs then cooled to rt. The reaction mixture was washed with 0.5 N NaOH and water and the organic layers were dried over magnesium sulfate. The solvents were removed in vctciio. The residue was stirred in diethyl ether, filtered, and dried under high vacuum to afford the title compound as a yellow solid (6.9 g, 63%). ]H-NMR (DMSO-d6): d S.53 (s, 1H), 8.14-8.16 (m, 1H), 7.98-8.05 (m, 2H), 7.62-7.67 (m, 1H). f) 4-(i-Bromo-benzenesulfonyl)-5-methyl$ulfanyl-thiophene-2- carbonitvile A solution of sodium thiomethoxide (1,87 g, 26.8 mmol) in EtOH (26.8 mL, anhydrous) was added to a suspension of 4-(3-bromo- benzenesulfonyl)-5-nitro-thiophene-2-carbonitrile (10 g, 26.8 mmol, Example 286: step e) in THF (67 mL, anhydrous) portionwise at -78 °C. The temperature of the reaction was maintained at -78 °C with stirring for 1 hour. The reaction was quenched with acetic acid (2 mL, 34.9 mmol) at-78 °C followed by warming the reaction mixture to rt and then filtered. The yellow solids were washed with diethyl ether and saved. The filtrate was concentrated in vacuo resulting in a residue that was suspended in diethyl ether and stirred at rt overnight. The solids were: filtered from the suspension. The combined yellow solids were dried under high vacuum to afford the title compound (8.77 g, 87.4 %). 1H-NMR (DMSO-dg): d 8.45 (s, IB), 7.97-8.16 (m, 3H), 7.62-7.67 (m, 1H), 2.71 (s, 3H). g) 5-Methylsulfanyl-4-(3-piperidw-l-yl-benzenesulfonyl)-thiophene-2- carbonitrile A mixture of 4-(3-Bromo-benzenesulfonyl)-5-methylsulfanyl- thiophene-2-carbonitrile {Example 286: step f , 200 mg, 0.534 mmol), pipendine (56 mg, 0.64 mmol), Pd(OAc)2 (24 mg, 0.11 mmol), BINAP (100 mg, 0.16 mmol) and CS2CO3 in 2 111L of toluene under At was stirred at 150 °C for 16 h, then cooled to RT. The mixture was purified directly by PTLC (30% EtO Ac/hex an e) to give 20 mg of product as a light yellow oil: 1H-NMR (CDCI3; 400 MHz) 5 7.68 (m, 1H), 7.67 (s, 1H), 7.54-7.52 (m, 1H), 7.39-7.32 (m, 2H), 3.16-3.12 (m, 4H), 2.45 (s, 3H), 1.64-1.59 (m, 4H), 1.55-1.50 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C17H1BN2O7S3, 379.1 (M+H), found 379.3. h) {Imino-[5-methylsulfanyl-4-(3-piperidin-l-yl-benzene.sulfonyt)- thiophen-2yl]-methyl}-carbamic acid tert-bntyl ester To a solution of carbamic acid tert-butyl ester (8 mg, 0.069 mmol, Aldrich Chemical Company) in 1 mL of THF at -78 °C was added 35 uL of n- BuLi under Ar. The mixture was stirred at -78 °C for 15 min. A solution of 5-methylsulfanyl-4-(3-piperidin-l-yl-benzenesulfonyl)-thiophene-2- carbonitrile (20 mg, 0.053 mmol, Example 286: step g) in 1 mL of THF was added. The resulting mixture was stirred at RT for 5 h, then at 50 °C overnight. Cooled to RT, the mixture was purified directly by PTLC (20% EtOAc/hexane) to give 10 mg (3S%) of product as colorless oil: 1H-NMR (CDCb; 400 MHz) 5 8.42 (s, IB), 7.74 (dd, 1H, J - 1.6, 1.6 Hz), 7.67 (s, 1H), 7.62 (ddd, 1H, J = 7.5, 1.6, 1.6 Hz), 7.57 (d, 1H, J = 7.5, 1.6, 1.6 Hz), 7.52 (dd, 1H, J = 7.5, 7.5), 3.42-3.40 (m, 4H), 2.54 (s, 3H), 1.64 (br s, 6H), 1.61 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C22H29N3O4S3, 496.1 (M+H), found 495.9. i) 5-Methylsulfanyl-4-(3-piperidin-l-yl-benzenesulfonyl)-thwphene-2- carboxamidine To a solution of 5-methylsulfanyl-4-(3-pipendin-l-yl- benzenesu]fony])-thiophene-2-carboxamidine (10 mg, 0.020 mmol, Example 286: step h) in 1 mL of CH2C12 under Ax at 0 °C was added 5 drops (- 200 ul) of TFA. The mixture was stirred at 0 °C for 1 h. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (5% MeOH/ CH2Cl2) gave 7.5 mg (77%) of product as colorless oil: !H-NMR (CD3OD, 400 MHz) 6 8.25 (s, 1H), 7.76 (dd, 1H, J = 1.6, 1.6 Hz), 7.62 (ddd, 1H, J = 7.5, 1.6, 1.6 Hz), 7.56 (ddd, 1H, J = 7.5, 1.6, 1.6 Hz), 7.51 (dd, 1H, J = 7.5, 7.5), 3.31-3.30 (m, 4H), 2.54 (s, 3H), 1.57-1.56 (m, 6H). Mass spectrum (ESI, m/z): Calcd. for Ci7H2iN3O2S3, 396.1 (M+H), found 396.2. Example 287 5-Methylsulfanyl-4-{3-[5-methyl-l-(2-trimethylsilanyl-ethoxymethyl)1H- benzoimidazol-4-yl]-benzenesulfonyl}-thiophen-2-carboxamidine a) 4-Iodo-5-methy!-lH"benzoimidazole A solution of 5-methyMH-benzoimidazole (132 mg, 10 nimol) and NIS (248 mg, 1.10 mmol) in 1 mL of TFA was reflux for 1 hr and then cooled to RT. Treated with 30 mL of EtOAc, the mixture was neutralized with sat. NaHCO3 solution. The organic layer was washed with H2O (10 mL), brine (10 mL) and dried (Na2SC)4). Removal of the solvent under reduced pressure followed by flash chxomatography of the residue on silica gel (5 % MeOH/CH2Cl2) gave 78 mg (30%) of product as a white solid: 1H-NMR (CDCl3; 400 MHz) 5 8.07 (d, 1H), 7.57 (br s, 1H), 7.22 (d, 1H, J = 8.4 Hz), 2.59 (s, 3H). Mass spectrum (ESI. m/z): Calcd. for C8H-.rN2, 259.0 (M+H), found 259.2. b) 4-Iodo-5-methyl-l-(2-tritnethylsilanyl-ethoxymethyl)1H- benzoimidazole To a solution of 4-Iodo-5-methyl1H-benzoimidazole (100 mg. 0.39 mmol, Example 287: step a) and SEMC1 (71 mg 0.43 mmol) in 2 mL of DMF under Ar was added Nat! (llmg. 0.43 mmol). The mixture was stirred at RT for 4 h and purified directly by PTLC (25% EtOAc/hexane) to give 122 mg (81 %) of product as a colorless oil: 1H-NMR (CDCl3; 400 MHz) 5 7.95 (s, 1H), 7.37 (d, 1H, J = 8.4 Hz), 7.21 (d, 1H, J = 8.4 Hz), 5.48 (s, 2H). 3.47 (t, 2H, J = 8.3 Hz), 2.59 (s, 3H), 0.S9 (t, 2H, J = 8.3 Hz), -0.06 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for Ci4H2iIN2OSi, 389.1 (M+H), found 3S9.0. c) [Iiuino-(5-methylsnlfanyl-4-{3-[5-methyl-l-(2-trimethylsilanyl- ethoxymethyl)1H-benzoimidazol-4-yl]-betizeiiesulfonyl}-thioplien-2-yl)- m ethyl]-carbamic acid tert-lmtyl ester A mixture of {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester. (20 mg, 0.044 mmol, Example 140: step a), 4-Iodo-5-methyl-1 -(2- trimethylsilanyl-ethoxymethyl)1H-benzoimidazoIe (21 mg, 0.054 mmol. Example 287: step b) and Pd(PPh3)4 in 1.2 ml of 1:1:2 EOH/2M Na2C03/toluene was stirred at 90 °C for 5 h, the cooled to RT. Treated with 3 mL of H2O, the mixture was extracted with EtOAc (3X5 mL)/ Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (30% EtOAc/hexane) gave 21 mg (71%) of product as a light yellow solid: 1H-NMR (CDCl3; 400 MHz) 8 8.42 (s, 1H). 8.08 (s, 1H), 8.05 (s, 1H), 8.01 (ddd, 1H, J = 7.2, 1.8, 1.7 Hz), 7.71-7.67 (m, 2H), 7.57 (d, 1H, J = 8.4 Hz), 7.39 (d, 1H, J = 8.7 Hz), 5.64 (s, 2H), 3.57 (t, 2H, J = 8.3 Hz), 2.61 (s, 3H), 2.33 (s, 3H), 1.51 (s, 9H), 0.95 (t, 2H, J = 8.3), -0.03 (s, 9H). ). Mass spectrum (ESI, m/z): Calcd. for C3,H4oN405S3Si, 673.2, (M+H), found 672.9. d) 5-Methylsulfanyl-4-{3-[5-methyl-l-(2-trimethylsilanyl- ethoxymethyl)1H-benzoimidazol-4-yl]-benzenesulfonyl}-thiophen-2- carboxam idin e To a solution of [Iraino-(5-methylsulfanyl-4-{3-[5-methyl-l-(2- trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-4-yl]-benzenesulfonyl} - thiophen-2-yl)-methyl]-carbamic acid tert-butyl ester (7 mg, 0.01 mmol. Example 287: step c) in 0.7 mL of CH2C12 was added 0.3 mL of T.FA. The resulting solution was stirred at RT for 1 h. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (5 - 10% MeOH/ CH2Cl2) gave 6 mg (S4%) of product as colorless oil: 1H- NMR (CD3OD; 400 MHz) 5 8.84 (s, 1H). 8.32 (s, 1H), 8.14 (ddd, 1H, J = 7.6, 1.6, 1.6 Hz). 8.08 (s, 1H), 7.83-7.77 (m, 3H), 7.52 (d, 1H, J = 8.4 Hz), 5.79 (s, 2H), 3.65 (t 2H, J = 8.0 Hz), 2.72 (s, 3H), 2.29 (s, 3H), 0.93 (t, 2H, J - 8.0 Hz), -0.04 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C26H32N4O3S3Si, 573.1, (M+H), found 573.0. Example 288 4-[3-(5-Methyl1H-benzoiinidazol-4-yl)-benzenesulfonyl]-5-raethyJsu]fanyl- thiophene-2-carboxamidine A solution of [Imino-(5-methylsulfanyl-4-{3-[5-methyl-l-(2- trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-4-yl]-benzenesulfonyl} - thiophen-2-yl)-methyl]-carbamic acid tert-butyl ester (14 mg, 0.021 mmol, Example 287: step c) in 1 mL of TFA was heated at 50 °C for 2 h under Ar, cooled to RT. Removal of the solvent under reduced pressure foliowed by flash chromatography of the residue on silica gel (10 - 15% MeOH/ CH2C12) gave 14 mg (100%) of product as colorless oil: 1H-NMR (CD3OD; 400 MHz) 5 9.28 (s, 1H). 8.35 (s, 1H), 8.20 (d, 1H, J = 7.6 Hz). 8.11 (s, 1H), 7.86 (dd, 1H, J = 7.7, 7.7), 7.80 (m, 2H), 7.63 (d, 1H, J = 8,6 Hz), 2.72 (s, 3H). 2.30 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C20H18N4O2S3, 443.1.00 (M+H). found 443.1. Example 289 4-[3-(3-Methyl-5-nitro-pyridin-2-yl)-benzenesulforiyl]-5-methylsulfanyl- thiophene-2-carboxamidine. TFA salt a) (lmino-{4-[3-(3-methyl-5-nitro-pyridin-2-yl)-benzenesulfonyl]-5- methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester A solution of {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5- methylsulfanyl-thiophen-2-y]]-imJno-methyl}-carbamic acid tert-butyl ester (0.05S mmol, 40 mg, Example 140: step a), 2-iodo-3-methyl-5-nitropyridine (0.08 mmol, 21.1 mg), Cul (0.01 mmol, 2.2 mg) and (Ph3P)4Pd (0.006 mmol) in DMF (0.6 mL) was heated at 100° under Ar for 3 hr. The reaction mixture was allowed to cool to RT and poured in to water ( 20 mL). The product was extracted with CH2Cl2 (3x10 mL). CH2Cl2 extracts were combined, dried (Na2SO4) and concentrated in vaccuo. The resulting residue was purified on silica (30% EtOAc:Hexane) to obtain (Imino-{4-[3-(3-methyl-5-nitro-pyridin- 2-yl)-benzenesulfonyl]-5-me1:hylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester. Yield: 48%; !H NMR (CDCl3) 5 9.36 (br, 1H), 8.37 and 8.25 ( s, 1H each), 8.1 and 7.8 (d, J=2.4 Hz, 1H each), 7.93 ( s, 1H), 7.74 (t, J=6.8 Hz, 1H), 2.7 and 2.5 (s, 3H each), 1.35 (s, 9H) b) 4-[3-(3-Methyl-5-nitro-pyridin-2-yl)-benzenesulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine. TFA salt (Imino-{4-[3-(3-methyl-5-:aitro-pyridin-2-yl)-benzenesulfonyl]-5- methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester ( 20 mg, Example 289: step a) was theao dissolved in 1:1 mixture of CH2Cl2 and TFA (1 mL). The resulting solution was stirred at RT for 1 hr. and concentrated in vaccuo to obtain a yellow oil which was dried in a high vaccum. Ether (10 mL) was then added and the precipitate formed was collected by suction filtration to yield 4-[3-(3-Methyl-5-nitro-pyridin-2-yl)-benzenesulfon>'l]-5- methylsulfanyl-thiophene-2-carboxamidine. TFA salt. Yield: 78%; 1H NMR (DMSO) 5 9.36 (br, 2H), 9.31 (d. J=2.4 Hz. 1H), 8.75 (brs, s), 8.65 ( d, J=2.4 Hz, 1H), 8.45 (s, 1H), 8.20 (m, 1H), 8.1? and 8.06 ( d, J= 6.6 Hz, 1H each), 7.84 (t, J=6.7Hz, 1H), 2.7 and 2.4 (s, 3H each); MS 448,03 (MT) calculated for C18H16N4O4S3; found 449.1 (M++l) Example 290 4-[3-(5-Amino-3methyl-pyridir!-2-yl)-benzenesulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine. TFA salt A solution of {[4-(3-dihydroxyboranyl-benzenesuIfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.058 mmol, 40 mg, Example 140: step a), 2-iodo-3-methyl-5-nitropyridine (0.08 mmol, 21.1 mg), Cul (0.01 mmol, 2.2 mg) and (Ph3P)4Pd (0.006 mmol) in DMF (0.6 mL) was heated at 100° under Ar for 3 hr. The reaction mixture was allowed to cool to RT and poured in to water (20 mL). The product was extracted with CH2C12 (3x10 mL). CH2C12 extracts were combined, dried (Na2SO4) and concentrated in vaccuo. The resulting residue was purified on silica (30% EtOAc:Hexane) to obtain the expected coupling product. The product (54.8 mg, 0.1 mmol) was suspended in EtOH:water (2:1, 10 mL) and NH4Cl (53.5 mg, 1 mmol) and Fe powder ( 28 mg, 0.5 mmol) were added. The resulting mixture was heated at reflux for 2 lir. The reaction mixture was cooled to RT and poured in to Std. Na2CO3 solution and the product was extracted with CH2C12 (3 x10 mL). CH2C12 extracts were combined, dried (Na2SO4) and concentrated in vaccuo to obtain a brownish yellow oil. This compound ( 29 mg) was then dissolved in 1:1 mixture of CH2C12 and TFA (1 mL). The resulting solution was stirred at RT for 1 hr. and concentrated in vaccuo to obtain a yellow oil which was dried in a high vaccum. Ether ( 10 mL) was then added and the precipitate formed was collected by suction filtration to yield the title compound. Yield: 2S%; 1H NMR (DMSO) 8 9.37 (br, 2H). 9.07 (br, 2H), 8.4 ( s, 1H), 8.05 (s, 1H), 7.9 (d, J=2.6 Hz, 1H), 7.85 (m, 2H),7.74 (t, J= 6.7 Hz. 1H), 7.1 ( s, 1H), 2.6 and 2.2 (s, 3H each); MS 418.06 (M+) calculated for C18H16N4O2S3; found 419.1 (b/t+l) Example 291 4-[3-(3-Methyl-pyrazin-2-yl)-beii2;enesulfonyl]-5-methylsulfanyl-thiophene-2- carboxamidine TFA salt a) (ImiHO-{4-{3-(3-methyl-pyrazine-2-yl}-benzeuesulfaiiyl-thiophene-2- yl}-ittethyl)-carbatnic acid tert-butyl ester To a flask containing {lmino-[5-methylsulfanyl-4-(3-tributylstannanyl- benzenesulfonyl)-thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester (22.3 mg, 0.031 mmol, Example 152: step a), methyl-iodopyrazine (8.3 mg, 0.038 mmol), Pd(PPh3)4 (10 mol%, 3.6 mg), and Cul (20 mol%, 1.2 mg) was added 0.5 mL of DMF. The flask was purged with Ar, and then heated to 100 °C for 16 h in an oil bath. The result was concentrated in vacuo and purified by preparative TLC (80 % EtOAc-Hexanes) to give the 7.2 mg (46%) of the product as a yellow solid contaminated with a small amount of tin. Mass spectrum. (ESI, m/z) calcd. for C22H24N4O4S3, 505.1 (M+H), found 405.1 (M+H-BOC). 1H NMR (CDCl3, 400 MHz): d 1.53 (s, 9H), 2.60 (s, 3H)? 2.65 (s, 3H), 7.70 (t, 1H, J=S.8 Hz), 7.87-7.89 (m, 2H), 8.10 (d, 1H, J=8.8 Hz), 8.25 (s, 1H), S.53 (m, 2H); b) 4-[3-(3-Methyl-pyrazin-2-yl)-benzenesulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine TFA salt To a solution of 7 mg of (Imino-{4-{3-(3-methyl-pyrazine-2-yl)- benzenesulfanyl-thiophene-2-yl}-methyl)-carbamic acid tert-butyl ester (Example 291: step a) in 0.3 mL of CH2C12 at 0°C was added 0.3 mL of TFA containing 10 µL H2O. The reaction was allowed to warm to ambient temperature. After 1 h, the solution was concentrated in vacuo with azeotropic removal using toluene (2x5 mL). The orange-brown solid was treated with 0.2 mL hexanes/0.5 mL CHCI3 and finely divided using somcation. The supernatant was removed via pipette. The solids were dried giving 4.8 mg (71%) of 4-[3-(3-Methyl-pyrazin-2-yl)-benzen.esulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine TFA salt as a yellow film. Mass spectrum (ESI, m/z) calcd. for C17H16N4O2S3, 404.5. (M+H), found 405.1 ; 1H NMR (CD3OD, 400 MHz): d 2.62 (s3 3H), 2.74 (s, 3H), 7.79 (t, 1H, J=8.9 Hz), 7.99- 8.01 (m, 1H), 8.17-8.19 (m, 1H), 8.29 (t, 1H, J=1.7 Hz), 8.35 (s, 1H), 8.56-8.58 (m, 2H); Example 292 4-[3-(4-Piperazin-l -yl)-be.nzenesulfonyl] -5-methylsulfanyl -thiophene-2- carboxamidine a) 4-[3-(4-Methyl-piperazin -1 -yl) -benzen esulfonylJ-5-m ethylsufanyl- thiophene-2-carbonitvile To a flask containing 0.15 g (0.4 nunol) of 4-(3-bromo- beiizenesulfonyl)-5-methylsulfanyl-thiophene-2-carbonitrile {Example 286: step j), 44.1 jiL (0.4 mmol) of N-methylpipirazine, 4.5 mg (0.02 mmol) of Pd(OAc)2, 24.8 mg (.04 mmol) of BINAP, and 195 mg (0.6 mmol) of CsCO3 was added 2.5 mL of toluene. The flask was purged with Ar, and heated to 100 °C for 16 h. The reaction was then concentrated in vacuo and purified by preparative TLC (50%-EtOAc-Hexane), isolating the low Rf material, which was subjected to preparative TLC again (10% MeO'H- CHCI3) to give 15.5 mg (10% yield) of 4-[3-(4-methyl-piperazin-l-yl)-benzenesulfonyl]-5- methylsufanyl-thiophene-2-ca.rbonitrile in greater than 98% purity. Mass spectrum (ESI, rn/z) calcd. for C17H19N3O2S3, 394.06 (M+H), found 394.1 ; 1H NMR (CDCl3, 400 MHz): d 2.36 (s, 3H), 2.57-2.59 (m, 4H), 2.62 (s, 3H), 3.29 (m, 4H), 7.11-7.13 (m, 1H), 7.38-7.40 (m, 2H), 7.49 (d, 1H, J=1.2Hz),7.84(s,lH); b) 4-[3-(4-Methyl-piperazin-l-yl)-benzenesulfonyl]-5-methylsuIfanyl- thiophene-2-carboximidic acid methyl ester To a flask containing 15 mg (0.03 mmol) of 4-[3-(4-methyl-piperazin- l-yl)-benzenesulfonyl]-5-methj'lsufanyl-thiophene-2-carbonitrile (Example 292: step a) was added 1 ml. of MeOH and the resultant solution was treated with 1 mL 2M NaOMe in MeOH (2 mmol) at room temperature. The reaction was heated to 50 °C for 2 h. At this time it was cooled to room temperature and 2 drops of H2O was added. Concentration of the mixture in vacuo followed by purification by preparative TLC (5% Me()H-CHCl3) yielded 12 mg (74%) of 4-[3-(4-methyl-piperazin-l-yl)-benzenesulfonyl]-5- methylsulfanyl-thiophene-2-carboximidic acid methyl ester as a yellow solid. Mass spectrum (ESI, m/z) calcd. for C1SH23N3O3S3, 426.09 (M+H), found 426.2; 1H NMR (CDC]3, 400 MHz): d 2.36 (s, 3H), 2.56-2.5S (m5 7 H), 3.27-3.30 (m, 4H), 3.88 (s, 3H), 7.09-7.11 (m, 1 H), 7.35-7.43 (m, 2H), 7.54 (s, 1H), 7.57 (s, 1H), 7.71 (s, 1H); c) 4-[3-(4-Piperazin-l-yl)-benzenesnlfonyl] -5-methylsulfanyl - thiophene-2-carboxamidine 4-[3-(4-Methyl-piperazin-l-yl)-benzenesulfonyl]-5-methylsulfanyl- thiophene-2-carboximidic acid methyl ester (10 mg, 0.023 mmol. Example 292: step b)\ NH4OAc (10 mg, 0.6 mmol) and 1 mL of 2M NH3 in MeOH were heated in a sealed tube at 60 °C for 3 h. The reaction was then concentrated in vacuo and purified by preparative TLC (10% MeOH-CHCl3- sat'dNH3) to give 8.7 mg (94%) of 4-[3-(4-Piperazin-l-yl)-benzenesulfonyl] - 5-methylsulfanyl -thiophene-2-carboxamidine as a yellow solid. Mass spectrum (ESI, m/z) calcd. for C18H23N3O3S3, 411.09 (M+H), found 411.2. 1H NMR (CD3OD, 400 MHz): d 2.36 (s, 3H), 2.61-2.64 (m, 4H), 2.67 (s, 3H), 3.28-3.31 (m, 4H), 7.24-7.27 (m, 1H), 7.42-7.44 (m, 2H), 7.54 (d, lH,J=1.3Hz), 8.00 (s, 1H); Example 293 4-[3-(4-Methyl-pyrimidin-5-yl)-beiizenesulfonyl]-5-methylsulfanyl-thiophene- 2-carboxamidine a) (Intino-{4-[3-(4-methyl-pyrimidin-5-yl)-benzenesulfonyl]-5- methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester To a flask with a reflux condenser under argon was added 5-Bromo-4- methyl-pyrimidine (9 mg, 0.044 rnmol), prepared according to the procedure of Yamanaka, Sakamoto, Nishimura, and Sagi, Chem. Pharm. Bull. 35(8), 3119-3126 (1987) . {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (20 mg, 0.044 mmol, Example 140: step a), Na2CO3 (2M, 0.220 mL, 0.44 mmol), Pd(PPh3)4 (S mg, 0.007 mmol), ethanol (0.220 mL) and toluene (0.440 mL). PdCl2(PPh3)2 (42 mg, 0.06 mmol), dioxane (4 mL), and triethylamine (420 µL, 3 mmol) and the mixture was stirred for 2 h 15 min at 90 °C. After cooling to rt, EtOAc (2 mL) and NaHCO3 (saturated, 2 mL) were added and the layers were separated. The organic layer concentrated in vacuo followed by purification of the crude material by preparative TLC (5% methanol in dichloromethane) to yield the title compound (19 ltng, 87%) as a white solid. 1H-NMR (CDCl3): d 9.12 (s, 1H), 8.54 (s, 1H), 8.10-7.29 (m, 7H), 2.59 (s, 3H), 2.50 (s, 3H), 1.51 (s, 9.H). ESI-MS (m/z): Calcd. for C22H24N4O4S3: 504.1 (M-BOQ+H; found: 405.1. b) 4-[3-(4-Methyl-pyrimidni-5-yl)-benzenesulfonylJ-5-methylsulfa>iyl- thiophcne-2-carboxamidine The (imino-{4-[3-(4-methyl-pyrimidin-5-yl)-betizenesulfonyl]-5- methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-buty] ester {{Example 293: step a) 15 nig, 0.03 mmol) was dissolved in dichloromethane (1 tnL), water (1 drop) was added, followed by trifluoroacetic acid (1 mL). The solution was stirred for 1 h 40 min at rt. The solvents were removed in vacuo, the residue was co-evaporated with dichloromethane and methanol, then purified by preparative TLC (10% methanol in dichloromethane) which yielded the title compound as a pale yellow glass (4 nig, 32%). 1H-NMR (CD3OD): d 9.05 (s, 1H), 8.61 (s, 1H), 8.13-8.08 (m, 2H), S.04 (s, 1H), 7.78- 7.76 (m, 2H), 2.66 (s, 3H), 2.49 (s, 3H). ESI-MS (m/z): Calcd. for C17H16N4O2S3: 404.5 (M+H); found: 405.1. Example 294 4-{4',6t-Bis-[3-(3-methanesulfonyl-propyl)-ureido]-2'-methyl-biphenyl-3- sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate a) 4-Bromo-5-methyl-3-nitrobenzoic acid methyl ester 4-Bromo-3-methylbenzoic acid methyl ester (10.13 g, 44 mmol) was dissolved in a mixture of H2SO4 120 mL and TFA (15 mL) at room temperature. The solution was cooled on an ice bath and KNO3 (4.65 g, 46 mmol) was added portionwise over 30 min. The mixture was stirred at ambient temperature for 4 hours during which it warmed to rt. TLC analysis (after mini aqueous workup) showed total disappearance of starting material (30% EtOAc/Hex). The solution was poured onto ice and the aqueous slurry was extracted with EtOAc (3 x 150 mL). The organic layer was washed with 5% Na2CO3 (3 x 75 mL), NaHCO3 (3 x 50 mL), water (2 x 100 mL), brine (100 mL), then was dried over sodium sulfate. Concentration of the solution yielded a yellowish solid/gel substance (11.6 g) which was one spot by TLC. 1H NMR analysis shows two (major) products in ~2:1 ratio, corresponding to the o- and m- nitrobenzoate derivatives.. The material was carried onto the next step without further purification. b) 4-Bromo-5-methyl-3-nitrobenzoic acid 4-Bromo-5-methyl-3-nitrobenzoic acid methyl ester ((Example 294: step a (11.6 g, 42.3 mrnol) was dissolved in MeOH (400 mL) at rt and 2N NaOH (43 mL) was added dropwise over 30 rnin via addition funnel. The solution was stirred for 12 hr during which, precipitate appeared, and sm disappeared (TLC shows only baseline spot in 30% EtOAc). The pH was adjusted to -2 with cone HC1 and the methanol was removed in vacua. EtOAc (300 mL) was added to the aqueous slurry and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 50 mL) and then discarded. TLC analysis of the combined organic extracts ishowed two products (40% EtOAc in Hexanes, 4% AcOH). The combined organic extracts were washed with a 3:1 solution of 0.5N NaH2PO4/0.5N NaOAc (-30 x 50 mL portions) until removal of the o-nitrobenzoic acid (lower spot on TLC, 40% EtOAc in Ilex, 4% AcOH) was complete. The organic layer was then washed with brine and dried over sodium sulfate. Concentration of the solution yielded 5.4 g (47%) of a white solid. 1H NMR (CD3OD) 8 8.10 (m, 2H), 2.54 (s, 3H). c) (4-Bromo-3-methyl-5-nitro-phenyl)-carbamic acid 2-trimethylsilanyl- ethyl ester Diphenylphosphorylazide (4.31 mL, 20 mmol)was added to a stirred solution of 4-bromo-3-methyl-5-nitro-benzoic acid (Example 294: step b (5.2 g, 20 mmol)) and diisopropylethylamine (3.66 mL, 21 mmol) in 1,4-dioxane (SO mL) at rt. After 30 minutes at rt, the reaction was heated to 90 °C for 5 min. Trimethylsilylethanol (5.73 mL, 40 mmol) was added and the solution was stirred for 16 h at 95 °C. The solvents were removed in vacua and the residue was partitioned between EtOAc (100 mL) and water (30 mL). The organic layer was further extracted with aq citric acid (3 x 30 mL), NaHCO3, (2 x 30 mL) and bnne (50 mL). Purification by column chromatography (9:1 Hex/EtOAc) yielded the title compound as a yellow solid. 'H NMR (CDCl3) S 7.73 (d, 1H, J=2.4 Hz), 7.41 (br dr 1H, J=1.7 Hz), 7.01 (s, 1H), 4.24 (m. 2H), 2.43 (s, 3H), 1.02 (m, 2H), 0.04 (s, 9H). d) (3-Amiiio-4-bronio-5-methyl-phenyl)-carbamic acid 2- trim ethyl silanyl-ethyl ester lion powder (6.1 g, 109 mmol) was added to a suspension of (4- bromo-3-methyl-5-nitro-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester {Example 294: step c (4.1 g, 10.9 mmol)) and NH4C1 (5.84 g, 109 mmol) in EtOH (27 mL) and water (54 mL). The reaction was heated at 85 °C for 14 h. The cooled mixture was filtered through celite arid the solids were washed with 1:1 EtOAc/MeOH (200 mL). The filtrate was concentrated in vacuo and the residue was partitioned between EtOAc (100 mL) and H2O (30 mL). The organic solution was washed with water (30 mL), and brine (50 mL). Drying and concentration of the solution yielded the title compound (3.24g, 86%) as a brown solid which was used without further purification. 1H NMR (CDCl3) 5 6.96 (s, 1H), 6.54 (s, 1H), 6.39 (s, 1H), 4.26 (m, 2H), 4.16 (s, 2H), 2.35 (s, 3H), 1.06 (m, 2H), 0.08 (s, 9H). e) [3-Amino-5-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- phenyl]-carbamic acid 2-trimethylsilanyl-ethyl ester Palladium acetate (106 mg, 0.47 mmol), 2- (dicyclohexylphosphino)biphenyl (658 mg, 1.88 mmol), (3-amino-4-bromo-5- methyl-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester {Example 294: step d (3.24 g, 9.38 mmol)) were combined in a flask and placed under an argon atmosphere. p-Dioxane (40 mL) was added, followed by triethylamine (5.23 mL, 38 mmol) and pinacolborane (4.08 mL, 28 mmol). The solution was stirred at 80 °C for lh during which a precipitate appeared. The solvent was removed in vacuo and the residue was partitioned between EtOAc (100 mL) and aq. NH4Cl (50 ml,). The organic layer was further extracted with NH4C1 (2 x 30 mL), NaHCO3 (30 mL), and brine (50 rnL). The organic layer was dried (MgSO4), concentrated in vacuo, and the; residue was purified by SiO2 flash column chromatography (8:2 Hex/EtOAc) to afford the product (2.44 g, 66%) as a brown solid. 1H NMR (CDCl3) 5 6.77 (s, 1H), 6.38 (s, 1H), 6.2S (d, 1H, J= 1.9 Hz), 4.91 (s, 2H), 4.23 (m, 2H), 2.42 (s, 3H), 1.32 (s, 12H), 1.03 (m,2H), 0.05 (s,9H). f) {6Amino-3'-[5-(tcrt-butoxycarbonylamin o-imino-methyl)-2- methylsulfanyl-thiophene-3-mlfonyl]-2-methyl-biphetiyl-4-yl}-carbiiinic acid 2-trim ethylsilanyl-ethyl ester A flask with a stirbar was charged with [3-amino-5-methyl-4-(4,4,5,5- tetramethyl-[ 1,3.2]dioxaborolan-2-y])-phenyl]-carbamic acid 2- trimethylsilanyl-ethyl ester ((Example 294: step e) 2.34 g, 5.96 mmol), {[4-(3- bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl] -imino-methyl} - carbamic acid f erf-butyl ester {(Example 27: step c) 2.93 g, 5.96 mmol), aqueous Na2CO3 (2M, 11.9 mL, 23.8 mmol), ethanol (12 mL) and toluene (24 mL). The solution was sparged with argon for 10 min and Pd(PPh3)4 (689 mg, 0.6 mmol) was added. The biphasic solution was vigorously stirred under inert atmosphere at 80 °C for 16 h, then was cooled to rt. EtOAc (80 mL) and water (20 mL) were added and the layers were separated. The organic layer was washed with saturated NaHCO3 (2 x 20 mL), brine (20 mL) and was dried over sodium sulfate. Removal of the solvents in vacuo followed by column chromatography (85:15 DCM/EtOAc) of the residue yielded the title compound (2.24 g, 55%) as a light brown solid. 1H-NMR (CDCl3): § 7.98 (ddd, 1H, J= 1.3, 1.9, 7.8 Hz), 7.89 (m, 2H), 7.61 (t, 1H, J = 7.7 Hz), 7.5 (dt, 1H, J= 1.3, 7.7 Hz), 6.88 (s, 1H), 6.55 (d, 1H, J= 1.7 Hz), 6.47 (s, 1H), 4.26 (m, 2H), 3.42 (s, 2H), 2.56 (s, 3H), 1.9 (s, 3H), 1.52 (s, 9H), 1.06 (m, 2H), 0.08 (s, 9H). g) {[4-(4', 6'-Diamino-2'-methyl-biphenyl-3-sulfonyl)-5-methyhulfanyl- thiopheti-2-yl]-imino-methyl}-carbamic acid tert-butyl ester A solution of tetrabutylammonium fluoride (1M in THF, 1 mL, 1 mmol) was added to a solution of {6-amino-3'-[5-(rerr-butoxycarbonylamino- imino-methyl)-2-methylsulfanyl-tbiophene-3-sulfonyl]-2-methyl-biphenyl-4- yl}-carbamic acid 2-trimethylsilanyl-ethy] ester {{Example 294: step 1) S6 mg, 0.11 mmol) in THF (1 mL). The solution was heated at 50 °C for 12 h, then the solution was partitioned between EtOAc (50 mL) and water (20 mL). The layers were separated and the organic layer was further extracted with water (5 x 10 mL) and brine (20 mL). The solution was dried over sodium sulfate and concentrated in vacuo to yield the title compound (71 mg, 84%) which was used without further purification. ESI-MS (m/z): Calcd. for C24H2SN4O4S3 (M+H): 533.1; found: 532.7. h) 4-{4',6'-Bis-[3-(3-methanesulfonyl-propyl)-ureido]-2'-methyl- biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine triflnoroacetate The procedure in Example 296 was followed using {[4-(4',6-diamino- 2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino- methyl}-carbamic acid tert-butyl ester (71 mg, 0.13 mmol), diphenylphosphoryl azide (250 µL, 1 mmol), 4-methanesulfonyl-butyric acid (166 mg, 1 mmol), and DIEA (183 µL, 1.05 mmol) in dioxane (4 mL). Analogous treatment of the crude intermediate with TFA/DCM and HPLC purification yielded the product (8 mg, 7%). 1H-NMR (CD3OD): d 8.30 (s, 1H), 8.04 (ddd, 1H, J= 1.1, 2.1, 8.1 Hz), 7.90 (t, 1H, J= 1.6 Hz), 7.73 (t, 1H, J= 7.9 Hz), 7.58 (m, 1H), 7.49 (m, 1H), 7.23 (dd;, 1H, J= 0.6, 2.1 Hz), 3.38 (t, 2H, J= 6.8 Hz), 3.20 (m, 4H), 3.0 (m, 2H), 3.01 (s, 3H), 2.97 (s, 3H), 2.74 (s, 3H), 2.05 (m, 2H), 2.02 (s, 3H), 1.87 (m, 2H). ESI-MS (m/z): Calcd. for C27H32N4O4S3 (M+H): 759.1; found: 759.1, 781.1 (M+Na). Example 295 ll-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4- guanidino-6-methyl-biphenyl-2-ylcarbamoyl]-undecanoic acid bis- trifluoroacetate a) 8-Methyl-1H-benzo[d][l,3]oxazin e-2,4-dione To a solution of 2-ammo-3-methylbenzoic acid (9.07 g, 60 mmol) in THF (60 mL) was added simultaneously diisopropylethylamine (20.9 mL) and a solution of triphosgene (5.94 g, 20 mmol) in dichloromethane (60 mL) over 30 minutes period. After the addition was completed, the mixture stirred at ambient temperature for 16 hours. Solid was filtered and washed with ether (2 x 100 mL) and H2O (3 x 50 mL), and dried in high vacuum to afford the title compound (10.02 g, 94 % yield) as a white solid. 1H NMR (DMSO) 5 11.02 (s, 1H), 7.76 (d, 1H, J=7.7 Hz), 7.57 (d, 1H, .7=7.5 Hz), 7.17-7.13 (m, 1H), 2.32 (s, 3H). b) 8-Methyl-6-nitro-1H-benzo[d][l,3]oxazine-2,4-dione To a flask charged with 8-methyl1H-benzo[d][l,3]oxazine-2.4-dione ((Example 295: step a) 9.27 g, 52.4 mmol) in an ice-water bath was added concentrated H2SO4 (90 mL) over 5 minutes period. After stirring for 10 minutes, fuming HNO3 (2.9 mL) was added over 15 minutes. The reaction mixture was stirred for further 30 minutes in the ice-water bath, 30 minutes at ambient temperature, then slowly poured into ice with stirring. The solid was collected, washed with H2O (3 x 50 mL), and dried in high vacuum to give the title compound (10.4 g, 89% yield) as a yellow solid. 1H NMR (DMSO) 6 11.65 (br s, 1H), 8.46-8.43 (m, 2H), 2.44 (s, 3H). c) 2-Amino-3-methyl-5-nitro-benzoic acid methyl ester To a suspension of S--memyl-6-rutro1H-benzo[d][l,3]oxazine-2,4- dione ((Example 295: step b) 1.04 g, 4.68 mmol) in methanol (30 mL) was added a solution of sodium methoxide (0.5 M, 0.94 mL. 4.7 mmol) in methanol. The mixture was stirred at ambient temperature for 1 hour and neutralized by addition of saturated NH4Cl. Methanol was removed under reduced pressure and the resulting mixture was filtered. The solids were washed with H2O (twice), dried in high vacuum to give the product (0.97 g, 99% yield) as a yellow solid. 1H NMR (DMSO) 5 8.48 (d, 1H, .7=2.7 Hz), 8.02-S.01 (m, 1H), 7.75 (br s, 2H), 3.86 (s, 3H), 2.20 (s, 3H). d) 2-Bromo-3-methyl-5-nitro-benzoic acid methyl ester To a flask charged with copper (II) bromide (7.40 g, 33.1 mmol) was added a solution of t-butyl nitrite (4.50 mL, 37.9 mmol) in MeCN (30 mL) at ambient temperature. After stirring for 5 minutes, a suspension of 2-amino-3- methyl-5-nitro-benzoic acid methyl ester ((Example 295: step c) 4.97 g, 23.7 mmol) in MeCN (50 mL) was added. The mixture was stirred at ambient temperature for 15 minutes, 65 °C for 20 minutes, then cooled back to ambient temperature. The reaction was filtered and the filtrate was concentrated to give a dark brown solid. The solid was triturated with hexane , filtered off, and washed with hexane (4 x 50 mL). All hexane layers were combined and concentrated to give the title product (5.7 g, 88 % yield) as a pale yellow solid. 1H NMR (CDCl3) 5 8.35 (d, 1H, .7=2.5 Hz), 8.21 (d, 1H, J=2.9 Hz), 3.99 (s, 3H), 2.59 (s, 3H). e) 2-Bromo-3-methyl-5-nitro-benzoic acid To a solution of 2-bromo-3-methyl-5-nitro-benzoic acid methyl ester ((Example 295: step d) 5.04 g) in ethanol (50 mL) was added a solution of aq NaOH (4M, 1.62 g, 40.5 mmol) and stirred at ambient temperature for 16 h. The resulting red colored solution was concentrated to dryness, dissolved in a minimum amount of H?O, and acidified with 1 N HC1 to pH 3-4. The solid was filtered, washed with H2O (3 x 50 mL) dried under high vacuum to afford the title compound (4.5 g, 94 % yield) as a pale yellow solid. 1H NMR (DMSO) 8 8.36-S.35 (m, 1H), 8.24-S.23 (m, 1H), 2.53 (s, 3H). f) (2-Bromo-3-methyl-5-nitro-phenyl)-carbamic acid tert-butyl ester Diphenylphosphorylazide (453 µL, 2.1 mmol) was added to a stirred solution of 2-bromo-3-methyl-5-nitro-benzoic acid ((Example 295: step e) 520 mg, 2 mmol) and triethylamine (1.4 mL, 2.1 mmol) in terf-butanol (25 ml.) at rt. After 15 minutes, the reaction was heated to 80 °C for 16 h. EtOAc (100 mL) was added and the solution was extracted with solutions of citric acid (3 x 30 mL), NaHCO3,(2 x 30 mL) and brine (50 mL). Purification by column chromatography yielded the title compound as a white solid. 1H NMR (CDCl3) 8 8.93 (d, 1H, J= 2.6 Hz), 7.77 (app dd, 1H,J= 0.7, 2.8 Hz), 7.26 (br s, 1H), 2.51 (s, 3H), 1.55 (s, 9H). g) 2-Bromo-3-methyl-5-nitro-phenylamine 2-Bromo-3-methyl-5-nitro-phenyl)-carbamic acid to-f-butyl ester ((Example 295: step d) 435 mg, 1.32 mmol) was dissolved in 10 mL of a 1:1 mixture of trifluoroacetic acid and DCM (10 mL total). After stirring for 1 h, the solvent was removed in vacito and the yellow solid residue (306 mg) was used without further purification. 1H NMR (CDCl3) 5 7.46 (d, 1H, J = 2.8 Hz), 7.42 (d, lHJ= 2.8Hz), 6.62 (br s, 2H), 2.42 (s, 3H). h) {[4-(6'-Amino-2'-methyl-4'-nitro-biphenyl-3-sulfonyl)-5- methylsulfanyl-thioplien-2-yl]-imino-methyl}-carbamic acid tert-butyl ester A flask with a stirbar was charged with {[4-(3-dihydroxyboranyl- benzenesulfonyl)-5-metIiy]sulfanyJ-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 140: step a (752 mg, 1.65 mmol), 2-bromo-3- methyl-5-nitro-phenylamine ((Example 295: step g) 306 mg, 1.32 mmol), aqueous Na2CO3 (2M, 4 mL, 8 mmol), ethanol (4 mL) and toluene (8 mL). The solution was sparged with argon for 10 min and Pd(PPh3)4 (294 mg, 0.25 mnio]) was added. The biphasic solution was vigorously stirred under inert atmosphere at 80 °C for 16 h, then was cooled to rt. EtOAc (40 mL) and water (20 mL) were added and the layers were separated. The organic layer was washed with saturated NaHCO3 (2 x 20 mL), brine (20 mL) and was dried over sodium sulfate. Removal of the solvents in vacua followed by column chromatography (10-40% EtOAc in hexanes) of the residue yielded the title compound (245 mg, 33%) as a yellow solid. 1H-NMR (CDCl3): d 8.03 (ddd, 1H, J= 1.2, 2.1, 8.1 Hz), 7.91 (s, 1H), 7.90 (t, 1H, J= 1.6 Hz), 7.69 (t, 1H, J = 7.9 Hz), 7.53 (app dd, 1H, .J= 0.7, 2.3 Hz), 7.50 (dt, 1H, J= 1.4, 7.7 Hz), 7.44 (app dd, 1H, J = 0.5, 2.3 Hz), 3.70 (s, 2H), 2.59 (s, 3H), 2.00 (s, 3H), 1.51 (s, 9H). i) ll-{4-Amino-3f-[5-(teirt-butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylcarbamoyl}- undecanoic acid methyl ester Triethylamine (139 µL, 1 mmol) was added to a solution of {[4-(6"- amino-2'-methyl-4'-nitro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2- yl]-imino -methyl) -carbamic acid tert-butyl ester ((Example 295: step h) 118 mg, 0.21 mmol) in DCM (10 mL). 11-chlorocaJ-bonyl-undecanoic acid ethyl ester (73 mg, 0.26 mmol) was added dropwise over 5 min. After 30 minutes of stirring, the reaction was not complete. Additional portions of acid chloride (3 x leq) were added in a similar manner, until the reaction was complete. Addition of EtOAc (40 mL) followed by aqueous workup with NaHCCh (2 x 20 mL) and brine (30 mL) yielded the crude amide (206 mg) as a glass. The residue was dissolved in EtOH (5 mL) and 4M aq NH4C1 (1 mL) was added. Iron powder (165 mg, 3 mmol) was added and the reaction was heated at 75°C for lh. The cooled mixture was filtered through a 0.22 urn filter and solids washed with 5 mL portions of MeOH and EtOAc. Additional EtOAc (80 mL) was added and the organic solution was washed with citric acid (2 x 20 mL). NaHCO3 (2 x 30 mL), water (30 mL), and brine (50 mL). Drying and concentration of the solution yielded the title compound (165 mg) which was used without further purification. j) 11-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophette-3-sulfonyl]-4-(N,N-bis-(tert- Butoxycarbonylamino))giianidino-6-methyl-biphenyl-2-ylcarbamoyl}- undecanoic acid Sodium hydroxide (1M, 1 mL) was added to a solution of 11-{4- amino-3'- [ 5 -(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfaii yl- thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylcarbamoyl}-undecanoic acid methyl ester ({Example 295: step i) 122 mg, 0.16 mmol) in MeOH (10 mL). The solution was stirred for 18 h at rt, the solution was quenched with AcOH (500 fiL), and the solvent was removed in vacuo. The residue was dissolved in MeOH (10 mL), AcOH (500 µL), and N,N-bis(tert-butoxycarbonyl)-S- methyl-isothiourea (145 mg, 0.5 mmol) was added. The solution was stirred at 40 °C for 16 h and the solvent removed in vacuo. The residue was partitioned between EtOAc (50 mL) and water (20 mL) and the organic layer was washed with brine (20 mL). Drying and concentration of the solution yielded a residue which was purified by SiO2 flash column chromatography (6:4 Hex/EtOAc, then 25:75:5 Hex/EtOAc/MeOH). The residue was further purified by RP-HPLC (C-18 column, CH3CN/H2O) to yield 115 mg of product). 1H-NMR (CD3OD): d 8.16 (s, 1H), 8.01 (ddd, 1H, J= 1.2, 1.9, 7.9 Hz), 7.87 (t, 1H, J= 1.6 Hz), 7.65 (t, 1H, J= 7.9 Hz), 7.53 (m, 1H), 7.50 (dt, 1H, J= 1.4, 7.7 Hz), 7.39 (m, 1H), 2.66 (s, 3H), 2.29 (t, 2H, 7= 7.4 Hz), 2.05 (s, 3H), 1.93 (m, 2H), 1.61 (m, 2H), 1.53 (s, 18H), 1.49 (s, 9H), 1.0-1.40 (m, 12H), 0.94 (m, 2H). k) ll-[3'-(5-Carbamimid.oyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4- guanidino-6-methyl-biphenyl-2-ylcarbamoyl]-undecanoic acid bis trifluoroacetate The procedure in Example 260: step b was followed using 11 -{3'-[5- (/e7-/-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3- sulfonyl]-4-(N,N-bis-(te7-r-butoxycarbonylamino))guanidino-6-methyl- biphenyl-2-ylcarbamoyl}-undecanoic acid ((Example 295: step j) 15 mg, 0.015 mmol) and 1:1 TFA/DCM (10 mL). Purification by HPLC yielded the product (8.2 mg, 55%) as an opaque glass. 1H NMR (CD3CN/D2O): 6 8.16 (s, 1H), 7.79 (ddd, J= 1.2, 2.1, 7.9 Hz), 7.82 (m, 1H), 7.67 (t, 1H, 7= 7.9 Hz), 7.49 (m, 1H), 7.18 (m, 1H), 7.14 (m, 1H), 2.65 (s, 3H), 2.26 (t, 2H, J= 7.4 Hz), 2.02 (s, 3H), 1.85 (m, 2H), 1.55 (m, 1H), 0.9-1.3 (m, 12H), 0.80 (m, 2H). ESI-MS (m/z): Calcd. for C32H42N6O5S3 (M+H): 687.2; found: 687.2. Example 296 4-{4'-[3-(3-Methanesulfonyl-propyl)-ureido]-2'-methyl-biphenyl-3-sulfonyl}- 5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate Diphenylphosphoryl azide (250 µL, 1 mmol) was added to a solution of 4-methanesulfonyl-butyric acid ((Example 209: part a) 166 mg, 1 mmol) and DIEA (183 µL, 1.05 mmol) in dioxane (4 mL). The solution was stirred at rt for 15 min, then stirred at 90 °C for 3 h. The solution was cooled, then an aliquot (250 u.L) was added to a solution of {[4-(4'-amino-2'-methyl-biphenyl- 3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester {(Example 220: step b) 76 nig) in DCM (2 mL). The reaction was stirred overnight and the solvent was removed in vacua. The residue was partially purified by SiCb flash column chromatography. The impure urea was treated with 1:1 TFA/DCM as described in Example 1: step d and was purified by HPLC to yield the title compound (31 mg, 19%). 1H-NMR (CD?OD): d S.32 (s, 1H), 8.0 (m, 1H), 7.97 (:m, 1H), 7.67 (m, 2H), 7.33 (m, 2H), 7.13 (d, 1H, J= 8.1 Hz). 3.37 (t 2H, 7= 6.8 Hz), 3.20 (m, 2H), 3.0 (s, 3H). 2.73 (s, 3H), 2.22 (s, 3H), 2.05 (m, 2H). ES1-MS (m/z): Calcd. for C24H28N4O5S4 (M+H): 581.1; found: 581.1. Example 297 4-[2'-Methyl-6'-(4-methyl-pipera2in-l-yhnethyl)-biphenyl-3-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidinebis-trifluoroacetate Methanesulfonyl chloride (100 µL) was added over 1 min to a 0 °C solution of {[4-(6'-hydroxymethyl-2'-metiiyl-biphenyl-3-sulfonyl)-5- methylsulfiinyl-thiophen-2-yl]-immo-methyl}-carbaimic acid tert-butyl ester ((Example 5: step c) (30 mg, 0.06 inmol) and diisopropylethylamine (0.25 ml) in DCM (10 mL). The solution was stirred for 1 h at 0 °C and warmed to rt. 1-Methylpiperazine was added (0.25 mL) and the solution was stirred for 3 h at rt. The volatile components were removed in vacuo and the residue was treated with 1:1 TFA/DCM (10 mL) for 2 h at rt. The solvent was removed in vacuo the residue was purified via preparative HPLC (C18 -column, 10-70% CH3CN over 30 min) which yielded the title compound as a opaque glass (8.2 mg). 1H-NMR (CD3OD): d 8.38 (s, 1H), 8.02 (ddd, 2H, .J= 1.2, 1.9, 7.9 Hz), 7.98 (t, 1H, J= 1.6 Hz), 7.72 (t, 1H. J= 7.9 Hz), 7.57 (dt, IK, J= 1.4, 7.7 Hz), 7.26-7.35 (m, 3H), 3.39 (d, III, J= 12.9 Hz), 3.21 (d, 1H, J= 12.9 Hz). 3.20 (br s, 4H), 2.87 (s, 3H), 2.75 (s. 3H), 2.50 (br s, 4H), 1.98 (s, 3H). ESI-MS (m/z): Calcd. for C25H30N4O2S3 (M+H): 515.2; found: 515.2 Example 298 4-(2>-Methyl-6'-morpholin-4-y]methyl-biphenyl-3-sulfbnyl)-5-methylsulfanyl- thiop'hene-2-carboxamidine Methanesulfonyl chloride (100 µL) was added over 1 min to a 0 °C solution of {[4-(6'-hydroxymethyl-2'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (Example 5: step c) (30 mg)) and diisopropylethylamine (0.25 mL) in DCM (10 mL). The solution was stirred for 1 h at 0 °C and warmed to it. 4- Methylmorpholine (0.5 mL) was added and the solution was stirred for 3 h at rt. The volatile components were removed in vacua and the residue was treated with 1:1 TFA/DCM (10 mL) for 2 h at rt. The solvent was removed in vacuo and the residue was purified by preparative HPLC (C18-column, 10- 70% CH3CN over 30 min) which yielded the title; compound as a opaque glass (6.8 mg). 1H-NMR (CD3OD): d 8.40 (s, 1H), 8.13 (ddd, 1H, J= 1.2, 1.9, 7.9 Hz), 7.97 (t, 1H, 7- 1.6 Hz), 7.82 (t, 1H, J= 7.9 Hz), 7.61 (m, 2H), 7.49 (m, 2H), 4.15 (d, 1H, J= 13.5 Hz), 4.07 (d, 1H, J= 13.5 Hz), 3.82 (br s, 4H), 2.75 (s, 3H), 2.18 (s, 2H), 2.03 (s, 3H), 1.31 (s, 2H). ESI-MS (m/z): Calcd. for C24H27N3O3S3 (M+H): 502.1; found: 502.1. Example 299 [3'-(5-Carbamimidoyl-2-methy]sulfany]-thiophene-3-sulfon)'])-6-mcthy]- biphenyl-2-ylmethoxy]-acetic acid trifluoroacetate a) (2-Iodo-3-methyl-benzyloxy)-acetic acid ten-butyl ester Sodium hydride (53 mg, 2.2 mmol) was added to a 0 °C solution of 2- iodo-3-methyl-phenyl-methanol ((Example 5: step a) 492 mg, 2 mmol) in DMF (20 mL). The solution was stirred at 0 °C for 30 min and tert-buiyl bromoacetate (0.4 mL, 2.5 mrnol) was added. The solution was warmed to rt over 15 min and stirred for 3 h at rt. EtOAc (80 mL) and water (40 mL) were added, the layers were separated, and the organic layer was washed with water (6 x 20 mL), brine (30 mL), amd was dried over sodium sulfate. Concentration of the solution followed by SiO2 flash column chromatography (5-10% EtOAc in hexanes) yielded the title compound (0.571 g, 79%) as an oil. 1H-NMR (CDCl3): d 7.36 (dd, 1H, J= 1.4, 7.4 Hz), 7.30 (t, 1H, 7.4 Hz), 7.24 (dd, 1H, J = 1.4, 7.4 Hz), 4.72 (s, 2H), 4.15 (s, 2H), 2.53 (s, 3H), 1.56 (s, 9H). b) [3-Methyl-2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- benzyloxyj-acetic acid tert-butyl ester The procedure used in Example 3: step b v/as followed using (2-iodo- 3-methyl-benzyloxy)-acetic acid tert-butyl ester ((Example 299: step a) 571 mg, 1.6 mmol), PdCl2(PPh3)2 (55 mg, 0.08 mmol), triethylamine (1.25 mL, 9.4 mmol), and 4,4,5,5-tetramethyl-[l.,3,2]dioxaborolane (0.91 mL, 6.4 mmol) in dioxane (5 mL) at a reaction temperature of 80 °C. Analogous aqueous workup and purification by SiO2 flash column cfaromatography yielded the title compound contaminated with the product resulting from halide reduction (542 mg, 95%). The material was used without further purification. 1H-NMR v: 6 7.20 (t, 1H, 7.4 Hz), 7.11 (d, 1H, J= 7.4 Hz), 7.07 (d, 1H, J= 7.4 Hz), 4.72 (s, 2H), 3.86 (s, 2H), 2.43 (s, 3H), 1.46 (s, 9H). 1.39 (s, 12H). c) [3'-(5-Carbamimidoyl-2-methylsulfaityl-thiophene-3-sulfonyl)-6- methyl-biphenylylmethoxyj-acetic acid trifluoroacetate The procedure used in Example 1: step c was followed using {[4-(3- bromo-benzenesu]fonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}- carbamic acid tert-bnty\ ester ((Example 27: step c) 123 mg, 0.25 mmol), [3- methyl-2-(4,475,5-tetramethy]-[l,3,2]dioxaboroIan-2-yl)-benzyloxy]-acetic acid tert-butyl ester ((Example 299: step c) 270 mg, 0.75 mmol), Na2CO3 (2M, 1.5 mL, 3 mmol), Pd(PPh3)4 (66 mg, 0.06 mmol), ethanol (1.5 mL) and toluene (3 mL). Analogous aqueous workup yielded 417 mg of crude material which was treated with 1:1 TFA/DCM as described in Example 1: step d. Analogous purification by C18-HPLC yielded the title compound (26.8 mg, 22%) as a white solid. 1H-NMR (CD3OD): d 8.35 (s, 1H), 8.07 (ddd, 1H, J = 1.2, 1.9, 7.9 Hz), 7.86 (t, 1H, J== 1.6 Hz), 7.71 (t, 1H, J== 7.9 Hz), 7.10-7.43 (m, 3H), 4.25 (m, 2H), 4.07 (br s, 1H), 3.78 (br s, 1H), 2.73 (s, 3H), 2.35 (s, 3H), 2.02 (s, 3H). ESI-MS (m/z): Calcd. for C22H22N2O5S3 (M+H): 490.1; found: 490.1. Example 300 [3'-(5-Carbamimidoyl-2-rnethylsulfanyl-thiophene-3-sulfonyl)-6-methyl- biphenyl-3-ylmethoxy]-acetic acid a) (3-Iodo-4-methyl-benzyloxy)-acetic acid tert-butyl ester The procedure used in Example 299: step a was followed using sodium hydride (53 mg, 2.2 mmol), 3-iodo-4-methyl-benzyl alcohol (992 rag, 4 mmol), tot-butyl bromoacetate (0.4 mL, 2.5 mraol) in DMF (10 mL). Analogous aqueous workup and purification by SiO2 flash column chxomatogiaphy yielded the title compound (1.30 g, 89%) as an oil. lH-NMR (CDCl3): d 7.84 (d, 1H, J= 1.4 Hz), 7.27 (d. 1H, J= 1.4 Hz), 7.23 (d. 1H, J = 1.1 Hz), 4.55 (s, 2H), 3.99 (s, 2H), 2.44 (s, 3H), 1.51 (s, 9H). b) [4-Methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)- benzyloxyj-acetic acid tert-butyl ester The procedure used in Example 3: step h was followed using (3-iodo- 4-methyl-benzyloxy)-acetic acid terr-butyl ester ((Example 300: step a) 600 mg, 1.65 mmol), PdCl2(PPh3);. (58 mg, 0.08 mmol), triethylamine (1.25 mL, 9.4 mmol), and 4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (0.91 mL, 6.4 mmol) in dioxane (5 mL). Analogous aqueous workup and purification by SiO2 flash column chromatography yielded the title compound contaminated with the product resulting from halide reduction (569 mg, 95%). The material was used without further purification. 1H-NMR (CDCl3): d 7.73 (d, 1H, J = 1.9 Hz), 7.38 (dd, 1H, J= 2.1, 7.9 Hz), 7.18 (d, 1H, J = 7.9 Hz), 4.61 (s, 2H), 3.97 (s, 2H), 2.55 (s, 3H), 1.50 (s, 9H), 1.37 (s, 9H). c) [3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6- tnethyl-biph enyl-2-ylmethoxy]-acetic acid trifluoroacetate The procedure used in Example 1: step c was followed using {[4-(3- bromo-beiizenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}- carbamic acid tert-butyl ester ((Example 27: step c) (239 mg, 0.24 mmol)), [4- methyl-3-(4,4,5,5-tetramethyl-[l,,3,2]dioxaborolan-2-yl)-benzyloxy]-acetic acid tert-butyl ester ((Example 300: step c) 530 mg, 1.46 mmol), Na2CO3 (2M, 3 mL, 6 mmol), Pd(PPh3)4 (70 mg, 0.06 mmol), ethanol (3 mL) and toluene (6 mL). Analogous aqueous workup yielded 629 mg of crude material which was treated with 1:1 TFA/DCM as described in Example 1: step d. Analogous purification by C18-HPLC yielded the title compound (47 mg, 38%) as a white solid. RP-HPLC (5 to 100% ACN over 8 min) analytical purity = 200%. ESI- MS (m/z): Calcd. for C22H22N2O5S3 (M+H): 491.1; found: 491.1. Example 301 3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-inethyl- biphenyl-3-carboxyiic acid (3-morpholin-4-yl-propyl)-amide bus trifluoroacetamide a) 3-Iodo-4-methyl-N-(3-morpholin-4-yl-propyl)-benzatnide Thionyl chloride (5.6 mL) was added over 1 min to a 0 °C solution of 3-iodo-4-methyl benzoic acid (5 g, 19.1 mmol) in THF (30 mL). The solution was stirred for 24 h at rt and the volatile components were removed in vacuo. A portion of the crude acid chloride (1 g, 3.57 mmol) was dissolved in DCM (10 mL) and was cooled to 0 °C. Diisopropylethylamine (0.78 mL, 4.46 mmol) was added followed by 3-morpholin-4-yl-propylamine (0.52 mL, 3.56 mmol) and the reaction was stiixed for 1 h at rt. EtOAc (80 mL) and aq. NH4Cl (20 mL) was added and 1he layers were separated. The organic layer was washed with aq NH4C1 (2 x 10 mL), NaOH (IN, 3 x 20 mL), water (20 mL), brine (50 mL) and was dried over sodium sulfate. Concentration of the solution and SiC»2 flash column chromatography of the residue (0-10% MeOH in DCM) yielded the product (695 mg, 50%) as a yellow glass. b) 4-Methyl-N-(3-morpholin-4-yl-propyl)-3-(4A,5,5-tetramcthy1- [l,3,2]dioxaborolau-2-yl)-benzainide The procedure used in Example 3: step b was followed using 3-iodo-4- methyl-N-(3-morpholin-4-yl-propyl)-benzamide ((Example 301: step a) 695 mg, 1.79 mmol), PdCl2(PPh3)2 (63 mg, 0.09 mmol), triethylamine (1.25 mL, 9.4 mmol), and 4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (0.91 mL, 6.4 mmol) in dioxane (5 mL). Analogous aqueous workup and purification by SiO? flash column chromatography (0-10% MeOH in DCM) yielded the title compound contaminated with the product resulting from halide reduction (653 mg, 94%). The material was used without further purification. c) 3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6- methyl-biphenyl-3-carboxylic acid (3-morpholin-4-yl-propyl)-amide bis trifluoroacetam ide The procedure used In Example 1: step c was followed using {[4-(3- bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}- carbamic acid tert-butyl ester ((Example 27: step c) (237 mg, 0.24 mmol)), 4- methyl-N-(3-morpholin-4-yl--propyl)-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-benzamide ((Example 301: step b) 563 mg, 1.45 mmol), Na2CO3 (2M, 3 mL, 6 mmol), Pd(PPh3)4 (67 mg, 0.06 mmol), ethanol (3 mL) and toluene (6 mL). Analogous aqueous workup followed by SiO2 flash column chromatography (0-10% MeOH in DCM) yielded 605 mg of material which was treated with 1:1 TFA/DCM as described in Example 1: step d. Analogous purification by C18-HPLC yielded the title compound (92 mg, 48%) as a white solid. RP-HPLC (5 to 100% ACN over 8 min) analytical purity = 100%. ESI-MS (m/z): Calcd. for C27H32N4O4S3 (M+H): 573.2; found: 573.2. Example 302 3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl- biphenyl-2-carboxylic acid (3-morpholm-4-yl-propyl)-amide bis trifluoroacetamide a) 2-lodo-3-methyl-N-(3-morpholin-4-yl-propyl)-benzamide The procedure and scale used in Example 301: step a was followed using 2-iodo-3-methyl benzoic acid. Concentration of the solution and SiCh flash column chromatography of the residue (0-10% MeOH in DCM) yielded the product (878 mg, 63%) as a yellow glass. b) 3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6- methyl-biphenyl-2-carboxylic acid (3-morpholin-4-yl-propyl)-amide bis trifluoroacetamide The procedure used in Example 295: step h was followed using 2-iodo- 3-raethyl-N-(3-morpholin-4-yl-propyl)-benzamide ((Example 302: step a) 150 mg, 0.39 mmol), {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5- methylsulfanyl-thiophen-2-yt]-irnino-methyl]-cai:bamic acid ten-butyl ester ((Example 140: step a (25 mg, 0.0S mmol), Na2CO3 (2M, 1 mL, 2 mmol), Pd(PPh3)4 (30 mg, 0.03 mmol), ethanol (1 mL) and toluene (2 mL). Analogous aqueous workup followed by SiO2 flash column chromatography (0-10% MeOH in DCM) yielded 60 mg of material which was treated with 1:1 TFA/DCM as described in Example 1: step d. Analogous purification by Cig- HPLC yielded the title compound (22 mg, 55%) as a white solid.1H-NMR (CD3OD): d 8.35 (s, 1H), 8.05 (ddd, 1H, J= 1.2, 1.9, 7.9 Hz), 7.96 (t, 1H, J = 1.6 Hz), 7.72 (t, 1H, J = 7.9 Hz), 7.66 (dt, 1H, 1.4, 7.7 Hz), 7.46 (m, 1H), 7.40 (m, 1H), 4.06 (m, 2H), 3.73 (m, 2H), 3.35 (m, 2H), 3.20 (m. 2H), 3.08 (ra, 2H), 2.94 (m, 2H), 2.73 (s, 3H), 2.09 (s, 3H), 1.75 (m, 2H). ESI-MS (ra/z): Calcd. for C27H32N4O4S3 (M+H): 573.2; found: 573.2. Example 303 4-[3-(6-Formyl-pyridin-2-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophene-2- carboxamidine a) 2-Bromo-6-dimethoxymethyl-pyridine The procedure in Example 6: step b was followed using 6-bromo- pyridine-2-carbaldehyde (600 mg, 3.23 mmol), trimethyl orthoformate (8 mL), and toluenesulfonic acid (100 mg) in MeOH (50 mL). Analogous aqueous workup yielded the product (743 mg) which was used without further purification. b) 4-[3-(6-Formyl-pyridin-2-yl)-benzenesulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine To a slurry of Rieke Zinc (370 mg, 5.64 mmol) in THF (7.4 mL) was added a solution of 2-bromo-6-dimeth.oxymethyl-pyrid.ine (400 mg, 1.7 mmol) in THF (2.6 mL). The suspension was heated to 65 °C for 2h and the solution was filtered through a 0.23 (am syringe filter into a THF solution of {[4-(3- bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}- carbamic acid /e/t-butyl ester ((Example 27: step c) (2.50 mg, 0.5 mmol)) and Pd(PPh3)4 (0.112 mg, 0.1 mmol).The reaction was heated at 80 °C for 30 min, cooled, and was poured into aqueous NaHCO3. EtOAc (70 mL) was added and the layers were separated. The organic layer was washed with NH4Cl (2 x 20 mL), NaHCCh (20 mL) and brine (30 mL) and was dried over sodium sulfate. Concentration of the solution followed by SiO2 flash column chromatography of the residue yielded 200 mg of the title compound which was contaminated with 2-dimethoxyrnethyl-pyridine. The material was treated with 1:1 TFA/DCM as described in Example 1: step d. Analogous purification by C18-HPLC yielded the title compound (118 mg, 38%) as a white solid. 1H-NMR (CD3OD) (aldehyde exists m hydrated form (acetal)) 5 8.60 (m, 2H), 8.44 (s, 1H), 8.33 (d, 1H, J= 7.9), 8.27 (d, 1H, J= 7.7)., 8.23 (d, 1H, 7= 7.7), 8.12 (d, 1H, J= 7.9), 7.9 (t, 1H, J = 7.7), 5.82 (s, 1H), 2.74 (s, 3H). ESI-MS (m/z) (sample in MeOH): Calccl. for C18H15N3O3S3 (M+H): 418.0; found: 449.9 (MeOH adduct). Example 304 4-[3-(6-Methyl-benzo[l,3]dioxol-5-yl)-benzenesulfonyl]-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate a) 5-bromo-6-methyl-benzo[l,3]dioxole Bromine (3.36 g, 21 mmol) was added to a solution of piperonal alcohol (3.0 g, 20 mmol) in chloroform (15 mL). The solution was heated to 60 °C for 12 h. After cooling, DCM (60 mL) was added and the solution was extracted with aq NaHCO3 (2 x 20 mL), brine (20 mL), and was dried over sodium sulfate. After concentration, the residue 5-bromo-6-bromomethyl- benzo[l,3]dioxole (5.8Sg, 100%), solidified upon standing. A portion of the crude solid (2.44g, 8.33 mmol) was dissolved in THF and cooled to -78 °C. Lithium aluminum hydride (348 mg, 9.16 mmol) was added and the solution was stirred for 3 h. An additional portion of LAH (80 mg, 2.03 minol) was added and the reaction was stirred an additional hour EtOAc was added carefully to quench the excess LAH, followed by addition of MeOH (20 mL). The salts were filtered and the filtrate was concentrated in vacuo, to yield the title compound (1.76 g, 99%) which was used without further purification. 1H-NMR (CDCl3): 6 7.01 (s, 1H), 6.73 (s, 1H), 5.95 (s. 2H), 2.32 (s, 3H). b) 4-[3-(6-Methyl-benzo[l,3]dioxol-5-yl)-benzenesulfonyl]-5- m ethylsulfanyl-th ioph en e-2-carboxam idin e trifluoroacetate Butyllithium (2.5 M, 2.4 mL, 6 mmol) was added dropwise to a -78 °C solution of 5-bromo-6-methyl-benzo[l,3]dioxole ({Example 304: step a) 64S mg, 3 mmol) in Et20 (12 mL). The solution was stirred for 4 h maintaining the temperature between -20 and -40 °C. The solution was cooled to -78 °C and trimethylborate (5 mL, 44 mmol) was quickly added in one portion. The solution was warmed to rt over 15 min and stirred for 1 h at rt (appearance of gelatin-like ppt). The volatile components were removed in vacuo to give the crude arylboronic acid as a yellow solid. A portion of the crude arylboronic acid (99 mg, 0.4 mmol) was combined with {[4-(3-bromo-benzenesulfonyl)-5- methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 27: step c) (50 mg, 0.1 mmol)), aq Na2CO3 (2M, 0.8 mL, 1.6 mmol), ethanol (0.8 mL), and toluene (1.6 mL). The procedure used in Example 1: step c was followed, and analogous workup yielded the product which was purified by preparative TLC. The purified material was treated with 1:1 TFA/DCM as described in Example 1: step d. Analogous purification by Cis-HPLC yielded the title compound (25 mg, 45%) as a white solid. 1H-NMR (CD3OD): d 8.32 (s, 1H), 7.99 (m, 1H), 7.93 (m, 1H), 7.64 (m, 2H), 6.79 (s, 1H), 6.68 (s, 1H), 2.72 (s, 3H), 2.12 (s, 3H),. ESI-MS (m/z): Calcd. for C20H18N2O4S3 (M+H): 447.0; found: 447.2. Example 305-306 4-[7-Bromo-3-(3-methyl-but-2-enyl)-3H-benzoimidazole-5-sulfony]J-5- methylsulfanyl-thiophene-2-carboxaniidine bis-trifluoroacetate 4-[7-Bromo-l-(3-methyl-but-2-enyl)1H-benzoimidazole-5-sulfonyl]-5- methylsulfanyl-tkiophene-2-carboxamidinebis-lnfluoroacetate A mixture of {[4-(7-bromo1H-benzoimidazole-5-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-immo-methyl}-carbamic acid tert-butyl ester {(Example 187-188; step c) 30 mg, 0.061 mmol), K2CO3 (10 rag, 0.072 mmol), and]-bromo-3-methyi-but-2-ene (60 µL, 0.5 mmol) were stirred in DMF (2.5 mL for 16 h at rt. EtOAc (50 mL) was added and the organic solution was washed with water (8 x 20 mL) and brine (20 mL) and was dried over sodium sulfate. Removal of the solvent in vacuo yielded 22 mg of material which was treated with 1:1 TFA/DCM as described in Example 1: step d. Analogous purification by C18-HPLC (10-55% CH3CN over 30 min) yielded the title compounds as white solids. 4-[7-Bromo-3-(3-methyl-but-2-enyl)-3H-benzoimidazole-5-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine bis-trifluoroacetate. lH-NMR (CDCl3): d 8.55 (s, 1H), S.34 (s; 1H), 8.27 (m, 1H), 8.06 (m, 1H), 5.44 (m, 1H), 5.01 (m, 2H), 2.72 (s, 3H), 1.96 (s, 3H), 1.83 (s, 3H). ESI-MS (m/z): Calcd. for Ci8Hi9BrN4O2S3 (M+H): 499.0; found: 498.9, 500.9 (m+2). 4-[7-Bromo-l-(3-methyl-bui-2-enyl)1H-benzoimidazole-5-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine bis-trifluoroacetate. H-NMR (CDCl3): S 8.50 (br s, 1H), 8.37 (br s, 1H), 8.32 (s, 1H), 8.09 (s, 1H), 5.43 (m, 1H), 5.27 (m, 2H), 2.72 (s, 3H). 1.85 (s, 3H), 1.77 (s, 3H). ESI-MS (m/z): Calcd. for QgH^BrN^Ss (M+H): 499.0; found: 498.9, 500.9 (m+2). Example 307-308 4-(3-Benzyl-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine bis-trifluoroacetate 4-(l-Benzyl1H-benzoimidazole-5-suIfonyl)-5-methylsulfanyl-thiopliene-2- carboxamidine bis-trifluoroacetate The procedure in Example 318: step e was followed using 4-(4-amino- 3-nitro-ben2;enesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 264: step a) 40 rag, 0.1 mmol) to yield the benzimidazole intermediate which was used without further purification. ESI- MS (m/z): Calcd. for C14H12N2O4S3: (M+H): 369.00; found: 369.1. The procedure in Example 305/306 was followed using 4-(3H- beiizoimidazole-5-sulfonyl)-5-methylsulfanyl-tbiophene-2-carboxylic acid methyl ester ((Example 187-188: step c) 20 mg, 0.037 mmol), K2CO3 (25 mg, 0.18 nimol)., and benzyl bromide (30 mg, 0.175 mmol) in DMF (2.5 mL). After analogous workup, the isomeric mixture of compounds was treated with dimethylaluminum amide reagent (5 mL) following the procedure in Example 12: step f. Analogous workup and purification by HPLC yielded the title compounds each as a white solid. 3-benzyl isomer: 1H-NMR (CD3OD): d 8.80 (br s, 1H), 8.26 (s, 1H), 8.20 (br s, 1H): 7.88 (s, 2H), 7.36 (m, 5H), 5.66 (s, 2H), 2.56 (s, 3H). ESI-MS (m/z): Calcd. for C20H1SN4O2S3 (M+H): 443.0; found: 443.1. 1-benzyl isomer: 1H-NMR (CD3OD): d S.62 (br s, 1H), 8.44 (s, 1H)5 8.32 (br s, 1H), 7.94 (dd, 1H, J= 1.6, 8.8 Hz), 7.88 (s, 2H), 7.70 (d, 1H, J= 8.8 Hz), 7.34 (m, 5H), 5.58 (s, 2H), 2.72 (s, 3H). ESI-MS (m/z): Calcd. for C2oHiSN.iO;)S3 (M+H): 443.0; found: 443.1. Example 309 4-[7-Bromo-lR-(l-phenyl-ethyl)1H-benzoimidazole-5-sulfonyr]-5- methylsulfanyl-thiophene-2-carboxarnidine bis-trifluoracetate The procedures used in Example 318: parts d-f were followed using with 4-(3-bromo-4-chloro-5-nitro-benzenesulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester ((Example 318: part c) 35 mg, 0.072 mmol), 1R-phenyl-ethylaimine (50 rag), and DD5A. (100 µL). All other reagent amounts, reaction conditions;, and purifications were identical to Example 318 d-f. 1H-NMR (CD3OD): d 8.86 (s, 1H), 8.23 (s, 1H), 8.01 (d, 1H, J= 1.4 Hz), 7.96 (d, 1H, J= 1.4 Hz), 7.35 (m, 5H), 5.95 (q, 1H, J= 7.2 Hz), 2.56 (s, 3H), 2.07 (d, 3H, J= 7.2 Hz). ESI-MS (m/z): Calcd. for CaiHigBrN^Sj (M+H): 535.0; found: 534.9, 536.9 (m+2). Example 310 4-[7-Bromo-1S-(1-phenyl-ethyl)-1H-benzoimidazole-5-sulfonyl] -5- methylsulfanyl-thiopbene-2-carboxamidine bis-trifluoracetate The procedures used in Example 318: parts d-f were followed using with 4-(3-bromo-4-chloro-5-nitro-benzenesulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester ((Example 318: part c) 35 mg. 0.072 mmol), 1S-phenyl-ethylamine (50 mg), and DIEA (100 µL). All other reagent amounts, reaction conditions, and purifications were identical to Example 318 d-f. 1H-NMR (CD3OD): d 8.86 (s, 1H), 8.23 (s, 1H), 8.01 (d, 1H, J= 1.4 Hz), 7.96 (d, 1H,J= 1.4 Hz), 7.35 (m, 5H), 5.95 (q, 1H, J= 7.2 Hz), 2.56 (s, 3H), 2.07 (d, 3H,J= 7.2 Hz). ESI-MS (m/z): Calcd. for C21H19BrN4O2S3 (M+H): 535.0; found: 534.9, 536.9 (m+2). Example 311 6-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-methyl- biphenyl-4-yl]-ureido}-hexanoic acid ethyl ester triiluoroacetate a) 6-(3-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2- methylsulfanyl-thiophene-3-sulfonyl]-2-methyl-biphenyl-4-yl}-ureido)- hexanoic acid ethyl ester Diisopropylethylamine (35 µL, 0.2 mrnol), 6-isocyanato-hexanoic acid ethyl ester (40 µL, 0.2 mmol), and {[4-(4'-amino-2'-methyl-bi.phenyl-3- sulfonyl)-5-methylsulfanyl-tkiophen-2-yl]-imino-inethyl}-carbamic acid tert- butyl ester ((Example 220: step b) 20 mg, 0.04 mmol) were stirred for 24 h in DCM (1 mL). The solution was partitioned between EtOAc (40 mL) and 0.1 N HC1 (10 mL) and was washed with additional 0.1N HC1 (2 x 10 mL), NaHCO3 (10 mL), and brine; (20 mL). The solution was dried, concentrated in vacuo, and purified by SiO2 preparative TLC to yield the product (12 mg, 43%). 1H-NMR (CDCl3): d 8.06 (s, 1H), 7.94 (m, 1H), 7.81 (m, 1H), 7.46 (m, 2H), 7.23 (br t, 1H, J= 5.4 Hz), 7.15 (m, 1H), 7.07 (m, 2H), 6.97 (m, 1H), 5.32 (br t, 1H), 4.15 (q, 2H, J= 7.2 Hz), 2.40 (s, 3H), 2.30 (t, 2H, J = 7.3 Hz), 2.11 (s, 3H), 1.54-1-70 (m, 4H), 1.51 (s, 9H) 1.35 (m, 2H), 1.25 (t, 3H, J= 7.3 Hz). b) 6-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)- 2-methyl-biphenyl-4-yl]-ureido}-hexanoic acid ethyl ester trifluoroacetate Following the procedure in Example 1: step d, 6-(3-{3'-[5-(ie/7- butoxycarbonylamino-iinino-methyl)-2-methylsulfanyl-thiophene-3-sulfonylj- 2-methy]-biphenyl-4-yl}-ureido)-hexanoic acid ethyl ester ((Example 311: step a) 12 mg) was treated with 1:1 TFA/DCM. Purification by HPLC yielded the product (8.3 mg) as a white solid. 1H-NMR (CD3OD): d 8.31 (s, 1H), 7.97 (m, 1H), 7.94 (m, 1H), 7.65 (m, 2H), 7.29 (m, 2H), 7.09 (m, 1H), 4.10 (q, 2H. 7.2Hz), 3.20 (t, 2H, 7.0 Hz), 2.71 (s, 3H), 2.33 (t, 2H, J = 7.3 Hz). 2.19 (s. 3H), 1.65 (m, 2H), 1.55 (m, 2H), 1.40 (m, 2H), 1.23 (t, 3H, J= 7.2 Hz). ESI- MS (m/z): Calcd. for C28H24N4O5S3 (M+H): 603.2; found: 603.2. Example 312 6-{3-[3l-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-methyi- biphenyl-4-yl]-ureido}-hexanoic acid trifluoroacetate Aqueous sodium hydroxide (1M, 0.75 µL), was added to a solution of 6-(3-{3'-[5-(tert-butoxycarbonylarnino-imino-methyl)-2-methylsulfai!yl- thiophene-3-sulfonyl]-2-methyl-biphenyl-4-yl} -ureido)-hexanoic acid ethyl ester {Example 311: step a) 52 mg, 0.07 mmol) in MeOH. The solution was stirred for 6 h at rt, AcOH was added (100 µL) and the solvent was removed in vacuo. The residue was treated with 1:1 TFA/DCM as in Example 1.step d and analogously purified via RP-HPLC to yield a white solid (26 mg, 54%). 1H-NMR (CD3OD): 6 8.34 (s, 1H), 8.00 (m, 1H), 7.95 (m, 1H), 7.67 (m, 2H), 7.32 (m, 2H), 7.11 (d, 1H, J= 8.4 Hz), 3.24 (t, 2H, 7.0 Hz), 2.74 (s, 3H), 2.34 (t, 2H, J= 7.3 Hz), 2.22 (s, 3H), 1.68 (m, 2H), 1.59 (m, 2H). 1.44 (m, 2H). ESI-MS (m/z): Calcd. for C26H30N4O5S3 (M+H): 575.1; found: 575.1. Example 313 6-{3-[3"-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl- biphenyl-2-yl]-ureido}-hexanoic acid ethyl ester trifluoroacetate The procedure used In Example 311: step a was followed using {[4- (6'-amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen--2-yl]- imino-methyl}-carbamic acid tert-butyl ester ((Example 25: step c) 60 mg, 0.12 mmol), 6-isocyanato-hexanoic acid ethyl ester (28 mg, 0.15 mmol), and DIEA (89 µL, 0.5 mmol). After analogous workup and purification, the crude material was treated with 1:1 TFA/DCM as in Example 1: step d. Analogous HPLC purification yielded the product (20 mg, 24%) as a white solid. 1H- NMR (CD3OD): d 8.31 (s, 1H), 8.06 (ddd, 1H, J - 1.2, 1.9, 7.9 Hz), 7.90 (t, 1H, J= 1.6 Hz), 7.72 (t, 1H,J= 7.9 Hz), 7.13 (m, 1H), 4.11 (q, 2H, 7.2Hz), 2.99 (m, 2H), 2.73 (s, 3H), 2.29 (t, 2H,J= 7.4 Hz), 2.01 (s, 3H), 1.65 (m, 2H), 1.55 (m, 2H), 1.35 (m, 2H), 1.23 (t, 3H, J= 7.2 Hz). ESI-MS (m/z): Calcd. for C28H34N4O5S3 (M+H): 603.2; found: 603.2. Example 314 4-(4'-Guanidino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene- 2-carboxamidine bis-trifiuoroacetate DIEA (89 (µL, 0.5 mmol) was added to solution of {[4-(4'-amino-2'- methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}- carbamic acid tert-butyl ester ((Example 220: step b) 26 mg, 0.05 mmol), 1,3- bis-(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (29 mg, 0.1 mmol) and HgCl2 (27 mg, 0.1 mmol) in DMF (2 mL). The solution became hazy after stirring for 5 min at rt. The solution was stirred for 24 h at rt and then was partitioned between EtOAc (40 mL) and water (20 mL). The layers were separated and the organic layer was extracted with citric acid (2x10 mL), NaHCO3 (20 mL), water (6 x 10 mL), and brine (20 mL). After drying (Na2SO4) and concentration in vacuo the residue was purified by preparative TLC. The protected guanidine was treated 1:1 TFA/DCM as in Example 1: step d. Analogous HPLC purification yielded the; product (8 mg, 24%) as a white solid. 1H-NMR (CD3OD): d 8.35 (s, 1H), 8.04 (m, 2H), 7.71 (m, 2H), 7.35 (d, 1H, J= 8.1 Hz), 7.28 (d, 1H, J= 2.3 Hz), 7.23 (dd, 1H, J= 2.3, 8.1 Hz), 2.74 (s, 3H), 2.28 (s, 3H). ESI-MS (m/z): Calcd. for C20H21N5O2S3 (M+H): 460.1; found: 460.2, 230.1 (m/2). Example 315 4-[2'-Methyl-4'-(N'-methoxyl-guanidino)-bipheny3-3-sulfonyl]-5- rnethylsulfanyl-thiophene-2-carboxamidmebis-trifluoroacetate a) {Imino-[4-(4'-isothiocyanato-2'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester A solution of l,l'-thiocarbonyldi-2(lH)-pyridone in DCM (0.25 M, 300 µL, 0.075 mmol) was added to {[4-(4'-amino-2'-methyl-biphenyl-3- sulfonyl)-5-methylsulfanyl-tbiophen-2-yl]-imino-methyl}-carbamic acid tert- butyl ester ((Example 220: step h) 26 mg, 0.05 mmol) at it. The orange color of the thiourea dissipated as the reagent was added, and a new higher spot appeared on TLC. The solvent was removed in vacuo and the residue was purified by preparative TLC to yield 23 mg of product. 1H-NMR (CDCl3): d 8.01 (br s, 1H), 7.96 (d, 1H, J= 7.4 Hz), 7.87 (s, 1H), 7.53 (m, 2H), 7.10 (d, 1H, J= 7.9 Hz), 6.93 (br s, Hi), 6.87 (d, 1H, J= 7.9 Hz), 2.51 (s, 3H), 2.2 7 (s, 3H), 1.50 (s, 9H). b) 4-[2'-Methyl-4'-(N'-methoxyl-guanidino)-biphenyl-3-sulfonyl]-5- methylsulfanyl-thiophene-2-carboxamidine bis-trifluoroacetate Methoxylamine hydrochloride (30 mg, 0.36 mmol), {imino-[4-(4'- isotliiocyanato-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2- yl]-methyl}-carbamic acid tert-butyl ester (Example 315: step a), 21 mg, 0.038 mmol), and triethylamine (100 µL) were stirred in DCM (2 mL)/CH3CN (lmL), was stirred for 1 h at rt. The solution was partitioned between EtOAc (40 m.L) and water (20 rnL) and the layers were separated. The organic layer was extracted with citric acid (3 x 10 mL), NaHCO3 (20 mL), and brine (20 mL). After drying (Na2SO4) and concentration in vacua, the residue was purified by preparative TLC. The purified material was dissolved in ammonia in MeOH (2M, 10 mL) and mercuric oxide (100 mg) was added. The mixture was stirred overnight at rt and at 40 °C for 3 h. The solution was filtered and the filtrate was concentrated in vacuo. The residue purified by preparative TLC and the product was treated with 1:1 TFA/DCM as in Example 1: step d. Purification by HPLC yielded the product (6 mg, 23%) as a white solid. 1H- NMR (CD3OD): 6 8.36 (s, 1H), 8.05 (m, 2H), 7.72 (m, 2H), 7.30 (m, 1H), 7.25 (ddd, 1H, J= 0.45, 2.3, 8.1 Hz), 7.36 (d, 1H, J= 8.1 Hz), 3.84 (s, 3H), 2.74 (s, 3H), 2.29 (s, 3H). ESI-MS (m/z): Calcd. for C21H23N5O3S3 (M+H): 490.1; found: 490.1. Example 316 4-[7-Bromo-3-(3,5-dimethyl-isoxazol-4-ylmethyl)-3H-benzoimidazole-5- sulfonyl]-5-methylsulfainyl-thiophene-2-carboxamidine bis-trifluoroacetate Example 317 4-[7-Bromo-l-(3;5-dimethyl-isoxazol-4-ylmethyl)1H-benzoimidazole-5- sulfonyl]-5-methylsulfainyl-thiophene-2-carboxamidine bis-trifluoroacetate The procedure in Example 305-306 was followed using {[4-(7-bromo- 1 H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imi no- methyl}-carbamic acid tert-butyl ester ((Example 187-188: step c) 20 mg, 0.037 mmol), K2CO3 (25 mg, 0.18 mmol), and 4-chloromethyl-3.5-dimethyl- isoxazole (25 µL, 0.15 mmol) in DMF (2.5 mL). The title compounds were isolated as white solids. Example 316: 1H-NMR (CDCl3): d 8.69 (s, 1H), 8.33 (s, 1H), 8.10 (d, 1H, J = 1.6 Hz), 7.98 (d, 1H, J = 1.6 Hz), 5.52 (s, 2H), 2.67 (s, 3H), 2.55 (s, 3H), 2.02 (s, 3H). ESI-MS (m/z): Called, for C19H18BrN5O3S3 (M+H): 540.0; found: 540.0, 542.0 (m+2). Example 317: :H-NMR (CDCl3): d 8.43 (br s, 1H), 8.40 (d, 1H, J= 1.6 Hz), 8.35 (s, 1H), 8.13 (d, 1H,J= 1.6 Hz), 5.73 (s, 2H), 5.27 (m, 2H), 2.73 (s, 3H), 2.19 (s, 3H), 2.03 (s, 3H). ESI-MS (m/z): Calcd. for C19H18BrN5O3S3 (M+H): 540.0; found: 540.0, 542.0 (m+2). Example 318 4-(7-Bromo-l-phenyl1H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxamidme trifluoroacetate a) 4-Amino-3-bromo-5-nitro-benzenesulfonyl chloride 4-Amino-3-bromo-5-nitrobenzenesulfonamide ((US 3987199) 1 g, 3.17 mmol) was heated at 95 °C for 3 h in chlorosulfonic acid (10 mL). The solution was cooled then poured onto ice and then filtered. The solid was redissolved in DCM and dried over sodium sulfate. Removal of the solvent yielded the product (960 mg) which was used without further purification. b) 4-(4-Amino-3-bromo-5-nitro-benzenesulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester Sodium sulfite (643 nig, 5.1 mmol) and NaHCO3 (4S0 mg. 5.7 mmol) were dissolved in water (20 mL) and 4-amino-3-bromo-5- nitrobenzenesulfonyl chloride ((Example 318: step b) 940 mg, 3 mmol) was added. The suspension was stirred for 1 h at rt and 5 mL of EtOH was added to aid dissolution. The mixture was stirred for 4 h at rt, during which nearly all of the sulfonyl chloride had dissolved and the major spot on TLC was at the baseline. The solvent was removed in vacuo and DMF was added (10 mL). The mixture was stirred for 15 min and the inorganic salts were allowed to settle. The DMF was removed via syringe, the salts were washed with a second portion of DMF (10 mL), and the combined DMF solution was slowly added to a 0 °C solution of 4-bromo-5-nitro-thiophene-2-carboxylic acid methyl ester ((Example 114: step c) 800 mg, 3 mmol) in DMF (20 mL). The solution was stirred for 0 °C for 1 h then overnight at rt. The DMF was removed in vacuo and the residue was partitioned between EtOAc (100 mL) and aq NaHCO3 (30 mL). The layers were separated and the organic layer was washed with aq NaHCO3 (2 x 20 mL), water (30 mL), and brine (30 mL), then dried over soldium sulfate. The solution was concentrated and the residue was dissolved in THF (20 mL) and cooled to -78 °C. A solution of sodium methoxide in methanol (1M, 3.75 mL, 3.75 mmol) was added dropwise and the reaction was stirred for 30 min. Acetic acid (500 µL) was added followed by EtOAc (100 mL). The solution was washed with NaHCO3 (3 x 30 mL,), brine (40 mL), and was dried over sodium sulfate. Concentration and chromatography of the residue yielded the product (430 mg). 1H-NMR (CDCl3): 6 8.88 (d, 1H, J= 2.1 Hz), 8.27 (d, 1H, J= 2.1 Hz), 8.06 (s, 1H), 3.93 (s, 3H), 2.67 (s, 3H). c) 4-(3-Bromo-4-chloro-5-nitro-benzenesulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid methyl ester To a mixture of CuCl2 (142 mg, 1.06 mmol), and terr-butylnitrite (157 µL, 1.32 mmol) in CH3CN (10 mL) was added a solution of 4-(4-amino-3- bromo-5-nitro-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester {(Example 318: step b) 410 mg, 0.88 mmol) in CEUCN (10 mL), dropwise over 5 min. After 1.5 h, extra CuCl2 (142 mg), and tert- butylrntrite (157 jaL) were added and the reaction was stirred an additional 1.5 h. The solution was cooled then partitioned between EtOAc (120 mL) and water (50 mL). The organic layer was washed with water (2 x 20 mL) and brine (30 mL) then was dried over sodium sulfate. Concentration of the solution followed by chromatography yielded an impure product (285 mg, 68%) that was used without further purification 1H-NMR (CDCl3): d 8.43 (d, 1H, J=- 2.1 Hz), 8.34 (d, 1H, J= 2.1 Hz), 8.02 (s, 1H), 3.90 (s, 3H), 2.66 (s, 3H). d) 4-(3-Brom o-5-nitro-4-ph enylam in o-ben zenesnlfonyl)-5- methylsulfanyl-thiophene-2-carboxylic acid methyl ester A mixture of aniline (112 mg, 1.35 mmol), 4-(3-bromo-4-chloro-5- nitro-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 318: step c) 53 mg, 0.11 mmol), and sodium acetate (16.5 mg, 0.2 mmol) in dioxane (3 mL) was heated at 80 ° C for 24 h. The mixture was partitioned between EtOAc (50 mL) and 0.5 N HC1 (10 mL) and the organic layer was further extracted with 0.5 N HC1 (2 x 10 mL), NaHCO3 (10 mL), and brine (20 mL). Drying of the solution over sodium sulfate followed by concentration yielded the product (58 mg) which was used without further purification. 1H-NMR (CDCl3): d 8.04 (s, 1H), 7.64 (d, 1H, J=2.1 Hz), 7.32 (d, 1H, J= 1.9 Hz), 7.25 (m, 2H), 6.95 (m, 1H), 6.69 (m, 2H), 5.70) (s, 1H), 3.90 (s, 3H), 2.66 (s, 3H). e) 4-(7-Bromo-l-phenyl1H-benzoimidazole-5-sulfonyl)-5- methylsnlfanyl-thiophene-2-carboxylic acid methyl ester Iron powder (110 mg, 2 ramol) was added to a solution of 4-(3-bromo- 5-nitro-4-phenylamino-benzenesulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid methyl ester {Example 318: step d) in EtOH (4 ml.) and 50% aqueous AcOH (1 mL). The reaction was stirred for 30 min at 60 °C during which a new lower spot became evident by TLC analysis. EtOAc (10 mL) was added and the mixture was filtered through a 0.22 µm polypropylene syringe filter. Additional EtOAc (30 mL) was added and the solution was extracted with aq NaHCO3 (3 x 10 mL) and brine (20 mL). The solution was dried and concentrated in vacuo. One-half of the residue (26 mg) was suspended in formic acid (3 mL) and was heated at 95 °C for 4 h. The formic acid was removed in vacuo and the residue was purified by chromatography to yield the product (23 mg). 1H-NMR (CDCl3): d 8.56 (d, 1H, J= 1.6 Hz), 8.13 (s, 1H), 8.07 (d, 1H, J= 1.6 Hz), 8.04 (s, 1H), 7.55 (m, 3H, 7.41 (m, 2H), 3.87 (s, 3H), 2.61 (s, 3H). f) 4-(7-Bromo-l-phenyl1H-benzoimidazole,-5-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate The procedure in Example 12: step f was followed using 4-(7-bromo-l- phenyl-1H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxylic acid methyl ester ((Example 318: step e) 23 mg, 0.044 mmol) and dimethylaluminum amide reagent (5 mL). Analogous workup and purification by HPLC yielded the title compound as a white solid (16 mg, 49%). 1H-NMR (CD3OD): d 8.53 (s, 1H), 8.47 (d, 1R J= 1.6 Hz), 8.37 (s, 1H), 8.10 (d, 1H, J = 1.6 Hz), 7.53-7.65 (m, 5H), 2.73 (s, 3H). ESI-MS (m/z): Caicd. for C19H15BrN4O2S3(M+H): 507.0; found: 507.1, 509.1 (m+2). Example 319 4-(6-Arnino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2- carboxamidine a) 3-Bromo-4-fluoro-phenylamine Sodium chlorite (6.78 g, 75 mmol) and 4-fluoro-3-bromobenzaldehyde (24.63 mmol) were dissolved in 1:1 THF/water (100 rnL) and stirred vigorously at 50 °C for 5 h. EtOAc (250 mL) and 1N HCl (50 mL) was added and the layers were separated. The organic layer was washed with water (3 x 50 mL), then was extracted with 0.5M Na2CO3 (10 x 50 mL). The combined basic aqueous layers were slowly acidified with concentrated HC1 while stirring, to precipitate the carboxylic acid product. The solid was collected via filtration and dried under high vacuum overnight (4.93 g, 91%). A portion of the solid carboxylic acid was dissolved in chloroform (30 mL) and concentrated sulfuric acid was added. A reflux condenser was attached to the flask and the solution was heated to 55 °C. Sodium azide (2.36 g, 36.45 mmol) was added in 3 portions over 1 h. After 4 h, additional sulfuric acid (10 mL) and sodium azide (1 g) were added and the reaction was stirred at 55 °C for 16 h. The mixture was transferred to a large cooled flask and the sulfuric acid was slowly quenched with 5N sodium hydroxide. The solution was adjusted to pH-8 and the aqueous solution was extracted with DCM (5 x 30 mL). The organic extracts were dried over sodium, sulfate and concentrated in vacuo to yield a dark brown oil (2.2 g, 95%) that solidified upon standing. 1H-NMR (CDCl3): d 6.94 (t, 8.4 Hz), 6.88 (dd, 1H, J = 2.8, 5.6 Hz), 6.58 (m, 1H), 3.62 (s, 2H). b) 3-Bromo-4-fluoro-benzenesulfonyl chloride Concentrated HC1 (1.93 mL, 23.16 mmol) was added to a solution of 3-bromo-4-fluoro-phenylamme ((Example 265: part a) 2.2 g, 11.58 mmol) in 15 ml, of 2:1 DCM/MeOH. A precipitate appeared and another 9 mL of 2:1 DCM/MeOH was added. The solution was cooled to -5 °C and tert- butylnitrate (2.71 mL, 23.16 mmol) was added dropwise over 8 mm. After stirring for 15 min, sulfur dioxide (-5 mL) was condensed into the reaction, followed by addition of copper (II) chloride (592 mg, 3.47 mmol) (gas evolution). The solvent was removed in vacuo and the residue was purified by SiO2 flash column chromatography to yield the title compound (1.9 g, 59%). 1H-NMR (CDCl3): d 8.31 (dd, 1H, J = 2.3, 5.8 Hz), S.04 (ddd, 1H, J = 2.6, 4.1, 8.8 Hz), 7.39 (dd, 1H, J = 7.7, 8.8 Hz). c) 4-(3-Brom o-4-fluoro-benz,en esulfonyl)-5-methylsulfanyl-thiophene- 2-carboxylic acid methyl ester 3-Bromo-4-fluoro-benzenesulfonyl chloride ((Example 319: part b) 1.9 g, 6.83 mmol) and sodium bicarbonate (1.15 g, 13.66 mmol) was suspended in 16 mL of water at 70 °C. A solution of sodium sulfite (1.64 g, 13 mmol) in 15 mL of water was added in 3 portions over 3 h. The mixture was stirred for 16 h, and the solvent was removed in vacuo. DMF (15 mL) was added, the mixture was stirred for 15 min, and the inorganic salts were then allowed to settle. The DMF was removed via syringe, the salts were washed with a second portion of DMF (10 mL), and the combined DMF solution was slowly added to a 0 °C solution of 4-bromo-5-nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 931 mg, 3.5 mmol) in DMF (15 mL). The solution was stirred for 0 °C for 1 h. The DMF wa:s removed in vacuo and the residue was partitioned between EtOAc (100 mL) and aq NaHCO3 (30 mL). The layers were separated, and the organic layer was washed with aq NaHCO3 (2 x 20 mL), water (30 mL), and brine (30 mL), then dried over sodium sulfate. The solution was concentrated and the residue (1.42 g) was dissolved in THF (20 mL) and cooled to —78 °C. A solution of sodium methoxide in methanol (1M, 5 mL, 5 mmol) was added dropwise and the reaction was stirred for 30 min at -78 °C. Acetic acid (500 µL) was added followed by EtOAc (100 mL). The solution was washed with NaHCO3 (3 x 30 mL), bnne (40 mL), and was dried over sodium sulfate. Concentration and chromatography of the residue yielded the title compound (502 mg:, 17%) as a yellow solid. 1H-NMR (CDCl3): 6 8.16 (dd, 1H, J = 2.3, 6.3 Hz), 7.94 (s, 1H), 7.91 (ddcl, 1H, J = 2.6, 4.4, 8.6 Hz), 7.39 (dd, 1H, J = 5.3, 8.6 Hz). d) 4- (4-A m in o-3-bromo-benzen esulfonyl)-5-methylsulfanyl-thiophene- 2-carboxylic acid amide The procedure in Example 124: step a was followed using 4-(3-bromo- 4-fluoro-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 319: part c) 100 mg, 0.24 mmol). After 24 h, the ammonia was allowed to evaporate and the solid product was used without further purification. 1H-NMR (CDCl3): d 7.73 (d, 1H, J = 2.1 Hz), 7.69 (s, 1H), 7.42 (dd, 1H, J = 2.1, 8.6 Hz), 6.57 (d, 1H), 3.14 (s, 2H), 2.36 (s, 3H). e) 4-(6-Amino-2'-methyl-biphenyl-5-sulfonyl)-5-methylsulfanyl- thiophene-2-carboxylic acid amide The procedure used in Example 1: step c was followed using 4-(4- amino-3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid amide ((Example 319: part d) 44 mg, 0.11 mmol), 2-methylphenylboronic acid (54 mg, 0.4 mmol), aq Na2CO3 (2M, 800 µL, 1.6 mmol), and Pd(PPh3)4 (29 mg, 0.025 mmol). Analogous workup and purification by preparative TLC yielded the title compound (24 mg, 56%). 1H-NMR (CDCl3): d 7.97 (s, 1H), 7.76 (dd, 1H, J = 2.3, 8.6 Hz), 7.67 (d, 1H, J = 2.3 Hz), 7.32 (m, 2H), 7.28 (m, 1H), 7.16 (m, 1H), 6.76 (d, 1H, J = 8.6 Hz), 4.11 (s, 2H)f 2.58 (s, 3H)7 2.13 (s, 3H). f) 4-(6-Amino-2'-methyl-biphenyl-3-sulfonyl)-5-metltylsulfanyl- thiophene-2-carboxamidine bis-trifluoroacetate The reaction conditions in Example 12: step f were followed using 4- (6-amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfany]-thiophene-2- carboxylic acid amide ((Example 319: part e) 24 mg. 0.06 rnmol) and dimethylaluminura amide reagent (5 mL). Analogous workup and HPLC purification yielded the title compound as an off-white solid (8.8 mg, 24 %). 1H-NMR (CD3OD): d 8.24 (s, 1H), 7.72 (dd, 1H, J = 2.3, 8.S Hz), 7.52 (d. 1H, 7= 2.3 Hz), 7.33 (m, 2H), 7.28 (m, 1H), 7.12 (m, 1H), 6.85 (d. 1H. J = 8.8 Hz), 2.71 (s, 3H), 2.10 (s, 3H). ESI-MS (m/z): Calcd. for C10H19N3O2S3 (M+H): 418.1; found: 41 S.I. Example 320 4-(6'-Methanesulfonylamino-2'-methyl-biphenyl-3-sulfonyl)-:5- methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate {[4-(2'-Amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl- thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (20 mg, 0.04 mmol, Example 25 : step c) and methane sulphonyl chloride (5 mg, 0.04 mmol) were dissolved into toluene (lmL) and heated to 100 ° C for 48 hours. The solvents were removed in vacuo resulting in the desired product with loss of the tert-butyl protection group. The resulting compound was purified as in Example 1: step d, yielding the title compound as an off-white solid (1.3 mg). 1H-NMR (CD3OD): d 8.29 (s, 1H), 8.07-8.05 (d, 1H, J= 7.21 Hz), 7.90 (m, 1H), 7.72-7.68 (t, 1H, J= 8.14 Hz, J= 7.67 Hz), 7.57-7.55 (d, 1H, J= 7.67 Hz) 7.35 (m, 2H), 7.26 (m, 1H), 2.75 (s, 3H), 2.50 (s, 3H). 1.30 (s, 3H). ESI- MS (m/z): Calcd. for C20H21N3O3S4: 496.0 (M+1); found: 496.1. Example 335 Tablet Preparation Tablets containing 25.0, 50.0, and 100.0 mg, respectively, of an active compound are prepared as illustrated below: TABLET FOR DOSES CONTAINING FROM 25-100 MG OF THE ACTIVE COMPOUND Amount-mg Active Compound 25.0 50.0 100.00 Microcrystalline cellulose 37.25 100.0 200.0 Modified food corn starch 37.25 4.25 8.5 Magnesium stearate 0.50 0.75 1.5 All of the active compound, cellulose, and a portion of the comstarch are mixed and granulated to 10% corn starch paste:. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 25.0, 50.0, and 100.0 mg, respectively, of active ingredient per tablet. Example 336 Intravenous Solution Preparation An intravenous dosage form of the above-indicated active compounds is prepared as follows: Active Compound 0.5-10.0 mg Sodium Citrate 5-50 mg Citric Acid 1-15 mg Sodium Chloride 1-8 mg Water for Injection (USP) q.s. to 1 ml Utilizing the above quantities, the active compound is dissolved at room temperature in a previously prepared solution of sodium chloride, citric acid, and sodium citrate in Water for Injection (LISP, see page 1636 of United States Pharmacopeia/National Formulary for 1995, published by United States Pharmacopeial Convention, Inc., Rockville, Maryland (1994). Example 33 7 In vitro Inhibition of C1s Reagents: All buffer salts were obtained from Sigma Chemical Company (St. Louis, MO), and were of the highest purity available. DTNB was purchased from Pierce (Rockford, IL). Z-Gly-Arg-S-Bzl was purchased from Enzyme Systems Products (Livermore, CA). Activated human C1s was purchased from Calbiochem (La Jolla, CA). K, Determinations: All assays are based on the ability of the test compound to inhibit the C1s-catalyzed hydrolysis of the substrate Z-Gly-Arg- S-Bzl, which is observed via a secondary reaction with 5,5'-dithio-bis(2- nitrobenzoic acid) (DTNB), In a typical K, determination, substrate is prepared in DMSO, and diluted into an assay buffer consisting of 50 mM HEPES, 200 mM NaCl, pH 7.5, 0.05% n-octyl-b-D-glucopyranoside. Substrate solutions were prepared at a concentration of 45 uM (Km = 190 uM) with DTNB at a concentration of 200 uM in assay buffer. Test compounds are prepared as a 10 uM solution in DMSO. Dilutions are prepared in DMSO yielding 7 final concentrations encompassing a 700-fold concentration range. Purified activated C1s was diluted into assay buffer for a working concentration of 66 nM. In a typical Ki determination, into each well of a 96-well plate is pipetted 280 µL of substrate solution, 10 µL of test compound solution, and the plate allowed to thermally equilibrate at 37°C for 15 minutes. Reactions were initiated by the addition of a 10 µL aliquot of the enzyme, and the absorbance increase at 405 nm is continuously recorded for 15 minutes in a Molecular Devices plate reader. Final DMSO concentration was 4.3%. Final reagent concentrations were: [Cls] = 2.3 nM, [Z-Gly-Arg-S-Bzl] = 45 µM, [DTNB] = 200 µM. The ratio of the velocity (rate of change in absorbance as a function of time) for a sample containing no test compound is divided by the velocity of a sample containing test compound, and is plotted as a function of test compound concentration. The data are fit to a linear regression, and the value of the slope of the line: calculated. The inverse of the slope is the experimentally determined Ki value. Complement Inhibition Data The following compounds have Ki values in the range of 0.006 to 0.023 micromolar (uM) for C1s: Examples 1-13, 15-20, 24-26, 28-30, 32-35, 37, 41-96, 98-110, 114-119, 121, 135-136, 171, 173, 184, 192, 194-195, 203, 207, 209-211, 219-220, 224, 228, 231, 233, 236-239, 240, 242, 246, 252, 254- 263, 275, 280, 282, 294-296 and 314-315. The compound of Example 11 has a Ki value of 0.023 µM for C1s. The compound of Example 61 has a Ki value of 0.006 µM for C1s. The results indicate that the compounds of the present invention are inhibitors of complement, specifically C1s. Having now fully described this invention, it will be understood to those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the invention or any embodiment thereof. All patents and publications cited herein are fully incorporated by reference herein in their entirety. WE CLAIM: 1. Thiophene amidines comprising a compound having the following formula: or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein: Z is-S(O2)-; R1 is C1-6 alkylthio or methylsulfonyl; and R5 is phenyl substituted by three substituents; one of the substituents being C1-4 alkyl or halo; the second substituent being C1-4 alkyl, C1-4 alkoxy, hydroxyl, amino, nitro, optionally-substituted ureido, or optionally substituted alkylcarbonylamino; and the third substituent being either optionally-substituted ureido, or optionally- substituted guanidino. 2. The compound as claimed in Claim 1 in which R1 is methylthio. 3. The compound as claimed in Claim 2 in which the C1-4 alkyl substituent on R5 is methyl. 4. A compound as claimed in claim 1, wherein said optionally-substituted ureido has the formula -N(L1)-C(O)-N(L2)-Y2a-X2-Y2b-Z2, wherein: L1 and L2 are both hydrogen, or L1 and L2 together represent ethylene or trimethylene; Y2a is a direct covalent bond or an a,?-diradical of a C1-10 straight or branched alkane; X2 is O or S, or a direct covalent bond; Y2b is an a,?-diradical of a d-10 straight or branched alkane, optionally substituted with a carboxy group; and Z2 is carboxy, (C1-6 alkoxy)carbonyl, phenoxy, carboxyphenoxy, C1-6 alkylsulfonyl, phenyl, benzyloxycarbonylamino, amino, C1-4 alkylamino, halophenyl, indolyl, diphenylmethyl, phenylsulfonylamino, N'-(carboxy(C1-4)alkyl) ureido, tetrazolyl, phosphono or phenylamino; or, Y2a-X2-Y2b-Z2 represents C1-4 alkylsulfonyl or -(CH2CH2-O-)m-(CH2)n-C(O) OR wherein m is an integer from 2 to 6, n is an integer from 2 to 4, and R is hydrogen or C1-4 alkyl. 5. A compound as claimed in claim 1, wherein said optionally-substituted guanidino has the formula -N(L3)-C(=NL4)-N(L5)-Z3, wherein: L3 is hydrogen or C1-4 alkyl; L4 and L5 are both hydrogen, or L4 and L5 together represent ethylene; and Z3 is hydrogen, C1-6 alkyl, phenyl(C1-6)alkyl, carboxy(C1-6)alkyl, C1-4 alkoxy, (C1-4 alkyl)carbonyl or C1-4 alkylsulfonyl(C1-6)alkyl. 6. A compound as claimed in Claim 1 wherein said optionally-substituted alkylcarbonylamino has the formula -N(H)-C(O)-C(H)(W1)-Y1a-X1-Y1b-Z1, wherein: W is hydrogen or amino; Y1a is a direct covalent bond or an a,?-diradical of a d-10 straight or branched alkane; X1 is O or S, or a direct covalent bond; Y1b is an a.w-diradical of a d-10 straight or branched alkane, optionally substituted with a carboxy group or an amino group; and Z1 is carbamoyl, carboxy, d-e alkylsulfonyl, (C1-6 alkoxy)carbonyl, C2-6 alkanoylamino, sulfo, phosphono, phenyl, aminosulfonyl, amino, C1-6 haloalkylsulfonylamino, formylamino, C1-6 alkylamino, d-e alkylaminosulfonyl, C1-6 alkylsulfonylamino or 2-oxo-hexahydro-thieno[3,4-d]imidazol-6-yl-(C1-6 alkyl) carbonylarnino; or, W1 is hydrogen and Y1a-X1-Y1b-Z1 represents hydrogen, halo, amino or tri-(C1-4 alkyl)ammonio; provided that, if Y1a is a direct covalent bond and X is O or S, then W1 is hydrogen. 7. A compound as claimed in claim 1, wherein R5 is phenyl substituted at the 2'-position by methyl and at the 4'-position by optionally-substituted guanidino, and in the 6' position by amino. 8. A compound as claimed in claim 1, wherein R5 is phenyl substituted at the 2'-position by methyl, at the 4-position by optionally-substituted ureido, and at the 6'-position by amino. 9. A compound as claimed in Claim 1 wherein: R5 is phenyl substituted by C1-4 alkyl, amino, and guanidino. 10. A compound as claimed in Claim 1 wherein: R5 is phenyi substituted by C1-4 alkyl, optionally substituted ureido, and optionally substituted guanidino. 11. A compound as claimed in Claim 10 wherein: R5 is phenyl substituted by methyl, optionally substituted ureido, and optionally substituted guanidino. 12. A compound as claimed in Claim 10 wherein: R5 is phenyl substituted by at the 2'-position with C1-4 alkyl, at the 4' position with optionally substituted guanidino, and at the 6' position with optionally substituted ureido. 13. A compound as claimed in Claim 1 wherein: R5 is phenyl substituted by three groups which are methyl, amino, and guanidino. 14. The compound as claimed in Claim 1 which is 4-(4'-Guanidino-2'-methyl- 6'-nitro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxamidine bis- trifluoroacetate; or 4-(6'-Amino-4'-guanidino-2'-methyl-biphenyl-3-sulfonyl)-5- methylsulfanyl-thiophene-2-carboxamidine bis-trifluoroacetate. 15. A compound as claimed in claim 1, wherein R5 is phenyl substituted at the 2'-position by methyl, at the 4'-position by optionally-substituted guanidino, and at the 6'-position by optionally-substituted alkylcarbonylamino or optionally- substituted ureido. 16. The compound as claimed in Claim 1 which is 4-{4'-Guanidino-2'-[3-(4- methanesulfonyl-butyl)-ureido]-6'-methyl-biphenyl-3-sulfonyl}-5-methylsulfanyl- thiophene-2-carboxamidine trifluoroacetate. Disclosed is a method for treating the symptoms of an acute or chronic disorder mediated by the classical pathway of the complement cascade, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula (I) or a solvate. hydrate or pharmaceutically acceptable salt thereof: wherein R1, R2, R3, R4 and R7 are defined in the spec- ification, Z is SO or SO2 and Ar is an aromatic or heteroaromatic group as defined herein.

Full Text

Thiophene Amidines
Background of the Invention
Field of the Invention
The present invention is in the field of medicinal chemistry. In
particular, the invention is directed to novel heterocyclic amidines and their
use for inhibiting the enzyme Cls, a protease in the classical pathway of the
complement system; and the use of this inhibition to treat or ameliorate acute
or chronic disorders in mammals.
Related Art
The immune system of the human body is equipped with several
defense mechanisms to respond to bacterial, viral, or parasitic infection and
injury. One such defense mechanism involves the complement system.
Complement consists of a complex series of approximately 30 plasma and
membrane protein components, many of which are proteinases. Once
activated, this system of enzymes non-specifically complements the
imrnunologically specific effects of antibody by modulating the immune
response, lysing target cells, stimulating vascular and other smooth muscle
cells, facilitating the transport of immune complexes, producing
anaphylatoxins which cause degranulation of mast cells and release of
histamine, stimulating chemotaxis (migration) of leukocytes toward the area of
complement activity, activating B lymphocytes and macrophages, and
inducing phagocytosis and lysis of cells (Eisen, H. N., Immunology, Harper &
Row Publishers, Inc., Hagerstown, Md., p. 512 (1974); Roitt, I. et al.,
Immunology, Gower Medical Publishing, London, New York, pp. 7.1-7.14
(1985); U.S. Patent Nos. 5,472,939 and 5,268,363).
The complement system functions as a "cascade." The enzyme
cascades are initiated when inactive enzyme precursor molecules are activated,
through limited proteolysis, by membrane-bound enzymes. A small fragment
is lost from the enzyme precursor and a nascent membrane binding site is
revealed. The major fragment then binds to the membrane as the next
functionally active enzyme of the complement cascade. Since each enzyme is
able to activate many enzyme precursors, the system forms an amplifying
cascade, resembling the reactions seen in blood clotting and fibrinolysis (Roitt,
I. et al., Immunology, Gower Medical Publishing, London, New York, pp. 7.1-
7,14(1985}).
The proteins of the complement system form two inter-related enzyme
cascades, termed the classical and alternative pathways. The classical
pathway is usually initiated by antigen-antibody complexes, while the
alternative pathway is activated by specific polysaccharides, often found on
bacterial, viral, and parasitic cell surfaces. The classical pathway consists of
components C1-C9, while the alternative pathway consists of components C3-
C9 (excluding C4) and several factors, such as Factor B, Factor D, and
Factor H.
The sequence of events comprising the classical complement pathway
consists of three stages: recognition, enzymatic activation, and membrane
attack leading to cell death. The first phase of complement activation begins
with C1. C1 is made up of three distinct proteins: a recognition submit, C1q,
and the serine proteinase subcomponents, C1r and C1s, which are bound
together in a calcium-dependent tetrameric complex, C1r2S2. An intact C1
complex is necessary for physiological activation of C1 to result. Activation
occurs when the intact C1 complex binds to immunoglobulin complexed with
antigen. This binding activates C1s which then cleaves both the C4 and C2
proteins to generate C4a and C4b, as well as C2a and C2b. The C4b and C2a
fragments combine to form the C3 convertase, which in turn cleaves C3 to
form C3a and C3b (Makrides, Pharmacol Rev. 5(9:59-87 (1998); and U.S.
Patent No. 5,268,363). Both the classical and alternative pathways are capable
of individually inducing the production of the C3 convertase to convert C3 to
C3b, the generation of which is the central event of the complement pathway.
C3b binds to C3b receptors present on neutrophils, eosinophils, monocytes
and macrophages, thereby activating the terminal lytic complement sequence,
C5-C9 (Roitt, I. et al.. Immunology, Gower Medical Publishing, London, New
York, pp. 7.1-7.14 (1985)).
Complement is designed to fight infection and injury; however, this
same mechanism, if inappropriately activated, can cause a significant amount
of inflammation and tissue damage as a result of the rapid and aggressive
enzyme activity. Complement-induced inflammation and tissue damage has
been implicated in a number of disease states, including: the intestinal
inflammation of Crohn's disease which is characterized by the lymphoid
infiltration of mononuclear and polymorphonuclear leukocytes (Ahrenstedt et
al., New Engl. J. Med. 322:1345-9 (1990)), thermal injury (burns, frostbite)
(Gelfand et al., J. Clin. Invest. 70:1170 (1982); Demling et a!., Surgery
106:52-9(1989)), hemodialysis (Deppisch et al., Kidney fast. 37:696-706
(1990); Kojima et al., Nippon Jenzo Gakkai Shi 31:91-7 (1989)), post pump
syndrome in cardiopulmonary bypass (Chenoweth et al., Complement.
Injlamm. 5:152-165 (1981); Chenoweth et al., Complement 3:152-165 (1986);
Salama et al., N. Engl. J. Med. .318:408-14 (1988)), and ischaemia (Huang et
al., Science 285:595 (1999); Naka et al., Transplantation (54:1248 (1997);
Pemberton et al., J. Immunol 750:5104 (1993); Chavez-Cartaya et al.,
Transplantation 59:1047 (1995); Hill et al., J. Immunol. 149:1723 (1992);
Weisman et al., Science 249:146 (1990)). Both complement and leukocytes
are reported to be implicated in the pathogenesis of adult respiratory distress
syndrome (Zilow et al., Clin. Exp. Immunol. 79:151-57 (1990); Langlois et al.,
Heart Lung 75:71-84 (1989)). Activation of the complement system is
suggested to be involved in the development of fatal complications in sepsis
(Hack et al., Am. J. Med. 86:20-26 (1989)) and causes tissue injury in animal
models of autoimmune diseases such as immune-complex-induced vasculitis
(Cochrane, Springer Seminar Immunopathol. 7:263 (1984)),
glomerulonephritis (Couser et al., Kidney Inst. 29:879 (1985)), type II
collagen-induced arthritis (Watson & Townes,J. Exp. Med. 7(52:1878 (1985)),
and experimental allergic neuritis (Feasby et al., Brain Res. 419:91 (1987)).
The complement system is also involved in hyperacute allograft and
hyperacute xenograft rejection (Knechtle et al., J. Heart Transplant 4(5):54l
(1985); Guttman, Transplantation 77:383 (1974); Adachi et al., Trans. Proc.
19(1):1145 (1987)). Complement activation during immunotherapy with
recombinant IL-2 appears to cause the severe toxicity and side effects
observed from IL-2 treatment (Thijs et al., J. Immunol. 144:2419 (1990)).
Complement fragments generated by the classical portion of the
complement cascade have been found to be present in the immune complexes
formed against indigenous tissue in autoimmune diseases. Such diseases
include, but are not limited to: Hashimoto's thyroiditis, glomerulonephritis
and cutaneous lesions of systemic lupus erythematosus, other
glomerulonephritides, bullous pemphigoid, dermatitis herpetiformis,
Goodpasture's syndrome, Graves' disease, myasthenia gravis, insulin
resistance, autoimmune hemolyic anemia, autoimmune thrombocytopenic
purpura, and rheumatoid arthritis (Biesecker et al. J. Exp. Med. 154: 1779
(1981); Biesecker et al., N. Engl J. Med. 306: 264 (1982); Falk et al.., Clin.
Research 32:503A (Abstract) (1984); Falk et al., J. Clin. Invest. 72:560
(1983); Dahl et al., J. Invest. Dennatol 52:132 (1984); Dahl et al., Arch.
Dermatol. 121:70 (1985); Sanders et al., Clin. Research 35:388A (Abstract)
(1985); and U.S. Patent Nos. 5,268,363 and 4,722,890).
Compounds that potently and selectively inhibit complement will have
therapeutic applications in several acute and chronic immunological and non-
immunological disorders, and a. variety of neurodegenerative diseases.
Evidence from both human and animal studies shows that activation of the
classical complement pathway is primarily involved in neurodegenerative
diseases of the central nervous system (CNS). Autoimmune diseases in which
these inhibitors of the complement cascade system will be therapeutically
useful include myasthenia gravis (MG), rheumatoid arthritis, and systemic
lupus erythematosus. Neurodegenerative diseases in which inhibitors of the
complement cascade system, will be therapeutically useful include the
demyelinating disorder multiple sclerosis (MS), the neuropathies Guillain-
Barre syndrome (GBS) and Miller-Fisher syndrome (MFS), Alzheimer's
disease (AID), and prion-related disease (variant Creutzfeld Jacob disease).
Other diseases and conditions include hereditary and acquired angioedema (in
which a deficiency in complement inhibitory protein leads to an active
complement consumption and repeated episodes of life-threatening
angiodema), septic shock, paroxysmal nocturnal hemoglobinuria, organ
rejection (transplantation), burns (wound healing), brain trauma, soft tissue
trauma, asthma, platelet storage, hemodialysis, isehemia-reperfusion injury,
and cardiopulmonary bypass equipment (Makrides, Pharmacol. Rev. 50:59-87
(1998); Spiegel et al., Strategies for Inhibition of Complement Activation in
the Treatment of Neurodegenerative Diseases in: Nenroinflammation:
Mechanisms and Management, Wood (ed.), Humana Press, Inc., Totowa, NJ,
Chapter 5, pp. 129-176; and U.S. Patent No. 4,916,219).
A number of strategies have been proposed for the inhibition of
primarily the classical complement pathway. Efforts to directly inhibit
complement activation have focused on chemical compounds that inhibit
complement components such as C1r and C1s. Small peptide inhibitors of
convertases, such as the C3 and C5 convertases., have also been described
(Liszewski and Atkinson, Exp. Opin. Invest. Drugs 7: 323-332 (1998). So far,
the best studied 'designer' complement inhibitor for treatment of CNS
disorders is soluble recombinant human complement receptor Type 1 (sCR1).
sCR1 has proven effective in animal models of CNS diseases and is under
investigation for use in man (Fearon, Clin. Exp, Immunol. 86 (Suppl.l):43-46
(1991)). However, there are several drawbacks to the use of sCRl in disorders
of the CNS: the agent is expensive, must be administered systemically, and
has a short half-life in vivo. The next generation of complement inhibitors are
likely to solve many of these drawbacks (Spiegel et al.., Strategies for
Inhibition of Complement Activation in the Treatment of Neurodegenerative
Diseases in: Nenroinflammation: Mechanisms and Management, Wood (ed.),
Humana Press, Inc., Totowa, NJ, Chapter 5, pp. 129-176).
A need continues to exist for non-peptidic compounds that are potent
inhibitors of complement, specifically C1s, and which possess greater
bioavailability and fewer side-effects than currently available C1s inhibitors.
Accordingly, novel C1s inhibitors, characterized by potent inhibitory capacity,
are potentially valuable therapeutic agents for a variety of conditions.
Summary of the Invention
The present invention provides a novel class of thienyl amidines. The
thienyl amides of Formula I inhibit the enzyme C1s, a protease in the classical
pathway of the complement system, and thus, can be used to treat or
ameliorate complement-mediated acute or chronic disorders in mammals.
Thus, a first aspect of the present invention is directed to novel
compounds of Formula I.
In a second embodiment, the present invention provides a
pharmaceutical composition comprising a compound of Formula I and a
pharmaceutically acceptable carrier or diluent.
The present invention further provides a method for treating acute and
chronic disorders associated with activation of the classical pathway of the
complement system by administering to a mammal in need of such treatment a
therapeutically effective amount of a compound of Formula I. These acute
and chronic conditions are caused either in whole or in part by inflammation
and tissue damage that result from aberrant activation of the complement
cascade.
In one embodiment, compounds of Formula I can be administered to a
mammal to treat complement-mediated inflammation and tissue damage.
Examples of conditions that can be treated include intestinal inflammation of
Crohn's disease, thermal injury (burns, frostbite), post pump syndrome in
cardiopulmonary bypass, and ischaemia (stroke, myocardial infarction,
ischaemic colitis, hemorrhagic shock, trauma, post-surgical tissue damage and
delayed or impaired function of organ or graft following transplant).
The complement system is activated in hyperacute allograft and
hyperacute xenograft rejection, and in acute humoral rejection mediated by
donor-specific antibodies. Thus, in yet another embodiment, compounds of
Formula I can be administered to a mammal before, during or after the
transplant of an organ or a graft to ameliorate the rejection of such organ or
graft by the mammal. Grafts can include an allograft or xenograft.
Complement activation during immunotherapy with recombinant IL-2
appears to cause acute vascular leak syndrome that results in the severe
toxicity and side effects observed from IL-2 treatment and other conditions
such as bone marrow transplantation and acute pancreatitis. In another
embodiment of the present invention, a compound of Formula I is
administered to a mammal before, during or after treatment of said mammal
with IL-2, bone marrow transplantation, or onset of pancreatitis, in an amount
effective to reduce the vascular leak syndrome that causes toxicity and side-
effects associated with the treatment or disorders.
In another embodiment., compounds of Formula I can be administered
to a mammal to treat complement-mediated tissue injury associated with
autoimmune diseases. Examples of autoimmune diseases that are treatable
according to the present invention include Hashimoto's thyroiditis, Addison's
disease, glomerulonephritis and cutaneous lesions of systemic lupus
erythematosus, other glomerulonephritides, bullous pemphigoid, pemphigus,
Goodpasture's syndrome, Graves' disease, immune-complex-induced
vasculitis, hemolytic anemia, myasthenia gravis, allergic neuritis, myasthenia
gravis, Type I diabetes mellitus, autoimmune hemolytic anemia, autoimmune
thrombocytopenic purpura, type II collagen-induced arthritis, and rheumatoid
arthritis. Autoimmune diseases preferred for treatment by inhibitors of the
present invention include myasthenia gravis (MG), rheumatoid arthritis, and
systemic lupus erythematosus.
Another embodiment of the present invention is directed to
administering a therapeutically effective amount of a compound of Formula I
to a mammal that has been diagnosed with a neurodegenerative disease.
Neurodegenerative diseases m winch inhibitors of the complement cascade
system will be therapeutically useful include the demyelinating disorder
multiple sclerosis (MS), the neuropathies Guillain-Barre syndrome (GBS) and
Miller-Fisher syndrome (MFS)., Alzheimer's disease (AD), and variant
Creutzfeldt-Jakob disease.
In another embodiment, compounds of the present invention can be
administered to a mammal to treat complement-mediated complications in
sepsis, or symptoms of adult respiratory distress syndrome.
Other diseases and conditions that can be treated include hereditary
and acquired angioedema, paroxysmal nocturnal hemoglobinuria, brain trauma
and other soft tissue trauma, asthma and hemodialysis.
Compounds of Formula I can also be employed in vitro for human
organ and graft storage as well as platelet storage.
Detailed Description of the Preferred Embodiments
Compounds useful in the present invention have the general Formula I:
or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein:
Z is-S(O)-or-S(O2)-;
R1 is C1-4 alkyl, halo, amino, C1-6 alkylthio, C2-6 alkenylthio, C1-6
alkoxy, trifluoromethyl, methylsulfonyl, or benzylthio; preferably halo, C1-4
alkylthio or C2-4 alkenylthio;
Ar is phenyl, naphthyl, pyridyl, imidazolyl, thiazolyl, furanyl, thienyl,
benzothiazolyl, pyrazolyl, pyrimidinyl, benzimidazolyl, benzofuranyl,
indolyl, benzothiophenyl or benzo[c]chromenyl, any of which is optionally
substituted;
R2, R3 and R4 are independently hydrogen, C1-4 alkyl, C6-10 aryl, C1-4
hydroxyalkyl, C1-4 aminoalkyl, mono(C1-4)alkylamino(C2-6)alkyl, di(C1-
4)alkylamino(C2-6)alkyl, carboxy(C1-4)alkyl, cyano, amino, nitro, C1-4 alkoxy,
or hydroxy, or -CO2RW, where
Rw is hydrogen, hydroxy, C1-4 alkoxy, cyano, C1-4
alkoxycarbonyl, C1-4 alkyl, C3-8 cycloalkyl, phenyl, benzyl,
where Rd and Re are independently hydrogen, C1-6 alkyl,
C2-6 alkenyl or phenyl,
Rf is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl,
Rg is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, and
Rh is C6-10 ar(C1-4)alkyl or C1-6 alkyl; and
R7 is hydrogen, chloro, fluoro or amino.
A first preferred group of compounds falling within the scope of the
present invention include compounds of Formula I wherein Ar is naphthyl or
phenyl substituted by one or two of C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, halo,
hydroxy, phenyl, phenoxy, amino or phenylamino. Useful values of Ar in
this aspect of the invention include 2-phenylphenyl, naphth-2-yl, 2-
methoxyphenyl, 4-methoxyphenyl, 4-chlorophenyl, 2-bromophenyl, 3,4-
dimethylphenyl, 3-methoxyphenyl, 3-bromophenyl, 4-ethylphenyl, 4-
bromophenyl, 4-phenylphenyl, 3,4-dimethoxyphenyl, 2-isopropylphenyl, 3,5-
dichlorophenyl, 3-hydroxyphenyl, 2-methyl-5-t-butylphenyl, 4-t-butylphenyl,
3-bromo-5-t-butoxyphenyl., 3-bromo-5-hydroxyphenyl, 3-bromo-5-
methoxyphenyl, 3-bromo-5-vinyloxyphenyl, 3-phenoxyphenyl, 5-bromo-3-
methylphenyl and 2-aminophenyl.
Another group of compounds falling within the scope of the present
invention include compounds of Formula I wherein Ar is phenyl substituted
by one or two of C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, halo, hydroxy, phenyl,
phenoxy, amino, phenylamino, hydroxytetrahydropyranyl, (C1-4 alkoxy)-
tetrahydropyranyl, hydroxypiperidinyl, hydroxy-N-(C1-4 alkyl)-piperidinyl,
hydroxy-pyridinyl-(C1-4)alkyl or (C1-4 alkoxy)carbonyl(C2-6)alkenyl.
Additional useful values of Ar in this aspect of the invention include 4-amino-
3-bromophenyl, 3-(4-hyiroxytetrahydropyran-4-yl)-phenyl, 3-(4-hydroxy-
1-methylpiperidin-4-yl)-phenyl, 3-(4-methoxytetrahydropyran-4-yl)-phenyl,
3-(hydroxy-pyridin-2-yl-methyl)-phenyl, 3-(1-ethoxycarbonyl-propen-2-yl)-
phenyl, 3-chloro-4-fluorophenyl and 3-iodophenyl.
Another group of compounds falling within the scope of the present
invention include compounds of Formula I wherein Ar is pyridyl, imidazolyl,
furanyl, thienyl, thiazolyl, benzothiazolyl, benzofuranyl, benzothiophenyl,
indolyl, benzimidazolyl or benzo[c]chromenyl, any of which is optionally
substituted by one or two of C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, halo,
hydroxy, amino, phenyl, phenoxy or tolyl. Useful values of Ar in this aspect
of the invention include pyrid-2-yl, pyrid-3-yl, imidazol-2-yl, 1-
methylimidazol-2-yl, 2-methylfuran-2-yl, thien-2-yl, thiazol-2-yl, 4-
phenylthiazol-2-yl, 5-ethoxybenzothiazol-2-yl, benzimidazol-2-yl, 7-bromo-1-
methyl-1H-benzoimidazolyl, 4-bromo-1 -methyl-1H-benzoimidazolyl, 4-
bromo-2-methyl-1H-benzoimidazolyl, 4-bromo-1H-benzoimidazolyl, 6-
bromo-benzimidazolyl, pyrrol-2-yl, and piperdin-2-yl. An additional useful
value of Ar in this aspect of the invention is 6H-benzo[c]chromen-2-yl.
Useful values of Ar in this aspect of the invention also include those of
Formula LA:
wherein:
Rx is halo, or phenyl substituted by one or two of C1-6 alkyl or C1-4
alkyl)oxy(C1-4)alkyl wherein one of the C1-4 alkyl portions is optionally
substituted by carboxy;
Ry is hydrogen, amino, halo, phenoxy or C1-6 alkylamino wherein the
alkyl portion is optionally substituted by one of phenyl, pyridyl,
tetrahydrofuranyl, imidazolyl, morpholinyl, (C1-4 haloalkyl)-pyridyl,
sulfonamidophenyl, hydroxy, (C1-4 alkyl)-thienyl or aminopyrimidinyl; and
Rz is hydrogen, halo or C1-4 alkyl.
Useful values of Rx include 2-methylphenyl,
2-carboxymethoxymethyl-6-methylphenyl and bromo.
Useful values of Ry include hydrogen, chloro, amino, phenoxy,
benzylamino, isopropylamino, pyrid-3-ylmethylamino, pyrid-
4-ylmethylamino, pyrid-2-ylmethylamino, tetrahydrofuran-2-ylmethylamino,
3-(imidazol-1-yl)-propylamino, 2-methyl-2-(morpholin-4-yl)-propylamino,
6-trifluoromethyl-pyrid-3-yl]tnethylamino, 2-(3H-imidazol-1-yl)-ethylamino,
4-sulfamoylbenzylamino, 2,2-dimethyl-3-hydroxypropylamino,
3-methylthien-2-ylmethylamino and 4-aminopyrimidin-5-ylmethylamino.
Useful values of Rz include hydrogen, methyl or ethyl.
Preferred values of Rx include bromo. Preferred values of Ry include
optionally-substituted C1-6, alkylamino. Preferred values of Rz include
hydrogen.
Useful values of Ar in this aspect of the invention also include those of
Formula IB:
wherein:
R13 and R14 are independently hydrogen, halo or C1-4 alkyl;
EL15 is hydrogen, halo or tolyl;
PL17 is hydrogen or C1-4 alkyl; and
one of R16 and R18 is an electron pair and the other is hydrogen, C1-6
alkyl, C2-6 alkenyl, cyclopropylmethyl, phenyl, benzyl, 1-phenylethyl,
pyridylmethyl or isoxazolylmethyl optionally substituted with one or two
methyl groups, wherein said benzyl is unsubstituted or is substituted with one
or two of halo, nitro, amino or (2-carboxyethyl)-sulfanylacetylamino.
Useful values of R13 and R14 include hydrogen, methyl and ethyl.
Useful values of R15 include hydrogen, bromo, chloro and o-tolyl.
Useful values of R17 include hydrogen, methyl and ethyl.
Useful values of R16 and R18, other than an electron pair, include
hydrogen, methyl, cyclopropylmethyl, allyl, 3-methylbut-2-enyl, pyrid-
2-ylmethyl, 3,5-dimethylisoxazol-4-ylmethyl, phenyl, 1-phenylethyl, benzyl,
2,6-dichlorobenzyl, 2,5-difluorobenzyl, 2.,6-difluorobenzyl, 2-fluoro-
5-nitrobenzyl, 2-fluoro-4-nitrobenzyl, 2-fluoro-5-aminobenzyl and
5-[(2-carboxyethyl)-sulfanylacetylamino]-2-fluorobenzyl.
Preferred R13 include hydrogen. Preferred R14 include hydrogen.
Preferred R15 include brorno and chloro. More preferred is bromo. Preferred
R17 include hydrogen. Preferred R16 and R18 ,other than an electron pair,
include hydrogen, phenyl, 1-phenylethyl, benzyl and benzyl substituted with
one or two, preferably two, of halo, amino or nitro. More preferred are benzyl
and benzyl substituted with two of fluoro, chloro, arnino or nitro.
In yet another aspect of the invention, Ar is a substituted phenyl group
having a required substituent in the 3-position of the phenyl ring and an
optional substituent on one of the remaining positions of the phenyl ring.
Thus, this aspect of the invention is directed to compounds of the overall
Formula II:
or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein:
R1, R2, R3, R4,R7 and Z are defined as above, and
R5 is phenyl., naphthyl, thienyl, furanyl, imidazolyl, oxazolyl,
isoxazolyl, pyridyl, pyrimidinyl, benzothienyl, benzofuranyl, benzimidazolyl,
quinolinyl, isoquinolinyl, pyrazinyl, piperidinyl or piperazinyl, any of which is
optionally substituted; and.
R6 is hydrogen, C1-4 alkyl., hydroxy, C1-4 alkoxy, C2-4 alkenyloxy,
phenoxy, benzyloxy, halo, ammo or nitro.
In one embodiment R5 is naphthyl, phenyl or phenyl substituted by one
to five, preferably one or two groups independently selected from the group
consisting of C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxyalkyl, C1-4 haloalkyl, C2-4
alkenyl. (C1-4 alkyl)carbonyl, cyano, amino, mono(C1-4)alkylamino,
di(C1-4)alkylamino, formyl, (C1-4 alkoxy)carbonyl, halo(C1-4 alkoxy)carbonyl,
phenyl, phenoxy, phenoxyphenyl, biphenyl, halo, C1-4 haloalkoxy, carboxy,
nitro, methylenedioxo (-O-CH2-O-), ethylenedioxo, C1-4 alkylsulfonyl, C1-4
alkylsulfinyl, C1-4 alkylthio, hydroxy, aminocarbonyl,
mono(C1-4alkyl)aminocarbonyl, di(C1-4alkyl)aminocarbonyl and halogenated
C1-4 hydroxyalkyl.
Useful values of R5 in this embodiment include phenyl,
2-methoxyphenyl, 2-methylphenyl, 2-vinylphenyl, 2-hydroxymethylphenyl,
2-(l-hydroxyethyl)phenyl, 2-trifluoromethylphenyl, 2-formylphenyl,
2-hydroxyphenyl, 2-chloromethylphenyl, 2-amino, 2-chlorophenyl,
3-methoxyphenyl, 3-methylphenyl, 3-formylphenyl, 3-hydroxymethylphenyl,
3-aminophenyl, 3-isopropylphenyl, 3-ethoxyphenyl, 3-ethoxycarbonylphenyl,
3-methylcarbonylphenyl, 3-ca.rboxyphenyl, 3-hydroxyphenyl, 3-nitrophenyl,
3-dimethylaminocarbonylphenyl, 3-trifluoromethylphenyl,
3-trifluoromethoxycarbonylphenyl, 4-vinylphenyl, 4-trifluoromethoxyphenyl,
4-methoxycarbonylphenyl, 4-methylphenyl, 4-hydroxymethylphenyl,
4-trifluoromethylphenyl, 4-cyanophenyl, 4-ethoxyphenyl,
4-dimethylaminophenyl, biphenyl, 4-phenoxyphenyl, 4-chloromethyl,
4-methylsulfonyl)phenyl, 4-hydroxyphenyl., 4-fluorophenyl,
2,5-dimethylphenyl, 2,2-dichlorophenyl., 2,3-dimethylphenyl,
2,5-dichlorophenyl, 3,,5-dichlorophenyl, 3-hydroxy-4-phenylphenyl,
3,5-bistrifluoromethylphenyl, 2-hydroxy-5-phenylphenyl, 4-methyl-3-
nitrophenyl, 3,4-rnethylenedioxophenyl, 3,5-dimethylphenyl,
2,4-dimethoxyphenyl, 2-ethoxy-6-methylphenyl, 3-isopropoxycarbonyl-2-
methylphenyl, 3-fluoro-4-phenylphenyl, 4-formylphenyl, 2-carboxy-6-
methylphenyl, 3-formyl-2-methylphenyl, 3-hydroxy-6-methylphenyl,
3-formyl-6-methylphenyl, 3-formyl-6-hydroxyphenyl, 3-formyl-6-
methoxyphenyl, 2-amino-6-methylphenyl, 3,4-dimethoxyphenyl, 3-[(2,2,2-
trifluoro-1 -hydroxy)ethyl]phenyl, 4-nitrophenyl, 2-fluoro-4-phenylphenyl,
2,4-dimethoxyphenyl, 4-hydroxy-3-formylphenyl, 2-tolyl-5-
morpholinephenyl, 4-methoxyphenyl, 3-hydroxyaminomethyl phenyl, 4-
phenyl-acetamide, 4-benzamide, 2,6-dimethylphenyl, phenoxyphenyl, 2-
methyl-6-hydroxym ethyl phenyl, 2-methyl-5-hydroxymethyl phenyl, 2-
hydroxy-3-phenylphenyl, naphthyl and 4-ethoxycarbonylphenyl. An
additional useful value of R5 is 6-methyl-3,4-methylenedioxophenyl.
In another embodiment R5 is phenyl substituted by one to three groups
independently selected from the group consisting of C1-4 alkyl, C1-4, alkoxy, C1-
4 hydroxyalkyl, C1-4 haloalkyl, C2-4 alkenyl, (C1-4 alkyl)carbonyl, cyano,
amino, mono(C1-4)alkylammo, di(C1-4)alkylamino, formyl, (C1-4
alkoxy)carbonyl, halo(C1-4 alkoxy)carbonyl, phenyl, phenoxy, phenoxyphenyl,
biphenyl, halo, C1-4 haloalkoxy, carboxy, nitro, methylenedioxo (-O-CH2-O-),
ethylenedioxo, C1-4 alkylsulfonyl, C1-4 alkylsulfinyl, C1-4 alkylthio, hydroxy,
aminocarbonyl, mono(C1-4alkyl)aminocarbonyl, di(C1-4alkyl)aminocarbonyl,
halogenated C1-4 hydroxyalkyl, carboxy(C1-4)alkoxy(C1-4)alkyl,
carboxy(C1-4)aIkoxy, C1-4 alkylthio(C1-4)alkyl wherein the alkyl portion of C1-4
alkylthio is optionally substituted with one or two carboxy groups,
phosphono(C2-4)alkenyl, phosphono(C1-4)alkylamino, C1-4
haloalkylsulfonylamino, phosphono(C1-4)alkoxy, C1-4 alkylsulfonylamino,
carboxy(C1-4)alkylamino, morpholinyl(C1-4)alkyl, morpholinyl,
morphol.inyl(C1-4)alkylaminocarbonyl, piperazinyl(C1-4)alkyl or piperazinyl
wherein either of said piperazinyl(C1-4)alkyl or piperazinyl is optionally
N-substituted with methyl or ethyl, formylamino,
morpholinyl (C1-4)alkylamino, optionally-substituted alkylcarbonylamino,
optionally-substituted ureido and optionally-substituted guanidino.
Useful optionally-substituted alkylcarbonylamino groups have the
formula -N(H)-C(O)-C(H)(W1)-Yla-X1-Ylb-ZI, wherein:
W1 is hydrogen or amino;
Yla is a direct covalent bond or an a,?-diradical of a C1-10 straight or
branched alkane;
X1 is O or S, or a. direct covalent bond;
Ylb is an a,?-diradical of a C1-10 straight or branched alkane,
optionally substituted with a carboxy group or an amino group; and
Z1 is carbamoyl, carboxy, C1-6 alkylsulfonyl, (C1-6 alkoxy)carbonyl,
C2-6 alkanoylamino, sulfo, phosphono, phenyl, aminosulfonyl, amino, C1-6
haloalkylsulfonylamino, fonnylamino, C1-6 alkylamino, C1-6
alkylaminosulfonyl, C1-6 alkylsulfonylamino or 2-oxo-hexahydro-
thieno[3,4-d]imidazol-6-yl-(C1-6 alkyl)carbonylamino;
or, W1 is hydrogen and Yla-X1-Y1b-Z1 represents hydrogen, halo,
amino or tri-(C1-4 alkyl)ammonio;
provided that, if Yla is a direct covalent bond and X is 0 or S, then W1
is hydrogen.
Useful optionally-substituted ureido groups have the formula
-N(L1)C(O)-N(L2)-Y2a-X2-Y2b-Z2, wherein:
L1 and L2 are both hydrogen, or L1 and L2 together represent ethylene
or trimethylene;
Y2a is a direct covalent bond or an a,?-diradical of a C1-10 straight or
branched alkane;
X2 is O or S, or a direct covalent bond;
Y2b is an a,?-diradical of a C1-10 straight or branched alkane,
optionally substituted with a carboxy group; and
Z2 is carboxy, (C1-6 alkoxy)carbonyl, phenoxy, carboxyphenoxy, C1-6
alkylsulfonyl, phenyl, benzyloxycarbonylamino, amino, C1-4 alkylamino,
halophertyl, indolyl, diphenylmethyl, phenylsulfonylamino,
N'-(carboxy(C1-4)alkyl)ureido, tetrazolyl, phosphono or phenylamino;
or, Y2a-X2-Y2b-Z2 represents C1-4 alkylsulfonyl or
-(CH2CH2-O-)m-(CH2)n-C(O)OR wherein m is an integer from 2 to 6, n is an
integer from 2 to 4, and R is hydrogen or C1-4 alkyl.
Useful optionally-substituted guanidino groups have the formula
-N(L3)-C(=NL4)-N(L5)-Z3, wherein:
L3 is hydrogen or C1-4 alkyl;
L4 and L5 are both hydrogen, or L4 and L5 together represent ethylene;
and
Z3 is hydrogen, C1-6 alkyl, phenyl(C1-6)alkyl, carboxy(C1-6)alkyl, C1-4
alkoxy, (C1-4 alkyl)carbonyl or C1-4 alkylsulfonyl(C1-6)alkyl.
One group of preferred compounds in this embodiment includes those
wherein R5 is phenyl substituted at the 2'-position by methyl and at the
4'-position by optionally-substituted guanidino. A more preferred group of
compounds in this embodiment includes those wherein R5 is phenyl
substituted at the 2'-position by methyl, at the 4'-position by optionally-
substituted guanidino, and at the 6'-position by optionally-substituted
alkylcarbonylamino or optionally-substituted ureido. Another group of
preferred compounds in this embodiment includes those wherein R5 is phenyl
substituted at the 2'-position by methyl and at the 6'-position by optionally-
substituted alkylcarbonylamino or optionally-substituted ureido. Within these
preferred groups, R1 is preferably methylthio, R2, R3, R4, R6 and R7 are
preferably hydrogen, and Z is preferably -SO2-.
Useful values of R5 in this embodiment also include those of
Formula IIA:
wherein:
R8 is hydrogen or methyl;
R9 is hydrogen, formylamino or carbamoyl;
R10 is methoxy, hydroxy, carboxymethoxy, phosphonomethylamino,
trifluoromethanesulfonylamino, phosphonomethoxy, carboxymethylamino,
amino, chloro, fluoro, 2-(morpholin-4-yl)-ethylamino, carboxy, carbamoyl,
(l,2-dicarboxyethyl)-sulfanylacetylamino, carboxymethoxyacetylamino,
4-amino-4-carboxybutyrylainino, 6-[5-(2-oxo-hexahydro-
thieno[3,4-d]imidazol-6-yl)--peritanoylamino]-hexanoylamino,
bromoacetylamino, 2-amino-4-carboxybutyrylamino,
triethylammonioacetylamino, 2-amino-4-methanesulfonylbutyrylamino,
aminoacetylamino, carbamoylmethylsulfanylacetylamino,
3-phosphonopropionylamino, ureido, N'-(5-carboxypentyl)-ureido,
N'-(5-ethoxycarbonylpentyl)-ureido, N'-(3-methanesulfonylpropyl)-ureido,
guanidino, N'-(3-phenylpropyl)-guanidino, N'-(2-phenylethyl)-guanidino,
N'-(3-methylbutyl)-guanidino, N'-acetylguanidino,
N'-(4-methanesulfonylbutyl)-guamdino, N'-(3-methanesulfonylpropyl)-
guanidino, N'-(6-methamesulfonylhexyl)-guanidino,
N'-(5-methanesulfonylpentyl)-guanidino, N'-methoxyguanidino,
N-methylguanidino, N'-hexylgiaanidino, N'-(5-carboxypentyl)-guanidino or
4,5-dihydro-1H-imidazol -2-ylamino;
R11 is hydrogen, 3-(morpholin-4-yl)-propylaminocarbonyl or
carboxymethoxymethyl; and
R12 is carboxymethoxymethyl, 2-carboxyethoxymethyl, nitro, amino,
methyl, (l,2-dicarboxyethyl)-sulfanylmethyl, 2-phosphonovinyl, morpholin-
4-ylmethyl, 4-methylpiperazin-1-ylmethyl, morpholin-4-yl, formylamino,
methanesulfonylamino, carboxymethylamino, 3-(morpholin-4-yl)-
propylaminocarbonyl, chloro, acetylamino,
carbamoylmethylsulfanylacetylamino, (2-carbox}'ethyl)-sulfanylacetylamino,
4-methanesulfonylbutyrylammo, (1,2-dicarboxyethyl)-sulfanylacetylamino,
methoxyciirbonylmethoxyacetylamino, carboxymethoxyacetylamino,
bromoacetylamino, 4-carboxybutyrylamino, carbamoylmethoxyacetylamino,
(2-acetylamino-2-carboxy-l,l-dimethylethyl)-sulfanylacetylamino,
(2-sulfoethyl)-sulfanylacetylarnino, (2-methoxycarbonylethyl)-
sulfanylacetylamino, (2-acetyliimino-2-carboxyethyl)-sulfanylacetylamino,
methanesulfonylacetylamino, 6-methanesulfonylhexanoylamino,
3-methanesulfonylpropionylamino, 2-methanesulfonylpropionylamino,
benzylsulfanylacetylamino, 4-aminosulfonylbutyrylamino,
11 -aminoundecanoylamino, 4-trifluoromethanesulfonylaminobutyrylamino,
5-carboxyvalerylamino, carboxyacetylamino, 3-carboxypropionylamino,
11-carboxyundecanoylamino, 5-methoxycarbonylvalerylamino.
N'-ethoxycarbonylmethylureido, N'-carboxymethylureido,
N'-[5-(4-carboxyphenoxy)-pentyl]-ureido, N'-(2-methanesulfonylethyl)-
ureido, N'-(5-carboxypentyl)-ureido, N'-(2-[2- {2-(2-carboxyethoxy)-ethoxy}-
ethoxy]-ethoxyethyl)-ureido, N'-methanesulfonylureido,
N'-(4-methanesulfonylbutyl)-ureido, N'-(3-phenylpropyl)-ureido,
N'-benzyiureido, N'-( 1 -carboxy-2-phenyleth yl)-ureido,
N'-(5-benzyloxycarbonylamino-5-carboxypentyl)-ureido, N'-(2-phenylethyl)-
ureido, N'-(5-amino-5-carboxypentyl)-ureido, N'-[2-(4-bromophenyl)-ethyl]-
ureido, N'-[2-(indol-3-yl)-ethyl]-ureido, N'-(3,3-diphenylpropyl)-ureido,
N'-(2-phenylsulfonylaminoethyl)-ureido, N'-(2-methanesulfonylaminoethyl)-
ureido, N'-[2-(N'-carboxyinethylureido)-ethyl]-ureido, N-[2-(2H-tetrazol-
5-yl)-ethyl]-ureido, N'-[4-(2H-tetrazol-5-yl)-butyl]-ureido, N'-[5-(2H-tetrazol-
5-yl)-pentyl]-ureido, N'-(5-phosphonopentyl)-ureido,
N'-(5-ethoxycarbonylpentyl)-ureido, N'-(3-methanesulfonylpropyl)-ureido,
N'-(2-phenylaminoethyl)-ureido or 2-oxo-imidazolidin-1-yl.
One preferred group of compounds in this embodiment includes those
wherein R8 is methyl, and R9 and R11 are both hydrogen. Another preferred
group of compounds in this embodiment includes those wherein R8 is methyl,
and R9, R11 and R12 are all hydrogen. Another preferred group of compounds
in this embodiment includes those wherein R8 is methyl, and R9, R10 and R11
are all hydrogen.
In an additional embodiment, R5 is thienyi, furanyl, imidazolyl,
oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, benzothienyl, benzofuranyl,
dibenzofuranyl, benzimidazolyl, qumolinyl, isoquinolinyl, indolyl or
pyrazinyl, optionally substituted by one or two groups independently selected
from the group consisting of C1-4 alkyl, C1-4 alkoxy, C1-4 hydroxyalkyl, C1-4
haloalkyl, C2-4 alkenyl, formyl, (C1-4 alkoxy)carbonyl, phenyl, C1-4
alkylphenyl, phenoxy, halo, C1-4 haloalkoxy, carboxy, hydroxy, nitro, amino,
C1-10 alkylsulfonyl(C1-4 alkyl)ureido, sulfo(C1-4)alkyl,
trimethylsilanyl(C1-4)alkoxy(CC1-4)alkyl and C1-4 alkoxy(C1-4)alkyl.
Where R5 is a heteroaryl group, useful values include thien-3-yl,
quinolin-7-yl, 3,5-dimethylisoxazol-4-yl, 5-chlorothien-2-yl, pyrid-3-yl,
pyrimidin-4-yl, quinolin-3-yl, benzothien-2-yl, benzofuran-2-yl, furan-2-yl,
furan-3-yl, 4-methylpyrid-3-yl, 3-methyl-pyrid-2-yl, 6-methylbenzimidazol-5-
yl, benzimidazol-6-yl, l-rnethyl-4-(2'-methylphenyl)benzimidazol-6-yl, 2-
methyl-4-(2'-methylphenyl)benzimidazol-6-yl, dibenzo furan-2-yl, 2-
methylirnidazolyl, 6-ethoxy-benzothiazolyl, 6-methyl-pyrid-3-yl, 6-chloro-
pyrid-3-yl, and 3-chloro-pyrid-2-yl.
Where R5 is a heteroaryl group, useful values also include 3-methyl-
5-nitropyrid-2-yl, 5-amino-3-methylpyrid-2-yl, 4-methylpyrimidin-5-yl,
3-methylpyrid-2-yl, 2-chloropyrid-3-yl, 6-formylpyrid-2-yl, 3-methyl-
5-[N'-(3-methanesulfonylprop-l-yl)]-ureidopyrid-2-yl, 3-methyl-pyrid-4-yl,
3-amino-5-methyl-pyrid-4-yl, 3-chloro-5-trifluoromethylpyrid-2-yl,
1H-benzimidazol-2-yl, 1 -methyl-1H-benzimidazol-2-yl, 3 -methyl-
3H-imidazol-4-yl, 1H-imidazol-2-yl, l-methyl-1H-tmidazol-2-yl, 1-ethyl-
1H-benzimidazol-2-yl, 2,5-dimethyl-1H-irnidazol-4-yl, l-(3-sulfoprop-l-yl)-
1H-benzimidazol-2-yl, 3-methylpyrazin-2-yl, 5-methyl-1-(2-trimethylsilanyl-
ethoxymethyl)-1H-benzimidazol-4-yl, 5-methyl-1H-benzimidazol-4-yl,
1-methyl-1H-benzimidazol-5-yl, 2-methoxymethyl-6-methyl-
1H-benzimidazol-5-yl, 2,6-dimei:hyl-iH-benzimidazol-5-yl and 1,6-dimethyl-
1H-benzimidazol-5-yl.
In an additional embodiment, R5 is -NRaRb, wherein Ra and Rb are
independently C1-6 alkyl, or Ra and Rb together with the nitrogen atom to
which they are attached form a ring selected from the group consisting of
piperidinyl, pyrroldinyl, piperazinyl, imidazolidinyl, pyrazolidinyl and
morpholinyl, wherein said ring is optionally substituted by one or two C1-4
alkyl groups. In this embodiment, useful values of R5 include piperidin-1-yl
and 4-methylpiperazin-1-yl.
Useful values of R6 include hydrogen, methyl, halo, amino, methoxy,
ethoxy, vinyloxy, hydroxy and benzyloxy.
For each embodiment above, preferred values of R1 include bromo,
methylthio, ethylthio or prop-2-en-l-ylthio, more preferably bromo or
methyltbio, most preferably methylthio.
One useful value of Z is SO2 An additional value of Z is SO.
Preferred values of R2, R3 and R4 are independently hydrogen, C1-6
alkyl, amino, cyano, C1-4 alkoxy or hydroxy, and are preferably all hydrogen.
Useful values of R2, R3 and R4 include hydrogen, methyl, ethyl, propyl,
n-butyl, hydroxy, methoxy, and ethoxy.
Additional preferred values of R2, R3 and R4 in Formula I also include
prodrugs such as -CO2RW, where Rw, in each instance, is preferably one of
C1-4alkyl, C4-7cycloalkyl or benzyl. Suitable values of R2. R3 and R4 include
hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy, methoxy, ethoxy, cyano,
-CO2CH3, -CO2CH2CH3 and -CO2CH2CH2CH3.
Also suitable at R2, R3 and R4 is the group -CO2RW, where Rw is one of
where Rd-Rh are defined as above. When R2, R3 and R4 are -CO2RW, where
Rw is one of these moieties, the resulting compounds are prodrugs that possess
desirable formulation and bioavailability characteristics. A preferred value for
each of Rd, Re and Rg is hydrogen, preferred Rf is methyl, and preferred values
for Rh include benzyl and /erf-butyl.
Specific compounds for use in the method of the invention include the
compounds described in the Examples, such as the following:
4-(4'-hydroxy-[l,l';3',l"]terphenyl-3"-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate,
4-(2'-methoxymethoxy-[ 1,1' :3',1"]terphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate,
3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-
methyl-biphenyl-3-carboxylic acid isopropyl ester trifluoroacetate,
3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-
methyl-biphenyl-2-carboxylic acid trifluoroacetate,
4-(6'-hydroxymethyl-2'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate,
4-(3'-formyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate,
4-(5'-hydroxymethyl-2'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate,
4-(5'-formyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate,
4-[3-(4-methyl-pyridin-3-yl)-benzenesulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate,
4-[3-(2-chloro-pyridm-3-yl)-benzenesulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate,
4-[3-(3-methyl-pyridin-2-yl)-benzenesulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidinebis-trifluoroacetate,
4-(3-allyloxy-5-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-
2-carboxamidine trifluoroacetate,
4-(3-bromo-5-methoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-
2-carboxamidine trifluoroacetate,
4-(5-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-tbiophene-2-
carboxamidine trifluoroacetate,
4-(5-methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine hydrochloride,
4-(5-allyloxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate.,
4-(5-benzyloxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine hydrochloride,
4-(2'-chloro-5-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate,
4-(2'-chloro-5-methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate,
5-bromo-4-(3'-formyl-biphenyl-3-sulfonyl)-thiophene-2-
carboxamidine trifluoroacetate,
5-amino-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxamidine
trifluoroacetate,
5-chloro-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-
carboxamidine trifluoroacetate,
4-(2'-methyl-bif)henyl-3--sulfonyl)-thiophene-2-carboxamidine
trifluoroacetate,
5-bromo-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-
carboxamidine trifluoroacetate, 4-(2'-amino-6'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate,
4-(3'-formyl-4'-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate,
{[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-
imino-methyl} -carbamic acid tert-butyl ester,
5-methylsulfanyl-4-[3'-(2,2,2-trifluoro-1-hydroxy-ethyl)-biphenyl-3-
sulfonyl]-thiophene-2-carboxamidine trifluoroacetate,
5-methylsulfanyl-4-[3'-(2,2,2-trifluoro-acetyl)-biphenyl-3-sulfonyl]-
thiophene-2-carboxamidine trifluoroacetate,
4-[3-(6-methyl-3H-benzoimidazol-5-yl)-benzenesulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine bis-trifluoroacetate,
N-hydroxy-4-[3-(6-methyl-3H-benzoimidazol-5-yl)-benzenesulfonyl]-
5-methylsulfanyl-thiophene:-2-carboxamidine trifluoroacetate,
4-[2'-(l-hydroxy-ethyl)-biphenyl-3-sulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate,
4-[4'-(l-hydroxy-ethyl)-biphenyl-3-sulfonyl]-5-methylsulfanyl-
thiophene-2-carboxarmdinetrifiuoroacetate,
4-(2'-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-(3'-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-biphenyl-
3-carboxylic acid trifluoroacetate,
4-(5'-formyl-2'-methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate,
4-(5'-formyl-2'-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidme trifluoroacetate,
N-[3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-
biphenyl-3-yl]-formimidic acid trifluoroacetate,
4-(3'-formylamino-biphenyl-3-sulfonyl)-5-methyl-sulfanyl-thiophene-
2-carboxamidine trifluoroacetate,
4-(4-tert-butyl-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-
carboxarnidine trifluoroacetate,
4-(l-methyl-1H-imidazole-2-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-(3,5-dichloro-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
5-bromo-4-(2-methoxy-benzenesulfbnyl)-thiophene-2-carboxamidine
trifluoroacetate,
5-methylsulfanyl-4-(napb.thalene-2-sulfonyl)-thiophene-2-
carboxamidine trifluoroacetate,
4-(2',4'-dimethoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-(4'-methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiopheme-2-
carboxatnidine trifluoroacetate,
4-(3',4'-dimethoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-(3'-methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-(2'-methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-tbiophene-2-
carboxamidine trifluoroacetate,
4-(3',5'-dicbioro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-(2',5'-dichloro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-(3',5'-bis-trifluoromethyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate,
4-(3-benzofuran-2-yl-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-(3-benzo[b]thiophen-2-yl-benzenesulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate,
4-(4'-methyl-3'-nitro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-
2-carboxamidine trifluoroacetate,
4-(4'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-(4'-chloro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
5-methylsulfanyl-4-(4"-trifluoromethyl-biphenyl-3-sulfonyl)-
thiophene-2-carboxamidine trifluoroacetate,
5-methylsulfanyl-4-(4'-trifluoromethoxy-biphenyl -3- sulfonyl)-
thiophene-2-carboxamidine trifluoroacetate,
5-methylsulfanyl-4-(4'-phenoxy-biphenyl-3-sulfonyl)-thiophene-2-
carboxamidine trifluoroacetate,
5-methylsulfanyl-{imino-[4-(4'-methanesulfonyl-biphenyl-3-sulfonyl)-
thiophen-2-yl]-rnethyl}-carbarnic acid tert-butyl ester,
4-(3-benzo[l,3]dioxol-5-yl-benzenesulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine tdfluoroacetate,
5-methylsulfanyl-4-(3-quinolin-7-yl-benzenesulfonyl)-thiophene-2-
carboxamidine trifluoroacetate,
4-(3'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxami dine trifluoroacetate,
4-(3'-forniyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-(3'-amino~biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
5 -methylsulfanyl-4-(3'-trifluoromethyl-biphenyl- 3 -sulfonyl)-
thiophene-2-carboxamidine trifiuoroacetate,
4-(3'-hydroxymethyl-biphenyl-3-sulfonyl)-5-methylsulfany]-
thiophene-2-carboxamidine trifluoroacetate,
5-methylsulfanyl-4-([1,1';3', 1"]terphenyl-3-sulfonyl)-thiophene-2-
carboxamidine trifluoroacetate,
4-(3-dibenzofuran-4-yl-benzenesulfonyl)-5-methylsulfanyl-thiophene-
2-carboxamidine trifluoroacetate,
5-methylsulfanyl-4-(2'-trifluoromethyl-biphenyl-3-sulfonyl)-
thiophene-2-carboxamidine trifluoroacetate,
4-(2'-hydroxymethyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate,
4-(2'-chloro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
5-methylsulfanyl-4-(3-pyridin-3-yl-benzenesulfonyl)-thiophene-2-
carboxamidine trifluoroacetate,
5-methylsulfanyl-4-(3-pyrimidin-5-yl-benzenesulfonyl)-thiophene-2-
carboxamidine trifluoroacetate,
4-(3-furan-3-yl-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
5-raethylsulfanyl-4-(3-quinolin-3-yl-benzenesulfonyl)-thiophene-2-
carboxamidine trifluoroacetate,
3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-biphenyl-
4-carboxylic acid methyl ester,
4-(3',5'-dimethyl-bipheny]-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-(3-furan-2-yl-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
5-methylsulfanyl-4-(3-thiophen-3-yl-benzenesulfonyl)-thiophene-2-
carboxamidine trifluoroacetate,
5-methylsulfanyl-4-(3'-nitro-biphenyl-3-sulfonyl)-thiophene-2-
carboxamidine trifluoroacetate,
4-(4'-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate.
4-(4'-formyl-biphenyl-3-sulfbnyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-(4'-fluoro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-(2'-fluoro-[l,l';4',1"]terphenyl-3"-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate,
4-(4'-hydroxymethyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate,
4-(4'-cyano-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-(4'-acetyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-(4'-dimethylamino-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-
2-carboxamidine trifluoroacetate,
5-methylsulfanyl-4-2'-vinyl-biphenyl-3-sulfonyl)-thiophene-2-
carboxamidine trifluoroacetate,
4-(4'-ethoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-[3-(3,5-dimethyl-isoxazol-4-yl)-benzenesulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate,
4-(2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
5-methylsulfanyl-4-(3-naphthalen-l-yl-benzenesulfonyl)-thiophene-2-
carboxamidine trifluoroacetate,
4-[3-(5-chloro-thiophen-2-yl)-benzenesulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate,
4-(2'-formyl-biphenyl--3-sulfbnyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
5-methylsulfanyl-4-(4'-vinyl-biphenyl-3-sulfonyl)-triophene-2-
carboxamidine trifluoroacetate,
4-(3'-ethoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-(2',6'-dirnethyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-(3'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-(3'-isopropyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-(2',3'-dimethyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-(2',3'-dichloro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate.,
4-(3'-acetyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-biphenyl-
3-carboxylic acid ethyl ester,
3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-biphenyl-
3-carboxylic acid dimethylamide,
3'-(5-carbamimidoy]-2-methylsulfanyl-thiophene-3-sulfonyl)-biphenyl-
3-carboxylic acid amide.,
N-[3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-
biphenyl-3-yl]-acetamide,
4-(2'-amino-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-[3-(lH-benzoimidazol-5-yl)-benzenesulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate.
4-(7-bromo-3-methyl-3H-benzoimidazole-5-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate,
4-(7-bromo-l-methyl-lH-benzoimidazole-5-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate,
5-methylsulfanyl-4-(3-methyl-7-o-tolyl-3H-benzoimidazole-5-
sulfonyl)-thiophene-2-carboxamidine trifluoroacetate,
5-methylsulfanyl-4-(2-methyl-7-o-tolyl-3H-benzoimidazole-5-
sulfonyl)-thiophene-2-carboxamidine trifluoroacetate,
5-methylsulfiany]-4-(7-o-tolyl-3H-benzoimidazole-5-sulfonyl)-
thiophene-2-carboxamidine trifluoroacetate,
4-(7-bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate,
4-(6-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-(2-methyl-furan-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
5-methylsulfanyl-4-(4-phenyl-thiazole-2-sulfonyl)-thiophene-2-
carboxamidine hydrochloride,
4-(6-etlioxy-berizothia:iole-2-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine hydrochlonde,
4-(6-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate,
4-(3-methoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine hydrochlon de,
5-methylsulfanyl-4-(3-phenoxy-benzenesulfonyl)-thiophene-2-
carboxamidine hydrochlonde, and
4-(Biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxamidine
trifluoroacetate,
as well as pharmaceutically acceptable salts thereof, or a prodrug
thereof.
Definitions
The term "alkyl" as employed herein by itself or as part of another
group refers to both straight and branched chain radicals of up to 12 carbons,
such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl,
isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl,
decyl, undecyl, dodecyl.
The term "alkenyl" is used herein to mean a straight or branched chain
radical of 2-20 carbon atoms, unless the chain length is limited thereto,
wherein there is at least one double bond between two of the carbon atoms in
the chain, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-
methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Preferably, the alkenyl
chain is 2 to 10 carbon atoms in length, more preferably 2 to 8 carbon atoms in
length, most preferably 2 to 4 carbon atoms in length.
In all instances herein where there is an alkenyl moiety as a substituent
group, the unsaturated linkage, i.e., the vinylene linkage, is preferably not
directly attached to a nitrogen, oxygen or sulfur moiety.
The term "alkylthio" as employed herein by itself or as part of another
group refers to a straight or branched chain radical of 1 to 20 carbon atoms,
unless the chain length is limited thereto, bonded to a sulfur atom, including,
but not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, and the
like. Preferably the alkylthio chain is 1 to 10 carbon atoms in length, more
preferably 1 to 8 carbon atoms in length.
The term "alkoxy" as employed herein by itself or as part of another
group refers to a straight or branched chain radical of 1 to 20 carbon atoms,
unless the chain length is limited thereto, bonded to an oxygen atom,
including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the
like. Preferably the alkoxy chain is 1 to 10 carbon atoms in length, more
preferably 1 to 8 carbon atoms in. length.
The term "cycloalkyl" as employed herein by itself or as part of
another group refers to cycloalkyl groups containing 3 to 9 carbon atoms.
Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl and cyclononyl.
The terms "halogen" or "halo" as employed herein by itself or as part
of another group refers to chlorine, bromine, fluorine or iodine, with chlorine
being preferred.
The term "monoalkylamine" as employed herein by itself or as part of
another group refers to an amino group which is substituted with one alkyl
group having from 1 to 6 carbon atoms.
The term "dialkylamine" as employed herein by itself or as part of
another group refers to an amino group which is substituted with two alkyl
groups, each having from 1 to 6 carbon atoms.
The term "aryl" as employed herein by itself or as part of another
group refers to monocyclic or bicyclic aromatic groups containing from 6 to
14 carbons in the ring portion, preferably 6-10 carbons in the ring portion,
such as phenyl, naphthyl or tetrahydronaphthyl.
The term "aralkyl" or "arylalkyl" as employed herein by itself or as
part of another group refers to C1-6alkyl groups as discussed above having an
aryl substituent, such as benzyl, phenylethyl or 2-naphthylmethyl.
The terms "heterocyclic," "heterocyclo" or "heterocycle" as employed
herein by themselves or as part of larger groups refer to a saturated or wholly
or partially unsaturated 3-7 membered monocyclic, or 7-10 membered bicyclic
ring system, which consists of carbon atoms and from one to four heteroatoms
independently selected from the group consisting of O, N, and S, wherein the
nitrogen and sulfur heteroatoms; can be optionally oxidized, the nitrogen can
be optionally quaternized, and including any bicyclic group in which any of
the above-defined heterocyclic rings is fused to a benzene ring, and wherein
the heterocyclic ring can be substituted on carbon or on a nitrogen atom if the
resulting compound is stable. Especially useful are rings containing one
oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur
combined with one or two nitrogen atoms. Examples of such heterocyclic
groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-
oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl,
pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl,
imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazmyl., oxazolyl,
oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl,
isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl,
benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl,
furyl, tetrahydrofuryl, tetrahydropyranyl, benzofuranyl, thienyl, benzothienyl,
thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and
oxadiazolyl. Morpholino is the same as morpholinyl.
The term "heteroatom" is used herein to mean an oxygen atom ("O"), a
sulfur atom ("S") or a nitrogen atom ("N"). It will be recognized that when the
heteroatom is nitrogen, it may form an NRyRz moiety, wherein Ry and Rz are,
independently from one another, hydrogen or C1 to C8 alkyl, or together with
the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6-, or
7-membered ring.
The term "heteroaryl" as employed herein refers to groups having 5 to
14 ring atoms; 6, 10 or 14 % electrons shared in a cyclic array; and containing
carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms (where
examples of heteroaryl groups are: thienyl, benzo[b]thienyl,
naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuranyl, pyranyl,
isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl,
2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl., indolyl, indazolyl, purinyl,
4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl,
quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, ß-carbolinyl,
phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl,
isothiazolyl, phenothiazlnyl, isoxazolyl, furazanyl and phenoxazinyl groups).
The expression "prodrug" denotes a derivative of a known direct acting
drug, which derivative has enhanced delivery characteristics and therapeutic
value as compared to the drug, and is transformed into the active drug by an
enzymatic or chemical process. Useful prodrugs are those where R2, R3 and/or
R4 are -CO2RW, where Rw is defined above. See U.S. Patent No. 5,466,811
and Saulnier et al., Bioorg. Med. Chem. Lett. 4:1985-1990 (1994).
The term "substituted," as used herein, means that one or more
hydrogens of the designated moiety are replaced with a selection from the
indicated group, provided that no atom's normal valency is exceeded, and that
the substitution results in a stable compound. When a substituent is keto (i.e.,
=0), then 2 hydrogens attached to an atom of the moiety are replaced.
By "stable compound" or "stable formula" is meant herein a compound
that is sufficiently robust to survive isolation to a useful degree of purity from
a reaction mixture and formulation into an efficacious therapeutic agent.
When any variable occurs more than one time in any constituent or in
any Formula, its definition on each occurrence is independent of its definition
at every other occurrence. Also, combinations of substituents and/or variables
are permissible only if such combinations result in stable compounds.
Methods of Use
The present invention provides a method for treating acute and chronic
disorders associated with activation of the classical pathway of the
complement system by administering to a mammal in need of such treatment a
therapeutically effective amount of a compound of Formula I.
These acute and chronic conditions include inflammation and tissue
damage that arise as a result of rapid and aggressive enzyme activity of the
complement cascade. Complement-mediated inflammation and the resultant
tissue damage has been implicated in a number of disease states including:
1) ischaemia reperfusion damage, such as occurs post myocardial infarction,
post transplant, post surgery and in hemorrhagic shock; 2) antibody-mediated
conditions, such as hyperacute allograft and xenograft rejection, organ
transplant rejection and auto-immune diseases; and 3) other disease states,
such as thermal injury., trauma, adult respiratory distress syndrome (ARDS),
sepsis and prion disease.
The compounds of the present invention are believed to inhibit the
functioning of the protease activity of C1s. This protease-inhibition activity
results in the inhibition or blocking of a variety of complement-mediated
immunological functions. Therefore, compounds of Formula I can be used to
ameliorate a number of disease states induced by complement-mediated
inflammation and tissue damage.
The term "treatment of inflammation" or "treating inflammation" is
intended to include the administration of compounds of the present invention
to a subject for purposes which can include prophylaxis, amelioration,
prevention or cure of an inflammatory response. Such treatment need not
necessarily completely ameliorate the inflammatory response. Further, such
treatment can be used in conjunction with other traditional treatments for
reducing the inflammatory condition known to those of skill in the art.
By an "efficacious level" of a composition of the invention is meant a
level at which some relief is afforded to the patient who is the recipient of the
treatment. By an "abnormal" host inflammatory condition is meant a level of
inflammation in the subject at a site which exceeds the norm for the healthy
medical state of the subject, or exceeds a desired level. By "secondary" tissue
damage or toxic effects is meant the tissue damage or toxic effects which
occur to otherwise healthy tissues, organs, and the cells therein, due to the
presence of an inflammatory response, including as a result of a "primary"
inflammatory response elsewhere in the body.
The "animals" referred to herein are preferably mammals and most
preferably humans, although the invention is not intended to be limited to
such.
In one embodiment, compounds of Formula I can be administered to a
mammal to treat complement-mediated inflammation and tissue damage that
is a consequence of ischaemia/reperfusion injury. Thus, the C1s inhibitors of
the present invention can be employed to prevent, or at least ameliorate,
inflammation and tissue damage: arising from a stroke, myocardial infarction,
hemorrhagic shock, and surgery. In particular, compounds of Formula I can
be employed to prevent inflammation of transplanted tissue and organs.
The compounds of Formula I can also be provided as a "preventive"
treatment before detection of an inflammatory state, so as to prevent the same
from developing in patients at high risk for the same, such as, for example,
transplant patients.
The compounds of Formula I can be used to treat chronic or acute
inflammation that is the result of an antibody-mediated reaction, such as
hyperacute allograft and xenograft rejection, organ transplant rejection and
auto-immune diseases, which include arthritis, rheumatoid arthritis, multiple
sclerosis (MS), type I diabetes, intestinal inflammation of Crohn's disease,
systemic lupus erythematosus (lupus), immune-complex-induced vasculitis,
restenosis and psoriasis.
The complement system is activated in hyperacute allograft and
hyperacute xenograft rejection, and in acute humoral rejection mediated by
donor-specific antibodies. In another embodiment, compounds of Formula I
can be administered to a mammal before, during or after the transplant of an
organ or a graft to ameliorate the rejection of such organ or graft by the
mammal.
Organ transplant and graft patients undergo concurrent
immunotherapy. Complement activation during immunotherapy with
recombinant IL-2 appears to cause acute vascular leak syndrome that results in
the severe toxicity and side effects observed from IL-2 treatment and other
conditions such as bone marrow transplantation and acute pancreatitis. Thus,
in a further embodiment of the present invention, a compound of Formula I is
administered to a mammal before, during or after treatment of said mammal
with IL-2, bone marrow transplantation, or onset of pancreatitis, in an amount
effective to reduce the vascular leak syndrome that causes toxicity and side-
effects associated with the treatment or disorders.
Another embodiment of the present invention is directed to
administering a therapeutically effective compound of Formula I to a mammal
that has been diagnosed with an autoimmune disease. Autoimmune diseases
that are treatable according to the present invention include Addison's disease.
Type I diabetes mellitus, Hashimoto's thyroiditis, glomerulonephritis and
cutaneous lesions of systemic lupus erythematosus, other
glomerulonephritides, bullous pemphigoid, dermatitis herpetiformis,
Goodpasture's syndrome, Graves' disease, myasthenia gravis, insulin
resistance, autoimmune hemolytic anemia, autoimmune thrombocytopenic
purpura, immune-complex-irtduced vasculitis glomerulonephritis, type II
collagen-induced arthritis, rheumatoid arthritis, and allergic neuritis.
Autoimmune diseases preferred for treatment by inhibitors of the present
invention include myasthenia gravis (MG), rheumatoid arthritis, and systemic
lupus erythematosus.
Another embodiment of the present invention is directed to
administering a therapeutically effective amount, of a compound of Formula I
to a mammal that has been diagnosed with a neurodegenerative disease.
Neurodegenerative diseases in which inhibitors of the complement cascade
system will be therapeutically useful include the demyelinating disorder
multiple sclerosis (MS)., the neuropathies Guillain-Barre syndrome (GBS) and
Miller-Fisher syndrome (MFS), Alzheimer's disease (AD) and variant
Creutzfeldt-Jakob disease (vCJD).
In another embodiment, efficacious levels of the C1s inhibitors of the
invention are administered so as to provide therapeutic benefits against the
secondary harmful inflammatory effects of inflammation.
In an additional embodiment, compounds of the present invention can
be administered to a mammal suffering from the symptoms of ARDS. ARDS
is a complex pulmonary disorder affecting 150,000 people in the U.S. yearly
with a 50% mortality rate. Leukocytes, platelets and the proteolytic pathways
of coagulation and complement mediate ARDS. ARDS involves activation of
the contact activation pathway and depletion of C1 inhibitor and may be
induced by either sepsis or trauma. Sepsis-induced ARDS results in more
severe Disseminated intravascular coagulation (DIG) and fibrinolysis, more
fibrin degradation products and reduced ATIII levels compared to trauma-
induced ARDS (Carvalho et al., J. Lab. Clin. Med. 112:270-277 (1988)).
In. a further embodiment, compounds of Formula I can be administered
to a person in septic shock. Septic shock is the most common cause of death
of humans in intensive care units in the United States (Parillo et al., Ann. Int.
Med. 113:227-242 (1990); Schmeichel C. J. & McCormick D., BioTechnol.
10 :264-267 (1992)). In recent years aggressive fluid infusion therapy has been
accepted as a primary means of treatment for septic shock.
The increase in cardiac output and vasodilation in septic shock is
attributed to the action of inflammatory mediators. In septic shock,
components of the kallikrein-kinin system are depleted, suggesting activation
of this system. This is not the case in cardiogenic shock, suggesting that the
kallikrein-kinin system is a key player in septic shock (Martinez-Brotons F. et
al., Thromb. Haemostas. 55:709-713 (1987)). While the actual events leading
to septic shock, DIC and hypotension have not been established, the known
interactions among various components of the many physiological systems
suggest that activation of the contact pathway may lead to a state of septic
shock, multi-organ failure, and death (Bone, R. C, Arch. Intern. Med.
752:1381-1389 (1992); Gorman, R. W., New Engl. J. Med. 32(9:1207-1209
(1989)). The contact activation pathway is also involved in both fibrin
deposition and lysis, as well as triggering neutrophil activation, activation of
complement and modulation of blood pressure.
Inhibition of the complement cascade is expected to lead to
downstream utilities associated with the contact system of coagulation and the
complement system. This interaction between components of the complement
and coagulation systems at the surface of blood platelets and endothelium can
generate inflammatory and chemotactic peptides at sites of vascular thrombus
formation and may contribute to the altered hemostasis associated with
immune disease states. In addition, immune reactions affecting blood platelets
and endothelium can lead to platelet aggregation, the secretion of proteolytic
enzymes and vasoactive amines from platelet storage granules, and increase
adherence of platelets and leukocytes to the endothelial lining of blood
vessels.
Other diseases and conditions that can be treated with compounds of
Formula I include hereditary angioedema, paroxysmal nocturnal
hemoglobinuria, wound healing, brain trauma, asthma, hemodialysis,
infection, dermatosis, inflammatory bowel disease, osteoporosis,
esteoarthritis, thermal injury (burns and frostbite), hemolytic anemia and post
pump syndrome in cardiopulmonary bypass.
It has been demonstrated that membrane-uptake of C3b and C5b-9
proteins can occur spontaneously during incubation of platelets in citrated
plasma. Complement activation can also occur during blood collection as a
result of exposure to plastic surfaces supporting the C3-convertase reaction.
While the implications of complement activation during blood collection and
in vitro storage for transfusion have not been directly addressed, it is
nevertheless known that plasma levels of coagulation factors V and VIII
rapidly decline in stored platelet concentrates at a rate considerably faster than
their decay in cell-free plasma, suggesting consumptive loss. Further, platelet
collection and storage is associated with an increase in vesicular plasma
membrane microparticles, a product of C5b-9 initiated platelet secretion.
These physiological and enzymatic changes greatly reduce the potential shelf
life of stored platelets, particularly platelet-rich plasma concentrates used for
transfusions, which is generally only 72 hours at best. Furthermore, this
interaction of activated C5b-9, platelets, and coagulation factors in stored
platelet concentrates will adversely affect the hemostatic effectiveness of these
units when infused.
In vitro human organ and tissue storage and survival of the
transplanted graft is also adversely affected by the spontaneous activation of
the complement system, resulting in membrane insertion of the C5b-9 proteins
into vascular endothelium. Activation of C5 to C5a and C5b can be catalyzed
by plastics and other synthetic membranes required to maintain perfusion of
vascular beds during in vitro tissue and organ storage. In addition, membrane
deposition of C5b-9 in vivo has been implicated in the acute rejection of
transplanted tissue due to immune activation of the recipient's plasma
complement system against the endothelial cells within the donor's organ.
Platelet and endothelial cell activation by C5b-9 also has ramifications
in autoimmune disorders and other disease states. The importance of
spontaneous complement activation and the resulting exposure of platelets and
endothelium to activated C5b-9 to the evolution of vaso-occlusive disease is
underscored by consideration that a) leukocyte infiltration of the
subendothelium, which is known to occur in regions of atheromatous
degeneration and suggests localized generation of C5a at the vessel wall, is
potentially catalyzed by adherent platelets; and b) local intravascular
complement activation resulting in membrane deposition of C5b-9 complexes
accompanies coronary vessel occlusion and may affect the ultimate extent of
myocardial damage associated with infarction.
It is therefore an aspect of the present invention to provide a means and
method for the modulation and inhibition of complement-mediated platelet
and endothelial cell activation in vivo and in vitro.
It is a further aspect of the present invention to provide a means and
method for increasing the survival and therapeutic efficacy of platelets and
tissues or organs collected and stored in vitro.
Preferably, the treatment methods of the invention deliver the C1s
inhibitor either by contacting cells of the animal with a C1s inhibitor described
above or by administering to the animal a C1s inhibitor described above.
The inhibitors can be used in vitro or in vivo. They can be
administered by any number of known routes, including orally, intravenously,
intramuscularly, subcutaneously, intrathecally, topically, transdermally, and
by infusion (Platt et al., U.S. Patent No. 4,510,130; Badalamente et al., Proc.
Natl. Acad. Sci. U.S.A. 55:5983-5987 (1989); Staubli et al., Brain Research
444:153-158 (1988)) and will generally be administered in combination with a
physiologically acceptable carrier (e.g., physiological saline) or diluent. The
effective quantity of inhibitor given will be determined empirically and will be
based on such considerations as the particular inhibitor used, the condition of
the individual, and the size and weight of the individual. It is to be expected
that the general end-use application dose range will be about 0.01 to 100 mg
per kg per day, preferably 0.1 to 75 mg per kg per day for an effective
therapeutic effect.
Amounts and regimens for the administration of C1s inhibitors and
compositions of the invention can be determined readily by those with
ordinary skill in the clinical art of treating inflammation-related disorders such
as arthritis, tissue injury and tissue rejection. Generally, the dosage of the
composition of the invention will vary depending upon considerations such as:
type of pharmaceutical composition employed; age; health; medical conditions
being treated; kind of concurrent treatment, if any; frequency of treatment and
the nature of the effect desired; extent of tissue damage; gender; duration of
the symptoms; and contraindications, if any, and other variables to be adjusted
by the individual physician. A desired dosage can be administered in one or
more applications to obtain the desired results. Pharmaceutical compositions
containing the C1s inhibitors of the invention can be provided in unit dosage
forms.
la one embodiment, dosing will be by intravenous injection or short-
term infusion. In a further embodiment, the C1s inhibitors of the present
invention will be administered orally, in the form of a tablet, pill, lozenge,
troche or capsule. To achieve optimal therapeutic effect, maintenance dosing
may be required. Such maintenance dosing may be given repeatedly during the
course of a day by, for instance, repeated individual injections, repeated oral
dosing, or by introduction of a continuous drip infusion. Effective dosages
can be readily determined by one of ordinary skill in the art through routine
trials establishing dose response curves.
Pharmaceutical Compositions
Pharmaceutical compositions for treating a complement-mediated
disease state, comprising a compound of Formula I in an amount effective to
inhibit C1s protease function in a mammal and a pharmaceutically acceptable
carrier or diluent, are within the scope of the present invention.
Pharmaceutical compositions comprising an effective amount of the
C1s inhibitors of the invention, in combination with any conventional
pharmaceutically acceptable carrier or diluent, are included in the present
invention.
For medicinal use, the pharmaceutically acceptable acid addition salts,
those salts in which the anion does not contribute significantly to toxicity or
pharmacological activity of the organic cation, are preferred. The acid
addition salts are obtained either by reaction of an organic base of Formula I
with an organic or inorganic acid, preferably by contact in solution, or by any
of the standard methods detailed in the literature available to any practitioner
skilled in the art. Examples of useful organic acids are carboxylic acids such
as maleic acid, acetic acid, tartaric acid, propionic acid, fumaric acid,
isethionic acid, succinic acid, cyclamic acid, pivalic acid and the like; useful
inorganic acids are hydrohalide acids such as HC1, HBr, and HI; sulfuric acid;
phosphoric acid and the like. Preferred acids for forming acid addition salts
include HC1 and acetic acid.
The pharmaceutical compositions of the invention can be administered
to any animal that can experience the beneficial effects of the compounds of
the invention. Foremost among such animals are humans, although the
invention is not intended to be so limited.
The pharmaceutical compositions of the present invention can be
administered by any means that achieve their intended purpose. For example,
administration can be by parenteral, subcutaneous, intravenous, intramuscular,
intraperitoneal, transdermal, buccal, or ocular routes. Alternatively, or
concurrently, administration can be by the oral route. The dosage
administered will be dependent upon the age, health, and weight of the
recipient, kind of concurrent treatment, if any, frequency of treatment, and the
nature of the effect desired..
In addition to the pharmacologically active compounds, the new
pharmaceutical preparations can contain suitable pharmaceutically acceptable
carriers comprising excipients and auxiliaries that facilitate processing of the
active compounds into preparations that can be used pharmaceutically.
The pharmaceutical preparations of the present invention are
manufactured in a manner that is, itself, known, for example, by means of
conventional mixing, granulating, dragee-making, dissolving, or lyophilizing
processes. Thus, pharmaceutical preparations for oral use can be obtained by
combining the active compounds with solid excipients, optionally grinding the
resulting mixture and processing the mixture of granules, after adding suitable
auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
Suitable excipients are, in particular, fillers such as saccharides, for
example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or
calcium phosphates, for example, tncalcium phosphate or calcium hydrogen
phosphate, as well as binders, such as, starch paste, using, for example, maize
starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl
cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose,
and/or polyvinyl pyrrolidone. If desired, disintegrating agents can be added,
such as, the above-mentioned starches and also carboxymethyl-starch, cross-
linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as,
sodium alginate. Auxiliaries are, above all, flow-regulating agents and
lubricants, for example, silica, talc, stearic acid or salts thereof, such as,
magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee
cores are provided with suitable coatings that, if desired, are resistant to gastric
juices. For this purpose, concentrated saccharide solutions can be used, which
may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene
glycol, and/or titanium dioxide, lacquer solutions and suitable organic solvents
or solvent mixtures. In order to produce coatings resistant to gastric juices,
solutions of suitable cellulose preparations, such as, acetylcellulose phthalate
or hydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs or pigments
can be added to the tablets or dragee coatings, for example, for identification
or in order to characterize combinations of active compound doses.
Other pharmaceutical preparations which can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules made of
gelatin and a plasticizer, such as, glycerol or sorbitol. The push-fit capsules
can contain the active compounds in the form of granules that may be mixed
with fillers such as lactose, binders such as starches, and/or lubricants such as
talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the
active compounds are preferably dissolved or suspended in suitable liquids,
such as, fatty oils or liquid paraffin.. In addition, stabilizers may be added.
Suitable formulations for parenteral administration include aqueous
solutions of the active compounds in water-soluble form, for example, water-
soluble salts, alkaline solutions and cyclodextrin inclusion complexes.
Especially preferred salts are hydrochloride and acetate salts. One or more
modified or unmodified cyclodextrins can be employed to stabilize and
increase the water solubility of compounds of the present invention. Useful
cyclodextrins for this purpose are disclosed in U.S. Patent Nos. 4,727,064,
4,764,604, and 5,024,998.
In addition, suspensions of the active compounds as appropriate oily
injection suspensions can be administered. Suitable lipophilic solvents or
vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid
esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400
(the compounds are soluble in PEG-400). Aqueous injection suspensions can
contain substances that increase the viscosity of the suspension, for example,
sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the
suspension may also contain stabilizers.
When employed as thrombin inhibitors, the compounds of the present
invention may be administered in an effective amount within the dosage range
of about 0.1 to about 500 mg/kg, preferably between about 0.1 and about 10
mg/kg body weight, on a regimen in single or 2-4 divided daily doses.
Methods of Making
Many synthetic methods used to form compounds of the present
invention generally involve the formation of an amidine from a carboxylic
acid derivative, such as an ester. In the process a Lewis acid, such as
trimethylaluminum, is added to a source of ammonia, such as ammonium
chloride, in an aprotic solvent, such as a toluene, under an inert atmosphere
(e.g., under an atmosphere of nitrogen or argon gas) at a temperature between
-15°C and 5°C, preferably at 0°C. An appropriate carboxylic acid derivative
is added to the mixture and the mixture is heated at reflux for a predetermined
period of time, preferably between 1 hr. and 24 hrs., and most preferably
between 1 hr. and 4 hrs. The resulting solution is allowed to cool to room
temperature and the amidine product is isolated by known methods.
Scheme 1 illustrates a general approach to compounds of Formula /
where X = O or S, and R1 = alkylthio, aralkylthio, arylthio, alkyloxy,
aralkyloxy or aryloxy. Starting with the heterocycle where X = O or S
appropriately substituted by a leaving group, the leaving groups can be
sequentially displaced by an appropriate thiol to produce the 4-substituted
heterocycles. In some cases a disulfide and a reducing agent such as
triphenylphosphine can be used for the in situ generation of the thiol.
Examples of leaving groups include chlorine, bromine or iodine. The resulting
sulfide is oxidized, either to the sulfoxide or the sulfone with an appropriate
oxidizing agent such as meta-chloroperoxybenzoic acid or hydrogen peroxide
in acetic acid. When the 4-substituent is a sulfone, the nitro group can then be
displaced by an appropriate; nucleophile (preferably the anion of the group R1
to be substituted) to produce a 5-substituted heterocycle. Preferable
nucleophiles include anions of thiols or alcohols having as the counter ion an
alkali or alkali earth metal such as sodium, lithium, potassium, magnesium or
cesium.
Scheme 2 illustrates approaches to providing the amidine
((R3R4N)CNR2) functionality of compounds of Formula / where X = O or S,
and R1 = halo, alkyl, alkylthio, aralkylthio, arylthio, alkyloxy, aralkyloxy or
aryloxy. Depending on the nature of the group W in 4, several methods may
be employed in the transformation of W to (R3R4N)CNR2.
When W in 4 is a cyano group (CN), primary amide (CONH2) or ester
(CO2R9), direct conversion to an unsubstituted amidine 6 (i.e., Formula /
where R2, R3, R4 = H) can be effected by treatment with a reagent consisting
of a Lewis acid complexed to ammonia. This complex is produced by
treatment of ammonia or an ammonium salt, preferably an ammonium halide
and most preferably ammonium chloride or bromide, with an appropriate
Lewis acid, preferably a trialkylaluminum and most preferably trimethyl- or
triethylaluminum in a solvent inert to the Lewis acid employed. For example,
when a trialkylaluminum Lewis acid is employed with an ammonium halide,
reaction occurs with loss of one equivalent of alkane to produce the
dialkylhaloaluminum complex of ammonia (see, for example, Sidler, D.R., et
al., J. Org. Chem., 59:1231 (1994)). Examples of suitable solvents include
unsaturated hydrocarbons such as benzene, toluene, xylenes, or mesitylene,
preferably toluene, or halogenated hydrocarbons such as dichloroethane,
chlorobenzene or dichlorobenzene. The amidination reaction is generally
carried out at elevated temperatures, preferably 40-200°C, more preferably
80-140 °C, and most preferably at the reflux temperature of a solvent in the
range of 80-120 °C. When W is a cyano group (CN), direct conversion to a
mono- or disubstituted amidine 6 is also possible by treatment with a reagent
consisting of a Lewis acid, preferably a trialkylaluminum, complexed to a
mono- or disubstituted amine H2NR3 or HNR-'R4 (Garigipati, R., Tetrahedron
Lett. 31: 1969 (1990)). Alternatively the same addition of a mono- or
disubstituted amine may be catalyzed by a copper salt such as Cu(I) chloride
(Rousselet, G., et al., Tetrahedron Lett. 34: 6395 (1993)).
When W in 4 is a carboxyl group (CO2H), indirect conversion to an
unsubstituted amidine 6 can be carried out by initial esterification to 5 by any
of a number of well-known dehydrating agents (for example,
dicyclohexylcarbodiimide) with an alcohol (R8OH). More preferably 5 can be
made by initial formation of an. acid chloride by treatment of 4 with any of a
number of anhydrides of HC1 and another acid, such as thionyl chloride,
POCl3, PCl3, PCl5, or more preferably oxalyl chloride, with or without an
added catalyst such as N,N-dimethylforrnamide (DMF), followed by the
alcohol R8OH. Conversion to the unsubstituted amidine 6 (R2, R3, R4 = H)
can be carried out by treatment with a. Lewis acid complexed to ammonia.
Amidines 6 can also be produced indirectly by conversion of 4 (W =
CN) to iminoethers 7 by exposure to a strong acid such as a hydrogen halide,
HBF4 or other non-nucleophilic acid, preferably gaseous HCl in the presence
of an alcohol R8OH (R8 = alkyl, branched alkyl or cycloalkyl, preferably Me
or Et) and most preferably with the alcohol as solvent. Alternatively when W
= CONH2, conversion to an iminoether can be carried out by treatment with a
trialkyloxonium salt (Meerwein's salts). In either case, treatment of the
iminoether with ammonia (R3, R4 = H) or a mono- or disubstituted amine
(HNR3R4) provides the corresponding, unsubstituted or substituted amidines 6
(i.e., via classical Pinner synthesis: Pinner, A., Die Iminoaether und ihre
Derivate, Verlag R. Oppenheim, Berlin (1892)).
Conversion to substituted amidine 6 (R2, R3 = H and, R4 = OH) can be
achieved by refluxing in ethanol the unsubstituted amidine 6 (R2, R3, R4 = H),
hydroxylamine, and a base, preferably triethylamixie.
scheme 3
Scheme 3 illustrates one approach to aryl thiols, which can be used in
Scheme 1 when such aryl thiols are not commercially available. Starting with
an aryl halide with sufficient stability to strong nucleophiles, the aryl halide
can be reacted with an alkali earth metal in an inert ethereal solvent such as
diethyl ether under reflux, yielding a reactive organometallic species.
Preferred metals include lithium, magnesium, and sodium, while the halide
can be an aryl iodide or bromide. Alternatively, the aryl-metal species can be
generated through a metal-halogen exchange with another organometallic
reagent at low temperature in am ethereal solvent. Useful organometallic
reagents include any of the isomeric butyllithiums and isopropylmagnesium
bromide or chloride. In this instance, the aryl halide must be an aryl bromide
or iodide and stable to strong nucleophiles.
The aryl-metal reagent may then be reacted with elemental sulfur to
provide a mixture of the aryl thiol (12) and the disulfide oxidation products
The disulfide can be reacted with a reducing agent such as sodium
borohydride, dithiothreitol, or triphenylphosphine, to give the aryl thiol (12).
scheme 4
Scheme 4 illustrates another approach to aryl thiols, which can be used
in Scheme 1 when such aryl thiols are not commercially available. An
arylamine 13 can be converted to the diazonimn salt and reacted with O-
ethylxanthic acid potassium salt (Aldrich Chemical Company) to give an O-
ethyl-S-aryl dithiocarbonate. which can subsequently be hydrolyzed to the aryl
thiol 15. In some cases hydrolysis can provide a mixture of the aryl thiol (15)
and the disulfide oxidation products (14). The disulfide can be reacted with a
reducing agent such as sodium borohydride, dithiothreitol, or
triphenylphosphine, to give the aryl thiol (15).
scheme 5
Scheme 5 illustrates a general approach to compounds of Formula I
where X = O or S, and R1 == halo. The nitroheterocycle 3 obtained in the
manner described in Scheme 1 is reduced to the aminoheterocycle 16.
Appropriate reagents to effect reduction of the nitro functionality include
hydrogen gas in the presence of a catalyst such as palladium or platinum metal
deposited on carbon or barium sulfate in any number of solvents such as
methanol, ethanol, ethyl acetate, DMF, or THF. Tin (II) chloride may be
employed as a reductant in a solvent such as methanol or ethanol.
Alternatively, metals such as zinc or iron (Stanetty, P. and Kremslehner, M..
Heterocycles 48: 259 (1998)) may also be used. More preferably, titanium
(III) chloride in HC1 (see Ho, Wong, Synthesis, 45 (1974)) can be used as the
reducing reagent. The aminoheterocycle 16 can then be converted to the halide
17 by diazotization. When X = C1 or Br, this reaction is carried out by
treating the aminoheterocycle 16 with t-butyl nitrite and copper (II) chloride or
bromide as described in the Sandmeyer reaction (see Doyle; Siegfried;
Dellaria, J. Org. Chem. 42: 242(5 (1977)).
Scheme 6A
Scheme 6a illustrates approaches to providing the biaryl functionality
present in compounds of Formula II, where R3 can be a substituted aromatic or
heteroaromatic ring (aryl or heteroaryl). Starting with either of two aryl
bromides, the methyl carboxylate 18 or the Boc-amidine 20, a transition-metal
catalyzed cross-coupling reaction can take place using an appropriately
substituted arylboronic acid, arylzincate, or arylstannane under Suzuki
(Miyaura, N.; Suzuki, A., Chem. Rev. 95:2457 (1995)), Negishi (Negishi, E. et
al., J. Org. Chem. 42:1821 (1977)), or Stille conditions (Stille, J. K. Angew.
Chem., Int. Ed. Engl. 25: 50S (1986), and references contained therein),
respectively.
The Stille-type cross-coupling reaction takes place under inert
atmosphere between an arylstannane and an aryl halide mediated by a catalyst
such as palladium tetrakis-triphenylphosphine. The reaction is usually
performed at temperatures ranging from room temperature to 150 °C in an
aprotic solvent of appropriate boiling point such as tetrahydrofuran, toluene, or
dimethylformamide. In some; cases, additives such as lithium chloride
(Curran, D.P. et al., J. Org. Chem. 61:6480 (1996)) or copper iodide
(Liebeskind, L. S.; Fengl, R. W., J. Org. Chem. .55:5359 (1990)) can facilitate
the cross-coupling reaction.
A more preferable cross-coupling reaction of aryl bromides 18 and 20
takes place under Negishi conditions, utilizing an aryl zinc reagent. The aryl
zinc reagent can be prepared by transmetalation of an aryl grignard or aryl
lithium reagent with a zinc halide salt, or more preferably, directly prepared
from an aryl halide and activated zinc (Reike, R.D., Tetrahedron 53:1925
(1997). The cross-coupling reaction generally takes place at temperatures
between 60 and 100 °C in THF or THF/polar aprotic co-solvent mixtures.
Palladium tetrakis(triphenylphosphine) is the most widely used catalyst,
although new catalysts such as palladium di-tert-butylphosphine (Dai, C; Fu,
G.C., J. Am. Chem. Soc. 123:2719 (2001)) can offer enhanced reactivities.
The most preferable and widely applicable biaryl-forming reaction
conditions for aryl bromides 18 and 20 take place under Suzuki conditions.
Many sets of reaction conditions can be employed to promote the Suzuki-type
cross-coupling reactions. These include appropriate combinations of
anhydrous or water-containing solvents, appropriate bases such as metal
carbonates, phosphates, and fluorides, and the transition-metal catalyst. For
the synthesis of biarylsulfones 21 and 23, the most universal reaction
conditions consisted of reacting aryl bromide 18 or 20 with an arylboronic
acid or an aryboronate ester (e.g. pinacolboronate) in a biphasic
toluene/ethanol/aqueous sodium carbonate solvent system. Palladium tetrakis-
triphenylphosphine is used as the catalyst under these aqueous conditions.
Under anhydrous conditions, new catalysts such as palladium di-tert-
butylphosphine (Littke, A.F. et al., J. Am. Chem. Soc. 122:4020 (2000)) and
bis (o-(dicyclohexylphosphino)biphenyl) palladium (Wolfe, J.P. et al., J. Am.
Chem. Soc. 121: 9550 (1999)) can offer enhanced reactivity at lower catalyst
loadings.
Scheme 6b describes an alternate route to compounds of Formula II
where R5 is an aryl, or heteroaryl. Boc-protected amidine 20 is converted to an
organoboron or organostannane 66, which is then reacted with a suitable
halide or trifiate in the presence of a palladium catalyst to give 21, which is
converted to the amidine 22 as described in scheme 6a. The preferred method
for the synthesis of 66 when E is a boron or tin species is to first treat 20 with
a base such isopropylmagnesium chloride, followed by lithiation with a
suitable reagent such as n-butyllithium, followed by reaction with an
electrophile such as trimethyl borate or tributyltin chloride.
Another approach to introduce heteroaromatics is to prepare 61. This is
accomplished by treatment of the organolithium species, prepared as outlined
above, with a suitable electrophile such as N,N-dimethylformamide.
Conversion of 67 to 21 can then be accomplished using diamine reagents such
as 1,2-phenyldiamine to give 2-substituted benzimidazoles or ammonium
acetate and glyoxal to give 2-substituted imidazoles, which is converted to the
amidine 22 as described in scheme 6a.
scheme 6C
Scheme 6c describes methods for the introduction of alkyl groups to
the phenyl ring of Formula I. Compound 20 is treated with a base such as
isopropylmagnesiurn chloride, followed by lithiation with a suitable reagent
such as n-butyllithium., followed by reaction with electrophiles such as
aldehydes and ketones to give 68 (Wakefield, B.J. The Chemistry of
Organolithium Compounds; Pergamon: Oxford, 1974; Wakefield, B.J.
Organolithium Methods; Academic: San Diego, 1990), which is converted to
the amidine 22 as described in scheme 6a.
Scheme 6d describes an approach to compounds of formula I, where
the Ar residue is substituted with amines at the meta-position. Transition metal
catalyzed coupling of the bromide 69 with amines is used to synthesize
arylamine 70. Examples of suitable transition metal catalyst include
palladium(0) or palladium(II) compounds such as Pd(II) acetate (Pd(OAc)2),
dipalladium tris(dibenzylidineacetone) (Pd2(dba)3),
tetrakis(triphenylphosphine) palladium(O) (Ph3P)3Pd), nickel(II) bis( 1,5-
cyclooctadiene) (Ni(COD)2), or (l,1'-bis(diphenylphosphino)ferrocenyl nickel
dichloride, in the presence or absence of coordinating ligand and in the
presence of a suitable base and solvent. Preferred catalyst include Pd(OAc)2
and Pd2(dba)3. Examples of coordinating ligands include tri-t-butylphosphine,
2,2'-bis(diphenylphosphino)-l,1'-binaphthyl (BINAP), 2,2'-
bis(ditolylphosphino)-l,l'binaphthyl (tol-BINAP), 1,1'-
bis(diphenylphosphino)ferrocene (DPPF), bis(2-
diphenylphosphinophenyl)ether(DPEphos), 2-(di-t-butylphosphino)biphenyl
(DBPB), 2-(di-cyclohexylphosphino)biphenyl (DCPB), 2-
dicyclohexylphosphino-2,-(N,N-dimethylamino)biphenyl (DCDMB).
Preferred ligands for palladium-catalyzed reactions include BINAP, DBPB,
DCPB, and DCDMB. Preferred ligands for nickel-catalyzed reactions include
DPPF or 1,10-phenanthroline. Examples of suitable bases include sodium t-
butoxiode, potassium t-butoxide, cesium carbonate, potassium carbonate,
potassium phosphate or cesium fluoride, with sodium t-butoxide, potassium
phosphate or cesium carbonate preferred depending on the other functionality
present in 70 and the amine being coupled. Suitable solvents include aromatic
hydrocarbons such as benzene, toluene, or xylenes; ethers such as
dimethoxyethane (DME) or 1,4-dioxane; or amides such as N,N-
dimethylformamide, N,N-dimiethylacetamide or N-methylpyrrolidinone.
Preferred solvents include toluene, DME and 1,4-dioxane. The coupling
reaction may be carried out at a temperature of 20-160 C, preferably 20-100 C,
and most preferably at the lowest possible temperature that provides reaction
times of less than 24 hours. For representative methodologies, catalysts,
examples of conditions and reviews of these types of palladium-catalyzed
coupling reactions see: J.P. Wolfe, et al., Acc. Chem. Res., 31:805-18(1998),
C.G. Frost, et al.., J. Chem. Soc., Perkin Trans 1, 2615-23 (1998) and J.P.
Wolfe, J. Org. Chem., 65:1158-74 (1998). For examples of nickel-catalyzed
reactions see J.P. Wolfe and S.L. Buchwald, J. Am. Chem. Soc, 119:6054-58
(1997). The nitrile 70 can be converted to the BOC-protected amidine by
treating with lithiated tert-butylcarbamate (Aldrich Chemical Company, WI,
USA). The amidine 72 is obtained by treating 71 with TFA.
After completion of the biaryl species, amidine 22 is completed either
through amidination of the methyl carboxylate 23 (Scheme 2), or by
deprotection of Boc-amidine 21 with trifluoroacetic acid or hydrochloric acid
in an organic solvent such as dioxane.
When not commercially available, arylboronic acids of formulas 25
and 26, where Ar is phenyl, naphthyl, or heterocycle, any of which are
optionally substituted, can be synthesized by the methods illustrated in
Scheme 7. When Y is Br, I, or C1 and Ar is tolerant to strong basic and/or
nucleophilic conditions, the preferred method involves lithium/halogen
exchange with n-BuLi followed by treatment with trimethyl borate,
triisopropyl borate, or triethyl borate to give compounds of formula 26 where
R10 is Me, Et, iPr, or H. Alternatively, regioselective metalation of 24 can be
directly achieved with n-BuLi or t-BuLi when Y is H and an ortho directing
group is present in Ar. La such cases, treatment of the metalated species with
trimethyl borate triisopropyl borate, or triethyl borate gives rise to compounds
of formula 26 where R10 is Me, Et, iPr or H. Examples of ortho directing
groups suitable for this transformation include but are not limited to
OCH2OCH3, SO2NR2, CONR2, CONHR, NHCOR, NHCO2R, and CSNHR
(Mark, R., et al., J. Org. Chem. 47: 2101 (1982); Townsend, C, et al.,
Tetrahedron Lett. 3923 (1981)). When Ar contains functional groups that are
sensitive to base and/or nucleophiles, conversion of 24, where Y is Br, I, Cl, or
OTf to arylboronic acids of formula 25 can be effected using one of several
methods involving palladium(O)-mediated boronation of arylhalides
(Ishiyama, T., et al., J. Org. Chem. 60: 7508 (1995)). Examples of this
transformation include but are not limited to treatment of 24 with: 1)
Pd(PPh3)4, (PPh3)2Pda2, or PdCl2(dppf), pinacolborane, and Et3N in dioxane
at 100 °C (Murata, M., et al., J. Org. Chem. 65:164 (2000)); 2) Pd(OAc)2, (2'-
Dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine,
bis(pinacolato)diboron, and K3PO4 in toluene at 95 °C (Old, D.W., et al., J.
Am. Chem. Soc. 120:9722 (1998)); 3) PdCl2(dppf), bis(pinacolato)diboron,
and KOAc in DMSO (Ishiyama, T., et al., J. Org. Chem. (50:7508 (1995)).
Suitable reaction times for this transformation are 12-24 hr.
Scheme 8 illustrates an alternate approach to compounds of Formula /
where X = O or S, and R1 = halo, alkylthio, aralkylthio, arylthio, alkyloxy,
aralkyloxy or aryloxy. A heterocycle 27 appropriately substituted with a
leaving group L may be substituted with an anion of R1 to give intermediate
28. When L = halo, the halide can be left alone to give R1 = halo. The amine
29 is then derived from reduction of the nitro group. Appropriate reagents to
effect reduction of the nitro functionality include hydrogen gas in the presence
of a catalyst such as palladium or platinum metal deposited on carbon or
barium sulfate in any number of solvents such as methanol, ethanol, ethyl
acetate, DMF, or THF. More preferably, tin (II) chloride may be employed as
a reductant in a solvent such as methanol or ethanol. Alternatively, metals
such as zinc or iron (Stanetty, P. and Kremslehner, M., Heterocycles 48: 259
(1998)) may also be used. When R1 is halo, titanium (HI) chloride in HC1 (see
Eo, Wong, Synthesis 45 (1974)) is the preferred reducing reagent. The amine
29 can then be converted to the sulfonyl chloride 30 by diazotization in the
presence of sulfur dioxide and copper (II) chloride (Ramsay, G. C. et al., J.
Am. Chem. Soc. 93:1166-1171 (1971), European Patent EP 983982). The
sulfonyl chloride 30 can then be treated with sodium sulfite and sodium
bicarbonate to afford the sodium sulfinate 31 (Field L. and Clark. R. D.,
Organic Synthesis Collective Vol. IV, 674-677, John Wiley and Sons, Inc.
1963). The sulfinate 31 can be converted to sulfone 32 by reacting the
sulfinate 31 with an alkyl or aryl group appropriately substituted with a
leaving group in a solvent such as ethanol (Field L. and Clark. R. D., Organic
Synthesis Collective Vol. IV, 674-677, John Wiley and Sons, Inc. 1963).
Scheme 9 illustrates a specific example of the method shown in
Scheme 8. The sulfinate 33 can be obtained by treating 4-nitro-5-bromo-
thiophene-2-carboxylic acid methyl ester (DelPErba, C. and Spinelli, D.,
Tetrahedron 21: 1061 (1965); Dell'Erba, C. et al., J. Chem. Soc, Perkin Trans
2, 1779 (1989)) according to scheme 8. The sulfinate 33, can be treated with
34 (Hazelton, C. J. et al., Tetrahedron, 51:5591 (1995)) in a solvent such as
aqueous ethanol with acetic acid as catalyst to give the sulfone 35. Sulfone 35
is treated with sodium dithionite in aqueous ethanol to afford 36 (Hazelton, C.
J. et al., Tetrahedron, 51:5591 (1995)), which can be cross-coupled to an aryl
residue using the methods described in Scheme 6 to give compounds of
formula 37. Both compound 36 and 37 can be treated with hot formic acid to
give compounds 42 and 38 respectively. Benzimidazoles 38 and 42 can then
be alkylated to give 39-41 and 43-44 respectively. These esters can be
converted to their amidines by the methods described in Scheme 2.
Scheme 9b illustrates approaches to 1-alkyl-5-sulfonyl-benzimidazoles
of compounds of Formula X, where R = H, halo, alkyl, alkyloxy, and Ri=
alkyl or aryl. Appropriately substituted sulfinate can be prepared from the
corresponding sulfonyl chloride in a manner similar to that described in
scheme 11. Reaction of the appropriately substituted arylsulfinate 74 with the
bromo-nitro-thiophene, 1 yields a mixture of mono- and bis-sulfone adducts.
Thiomethoxide addition at—78 °C chemoselectively occurs at the 5-position of
the thiophene for both adducts, giving the intermediate 75. The aniline 75 is
converted to the arylhalide 76 under Sandmeyer diazotization conditions
(Doyle, M. P. et al.. J. Org. Chem. 42, 2426 (1977)). Heating this halo-
nitroarene with an amine or arylamine at 60-80 °C in the presence of a base
(NaOAc or DIEA) yields the substituted aniline 77. Reduction of the nitro
group (e.g. Fe/AcOH in ethanol) followed by heating in formic acid gives the
benzimidazole 78, which can be converted to the amidine 79 as described in
Scheme 2.
The synthesis of compounds of formulas 48 and 49, having two meta-
substitutions on the phenyl ring with respect to the sulfone are described in
Scheme 10. The tert-butyl phenol ether in compound 45 can be deprotected
using a strong acid treatment such as TFA or HC1 in DCM or dioxane,
respectively. The free phenol as in compound 46 can be alkylated under
standard conditions with alkyl halide and a base, preferably CS2CO3 in
acetone, to furnish compounds described by formula 47. Examples of
alkylating agents (R11) include but are not limited to allyl bromide, benzyl
bromide, methyl iodide, 2-bromoacetate, and 2-bromoacetamide. The
carboxylic acid ester in formula 47 can be directly converted to the amidine or
a masked amidine as described in Scheme 2 to give compounds of formula 48.
Alternatively, 47 can be cross-coupled with a variety of arylboronic acids and
heterocyclic boronic acids as shown in Scheme 6, followed by amidination as
previously described to afford compounds contained in formula 49.
Scheme 11 illustrates yet another approach to compounds of Formula I
where X = O or S, R1 = halo, alkylthio. aralkylthio, arylthio, alkyloxy,
aralkyloxy or aryloxy. A sulfonyl chloride 50, where Ar is aryl or heteroaryl,
is treated with sodium sulfite and sodium bicarbonate to afford the sodium
sulfinate 51 (Field L. and Clark. R. D., Organic Synthesis Collective Vol. IV,
pp. 674-677, John Wiley and Sons, Inc. (1963)). The sulfinate 51 can be
converted to sulfone 3 by reacting the sulfinate 51 with 1. The sulfone 3 can
then be treated as described in scheme 1 to give intermediate 4, which can be
converted to an amidine by the methods described in scheme 2.
Scheme 12 illustrates a specific example of the method shown in
scheme 11. Pyridylsulfonylchloridie (Aldrich), 52 is converted to the sulfinic
acid and reacted with thiophene ester 54 to give the sulfone, 55. The sulfone
(55) is then treated as described in scheme 1 to give the intermediate 56.
Intermediate 56 can be treated with ammonia or zinc dust in acetic acid
(Krutosikova, A.; Sleziak, R. Collect. Czech. Chem. Commun. (1996) 61,
1627-1636) to give compounds 58 or 59 respectively. The amide 58 can be
converted to the biaryl compound 60 using methods described in scheme 6.
Compounds 56, 58, 59, and 60 can be converted to the corresponding
amidines 57, 61, 62, and 63 respectively, as described in scheme 2.
Scheme 13 illustrates a general route to compounds of formula I where
Ar is substituted 3-pyridyl (when A = N) and compounds of formula II where
the phenylsulfone moiety has an amino group at the 4-position (A = N, C).
The sulfone 56 is prepared as described in scheme 12 and then treated as
described in scheme 1 to give the corresponding amidine, which is BOC-
protected to give intermediate 64. The C1 group in intermediate 64 can be
displaced with an amine to give a substituted aminopyridine, which upon
treatment with trifluoroacetic acid gives compound 65. Intermediate 56 can be
treated with Zn dust (Krutosikova, A.; Sleziak, R. Collect. Czech. Chem.
Commun. (1996) 61, 1627-1636) to give the dehalogentaed product 59, which
can also be converted to the amidine 63. The halogen Y in intermediate 56
(when A = N or C) can also be substituted with ammonia to give 58, which
can be converted to the amidine 62. Alternatively, 58 can be converted to the
biaryl compound 60 using methods described in scheme 6.
Scheme 14 illustrates this general approach to the synthesis of
compounds of formula n, where R5 is 2-aminophenyl or 2-amino-4-pyridyl
and the amino groups are further substituted. The Biaryl-intermediate 80 can
be prepared either by treating 20 with an appropriately substituted
arylboronate or boronic acid using conditions similar that described in scheme
6a or by treating 66 with an appropriately substituted arylhalide or triflate
using conditions similar to that described in scheme 6b. Intermediate 2 can be
converted to the corresponding substituted ureas 81 using conditions such as
p-nitrophenylchloroformate in the presence of a base such as pyridine,
followed by addition of a substituted amine, followed by treatment with an
acid such as trifluoroacetic acid. In an alternative approach intermediate 80
can be treated with reagents such as substituted isocyanates in the presence of
a base such as triethylamine, followed by treatment with an acid such as
trifluoroacetic acid to give the corresponding substituted ureas 81. The
intermediate 2 can also be converted to the corresponding amides 82 using
reagents such as substituted acids in the presence of coupling reagents such as
EDCI and HOBt, followed by treatment with an acid such as trifluoroacetic
acid. The intermediate 80 can also be converted to the corresponding amides
or sulfonamides 82 by treating with acid chlorides, sulfonyl chlorides,
anhydrides, or activated esters in the presence of a base such as triethylamine,
followed by treatment with an acid such as trifluoroacetic acid.
Scheme 15 illustrates a general approach to the synthesis of
compounds of formula II, where R5 is 2,4-diaininophenyl and the amino
groups are further substituted. Intermediate 83 can be synthesized in a manner
similar to that described in scheme 14. When R23 is a masked amine such as
nitro. or trimethylsilylethyl carbamate (Teoc), the ortho-aniline may be
functionalized with a variety of reagents such as acid chlorides, sulfonyl
chlorides, activated carboxylic esters, and isocyanates to give compound 84.
When R" of compound 84 is a nitro-group it can be reduced to an amino-
group under mild conditions using iron powder in ethanolic aqueous
ammonium chloride (R1 = NO2) and further reacted with reagents such as acid
chlorides, sulfonyl chlorides, activated carboxylic esters, isocyanates,
guanidinylating reagents, alkyl halides, and aldehydes (reductive animation) to
give compound 86. When R23 is a protected aniline it can be deprotected. For
example a Teoc group is removed by treatment with a fluoride anion source
such as tetrabutylammonium fluoride in THF to give compound 85. This can
be further functionalized in the manner described above.
Scheme 16 illustrates approaches to providing the arylguanidine
functionality of compounds of Formula II where R5 is a substituted phenyl
group with a 4-araino functionality. Depending on the nature of the group R,
several methods may be employed in the guandinylation of the aniline 87 to
compounds 89, 90 or 92. When R1 is H or alkyl, unsubstituted or N,N'-bis-
substituted arylguanidines 90, can be synthesized by the reaction of the aniline
with a diprotected S-alkyl isothiourea (e.g. bis-Boc-SMe-isothiourea). This
reaction can generally be promoted by either of two reaction conditions; 1) a
mercury salt (e.g. HgCl2) with triethylamine at 50 °C [WO-99/206208] or 2)
acetic acid in methanol at 40 °C [Tetrahedron Lett., 43, 6563-6566 (2000)].
When R' is a strong electron-withdrawing group (e.g. nitro), or contains other
acid-sensitive functionality, the mercury reagent is preferred. When R31 is, or,
contains an amino-group, selective guanidinylation at the 4-amino group can
be achieved using the acetic acid/methanol conditions. Monosubstituted N'-
arylguanidines 89 can be synthesized by reaction of the aniline (R1 =: H, alkyl)
with a substituted diprotected S-alkyl isothiourea (e.g. alkylN(Boc)-
C(SMe)=NBoc). The acetic acid in methanol reaction condition is the method
of choice for this transformation. The monoalkyl isothiourea starting materials
can be synthesized via alkylation of the bis-Boc-SMe-isothiourea with a
hydride base/alkyl halide [J. Med. Chem., 36, 2956-2963 (1993)] or
Mitsunobu reaction [J. Med. Chem., 43, 2362-2370 (2000)}.
Alternatively, arylguanidines can be prepared from corresponding
thiourea intermediates 91 and 94. Preparation of 91 is achieved by reacting the
aniline scaffold with an isothiocyanate. Alternatively, the aniline scaffold may
be converted to the isothiocyanate [J. Org. Chem., 51, 2613-2615 (1986)]
followed by reaction with an alkylamine, aniline, hydrazide, or alkoxylamine
to give 94. The thiourea may then be converted to the guanidine using
mercuric oxide in the presence of excess amine (e.g. ammonia, methylamine,
etc.) [J. Chem. Soc, 475, 479 (1949)].
Scheme 17 illustrates the general approach to the synthesis of
compounds of formula II, represented by examples 213-214. The alcohol 95
can be converted to the corresponding mesyiate 98 in the presence of a
methanesulfonyl chloride and a base such as triethylamine, in a solvent such
as dichloromethane. Mesyiate 98 can be treated with a variety of substituted
nucleophiles in the presence of a base such as triethylamine in a solvent such
as dichloromethane, followed by treatment with an acid such as trifluoroacetic
acid to give the corresponding product 99. Alternatively, compound 95 can be
converted to the corresponding aldehyde 96 in the presence of an oxidizing
agent such as manganese dioxide. Aldehyde 96 can then be treated with a
variety of phosphorus ylides to give the corresponding olefin, (see Paterson, I.,
et al., Org. Lett. 5(I):35-38 (2003)), followed by treatment with an acid such
as trifluoroacetic acid to give compound 100. For example, aldehyde 96 is
treated with (diethoxy-phosphorylmethyl)-phosphonic acid diethyl ester in the
presence of a base such as sodium hydride in a solvent such as
tetrahydrofuran, followed by treatment with trimethylsilyl iodide and a solvent
such as dichloromethane to give compound 91 (see Ruzziconi, R. el al, J
Org. Chem. 68(3):736-142 (2003)).
The following examples are illustrative, but not limiting, of the method
and compositions of the present invention. Other suitable modifications and
adaptations of the variety of conditions and parameters normally encountered
and obvious to those skilled in the art are within the spirit and scope of the
invention.
EXAMPLES
Example 1
a) 4-Methoxymethoxy-biphenyl
To an oven-dried flask containing a stirbar was added 4-
hydroxybiphenyl (1.70 g, 10 mmol), toluenesulfonic acid (190 mg, 1.1 mmol),
dichloromethane (DCM, 5 mL), and dimethoxypropane (5 mL)- The solution
was heated and stirred at 40 °C for 48 h. Solid NaHCO3 (200 mg) was added,
followed by EtOAc (100 mL) and NaOH (1N, 20 mL). The layers were
separated and the organic layer was further extracted with NaOH (1N, 12 x 20
ml), brine (30 mL), and was dried over sodium sulfate. Removal of the
solvents in vacuo yielded the title compound (385 mg, 18%) which was used
without further purification. 1H-NMR (CDCl3); d 7.56 (m, 4H), 7.44 (m, 2H),
7.34 (m, 1H), 7.14 (m, 2H), 5.24 (s, 2H), 3.54 (s, 3H).
b) 4-Methoxymethoxy-biphenyl-3-yl-boronic acid
Butyllithium (2.5M, 1.44 mL, 3.6 mmol) was added over 5 min to a
stirred solution of 4-methoxymethoxy-biphenyl (from the previous step 385
mg, 1.8 mmol) in Et2O (18 mL) at 0 °C. The reaction was allowed to warm to
rt and stirred for 2 h. The solution was cooled to -78 °C and trimethylborate
(1.23 mL, 10.8 mmol) in THF (10 mL) was quickly added. The reaction
wanned to rt over 1 h and was stirred 1 h at rt, during which it became cloudy
and a gelatin-like residue appeared. EtOAc (70 mL) and water (30 mL) were
added along with HC1 (IN, 1 mL). The biphasic solution was stirred for 10
min and the layers were separated. The organic layer was further extracted
with HC1 (0.1N, 3 x 20 mL)., brine (60 mL), and was dried over sodium
sulfate. Removal of the solvents in vacuo followed by chromatography of the
residue (20-40% EtOAc in hexaries) yielded the title compound (135 mg,
29%) as a light-brown solid. The title compound exists as a mixture of
boronic acids and anhydrides in CDCl3, therefore the reported NMR signals
represent pairs or groups of related signals. 1H-NMR (CDCl3): d 8.07 (d, 1H,
J = 2.6 Hz), 7.60 (m, 3H);, 7.42 (m, 2H), 7.31 (m, 1H), 7.19 (d, 1H, J = 8.6
Hz), 6.20 (s, 1H), 5.32 (s, 2,H), 3.77 (s, 1H), 3.53 (s, 3H).
c) {Imino-[4-(4'-methoxymethoxy-[1,1';3;1']terphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester
A 2-dram vial with a septa-containing screwcap was charged with {[4-
(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-
carbamic acid tert-butyl ester (Example 27 (50 mg, 0.1 mmol)), 4-
methoxyrnethoxy-biphenyl-3-yl-boronic acid (from the previous step 103 mg,
0.4 mmol), aqueous Na2CO3 (2M, 0.8 mL, 1.6 mmol), ethanol (0.8 mL) and
(1.6 mL). A stirbar was added, the vial was capped, the solution was
sparged with argon for 10 min, and Pd(PPh3)4 (29.4 mg, 0.025 mmol) was
added. The biphasic solution was vigorously stirred under inert atmosphere at
80 °C for 16 h, then was cooled to rt. EtOAc (20 mL) and water (10 mL) were
added and the layers were separated. The organic layer was washed with
saturated NaHCO;, (2 x 10 mL), brine (10 mL) and was dried over sodium
sulfate. Removal of the solvents in vacuo followed by preparative TLC (25%
EtOAc in hexanes) of the residue yielded the title compound (15 mg, 24%) as
a light-yellow glass. 1H-NMR (CDCl3): 6 8.27 (t, 1H, J = 1.9), 7.99 (ddd, 1H,
J = 1.2, 1.6, 7.9 Hz), 7.96 (s, 1H), 7.84 (dt, 1H, J = 1.4, 7.9 Hz), 7.57 (m, 5H),
7.45 (m, 2H), 7.36 (m, 1H), 7.30 (m, 1H), 5.18 (s, 2H), 3.41 (s, 3H), 2.59 (s,
3H), 1.52 (s, 9H). ESI-MS (m/z): Calcd. for C31H32N2O6S3: 624.8; found:
624.9.
d) 4-(4'-Hydroxy-[1,1';3',1 ']terphenyl-3'-sulfonyl)-5-methylsulfonyl-
thiophene-2-carboxamidine trifluoroacetate
The {imino-[4-(4'-methoxymethoxy-[ 1,1 ';3',1']terphenyl-3-sulfonyl)-
5-methylsulfanyl-thiophen-2-yl}-methyl}-carbamic acid tert-butyl ester
((Example 1: step c) 15 mg, 0.024 mmol) was dissolved in DCM (5 mL),
water (3 drops) was added, followed by trifluoroacetic acid (5 mL). The
solution was stirred for 2 h at rt and the solvents were removed in vacuo. The
residue was purified via HPLC (C18-column, 10-70% CH3CN over 30 min)
which yielded the title compound as a white solid (11 mg, 73%). 1H-NMR
(CD3OD): d 8.34 (t, 1H, J = 1.6 Hz), 8.32 (s, 1H), 7.98 (m, 2H), 7.66 (t, 1H, J
= 7.9 Hz), 7.58 (m, 2H), 7.53 (d, 1H, J = 2.1 Hz), 7.50 (dd, 1H, J = 2.3, 8.4
Hz), 7.41 (m, 2H), 7.29 (m, 1H), 7.02 (d, 1H, J = 8.4 Hz), 2.71 (s, 3H). ESI-
MS (m/z): Calcd. for C24H20N2O3S3: 481.6 (M+H); found: 481.3.
Example 2
4-(2'-Methoxymethoxy-[1,1';3',1']terphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
a) 2-Methoxym ethoxy-biphenyl
The procedure as in Example 1: step a was followed using 2-
hydroxybiphenyl (1.70 g, 10 mmol), p-toluenesulfonic acid (190 mg, 1.1
mmol), DCM (5 mL), and dimethoxypropane (5 mL). Analogous aqueous
workup yielded the title compound (225 mg, 11%) which was used without
further purification. 1H-NMR (CDCl3): d 7.58 (m, 2H), 7.44 (m, 2H), 7.36 (m,
2H), 7.32 (m, 1H), 7.25 (dd, 1H, J = 1.2, 8.1 Hz), 7.12 (dt, 1H, J = 1.2, 7.4
Hz), 5.14 (s,2H), 3.42 (s, 3H).
b) 4-Methoxymethoxy-biphenyl-3-yl-boronic acid
The procedure used in Example 1: step b was followed using 2-
methoxymethoxy-biphenyl ((Example 2: step a) 225 mg, 1.05 mmol),
butyllithium (2.5M, 1.44 mL, 3.6 mmol), and trimethylborate (1.23 mL, 10.8
mmol). Analogous aqueous workup and SiO2 flash chromatography yielded
the title compound (123 mg, 45%) as a light brown solid. The title compound
exists as a mixture of boronic acids and anhydrides in CDCl3; therefore the
reported NMR signals represent pairs or groups of related signals. 1H-NMR
(CDCl3): d 7.53 (m, 1H), 7.23 (m, 2H), 7.12 (m, 3H), 7.05 (m, 1H), 6.94 (m,
1H), 4.2S (s, 2H), 3.51 (s, 1H), 2.96 (s, 3H).
c) {Imino-[4-(2'-methoxymethoxy-[1,l';3',1']terphenyI-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-methyI}-carbamic acid tert-butyl ester
The procedure used in Example 1: step c was followed using {[4-(3-
bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-
carbamic acid tert-butyl ester (Example 27 (50 mg, 0.1 mmol)), 2-
methoxymethoxy-biphenyl-3-yl-boronic acid ((Example 2: step b) 103 mg, 0.4
mmol), Na2CO3 (2M, 0.8 mL, 1.6 mmol), Pd(PPh3)4 (29.4 mg, 0.025 mmol),
ethanol (0.8 mL), and toluene (1.6 mL). Analogous aqueous workup and
purification of the crude material by preparative TLC (25% EtOAc in
hexanes) yielded the title compound (18 mg, 29%) as a light-yellow glass. 1H-
NMR (CDCl3): d 8.24 (t, 1H, J = 1.7 Hz), 8.06 (s, 1H), 7.95 (ddd, 1H, J = 1.2,
1.9, 7.9 Hz), 7.86 (dt, 1H, J == 1.4, 7.7 Hz), 7.60 (t, 1H, J - 7.9 Hz), 7.56 (m,
2H), 7.2-7.45 (m, 6H), 4.22 (s, 2H), 2.60 (s, 3H), 2.47 (s, 3H), 1.48 (s, 9H).
ESI-MS (m/z): Calcd. for C31H32N2O6S3: 624.8; found: 624.9.
d) 4-(2'-Methoxymethoxy-[1,1';3',1']terphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
The procedure used in Example 1: step d was followed using {imino-
[4-(2'-methoxymethoxy- [ 1,1'; 3', 1' ]terphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester ((Example 2: step c) 18
mg, 0.029 mmol). Analogous purification by HPLC yielded the title
compound as a white solid (17 mg, 94%). 1H-NMR (CD3OD): d 8.32 (s, 1H),
8.27 (t, 1H, J = 1.7 Hz), 7.99 (ddd, 1H: J = 1.2, 1.9, 7.9 Hz), 7.92 (ddd, 1H, J
= 1.2, 1.6, 7.9 Hz), 7.66 (dt, 1H, J = 0.5, 7.9 Hz), 7.52 (m, 2H), 7.45 (m, 2H),
7.36 (m, 2H), 7.26 (ddd, 2H, J = 1.7, 3.5, 7.2 Hz), 7.07 (t, 1H, J = 7.9 Hz),
2.71 (s, 3H). ESI-MS (m/z): Calcd. for C24H20N2O3S3 (M+H): 481.6; found:
481.2.
Example 3
3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-methyl-
biphenyl-3-carboxylic acid isopropyl ester trifluoroacetate
a) 3-Bromo-2-methyl-benzoic acid isopropyl ester
Thionyl chloride (6 mL) was added over 1 min to a 0 °C suspension of
3-bromo-2-methyl benzoic acid (2.15 g, 10 mmol) in DCM (10 mL). After 30
min of stirring, THF (5 mL) was added to induce dissolution. The now
homogeneous solution was stirred for 24 h at rt and the volatile component
were removed in vacuo. A portion of the crude acid chloride was dissolved in
dry isopropyl alcohol (10 mL) and pyridine (2 mL) was added. After stirring
for 4 h at rt, the volatile components were removed in vacuo. The residue was
partitioned between EtOAc (70 mL) and HC1 (1M, 30 mL) and the layers were
separated. The organic layer was washed with HC1 (1M, 10 mL), NaHCO3 (3
x 20 mL), water (30 mL), brine (30 mL), and was dried over sodium sulfate.
Removal of solvent in vacuo yielded the title compound as a light-yellow oil
which was used without further purification. 1H-NMR (CDCl3): d 7.69 (d, 2H,
J = 7.7 Hz), 7.11 (t, 1H, J = 7.9 Hz), 5.26 (heptet, 1H, J = 6.3 Hz), 2.63 (s,
3H), 1.39(d,6H,J = 6.3Hz).
b) 2-Methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzoic
acid isopropyl ester
A 2-dram vial with a septa-containing screwcap was charged with a
stirbar, 3-bromo-2-methyl-benzoic acid isopropyl ester ((Example 3: step a)
257 mg, 1 mmol), PdCl2(PPh3)2 (42 mg, 0.06 mmol), dioxane (4 mL), and
triethylamine (420 µL, 3 mmol). Upon dissolution, 4,4,5,5-tetramethyl-
[l,3,2]dioxaborolane (220 µL, 1.5 mmol) was added and the solution was
vigorously stirred for 16 h at 100 °C. After cooling to rt. EtOAc (30 mL) and
water (10 mL) were added (gas evolution!) and the layers were separated. The
organic layer was washed with NaHCO3 (2 x 10 mL), brine (10 mL), and was
dried over sodium sulfate. Removal of the solvents in vacuo followed by SiO2
flash chromatography of the residue yielded the title compound (130 mg,
43%) as a light-yellow glass. 1H-NMR (CDCl3): d 7.86 (dd, 1H, J = 1.4, 7.4
Hz), 7.80 (dd; 1H, J = 1.6, 7.7 Hz), 7.23 (t, 1H, J = 7.7 Hz), 5.26 (heptet, 1H, J
= 6.3 Hz), 2.75 (s, 3H), 1.37 (m, 18H).
c) 3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-
thiophene-3-sulfonyl]-2-methyl-biphenyl-3-carboxylic acid isopropyl ester
The procedure used in Example 1: step c was followed using {[4-(3-
bromo-berizenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-memyl}-
carbamic acid tert-butyl ester (Example 27 (50 mg, 0.1 mmol)), 2-methyl-3-
(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzoic acid isopropyl ester
((Example 3: step b) 92 mg, 0.3 mmol), Na2CO3 (2M, 0.4 mL, 0.8 mmol),
Pd(PPh3)4 (29.4 mg, 0.025 mmol), ethanol (0.4 mL) and toluene (0.8 mL).
Analogous aqueous workup and purification of the crude material by
preparative TLC (25% EtOAc in hexanes) yielded the title compound (29 mg,
49%) as a colorless glass. 1H-NMR (CDCl3): d 7.98 (dt, 1H, J = 1.6, 7.6 Hz),
7.93 (m, 2H), 7.79 (t, 1H, J = 1.7 Hz), 7.58 (t, 1H, J = 7.6 Hz), 7.53 (dt, 1H, J
= 1.6, 7.6 Hz), 7.36 (s, 1H), 7.30 (d, 1H, J = 4.5 Hz), 5.27 (heptet, 1H, J = 6.2
Hz), 2.58 (s, 3H), 2.35 (s, 3H), 1.51 (s, 9H), 1.39 (d, 1H, J = 6.2 Hz). ESI-MS
(m/z): Calcd. for C28H32N2O6S3: 588.8; found: 588.9.
d) 3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfouyl)-2-
methyl-biphenyl-3-carboxylic acid isopropyl ester trifluoroacetate
The procedure used in Example 1: step d was followed using 3'-[5-
(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-
sulfonyl]-2-methyl-biphenyl-3-carboxylic acid isopropyl ester ((Example 3:
step c) 29 mg, 0.049 mmol). Analogous purification by HPLC yielded the title
compound (25 mg, S3%) as a white solid. 1H-NMR (CD3OD): d 8.32 (s. 1H),
8.05 (dt, 1H, J = 1.7, 7.7 Hz), 7.95 (t, 1H, J - 1.7 Hz), 7.78 (m. 1H). 7.70 (t,
1H, J = 7.7 Hz), 7.66 (dt, 1H, J = 1.4, 7.7 Hz), 7.36 (s, 1H), 7.35 (d, 1H, J =
1.2 Hz), 5.22 (heptet, 1H, J = 6.3 Hz), 2.71 (s, 3H), 2.31 (s, 3H), 1.38 (d, 1H, J
= 6.3 Hz). ESI-MS (m/z): Calcd. for C23H24N2O4S3: 489.7 (M+H); found:
489.2.
Example 4
3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyI-
biphenyl-2-carboxylic acid trifluoroacetate
a) 2-Iodo-3-methyl-benzoic acid tert-butyl ester
A 100-mL RB flask was charged with 2-iodo-3-methylbenzoic acid
(l.lg, 4.2 mmol), a stirbar, Et2O (15 mL) and DCM (35 mL) and was cooled
to —78 °C under an argon atmosphere. Trifluoromethanesulfonic acid (250
µL) was added over 30 sec and isobutylene was bubbled into the solution
(until the solution became cloudy) using a 8"/20 gauge steel needle. The
reaction was stirred for 6 h between -78 and -20 °C. Solid NaHCO3 (250 mg)
was added and the solution was allowed to warm to it with stirring. After 20
min, the solution was poured into an extraction funnel containing DCM (50
mL) and Na2CO3 (2M, 20 mL). The layers were separated and the organic
layer was washed with Na2CO3 (2M, 2 x 10 mL), water (20 mL), brine (30
mL) and dried over sodium sulfate. Removal of the solvent in vacuo yielded
the title compound (1.05 g, 78%) which was used without further purification.
1H-NMR (CDCl3): d 7.25 (m, 3H), 2.50 (s, 3H), 1.62 (m, 9H).
b) 4-Methyl-2'(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic
acid tert-butyl ester
The procedure used in Example 3: step b was followed using 2-iodo-3-
methyl-benzoic acid tert-butyl ester ((Example 4: step a) 960 mg, 3 mmol),
PdCl2(PPh3)2 (126 mg, 0.18 mmol), triethylamine (1.25 mL, 9 mmol), and
4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (660 (µL, 4.5 mmol) in. dioxane (12
mL) at a reaction temperature of 80 °C. Analogous aqueous workup and
purification by SiO2 flash chromatography yielded the title compound (618
mg, 64%). 1H-NMR (CDCl3): d 7.67 (m, 1H), 7.25 (m, 2H), 2.43 (s, 3H), 1.57
(m,9H), 1.44 (m, 12H).
c) 3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-
thiophene-3-sulfonyl]-6-methyl-biphenyl-2-carboxylic acid tert-butyl ester
The procedure used in Example 1: step c was followed using {[4-(3-
bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-
carbamic acid tert-butyl ester (Example 27 (50 mg, 0.1 mmol)), 4-methyl-2-
(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzoic acid tert-butyl ester
((Example 4: step b) 127 mg, 0.4 mmol), Na2CO3 (2M, 0.8 mL, 1.6 mmol),
Pd(PPh3)4 (29.4 nag, 0.025 mmol), ethanol (0.8 mL) and toluene (1.6 mL).
Analogous aqueous workup and purification of the crude material by
preparative TLC (25% EtOAc in hexanes) yielded the title compound (35 mg,
58%) as a light-yellow glass. 1H-NMR (CDCl3): d 8.01 (ddd, 1H, J = 1.2,
1.9, 7.9 Hz), 7.92 (s, 1H), 7.83 (t, 1H, J = 1.7 Hz), 7.65 (m, 1H), 7.56 (t, 1H, J
= 7.8 Hz), 7.43 (dt, 1H, J = 1.4, 7.7 Hz), 7.36 (m, 2H), 2.58 (s, 3H), 2.00 (s,
3H), 1.51 (s, 9H). ESI-MS (m/z): Calcd. for C29H34N2O6S3: 602.8; found:
602.9.
d) 3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-
methyl-biphenyl-2-carboxylic acid trifluoroacetate
The procedure used in Example 1: step d was followed using 3'-[5-
(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-
sulfonyl]-6-methyl-biphenyl-2-carboxylic acid tert-butyl ester ((Example 4,
step c) 29 mg, 0.048 mmol). Analogous punfication by HPLC yielded the title
compound (23 mg, 70%) as a white solid. 1H-NMR (CD3OD): d S.28 (s. 1H).
7.99 (ddd, 1H, J = 1.2, 1.9, 7.9 Hz), 7.83 (m, 1H, J = 0.5, 1.9 Hz), 7.76 (ddd,
1H, J = 0.5, 1.4, 7.7 Hz), 7.63 (dt, 1H, J = 0.5, 7.7 Hz), 7.50 (ddd, 1H, J = 1.2,
1.6, 4.9 Hz), 7.49 (ddd, 1H, J -0.7, 1.4, 7.7 Hz), 7.40 (t, 1H, J = 7.7 Hz), 2.72
(s, 3H), 2.02 (s, 3H). ESI-MS (m/z): Calcd. for C20H18N2O4S3 (M+H): 447.6;
found: 447.1.
Example 5
4-(6'-Hydroxymethyt-2'-methyl-biphenyl-3-suIfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine
a) (2-Iodo-3-methyl-phenyl)-methanol
Thionyl chloride (6 miL) was added over 1 min to a 0 °C solution of 2-
iodo-3-methyl benzoic acid (3.0 g, 11.4 mmol) in DCM (10 mL). The
solution was stirred for 24 h at rt and the volatile components were removed in
vacuo. A portion of the crude acid chloride (955 mg) was dissolved in THF
(15 mL) and NaBH4 (380 mg, 10 mmol) was added. After stirring for 90 min,
multiple spots were evident by TLC analysis. The reaction mixture was
cooled to -78 °C and solid LiAlH4, (300 mg, 7.91 mmol) was added. The
reaction was stirred for 30 min, after which TLC analysis showed one major
spot. The reaction was quenched by addition of EtOAc (10 mL) and was
slowly poured into a vigorously stirred solution of HC1 (1M, 30 mL). EtOAc
(70 mL) was added, the layers were separated, and the organic layer was
washed with NaHCO3 (3 x 15 mL), water (15 mL), brine (40 mL), and was
dried over sodium sulfate. Removal of the solvent in vacuo yielded the title
compound (752 mg, 89%) as a thick oil which was used without further
purification. 1H-NMR (CDCl3): d 7.27 (m, 2H), 7.20 (m, 2H), 4.74 (m, 2H),
2.50 (s, 3H), 2.0 (br s, 1H).
b) 7-Methyl-3H-benzo[c][1,2]oxaborol-1-ol
Butyllithium (2.5 M, 2.91 mL, 7.3 mmol) was added dropwise to a
-78°C solution of aryl halide ((Example 5: step a) 723 mg, 2.91 mmol) in Et2O
(12 mL). The solution was stirred at -78°C for 2 h and trimethylborate (3.3
mL, 29.1 mmol) was added in one portion. The solution was warmed to rt
over 15 min and stirred for 1 h at rt (appearance of gelatin-like ppt). EtOAc
(80 mL) and HC1 (0.1 N, 30 mL) were added and the biphasic solution was
stirred for 15 min. The layers were separated and the organic layer was
washed with HC1 (0.1N, 2 x 10 mL), water (10 mL), brine (30 mL), and was
dried over sodium sulfate. Concentration of the solution in vacuo yielded an
oily solid which further solidified upon trituration with hexanes. The crude
title compound (contaminated with butylboronate products) was used without
further purification, existing as a mixture of the cyclic half-ester and the free
boronic acid. 1H-NMR (CDCl3): d 7.1-7.4 (m, 3H), 5.23 (m, 2H), 2.57 (s,
3H).
c) {[4-(6'-Hydroxymethyl-2'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-immo-inethyl}-carbamic acid ten-butyl ester
The procedure used in Example 1: step c was followed using {[4-(3-
bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-
carbamic acid tert-butyl ester (Example 27 (50 mg, 0.1 mmol)), 7-methyl-3H-
benzo[c][l,2]oxaborol-1-ol ((Example 5: step b) 59 mg, 0.4 mmol), Na2CO3
(2M, 0.8 mL, 1.6 mmol), Pd(PPh3)4 (29.4 mg, 0.025 mmol), ethanol (0.8 mL)
and toluene (1.6 mL). Analogous aqueous workup and purification of the
crude material by preparative TLC (40% EtOAc in hexanes) yielded the title
compound (21 mg, 40%) as a light-yellow glass. 1H-NMK- (CDCl3): d 7.96
(m, 2H), 7.86 (m, 1H), 7.54 (m, 1H), 7.43 (m, 1H), 7.18-7.38 (m, 3H), 4 53 (d,
1H= 13.3 Hz), 4.45 (d, 1H. J = 13.3 Hz), 2.54 (s, 3H), 1.96 (s, 3H), 1.49 (s,
9H). ESI-MS (m/z): Calcd. for C25H28N2O5S3: 532.7; found: 532.9.
d) 4-(6'-Hydroxymethyl-2'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxamidine
The procedure used in Example 2: step d was followed using {[4-(6'-
hydroxymethyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-
yl]-imino-rnethyl}-carbamic acid tert-butyl ester ((Example 5, step c) 21 mg,
0.039 mmol). Analogous purification by C18-HPLC yielded the title
compound (19 mg, 86%) as a white solid. 1H-NMR (CD3OD): d S.33 (s, 1H),
8.04 (ddd, 1H, J = 1.2, 1.9, 7.9 Hz), 7.S8 (m, 1H), 7.71 (dt, 1H, J = 0.5, 7.7
Hz), 7.57 (ddd. 1H, J = 1.2, 1.6, 7.7 Hz), 7,42 (m, 1H), 7.34 (t, 1H, J = 7.7
Hz), 7.26 (m, 1H), 4.20 (s, 2H), 2.72 (s, 3H), 1.99 (s, 3H). ESI-MS (m/z):
Calcd. for C20H20N2O3S3 (M+H): 433.6; found: 433.1.
Example 6
4-(3'-formyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate
a) 3-Bromo-N-methoxy-2,N-dimethyl-benzamide
Thionyl chloride (6 mL) was added over 1 min to a 0 °C solution of 2-
iodo-3-methyl benzoic acid (3.0 g, 11.4 mmol) in DCM (10 mL). The
solution was stirred for 24 h at rt and the volatile components were removed in
vacuo. A portion of the crude acid chloride (1.56 g, 6.7 mmol) was dissolved
in dry DCM (15 mL). N,O-dimethylhydroxylamine (814 mg, 8.35 mmol) was
added followed by triethylamine (2.80 mL, 20.1 mmol). After stirring for 18 h
at rt the solvents were removed in vacuo. After partitioning the residue
between EtOAc (60 mL) and aqueous HC1 (1N, 20 mL), the organic layer was
further extracted with HCl (1N, 10 mL), NaOH (1N, 3 x10 mL), water (10
mL), brine (20 mL), and was dried over sodium sulfate. Removal of the
solvent in vacuo yielded the title compound (1.58 g, 92%) which was used in
subsequent reactions without further purification. 1H-NMR (CDCl3): d 7.57
(dd, 1H, J = 1.2, 7.9 Hz), 7.21 (d, 1H, J = 7.4 Hz), 7.08 (t, 1H, J = 7.7 Hz),
3.39 (br s, 3H), 3.35 (br s, 3H), 2.36 (s, 3H).
b) 3-Bromo-2-methyl-benzaldehyde
Lithium aluminum hydride (201 mg, 5.31 mmol) was added in one
portion to a -78 °C solution of 3-bromo-N-methoxy-2,N-dirnethyl-benzamide
((Example 6: step b) 1.1 g, 4.24 mmol) in THF (25 mL). After stirring for 1 h
at -78 °C, the hydride reagent was quenched with EtOAc (10 mL), and the
solution was slowly poured into a vigorously stirred mixture of citric acid
(10%, 30 mL) and EtOAc (50 mL). After separating the layers, the organic
layer was washed with NaHCO3 (3 x 20 mL), water (20 mL), and brine (30
mL). The solution was dried (sodium sulfate) and the solvent was removed in
vacuo, giving the title compound (813 mg, 96%) as a colorless oil which was
used without further purification. 1H-NMR (CDCl3): d 10.28 (s, 1H), 7.80 (m,
2H), 7.25 (m, 1H), 2.78 (s, 3H).
c) l-Bromo-3-dimethoxymethyl-2-methyl-benzene
The 3-bromo-2-methyl-benzaldehyde ((Example 6: step c) 813 mg,
4.08 mmol) was dissolved in dry MeOH (50 mL) and trimethyl orthoformate
(8 mL). Toluenesulfonic acid (100 mg) was added and the solution was stirred
for 6 h at rt. Solid NaHCO3 (200 mg) was added, the solution was stirred for
30 min, and the volatile components were removed in vacuo. The residue was
dissolved in dry EtOAc (10 mL), the solution was filtered (45 micron filter),
and the solvent was removed in vacuo. 1H NMR analysis of the crude
material (918 mg, 92%) revealed approximately a 90% conversion of the
starting material to the title compound, which was used without further
purification. 1H-NMR (CDCl3): d 7.47 (dd, 1H, J = 1.2, 8.1 Hz), 7.44 (dd, 1H,
J = 0.9, 7.9 Hz), 6.99 (t, 1H, J == 7.9 Hz), 5.37 (s, 1H), 3.25 (s, 6H), 2.37 (s,
3H).
d) 2-Formyl-1-methyl-phenylboronic acid
The 1-bromo-3-dimethoxymethyl-2-methyl-benzene ((Example 6: step
c) 500 mg, 2 mmol), butyllithium (2.5 M, 1 mL, 2.5 mmol), and
trimethylborate (2.3 mL, 20 mmol) were reacted as in Example 5: step b.
After aqueous workup, the residue was dissolved in acetone (18 mL) and HCl
(1N, 2 mL). After standing for 18 h at rt, the volatile components were
removed in vacuo and the residue was purified by SiO2 flash chromatography
(25-40% EtOAc in hexanes) to give the title compound (126 mg, 38%). The
title compound exists as a mixture of boronic acids and anhydrides in CDCl3,
therefore the reported NMR signals represent pairs or groups of related
signals. 1H-NMR (CDCl3): d 10.44 (s, 1H), 8.38 (dd, 1H, J = 1.4, 7.4 Hz),
7.49 (t, 1H, J = 7.5 Hz), 3.12 (s, 3H).
e) [4-(3'-Formyl-2'-methyl-biphenyl-3-sulfonyl)-5-methyIsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
The procedure used in Example 1: step c was followed using {[4-(3-
bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-
carbamic acid tert-butyl ester ((Example 27) 50 mg, 0.1 mmol), Pd(PPh3)4
(29.4 mg, 0.025 mmol), 2-formyl-1-methyl-phenylboronic acid ((Example 6:
step d) 65 mg, 0.4 mmol), Na2CO3 (2M, 0.8 mL, 1.6 mmol), ethanol (0.8 mL)
and toluene (1.6 mL). Analogous aqueous workup and purification of the
crude material by preparative TLC (25% EtOAc in hexanes) yielded the title
compound (30 mg, 56%) as a light-yellow glass. 1H-NMR (CDCl3): d 10.36
(s, 1H), 8.02 (s, 1H), 7.99 (ddd, 1H, J = 1.4, 1.9, 7.7 Hz), 7.93 (t 1H, J = 1.6
Hz), 7.87 (dd, 1H, J = 3.0, 6.3 Hz), 7.60 (dt, 1H, J = 0.5, 7.7 Hz), 7.54 (dt, 1H,
J = 1.5, 7.7 Hz), 7.43 (m, 2H), 2.57 (s, 3H), 2.49 (s, 3H), 1.51 (s, 9H). ES1-
MS (m/z): Calcd. for C25H26N2O5S3: 530.7; found: 530.9.
f) 4-(3'-Formyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
The procedure used in Example 1: step d was followed using {[4-(3'-
formyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-
irnino-methyl}-carbamic acid tert-butyl ester ((Example 6: step e) 30 mg,
0.056 mmol). Analogous purification by HPLC yielded the title compound
(22 mg, 73%) as a white solid. The aldehyde is hydrated according to proton
NMR analysis. 1H-NMR (CD3OD): d 8.36 (s, 1H), 8.07 (ddd, 1H, J = 1.4,
1.9, 7.7 Hz), 7.98 (t, 1H, J = 1.5 Hz), 7.72 (dt, 1H, J = 0.5, 7.7 Hz), 7.67 (dt,
1H, J = 1.5, 7.9 Hz), 7.63 (dd, 1H, J = 1.4, 7.7 Hz), 7.33 (t, 1H, J = 7.7 Hz),
7.22 (dd, 1H, J = 1.4, 7.4 Hz), 5.56 (s, 1H), 2.76 (s, 3H), 2.22 (s, 3H). ESI-MS
(m/z): Calcd. for C20H18N2O3S3: 431.6 (M+H); found: 431.3, 448.2 (M+H2O).
Example 7
4-(5'-Hydroxymethyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
a) 3-Hydroxymethyl-2-melhyl-phenylboronic acid
Butyllithium (2.5 M, 4 mL, 10 mmol), 3-iodo-4-methyl-benzyl alcohol
(1 g, 4 mmol), and trimethylborate (6 mL, 53 mmol) were reacted as in
Example 5: step b. Aqueous workup and purification by SiO2 flash
chromatography (40-50% EtOAc in hexanes) yielded the title compound (180
mg, 27%). The title compound exists as a mixture of boronic acids and
anhydrides in CDCl3, therefore the reported NMR signals represent pairs or
groups of related signals. 1H-NMR (CDCl3): d 7.06-7.30 (m, 3H), 4.56 (s, 3H),
4.16 (brs, 1H), 2.32 (s, 3H).
b) {[4-(5'-Hydroxymethyl-2'-methyl-biphenyI-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yI]-imino-methyl}-carbamic acid tert-butyl ester
The procedure used in Example 1: step c was followed using {[4-(3-
bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-
carbamic acid tert-butyl ester (Example 27 (100 mg, 0.2 mmol)), Pd(PPh3)4
(59 mg, 0.05 mmol), 3-hydroxymethyl-2-methyl-phenylboronic acid
((Example 7: step a) 105 mg, 0.63 mmol), Na2CO3 (2M, 0.8 mL, 1.6 mmol),
ethanol (0.8 mL) and toluene (1.6 mL). Analogous aqueous workup and
purification of the crude material by SiO2 flash chromatography (25-50%
EtOAc in hexanes) yielded the title: compound (72 mg, 67%) as a light-yellow
glass. 1H-NMR (CDCl3): d 8.00 (s, 1H), 7.96 (dt, 1H, J = 2.1, 4.4 Hz), 7.93
(m, 1H), 7.54 (m, 2H), 7.27 (m, 2H), 7.18 (d, 1H, J = 1.4 Hz), 4.68 (s, 2H),
2.54 (s, 3H), 2.20 (s, 3H), 1.51 (s, 9H).
c) 4-(5'-Hydroxymethyl-2'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
The procedure used in Example 1: step d was followed using {[4-(3'-
formyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-
imino-methyl}-carbamic acid tert-butyl ester ((Example 7: step b) 15 mg,
0.028 mmol). Analogous purification by HPLC yielded the title compound
(12 mg, 80%) as a white solid. 1H-NMR (CD3OD): d 8.32 (s, 1H), 8.02 (m,
1H), 7.99 (m, 1H), 7.68 (m, 2H), 7.29 (d, 2H, J = 1.8 Hz), 7.21 (br s, 1H), 4.61
(s, 2H), 2.72 (s, 3H), 2.22 (s, 3H). ESI-MS (m/z): Calcd. for C20H20N2O3S3
(M+H): 433.6; found: 433.1.
Example 8
4-(5'-Formyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiopherte-2-
carboxamidine trifluoroacetate
a) {[4-(5'-formyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
The {[4-(5'-hydroxymethyl-2'-methyl-biphenyl-3-sulfony])-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbarmic acid tert-butyl ester
((Example 7: step b) 30 mg, 0.056 mmol) was dissolved in a mixture of
DMSO (1 mL) and DCM (1 mL) and cooled to 0 °C. Triethylamine (12 µL,
0.084 mmol) and sulfur trioxide-pyridine complex (11 mg, 0.068 mmol) were
added and the solution was stilted for 1 h at 0 °C. Partial conversion was
evident by TLC. Additional triethylamine (20 µL, 0.14 µL) and sulfur
trioxide-pyridine complex (18 mg, 0.11 mmol) were added and the solution
was stirred for 3 h at rt. Isopropanol (250 µL) was added, the reaction was
stirred for 15 min, and EtOAc (40 mL) was added. The EtOAc solution was
extracted with citric acid (2 x 10 mL), NaHCO3 (2 x 10 mL), water (5 x 10
mL), and brine (20 mL), and was dried over sodium sulfate. Removal of the
solvent in vacuo yielded the title compound (26 mg, 87%) which was used
without further purification. 1H-NMR (CD3OD): d 10.00 (s, 1H), 7.99 (m,
3H), 7.81 (dd, 1H, J = 1.6 7.7 Hz), 7.72 (d, 1H, J = 7.7 Hz), 7.59 (m, 2H), 7.46
(d, 1H, J = 7.7 Hz), 2.58 (s, 3H), 2.30 (s, 3H), 1.51 (s, 9H).
b) 4-(5'-Formyl-2'-methyl-biphenyI-3-sulfonyl)-S-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
The procedure used in Example 1: step d was followed using {[4-(5'-
formyl-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-
imino-methyl}-carbamic acid tert-butyl ester ((Example 8: step b) 15 mg).
Analogous purification by HPLC yielded the title compound (12 mg, 80%) as
a white solid. The aldehyde is apparently 80% hydrated according to proton
NMR analysis. 1H-NMR (CD3OD): d 8.33 (s, 1H), 8.03 (m, 1H), 7.9S (m,
1H), 7.68 (m, 2H), 7.35 (m, 2H), 7.26 (d, 1H, J = 1.6 Hz), 5.39 (s, 1H), 2.73
(s, 3H), 2.24 (s, 3H). ESI-MS (m/z): Calcd. for C20H18N2O3S3 (M+H): 431.6;
found: 431.2.
Example 9
4-[3-(4-Methyl-pyridin-3-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophene-
2-carboxamidine trifluoroacetate
a) (Imino-{4-[3-(4-methyl-pyridin-3-yl)-benzenesulfonyl]-5-
methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester
Butyllithium (2.5 M, 1.88 mL, 4.5 mmol) was added dropwise to a
-78°C solution of 3-bromo-4-methylpyridine (645 mg, 3.75 mmol) in Et2O (15
mL). The solution was stirred at -78 °C for 1 h and trimethylborate (5 mL, 44
mmol) was added in one portion. The solution was wanned to rt over 15 min
and stirred for 2 h at rt. The volatile components were removed in vacuo and
the solid residue was dried under high vacuum for 2 h. A portion of the crude
solid (81 mg, 0.4 mmol) was reacted with {[4-(3-bromo-benzenesulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(Example 27 (50 mg, 0.1 mmol)), Pd(PPh3)4 (29 mg, 0.025 mmol), Na2CO3
(2M, 0.8 mL, 1.6 mmol), ethanol (0.8 mL) and toluene (1.6 µL) according to
the procedure used in Example 1: step c. Analogous aqueous workup and
purification of the crude material by preparative TLC (50% EtOAc in
hexanes) yielded the title compound (36 mg, 71%) as a light-yellow glass. 1H-
NMR (CDCl3): d 8.50 (d 1H, J = 5.1 Hz), 8.42 (s, 1H), 8.07 (s, 1H), 7.99 (m,
2H), 7.45-7.70 (m, 5H), 7.24 (d, 1H, J = 5.1 Hz), 2.59 (s, 3H), 2.27 (s, 3H),
1.52 (s, 9H). ESI-MS (m/z): Calcd. for C23H25N3O4S3: 503.7; found: 503.8.
b) 4-[3-(4-Methyl-pyridin-3-yl)-benzenesulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine bis-trifluoroacetate
The procedure used in Example 1: step d was followed using (imino-
{4-[3-(4-methyl-pyridin-3-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophen-2-
yl}-methyl)-carbamic acid tert-butyl ester ((Example 9: step a) 36 mg, 0.071
mmol). Analogous purification by C18-HPLC (10-40% CH3CN over 30 min)
yielded the title compound (22 mg, 49%) as a white solid. 1H-NMR
(CD3OD): d 8.74 (br s, 2H), 8.37 (s, 1H), 8.19 (m, 2H), 8.01 (d, 1H, J = 5.6
Hz), 7.85 (m, 2H), 2.74 (s, 3H), 2.55 (s, 3H). ESI-MS (m/z): Calcd. for
C18H17N3O2S3 (M+H): 404.5; found: 404.1.
Example 10
4-[3-(2-Chloro-pyridin-3-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophene-
2-carboxamidine; bis-trifluoroacetate
a) ({4-[3-(2-Chloro-pyridin-3-yl)-benzenesulfonyl]-5-methylsulfanyl-
thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester
Butyllithium (2.5 M, 1.0 mL, 2.5 mmol) was added dropwise to a
-78°C solution of 3-bromo-2-chloropyridine (384 mg, 2.0 mmol) in Et2O (10
mL). The solution was stirred at -78 °C for 1 h and trimethylborate (2.3 mL,
20 mmol) was added in one portion. The solution was warmed to rt over 15
min and stirred for 2 h at rt . The: volatile components were removed and the
solid material was dried under high vacuum for 2 h. A portion of the crude
solid (105 mg, 0.63 mmol) was reacted with {[4-(3-bromo-benzenesulfonyl)-
5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(Example 27 (50 mg, 0.1 mmol)), Pd(PPh3)4 (29 mg, 0.025 mmol), Na2CO3
(2M, 0.8 mL, 1.6 mmol), ethanol (0.8 mL) and toluene (1.6 mL) according to
the procedure used in Example 1: step c. Analogous aqueous workup and
purification of the crude material by preparative TLC (50% EtOAc in
hexanes) yielded the title compound (31 mg, 58%) as a light-yellow glass.
b) 4-[3-(2-Chloro-pyridin-3-yl)-benzenesulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine; bis-trifluoroacetate
The procedure used in Example 1: step d was followed using ({4-[3-(2-
chloro-pyridin-3-yl)-benzenesulfonyl]-5-methylsulfanyl-miophen-2-yl}-
imino-methyl)-carbamic acid tert-butyl ester ((Example 10: step b) 31 mg,
0.0.9 mmol). Analogous purification by C18-HPLC (10-40% CH3CN over 30
min) yielded the title compound (29 mg, 74%) as a white solid. 1H-NMR
(CD3OD): d 8.45 (dd, 1H, J = 1.9, 4.9 Hz), 8.36 (s, 1H). 8.16 (t, 1H. 3 = 1.5
Hz), 8.12 (ddd, 1H, J = 1.2, 1.9, 7.7 Hz), 7.90 (dd, 1H, J = 1.9, 7.7 Hz). 7.83
(dt, 1H, J = 1.5, 7.7 Hz), 7.75 (dt, 1H, J = 0.5, 7.7 Hz), 7.53 (dd, 1H, J - 4.9,
7.7 Hz), 2.73 (s, 3H). ESI-MS (m/z): Calcd. for C17H14CIN3O2S3 (M+H):
424.0; found: 424.1.
Example 11
4-[3-(3-Methyl-pyridin-2-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophene-
2-carboxamidine bis-trifluoroacetate
A 2-dram vial with a septa-containing screwcap was charged with {[4-
(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-
carbamic acid tert-butyl ester (Example 27 (100 mg, 0.2 mmol)) and
Pd(PPh3)4 (59 mg, 0.025 mmol). Tetrahydrofuran was added followed by 3-
methyl-2-pyridylzinc bromide (Aldrich Chemical Company) (0.5 M in THF,
800 uL, 0.4 mmol). The reaction was heated to 80 °C for 1 h and was worked
up as in Example 1:step c Flash chromatography (SiO2) of the crude material
(25-50% EtOAc in hexanes) yielded a light-yellow glass (74 mg, 73%) which
was treated with trifluoroacetic acid and purified by C18-HPLC (10-40%
CH3CN over 30 min) as in Example 1: step d, giving the title compound (46
mg, 61%) as a white solid. 1H-NMR (CD3OD): d 8.59 (dd, 1H, J = 0.9, 5.1
Hz), 8.34 (s, 1H), 8.22 (m, 2H), 8.16 (ddd, 1H, J = 0.7, 1.4, 7.9 Hz), 7.92 (ddd,
1H, J = 0.5, 1.1, 7.7 Hz), 7.82 (dt, 1H, J = 0.7, 7.7 Hz), 7.68 (dd, 1H, J = 5.4,
7.9 Hz), 2.73 (s, 3H), 2.39 (s, 3H). ESI-MS (m/z): Calcd. for C18H17N3O2S3
(M+H): 404.5; found: 404.1.
Example 12
4-(3-Allyloxy-5-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine hydrochloride
a) l,3-Dibromo-5-tert-butoxy-benzene
To a vigorously stirred solution of 1,3-dibromophenylboronic acid (4.5
g, 16.1 mmol) in MeOH (50 mL) and THF (50 mL) was alternately added
(dropwise) aqueous hydrogen peroxide (30%, 10 mL) and NaOH (1M, 20 mL)
(dropwise), maintaining pH~10. The solution became cloudy and was stirred
for 30 min (pH maintained at ~10 using 10 N NaOH). EtOAc (200 mL) and
sat'd NaHCO3 (50 mL) were added and the layers were separated. The
organic layer was extracted with NaHCO3 (50 mL), water (20 mL), brine (50
mL), and was dried over sodium sulfate. The solvent was removed in vacuo
and the residue was dissolved in DCM (80 mL). After cooling to -78°C,
isobutylene was added (~20 mL) followed by trifluoromethanesulfonic acid
(300 µL). The cloudy solution was stirred for 15 min at -78 °C and for lh at
-2,0 to -10°C. Additional amounts of isobutylene (~10 mL) and
trifluoromethanesulfonic acid (200 µL) were added and the solution was
stirred for 1 h. Solid K2CO3 (1 g) was carefully added, the solution was stirred
for 10 min at rt, and NaOH (1N, 30 mL) was added. The layers were
separated and the organic layer was further extracted with NaOH (1N, 5 x 10
mL), water (10 mL), and brine (30 mL). After drying and removal of the
solvent in vacuo, the residue was purified by SiO2 flash chromatography (2-
5% EtOAc in hexanes) to yield the title compound (3.80 g, 77%). 1H-NMR
(CDCl3): d 7.38 (t, 1H. J = 1.6 Hz), 7.09 (d, 2H, J = 1.6 Hz), 1.36 (s. 9H).
b) 4-(3-Bromo-5-tert-butoxy-benzenesulfonyl)-5-nitro-thiophene-2-
carboxylic acid methyl ester
Butyllithium (2.5 M, 3.25 mL, 8.13 mmol) was added dropwise to a
-78 °C solution of l,3-dibromo-5-tert-butoxy-benzene ((Example 12: step a)
2.4 g, 7.71 mmol) in Et2O (80 mL). The solution was stirred at -78 °C for 2 h
and sulfur (310 mg, 9.69 mmol) was added in one portion. The solution was
warmed to rt over 30 min and stirred for 2 h at rt. EtOAc. (50 mL) and citric
acid (5%, 30 mL) were added and the layers were separated. The organic
layer was washed with NaHCO3 (2 x 30 mL), water (10 mL) and brine (30
mL), and was dried over sodium sulfate. The solvent was removed in vacuo
and the residue was redissolved in THF (40 mL). Triphenylphosphine (2.03 g,
7.74 mmol), 4-bromo-5-nitro-thiophene-2-carboxylic acid methyl ester
((Example 114, step c) 2.13 g, 8.0 mmol), water (1 mL), and DMAP-resin (7.0
g, 10 mmol) were added and the mixture was stirred for 18 h at rt The
solution was filtered, the solids were washed with DCM, and the solvent was
removed in vacuo. The residue was partially purified by SiO2 flash
chromatography (25% EtOAc in hexanes) to yield a mixture of the title
compound and 4-bromo-5-nitro-thiophene-2-carboxylic acid methyl ester
starting material. The crude material was redissolved in DCM (60 mL),
mCPBA (77%, 6.04 g, 27.1 mmol) was added, and the solution was stirred for
5 h at 40 °C. DCM (50 mL) and aqeous sodium thiosulfate were added
(exothermic), and the layers were separated. The organic layer was extracted
with Na2CO3 (2M, 6 x 30 mL), brine (50 mL), and was dried over sodium
sulfate. Concentration of the solvent in vacuo followed by SiO2 flash
chromatography (25-75% DCM in hexanes) yielded the title compound as a
colorless glass (2.85 g, 77%). lH-NMR (CDCl3): d 8.28 (d, 1H, J = 0.5 Hz),
7.71 (t, 1H, J = 1.6 Hz), 7.68 (m, 1H), 7.39 (m, 1H), 4.00 (s, 3H), 1.42 (s, 9H).
c) 4-(3-Bromo-5-tert-butoxy-benzenesulfonyl)-5-methylsnlfanyl-
thiophene-2-carboxylic acid methyl ester
Sodium thiomethoxide (1M in EtOH, 4.4 mL, 4.4 mmol) was added
dropwise to a -78 °C solution of 4-(3-bromo-5-tert-butoxy-benzenesulfonyl)-
5-nitro-thiophene-2-carboxylic acid methyl ester (1.91 g, 4.0 mmol) in THF
(40 mL). The solution was stirred for 30 min at -78 °C and glacial acetic acid
(1 mL) was added. The solution was diluted with EtOAc (60 mL), extracted
with NaHCO3 (2 x 30 mL), water (2 x 20 mL), brine (30 mL), and was dried
over sodium sulfate. Concentration of the solution in vacuo followed by SiO2
flash chromatography of the residue yielded the title compound (1.48 g, 76%).
1H-NMR (CDCl3): d 8.01 (d, 1H, J = 0.5 Hz), 7.74 (m, 1H), 7.66 (m, 1H), 7.37
(m, 1H), 3.99 (s, 3H), 2.48 (s, 3H), 1.41 (s, 9H).
d) 4-(3-Bromo-5-hydroxy-benzenesulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester
Trifluoroacetic acid (5 mL,) was added to a solution of 4-(3-bromo-5-
tert-butoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid
methyl ester ((Example 12: step c) 240 mg, 0.5 mmol) in DCM (5 mL). The
solution was stirred at rt for 2 h and the solvents were removed in vacuo,
yielding 214 mg of an oil (quantitative) which was used without further
purification.
e) 4-(3-Allyloxy-5-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-
2-carboxylic acid methyl ester
Cesium carbonate (33 mg., 0.1 mmol) and allylbromide (30 µL, 0.35
mmol) were added to a solution of 4-(3-bromo-5-hydroxy-benzenesulfonyl)-5-
methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 12: step
d) 30 mg, 0.71 mmol) dissolved in dry DMF (3 mL). After stirring for 16 h at
rt, the solution was poured into a mixture of water (20 mL) and EtOAc (30
mL). The layers were separated and the organic layer was extracted with
water (5 x 5 mL), brine (20 mL), and was dried over sodium sulfate. The
solvent was removed in vacuo to yield the title compound, which was used
without further purification.
f) 4-(3-Allyloxy-5-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-
2-carboxamidine hydrochloride
AIM stock solution of dimethylaluminum amide was freshly prepared
by careful addition of trimethylalummum (2M in toluene, 10 mL) to a
suspension of NH4CI (1.08 g, 11 rnmol) in toluene (10 mL). 4-(3-Allyloxy-5-
bromo-benzenesulfonyl)-5-methyli;ulfanyl-thiophene-2-carboxylic acid methyl
ester (33 mg, 0.07 mmol) was treated with the dimethylaluminum amide
solution (2 mL, 20 mmol) and was heated to 100 °C for 2 h, during which a
precipitate formed. The solution was poured into a vigorously stirred mixture
of SiO2 (20 g) in CHC13 (70 mL). The flask was rinsed with methanol (10
mL) and the SiO2 mixture was stirred for 10 min. The solution was filtered
through a fritted column and the SiO2 was eluted with 15% MeOH in DCM
(150 mL). Concentration of the eluent and purification of the residue by
preparative TLC (10% MeOH in DCM) yielded the title compound (15 mg,
44%) as a white solid. 1H-NMR (CD3OD): d 8.27 (s, 1H), 7.69 (t, 1H, J = 1.6
Hz), 7.52 (dd, 1H, J = 1.6, 2.3 Hz), 7.44 (dd, 1H, J = 1.6, 2.3 Hz), 6.03 (m,
1H), 5.41 (ddd, 1H, J = 1.6, 3.3, 17.2 Hz), 5.29 (ddd, 1H, J = 1.4, 2.8, 10.5
Hz), 4.64 (dt, 2H, J = 1.6, 5.4 Hz), 2.74 (s, 3H). ESI-MS (m/z): Calcd. for
C15H15BrN2O3S3: 447.4; found: 447.1.
Example 13
4-(3-Brom o-5-m ethoxy~benzenesulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine hydrochloride
Following the procedure for Example 12: step e, 4-(3-bromo-5-
hydroxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl
ester ((Example 12: step d) 30 mg, 0.71 mmol) was alkylated using cesium
carbonate (33 mg, 0.1 mmol) and methyl iodide (44 µL, 0.71 mmol). After
analogous workup, the residue was subjected to amidination conditions as
Example 12: step f. Analogous purification procedures yielded the title
compound (17 mg, 53%) as a white solid. 1H-NMR (CD3OD): d 8.27 (s, 1H),
7.69 (t, 1H, J = 1.6 Hz), 7.52 (dd, 1H, J = 1.6, 2.3 Hz), 7.37 (dd, 1H, J = 1.6,
2.3 Hz), 3.87 (s, 3H), 2.72 (s, 3H). ESI-MS (m/z): Calcd. for
C13H13BrN2O3S3: 421.4; found: 421.1.
Example 14
4-(5-Hydroxy-biphenyI-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidin e hydro chloride
a) 4-(5-tert-Butoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid ethyl ester
The procedure used in Example 1: step d was followed using
benzeneboronic acid (42 mg, 0.35 mmol), 4-(3-bromo-5-tert--butoxy-
benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester
((Example 12: step c) (83 mg, 0.17 mmol)), Na2CO3 (2M, 1.4 mL, 2.8 mmol),
Pd(PPh3)4 (48 mg, 0.04 mmol), toluene (5.6 mL), and ethanol (2.8 mL).
Analogous aqueous workup and SiO2 flash chromatography (20 % EtOAc in
hexanes) yielded the title compound (55 mg, 65%). 1H-NMR (CDCl3): d 8.03
(s, 1H), 7.91 (t, 1H, J = 1.6 Hz), 7.63 (t, 1H, J = 2.0 Hz), 7.57 (m, 2H), 7.47
(m, 2H), 7.41 (m, 2H), 4.33 (q, 2H, J = 7.2 Hz), 2.60 (s, 3H), 1.42 (s, 9H),
1.36 (t, 3H,J = 7.2Hz).
b) 4-(5-Hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid ethyl ester
4-(5-tert-butoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid ethyl ester (55 mg, 0.11 mmol) was dissolved in 1:1
TFA/DCM (10 mL) and stirring for 1 h. Removal of the solvent in vacuo
yielded the title compound (48 mg, 98%), which was used without further
purification.
c) 4-(5-Hydroxy-biphenyl-3-sulfonyI)-5-methylsulfanyl-thiophene-2-
carboxamidine hydrochloride
4-(5-Hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid ethyl ester ((Example 14: step b) 12 mg, 0.02S mmol) was
treated with dimethylaluminum amide reagent (2 mL, 2 mmol) as in
Example 12: step f. Analogous quench, workup, and purification procedures
yielded the title compound (10 mg? 89%) as a white solid. 1H-NMR
(CD3OD): d 8.30 (s, 1H), 7.69 (t, 1H, J = 1.6 Hz), 7.59 (m, 2H), 7.47 (m, 2H),
7.40 (m, 2H), 7.32 (m, 1H), 2.74 (s, 3H). ESI-MS (m/z): Calcd. for
C13H13BrN2O3S3: 421.36; found: 421.1.
Example 15
4-(5-Methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine hydrochloride
Following the procedure in Example 12: step e, 4-(5-hydroxy-
biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester
((Example 14: step b) 12 mg, 0.028 mmol) was alkylated using cesium
carbonate (13.5 mg, 0.041 mmol) and iodomethane (9 µL, 0.138 mmol) in
DMF (1.2 mL). After analogous workup, the residue was treated with
dimethylaluminum amide reagent (2 mL) following the procedure in Example
12: step f. The title compound was isolated as a white solid (10 mg, 86 %)
after preparative TLC purification (15% MeOH in DCM). 1H-NMR
(CD3OD): d 8.32 (s,1H), 7.82 (t, 1H, J = 1.6 Hz), 7.65 (m, 1H), 7.63 (m, 1H),
7.53 (dd, 1H, J = 1.6, 2.3 Hz), 7.46-7.50 (m, 3H), 7.41 (m, 1H), 3.93 (s, 3H),
2.7 (s, 3H). ESI-MS (m/z): Calcd. for C13H13BrN2O3S3: 421,4; found:
421.1.
Example 16
4-(5-Allyloxy-biphenyI-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine
Following the procedure in Example 12: step e, 4-(5-hydroxy-
biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester
((Example 14: step b) 12 mg3 0.028 mmol) was alkylated using cesium
carbonate (13.5 mg, 0.041 mmol) and allyl bromide (12 µL, 0.138 mmol) in
DMF (1.2 mL). After analogous workup, the residue was treated with
dimethylaluminum amide reagent (2 mL) following the procedure in Example
12: step f. The title compound was isolated as a white solid (10 mg, 81 %)
after preparative TLC purification (15% MeOH in DCM). 1H-NMR
(CD3OD): d 8.32 (s, 1H), 7.82 (t, 1H, J = 1.6 Hz), 7.63 (m, 2H), (dd, 1H, J =
1.6, 2.3 Hz), 7.48 (m, 3H), 7.42 (in, 1H), 6.08 (m, 1H), 5.45 (ddd, IH, J = 1.6,
3.3, 17.2 Hz). 5.31 (ddd, 1H, J = 1.4; 2.8, 10.5 Hz), 4.64 (dt, 2H, J = 1.6, 5.1
Hz), 2.75 (s, 3H).
Example 17
4-(5-Benzyloxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine hydrochloridc
Following the procedure in Example 12: step e, 4-(5-hydroxy-
biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester
((Example 14: step b) 12 mg, 0.028 mmol) was alkylated using cesium
carbonate (13.5 mg, 0.041 mmol) and benzyl bromide (17 µL, 0.138 mmol) in
DMF (2 mL). After analogous workup. the residue was treated with
dimethylaluminum amide reagent (2 mL) following the procedure in Example
12: step f. The title compound was isolated as a white solid (9 mg, 66 %) after
preparative TLC purification (15% MeOH in DCM). 1H-NMR (CD3OD): d
8.26 (s, 1H), 7.82 (t, 1H, J = 1.6 Hz), 7.62 (m, 2H), 7.54 (m, 2H), 7.30-7.50
(m, 8H), 5.26 (s, 2H), 2.70 (s, 3H). ESI-MS (m/z): Calcd. for
C13H13BrN2O3S3: 421.4; found: 421.1.
Example 18
4-(2'-Chloro-5-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2~
carboxamidine trifluoroacetate
a) {[4-(3-Bromo-5-hydroxy-benzenesulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid teri-butyl ester
Following the procedure and workup in Example 14: step f, the 4-(3-
bromo-5-tert-butoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid methyl ester ((Example 12: step c) 1.48 g, 3.1 mmol) was
converted to the amidine (40 mL of dimethylaluminum amide reagent) with
concomitant removal of the tert-butyl ether. A portion of the crude amidine
(800 mg) was dissolved in DMF and di-tert-butyl dicarbonate (436 mg, 2
mmol), diisopropylethylamine (350 µL, 2 mmol), and DMAP (50 mg) were
added. After stirring for 16 h, the solution was poured into EtOAc (60mL)
and citric acid (20 mL). The layers were separated and the organic layer was
further extracted with citric acid (10 mL), NaHCO3 (2 x 20 mL), water (5 x 10
mL), and brine (30 mL). After drying over sodium sulfate and removal of
solvent in vacuo, the residue was dissolved in MeOH and solid K2CO3 was
added. The mixture was stirred overnight, the solution was filtered, and the
solvent was removed in vacuo. Purification of the residue by SiO2 flash
chromatography yielded the title compound (80 mg, 0.158 mmol).
b) {[4-(2'-Chloro-5-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
Following the procedure outlined in Example 1: step c, {[4-(3-bromo-
5-hydroxy-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-y]]-imino-methyl}-
carbamic acid tert-butyl ester (80 mg, 0.158 mmol) was reacted with 2-
chlorophenylboronic acid (98.6 mg, 0.631 mmol), Na2CO3 (134 rng, 1.26
mmol), and Pd(PPh3)4 (45.5 mg, 0.039 mmol). Aqueous workup followed by
SiO2 flash chromatography yielded the title compound (20 mg, 24 %).
c) 4-(2'-Chloro-5-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
The procedure used in Example 1: step d was followed using {[4-(2'-
chloro-5-methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-
imino-methyl}-carbamic acid tert-butyl ester (10 mg, 0.0185 mmol).
Analogous purification by C18-HPLC yielded the title compound (4 mg, 50%)
as a white solid. 1H-NMR (CD3OD): d 8.28 (s, 1H), 7.51 (m, 2H), 7.44 (dd,
1H, J = 1.6, 2.3 Hz), 7.40 (m, 2H), 7.38 (m, 3H), 7.13 (dd, 1H, J = 1.6, 2.3
Hz), 2.73 (s, 3H). ESI-MS (m/z): Calcd. for C13H13BrN2O3S3: 421.4; found:
421.1.
Example 19
4-(2'-Chloro-5-methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate
a) {[4-(2'-Chloro-5-methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
Iodomethane (3 µL, 0.045 mmol) and tetrabutylammonium fluoride
(1M in THF, 14 µL, 0.014 mmol) was added to a solution of {[4-(2'-chloro-5-
hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-y.l]-imino-
methyl}-carbamic acid tert-butyl ester ((Example 19: step b) 5 mg, 0.009
mmol) in THF. After stirring for 2 hours, the solution was diluted with EtOAc
(20 mL). The organic layer was washed with water (2 x 4 mL) and brine (5
mL), and was dried over MgSO4. Removal of the solvent in vacuo followed
by purification of the residue (preparative TLC; 30% EtOAc in hexanes)
afforded the title compound (3.1 mg, 62%). 1H-NMR (CDCl3): d 7.84 (s, 1H),
7.64 (t, 1H, J = 1.6 Hz), 7.53 (dd, 1H, J = 1.6, 2.6 Hz), 7.47 (m, 1H), 7.33 (m,
3H), 7.21 (dd, 1H, J = 1.6, 2.6 Hz), 3.89 (s, 3H), 2.60 (s, 3H), 1.52 (s, 9H).
ESI-MS (m/z): Calcd. for C13H13BrN2O3S3: 421.4; found: 421.1.
b) 4-(2t-Chloro-5-methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
The procedure used in Example 1: step d was followed using {[4-(2'-
chloro-5-me1:hoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-
imino-methyl}-carbamic acid tert-butyl ester (3.1 mg, 0.008 mmol).
Analogous purification by C18-HPLC yielded the title compound (1.8 mg,
50) as a white solid. 1H-NMR (CD3OD): d 8.32 (s, 1H), 7.64 (t, 1H, J = 1.6
Hz).. 7.59 (dd, 1H, J = 1.4, 2.6 Hz), 7.55 (m, 1H), 7.42 (m, 3H), 7.13 (dd, 1H, J
= 1.4, 2.6 Hz), 3.93 (s, 3H), 2.75 (s, 3H). ESI-MS (m/z): Calcd. for
C13H13BrN2O3S3: 421.4; found: 421.1.
Example 20
5-Brorno-4-(3'-formyl-biphenyl-3-sulfonyl)-thiophene-2-carboxamidine
trifluoroacetate
a) 4-(3-Bromo-phenylsulfanyl)-5-nitro-thiophene-2-carboxylic acid
methyl ester
4-Bromo-5-nitro-thiophene-2-carboxylic acid methyl ester ((Example
114, step c) 1 g, 3.75 mmol) and Et3N (523 µL, 3.75 mmol) were dissolved
with THF (10 mL) into a round bottom flask with stir bar. To this 3-
bromothiophenol (467 µL., 4.51 mmol) was added with stirring. The reaction
became turbid therefore additional THF (12 mL) was added. The reaction was
stirred at rt for 12 hours. The reaction mixture was concentrated in vacuo and
then dissolved into EtOAc. The organic layer was washed several times with
saturated NaHCO3 and brine. The combined organic layers were dried over
sodium sulfate. Removal of the solvents in vacuo yielded the title compound
(1.40 g, quantitative yield), which was used without further purification. 1H-
NMR (CDCl3): d 7.79 (t, 1H, J = 1.8 Hz), 7.67-7.70 (m, 1H), 7.54-7.85 (m,
1H), 7.37-7.41 (t, 1H, J = 7.9 Hz), 6.87 (s, 1H), 3.88 (s, 1H).
b) 4-(3-Bromo-benzenesulfonyl)-5-nitro-thiophene-2-carboxylic acid
methyl ester
4-(3-Bromo-phenylsulfanyl)-5-nitro-thiophene-2-carboxylic acid
methyl ester (1.40 g, 4 mmol) and m-CPBA (6.1 g, 20 mmol) were dissolved
into DCM (25 mL) with heating at 40 °C for 2 hours. The reaction mixture
was quenched by the addition of saturated sodium thiosulfate followed by
aqueous workup with brine and saturated NaHCO3. The combined organic
layers were dried over sodium sulfate. Removal of the solvents in vacuo
yielded the title compound (1.60 g, quantitative yield) which was used without
further purification. 1H-NMR (CDCl3): d 8.31 (s, 1H), 8.12-8.14 (t, 1H, J=
1.9 Hz), 8.02-8.05 (m, 1H), 7.78-7.82 (m, 1H), 7.44-7.50 (t 1H, J = 7.9 Hz),
4.01 (s, 3H).
c) 5-Amino-4-(3-bromo-benzenesulfonyl)-thiophene-2-carboxylic acid
methyl ester
4-(3-Bromo-benzenesulfonyl)-5-nitro-thiophene-2-carboxylic acid
methyl ester (407 mg, 1.0 mmol, Example 20: step b) was dissolved into EtOH
(6mL). To this was added ammonium chloride (535 mg, 10 mmol) dissolved
into water (3 mL). This mixture was heated to 50°C with stirring and then iron
(277 mg, 5 mmol) was added. The reaction was then heated to 80°C with
stirring for 12 hours. The reaction mixture was then filtered through Celite
and washed with 10% DCM/MeOH. Removal of the solvents in vacuo
yielded the title compound (598 mg, quantitative yield) which was used
without further purification. 1H-NMR (CDCl3): d 8.05 (s, 1H), 7.84-7.86 (m,
1H), 7.70-7.75 (m, 1H), 7.56 (s, IH), 7.40 (m, 1H), 6.02 (br s, 2H), 3.85 (s,
3H). ESI-MS (m/z): Calcd. for C12H10BrNO4S2: 375.9 (M+H); found: 376.1.
d) 5-Amin o-4-(3'-formyl-biphenyl-3-sulfonyl)-thiophene-2-carboxylic
acid methyl ester
The procedure as in Example 1: step c was followed using 5-amino-4-
(3-bromo-benzenesulfonyl)-thiophene-2-carboxylic acid methyl ester (754.2
mg, 2 mmol, Example 20: step e), 3-formyl phenyl boronic acid (599.7 mg, 4
mmol), Pd(PPh3)4 (462.2 mg, 0.4 mmol), aqueous Na2CO3 (2M, 8 mL, 16
mmol), ethanol (8 mL) and toluene (16 mL). Purification by flash column
chromatography (Biotage Flash™ System - 40 M SiO2 column) (25% EtOAc
in hexanes) of the residue yielded the title compound (317 mg, 40%) as a
brown solid. 1H-NMR (CDCl3): d 10.10 (s, 1H), 8.10-8.17 (m, 2H), 7.92-7.95
(m, 2H), 7.82-7.89 (t, 2H, J = 8.1 Hz), 7.58-7.70 (m, 3H), 6.05 (br s, 2H), 3.80
(s, 3H).
e) 5-Bromo-4-(3'-formyl-biphenyl-3-sulfonyl)-thiophene-2-carboxylic
acid methyl ester
A dry 3-neck flask fitted with addition funnel, condenser and septa cap
was purged with argon. To this flask t-butylnitrite (121 µL, 1.58 mmol) and
copper (II) bromide (36.8 mg, 1.58 mmol) were dissolved with acetonitrile (2
mL) and heated to 60°C A solution of 5-arnino-4-(3'-forrnyl-biphenyl-3-
sulfonyl)-thiophene-2-carboxylic acid methyl ester (317.2 mg, 0.79 mmol,
Example 20: step d) in acetonitrile (2 mL) was added dropwise with continued
stirring and heat for 1.5 hours. The reaction mixture was dissolved into
EtOAc and washed with brine. The organic layer was dried over sodium
sulfate. Removal of the solvents in vacuo followed by flash column
chromatography (Biotage Flash™ System - 40 M SiO2 column) (25% EtOAc
in hexanes) of the residue yielded the title compound (128 mg, 34%) as a
brown solid. 1H-NMR (CDCl3): d 10.10 (s, 1H), 8.26-8.28 (m, 1H), 8.08-8.16
(m, 2H) 8.01-8.06 (m, 1H), 7.86-7.89 (m, 3H), 7.64-7.70 (t, 2H, J = 8.1 Hz),
3.90 (s, 3H).
f) 5-Bromo-4-(3'-formyl-biphenyl-5-sulfonyl)-thiophene-2-
carboxamidine trifluoroacetate
A 1M solution of dimethyl aluminum amide was prepared by
combining NH4Cl (426 mg, 8 mmol), AlMe3 (2M solution in toluene, 4 mL,
8 mmol) and toluene (4mL). This solution was then heated to 80 °C for 15
and then allowed to cool to it. The 1M solution of dimethyl
aluminum amide was then added to a dry flask containing 5-bromo-4-(3'-
formyl-biphenyl-3-sulfonyl)-thiophene-2-carboxylic acid methyl ester (128
mg, 0.28 mmol) and the reaction was heated 90 °C for 2 hours. The reaction.
was quenched by adding silica (1g) to the solution with stirring followed by
filtration and elution with 10% MeOH in DCM. Concentration of the filtrate
in vacuo followed by purification by C18-HPLC (10-80% CH3CN over
25 min) yielded the title compound (49 mg, 38%) as an off-white solid. lH-
NMR (CD3OD and CD3C1): d: 10.10 (s, 1H), 8.35 (s, 1H), 8.31-8.33 (m, 1H),
8.17-8.18 (t, 1H, J = 1.39 Hz), 8.04-8.10 (m, 2H), 7.96-7.99 (m, 2H), 7.75-
7.77 (m, 2H). ESI-MS (m/z): Calcd. for C13H13BrN2O3S2: 448.9 (M+H) ;
found: 449.2.
Example 21
5-Amino-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxamidine
trifluoroacetate
5-Amino-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxylic
acid methyl ester was prepared following the procedure as in Example 1:
step c using 5-amino-4-(3-bromo-benzenesulfonyl)-thiophene-2-carboxylic
acid methyl ester (598.9 mg, 1.6 mmol) (Example 20: steps a-c), o-tolyl-
phenyl boronic acid (435.6 mg, 3.2 rnmol), pd(PPh3),, (366.6 mg, 0.32 mmol),
aqueous Na2CO3 (2M, 6.4 mL, 12.8 mmol), etbanol (6.4mL) and toluene (128
mL). Purification by flash column chromatography (Biotage FlashTM System -
40 M SiO2 column) (25% EtOAc in hexanes) of the residue yielded the adduct
(137 mg, 23%) as a light brown solid. ESI-MS (m/z): Calcd. for
C19H17NO4S2. 387.02; found: 388.3. 5-Ammo-4-(2'-methyl-biphenyl-3-
sulfonyl)-thiophene-2-carboxylic acid methyl ester (61 mg, 16 mmol) was
then converted to the amidine and purified as described in Example 20: step f
to isolate the title compound (6 mg, 10 %) as a light brown solid, !H-NMR
(CD3OD): d: 7.96-7.99 (m, 1H), 7.95 (s, 1H), 7.93-7.94 (m, 1H), 7.63-7.69 (m,
3H), 7.18-7.32 (m, 3H), 2.22 (s, 3H). ESI-MS (m/z): Calcd. for
C18H17N3O2S2: 372.0 (M+H); found: 372.2.
Example 22
5-Chloro-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxamidine
trifluoroacetate
a) 5-Chloro-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-carhoxylic
acid methyl ester
The procedure as in Example 20: step e was followed using t-
butylnitrite (104 µL, 88 mmol) and copper (II) chloride (118.5 mg, 0.88
mmol), acetonitrile (2 mL) and 5-amino-4-(2'-methyl-biphenyl-3-sulfonyl)-
thiophene-2-carboxylic acid methyl ester (170.2 mg, 0.43 mmol, Example 21)
in acetonitrile (2mL). Purification by flash column chromatography (Biotage
Flash™ System - 12 M SiO2 colunm) (25% EtOAc in hexanes) of the residue
yielded the title compound (128 mg, 34%) as a brown solid. 1H-NMR
(CDCl3): d 8.26 (1H, s), 7.92-7.98 (3H, m), 7.56-7.60 (2H, m) 7.28-7.32 (3H,
m), 3.90 (3H, s), 2.24 (3H, s).
b) 5-Chloro-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-
carboxamidine trifluoroacetate
5-Chloro-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxylic
acid methyl ester (36 mg, 0.09 rnmol) was then converted to the amidine and
purified as described in Example 20: step f to isolate the title compound (7.1
mg, 20 %) as a white solid. 1H-NMR (CD3OD): d: 8.35 (s, 1H), 8.03-8.06 (m,
1H), 7.95-7.97 (m, 1H), 7.71-7.74 (m, 2H), 7.30-7.33 (m, 2H), 7.25-7.30 (m,
1H), 7.19-7.21 (d, 1H, J = 6.74 Hz), 2.24 (s, 3H). ESI-MS (m/z): Calcd. for
C18H15CIN2O2S2: 391.0 (M+H); found: 391.2.
Example 23
4-(2'-Methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxamidine
trifluoroacetate
4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene- 2-carboxylic acid methyl
ester (4.0 mg, 0.01 mmol) was isolated as a byproduct from Example 22: step
a. The molecule was then converted to the amidine and purified as described
in Example 20: step f to isolate the title compound (0.9 mg, 25%). 1H-NMR
(CD3OD): d: 8.80 (s, 1H), 8.25-8.26 (d, 1H, J = 1.6 Hz), 8.02-8.05 (m, 1H),
7.95-7.96 (m, 2H), 7.68-7.71 (m, 2H), 7.17-7.21 (m, 1H), 2.24 (s, 3H). ESI-
MS (m/z): Calcd. for C18H16N2O2S2: 357.0 (M+H); found: 357.3.
Example 24
5-Bromo-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxamidine
trifluoroacetate
a) 5-Chloro-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxylic
acid methyl ester
The procedure as in Example 20: step e was followed using t-
butylnitrite (10 µL, 0.05 mmol) and copper (II) bromide (11 mg, 0.05 mmol)
and 5-amino-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxylic acid
methyl ester (9.1 mg, 0.03 mmol, Example 21) in acetonitrile (1 mL).
Purification by flash column chromatography (Biotage Flash™ System - 12 M
SiO2 column) (25% EtOAc in hexanes) of the residue yielded the title
compound (5.1 mg, 42%) as an off-white solid. 1H-NMR (CDCl3): d 8.08 (s,
1H), 7.92-7.98 (m, 2H), 7.59-7.61 (m, 2H) 7.29-7.30 (m, 3H), 7.19-7.21 (m,
1H), 3.90 (s, 3H), 2.24 (s, 3H).
b) 5-Bromo-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-
carboxamidine trifluoroacetate
5-Bromo-4-(2'-methyl-biphenyl-3-sulfonyl)-thiophene-2-carboxylic
acid methyl ester (5.1 mg, 0.01 mmol, Example 24: step a) was then converted
to the amidine and purified as described in Example 20: step f to isolate the
title compound (1.1 mg, 21%). 1H-NMR (CD3OD): d: 8.33 (s, 1H), S.04-8.07
(m, 1H), 7.98-7.99 (m, 1H) 7.71-7.73 (m, 2H), 7.30-7.32 (m, 3H), 7.25-7.30
(m, 1H), 7.19-7.21 (m, 1H), 2.24 (s, 3H). ESI-MS (m/z): Calcd. for
C13H13BrN2O2S2: 434.0 found: 437.1.
Example 25
4~(2'-Amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate
a) 2-Bromo-3-methyl-phenylamine
The procedure as in Example 20: step c was followed using 2-bromo-
1-methyl-3-nitro-benzene (lg, 4.6 mmol dissolved in 12 mL EtOH, Aldrich
Chemical Company), ammonium chloride (2.5g, 46 mmol dissolved in 6 mL
H2O) and iron (1.3g, 23 mmol). The title compound was obtained (1.0 g,
quantitative yield) which was used without further purification, 1H-NMR
(CDCl3): d 6.95-7.00 (t, 1H, J = 7.6 Hz), 6.60-6.65 (dd, 2H, J = 8.1, 4.4 Hz),
4.10 (brs,2H), 2.35 (s,3H).
b) 3-Methyl-2-(4,4,5,5-tetramethyl-[l,3,2}dioxaborolan-2-yl)-
phenylamine
The procedure described in Example 3: step b was followed using 2-
bromo-3-methyl-phenylamine (185 mg, 1.0 mmol, Example 25: step a),
PdCl2(PPh3)2 (70.2 mg, 0.1 mmol), dioxane (3 ml.), and Et3N (729 µL, 6
mmol), 4,4,5,5,-tetramethyl-[l,3,2]-dioxaborolane (453 µL, 3 mmol).
Purification by preparative SiO2 TLC (25% EtOAc in hexanes) of the residue
yielded the title compound (94 mg. 40%) as a yellow solid. ESI-MS (m/z):
Calcd. for C13H20BNO2:234.1 (M+H) found:234.1.
c) {[4-(2'-Amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
The procedure described in Example 1: step c was followed using 3-
methyl-2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenylamine (95 mg
0.41 mmol. Example 25: step b), {[4-(3-bromo-benzenesulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(100.7 mg, 0.21 mmol, Example 27: step c), Pd(PPh3)4 (47 mg, 0.04 mmol),
aqueous Na2CO3 (2M, 0.8 ml,, 1.6 mmol), ethanol (0.8 mL) and toluene (1.6
mL). Purification by preparative SiO2 TLC (33% EtOAc in hexanes) of the
residue yielded the title compound (30 mg, 28%) as an off-white solid. ESI-
MS (m/z): Calcd. For C24H27N3O4S3: 517.2; found: 517.8.
d) 4-(2'-Amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
{[4-(2'-Amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (30 mg, 0.058
mmol, Example 25: step c) was deprotected and purified as in Example 1:
step d, yielding the title compound as an off-white solid (28.1 mg, 94%). 1H-
NMR (CD3OD): d 8.36 (s, 1H), 8.08-8.12 (m, 1H), 7.96 (t, 1H, J = 1.6 Hz),
7.76-7.80 (t, 1H, J = 7.6 Hz), 7.60-7.64 (dd, 1H, J = 1.6, 7.6 Hz), 7.22-7.25 (t,
1H, J = 7.9 Hz), 6.98-7.03 (m, 2H), 2.73 (s, 3H), 1.97 (s, 3H). ESI-MS (m/z):
Calcd. for C19H19N3O2S3: 418.1 (M+l); found: 418.1.
Example 26
4-(3'-Formyl-4'-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-
2-carboxamidine trifluoroacetate
a) 4-Bromo-2-dimethoxymethyl-phenol
To a solution of 5-bromo-2-hydroxy-benzaldehyde (lg, 4.9 mmol,
Aldrich Chemical Company) in MeOH (25 mL) at 0 °C, sodium borohydride
(226 mg, 5.9 mmol) was added slowly with stirring. After the addition, the
reaction was allowed to warm to rt and stir for an additional hour. Reaction
mixture was dissolved into EtOAc and washed with brine (20 mL x 2). The
organic layer was dried over sodium sulfate. Removal of the solvents in vacuo
gave the title compound (1.2 g, quantitative) a yellow oil which was used with
out further purification. lH-NMR (CD3OD): d 7.35 (m, 2H), 6.75-6.77 (d,lH,
J - 7.2 Hz), 5.55 (s, 1H), 3.33 (s, 6H).
b) {[4-(3'-Dimethoxymethyl-4'-hydroxy-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
2-Dimethoxymethyl-4-hydroxyl phenylboronic acid (212 mg. 1.0
mmol) was prepared using the procedure described in Example 1: step b using
butyllithium (2.5M, 2.8 mL, 7 mmol), trimethylborate (0.812 mL, 5.6 mmol),
4-bromo-2-dimethoxymethyl-phenol (685 mg, 2.8 mmol, Example 26: step a)
in THF (5 mL) and was used in the next step without purification. The
procedure described in Example 1: step c was followed using {[4-(3-bromo-
berizenesulfonyl)-5-rnethylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic
acid tert-butyl ester (100 mg, 0.21 mmol, Example 27: step c), Pd(PPh:,)4 (47
mg, 0.04 mmol), aqueous Na2CO3 (2M, 0.8 mL, 1.6 mmol), ethanol (0.8 mL),
toluene (1.6 mL) and 2-diniethoxymethyl-4-hydroxy-phenylboronic acid (212
mg, 1.0 mmol). Purification by preparative SiO2 TLC (33% EtOAc in
hexanes) of the residue yielded the title compound (37 mg, 28%) as a white
solid. ESI-MS (m/z): Calcd. for C26H30N2O7S3: 579.1 (M+l); found: 579.9.
c) 4-(3'-Formyl-4'-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
{[4-(3'-Dimethoxymethyl-4'-hydroxy-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(37 mg) (Example 26: step b) was deprotected and purified as in Example 1:
step d, yielding the title compound as an off-white solid (5 mg, 14%). 1H-
NMR (CD3OD): d 10.34 (s, 1H), 8.46 (m, 1H), 8.25-8.27 (m, 1H), 7.89-7.94
(m, 3H), 7.72-7.75 (m, 1H), 7.13-7.16 (m, 1H), 2.49 (s, 3H). ESI-MS (m/z):
Calcd. for C19H16N2O4S3: 433.0 (M+l); found: 433.2.
Example 27
{[4-(3-Bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-
methyl}-carbamic acid tert-butyl ester
a) 4-(3-Bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid methyl ester
4-(3-Bromo-benzenesulfonyl)-5-nitro-thiophene-2-carboxylic acid
methyl ester (5.9 g, 0.015 mol, Exstmple 20: step b) was dissolved into 40 mL
THF and cooled to -78°C. To this was added sodium thiomethoxide (1M, 15
mL, 0.015 mmol, in EtOH) dropwise for an hour. The reaction was quenched
with acetic acid (878 µL, 0.015 mol) and the reaction mixture was
concentrated in vacuo. The residue was then dissolved into EtOAc and
washed with saturated NaHCO3 and brine solutions. The organic layer was
dried over sodium sulfate. Removal of the solvents in vacuo followed by flash
column chromatography SiO2 (25% EtOAc in hexanes) of the residue yielded
the title compound (3.0g, 50%) as a yellow solid. 1H-NMR (CDCl3): d 8.14 (t,
1H, J - 1.8 Hz), 8.02 (s 1H), 7.94-7.96 (m, 1H), 7.72-7.74 (m, 1H), 7.38-7.42
(t, 1H, J = 7.9 Hz), 7.26 (s 1H), 3.88 (s 1H), 2.62 (s 1H).
b) 4-(3-Bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate
4-(3-Bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid methyl ester (1.9 g, 0.004 mol) was converted to the amidine
and purified as described in Example 20: step f to isolate the title compound
(1.9 g, quantitative yield). 1H-NMR (CD3OD): d: 8.31 (s, 1H), 8.16 (t, 1H, J =
1.8 Hz), 8.01-8.04 (m, 1H), 7.86-7.90 (m, 1H), 7.52-7.57 (t, 1H, J = 7.9Hz),
2.74 (s, 3H).
c) {[4-(3-Bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-
imino-methyl}-carbamic acid tert-butyl ester
4-(3-Bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine (1.9 g, 0.0048 mol, Example 27: step b) was dissolved into
DMF (35 mL) with sonication. To this was added DIEA (1.67 mL, 0.0096
mol) and di-tert-butyl-dicarbonate (1.27 g, 0.0058 mol) and reaction stirred at
rt for 16 hours. The reaction mixture was dissolved into EtOAc and washed
with 20% citric acid and then brine. The organic layer was dried over Na2SO4
and concentrated in vacuo. The remaining residue was triturated with hexane
to isolate the title compound (1.84g, 76%). 1H-NMJR. (CDCl3): d: 8.15 (s, 1H),
8.13-8.14 (t, 1H, J - 1.6 Hz), 7.95-7.99 (m, 1H), 7.79-7.84 (m, 1H), 7.72 (s,
1H), 7.48-7.52 (t, 1H, J - 7.9 Hz), 7.19-7.21 (m, 1H), 2.66 (s, 3H), 1.51 (s,
9H). ESI-MS (m/z): Calcd. for C17H19BrN2O4S3: 492.4 (M+l); found: 492.6.
Example 28
5-Methylsulfanyl-4-{3'-(2,2,2-trifluoro-l-hydroxy-ethyl)-biphenyl-3-
sulfonyl]-thiophene-2-carboxamidine trifluoroacetate
a) l-(3-Bromo-phenyl)-2,2,2-trifluoro-ethanone
In a dry round bottom flask, 3-bromo-benzoic acid methyl ester (2 g,
9.3 mmol, Aldrich Chemical Company) and trimethyl(trifluoromethyl)silane
(1.72 mL, 11.6 mmol, Aldrich Chemical Company) were dissolved in dry
toluene (50 mL). Upon cooling the solution to -78 °C, TBAF (232 uL, 0.23
mmol) was added and the reaction was allowed to warm up slowly to it
overnight. After stirring for 20 hr, 2N HC1 (50 mL) and EtOAc (100 mL) were
added, the layers were separated, and the aqueous layer was extracted with
another portion of EtOAc, The combined organic fractions were dried
(MgSO4), concentrated in vacua, and resulting crude oil was purified using
SiO2 flash chromatography (elution: 5-20% EtOAc in hexanes) to give 1.5 g
(65%) the title compound as a light yellow oil. 1H-NMR (CDCl3; 400 MHz)
d 8.18 (br s, 1H), 7.98-8.00 (m, 1H), 7.82-7.85 (m, 1H), 7.42-7.46 (m, 1H).
19F-NMR (CDCl3; 400 MHz) 5 -72.06 (s).
b) 2,2,2-Trifluoro-l-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
phenyl]-ethanol
To an oven-dried round bottom flask fitted with a stir bar and a rubber
septum was added l-(3-bromo-phenyl)-2,2,2-trifluoro-ethanone (560 mg, 2.2
mmol, as prepared in Example 28, step a), 4,4,5,5-tetramethyl-
[l,3,2]dioxaborolane (0.96 mL, 6.6 mmol, Aldrich Chemical Company),
(PPh3)2PdCl2 (93 mg, 0.132 mmol, Streni Chemicals, Inc., Newburyport,
MA), and Et3N (1.8 mL, 13.2 mmol). The reaction mixture was evacuated,
purged with argon, and then suspended in dioxane (16 mL). After stirring for
18 hr at 95 °C, the reaction was allowed to cool and then filtered through
Celite.® The filtrate was concentrated in vacuo and the residue was purified by
chromatography (SiCh, flash elution: 5% EtOAc in hexanes) to give 350 mg
(53%) of an oil that was used without further purification.
c) (Imino-{5-methylsulfanyl-4-[3'-(2,2,2-trifluoro-1-hydroxy-ethyl)-
biphenyl-3-sulfonyl]-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester
Following the same procedure in Example 1, step c, reaction of 2,2,2-
trifluoro-l-[3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-ethanol
(123 mg, 416 mmol, as prepared in Example 28, step b), {[4-(3-bromo-
benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic
acid tert-butyl ester (100 mg, 0.2 mmol, as prepared in Example 27, step c),
tetrakis(triphenylphosphine)palladium(0) (59 mg, 0.05 mmol, Strem
Chemicals Inc, Newburyport, MA), Na2CO3 (800 µL, 2M aqueous), and
toluene/EtOH mixture (2:1, 2.4 mL) afforded 100 mg (85%) after purification
(SiO2, flash elution: 30% EtOAc in hexanes) of the title compound as a white
foam. 1H-NMR (CDCl3; 400 MHz) d 8.20 (t, 1H, J = 1.7 Hz), 7.94-7.99 (m,
2H), 7.77-7.81 (m, 1H), 7.67 (br s, 1H), 7.57 (m, 1H), 7.27-7.34 (m, 1H),
7.15-7.21 (m, 2H), 5.11 (q, 1H, J = 6.8 Hz), 2.51 (s, 3H), 1.49 (s, 9H). 19F-
NMR (CDCl3; 400 MHz) 5 -78.51 (d, J = 6.9 Hz). ESI-MS (m/z): Calcd. for
C25H25F3N2O5S3: 586.7; found: 586.7.
d) 5-MethylsuIfanyl-4-[3'-(2,2,2-trifluoro-l-hydroxy-ethyl)-biphenyl-3-
sulfonyl]-thiophene-2-carboxamidine trifluoroacetate
(Imino-{5-methylsulfanyl-4-[3'-(2,2,2-trifluoro-l-hydrcxy-ethyl)-
biphenyl-3-sulfonyl]-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester (25
mg, 0.043 mmol, as prepared in Example 28, step c) was treated with
trifluoroacetic acid (50% in DCM) for 1 hr at rt. The reaction mixture was
concentrated in vacuo and the residue obtained was purified using C18-HPLC
(10-80% CH3CN in H2O (0.1% TFA) over 25 min) to give 18 mg (86%) of the
title compound as a white solid. 1H-NMR (CD3OD; 400 MHz) d 8.33 (s, 1H),
8.30 (t, 1H, J = 1.7), 7.97-8.05 (m, 2H), 7.91 (br s, 1H), 7.68-7.74 (m, 2H),
7.53-7.56 (m, 2H), 5.15 (q, 1H, J = 7.0 Hz), 2.74 (s, 3H). 19F-NMR (CD3OD;
400 MHz) 5 -80.09 (d, J = 6.9 Hz). ESI-MS (rn/z): Calcd. for
C20H17F3N2O3S3: 487.6 (M+H); found: 487.3.
Example 29
5-Methylsulfanyl-4-[3'-(2f2,2-trifluoro-acetyl)-biphenyl-3-sulfonyl]-
thiophene-2-carboxamidine trifluoroacetate
a) (Imino-{5-methylsulfanyl-4-[3'-(2,2,2-trifluoro-acetyl)-biphenyl-3-
sulfonyl]-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester
In a reaction vial, (imino-{5-methylsulfanyl-4-[3'-(2,2,2-trifluoro-l-
hydroxy-ethyl)-biphenyl-3-sulfonyl]-thiophen-2-yl}-methyl)-carbamic acid
tert-butyl ester (30 mg, 0.051 mmol, as prepared in Example 28, step c) and
l,l,l-triacetoxy-l,l-dihydro-l,2-benziodoxol-3(lH)-one (31 mg, 0.072 mmol.
Lancaster Synthesis, Windham, NH) were dissolved in DCM (2 ml,). To that
solution, wet DCM (1 mL, 4 µL H2O) was added slowly via a syringe. After 1
hr of stirring at rt, the reaction was evaporated and the residue was partitioned
between Et2O (30 mL) and 10% Na2S2O3-saturated NaHCO3 (1:1, 15 mL).
The aqueous layer was washed with an additional portion of Et2O. The
combined organic washes were dried with MgSQ4 and concentrated in vacuo
to give 30 mg (quantitative yield) of the title compound that was used without
purification. 1H-NMR (CDCl3; 400 MHz) d 8.28 (br s, 1H), 8.26 (t, 1H, J =
1.7 Hz), 8.0S-S.13 (m, 1H), 7.99-8.04 (m, 1H), 7.96 (s, 1H), 7.91-7.95 (m,
1H), 7.82-7.86 (m, 1H), 7.62-7.71 (m, 2H), 2.59 (s, 3H), 1.51 (s, 9H). 19F-
NMR (CDCl3; 400 MHz) 6 -84.93 (s). ESI-MS (m/z): Calcd. for
C25H23F3N2O5S3: 487.6 (M+H); found: 487.2.
b) 5-Methylsulfanyl-4-[3'-(2,2,2-trifluoro-acetyl)-biphenyl-3-sulfonyl]-
thiophene-2-carboxamidine trifluoroacetate
(Imino-{5-methylsulfanyl-4-[3'-(2,2,2-trifluoro-acetyl)-biphenyl-3-
sulfonyl]-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester (30 mg, 0.051
mmol, as prepared in Example 29, step a) was treated with trifluoroacetic acid
(50% in DCM) for 1 hr at rt. The reaction mixture was concentrated in vacuo
and the residue obtained was purified using C18-HPLC (20-60% CH3CN in
H2O (0.1% TFA) over 25 min) to give 20 mg (80%) of the title compound as a
white solid. 1H-NMR (CD3OD; 400 MHz) d 8.35 (s, 1H), 8.33 (t, 1H, J = 1.7
Hz), 7.98-8.07 (m, 2H), 7.90-7.93 (m, 1H), 7.68-7.78 (m, 3H), 7.60 (t, 1H, J =
7.8 Hz), 2.77 (s, 3H). 19F-NMR (CDCl3; 400 MHz) 5 -84.99 (s). ESI-MS
(m/z): Calcd. for C20H15F3N2O3S3: 485.5 (M+H); found: 485.3, 503.3
(M+H2O), 517.3 (M+CH3OH).
Example 30
4-[3-(6-Methyl-3H-benzoimidazol-5-yl)-benzenesulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine bis-trifluoroacetate
a) 5-Chloro-6-methyl-benzoimidazole-1-carboxylic acid tert-butyl ester
and 5-Chloro-6-methyl-benzoimidazole-3-carboxylic acid tert-butyl ester
4-Chloro-5-methyl-benzene-l,2-diarnine (560 mg, 3.6 mmol,
Maybridge Chemical Co. Ltd., Cornwall, UK) was dissolved in formic acid
(10 mL) and the solution was refluxed at 100°C for 18 hr. The reaction was
allowed to cool and then evaiporated to dryness in vacuo to give 5-chloro-6-
methyl-lH-benzoimidazole as a tan solid (quantitative yield) that was used
without further purification. The solid obtained above (410 mg, 2.4 mmol), di-
tert-butyl dicarbonate (1.6 g, 7.4 mmol), and DMAP (29 mg, 0.24 mmol) were
dissolved in CH3CN (20 mL). To the mixture, DIEA (1.3 mL, 7.4 mmol) was
added and the reaction was stirred for 18 hr at rt. The solvents were
evaporated in vacuo and the residue partitioned between EtOAc (100 mL) and
saturated aqueous NaHCO3 (75 mL). The aqueous layer was separated and
washed with EtOAc (100 mL). The combined organic layers were dried with
MgSO4 and concentrated in vacua. The crude residue was purified using flash
SiO2 chromatography (20% EtOAc in hexanes) to give 620 mg (97%) of the
title compound as a 1:1 mixture of regioisomers that were used without
separation. 1H-NMR (CDCl3; 400 MHz, 1:1 mixture of isomers) d 8.35 and
8.36 (s, 1H), 7.89 and 7.99 (s, 1H), 7.62 and 7.75 (s, 1H), 2.48 and 2.50 (s,
3H), 1.698 and 1.700 (s, 9H). ESI-MS (m/z): Calcd. for C13H15ClN2O2: 266.7;
found: 266.9, 167.2 (M-Boc).
b) 5-Methyl-6-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-
benzoimidazole-1-carboxylic acid tert-butyl ester and 5-Methyl-6-(4,4,5,5-
tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzoimidazole-1-carboxylic acid tert-
butyl ester
To a dry reaction vial fitted with a stir bar and a Teflon-lined screw
cap, a mixture of 5-chloro-6-methyl-benzoimidazole-l-carboxylic acid tert-
butyl ester and 5-chloro-6-methyl-benzounidazole--3-carboxylic acid tert-butyl
ester (150 mg, 0.56 mmol, as prepared in Example 30, step a),
4,4.5,5,4',4',5',5'-octaraethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (284 mg. 1.12
mmol, Aldrich Chemical Company), (2'-dicyclohexylphosphanyl-biphenyl-2-
y3)-dimethyl-amine (17.7 mg, 0.045 mmol, Strem Chemicals Inc,
Newburyport, MA), Pd(OAc)2 (6.7 mg, 0.03 mmol. Strem Chemicals Inc,
Newburyport, MA), and K3PO4 (238 mg, 1.12, mmol) were added, The vial
was capped, purged with argon, and then suspended in toluene (3 mL). After
stirring for 18 hr at 95 °C, the reaction was allowed to cool and then filtered
through Celite.® The filtrate was concentrated in vacuo and the residue was
purified using preparative thin layer chromatography (1:3 EtOAc/hexanes,
2000 µ SiO2 plate) to afford 100 mg (50%) of the title compound (1:1 mixture
of regioisomers) as a yellow oil. ES1-MS (m/z): Calcd. for C19H27BN2O4:
358.2; found: 303.2 (M-'Bu), 259.3 (M-Boc),
c) 4-[3-(6-Methyl-3H-benzoimidazol-5-yl)-benzenesuIfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine bis-trifluoroacetate
Following the same procedure in Example 1, step c, 5-methyl-6-
(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-berizomiidazo]e-l -carboxylic
acid tert-butyl ester and 5-methyl-6-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-
2-yl)-benzoitnidazole-l-carboxylic acid tert-butyl ester (90 mg, 0.25 mmol, as
prepared in Example 30, step b), {[4-(3-bromo-benzenesulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(62 mg, 0.126 mmol, as prepared in Example 27, step c),
tetrakis(triphenylphosphine)palladium(0) (37 mg, 0.032 mmol Strem
Chemicals, Inc., Newburyport, MA), Na2CO3 (400 µL, 2M aqueous), and
tolueae/EtOH mixture (2:1, 1.2 mL) were reacted to give 170 mg of a tan
foam. This crude material was separated using preparative thin layer
chromatography (1:2 EtOAc/hexanes, 2000 µ SiO2 plate). From several bands
that were isolated and analyzed by ESI-MS, two bands exhibited an observed
mass consistent with the di-Boc (7 mg) and mono-Boc (47 mg) products,
respectively. Both of these compounds were combined and then treated with
trifluoroacetic acid (50% in DCM) for 1 hr at rt. The reaction mixture was
concentrated in vacuo and the residue obtained was purified using C18-HPLC
(15-35% CH3CN in H2O (0.1% TFA) over 25 min) to give 8 mg (15%) of the
title compound as a white solid. 1H-NMR (CD3OD): d 9.34 (s, 1H), 8.34 (s,
1H), 8.04-8.10 (m, 2H). 7.79 (br s, 1H), 7.74-7.75 (m, 2H), 7.67 (br s, 1H),
2.72 (s, 3H), 2.37 (s, 3H). ESI-MS (m/z): Calcd. for C20H18N4O2S3: 443.6
(M+H); found: 443.1, 222.3 (M++).
Example 31
N-Hydroxy-4-[5-(6-methyl-3H-benzoimidazol-5-yl)-benzenesulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
a) N-Hydroxy~4-[3-(6-methyl-3H-benzoimidazol-5-yl)-benzenesulfonyl]-
5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
4-[3-(6-Methyl-3H-benzoimidazol-5-yl)-benzenesulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine bis-trifluoroacetate (5 mg, 7.5
µmol, as prepared in Example 30, step c), hydroxylamine hydrochloride (50
mg, 720 mmol), and Et3N (139 µL, 1 mmol)) were suspended in EtOH (3 mL).
The reaction mixture was refluxed for 2 hr at which time thin layer
chromatography showed complete disappearance of the starting material. The
reaction mixture was concentrated in vacuo and the residue was purified using
C18-HPLC (10-50% CH3CN m H2O (0.1% TFA) over 20 mm) to give 4.9 rag
(quantitative yield) of the title compound as a hygroscopic white solid. 1H-
NMR (CD3OD): 5 9.38 (s, 1H), 8.0S-8.12 (m, 2H), 8.05-8.07 (m, 1H), 7.82 (br
s, 1H), 7.73-7.77 (m, 2H), 7.70 (br s, 1H), 2.70 (s, 3H), 2.38 (s, 3H). ESI-MS
(m/z): Calcd. for C20Hl8N403S3: 459.6 (M+H); found: 459.2.
Example 32
4-[2'-(1-Hydroxy-ethyl)-biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate
a) {Imin o-[5-m ethylsulfanyl-4-(2'-vinyl-biphenyl-3-sulfonyl)-thiophen -
2-yl]-methyl}-carbamic acid tert-butyl ester
Following the procedure outlined for Examples 41-107, reaction of 2-
vinyl-phenylboronic acid (30 mg, 0.20 mmol, Aldrich Chemical Company),
{[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-
methyl}-carbamic acid tert-butyl ester (SO mg, 0.1 mmol, as prepared in
Example 27, step c), tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025
mmol Strem Chemicals, Inc., Newburyport, MA), Na2CO3 (400 µL, 2M
aqueous), and toluene/EtOH mixture (2:1, 1.2 mL) afforded 25 mg (50%) after
purification (1:3 EtOAc/hexanes, 2000 µ SiO2 plate) of the title compound as
a white foam.
b) 4-[2'-(1-Hydroxy-ethyl)-biphenyl-3-sulfonyl]-5-metltylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
{Imino-[5-methylsulfanyl-4-(2'-vinyl-biphenyl-3-sulfonyl)-thiophen-2-
yl]-methyl}-carbamic acid tent-butyl ester (25 mg, 0.05 mmol) was treated
with trifluoroacetic acid (50% in DCM) for 1 hr at rt. The reaction mixture
was concentrated in vacuo and then basified with 1 M NaOH to pH 8 and
allowed to stand for 10 min. The solution was then re-acidified with TFA and
purified using C18-HPLC (10-80% CH3CN in H2O (0.1% TFA) over 30 mm)
to give 7 mg (33%) of the title compound as a white solid (Rt: 12.3 min). 1H-
NMR (CD2OD): d 8.32 (s, 1H), 8.01-8.05 (m, 1H), 7.98-8.00 (m, 1H), 7.64-
7.71 (m, 3H), 7.44-7.49 (m, 1H), 7.32-7.36 (m, 1H), 7.16-7.18 (m, 1H), 4.75
(q, 1H, J = 6.5 Hz), 2.72 (s, 3H), 1.28 (d, 3H, J = 6.5 Hz). ESI-MS (m/z):
Calcd. for C20H20N2O3S3: 433.6 (M+H); found: 433.1.
Example 33
4-[4'-(1-Hydroxy-ethyl)-biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophene-2-
carboxamidine Trifluoroacetate
a) {Imino-[5-methylsulfanyl-4-(4'-vinyl-biphenyl-3-sulfouyl)-thiophen-
2-yl]-methyl}-carbamic acid tert-butyl ester
Following the procedure outlined in Example 1, step c, reaction of 4-
vinyl-phenyl-boronic acid (181 mg, 1.22 mmol), {[4-(3-bromo-
benzenesulfonyl)-5-methylsulfariyl-thiophen-2-yl]-imino-methyl}-carbamic
acid tert-butyl ester (300 mg, 0.61 mmol, as prepared in Example 27, step c),
tetrakis(triphenylphosphine)palladium(0) (141 mg, 0.122 mmol, Strem
Chemicals, Inc., Newburyport, MA), Na2CO3 (2.4 mL, 2M aqueous), and
toluene/EtOH mixture (2:1, 7.2 mL) afforded 138 mg (45%) of the title
compound as a white glassy solid after SiO2 flash chromatography (1:3
EtOAc/hexanes). 1H-NMR (CDCl3): d 8.21 (t, 1H, 1.7 Hz), 8.00 fbrs, 1H);
7.92-7.95 (m, 1H), 7.79-7.81 (m, 1H), 7.48-7.58 (m, 5H), 6.75 (dd, 1H, J =
17.7, 10.9 Hz), 5.S2 (d, 1H, J = 17.5), 5.31 (d, 1H, J = 10.9 Hz), 2.54 (s, 3H),
1.50 (s,9H).
b) 4-[4'-(l-Hydroxy-ethyt)-biphenyl-3-sulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine Trifluoroacetate
{Imino-[5-methylsulfaiiyl-4-(4'-vinyl-biphenyl-3-sulfonyl)-thiophen-2-
yl]-methyl}-carbamic acid tert-butyl ester (14 mg, 0.027 mmol, as prepared in
Example 33, step a) was treated with trifluoroacetic acid (50% in DCM) for 1
hr at rt. The reaction mixture was concentrated in vacuo and then brought to
pH 8 with 1 M NaOH and allowed to stand for 10 min. The solution was then
re-acidified with TFA and purified using C18-HPLC (10-80% CH3CN in H2O
(0.1% TFA) over 30 min) to give 9 mg (81%) of the title compound as a white
solid (Rt: 11.8 min). 1H-NMR (CD3OD): d 8.33 (s, 1H), 8.25 (t, 1H, 1.7 Hz),
7.95-8.01 (m, 2H), 7.61-7.71 (m, 3H), 7.49-7.53 (m, 2H), 4.89 (q, 1H, J = 6.5
Hz), 2.73 (s, 3H), 1.47 (d, 3H, J = 6.5 Hz). ESI-MS (m/z): Calcd. for
C20H20N2O3S3: 433.6 (M+H); found: 433.2.
Example 34
4-(2'-Hydroxy-biphenyl-3-Sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate
a) 4-(2'-Methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoracetate
Following the procedure outlined in Example 1, step c, reaction of 2-
methoxy-phenyl-boronic acid (181 mg, 1.22 mmol), {[4-(3-bromo-
benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-rnethyl}-carbamic
acid tert-butyl ester (100 mg, 0.2 mmol, as prepared in Example 27, step c),
terrakis(triphenylphosphine)palladium(0) (141 mg, 0.122 mmol, Strem
Chemicals, Inc., Newburyport, MA), Na2CO3 (800 µL, 2M aqueous), and
toluene/EtOH mixture (2:1, 2.4 mL) afforded 100 mg (96%) of a white glassy
solid after SiO2 flash chromatography (1:3 EtOAc/hexanes). This material was
treated with trifluoroacetic acid (50% in DCM) for 1 hr at rt and the crude
product was purified using C18-HPLC to give 65 mg (80%) of the title
compound as a white solid. 1H-NMR (CD3OD): d S.29 (s, 1H), 8.12 (brs, 1H),
8.02 (brd, 1H, J = 7.9 Hz), 7.86-7.90 (m, 1H), 7.54 (t, 1H, J = 8.0 Hz), 6.88-
7.36 (m, 4H), 3.30 (s, 3H), 2.73 (s, 3H). ESI-MS (m/z): Calcd. for
C19H18N2O3S3: 419.5 (M+H); found: 419.3.
b) 4-(2'-Hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate
4-(2'-Methoxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate (46 mg, 0.086 mmol, as prepared in Example
34, step a) was treated with BBr3 (1 M in DCM) for 18 hr at rt. The reaction
was quenched with MeOH at 0°C and then concentrated in vacuo to a solid.
Purification of this solid using C18-HPLC (10-80% CH3CN in H2O (0.1%
TFA) over 25 min) afforded 34 mg (77%) of the title compound as a white
solid. 1H-NMR (CD3OD): d 8.30 (s, 1H), 8.27 (t, 1H, J = 1.9 Hz), 7.89-7.96
(m, 2H), 7.61 (t, 1H, J = 7.9 Hz), 7.26-7.30 (m, 1H), 1.19-1.24 (m, 1H), 6.90-
6.95 (m, 2H), 2.70 (s, 3H). ESI-MS (m/z): Calcd. for C18H16N2O3S3: 405.5
(M+H); found: 405.2.
Example 35
4-(3'-Hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate
4-(3'-Methoxy-biphenyl-3-s;ulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate (1.4 mg, 3.3 µmol, as prepared in Example 44)
was treated with BBr3 (1 M in DCM) for 18 hr at rt. The reaction was
quenched with MeOH at 0 °C and then concentrated in vacuo to a solid.
Purification of this solid using C18-HPLC (10-80% CH3CN in H2O (0.1%
TFA) over 25 min) afforded 1.0 mg (77%) of the title compound as a white
solid. 1H-NMR (CD3OD): d 8.33 (s, 1H), 8.23 (t, 1H, J = 1.6 Hz), 7.98-8.01
(m, 1H), 7.92-7.95 (m, 1H), 7.68 (t, 1H, J = 7.8 Hz), 7.31 (t, 1H, J = 7.8 Hz),
7.05-7.12 (m, 2H), 6.84-6.87 (m, 1H), 2.74 (s, 3H). ESI-MS (m/z): Calcd. for
C18H16N2O3S3: 405.5 (M+H); found: 405.2.
Example 36
5-Bromo-4-(2-methoxy-benzenesulfonyl)-thiophene-2-carboxamidine
triflouroacetate
The procedure as in Example 20: step a was followed using 4-bromo-
5-nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 200
mg, 0.75 mmol) and 2-methoxy-benzenethiol (109 µL, 1.25 mmoL Aldrich
Chemical Company) to isolate 4-(2-methoxy-phenylsulfanyl)-5-nitro-
thiophene-2-carboxylic acid methyl ester. 4-(2-Methoxy-phenylsulfanyl)-5-
nitro-thiophene-2-carboxylic acid methyl ester (200 mg, 0.61 mmol) was then
treated with TiCl3 (20% aq. HC1 solution, 5 mL, 6.1 mmol) in THF (6mL).
The reaction was stirred for 20 minutes at rt. The reaction mixture was
concentrated in vacuo and then dissolved into EtOAc. The organic layer was
washed several times with saturated NaHCO3. The combined organic layers
were dried over sodium sulfate. Removal of the solvents in vacuo yielded 5-
amino-4-(2-methoxy-phenylsulfanyl)-thiophene-2-carboxylic acid methyl
ester. The procedure as in Example 20: step e was followed using 5-amino-4-
(2-methoxy-phenylsulfanyl)-thiophene-2-carboxylic acid methyl ester (160
mg, 0.54 mmol), t-butylnitrite (96 µL, 0.81 mmol), and copper (II) bromide
(112.6 mg, 0.65 mmol) resulting in 5-bromo-4-(2-methoxy-phenylsulfanyl)-
thiophene-2-carboxylic acid methyl ester. The procedure as in Example 20:
step b was followed using 5-brorno-4-(2-methoxy-phenylsulfanyl)-thiophene-
2-carboxylic acid methyl ester (18 mg, 0.05 mmol) and m-CPBA (32 mg, 0.25
mmol) resulting in 5-bromo-4-(2-methoxy-benzenesulfonyl)-thiophene-2-
carboxylic acid methyl ester. The procedure as in Example 20: step f was
followed using 5-bromo-4-(2-methoxy-benzenesulfonyl)-thiophene-2-
carboxylic acid methyl ester (45 mg, 11 mmol) and dimethyl aluminum amide
(1M, 0.57 mL, 0.55 mmol) resulting in the title compound 5-bromo-4-(2-
methoxy-benzenesulfonyl)-thiophene-2-carboxamidine (4mg, 13%). 1H-NMR
(CD3OD): d: 8.30 (s, 1H), 8.12-S.14 (d of d, J = 6.1, 1.8 Hz, 1H), 7.70-7.74
(m, 1H), 7.16-7.24 (m, 2H), 3.79 (s, 3H).
Example 3 7
5-Methylsulfanyl-4-(naphthalene-2-sulfonyl)-thiophene-2-carboxamidine
triflouroacetate
To a suspension of NaH (30 mg, 1.24 mmol) in DMF was slowly
added dropwise naphthalene-2-thiol (199 mg, 1.24 mmol, Aldrich Chemical
Company) in DMF at rt. This clear solution was then added dropwise to a
solution of 4-bromo-5-nitro-thiophene-2-carboxylic acid methyl ester
((Example 114, step c) 300 mg, 1.27 mmol) in DMF at rt. Aqueous workup
resulted in isolation of 4-(naphthalen-2-ylsulfanyl)-5-nitro-thiophene-2-
carboxylic acid methyl ester. The procedure as in Example 20: step b was
followed using 4-(naphthalen-2-ylsulfanyl)-5-nitro-thiophene-2-carboxylic
acid methyl ester (194 mg. 0.56 mmol) and m-CPBA (354.4 mg, 1.2 mmol)
resulting in 4-(naphthalene-2-sulfonyl)-5-nitro-thiophene-2-carboxylic acid
methyl ester. The procedure as in Example 27: step a was followed using 4-
(naphthalene-2-sulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (32
mg, 0.085 mmol) sodium thiomethoxide (7.55 mg, 0.94 mmol) resulting in 5-
methylsulfanyl-4-(naphthalene-2-sulfonyl)-thiophene-2-carboxylic acid
methyl ester. The procedure as in Example 20: step f was followed using 5-
methylsulfanyl-4-(naphthalene-2-sulfonyl)-thiophene-2-carboxylic acid
methyl ester (29 mg, 0.77 mmol) and dimethyl aluminum amide (0.39 mL,
0.39 mmol) resulting in the title compound 5-methylsulfanyl-4-(naphthalene-
2-sulfonyl)-thiophene-2-carboxamidine triflouroacetate (19 mg, 70%). 1H-
NMR (CD3OD): d: 8.67 (m, 1H), 8.37 (s, 1H), 8.05-8.15 (m. 2H), 7.95-8.01
(d, J = 7.21 Hz, 1H), 7.90-7.95 (d of d, J = 6.7, 2.0 Hz), 7.65-7.75 (m, 2H),
2.70 (s, 3H).
Example 38
4-(7-Bromo-3H-benzoimidazole-5-sulfonyI)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate
a) 4-Chlorosulfonyl-5-methylsulfanyl-thiophene-2-carboxylic acid
methyl ester
To a —5°C solution of 4-amino-5-methylsulfanyl-thiophene-2-
carboxylic acid methyl ester (Illig et al.. US 6,291,514, 24 g, 0.12 mol) in
methylene chloride:methanol (2:1, 40 mL), CuCl2-2H2O (6.04 g, 0.035 mol),
and concentrated HC1 (19.7 mL, 0.24 mol) was added. Excess SO2 was
condensed into the reaction mixture. To this mixture, was added t-butyl nitrite
(27.6 mL, 0.24 mol) dropwise at -5°C and then stirred at same temperature for
2 hours. The reaction mixture was allowed to warm up to room temperature,
and the solvents were removed in vacuo. The residue was diluted in
methylene chloride (500 mL), washed with water (100 mL) and brine (50 mL),
and dried over Na2SO4. The solvent was removed in vacuo and the residue
was purified by flash chromatography in 30-50% ethyl acetate in hexanes to
afford 4-chlorosulfonyl-5-methylsulfanyl-thiophene-2-carboxylic acid methyl
ester as a solid (12 g, 35%).
b) Sodium salt of 5-methylsulfanyl-4-sulfino-thiophene-2-carboxylic
acid methyl ester
To a solution of Na2SO3 (7.51 g, 0.06 mol) and NaHCO;, (5.22 g. 0.06
mol) in water (27 mL) at 75°C was added 4-chlorosulfonyl-5-rnethylsulfanyl-
thiophene-2-carboxylic acid methyl ester ((Example 38, step a) 12 g, 0.05
mol) portion-wise over 3 hours and then stirred for an additional hour. Water
was removed in vacuo, and the residue was dissolved in hot water (10 mL).
This solution was cooled in a refrigerator for 1 week at which time the product
precipitated out. This solid was filtered, washed with cold water and dried to
give 12 g (87 %) of the sodium salt of 5-methylsulfanyl-4-sulfino-thiophene-
2-carboxylic acid methyl ester. 1H-NMR (DMSO-d6): d 7.64 (s, 1H), 3.78 (s,
3H), 2.57 (s, 3H).
c) 4-(7-Bromo-spiro[benzoimidazole-2,1'-cyclohex]e-5-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxylic acid methyl ester
To a solution of 4,6-dibromo-spiro[benzoimidazole-2,1'-cyclohexane]
(200 mg, 0.58 mmol, prepared according to Hazelton et al.,
Tetrahedron:51:5597 (1995)) in ethanol (15 mL) was added an aqueous
solution of the sodium salt of 5-methylsulfanyl-4-sulfino-thiophene-2-
carboxylic acid methyl ester ((Example 38, step b) 175 mg, 064 mmol, 15 mL
H2O) and acetic acid (40 µL, 0.70 mmol). This mixture was stirred for 2.5
hours at room temperature and poured into an ice-water slurry. The resulting
aqueous solution was extracted with methylene chloride (100 mL, 3x). The
organic layer was separated, washed with brine (25 mL), and dried over
MgSO4. The solvents were removed in vacuo to afford 4-(7-bromo-
spiro[benzoimidazole-2,r-cyclohex]e-5-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester as a brown solid (200 mg, 67 %).
1H-NMR (CDCl3): d 8.08 (m, 1H), 8.04 (s, 1H), 7.60 (m, 1H). 3.91 (s. 3H),
2.66 (s, 3H), 2.00-1.24 (m, 10.H).
d) 4-(3,4-Diamino-5-bromo-benzenesulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester
To a solution of 4-(7-bromo-spiro[benzoimidazole-2-cyclohex]e-5-
sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester
((Example 38, step c) 200 mg, 039 mmol) in 1:1 ethanol:water (30 mL) was
added sodium dithionite (159 mg, 0.78 mmol) and heated to 80°C for 45
minutes. The solution was cooled to room temperature and poured into an ice-
water slurry. This aqueous mixture was extracted with methylene chloride (50
mL, 3x). The organic layer was separated, washed with brine (25 mL), and
dried over MgSO4. The solvents were removed in vacuo to afford 170 mg of
4-(3,4-diamino-5-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid methyl ester as a brown oil. This was used in the next step
without further purification.
e) 4-(7-Bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester
4-(3,4-Diamino-5-bromc)-benzenesulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester ((Example 38, step d) 170 mg, 0.39
mmol) was dissolved in formic acid (2.5 mL) and heated to 100°C for 2 hours.
The resulting solution was cooled to room temperature, poured over ice-water
slurry, and basified to pH 8 with NaHCO3 This aqueous solution was
extracted with ethyl acetate (75 mL, 3x). The organic layer was separated and
washed with water, brine, and dried over MgSO4- Solvents were removed in
vacuo to afford 100 mg (57 %) of 4-(7-bromo-3H-benzoimidazole-5-
sulfonyl)-5-methylsulfanyl-thiophene-2-carboxyhc acid methyl ester as a
brown oil. ESI-MS (m/z): Calcd. for C14H11BrN2O4S3: 447 (M+H); found:
447.1 and 449.1.
f) 4-(7-Bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
1M stock solution of dimethylaluminum amide reagent was made by
the addition of AlMe3 solution (2M in toluene, 5 mL, 10 mmol) to a
suspension of NH4Cl (0.54 g, 10 mmol) in toluene (5 mL) under inert
conditions, and then heated to 80°C for 5 minutes. This solution (2.5 mL, 2.5
mmol) was added to 4-(7-bromo-3H-benzoimidazole-5-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 38, step e)
15 mg, 0.034 mmol) and then heated to 100°C for 2 hrs. The resulting
solution was cooled to room temperature and added to a slurry of silica gel in
methylene chloride (15 g silica gel in methylene chloride 120 mL). and stirred
for 30 minutes. The slurry was filtered and the silica was washed with
methanol. The filtrate and methanol fractions were combined and evaporated
under vacuum. The residue was purified by HPLC (C18-column, 10-70%
CH3CN over 30 min) to afford 3.0 mg (21%) of 4-(7-bromo-3H-
benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxamidine
trifluoroacetate as a white solid. 1H-NMR (CD3OD): d S.51 (s, 1H), S.36 (d,
1H, J = 1.6), 8.33 (s, 1H), 8.05 (d, 1H, J = 1.6), 2.72 (s, 3H). ESI-MS (m/z):
Calcd. for C13H11BrN4O2S3,: 430.92 (M+H); found 431.2 and 433.1.
Examples 39-40
4-(7-Bromo-3-methyl-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate and 4-(7-Bromo-l-methyl-lH-
benzoimidazole-5-sulfonyl)~S-methylsulfanyl-thiophene-2-carboxamidine
trifluoroacetate.
a) 4-(7-Bromo-3-tnethyl-3H-benzoimidazole-5-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxylic acid methyl ester and 4-(7-Bromo-l-
methyl-lH-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid methyl ester
To a solution of 4-(7-bromo-3H-benzoimidazole-5-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxylic acid methyl ester (as prepared in
Example 38, step e) (100 mg, 0.22 mmol) in dimethylformamide (2 mL) was
added Mel (13.9 µL, 0.22 mmol) and K2CO3 (61.8 mg, 0.45 mmol). then
stirred overnight at room temperature. The solvents were removed in vacuo
and the residue was diluted with ethyl acetate (100 mL). The ethyl acetate
layer was washed with water (15 mL) and biine (25 mL), and dried over
MgSO4. The solvent was removed in vacuo to afford 20 mg (19 %) of 4-(7-
bromo-3-methyl-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-
2-carboxylic acid methyl ester and 4-(7-bromo-1-methyl-1H-benzoimidazole-
5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester as a
mixtuire. This mixture was used directly in the following step.
b) 4-(7-Bromo-3-methyl-3H-benzoimidazole-5-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxamidine triflnoroacetate and 4-(7-
Bromo-l-methyl-lH-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
1M stock solution of dimethylaluminum amide reagent was made by
the addition of AlMe3 solution (2M in toluene, 5 mL, 10 mmol) to a
suspension of NH4CI (0.54 g, 10 mmol) in toluene (5 mL) under inert
conditions, and then heated to 80°C for 5 minutes. To the mixture from above
((Examples 39-40, step a) 20 mg, 0.043 mmol) was added dimethylaluminum
amide reagent (2.5 mL, 2.5 mmol), and then heated to 100°C for 2 hrs. This
solution was cooled to room temperature, added to 15 g silica gel and
methylene chloride (120 mL) slurry, and stirred for 30 minutes. The slurry
was filtered and washed with rnethanol. The solvents were removed in vacuo,
and the crude material was purified by HPLC (C18-column, 10-70% CH3CN
over 30 min) to afford 4-(7-bromo-3-methyl-3H-benzoimidazole-5-sulfonyl)-
5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate, 39 (4.5 mg) and
4-(7-bromo-1-methyl-1H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate, 40 (2.5 mg).
Example 39: 1H-NMR (CD3OD): d 8.48 (s, 1H), 8.34 (s, 1H). 8.33 d,
1H, J = 1.6), 8.06 (d, 1H, J = 1.6), 4.01 (s, 3H), 2.72 (s, 3H). ESI-MS (m/z):
Calcd. for C14H13BrN4O2S3: 445 (M+H); found 445.1 and 447.1.
Example 40: 1H--NMR (CD3OD): d 8.39 (s, 1H), 8.34 (d, IH, J = 14),
8.33 (s, 1H), 8.07 (d, 1H, J = 1.2), 4.21 (s, 3H), 2.72 (s, 3H). ESI-MS (m/z):
Calcd. forC14H13BrN4O2S3: 445 (M+H); found 445.1 and 447.1.
Examples 41-107
The compounds in examples 41 to 107 (see table 1) were synthesized
in a parallel fashion as follows: To dry 2-dram vials, each fitted with a stir bar
and a Teflon®-lined screw cap was added {[4-(3-bromo-benzenesulfonyl)-5-
methylsulfanyl-thiophen-2-yr|-imino-methyl}-carbamic acid tert-butyl ester
(0.1 mrnol, as prepared in Example 27, step c), the appropriate boronic acid
(0.2 mrnol), and tetrakis(triphenylphosine)palladium(0) (0.025 mmol). Each
vial was twice treated with an argon purge/evacuation cycle and then charged
with a mixture of toluene/EtOH (2:1, 1.2 mL) and 2 M Na2CO3 (0.4 mL) via a
syringe. The vials were placed in an oil bath at 80 °C and stirred overnight. To
the cooled reaction mixtures was added EtOAc (4 mL), the organic layer was
filtered (1-g silica SPE column), and the filtrate was evaporated in vacuo. The
resulting residue was purified using preparative TLC (SiO2) to afford the Boc-
protected amidine product. After treatment of this material with trifluoroacetic
acid (50% in DCM) for 1 hr at rt, the solvents were removed in vacuo and the
residue was purified using C18;-HPLC (typical HPLC method: 10% to 80 %
CH3CN in H2O (0.1% TFA) over 25 min) to afford the desired compound.
Example 94 was prepared in an identical fashion except for removal of the
Boc protecting group which was achieved by treatment with 4 N HCl in
dioxane for 1 hr at it. This was found to minimize side reactions involving the
vinylic group (see Example 32).
Examples 108-110
5-MethylsuIfanyl-4-(3-methyl-7-o-tolyl-3H-benzoimidazole-5-sulfonyl)-
thiophene-2-carboxamidine trifluoroacetate, 5-Methylsulfanyl-4-(2-methyl-
7-o-tolyl-3H-benzoimidazole-5-sulfonyl)-thiophene-2-carboxamidine and
5-Methylsulfanyl-4-(7-o-tolyl-3H-benzoimidazole-5-sulfonyl)-thiophene-2-
carboxamidin e
a) 4-(7-Bromo-l,3-dihydro-spiro[benzoimidazole-2,1'-cyclohex]e-5-
sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester
4-(7-Bromo-spiro[benzoimidazole-2,1'-cyclohex]e-5-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 38, step c)
300 mg, 0.58 mmol) in ethanol:water solution (1:1, 60 mL) was treated with
sodium dithionite (203 mg, 1.16 mmol) as in Example 38, step d. A brown
precipitate formed upon addition of sodium dithionite. This precipitate was
filtered and dried under vacuum to give 163.6 mg of 4-(7-bromo- 1,3-dihydro-
spiro[benzoimidazole-2,1'-cyclohex]e-5-sulfonyl)-5-methylsulfany]-
thiophene-2-carboxylic acid methyl ester as a brown solid. This solid was
used in the next step without further purification.
b) 5-Methylsulfanyl-4-(7-o-tolyl-l,3-dihydro-spiro[benzoimidazole-2,1'-
cyclohex]e-5-sulfonyl)-thiophene-2-carboxylic acid methyl ester and 5-
Methylsulfanyl-4-(7-o-tolyl-1,3-dihydro-spiro[benzoimidazole-2,1'-
cyclohex]e-5-sulfonyl)-thiophene-2-carboxylic acid ethyl ester
To a dried flask was added 4-(7-bromo-l,3-dihydro-
spiro[benzoimidazole-2,r-cyclohex]e-5-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester (129 mg, 0.249 mmol) from above
step a, o-tolyl boronic acid (136 mg, 0.779 mmol), aqueous Na2CO3 (2M, 1
mL, 43 mmol), ethanol (1 mL)., and toluene (2 mL). The flask was sparged
with argon, and Pd(PPh3)4 (72 mg, 0.062 mmol) was added. The reaction
mixture was stirred and heated at 80° for 18 hrs, and then cooled to room
temperature. The solvents were removed in vacuo. The residue was dissolved
in ethyl acetate (150 mL), washed with water (20 mL) and brine (20 mL), and
then dried over MgSO4. Ethyl acetate was removed in vacuo and the residue
was purified via preparative TLC (20-30% ethyl acetates/hexanes) to afford a
mixture of 5-methylsulfanyl-4-(7-o-tolyl-l,3-dihydro-spiro[benzoimidazole-
2,1'-cyclohex]e-5-sulfonyl)-thiophene-2-carboxylic acid methyl ester and 5-
methylsulfanyl-4-(7-o-tolyl-l ,3-dihydro-spiro[benzoimidazole-2,1'-
cyclohex]e-5-sulfonyl)-thiophene-2-carboxylic acid ethyl ester as a brown oil
(130 mg). ESI-MS (m/z): Calcd. for C26H28N2O4S3 and C27H30N2O4S3:
529.12 (M+H); found 529.3 and 543.3.
c) 5-Methylsulfanyl~4-(7-o-tolyl-3H-benzoimidazole-5-sulfonyl)-
thiophene-2-carboxylic acid methyl and ethyl esters
A mixture of 5-methylsulfanyl-4-(7-o-tolyl-l,3-dihydro-
spiro[benzoimidazole-2,1'-cyclohex]e-5-sulfonyl)-thiophene-2-carboxylic acid
methyl and ethyl esters (130 mg) from above step b was treated with formic
acid as in Example 38: step e followed by analogous work up to afford a crude
mixture of 5-methylsulfanyl-4-(7-o-tolyl-3H-benzoimidazole-5-sulfonyl)-
thiophene-2-carboxylic acid methyl and ethyl esters as a brown oil (100 mg).
This mixture was used in the following step without further purification. MS
(m/z): Calcd. for C21H18N2O4S3: 459.04 (M+l); found 459.2 and 473.2.
d) 5-Methylsulfanyl-4-(3-methyl-7-o-tolyl-3H-benzoimidazole-5-
sulfonyl)-thiophene-2-carboxamidine trifluoroacetate, 5-Methylsulfanyl-4-
(2-methyl-7-o-tolyl-3H-benzoimidazole-5-sulfonyl)-thiophene-2-
carboxamidine trifluoroacetate and 5-Methylsulfanyl-4-(7-o-tolyl-3H-
benzoimidazole-5-sulfonyl)-thiophene-2-carboxamidine trifluoroacetate
A mixture of 5-rnethylsulfanyl-4-(7-o-tolyl-3H-benzoimidazole-5-
sulfonyl)-thiophene-2-carboxylic acid methyl and ethyl esters (100 mg, 0.22
mmol) from above step c was treated with methyl iodide (13.6 µL, 0.22 mmol)
and K2CO3 (60.2 mg, 0.44 ;m-mol) in dimethylformamide (2 mL) as in
Example 39: step a, followed by analogous work up to afford 40 mg of a crude
mixture. This mixture was treated with the dimethyl aluminum amide reagent
(5 mL, 5 mmol) as in Example 39: step b. After 1 hour, additional
dimethylaluminum amide reagent (5 mL, 5 mmol) was added. After 1.5
hours, the reaction was quenched as in Example 39: step b followed by HPLC
(CIS-column, 10-70% CH3CN over 30 min) purification to afford 5-
methylsulfanyl-4-(3-methyl-7-o-tolyl-3H-benzoimidazole-5-sulfonyl)-
thiophene-2-carboxamidine trifluoroacetate (108), 5-methylsulfanyl-4-(2-
methyl-7-o-tolyl-3H-ben2:oimidazole-5-sulfonyl)-thiophene-2-carboxamidine
trifluoroacetate (109) and 5-methylsulfanyl-4-(7-o-tolyl-3H-benzoimidazole-
5-sulfonyl)-thiophene-2-carboxamidine trifluoroacetate (110). 108: 1H-NMR
(CD3OD): d 8.63 (s, 1H), 8.41 (m, 1H), 8.36 (m, 1H), 7.82 (m, 1H), 7.38-7.26
(m, 4H), 4.08 (s, 3H), 2.72 (s, 3H), 2.09 (s, 3H). 109: 1H-NMR (CD3OD): d
S.41 (m, 1H), 8.35 (s, 1H), 7.73 (m, 1H), 7.46-7.28 (m, 4H), 3.32 (s, 3H), 2.70
(s, 3H), 2.02 (s, 3H). 110: 1H-NMR (CD3OD) C: 5 8.56 (s, 1H), 8.41 (m, 1H),
8.36 (m, 1H), 7.78 (m, 1H), 7.44-7.27 (m, 4H), 2.71 (s, 3H), 2.10 (s, 3H).
Example 111
4-(2-Methyl-furan-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxamidine
hydrochloride
a) 4-(2-Methyl-furan-3-ylsulfanyl)-5-nitro-thiophene-2-carboxylic acid
methyl ester
4-Bromo-5-nitro-thiophene-2-carboxylic acid methyl ester
((Example 114, step c) 532 mg, 2 mmol), 2-methyl-furan-3-thiol (600 mg,
5.26 mmol), and DMAP-polystyrene resin (2 g, 2.86 rnmol) were stirred in
THF (10 mL) for 12 h at rt. The resin was filtered and washed with several
portions of DCM (100 mL total volume). The filtrate was concentrated in
vacuo and the yellow residue (480 mg, 80%) was used without further
purification. 1H-NMR (CDCl3): d 7.46 (d, 1H, J - 1.9 Hz), 7.05 (s, 1H), 6.43
(d, 1H, J = 1.9 Hz), 3.90 (s, 3H), 2.38 (s, 3H).
b) 4-(2-Methyl-furan-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid methyl ester
m-Chloroperbenzoic acid (276 mg, 4 mmol) and 4-(2-methyl-furan-3-
ylsulfanyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (117 mg, 0.39
mmol) were dissolved in DCM (15 mL) and stirred for 6 h at 40 °C. DCM (50
mL) and aqueous sodium thiosulfate were added (exothermic), and the layers
were separated. The organic layer was extracted with Na2CO3 (2M, 6 x 30
mL), brine (50 mL), and was dried over sodium sulfate. Concentration of the
solvent in vacuo followed by SiO2 flash chromatography (25-75% DCM in
hexanes) yielded the sulfone compound (85 mg, 66%) which was redissolved
THF (5 mL). The procedure in Example 12: step c was followed, using 275
µL (0.275 mmol) of sodium thiomethoxide. Analogous aqueous workup and
purification by SiO: flash chromatography yielded the title compound (72 mg,
85%) as a colorless solid.
c) 4-(2-Methyl-furan-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine hydrochloride
Following the procedure used in Example 12: step f, 4-(2-methyl-
furan-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester
(26 mg, 0.078 mmol) was converted to the amidine using 3 mL of
dimethyl aluminum amide reagent. The title compound was isolated as a white
solid (16 mg, 58%) after preparative TLC purification (15% MeOH in DCM).
1H-NMR (CD3OD): d 8.26 (s, 1H), 7.49 (d, 1H, J = 2.1 Hz), 6.69 (d, 1H, J =
2.1 Hz), 2.74 (s, 3H), 2.63 (s, 3H). ESI-MS (m/z): Calcd. for C11H12N2O3S3
(M+H): 317.4; found: 317.2.
Example 112
5-Methylsulfanyl-4-(4-phenyl-thiazole-2-sulfonyl)-thiophene-2-
carboxamidine hydrochloride
a) 5-Nitro-4-(4-phenyl-thiazole-2-sulfonyl)-thiophene-2-carboxylic acid
methyl ester
The procedure in Example 111: step a was followed, using 4-bromo-5-
mtro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 532 mg,
2 mmol), 4-phenyl-thiazole-2-thiol (483 mg, 2.5 mmol), and DMAP-
polystyrene resin (2 g, 2.86 mmol) in THF (10 mL). Analogous workup
yielded the crude sulfide which was treated with m-chloroperoxybenzoic acid
(1.38 g, 8 mmol) in DCM (30 mL) as in Example 111: step b. Analogous
workup and purification by SiO2 flash chromatography (25-50 % EtOAc in
hexanes) yielded the title compound (245 mg, 30%) as a white solid. 1H-
NMR (CDCl3): d 8.25 (s, 1H), 7.80 (m, 2H), 7.75 (s, 1H), 7.34-7.44 (m, 3H),
7.05 (s, 1H), 6.43 (d, 1H, J = 1.9 Hz), 3.98 (s, 3H).
b) 5-Methylsulfanyl-4-(4-phenyl-thiazole-2-sulfonyl)-thiophene-2-
carboxamidine hydrochloride
Following the procedure in Example 12: step c, 5-nitro-4-(4-phenyl-
thiazole-2-sulfonyl)-thiophene-2-carboxylic acid methyl ester (110 mg, 0.27
mmol) was reacted with sodium thiomethoxide (1M in EtOH, 325 µL, 0.325
mmol) in THF (5 mL). Analogous aqueous workup and purification by SiO2
flash chromatography yielded the thiomethylated intermediate (82 mg, 75%)
as a white solid. A portion of the solid (52 mg, 0.126 mmol) was treated with
dimethyl aluminum amide reagent (5 mL) as in Example 12: step f. Analogous
workup and purification by preparative TLC (15% MeOH in DCM) resulted in
the title compound (21 mg, 38%) as a white solid. 1H-NMR (CD3OD): d 8.38
(s, 1H), 8.31 (s, 1H), 7.90 (m, 2H), 7.36-7.46 (m, 3H), 2.76 (s, 3H). ESI-MS
(m/z): Calcd. for C15H13N3O2S4 (M+H): 396.6; found: 396.1.
Example 113
4-(6-Ethoxy-benzothiazole-2-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine hydrochloride
a) 4-(6-Ethoxy-benzothiazole-2-sulfonyl)-5-nitro-thiophene-2-
carboxylic acid methyl ester
The procedure in Example 111: step a was followed, using 4-bromo-5-
nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 266 mg,
1 mmol), 6-ethoxy-benzothiazole-2-thiol (264 mg, 1.25 mmol), and DMAP-
polystyrene resin (0.75 g, 1.05 mmol) in THF (6 mL). Analogous workup
yielded the crude sulfide, which was treated with m-chloroperoxybenzoic acid
(692 mg, 4 mmol) in DCM (30 mL) as in Example 111: step b. Analogous
workup and purification by SiO2 flash chromalography (25-50 % EtOAc in
hexanes) yielded the title compound (250 mg, 58%) as a colorless glass, 1H-
NMR (CDCl3): d 8.40 (s, 1H), 7.94 (d, 1H, J = 9.1 Hz), 7.38 (d, 1H, J = 2.6
Hz), 7.17 (dd, 1H, J-= 2.6, 9.1 Hz), 4.13 (q, 2H, J = 7.0 Hz), 4.00 (s, 3H), 1.47
(t, 3H, J = 7.0 Hz). ESI-MS (m/z): Calcd. for C15H12N2O7S3 (M-H): 429.5;
found: 429.1.
b) 4-(6-Ethoxy-benzothiazole-2-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine hydrochloride
Following the procedure in Example 12: step c, 4-(6-ethoxy-
benzothiazole-2-sulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester
(65 mg, 0.15 mmol) was reacted with sodium thiomethoxide (1M in EtOH,
175 µL 0.175 µmol) in THF (5 mL). Analogous aqueous workup and
purification by SiO2 flash chromatography yielded the thiomethyl intermediate
(53 mg, 82%) as a colorless glass. A portion of the material (41 mg, 0.10
mmol) was treated with dimethylaluminum amide reagent (3 mL) as in
Example 12: step f. Analogous workup and purification by preparative TLC
(15% MeOH in DCM) yieded the title compound (18 mg, 42%) as a white
solid. 1H-NMR (CD3OD): d 8.37 (s, 1H), 7.96 (d, 1H, J = 9.1 Hz). 7.62 (d,
1H, J = 2.6 Hz), 7.22 (dd, 1H, J = 2.6, 9.1 Hz), 4.14 (q, 2H, J = 7.0 Hz), 2.74
(s, 3H), 1.44 (t, 3H, J = 7 0 Hz). ESI-MS (m/z): Calcd. for C15H15N3O3S4
(M+H): 414.6; found: 414.1.
Example 114
4-(3-Methoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine hydrochloride HCl
a) 4-Bromothiophene-2-carboxylic acid
To a flask equipped with a mechanical stirrer was added 25 g (130
mmol) 4-bromothiophene-2-carbaldehyde (Aldrich Chemical Company),
acetonitrile (200 mL), and 4.5 g (37.5 mmol) of sodium dihydrogen phosphate
dissolved in 35 mL of water. After cooling this mixture on an ice-salt bath, 15
mL (169 mmol) of 35% hydrogen peroxide and 15.3 g (169 mmol) of sodium
chlorite were added, and the mixture was stirred for 1 h. The reaction mixture
was then stirred at room temperature for 3 h. The solvent was removed in
vacuo, and the solid was suspended in a mixture of water (175 mL) and 1 N
hydrochloric acid (4 mL) and stirred for 10 min at rt. The solid was collected
on a Buchner funnel and washed with water (2 x 150 mL) to afford 26 g (97%)
of 4-bromothiophene-2-carboxylic acid, which was used in the next step
without further purification.
b) 4-Bromothiophene-2-carboxylic acid Methyl Ester
To a dry flask under N2 with a stirbar was added 6 g (29.1 mmol) of 4-
bromothiophene-2-carboxylic acid (as prepared in the previous step) and dry
methanol (100 mL). The solution was cooled in an ice-salt bath for 15 min
and 2.55 mL (34.9 mmol) of thionyl chloride was added over 15 min. keeping
the temperature for an additional 15 min, then for 1 h at rt, and finally refluxed for S h under
N2. The resulting solution was cooled and concentrated to 6.7 g of pale amber
oil. This oil was passed through 150 g of silica with ~600 mL CH2Cl2
(discarded the first 120 mL wliich contained minor impurities and no ester).
The solvent was removed in vacuo to afford 6.11 g (95% yield) of the title
compound as a colorless solid, which was used in the next step without further
purification.
c) 4-Bromo-5-nitrothiophene-2-carboxylic acid Methyl Ester
The nitrating mixture (HNO3 d =1.42, 2 mL; concentrated H2SO4, 6
mL) was slowly added with stirring, at -5° to -10°C, to 4-Bromothiophene-2-
carboxylic acid methyl ester (3 g, 13.57 mmol) dissolved in concentrated
H2SO4 (10 mL). After being kept at -5 to -10°C for 30 min. the mixture was
poured over crushed ice. The solid precipitate was separated by filtration and
washed with water and dried over P2O5 to give 3.7 g of 4-bromo-5-
nitrothiophene-2-carboxylic acid methyl ester as a tan solid, which was used in
the next step without further purification.
d) 4-(3-Methoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid methyl ester
To a cooled (ice bath) solution of 4-bromo-5-nitrothiophene-2-
* carboxylic acid methyl ester (0.5 g, 1.88 mmol) from above step c, in
dimethylformamide (DMF) was added 3-methoxybenzenethiol ( 0.29 g, 2.1
mmol) and Cs2CO3 (0.67 g, 2.1 mmol). The resulting mixture was heated at 50
°C for 3 h. DMF was removed under vacuum and the residue was partitioned
between EtOAc and 10 % HC1. The EtOAc layer was washed with brine, dried
over Na2SO4 and concentrated in vacuo to give an oil. This oil was purified by
silica gel column chrormatography (EtOAc:hexane) to give 0.56 g (91 %) of 4-
(3-Methoxy-phenylsulfanyl)-5-mtro-thiophene~2-carboxylic acid methyl ester.
This ester was dissolved in CH2Cl2 (6 mL) and treated with m-
chloroperoxybenzoic acid (MCPBA, 1.1 g) and heated at reflux for 6 h. The
resulting mixture was diluted with CH2Cl2 (10 mL) and washed with sat.
sodium thiosulfate, IN NaOH and brine. The organic layer was dried over
Na2SO4 and concentrated in vacuo. The residue was purified by silica gel
column chromatography (EtOAc:hexane) to give an oil. This oil was dissolved
in DMF (5 mL) and cooled in an ice bath. To this solution sodium
thiomethoxide (126 mg, Aldrich Chemical Company) was added and the
mixture was stirred for 5 h. The reaction was quenched with 10% HC1 and the
solvents were removed in vacuo. The residue was dissolved in EtOAc, washed
with brine and dried over Na2SO4 The solvent was removed in vacuo and the
residue was purified by preparative thin-layer chromatography to give 171 mg
of 4-(3-methoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic
acid methyl ester, which was directly used in the next step.
e) 4-(3-Methoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine
4-(3-methoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid methyl ester from above step d (171 mg, 0.48 mmol) was
treated with dimethylaluminum amide reagent (2 mL) as in Example 12:
step f. Analogous workup and purification by preparative TLC (15% MeOH
in DCM) gave the title compound (50 mg, 30%) as a white solid. 1H-NMR
(DMSO-de): d 9.24 (broad s, 4H), 8.43 (s, 1H), 7.64-7.51 (m, 2H), 7.44 (s,
H), 7.31 (d, 1H, J = 9.3 Hz), 3.83 (s, 3H), 2.70 (s, 3H). ESI-MS (m/z):
Calcd. for C13H14N2O3S3 (M+H): 343.0; found: 343.2.
Example 115
4-(6-Methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate
a) 6-Methyl-biphenyl-3-ylamine
To a dried flask was added 3-bromo-4-methyl-phenylamine (1 g, 5.37
mmol), phenyl boronic acid (2.62 g, 21.5 mmol), aqueous Na2CO3 (2M, 21.5
mL, 43 mmol), ethanol (21.5 mL), and toluene (43 mL). The flask was
sparged with Ar, and Pd(PPh3)4 (1.55 g, 1.34 mmol) was added. The reaction
mixture was stirred and heated at 80° for 18 hrs, then cooled to room
temperature. The solvent was removed in vacua and the residue was
dissolved in ethyl acetate. The organic layer was washed with water and
brine, then dried over MgSO4. The solvent was removed in vacuo and the
residue was purified via column chromatography (SiO2, 5% DCM/hexane) to
afford a yellow oil (463 mg, 47%). This was directly used in the next step.
b) 6-Methyl-biphenyl-3-thiol
To a cooled solution of 6-methyl-biphenyl-3-ylamine (463 mg, 2.53
mmol) from above step a, in hydrochloride solution (0.42 mL cone. HC1 in 0.5
mL H2O, 5 mmol) was added dropwise a solution of NaNO2 (Aldrich, 0.18 g
in 0.3 mL H2O, 2.6 mmol) at -2°C. The resulting diazonium ion solution was
stirred for 20 min and added to a solution of KS2COEt in H2O (0.61 g in 0.8
mL of H2O, 3.81 mmol) with stirring. The resultant mixture was heated to
80°C for a few minutes, then cooled to room temperature and extracted with
diethyl ether. Ether was removed in vacuo and the residue was treated with a
potassium hydroxide solution (0.5 g in 1.5 mL in ethanol, 8.91 mmol, 3.56 eq)
and heated at reflux for 8 h. The reaction mixture was cooled to room
temperature, diluted with H2O, and acidified with HC1 to pH~3. This solution
was extracted with Et20 and the organic layer was washed with H2O and
brine, then dried over MgSO4. The solvent was removed in vacua to afford a
yellow oil (510 mg, 100%). This was directly used in the next step.
c) 4-(6-Methyl-biphenyl-3-ylsulfanyl) -5-nitro-thiophene-2-carboxylic
acid methyl ester
To a solution of triphenylphosphine (0.67 g, 2.55 mmol), 4-bromo-5-
nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 1 g,
3.76 mmol) and 4-(dimethyl)aminopyridme resin (1 eq) in THF was added 6-
methyl-biphenyl-3-thiol from above step b. This mixture was stirred for 3 hrs.
The reaction mixture was filtered and the solvents were removed in vacuo.
The residue was purified via column chromatography (SiO2, 15% ethyl
acetate/hexane) to afford a yellow glass (600 mg, 61%), which was used in the
following step.
d) 4-(6-Methyl-biphenyl-3-sulfonyl)-5-nitro-thiophene-2-carboxylic
acid methyl ester
To a solution of 4-(6-methyl-biphenyl-3-ylsulfanyl)-5-nitro-thiophene-
2-carboxylic acid methyl ester (0.6 g, 1.56 mmol, 1 eq) from above step c, in
DCM was added 3-chloroperoxybenzoic acid (1.04 g, 3.42 mmol, 2.2 eq).
The reaction mixture was heated to reflux for 2 hrs, then cooled to room
temperature. The reaction mixture was quenched with saturated Na2S2O3
solution, then washed with saturated Na2CO3 solution, water, brine, and was
dried over MgSO4. The solvent was removed in vacua to afford a yellow solid
(170 mg, 26%), which was taken on to the next step.
e) 4-(6-Methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid methyl ester
To a solution of 4-(6-methyl-biphenyl-3-sulfonyl)-5-nitro-thiophene-2-
carboxylic acid methyl ester (170 mg, 0.41 mmol) from above step d, in
anhydrous THF at -78°C was added dropwise a 1M solution of NaSMe in
ethanol (0.4 rnL, 0.41 mmol). The reaction mixture was stirred for .2 hrs. at
-78° C, quenched with acetic acid (23 p.1, 0.41 mmol), and wanned to room
temperature. The reaction mixture was diluted with ethyl acetate, washed with
saturated NaHCO3 solution (2x), water, and brine. The organic layer was
dried over MgSO4 and removed in vacuo. The residue was purified via
column chromatography (SiO2, 15% DCM/hexane) to afford a yellow glass
(130mg,76%).
f) 4-(6-Methyl-biphenyl-3-sulfonyl)-5-methylsulfunyl-thiophene-2-
carboxamidine trifluoroacetate
In a dried flask was suspended NH4Cl (Aldrich, 1.08 g, 20 mmol) in
anhydrous toluene (10 mL) under argon. To this suspension was added 2M
solution of AlMe3 in toluene (10 mL, 20 mmol). This mixture was heated to
100°C for a few minutes. This dimethylaluminum amide reagent (5 mL,
5 mmol) was added to 4-(6-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
fhiophene-2-carboxylic acid methyl ester (130 mg, 0.31 mmol) from above
step e, under Ar. This reaction mixture was heated to reflux for 1.5 h then
cooled to room temperature. The reaction mixture was quenched by pouring it
into a slurry of silica gel in CHCl3. The slurry was stirred for 30 minutes, and
then filtered with 10% MeOH/DCM and MeOH. The solvents were removed
in vacuo and the residue was dissolved in 10% MeOH/DCM, and filtered
through a syringe filter. The solvent was removed in vacuo and the residue
was purified via preparatory HPLC to afford a beige solid (5 mg, 4 %). 1H-
NMR (DMSO-d6): d 9.39 (bs, 1H), 8.96 (bs, 2H), 8.41 (s, 1H), 7.88 (dd, 1H),
7.74 (m, 1H), 7.61 (m, 1H), 7.52-7.35 (m, 5H). Calcd. for C19H1SN2O2S3:
402.05; found: 403.2.
Example 116
5-Methylsulfanyl-4- (3-phenoxy-benzenesulfonyl)-thiophene-2-
carboxamidine hydrochloride salt
a) 3-Phenoxy-benzenethiol
To a cooled solution of 3-phenoxyainiline (2 g, 0.01 mol) in
hydrochloride solution (1.69 mL cone. HC1 in 2 mL H2O, 0.02 mol) was
added dropwise a solution of NaNO2 (Aldrich, 0. 8 g in 2 mL H2O, 0.01 mol)
at 0-2°C. The resulting diazonlum ion solution was stirred for 20 min and
then added to a solution of KS2COEt in H2O (2.6 g in 4 mL of H2O, 0.02 mol)
with stirring. This mixture was heated to 80°C for a 20 minutes, then cooled
to room temperature, and extracted with diethyl ether. The ether layer was
washed with water, brine and dried over Na2SO4. Ether was removed in vacuo
and the residue was taken in ethanol and treated with a sodium hydroxide
solution (12 N, 0.04 mol, 3.56 eq) and heated at reflux for 8 h. The reaction
mixture was cooled to room temperature, diluted with H2O, and acidified with
H2SO4 to pH~3. This solution was extracted with Et2O and the organic layer
was washed with H2O and brine, and then dried over MgSO4. The solvent was
removed in vacuo to afford a yellow oil which was purified by silica gel
column chromatography to give a mixture of 3-Phenoxy-benzenethiol and the
corresponding disulfide (1.2 g). This was directly used in the next step.
h) 5-Nitro-4-(3-phenoxy-phenylsulfanyl)-thiophene-2-carboxylic acid
methyl ester
The mixture from above step a (171 mg, 0.48 mmol) was treated with
triphenylphosphine (1.98 g, 7.52 mmol), 4-bromo-5-nitro-thiophene-2-
carboxylic acid methyl ester ((Example 114, step c) 0.5 g, 1.8S mmol) and 4-
(dimethyl)ammopyridine resin (1 eq) in THF (25 mL). This mixture was
stirred for 18 h. The reaction mixture was filtered and the solvents were
removed in vacuo. The residue was purified via silica gel column
chromatography to afford a yellow glass (420 mg), which was used in the
following step.
c) 5-Nitro-4-(3-phenoxy-benzenesuIfonyl)-thiophene-2-carboxylic acid
methyl ester
To a solution of 5-nitro-4-(3-phenoxy-phenylsulfanyl)-thiophene-2-
carboxylic acid methyl ester (42:0 mg, 1.1 mmol) from above step b, in DCM
was added 3-chloroperoxybenzoic acid (1.31 g, 4.34 mmol, 4 eq). The
reaction mixture was heated to reflux for 18 h, then cooled to room
temperature. The reaction mixture was quenched with saturated Na2S2O3
solution, then washed with 1N KaOH solution, brine, and dried over MgSO4.
The solvent was removed in vacuo and the residue was taken on to the next
step.
d) 5-Methylsulfanyl-4-(3-phcmoxy-benzenesulfonyl)-thiophene-2-
carboxylic acid methyl ester
To a solution of 5-Nitro-4-(3-phenoxy-benzenesulfonyl)-thiophene-2-
carboxylic acid methyl ester from above step c, in anhydrous THF at -78° C
was added dropwise a 1M solution of NaSMe in ethanol (1.06 mL, 1.08
mmol). The reaction mixture was stirred for 5 h at -78° C, quenched with
acetic acid (61 µL, 1.08 mmol). and warmed to room temperature. The
reaction mixture was diluted with ethyl acetate, washed with 10% HCl,
saturated NaHCO3 solution (2x), water, and brine. The organic layer was
dried over Na2SO4 and removed in vacuo. The residue was purified via silica
gel column chromatography to afford 250 mg (55 %) of 5-methylsulfanyl-4-
(3-phenoxy-benzenesulfonyl)--thiophene-2-carboxylic acid methyl ester.
e) 5-Methylsulfanyl-4-(3-phenoxy-benzenesulfonyl) -thiophene-2-
carboxamidine hydrochloride salt
5-Methylsulfanyl-4-(3-phenoxy-benzenesulfonyl)-thiophene-2-
carboxylic acid methyl ester from above step d (200 mg, 0.48 mmol) was
treated with dimethylaluminum amide reagent (2 mL) as in Example 12:
step f. Analogous workup and purification by preparative TLC (10% MeOH
in DCM) gave the title compound (120 mg, 62 %) as a white solid: 1H-NMR
(DMSO-d6): d 9.46 (bs, 2H), 9.20 (bs, 2H), 8.43 (s, 1H), 7.71-7.63 (m, 2H),
7.49-7.43 (m, 3H), 7.35 (d, 1H, J = 7.9 Hz), 7.24 (t, 1H, J = 7.2 and 7.4 Hz),
7.1 (d, 2H, J = 7.7 Hz), 2.68 (s, 3H). Calcd. for C18H15N2O3S3: 405.03
(M+H); found: 405.2.
Example 117
4-(Biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxamidine
trifluoroacetate
To a dry 2-dram vial, fitted with a stir bar and a Teflon-lined screw
cap was added {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-
yl]-imino-methyl}-carbarnic acid tert-butyl ester (100 mg, 0.2 mmol, as
prepared in Example 27, step c), phenylboronic acid (0.3 mmol), and
tetrakis(triphenylphosine)palladium(0) (0.025 mmol). Each vial was twice
treated with an argon purge/evacuation cycle and then charged with a mixture
of toluene/EtOH (2:1, 2.4 mL) and 2 M Na2CO3 (0.8 mL) via a syringe. The
vials were placed in an oil bath at 80 °C and stirred overnight. To the cooled
reaction mixtures was added EtOAc (4 mL), the organic layer was filtered (1-g
silica SPE column), and the filtrate was evaporated in vacuo. The resulting
residue was purified using preparative TLC (SiO2) to afford the Boc-protected
amidine product. After treatment of this material with trifluoroacetic acid
(50% in DCM) for 1 hr at rt, the solvents were removed in vacuo and the
residue was purified using C18-HPLC (20% to 100 % CH3CN in H2O (0.1%
TFA) over 15 min) to afford 10 mg (13 %) 4-(biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate: lH-NMR
(DMSO-d6): d 8.32 (s, 1H), 8.25 (m, 2H), 8.02-7.95 (m, 2H), 7.72-7.63 (m,
3H), 7.52-7.47 (m, 2H), 7.44-7.39 (m, 1H), 2.72 (s, 3H). Calcd. for
C13H16N2O2S3: 389.04 (M+H); found: 389.2.
Example 118
4-(5-Bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine
a) 5-Bronio-6-chloro-pyridine-3-sulphenic acid
5-Bromo-6-chloro-pyridine-3-sulfonyl chloride (2.5 g, 8.6 mmol),
sodium sulfite (2.0 g, 16.1 mmol), and sodium bicarbonate (1.4 g, 16,9 mmol)
were dissolved into water (8 mL) and EtOH (3 mL). The reaction mixture was
allowed to stir at RT for 12 hours. TLC analysis showed loss of SM and
formation of a very polar new spot. Reaction mixture was concentrated in
vacua resulting in a white solid and was used without further purification.
ESI-MS (m/z): Calcd. for C5H3BrClNO2S: 255.8 (M+H); found: 256.0. 1H-
NMR (CD3OD): d 8.55 (m, 1H), 8.29 (m, IH).
b) 4-(5-Bromo-6-chloro-pyridine-3-sulfonyl)-5-nitro-thiophene-2-
carboxylic acid methyl ester
4-Bromo-5-nitro-thiophene-2-carboxylic acid methyl ester (5.0 g, 19.9
mmol) was dissolved into DMF (20 mL) and cooled to 0°C. To this was
added a solution of 5-bromo--6-chloro-pyridine-3-sulphenic acid (Example
118, step a) (1.8 g, 6.6 mmol) in DMF (20 mL) dropwise for 2 hours. The
reaction was then wanned to RT and allowed to continue to stir for an
additional 2 hours. The reaction was concentrated in vacuo and purified by
SiOi flash column chrornatography (Biotage - 40 M, 25 % EtOAc in
hexanes). The product was isolated as a white solid (2.5 g, 48%). ESI-MS
(m/z): Calcd. for C11H6BrCIN2O6S2: 440.8 (M+H); found: 441.0.
c) 4-(5-Bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester
The procedure as in Example 27, a was followed using 4-(5-bromo-6-
chloro-pyridine-3-sulfonyl)-5-mtro-thiophene-2-carboxylic acid methyl ester
(3.5 g, 8.10 mmol, Example 118, step b) and sodium thiomethoxide (560 mg,
8.10 mmol as 1M solution in EtOH). The reaction was allowed to stir for 2.5
hours and was quenched with acetic acid. The resulting mixture was dissolved
into EtOAc, and aqueous work up with brine and saturated NaHCO3 resulted
in isolation of a mixture. This mixture was purified by SiO2 flash column
chromatography (Biotage - 40 M, 100 % hexanes to 25 % EtOAc in hexanes).
The product was isolated as a yellow solid (750 mg, 21 %). ESI-MS (m/z):
Calcd. for C12Hl0BrClNO4S3: 441.8 (M+H); found: 442.1. 1H-NMR (CD3OD
+ CDCl3): 5 8.93 (m, 1H), 8.50 (m, 1H), 8.06 (s, 1H), 3.91 (m, 3H), 2.67 (m,
3H).
d) 4-(5-Bromo-6-chloro-pyridine-3-sulfonyl)-5-ntethylsulfanyl-
thiophene-2-carboxamidine
The procedure as in Example 20, f was followed using 4-(5-bromo-6-
chloro-pyridine-3-sulfonyl)-5-raethylsulfanyl-thiophene-2-carboxylic acid
methyl ester (14 mg, 0.03 mmol, Example 118, step c) dimethylaluminuim
amide (1M, 5 mL). The reaction was stirred for 3 hours at 90 °C and TLC
analysis indicated that the reaction was complete. The reaction was quenched
with SiCh and filtered. The resulting filtrate was concentrated in vacuo
followed by purification by C18-HPLC (10-70% CH3CN over 30 minutes).
The title compound was isolated as a white solid (6.4 mg, 46%). ESI-MS
(m/z): Calcd. for C11H9BrClN3O2S3: 425.9 (M+H); found: 426.1. 1H-NMR
(CD3OD): 6 8.96 (s, 1H), 8.65 (s, 1H), 8.33 (s, 1H), 2.76 (s, 3H).
Example 119
4-(6-Amino-5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine
a) 4-(6-Amino-5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid amide
An ammonia bomb was; used to prepare the title compound. Ammonia
gas (5mL) was condensed into the Teflon core of a metal bomb with a stir
bar and 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester (321 mg, 0.73 mmol, Example 118,
step c). The Teflon® core was kept at -78°C during the addition of reagents.
Following the addition of reagents, the bomb was assembled and then sealed
tight by hand and then tightened by wrench action. The sealed bomb was
checked for leaks by use of pH paper. The bomb was then added to an oil bath
and heated to 80°C overnight with a shield in place. The following day the
bomb was allowed to cool to rt and then was cooled further to —78°C in an dry
ice/acetone bath. The cooled vessel was then opened and remaining ammonia
was allowed to evaporate. The: resulting red solid obtained was used without
further purification (306 mg, 95%). ESI-MS (m/z): Calcd. for
C11H10BrN3O3S3: 407.9 (M+H); found: 408.1. 1H-NMR (CD3OD): d 8.56 (m,
1H), 8.18 (m, 1H), 8.07 (s, 1H), 2.72 (s, 3H).
b) 4-(6-Amino-5-bronto-pyridine-3-sulfonyl)-5-methylsulfanyl-
th ioph en e-2-carboxam idin e
The procedure as in Example 20, /was followed using 4-(6-amino-5-
bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid
amide (14 mg, 0.03 mmol. Example 119, step a) dimethylaluminuim amide
(1M, 5 mL). The reaction was stirred for 3 hours at 90 °C and TLC analysis
indicated that the reaction was complete. The reaction was quenched with
SiO2 and filtered. The resulting filtrate was concentrated in vacuo followed by
purification by C18-HPLC (10-70% CH3CN over 30 minutes). The title
compound was isolated as a white solid (4.9 mg, 39%). ESI-MS (m/z):
Calcd. for C11H11BrN4O2S3: 406.9 (M+H); found: 407.1. 1H-NMR (CD3OD):
d 8.54 (m, 1H), 8.26 (m, 1H), 8.15 (m, 1H), 2.74 (s, 3H).
Example 120
4-(5-Bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine
a) 4-(5-Bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid methyl ester
A flask with 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxylic acid methyl ester (25 mg, 0.06 mrnol,
Example 118, step c) and zinc dust (4 mg, 0.06 mmol) was dissolved with mL acetic acid and heated to 50°C for 4 hours. TLC analysis indicated the
formation of a new spot. The reaction mixture was concentrated in vacuo and
purified by elution through Celite® using 10% MeOH in DCM. The crude
product was carried on without further purification. ESI-MS (m/z): Calcd. for
C12H10BrNO4S3: 407.9 (M+H); found: 408.1.
b) 4-(5-Bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine
The procedure as in Example 20, /was followed using 4-(5-bromo-
pyridine-3-sulfonyl)-5-melhylsulfanyl-thiophene-2-carboxylic acid methyl
ester (5 mg, 0.01 mmol, Example 120, step a) dimethylaluminuim amide (1M,
5 mL). The reaction was stirred for 3 hours at 90 °C and TLC analysis
indicated that the reaction was complete. The reaction was quenched with
SiO2 and filtered. The resulting filtrate was concentrated in vacuo followed by
purification by C18-HPLC (10-70% CH3CN over 30 minutes). The title
compound was isolated as a white solid (4.6 mg, 92%). ESI-MS (m/z):
Calcd. for C11H10BrN3O2S3: 391.9 (M+H); found: 392.1. 1H-NMR (CD3OD):
d 9.14 (m, 1H), 8.97 (m, 1H), 8.55 (m, 1H), 8.34 (s, 1H), 2.76 (m, 3H).
*************Example 121
4-(6-Amino-5-o-tolyl-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
earboxamidine
a) 4-(6-Amino-5-o-tolyl-pyridine-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid amide
The procedure as in Example 1: step c was followed using 4-(6-amino-
5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid
amide (25 mg, 0.06 mmol. Example 120: step a), o-tolyl phenyl boronic acid
(33 mg, 0.25 mmol), Pd(PPh3)4 (14 mg, 0.01 mmol), aqueous Na2CO3 (2M,
0.4 mL), ethanol (0.4 mL) and toluene (0.8 mL). Purification by preparative
SiO2 chromatography (25% EtOAc in hexanes) of the residue yielded the title
compound (7.4 mg, 32%) as a brown solid. ES1-MS (m/z): Calcd. for
C18H17N3O3S3: 420.0 (M+H); found: 420.2.
b) 4-(6-Amino-5-o-tolyl-pyridine-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine
The procedure as in Example 20, f was followed using 4-(6-amino-5-o-
tolyl-pyridine-3-sulfonyl)-5--me1:hylsulfanyl-thiophene-2-carboxylic acid
amide (7.4 mg, 0.02 mmol, Example 121, step a) dimethylaluminuim amide
(1M, 5 mL). The reaction was stirred for 3 hours at 90 °C and TLC analysis
indicated that the reaction was complete. The reaction was quenched with
S1O2 and filtered. The resulting filtrate was concentrated in vacuo followed by
purification by C18-HPLC (10-70% CH3CN over 30 minutes). The title
compound was isolated as a white solid (2.6 mg, 35%). ES1-MS (m/z):
Calcd, for C18H18N4O2S3: 419.0 (M+H); found: 419.1. 1H-NMR (CD3OD):
d S.6 (m, 1H), 8.28 (s, 1H), 7.74 (m, 1H), 7.36 (m, 3H), 7.16 (m, 1H), 2.74 (m,
3H),2.13(m,3H).
Example 122
4-(6'-Methyl-2'-morpholin-4-yl-biphenyl-3-sulfonyl)-5-methyisulfanyl-
thiophene-2-carboxaniidine trifluoroacetate
a) {Imino-[4-(6'-methyl-2'-morpholin-4-yl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester
{[4-(2'-Amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (20 mg, 0.04
mmol, Example 25 : step c). K2CO3 (8 mg, 0.06 mmol), 2,6-lutidine (8 mg,
0.08 mmol) and 2-bromoethyl ether (18 mg, 0.08 mmol) were dissolved in
acetonitrile (1 mL) and heated to 80 °C with stirring under argon. After 6
hours, Et3N (8 µL, 0.06 mmol) was added and the reaction continued stirring
for 20 hours. Purification of the residue by preparative SiO2 TLC (50%
EtOAc in hexanes) yielded the title compound (7.5 mg, 32%) as a yellow
solid. ESI-MS (m/z): Calcd. for C28H33N3O5S3: 588.2 (M+l); found: 588.0.
b) 4-(6'-Methyl-2f-morp}wlin-4-yl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
{Imino-[4-(6'-methyl-2'-morpholm-4-yl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester (7.5 mg,
0.013 mmol, Example 122 : step a) was deprotected and purified as in
Example 1: step d, yielding the title compound as a clear glass (2.2 mg, 35%).
1H-NMR (CD3OD): d S.34(s, 1H), 8.02-8.05 (m, 1H), 7.94-7.92 (t, 1H, J= 1.6
Hz), 7.66-7.70 (t, 1H, J= 7.2 Hz), 7.61-7.64 (m, 1H, J= 7.9 Hz), 7.23-7.28 (t,
1H,J= 7.67 Hz), 6.98-7.05 (m, 2H), 3.13-3.27 (m, 4H), 2.71 (s, 3H), 2.63-
2.67 (m, 4H), 2.05 (s, 3H). ESI-MS (m/z): Calcd. for C23H25N3O3S3: 488.1
(M+l); found: 488.3.
Example 123
4-(6-Bromo-5-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate
a) 6-Bromo-5-chloro-pyridine-3-sodium sulphonate
Sodium sulfite (794 mg. 6.3 mmol) and sodium bicarbonate (554 mg,
6.6 mmol) were dissolved into water (4 mL) with heat (70 °C). 6-Bromo-5-
chloro-pyridine-3-sulfonyl chloride (1000 mg, 3.4 mmol) was added slowly as
a solid over one hour. The reaction was heated at 70 °C for two additional
hours followed by standing at RT overnight. The solvents were removed in
vacuo resulting in the title compound that was used without further
purification or characterization.
b) 4-(6-Bromo-5-chloro-pyridine-3-sulfonyl)-5-nitro-thiophene-2-
carboxylic acid methyl ester
4-Bromo-5-nitro-thiophene-2-carboxylic acid methyl ester (2.6 g, 10.2
mmol, Example 27: step c) was dissolved into DMF (15 mL) and 6-Bromo--5-
chloro-pyridine-3-sodium sulphonate (946 mg, 3.4 mmol, Example 123: step
a) was partially dissolved into DMF (15 mL). The solution of 4-Bromo-5-
nitro-thiophene-2-carboxylic acid methyl ester was cooled to -20 °C and to
this was added the solution of 6-Bromo-5-chloro-pyridine-3-sodium
sulphonate, dropwise over one hour. The reaction mixture was maintained at
-20 °C with stirring for 3 hours. The solvents were removed in vacuo
followed by purification by flash column chromatography (Biotage Flash
System - 40 M SiO2 column) (30% EtOAc in hexanes) that yielded the title
compound (430 mg, 29%) as a white solid. ESI-MS (m/z): Calcd. for
C11H6BrClN2O2S2: 440.9 (M+l); found: 441.1
c) 4-(6-Bromo-5-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester
The procedure described in Example 27: step a was followed using 4-
(6-Bromo-5-chloro-pyridine-3-sulfonyl)-5-nitro-thiophene-2-carboxylic acid
methyl ester (63 mg, 0 14 mmol. Example 123: step b) and sodium
thiomethoxide (0.5 M in EtOH, 0.18 mmol, 360 µL). The reaction was
quenched with acetic acid (10 uL, 0.18 mol) followed by concentration in
vacuo. The residue was then dissolved into EtOAc and washed with saturated
NaHCO3 and brine solutions. The organic layers were dried (Na2SO4) and
removal of the solvents in vacuo was followed by purification by preparative
SiO2 TLC (30% EtOAc in hexanes) that yielded the title compound (14.2 mg,
23%) as a yellow solid. ESI-MS (m/z): Calcd. for C12H9BrClNO4S3: 441.9
(M+l) found: 442.0.
d) 4-(6-Bromo-5-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoro acetate
4-(6-Bromo-5-chloro-pyridine-3-sulfonyl)-5-methylsulfany]-
thiophene-2-carboxylic acid methyl ester {Example 123: step c) was then
converted to the amidine and purified as described in Example 20: step f to
isolate the title compound (6.4 mg, 50%). 1H-NMR (CD3OD): d: 8.97 (s, 1H),
8.66 (s, 1H), 8.33 (s, 1H), 2.76 (s, 3H). ESI-MS (m/z): Calcd. for
C11H9BrClN3O2S3: 425.9 (M+l) found: 426.1.
Example 124
4-(6-Amino-5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate
a) 4-(6-Amino-5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester
Ammonia gas was condensed with a cold finger into the Teflon core of
a stainless steel bomb. Approximately 5 mL of liquid ammonia was collected
and maintained at -78 °C. To this was added 4-(6-Bromo-5-chloro-pyridine-
3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (15
mg, 0.034 mmol, Example 123: step c). The reaction vessel was capped,
sealed and heated to 80°C overnight protected by shield. The reaction bomb
was cooled to RT then to —78°C before opening. The remaining ammonia
mixture was allowed to evaporate to dryness in hood resulting in title
compound and 4-(6-Amino-5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid amide (14 mg, 98%). ESI-MS (m/z): Calcd. for
C12H11BrN2O4S3: 422.9 (M+l) found: 423.0.
b) 4-(6-Amino-5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
The mixture of 4-(6-Amino-5-bromo-pyridine-3-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxylic acid methyl ester and 4-(6-Amino-5-
bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid
amide (Example 124: step a) was then converted to the amidine and purified
as described in Example 20: step f to isolate the title compound (4.9 mg, 36%).
H-NMR (CD3OD): d: 8.55 (s, 1H), 8.27 (s, 1H), 8.14 (s, 1H), 2.74 (s, 3H).
ESI-MS (m/z): Calcd. for C11H11BrClN4O2S3: 406.9 (M+l) found: 407.1.
Example 125
4-(6-Amino-5-o-tolyl-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate
a) 4-(6-Amino-5-o-toly!-pyridine~3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester
The procedure as in Example 1: step c was followed using 4-(6-
Amino-5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid methyl ester (2.5 mg, 0.06 mmol, Example 124: step a), 2-
methyl phenyl boronic acid (33 mg, 0.25 mmol), Pd(PPh3)4 (14 mg, 0.01
mmol), aqueous Na2CO3 (2M, 400 µL, 0.5 mmol), ethanol (400 uL) and
toluene (800 µL). The reaction was heated to 80°C for 12 hours. The residue
was dissolved into EtOAc and washed with brine. The organic layers were
dried (MgSO4) and removal of the solvents in vacuo was followed by
preparative SiO2 TLC purification (20% MeOH in DCM) that yielded the title
compound (7.4 mg, 29%) as a white solid. ESI-MS (m/z): Calcd. for
C19H18N2O4S3: 420.0 (M+l) found: 420.2.
b) 4-(6-Amino-5-o-tolyl-pyridine-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-Carboxamidine trifluoroacetate
4-(6-Amino-5-o-tolyl-pyridine-3-sulfonyl)-5-memylsulfanyl-
thiophene-2-carbox.ylic acid methyl ester {Example J25: step a) was then
converted to the amidine and purified as described in Example 20: step f to
isolate the title compound (2.6 mg, 35%). 1H-NMR (CD3OD): d: 8.60 (s, 1H),
8.28 (s, 1H), S.14 (s, 1H), 7.74-7.73(d, 1H, J = 2.74 Hz) 7.36 (s. IK), 7.32-
7.2S (m, 1H), 7.16-7.14 (d, 1H, J= 8.14 Hz), 2.74 (s, 3H), 2.13 (s, 3H). ESI-
MS (m/z): Calcd. for Ci8Hj8N4O2S3: 419.0 (M+l) found: 419.1.
Example 126
4-(5-Bromo-6-phenoxy-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate
a) 4-(5-Bronto-6-phenoxy-pyridine-3-sulfonyl)-5-methylmlfanyl-
thiophene-2-carboxylic acid methyl ester
4-(6-Brorno-5-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylie acid methyl ester (110 mg, 0.24 mmol, Example 123,
step c), cesium carbonate (156 mg, 0.48 mmol), phenol (180 rag. 1.92 mmol),
copper (II) trifluoromethanesulfonate benzene complex (4 mg, 0.006 mmol)
and EtOAc (1.0 mg, 0.02 mmol) were all dissolved into toluene (10 mL) and
heated to 110 °C for 12 hours. The reaction mixture was dissolved into EtOAc
and washed with brine. The organic layers were dried (MgSO4) and removal
of the solvents in vacuo was followed by purification by flash column SiO2
(30% EtOAc in hexanes) that yielded the title compound. ESI-MS (m/z):
Calcd. for C18H14BrNO5S3: 599.9 (M+l) found: 500.1.
b) 4-(5-Bromo-6-phenoxy~pyridine-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoro acetate
4-(5-Bromo-6-phenoxy-pyridine-3-sulfonyl)-5-methylsulfany]-
thiophene-2-carboxylic acid methyl ester (Example 126: step a) was then
converted to the amidine and purified as described in Example 20: step f to
isolate the title compound (1.0 mg). 1H-NMR (CD3OD): d: 8.66-8.65 (m, 1H),
8.59-8.58 (m, 1H), 8.33 (s, 1H), 7.48-7.44(m, 2H), 7.33-7.29 (r.n, 1H), 7.18-
7.15 (m, 2H), 2.76 (s, 3H). ESI-MS (m/z): Calcd. for Ci7HKBrNjO3S3: 483.9
(M+l) found: 484.1.
Example 127
4-(5-Bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate
a) Di-5-bromo-3-pyridyl dteulfide
2,4-dibromopyridine (2000 mg, 8.4 nimol) was dissolved into ether (1.0
mL) at RT. The reaction mixture was cooled to -78°C and n-butyllithium
(2.5M, 3.4 mL, 8.4 mmol) was added dropwise. The reaction was stirred at -
78°C for an hour followed by quenching with sulfur (269 mg, 8.4 mmol). The
reaction was allowed to warn to RT over 2 hours. Removal of the solvents in
vacuo was followed by purification by flash column SiO2 (30% EtOAc in
hexanes). The product was used without further characterization or
purification.
b) 4-(5-Bromo-pyridin-3-ylsulfanyl)-5-nitro-thiophene-2-carhoxylic
acid methyl ester
Di-5-bromo-3-pyridyl disulfide (600 mg, 1.6 mmol, Example 127:step
a), Et3N (223 uL, 1.6 mmol), triphenylphosphine (419 mg, 1.6 mmol) and 4-
Bromo-5-nitro-thiophene-2-carboxylic acid methyl ester (427 mg, 1.6 mmol,
Example 114: step c) were dissolved into THF (5 mL) and stirred at RT for 3
days. Removal of the solvents in vacuo was followed by flash column SiO2
purification (25% EtOAc in hexanes) to isolate the title compound (200 mg,
33%). ESI-MS (m/z): Calcd. for C11H7BrN2O4374.9(M+1) found: 377.1.
c) 4-(5-Bromo-pyridine-3-sulfonyl)-5-nitro-thiophene-2-carboxylic acid
methyl ester
4-(5-Bromo-pyridin-3--ylsulfanyl)-5-nitro-thiophene-2-carboxylic acid
methyl ester (126 mg, 0.33 mmol, Example 127:step b) and m-CPBA (438
mg, 1.67 mmol, 77%) were dissolved into DCM (10 mL) and heated to 38°C
with stirring for 2 hours. The reaction was quenched with Na2S2O3, dissolved
into DCM and washed with NaHCO3. The organic layers were dried (MgSO4)
and the solvents were removed in vacuo followed by flash column SiO2
purificeition (25% EtOAc in hexanes) to isolate the title compound (151 mg,
99%) as a yellow solid. ESI-MS (m/z): Calcd. for C11H7BrN2O6S2: 406.9
(M+l) found: 407.1
d) 4-(5-Brom o-pyridin e-3-sulfonyl)-5-m ethylsulfanyl-th ioph en e-2-
carboxylic acid methyl ester
The procedure described in Example 27: step a was followed using 4-
(5-Bromo-pyridine-3-sulfonyl)-5-mtro-thiophene-2-carboxylic acid methyl
ester (151 mg, 0.37 mmol, Example 127: step c) and sodium thiomethoxide
(1.0 M in EtOH, 26.3 mg, 0.37 mmol). The reaction was quenched with acetic
acid (21 uL, 0.37 mol) and the solvents were removed in vacuo. The residue
was then dissolved into EtOAc and washed with saturated NaHCO3 and brine
solutions. The organic layer was dried (Na2SO4) and removal of the solvents
in vacuo was followed by purification by flash column chromatography SiO2
(30% EtOAc in hexanes) to yield the title compound. ESI-MS (m/z): Calcd.
for C12H10BrNO4S3: 407.9 (M+l) found: 408.1.
e) 4-(5-Bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate
4-(5-Bromo-p;/ridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid methyl ester {Example 127: step d) was then converted to the
amidine and purified as described in Example 20: step f to isolate the title
compound (2.7 mg). 1H-NMR (CD3OD): d: 9.15 (m, 1H), 9.00 (m, 1H), 8.58
(m, 1H), S.35(s, 1H), 2.77 (s, 3H). ESI-MS (m/z): Calcd. for
C11H10BrN3O2S3: 391.9 (M+l) found: 392.2.
Example 128
5-Methylsulfanyl-4-(5-o-tolyl-pyridine-3-sulfonyl)-thiophene-2-
Carboxamidine trifluoroacetate
a) {[4-(5-Bromo-pyridin e-3-sulfonyl)-5-m ethylsulfanyl-thiophen -2-yl]-
imino-methylj-carbamic add tert-butyl ester
4-(5-Bromo-pyridine-3-!3ulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine (300 mg, 0.77 mmol, Example 127:step e) was dissolved mto
DMF (10 mL). To this was added DIEA (267 ul mg, 1.53 mmol) and
(Boc)2O (201.6, 0.92 mmol). The reaction was stirred at RT for 12 hours.
The solvents were removed in vacuo and the residue was dissolved into DCM
and washed with 20% citric acid and brine. The organic layers were dried
(MgSO/t) and the solvents were removed in vacuo followed by purification by
flash column chromatography SiO2 (50% EtOAc in hexanes) that resulted in
the title compound. ESI-MS (m/z): Calcd. for C16H18BrN3O4S3: 491.9 (M+l)
found: 491.1.
b) {Imino-[5-methylsulfanyl-4-(5-o-tolyl-pyridine-3-sulfonyl)-thiophen-
2-yl]-methyl}-carbamic acid tert-bntyl ester
The procedure described in Example 1: step c was followed using {[4-
(5-Bromo-pyridine-3-sulfonyl)-5-methylsulfany]-thiophen-2-yl]-imino-
methyl}-carbamic acid tent-butyl ester (50mg, 0.08 mmol), 2-methyl phenyl
boronic acid (23 mg, 0.17 minol), Pd(PPh3)4 (19 mg, 0.02 mmol), aqueous
Na2CO3 (2M, 800 µL, 0.4 mmol), ethanol (800 µL) and toluene (1600 µL).
The reaction was heated to 80°C for 12 hours. The residue was dissolved into
EtOAc and washed with brine. The organic layers were dried (MgSO4) and
removal of the solvents in vacua resulted in a crude mixture of the product that
was used without further purification or characterization.
c) 5-Methylsulfanyl-4-(5-o-tolyl-pyridine-3-sulfonyl)-thiophene-2-
carboxamidine trifluoroacetate
{Imino-[5-methylsulfanyl-4-(5-o-tolyl-pyridine-3-sulfonyl)-thiophen-
2-yl]-methyl}-carbamic acid tert-butyl ester (127 mg. Example! 28: step b)
was deprotected and purified as in Example 1: step d, yielding the title
compound as an off-white solid (8 mg, 8 %). 1H-NjVIR (CD3OD): d 9.15 (s,
1H), 8.84 (s, 1H), 8.37 (rn, 2H), 8.36 (m, 4H), 2.75 (s, 3H), 2.56 (s, 3H). ESI-
MS (m/z): Calcd. for C18H17BrN3O2S3: 404.1 (M+l); found: 404.1
EXAMPLE 129
4-(2'-Formylamino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsuifanyl-
thiopherie-2-carboxamidine trifluoroacetate
{[4-(2'-Amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-immo-methyl}-carbamicacid tert-butyl ester (5S mg, 0.11
mmol, Example 25 : step c) was dissolved into formic acid (3mL, 96%) and
heated to 100 ° C for 24 hours. The solvents were removed in vacuo resulting
in the desired product with removal of the tert-butyl protection group. The
resulting compound was purified as in Example 1: step d, yielding the title
compound as an off-white solid (11 mg, 22%). ESI-MS (m/z): Calcd. for
C20H19N3O3S3: 446.1 (M+l); found: 446.1.
Example 130
[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-
biphenyl-2-ylamino]-acetic acid
{[4-(2'-Ammo-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-immo-methyl}-carbamic acid tert-butyl ester (75 mg, 0.15
mmol, Example 25 : step c), tert-butyl bromoaeetate (43 µL, 0.29 mmol),
-potassium carbonate (29 mg, 0.21 mmol) and 2,6-lutidine (33 µL, 0.29 mmol)
were dissolved into toluene (2mL). The reaction was stirred and heated to 80
°C for 12 hours. Et3N (41 pL, 0.3 mmol) was added to reaction and heated to
80 °C for another 12 hours. The reaction mixture was dissolved into EtOAc
and washed with brine. The organic layers were dried (MgSO4), the solvents
were removed in vacua followed purified by preparative SiO2 TLC
purification (20% MeOH in DCM) resulting in {3'-[5-(tert-
Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-
6-methyl-biphenyl-2-ylamino}-acetic acid tert-butyl ester. ESI-MS (m/z):
Calcd. for C30H37N3O6S3: 632.2 (M+l) found: 631.9. {3'-[5-(tert-
Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-
6-methyl-biphenyl-2-ylamino} -acetic acid tert-butyl ester was deprotected and
purified as Example 1: step d, yielding the title compound as brown solid (1.7
mg). 1H-NMR (CD3OD): d 8.35 (s, 1H), S.08-8.06 (d, 1H, J= 8.83 Hz), 7.77
(t, 1H, .7=7.44 Hz, .7=7.67 Hz), 7.63-7.61 (d, 1H,J= 7.67 Hz), 7.16 (t, 1H,J
= 7.91 Hz, J= 7.91 Hz), 7.05-6.68 (d, 2H, 7= 7.67 Hz), 6.52-6.50 (d, 1H, J =
8.14 Hz), 3.81 (s, 1H), 2.72 (s, 3H), 2.17 (s, 3H). ESI-MS (m/z): Calcd. for
C21H21N3O4S3: 476.1 (M+l); found: 476.1.
Example 131
{2-[5-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfony])-pyridin-3-
yl]-3-methyl-benzyIoxy} -acetic acid
a) 2-lodo-i-methyl-benzoyl chloride
2-iodo-3-methyl benzoic acid (1310 mg, 5 mmol) and thionyi chloride
(730 uL, 10 mmol) were dissolved into THF (10 mL) and stirred at RT for 4
days. The solvents were removed in vacua and the resulting residue was
dissolved into EtOAc, washed with brine. The combined organic layers were
dried (MgSO4) and the solvents were removed in vacuo resulting in an oil that
was used without further purification or characterization.
b) (2-Iodo-3-methyl-phenyl)-methanol
2-Iodo-3-methyl-benzoyl chloride (1360 mg, 4.86 mmol. Example
131: a) was dissolved into THF (2 mL) and cooled to -78 °C. To this was
slowly added a slurry of lithium aluminum hydride (184.3 mg, 4.86 mmol)
that was carefully weighed into a dry flask and cooled to 78 °C, before THF (2
mL) was added. The reaction was warmed to RT slowly and stirred for an
hour. The reaction was quenched by cooling back to —78 °C and adding 200
µL water. 200 µL 15% NaOH, 600 µL water and then poured over celite and
filtered with THF. The title compound was obtained as a yellow solid. 1H-
NMR (CDCl3): d 7.21-7.19 (m, 2H), 7.14-7.11 (m, 1H,), 4.61 (s, 2H), 2.43 (s,
3H).
c) (2-Iodo-3-methyl-benzyloxy)-acetic acid tert-butyl ester
(2-Iodo-3-methyl-phenyl)-methanol (1608 mg, 6.8 mmol, Example
131: step b) was dissolved into DMF (10 mL). The solution was cooled to
0°C. To this was added sodium hydride in one portion and the reaction
continued to stir at 0 °C for 30 minutes. To the cooled solution was added t-
butylbromoacetate (1.3 mL, 8.9 mmol) and then the reaction was wanned to
RT and then heated to 50 °C for 4 hours. The solvents were removed in vacuo
and the resulting residue was dissolved into EtOAc and washed with brine.
The combined organic layers were dried (MgSO4) and the solvent was
removed in vacuo resulting in the title compound (1.29 g, 53%) that was used
with out further purification. 1H-NMR (CDCl3): d 7.28-7.13 (m, 3H), 4.63 (s,
2H), 4.07 (s, 2H), 2.44 (s? 3H), 1.47 (s, 9H).
d) [3-Methyl-2-(4,4,S,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-
benzyloxy]-acetic acid tert-butyl ester
(2-Iodo-3-methyl-benzyloxy)-acetic acid tert-butyl ester (360 mg, 1.46
mmol, Example 131: step c), trans-
Dichlorobis(triphenylphosphine)palladium(II) (102 mg, 0.15 mmol) and Et3N
(1.2 mL, 8.76 mmol) were dissolved into dioxane (10 mL). To this was
slowly added 4.4,4,5,5,5-tetrarnethyldioxaborolane (423 µL, 2.91 mmol) and
reaction was heated to 80 °C for 2 hours. Catalytic amounts of 4,4,4,5,5,5-
tetramethyldioxaborolane and dichlorobis(triphenylphosphine)palladium(II)
were added and the reaction continued heating at 50 °C overnight. The
solvents were removed in vacuo and the residue was dissolved into EtOAc
followed by washing with brine. The combined organic layers were dried
(MgSO4) and the solvents were removed in vacuo. The crude reaction mixture
was purified by flash column chromatography (30% EtOAc/hexanes) yielding
the title compound (335 mg, 63 %) as a brown oil. 1H-NMR (CDCl3): d 7.23-
7.06 (m, 3H), 4.72 (s, 2H), 4.09 (s, 2H), 2.42 (s, 3H), 1.45 (m, 12H), 1.38 (s,
9H).
e) (2-{5-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-
thiophene-3-sulfonyl]-pyridin-3-yl}-3-methyl-benzyloxy)-acetic acid tert-
butyl ester
The procedure as in Example 1: step c was followed using [3-Methyl-
2-(4,4,5,5-tetramethyl-[l,3.2]dioxaborolan-2-yl)-benzyloxy]-acetic acid tert-
butyl ester (252.2 mg, 0.62 mmol, Example]31: step d), {[4-(5-Bromo-
pyridine-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-
carbamic acid tert-butyl ester (75.9 mg, 0.15 mmol. Example 128: step a),
Pd(PPh3)4 (35 mg, 0.03 mmol), aqueous Na2CO3 (2M, 1 mL), ethanol (1 mL)
and toluene (2 mL). The reaction was heated to 80°C for 24 hours. The
reaction mixture was dissolved into EtOAc and washed with brine. The
organic layers were dried (MgSO4) and removal of the solvents in vacuo was
followed by purification by flash column chromatography (SiO2) (30% EtOAc
in hexanes) of the residue yielded the title compound (460 mg) as a brown oil.
ESI-MS (ni/z): Calcd. for C30H37N3O7S3: 648.2 (M+l) found: 647.9.
j) {2-[5-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-
pyridin-3-yl]-3-methyl-benz.yloxy}-acetic acid
(2-{5-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-
thiophene-3-sulfonyl]-pyridin-3-yI} -3-methyl-benzyloxy)-acetic acid tert-
butyl ester (127 mg) {Example 11: step e) was deprotected and purified as in
Example 1: step d, yielding the title compound as an off-white solid. 1H-
NMR (CD3OD): S 9.05 (s, 1H), 8.65 (s, 1H), 8.26 (m, 1H), 8.19 (s, 1H), 7.28-
7.24 (m, 3H), 4.12 (s, 2H), 3.67 (s, 2H ), 2.63 (s, 3H), 1.92 (s, 3H). ESI-MS
(m/z): Calcd. for C21H21N3O5S3: 492.1 (M+l); found: 492.1.
Example 132
N-[3(-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-
biphenyl-2 -yl] -malonamic acid
a) N-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-malonamic
acid methyl ester
{[4-(2'-Amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-rnethyl}-carbamic acid tert-butyl ester (22 mg, 0.04
mmol, Example 25: step c ) was dissolved into THF (lmL) and to this was
added chlorocarbonyl-acetlc acid methyl ester (9 µL, 0.085 mmol). The
reaction was heated to 50°C for 5 hours and then allowed to stir at RT for 48
hours. The reaction mixture was dissolved into EtOAc and washed with brine.
The organic layers were dried (MgSO4) and removal of the solvents in vacuo
was followed by purification by preparative TLC (SiO2) (30% EtOAc in
hexanes) that yielded the title compound. ESI-MS (m/z): Calcd. for
C28H31N3O7S3: 618.1 (M+l) found: 617.9.
b) N-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3sulfonyl]-6-methyl-biphenyl-2-yl}-malonamic
acid
N-{3'-[5-(tert-Butoxycarbonylammo-immo-methyl)-2-methylsulfanyl-
thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-malonamic acid methyl ester
(20 mg, 0.03 mmol, Example 132: step a) and NaOH (1M, 90 µL, 0.09 mmol)
were dissolved into MeOH (1.5 mL). The reaction was stirred for 2 hours.
LiOH (1.0 mg, 0.05 mmol) was added and the reaction was stirred at RT
overnight. The solvents were removed in vacuo and used with out further
purification in the next step. ESI-MS (m/z): Calcd. for C27H29N3O7S3: 604.1
(M+l); found: 504.0 (loss of boc).
c) N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-
methyl-biphenyl-2-yl]-malonamic acid
N-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-
thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-malonamic acid (Example
132: step b) was deprotected and purified as in Example 1: step d, yielding the
title compound as a glassy solid. 1H-NMR (CD3OD): d 8.28 (s, 1H), 8.07-
8.05 (m, 1H), 7.85 (s, 1H), 7.72-7.68 (t, 1H, J = 7.67 Hz, J= 7.90 Hz), 7.57-
7.55 (m, 1H), 7.43-7.26 (m, 3H), 2.74 (s, 3H ), 2.07 (s, 3H), 2.05 (s, 2H). ESI-
MS (m/z): Calcd. for C22H21N3O5S3: 504.1 (M+l); found: 503.9.
Example 133
N-[3'-(5-Carbamiinicloy]-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-
biphenyl-2-yl]-succinamic acid trifluoroacetate
a) N-{3'-[5-(tert-Butoxycarbonylamino-immo-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-succinamic
acid ethyl ester
{[4-(2'-Amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid teit-butyl ester (38.5 mg, 0.07
mmol, Example 25: step c) and 3-chlorocarboriyl-propionic acid ethyl ester
(13 µL 0.09 mnioi) were dissolved into THF (1 mL) and heated to 50 °C for
one hour. The reaction was dissolved into EtOAc and washed with brine. The
combined organic layers were dried, (MgSO4) and the solvents were removed
in vacuo. Purification by preparative TLC (30% EtOAc/hexanes) yielded the
title compound. ESI-MS (m/z): Calcd. for C30H35N3O7S3: 646.2 (M+l);
found: 645.8.
b) N{3'-[5-(tert-Butoxycatbonylamino-imino-met/iyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphe}iyl-2-yl}-succinamic
acid
N-{3'-[5-(tert-Butoxycarbonylammo-immo-methyl)-2-methyl5uifanyl-
thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-succinamic acid ethyl ester
{Example 133: step a) and LiOH were dissolved into MeOH and stirred at RT
for 2 hours. The solvents were removed in vacua yielding the title compound
that was used with out further purification or characterization.
c) N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-
methyl-biphenyl-2-yl]-maionamic acid triflnoroacetate
N-{3'-[5-(tert-Butoxycarbonylamino-imino-met.hyl)-2-methylsulfaiwl-
thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-succinamic acid {Example
133: step c) was deprotected and purified as in Example 1: step d, yielding the
title compound as a white solid. 1H-NMR (CD3OD): d 8.31 (s, 1H), S.07-8.05
(m, 1H), 7.85 (s, 1H), 7.72-7.68 (t, 1H, J= 7.67 Hz, J= 7.90 Hz), 7.56-7.53
(m, 1H), 7.37-7.35 (t, 1H, J= 7.67 Hz, J= 7.67 Hz), 7.29-7.21 (m, 1H), 3.36
(s, 4H), 2.74 (s, 3H), 2.09 (s, 3H). ESI-MS (m/z): Calcd. for C23H23N3O5S3:
518.1 (M+l); found: 518.1.
Example 134
4-(4l-Amino-2'-chloro-6'-me1.hyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
a) {[4-(2'-Chloro-6'-methyl-4'-mtro-bip1ienyl-3-sulfony1)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
2-Bromo-l-chloro-3-methyl-5-nitro-benzene (45 mg, 0.219 mmol),
{[4-(3-Boranyl-dihydroxy-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-
imino-methyl}-carbamic acid tert-butyl ester (50 mg, 0.11 mmol, Example
140: step a) and Pd(PPh3)4 (25 mg, 0.02 mmol) were combined in aqueous
Na2CO3 (2M, 500 µL), ethanol (500 µL) and toluene (1 mL). The reaction
was heated to S0°C overnight. The resulting residue was dissolved into
EtOAc and washed with brine. The organic layers were dried (MgSO4) and
the solvent was removed in vacuo followed by preparative TLC purification
(30% EtOAc/hexanes) that yielded the title compound (20mg, 29%). ESI-MS
(m/z): Calcd. for C24H24CIN3O6S3: 5S2.1 (M+l); found: 582.1.
b) {[4-(4'-Amino-2'-chloro-6'-methyl-biphenyl-3-sulfonyl)-5-
nietliylsulfanyl-thiophen-2-yl)-imino-methyl}-carbamic acid tert-butyl ester
{[4-(2'-Chloro-61-methyl-4'-nitro-bipheny]-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(20 mg, 0.034 mmol, Example 134: step a) was dissolved into EtOH (2 mL).
To this was added ammonium chloride (18 mg, 0.34 mmol) dissolved into
water (4 mL). The reaction was heated to 50°C and iron (9.6 mg, 0.34 mmol)
was added. The reaction was then heated to 80°C for 12 hours followed by
filtration through celite with methanol and EtOAc. The solvents were
removed in vacuo resulting in desired product that was used with out further
purification or characterization.
c) 4-(4'-Amino-2'-chloro-6'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
{[4-(4'-Amino-2'-chloro-6'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
{Example 134: step b) was deprotected and purified as in Example 1: step d,
yielding the title compound as a dark yellow solid. 1H-NMR (CD3OD):
d 8.33 (s, 1H), 8.03-8.00 (m, 1H), 7.85-7.84 (m, 1H), 7.70-7.66 (t, 1H, J =
7.67 Hz, J= 7.67 Hz), 7.54-7.52 (m, 1H), 6.94 (s, 1H), 6.84 (m, 1H), 2.70 (s,
3H), 1.99 (s, 3H). ESI-MS (m/z): Calcd. for C19H18N3O2S3: 452.0 (M+l);
found: 452.1.
Example 135
N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-chloro-6-
methyl-biphenyl-2-yl]-4-methanesulfonyl-butyramidetrifluoroacetate
a) 4-Brom o-3-methyl-5-nitro-phenylamin e
(4-Bromo-3-methyl-5-nitro-phenyl)-carbainic acid tert-butyl ester
(1000 mg, 2.9 mmol) was dissolved into DCM (10 mL). To this was added
TFA (10 mL) and the reaction was stirred at RT for 1 hour. The pH was
adjusted to 8 with 1 N NaOH and the solvents were removed in vacuo. The
reaction mixture was dissolved into EtOAc and the layers were separated. The
organic layers were dried (MgSO4) and the solvents were removed in vacuo
resulting in title compound (756 mg, quantitative) as a brown oil. 1H-NMR
(CDCl3): d 8.44 (s, 1H), 8.02 (s, 1H), 7.61 (s, 1H), 3.05 (s, 3H).
b) 2-Brom o-5-chIoro-l-m ethyl-3-n itro-benzen e
A 3-neck flask fitted with septa, addition funnel and condenser was
charged with t-butylnitrite (966 µ, 8.12 mmol) and copper (II) chloride (1090
mg, 8.12 mmol) in acetonitrile (10 mL). 4-Bromo-3-methyl-5-nitro-
phenylamine (756 mg, 4.06 mmol, Example 135: step a) was dissolved in
acetonitrile (6 mL) and added slowly through the addition funnel while
heating to 60°C. The reaction was quenched with EtOAc and washed with
water. The organic layers were dried (MgSO4) and the solvents were removed
in vacuo resulting in the title compound as a brown solid (721 mg, 72%). 1H-
NMR (CDCl3): d 7.54 (d, 1H, J= 2.33), 7.44 (d, 1H, J = 2.56 Hz), 2.55 (s,
3H).
c) 2-Bromo-5-chloro-3-methyl-pheuylamine
2-Bromo-5-chloro-l-methyJ-3-nitro-benzene (721 mg, 3.5 rrunol,
Example 135: step b) was dissolved into EtOH (6 mL). To this was added
ammonium chloride (1.9 g, 35 mmol) dissolved into water (10 mL). The
reaction was heated to 50°C, iron (9.6 mg, 0.34 mmol) was added and the
reaction was then heated to 80°C for 12 hours. The reaction mixture was
filtered through celite, washed with methanol and EtOAc and the solvents
were removed in vacua. The residue was dissolved into EtOAc and washed
with brine to remove salts. The organic layers were dried (MgSO4) and the
solvents were removed in vacuo resulting in the title compound (595 mg,
78%) as a brown solid. 1H-NMR (CDCl3): d 6.63-6.61 (m, 2H), 2.33 (s, 3H).
d) 5-Chloro-3-methyl-2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-
phenylamine
2-Bromo-5-chloro-3-methyl-phenylamine (595 mg, 2.7 mmol,
Example 135: step c), Pd(OAc)2 (30.3 mg, 0.14 mmol), 2-
(dicyclohexylphosphino)biphenyl (189.2 mg, 0.54 mmol) and Et3N (1.5 mL,
10.8 mmol) were dissolved into dioxane (10 mL). To this was added 4,4,5,5-
Tetramethyl-[l,3,2]dioxaborolane (1.2 mL, 8.1 mmol) slowly. The reaction
was heated to 80°C overnight. The solvents were removed in vacuo and the
resulting residue was dissolved into EtOAc amd washed with brine. The
combined organic layers were dried (MgSO4) and removal of the solvents in
vacuo resulted in a mixture of the title compound and 3-Methyl-2,5-bis-
(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenylamine were obtained and
used with out further purification.
e) {[4-(2'-Amino-4'-chloro-6'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
The procedure as in Example 1: step c was followed 5-Chloro-3-
methyl-2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenylamine (663
mg, 2.5 mmol, Example 135, step d), {[4-(3-Bromo-benzenesulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(1.2 g, 2.5 mmol, Example 27: step c), Pd(PPh3)4 (577 mg, 0.5 mmol), aqueous
Na2CO3 (2M, 10 mL), ethanol (10 mL) and toluene (20 mL). The reaction
was heated to 80°C for 24 hours. The reaction mixture was dissolved into
EtOAc and washed with brine. The organic layers were dried (MgSO4) and
removal of the solvents in vacuo was followed by purification by flash column
chromatography (SiO2) (30% EtOAc in hexanes) that yielded the title
compound as a brown oil. ESI-MS (m/z): Calcd. for C24H26CIN3O4S3: 552.1
(M+l) found: 551.7.
f) ({4-[4'-Chloro-2'-(4-methanesulfonyl-butyrylamino)-6'-methyl-
biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-
carbamic acid tert-butyl ester
{[4-(2'-Amino-4'-chloro-6l-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(120 mg, 0.22 mmol, Example 135, e) and Et3N (0.91 µL, 0.65 mmol) were
dissolved into DCM (4 mL). To this was added (4-Methanesulfonyl-butyryl
chloride (0.144 M, 3.1 mL, 0.44 mmol, Example 209: a) and the reaction was
stirred at RT overnight. The solvents were removed in vacuo followed by
purification by flash column, chromatography (20% EtOAc/hexanes) that
yielded the title compound as an orange solid (124 mg, 81%). ESI-MS (m/z):
Calcd. for C29H34CIN3O7S4: 700.1 (M+l) found: 700.1.
g) N-[3'-(5-Carbamimidoyl-2-methyhulfanyl-thiophene-3-sulfonyl)-4-
chloro-6-methyl-biphenyl-2-y!]-4-methanesulfonyl-butyramide
trifluoroacetate
({4-[4'-Chloro-2'-(4-methanesuIfonyl-butvrylamino)-6'-methyl-
biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-iinino-methyl)-
carbamic acid tert-butyl ester (124mg, 0.18 mmol, Example 135: step/) was
deprotected and purified as in Example 1: step d, yielding the title compound
as a clear glass (70 mg, 65%). 1H-NMR (CD3OD): d 8.32 (s, 1H), 8.08-8.06
(d, 1H, 7 = 10.00 Hz), 7.87 (m, 1H), 7.71 (t, 1H, J= 7.91 Hz, J= 8.61 Hz),
7.56-7.54 (d, 1H, J= 9.07), 7.33 (m, 2H), 2.92 (s, 3H), 2.85 (t, 2H, J = 7.91
Hz, J= 7.67 Hz), 2.73 (s, 3H), 2.21 (t, 2H, J= 5.35 Hz, J = 7.91 Hz), 2.07 (s,
3H), 1.82-1.73 (m, 2H). ESI-MS (m/z): Calcd. for C24H26CIN3O5S4: 600.1
(M+l); found: 600.1.
Example 136
4-[4'-(N'-Hexyl-guanidino)-2'-methyl-biphenyl-3-sulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
a) ({4-/4'-(3-Hexyl-thioureido)-2'-methyl-biphenyl-3-sulfonyl]-5-
methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester
4-(4'-Amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine (26 mg, 0.05 mmol, Example 220: step b) was
dissolved into EtOH. To this was added hexylisothiocyanate (30µL) and the
reaction was heated for 4 hour at S0°C. The solvent was removed in vacuo
and the reaction was purified by preparative TLC resulting in the title
compound that was used without further purification or characterization.
b) ({4-[4'-(N'-Hexyl-guanidino)-2'-methyl-biphenyl-3-sulfonyl]-5-
methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester
({4-[4'-(3-Hexyl-thioureido)-2'-methyl-biphenyl-3-sulfonyl]-5-
methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbanric acid tert-butyl ester
(33 mg, .14 mrnol. Example 136: step a) was dissolved into ammonia in
methanol (2.0 M, 4 mL). To this was added mercury (II) oxide (33.9 mg, 0.16
mmol) and the reaction stirred at RT for 2 hours. Additional mercury (II)
oxide (154 mg, 0.08 mmol) was added and the reaction was heated to 40°C
overnight. The reaction was filtered with 0.2 µM disk and washed with
EtOAc followed by removal of solvents in vacua that yielded the title
compound which was used without further purification (30 mg). ESI-MS
(m/z): Calcd. for C31H41N5O4S3: 644.2 (M+l); found: 644.1.
c) 4-[4'-(N'-Hexyl-guanidino)-2'-methyl-biphenyl-3-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
({4-[4'-(N'-Hexyl-guanidino)-2'-methyl-biphenyl-3-sulfonyl]-5-
methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert--butyl ester
(30 mg, Example 136: step b) was deprotected and purified as in Example 1:
step d, yielding the title compound as a yellow glass (11.5 mg, 43%). H-
NMR (CD3OD): d 8.34 (s, 1H), 8.03-8.00 (m, 2H), 7.73-7.67 (m, 2H), 7.33-
7.31 (m, 1H), 7.24-7.18 (m, 2H), 3.63 (m, 2H), 2.72 (s, 3H), 2.27 (s, 3H),
1.69-1.62 (m, 2H), 1.44-1.33 (m, 6H). ESI-MS (m/z): Calcd. for
C26H33N5O2S3: 544.2 (M+l); found: 544.1.
Example 137
5-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-
biphenyl-2-ylcarbamoyl]-pentanoic acid trifluoroacetate
a) 5-{3'-[5-(tert-Butoxycarbonylam in o-im in o-m ethyl)-2-m ethylsulfanyl-
thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylcarbamoyl}-pentanoic acid
methyl ester
{[4-(2'-Amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (100 mg, 0.19
mmol, Example 25 : step c) was dissolved into THF (3 mL). To this was
added 5-Chlorocarbonyl-pentanoic acid methyl ester (41.5 mg, 0.23 mmol)
and the reaction was stirred at RT for 2 hours. The reaction was dissolved into
EtOAc and washed with brine. The combined organic layers were dried
(MgSO4) followed by removal of solvents in vacuo resulted in the title
compound that was used without further purification. ESI-MS (m/z): Calcd.
for C31H37N3O7S3: 660.2 (M+l); found: 660.8.
b) 5-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-
thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylcarbantoyl}-pentanoic acid
5-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-
thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylcarbamoyl}-pentanoic acid
methyl ester (125 mg, 0.19 mmol, Example 137: step a) and LiOH (12.5 nag,
0.54 mmol) were dissolved into MeOH (3 mL) and heated to 60°C for 12
hours. The reaction was dissolved into EtOAc and washed with 20 % citric
acid. The aqueous layers were acidified with acetic acid (pH 3) and extracted
with EtOAc. The organic layers were combined and dried (MgSO4) followed
by removal of solvents in vacuo. The resulting material was purified by
preparative RP -HPLC (0-100% water/acetonitrile - both solvents were free of
TFA, 45 minutes, ? = 245 ran). 1H-NMR (CDCl3): d 7.95-7.93 (d, 1H, i = 9.3
Hz), 7.81-7.78 (d, 1H, J - 7.91 Hz), 7.63-7.59 (m, 1H), 7.55-7.53 (t, 1H, J =
8.35, Hz, J = 7.59 Hz), 7.38-7.36 (d, 1H, J = 9.35 Hz), 7.25-7.21 (m, 1H),
7.07-7.05 (d, 1H, J - 7.07 Hz), 6.78 (s, 1H), 3.55 (s, 2H), 2.51 (s, 3H), 2.15-
2.12 (m, 2H), 1.96-1.95 (m, 2H), 1.93 (s, 3H).
c) 5-[3'-(5-Carbammimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6'
methyl-biphenyl-2-ylcarbamoyl]-pentanoic acid trifluoroacetate
5-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-
thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylcarbamoyl}-pentanoic acid
(Example 137: step b) was depirotected and purified as in Example 1: step d,
yielding the title compound as a white glass. 1H-NMR (CD3OD): d S.29 (s,
1H), 8.06-8.04 (m, 1H), 7.89 (s, 1H), 7.68 (t, 1H, J = 7.67 Hz, J = S.S4 Hz),
7.54-7.52 (d, 1H, J = 7.91 Hz), 7.38-7.29 (m, 2H), 7.18-7.16 (d, 1H, J = 7.67
Hz), 2.75 (s, 3H), 2.11-2.09 (m, 2H), 2.08 (s, 3H), 2.03 - 1.91 (m, 2H), 1.27-
1.08 (m, 4H). ESI-MS (m/z): Calcd. for C25H27N3O5S3: 546.1 (M+l); found:
546.1.
Example 138
4-[3-(3-Methyl-pyridin-4-yl)-benzenesulfbnyl]-5-methylsulfanyl-thiophene-2-
carboxamidine trifiuoroacetate
a) 4-Bromo-3-methyl-pyridin~l~ol
Acetyl bromide (5 mL) was cooled to 0°C. To this was added 4-Nitro-
3-methyl-pyridin-1-ol (1000 mg, 6.48 mmol) portionwise while maintaining
temperature. After the addition was complete, the reaction was heated to 50°C
and stirred for 2 hours. The reaction was then cooled to 0°C, quenched with
ice and neutralized with solid Na2CO3 (pH = 8). The neutral aqueous reaction
mixture was extracted into DCM. The organic layer was dried (MgSO4), the
solvents were removed in vacuo resulting in the title compound as a yellow
solid (1.05 mg, 86%). ESI-MS (m/z): Calcd. for C6H6BrNO: 188.0 (M+l);
found: 188.0.
b) 4-Bromo-3-methyl-pyridine
4-Bromo-3-methyl-pyridin-l-ol (1050 mg, 5.6 mmol, Example 138:
step a) was dissolved into DCM (10 ml.) and cooled to -20°C. To this was
slowly added PCl3 and the reaction was stirred at -20°C for 15 minutes. The
reaction was then warmed to RT for 15 minutes. The reaction was then
quenched with water (5mL) after cooling back to -20°C. The reaction was
then warmed to RT and quenched with NaOH (246 mg. 1.1 mmol) in water
(5mL). The reaction mixture was separated and the organic layers were
washed with brine. The water layer was adjusted with 10N NaOH to pH = 10.
The aqueous layer was then extracted with DCM and EtOAc, all organic
layers were combined and dried with (MgSO4) and the solvents were removed
in vacuo. 1H-NMR (CDCl3): d 8.26 (s, 1H), 8.08-8.06 (d, 1H, J == 5.14 Hz),
7.30-7.29 (d, 1H, J = 5.35 Hz), 2.21 (s, 3H).
c) (Imino-{4-[3-(3-m ethyl-pyridin -4-yl)-benzenesulfonyl]-5-
methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester
4-Bromo-3-methyl-pyridine (100 mg, 0.219 mmol, Example 138: step
b), {[4-(3-Boranyl-dihydroxy-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-
yl]-imino-methyl}-carbamic acid tert-butyl ester (266 mg, 0.58 mmol,
Example 140: step a) and Pd(PPh3)4 (134 mg, 0.12 mmol) were combined in
aqueous Na2CO3 (2M, 2 mL), ethanol (2 mL) and toluene (4 mL) and heated
to 80°C overnight. The reaction mixture was dissolved into EtOAc and
washed with brine. The organic layers were dried (MgSO4) and the solvent
was removed in vacuo. Purification by flash column chromatography (10%
DCM/MeOH) afforded the title compound (120mg, 41%). ESI-MS (m/z):
Calcd. for C23H25N3O4S3: 504.1 (M-l); found: 503.7.
d) 4-[3-(3-Methyl-pyridin-4-yl)-benzenesulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidin e trifluoroacetate
(Imino-{4-[3-(3-methyl-pyridin-4-yl)-benzenesulfonyl]-5-
methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester
(Example 138 : step c) was deprotected and purified as in Example 1: step d,
yielding the title compound as a white glass. 1H-NMR (CD3OD): d 8.85 (s,
1H), 8.78-8.76 (d, 1H, J = 5 78 Hz), 8.38 (s, 1H), 8.24-8.21 (m, 2H), 7.92-7.84
(m, 3H); 2.75 (s, 3H), 2.47 (s, 3H). ESI-MS (m/z): Calcd. for C18H17N3O2S3:
404.1 (M+l); found: 404.1.
Example 139
4-[3-(3-Amino-5-methyl-pyridin-4-yl)-benzenesulfonyl]-5-methylsulfanyl-
thiophene-2-Carboxamidine trifluoroacetate
a) (5-Methyl-pyridin-3-yl)-carbamic acid tert-butyl ester
5-Methyl-nicotinic acid (2g, 14.6 mmol) was dissolved into t-Butanol
(59 mL). To this was added N,N-Diisopropylethylamine (7.6 mL, 43.8 mmol)
and diphenylphosphoryl azide (3.8 mL, 17.5 nrniol). The reaction was heated
to 80°C overnight in a flask fitted with septa and argon gas line. The solvents
were evaporated in vacuo arid the resulting residue was dissolved into EtOAc,
washed with saturated NaHCO3 and water. The combined organic layers were
dried (MgSO4) and the solvents were removed in vacuo. The residue was
purified by flash column chromatography (SiO2) (50% EtOAc in hexanes) that
yielded the title compound as a white solid (2.03 g, 67%). 1H-NMR (CDCl3):
d 8.22 (m, 1H), 8.14 (m, 1H), 7.88 (br s, 1H), 6.58 (br s, 1H), 2.34 (s, 3H),
1.55 (s,9H).
b) (4-Iodo-5-methyl-pyridin-3-yl)-carbamic acid tert-butyl ester
(5-Methyl-pyridin-3-yl)-earbamic acid tert-butyl ester (255 mg, 1.2
mmol, Example 139: step a) and trimethylethylenediamine (905 µL, 6.0
mmol) v/ere dissolved into THF (4 mL) and cooled to -78 °C. To this was
added n-Butyllithium (2.5M, 2.4 mL, 6.0 mmol). The reaction was stirred at -
78°C for 30 minutes and then warmed to RT for 30 minutes. Iodine (L.5 g, 6.0
mmol) was dissolved into THF (4 mL) and added to the reaction mixture at -
78°C slowly. The reaction was wanned to RT for 1 hour and the solvents
were removed in vacuo. The residue was dissolved into EtOAc and washed
with brine and water. The combined organic layers were dried (MgSO4) and
solvents were removed in vacuo followed by purification by flash column
chromatography (SiO2) (50% EtOAc in hexanes) that yielded the title
compound as a yellow solid (55 mg, 14 %). 1H-NMR (CDCl3): d S.91 (s, 1H),
8.07 (s, 1H), 6.81 (br s, 1H), 2.44 (s, 3H), 1.56 (s, 9H). ESI-MS (m/z): Calcd.
for C11H15IN2O2: 335.0 (M+l); found: 334.9.
c) ({4-[3-(3-Amino-S-methyl-pyridin-4-yl)-benzenesulfonyl]-5-
methylsulfanyl-thiophen-2-yt}-imino-methyl)-carbamic acid tert-butyl ester
(4-Iodo-5-methyl-pyridm-3-yl)-carbamic acid tert-butyl ester (106 mg,
0.32 mmol, Example 139: step b), {[4-(3-Boranyl-dihydroxy-
benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic
acid tert-butyl ester (145 mg, 0.32 mmol, Example 140: step a) and Pd(PPh3)4
(74 mg, 0.06 mmol) were combined in aqueous Na2CO3 (2M, 1.2 mL), ethanol
(1.2 mL) and toluene (2.4 mL) and was heated to 80°C overnight. The
reaction mixture was dissolved into EtOAc and washed with brine. The
organic layers were dried (MgSO4) and solvents were removed in vacuo.
Purification by flash column chromatography (40% EtOAc/hexanes) afforded
the title compound. ESI-MS (m/z): Calcd. for C28H34N4O6S3: 619.2 (M+l);
found: 618.8.
d) 4-[3-(3-Amino-5-methyl-pyridin-4-yl)-benzenesulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
({4-[3-(3-Amino-5-methyl-pyridin-4-yl)-benzenesuIfonyl]-5-
methylsulfanyl-thiophen-2-yl}-iraino-methyl)-carbamic acid tert-butyl ester
(Example 139 : step c) was deprotected and purified as in Example 1: step d,
yielding the title compound as a white solid. 1H-NMR (CD3OD): d 8.37 (s,
1H), 8.18-8.16 (d, 1H, J = 8.84 Hz), 8.06 - 8.05(m, 2H), 7.99 (s, 1H), 7.87 (t,
1H, J = 7.67 Hz, J = 7.44 Hz), 7.71-7.68 (d, IH, J - 7.67 Hz), 2.73 (s, 3H),
2.09 (s, 3H). ESI-MS (m/z): Calcd. for C18H18N4O2S3: 419.1 (M+l); found:
419.1
Example 140
4-[3-(2,5-Dimethyl-1H-imidazol-4-yl)-benzenesulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
a) {[4-(3-Dihydroxyboranyl-benzenesulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester.
A solution of 2M i-PrMgCl in THF (1.1 mL, 2.2 mmol) was added
dropwise at 0 °C to {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.5 g, 1.0 mmol)
(Example 27c) in 5.0 mL THF. The solution was stirred for 20 mins at 0 °C,
then cooled to -78 °C and a solution of 2.5 M n-BuLi in hexanes (0.6 mL, 1.5
mmol) was added. The mixture was stirred for 5 mins then trimethylborate
(0.35 mL, 3.3 mmol) was added at -78 C °C and the mixture allowed to attain
RT. The reaction was quenched with sat. NH4Cl (10 mL) and extracted with
EtOAc (3 x 20 mL), dried over Na2SO4 and evaporated. The crude solid was
purified by elution from a 5 g SPE with 10% MeOH/DCM to give 0.45 g
(95%) of the title compound as a yellow solid:: 1H NMR (400 MHz, CD3OD)
5 8.28 (m, 1H), 8.05 (m, 1H), 7.95 (m, 1H), 7.60 (m, 2H), 2.66 (s, 3H), 1.51 (s,
9H). Mass spectrum (ESI, m/z) calcd. for C17H21N3O4S3 456.1, found 456.7
(M+H).
General Procedure for Suzuki Coupling:
To a flask charged with 0.50 g (1.1 mmol) of {[4-(3-dihydroxyboranyl-
benzenesulfonyl)-5-m.ethy[sulfanyl-thiophen-2-yl]-imino-methyl}-carbamic
acid tert-butyl ester, 0.22 g (1 mmol) of 5-iodo-2,4-dimethyl-lH-imidazole
and 0.006 g of Pd(PPh3)4 (5 mol %) is added S ml of toluene, 4 mL of EtOH,
and 4 mL of 2 M Na2CO3. The mixture is backfilled with argon and then
heated at SO °C for 4 hrs. The mixture is diluted with water (10 mL) and the
product extracted with EtOAc (3 x 10 mL), dried (Na2SO4), filtered and
evaporated. The crude product is purified by flash chromatography to give the
title compound as a BOC-protected amidine. The BOC-protected amidine is
stirred at 25 °C for 1 hr in 2 mL of 50% TFA/DCM, and then the solvents are
evaporated and the crude product purified by RP-HPLC, eluting with a linear
gradient of 10% CH3CN to 50% CH3CN in 0.1% TFA/H2O over 30 mins to
give 0.39 g (75%) of the title compound as a yellow solid: 1H NMR (400
MHz, CD3OD) 5 8.37 (s, 1H), S.25 (m, 1H), 8.14 (m, 2H), 7.88 (m, 1H), 7.63
(s, 1H), 2.74 (s, 3H), 2.68 (s, 3H), 2.49 (s, 3H). Mass spectrum (ESI, m/z)
calcd. for C17H1SN4O2S;3 406.1, found 407.1 (M+H).
Example 141
4-[3-(3-Methyl-3H-imidazol-4-yl)-benzenesulfonyl]-5-methylsuifanyl-
thiophene-2-carboxaraidine trifluoroacetate
Prepared according to the general procedure in Example 140 H NMR
(400 MHz, CD3OD) 5 9.08 (s, 1H), 8.38 (s, 1H), 8.29 (m, 1H), 8.24 (m, 1H),
7.96 (m, 1H), 7.85 (m, 1H), 7.81 (s, 1H), 3.92 (s, 3H), 2.75 (s, 3H). Mass
spectrum (ESI, m/z) calcd. for C16Hi6N4O2S3 392.1, found 393.1 (M+H).
Example 142
4-[3-(l-Methyl-lH-imidazol-2-yl)-benzenesulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
Prepared according to the general procedure in Example 140. 1H NMR
(400 MHz, CD3OD) 5 8.37 (s, 1H), 8.25 (m, 1H), 8.14 (m, 1H), 7.91 (m, 1H),
7.81 (m, 1H), 2.74 (s, 3H), 2.68 (s, 3H), 2.49 (s, 3H). Mass spectrum (ESI,
m/z) calcd. for C23H25N3O4S3 392.1, found 393.1 (M+H).
Example 143
4-[3-(l -Methyl-1H-benzoimidazol-2-yl)-benzenesulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
a) {[4-(3-Formyl-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-
imino-methyl}-carbamic acid tert-butyl ester
A solution of 2 M i-PrMgCl in THF (1.1 mL. 2.2 mmol) was added
dropwise at 0 °C to {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.5 g, 1.0 mmol)
(Example 27c) in 5.0 mL THF. The solution was stirred for 20 m:ins at 0 °C,
then cooled to -78 °C and a solution of 2.5 M n-BuLi in hexanes (0.6 mL, 1.5
mmol) was added. The mixture was stirred for 5 mins then N,N-
dimethylformamide (0.30 mL, 3.8 mmol) was added at -78 °C and the mixture
allowed to attain RT. The reaction was quenched with sat. NH4Cl (10 mL)
and extracted with EtOAc (3 x 20 mL), dried over Na2SO4 and evaporated.
The crude solid was purified by elution from a 20g SPE with 50% EtOAe/hex
to give 0.33 g (75%) of the title compound as a yellow solid: 1H NMR (400
MHz, CDCl3) 5 10.06 (s, 1H), 8.48 (s, 1H), 8.26 (m, 1H), 8.10 (m, 1H), 8.06
(s, 1H), 7.71 (s, 1H), 2.50 (s, 3H), 1.51 (s, 9H). Mass spectrum (ESI, m/z)
calcd. for C18H20N205S3 440.1, found 440.8 (M+H).
The above aldehyde (0.026g, 0.06 mmol) and N-methyl-1,2-
phenylenediamine (0.014g, 0.12 mmol) in 0.2 mL of ethanol was heated at 80
°C for 12 hours. The solvent was evaporated and the residue taken up in 1 mL
of 50% TFA/DCM and stirred for 30 mins at 25 °C. The solvent was
evaporated and the crude product purified by RP-HPLC, eluting with a linear
gradient of 10% CH3CN in 0,1% TFA/H2O to 50 % CH3CN over 30 mins, to
give 0.028 g (87 %) of the title compound as red solid: 1H NMR. (400 MHz,
CD3OD) 5 8.62 (m, 1H), 8.45 (m, 1H), 8.41 (s, 1H), 8.28 (m, 1H), 8.03 (m,
1H), 8.00 (m, 1H), 7.90 (m, 1H), 7.75 (m, 2H), 4.13 (s, 3H), 2.76 (s, 3H).
Mass spectrum (ESI, m/z) calcd. for C20H18N4O2S3 442.1, found 443.1
(M+H).
Example 144
4-[3-(lH-Benzoimidazol-2-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophene-
2-carboxamidine trifluoroacetate
This compound was prepared according to Example 143 using 1,2-
phenylenediamine. 1H NMR (400 MHz, CD3OD) 5 8.85 (m, 1H), 8.44 (m,
1H), 8.42 (s, 1H), 8.33 (m, 1H), 7.95 (m, 1H), 7.82 (m, 2H), 7.56 (m, 2H),
2.74 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C19H16N4O2S3 428.0, found
429.1 (M+H).
Example 145
4-[3-(l-Ethyl-lH-benzoimidazol-2-yl)-benzenesulfonyl]-5-methy].sulfanyl-
thiophene-2-earboxamidine trifluoroacetate
A mixture containing ({4-[3-(lH-benzoimidazol-2-yl)-
benzenesulfonyl]-5-methy]sulfanyl-thiophen-2-yl}-imino-methyl)-carbamic
acid tert-butyl ester (prepared in Example 144) (25 mg, 0.05 mmol), K2CO3
(13 mg, 0.10 mmol), and iodoethane (12 mg, 0.08 mmol) in 0.5 mL acetone
was heated to 60 °C for 2 hrs. The mixture was filtered then concentrated, and
the residue dissolved in 0.5 ml of 50% TFA/DCM and stirred at 25 °C for 30
mins. The solvent was evaporated and the crude product purified by RJP-
HPLC, eluting with a linear gradient of 10% CH3CN in 0.1% TFA/H2O to 50
% CH3CN over 30 mins, to give 26 mg (93%) of the title compound as yellow
solid: 1H NMR (400 MHz, CD3OD) 5 8.58 (m, 1H), 8.44 (m, 1H), 8.41 (s,
1H), 8.20 (m, 1H), 8.02 (m, 2H), 7.90 (m, 1H), 7.71 (m, 2H), 4.55 (q, 2H),
2.75 (s, 3H), 1.59 (t, 3H). Mass spectrum (ESI, m/z) calcd. for C21H2oN4O2S3
456.1, found 457.1 (M+H).
Example 146
3-{2-[3-(5-Carbarnimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-phen}'l]-
benzoimidazol-l-yl}-propane-1-sulfonic acid trifluoroacetate
This compound was prepared in a similar manner to Example 145
using 1,3- propane sultone in DMF. lH NMR (400 MHz, CD3OD) 8 8.58 (m,
1H), 8.43 (m, 1H), 8.36 (s, 1H), 8.25 (m, 1H), 8., 10 (m, 1H), 8.00 (m, 1H),
7.88 (m, 1H), 7.71 (m, 2H), 4.72 (t, 2H), 2.79 (t, cH), 2.77 (s, 3H), 2.32 (m,
2H). Mass spectnim (ESL m/z) calcd. for C22H22N4O5S4 550.1, found 550.1
(M+H).
Example 147
4-[3-(Hydroxy-pyridin-2-yl-]methyl)-benzenesulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
A solution of 2 M i-PrMgCl in THF (0.16 mL 0.36 mmol) was added
dropwise at 0 °C to {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.08 g. 0.16
mmol) (Example 27c) in 0.75 mL THF. The solution was stirred for 20 mins
at 0 °C, then cooled to -78 °C and a solution of 2-5 M n-BuLi in hexanes (0.084 mL, 0.21 mmol) was added. The mixture was stirred for 5 mins then 2-
pyridinecarboxyaldehyde (0.023 mL, 0.24 mmol) was added at -78 °C and the
mixture allowed to attain RT. The reaction was quenched with sat. NH4Cl (5
mL) and extracted with EtOAc (3 x 10 mL), dried over Na2SO4 and
evaporated. The crude solid was purified by flash chromatography to give the
title compound as a BOC-protected amidine, which was deprotected in 2 mL
of 50% TFA/DCM (25 °C, 1 hr) to give 0.035 g (40%) of the title compound
as a yellow solid: 1H NMR (400 MHz, CDCl3) 5 8.79 (m, 1H), 8.53 (m, 1H),
8.33 (s. 1H), 8.24 (m, 1H), 7.97 (m, 3H), 7.86 (m, 1H), 7.67 (m, 1H), 6.32 (s,
1H), 2.50 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C18H17N3O3S3 419.0,
found 420.0 (M+H).
Example 148
4-[3-(4-Hydroxy-l-methyl-piperidin-4-yl)-benzenesulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
Prepared in a similar manner to Example 147 using l-methyl-4-
piperdone. 1H NMR (400 MHz, CD3OD) 5 8.34 (s, 1H), 8.2S (in, 1H), 7.96
(m, 1H), 7.84 (m, 1H), 7.66 (m, 1H), 3.48 (ni, 4H), 2.96 (s, 3H), 2.73 (s, 3H),
2.38 (m, 2H), 1.98 (m, 2H). Mass spectrum (ESI, m/z) calcd. for
C18H23N3O3S3 425.1, found 426.1 (M+H).
Example 149
4-[3-(4-Hydroxy-tetraliydro-pyran-4-yl)-benzenesulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
Prepared in a similar manner to Example 147 using tetrahydro-4H-
pyran-4-one. 1H NMR (400 MHz, CD30D) 5 8.30 (s. 1H), 8.24 (m, 1H), 7.92
(m, 1H), 7.83 (m, 1H), 7.60 (m, 1H), 3.88 (m, 4H), 2.71 (s, 3H), 2 12 (m, 2H),
1.63 (m, 2H). Mass spectrum (ESI, m/z) calcd. for C17H20N2O4S3 412.1, found
413.0 (M+H).
Example 150
4-[3-(4-Methoxy-tetratiydro-pyran-4-yl)-benzenesulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
To a solution of the BOC-protected amidine (46 mg, 0.09 mmol)
(prepared in example 149) in 0.2 mL of DMF at 25 °C was added NaH (60%
oil dispersion, 5.7 mg, 0,14 mmol). The reaction was allowed to stir for 20
mins then iodomethane (6 uL, 0.09 mmol) was added and the reaction stirred
for additional 12 hrs. The solvent was evaporated and the crude material
purified by flash chromatography to give the title compound as a BOC
protected amidine, which was deprotected in 2 mL of 50% TFA/DCM (25 °C,
1 hr) to give the title compound (11.5 mg, 20%) as a yellow solid: 1H NMR
(400 MHz, CD3OD) 5 8.34 (s, 1H), 8.14 (m, 1H), 7.92 (m, 1H), 7.80 (m, 1H),
7.66 (m, 1H), 3.89 (m, 4H), 3.00 (s, 3H), 2.74 (s, 3H), 2.02 (m, 4H). Mass
spectrum (ESI, m/z) calcd. for C18H22N2O4S3 426.1, found 427.1 (M+H).
Example 151
4-(3-Furan-2-yl-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-
caiboxamidine trifluoroacetate
A solution containing 50 mg (0.10 mmol) of {[4-(3-bromo-
benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic
acid tert-butyl ester (prepared in Example 27c), 54 mg (0.15 mmol) of 2-
tributylstannylfuran, and 12 mg (10 mol%) of Pd(PPh3)4 in 0.5 mL of THF
was healed at 80 °C under Argon for 10 hrs. The reaction was quenched with
NH4AC (5 mL), extracted with EtOAc (3 x 5mL), dried over Na2SO4 and
concentrated under reduced pressure. The crude material was stirred in 1 mL
of 50 % TFA/DCM for 1 hr at 25 °C and then concentrated and purified by
RP-HPLC to give 19 mg (50%) of the title compound as a yellow solid: 1H
NMR (400 MHz, CD3OD) 5 8.35 (s, 1H), 8.32 (m, 1H), 8.01 (m, 1H), 7.90 (m,
1H), 7.66 (m, 1H), 7.65 (m, 1H), 6.98 (m, 1H), 6.60 (m, 1H), 2.75 (s, 3H).
Mass spectrum (ESI, m/z) calcd. for C16H14N2O3S3 378.0, found 379.1 (M+H).
Example 152
3-[3-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-phenyl]-but-
2-enoic acid ethyl ester trifluoroacetate
a) Imino-[5-methylsulfanyl-4-(3-tributylstannanyl-benzenesulfonyl)-
thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester
A solution of 2 M i-PrMgCl in THF (1.1 mL, 2.2 mmol) was added
dropwise at 0 °C to {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.5 g, 1.0 mmol)
(Example 27c) in 5.0 mL THF. The solution was stirred for 20 mins at 0 °C,
then cooled to -78 °C and a solution of 2.5 M n-BuLi in hexanes (0.6 mL, 1.5
mmol) was added. The mixture was stirred for 5 mins then tributyltin chloride
(0.65 g, 2.0 mmol) was added at —78 °C and the mixture allowed to attain RT.
The reaction was quenched with sat. NH4Cl (10 mL) and extracted with
EtOAc (3 x 20 mL), dried over Na2SO4 and evaporated. The crude solid was
purified by flash chromatography to give 0.35 g (50%) of the title compound
as a yellow solid: 1H NMR (400 MHz, CDCl3) d 8.14 (m, 1H), 8.00 (s, 1H),
7.S7 (m, 1H), 7.71 (m, 1H), 7.46 (m, 1H), 2.59 (s, 3H), 1.53 (s, 9H), 1.51 (m,
6H), 1.34 (m, 6H), 1.11 (m, 6H), 0.89 (m, 9H). Mass spectrum (ESI m/z)
calcd. for C29H46N2O4S3Sn 702.2, found 702.7 (M+H).
A mixture containing 42 mg (0.06 mmol) of {imino-[5-methylsulfanyl-
4-(3-tributylstannanyl-benzenesulfonyl)-thiophen-2-yl]-methyl}-carbamic acid
tert-butyl ester, 21 mg (0.09 mmol) of ethyl cis-3-iodocrotonate, 3 mg (5
mol%) of Pd(PPh3)4 and 1 mg (10 mol%) of Cul in 0.3 mL of DMF was
heated under argon at 100 °C for 12 hrs. The DMF was evaporated and the
crude material stirred m 1 mL of 50% TFA/DCM for 1 hr at 25 °C. The
solvents were evaporated and the crude product was purified by RP-HPLC to
give 7 mg (23%) of the title compound as a yellow solid: 1H NMR (400 MHz,
CD3OD) d 8.30 (s, 1H), 8.02 (m, 1H), 7.88 (m, 1H), 7.61 (m, 2H), 6.05 (s,
1H), 3.90 (q, 3H), 2.78 (s, 3H), 2.22 (s, 3H), 1.02 (t, 3H). Mass spectrum
(ESI, m/z) calcd. for C18H20N2O4S3 424.1, found 425.1 (M+H).
Example 153
4-[3-(lH-Imidazol-2-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate
A mixture containing 20 mg (0.04 mmol) of {[4-(3-formyl-
benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic
acid tert-butyl ester (Example 143a), 10 uL (0.06 mmol) of 40% aqueous
glyoxal, and 65 mg (0.84 mmol) of NH4Ac was heated at 80 °C for 12 hrs in
methanol. The solvents were evaporated and the residue stirred in 1 mL of
50% TFA/DCM for 1 hr at 25 °C. The solvents were again evaporated and the
crude material purified by RP-HPLC to give 4 mg (18%) of the title
compound as a yellow solid: 1H NMR (400 MHz, CD3OD) 5 8.64 (m, 1H),
8.39 (s, 1H), 8.24 (m, 2H), 7.88 (m, 1H), 7.63 (s, 1H), 2.73 (s, 3H). Mass
spectrum (ESI, m/z) calcd. for C15H14N4O2S3 378.0, found 379.1 (M+H).
Example 154
N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-biphenyl-2-
yl]-acetamide trifluoroacetate
A solution containing 30 mg (0.06 mmol) of {[4-(2'-amino-biphenyl-3-
sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl} -carbamic acid tert-
butyl ester (prepared according to the general procedure for Suzuki coupling
in Example 140 using 2-aminophenyl boronic acid), 10 mg (0.09 mmol) of
2,6-lutidine, and 7 mg (0.07 mmol) of acetic anhydride was stirred in 2 mL of
DCM at 25 °C for 12 hrs. The crude material was purified by flash
chromatograpy to give the title compound as a BOC protected amidine which
was deprotected by stirring at 25 °C for 1 hr in 1 mL of 50% TFA/DCM. The
solvent was evaporated and the crude material purified by RP-HPLC to give
20 mg (60 %) of the title compound as a yellow solid: 1H NMR (400 MHz,
CD3OD) 5 8.31 (s, 1H), 8.18 (m, 1H), 8.07 (m, 1H), 7.76 (m, 1H), 7.71 (s,
1H), 7.47 (m, 4H), 2.82 (s, 3H), 2.74 (s, 3H). Mass spectrum (ESI, m/z) calcd.
for C20H19N3O3S3 445.1, found 446.1 (M+H).
Example 155
4-(2'-Methanesulfonylamino-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
A solution containing 30 mg (0.06 mmol) of {[4-(2'-amino-biphenyl-3-
sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-
butyl ester (prepared according to the general procedure for Suzuki coupling
in Example 140 using 2-aminophenyl boronic acid), 10 mg (0.09 mmol) of
2,6-lutidine, and 8 mg (0.07 mmol) of methanesulfonyl chloride was stirred in
2 mL of DCM at 25 °C for 12 hrs. The crude material was purified by flash
chromatograpy to give the title compound as a BOC protected amidine which
was deprotected by stirring at 25 °C for 1 hr in 1 mL of 50% TFA/DCM. The
solvent was evaporated and the crude material purified by RP-HPLC to give
25 mg (70 %) of the title compound as a yellow solid: 1H NMR (400 MHz,
CD3OD) 5 8.29 (s, 1H), 8.06 (m, 1H), 8.03 (m, 1H), 7.73 (m, 2H), 7.42 (m,
4H), 2.73 (s, 3H), 1.96 (s, 3H). Mass spectrum (ESI, m/z) calcd. for
C19H19N3O4S4 481.0, found 482.1 (M+H).
Example 156
4-[5-Bromo-6-(3-imidazol-l-yl-propylamino)-pyridine-3-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
a) 4-[5-Bromo-6-(3-imidazol-l-yl-propylamino)-pyridine-3-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxylic acid methyl ester
To a vial containing a stirbar was added 4-(5-bromo-6-chloro-pyridine-
3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.050
g, 0.113 mmol), (Example 2:step c), 3-imidazol-l-yl-propylamine (0.018 g,
0.146 mmol), diisopropylethylamine (0.073 g, 0.565 mmol), THF [0.50 mL],
DMF [0.50 mL]. The reaction vessel was sealed and the solution was heated
to 80 °C for 18 hours. Removal of the solvents in vacuo followed by
chromatography (5% MeOH/DCM) yielded the title compound. 1H-NMR
(CDCl3): d 8.69 (d, 1H, J=2.1 Hz), 8.10 (d, 1H .7=2.1 Hz), 8.03 (s, 1H), 8.02
(s, 1H), 7.57 (s, 1H), 7.10 (s, 1H), 6.97 (s 1H), 5.70 (t, 1H, J=5.S Hz), 4.06 (t,
2H, 7=6.8 Hz), 3.89 (s, 3H), 3.57 (m, 2H), 2.97 (s, 2H), 2.90 (s, 2H), 2.64 (s,
3H), 2.17 (m, 2H). ESI-MS (m/z): Calcd. For C18H19BrN4O4S3: 532.5
(M+H); found 530.9, 532.9.
b) 4-[5-Bromo-6-(3-imidazol-l-yl-propylamino)-pyridine-3-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
Trimethyl aluminum [2M in toluene], (1.12 mL, 2.26 mmol) was
added slowly to a flask containing a stirbar and ammonium chlonde (0.120 g,
2.26 mmol). This solution was placed in a 90°C oil bath for 5 minutes under
argon. Solution was allowed to cool to room temperature. This solution was
then added to 4-[5-Bromo-6-(3-imidazol-l-yl-propylamino)-pyridine-3-
sulfonyl]-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (100 mg,
0.22 mmol) which was dissolved in toluene [2 mL]. Reaction was heated at
80 °C for two hours. Reaction was added to a slurry of silica gel in DCM.
The slurry was filtered using 15% MeOH/DCM. Removal of the solvents in
vacuo followed by reverse-phase HPLC of the residue [acetonitrile/water
(0.01 %TFA)] yielded the title compound. 1H-NMR (MeOH): d 8.96 (s, 1H),
8.62 (d, 1H, y=2.0 Hz), 8.26 (s, 1H), 8.12 (d, 1H, J =2.3 Hz), 7.68 (t, 1H,.J =1.7 Hz), 7.56 (t, 1H, .7=1.6 Hz), 4.32 (t, 2H, J =7.2 Hz), 3.60 (t, 2H, J =6.7
Hz), 2.72(s, 3H), 2.24 (m, 2H). ESI-MS (m/z): Calcd. For C17H19BrN6O2S3:
515.47 (M+H); found 515.1, 517.0.
Example 157
4-[5-Bromo-6-(2-methyl-2-morpholin-4-yl-propylamino)-pyridine-3-
sulfonyl]-5-methylsulfanyl-thiophene-2-carboxamidinetrifluoroacetate
a) 4-[5-Bromo-6-(2-methyl-2-morpholin-4-yl-propylainino)-pyridin e-3-
sulfonyl]-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester
The reaction was conducted following the procedure for Example
156:step a, using 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester (0.050 g, 0.113 mmol), (Example
2:step c), 2-methyl-2-morpholin-4-yl-propylarn.ine (0.023 g, 0.146 mmol),
diisopropylethylamine (0.073g, 0.565 mmol), THF [0.5 mL], DMF [0.5 mL].
Chromatography of the residue (25%-50%EtOAc/Hx) yielded the title
compound. 1H-NMR (CDCl3): d 8.70(d, 1H, J =2.1 Hz), 8.0S(d, 1H, J =2.1
Hz), 8.02 (s, 1H), 6.82 (t, 1H, J =4.1), 3.90 (s, 3H), 3.76 (t, 4H, J =4.1), 3.37
(d, 2H, J=4.1), 2.64 (s, 3H), 2.57 (t, 4H, J =4.5),1.59 (s, 3H), 1.13 (s, 6H).
ESI-MS (m/z): Calcd. For C20H26BrN3O5S3: 565.54 (M+H); found 564.0,
565.9.
b) 4~[5-Bromo-6-(2-methyl-2-morpholin-4-yl-propylamino)-pyridine-3-
sulfonyl]-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
The reaction was conducted following the procedure for Example
156:step b, using trimethyl aluminum [2M in toluene], (0.194 mL, 0.389
mmol), ammonium chloride (0.021 g, 0.389 mmol), 4-[5-bromo-6-(2-methyl-
2-morpholin-4-yl-propylamino)-pyridine-3-sulfonyl]-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester (0.022 g, 0.039 mmol), toluene
[lmL|. Reverse-phase HPLC yielded title compound. ESI-MS (m/z): Calcd.
for C19H26N5O3S3: 549.54 (M+H); found 547.9,549.9.
Example 158
4-{5-Bromo-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridine-3-
sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
a) 4-{5-Bromo-6-[(6-triflttoromethyl-pyridin-3-ylmethyl)-amino]-
pyridine-3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxylic acid methyl
ester
The reaction was conducted following the procedure for Example
156:step a, using 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester (0.050 g, 0.113 mmol), (Example
2:step c), 3-aminomethyl-6-trifluoromethyl pyridine (0.026 g, 0.146 mmol),
diisopropylethylamine (0.073 g. 0.565 mmol), THF [0.5 mL], DMF [0.5 mL].
Chromatography of the residue (25%-50%EtOAc/Hx) yielded the title
compound. ESI-MS (m/z): Calcd. For C19H15BrN3O4S3: 583.44 (M+H); found
582.0, 583.9.
b.) 4-{5-Bromo-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-
pyridine-3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine
trifluoroacetate
The reaction was conducted following the procedure for Example
156:step b, using trimethyl aluminum [2M in toluene], (0.463 mL, 0.927
mmol), ammonium chloride (0.049 g, 0.927 mmol), 4-{5-bromo-6-[(6-
trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridine-3-sulfonyl}-5-
methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.054 g, 0.093
mmol), toluene [lmL]. Reverse-phase HPLC yielded title compound. ESI-
MS (m/z): Calcd. For C18H15BrF3N5O2S3: 567.44 (M+H); found 566.0, 567.9.
Example 159
4-{5-Bromo-6-[2-(3H-imidazol-4-yl)-ethylamino]-pyridine-3-sulfonyl}-5-
5 methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
a) 4-{5-Bromo-6-[2-(3H-imidazol-4-yl)-ethylamino]-pyridine-3-
sulfonyl}-5-methylsulfanyl~thiophene-2-carboxylic acid methyl ester
The reaction was conducted following the procedure for Example
156:step a, using. 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester (0.050 g, 0.113 mmol), (Example
2:step c), 2-(3H-imidazol-4-yl)-ethylamine (0.027 g, 0.146 mmol),
diisopropylethylamine (0.073 g, 0.565 mmol), THF [0.5 mL], DMF [0.5 mL].
Chromatography of the residue (0%-6%MeOH/DCM) yielded the title
compound. ESI-MS (m/z): Calcd. for C17H17BrN4O4S3: 518.44 (M+H); found
517.0,519.
b) 4-{5-Bromo-6-[2-(3H-imidazol-4-yl)-ethyiamino]-pyridine-3-
sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
The reaction was conducted following the procedure for Example
156:step b, using trimethyl aluminum [2M in toluene], (0.773 mL, 1.546
mmol), ammonium chloride (0.082 g, 1.546 mmol), 4-{5-bromo-6-[2-(3H-
imidazol-4-yl)-ethylamino]-pyridine-3-sulfonyl}-5-methylsulfanyl-thiophene-
2-carboxylic acid methyl ester (0.080 g, 0.155 mmol), toluene [2mL]. HPLC
yielded title compound. ESI-MS (m/z): Calcd. for C17H17BrN4O4S3: 501.45
(M+H); found 502.2, 504.2.
Example 160
4-[5-Bromo-6-(4-sulfamoyl-benzylamino)-pyndine-3-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
a) 4-[5-Bromo-6-(4-sulfamoyl-benzylamino)-pyridine-3-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxylic acid methyl ester
The reaction was conducted following the procedure for Example
156:step a, using. 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester (0.050 g, 0.113 mmol), (Example
2:step c), 4-aminomethyl-benzenesulfonamide (0.033 g, 0.146 mmol),
diisopropylethylamine (0.073 g, 0.565 mmol), THF [0.5 mL], DMF [0.5 mL].
Chromatography of the residue (0%-5%MeOH/DCM) yielded the title
compound. ESI-MS (m/z): Calcd. for C19H18BrN3O6S4: 592.53 (M+H); found
592.0, 593.9.
b) 4-[5-Bromo-6-(4-sulfamoyl-benzylamino)-pyridine-3-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
The reaction was conducted following the procedure for Example
156:step b, using triraethyl aluminum [2M in toluene], (0.773 mL, 1.546
mmol), ammonium chloride (0.082 g, 1.546 itnmol), 4-{5-bromo-6-[2-(3H-
imidazol-4-yl)-ethylamino]-pyridine-3-sulfonyl}-5-methylsulfanyl-thiophene-
2-carboxylic acid methyl ester (O.OSO g, 0.155 mmol), toluene [2mL].
Reverse-phase HPLC yielded the title compound. ESI-MS (m/z): Calcd. for
C17H17BrN4O4S3: 501.45 (M+H); found 502.2, 504.2.
Example 161
4-(6-Benzylamino-5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-
2-ca.rboxamidine trifluoroacetate
a) 4-(6-Benzylamino-5-bromo-pyridine-3-snlfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester
To a vial containing a stirbar was added 4-(5-bromo-6-chloro-pyridine-
3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.020
g, 0.045 mmol), (Example 2:step c), benzylamine (0.005 g, 0.407 mmol),
MeOH [2.0 mL]. Reaction vessel was sealed and heated to 50°C for 72 hours.
Removal of the solvents in vacuo followed by chromatography of the residue
(10%-20% EtOAc/Hx) yielded the title compound. ESI-MS (m/zl: Calcd. for
C19H17BrN2O4S3: 514.45 (M+H); found 513.2,515.1.
b) 4-(6-Benzylamino-5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
The reaction was conducted following the procedure for Example
156:step b, using trimethyl aluminum [2M in toluene], (0.120 mL, 0.253
mmol), ammonium chloride (0.014 g, 0.253 mmol), 4-(6-Benzylamino-5-
bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid
methyl ester (0.013 g, 0.0253 mmol), toluene [2mL]. Reverse-phase HPLC
yielded title compound. ESI-MS (m/z): Calcd. for C19H18BrN3O2S3: 497.47
(M+H); found 497.3, 499.1.
Example 162
4-(5-Bromo-6-isobutylamino-pyridine-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidmetrifluoroacetate
a) 4-(5-Bromo-6-isopropylamino-pyridine~3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester
To a vial containing a stirbar was added 4-(5-bromo-6-chloro-pyridme-
3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.100
g, 0.226 mmol), (Example 2:step c), isopropylamine (0.012 g, 0.204 mmol),
THF [2.0 mL]. Reaction vessel was sealed and heated to 70°C for 72 hours.
Removal of the solvents in vacuo followed by chromatography (0%-15%
EtOAc/Hx) yielded the title compound. ESI-MS (m/z): Calcd. lor
C15H17BrN2O4S3: 466.41 (M+H); found 466.9.
b) 4-(5-Bromo-6-isobutylamino-pyridine-3-sulfotiyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
The reaction was conducted following the procedure for Example
156:step b, using trimethyl aluminum [2M in toluene], (0.620 mL, 1.247
mmol), ammonium chloride (0.067 g, 1.247 mmol), 4-(5-bromo-6-
isopropy]amino-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic
acid methyl ester (0.058 g, 0.125 mmol), toluene [2mL]. Reverse-phase
HPLC yielded title compound. ESI-MS (m/z): Calcd. for C14H13BrN4O2S3:
450.41 (M+H); found 449.1, 451.0.
Example 163
4-{5-Bromo-6-[(pyridin-3-ylmethyl)-amino]-pyridine-3-sulfonyl}-5-
methylsulfanyl-thiophaene-2-carboxamidine trifluoroacetate
a) 4-{5-Bromo-6-[(pyridm-3-ylmethyl)-amino]-pyridine-3-sulfonyl}-5-
methylsulfanyl-thiophene-2-carboxylic acid methyl ester
The reaction was conducted following the procedure for Example
162:step a, using 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester (0.100 g, 0.226 mmol). (Example
2:step c), 3-aminomethyl pyridine (0.046 g, 0.430 mmol), THF [4.0 mL].
Chromatography of the residue (25%-50% EtOAc/Hx) yielded the title
compound. ESI-MS (m/z): Calcd. for C18H16BrN3O4S3: 515.44 (M+H); found
514.1,516.0.
b) 4-{5-Bromo-6-[(pyridin-3-ylmethyl)-amino]-pyridine-3-sulfonyl}-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
The reaction was conducted following the procedure for Example
156:step b, using trimethyl aluminum [2M in toluene], (0.710 mL, 1.439
mmol), ammonium chloride (0.077 g, 1.439 mmol) 4-{5-Bromo-6-[(pyridin-3-
ylmethyl)-amino]-pyridine-3-sulfonyl}-5-methylsulfanyl-thiophene-2-
carboxylic acid methyl ester (0.074 g, 0.1439 mmol), toluene [2 mL].
Reverse-phase HPLC yielded title compound. ESI-MS (m/z): Calcd. for
C17H16BrN5O2S3: 499.44 (M+H); found 499.1, 501.0.
Example 164
4-{5-Bromo-6-[(pyridin-4-ylmethyl)-arnino]-pyridine-3-sulfonyl}-5-
methylsulfanyl+thiophene-2-carboxamidine trifluoroacetate
a) 4-(5-Bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine
Trimethyl aluminum [2M in toluene], (0.S50 mL, 1.694 mmol) was
added slowly to a flask containing ammonium chloride (0.091 g, 1.694 mmol)
and a stir bar. This solution was placed in a 90°C oil bath for 5 minutes under
argon. Solution was then allowed to cool to room temperature. This solution
was then added 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester (0.075 g, 0.1694 mmol), (Example
2:step c), which was dissolved in toluene [1 mL]. Reaction was heated at 80
°C for two hours. Reaction was added to a slurry of silica gel in DCM. The
slurry was filtered using 15% MeOH/DCM. Used crude material in next step.
ESI-MS (m/z): Calcd. for C11H9BrClN3O2S3: 427.76 (M+H); found 426.0,
428.0.
b) {[4-(5-Broino-6~chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
To a flask containing a stir bar was added 4-(5-bromo-6-chloro-
pyridine-3-sulfonyl)-ethylsu[fanyl-thiophene-2-carboxamidine (0.96 g, 2.25
mmol), di-tert-butyl dicarbonate (0.74 g, 3.39 mmol), diisopropylamine (1.16
g, 9.03 mmol), DMF (60.0 mL). Solution was stirred at room temperature for
18 hours. Removal of the solvents in vacuo followed by chromatography
(10%-15% EtOAc/Hx). Compound contained residual di-tert-butyl
dicarbonate. Compound was dissolved in hexane, heated to 40°C for 1 hour.
Solution was filtered to yield title compound. ESI-MS (m/z): Calcd. for
C11H9BrClN3O3S3: 527.76 (M+H); found 426.0, 428.0.
c) [(4-{5~Bromo-6-[(pyridin-4-ylmethyl)-amino]-pyridine-3-sulfonyl}-5-
methylsulfanyl-thiophen-2-yl)-imino-methyl]-carbamic acid ten-butyl ester
To a vessel containing a stir bar was added {[4-(5-bromo-6-chloro-
pyridme-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-
carbamic acid tert-butyl ester (0.035 g, 0.066 mmol), 4-aminomethylpyridine
(0.015 g, 0.133 mmol), THF [3 mL]. The reaction vessel was sealed and
heated to 70°C for 18 hours, cooled to room temperature and concentrated in
vacuo. The crude; residue was dissolved in a solution of
chloroform/trifluoroacetic acid (1/1) [2 mL] and was allowed to stir at room
temperature for 2 hours. The reaction was concentrated in vacuo followed by
reverse-phase HPLC [acetonitrile/water (0.01%TFA)] to give the title
compound. ESI-MS (m/z): Calcd. for C17H16BrN5O2S3: 499.44 (M+H); found
498.0, 500.0.
Example 165
4-{5-Bromo-6-[(pyridin-2-ylmethyl)-amino]-pyridine-3-sulfonyl}-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
a) 4-{5-Bromo-6-[(pyridin~2-ylmethyl)-amino]-pyridine-3-sulfonyl}~5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
The reaction was conducted following the procedure for Example 164:
step c, using {[4-(5-bromo-6-chloro-pyridme-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.035 g, 0.066
mmol), (example 164:step b), 2-aminomethylpyridine (0.014 g, 0.133 mmol),
THF [3 mL], followed by chloroform/TFA (1:1) to yield the title compound.
ESI-MS (m/z): Calcd. for C17H16BrN5O2S3: 499.44 (M+H); found 499.1,
501.0.
Example 166
4-{6-[(4-Amino-pyrimidin-5-y]methyl)-amino]-5-bromo-pyridine-?-sulfonyl}-
5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
The reaction was conducted following the procedure for Example
164:step c, using {[4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(0.035 g, 0.067 mmol), 4-amino-5-aminomethyl-2-methylpyrimidine (0.018 g,
0.135 mmol), THF [2 mL], followed by DCM/TFA (1:1) and reverse-phase
HPLC to yield the title compound. ESI-MS (m/z): Calcd. for
C18H19BrN6O2S3: 528.48 (M+H); found 528.0, 529.9.
Example 167
4-[5-Bromo-6-(3-hydroxy-2,2-dimethyl-propylamino)-pyridine-3-sulfonyl]-5-
methylsulfanyl-thiopbene-2-carboxamidine trifluoroacetate
The reaction was conducted following the procedure for Example
164:step c, using {[4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(0.035 gr 0.066 mmol), 3-amino-2,2-dimethylpropanol (0.013 g, 0.133 mmol),
THF [2 mL], followed by DCM/TFA (1:1) and reverse-phase HPLC to yield
the title compound. ESI-MS (m/z): Calcd. for C17H22BrN3O3S3: 493.48
(M+H); found 493.1, 495.0.
Example 168
4-{5-Brorno-6-[(3-rnethyl-thiophen-2-ylmethyl)-amino]-pyridine-3-sulfonyl}-
5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
To a vessel containing a stir bar was added {[4-(5-bromo-6-chloro-
pyridine-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-
carbamic acid tert-butyl ester (0.035 g, 0.066 mmol), 3-methylthiophene-2-
methylamine (0.016 g, 0.133 mmol), THF [2 mL]. The reaction vessel was
sealed and heated to 70°C for 18 hours, cooled to room temperature and
concentrated in vacua. Chromatography of crude material (10%-25%
EtOAC/Hx) yielded the intermediate which was dissolved in a solution of
chloroform/trifluoroacetic acid (1/1) [2 mL] and was allowed to stir at room
temperature for 2 hours. The reaction was concentrated in vacuo followed by
reverse-phase HPLC [acetonitrile/water (0.01 %TF A)] to give the title
compound. ESI-MS (m/z): Calcd. for C18H18BrN3O2S4: 517.52 (M+H); found
516.9,518.9.
Example 169
4-{5-Bromo-6-[(tetrahydro-furan-2-ylmethy])-amino]-pyridine-3-sulfony!}-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
a) 4-{5-Bromo-6-[(tetrahydro-furan-2-ylmethyl)~amino]-pyridine-3-
sulfonyl}-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester
The reaction was conducted following the procedure for Example
156:step a, using. 4-(5-bromo-6-chloro-pyridine-3-sulfbnyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester (0.050 g, 0.113 mmol), (Example
2:step c), c-(tetrahydro-furan-2-yl)-methylarnine (0.015 g, 0.146 mmol),
diisopropylethylamine (0.073 g, 0.565 mmol), THF [0.5 mL], DMF [0.5 mL].
Chromatography of the residue (10%-35% EtOAc/Hx) yielded the title
compound. ESI-MS (m/z): Calcd. for C17H19BrN2O5S4: 508.45 (M+H); found
507.1,509.0
b) 4-{5-Bromo-6-[(tetrahydro-furan-2-ylmethyl)-amino]-pyridine-3-
sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
The reaction was conducted following the procedure for Example
156:step b, using trimethyl aluminum [2M in toluene], (0.443 mL, 0.867
mmol), ammonium chloride (0.046 g, 0.867 mmol), 4-{5-bromo-6-
[(tetrahydro-furan-2-ylmethyl)-aimno]-pyridme-3-sulfonyl}-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester (0.044 g, 0.087 mmol), toluene
[lmL]. Reverse-phase HPLC yielded title compound. ESI-MS (m/z): Calcd.
For C16H19BrN4O3S3: 492.45 (M+H); found 4911, 493.0.
Example 170
4-{4'--[N'-(4-Methanesulfonyl-butyl)-guanidino]-2'-methyl-biphenyl-3-
sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
a) 2-methyl-l-(4-methanesulfonyl-butyl)-l,3-bis (carbamic acid-tert-
butyl ester)-isothiourea
The reaction was conducted following the procedure for Example
171:step b, using 4-methariesulfonyl-butylamine (0.058 g, 0.378 mmol), 2-
methyl-l-(3-methanesulfonyl-propyl)-l,3-bis (carbamic acid-tert-butyl ester)-
isothiourea (0.100 g, 0.344 tnmol), Triphenylphosphine (0.098 g, 0.378
mmol), THF[ 6 mL]. To this was added Diisopropyl azodicarboxylate (0.076
g, 0.378 mmol). Chromatography of the residue (50% EtOAc/Hx) yielded the
title compound.
b) [Imino-(4-{4'-[N'-(4-metlianesulfonyl-butyl)-N',N"--(carbamic acid
tert-butyl ester)-guanidino]-2'-methyl-biphenyl-3-sulfonyl}-5-
methylsulfanyl-thiophen-2-yl)-methyl]-carbamic acid tert-butyl ester
The reaction was conducted following the procedure for Example
171-.step c, using {[4-(4'-amino-2'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(0.025 g, 0.480 mmol), (Example 120:step b), 2-methyl-l-(4-methanesulfonyl-
butyl)-l,3-bis (carbamic acid-tert-butyl ester)-isothiourea (0.101 g, 0 240
mmol), MeOH [2 mL], acetic acid (0.029 g, 0.480 mmol). Chromatography
(10%-20% EtOAc/Hx). The compound was dissolved in trifluoroacetic
acid/dichloromethane (1:1). [4 mL]. Solvent was removed in vacuo followed
by reverse-phase HPLC to yield the title compound. ESI-MS (m/z): Calcd.
for C25H31N5O4S4: 594.81 (M+H); found 594.1.
Example 171
4-{4'-[N'-(3-Methanesulfonyl-propyl)-guanidino]-2'-methyl-biphenyl-3-
sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
a) 3-Methatiesulfonyl-propan-l-ol
3-bromo-propan-l-ol was dissolved in EtOH [2 mL], methane sulfinic
acid was dissolved in H2O [2 mL]. The two solutions were added together and
heated to 50°C for 18 hours. Reaction was cooled to room temperature and
the compound was extracted with EtOAc, dried using sodium sulfate, and the
solvent was removed in vacuo. Chromatography of the residue (l%-7%
MeOH/DCM) yielded the title compound. 1H-NMR (CDCl3): d 3.69 (m, 2H),
3.14 (m, 2H), 2.91 (s, 3H), 2.02 (m, 2H).
b) 2-methyl-l-(3-methanesulfonyl-propyl)-l,3-bis (carbamic acid-tert-
butyl ester)-isothionrea
Under argon, 3-metfaanesulfonyl-propan-l-ol (0.059 g, 0.362mmol), 2-
methyl-l-(3-methanesulfonyl-propyl)-l,3-bis (carbamic acid-tert-butyl ester)-
isothiourea (0.123 g, 0.329 mmol), Triphenylphosphine (0.112 g, 0.362
mmol), THF [8 mL] was charged to a flask containing a stirbar. To this was
added diisopropyl azodicarboxylate (0.095 g, 0.362 mmol). Reaction stired at
room temperature for 18 hours. Solvent was removed in vacuo followed by
chromatography (0%-25% EtOAc/Hx) to yield title compound (0.089 g). 1H-
NMR (CDCl3): d 3.75 (t, 2H, 1=6.7 Hz), 3.14 (m, 2H), 2.94 (s, 3H), 2.42 (s,
3H), 2.20 (m, 2H), 1.52 (s, 9H), 1.50 (s, 9H).
c) [Immo-(4-{4'-[N'-(3-methanesulfonyl-propyl)-Nr,N"-(carbamic acid
tert-butyl ester)-guanidino)-2'-methyi-biphenyl-3-sulfonyl}-5-
methylsulfanyl-thiophen-2-yl)-methyl]-carbamic acid tert-butyl ester
2-methyl-1 -(3-methanesulfonyl-propyl)-1,3-bis (carbamic acid-tert-
butyl ester)-isothiourea (0.089 g, 0.217 mmol), {[4-(4'-Amino-2'-methyl-
biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-
carbamic acid tert-butyl ester (0.022 g, 0.043 mmol), (Example 1.20:step b),
MeOH [2 mL] was added to a flask containing a stirbar. To this was added
acetic acid (0.026 g, 0.434 mmol) and the solution was heated to 40°C for 18
hours. Reaction was cooled to room temperature, solvent was removed in
vacuo, and residue was chromatographed (10%-20% EtOAc/DCM) giving the
title compound (0.026 g, 68%). ESI-MS (rn/z): Calcd. for C39H53N5O10S4:
881.13 (M+H); found 879.8, 880.8.
d) 4-{4'-[N'-(3-Methanesulfonyl-propyl)-guanidino]-2'-methyl-
biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine
trifluoroacetate
[Imino-(4-{4'-[N'-(3--methanesulfonyl-propyl)-N',N"-(carbamic acid
tert-butyl ester)-guanidino]-2'-methyl-biphenyl-3-sulfonyl}-5-methylsulfanyl-
thiophen-2-yl)-methyl]-carbamic acid tert-butyl ester (0.026 g, 0.029 mmol)
was dissolved in 1:1 solution of trifluoroacetic acid: dichloromethane [1.5
mL:1.5mL]. Solution was allowed to stir at room temperature for 2 hours.
The reaction was concentrated in vacuo followed by reverse-phase HPLC
[acetonitrile/water (0.01 %TFA)] to give the title compound (0.017 g). ESI-MS
(m/z): Calcd. for C24H29N5O4S4: 580.78 (M+H); found 580.1.
Example 172
4-{4'-[N'-(6-Methanesulfonyl-hexyl)-guanidino]-2'-methyl-biphenyl-3-
sulfonyl}-5-methylsulfany]-thiophene-2-carboxamidinetrifluoroacetate
a) 6-Methanesulfonyl-hexan-1-ol
The reaction was conducted following the procedure for Example
171:step a, using 6-bromo-hexan-l-ol (0.300 g, 1.660 mmol), methane sulfinic
acid, (0.844 g, 8.280 mmol), EtOH [2 mL], H2O, [2 mL]. Chromatography of
the residue (l%-5% MeOH/DCM) yielded the title compound (0.141 g 48%).
1H-NMR (CDCl3): d 3.67 (t, 2H, J =6.2 Hz), 3.03 (t, 2H, J =8.0 Hz), 2.92 (s,
3H), 1.89 (m, 2H), 1.60 (m, 2H), 1-46 (m, 4H).
b) 2-methyl-l-(6-methanesulfonyl-hexyl)-l,3-bis (carbamic acid-tert-
butyl ester)-isothiourea
The reaction was conducted following the procedure for Example
171:step b, using 6-methanesulfonyl-hexan-l-oi (0.141 g, 0.782 mmol), 2-
methyl-l-(3-methanesulfonyl-propyl)-l,3-bis (carbamic acid-tert-butyl ester)-
isothiourea (0.206 g, 0.711 mmol), Triphenylphosphine (0.205 g, 0.782
mmol), THF [5 mL]. To this was added Diisopropyl azodicarboxylate (0.158
g, 0.782 mmol). Chromatography of the residue (0%-100%EtOAc/Hx)
yielded the title compound (0.213 g, 66%) ESI-MS (m/z): Calcd. for
C19H36N2O6S2: 453.63 (M+H); found 253.1.
c) [Imino-(4-{4'-[N'-(6-methanesulfonyl-hexyl)-N',N"--(carbamic acid
tert-butyl ester)-guanidino]-2'-methyl-biphenyl-3-sulfonyl}-5-
methylsulfanyl-thiophen-2-yl)-methyl]-carbamic acid tert-butyl ester
The reaction was conducted following the procedure for Example
171:step c, using 2-methyl-l-(6-methanesulfonyl-hexyl)-l,3-bis (carbamic
acid-tert-butyl ester-isothiourea (0.213 g, 0.471 mmol), {[4-(4'-amino-2'-
methyl-biphenyl-3 -sulfony l)-5 -methylsulfanyl-thiophen-2 -yl] -imino-methyl} -
carbamic acid tert-butyl ester (0.081 g, 0.157 mmol), (Example 120:step b),
MeOH [4 mL], acetic acid (0.094 g, 1.570 mmol). Chromatography (0%-20%
EtOAc/Hx) yielded the title compound. (0.086 g 60%) ESI-MS (m/z): Calcd.
for C42H59N5O10S4: 923.21 (M+H); found 921.8.
d) 4-{4'-[N'-(6-Methanesulfonyl-hexyl)-guanidino]-2'-methyl-biphenyl-
3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
The reaction was conducted following the procedure for Example
171:step d, using imino-(4-{4'-[N'-(6-methanesulfonyl-hexyl)-N',N"-(carbamic
acid tert-butyl ester)-guanidino]-2'-methyl-biphenyl-3-sulfonyl} -5-
methylsulfanyl-thiophen-2-yl)-rnethyl]-carbamic acid tert-butyl ester (0.086 g,
0.093 mmol), trifluoroacetic acid [2mL], DCM [2mL]. Reverse-phase HPLC
yielded the title compound (0.021 g, 38%). ESI-MS (m/z): Calcd. for
C27H35N5O4S4: 622.86 (M+H); found 622.2.
Example 173
4-{4'-[N'-(5-Methanesulfonyl-pentyl)-guanidino]-2'-methyl-biphenyl-3-
sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidinetrifluoroacetate
a) l-Chloro-5-methanesulfonyl-pentane
The reaction was conducted following the procedure for Example
171:step a, using l-bromo-5-chloro-pentane (0.400 g, 2.150 mmol), methane
sulfmic acid, (1.090 g, 10.75 mmol), EtOH [3 mL], H2O, [3 ml.].
Chromatography of the residue (0%-25% MeOH/DCM) yielded the title
compound (0.213 g 53%). 1H-NMR (CDCl3): d 3.55 (t, 2H, J=6.3 Hz), 3.03
(t, 2H, J =8.0 Hz), 2.91 (s, 3H), 1.85 (m, 4H), 1.63 (m, 2H)
b) 2-methyl-l-(5-methanesulfonyl-pentyl)-l,3-bis (carbamic acid-tert-
butyl ester)-isothiourea
l-chloro-5-methanesulfonyl-pentane (0.021 g, 1.153 mmol), sodium
iodide (0.086 g, 5.765 mmol), acetone [5mL] were heated to 50°C for 1 hour.
Reaction was cooled to room temperature, extracted EtOAc, and concentrated
in vacuo. This solid was then taken up in DMF [1 mL] and added to a solution
of sodium hydride (0.020 g, 0.865 mmo;) and 2-methyl-l-(3-methanesulfonyl-
propyl)-l,3-bis (carbamic acid-tert-butyl ester)-isothiourea (0.016 g, 0.576
mmol) in DMF [3 mL] at 0°C. To this was added sodium iodide (0.864 g,
5.765 mmol) and the reaction was heated at 50°C for 18 hours. The reaction
was cooled to room temperature and filtered to give the title compound (0.124
g, 49%). ESI-MS (m/z): Calcd. for C18H34N2O6S4: 439.60 (M+H); found
239.2.
c) [Imino-(4-{4'-[N'-(6-methanesulfonyl-hexyl)-N',N"-(carbamic acid
tert-butyl ester)-guanidino]-2'-methyl-biphenyl-3-sulfonyl}-5-
methylsulfanyl-thiophen-2-yl)-methyl]-carbamic acid tert-bntyl ester
The reaction was conducted following the procedure for Example
171:step c, using 2-methyl-l-(5-methanesulfonyl-pentyl)-l,3-bis (carbamic
acid-tert-butyl ester)-isothiourea (0.124 g, 0.2S3 mmol), {[4-(4'-amino-2'-
methyl-biphenyl-3-sulfonyl)-5-rnethylsulfanyl-thiophen-2-yl]-imino-methyl}-
carbamic acid tert-butyl ester (0.048 g, 0.094 mmol), (Example 120:step b),
MeOH [4 mL], acetic acid (0.057 g, 0.942 mmol). Chromatography (5%-40%
EtOAc/Hx) yielded the title compound (0.049 g 18%). ESI-MS (m/z): Calcd.
for C41H57N5O10S4: 909.18 (M+H); found 907.8, 908.9.
d) 4-{4'-[N'-(5-Methanesulfonyl-pentyl)-guanidino]-2'-methyl-
biphenyl-3-sulfonyl}-5~methylsulfanyl-thiophene-2-carboxamidine
trifluoroacetate
[Imino-(4-{4'-[N'-(6-methanesulfonyl-hexyl)-N',N"-(carbarnic acid
tert-butyl ester)-guanidino]-2'-methyl-biphenyl-3-sulfonyl}-5-methylsulfanyl-
thiophen-2-yl)-methyl]-carbamic acid tert-butyl ester (0.049 g, 0.054 mmol)
was dissolved in 1:1 solution of trifluoroacetic acid:dichloromethane [3 mL:3
mL]. Solution was allowed to stir at room temperature for 2 hours. The
reaction was concentrated in vacuo followed by reverse-phase HPLC
[acetomtrile/water (0.01%TFA)] to give the title compound (0.030 g, 92%).
ESI-MS (m/z): Calcd. for C26H33N5O4S4: 608.84 (M+H); found 608.2.
Example 174
(5-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-
methyl-biphenyl-2-yl]-ureido}-pentyl)-phosphonic acid trifluoroacetate
a) [5-(l,3-Dioxo-l,3-dihydro-isoindol-2-yl)-pentyl]-phosphonic acid
diethyl ester
Added bromophthalamide (0.400 g, 1.351 mmol) and
trimethylphosphite (0.900 mL, 5.250 mmol) together in flask containing
stirbar. Heat reaction to 80°C for 18 hours. Reaction was cooled to room
temperature followed by chrornatography (50%-100% EtOAc/Hx) to yield the
title compound (0.300 g, 62%). ESI-MS (m/z): Calcd. for C21H24NO5P:
354.35 (M+H); found 354.1.
b) (5-Amino-pentyl)-phosphonic acid diethyl ester
[5-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-pentyl]-phosphonic acid
diethyl ester (0.300 g, 0.849 mmol) was dissolved in THF [2 mL], IPA [4
mL]. Hydrazine (0.081 g, 2.540 mmol) was added to this solution and stirred
at room temperature for 18 hours. The white precipitate was filtered and
washed with dichloromethane. Removal of the solvent in vacuo yielded the
title compound (0.136 g, 72%) 1H-NMR (CDCl3): d 4.07 (m, 4H), 2.68 (t, 2H,
J=6.74 Hz), 1.72 (m, 2H), 1.60 (m, 2H), 1.43 (m, 4H), 1.31 (m, 6H).
c) [5-(3-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-ureido)-
pentyl]-phosphonic acid
{[4-(6'-Amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiopheri-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.100 g, 0.204
mmol), (Example 25:step c), 4-nitrophenyl chloroformate (0.041 g, 0.204
mmol), pyridine (0.018 g, 0.224 mmol), DCM [3 mL] were added to a flask
containing a stirbar. This solution was stirred at room temperature for 2.5
hours. To this solution was added (5-Amino-pentyl)-phosphonic acid diethyl
ester (0.136 g, 0.611 mmol) and Triethylamine (0.062 g, 0.611 mmol).
Solution was stirred at room temperature for 18 hours. Reaction was
concentrated in vacuo followed by chromatography (50%-100% EtOAc/Hx) to
yield title compound (0.138 g, 88%). ESI-MS (m/z): Calcd. for
C34H47N4O8PS3: 767.93 (M+H); found 667.1.
d) (5-{3-[3'-(5-Carbaniimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-
6-methyl-biphenyl-2-yl]-ureido}-pentyl)-phosphonic acid
[5-(3-{3'-[5-(teit-Butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-ureido)-
pentyl]-phosphonic acid (0.058 g, 0.076 mmol), trimethylsilyl iodide (0.162 g,
0.756 mmol) and DCM [5 mL] were added to a flask and heated to 40°C for
10 minutes. The reaction was removed from the heat bath and allowed to stir
at room, temperature for 1 hour. H2O [56 µL] was added to this solution and
stirred for 1 hour. The reaction was concentrated in vacuo. MeOH [2 mL]
and 20 wt.% HC1 (aq.) [84 µL] were added to the concentrate and allowed to
stir at room temperature for 18 hours. Reaction was concentrated in vacuo
followed by reverse-phase HPLC [acetonitrile/water (0.01 %TFA)] to yield the
title compound. ESI-MS (m/z): Calcd. for C25H31N4O6PS3: 611.71 (M+H);
found 611.0.
Example 175
N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfony])-6-methyl-
biphenyl-2-yl]-4-methanesulfonyl-butyratnidehydrochloride
a) (Imino-{4-[6'-(4-methanesulfonyl-butysylamino)-2'-methyl-biphenyl-
3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-
butyl ester
{[4-(6'-Amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.500 g, 2.020
mmol), (Example 25:step c), triethylamine (0.153 g, 3.030 mmol), and DCM
[30mL] were added to a flask containing a stirbar. 4-Methanesulfonyl-butyryl
chloride (0.013 g, 0.611 mmol) was added slowly while monitoring reaction.
Reaction was concentrated in vacuo followed by chromatography (50%-80%
EtOAc/Hx). Material was dissolved in a solution of trifluoroacetic
acid/dichloromethane (1:1), [4mL]. This solution stirred at room temperature
for 2 hours. Reaction was concentrated in vacuo followed by reverse-phase
HPLC [acetonitrile/water (0.01%TFA)] to yield title compound (0.138 g,
88%). ESI-MS (m/z): Calcd. for C24H27N3O5S4: 566.75; found 566.1.
Example 176
{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-methyl-
biphenyl-4-ylamino]-methyl}-phosphonic acid
a) ({3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-
thiophetie-3-sulfonyl]-2-methyl-biphenyl-4-ylamino}-methyl)-phosphonic
acid diethyl ester
To a mixture of {[4-(4'-amino-2'-raethyl-biphenyl-3-sulfonyl)--5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(30 mg, 58.0 µmol), as prepared according to the procedure of step b of
Example 120, cesium carbonate (19 mg, 58 µmol), and N,N-
dimethylacetamide (0.4 mL) was added a solution of trifluoro-
methanesulfonic acid diethoxy-phosphorylmethyl ester (18 mg, 58 µmol) (Xu,
Y. et al., J. Org. Chem. 61, 7697 (1996); Phillion, D. et al., Tetrahedron Lett.
27, 1477 (1986)), and heated at 50 °C for 48 h. Additional trifluoro-
methanesulfonic acid diethoxy-phosphorylmethyl ester (18 mg, 58 µmol) was
added. The mixture was heated at 50 °C for additional 24 h. Solvent was
evaporated. The resulting mixture was partitioned between DCM and H2O.
Aqueous layer was separated and extracted with DCM. All the DCM layers
were combined, washed with H2O and brine, dried over Na2SO4, concentrated,
and flash chromatographed on silica gel column, eluting with EtOAc/DCM
(20 and 30 %) to give the title compound (38 mg, 98 % yield) as an orange oil.
1H NMR (CDCl3): d 8.23 (s, 1H), 7.92-7.88 (m, 2H), 7.53-7.46 (m, 2H), 6.98
(d, IH,J= 8.0 Hz), 6.56-6.53 (m, 2H), 4.23-4.15 (m, 4H), 3.56 (d, 2H, J =
12.5 Hz), 2.43 (S, 3H), 2.16 (S, 3H), 1.52 (S, 9H), 1.35 (t, 6H, ./= 7.0 Hz).
ESI-MS (m/z): Cald. For C29H39N3O7PS3: 668.2 (M+H); found: 667.8.
b) {[3'-(5-Carbamunidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-
methyl-biphenyl-4-ylamino]-methyl}-phosphonic acid
To a solution of ({3'-[5-(tert-butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-svilfonyl]-2-methyl-biphenyl-4-ylamino}-methyl)
phosphonic acid diethyl ester (38 mg, 0.057 mmol) in DCM (1.2 mL) at 0 °C
was added iodotrimethylsilane (25 µL) over 3 minutes period. After 1 h at 0
°C, H2O was added. The mixture was stirred for 30 minutes, and then
concentrated to give a brown solid. The solid was dissolved in MeOH (1.32
mL), 20 % HC1 was added, and stirred at ambient temperature for 3h. The
mixture was concentrated to give a brown solid. To this solid was added
TFA/DCM (1:1, 3 mL) and stirred at ambient temperature for 40 minutes.
The reaction mixture was then concentrated and purified by HPLC (C18
column, 10-70 % CH3CN over 30 minutes) to give the title compound (11 mg,
38 % yield) as a white solid.
ESI-MS (m/z): Cald. For C20H23N3O5PS3: 512.1 (M+H); found: 512.1.
Example 177
5-Methylsulfanyl-4-(2'-methyl-4'-trifluoromethanesulfonylamino-biphenyl-3-
sulfonyl)-1:hiophene-2-carboxamidine trifhioroacetate
a) {Imino-[5-methylsulfanyl-4-(2'-methyl-4'-
trifluoromethanesulfonylamino-biph enyl-3-sulfonyl)-thiophen -2-yl]-
methyl]-carbamic acid tert-butyl ester
To a solution of {[4-(4'-amino-2'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid ten-butyl ester
(34 mg, 66 µmol), as prepared according to the procedure of step b of
Example 120, and DIEA (28 µL, 0.16 mmol) in DCM (1.0 mL) in an ice-H2O
bath was added trifluoromethanesulfonic anhydride (12 µL, 72 µmol) with
stirring. After the ice bath expired, the mixture was continued to stir at
ambient temperature for 16 h, and then poured into saturated NaHCO3, and
extracted with EtOAc (2 x). The extracts were combined, washed with H2O
and brine, dried over Na2SO4, concentrated, and flash chromatographed on
silica gel column, eluting with EtOAc/hexane (20 to 40 %) to give the title
compound (9 mg, 21% yield) as an oil.
ESI-MS (m/z): Cald. For C15H27F3N3O6S4: 650.1 (M+H); found: 649.6.
b) 5-Methylsulfanyl-4-(2'-methyl-4'-trifluoromethanesulfonylainino-
biphenyl-3-sulfonyl)-thiophene-2-carboxamidine trifluoroacetaie
A mixture of {imino-[5-methylsulfanyl-4-(2'-methyl-4'-
trifluoromethanesulfonylamino-biphenyl-3-sulfonyl)-thiophen-2-yl]-methyl}-
carbamic acid tert-butyl ester (9 mg, 14 µmol) in TFA/DCM (1:1, 3mL) was
stirred at ambient temperature for 40 min. The mixture was concentrated, and
flashed chromatographed on silica gel column, eluting with MeOH/DCM (5 to
8%) to give the title compound (5 mg, 54% yield) as a pale yellow solid.
1H KMR (CDCl3): d S.32 (s, 1H), 8.04-8.01 (m, 1H), 7.96-7.95 (m, 1H), 7.68-
7.66 (m, 2H), 7.17 (m, 3H), 2.72 (s, 3H), 2.21 (s, 3H),
ESI-MS (m/z): Cald. For C20H19 F3N3O4S4: 550.0 (M+H); found: 550.0.
Example 178
3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-
biphenyl-2-ylmethoxy]-propionic acid
a) 3-{3'-[5-(tert-Butoxycarbonylamino-imino-inethyl)-2-methylsulfanyl-
thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylmethoxy}-propionic acid ethyl
ester
To a suspension of NaH (2.7 mg, 68 µmol, 60% oil dispersion) in
DMF (0.1 mL) was added a solution of {[4-(2'-hydroxymethy[-6'-methyl-
biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen--2-yl]-imino-methyl}-
carbamie acid tert-butyl ester (30 mg, 56.4 µmol) in DMF (0.1 mL), as
prepared according to the procedure of step b of Example 213. The mixture
was stirred at ambient temperature for 30 min, and then placed in an ice-water
bath. After 20 min, a solution of ethyl 3-bromopropionate (8.6 µL, 67.0 µmol)
in DMF (0.05 mL) was added once. Ice-water bath was removed, and the
mixture was stirred for 16 h. H2O was added, and the mixture was extracted
with EtOAc (3x). The extracts were combined, washed with H2O, dried over
Na2SO4, concentrated, and flash chromatographed on silica gel, eluting with
EtOAc/DCM (15 %) followed by EtOAc/hexane (40%) to give the title
compound (9 mg, 25%) yield) as an oil.
1H NMR (CDCl3): 8 7.99 (d, 1H, J= 7.7 Hz), 7.88 (s, 1H), 7.68 (s, 1H), 7.60-
7.56 (m, 1H), 7.44 (d, 1H, J= 7.6 Hz), 7.38 (d, 1H, .7=7.4 Hz), 7.34-7.30 (m,
1H), 7.23 (d, 1H, J = 7.3 Hz), 4.27-4.09 (m, 4H), 3.78 (bs, 2H), 2 67 (t, 2H, J
= 5.9 Hz), 2.57 (s, 3H), 2.02 (s, 3H), 1.47 (s, 9H), 1.28 (t, 3H,J= 7.1 Hz).
ESI-MS (m/z): Cald. For C30H37N2O7S3: 633.2 (M+H); found: 632.9.
b) 3-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-
thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylmethoxy}-propionic acid
To a solution of 3-{3'-[5-(tert-butoxycarbonylammo-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylmethoxy}-
propionic acid ethyl ester (7.0 mg, 11 µmol) in THF (0.5 mL) and MeOH
(0.25 mL) was added a solution of lithium hydroxide monohydrate (0.56 mg,
13 µmol) in H2O (50 mL). The mixture was microwaved at 80 °C for 150
seconds, acidified with 0.25 N HC1. to ~ pH 3, extracted with EtOAc/DCM
(1:1, 3x). The extracts were combined, washed with H2O, dried over Na2SO4,
concentrated, and flash chromatographed on silica gel column, eluting with
MeOH/DCM (2 to 4%) to give the title compound (5.1 mg, 76% yield) as a
white solid.
1H NMR (CDCl3): d 8.03-8.00 (m, 1H), 7.88-7.87 (m, 1H), 7.70 (bs, 1H), 7.57
(t, 1H, J= 7.7 Hz), 7.43-7.40 (m, 1H), 7.36-7.28 (m, 2H), 7.23 (d, 1H, J= 6.9
Hz), 4.28-4.15 (m, 2H), 3.65-3.75 (m, 2H), 2.65 (t, 2H, J =6.0 Hz), 2.58 (s,
3H),2.01 (s, 3H).
ESI-MS (m/z): Cald. For C28H33N2O7S3: 605.1 (M+H); found: 604.8.
c) 3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-
methyl-biphenyl-2-ylm ethoxy]-propionic acid
A mixture of 3-{3'-[5-(tert-butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylmethoxy}-
propionic acid (5.1 mg, 8.4 µmol) in TFA/DCM (1:1, 1.5 mL) was stirred at
ambient temperature for 1 h. The mixture was concentrated and flash
chromatographed on silica gel, eluting with MeOH/DCM (5 to 12 %) to give
the title compound (3.0 mg, 69 % yield) as a white solid.
1H NMR (CD3OD): d 8.18 (s, 1H), 8.03-8.00 (m, 1H), 7.88 (t, 1H, 7= 1.6 Hz),
7.68 (t, 1H, J= 7.8 Hz), 7.54-7.52 (m, 1H), 7.41 (d, 1H, J= 7.6 Hz), 7.33 (t,
1H, J= 1.6 Hz), 7.24 (d, 1H, J= 7.4 Hz), 4.23-4.16 (m, 2H), 3.64 (t, 2H, .J=
6.1 Hz), 2.69 (s, 3H), 2.54 (t, 2H,J= 6.0 Hz), 1.99 (s, 3H).
ESI-MS (m/z): Cald. for C23H24N2O5S3: 505.1 (M+H); found: 505.1.
Example 179
5-Methylsulfanyl-4-(6'-methyl-2'- {3-[4-(2H-tetrazol-5-yl)-butyl]-ureido} -
biphenyl-3-sulfonyl)-thiophene-2-carboxamidinetrifluoroacetate
a) 5-(l,3-Dioxo-l,3-dihydro-isoindol-2-yl)-pentanenitrile
To a solution of 5-bromovaleronitrile (5.12 g, 30.0 mmol) in DMF (40
mL) was added potassium phthalimide (6.00 g, 32.4 mmol). The above
suspension was heated at 60 °C for 16 h, concentrated, and partitioned
between H2O and DCM. The DCM layer was separated, washed with H2O
(3x) and brine, dried over Na2SO4, and concentrated to give the title
compound (6.84 g, quantitative yield) as a white solid.
lH NMR (CDCl3): 8 7.87-7.80 (m, 2H), 7.76-7.70 (m, 2H), 3.73 (t, 2H, J =
6.1Hz), 2.43 (t, 2H, J= 7.1 Hz), 1.89-1.82 (m, 2H), 1.74-1.67 (m, 2H).
ESI-MS (m/z): Cald. For C13H13N2O2: 229.1 (M+H); found: 229.1.
b) 2-[4-(2H-Tetrazol-5-yl)-butyl]-isoindole-l,3-dione
To a solution of 5-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-pentanenitrile
(6.84 g, 30 mmol) and azidotrimethylsilane (14 mL, 108 mmol) in toluene (40
mL) was added dibutyltin oxide (2.1g, 6.0 mmol). The mixture was heated at
100 °C for 48 h, concentrated, and flash chromatographed on silica gel
column, eluting with EtOAc/DCM (30 and 60 %) followed by methanol/DCM
(2.5 and 5%) to give the title compound (6.72 g, 83 % yield) as a white solid.
1H NMR (DMSO): 6 7.86-7.80 (m, 4H), 3.59 (t, 2H,.J = 6.8 Hz), 2.90 (t, 2H, J
= 7.1 Hz), 1.74-1.58 (m,4H).
ESI-MS (m/z): Cald. For C13H14N5O2: 272.1 (M+H); found: 272.0.
c) 2-[4-(2-Trityl-2H-tetrazol-5-yl)-butyl]-isoindole-l,3-dione
To a solution of 2-[4-(2H-tetrazol-5-yl)-butyl]-isoindole-l,3-dione
(4.07 g, 15.0 mmol) and diisopropylethylamine (7.8 mL, 45.0 mmol) in DCM
(60 mL) was added trityl chloride (5.86 g, 21.0 mmol). The solution was
stirred at ambient temperature; for 14 h, and concentrated. The resulting
residue was partitioned between EtOAc/DCM (3:1) and H2O. Organic layer
was separated, washed, with H2O and brine, dried over Na2SO4, concentrated,
and flash chromatographed on silica gel, eluting with DCM/hexane (40, 80,
and 100 %) followed by EtOAc/DCM (1 and 2%) to give the title compound
(5.08 g, 66% yield) as a pale yellow solid.
1H NMR (CDCl3): d 7.S7-7.82 (m, 2H), 7.74-7.70 (m, 2H), 7.36-7.31 (m, 9H),
7.12-7.09 (m, 6H), 3.71 (t, 2H, J= 7.1 Hz), 2.99 (t, 2H,./= 7.2 Hz), 1.89-1.71
(m, 4H).
d) 4-(2-Trityl-2H-tetrazol-5-yl)-butylamine
To a solution of 2-[4-(2-trityl-2H-tetrazol-5-yl)-butyl]-isoindole-l,3-
dione (175 mg, 0.313 mmol) in 2-propanol / THF (2:1, 3.0 mL) was added
hydrazine (30 mL, 0.939 mmol). The solution was stirred at ambient
temperature for 16 h. White solid was filtered off and washed with DCM (5x).
The filtrate and the washings were combined, concentrated, dissolved in
DCM, washed with H2O (2x) and brine, dried over Na2SO4, and concentrated
to give the title compound (131 mg, 97 % yield) as apale yellow oil.
1H NMR (CDCl3): d 7.36-7.28 (m, 9H), 7.12-7.09 (m, 6H), 2.93 (t. 2H, J= 7.6
Hz), 2.69 (t, 2H, J= 7.0 Hz), 1.S4-1.77 (m, 2H), 1.52-1.45 (m, 2H).
e) {Imino-[5-methylsulfanyl-4-(6'-methyl-2'-{3-[4-(2-trityl-2H-tetrazol-
5-yl)-butyl]-ureido}-biphenyl-3-sulfonyl)-thiophen-2-yl]-methyl}-carbamic
acid tert-butyl ester
To a solution of {[4-(2'-ammo-6'-methyl-biphenyl-3-sulfonyl)5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(60 mg, 0.116 mmol), as prepared according to the procedure of step c of
Example 25, and pyridine (10 mg, 0.12S mmol) in DCM (1.1 mL) was added
4-nitrophenyl chloroformate (23 mg, 0.116 mmol), and stirred at ambient
temperature for 4 h. To the above mixture was added a solution of 4-(2-trityl-
2H-tetrazol-5-yl)-butylamine (65 mg, 0.151 mmol) in DCM (0.65 mL), and
stirred for 4S h. The mixture was concentrated and purified on a preparative
TLC plate (1000 µm), developing with EtOAc/DCM (5 and 20 %) to give the
title compound (15 mg, 14% yield) as a yellow solid.
1H NMR. (CDCl3): d 7.95 (d, 1H, J= 7.93 Hz), 7.88 (t, 1H, J= 1.6 Hz), 7.74
(s, 1H), 7.56 (t, 1H, J= 7.7 Hz), 7.44-7.42 (m, 1H), 7.35-7.28 (m, 13 H), 7.23-
7.19 (m, 1H), 7.11-7.08 (m, 7H), 4.94 (t, 1H, J == 5.5 Hz), 3.26-3.16 (m, 2H),
2.91 (t, 2H, J= 7.3 Hz), 2.62 (s, 3H), 2.10 (s, 3H), 1.80-1.72 (m, 2H), 1.56-
1.44 (m, 1H).
ESI-MS (m/z): Cald. For C49H51N8O5S3: 927.3 (M+H); found: 926.8.
f) 5-Methylsulfavyl-4-(6'-methyl-2'-{3-[4-(2H-tetrazol-5-yl)-butyl]-
ureido}-biphenyl-3-sulfonyl)-thiophene-2-carboxamidine trifluoroacetate
A solution of {immo-[5-methylsulfanyl-4-(6'-methyl-2T-{3-[4-(2-trityl-
2H-tetrazol-5-yl)-butyl]-ureido}-biphenyl-3-sulfonyl)-thiophen-2-yl]-methyl}-
carbamic acid tert-butyl ester (15 mg, 16 µmol) in TFA/DCM (1:1, 2.0 mL)
was stirred at ambient temperature for 1 h. The mixture was concentrated, and
flash chromatographed on silica gel column, eluting with MeOH/DCM (3 to
7.5 % containing 0.1 % TFA) to give the title compound (5 mg, 45% yield) as
a white solid.
1H NMR (CDCl3): d 8.29 (s, 1H), 8.02-8.00 (m, 1H), 7.88 (t, 1H, J= 1.7 Hz),
7.67 (t, 1H, J= 7.7 Hz), 7.56-7.53 (m, 1H), 7.42 (d, 1H, J= 7.8 Hz), 7.28 (t,
1H, J= 7.7 Hz), 7.12 (d, 1H, J= 7.5 Hz), 3.05 (t, 2H, J= 6.4 Hz), 2.92 (t, 2H,
J= 7.5 Hz), 2.70 (s, 3H), 2.92 (s, 3H), 1.73-1.65 (m, 2H), 1.44-1.36 (m, 2H)
ESI-MS (rn/z): Cald. For C25H29N8O5S3: 585.1 (M+H); found: 5S5.0.
Example ISO
5-Methylsulfanyl-4-(6'-methyl-2'-{3-[5-(2H-tetrazol-5-yl)-pentyl]-ureido}-
biphenyl-3-sulfonyl)-thiophene-2-carboxamidine trifluoroacetate
The title compound was; prepared from 6-bromohexanenitrile
according to the procedures in Example 179.
1H NMR (CD3OD): d 8.30 (s, 1H), 8.05-8.02 (m, 1H), 7.89 (t, 1H, J= 1.6 Hz),
7.69 (t, 1H, J= 7.8 Hz), 7.56-7.54 (m, 1H), 7.42 (d, 1H, J= 7.8 Hz), 7.28 (t,
1H,J= 7.8 Hz), 7.11 (d, 1H, J= 7.5 Hz), 3.00 (t, 2H, J= 6.5 Hz), 2.93 (t, 2H,
J= 7.5 Hz), 2.70 (s, 3H), 1.99 (s, 3H), 1.78-1.71 (m, 2H), 1.42-1.34 (m, 2H),
1.30-1.25 (m,2H).
ESI-MS (m/z): Cald. For C26H31N8O3S3: 599.2 (M+H); found: 599.0.
Example 181
5-Methylsulfanyl-4-(6'-methyl-2'-{3-[2-(2H-tetrazol-5-yl)-ethyl]-ureido}-
biphenyl-3-sulfonyl)-thiophene-2-carboxamidine trifluoroacetate
a) {Imino-[5-methylsulfanyl-4-(6'-methyl-2'-{3-[2-(2H-tetrazol-5-yl)-
ethyl]-ureido}-biphenyl-3-sulfonyl)-thiophen-2-yl]-methyl}-carbamic acid
tert-butyl ester
A mixture of [(4-{2'-[3-(2-cyano-ethyl)-ureido]-6'-methyl-biphenyl-3-
sulfonyl} -5-methylsulfanyl-thiaphen-2-yl)-immo-methyl]-carbamic acid tert-
butyl ester (31 mg, 51 µmol), as prepared from {[4-(2'-amino-6'-methyl-
biphenyl-3-sulfonyl)-5-methylsulfany]-thiophen-2-yl]-imino-methyl}-
carbamic acid tert-butyl ester and 3-aminopropionitrile according to the
procedure of step e of Example 179, azidotrimethylsilane (40 µL, 0.30 mmol),
dibutyltin oxide (3.5 mg, 10 µmol), and toluene (1.5 mL) was heated at 70 °C
for 16 h and 80 °C for 4h. The mixture was concentrated and purified by flash
chromatography on silica gel, eluting with EtOAc/DCM (50, 100 %) followed
by MeOH/DCM (5, 10 %) to give the title compound (14 mg, 42 % yield) as a
colorless oil.
1H NMR (CDCl3): d 8.00 (s, 1H), 7.75-7.71 (m, 2H), 7.34-7.29 (m, 3H), 7.21
(t, 1H, J = 7.8 Hz), 7.10-1.01 (m, 2H), 6.58 (bs, 1H), 6.00 (bs, 1H), 3.60 (bs,
2H), 3.04 (bs, 2H), 2.52 (s, 3H), 1.93 (s, 3H), 1.49 (s, 9H).
ESI-MS (m/z): Cald. For C28H33N8O5S3: 657.2 (M+H); found: 656.8.
b) S-Methylsulfanyl-4-(6'-methyl-2'-{3-[2-(2H-tetrazol-5-yl)-ethyl]-
ureido}-biphenyl-3-sulfonyl)-thiophene-2-carboxamidine trifluoroacetate
A solution of {imino-[5-methylsuIfanyl-4-(6'-methyl-2'-{3-[2-(2H-
tetrazol-5-yl)-ethyl]-ureido}-biphenyl-3-sulfonyl)-thiophen-2-yl]-methyl}-
carbamic acid tert-buryl ester (10 mg, 15.3 fimol) in TFA/DCM (2.0 mL, 1:1)
was stirred at ambient temperature for 1.5 h. The reaction mixture was
concentrated to dryness, and flash chromatographed on silica gel column,
eluting with 10% MeOH/DCM containing 0.1 % TFA to give the title
compound (4.7 mg, 46 % yield) as a white solid.
1H NMR (CD3OD): d 8.29 (s, 1H), 8.03-S.01 (m, 1H), 7.86 (t, 1H, J=1.6 Hz),
7.68 (t, 1H, J= 7.8 Hz), 7.52-7.50 (m, 1H), 7.42 (d, 1H, J= 7.9 Hz), 7.2S (1,
1H, J= 7.7 Hz), 7.12 (d, 1H, J- 7.5 Hz), 3.48-3.41 (ra, 2H), 3.00 (t, 2H, .J =
6.7 Hz), 2.70 (s, 3H), 1.99 (s, 3H).
ESI-MS (m/z): Cald. For C23H25N8O3S3: 557.1 (M+H); found: 557.0.
Example 182
5-Methy]sulfanyl-4-(2'-methyl-4'- {3-[4-(2H-tetrazol-5-yl)-butyl ]-ureido} -
biphenyl-3-sulfonyl)-thiophene-2-carboxamidine trifluoroacetate
According to the procedures of Example l79, the title compound was
synthesized from {[4-(4'-amino-2'-methyl-biphenyl-3-sulfonyr)-5-
methylsulfariyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester,
which was prepared using the procedure of step b of Example 120.
1H NMR (CD3OD): d 8.32 (s, 1H), 8.00-7.95 (m, 2H), 7.66-7 65 (m, 2H),
7.31-7.27 (m, 2H), 7.10 (d, 1H, J= 8.3 Hz), 3.26 (t, 2H, J= 6.8 Hz), 3.00 (t,
2H, J= 7.5 Hz), 2.72 (s, 3H), 2.20 (s, 3H), 1.90-1.82 (m, 2H), 1.64-1.57 (m,
2H)
ESI-MS (m/z): Cald. For C25H29N8O5S3: 585.1 (M+H); found: 585.0.
Example 183
4-[4'-(N'-Acetyl-guanidino)-2'-methyl-biphenyl-3-sulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
a) l-Acetyl-l,3-bis-tert-butoxycarbonylimino-2-methyl-isothiourea
To a solution of l,3-bis-tert-butoxycarbonylimino-2-methyl-
isothiourea (2.33 g, 8.0 mmol) in dichloromethane (DCM) (8.0 mL) was
added diisopropylethylamirte (DIEA) (2.79 mL, 16.0 mmol) and acetyl
chloride (0.60 mL, 8.4 mmol) and stirred at ambient temperature for 2 hours.
Additional DIEA (2.79 mL, 16.0 mmol) and acetyl chloride (0.60 mL, 8.4
mmol) were added. After 1 hour the mixture was concentrated to dryness,
partitioned between dichloromethane and saturated NaHCO3. Organic layer
was separated, washed with H2O and brine, dried over Na2SO4, concentrated,
and flash chromatographed on silica gel column, eluting with DCM/hexane
(40 %, 100 %) to give the title compound (2.60 g, 97% yield) as a yellow oil.
1H NMR (CDCl3): d 2.48 (s, 3H), 2.46 (s, 3H), 1.52 (s, 9H), 1.47 (s, 9H).
b) 4-[4'-(N'-Acetyl-guanidino)-2'-methyl-biphenyl-3-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
To a solution of {[4-(4'-amino-2'-rnethyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(60 mg, 0.116 mmol), as synthesized from {[4-(4'-amino-2'-methyl-biphenyl-
3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid
tert-butyl ester using the procedure of step b of Example 120, and 1-acetyl-
l,3-bis-tert-butoxycarbonylimino-2-methyl-isothiourea (193 mg, 0.5S mmol)
in methanol (4.0 mL) was added acetic acid (66 µL, 1.16 mmol) and heated at
40 °C for 16 h. Triethylamine (0.25 mL) was added. The mixture was
concentrated to dryness followed by flash chromatography on silica gel
column, eluting with ethylacetate / DCM (5, 10 15%) to deliver the
guanidinated product (60 mg) as a yellow solid. This solid was treated with
trifluoroacetic acid/DCM (6 mL, 1:1) at ambient temperature for 1 h, and
concentrated to dryness. The resulting residue was purified via HPLC (C18-
column, 20-65 % CH3CN over 25 min) to give the title compound (33 mg, 49
% yield) as a white solid.
1H NMR (CD3OD): d 8.32 (s, 1H), 8.02-7.98 (m, 1H), 7.96 (s, 1H), 7.67-7.66
(m, 2H), 7.50-7.48 (m, 2H), 7.15 (d, 1H, J = 8.0 Hz), 2.72 (s, 3H), 2.22 (s,
3H),2.14(s, 3H).
Example 184
4-{4'-Guanidino-2'-[3-(4-methanesulfonyl-butyl)-ureido]-6'-methyl-biphenyl-
3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxarnidine trifluoroacetate
a) [(4-{4'-Amino-2'-[3-(4-methanesulfonyl-butyl)-ureido]-6'-metltyl-
biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophen-2-yl)-imino-methyl]-
carbamic acid tert-butyl ester
To a solution of a) {3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-
3-sulfonyl)-2-[3-(4-methanesu]fonyl-butyl)-ureido]-6-methyl-biphenyl-4-yli-
carbamic acid 2-trimethyl silanyl-ethyl ester (148 mg, 0.173 mmol), as
prepared from 4-methanesulfonyl-butylamine (step c of Exampl 202) and [2-
ammo-3'-(5-carbamoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-
biphenyl-4-yl]-carbamic acid 2-trimethylsilanyl-ethyl ester (step c of Example
294) using the procedure of step e of Example 179, in THF (5.0 rnL) was
added a solution of tetrabutylammonium fluoride in THF (0.87 mL, 0.87
mmol, 1.0 M) over 5 minutes period. The mixture was then heated at 50 °C
for 30 minutes, concentrated, and flash chromatographed on silica gel column,
eluting with EtOAc followed by methanol/DCM (2.5, 5%) to give the title
compound (100 mg, 82% yield) as a yellow solid.
1HNMR (CD3OD): d 8.16 (s, 1H), 7.98-7.95 (m, 1H), 7.85 (t, 1H, J = 1.6 Hz),
7.64 (t, 1H, J = 7.8 Hz), 7.50-7.48 (m, 1H), 6.82 (d, 1H, J = 2.2 Hz), 6.49-6.48
(m, 1H), 3.11-3.02 (m, 4H), 2.94 (s, 3H), 2.65 (s, 3H), 1.90 (s, 3H), 1.73-1.67
(m, 2H), 1.51-1.46 (m, 1H).
b) l(4-{4'-(N',N'-Di-tert-tert-butoxycarbonyl-guanidino)-2'-[3-(4-
methanesitlfonyl-butyl)~ureido]-6'-methyl-biphenyl-3-sulfonyl}-5-
niethylsulfanyl-thiophen-2-yl)-imino-methyl]-carbamic acid tert-butyl ester
To a mixture of [(4-{4'-amino-2'-[3-(4-methanesulfonyl-butyl)-ureido]-
6'-methyl-biphenyl-3-sulfonyl}-;i-methylsulfanyl-thiophen-2-yr)-imino-
methylj-carbamic acid tert-butyl ester (100 mg, 0.141 mmol), 1,3-bis-tert-
butoxycarbonylimino-2-methyl-isothiourea (205 mg, 0.705 mmol), and
methanol (5.0 mL) was added acetic acid (0.081 mL, 1.41 mmol), and heated
at 40 °C for 16 h. Triethylamine (0.3 mL) was added. The mixture was
concentrated, and flash chromatographed on silica gel column, eluting with
EtOAc /DCM (0 to 40 %) to afford the title compound (110 mg, S2 % yield)
as an off-white solid,
1H NMR (CD3OD): S 8.19 (s, 1H), 8.04-8.02 (m, 1H), 7.S7 (t, 1H, ./= 1.6 Hz),
7.70 (t, 1H, J= 7.9 Hz), 7.63 (bs, 1H), 7.51-7.54 (m, 1H), 7.35 (bs, 1H), 3.11-
3.04 (m, 4H), 2.93 (s, 3H), 2.64 (s, 3H), 1.98 (s, 3H), 1.76-1.68 (m, 2H), 1.58
(bs, 9H), 1.54-1.46 (m, 20 H).
c) 4-{4'-Guanidino-2'-[3-(4-methanesulfonyl-butyl)-ureido}-6'-methyl-
bipheny1-3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine
trifluoroacetate
To a flask charged with [(4-{4'-(N',N"-di-tert-butoxycarbonyl-
guanidino)-2'-[3-(4-methanesulfonyl-butyl)-ureido]-6'-methyl-bipiienyl-3-
sulfonyl}-5-methylsulfanyl-thiophen-2-yl)-imino-methyl]-carbam]c acid tert-
butyl ester (110 mg, 0.116 mmol) was added a solution of trifluoroacetic acid
in DCM (3.0 mL, 50 %) and stirred at ambient temperature for 1h. The
mixture was concentrated, and purified by HPLC (C18-column, 5-50% CH3CN
in H2O over 15 min.) to give the title compound (63 mg, 62 % yield) as a
white solid.
1H NMR (CD3OD): d 8.34 (s, 1H), 8.08-8.05 (m, 1H), 7.91 (t, 1H, J= 1.7 Hz),
7.76 (t, 1H, J= 7.9 Hz), 7.57-7.52 (m, 2H), 7.00 (d, 1H, J= 1.7 Hz), 3.13-3.10
(m, 4H), 2.95 (s, 3H), 2.71 (s, 3H), 2.00 (s, 3H), 1.78-1.71 (m, 2H), 1.57-1.50
(m, 2H).
ESI-MS (m/z): Cald. For C26H34N7O5S4: 652.1 (M+H); found: 652.1.
Examples 185-186
4-[7-Cliloro-3-(2,6-difluoro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidme trifluoroacetate
4-[7-Chloro-l-(2,6-difluoro-benzyl)-lH-benzoimidazole-5-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
a) Sodium salt of5-methyisulfanyl-4-sulfino-thiophene-2-carboxylic
acid methyl ester
4,6-Dichloro-spiro[benzoimidazole-2,1'-cyclohexane]
4-(7-Chloro-spiro[benzoimidazole-2,1'-cyclohex]e-5-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxylic acid methyl ester
A solution of 4.6-dk:hloro-spiro[benzoimidazole-2,1'-cyclohexane]
{{made according to literature preparation: Hazelton, C. J. et al..,
Tetrahedron, 51:5597 (1995)) 0.200 g, 0.729 mmol) in absolute ethanol (5
mL) was treated with the sodium salt of 5-methylsulfanyl-4-sulfino-thiophene-
2-carboxylic acid methyl ester {{Example 38: step b) 0.200 g, 0.729 mmol) as
a solution in watenethanol (2:1, 3.3 mL). Acetic acid was added and the
reaction stirred at room temperature 21.5 h. The reaction mixture was poured
over ice water and the ethanol was removed in vacuo. The resulting aqueous
mixture was extracted with CH2Cl2 (4 x 25 mL). The combined organic layers
were washed with brine and dried over Na2SO4. The solvents were removed
in vacuo to afford the product 4-(7-chloro-spiro[benzoimidazole-2,1'-
cyclohex]e-5-sulfonyl)-5-rnethylsulfanyl-thiophene-2-carboxylic acid methyl
ester (0.307 g, 89%) as a brown oil. 1H NMR (CDCl3): d 3.051 (d, 1H, J= 1.2
Hz), 8.038 (s, 1H), 7.381 (d, 1H, J = 1.2 Hz), 3.908 (s, 3H), 2.662 (s, 3H),
1.964 (m, 1 OH).
b) 4-(3,4-Diamino-5-chloro-benzenesulfonyl)-5~methylsulfanyl-
thiophene-2-carboxylic acid methyl ester
A solution of 4-(7-chloro-spiro[benzoimidazole-2,1'-cyclohex]e-5-
sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (from
above step a, 0.307 g, 0.652 Mmol) in ethanol:water (1:1, 6.4 mL) was treated
with Na2S2O4 and heated to 80 °C 1.5 h. The mixture was cooled, poured over
ice water, and extracted with CH2CI2 (4 x 25 mL). The combined organic
layers were washed with brine and dried over Na2SO4. The solvents were
removed in vacuo to afford the product 4-(3,4-diamino-5-chloro-
benzenesuifonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester
(0.224 g, 87%) as a brown oil. Formic acid (4.5 mL) was added and the
resulting solution was refrigerated for storage overnight due to the instability
of the free diamine.
c) 4-(7-Chloro-lH-benzoimidazole-5-sulfofiyl)-5-methylsulfanyl-
thiophette-2-carboxylic acid methyl ester
The refrigerated solution of 4-(3,4-diamino-5-ch[oro-berv2eiiesuIfonyi)~
5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((from above step
b) 0.224 g, 0.570 mmol) in formic acid (4.5 mL) from above was allowed to
slowly warm to room temperature and then heated to reflux (110 °C) 5 h. The
mixture was cooled to room temperature and poured over ice. The pH was
adjusted to pH 8 by carefully adding solid NaHCO3 portionwise with stirring.
The aqueous solution was extracted with EtOAc (2 x 150 mL). The combined
organic layers were washed with brine and dried over Na2SO4. The solvent
was removed in vacuo to afford the product 4-(7-chloro-lH-benzoimidazole-
5-sulfonyl)-5-methylsulfanyl-1:hiophene-2-carboxylic acid methyl ester (0.201
g, 87%) as a brown foamy solid. The crude material was used directly in the
next reaction.
d) 4-[7-Chloro-3-(2,6-difluoro-benzyl)-3H-benzoimidazole-5-sulfonyl]-
5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester
4-[7-Chloro-l-(2,6-difluoro-benzyl)-lH-benzoimidazole-5-sulfonyl]-
5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester
A solution of 4-(7-chloro-lH-benzoimidazole-5-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((from above step c)
0.201 g, 0.499 mmol) in DMF (4 mL) was treated with a-bromo-2,6-
difluorotoluene (0.114 g, 0.549 mmol) and solid K2CO3 (0.152 g, 1.10 mmol).
The reaction was stirred at room temperature 17 h, diluted with EtOAc and
washed well with water (5 x 150 mL). The organic layer was dried over
MgSO4 and concentrated in vacuo. Silica gel chrornatography (2% MeOH
with 2 M NH3 in CH2C12) afforded the products 4-[7-chloro-3-(2,6-difluoro-
benzyl)-3H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophene-2-
carboxylic acid methyl ester and 4-[7-chloro-l-(2,6-difiuoro-benzyl)-IH-
benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophene-2-carboxyhc acid
methyl ester (0.102 g, 38%). These isomers were not separable by silica gel
chromatography, but they were carried on together into the next reaction.
e) 4-[7-Chloro-3-(2,6-difluoro-benzyl)-3H-benzoimidazole-5-sulfonyl]-
5-methylsulfanyl-thiophene-2-earboxamidine trifluoroacetate
4-[7-Chloro-l-(2,6~difluoro-benzyl)-lH-benzoimidazole-5sulfonyl]-
5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
A solution of 4-[7-chloro-3-(2,6-difluoro-benzyl)-3H-benzoimidazole-
5-sulfonyl]-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester and 4-
[7-chloro-l-(2,6-difluoro-benzyl)-1H-benzoimidazole-5-sulfonyl]-5-
methylsulfanyl-thiophene-2--carboxylic acid methyl ester {{from above step d)
0.101 g, 0.191 mmol) in dry toluene (5 mL) was treated with preformed
dimethylaluminum amide and heated to 100 CC 2.5 h. The reaction mixture
was cooled to room temperature and added portionwise to silica suspended in
CH2Cl2. The suspension was stirred 20 min. then was filtered through a fine
porosity fritted funnel. The silica was rinsed with 10% MeOH in CH2Cl2
(1000 mL), and the filtrate was concentrated in vacuo. Preparatory HPLC (10-
55% acetonitrile in 1% TFA/water over 30 min.) afforded products 4-[7-
chloro-3-(2,6-difluoro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate (0.006 g, 6%) and
4-[7-chloro-l-(2,6-difluoro-benzyl)-1H-benzoimidazole-5-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate (0.007 g, 7%) as
white solids.
Example 185
4-[7-chloro-3-(2,6-difluoro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate 1H NMR
(MeOD): d 8.479 (s, 1H), 8.348 (d, 1H, J= 1.6 Hz), 8.341 (s, 1H), 7.931 (d,
1H, J = 1.6 Hz), 7.460 (m, 1H), 7.049 (t, 2H, J = 8.4 Hz), 6.004 (s, 2H), 2.736
(s, 3H). C20H15CIF2N4O2S3: 513.00 (M+l) found: 513.10.
Example 186
447-chloro-l-(2,6-difluoro-benzyl)-lH-benzoimidazole-5-sulfbnyl]-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate 1H NMR (MeOD):
d 9.001 (s. 1H), 8.384 (d, 1H, J= 2.0 Hz), 8.372 (s, 1H), 7.984 (d, 1H, J= 1.6
Hz), 7.532 (m, 1H), 7.141 (t, 2H, J= 8.0 Hz), 5.825 (s, 2H), 2.674 (s, 3H).
C20H15CIF2N4O2S3: 513.00 (M+l) found: 513.10
Example 187-188
4-[7-Bromo-3-(2-fluoro-5-nitro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5-
methylsulfanyl-thLlophene-2-carboxamidme trifluoroacetate
4-[7-Bromo-l-(2-fluoro-5-nitro-benzyl)-lH-benzoimidazole-5-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
a) 4-(7-Bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester
4-(7-Bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine
A solution of 4-(7-bromo-3H-benzoimidazole-5-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 38: step
e) 2.19 g, 4.90 mmol) in dry toluene (20 mL) was treated with a solution of 2
M AlMe3 (39.0 mL, 78.0 mmol) and NH4Cl (4.21 g, 78.7 mmol) in dry
toluene (39 mL) as described in Example 20: step f. The crude material (2.11
g, 100%) was used directly in the next reaction.
b) 4-Bromo-6-[5-(tert-butoxycarbonylamino-imino-metltyl)-2~
methylsulfanyl-thiophene-3-sulfonyl]-benzoimidazole-1-carboxylic acid tert-
butyl ester
A solution of 4-(7-bromo-3H-benzoimidazole-5-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxamidine ((from above step a) 2.11 g, 4.89
mmol) in dry DMF (30 mL) was treated with di-tert-butyl dicarbonate (4.27 g,
19.6 rrµmol) and N,N-diisopropylefhylamine (3.40 rnL, 19.5 nimol). The
reaction mixture was stirred at room temperature 2 days, and the solvents were
removed in vacuo. Silica gel chromatography (30-50% EtOAc in hexanes
raised in 5% increments) afforded the product 4-bromo-6-[5-(tert-
butoxycarbonylamino-immo-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-
benzoimidazole-1-carboxylic acid tert-butyl ester (1.30 g, 42%) as a brown
oil. 1H NMR (CDCl3): d 8.675 (m, 1H), 8.62 (s, 1H), 8.16 (d, 1H, J = 1.6
Hz), 7.89 (s, 1H), 2.56 (s, 3H), 1.73 (s, 9H), 1.52 (s, 9H).
c) {[4-(7-Bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
A solution of 4-bromo-6-[5-(tert-butoxycarbonylamino-imino-methyl)-
2-methylsulfanyl-thiophene-3-sulfonyl]-benzoimidazole-1 -carboxylic acid
ten-butyl ester {(from above step b) 1.00 g, 1.58 mmol) in MeOH (10 mL) was
treated with aqueous Na2CO3 (0.340 g, 3.17 mmol in 2 mL water). The
reaction mixture was stirred at room temperature 30 min., and solvents were
removed in vacuo. The residue was taken up in. EtOAc and washed with water
(1 x 50 mL) and brine (1 x 50 mL). The organic layer was dried over MgSO4
and concentrated in vacuo to afford the product {[4-(7-bromo-3H-
benzoimidazole-5-sulfbnyl)-5-methylsulfanyl-t]iiophen-2-yl]-imino-methyl}-
carbamic acid tert-butyl ester (0.755 g, 90%) as a brown solid. 1H NMR
(MeOD): d 8.48 (s, 1H), 8.32 (m, 1H), 8.20 (s, 1H), 8.03 (d, 1H, J= 1.6 Hz),
2.63 (s,3H), 1.48 (s, 9H).
d) ({4-[7-Bromo-l-(2-fluoro-5-nitro-benzyl)-lH-benzoimidazole-5-
sulfonyl]-5-methylsulfanyl-tlriophen-2-yl}-imino-methyl)-carbamic, acid tert-
butyl ester
{4-[7-Bromo-3-(2-fluoro-5-nitro-benzyl)-3H-benzoimidazole-5-
sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyt)-carbamic acid tert-
butyl ester
A solution of {[4-(7-bromo-3H-benzoimidazole-5-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
((from above step c) 0.132 g, 0.248 mmol) in dry DMF (3 mL) was treated
with 2-fluoro-5-nitrobenzylbromide (0.087 g, 0.373 mmol) and
diisopropylamine (0.070 mL, 0.497 mmol) and heated to 40 °C 24 h. The
solution was diluted with EtOAc and washed well with water (4 x 35 mL).
The organic layer was dried over MgSO4 and concentrated in vacuo to afford
the products ({4-[7-bromo-l -(2-fluoro-5-nitro-benzyl)-1H-benzoimidazole-5-
sulfonyl]-5-methylsulfanyl-th:iophen-2-yl} -irnino-methyl)-carbamic acid tert-
butyl ester and ({4-[7-bromo-3-(2-fluoro-5-nitro-benzyl)-3H-benzoimidazole-
5-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid
tert-butyl ester (0.015 g, 9%) as a brown solid. C25H23BrFN5O6S3: 684..00
(M+l) found 684.60.
e) 4-[7-Bromo-3-(2-fluoro-5-nitro-benzyl)-3H-benzoimidazole-5-
sulfonyl]-5-methylsulfanyl~thiophene-2-carboxamidine trifluoroacetate
4-[7-Bromo-l-(2-fluoro-5-nitro-benzyl)-lH-benzoimidazole-5-
sulfonyl]-S-methysulfanyl-thiophene-2-carboxamidine trifluoroacetate
A solution of ({4-[7-bromo-1-(2-fluoro-5-nitro-henzyl)-1H-
benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-
carbamic acid tert-butyl ester and ({4-[7-bromo-3-(2-fluoro-5-nitro-benzyl)-
3H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-
methyl)-carbamic acid tert-butyl ester ((from above step d) 0.015 g,
0.022mmol) in CH2C12 (1 mL) was cooled to 0 °C and treated with 25%
trifluoroacetic acid in CH2Cl2 (1.00 mL). The mixture was allowed to warm
to room temperature and was stirred 3.2 h. The solvents were removed in
vacuo. Preparatory HPLC (10-80% acetonitrile in 1% TFA/water over 30
min.) afforded the products 4-[7-bromo-3-(2-fluoro-5-nitro-benzyl)-3H-
benzoimidazole-5-sulfonyl]-5-methylsulfany3-tbiophene-2-carboxamidine
trifluoroacetate (0.002 g, 47%) and 4-[7-bromo-l-(2-fluoro-5-nitro-benzyl)-
1H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophene-2-carboxamidine
trifluoroacetate (0.002 g, 47%) as white solids.
Example 187
4-[7-bromo-3-(2-fluoro-5-nitro-benzyl)-3H-benzoimidazole-5-
sulfonyl]-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate 1H
NMR (MeOD): d 8.728 (s, 1H), 8.355 (m, 2H), 8.309 (s 1H), 8.286 (d, 1H, J
= 1.6 Hz), 8.060 (d, 1H, J = 1.6 Hz), 7.468 (t, 1H, J= 9.6 Hz), 5.832 (s, 2.H),
2.623 (s, 3H). C20H15BrFN504S3: 583.95 (M+l.) found 585.0.
Example 188
4-[7-bromo-l-(2-fluoro-5-nitro-benzyl)-1H-benzoimidazole-5-
sulfonyl]-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate 1H
NMR (MeOD): d 8.636 (s, 1H), 8.455 (d, 1H, J= 1.6 Hz), 8.337 (s. 1H),
8.295 (m, 1H), S.098 (d, 1H, J= 2.0 Hz), 7.610 (dd, 1H, J= 6.4 Hz, J = 2.8
Hz), 7.468 (t, 1H, J= S.8 Hz), 6.054 (s, 2H), 2.722 (s, 3H). C20H15BrFN5O4S3:
583.95 (M+l) found 585.0.
Example 189
4-[7-Bromo-3-(2-fluoro-4-nitro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidinetrifluoroacetate
a) ({4-[7-Bromo-l-(2-fluoro-4-nitro-benzyl)-lH-benzoimidazole-5-
sulfonyl]-5-methylsulfanyl-thiophen-2-yl)-imino0methyl)-carbamic acidtert-
butyl ester
{4-[7-Bromo-3-(2-fluoro-4-mtro-benzyl)-3H-benzoimidazole-5-
sulfonyl]-5-methylsulfanyl-thiophen-2-yl)-imino-methyl)-carbamic acid tert-
butyl ester
A solution of {[4-(7-bromo-3H-benzoimidazole-5-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
((Example 187-188: step c) 0.097 g, 0.183 mmol) in DMF (3 mL) was treated
with 2-fluoro-4-nitrobenzylbromide (0.064 g, 0.274 mmol) arid
diisopropylamine (0.051 mL, 0.365 mmol) and heated to 40 C 24 h. The
solution was diluted with EtOAc and washed well with water (4 x 35 mL).
The organic layer was dried over MgSO4 and concentrated in vacuo to afford
the products ({4-[7-bromo-l-(2-fluoro-4-nitio-benzyl)-lH-benzoimidazole-5-
sulfonyl]-5-methylsulfanyl-thiophen-2-yl)-imino-methyl)-carbamic acid tert-
butyl ester and ({4-[7-bromo-3-(2-fluoro-4-nitTo-benzy])-3H-benzoimidazole-
5-sulfonyl]-5-methylsulfanyl-thiophen-2-yl)-imino-methyl)-carbamic acid
tert-butyl ester (0.012 g, 10%) as a brown solid. C25H23BrFN5O6S3: 684.00
(M+l) found 684.50.
b) 4-[7-Bromo-3-(2-fluoro-4-nitro-benzyl)-3H-benzoimidazole-5-
sulfonyl]-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
A solution of ({4-[7-bromo-l-(2-fluoro-4-nitro -benzyl)-1H-
benzoirnidazole-5-sulfonyl]-5-methylsulfanyl-thiophen-2-yl)-imino-methyl)-
carbamic acid tert-butyl ester and ({4-[7-broino-3-(2-fluoro-4-nitro-benzyl)-
3H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophen-2-yl)-imino-
methyl)-carbamic acid tert-butyl ester {(from above step a) 0.005 g, 0.007
mmol) in CH2C12 (1 mL) v/as cooled to 0 °C and treated with 2.5%
trifluoroacetic acid in CH2Cl2 (1.00 mL). The mixture was allowed to warm
to room temperature and was stirred 3 h. Solvents were removed in vacuo.
Preparatory HPLC (10-80% acetonitrile in 1% TFA/water over 30 min.)
afforded the product 4-[7-bromo-3-(2-fluoro-4-nitro-benzyl)-3H-
benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophene-2-carboxamidine
trifluoroacetate (0.002 g, 47%) as a white solid. 1H NMR (MeOD): d 8.714 (s,
1H), S.308 (s, 1H), 8.231 (d, 1H, J= 1.6 Hz), 8.106 (m, 2H), 8.047 (d, 1H, J =
0.8 Hz), 7.556 (t, 1H, J = 8.4 Hz), 5.854 (s, 2H), 2.630 (s, 3H).
C20H15BrFN5O4S3: 583.95 (M+l) found 585.05.
Example 190
4-[l-(5-Amino-2-fluoro-benzyl)-7-bromo-lH-benzoimidazole-5-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxarnidine trifluoroacetate
A solution of ({4-[7-bromo-l-(2-fluoro-5-nitro -benzyl)-1H-
benzoimidazole-5-sulfbnyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-
carbamic acid tert-butyl ester {{Example 187-188: step d) 0.030 g, 0.044
mmol) in EtOH (3 mL) was treated with NH4C1 (0.023 g, 0.438 rnmol) as an
aqueous solution and heated to 50 °C. Iron powder (0.012 g, 0.219 mmol) was
added and the reaction heated to 80 °C for 4 h. The mixture was cooled and
filtered through Celite. The filter cake was rinsed with EtOH, and the EtOH
was removed in vacuo. The remaining aqueous solution was basified to pH 10
with saturated aqueous NaHCO3 and extracted with EtOAc (2 x 25 mL). The
combined organic layers were dried over MgSO4 and concentrated in vacuo.
The residue was taken up in CH2Cl2 (3 mL) and treated with tnfluoroacetic
acid (0.75 mL). The mixture: was stirred at room temperature 1.5 h, and
solvents were removed in vacuo. Preparatory HPLC (10-50% acetonitrile in
1% TFA/water over 30 min.) afforded the product 4-[3-(5-amino-2-fluoro-
benzyl)-7-bromo-3H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophene-
2-carboxamidine trifluoroacetate (0.014 g, 49%) as a white solid. 1H NMR
(MeOD): d 8.714 (s, 1H), 8.308 (s, 1H), 8.231 (d, IK J= 1.6 Hz), 8.106 (m,
2H), 8.047 (d, 1H, J= 0.8 Hz), 7.556 (t, 1H, J= 8.4 Hz), 5.854 (s, 2H), 2.630
(s, 3H).
Example 191
3-({3-[4-Bromo-6-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-
ben2oimidazol-l-ylmethy]]-4-fluoro-phenylcarbamoyl}-methylsulfanyl)-
proplonic acid trifluoroacetate
a) [(4-{7-Bromo-3-[5-(2-bromo-acetylamino)-2-fluoro-benzyl]-3H-
benzoimidazole-5-sulfonyl}-5-methylsulfanyl-thiophen-2-yl)-imino-methyl]-
carbamic acid tert-butyl ester
A solution of ({4-[3-(5-amino-2-fluoro-benzyl)-7-bromo-3H-
benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophen-2-yl)-imino-methyl)-
carbamic acid tert-butyl ester ((Example 190) 0.012 g, 0.018 mmol) in CH2C12
(3 mL) was treated with bromoacetylbromide (0.007 g, 0.037 mmol) and
triethylamine (0.006 mL, 0.046 mmol) and stirred at room temperature 3 h.
The reaction mixture was diluted with CH2Cl2 and washed with water (2 x 10
mL). The organic layer was dried over MgSO4 and concentrated in vacuo to
afford the product [(4-{7-bromo-3-[5-(2-bromo-acetylamino)-2-lluoro-
benzyl]-3H-benzoimidazole-5-sulfonyl}-5-methylsulfanyl-thiophen-2-yl)-
imino-methyl]-carbamic acid tert-butyl ester (0.014 g, 92%) as a tan solid.
C27H26Br2FN5O5S3: 773.94 (M+l) found 774.10.
b) 3-[(3-{4-Bromo-6-[5-(iert-butoxycarbonylamino-imin o-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-benzoimidazol-l-ylmethyl}-4-fluoro-
pheny!carbamoyl)-methylsulfanyl]-propionic acid methyl ester
A solution of [(4-{7-bromo-3-[5-(2-bromo-acetylamirio)-2-fluoro-
benzyl]-3H-benzoimidazole-5-sulfonyl}-5-methylsuIf;myl-thiophen-2-yl)-
imino-methyl]-carbamic acid tert-butyl ester ((Example 191: step a) 0.014 g,
0.017 mmol) in CH.2C12 (2 mL) was treated with methyl 3-
mercaptopropionoate (2.50 µL, 0.025 mmol) and stirred at room temperature
30 min. The reaction was diluted with CH2Cl2 and washed with water (1 x 10
mL). The organic layer was dried over MgSO4 and concentrated in vacua to
afford the product 3-[(3-{4-bromo-6-[5-(tert-butoxycarbonylammo-imino-
methyl)-2-methylsulfanyl- thiopihene-3-sulfonyl]-benzoimidazol-1-ylmethyl} -
4-fluoro-phenylcarbamoyl)-methylsulfanyl]-propionic acid methyl ester
(0.011, 85%) as a tan solid. C31H33BrFN5O8S4: 814.04 (M+l) found 814.70.
c) 3-({3-[4-Bromo-6-(5-carbamimidoyl-2-metbylsulfanyl-tbiophene-3-
sulfonyl)-benzoimidazol-l-ylmethyl]-4-fluoro-phenylcarbamoyl}-
methylsulfanyl)-propionic acid trifluoroacetate
A solution of 3-[(3-{4-bromo-6-[5-(tert-butoxycarbonylaimno-imino-
methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-benzoimidazol-1 -ylmethyl) -
4-fluoro-phenylcarbamoyl)-methylsulfanyl]-propionic acid methyl ester
((Example 191: step b) 0.011 g, 0.014 mmol) in MeOH:H2O (2:1, 3 mL) was
treated with LiOH (1.61 mg, 0.070 mmol) and the reaction stirred at room
temperature 2 h. The solvents were evaporated in vacuo and the residue taken
up in CH2Cl2 (3 mL). Trifluoroacetic acid (0.750 mL) was added and the
reaction stirred at room temperature 45 min. Solvents were evaporated in
vacuo. Preparatory HPLC (10-50% acetonitnle in 1% TFA/wav.er over 30
min.) afforded the product 3-({3-[4-bromo-6-(5-carbamimidoyl-2-
metbylsulfanyl-thiophene-3-sulfonyl)-benzoimidazol-l-ylmethyl]-4~fluoro-
phenylcarbamoyl}-methylsulfanyl)-propionic acid trifluoroacetate (0.004 g,
43%) as a white solid. 1H NMR (MeOD): d 8.691 (s, 1H), 8.140 (s, 1H),
8.068 (s, 1H), 8.018 (s, 1H), 7.647 (m, 1H), 7.547 (dd, 1H, J= 6.4 Hz, J= 2.4
Hz), 7.176 (t, 1H. J = 9.6 Hz), 5.692 (s, 2H), 3.498 (quint, 1H, J = 1.6 Hz),
3.148 (quint, 1H, 7= 1.6 Hz), 2.875 (d, 2H, J= 7.2 Hz), 2.651 (d, 2H, J = 7.2
Hz), 2.529 (s, 3H). C25H23BrFN5O5S4: 699.97 (M+l) found 700.90.
Example 192
[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-methoxy-6-
methyl-bipheny]-2-ylmethoxy]-acetic acid trifluoroacetate
a) 2-Bromo-5-methoxy-l,3-dimethyl-benzene
A solution of 4-bromo-3,5-dimethylphenol (1.00 g, 4.97 mmol) in
acetone (40 mL) was treated with solid CsCO3 (1.17 g, 4.97 mmol) and methyl
iodide (0.310 mL, 4.97 mmol) and heated to 40 °C for 3 h. Additional methyl
iodide (0.310 mL, 4.97 mmol) was added over the course of the reaction to
replace that lost to evaporation. The acetone was removed in vacuo. The
resulting white solid residue was partitioned between water and CH2Cl2. The
layers were separated and the aqueous layer was further extracted with CH2Cl2
(2 x 25 mL). The combined organic layers were washed with water (1 x 25
mL) and dried over MgSO4. The solvent was removed in vacuo to afford the
product 2-bromo-5-methoxy-l,3-dimethyl-benzene (1.01 g, 94%) as a
colorless oil, which slowly solidified upon standing. 1H NMR (CDCl3): d
6.644 (s, 2H), 3.762 (s, 3H), 2.382 (s, 6H).
b) 2-Brom o-l -bromom ethyl-5-m eth oxy-3-m ethyl-ben zen e
A solution of 2-bromo-5-methoxy-l,3-dimethyl-benzene {{Example
192: step a) 1.01 g, 4.70 mmol) in CC14 (50 mL) was treated with N-
bromosuccinamide and AIBN (catalytic amount) and heated to 75 °C 3.5 h.
The reaction was diluted with CH2C12 and washed with saturated aqueous
NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo
to afford the product 2-bromo-l-bromomethyl-5-methoxy-3-mei:hyl-benzene
(1.27 g, 92%) as a pale orange solid. 1H NMR (CDCl3): d 6.641 (s, 2H),
4.601 (s, 2H), 3.760 (s, 3H), 2.380 (s, 3H).
c) (2-Bromo-5-methoxy-3-methyl-phenyl)-methanol
A solution of 2-brorao-l-bromoniethyl-5-methoxy-3-methyl-benzene
({Example 192: step b) 10.8 g, 36.7 mmol) in dioxane:water (1:1, 200 mL)
was treated with CaCO3 and heated to reflux (110 °C)18 h. The reaction
mixture was cooled to room temperature and filtered by gravity to remove
solid salts. The dioxane was removed in vacuo. Dilute HC1 (10 mL) was
added, and the mixture was extracted with CH2Cl2 (2 x 150 mL). The
combined organic layers were dried over MgSO4. The solvents were removed
in vacuo to afford a pale orange oil, which slowly solidified upon standing.
Silica gel chromatography (25% EtOAc in hexanes) yielded the product (2-
bromo-5-methoxy-3-methyl-phenyl)-methanol (1.03 g, 12%) as a yellow oil.
1H NMR (CDCl3): d 6.905 (d, 1H, J = 3.2 Hz), 6.746 (d, 1H, J = 3.2 Hz),
4.720 (d, 2H, J= 3.6 Hz), 3.798 (s, 3H), 2.390 (s, 3H).
d) (2-Bromo-5-methoxy-3-methyl-benzyloxy)-acetic acid tert-butyl ester
A solution of (2-bromo-5-methoxy-3-methyl-phenyl)-methanol
{{Example 192: step c) 0.800 g, 3.46 mmol) in DMF (10 mL) was cooled to 0
C and treated with NaH (0.100 g of 95% dispersion, 4.15 mmol) and allowed
to warm to room temperature 30 min. The mixture was then treated with tert-
butyl bromoacetate (0.614 mL, 4.15 mmol) and stirred at room temperature 1
h. The reaction was diluted with water and extracted with EtOAc (2 x 125
mL). The combined organic layers were washed well with water (3 x 300
mL), dried over MgSO4, and concentrated in vacuo to afford the product (2-
bromo-5-methoxy-3-methyl-benzyloxy)-acetic acid tert-butyl ester (1.19 g,
98%) as a yellow oil. lH NMR (CDCl3): d 6.967 (d, 1H, J= 2.8 Hz), 6.745
(d, 1H, J= 3.2 Hz), 4.6S3 (s, 2H), 4.086 (s, 2H), 3.794 (s, 3H), 2.3S0 (s, 3H),
1.496 (s,9H).
e) [5-Methoxy-3-methyl-2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolait-2-
yl)-benzyloxy]-acetic acid tert-butyl ester
A solution of (2-brorno-5-methoxy-3-methyl-benzyloxy)-acetic acid
tert-butyl ester ((Example 192: step d) 1.19 g, 3.45 mmol) in dioxane (10 mL)
was treated with PdCl2(PPh3)2 (0.242 g, 0.345 mmol) and triethylamine (2.38
mL, 20.7 mmol). 4,4;,5,5-Tetramethyl-l,3,2-dioxaborolane (1.00 mL, 6.89
mmol) was added slowly and the mixture heated to 80 °C 15 h. The reaction
was diluted with EtOAc and washed with brine (2 x 50 mL). The organic
layer was dried over MgSO4 and concentrated in vacuo. Silica gel
chromatography (25% EtOAc in hexanes) afforded the product [5-methoxy-3-
methyl-2 -(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyloxy]-acetic
acid tert-butyl ester (0.793 g, 58%) as a brown oil. The crude material was
used directly in the next reaction.
f) 3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-
thiophene-3-sulfonyl]-4-methoxy-6-methyl-biphenyl-2-ylmethoxy}-acetic
acid tert-butyl ester
A solution of [5-methoxy-3-methyl-2-(4,4,5,5-tetramethyl-
[l,3,2]dio 192: step e) 0.790 g, 2.01 mmol) in tolutene:EtOH (2:1, 15 mL) was treated
with {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-
methyl}-carbamic acid tert-buty! ester ((Example27: step c) 0.247 g, 0.503
mmol), aqueous Na2CO3 (2 M, 2.01 mL, 4.03 mmol), and Pd(PPh3)4 (0.116 g,
0.101 mmol). The mixture was heated to 80 C 16.3 h. The reaction wa:3
diluted with EtOAc and washed with brine (2 x 25 mL). The organic layer
was dried over MgSO4 and concentrated in vacuo. Silica gel chromatography
(5%-60% EtOAc in hexanes raised in 5% increments) afforded the product 3'-
[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-
sulfonyl]-4-methoxy-6-methyl-biphenyl-2-ylmethoxy} -acetic acid tert-butyl
ester (0.107 g, 31%) as an off-white solid. !H NMR (CDCl3): d 8.013 (d, 1H,
J = 7.6 Hz), 7.961 (s, 1H), 7.934 (t, 1R J - 1.6 Hz), 7.570 (t, 1H, J = 7.6 Hz),
7.440 (d, 1H, J = 2.0 Hz): 6.896 (d, 1H, J = 2.4 Hz), 6.S32 (d, 1H, J = 2.4 Hz),
4.200 (s, 2H), 3.876 (s, 3H), 3.868 (s, 2H), 2.630 (s, 3H), 2.036 (s. 3H), 1.585
(s, 9H), 1.540 (s, 9H). C32H40N2O8S3: 677.19 (M+l) found 676.90.
g) [3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonylj-4-
methoxy-6-methyl-biphenyl-2-ylmethoxy]-acetic acid trifluoroacetate
A solution of 3'-[5-(tert-butoxyccirbonylamino-iraino-methyl)-2-
methylsulfanyl-thiophene-3-suIfonyl]-4-methoxy-6-methyl-biphenyl-2-
ylmethoxy}-acetic acid tert-butyl ester {{Example 192: step f) 0.107 g, 0.158
mmol) in CH2Cl2 (10 mL) was treated with 50% trifluoroacetic acid in CH2Cl2
(10 mL) and stirred at room temperature 4 h. Solvents were evaporated in
vacuo. Preparatory HPLC (5-50% acetonitrile in 1% TFA/water over 30 min.)
afforded the product [3'-(5-carbamimidoyl-2-methylsulfanyl-thjophene-3-
sulfonyl)-4-methoxy-6--methyl-biphenyl-2-ylmethoxy]-acetic acid
trifluoroacetate (0.080 g, 97%) as a white glassy solid. 1H NMR (MeOD): d
8.345 (s, 1H), 8.047 (d, 1H, J= 8.8 Hz), 7.848 (t, 1H, J= 1.6 Hz), 7.692 (t,
1H, J= 7.6 Hz), 7.554 (d, 1H, J= 7.6 Hz), 6.992 (d, 1H, J = 2.0 Hz), 6.871 (d,
1H, J = 2.0 Hz), 4.202 (d, 2H, J= 5.6 Hz), 3.852 (s, 3H), 3.818 (d, 2H, J= 2.4
Hz), 2.736 (s, 3H), 1.999 (s, 3H). C23H24N2O6S3: 521.08 (M+l) found
521.00.
Example 193
a) [3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-
hydroxy-6-methyl-biphenyl-2-ylmethoxy]-acetic acid triflnoroacetate
A solution of [3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-
sulfonyl)-4-methoxy-6-metfayl-biphenyl-2-ylmethoxy]-acetic acid {(Example
192: step g) 0.077 g, 0.0148 mmol) in dry CH2C12 (10 mL) was cooled to 0 °C
and treated with BBr3 (0.592 mL, 0.592 mmol) dropwise. The reaction stirred
at 0 CC for 30 min. then was allowed to warm to room temperature and stir 27
h. The reaction mixture was cooled to 0 °C and quenched with MeOH. Some
HBr evolution was seen. All solvents were evaporated in vacuo, and the
residue was taken up in EtOAc (100 mL) and washed with water (1 x 75 mL)
and brine (2 x 50 mL). The organic layer was dried over MgSO4 and
concentrated in vacuo. Preparatory HPLC (5-50% acetonitrile in 1%
TFA/water over 30 min.) afforded the product [3'-(5-carba:mimidoyl-2-
methylsulfanyl-thiophene-3-sulfonyl)-4-hydroxy-6-methyl-biphenyl-2-
ylmethoxy]-acetic acid trifloroacetate (0.039, 52%) as a white glassy solid. 1H
NMR (MeOD): d 8.344 (s, 1H), 8.090 (d, 1H, J= 8.0 Hz), 7.877 (t, 1H, J =
2.0 Hz), 7.721 (t, 1H, J= 7 6 Hz), 7.572 (d, 1H, J= 7.6 Hz), 6.778 (d, 1H, J =
2.8 Hz), 6.735 (d, 1H, .7= 2,0 Hz), 2.710 (s, 3H), 2.028 (s, 2H), 1.935 (s, 3H),
1.254 (t,2H,J= 7.6 Hz).
Example 194
4-{2'-[3-(2-Benzenesulfonylamino-ethyl)-ureido]-6'-methyl-biphenyl-3-
sulfonyl}-5-methylsulfanyl-miophene-2-carboxamidme trifluoroacetate
a) (4-{2'-[3-(2-Amino-ethyl)-ureido]-6'-methyl-biphenyl-3-sulfonyl}-5-
methylsulfanyl-thiophen-2-yl)-imino-methyl]-carbarnic acid tert-butyl ester
A solution of [4-(2'-amino-6'-methyl-biphenyl-3--sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
{{Example 25: step c) 0.150 g, 0.290 mmol) in dry CH2C12 (10 mL) was
treated with pyridine (0.026 mL, 0.319 mol) and p-nitrophenyl chloroformate
(0.064 g, 0.319 mmol) and stirred 1.7 h. The reaction mixture was treated
with ethylene diamine (0.194 mL, 2.90 mmol) and triethylamine (0.485 mL,
3.4S mmol) and stirred at room temperature 16 h. The reaction was diluted
with CH2Cl2 and washed with water (3 x 50 mL). The combined organic
layers were dried over MgSO4 and concentrated in vacuo to afford the product
[(4-{2'-[3-(2-amino-ethyl)-ureido]-6'-methyl-biphenyl-3-sulfonyl}-5-
methylsulfanyl-thiophen-2-yl)-imino-methyl]-carbamic acid tert-butyl ester
(0.145 g, 82%) as a tan solid. 1H NMR (MeOD): d 8.195 (s, 1H), 8.057 (d,
1H, J= 8.0 Hz), 7.902 (t, 1H, J= 1.6 Hz), 7.718 (t, 1H, J= 8.0 Hz), 7.554 (d,
1H, J= 8.0 Hz), 7.511 (d, 1H, 7= 8.0 Hz), 7.289 (t, 1H, J= 1.6 Hz), 7.119 (d,
1H, J= 1.1 Hz), 3.099 (m, 2H), 2.676 (s, 3H), 2.621 (m, 2H), 2.007 (s, 3H),
1.511 (s, 9H). C27H33N5O5S3: 604.16 (\l+l) found 603.90.
b) 4-{2'-[3-(2-Benzenesulfoiiylamino-ethyi)-ureido]-6'-methyl-biphenyl-
3-sulfonyl}-5-inethylsulfanyl-thiopheite-2-carhoxamidine trifluoroacetate
A solution of [(4{2'-[3-(2-amino-ethyl)-ureido-6'-melhyl-biphenylo-
sulfonyl}-5-methylsulfanyl--thiophen-2-y])-imino-methyl]-carbamic acid tert-
butyl ester ((Example 194: step a) 0.060 g, 0.099 mmol) in CH:C12 (10 mL)
was treated with phenylsulfonyl chloride (0.015 mL, 0.119 rnmol) and
triethylamine (0.033 mL, 0.238 mmol) and stirred 16 h. The reaction mixture
was diluted with CH2Cl2 and washed with water (2 x 25 mL). The organic
layer was dried over MgSO4 and concentrated in vacuo. The residue was
taken up in CH2Cl2 (10 mL), treated with trifluoroacetic acid (2 mL), and
stirred at room temperature 1.5 h. The solvents were evaporated in vacuo.
Preparatory HPLC (10-80% acetonitrile in 1% TFA/water over 30 min.)
afforded, the product 4-{2'-[3-(2-benzenesulfonyhimino-ethyl)-ure\do]-6'-
methyl-biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine
trifluoroacetate (0.026 g, 41%) as a white glassy solid. 1H NMR (MeOD): d
8.292 (s, 1H), 8.036 (d, 1H, J = 8.0 Hz), 7.878 (t, IK, J = 1.6 Hz), 7.820 (d,
2H, J = 6.8 Hz), 7.534 (t, 1H, J = 1.6 Hz), 7.694 (t, 1H, J = 8.0 Hz), 7.616 (m,
1H), 7.562 (d, 2H, J = 7.6 Hz), 7.438 (d, 1H, J = 7.6 Hz). 7.276 (t, 1H, J = 7.6
Hz), 7.212 (d, 1H, J = 7.2 Hz), 3.075 (q, 2H, J = 4.8 Hz), 2.448 (dt, 2H, J = 6.0
Hz, J = 2.4 Hz), 2.710 (s, 3H), 2.003 (s, 3H).
Example 195
a) 4-{2'-[3-(2-Methanesulfonylamino-ethyl)-ureido]-6'-methyl-
biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine
trifluoroacetate
A solution of [(4-{2'-[3-(2-amino-ethyl)-ureido]-6'-methyl-biphenyl-3-
sulfonyl} -5-methylsulfanyl-thiophen-2-yl)-immo-methyl]-carbamic acid tert-
butyl ester ((Example 194: step a) 0.050 g, 0.083 mmol) in CH2C12 (10 mL)
was treated with methylsulfonylchloride (9.50 µL, 0.099 mmol) and
triethylamine (27.7 µL, 0.199 mmol) and stirred at room temperature 7 h. The
reaction was diluted with CH2Cl2 and washed with water (1 x 50 mL). The
organic layer was dried over MgSO4, concentrated in vacuo, taken up in
CH2Cl2 (8 mL), treated with trifluoroacetic acid (0.4 mL) and stirred at room
temperature 2 h. Solvents were evaporated in vacuo. Preparatory HPLC (10-
50% acetonitrile in 1% TF A/water over 30 min.) afforded the product 4-{2'-
[3-(2-methanesulfonylamino-ethyl)-ureido]-6'-methyl-biphenyl-3-sulfonyl}-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate (0.023 g, 48%) as
a white glassy solid. 1H NMR (MeOD): d 8.305 (s, 1H), 8.052 (d 1H, J = 9.2
Hz), 7.887 (t 1H, J - 1.6 Hz), 7.719 (t, 1H, J = 7.6 Hz), 7.571 (d, 1H, J= 7.2
Hz), 7.450 (d, 1H, J= 7.2 Hz), 7.2S4 (t, 1H, J= 8.0 Hz), 7.131 (d, 1H, J= 7.6
Hz), 3.140 (m, 2H), 3.040 (m, 2H), 2.898 (s, 3H), 2.718 (s, 3H), 2.005 (s, 3H).
C23H27N5O5S4: 582.09 (M+l) found 582.00.
Example 196
[3-(2-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-
methyl-biphenyl-2-yl]-ureido}-ethyl)-ureido]-acetic acid trifluoroacetate
a) {3-[2-(3-{3'-[5-(tert-Butoxycarbonylamino-imino-metltyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-ureido)-
ethyl]-ureido}-acetic acid methyl ester
A solution of [(4-{2'-[3-(2-amino-ethyl)-ureido]-6'-methyl-biphenyl-3-
sulfonyl }-5-methylsulfanyl-thiophen-2-yl)-imino-methyl]-carbamic acid tert-
butyl ester ((Example 194: step a) 0.030 g, 0.050 rnmol) in CH2C12 (10 mL)
was treated with ethyl isocyanatoacetate (6.70 µL, 0.060 mmol) and stirred at
room temperature 35 min. The reaction was diluted with CH2Cl2 and washed
with water (1 x 15 mL). The organic layer was dried over MgSO4 and
concentrated in vacuo to afford the product {3-[2-(3-{3'-[5-(tert-
butoxycaLrbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-
6-methyl-biphenyl-2-yl}-ureido)-efhyl]-ureido}-acetic acid methyl ester
(0.031 g, 86%) as an off-white solid. C32H40N6O8S3: 733.21 (M+l) found
732.90.
b) {3-[2-(3-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-ureido)-
ethyl]-iweido}-acetic acid
A solution of {3-[2-(3-{3'-[5-(tert-butoxycarbonylarnino-imino-
methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-raethyl-bipheny[-2-yl}-
ureido)-ethyl]-ureido}-acetic acid methyl ester ((Example 197: step a) 0.031 g,
0.042 mmol) in MeOH:water (2:1, 15 mL) was treated with NaOH (10 N,
0.042 mL, 0.420 mmoi) and stirred at room temperature 18 h. MeOH was
evaporated in vacuo and the remaining aqueous solution was acidified to pH 5
with glacial acetic acid. The solution was extracted with CH2Cl2 (3 x 50 mL).
The combined organic layers were dried over MgSO4 and evaporated in vacuo
to afford the product {3-[2-(3-{3'-[5-(tert-butoxycarbonylamino-imino-
methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-
ureido)-ethyl]-ureido}-acetic acid (0.025 g, 83%) as an off-white solid. The
crude material was used directly in the next reaction.
c) l3-(2-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophen e-3-
sulfonyl)-6-methyl-biphenyl-2-yl]-ureido}-ethyl)-ureido]-acetic acid
trifluoroacetate
A suspension of {3-[2-(3-{3'-[5-(tert-butoxycarbonylamino-imino-
methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-
ureido)-ethyl]-ureido}-acetic acid ({Example 196: step b) 0.025 g, 0.035
mmol) in CH2Cl2 (10 mL) was treated with trifluoroacetic acid (1.00 mL) and
stirred at room temperature 1.2 h. Solvents were removed in vacuo.
Preparatory HPLC (10-80% acetonitrile in 1% TFA/water over 30 min.)
afforded the product [3-(2-{3-[3'-(5-caxbamimidoyl-2-rnethylsulfanyl-
thiophene-3-sulfonyl)-6-methyl-biphenyl-2-yl]-ureido}-ethyl)-ureido]-acetic
acid trifluoroacetate (0.013 g, 60%) as a white glassy solid. 1H NMR.
(CD3CN): d 8.099 (s, 1H), 8.048 (d, 1H, J = 9.6 Hz), 7.815 (t, 1H, J = 1.6
Hz), 7.709 (t, 1H, J= 8.0 Hz), 7.575 (d, 1H, J= 7.6 Hz), 7.498 (d, 1H, J = 8.0
Hz), 7.295 (t, 1H, J= 7.6 Hz), 7.161 (d, 1H, J= 8.0 Hz), 3.756 (s, 2H), 2.979
(s br, 4H), 2.681 (s, 3H), 2.079 (s, 3H).
Example 197
a) 5-methylsulfanyl-4-[6'-methyl-2'-(N'-methanesulfonyhireido)-
biphenyl-3-sulfonyl]-thiophene-2-carboxamidine
A solution of [4-(2'-amino-6'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
((Example 25: step c) 0.050 g, 0.097 mmol) in CH2C12 (5 mL) was treated
with pyridine (8.6 µL, 0.106 mmol) and p-nitrophenylchloroformate (0.021 g,
0.106 mmol) and stirred 2 h. The mixture was treated with methane
sulfonamide (0.018 g, 0.193 mrnol) and triethylamine (0.108 mL, 0.773 mmol)
and stirred 2 h. The reaction mixture was diluted with CH2Cl2 and washed
with water (2 x 25 mL). The organic layer was dried over MgSO4 and
concentrated in vacuo. The residue was taken up in CH2C12 (5 mL), treated
with trifluoroacetic acid (1.00 mL), and stirred 1 h. Solvents were evaporated
in vacuo. Preparatory HPLC (10-80% acetonitrile in 1% TFA/water over 30
min.) afforded the title compound (0.015 g, 57%) as a white glassy solid. lH
NMR (MeOD): d 8.359 (s, 1H), 8.123 (d, 1H, J = 9.6 Hz), 7.993 (t, 1H J = 1.6
Hz), 7.790 (t, 1H, J = 8.4 Hz), 7.625 (d, 1H, J - 7.6 Hz), 7.370 (t, 1H, J = 8.0
Hz), 7.244 (d, 1H, J = 7.2 Hz), 7.170 (d, 1H, J = 7.2 Hz), 3.008 (s, 3H), 2.722
(s, 3H), 2.003 (s, 3H). C21H22N4O5S4: 539.05 (M+l) found 538.90.
Example 198
4-[4'-Methoxy-6'-methyl-2'-(2-oxo-imidazolidin-l-yl)-biphenyl-3-sulfonyl]-5-
methylsulfanyl-thiopbene-2-carboxamidme trifluoroacetate
a) 2-Bromo-5-methoxy-3-methyl-benzoic acid
A solution of (2-bromo-5-methoxy-3-methyl-phenyl)-methanol
((Example 192: step c) 7.85 g, 34.0 mmol) in acetone (300 mL) was heated to
60 °C and treated over 25 min. with KMnO4 (12.6 g, 79.8 mmol) as an
aqueous solution (175 mL). The mixture was heated to 60 °C for an additional
35 min. A saturated aqueous solution of NaHSC)3 was added until the solution
turned beige in color. Concentrated NH4OH was added to pH 10 and the
solids were filtered through a medium porosity fritted funnel. The filtrate was
acidified to pH 4 with concentrated HC1, and the solution was extracted with
ether (2 x 200 mL). The combined organic layers were dried over MgSO4 and
concentrated in vacuo to afford the product 2-bromo-5-methoxy-3-methyl-
benzoic acid (4.15 g, 50%) as a white solid. 1H NMR (MeOD): d 6.968 (d,
1H, J= 2.8 Hz), 6.775 (d, 1H, J= 3.2 Hz), 3.776 (s, 3H), 2.352 (s, 3H).
b) (2-Bromo-5-methoxy-3-methyl-phenyl)-carbamic acid tert-butyl ester
A solution of 2-bromo-5-methoxy-3-methyl-benzoic acid ({Example
198: step a) 3.39 g, 13.8 mmol) in dry tert-butanol was treated with DPPA
(3.58 mL, 16.6 mmol) dropwise and stirred 5 min. The solution was treated
with diisopropylethylamine (2.89 mL, 16.6 mmol) and heated to 80 °C 17.5 h.
Terc-butanol was removed in vacuo. The residue was taken up in EtOAc and
washed with saturated aqueous NaHCO3 (2 x 60 mL) and water (1 x 60 mL).
The combined organic layers were dried over MgSO4 and concentrated in
vacuo. Silica gel chromatography (10% EtOAc in hexanes) afforded the
product (2-bromo-5-methoxy-3-methyl-phenyl)-carbamic acid ten-butyl ester
(3.05 g, 70%) as a colorless oil. 1H NMR (CDCl3): d 7.701 (d, 1H, J= 1.6
Hz), 7.146 (s, NH), 6.517 (d, 1H, J= 3.2 Hz), 3.797 (s, 3H), 2.360 (s, 3H),
1.534 (s,9H).
c) 2-Bromo-5-methoxy-3-methyl-phenylamine
A solution of (2-bromo-5-methoxy-3-methyl-phenyl)-carbamic acid
tert-butyl ester ({Example 198: step b) 3.00 g, 9.49 mmol) in CH2C12 (50 mL)
was treated with trifluoroacetic acid (7.00 mL) dropwise. The solution was
stirred at room temperature 1.3 h. The solvents were evaporated in vacuo to
yield the product 2-bromo-5-methoxy-3-methyl-phenylamine (2.04 g, 65%) as
a yellow solid trifluoroacetate salt. The crude mixture was used directly in the
next reaction.
d) 5-Methoxy-3-m ethyl-2-(4,4,5,5-tetram ethyl-[1,3,2]dioxaborolan -2-
yl)-phenylamine
A solution of 2-bromo-5-methoxy-3-niethyl-phenylamine ((Example
198: step c) 2.04 g, 6.18 mmol) in dry dioxane (100 mL) was treated with
triethylamine (5.26 mL, 37.7 mmol), 2-(dicyclohexylphosphino)biphenyl
(0.662 g, 1.89 mmol), and Pd(OAc)2 (0.106 g, 0.472 mmol). 4,4,5,5-
Tetramethyl-l,3,2-dioxaborolane (4.09 mL, 28.3 mmol) was added slowly and
the mixture heated to reflux for 1 h. The dioxane was evaporated in vacuo.
The residue was taken up in EtOAc and washed with water (2 x 75 mL). The
organic layer was filtered by gravity to remove the palladium residue, dried
over MgSO4 and concentrated in vacuo. Silica gel chromatography (10-25%
EtOAc in hexanes raised in 5% increments) afforded the product 5-methoxy-
3-methyl-2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenylarnine (1.61
g, 98%) as a light brown solid. 1H NMR (CDCl3): d 7.361 (d, 1H, J = 7.6
Hz), 7.279 (d, 1H,J= 8.0 Hz), 3.815 (s, 3H), 2.46 (s, 3H), 1.356 (s, 12H).
e) {[4-(2'-Amino-4'-methoxy-6'-methyl-biphenyl-3-sulfonyl)-5-
methylsidfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
A solution of {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 27:
step c) 1.50 g, 3.05 mmol) in toluene:EtOH (2:1, 45 raL) was treated with 5-
methoxy-3-methyl-2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-
phenylamine (((Example 1.98: step d) 1.61 g, 6.11 mmol), aqueous Na2CO3 (2
M, 12.2 mL, 24.4 mmol) and Pd (PPh3)4 (0.706 g, 0.611 mmol). The mixture
was heated to 80 °C 4 h. The reaction was cooled to room temperature,
diluted with EtOAc, washed with brine (1 x 75 mL) and water (2 x 75 mL),
dried over MgSO4 and concentrated in vacuo. Silica gel chromatography
(25% then 35% then 50% EtOAc in hexanes) afforded the product {[4-(2'-
amino-4'-methoxy-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-
2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.680 g, 40%) as a yellow-
brown solid. 1H NMR (MeOD): 8 8.223 (s, 1H), 8.001 (d, 1H, J = 7.2 Hz),
7.879 (t, 1H, J = 1.6 Hz), 7.698 (t, 1H, J = 8.0 Hz), 7.549 (d, 1H, J = 8.0 Hz),
6.287 (dd, 2H, J = 7.2 Hz, J == 2.4 Hz), 3.770 (s, 3H), 2.669 (s, 3H), 1.900 (s,
3H), 1.510 (s, 9H). C25H29N3O5S3: 548.13 (M+l) found 547.70.
f) 4-[4'-Methoxy-6'-methyl-2'-(2-oxo-imidazolidin-l-yl)-biphenyl-3-
sulfonyl]-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
A solution of {[4-(2'-amino-4'-methoxy-6'-methyl-biphenyl-3-
sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-rnethyl}-carbarnic acid tert-
butyl ester {{Example 198: step e) 0.050 g, 0.091 mmol) in dry CH2C12 (10
mL) was treated with bromoethylisocyanate (0.010 mL, 0.110 mmol) and
stirred at room temperature 4 h. Additional bromoethylisocyanate (0.010 mL,
0.110 mmol) was added and the reaction stirred at room temperature 15 h.
The reaction mixture was washed with water (1x15 mL), dried over MgSO4,
and concentrated in vacua. The residue was taken up in CH2Cl2 (10 mL),
treated with trifluoroacetic acid (1.00 mL), and stirred at room temperature 1
h. The solvents were evaporated in vacito. Preparatory HPLC (10-80%
acetonitrile in 1% TFA/water over 30 min.) afforded the product 4-[4'-
methoxy-6'-methyl-2'-(2-oxo-irnidazolidin-l-yl)-biphenyl-3-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate (0.010 g, 21%) as
a white glassy solid. 1H NMR (MeOD): d 8.354 (s, 1H), 8.032 (d, 1H, .J =
7.6 Hz), 7.946 (s, 1H), 7.733 (t, 1H, J = 7.6 Hz), 7.574 (d, 1H, J = 8.0 Hz),
7.059 (s, 1H), 6.967 (s, 1H), 3.877 (s, 3H), 2.730 (s, 3H), 2.101 (s, 3H), 3.841
(dt, 4H, J= 8.8 Hz, J= 2.4 Hz). C23H24N4O4S3: 517.10 (M+l) found 517.10.
Example 199
N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-methoxy-
6-methyl-biphenyl-2-yl]-4-methanesulfonyl-butyramide trifluoroacetate
A solution of {[4-(2'-amino-4"-methoxy-6'-methyl-biphenyl-3-
sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl} -carbamic acid tert-
butyl ester {{Example 198: step e) 0.050 g, 0.091 mmol) in CH2C12 (10 mL)
was treated with triethylamine (38.0 µL, 0.274 mmol) and 4-methanesulfonyl-
butyryl chloride ( 0.025 g, 0.137 mmol) as a solution in CH2Cl2 (3 mL) and
stirred at room temperature 3 h. The reaction mixture was washed with
saturated aqueous NaHCO3 (1 x 15 mL). The organic layer was dried over
MgSO4 and trifluoroacetic acid (0.5 mL) was added. The solution stirred at
room temperature 1 h and solvents were removed in vacuo. Preparatory
HPLC (10-50% acetonitrile in 1% TFA/water over 30 min.) afforded the
product N-[3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-
methoxy-6-methyl-biphenyl-2-yl]-4-methanesulfonyl-butyramide
trifluoroacetate (0.013 g, 24%) as a white glassy solid. 1H NMR (MeOD): 8
8.309 (s, 1H), 8.032 (d, 1H, J= 8.8 Hz), 7.868 (t, 1H, J= 1.6 Hz), 7.684 (t,
1H, J= 8.0 Hz), 7.543 (d, 1H, J= 8.0 Hz), 6.871 (s, 1H), 6.817 (d: 1H, J= 2.4
Hz), 3.841 (s, 3H), 2.922 (s, 3H), 2.822 (t, 2H, J = 7.6 Hz), 2.742 (s, 3H),
2.202 (t, 2H, J= 6.8 Hz), 2.063 (s, 3H), 1.765 (m, 2H). C25H29N3O6S4: 596.09
(M+l) found 596.10.
Example 200
a) 4-{2'-[3-(2-Methanesulfonyl-ethyl)-ureido]-4'-methoxy-6'-methyl-
biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine
trifluoroacetate
A solution of {[4-(2'-amino-4'-methoxy-6'-methyl-biphenyl-3-
sulfonyl)-5-methylsulfanyl-thicphen-2-yl]-imino-methyl} -carbamic acid tert-
butyl ester {{Example 198: step e) 0.070 g, 0.128 mmol) in dry CH2C12 (3 mL)
was treated with l-isocyanato-2-methanesulfonyl-ethane (0.019 g, 0.128
mmol) as a solution in CH2Cl2 (2 mL) and stirred 20 min. The reaction
mixture was washed with saturated aqueous NaHCO3 (1 x 25 mL). The
organic layer was dried over MgSO4 and concentrated in vacuo. The residue
was taken up in CH2Cl2 (10 rnL) and treated with trifluoroacetic acid (2.00
mL), stirring at room temperature 30 min. The solvents were removed in
vacuo. Preparatory HPLC (10-80% acetonitrile in 1% TFA/water over 30
min.) afforded the product 4-{2'-[3-(2-methanesulfonyl-ethyl)-ureido]-4'-
methoxy-6'-methyl-biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate (0.040 g, 53%) as a white glassy solid. 1H NMR (MeOD): d 8.300 (s, 1H), 8.031 (d, 1H, J= 8.0 Hz), 7.865 (t, 1H, J =
1.6 Hz), 7.688 (t, 1H, 7= 7.6 Hz), 7.568 (d, 1H, J= 8.0 Hz), 7.063 (d, 1H, J =
1.6 Hz), 6.730 (d, 1H, J== 1.6 Hz), 3.818 (s, 3H), 3.507 (t, 2H, J= 6.4 Hz),
3.171 (t, 2H, J = 6.0 Hz), 2.928 (s, 3H), 2.725 (s, 3H), 2.315 (s, 3H).
C24H28N4O0S4: 597.09 (M+l) found 597.00.
Example 201
4-{2'-[3-(4-Methanesulfonyl-butyl)-ureido]-6'-methyl-biphenyl-3-sulfonyl}-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
a) 2-(4-Methylsulfattyl-butyl)-isoindole-l,3-dione
A solution of 2-(4-bromo-butyl)-isoindole-l,3-dione (l.00g, 3.54
mmol) in MeOH (60 mL) was treated with sodium thiomethoxide (0.298 g,
4.25 mmol) and heated to reflux 18 h. The solvent was evaporated in vacuo
and the residue partitioned between EtOAc and water. The aqueous layer was
further extracted with EtOAc (1 x 75 mL). The organic layers were dried over
MgSO4 and concentrated in vacuo to afford the product 2-(4-methylsulfanyl-
butyl)-isoindole-l,3-dione (0.803 g, 91%). 1H NMR (MeOD) 7.844 (m, 4H),
3.704 (t, 2H, J = 7.2 Hz), 2.549 (t, 2H, J = 7.2 Hz), 2.063 (s, 3H), 1.792 (quint,
2H, J = 7.2 Hz), 1.731 (quint, 2H, J = 7.2 Hz).
b) 2-(4-Methanesulfonyl-butyl)-isoindole-l,3-dione
A solution of 2-(4-methylsulfanyl-butyl)-isoindole-l,3-dione
((Example 201: step a) 1.35 g, 5.42 mmol) in CH2Cl2 (50 mL) was treated
with 3-chloroperbenzoic acid (mCPBA, 3.03 g, 13.5 mmol) and stirred at
room temperature 17 h. The solution was washed with aqueous Na2S2O3 (2 x
40 mL) and water (1 x 40 mL). The organic layer was dried over MgSO4 and
concentrated in vacuo to afford the product 2-(4-methanesulfonyl-butyl)-
isoindole-l,3-dione (0.866 g, 57%). 1H NMR (MeOD): d 7.S27 (m, 4H),
3.732 (t, 2H, J = 6.4 Hz), 3.193 (t, 2H, J = 7.2 Hz), 2.939 (s, 3H), 1.843 (m,
4H).
c) 4-Methanesulfonyl-butylamine
A solution of 2-(4-metlianesulfonyl-butyl)-isoindole-l,3-dione
((Example 201: step b) 0.866 g, 3.08 mmol) in EtOH (30 mL) was treated with
hydrazine and stirred at room temperature 18 h. The solid precipitate was
removed by filtration and the filtrate was concentrated in vacuo. To remove
any excess hydrazine, the resulting waxy solid was titrated with toluene and
with THF and placed under liigh vacuum overnight to afford the product
(0.400 g, 86%) as a waxy, off-white solid. +NMR (MeOD): d 3.153 (dd, 2H, J
- 8.8 Hz, J = 0.0 Hz), 2.962 (s, 3H), 2.582 (dd, 2H, J = 7.6 Hz, J = 0.0 Hz),
1.811 (m,2H) 1.747 (m,2H).
d) 4-{2'-[3-(4-Methanesulfonyl-butyl)-ureido]-6'-methyl-biphenyl-3-
sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
A solution of [4-(2'-arnino-6'-methyl-biphenyl-3-sulfonyl)-5-
methylsu]fanyl-thjophen-2-y]]-immo-methy3}-carbamic acid tent-butyl ester
((Example 25: step c) 0.100 g, 0.193 mmol) in CH2C12 (10 mL) was treated
with pyridine (0.017 mL, 0.213 mmol) and p-nitrophenylchloroformate (0.043
g, 0.213 mmol) and stirred 2 h. The solution was treated with 4-
methanesulfonylbutylaimine (Example 201: step c, 0.035 g, 0.232 mmol) and
triethylamine (0.215 mL, 1.54 mmol) and stirred 2 h. The mixture was diluted
with CH2Cl2 and washed with water (1 x 50 mL). The organic layer was dried
over MgSO4 and filtered. The remaining CH2Cl2 solution was treated with
trifluoroacetic acid (1.00 mL) and stirred 1.5 h, The solvents were evaporated
in vacuo. Preparatory HPLC (10-50% aeetomtrile in 1% TFA/water over 30
min.) afforded the product 4-{2'-[3-(4-methanesulfonyl-butyl)-ureidoJ-6'-
methyl-biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine
trifluoroacetate (0.022 g, 19%) as a white glassy solid. !H NMR (MeOD): d
8.326 (s, 1H), 8.069 (d, 1H, J = 8.0 Hz), 7.917 (t, 1H, J = 1.6 Hz), 7.740 (t,
1H, J = 8.0 Hz), 7.586 (d, 1H, J = 7.6 Hz), 7.441 (d, 1H, J = 7.2 Hz), -7.305 (t,
1H, J = 8.0 Hz), 7.151 (d 1H, J = 8.0 Hz), 3.116 (dd, 2H, J - 8.8 Hz, J = 6.4
Hz), 3.069 (t, 2H, J = 6.8 Hz), 2.962 (s, 3H), 2.739 (s, 3H), 2.025 (s, 3H) 1.732
(quint, 2H, J = 7.6 Hz), 1.506 (quint, 2H, J = 7.6 Hz). C25H30N4O5S4: 595.11
(M+l) found 595.10.
Examples 202-208
A solution of [4-(2'-amino-6'-inethyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
((Example 25: step c) 1.00 g, 1.93 mmol) in dry CH2C12 (20 mL) was treated
with pyridine (0.172 mL, 2.13 mmol) and p-nitrophenylchloroformate (0.428
g, 2.13 mmol). The mixture was stirred at room temperature 2 h. The solution
of the resulting carbatnate, {3'-[5-(tert-butoxycarbonylamino-imino-methyl)-
2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-carbamic
acid 4-nitro-phenyl ester, was divided into vials and treated with the following
amines (1.1 equivalents) and triethylamine (8.0 equivalents).
Example 202
2-((4-Bromo-phenyl)-ethylamine)
Example 203
(3-Phenyl-propylamine)
Example 204
(Berizylamine)
Example 205
(2-Aniino-3-phenyl-propionic acid)
Example 206
(6-Amino-2-tert-butoxycarbonylamino-hexanoic acid)
Example 207
(2-(lH-Indol-3-yl)-ethylamine)
Example 208
(3,3-Diphenyl-propylamine)
The reaction mixtures stirred at room temperature 4 h. The solutions
were washed with water and the organic layers dried over MgSO4 and
concentrated in vacuo. The residues were taken up in CH2Cl2 (1 mL) and
treated with trifluoroacetic acid (0.25 mL) for 2 h. Solvents were evaporated
in vacuo. Preparatory HPLC (10-80% acetonitrile in 1% TFA7water over 30
min.) afforded the products shown in Examples 203-208. All were white
glassy solids.
Example 202
4-(2'-{3-[2-(4-Bromo-phenyl)-ethyl]-ureido}-6'-methyl-biphenyl-3-sulfonyl)-
5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
1H NMR (MeOD): d 8.299 (s, 1H), 8.075 (d, 1H, J= S.4 Hz), 7.894 t, 1H, J =
1.6 Hz), 7.708 (t, 1H, J= 8.0 Hz), 7.529 (d, 1H, J= 8.4 Hz), 7.376 (d, 2H, J =
8.4 Hz), 7.834 (t, 1H, J= 8.4 Hz), 7.279 (t, 1H, J= 7.6 Hz), 7.134 (d, 1H, J =
7.6 Hz), 6.957 (d, 2H, J= 7.6 Hz), 3.20 (m, 2H), 2.656 (s, 3H), 2.555 (m, 2H),
1.995 (s,3H). C28H27BrN4O3S3: 643.04 (M+l) found 643.00.
Example 203
4-{6'-Methyl-2'-[3-(3-phenyl-propyl)-ureido]-biphenyl-3-sulfonyl}-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
1H NMR (MeOD): d 8.293 (s, 1H), 8.056 (d, 1H, J= 8.0 Hz), 7.916 (t, 1H, J
- 1.6 Hz), 7.715 (t, 1H, J= 7.6 Hz), 7.592 (d, 1H, J= 7.6 Hz), 7.449 (d, 1H, .7
= 7.6 Hz), 7.308 (t, 1H, J = 7.6 Hz), 7.255 (d, 2H, J= 7.2 Hz), 7.166 (t, 2H, J
= 7.2 Hz), 7.147 (d, 2H, J = 8.0 Hz), 3.021 (t, 2H, J= 6.4 Hz), 2.697 (s, 3H),
2.515 (t, 2H, J = 7.6 Hz), 2.026 (s, 3H), 1.638 (quint, 2H, J = 7.6 Hz).
C29H30N4O3S3: 579.15 (M+l) found 579.10.
Example 204
4-[2'-(3-Benzyl-ureido)-6'-methyl-biphenyl-3-sulfonyl]-5-methylsulfanyl-
thiophene -2-carboxamidme trifiuoroacetate
1H NMR (MeOD): d 8.243 (s, 1H), 8.073 (d, 1H, J= 9.2 Hz), 7.951 (t, 1H, J
= 1.6 Hz), 7.685 (t, 1H, J = 8.0 Hz), 7.558 (d, 1H, J= 7.(5 Hz), 7.406 (d, 1H, J
= 8.8 Hz), 7.301 (t, 1H, J= 8.0 Hz), 7.232 (m, 4H), 6.977 (d, 2H, .7= 8.4 Hz),
4.137 (q, 2H, J= 16 Hz), 2.649 (s, 3H), 2.029 (s, 3H). C27H26N4O3S3: 55.12
(M+l) found 551.10.
Example 205
2-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-
biphenyl-2-yl]-ureido}-3-phenyl-propionic acid trifluoroacetate

1H NMR (CD3CN): d 10.027 (s br, 1H), 8.083 (s, 1H), 7.875 (s, 1H), 7.807 (s,
1H), 7.729 (t, 1H, y = 7.525 Hz), 7.525 (d, 1H, J= 6.8 Hz), 7.429 (m, 1H),
7.272 (m, 5H), 7.101 (m, 2H), 5.446 (t, 1H, J= 10.4 Hz), 3.077 (m, 2H), 2.674
(s, 3H), 2.018 (s, 3H). C29H28N4O5S3: 609.12 (M+l) found 609.10.
Example 206
2-Ammo-6-{3-[3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-
6-methyl-biphenyl-2-yl]-ureido}-hexanoic acid tnfluoroacetate
1H NMR (CD3CN): d 8.135 (s, 1H), 8.037 (d, 1H, J= 7.6 Hz), 7.839 (s, 1H),
7.702 (t, 1H, J = 7.6 Hz), 7.566 (d, 1H, J= 8.0 Hz), 7.413 (d, 1H, ./= 8.0 Hz),
7.297 (t. 1H, J= 7.6 Hz), 7.186 (d, 1H, J= 7.2 Hz), 3.951 (s br, 1H), 2.939 (t,
2H, 7= 1.6 Hz), 2.674 (s, 3H), 2.043 (s, 3H), 1.854 (m, 2H), 1.311 (m, 4H).
C26H31N5O5S3: 590.15 (M+l) found 590.10.
Example 207
4-(2'- {3-[2-(lH-Indol-3-yl)-ethyl]-ureido} -6'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxamidine tnfluoroacetate
1H NMR (MeOD): d 8.270 (s, 1H), 8.069 (d, 1H, J= 8.0 Hz), 7.901 (t, 1H, J
= 1.6 Hz), 7.661 (t, 1H, J= 7.2 Hz), 7.467 (t, 2H,J= 8.8 Hz), 7.351 (t, 2H, J =
6.8 Hz), 7.296 (t, 1H, J= 7.6 Hz), 7.163 (d, 1H, J= 8.0 Hz), 7.103 (t, 1H, J =
7.2 Hz), 6.991 (t, 1H, J= 6.8), 6.855 (s, 1H), 3.428 (m, 2H), 2.712 (t, 2H,J =
8.8 Hz), 2.575 (s, 3H), 2.028 (s, 3H). C30H29N5O3S3: 604.14 (M+l) found
604.10.
Example 208
4-{2'-[3-(3,3-Diphenyl-propyl)-ureido]-6'-methyl-biphenyl-3-sulfonyl}-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
1H NMR (MeOD): d 8.263 (s, 1H), 8.022 (d, 1H, J= 8.8 Hz), 7.913 (t, 1H, J
= 1.6 Hz), 7.679 (t, 1H, J-= 7.6 Hz), 7.585 (d, 1H, J= 7.6 Hz), 7.416 (d, 1H, J
= 7.416 Hz), 7.253 (m, 9H), 7.163 (t, 3H, J = 6.8 Hz), 3.878 (t, 1H,./= 7.6
Hz), 2.944 (dt, 2H, J= 6.8 Hz, J= 2.4 Hz), 2.689 (s, 3H), 2.081 (q, 2H, J = 7.6
Hz), 2.032 (s, 3H). C35H34N4O3S3: 655.18 (M+l) found 655.10.
Example 209
N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-
biphenyl-2-yl]-4-methanesulfonyl-butyiramide trifluoroacetate
a) 4-Methanesulfonyl-butyryl chloride
4-Methylsulfanyl-butyriic acid methyl ester (0.50 g, 3.37 mmol) in
dichloromethane [5 mL] was added dropwise to a solution of mCPBA (1.57 g,
9.11/ mmol) in dichloromethane [15 mL] at room temperature and then
refluxed for 1 hour.. The solution was then cooled to room temperature and
solid sodium sulfite was added. The reaction was filtered, washed with IN
NaOH, brine and dried with magnesium sulfate and evaporated. The crude
residue was then dissolved in THF/methanol/water [2/1/0.1 mL] and lithium
hydroxide (0.18 g, 4.38 mmol) was added. The reaction was heaved to 50°C
for 24 hours. The reaction was cooled to room temperature and IN HC1 was
added and the product was extracted with ethyl acetate, dried with magnesium
sulfate to give the product (0.12 g, 21%). 1H-NMR (CDCl3): d 3.20 (t, 2H,
J=7.6 Hz), 2.98 (s, 3H), 2.52 (t, 2H, J=7.2 Hz), 2.09 (m, 2H). The acid was
dissolved in dichloromethane [5 mL] and thionyl chloride [5mL] was added.
The reaction was stirred at room temperature for 3 hours, evaporated and used
directly in the next step.
b) (Imino-{4-[2'-(4-methanesulfonyl-butyrylamino)-6'-methyl-biphenyl-
3-sulfonyl]-5-methyhulfanyl-thiophen-2-yl}-methyl)-carbamic acidtert-
butyl ester
4-Methanesulfonyl-butyryl chloride (0.333 g, 1.81 mmol) 1 example
209, step a] was added to a solution of {[4-(2'-amino-6'-methyl-biphenyl-3-
sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl} -carbamic acid tert-
butyl ester (0.468 g, 0.905 mmol) [example 25, step c] and triethylamine (1.S3
g, 18.1 mmol) in dichloromethaxie at room temperature. The reaction was
stirred for 24 hours and then evaporated. Column chiomatography (25%
EtOAc in hexanes) of the residue yielded the title compound (0.520 g, 78%) as
a solid. ESI-MS (m/z): Calcd. for C29H35N3O7S4: 665.14; found: 665.8.
c) N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-
methyl-biphenyl-2--yll-4-niethanesulfonyl-butyrami.de trifluoroacetate
A solution of dichloromethane/ trifiuoroacetic acid (1/1) [1 mL] was
added to (imino- {4-[2'-(4-methcinesulfonyl-butyrylamino)-(5'-methy]-biphenyl-
3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl
ester (0.011 g, 0.017 mmol) [example 209, step b] at room temperature and
stirred for 1 hour. The reaction mixture was evaporated and purified via
reverse-phase HPLC [acetonitrile/water (0.01 %TFA)] to give the title
compound (0.004 g, 36%) as a solid. 1H-NMR (MeOD): 6 8.29 (s, 1H), 8.04
(md, 1H, J=6A Hz), 7.87 (t, 1H, .7=2.0 Hz), 7.69 (t, 1H, .7=7.6 Hz), 7.54 (md,
1H, .7=7.6 Hz), 7.34 (t, 1H, J=7.6 Hz), 7.28 (d, 1H, .7=7.2 Hz), 7.18 (d, 1H,
7=7.2 Hz), 2.91 (s, 3H), 2.78 (t, 2H, J=7.6 Hz), 2.72 (s, 3H), 2.18 (t, 2H, J=7.6
Hz), 2.07 (s, 3H), 1.74 (m, 2H). ESI-MS (m/z): Calcd. for C24H27N3O5S4:
566.1; found: 566.8.
Example 210
N-[3l-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-
biphenyl-2-yl]-4-sulfamoyl-butyramide trifluoroacetate
a) (Imino-{4-[6'-methyl-2'-(4-siilfamoyl-butyrylamino)-biphenyl-3-
sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl
ester
{[4-(2'-Amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.013 g, 0.025
mmol) [example 25, step c] was added to a solution of 4-sulfamoyl-butyric
acid (0.011 g, 0.068 mmol), EDCI (0.013 g, 0.068 mmol) and HOBt (0.009 g,
0.068 mmol) in DMF [0.5 mL] at room temperature. The reaction was stirred
for 24 hours and then evaporated. Column chromatography (25% EtOAc in
hexanes) of the residue yielded the title compound (0.010 g, 60%) as a solid.
ESI-MS (m/z): Calcd. for C28H34N4O7S4: 666.13; found: 666.8.
b) N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-
methy1-biphenyl-2-yl]-4-sulfamoylbntyramide trifluoroacetate
A solution of dichloromethane/ trifluoroacetic acid (1/1) [1 mL] was
added (irnino-{4-[6'--methyl-2'-(4-sulfamoyl-butyrylarnino)-biphenyl-3-
sulfonyl]-5-methylsulfanyl-thiophen-2-yl} -methyl)-carbamic acid tert-butyl
ester (0.010 g, 0.015 mmol) [example 210, step a] at room temperature and
stirred for 1 hour. The reaction mixture was evaporated and purified via
reverse-phase HPLC [acetonitrile/water (0.01%TFA)] to give the title
compound (0.005 g, 36 %) as a solid. 1H NMR (MeOD): d 8.30 (s, 1H), 8.04
(md, 1H, 7=7.6 Hz), 7.88 (t, 1H, .7=1.6 Hz), 7.70 (t, 1H, .7=7.6 Hz), 7.54 (md,
1H, .7-7.6 Hz), 7.36 (t, 1H, .7=7.6 Hz), 7.29 (d, 1H, .7=6.8 Hz), 7.19 (d, 1H,
.7=8.0 Hz), 2.77-2.72 (m, 5H), 2.16 (t, 2H, .7=7.2 Hz), 2.09 (s, 3H), 1.76 (m,
2H). ESI-MS (m/z): Calcd. for C23H26N4O5S4: 566.08; found: 567.1.
Example 211
11-Amino-undecanoic acid [3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-
3-sulfonyl)-6-methyl-biphenyl-2-yl]-amidebistrifluoroacetate
a) (10-{3'-[5-(tert-Butoxycarbonylamino-imino-niethyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl--biphenyl-2-ylcarbamoyl}-
decyl)-carbamic acid 9H-fluoren-9-ylmethyl ester
Thionyl chloride (0.86 mL, 2.36 mmol) was added to a solution of 11-
(9H-fluoren-9-ylmethoxycarbonylamino)-undecanoic acid (0.086 g, 0.194
mmol) in dichloromethane/DMF [1 mL/1 drop] and stirred at room
temperature for 3 hours. The reaction mixture was evaporated, dissolved in
dichloromethane [5 mL] was added dropwise to a solution of {[4-(2'-amino-6'-
methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-
carbamic acid tert-butyl ester (0.050 g, 0.097 mmol) [example 25, step c] and
triethylamine (0.03 mL, 0.19 mmol) in dichloromethane [3 mL] at room
temperature and stirred for several hours. The crude reaction was evaporated
and column chromatography (25% EtOAc in hexanes) of the residue yielded
the title compound (0.042 g, 47 %) as a solid. ESI-MS (m/z): Calcd. for
C50H58N4O7S3: 922.35; found: 923.0.
b) ({4-12'-(ll-Amino-undecanoylamino)-6'-methyl-biphenyl-3-
sulfonyl]-5-methylsulfanyl-thiopheii-2-yl}-imino-methyl)-carbamicacidtert-
butyl ester
A solution of 50% piperidine in DMF [1 mL] was added to (10-{3'-[5-
(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3 -
sulfonyl]-6-methyl-biphenyl-2-ylcarbamoyl}-decyl)-carbamic acid 9H-
fluoren-9-ylmethyl ester (0.040 g, 0.043 mmol) [example 211, step a] and
stirred for 0.5 hours, followed by evaporation. Column chromatography (10%
MeOH in dichloromethane) of the residue yielded the title compound (0.024 g,
77 %) as a solid. ESI-MS (m/z): Calcd. for C35H48N4O5S3: 700.28; found:
701.0.
c) 11-Amino-undecanoic acid [3'-(5-carbamimidoyl-2-methylsulfanyl-
thiophene-3-sulfonyl)- 6-methyl-biphenyl-2-yl]-amide bistrifluoroacetate
A solution of dichloromethane/ trifluoroacetic acid (1/1) [1 mL] was
added to ({4-[2'-(! l-amino-undecanoylamino)-6'-methyl-biphenyl-3-
sulfonyl]-5-methylsulfanyl-miophen-2-yl}-imino-methyl)-carbamic acid tert-
butyl ester (0.005 g, 0.007 mmol) [example 211, step b] at room temperature
and stirred for 1 hour. The reaction mixture was evaporated and purified via
reverse-phase HPLC [acetonitrile/water (0.01%TFA)] to give the title
compound (0.003 g, 76 %) as a solid. 1H-NMR (MeOD): d 8.28 (s, 1H), 8.02
(d, 1H, J=7.2 Hz), 7.87 (m, Hi), 7.66 (t, 1H, J=8.0 Hz), 7.53 (d, 1H, 7=8.0
Hz), 7.34 (t, 1H, y=7.6 Hz), 7.27 (d, 1H, J=7.6 Hz), 2.91 (t, 2H, .7=8.0 Hz),
2.71 (s, 3H), 2.03 (s, 3H), 1.96 (q, 2H, .7=7.2 Hz), 1.65 (m, 2H), 1.41-1.12 (m,
14H). ESI-MS (m/z): Calcd. for C30H40N4O3S3: 600.23; found: 601.2.
Example 212
N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-
biphenyl-2-yl]-4-trifluoromethanesulfonylamino-butyramide trifluoroacetate
a) 4-Trifliioromethanesulfonylamino-biitync acid methyl ester
Trifluoromethanesulfonyl chloride (0.23 mL, 2.16 mmol) was added
dropwise to a solution of 4-amino-butyric acid methyl ester hydrochloride
(0.30 g, 1.96 mmol) and triethylamine (0.68 mL, 4.90 mmol) in
dichloromethane and stirred at room temperature for 18 hours. 1N HC1 was
added and the product, was extracted with dichloromethane, dried with
magnesium sulfate and evaporated to give the title compound (0.42 g, 85 %).
1H-NMR (CDCl3): d 4.89 (s, 1H), 3.12 (t, 2H, J-7.2 Hz), 2.94 (s, 3H), 2.41 (t,
2H, J=7.2 Hz), 1.84 (m, 2H, J=l2 Hz).
b) 4-Trifluoromethanesulfonylamino-butyryl chloride
4-Trifluorometbanesulfonylamino-butyrie acid methyl ester (0.42 g,
1.77 mmol) [example 212, step a] was taken up in methanol [2 mL] and 1N
NaOH was added [2.66 mL] and stirred for 2 hours. 1N HCl was added and
the product was extracted with ethyl acetate, dried with magnesium sulfate and
evaporated. The crude product (0.13 g, 0.57 mmol) was dissolved in
dichloromethane/DMF [1 mL/1 drop] and thionyl chloride (0.08 mL, 1.14 was
added. The reaction was stirred at room temperature for 2 hours and then
evaporated and used directly in the next step.
c) (Imino-{5-methylsnlfanyl-4-[6'-methyl-2'-(4-
trifluoromethanesulfonylaminobutyrylamino)-biphenyl-3-sulfonyl]-
thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester
A solution of 4-trifluoromethanesulfonylamino-butyryl chloride (0.015
g, 0.058 mmol) [example 212, step b] in dichloromethane [1 mL] was added to
a solution of {[4-(2'-amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-iniino-methyl}-carbamic acid tert-butyl ester (0.025 g, 0.049
mmol) [example 25, step c] in dichloromethane [1 mL] at room temperature
with vigorous stirring for 0.5 hours. The reaction mixture was evaporated and
column chromatography (25% EtOAc in hexanes) of the residue yielded the
title compound (0.020 g, 57%) as a solid. ESI-MS (m/z): Calcd. for
C29H33F3N4O7S4: 734.12; found: 734.7.
d) N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfoityl)-6-
methyl-biphenyl-2-yl]-4-trifluoromethanesulfonylamino-butyramide
triflnoroacetate
A solution of dichloromethane/ trifluoroacetic acid (1/1) [2 mL] was
added to (imino-{5-methylsulfanyl-4-[6'-methyl-2'-(4-
trifluoromethanesulfonylanunobutyrylamino)-biphenyl-3-sulfonyl]-thiophen-
2-yl}-methyl)-carbamic acid tert-butyl ester (0.020 g, 0.027 mmol) [example
212, step c] at room temperature and stirred for 1 hour. The reaction mixture
was evaporated and purified via reverse-phase HPLC [acetonitrile/water
(0.01 %TFA)] to give the title compound (0.009 g, 54%) as a solid. 1H-NMR
(MeOD): d 8.29 (s, 1H), 8.03 (md, 1H, J=8.4 Hz), 7.87 (m, 1H), 7.68 (t, 1H,
.1=7.6 Hz), 7.53 (md, 1H, J=1.6 Hz), 7.34 (t, 1H, 1=1.6 Hz), 7.2S (d, 1H, J=7.2
Hz), 7.19 (d, 1H, J=7.2 Hz), 2.98 (m, 2H), 2.72 (s, 3H), 2.06 (s, 3H), 2.05 (t,
2H, J=7.6 Hz), 1.48 (m, 2H). ESI-MS (m/z): Calcd. for C24H25F3N4O5S4:
634.07; found: 635.1.
Example 213
E/Z-{2-[3'-(5-Carbamiraido)d-2-methylsulfanyl-thiophene-3-suifonyl)-6-
methyl-biphenyl-2-yl]-vinyl} -phosphonic acid trifluoroacetate
a) (2-Iodo-3-methyl-phenyl)-m ethanol
Thionyl chloride [5 ml,] was added to 2-iodo-3-methyl-benzoic acid
(2.00 g, 7.63 mmol) at room temperature and heated to 50°C for 1 hour. The
solution was then cooled and evaporated. The crude residue was dissolved in
ethyl acetate, washed with brine and dried with magnesium sulfate. The crude
product was then dissolved in THF [5 mL] and a 1M solution of lithium
aluminum hydride [10.7 mL] was added at room temperature and stirred for 1
hour. Water [0.1 mL] and 15% NaOH [0.1 mL] were added followed by
evaporation. Column chromatography (50% EtOAc in hexanes) of the residue
yielded the title compound (0.50 g, 26 %) as a solid. 1H-NMR (CDCl3): d
3.20 (t, 2H, J=7.6 Hz), 2.98 (s, 3H), 2.52 (t, 2H, J=7.2 Hz), 2.09 (m, 2H).
b) {[4-(2'-Hydroxymethyl-6'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
n-Butyllithium (2.5.M) [4.03 mL] was added to a solution of (2-iodo-3-
methyl-phenyl)-methanol (1.00 g, 4.04 mL) [example 213, step a] in ether [20
mL] at -78°C and stilted for 0.5 hours. Trimethyl borate [1.13 mL, 10.1
mmol) was added and the solution was stirred for 2 hours at room temperature,
followed by evaporation. The crude residue was dissolved in ethanol/toluene
(1/2) [30 mL] and 2M sodium carbonate [16.2 mL] followed by addition of
{[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-
methyl}-carbamic acid tert-butyl ester (0.49 g, 1.01 mmol) [example 27, step
c]. The solution was bubbled with argon and then tetrakis
(triphenylphosphine) palladium (0) (0.18 g, 0.15 mmol) was added. The
reaction was refluxed for 3 hours and then cooled to room temperature. Ethyl
acetate was added and the crude reaction was washed with brine, dried over
magnesium sulfate and evaporated. Column chromatography (50% EtOAc in
hexanes) of the residue yielded the title compound (0.40 g, 74 %) as a solid.
ESI-MS (m/z): Calcd. for C25H28N2O5S3: 532.12; found: 532.7.
c) E/Z-(2-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-vinyl)-
phosphonic acid diethylester
Manganese dioxide (0.041 g, 0.470 mmol) was added to a solution of
({[4-(2'-hydroxymethyl-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.025 g, 0.047
mmol) [example 213, step b] in dichloromethane [5 mL] and refluxed for 3
hours. The reaction was filtered through Celite and evaporated.. The crude
residue was dissolved in anhydrous THF [2 mL] and added to a solution of
(diethoxy-phosphorylmethyl)-phosphonic acid diethyl ester (0.011 g, 0.061
mmol) and sodium hydride (0.003 g, 0.056 mmol) in THF [2 mL] at room
temperature and stirred for 0.5 hours. A solution of 1N NaOH/MeOH (1/1)
[10 mL] was added and the crude product was extracted with ether, dried with
magnesium sulfate and evaporated. Column chromatography (50% EtOAc in
hexanes) of the residue yielded the title compound (0.019 g, 57%) as a solid.
ESI-MS (m/z): Calcd. for C30H37N2O7PS3: 664.15; found: 664.8.
d) E/Z-{2-[3'-(5-Carbam im idoyl-2-m ethyhulfanyl-th ioph en e-3-
sulfonyl)-6-methyl-biphenyl-2-yl]-vinyl}-phosphonic acid trifluoroacetate
Trimethylsilyl iodide (0.058 g, 0.271 mmol) was added dropwise to a
solution of E/Z-(2- {3'-[5-(tert-butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene--3-sulfonyl]-6-methyl-biphenyl-2-yl}-vinyl)-
phosphonic acid diethylester (0.018 g, 0.027 mmol) [example 213, step c| in
dichloromethane [3 mL] and heated to 45°C for 3 hours. The reaction was
quenched with water [0.025 mL], stirred for 0.5 hours and evaporated. The
crude residue was the dissolved in methanol and 20% HC1 was added [020
mL], stirred for 1 hour and concentrated. The reaction mixture was purified
via reverse-phase HPLC [acetonitrile/water (0.01 %TFA)] to give the title
compound (0.005 g, 28%) as a solid. 1H-NMR (MeOD): d 8.28 (s, 1H), 8.04
(t, 1H, .7=7.6 Hz), 7.83 (s, 1H), 7.71 (t, 1H, .7=7.6 Hz), 7.63 (m, 1H), 7.52 (m,
1H), 7.38 (m, 1H), 7.26 (m, 1H), 7.18 (t, 1H, J=7.2 Hz), 6.92 (t. 1H, J=17.6
Hz), 6.34 (t, 1H, J=18.0 Hz), 2.74 (s, 3H), 2.02-1.95 (d, 3H). ESI-MS (m/z):
Calcd. for C21H21N2O5PS3: 508.04; found: 509.1.
Example 214
2-[3'-(5-Carbaniimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-niethy]-
biphenyl-2-ylmethylsulfanyl]-succinic acid trifluoroacetate
a) Methanesulfonic acid 3'-[5-(tert-butoxycarbonylamiiw-imino-
methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-
ylmethyl ester
Methanesulfonyl chloride (0.027 g, 0.241 mmol) was added to a
solution of {[4-(2'-hydroxymethyl-6'-methyl-biphenyl-3-suifonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(0.100 g, 0.188 mmol) [example 213, step b] and triethylamine (0.048 g: 0.470
mmol) in THF [3 mL] at room temperature and stirred for 18 hours. Column
chromatography (25% EtOAc in hexanes) of the residue yielded the title
compound (0.017 g, 14%). ESI-MS (m/z): Calcd. for C26H30N2O7S4: 610.09;
found: 611.8.
b) 2-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-suIfonyl)-6-
methyl-biphenyl-2-ylmethylsulfanylJ-succinic acid trifluoracetate
2-Mercapto-succinic acid (0.004 g, 0.028 mmol) was added to a
solution of methanesulfonic acid 3'-[5-(ter1:-butoxycarbonylarnino-imino-
methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-
ylmethyl ester (0.017 g, 0.028 mmol) [example 214, step a] and triethylamme
(0.009 g, 0.084 mmol) in dichloromethane [0.5 mL] at 40°C, stirred for 2
hours and then evaporated. The crude reaction was dissolved in a solution of
dichloromethane/ trifluoroacetic acid (1/1) [2 mL] and stirred for 1 hour. The
reaction mixture was evaporated and purified via reverse-phase HPLC
[acetonitrile/water (0.01%TFA)] to give the title compound (0.005 g, 42 %) as
a solid. 1H-NMR (MeOD): d 8.31 (s, 1H), 8.06 (t, 1H, J=8.0 Hz), 7.83 (d, 1H,
.7=16.8 Hz), 7.70 (q, 1H, .7=6.8 Hz), 7.57 (t, 1H, J=7.2 Hz), 7.29-7.21 (m, 3H),
3.60-3.48 (m, 1H), 3.54 (s, 3H), 3.37-3.34 (m, 1H), 2.70 (s, 3H), 2.68-2.57 (m,
1H), 2.31-2.14 (m, 1H), 1.97 (s, 3H). ESI-MS (m/z): Calcd. for
C24H24N2O6S4: 564.05; found: 565.1.
Example 215
[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2,6-dimethyl-
biphenyl-4-yloxy]-acetic acid trifluoroacetate
a) {3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-
thiophene-3-sulfonyl]-2,6-dimethyl-biphenyl-4-yloxy}-acetic acid tert-butyl
ester
Bromo-acetic acid tert-butyl ester (0.013 mL, 0.0S5 mmol) was added
dropwise to a solution of {[4-(4'-hydroxy-2',6'-dimetriyl-biphenyl-3-sulfonyl)-
5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbarnic acid tert-butyl ester
(0.050 g, 0.077 mmol) [example 124, step b] and potassium carbonate (0.021
g, 0.154 mmol) in acetone [1 mL] at room temperature and stirred for 18
hours. The reaction was evaporated and column chromatography (25%
EtOAc in hexanes) of the residue yielded the title compound (0.011 g, 28%) as
a solid. ESI-MS (m/z): Called, for C31H38N2O7S3: 646.18; found: 646.8.
b) [3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2,6-
dimethyl-biphenyl-4-yloxy]-acetic acid trifluoroacetate
A solution of dichloromethane/ trifluoroacetic acid (1/1) [2 mL] was
added to {3'-[5-(tert-bu1:oxycarbonylamino-imino-methyl)-2-methylsulfanyl-
thiophene-3-sulfonyl]-2,6-climethyl-biphenyl-4-yloxy}-acetic acid tert-butyl
ester (0.020 g, 0.030 mmol) [example 215, step a] at room temperature and
stirred for 1 hour. The reaction mixture was evaporated and purified via
reverse-phase HPLC [acetonitrile/water (0.01 %TFA)] to give the title
compound (0.011 g, 75%) as a solid. 1H-NMR (MeOD): d 8.36 (s, 1H), 8.01
(md, 1H, J=7.6 Hz), 7.81 (m, 1H), 7.72 (m, 1H), 7.51 (d, 1H, J=7.6 Hz), 7.26
(d, 1H, 7=8.0 Hz), 6.74 (s, 2H), 4.67 (s, 2H), 2.73 (s, 3H), 1.96 (s, 6H). ESI-
MS (m/z): Calcd. for C22H22N2O5S3: 490.07; found: 491.2.
Example 216
4-{4'-Guanidino-6'-methyl-2'-[3-(2-phenylamino-ethyl)-ureido]-biphenyl-3-
sulfonyl}-5-methylsulfianyl-thiophene-2-carboxamidine trifluoroacetate
a) [(4-{4'-Amino-6'-methyl-2'-[3-(2-phenylamino-ethyl)-ureido]-
biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophen-2-yl)-imino-methyl]-
carbamic acid tert-butyl ester
4-Nitrophenylchloroformate (0.047 g, 0.232 rnrriol) was added to a
solution of {2-arnino-3'-[5-(tert-butoxycairbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3 -sulfonyl]-6-methyl-biphenyl-4-yl} -carbamic acid
2-trimethylsilanyl-ethyl ester (0.150 g, 0.222 mmol) [example 294, step f] and
pyridine (0.018 g, 0.232 mmol) in dichloromethane [5 mL] and stirred at room
temperature for 1 hour. N-l-Phenyl-ethane-l,2-diamine (0.060 g, 0.444
mmol) was added and the reaction was stirred for an additional hour. The
reaction was evaporated and column chrornatography (50% EtOAc in
hexanes) of the residue yielded the title compound (0.150 g, 81%) as a solid.
This solid was dissolved in THF [1 mL] and tetrabutylammonium fluoride
[0.536 mL] was added. The reaction was heated to 50°C and stirred for 2
hours. The reaction was evaporated and column chromatography (50% EtOAc
in hexanes) of the residue yielded the title compound (0.079 g, 64%) as a
solid. ESI-MS (m/z): Calcd. for C33H38N6O5S3: 694.21; found: 694.9.
b) [(4-{4'-(N',N"-di-tert-butoxycarbonyl-guanidino)-6'-methyl-2'-[3-(2-
phenylamino-ethyl)-ureido]-biphenyl-3-sulfonyl}-5-methylsulfanyl-
thiophen-2-yl)-imin o-methyl]-carbarnic acid tert-butylester
l,3-Bis-t-butoxycarbonyl-2-methyl-2-thiopseudourea (0.033 g, 0.114
mmol) was added to a solution of [(4-{4'-amino-6'-methyl-2'-[3-(2-
pheny]amino-ethyl)-u;reido]-biphenyl-3-sulfonyl}-5-niethylsulfanyl-thiophen-
2-yl)-i]mino-methyl]-carbainic acid tert-butyl ester [example 216, step a] in
methanol [1 mL] and 1 drop of acetic acid. The reaction was stirred at room
temperature for 1 hour and evaporated. The reaction was evaporated and
column chromatography (25% EtOAc in hexanes) of the residue yielded the
title compound (0.072 g, 6S%) as a solid. ESI-MS (m/z): Calcd. for
C44H56N8O9S3: 936.33; found: 936.9.
c) 4-{4'-Guanidiiio-6'-methyl-2'-[3-(2-phenylamino-ethyl)-ureido]-
biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxainidine
bistrifluoroacetate
A solution of dichioromethane/ trifluoroacetic acid (1/1) [1 mL] was
added to [(4-{4'-(N\ N"-di-tert-butoxycarbonyl-guanidino)-6'-methyl-2l-[3-(2-
phenylamino-ethyl)-ureido|-biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophen-
2-yl)-imino-methyl]-carbamic acid tert-butylester (0.007 g, 0.007 mmol)
[example 216, step b] at room temperature and stirred for 1 hour. The reaction
mixture was evaporated and purified via reverse-phase HPLC
[acetonitrile/water (0.01%TFA)] to give the title compound as a solid. 1H-
NMR (MeOD): d 8.35 (s, 1H), 8.05 (md, 1H, 7=8.0 Hz), 7.95 (m, 1H), 7.73 (t,
1H, 7=8.0 Hz), 7.57 (m, III), 7.39 (m, 2H), 7.14 (m, 3H), 7.05 (m, 1H), 3.37
(m, 4H), 2.71 (s, 3H), 2.03 (s, 3H). ESI-MS (m/z): Calcd. for C29H32N8O.1S3:
636.18; found: 637.1.
Example 217
4-(3'-Formylamino-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate
a) {(4-(3'-Amino-biphenyl-3-sulfonyl)-5-metltylsulfanyl-thiophen-2-yl]-
imino-methyl]-carbamic acid tert-butyl ester
Following the same procedure as in Example 1, step c, reaction of 3-
amino-phenyl boronic acid (27 mg, 0.2 mmol), {[4-(3-bromo-
benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic
acid tert-butyl ester (50 mg, 0.1 mmol, as prepared in Example 27, step c),
tetrakis(triphenylphosine)palladium(0) (29 mg, 0.025 mmol, Strem Chemicals
Inc, Newburyport, MA), Na2CO3 (400 \£L, 2M), and toluene/EtOH mixture
(2:1, 1.2 mL) afforded 35 ing (70%) after purification (SiO2, flash elution:
30% EtOAc in hexanes) of the title compound as a white foam. ESJ-MS (m/z):
Calcd. for C23H25N3O4S;,: 503.6; found: 503.9, 404.1 (M-Boc).
b) 4-(3'-Formylamino-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
{[4-(3'-Amino-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-
imino-methyl}-carbamic acid tert-butyl ester (30mg, 0.06 mmol, as prepared
in Example 217, step a) was dissolved in formic acid (5 mL) and the reaction
mixture was refluxed overnight. The formic acid was removed in vacuo and
the residue was treated with trifluoacetic acid (50% in DCM) for 1 h at rt. The
mixture v/as concentrated in vacuo and the residue obtained was purified using
C18-HPLC (10-80% CH3CN in H2O (0.1% TFA) over 25 min) to give the title
compound as a white solid. 1H-NMR (CD3OD; 400 MHz): d 8.34 (s, 1H), 8.33
(s, 1H), 8.29 (t, 1H, J= 1.6 Hz), 8.11-8.13 (m, 1H), 7.96-8.03 (m, 2H), 7.70 (t,
1H, J = 7.7 Hz), 7.42-7.50 (m, 3H), 2.75 (s, 3H). ESI-MS (m/z): Calcd. for
C19H17N3O3S3: 432.1 (M+H); found: 432.1.
Example 218
3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-biphenyl-3-
carboxylic acid amide trifluoracetate
Following the same procedure as in Example 1: step c, reaction of 3-
carbamoyl-phenyl boronic acid (33 mg, 0.2 mrnol), {[4-(3-bromo-
benzenesulfonyl)-5-methylsulf£Lnyl-tbiophen-2-yl]-iniino-methyl}-carbamic
acid tert-butyl ester (50 mg, 0.1 mmol, as prepared in Example 27, step c),
tetrakis(triphenylphosine)palladiurn(0) (29 mg, 0.025 mmol, Strem Chemicals
Inc, Newburyport, MA), Na2CO3 (400 µL, 2M), and toluene/EtOH mixture
(2:1, 1.2 mL) afforded 38 mg (72%) after purification (SiO2, flash elution:
30% EtOAc in hexanes) of a white foam whose mass was consistent with the
Boc protected title intermediate. ESI-MS (m/z): Calcd. for C24H25N3O5S3:
531.7; found: 531.9, 432.1 (M-Boc). Treatment of this intermediate with
trifluoacetic acid (50% in DCM) for 1 h at rt and purification using C18-HPLC
(10-65% CH3CN in H2O (0.1% TFA) over 30 min) provided the title
compound as a white solid (25 mg, 66%). 1H-NMR (CD3OD; 400 MHz): d
8.34 (s, 1H), 8.33 (t, 1H, J= 1.9 Hz), 8.19 (t, 1H, J=l.9 Hz), 8.00-8.05 (m,
2H), 7.85-7.88 (m, 2H), 7.73 (t, 1H, J= 7.8 Hz), 7.62 (t, \R,J= 7.8 Hz), 2.74
(s, 3H). ESI-MS (m/z): Calcd. for C19H17N3O3S3: 432.2 (M+H); found: 432.2.
Example 219
4-(4'-Fluoro-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine trifluoroacetate
Following the same procedure as in Example 1, step c, reaction of 4-
fluoro-2-methyl-phenyl boronic acid (35 mg, 0.2 mmol), {[4-(3-bromo-
benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-rnethyl}-carbamic
acid tert-butyl ester (50 mg, 0.1 mmol, as prepared in Example 27, step c),
tetrakis(triphenylphosme)palladium(0) (29 mg, 0.025 mmol, Strem Chemicals
Inc, Nev/buryport, MA), Na2CO3 (400 µL, 2M), and toluene/EtOH mixture
(2:1, 1.2 mL) afforded after purification (Preparative TLC, 1:3
EtOAc/hexanes, 2000 µ SiO2 plate) 62 mg of {[4-(4'-fluoro-2'-methyl-
biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-
carbamic acid tert-butyl ester as a tan oil. NMR (CDCl3; 400 MHz) 5 8.02 (s,
1H), 7.91-7.97 (m, 2H), 7.51-7.57 (m, 2H), 7.14 (dd, 1H, J = 8.4, 5.8 Hz),
6.92-7.00 (m, 2H), 2.57 (s, 3H), 2.20 (s, 3H), 1.51 (s, 9H). Treatment of this
intermediate with trifluoacetic acid (50% in DCM) for 1 h at rt and
purification using Cl8-HPLC (20-70% CH3CN in H2O (0.1% TFA) over 30
min) provided the title compound as a white solid (30 mg, 60%). 1H-NMR
(CD3OD; 400 MHz) 5 8.32 (s, 1H), 8.03 (dt, 1H, J= 7.0, 1.9 Hz), 7.94-7.96
(m, 1H), 7.64-7.70 (m, 2H), 7.22 (dd, 1H, J= 8.6, 5.8 Hz), 6.98-7.09 (m, 2H),
2.72 (s, 3H), 2.22 (s, 3H). ESI-MS (m/z): Calcd. for C19H17FN2O2S3: 421.2
(M+H); found: 421.2.
Example 220
4-(4'-Amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine bis-trifluoroacetate
a) 3-Methyl-4-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-
phenylamine
To an oven-dried round bottom flask fitted with a stir bar was added 4-
bromo-3-methylaniline (5.7 gm, 31 mmol), 4,4,5,5-tetramethyl-l, 3,2-
dioxaborolane (13.3 ml., 92 mmol, Aldrich Chemical Company), and
PdCl2(PPh3)2 (2.2 gm, 3.1 mmol, Strem Chemicals Inc, Newburyport, MA).
The flask was sealed with a rubber septum, purged with Argon, and then
charged with dry dioxane (100 mL) and triethylamine (26 mL). The reaction
mixture was stirred vigorously at 95 °C for 16 h. After cooling to rt, the
dioxane was removed hi vacuo and the residue was partitioned between
EtOAc (200 mL) and water (100 mL). The organic layer was washed with
saturated NaHCO3 (2 x 75 ml.), brine (50 mL), and was dried over MgSO4.
Removal of the solvents in vacuo followed by flash chromatography of the
residue yielded the product (3.3 gm, 46%) as a tan oil. 1H-NMR (CDCl3; 400
MHz): d 7.61-7.64 (m, 1H), 6.48-6.58 (m, 2H), 3.60-3.90, (br s, 2H), 2.49 (s,
3H), 1.34 (s, 12H). ESI-MS (m/z): Calcd. for Cl3H2oBN02: 234.1 (M+H);
found: 234.2
b) {4-(4'-Amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
Following the same procedure as in Example 1, step c, reaction of 3-
methyl-4-(4,4,5,5-tetramethyl-[ 1,3,2]dioxaborolan-2-yl)-phenylamine (432
mg, 1.86 mmol, as prepared in Example 220, step a), {[4-(3-bromo-
benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic
acid tert-butyl ester (610 mg, 1.24 mmol, as prepared in Example 27, step c),
tetrakis(triphenylphosirie)palladium(0) (215 mg, 0.186 mmol, Strem
Chemicals Inc, Newburyport, MA), Na2CO3 (5 mL, 2M), and toluene/EtOH
mixture (2:1, 15 mL) afforded 403 mg (63%) after purification (SiO2, flash
elution: 30% to 50% EtOAc in hexanes) of the title compound as a white
foam. 1H-NMR (CDCl3, 400 MHz): S 8.00 (s, 1H), 7.87-7.92 (m, 2H), 7.47-
7.55 (m, 2H), 6.98 (d, 1H, J = 7.9 Hz), 6.55-6.61 (m, 2H), 3.65-3.82 (br s,
2H), 2.53 (s, 3H), 2.15 (s, 3H), 1.51 (s, 9H). ESI-MS (m/z): Calcd. for
C24H27N3O4S3: 517.7; found: 517.7, 418.1 (M-Boc).
c) 4-(4'-Amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine bis-trifluoroacetate
{4-(4'-Amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (32 mg, 0.06
mmol, as prepared in Example: 220, step b) was treated with trifluoroacetic
(50% in DCM) for 1 h at rt and purified using C18-HPLC (20-70% CH3CN in
H2O (0.1% TFA) over 30 niin) affording the title compound as a white solid
(20 mg, 55%). 1H-NMR (CD3OD; 400 MHz) 5 8.35 (s, 1H), 7.99-8.05 (m,
2H), 7.67-7.73 (m, 2H), 7.28 (d, 1H, J= 8.1 Hz), 7.10-7.17 (m, 2H), 2.74 (s,
3H), 2.27 (s, 3H). ESI-MS (m/z): Calcd. for C19H19N3O2S3: 418.1 (M+H);
found: 418.1.
Example 221
4-[2'-Methyl-4'-(2-morpholin-4-yl-ethylamino)-biphenyl-3-sulfonylJ-5-
methylsulfanyl-thiophene-2-carboxamidine bis-trifluoroacetate
a) (4-Bromo-3-methyl-phenyl)-(2-morpholin-4-yl-ethyl)-amine
4-Bromo-3-methylaniline (0.96 gm, 5.14 mmol), 4-(2-chloro-ethyl)-
morpholine (1 gm, 5.4 mmol), K2CO3 (1.5 gm, 10.8 mmol), and Nal (0.81 gm,
5.4 mmol) were suspended in DMSO (10 mL) and the mixture was stirred
vigorously at reflux for 12 h. The mixture was; cooled, diluted with EtOAc,
and washed with saturated NaHCO3. The organic layer was washed with
another portion of NaHCO3, brine (50 mL). arid was dried over MgSO4,
Removal of the solvents in vacuo followed by flash chromatography of the
residue (Biotage Flash System - 40 M SiO2 column, 10% EtOAc in hexanes to
100% EtOAc) yielded the product (500 mg, 31%) as a tan oil. 1H-NMR
(CDCl3; 400 MHz): 8 7.36 (d, 1H, J = 8.6 Hz), 6.61 (d, 1H, J = 2.8 Hz), 6.43
(dd, 1H, d, 8.6, 2.8 Hz), 4.36 (br s, 1H), 3.80 (t, 4H, J = 4.6 Hz), 3.20 (t, 2H, J
= 5.8 Hz), 2.69 (t, 2H, J = 6.0 Hz), 2.54 (t, 4H, J = 4.4 Hz), 2.40 (s, 3H). ESI-
MS (m/z): Calcd. for C13H19BrN2O: 299.2; found: 299.1, 301.1.
b) 4-[2'-Methyl-4'-(2-morpholin-4-yl-ethylamino)-biphenyl-3-sulfonyl]-
5-methylsulfanyl-thiophene-2-carboxamidine
Following the same procedure as in Example 220, step a, reaction of
(4-bromo-3-methyl-phenyl)-(2-morpholin-4-yl-ethyl)-amine (440 mg, 1.9
mmol, as prepared in Example 221, step a), 4,4,5,5-tetramethyl-l,3,2-
dioxaborolane (13.3 mL, 92 mmol, Aldrich Chemical Company),
PdCl2(PPh3)2 (2.2 gm, 3.1 mmol, Strem Chemicals Inc, Newburyport, MA),
Et3N (1.6 mL, 11.4 mmol), and dioxane (5 mL) afforded 520 mg (79%) after
purification (SiO2, flash elution: 30% EtOAc in hexanes) of a tan oil. ESI-MS
(m/z): Calcd. for C19H31BN2O3: 347.3 (M+H); found: 347.2. The above
boronate ester (520 mg, 1.5 mmol) was reacted according to the procedure
used in Example 1, step c, with {[4-(3-bromo-benzenesulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(368 mg, 0.75 mmo 1, as prepared in Example 27, step c),
tetrakis(triphenylphosine)palladium(0) (217 mg, 0.19 mmol, Strem Chemicals
Inc, Nev/buryport, MA), Na2CO3 (3 mL, 2M), and toluene/EtOH mixture (2:1,
9 mL) to afford 400 mg (85%) of (imino-{4-[2'-methyl-4'-(2-morpholin-4-yl-
ethylamino)-biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-methyl)-
carbamic acid tert-butyl ester after purification (SiO2, flash elution: EtOAc in
hexanes). ESI-MS (m/z): Calcd. for C30H38N4O5S3: 630.8; found: 630.9, 531.1
(M-Boc). Treatment of this intermediate with trifluoroacetic acid and
purification using C18-HPLC (as in Example 220, step c) provided 312 mg
(78%; of the title compound as a white solid. 1H-NMR (CD3OD, 400 MHz): d
8.31 (s, 1H), 7.90-7.95 (m: 2H), 7.60-7.65 (m, 2H), 7.04 (d, 1H. J= 8.1 Hz),
6.61-6.66 (m, 2H), 3.95 (br s, 4H), 3.61 (t, 2H, J = 6.3 Hz), 3.41 (m, 6H), 2.71
(s, 3H), 2.19 (s, 3H). ESI-MS (m/z): Calcd. for C25H30N4O3S3: 531.2 (M+H);
found: 531.1, 266.2 (M2+).
Example 222
3'-(5-Carbamimidoyl-2-meth.ylsulfanyl-thiophene-3-sulfonyl)-2-methyl-
biphenyl-4-carboxylic acid trifluoroacetate
Following the same procedure as in Example 220, step a, reaction of 4-
bromo-3-methyl-benzoic acid methyl ester (1.75 gm, 7.6 mmol), 4,4,5,5-
tetramethyl-l,3,2-dioxaborolane (3.3 mL, 23 mmol, Aldrich Chemical
Company), PdCl2(PPh3)2 (530 mg, 0.76 mmol, Strem Chemicals Inc,
Newburyport, MA), Et3N (6.3 mL, 46 mmol), and dioxane (30 mL) afforded
1.2 gm of a clear oil (79%) after purification (SiO2, flash elution: 30% EtOAc
in hexanes. The above boronate ester (220 mg, 0.8 mmol) was reacted
according to the procedure used in Example 1, step c, with {[4-(3-bromo-
benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic
acid tert-butyl ester (100 mg, 0.8 mmo 1, as prepared in Example 27, step c),
tetrakis(triphenylphosine)palladiurn(0) (58 mg, 0.05 mmol, Strem Chemicals
Inc, Newburyport, MA), Na2CO3 (1.6 mL, 2 M), and toluene/EtOH mixture
(2:1, 2.4 mL) to afford 3'-[5-(tert-butoxycarbonylammo-imino-methyl)-2-
methylsulfanyl-thiophene-3-su].fonyl]-2-methyl-biphenyl-4-carboxylic acid
methyl ester after purification (preparative TLC, 1:3 EtOAc/hexanes, 2000 µ
SiO2 plate). ESI-MS (m/z): Calcd. for C26H28N2O6S3: 560.7; found: 461.1 (M-
The above methyl benzoate (45 mg. 0.08 mmol) was treated with 1 N
NaOH in MeOH (1:1) and stirred at 50 °C overnight. The reaction mixture was
neutralized with acetic acid, the solvents were removed in vacuo, and the
residue was subjected to TFA treatment followed by C18-HPLC purification as
described in Example 220, step c to afford the title compound as a white solid.
1H-NMR (CD3OD; 400 MHz) 5 8.35 (s, 1H), 8.06-8.11 (m, 1H), 8.00-8.03 (m,
2H), 7.95 (m, 1H), 7.72-7.76 (m, 2H), 7.35 (d, 1H, J= 7.9 Hz), 2.75 (s, 3H),
2.30 (s, 3H). ESI-MS (m/z): Calcd. for C20H18N2O4S3: 447.1 (M+H); found:
447.1.
Example 223
2-Amino-N-[3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-
methyl-biphenyl-4-yl]-acetamide trifluoroacetate
To a solution of {4-(4'-amino-2'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophene-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(80 mg. 0.15 mmol, as prepared in Example 220, step b) in DCM (2.2 mL)
was added Boc-gly-N-hydroxysuccinimide ester (126 mg, 0.5nimol), and
triethylamine (69 µL, 0.5 mmol). The reaction mixture was stirred at rt
overnight (16 h). The reaction mixture was then diluted with EtOAc and
extracted with water and saturated NaHCO3. The separated organic layer was
dried with MgSO,}, filtered, and concentrated in vacuo to give a residue that
was purified using preparative TLC (1:3 EtOAc/hexanes, 1000 µ SiO2 plate)
to provide 100 mg (99%) of a tan glassy solid. ESI-MS (m/z): Calcd. for
C31H38N4O7S3: 674.8 (M+); found: 674.8, 575.0, 519.0, 475.1. Treatment of
this intermediate with trifluoroacetic acid and purification using C18-HPLC (as
in Example 220, step c) provided the title compound as a white solid in 78%
yield. 1H-NMR (CD3OD, 400 MHz): 6 8.34 (s, 1H), 7.99-8.05 (m, 2H), 7.67-
7.72 (m, 2H), 7.57 (m, 2H), 7.22 (d, 1H, J= 8.1 Hz), 3.90 (s, 2H), 2.74 (s,
3H), 2.25 (s, 3H). ESI-MS (rn/z): Calcd. for C21H22N4O3S3: 475.1 (M+H);
found: 475.1.
Example 224
4-(4'-Hydroxy-2',6'-dimethyl-biphenyl-3-sulfonyl)-5-methylsulf'anyl-
thiophene-2-carboxamidine trifluoroacetate
a) 3,5-Dimethyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenol
Following the procedure described in Example 220, step a, reaction of
4-bromo-3,5-dirnethy[-phenol (1.5 gm, 7.6 mmol), 4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (3.3 mL, 23 mmol, Aldrich Chemical Company), PdCl2(PPh3)2
(530 mg, 0.76 mmol, Strem Chemicals Inc., Newburyport, MA), Et3N (634 p.L,
46 mmol), and dioxane (30 mL) afforded 3.4 gm of a tan glassy solid after
chromatography (50 gm, silica SPE column) which was used without further
purification. 1H-NMR (CDCl3; 400 MHz): d 6.4 (s, 2H), 2.3 (s, 6H), 1.4 (s,
12H).
b) {[4-(4'-Hydroxy-2', 6'-dimethyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
Following the same procedure as in Example 1, step c, reaction of 3,5-
dimethyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenol (355 mg,
0.8 mmol, assuming quantitative yield from Example 224. step a), {[4-(3-
bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-
carbamic acid tert-butyl ester (100 mg, 0.2 mmol, as prepared in Example 27,
step c), tetrakis(triphenylphosme)palladium(0) (58 mg, 0.05 mmol, Strem
Chemicals Inc, Newburyport, MA), Na2CO3 (0.8 mL, 2M), and toluene/EtOH
mixture (2:1, 2.4 mL) afforded 35 mg (13%) after purification (PTLC) of the
title compound as a tan solid. ESI-MS (m/z): Calcd. for C25H28N2O5S3: 532.7;
found: 532.8, 477.0, 433.1 (M-Boc).
c) 4-(4'-Hydroxy-2',6'-dimethyl-biphenyl-3-snlfonyl)-5-methylsnlfanyl-
thiophene-2-carboxamidine trifluoroacetate
{[4-(4'-Hydroxy-2',6'-dimethyl-bipheny]-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (15 mg, 0.03
mmol, as prepared in Example 224, step c) was treated with tnfluoroacetic
(50% in DCM) for 1 h at rt and purified using C18-HPLC (10-60% CH3CN in
H2O (0.1% TFA) over 30 min) affording the title compound as a white solid (8
mg, 53%). !H-NMR (CD30D; 400 MHz) 5 8.35 (s, 1H), 8.00 (m, 1H), 7.80 (t,
1H, 7= 1.6 Hz), 7.68 (t, 1H, J = 7.7 Hz), 7.50 (m, 1H), 6.58 (s, 2H), .67-7.73
(m, 2H), 7.28 (d, 1H, J= 8.1 Hz), 7.10-7.17 (m, 2H), 2.73 (s, 3H), 1.91 (s,
6H). ESI-MS (m/z): Calcd. for C20H20N2O3S3: 433.1 (M+H); found: 433.1.
Example 225
3'-(5-Carbamimidoyl-2-rnethylsulfanyl-thiophene-3-sulfonyl)-2-methyl-
biphenyl-4-carboxylic acid amide trifluoroacetate
Following the same procedure as in Example 220, step a, reaction of 4-
bromo-3-methyl-benzamide (200 mg, 0.93 mmol), 4,4,5,5-tetramethyl-l,3,2-
dioxaborolane (0.41 mL, 2.8 mmol, Aldrich Chemical Company),
PdCl2(PPh3)2 (65 mg, 0.093 mmol, Strem Chemicals Inc, Newburyport, MA),
Et3N (700 [iL, 46 mmol), and dioxane (5 mL) afforded 140 mg of a brown oil
(58%) after purification (SIO2, flash elution: 30% EtOAc in hexanes. The
above boronate ester (140 mg, 0.54 mmol) was reacted according to the
procedure used in Example 1, step c, with {[4-(3-bromo-benzenesulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-ca.rbamic acid tert-butyl ester
(88 mg, 0.18 mmo 1, as prepared in Example 27, step c),
tetrakis(triphenylphosine)palladLum(0) (52 mg, 0.05 mmol, Strem Chemicals
Inc, Newburyport, MA), Na2CO3 (0.7 mL, 2 M), and toluene/EtOH mixture
(2:1, 2.1 mL) to afford {[4-(4'-Carbamoyl-2'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
after purification (preparative TLC, 1:3 EtOAc/hexanes, 3 x 1000 µ SiO2
plate). ESI-MS (m/z): Calcd. for C25H27N3O5S3: 545.7; found: 446.1 (M-Boc).
The above benzamide (44 mg. 0.08 mmol) was subjected to TEA treatment
followed by C18-HPLC purification as described in Example 220, step c to
afford 26 mg (59%) of the title compound as a white solid. lH-NMIR. (CD3OD;
400 MHz) 5 8.33 (s, 1H), 8.04-8.08 (m, 1H), 7.99-8.01 (m, 1H), 7.85 (m, 1H),
7.78 (m, 1H), 7.70-7..73 (m, 2H), 7.32 (d, 1H, J= 7.9 Hz), 2.72 (s, 3H), 2.29
(s, 3H). ESI-MS (m/z): Calcd. for C20H19N3O3S3: 446.1 (M+H); found: 446.1.
Example 226
{2-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-methyl-
biphenyl-4-ylcarbamoyl]-ethyl}-phosphonic acid trifluoroacetate
Thionyl chloride (1.7 mL, 23.0 mmol) was added dropwise to a
suspension of 3-(diethylphosphono)propanoic acid (0.5 gm, 2.3 mmol,
Epsilpon Chimie, Brest, France) in DCM (2 mL) at 0 °C. The reaction mixture
became clear upon addition of acid chloride. The ice bath was removed and
stirring was continued overnight at rt. The solvents were removed in vacuo
and the resulting solid was stored under high vacuum before further use. The
acid chloride prepared above (53 mg, 0.232 mmol) was transferred to a
solution of {4-(4'-amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (40 mg, 0.077
mmol, as prepared in Step 220, step b) and Et3N (900 µL, 0.62 mmol) in DCM
(2 mL). The mixture was stirred for 4 h at rt and then another 40 mg of the
acid chloride was added. After stirring for ~12 h, the volatiles were removed
and the residue was partitioned between EtOAc and water. The organic layer
was washed with another portion of water and saturated NaHCO3 dried over
MgSO4, and filtered. The crude product was chromatographed (PTLC 1000 µ.
plate) to give 33 mg (61%) of the desired (diethylphosphono)propanamide.
ESI-MS (m/z): Calcd. for C31H40N3O8PS3: 709.8 (M+); found: 709.8, 610.1
(M-Boc),
Using a modification of the procedure reported by Zhang, Z.Y., et al., (J.
Med. Chem., 1999, 42:3199-3202), the above (diethylphosphono)propanamide
(33 mg, 0.046) in DCM (2 mL) was treated with iodotrimethylsilane (20 µL,
0.14 mmol) at 0 °C for 1 h. Water was added to quench the reaction. After
stirring for 20 minutes, 2.0 N HC1 (2 mL) and MeOH (2 mL) were added to
the reaction mixture. The reaction mixture became clear following the
addition. Stirring was continued for 3 h at rt, solvents were removed in vacuo,
and the resulting residue was treated with TFA and purified using C18-HPLC
as described in Example 220, step c to afford 12 mg (50%) of the title
compound as a white solid. 1H-NMR (CD3OD; 400 MHz): d 7.61-7.69 (m,
3H), 6.95-7.27 (m, 4H), 6.55 (d, 1H, J= 8.6 Hz), 2.41-2.50 (m, 2H), 2.19 (s,
3H), 1.76 (s, 3H), 1.58-1.63 (m, 2H). ESI-MS (m/z): Calcd. for
C22H24N3O6PS3: 554.1 (M+H); found: 554.1.
Example 227
{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-methyl-
biphenyl-4-ylcarbamoyl]-methoxy}-acetic acid trifluoroacetate
To a solution of {4-(4'-amino-2'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophene-2-yl]-iniino-methyl}-carbamic acid tert-butyl ester
(25 mg, 0.048 mmol, as prepared in Step 220, step b) and Et3N (33 µL, 0.24
mmol) in DCM (1 mL) was added diglycolic anhydride (17mg, 0.144 mmol).
The reaction was stirred overnight at rt. The solvents were removed in vacuo
and the residue was treated with TFA (as in Example 220, step c). Purification
using a C18-HPLC provided 17 mg (68%) of the title compound as a white
solid. 1H-NMR (CD3OD, 400 MHz): d 8.32 (s, 1H), 7.96-8.03 (m, 2H), 7.65-
7.70 (m, 2H), 7.57-7.62 (m, 2H), 7.19 (d, 1H, J= 8.6 Hz), 4.31 (s, 2H), 4.24
(s, 2H), 2.72 (s, 3H), 2.23 (s, 3H). ESI-MS (m/z): Calcd. for C23H23N3O6S3:
534.1 (M+H); found: 534.1.
Example 228
5-Methylsulfanyl-4-(2'-methy]-4'-ureido-biphenyl-3-sulfonyl)-thiophene-2-
carboxamidine trifluoroacetate
According to the procedure by Rivier et al.. (J. Med. Chem. 2001, 44,
453-467) trimethylsilyl isocyante (45 |xL, 0.29 mmol) was added to a solution
of {4-(4'-Amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiopherie-
2-yl]-irnino-methyl}-carbarnic acid tert-butyl ester (43 mg, 0.083 mmol, as
prepared in Step 220, step b) in DMF (0.2 mL). The reaction was stirred for 3
days at rt. The DMF was removed in vacuo and the residue was treated with
TFA (as in Example 220, step c, except 1% w-cresol was added in the
deprotection mixture). The crude reaction mixture was concentrated to an oily
residue that was triturated with Et2O to remove m-cresol. Purification using
C18-HPLC provided 10 mg (25%) of the title compound as a white solid. 1H-
NMR (CD3OD, 400 MHz): d 8.34 (s, 1H), 7.96-8.04 (m, 2H), 7.65-7.70 (m,
2H), 7.31.738 (m, 2H), 7.13 (d, 1H, J= 7.9 Hz), 2.74 (s, 3H), 2.22 (s, 3H).
ESI-MS (m/z): Calcd. for C20H20N4O3S3: 461.1 (M+H); found: 461.1.
Example 229
2-Amino-4-[3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-
methyl-biphenyl"4-ylcarbamoyl]-butyric acid bis-trifluoroace:tate
Following the same procedure described for Example 223, but
substituting Boc-L-glu(OSu)-OtBu for Boc-gly-N-hydroxysuccinimide ester,
provided the title compound as a white solid in 75% yield. 1H-NMR (CD3OD,
400 MHz): d 8.34 (s, 1H), 7.97-8.03 (m, 2H), 7.66-7.71 (m, 2H), 7.52-7.56
(m, 2H), 7.18 (d, 1H, J= 8.1 Hz), 4.12 (t, 1H, J= 6.5 Hz), 2.73 (s, 3H), 2.71-
2.75 (m, 2H), 2.24 (s, 3H), 2.24-2.38 (m, 2H). ES1-MS (m/z): Calcd. for
C24H26N4O5S3: 547.1 (M+H); found: 547.1.
Example 230
6-[5-(2-Oxo-hexahydro-thieno[3,4-d]imidazol-6-yl)-pentanoylamino]-
hexanoic acid [3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-
2-methyl-biphenyl-4-yl]-amide trifluoroacetate
Following the same procedure described for Example 223, but
substituting N-(+)-biotmyl-6-aminocaproic acid N-succinimidyl ester for Boc-
gly-N-hydroxysuccinimide ester, provided the title compound as a white solid
in 11% yield. 1H-NMR (CD3OD, 400 MHz): d 8.33 (s, 1H), 7.99-8.02, (m,
1H), 7.95-7.97 (m, 1H), 7.66-7.69 (m, 2H), 7.49-7.53 (m, 2H), 7.17 (d, 1H, J =
8.4 Hz), 4.47 (dd, 1H, J= 7.9, 4.2 Hz), 4.27 (dd, 1H, J= 7.8, 4.2 Hz), 3.15-
3.22 (m, 4H), 2.91 (dd, lH,J= 12.6, 4.9 Hz), 2.73 (s, 3H), 2.41 (t, 2H, J= 7.6
Hz), 2.23 (s, 3H), 2.19 (t, 2 H,./= 7.4 Hz), 1.35-1.80 (m, 12H). ESI-MS (m/z):
Calcd. for C35H44N6O5S4: 757.2 (M+H); found: 757.3
Example 231
4-Ammo-4-[3'-(5-carbamimidoyl-2-methylsulfEinyl-thiophene-3-sulfonyl)-2-
methyl-biphenyl-4-ylcarbamoyl]-butyric acid bis-trifluoroacetate
Following the same procedure described for Example 223, but
substituting Boc-L-glu(OtBu)-OSu for Boc-gly-N-hydroxysuccinimide ester,
provided the title compound as a white solid in 64% yield. 1H-NMR (CD3OD,
400 MHz): d 8.34 (s, 1H), 7.99-8.05 (m, 2H), 7.67-7.73 (m, 2H|, 7.56-7.61
(m, 2H), 7.23 (d, 1H, J= 8.1 Hz), 4.10 (t, 1H, J= 6.0 Hz), 2.74 (s, 3H), 2.58
(t, 2H, J= 7.4 Hz), 2.26 (s, 3H), 2.20-2.35 (m, 2H). ESI-MS (m/z): Calcd. for
C24H26N4O5S3: 547.1 (M+H); found: 547.1.
Example 232
2-Amino-N-[3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-
methy]-biphenyl-4-yl]-4-methanesulfonyl-butyramide bis-trifluoroacetate
In a scintillation vial, Boc-L-methionine sulfone (124 mg, 0.44 mmol,
Chem-Impex, International, INC., Wood Dale, IL) was dissolved in DMF (2
mL). To the solution was added HBTU (159 mg, 0.42 mmol), HOBT (60 mg,
0.44 mmol), and D1EA (400 µL, 2.1 mmol). After 10 min of vigorous stirring
(solution turned pale yellow), the mixture was transferred to a reaction vial
charged with a stir bar and {4-(4'-amino-2'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophene-2-yr]-imino-methyl}-carbamic acid tert-butyl ester
(73 mg, 0.14 mmol, as prepared in Step 220, step b). The resulting mixture
was stirred overnight at rt. Analogous work up as described for Example 223
followed by TFA treatment and RP-HPLC provided 5S mg (72%) of the title
compound as the bis-trifiuoroacetate salt. 1H-NMR (CD3OD, 400 MHz): S
8.33 (s, 1H), 7.97-8.03 (m, 2H), 7.66-7.71 (m, 2H), 7.57-7.62 (m, 2H), 7.23 (d,
1H, J = 8.1 Hz), 4.24 (t, 1H, J = 6.4 Hz), 3.25-3.39 (m, 2H), 3.06 (s, 3H), 2.72
(s, 3H), 2.40-2.56 (iri, 211), 2.25 (s, 3H). ESI-MS (m/z): Calcd. for
C24H28N4O5S4: 581.1 (M+H); found: 581.0.
Example 233
4-[4'-(4,5 -Dihydro-1H-imidazol-2-ylamino)-2'-methyl-biphenyl-3 -sulfonyl] - 5-
methylsulfanyl-thiophene-2-carboxamid:inebis-trifluoroacetate
a) 2-Methylsulfanyl-4,5-dihydro-imidazole-l-carboxylic acid tert-butyl
ester
4,5-Dihydro-2-methylthioimidazole hydroiodide (3 gm, 12 mmol,
Aldrich Chemical Company), di-tert-butyl-dicarbonate (5.4 gm, 24.8 mmol),
Et3N (5 mL, 36 mmol), and DMAP (70 mg, 0.57 mmol) were dissolved in
DCM (35 mL). The reaction was stirred at rt for 16 h then diluted, with more
DCM and washed with water and saturated NaHCO3 The organic layer was
dried (MgSC^), filtered, and evaporated in vacuo to give 1 gm (38%) of the
title compound as a white crystalline solid. 1H-NMR (CDCl3; 400 MHz):
d 3.82-3.86 (m, 4H), 2.39 (s, 3H), 1.51 (s, 9H). ESI-MS (m/z): Calcd. for
C9H16N2O2S: 217.1 (M+H); found: 216.8, 161.0, 117.2 (M-Boc).
b) 4-[4'-(4,5-Dihydro-lH-imidazol-2-ylamino)-2'-methyl-biphenyl-3-
sulfonyl]-5-methylsulfanyl-thiophene-2-carboxainidine bis-trifluoroacetate
According to a procedure by Mundla et al.. (Tetrahedron Lett. 2000,
41, 6563-6566), {4-(4I-amino-2'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophene-2-yl]-imino-methyl}-Ci3rbamic acid tert-butyl ester
(18 mg, 0.035 mmol., as prepared in Example 220, step b) and 2-
methylsulfanyl-4,5-dihydro-irnidazole-l-carboxylic acid tert-butyl ester (23
mg, 0.1 mmol, as prepared in Example 233, step a) were dissolved in a MeOH
/ Acetic acid mixture (10:1, 1 mL). The reaction mixture was stirred overnight
at 55 "C and then concentrated to dryness. The resulting residue was treated
with TFA and purified using C18-HPLC as described in Example 220, step c to
afford 12 mg (70%) of the title compound as a white solid. 1H-NMR (CD3OD;
400 MHz): d 8.00-8.05 (m, 2H), 7.66-7.73 (m, 2H), 7.19-7.33 (m, 3H), 3.84
(s, 4H), 2.72 (s, 3H), 2.27 (s, 3H). ESI-MS (m/z): Calcd. for C22H23N5O2S3:
486.1 (M+H); found: 486.1.
Example 234
2-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-methyl-
biphenyl-4-ylcarbamoyl]-methylsulfanyl}-acetamide trifluoroacetate
a) ({4-[4'-(2-Bromo-acetylamino)-2'-methyl-biphenyl-3-sulfonyl]-5-
ntethylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester
{4-(4'-Amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-yl]-imino-methyl}-earbamic acid tert-butyl ester (110 mg, 0.21
mmol, as prepared in Example 220, step b), bromoacetyl bromide (19 µL, 0.21
mmol), and Et3N (33 µL, 0.23 mmol) were dissolved in chloroform (2 mL)
and the reaction was stirred for 3 h at rt As TLC indicated small amount of
aniline remaining in the reaction mixture, 4 µL of bromoacetyl bromide were
added and the reaction was stirred for 2 more hours. The volatiles were
removed in vacuo and the residue was partitioned between EtOAc and 20 %
citric acid. The organic layer was washed with saturated NaHCO3, water, and
brine, then dried (MgSO4), and concentrated in vacuo to give 135 mg (100%)
of crude product as a tan solid. Purification of this material using PTLC (1:1
EtOAc/hexanes, 2 x 1500 µ SiO2 plate) provided the title compound in 89 %
yield as a pale yellow solid. 1H-NMR (CDCI3, 400 MHz): S 8.24 (s, 1H), S.00
(dt, 1H,J= 7.3, 1.8 Hz), 7.96 (br s, 1H), 7.92 (m, 1H), 7.55-7.62 (m, 2H),
7.41-7.47 (m, 2H), 7.19 (d, 1H, J= 8.1 Hz), 4.09 (s, 2H), 2.52 (s, 3H), 2.25 (s,
3H), 1.54 (s, 9H). ESI-MS (m/z): Calcd. for C24H27N3O4S3: 517.7; found:
517.7,418.1 (M-Boc).
b) 2-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-
methyl-biphenyl-4-ylcarbamoyl]-methylsulfanyl}-acetamidetrifluoroacetate
To a solution of ({4-[4'-(2-bromo-acetylammo)-2'-methyl-biphenyl-3-
sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-
butyl ester (44 mg, 0.069 mmol, as prepared in Example 234, step a) in MeOH
(0.6 mL) was added 2-mercapto acetamide (100 u.L of 10% methanolic
solution, Maybridge pic) and Et3N (30 µL, 0.21 mmol). The reaction mixture
was stirred at rt for 0.5 h and then concentrated in vacuo. The residue was
treated with TFA and purified using C18-HPLC as described in Example 220,
step c to afford 32 mg (84%) of the title compound as a white solid. 1H-NMR
(CD3OD; 400 MHz): d 8.32 (s, 1H), 7.99-8.02 (m, 1H), 7.95-7.97 (m, 1H),
7.66-7.68 (m, 2H), 7.51-7.55 (m, 2H), 7.17 (d, 1H, J = 8.1 Hz), 3.48 (s, 2H),
3.37 (s, 2H), 2.72 (s, 3H), 2.23 (s, 3H). ESI-MS (m/z): Calcd. for
C24H25N3OSS4: 664.1 (M+H); found: 564.1.
Example 235
2-{[3'-(5-Carbamimidoyl-2-raethylsulfanyl-thiophene-3-sulfonyl)-2-methyl-
biphenyl-4-ylcarbamoyl]-methylsulfanyl} -succinic acid trifluoroacetate
Following the same procedure as described in Example 234, step b,
reaction of ({4-[4'-(2-bromo-acetylamino)-2'-methyl-biphenyl-3 -sulfonylj-5-
methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester
(17 mg. 0.027 mmol, as prepared in Example 234, step a), mercaptosuccinate
(6 mg, 0.04 mmol), Et3N (12 pL, 0.08 mmol), a.nd MeOH (3 mL) provided 12
mg (75%) of the title compound as a white solid after RP-HPLC purification.
1H-NMR (CD3OD; 400 MHz): 6 8.34 (s, 1H), 7.99-8.00-8.05 (m, 1H), 7.97-
7.99 (m, 1H), 7.68-7.70 (m, 2H), 7.54-7.58 (m, 2H), 7.19 (d, 1H, .J= 7.9 Hz),
3.85 (dd, 1H, J= 9.5, 5.6 Hz), 3.56 and 3.69 (AB quartet, 2H, J = 15.1 Hz),
2.97 (dd, 1H, J= 17.2, 9.8 Hz), 2.76 (dd, 1H,J= 17.0, 5.6 Hz), 2.74 (s, 3H),
2.25 (s, 3H). ESI-MS (m/z): Calcd. for C25H25N3O7S4: 608.1 (M+H); found:
608.1.
Example 236
4-(4'-Guanidino-2'-meth)'l-6'-nitro-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine bis-trifluoroacetate
a) {[4-(4'-Amino-2'-methyl-6'-nitro-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acidtert-butyl ester
Following the procedure used for Example 295, step h, reaction of 4-
bromo-3-methyl-5-nitro-phenylamine (350 mg, 1.5 mmol, as prepared in
Example 135, step a), {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(1.0 gm, 2.27 mmol, as prepared in Example 140, step a),
tetrakis(triphenylphosine)palladium(0) (433 mg, 0.375 mmol, Strem
Chemicals Inc, Newburyport, MA), Na2CO3 (6 mL, 2M), and toluene/EtOH
mixture (2:1, 18 mL) at 80 "C for 24 h afforded 250 mg (30%) after
purification (SiO2, flash elution: 5% to 50% EtOAc in hexanes) of the title
compound as a yellow solid. ESI-MS (m/z): Calcd. for C24H26N4O6S3: 563.1
(M+H); found: 562.8, 463.1 (M-Boc).
b) ({4-[4'-(N,N'-Bis-tert-butoxycarbonyl)-guanidino-2'-methyl-6'-tiitro-
biphenyl-3-sulfonyl]-5-methyhulfanyl-thiophen-2-yl}-imino-methyl)-
carbamic acid tert-butyl ester
According to a previously published procedure (Bergerson et al.., J.
Org. Chem. 1987, 52, 1700-1703; WO 99/20608), mercury (II) chloride (190
mg, 0.7 mmol) was added in one portion to a stirred mixture of {[4-(4'-amino-
2'-methyl-6'-nitro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-
imino-methyl}-carbamic acid tert-butyl ester (130 ing, 0.23 mmol.. as prepared
in Example 236, step a), N,N'-bis(tert-butoxycarbonyl)-S-methylisothiourea
(203 mg, 0.7 mmol, Aldrich Chemical Company), and Et3N (173 µL, 1.15
mmol) in DCM (3 mL). The mixture was stirred for 24 h at rt and then
purified using flash chromatorgraphy (Biotage Flash System - 40 M SiO2
column, 10% to 30 % EtOAc in hexanes) to afford 145 mg (78%) of the title
compound as a clear oil. ESI-MS (m/z): Calcd. for C35H44N6O10S3: 805.2
(M+H); found: 804.7, 704.9, 604.9, 505.1 (M-3xBoc).
c) 4-(4'-Guanidino-2'-methyl-6'-nitro-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxamidinebis-trifluoroacetate
({4-[4'-(N,N'-Bis-tert-hutoxycarbonyl)-guanidino-2'-methyl-6'-nitro-
biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-
carbamic acid tert-butyl ester (10 mg, 12.4 µmol, as prepared in Example 236,
step b) was treated with TFA and purified using C18-HPLC as described in
Example 220, step c to afford 1.1 mg (17%) of the title compound as a white
solid. 1H-NMR (CD3OD; 400 MHz): d 8.34 (s, 1H), 8.04 (ddd, 1H, J= 7.9,
1.9, 1.2 Hz), 7.92-7.94 (m, 1H), 7.72-7.79 (m, 2H), 7.62 (ddd, 1H, J= 7.7, 1.6,
1.2 Hz), 7.60 (dd, 1H, J= 2.1, 0.7 Hz), 2.72 (s, 3H), 2.18 (s, 3H). ESI-MS
(m/z): Calcd. for C20H20N6O4S3: 505.1 (M+H); found: 505.1.
Example 237
4-(6'-Amino-4'-guan:idino-2'-]tnethyl-biphenyl--3-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidinebis-trifluoroacetate
a) {[4-(2',4'-Diamino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-nrethyl}-carbamic acid tert-butyl ester
{2-Amino-3'-[5-(teit-butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-4-yl} -carbamic acid
2-trimethylsilanyl-ethyl ester (1000 mg, 1.48 mmol, Example 294, step f) was
dissolved into THF (25 rnL). To this was added TB.AJF' (1M, 1.62 mL, 1.62
mmol) and the reaction was wanned to 40°C with stirring for 3 hours.
Additional TBAF (1.48 mL, 1.48 mmol) was added and the reaction was
stirred at rt overnight. The solvents were removed in vacuo, the residue was
dissolved into EtOAc and washed with water several times (5 washes). The
combined organic layers v/ere dried (MgSO4) and the solvents were removed
in vacuo resulting in the title compound as a yellow solid (800 mg, 100%). 1H-
NMR (CDCl3): d: 8.03 (s, 1H), 7.95-7.93 (m, 1H), 7.89-7.88 (m, 1H), 7.59 -
7.53 (m, 2H), 6.08 (m, 1H), 5.99 (m, 1H), 2.55 (s, 3H), 1.85 (s, 3H), 1.52 (s,
9H).
b) 4-{4'-[N',N"-Bis(tert-butoxycarbonyl)]-}-{f4-(2'-amino-6'-methyl-
biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-
carbamic acid tert-butyl ester
{[4-(2',4l-Diamino-6l-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (342 mg, 0.64
mmol, Example 237, step a) was dissolved into MeOH (4 mL) and acetic acid
(200 µL). To this was added l,3-bis(tert-butoxycarbonyl)-2-methyl-2-
thiopseudourea (203 mg, 0.70 mmol) slowly as a suspension in MeOH and the
reaction was stirred ait rt overnight. The solvents were removed in vacuo
followed by flash column chromatography purification (SiCb) (40% EtOAc in
hexanes) that yielded the title compound (235 mg, 47%) as a white solid. ESI-
MS (m/z): Calcd. for C35H46N6O8S3: 775.3 (M+l); found: 774.8.
c) 4-(6'-Amino-4'-guanidino-2'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxamidinebis-trifluoroacetate
4- {4'-[N',N"-Bis(tert-butoxycarbonyl)]-} - {[4-(2'-amino-6'-methyl-
biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-
carbamic acid tert-butyl ester (10 mg, 12.9 µmol, as prepared in Example 237,
step b) was treated with TFA and purified using C18-HPLC as described in
Example 220, step c to afford 3 mg (50%) of the title compound as a white
solid. 1H-NMR (CD3OD; 400 MHz): d 8.35 (s, 1H), 8.04 (ddd, 1H, J= 7.9,
1.9, 1.1 Hz), 7.92-7.95 (m, 1H), 7.75 (t, 1H, J = 7.8 Hz), 7.58 (dt, 1H, J= 7.6,
1.1 Hz), 6.65-6.63 (m, 2H), 2.71 (s, 3H), 1.94 (s, 3H). ESI-MS (m/z): Calcd.
for C20H22N6O2S3: 475.1 (M+H); found: 475.1.
Example 238
3-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-
guanidino-6-methyl-biphenyl--2-ylcarbamoyl]-methylsulfanyl}-propionic acid
methyl ester bis-trifluoroacetate
a) ({4-[6'-(2-Hydroxy-acetylamino)-2'-methyl-4'-nitro-biphenyl-3-
sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-
butyl ester
To a solution of {[4-(6'-amino-2'-methy]-4'-nitro-biphenyl-3-sulfonyl)-
5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(216 mg, 0.384 mmol, as prepared in Example 295, step h) in DCM (2 mL)
was added DIEA (212 µL, 1.15 mmol) and acetoxyacetyl chloride (54 mL, 0.5
mmol). The solution was stirred at rt for 3 hr. The reaction mixture was diluted
with EtOAc and washed with saturated NaHCO3, water, and brine. The
organic layer was dried over MgSO4, filtered, and concentrated in vacuo to
provide 256 mg of a crude: oil that was used without further purification. ESI-
MS (m/z): Calcd. for C28H30N4O9S3: 663.1 (M+H); found: 662.7, 563.0 (M-
Boc). To a solution of the crude intermediate obtained above in MeOH (2.5
mL) was added 1 N NaOH (2.5 mL) and the mixture was stirred at rt for 45
min at which time TLC was consistent with complete conversion. The reaction
mixture was neutralized with acetic acid, concentrated in vacuo, and the
residue partitioned between EtOAc and saturated NaHC03. The organic layer
was washed with water and brine, dried over MgSO4, filtered, and
concentrated in vacuo to give 220 mg (92%, crude yield over two steps) of the
title compound which was used without further purification. ESI-MS (m/z):
Calcd. for C26H28N4O8S3: 621.1 (M+H); found: 620.7, 521.0 (M-Boc).
b) ({4-[4'-(N,N'-Bis-tert-butoxycarbonyl)-guanidino-6'-(2-hydroxy-
acetylamino)-2'-methyl-biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-
yl}-imino-methyl)-carbamic acid tert-butyl ester
To a solution of ({4-[6'-(2-hydroxy-acetylamino)-2'-methyl-4'-nitro-
biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-
carbamic acid tert-butyl ester (220 mg, .354 mmol, as prepared in Example
237, step a) in EtOH (2.2 mL) was added a solution of NH4Cl (1.1 mL, 3.2 M,
3.54 mrnol). The mixture was stirred vigorously at 50 °C for 30 min. Iron
powder (100 mg, 1.77 mmol) was added and the mixture was heated to 80 °C
for 3.5 h. The reaction mixture was filtered (0.2 \i , Wheaton syringe filter)
and the filtrate was concentrated to a solid that was partitioned between
EtOAc and 1 N Na2CO3. The organic layer was washed with another portion
of Na2CO3, dried (MgSO4), filtered, and concentrated to give the crude desired
product. Purification using PTLC (4 x 1500 p. plate, 5% MeOH in DCM)
provided 58 mg of the desired aniline. ESI-MS (m/z): Calcd. for
C26H30N4O6S3: 591.1 (M+H); found: 591.0, 491.0 (M-Boc). To a solution of
this aniline (55 mg, 0.09 mmol) in MeOH / AcOH (10:1, 5 mL), N,N'-bis(tert-
butoxycarbonyl)-S-methylisothiourea (78 mg, 0.27 mmol, Aldrich Chemical
Company) was added. The reaction mixture was warmed to 40 °C and stirred
for 3 h. The mixture was concentrated in vacuo to a solid that was purified on
PTLC (2 x 1000 µ plate, 1:1 EtOAc/hexanes) to give 45 mg (60%) of the title
compound as a clear oil. 1H-NMR (CDCl3; 400 MHz): d 11.60 (s, 1H), 10.27
(s, 1H), 8.20 (m, 2H), 8.04 (d, 1H, J= 6.7 Hz), 7.90 (br s, 1H), 7.64 (t, 1H, J =
7.8 Hz), 7.40-7.45 (m, 2H), 4.42 (br s, 1H), 3.84 and 3.99 (AB quartet, 2H, J
= 15.4 Hz), 2.55 (s, 3H), 1.93 (s, 3H), 1.57 (s, 9H), 1.53 (s, 9H), 1.48 (s, 9H).
ESI-MS (m/z): Calcd. for C17H48N6O10S3: 833.2 (M+H); found: 832.8, 732.8,
632.9,533.1.
c) Methanesulfonic acid (3'-[5-(tert-butoxycarbonylamino-imino-
methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-4-(N,N'-bis-tert-
butoxycarbonyl)-guanidino-6-methyl-biphenyl-2-ylcarbamoyl}-methyl ester
To a solution of ({4-[4'-(N,N'-bis-tert-butoxyciirbony])-guanidino-6'-
(2-hydroxy-acetylamino)-2'-met:hyl-biphenyl-3-sulfonyl]-5-methylsulfanyl-
thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester (40 mg, 48
µmmol, as prepared in Example 238, step b) and diisopropyl ethylamine (100
µL, 192 µmol) in DCM (I mL) at 0 °C was added methanesulfonyl chloride
(10 µL, 130 µmol). The solution was stirred at 0 °C for 30 min and then
allowed to warm up and stirred at it for 5 h. The reaction mixture was
concentrated in vacuo and the residue was chromatographed (PTLC, 1:1
EtOAc/hexanes, 1000 µ SiO2 plate) to afford 40 mg (97%) of the desired title
compound as a glassy solid. ESI-MS (m/z): Calcd. for C38H50N6O14S4: 911.2
(M+H); found: 910.7, 810.3, 710.8, 611.1.
d) 3-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-
guamdino-6-methyl-biphenyl-2-ylcarbamoyl]-methylsulfanyl}-propionic
acid methyl ester bis-trifluoroacelate
Methyl 3-mercapto propionate (large molar excess) was added to a
solution of (Methanesulfonic acid {3'-[5-(tert-butoxycarbonylamino-imino-
methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-4-(N,N'-Bis-tert-
butoxycarbonyl)-guanidino-6-methyl-biphenyl-2-ylcarbamoyl}-methyl ester
(7 mg, 7.7 µmol, as prepared in Example 238, step c) and Et3N (20 µL) in
DCM (200 µL). The solution was; stirred for 1 hr at rt then concentrated in
vacuo. The resulting residue was treated with TFA and purified using C18-
HPLC as described in Example 220, step c to afford 3 mg (45%) of the title
compound as a white solid. 1H-NMR (CD3OD; 400 MHz): 6 8.32 (s, 1H), 8.08
(ddd, 1H, .1 = 8.07 2.0, 1.2 Hz), 7.92 (t, 1H, J = 1.6 Hz), 7.74 (t, lH, 3 = 8.0
Hz), 7.57 (dt, 1H, J = 7.6, 1.6 Hz), 7.45 (d, 1H, J = 2.3 Hz), 7.20 (dd, 1H, J =
2.3, 0.7 Hz), 3.67 (s, 3H), 5.05 and 3.10 (AB quartet, 2H, J = 15.5 Rz), 2.73 (s,
3H), 2.40-2.44 (m, 2H), 2.27-2.33 (m, 2H), 2.08 (s, 3H). ESI-MS (m/z):
Calcd. for C26H30N6O5S4: 635.1 (M+H); found: 635.1.
Example 239
3-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-
guanidino-6-methyl-biphenyl-2-ylcarbamoyl]-methylsulfanyl}-propionic acid
bis-trifluoroacetate
3-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-
guanidino-6-methyl-biphenyl-2-ylcarbamoyl]-methylsulfanyl}-propionic acid
methyl ester bis-trifluoroacetate (5.7 mg, 6.3 µmol, as prepared in Example
238, step d), dissolved in MeOH (200 µL), was treated with 1 N NaOH (200
µL) at rt for 2 hr. The reaction was acidified with acetic acid and the crude
product was purified using C18-HPLC as described in Example 220, step c to
provide 4 mg (75%) of the title compound as a white solid. 1H-NMR (CD3CN;
400 MHz): d 9.67 (br s, 1H), 9.44 (br s, 2H), 8.36 (s, 1H), 8.19 (s, 1H), 8.12
(ddd, 1H, J = 8.1, 1.9, 1.1 Hz), 7.88 (t, 1H, J = 1.6 Hz), 7.75-7.81 (m, 3H),
7.55 (dt, 1H, J = 7.7, 1.5 Hz), 7.10 (d, 1H, J = 1.9 Hz), 6.84 (br s, 4H), 3.01
and 3.08 (AB quartet, 2H, J = 16.2 Hz), 2.69 (s, 3H), 2.24-2.36 (m, 4H), 2.04
(s, 3H). ESI-MS (m/z): Calcd. for C25H28N6O5S4: 621.1 (M+H); found: 621.0.
Example 240
6-{3-[3"-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-
biphenyl-2-yl]-ureido}-hexanoic acid trifluoroacetate
To a solution of {[4-(6'-amino-2'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(23 mg, 0.044 mmol, as prepared in Example 25, step c) and Et3N (50 µL,
0.36 mmol) in DCM (2 mL) v/as added 6-isocyanato-hexanoic acid ethyl ester
(40 µL, 0.22 mmol) and the mixture was stirred for 3 h at rt. The reaction
mixture was diluted with EtOAc and then washed with water and saturated
NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated
in vacuo. The resulting crude product was taken up in MeOH (3 mL) and
treated with 1 N NaOH (3 mL) at rt for 2 h. The reaction was acidified with
acetic acid, concentrated in vacuo, and the residue was subjected to TFA
treatment followed by C18-HPLC purification as described in Example 220,
step c to afford the title compound as a white solid. 1H--NMR (CD3OD; 400
MHz) 5 8.30 (s, 1H), 8.05 (ddd, 1H, J = 7.9, 1.9, 1.2 Hz), 7.89 (t, 1H, J = 1.6
Hz), 7.71 (t, 1H, J = 7.8 Hz), 7.54-7.58 (m, 1H), 7.43 (d, 1H, J = 7.7 Hz), 7.28
(t, 1H, J = 7.8 Hz), 7.10-7.14 (m, 1H), 2.97 (td, 2H, J = 6.8, 2.2 Hz), 2.72 (s,
3H), 2.26 (t, 2H, J = 7.4 Hz), 2.00 (s, 3H), 1.51-1.59 (m, 2H), 1.19-1.36 (m,
4H). ESI-MS (m/z): Calcd. for C26H30N4O5S3: 575.1 (M+H); found: 575.1.
Example 241
3-(2-{2-[2-(2-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-
sulfonyl)-6-methyl-biphenyl-2-yl]-ureido} -ethoxy)-ethoxy]-ethoxy) -ethoxy)-
propionic acid trifluoroacetate
As described in Example 194, step a, {[4-(6'-amino-2'-methyl-
biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-immo-methyl}-
carbamic acid tert-butyl ester (75 mg, 0.145 minol, as prepared in Example 25,
step c), p-nitrophenyl chloroformate (31 mg, 0.152 mmol), pyridine (40 µL,
0.435 mmol) in DCM (1 niL) were stirred at it for 3 h. To the mixture was
added amino-dPEG4-™-t-butyl ester (93 mg, 0.29 mmol, Quanta Biodesign,
Powell, Ohio) and the reaction was stirred for another 1(5 h at rt. The mixture
was concentrated and the residue was subjected to TFA treatment followed by
C18-HPLC purification as described in Example 220, step c to afford 25 mg
(24%) of the title compound as a glassy solid. 1H-NMR (CD3OD; 400 MHz) 8
8.31 (s, 1H), 8.07 (ddd, 1H, J= 7.9, 1.9, 1.1 Hz), 7.87-7.90 (m, 1H), 7.72 (t,
1H, J= 7.8 Hz), 7.55-7.58 (m, 1H), 7.45 (d, 1H, J= 8.1 Hz), 7.28, (t, m,J =
7.8 Hz), 7.12 (d, 1H, J= 7.3 Hz), 3.68 (t, 2H, J = 6.3 Hz), 3.50-3.62 (m, 12H),
3.39 (t, 2H, J= 5.2 Hz), 3.16 (t, 2H, J= 5.3 Hz), 2.72 (s, 3H), 2.50 (t, 2H, J =
6.3 Hz), 2.00 (s, 3H). ESI-MS (m/z): Calcd. for C31H40N4O9S3: 709.2 (M+H);
found: 709.2.
Example 242
4-[2'-Methyl-6'-(3-phene1:hyl-ureido)-biphenyl-3-sulfonyl]-5-methylsulfanyl-
thiopheme-2-carboxamidine trifluoroacetate
To a solution of {[4-(6'-amino-2'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(30 mg, 0.058 mmol, as prepared in Example 25, step c) and DEEA (100 µL,
0.57 mmol) in DCM (1.5 mL) was added (2-Isocyanato-ethyl)-benzene (100
p.L, 0.68 mmol) and the mixture was stirred for 4 h at rt. The reaction mixture
was diluted with EtOAc and then washed with water and saturated NaHCCh.
The organic layer was dried over MgSO4 filtered, and concentrated in vacuo.
The resulting residue was subjected to TFA treatment followed by C18-HPLC
purification as described in Example 220, step c to afford 20 mg (62%) of the
title compound as a white solid. 1H-NMR (CD3OD; 400 MHz) 5 8.30 (s, 1H),
8.08 (ddd, 1H, J= 7.9, 1.9, 1.1 Hz), 7.90 (t, 1H, J= 1.6 Hz), 7.71 (t, 1H, J =
7.8 Hz), 7.51-7.55 (m, 1H), 7.36-7.39 (m, 1H), 7.22-7.30 (m, 3H), 7.12-7.19
(m, 2H), 7.02-7.06 (m, 2H), 3.14-3.24 (m, 2H), 2.64 (s, 3H), 2.52-2.62 (m,
2H), 2.00 (s, 3H). ESI-MS (m/z): Calcd. for C28H28N4O3S3: 565.1 (M+H);
found: 565.1.
Example 243
{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-
biphenyl-2-yl]-ureido}-acetic acid ethyl ester trifluoroacetate
To a solution of {[4-(6'-amino-2'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(15 mg, 0.029 mmol, as prepared in Example 25, step c) and Et3N (20 µL,
0.15 mmol) in DCM (1.0 mL) was added isocyanato-acetic acid ethyl ester (10
µL, 0.087 mmol) and the; mixture was stirred for 4 h at rt. The reaction
mixture was diluted with EtOAc and then washed with water and saturated
NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated
in vacuo. The resulting crude product was split in two equal portions. One
portion was subjected to TFA treatment followed by C18-HPLC purification as
described in Example 220, step c to afford the title compound as a white solid.
1H-NMR (CD3OD; 400 MHz): S 8.31 (s, 1H), 8.07 (ddd, 1H, J= 7.9, 1.9, 1.2
Hz), 7.90 (t, 1H, J = 1.6 Hz), 7.72 (t, 1H, J= 7.S Hz), 7.56-7.60 (m, 1H), 7.46-
7.50 (m, 1H), 7.30 (t, 1H, J= 7.8 Hz), 7.12-7.16 (m, 1H), 4.16 (q, 2H,.J= 7.2
Hz), 3.76 (d, 2H, J= 4.2 Hz), 2.72 (s, 3H), 2.01 (s, 3H), 1.26 (t, 3H, J= 7.2
Hz). ESI-MS (m/z): Calcd. for C24H26N4O5S3: 547.1 (M+H); found: 547.1.
Example 244
{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-
biphenyl-2-yl]-ureido}-acetic acid trifluoroacetate
The other portion of the crude ethyl ester obtained in Example 244 was
saponified by treatment with a mixture of MeOH/1 N NaOH (l:1, 2 mL) at rt
for 4 h. The crude reaction mixture was acidified with acetic acid,
concentrated in vacuo, and the residue was subjected to TFA treatment
followed by Cis-HPLC purification as described in Example 220, step c to
afford the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): d
8.31 (s, 1H), 8.07 (ddd, lH,.J=7.9, 1,9, 1.2 Hz), 7.88 (t, 1H,J= 1.8 Hz), 7.72
(t, 1H, J= 7.8 Hz), 7.56-7.60 (m, 1H), 7.47-7.51 (m, 1H), 7.30 (t, 1H, J= 7.9
Hz), 7.12-7.15 (m, 1H), 3.6S-3.80 (m, 2H), 2.72 (s, 3H), 2.01 (s, 3H). ESI-MS
(m/z): Calcd. for C22H22N4O5S3: 519.1 (M+H); found: 519.1.
Example 245
{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-
biphenyl-2-y]carbarnoyl]-methoxy}-acetic acid trifluoroacetate
Following the same procedure as in Example 227, reaction of {[4-(6'-
amino-2'-methyl-bipheny]-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-
methyl}-carbamic acid tert-butyl ester (28 trig, 0.054 mmol, as prepared in
Example 25, step c), Et3N (45 µL, 0.32 mmol), and diglycolic anhydride
(20mg, 0.16 mmol) in DCM (2 mL) followed by analogous work up and
purification provided the title compound (50% yield over two steps). 1H-NMR
(CD3OD; 400 MHz): d 8.28 (s, 1H), 8.0S (ddd, 1H, J= 7.9, 1.9, 1.2 Hz), 7.S5
(t, 1H, J = 1.5 Hz), 7.72 (t, 1H, J= 7.8 Hz), 7.56-7.60 (m, 1H), 7.53 (d, 1H, J
= 8.1 Hz), 7.36 (t, 1H, J= 7.8 Hz), 7.26 (d, 1H, J = 7.7 Hz), 3.70-3.91 (in,
4H), 2.72 (s, 3H), 2.08 (s, 3H). ESI-MS (m/z): Calcd. for C23H23N3O6S3:
534.1 (M+H); found: 534.1.
Example 246
2-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-
biphenyl-2-ylcarbamoyl]-methylsulfanyl}-acetamide trifluoroacetate
a) ({4-[6'-(2-Brom o-acetylamino)-2'-methyl-biphenyl-3-sulfonyl]-5-
methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester
Following the procedure described for Example 234, step a, reaction of
{[4-(6'-i3mino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-
yl]-imino-methyl}-carbamic acid tert-butyl ester (137 mg, 0.265 mmol, as
prepared in Example 25, step c), bromoacetyl bromide (28 µL, 0.32 mmol),
and DIEA (70 µL, 0.40 mmol) in chloroform (3 mL) afforded 129 mg (76%)
of the title compound as a yellow foamy solid after chromatography (PTLC,
10% EtOAc in DCM, 2 x 1500 µ SiO2 plate). 1H-NMR (CDCl3; 400 MHz): d
8.05-8.10 (m, 1H), 7.85-7.95 (m, 2H), 7.65-7.73 (m, 2H), 7.46-7.51 (m, 1H),
7.35 (t, 1H, J= 7.9 Hz), 7.16 (d, 1H, J= 7.7 Hz), 3.64 and 3.74 (AB quartet,
2H, J = 14.0 Hz), 2.60 (s, 3H), 2.03 (s, 3H), 1.52 (s, 9H). ESI-MS (m/z):
Calcd. for C26H28BrN3O5S3: 637.0 (M+H); found: 637.8, 639.8, 538.0, 540.0
(M-Boc).
b) 2-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-
methyl-biphenyl-2-ylcarbamoyl]-methylsulfanyl}-acetamide trifluoroacetate
To a solution of ({4-[6'-(2-bromo-acetylamino)-2'-methy]-biphenyl-3-
sulfonyl]-5-methylsulfanyl-thiophen-2-yl} -imino-methyl)-carbamic acid tert-
butyl ester (9 mg, 0.014 rnmol, as prepared in Example 246, step a) in MeOH
(0.1 mL) was added 2-mercapto acetamide (20 µL of 10% methanolic
solution, Maybridge pic) and Et3N (6 µL, 0.042 mmol). The reaction mixture
was stirred at rt for 0.5 h and then concentrated in vacuo. The residue was
treated with TFA as described in Example 220, step c and then purified using
C18-HPLC (10-60% CH3CN in H2O with 0.1% TFA) to afford 8.7 mg (94%)
of the title compound as a clear glassy solid. 1H-NMR (CD3OD; 400 MHz): d
8.30 (s, 1H), 8.09 (ddd., 1H, J= 7.9, 1.9, 1.2 Hz), 7.88 (t, 1H, J= 1.6 Hz), 7.72
(t, 1H, J= 7.9 Hz), 7.57-7.60 (m, 1H), 7.35-7.40 (m, 2H), 7.27-7.31 (m, 1H),
3.05 and 3.11 (AB quartet, 2H, J = 14.9 Hz), 2.78 and 2.85 (AB quartet, 2H, J
= 14.9 Hz), 2.74 (s, 3H), 2.08 (s, 3H). ESI-MS (m/z): Calcd. for
C23H24N4O4S4: 549-1 (M+H); found: 549.1.
Example 247
3-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-
biphenyl-2-ylcarbamoyl]-methylsulfanyl}-propionic acid trifluoroacetate
Following the same procedure as described in Example 246, step b,
reaction of ({4-[6'-(2-bromo-acetylamino)-2'-methyl-biphenyl-3-sulfonyl]-5-
methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester
(15.2 mg, 0.029 mmol, as prepared in Example 246, step a), 3-
mercaptopropionate (8 µL, 0.09 mmol), Et3N (20 µL, 0.12 mmol), in MeOH
(1 mL) for 1 h afforded 9 mg (56%) of the title compound as a white solid
after TFA treatment and RP-HPLC purification. 1H-NMR (CD3OD; 400
MHz): d 8.28 (s, 1H), 8.06-8.09 (m, 1H), 7.88 (t, 1H,J = 1.9 Hz), 7.70 (t, 1H,
J= 7.8 Hz), 7.53-7.57 (m, 1H), 7.33-7.38 (m, 2H), 7.25-7.29 (m, 1H), 2.95
and 3.04 (AB quartet, 2H, J = 15.4 Hz), 2.73 (s, 3H), 2.31-2.36 (m ,2H), 2.16-
2.20 (m ,2H), 2.04 (s, 3H). ESI-MS (m/z): Calcd. for C24H25N3O5S4: 564.1
(M+H); found: 564.1.
Example 248
2-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-
biphenyl-2-ylcarbamoyl]-methylsulfanyl}-succinic acid trifluoroacetate
Following the same procedure as described in Example 246, step b,
reaction of ({4-[6'-(2-bromo-acetylamino)-2'-methyl-biphenyl-3-sulfonyl]-5-
methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester
(15.3 mg, 0.03 mmol, as prepared in Example 246, step a), mercaptosuccinate
(14 mg, 0.09 mmol), Et3N (20 µL, 0.12 mmol), and MeOH (1 mL) for 2 h
provided 12 mg (67%) of the: title compound as a white solid after TFA
treatment and RP-HPLC purification. 1H-NMR (CD3OD; 400 MHz, (+) and (-
) enantiomers appear as two distinct diastereomers on NMR presumably due
to conformational restriction around o-methyl-biphenyl ring system): d 8.27
(s, 1H), 8.04-8.09 (m, 1H), 7.84-7.S8 (m, 1H), 7.66-7.73 (m, 1H), 7.53-7.57
(m, 1H), 7.32-7.44 (m, 2H), 7.27 (t, 1H, J = 6.7 Hz), 3.38-3.42 (m, 0.5H),
3.09-3.29 (m, 2H), 2.62-2.79 (m, 2.5H), 2.75 (s, 3H), 2.44-2.50 (m, 0.5II),
2.22-2.28 (m, 0.5H), 2.06 (s, 3H). ESI-MS (m/z): Calcd. for C25H25N3O7S4:
608.1 (M+H); found: 608.1.
Example 249
2-Bromo-N-[3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-
methyl-biphenyl-2-yl]-acetamide trifluoroacetate
({4-[6'-(2-bromo-acetylamino)-2'-methyl-biphenyl-3-sulfonyl]-5-
methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester
(22 mg, 0.034 mmol, as prepjjred in Example 246, step a) was stirred in a
mixture of TFA / DCM (1:1, 4 mL) for 1 h at it. The reaction was
concentrated in vacuo and the resulting residue was purified using RP-HPLC
(10-50% CH3CN in H2O with 0.1% TFA over 30 min) to afford 15 mg (68%)
of the title compound as a clear glassy solid (purity >99.9% by analytical RP-
HPLC). ESI-MS (m/z): Calcd. for C21H20BrN3O3S3: 538.0 (M+H); found:
538.0 and 540.0
Example 250
2-Acetylamino-3-{|[3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-
sulfonyl)-6-methyl-biphenyl-2-ylc arbamoyl]-methylsulfanyl}-3-methyl-
butyric acid trifluoroacetate
N-Acetyl-penicilla.mine (3.0 mg, 0.0154 mmol, racemic) and DIEA (7
µL, 0.04 mmol) were dissolved in DMSO (223 µL) and then transferred to a
solution of 2-bromo-N-[3'-(5-carbamimidoyl-2-methylsulfanyl-thiophene-3-
sulfonyl)-6-methyl-biphenyl-2-yl]-acetamide trifluoroacetate (20 mM in
DMSO, 230 µL, 0.0046 mmol, prepared from the title compound described in
Example 249). The reaction was mixed on a shaker for 1 h at rt. Bromomethyl
wang resin (16 mg, 1.47 mmol/gm) was added to scavenge the excess thiol.
After 2 h of shaking, the resin was filtered and the filtrate was directly purified
using PP-HPLC as previously described in Example 246, step b, to afford 1.5
mg (50%, single peal: on analytical RP-HPLC) of the title compound as a
glassy solid. ESI-MS (m/z): Calcd. for C28H32N4O6S4: 649.1 (M+H); found:
649.1.
Example 251
2-Acetylamino-3-{[3'-(5-carbamirnidoyl-2-methylsulfanyl-thiophene-3-
sulfonyl)-6-methyl-biphenyl-2-ylcarbamoyl]-methylsulfany]}-propionic acid
trifluoroacetate
Following the same procedure as described in Example 246, step b,
reaction of ({4-[6'-(2-bromo-acetylamino)-2'-methyl-biphenyl-3-sulfonyl]-5-
methylsulfanyl-thiophen-2-yl}-]jnino-methyl)-carbamic acid tert-butyl ester
(10 mg, 0.016 mmol, as prepared in Example 246, step a), (L)-N-
acetylcysteine (22 mg, 0.135 mmol), Et3N (50 µL, 0.12 mmol), and DCM (0.5
mL) for 2 h provided 7 mg (71%) of the title compound as a white solid after
TFA treatment and RP-HPLC purification. 1H-NMR (CD3OD; 400 MHz): 6
8.30 (s, 1H), 8.06-8.09 (m, 1H), 7.87 (t, 1H, J= 1.6 Hz), 7.68-7.'73 (m, 1H),
7.54-7.59 (m, 1H), 7.34-7.39 (m, 2H), 7.26-7.30 (m, 1H), 4.41-4.48 (m, 1H),
2,94-3.10 (m, 2H), 2.74 (s, 3H),.2.59-2.64 (m ,1H), 2.43-2.49 (m, 1H), 2,06 (s,
3H). 2.00 (d, 3H, 2.1 J = 2.1 Hz). ESI-MS (m/z): Calcd. for C26H28N4O6S4:
621.1 (M+H); found: 621.1.
Example 252
3-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-methoxy-
6-methyl-biphenyl-2-ylcarbamoyl]-methylsulfanyl}-propionic acid
trifluoroacetate
a) ({4-[6'-(2-Brom o-acetylamino)-4'-m eth oxy-2'-methyl-biphenyl-3-
sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-
butyl ester
Following the procedure described for Example 234, step a, reaction of
{[4-(6'-amino-4'-methoxy-2'-raethyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (204 mg, 0.37
mmol, as prepared in Example 198, step e), bromoacetyl bromide (39 µL, 0.45
mmol), and Et3N (77 µL, 0.56 mmol) in DCM (5 mL) afforded 170 mg (69%)
of the title compound as a yellow foamy solid after chromatography (PTLC,
50% EtOAc in hexanes, 4 x 1000 µ SiO2 plate). 1H-NMR (CDCl3; 400 MHz):
8 8.02-8.05 (m, 1H), 7.91 (s, 1.H), 7.87 (t, 1R, J = 1.6 Hz), 7.73 (br s, 1H),
7.63-7.67 (m, 2H), 7.45-7.49 (m, 1H), 6.69 (d, 1H, J= 2.1 Hz), 3.85 (s, 3H),
3.69 and 3.74 (AB quartet, 2H, J = 14.1 Hz), 2.59 (s, 3H), 2.00 (s, 3H), 1.52
(s, 9H). ESI-MS (m/z): Calcd. for C27H30BrN3O6S3: 668.0 (M+H); found:
669.6, 667.6, 570.0, 568.0 (M-Boc).
b) 3-{[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-
methoxy- 6-methyl-biphenyl-2-ylcarbamoyl]-in ethylsulfanyl]-propionic acid
trifluoroacetate
Following the same procedure as described in Example 246, step b,
reaction of ({4-[6'-(2-bromo-acetylamino)-4'-methoxy-2'-methyl-biphenyl-3-
sulfonyl]-5-methylsulfanyl-thiophen-2-yl} -imino-methyl)-carbamic acid tert-
butyl ester (12 mg, 0.018 rnmol, as prepared in Example 252, step a), 3-
mercaptopropionate (8 u.L, 0.09 mmol), Et3N (20 µL, 0.12 mmol), in MeOH
(1 mL) for 1 h afforded 9 3 mg (62%) of the title compound as a white solid
after TFA treatment and RP-HPLC purification. 1H-NMR (CD3OD; 400
MHz): d 8.29 (s, 1H), 8.07 (ddd, 1H, J= 7.9, 1.9, 1.2 Hz), 7.87 (t, 1H, J= 1.6
Hz), 7.70 (t, 1H, J= 7.8 Hz), 7.53-7.57 (m, 1H), 7.05 (d, 1H, J= 2.5 Hz), 6.84
(d, 1H, J = 2.5 Hz), 3.83 (s, 3H), 2.98 and 3.06 (AB quartet, 2H,.J = 15.4 Hz),
2.73 (s, 3H), 2.32-2.36 (m ,2H), 2.19-2.23 (m ,2H), 2.02 (s, 3H). ESI-MS
(m/z): Calcd. for C25H27N3O6S4: 594.1 (M+H); found: 594.0.
Example 253
3-{|'3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyri-4-methoxy-
6-methyl-biphenyl-2-ylcarbamoylj-methylsulfanyl}-propionic acid methyl
ester trifluoroacetate
Following the same procedure as described in Example 246. step b,
reaction of ({4-[6'-(2-bromo-acetylamino)-4'-methoxy-2'-methyl-biphenyl-3-
sulfonyl]-5-methylsulfanyl-thiophen-2-yl} -imino-methyl)-carbamic acid tert-
butyl ester (22 mg, 0.04 mmol, as prepared in Example 252, step a), methyl 3-
mercaptopropionate (10 µL, 0.09 mmol), Et3N (20 µL, 0.12 mmol), in MeOH
(1 mL) for 1 h afforded the; title compound as a white solid after TFA
treatment and RP-HPLC purification. 1H-NMR (CD3OD; 400 MHz): d 8.31 (s,
1H), 8.07 (ddd, 1H, J= 7.9, 1.9, 1.2 Hz), 7.87 (t, 1H, .J== 1.6 Hz). 7.70 (t, 1H,
J = 7.8 Hz), 7.53-7..57 (m, 1H), 7.06 (d, 1H, J = 2.4 Hz), 6.85 (d, 1H, J= 2.4
Hz), 3.84 (s, 3H), 3.68 (s, 3H), 3.00 and 3.07 (AB quartet, 2H, J = 15.4 Hz),
2.74 (s, 3H), 2.39-2.42 (m, 2H), 2.23-2.27 (m, 2H), 2.03 (s, 3H). ESI-MS
(m/z): Calcd. for C26H29N3O6S4: 608.1 (M+H); found: 608.1.
Example 254
N-[3'-(5-Carbamimidoyl-2-me1:hylsulfanyl-thiophene-3-sulfonyl)-4-methoxy-
6-methyl-biphenyl-2-yl]-2-methanesulfonyl-acetamidetrifluoroacetate
Following the same procedure as described in Example 257, reaction
of ({4-[6'-(2-bromo-acetylamino)-4'-methoxy-2'-methyl-biphenyl-3-sulfonyl]-
5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester
(37 mg, 0.065 mmol, as prepared in Example 252, step a) and sodium
methanesulfinate (25 mg, 0.195 mmol, Aldrich Chemical Company) in
EtOH/CH3CN (1:1, 2 mL) provided 29 mg (66%) of the title compound as a
white solid after TFA treatment and RP-HPLC purification. 1H-NMR
(CD3OD; 400 MHz): v 8.30 (s, 1H). 8.03 (ddd, 1H, J= 7.9, 1.9, 1.2 Hz), 7.84
(t, 1H, J= 1.6 Hz), 7.66 (t, 1H, J= 7.8 Hz), 7.51-7.54 (m, 1H), 6.99 (d, 1H, J
= 2.6 Hz), 6.84 (d, 1H, J = 2.6 Hz), 3.89 and 3.93 (AB quartet, 2H, J = 14.1
Hz), 3.82 (s, 3H), 2.86 (s, 3H), 2.72 (s, 3H), 2.01 (s, 3H). ESI-MS (m/z):
Calcd. for C23H25N3O6S4: 568.1 (M+H); found: 568.0.
Example 255
6-Methanesulfonyl-hexanoic acid [3'-(5-carbamimidoyl-2-rnethylsulfanyl-
thiophene-3-sulfonyl)-4-methoxy-6-methyl-biphenyl-2-yl]-amide
trifluoroacetate
Following the procedure described for Example 234, step a, reaction of
{[4-(6'-amino-4'-methoxy-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (60 mg, 0.11
mmol, as prepared in Example 198, step e), 6-bromo-hexanoyl chloride (26
µL, 0.17 mmol), and Et3N (79 µL, 0.55 mmol) in DCM (1 mL) afforded the
title compound as a crude oil after aqueous work up. ESI-MS (m/z): Calcd. for
C31H38BrN3O6S3: 724.1 (M+H); found: 626.1, 624.1 (M-Boc). The crude
bromide intermediate obtained above was suspended in a EtOH-water mixture
(1:1, 3 mL) and to the mixture was added sodium methanesulfinate (45 mg,
0.33 mmol, Aldrich Chemical Company). The reaction mixture was heated at
50 °C for 48 h and then concentrated in vacua. The residue was treated with
TFA as described in Example 220, step c and then purified using Cis-HPLC
(10-60% CH3CN in H2O with 0.1% TFA) to afford 12 mg (18% from the
aniline) of the title compound as a clear glassy solid. 1H-NMR (CD3OD; 400
MHz): d 8.30 (s, 1H), 8.02 (ddd, 1H,7=7.9, 1.9,1.1 Hz), 7.86 (t, 1H,7 = 1.6
Hz), 7.67 (t, 1H, J= 7.9 Hz), 7.52 (dt, 1H, 7 = 7.7, 1.2 Hz), 6.85 (d, 1H, 7 =
2.5 Hz), 6.77 (d, 1H, 7=2.5 Hz), 3.82 (s, 3H), 2.98-3.04 (m, 2H), 2.96 (s, 3H),
2.72 (s, 3H), 1.99-2.04 (m, 2H), 2.03 (s, 3H), 1.57-1.66 (m, 2H), 1.05-1.25 (m,
4H). ESI-MS (m/z): Calcd. for C27H33N3O6S4: 624.1 (M+H); found: 624.1
Example 256
N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-methoxy-
6-methyl-biphenyl-2-yl]-3-methanesulfonyl-propionamide trifluoroacetate
Following the procedure described for Example 234, step a, reaction of
{[4-(6'-amino-4'-methoxy--2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-rnethyl}-carbamic acid tert-butyl ester (60 mg, 0.11
mmol, as prepared in Example 198, step e), acryloyl chloride (22 µL, 0.22
mmol), and Et3N (80 µL, 0.55 mmol) in THF (1 mL) afforded the title
compound as a crude oil after aqueous work up. ESI-MS (m/z): Calcd. for
C28H31N3O6S3: 602.1 (M+H); found: 601.9, 502.1 (M-Boc). The crude
acrylamide intermediatte obtained above was suspended in a EtOH-water
mixture (1:1, 3 mL) and to the mixture was added sodium metlianesulfmate
(45 mg., 0.33 mmol, Aldrich Chemical Company). The reaction mixture was
heated at 50 °C for 48 h and then concentrated in vacuo. The residue was
treated with TFA as described in Example 220., step c and then purified using
C18-HPLC (10-60% CH3CN in H2O with 0.1% TFA) to give 15 mg (23% from
the aniline) of the title compound as a white solid. 1H-NMR (CD3OD; 400
MHz): d 8.30 (s, 1H), 8.03 (ddd, 1H, J- 7.9, 1.9, 1.1 Hz), 7.83 (t, lH,J= 1.6
Hz), 7.67 (t, 1H, J= 7.8 Hz), 7.54 (dt, 1H, J= 7.7, 1.3 Hz), 6.84-6.87 (m, 2H),
3.82 (s, 3H), 3.07 (t, 2H, J= 7.8 Hz), 2.86 (s, 3H), 2.73 (s, 3H), 2.44-2.51 (m,
2H), 2.06 (s, 3H). ESI-MS (m/z): Calcd. for C24H27N3O6S4: 582.1 (M+H);
found: 582.1.
Example 257
N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-
biphenyl-2-yl]-2-methanesuIfonyl-acetarnide trifluoroacstate
To a solution of ({4-[6'-(2-bromo-acetylamino)-2'-methyl-biphenyl-3-
sulfonyl]-5-methylsulfanyl-thk>pb.en-2-yl} -immo-methyl)-carbam:ic acid tert-
butyl ester (8 mg, 0.0125 mmol, as prepared in Example 246, step a) in EtOH
(1.0 mL) was added sodium methanesulfinate (13 mg, 0.127 mmol, Aldrich
Chemical Company) and the reaction was stirred overnight and monitored by
MS and TLC. After ~16 h at n:, the starting material had disappeared and the
reaction was concentrated in vacuo to give an oil. Treatment of this
intermediate with trifluoroacetic acid for 2 h followed by RP-HPLC
purification afforded 5.2 mg (78%) of the title compound as a white solid. 'H-
NMR (CD3OD; 400 MHz): 6 8.31 (s, 1H), 8.05 (ddd, lH,J= 7.9, 1.9,1.2 Hz),
7.87 (t, 1H, J= 1.6 Hz), 7.68 (t, 1H, 7= 8.0 Hz), 7.53-7.56 (m, 1H), 7.33-7.37
(m, 2H), 7.26-7.30 (m, 1H), 3.85-3.94 (m, 2H) 2.84 (s, 3H), 2.72 (s, 3H), 2.04
(s, 3H). ESI-MS (m/z): Calcd. for C22H23N3O5S4: 538.0 (M+H); found: 538.0.
Example 258
N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-
biphenyl-2-yl]-2-methanesulfonyl-propionamide trifluoroacetate
a) ({4-[6'-(2-Bromo-propionylamino)-2'-methyl-biphenyl-3-sulfonyl]-5-
methylsulfanyl-thiophen-2-yl}-imitw-methyl)-carbamic acid tert-butyl ester
Following the procedure described for Example 234, step a, reaction of
{[4-(6'-amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-
yl]-imino-methyl}-carbamic acid tert-butyl ester (65 mg, 0.126 mmol, as
prepared in Example 25, step c), racemic 2-bromo-propionyl bromide (19 µL,
0.189 mmol), and Et3N (52 µL, 0.37S mmol) in DCM (2 mL) afforded 55 mg
(67%) of the title compound as a glassy solid after chromatography (PTLC,
10% EtOAc in DCM, 2 x 1500 µ SiO2 plate). ESI-MS (m/z): Calcd. for
C27H30BrN3O5S3: 652.0 (M+H); found: 653.6, 651.7, 553.9, 552.0 (M-Boc).
b) N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-
methyl-biphenyl-2-yl]-2-methanesulfonyl-propionamide trifluoroacetate
Following the procedure described for Example 257, reaction of ({4-
[6'-(2-bromo-propionylamino)-2'-methyl-biphenyl-3-sulfonyl]-5-
methylsulfanyl-thiophen-2-y!}-imino-methyl)-carbamic acid tert-butyl ester
(30 mg, 0.046 mmol, as prepared in Example 258, step a) and sodium
methanesulfmate (48 mg, 0.46 mmol, Aldrich Chemical Company) in EtOH (1
mL) provided 18 mg (72%) of the title compound as a white solid after TFA
treatment and RP-HPLC purification. 1H-NMR (CD3OD; 400 MHz, (+) and (-
) enantiomers appear as two distinct diastereomers on NMR presumably due
to conformational restriction around o-methyl-biphenyl ring system): 6 8.32,
8.31 (2 x s, 1H), 8.05-8.08 (m, 1H), 7.87-7.88 (m, 1H), 7.69 (t, 1H, J= 7.8
Hz), 7.52-7.55 (m, 1H), 7.27-7.39 (m, 3H), 3.67-3.74 (m. 1H); 2.78, 2.724,
2.718, 2.16 (4 x s, 6H), 2.06, 2.03 (2 x s, 3H), 1.30, 1.28, 1.17, 1.15 (4 x s,
3H). ESI-MS (m/z): Calcd. for C23H25N3O5S4: 552.1 (M+H); found: 652.0.
Example 259
6-{3-[3'-(5-Carbaminiidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-
guanidino-biphenyl-2-yl]-ureido}-hexanoic acid
a) 6-{3-[3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-4-(2-trimethylsilanyl-
ethoxycarbonylamino)-biphenyl-2-yl]-ureido}-hexanoic acid ethyl ester
A solution of {2-amino-3'-[5-(imino-methoxycarbonylamino-methyl)-
2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyi-4-yl}-carbarnic
acid 2-trimethylsilanyl-ethyl ester {{Example 294: step f) 0.020 g, 0.030
mmol) in dry CH2Cl2 (3 mL) was treated with 6-isocyanato-hexanoic acid
ethyl ester (5.30 µL, 0.030 mmol) and stirred at room temperature 40 min.
The reaction mixture was diluted with CH2Cl2 and washed with water (1 x 15
mL). The organic layer was dried over MgSO4 and concentrated in vacuo to
afford the product 6-{3-[3'-[5-(tert-butoxycarbonylamino-imino-:rnethyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-4-(2-trimethylsilanyl-
ethoxycarbonylamino)-bipheny]-2-yl]-ureido}-hexanoic acid ethyl ester (0.025
g, 98%) as an off-white solid. 1H NMR (CD3OD): d 8.217 (s, 1H), 8.062 (d,
1H, J= 8.0 Hz), 7.920 (t, 1H, J= 1.6 Hz), 7.718 (t, 1H, J= 8.0 Hz), 7.647 (d,
1H, J = 1.6 Hz), 7.556 (d, 1H, J= 7.6 Hz), 7.282 (s, 1H), 4.292 (dd, 2H, J =
8.4 Hz, J= 1.6 Hz), 3.063-3.002 (m, 2H), 2.699 (s, 3H), 2.327 (t, 2H, J= 7.2
Hz), 2.011 (s, 3H), 1.604 (quint, 2H, J= 7.2 Hz), 1.538 (s, 9H), 1.403-1.362
(m, 2H), 1.124 (dd, 2H, J= 7.2 Hz, 7= 1.6 Hz), 1.281 (t, 3H, J = 7.2 Hz).
ESI-MS (m/z): Calcd. for C39H55N5O9S3Si (M+H): 862.3; found 861.90.
A) 6-{3-[3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-4-(2-trimethylsilanyl-
ethoxycarbonylamino)-biphenyl-2-yl]-ureido}-hexanoic acid
A solution of 6-{3-[3'-[5-(tert-butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-4-(2-trimethylsilanyl-
ethoxycarbonylamino)-biphenyl-2-yl]-ureido}-hexanoic acid ethyl ester
((Example 259: step a) 0.437 g, 0.507 mmol) in THF:water (2:1, 15 mL) was
treated with solid LiOH (0.097 g, 4.06 mmol) and stirred at room temperature
18.5 h. The THF was removed in vacuo, and the remaining aqueous solution
was acidified to pH 5 with glacial acetic acid. The solution was extracted with
CH2Cl2 (3 x 50 mL). The combined organic layers were dried over MgSO4
and concentrated in vacuo to afford the title compound (0.4222 g, 99%) as an
off-white solid. ESI-MS (m/z): Calcd. for C37H51N5O9S3S1 (M+H): 834.3;
834.2.
c) 6-(3-{4-Amino-3'-l5-(tert-butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-1hiophene-3-sulfonyl]-6-methyl-biphenyl-2-yl}-ureido)-
hexanoic acid
A solution of 6-{3-[3'-[5-(tert-butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-4-(2-trimethylsilanyl-
ethoxycarbonylamino)-biphenyl-2-yl]-ureido}-hexanoic acid {{Example 259:
step b) 0.422 g, 0.506 mmol) in dry THF (20 mL) was treated with
tetrabutylamrnonium fluoride (1 M in hexanes, 3.39 mL, 3.39 mmol) and
stirred at 40 °C 4 h. Solvents; were evaporated in vacuo. The residue was
taken up in CH2Cl2 and washed with water (4 x 50 mL). The organic layer
was dried over MgSO4 and concentrated in vacuo. Silica gel chromatography
(4% MeOH in CH2C12) afforded the product 6-(3-{4-amino-3'-[5-(tert-
butoxycarbonylamirio-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-
6-methyl-biphenyl-2-yl}-ureido)-hexanoic acid (0.200 g, 57%) as an off-white
solid. The material was combined with 1,3-bis(tret-butoxycarbonyl)-2-
methyl-2-thiopseudourea (0.252 g, 0.870 mmol) and acetic acid (0.5 mL) in
MeOH (10 mL) and was stirred at 40 °C 2 h. The solvent was removed in
vacuo. Silica gel chromatography (4% MeOH in CH2C12 then 10% MeOH in
CH2C12) afforded the title compound (0.215 g, 80%) as a white solid. VH-
NMR (CD3OD): d 8.22 (s, 1H), 8.06 (m, 1H), 7.89 (m, 1H), 7.72 (m, 1H),
7.69 (m, 1H), 7.53 (m, 1H), 7.32 (m, 1H), 3.01 (m, 2H), 2.66 (s, 3H), 2.27 (t,
2H, 7.4 Hz), 1.97 (s, 3H), 1.57 (m, 2H), 1.54 (s, 18H), 1.51 (s, 9H), 1.37 (m,
2H), 1.27 (m,2H).
d) 6-{3-[3'-(5-Carbainimidoyl-2-methylsulfanyl-thiophetie-3-sulfonyl)-
4-guanidino-biphenyl-2-yl]-ureido}-hexanoic acid bis-trifluoroacetate
The reaction conditions used in Example 1: step d were followed using
6-(3-{3'-[5-(tret-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-
thiophene-3-sulfonyl]-4-(N',N"-bis-tret-butoxycarbonyl-guanidino)-6-methyl-
biphenyl-2-yl}-ureido)-hexanoic acid ((Example 259: step c) 80 mg, 0.086
mmol). Analogous purification by HPLC yielded the title compound as a
white solid (70 mg, 95%). 1H-NMR (CD3CN/D2O): d 8.23 (s, 1H), 8.04 (m,
1H), 7.83 (m, 1H), 7.74 (m, 1H), 7.55 (m, 1H), 7.48 (m, 1H), 6.99 (m, 1H),
2.92 (m, 2H), 2.66 (s, 3H), 2.24 (t, 2H, 7.4 Hz), 1.95 (s, 3H), 1.48 (m, 2H),
1.27 (m, 2H), 1.25 (m, 2H). ESI-MS (m/z): Calcd. for C27H33N7O5S3 (M+H):
632.2; found: 632.1.
Example 260
N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-guanidino-
6-methyl-biphenyl-2-yl]-4-methanesulfonyl-butyraniidebis-trifluoroacetate
a) ({4-[4'-Amino-6 '-(4-methanesulfonyl-butyrylamino)-2'-methyl-
biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-
carbamic acid tert-butyl ester
The procedure in Example 261: step b was followed using 4-
methanesulfonyl-butyryl chloride {Example 209; step a (53 mg, 0.29)), {[4-
(6'-arnino-2'-methyl-4'-nitro-biph.enyl-3-sulfonyl)-5-methylsulfanyl-thiophen-
2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 295: step h) 130
mg, 0.23 mmol), and Et3N (192 µL, 1.38 mmol) in DCM (5 mL). After
stirring for 1 h, starting material remained and an additional 20 mg of acid
chloride was added. The solution was partitioned between EtOAc (70 mL)
and aq NH4Cl (30 mL) and the layers were separated. The organic layer was
washed with NaHCO3 (20 mL) and brine (30 mL) and was dried over sodium
sulfate. The solution was concentrated and the residue was purified by SiO2
flash column chromatography to yield 126 mg of the amide product. The
residue dissolved in EtOH (5 mL). Saturated aqueous NH4Cl (1.5 mL) was
added followed by iron powder (110 mg, 2 mmol). The mixture was
vigorously stirred at 80 °C for 30 min. The solution was filtered through a
0.22 urn filter and was then partitioned between EtOAc (70 mL) and water (20
mL). The layers were separated, the organic solution was dried over sodium
sulfate, and the solution was concentrated to give the crude title compound
which was used without further purification. 1H-NMR (CDCl3): 8 7.99 (s,
1H) 7.96 (m, 2H), 7.77 (s, 1H), 7.57 (t, 1H, J= 7.9 Hz), 7.43 (dr., 1H, J= 1.3,
7.7 Hz), 7.10 (br s, 1H), 7.04 (br s, 1H), 6.43 (br s, 1H), 3.85 (br s, 2H), 2.92
(m, 2H), 2.88 (s, 3H), 2.56 (s, 3H), 2.20 (t, 2H, J= 6.7 Hz), 1.98 (m, 2H), 1.90
(s,3H), 1.50 (s, 9H).
b) N-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-
guanidino-6-methyl-biphenyl-2-yl]-4-methanesulfonyl-butyramidebis-
triflnoroacetate
Acetic acid (500 µL) was added to a solution of ({4-[4'-amino-6'-(4-
methanesulfonyl-butyrylammo)-2'-methyl-biphenyl-3-sulfonyl]-5-
methylsulfanyl-thiophen-2-yl}-imino-methy])-carbamic acid ten -butyl ester
{{Example 260: step a) 136 mg., 0.2 mmol) and l,3-bis-(tert-butoxycarbonyl)-
2-methyl-2-thiopseudourea (145 mg, 0.5 mmol) in MeOH (10 mL). The
solution was stirred for 16 h at 40 °C, then was partitioned between EtOAc (80
mL) and water (40 mL). The layers were separated and the organic layer was
washed with aq NaHCO3 (2 x 30 mL) and brine (30 mL) and was dried over
sodium sulfate. After concentration, the residue was purified by preparative
TLC. The residue was treated with 1:1 TFA/DCM as in Example 1: step d and
analogously purified by HPLC to yield the title compound (47 mg, 23%) as a
white solid. 1H-NMR (CD;OD): S 8.39 (s, 1H), 8.09 (ddd, 1H, J - 0.9, 1.9,
8.1 Hz), 7.92 (t, 1H, J = 1.6 Hz), 7.74 (t, 1H, J= 7.7 Hz) 7.58 (m, 1H),
7.24 (m, 2H), 2.94 (s, 3H), 2.86 (t> 2H, J- 7.7 Hz), 2.76 (s, 3H), 2.24 (m, 2H),
2.12 (s, 3H), 1.80 (m, 2H). ESI-MS (m/z): Calcd. for C15H10N4O5S4 (M+H):
623.1; found: 623.1.
Example 261
5-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-guanidino-
6-methyl-biphenyl-2-ylcarbamoyl]-pentanoic acid bis-trifluoroacetate
a) 5-{4-Amino-3'-[5-(tert-butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylcarbamoyl}-
pentanoic acid methyl ester
To a solution of {[4-(6l-amino-2'-methyl-4'-nitro-biphenyl-3-sulfonyl)-
5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tot-butyl ester
{{Example 295: step h) 130 mg, 0.23 nimol), and Et3N (192 yL, 1.38 mmol) in
DCM (5 mL) at 0° C was added 5-chlorocarboriyl-pentanoic acid methyl ester
(53 mg, 0.29). After stirring for 1 h, the solution was partitioned between
EtOAc (70 mL) and aq NH4Cl (30 mL) and the layers were separated. The
organic layer was washed with NaHCO3 (20 mL) and brine (30 mL) and was
dried over sodium sulfate. The; solution was concentrated and the residue was
purified by SiO2 flash column chromatography to yield 36 mg of the amide
product. The residue dissolved in EtOH (5 mL). Saturated aqueous NH4C1
(1.5 mL) was added followed by iron powder (110 mg, 2 mmol). The mixture
was vigorously stirred at 80 °C for 30 min. The solution was filtered through
a 0.22 fim filter and was then partitioned between EtOAc (70 mL,) and water
(20 mL). The layers were separated, the organic solution was dried over
sodium sulfate, and the solution was concentrated to give the crude title
compound which was used without further purification. 1H-NMR (CDCl3):
d 8.0 (m, 2H), 7.84 (s, 1H), 7.96 (m, 2H), 7.59 (t, 1H, J= 7.7 Hz), 7.43 (m,
1H), 7.23 (br s, 1H), 6.86 (br s, 1H), 6.45 (br s, 1H), 3.85 (br s, 2H), 3.65 (s,
3E), 2.60 (m, 3H), 2.35 (m, 2H), 2.00 (m, 2H), 1.90 (s, 3H), 1.67 (m, 2H),
1.90 (s,3H), 1.53 (s,9H).
b) 5-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-
guanidino-6-methyl-biphenyl-2-ylcarbamoyl]-pentanoic acid bis-
trifluoroacetate
Acetic acid (500 µL) was added to a solution of 5-{4-amino-3'-[5-(tert-
butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-
6-methyl-biphenyl-2-ylcarbamoyl}-pentanoic acid methyl ester ((Example
260: step b) 136 mg, 0.2 mmol) and l,3-bis-(tert-butoxycarbonyl)-2-methyl-2-
thiopseudourea (145 mg, 0.5 mmol) in MeOH (10 mL). The solution was
stirred for 16 h at 40 °C, then was partitioned between EtOAc (80 mL) and
water (40 mL). The layers were separated and. the organic layer was washed
with aq NaHCO3 (2 x 30 mL) and brine (30 mL) and was dried over sodium
sulfate. After concentration, the residue was purified by preparative TLC.
The residue was dissolved in MeOH (10 mL) and 1N NaOH was added (400
µL, 0.4 mmol). After stirring for 6 h, the solution was neutralized with AcOH
(100 µL) and the solvent was removed in vacuo. The residue was treated with
1:1 TFA/DCM as in Example 1: step d and analogously purified by HPLC to
yield the title compound (12 mg, 19%) as a white solid. 1H-NMR (CD3OD):
S 8.30 (s, 1H), 8.09 (ddd, 1H, J= 1.2, 2.1, 7.9 Hz), 7.88 (t, 1H, J= 1.6 Hz),
7.70 (t, 1H, J= 1.1 Hz) 7.52 (m, 1H), 7.22 (m, 1H), 7.17 (m, 1H), 2.72 (s, 3H),
2.12 (m, 2H), 2.08 (s, 3H), 2,02 (m, 2H), 1.25 (m, 2H). ESI-MS (m/z): Calcd.
for C26H30N6O5S3 (M+H): 603.1; found: 603.2.
Example 262
4-[2'-Methyl-4'-(N-methyl-guanidino)-biphenyl-3-sulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidinebis-trifluoroacetate
a) (4-Brom o-3-m ethyl-ph enyl)-m ethyl-am ine
A solution of 4-bromo-3-methylaniline (3.72 g, 20 mmol) in formic
acid (15 mL) was heated a.t 100 °C for 8 h. The solvent was removed in vacuo
and the residue was partitioned between EtOAc (100 mL) and aq NaHCO3 (50
mL). The layers were separated and the organic layers was dried (Na2SO4)
and concentrated. The residue was dissolved in THF (80 mL) and cooled to 0
°C. Lithium aluminum hydride (1.52 g, 40 mmol) was added portionwise over
10 min. The mixture v/as stirred at rt for 8 h and an additional equivalent (750
mg) of LAH was added. After 16 h, the mixture was quenched with EtOAc
and MeOH and the solids were filtered. The material was purified by SiO2
flash column chromatography to yield the title compound (2.56 g, 64%) as a
colorless oil. 1H-NMR (CDCl3): d 7.29 (d, 1H, J= 8.6 Hz), 6.33 (dd, 1H, J =
2.8 Hz), 7.29 (d, 1H, J= 2,8, 8.6 Hz), 3.66 (s, 2H), 2.81 (d, 1H, J= 5.4 Hz),
2.33 (s, 3H).
b) {Imino-[4-(2'-methyl-4'-methylamino-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester
The procedure in Example 294: step e was followed using (4-bromo-3-
methyl-phenyl)-methyl-amine {{Example 262: step a) 600 mg, 3 mmol),
palladium acetate (34 mg, 0.15 mmol), and 2-
•(dicyclohexylphosphino)biphenyl (210 mg, 0.6 mmol) in dioxane (20 mL).
Analogous workup yielded the crude pinacolboronate ester (720 mg, 98%)
which was used without further purification. Following the procedure in
Example 294: step /the crude boronate (540 mg, 2.1S mmol) was; reacted with
{[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-
methyl}-carbarmc acid tert-butyl ester {(Example 27: step c) 715 mg, 1.46
mmol), aq Na2CO3 (2M, 4.4 mL, 8.8 mL), and Pd(PPh3)4 (407 mg, 0.37
mmol) in ethanol (4.4 mL) and toluene (8.8 mL). Analogous workup and SiO2
flash column chromatography yielded the title compound (482 mg, 62%) as a
yellow glass. 1H-NMR (CDCl3): d 8.0 (s, 1H), 7.95 (m, 1H), 7.90 (m, 1H),
7.55 (m, 1H), 7.51 (m, 1H), 7.05 (m, 1H), 6.53 (m, 2H), 2.9 (s, 3H), 2.56 (s,
3H), 2.56 (s, 3H), 2.22 (s, 3H), 1.52 (s, 9H).
c) 4-[2'-Methyl-4'-(N-methyl-guanidino)-biphenyl-3-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine bis-trifluoroacetate
The procedure in Example 314 was followed using {imino-[4-(2'-
methyl-4'-methylamino-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-
methyl}-carbamic acid tert-butyl ester ({Example 262: step b) 106 mg, 0.2
mmol), HgCl2 (109 mg, 0.4 mmol), l,3-bis-(ferr-butoxycarbonyl)-2-methyi-2-
thiopseudourea (116 mg, 0.4 mmol), and DIEA (350 µL, 2 mmol) in DMF (3
mL) at 50 °C. After analogous workup and purification by SiO2 flash column
chromatography, the material was treated with 1:1 TFA/DCM as iin Example
1: step d. Purification by HPLC yielded the title compound as a white solid.
1H-NMR. (CD3OD): ft 8.35 (s, 1H), 8.04 (m, 2H), 7.72 (m, 2H), 7.39 (m, 2H),
7.31 (m, 1H), 3.40 (s, 3H), 2.72 (s, 3H), 2.29 (s, 3H). ESI-MS (m/z): Calcd.
for C21H23N5O2S3 (M+H); 474.1; found: 474.1.
Example 263
6-{N'-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-
methyl-biphenyl-4-yl]-guanidmo} -hexanoic acid
a) l,3-bis-(tert-butoxycarbonyl)-l-(trimethylsilylethyl-6-hexanoate)-2-
methyl-2-thiopseudourea
Diisopropylcarbodiimide (1.72 mL, 11 mmol) was added dropwise to a
0 °C solution of 6-bromohexanoic acid (1.95 g, 10 mmol),
trimethylsilylethanol (2.4 g, 20 mmol), and DMAP (122 mg, 1 mmol) in DCM
(20 mL). The mixture warmed to rt over 1 h and was allowed to stir at rt for
16h. The solvent was removed in vacuo, the residue was dissolved in EtOAc
(100 mL), and the solution was filtered. The solution was extracted with 5%
citric acid (3 x 20 mL), NaHCO3 (3 x 20 mL), and brine (30 mL), then was
dried over sodium sulfate. Concentration of the solution in vacuo yielded the
TMSE ester as a non-viscous oil (2.25 g, 76%) which was used without further
purification. 1H-NMR (CDCl3): d 4.16 (m, 2H), 2.41 (s, 3H), 3.41 (t, 2H, J =
6.75 Hz), 2.30 (t, 2H, J= 6.75 Hz), 1.8S (m, 2H), 1.65 (m, 2H), 1.47 (m, 2H).
Sodium hydride was added to a 0 °C solution of l,3-bis-(/er/-
butoxycarbonyl)-2-methyl-2-thiopseudourea (581 mg> 2 mmol) in DMF (10
mL). After stirring for 30 min at 0 °C, a solution of 2-trimethylsilyethyl-6-
bromohexanoate (738 mg, 2.5 mmol) was added and the reaction was warmed
to rt. The reaction was stirred at rt for 2 h, 60 "C for 1 h, then at 80 °C for 18
h. The solution was partitioned between EtOAc (120 mL) and water (50 mL)
and the layers were separated. The organic layer was extracted with water (8
x 30 mL) and brine (50 mL), then was dried over sodium sulfate.
Concentration of the solution followed by SiO2 flash column chromatography
yielded the title compound (526 mg, 52%). 1H-NMR (CDCl3): d 4.13 (m,
2H), 2.41 (s, 3H), 2.30 (t, 2H, J= 7.4 Hz), 1.69 (m, 4H), 1.53 (s, 9H), 1.50 (s,
9H), 1.34 (m, 4H), 1.00 (m, 2H).
b) 6-{N'-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-
2-methyl-biphenyl-4-yl]-guanidino}-hexanoic acid
Acetic acid (0.5 ml,) was added to a solution of {[4-(4'-amino-2'-
methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-
carbamic acid tert-butyl ester ((Example 220: step b) 130 mg, 0.25 mmol) and
1,3-bis-(tert-butoxycarbonyl)-1 -(trimethylsilylethyl-6-hexanoate)-2-methyl-2-
thiopseudourea {{Example 263: step a) 245 mg, 0.5 mmol) in MeOH (10 mL).
The solution was heated at 40 °C for 24 h. The solvent was removed in vacuo
and the residue was purified by SiO2 flash column chromatography to yield
the protected guanidine (112 mg, 46%). A portion of the material (15 mg)
was treated with 1:1 TFA/DCM as in Example 1: step d. Purification by
HPLC yielded the title compound (9.3 mg, 75%) as a white solid. 1H-NMR
(CD3OD): d 8.36 (s, 1H), 8.04 (m, 2H), 7.71 (m, 2H), 7.35 (d, 1H, J= S.I Hz),
7.27 (d, 1H, J = 1.9 Hz), 7.22 (dd, 1H, J= 1.9, 8.1 Hz), 3.34 (m, 2H), 2.74 (s,
3H), 2.36 (t, 2H, J= 7.4 Hz), 2.29 (s, 3H), 1.70 (rn, 4H), 1.48 (m, 2H). ESI-
MS (m/z): Calcd. for C26H31N5O4S3 (M+H): 574.2; found: 574.2.
a) 4-(4-Amino-3-nitro-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid methyl ester
Sodium sulfite (1.5. g, 11.9 mmol) and NaHCO3 (1.12 g, 13.3 mmol)
were dissolved in water (30 mL) and 4-acetylamino-3-nitro-benzenesulfonyl
chloride (1.94 g, 7 mmol) was added. Ethanol (10 mL) and the mixture was
stirred for 6 h at rt. Aqueous NaOH (10N, 6 mL, 60 mmol) was added and the
reaction was heated to 80 °C for 2 h. The solution was brought to pH-8 with
cone. HC1, and the solvent was removed in vacua. DMF (15 mL) was added,
the mixture was stirred for 15 rnin, and the inorganic salts were then allowed
to settle. The DMF was removed via syringe, the salts were washed with a
second portion of DMF (10 mL), and the combined DMF solution was slowly
added to a 0 °C solution of 4-bromo-5-nitro-thiophene-2-carboxylic acid
methyl ester {{Example 114, step c) 931 mg, 3.5 mmol) in DMF (15 mL). The
solution was stirred for 0 "C for 1 h then overnight at rt. The DMF was
removed in vacuo and the residue was partitioned between EtOAc (100 mL)
and aq NaHCO3 (30 mL). The layers were separated and the organic layer
was washed with aq NaHCO3 (2 x 20 mL), water (30 mL), and brine (30 mL),
then dried over sodium sulfate. The solution was concentrated and the residue
was dissolved in THF (20 mL) and cooled to -78 °C. A solution of sodium
methoxide in methanol (1M, 7 mL, 7 mmol) was added dropwise and the
reaction was stirred for 30 min. Acetic acid (500 µL) was added followed by
EtOAc (100 mL). The solution was washed with NaHCO3 (3 x 30 mL), brine
(40 mL), and was dried over sodium sulfate. Concentration and
chromatography of the residue yielded the title compound (381 mg, 28%) as a
yellow solid. 1H-NMR (CDCl3): d 10.56 (br s, 2H), 9.04 (d, 1H, .J= 8.8 Hz),
8.89 (d, 1H, J= 2.3 Hz), 8.22 (dd, 1H, J= 2.3, 9.1 Hz), 8.04 (s, 1H), 3.90 (s,
3H), 2.64 (s, 3H), 2.35 (s, 3H).
b) 4-(4-Bromo-3-nitro-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid methyl ester
The procedure used in Example 318: part c was followed using 4-(4-
amino-3-nitro-benzenesulfonyl)-5-memylsulfanyl-thiophene-2-carboxylic acid
methyl ester {{Example 264: step a) 100 mg, 0.26 mmol), CuBr2 (73 mg, 0.31
mmol), and tert-butylnitrite (46 µL, 0.39 mmol) in acetonitrile (8 mL total).
The title compound (118 mg, 100%) was used without further purification.
1H-NMR (CDCl3): d 8.46 (m, 1H), 8.03 (m, 2H), 7.94 (d, 1H, J'= 8.4 Hz),
3.90 (s, 3H), 2.65 (s, 3H).
c) 5-Methylsulfanyl-4-{3-nitro-4-[(pyridin-2-ylmethyl)-amino]-
benzenesulfonyl}-thiophene-2-carboxylic acid methyl ester
Pyridin-2-yl-methylamine (60 µL), DIEA (175 µL, 1 mmol), and 4-(4-
bromo-3-nitro-benzenesulfbnyl)-5-methylsulfanyl-thiophene-2-carboxylic
acid methyl ester ((Example 264: step b) 56 mg, 0.12 mmol) were heated at 60
°C in THF (3 mL) for 30 min. The solvent was removed in vacuo and the
residue was purified by SiO2 flash column chromatography to yield the title
compound (41 mg, 69%). 1H-NMR (CDCl3): 8 9.46 (m, 1H), 8.90 (m, 1H),
8.64 (m, 1H), 8.01 (d, 1H, J = 2.6 Hz), 7.94 (m, 1H), 8.03 (m, 2H);, 7.71 (dt,
1H, J = 1.9, 7.7 Hz), 7.28 (m, 2H), 6.95 (d, 1H, J = 9.0 Hz), 4.67 (d, 1H, J =
5.1 Hz), 3.87 (s, 3H), 2.60 (s, 3H).
d) 5-Methylsulfanyl-4-(l-pyridin-2-ylmethyl-lH-benzoimidazole-5-
sulfonyl)-thiophene-2-carboxylic acid methyl ester
The procedure in Example 318: part e was followed using 5-
methylsulfanyl-4-{3-nitro-4-[(pyridin-2-ylmethyl)-amino]-benzenesulfonyl} -
thiophene-2-carboxylic acid methyl ester ((Example 264: step c) 41 mg, 0.08
mmol), iron (110 mg, 2 mmol), and EtOH /aq. AcOH, followed by treatment
with formic acid to yield the title compound. 1H-NMR (CD3OD): d 8.50 (m,
1H), 8.42 (s, 1H), 8.08 (m, 1H), 7.97 (d, 1H, J = 2.5 Hz), 7.85 (m, 1H), 7.72
(m, 1H), 7.71 (dt, 1H, J = 1.9, 7.7 Hz), 7.57 (m, 1H), 7.29 (m, 1H), 7.22 (d, 1H
J = 7.8 Hz), 6.95 (d, 1H, J = 9.0 Hz), 5.57 (s, 2H), 3.82 (s, 3H), 2.56 (s, 3H).
e) 5-Methylsulfanyl-4-(l-pyridin -2-ylm ethyl-1H-benzoimidazole-5-
sulfonyl)-thiophene-2-carboxamidine bis-trifnoroacetate
The procedure in Example 12: step f was followed using 5-
methylsulfanyl-4-(l-pyridin-2-ylmethyl-lH-benzoimidazole-5-sulfonyl)-
thiophene-2-carboxylic acid methyl ester ((Example 264: step d) 36 nig) and 5
mL (5 mmol) of dimethylaluminum amide solution. Analogous workup and
purification yielded the title compound (13.2 mg, 23%) as a white solid. 'H-
NMR (CD3OD): d 8.63 (ddd, 1H, J = 0.9, 1.6, 5.35 Hz), 8.58 (m, 1H), 8.34 (s,
1H), 8.19 (dt, 1H, J = 1.6, 7.8 Hz), 8.08 (dd, 1H, J = 1.6, 8.7 Hz), 7.85 (d, 1H,
J = 8.7 Hz), 7.69 (m, 1H), 7.66 (m, 1H), 5.98 (s, 1H), 2.72 (s, 3H). ESI-MS
(m/z): Calcd. for C19H17N5O2S3 (M+H): 444.1; found: 444.1.
Examples 265-266
4-(3-Benzyl-7-bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate and 4-(l-Benzyl-7-brorao-lH-
benzoiraidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxamidine
trifluoroacetate
a) 4-(3-Benzyl-7-bromo-3H-benzoimidazole-5-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxylic acid methyl ester and 4-(l-Benzyl-7-
bromo-lH-benzoimidazole-5-sulfonyl)-S-methylsulfanyl-thiophene-2-
carboxylic acid methyl ester
The procedure as in Example 39: step a was followed using 4-(7-
bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid methyl ester (20 mg, 44.7 µmol, Example 38: step e), benzyl
bromide (5.3 µL, 44.7 µmol), K2CO3 (12.4 mg, 89.4 µmol), and DMF (1.5
mL). Removal of the solvents in vacuo was followed by preparative TLC (2-4
% 2.0 M NH3 in methanol/CH2Cl2) to afford a mixture of 4-(3-benzyl-7-
bromo-3 H-benzoimidazole-5-sulfonyl)-5-methylsuifanyl-thiophene-2-
carboxylic acid methyl ester and 4-(l-benzyl-7-bromo-lH-benzoimidazole-5-
sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester
compound as a brown oil (27.7 mg, quantitative). This mixture was used
directly in the following step. ESI-MS (m/z): Calcd. for C21H17BrN2O4S3:
536 (M+l); found: 538.9.
b) 4-(3-Benzyl-7-bromo-3H-benzoimidazole-5-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate and 4-(l-
Benzyl- 7-brom o-lH-ben zoim idazole-5-sulfonyl)-5-m ethylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
The mixture from Examples 265-266: step a (27.7 mg, 44.7 µmol)
was converted to the amidine and purified as described in Examples 39-40:
step a to afford the 2 regioisomers: the 3-benzyl (1.6 mg, beige solid) and the
1-benzyl (2.0 mg, white solid). lH-NMR (CD3OD, 3-benzyl): d 9.08 (s, 1H),
8.27 (s, 1H), 8.23 (s, 1H), 8.10 (s, 1H), 7.35-7.45 (m, 5H), 5.70 (s, 2H), 2.58
(s, 3H). ESI-MS (m/z): Calcd. for C20H17BrN4O2S3: 521.0 (M+l); found:
523.0. 1H-NMR (CD3OD, 1-benzyl): 6 S.73 (s, 1H), 8.44 (s, 1H), 8.32 (s,
1H), 8.10 (s, 1H), 7.27-7.37 (m, 3H), 7.06-7.11 (m, 2H), 5.93 (s, 2H), 2.72 (s,
3H). ESI-MS (m/z): Calcd.. for C20H17BrN4O2S3: 521.0 (M+l); found: 523.0.
Example 267-268
4-(3-Allyl-7-bromo-3H-berizoimidazole-5-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate and 4-(l-Allyl-7-bromo-3H-
benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxamidine
trifluoroacetate
a) 4-(3-Allyl-7-bromo-3H-benzoimidazole-5-sulfonyi)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester and 4-(l-Allyl-7-bromo-lH-
benzoiinidazole-S-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid
methyl ester
The procedure as in Example 39: step a was followed using 4-(7-
bromo-3i^-benzoimida2:ole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid methyl ester (2.0 mg, 44.7 jamol, Example 38: step e), ally!
bromide (3.9 jiL, 44.7 jimol), K2CO3 (12.4 mg, 89.4 fimol), and DMF (1.5
mL). The crude was purified by preparative TLC (2-4 % 2.0 M NH3 in
methanol/CH2Cl2) to afford a mixture of 4-(3-allyl-7-bromo-3H-
benzoim.idazole-5-sulfonyl)-5-methylsulfanyl-thiiophene-2-carboxylic acid
methyl ester and 4-(l-allyl-7-bromo-lH-benzoimidazole-5-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxylic acid methyl ester as a brown oil (22.4
mg, quantitative). This mixture was used directly in the following step. ESI-
MS (m/z): Calcd. for CnH^BrNsCljSa: 486.9 (M+l); found: 488.9.
b) 4-(3-Allyl-7-bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate and 4-(3-Allyl-7-bromo-3H-
benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxamidine
trifluoroacetate
The mixture from Example 267-268: step a (22.4 mg, 44.7 famoi) was
converted to the amidine and purified as described in Example 20; step b to
afford the 2 regioisomers: the 3-allyl (1.0 mg, beige solid) and the 1-allyl (2.5
mg, beige solid). 1H-NMR (CD3OD, 3-allyl): d 8.54 (s, 1H), 8.31-8.34 (m,
2H), 8.04-8.05 (m, 1H), 6.05-6.14 (m, 1H), 5.33-5.36 (m, 1H), 5.21-5.26 (m,
1H), 5.05-5.0S (m, 2H), 2.71 (s, 3H). ESI-MS (m/z): Calcd. for
Ci6H,5BrN4O2S3: 471.0 (M+l); found: 473.0. !H-NMR (CD3OD. 1-allyl):
d 8.31-8.55 (m, 3H), 8.05-8.11 (m, 1H), 6.10-6.22 (m, 1H), 4.92-5.32 (m,
4H), 2.72 (s, 3H). ESI-MS (m/z): Calcd. for CieHisBrN^Sj: 471.0 (M+l);
found: 473.0.
Example 269
4-(7-Bromo-3-phenyl-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
a) 4-(7-Bronw-3-phenyl-3H-benzoimidazole-5-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxylic acid methyl ester
4-(7-Bromo-3-phenyl-3H-benzoimidazole-5-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxylic acid methyl ester was prepared
according to literature (Lam, P. Y. S. et al., Tetrahedron Letters, 42:3415
(2C 01)) using 4-(7-broma-3J7-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester (20 mg, 44.7 µmol, Example 38: step
e), phenylboronic acid (1L4 mg, 93.5 µmol), Cu(OAc)2 (8.5 rag, 46.S µmol),
pyridine N-oxide (4.7 mg, 49.2 jamol), triethylamine (13jliL, 93.3 µmol), and
CH2Cl2 (1.5 mL) in a loosely-capped, 1-dram vial. The reaction mixture was
diluted in CH2Cl2 and washed with water and brine. The organic layer was
dried over magnesium sulfate. Removal of solvents in vacuo followed by
preparative TLC afforded the title compound as a brown oil (12 mg, 51%).
ESI-MS (m/z): Calcd. for C20H15BrN2O4S3: 522.9 (M+l); found: 525.0.
b) 4-(7-Bromo-3-phenyl-3H-benzoimidazole-5-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
4-(7-Bromo-3-phenyl-3H-benzoimidazole-5-suifonyl)-5-
methylsulfanyl-thiophene-2-carboxylic acid methyl ester (12 mg, 22.9 µmol)
was converted to the amidine and purified as described in Example 20: step f
to afford the title compound as a beige solid (1.6 mg, 14 %). 1H.-NMR
(CD3OD): d S.80 (s, 1H), S. 13-8.32 (m, 3H), 7.63-7.74 (m, 5H), 2.73 (s, 3H).
ESI-MS (m/z): Calcd. for C19H15BrN4O2S3: 507.0 (M+l); found: 509.0.
Example 2 70-271
4-(7-Bromo-3-cyclopropylmethyl-3H-benz;oimidazole-5-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxainidine trifluoroacetate and 4-(7-Bromo-
l-cyclopropylmethyl-lH-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-
thiophene-2-c arboxaniidine tri fluoroacetate
a) 4-(7-Bromo-3-cyclopropylmethyl-3H-benzoimidazole-5-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxylic acid ethyl ester
The procedure as in Example 39: step a was followed using 4-(7-
bromo-3/f-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid ethyl ester (100 mg, 0.217 mmol, Example 38: step e),
(bromomethyl)cyclopropane (21 µL, 0.217 mmol), K2CO3 (60 mg, 0.434
mmol), and DMF (3 mL). The crude was purified by preparative TLC (2-4 %
2.0 M NH3 in methanol/CH2Cl2) to afford a mixture of 4-(7-bromo-3-
cyclopropylmethyl-3H-beniioimidazole-5-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid ethyl ester and 4-(7-bromo-l-cyclop.ropylmethyl-
lH-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid
ethyl ester as a brown oil (72 mg, 64 %). This mixture was used directly in
the following step. ESI-MS (m/z): Calcd. for C18H17BrN2O4S3: 515 (M+l);
found: 516.9.
b) 4-(7-Bromo-3-cyclopropylmethyl-3H-benzoimidazole-5-tnilfonyl)-5-
methylsulfanyl-thiophene-2-earboxamidine trifliioroacetate and 4-(7-
Bromo-l-cyclopropylmethyl-lH-benzoimidazole-S-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoloacetate
The mixture from Examples 270-271: step a (72 mg, 0.14 mmoi) was
converted to the amidine and purified as described in Examples 39-40: step b
to afford 2 regioisomers: the 3-cyclopropylmethyl (3-CPM) (2.S mg, beige
solid) and the 1-cyclopropylmethyl (1-CPM) (3,3 mg, beige solid). 1H-NMR
(CD3OD, 3-CPM): d 8.63 (s, 1H), 8.40 (d, 1H, J = 1.40 Hz), 8.35 (s, 1H),
8.05 (d, 1H, J= 1.40 Hz), 4.27 (d, 2H, J= 7.21 Hz), 2.72 (s, 3H), 135-1.42(m,
1H), 0.68-0.73 (m, 2H), 0.5-0.54 (m, 2H). ESI-MS (m/z): Calcd. for
C17H17BrN4O2S3: 485.0 (MM); found: 4S7.0. 1H-NMR (CD3OD, 1-CPM):
d 8.55 (s, 1H), 8.37-8.38 (m, 1H), 8.34 (s, 1H), 8.10-8.11 (m, 1H)7 4 52 (d,
2H, J= 7.21 Hz), 2.72 (s, 3H), 1.43-1.51 (m, 1H), 0.62-0.67 (m, 2H), 0.47-
0.52 (m, 2H). ESI-MS (m/z): Calcd. for C17H17BrN4O2S3: 485.0 (M+1);
found: 487.0.
Examples 272-273
4-[7-Bromo-3-(2,6-dichloro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate and 4-[7-Bromo-
l-(2,6-dichloro-benzyl)-lH-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-
thiophene- 2-carboxamidine tif luoroacetate
a) 4-[7-Bromo-3-(2,6-dichloro-benzyl)-3H-benzoimidazole-5-sulfonyl]-
5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester and 4-[7-Bromo-1-
(2,6-dichloro-benzyl)-lH-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-
thiophene-2-carboxylic acid ethyl ester
The procedure as in Example 39: step a was followed using 4-(7-
bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid ethyl ester (100 nig, 0.217 minol, Example 38: step e), 2-
bromomethyl-l,3-dichloro-benzene (52 mg, 0.217 mmol), K2CO3 (60 mg,
0.434 mmol), and DMF (3 mL). The crude was purified by preparative TLC
(2-4 % 2.0 M NH3 in methanoly/CH2Cl2) to afford a mixture of 4-[7-bromo-3-
(2,6-dichloro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-
thiophene-2-carboxylic acid ethyl ester and 4-[7-bromo-l-(2.6-dichloro-
benzyl)-lH-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophene-2-
carboxylic acid ethyl ester as brown oil (70 mg, 52.2 %). This mixture was
used directly in the following step. ESI-MS (m/z): Calcd. for
C21H,5BrCl2N2O4S3: 618.9 (M+1); found: 620.9.
b) 4-[7-Bromo-3-(2,6-dichloro-benzyl)-3H-benzoimidazole-5-snlfonyl]-
5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate and 4-[7-
Bromo-l-(2,6-dichloro-benzyl)-lH-benzoimidazole-5-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidiiie tifluoroacetate
The mixture from Examples 272-273: step a (70 mg, 0.11 mmol) was
converted to the amidine and purified as described in Examples 39-40: step b
to afford 2 regioisomers: the 3-(2,6-dichlorobenzyl) (3-DCB) (2.5 mg, beige
solid) and the l-(2,6-dichlorobenzyl) (1-DCB) (2.2 mg, beige solid). 1H-NMR
(CD3OD, 3-DCB): d 8.58 (s, 1H), 8.30-8.33 (m, 2H), 8.00 (d, 1H, J= 1.63
Hz), 7.55-7.58 (m, 2H), 7.44-7.49 (m, 1H), 5.90 (s, 2H), 2.64 (s, 3H). ESI-MS
(m/z): Calcd. for C20H15BrCl2N4O2S3: 588.9 (M+1); found: 590.9. ]H-NMR
(CD3OD, 1-DCB): § 8.34-8.40 (m, 2H), 8.16-S.1S (m, 1H), 7.86-7.90 (m,
1H), 7.46-7.60 (m, 3H), 6.22 (s, 2H), 2.64 (s, 3H). ESI-MS (m/z): Calcd. for
C20H15BrCl2N4O2S3: 588.9 (M+1); found: 590.9.
Examples 274-275
4-[7-Bromo-3-(2,5-difluoro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidme trifluoroacetate and 4-[7-Bromo-
l-(2,5-difluoro-benzyl)1H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-
tWophene-2-carboxamidine trifluoroacetate
a) 4-[7-Bromo-3-(2,5-difluoro-benzyl)-3H-benzoimidazole-5-sulfonyl]-
5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester and 4-[7-Bromo-l-
(2,5-difluoro-benzyl)1H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-
thiophene-2-carboxylic acid ethyl ester
The procedure as in Example 39: step a was followed using 4-(7-
bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid ethyl ester (100 mg, 0.217 minol, Example 3S: step e), 2-
bromomethyl-l,4-difluoro-benzene (28 µL, 0.217 mmol), K2CO3 (60 mg,
0.434 nµmol), and DMF (3 mL). The crude was purified by preparative TLC
(2-4 % 2.0 M NH3 in methanol/CH2Cl2) to afford a mixture of 4-[7-bromo-3-
(2,5-difluoro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-
thiophene-2-carboxylic acid ethyl ester and 4-[7-bromo-l-(2,5-difluoro-
benzyl)1H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophene-2-
carboxylic acid ethyl es;ter as a brown oil (70 mg, 55 %).. This mixture was
used directly in the next step. ESI-MS (m/z): Calcd. for C21H15BrF2N2O4S3:
586.0 (M+1); found: 588.9.
b) 4-[7-Bromo-3-(2,5-diftuoro-benzyl)-3H-benzoimidazole-5-sulfonyl]-
5-methylsulfanyl-thiophene-2-carboxamiditte trifluoroacetate and 4-[7-
Bromo-l-(2,5-difluoro-benzyl)1H-benzoimidazole-5-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidwetrifluoroacetate
The mixture from Examples 274-275: step a (70 mg, 0.12 mmol) was
converted to the amidine and purified as described in Examples 39-40: step b
to afford 2 regioisomers: the 3-(2,5-difluorobenzyl) (3-DFB) (3.0 mg, white
solid) and the l-(2,5-difluorobenzyl) (1-DFB) (3.2 mg, white solid). 1H-NMR
(CD3OD, 3-DFB): d 8.58 (s, 1H), 8.30-S.33 (m, 2H), 8.00 (d, IB., J = 1.63
Hz), 7.55-7.58 (m, 2H), 7.44-7.49 (m, 1H), 5.90 (s, 2H), 2.64 (s, 3H). ESI-MS
(m/z): Calcd. for C2oHi5BrCl2N402S3: 588.9 (M+1); found: 590.9. 1H-NMR
(CD3OD, 1-DFB): d 8.57 (s, 1H), 8.41-8.45 (m, 1H), 8.32-8.36 (m, 1H), 8.07-
S.ll (m, 1H), 7.05-7.27 (m, 2H), 6.43-6.54 (m, 1H), 5.94 (s, 2H), 2.72 (s, 3H).
ESI-MS (m/z): Calcd. for C20H15BrCl2N4O2S3: 588.9 (M+1); found: 590.9.
Examples 276-277
4-[7-Bromo-3-(2,6-difluoro-benzyl)-3H-benzoimidazole-5-sulfonyl]-5-
methylsulfanyl-thiophene-2-cai-boxamidine trifiuoroacetate and 4-[7-Bromo-
l-(2,6-difluoro-benzyl)1H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
a) 4-[7-Brom o-3-(2,6-difluoro-benzyl)-3H-benzoimidazole-5-sulfonyl]-
5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester and 4-[7-Bromo-
l-(2,6-difluoro-benzyl)1H-benzoimidazole-5-sulfonyl]-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester
The procedure as in Example 39: step a was followed using 4-(7-
bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid methyl ester (50 mg, 0.11 rrµmol, Example 38: step e), 2-
bromomethyl-l,3-difluoro-benzene (23 mg, 0.11 mmol), K2CO3 (31 mg, 0.22
mmol), and DMF (1.5 mL). The crude was purified by preparative TLC (2-4
% 2.0 M NH3 in methano]yCH2Cl2) to afford a mixture of 4-[7-bromo-3-(2,6-
difluoro-benzyl)-3H-benzoi:tnidazole-5-sulfonyl]-5-methylsulfanyl-thiophene-
2-carboxylic acid methyl ester and 4-[7-bronio-l-(2,6-difluoro-benzyl)1H-
benzoimidazole-5-sulfonyl]-5-methylsulfanyl-thiophene-2-carboxylic acid
methyl ester as a brown oil (67 mg, quantitative). ESI-MS (m/z): Calcd. for
C21H15BrF2N2O4S3: 572.9 (M+1); found: 574.9.
b) 4-[7-Bromo-3-(2,6-difluoro-benzyl)-3H-benzoimidazole-5-sulfonyl]-
5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate and 4-[7-
Bromo-l-(2,6-difluoro-benzyl)1H-benzoiniidazole-5-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
The mixture from Examples 276-277: step a (67 mg, 0.11 rrunol) was
converted to the amidine and purified as described in Example 39-40: step a to
afford 2 regioisomers: the 3-(2,6-difluorobenzyl) (3-DFB) (3.5 mg. beige
solid) and the l-(2,6-difluorobenzyl) (1-DFB) (1.6 mg? white solid). 1H-NMR
(CD3OD, 3-DFB): d 8.64 (s, 1H), 8.31-S.35 (m, 2H), 8.02 (s, 1H). 7.45-7.54
(m, 1H), 7.08-7.14 (m, 2H), 5.74 (s, 2H), 2.65 (s, 3H). ESI-MS (m/'z): Calcd.
for C20H15BrF2N402S3: 556.0 (M+1); found: 559.0. 1H-NMR (CD3OD,
1-DFB): d 8.42 (s, 1H), 8.35-S.37 (m, 1H), 8.32 (s, 1H), 7.39-7.4S (m, 1H),
6.99-7.06 (m, 1H), 7.03 (t, 2H, J= 8.34), 6.02 (s, 2H), 2.71 (s, 3H). ESI-MS
(m/z): Calcd. for C20H15BrF2N4O2S3: 556.0 (M+1); found: 559.0.
Example 278
6-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-(4-
carboxy-butyrylamino)-6-methyl-biphenyl-4-yl]-ureido}-hexanoic acid
trifluoroacetate
a) 6-[3-(4-Bromo-3-methyl-5-nitro-phenyl)-ureido]-hexanoic acid ethyl
ester
6-Isocyanato-hexanoic acid ethyl ester (370 p.L, 2.16 mmol) was added
to a solution of 4-bromo-3-methyl-5-nitro-phenylamine (250 mg, 1.08 mmol,
Example 135: step a) in CH2Cl2 (5 mL, anhydrous) at rt. The reaction mixture
was stirred overnight, then diluted in EtOAc and washed with saturated NH4Cl
solution, water, and brine. The organic layer was dried over magnesium
sulfate. Removal of solvents in vacuo was followed by flash chromatography
(50-75% EtOAc/hexanes) to afford the title compound as a brown oil (162 mg,
36%). 1H-NMR (CDCl3): d 7.59 (d, 1H, J = 2.56 Hz), 7.42-7.48 (m, 1H),
4.10-4.17 (m, 2H), 3.20-3.28 (m, 2H), 2.39 (s, 3H), 2.29-2.35 (m, 2H), 1.47-
1.68 (m, 4H), 1.23-1.41 (m, 5H).
b) 6-(3-{3'-[5-(tert-Buioxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-2-nitro-biphenyl-4-yl}-
ureido)-hexanoic acid ethyl ester
A 25 mL round bottom flask was charged with 6-[3-(4-bromo-3-
methyl-5-nitro-phenyl)-ureido]-hexanoic acid ethyl ester (110 mg, 0.264
mmol, Example 278: step a), {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5-
methylsulfanyl-tbiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(234 mg, 0.529 mmol, Example 140: step a), aqueous Na2CCh (2M, 1.06 mL,
2.12 mmol), ethanol (1.06 mL, anhydrous) and toluene (2.11 mL, anhydrous).
A stir bar was added, the solution was degassed for 10 min, and Pd(PPh3 )4 (76
mg, 65.8 µmol) was added. The reaction mixture was stirred under Ar at 80 °
C for 5 hrs, then cooled to rt. The solvents were removed in vacuo. The
residue was diluted in EtOAc, washed with brine, and dried over magnesium
sulfate. Removal of solvents in vacuo followed by preparative TLC (50-100%
EtOAc/hexanes) afforded the title compound as a brown oil (74 mg, 37%).
ESI-MS (m/z): Calcd. for C33H41N5O9S3: 748.2 (M+1); found: 747.8.
c) 6-(3-{2-Amino-3'-[5-(tert-butoxycarbonylamino-imino-methyl)-2-
methylsnlfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-4-yl}-ureido)-
hexanoic acid ethyl ester
6-(3- {3'-[5-(/e/t-Butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-2-nitro-biphenyl-4-yl}-
ureido)-hexanoic acid ethyl ester (74 mg, 98.9 µmol, Example 278: step b) in
EtOH (5 mL) was reduced as in Example 20: step c using Fe (28 mg, 0.50
mmol) and aqueous NH4Cl solution (50 mg, 0.93 mmol, 10 mL). The solvents
were removed from the filtrate in vacuo. The crude was diluted in EtOAc and
washed with water and brine. The organic layer was dried over magnesium
sulfate. The solvents were removed in vacuo to yield the title compound as a
brown oil (70.8 mg, quantitative). ESI-MS (m/z): Calcd. for C33H43N5O7S3:
718.2 (M+1); found: 718,1.
d) 6-{3-[3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-2-(4-methoxycarbonyl-butyrylamino)-
6-methyl-biphenyl-4-yl]-ureido}-hexanoic acid ethyl ester
4-Chlorocarbonyl-butyric acid methyl ester (20.4 µL, 0.148 mmol) was
added to a solution of 6-(3-{2-amino-3'-[5-(re;-r-butoxycarbonylamino-imino-
methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-4-yl}-
ureido)-hexanoic acid ethyl ester (70.8 mg, 96.4 µmol, Example 278: step c)
and triethylamine (41.2 µL, 0.296 nimol) in CH2Cl2 (5 mL, anhydrous) at rt.
The reaction mixture was stirred overnight at rt, then diluted in EtOAc,
washed with water and brine, and dried over magnesium sulfate. Removal of
solvents in vacuo followed by flash chromatography (75-100 %
EtOAc/hexanes) yielded the title compound as a brown oil (45.5 mg, 54.5%).
ESI-MS (m/z): Calcd. for C39H51N5O10S3: 846.3 (M+1); found: 845.9.
e) 6-{3-[3'-[5-(tert-Butoxycarbonylamino-imitw-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-2-(4-carboxy-butyrylamino)-6-methyl-
biphenyl-4-yl]-ureidoj-hexanoic acid
Lithium hydroxide (53.8 |U.L, 0.215 mmol. 4N aqueous) was added to a
solution of 6-{3-[3'-[5-(tert-butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-2-(4-methoxycarbonyl-butyrylamino)-6-
methyl-biphenyl-4-yl]-ureido}-hexanoic acid ethyl ester (45.5 mg, 53.8 µmol,
Example 278: step d) in MeOH/H2O (10 mL, 2:1) at 0 °C. The reaction
mixture was warmed to rt and stirred overnight. The solvents were removed
in vacuo to afford the title compound as a yellow solid (50 mg, quantitative).
ESI-MS (m/z): Calcd. for C36H45N5O10S3: 804.2 (M+1); found: 803.9.
f) 6-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-$ulfonyl)-
2-(4-carboxy-butyrylamino)-6-inethyl-biphenyl-4-yl]-ureido}-hexanoicacid
trifluoroacetate
6-{3-[3'-[5-(te7t-ButoxycarbonylaiTiino-iinino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-2-(4-carboxy-butyrylamino)-6-methyl-
biphenyl-4-yl]-ureido}-hexanoic acid (43.2 mg, 53.7 (imol, Example 278: step
e) was deprotected and purified as in Example 1: step d to afford the title
compound as a white solid (15 mg, 40 %). 1H-NMR (CD3OD): d 8.27 (s,
1H), 8.00-8.04 (m, 1H), 7.87-7.89 (m, 1H), 7.63-7.71 (m, 1H). 7.49-7.54 (m.
1H), 7.32-7.35 (m, 1H), 7.25-7.26 (m, 1H), 3.22 (t, 2H, J= 6.98 Hz), 2.73 (s,
3H), 2.34 (t, 2H, J = 7.44 Hz), 2.05 (s, 3H), 1.88-2.03 (m, 4H). 1.54-1.71 (m,
4H), 1.34-1.48 (m, 4H). ESI-MS (m/z): Calcd. for C31H37N5O8S3: 704.2
(M+1); found: 704.1.
Example 279
6-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-(4-
methanesulfonyl-butyrylamino)-6-methyl-biphenyl-4-yl]-ureido}-hexanoic
acid trifluoroacetate
a) 6-{3-[3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-2-(4-methanesulfonyl-butyrylamino)-
6-methyl-biphenyl-4-yl]-ureido}-hexanoic acid ethyl ester
The procedure as in Example 278: step d was followed using 6-{3-[3'-
[5-(tert-butoxycarbonylamino-imino-rnethyl)-2-rnethylsulfanyl-thiophene-3-
sulfonyl]-2-(4-methanesulfonyl-butyrylamino)-6-methyl-biphenyl-4-yl]-
ureido}-hexanoic acid ethyl ester (39 mg, 54.3 µmol, Example 278: step b),
triethylamine (22.7 µL, 0.163 mmol), 4-methanesulfonyl-butyryl chloride (15
mg, 81.5 µmol, Example 209: step a), and CH2C12 (3 mL, anhydrous). The
reaction mixture was diluted in EtOAc, washed with water and brine, and
dried over magnesium sulfate. The solvents were removed in vacuo to afford
the title compound as a brown oil (48 mg, quantitative). ESl-MS (m/z):
Calcd. for C38H51N5O10S4: 866.3 (M+1); found: 865.8.
b) 6-{3-[3'-[5-(tert-Butoxycarbonylamwo-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-2-(4-methanesulfonyl-buty}ylanrino)-
6-methyl-biphenyl-4-yl]-ureido}-hexanoic acid
The procedure as in Example 278: step e was followed using 6-{3-[3'-
[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-
sulfonyl]-2-(4-methanesulfonyl-butyrylamino)-6-methyl-biphenyl-4-yl]-
ureido}-hexanoic acid ethyl ester (48 mg, 54.3 µmol, Example 279: step a) in
a MeOH/H2O (2:1) solution and 4N LiOH (54.3 µL, 0.217mmol). The crude
was taken on directly to the next step. ESI-MS (m/z): Calcd. for
C36H47N5O10S4: 838.2 (M+1); found: 837.8.
c) 6-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-
2-(4-methanesulfonyl-butyrylamino)-6-methyl-biphenyl-4-yl]-ureido}-
hexanoic acid trifluoroacetatc
6-{3-[3'-[5-(rer/-Butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-2-(4-methanesulfonyl-butyrylamino)-6-
methyl-biphenyl-4-yl]-ureido}-hexanoic acid (45.5 mg, 54,3 µmol, Example
279; step b) was deprotected and purified as in Example 1: step d to afford the
title compound as a beige solid (10 mg, 25 %). 1H-NMR (CD3OD): d 8.30 (s,
1H), 8.01-8.05 (m, 1H), 7.86-7.89 (m, 1H), 7.68 (t, 1H, J = 7.91 Hz), 7.52-
7.57 (m, 1H), 7.23-7.37 (m:, 2H), 3.23 (t, 2H, J=- 6.98 Hz), 2.92 (s, 3H), 2.80
(t, 2H, J= 7.68 Hz), 2.74 (s, 3H), 2.34 (t, 2H, J= 7.44 Hz), 2.18 (t, 2H, J =
7.21 Hz), 2.05 (s, 3H), 1.72-1.79 (m, 2H), 1.63-1.71 (m, 2H), 1.54-1.62 (m,
2H), 1.39-1.47 (m, 2H). ESI-MS (m/z): Calcd. for C31H39N5O8S4: 738.2
(M+1); found: 738.1.
Example 280
4-{2'-Methy]-4'-[N'-(3-phenyl-propyl)-guanidino]-biphenyl-3-sulfonyl}-5-
methylsulfanyl-thiophene-2-carboxamidine bistrifluoroacetate
a) l,3-bis(tert-butoxycarbonyl)-3-(3-phenylpropyl)-2-methyl-2-
thiopseiidourea
Sodium hydride (95.Smg, 2.40 mmol, 60% dispersion in mineral oil)
was added to a solution of l,3-bis(tert-butoxycarbonyl)-2-rnethyl-2-
thiopseudourea (580 mg, 2.0 mmol) in DMF (4 mL, anhydrous) at 0 °C in 2
portions. The reaction mixture was stirred for 10 rain, at 0 °C, then (3-bromo-
propyl)-benzene (607 µL, 3.99 mmol) was added and the reaction mixture was
heated to 60 °C for 16 hr". The reaction mixture was cooled to rt, diluted in
EtOAc, and washed with water and brine. The organic layer was dried over
magnesium sulfate. Removal of solvents in vacuo was followed by
preparatory TLC (5-10% EtOAc/hexanes) to afford the title compound as a
pale yellow oil (310 mg, 38%). 1H-NMR (CDCl3): d 7.16-7-30 (m, 5H), 3.53-
3.58 (m, 2H), 2.62-2.66 (m, 2H), 2.38 (s, 3H), 1.95-2.05 (m, 2H), 1.5 (s, 9H),
1.46 (s,9H).
b) 4-{4'-[N\N' - bis(tert-butoxycarbonyl)-N'-(3-phenyl-propyl)-
guanidino]-2'-methyl-biphenyl-3-sulfonyl}-N-methyl-5-methylsulfanyl-
thiophene-2-carboxamidine
{[4-(4'-Amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (40 mg, 77.3
µmol, Example 220: step b) and l,3-bis(tert-butoxycarbonyl)-3-(3-
phenylpropyl)-2-methyl-2-thiopseudourea (63 mg, 0.154 mmol. Example 280:
step a) were dissolved in 5 % acetic acid/MeOH (1.5 mL) solution and heated
to 40 ° C overnight. The reaction mixture was cooled to it and the solvents
were removed in vacuo. The crude was purified by preparative TLC (5-10 %
EtOAc/CH2Cl2) to afford the title compound as a red oil (26.9 mg. 40%). ESI-
MS (m/z): Calcd. For C44H55N5O8S3: 878.3 (M+1); found: 877.9.
c) 4-{2'-Methyl-4'-[N'-(3-phenylpropyl)-guanidino]-biphenyl-3-
sulfonyl}-5-methylsulfanyl-thwphene-2-carboxamidinebistrifluoroacetate
4-{4'-[N',N"- bis(toY-Butoxycarbonyl)-N'-(3-phenyl-propyl)-
guanidino]-2'-methyl-biphenyl-3-sulfonyl}-N-methyl-5-methylsulfanyl-
thiophene-2-carboxamidine (26.9 mg, 30.6 {imol, Example 280: step b) was
deprotected and purified as in Example 1: step d to afford the title compound
as a white solid (11 mg, 62 %). 1H-NMR (CD3OD): d 8.34 (s, 1H), S.00-8.04
(m, 2H), 7.69-7.73 (m, 2H), 7.17-7.34 (m, 8H), 3.30-3.34 (m, 2H), 2.71-2.76
(m, 5H), 2.27 (s, 3H), 1.93-2.02 (m, 2H). ESI-MS (m/z): Calcd. for
C29H3JN5O7S3: 578.2 (M+1); found: 57S.2.
Example 281
4-[2'-Methyl-4'-(N'-phenethyl-guanidino)-biphenyl-3-sulfony]]-5-
methylsulfanyl-thiophene-2-carboxamidine bistrifluoroacetate
a) l,3-bis(tert-butoxycarbonyl)-3-(3-phenylethyl)-2-methyl-2-
thiopseudourea
The procedure as in Example 280: step a was followed using 1,3-
bis(re/'/-butoxycarbonyl)-2-methyl-2-thiopseudourea (580 mg, 2.0 mmol),
NaH (95.8mg, 2.40 mmol, 60% dispersion in mineral oil), (2-iodo-ethyl)-
benzene (578 yiL, 3.99 mmol), and DMF (4 mL, anhydrous). The reaction
mixture was cooled to rt, diluted in EtOAc, and washed with water and brine.
The organic layer was dried over magnesium sulfate. Removal of solvents in
vacuo was followed by preparatory TLC (5-10% EtOAc/hexanes) to afford the
title compound as a pale yellow oil (146 mg, 19%). 1H-NMR (CDCl3):
d 7.18-7.33 (m, 5H), 3.71-3.75 (m, 2H), 2.96-3.01 (m, 2H), 2.37 (s, 3H), 1.51
(s,9H), 1.49(s,9H).
b) ({4-[4'-(N',N"-bis(tert-butoxycarbonyl)-N'-phenethyl-guanidino)-2'-
methyl-biphenyl-3-sulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-
carbamic acid tert-butyl ester
The procedure as in Example 280: step b was followed using {[4-(4'-
amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-
methyl}-carbamic acid tert-butyl ester (40 mg, 77.3 µmol, Example 220: step
b), l,3-bis(tert-butoxycarbonyl)-3-(3-phenylethyl)-2-methyl-2-thiopseudourea
(61 mg, 0.155 mmol, Example 281: step a), and 5 % acetic acid/MeOH (1.5
mL) solution. The reaction mixture was cooled to rt, then concentrated in
vacuo. The crude was purified by preparative TLC (5-10 % EtOAc/CH:Cl2)
to afford the title compound as a red oil (31.5 mg, 47%). ESI-MS (m/z):
Calcd. for C13H53N5O8S3: 864.3 (M+1); found: 863.9.
c) 4-[2f-Methyl-4'-(N'-phenethyl-guaniduw)-biplienyl-3-sulfonylJ-5-
methylsulfanyl-thiophene-2-carboxamidine bistrifluoroacetate
({4-[4'-(N',N"-bis(tert-butoxycarbonyl)-N'-phenethyl-guanidino)-2'-
methyl-biphenyl-3-suIfbnyl] -5-rnethy3sulfanyl-thiophen-2-yl} -imino-methyl)-
carbamic acid tert-butyl ester (31.5 mg, 36.5 µmol, Example 281: step b) was
deprotected and purified as in Example 1: step d to afford the title compound
as a white solid (14.2 mg, 68.9 %). 1H-NMR (CD3OD): d 8.34 (s, ] H), 7.99-
8.05 (m, 2H), 7.65-7.72 (m, 2H), 7.24-7.39 (m, 6H), 7.03-7.09 (m, 2H), 3.60
(t, 2H, J= 7.02 Hz), 2.96 (t, 2H, J= 7.02 Hz), 2.72 (s, 3H), 2.23 (s, 3H). ESI-
MS (m/z): Calcd. for C28H29N5O2S3: 564.2 (M+1); found: 564.2.
Example 282
4-{21-Methy]-4'-[N'-(3-methy]-butyl)-guanidino]-bipheny]-3-sulfonyl]}-5-
methylsulfanyl-thiophene-2-carboxamidinebistrifluoroacetate
a) l,3-bis(tert-butoxycarbonyl)-3-(3-phetiylethyl)-2-methyl-2-
thiopseudonrea
The procedure as in Example 280: step a was followed using 1,3-
bis(te/t-butoxycarbonyl)-2-methyl-2-thiopseudourea (580 mg, 2.0 mmol),
NaH (95.8mg, 2.40 mmol, 60% dispersion in mineral oil), l-iodo-3-methyl-
butane (528 \xL, 3.99 mmol), and DMF (4 mL, anhydrous). The reaction
mixture was cooled to rt, diluted in EtOAc, and washed with water and brine.
The organic layer was dried over magnesium sulfate. Removal of solvents in
vacuo was followed by preparatory TLC (5-10% EitOAc/hexanes) to afford the
title compound as a pale yellow oil (235 mg, 33%). 1H-NMR (CDCl3):
d 3.49-3.56 (m, 2H), 2.39 (s, 3H), 1.52-1.60 (m, 3H), 1.51 (s, 9H), 1.48 (s,
9H), 0.89-0.94 (m, 6H).
b) 4-{4 r-[N',N'-bis(tert-butoxycarbonyl)-N'-(3-methyl-butyl)-
guamdino]-2'-methyl-biphenyl-3-sulfonyl}-N-tert-butoxycarbonyl-S-
m ethylsulfanyl-th ioph en e-2-carboxant idin e
The procedure as in Example 280: step b was followed using {[4-(4'-
amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-
methyl}-carbamic acid tert-butyl ester (40 mg, 77.3 µmol, Example 220: step
b), l,3-bis(tert-butoxycarbonyl)-l-(3-methylbutyl)-2-methyl-2-thiopseudourea
(56 mg, 0.155 mmol, Example 282: step a), and 5 % acetic acid/MeOH (1.5
mL) solution. The reaction mixture was cooled to rt, then concentrated in
vacuo. The crude was purified by preparative TLC (5-10 % EtOAc/CH:Cl2)
to afford the title compound as a red oil (29.2 nig, 46 %). ESI-MS (m/z):
Calcd. forC40H55N5O8S3: 830.3 (M+1): found: 829.9.
c) 4-{2'-Methyl-4'-[N'-(3-phenyl-propyl)-guanidino]-biphenyl-3-
sulfonylf-5-m ethylsulfanyl-thiophene-2-carboxamidine bistrifluoroacetate
4-{4'-[N',N"-bis(/erf-Butoxycarbonyl)-N'-(3-methyl-butyl)-guanidino]-
2'-methyl-biphenyl-3-sulfonyl}-N-te7-r-butoxycarbonyl-5-methylsulfanyl-
thiophene-2-carboxamidine (29.2 mg, 35.2 jimol, Example 282: step b) was
deprotected and purified as in Example 1: step d to afford the title compound
as a white solid (13.6 mg, 73 %). 1H-NMR (CD3OD): d 8.34 (s, 1H), 8.00-
8.05 (m, 2H), 7.67-7.73 (m, 2H), 7.18-7.34 (m, 3H), 3.30-3.34 (m, 2H), 2.72
(s, 3H), 2.27 (s, 3H), 1.66-1.79 (m, 1H), 1.52-1.59 (m, 2H), 0.99 (d, 6H, J =
6.64 Hz). ESI-MS (m/z): Calcd. for C25H31N5O2S3: 530.2 (M+1); found:
530.2.
Example 283
4-(5-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfanyl)-4-
guanidino-6-methyl-biphenyl-2-yl]-ureido}-pentyloxy)-benzoic acid
bistrifluoroacetate
a) 4-[5-(l,3-Dioxo-l,3-dihydro-isoindol-2-yl)-petityloxy]-benzoic acid
methyl ester
A mixture of 4-hydroxy-benzoic acid methyl ester (3.01 g, 19 8 mmol),
2-(5-bromo-pentyl)-isoindole-l,3-dione (3.9 g, 13.2 rnmol), and K1CO3 (1.82
g, 13.2 rnmol) in acetone (150 mL) was heated to reflux for 24 hrs. The
reaction mixture was cooled to rt and the solvents were removed in vacuo.
The crude was diluted in EtOAc: and washed with 1N NaOH and brine. The
organic layer was dried over sodium sulfate. The solvents were removed in
vacuo. The crude was recrystallized from EtOAc to afford the title compound
as a white solid (4 g, 83%). 1H-NMR (CDCh): d 7.95-7.98 (m, 2H), 7.83-
7.86 (m, 2H), 7.70-7.73 (m, 2H), 6.86-6.89 (m, 2H), 4.00 (t, 2H, J= 6.22 Hz),
3.88 (s, 3H), 3.73 (t, 2H? J = 7.29 Hz), 1.82-1.89 (m, 2H), 1.73-1.81 (m, 2H),
1.50-1.57 (m,2H).
b) 4-(5-Amino-pentyfoxy)-benzoic acid methyl ester
A suspension of 4-[5-(l,3-dioxo-l,3-dihydro-isoindol-2-yl)-
pentyloxy]-benzoic acid methyl ester (1 g, 2.72 mmol, Example 283: step a)
and hydrazine (98.4µL, 3.13 rnmol) in MeOH:H2O (10 mL, 4:1) was heated
to 65 °C for 2 hrs. Additional hydrazine was added (171 µL, 5.44 mmol) to
the reaction mixture at rt. The reaction mixture was heated to 70 °C for 2 hrs
then stirred overnight at it. Potassium carbonate (30 mL, IN aqueous) and
methylene chloride (200 mL) were added to the reaction. The organic layer
was dried over magnesium sulfate. The solvents were removed in vacuo to
afford the title compound as a white solid (500 mg, 77%). 1H-NMR (CDCl3):
d 7.95-8.00 (m, 2H), 6.88-6.92 (m, 2H), 4.02 (t, 2H, J = 6.43 Hz), 3.88 (s,
3H), 2.71-2.76 (m, 2H), 1.79-1.86 (m, 2H), 1.49-1..56 (m, 411).
c) 4-(5-{3-[3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-4-(2-trimethylsilanyl-
ethoxycarbonylamino)-biphenyl-2-yl]-ureido}-pentyloxy)-benzoic acid
methyl ester
4-Nitrophenyl chloroformate (99.2 mg, 0.49 mmol) was added to a
solution of {2-amino-3"-[5-(tert-butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-bi.phenyl-4-yl}-carbamic acid
2-trimethylsilanyl-ethyl ester (303 mg, 0.45 mmol. Example 294: step i) and
pyridine (39.8 p.L, 0.49 mmol) in methylene chloride (5 mL) at rt. The
reaction mixture was stirred for 2 hrs at rt. 4-(5-Arnino-pentyloxy)-benzoic
acid methyl ester (117 mg, 0.49 mmol, Example 283: step b) and triethylamine
were added to the reaction mixture and stirred for 2 hrs at rt. The reaction
mixture was diluted in EtOAc, washed with water and brine, and dried over
magnesium sulfate. Removal of solvents in vacuo was followed by flash
chromatography (50-60% EtOAc/hexanes) to afford the title compound as a
yellow solid (280 mg, 66.5%). ESI-MS (m/z): Calcd. for C44H57N5O10S3Si:
940.3 (M+1); found: 939.9.
d) 4-(5-{3-[3'-[5-(tert-Butoxycarbonylamino-imiuo-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-4-(2-trimethylsilaiiyl-
e.thoxycarbonylamino)-biphenyl-2-yl]-ureido}-pentyloxy)-benzoic acid
Lithium hydroxide (45.8 mg, 2.08 mmol) was added to a solution of 4-
(5-{3-[3'-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-
thiophene-3-sulfonyl]-6-methyl-4-(2-trimethylsilanyl-ethoxycarbonylamino)-
biphenyl-2-yl]-ureido}-pentyloxy)-benzoic acid methyl ester (280 mg, 0.298
mmol. Example 283: step c) in l,4-dioxane:water (10 mL, 2:1) over 2 days at
rt. The solvents were removed in vacuo. The residue was diluted in water,
acidified to pH - 5 with acetic acid, and extracted with EtOAc. The organic
layer was washed with brine and dried over magnesium sulfate. The solvents
were removed in vacuo to afford the title compound as a yellow solid (276
mg, quantitative). 1H-NMR (CDCI3/CD3OD): d 7.93-7.99 (m, 3H), 7.83-7.S6
(m, 2H), 7.52-7.59 (m, 2H), 7.15-7.20 (m, 2H), 6.85-6.89 (m, 2H), 4.21-4.26
(m, 2H), 3.99 (t, 2H, J = 6.43 Hz), 3.13-3.24 (m, 2H), 2.61 (s; 3H), 2.02 (s,
3H), 1.75-1.83 (m, 2H), 1.43-1.56 (m, 13H), 1.02-1.08 (m, 2H), 0.07 (s, 9H).
e) 4-[5-(3-{4-Amino-3'-[5-(tert-butoxycarbonylamitw-imino-methyl)-2-
methylsutfanyl-thiophene-3-sidfoityl]-6-methyl-biphenyl-2-yl}-ureido)-
pentyloxyj-benzoic acid
Tetrabutyl ammonium fluoride solution (2.38 mL, 1M in THF) was
added to a solution of 4-(5-{3-[3'-[5-(tert-butoxycarbonylamiiio-imino-
methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-4-(2-
trimethylsilanyl-ethoxycarbonylaraino)-biphenyl-2-yl]-ureido}-pentyloxy)-
benzoic acid (276 mg, 0.298 mmol. Example 283: step d) in THF (10 mL)
over 2 days at 35 °C. The solvents were removed in vacuo. The residue was
diluted in EtOAc, washed with water and brine, and dried over magnesium
sulfate. The solvents were removed in vacuo to afford the title compound as a
brown solid (300 mg, quantitative). ESI-MS (m/z): Calcd. for C37H44N5O8S3:
782.2 (M+1); found: 781.8.
J) 4-(5-{3-[3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-4-(Nt,N"'bis(tertbutoxycarbonyl)-
guanidino)-6-methyl-biphenyl-2-yl]-ureido}-pentyloxy)-benzoic acid
l,3-bis(tert-Butoxycarbonyl)- 2-methyl-2-thiopseudourea (433 mg,
1.49 mmol) was added to a solution of 4-[5-(3-{4-amino-3'-[5-(tert-
butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-
6-methyl-biphenyl-2-yl}-ureido)-pentyloxy]-benzoic acid (233 mg, 0.298
mmol, Example 283: step e) in 5% AcOH/MeOH (10 mL) over 2 days at 35
°C. The solvents were removed m vacuo and the residue was purified by flash
chromatography (1-6% MeOH/methylene chloride) to afford the title
compound as a yellow solid (70 mg, 23%). ESI-MS (m/z): Calcd. for
C48H61N7O12S3: 1024.4 (M+1); found: 1024.0.
g) 4-(5-{3-[3'-(5-Carbamimidoyl-2-methylsnlfanyl-thiophene-3-
sulfonyl)-4-guanidino-6-methyl-biphenyl-2-yl]-ureido}-pentyloxy)-beiiz.oic
acid bistrifluoroacetate
4-(5-{3-[3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-4-(N', N"-bis(tert-butoxycarbonyl)-
guanidino)-6-methyl-biphenyl-2-yl]-ureido}-pentyloxy)-benzoic acid (15 mg,
14.6 jamol, Example 283: step f) was deprotected and purified as in Example
1: step d to afford the title compound as a white solid (4.2 mg, 39.6%). 1H-
NMR (CD3CN/D2O): d 8.19 (s, 1H), 7.98-8.03 (m, 1H), 7.90-7.95 (m, 2H),
7.80-7.83 (m, 1H), 7.69-7.74 (m, 1H). 7.49-7.55 (m, 2H), 6.93-6.97 (m, 3H),
4.01 (t, 2H, J - 6.43 Hz), 2.88-3.03 (m. 2H), 2.64 (s, 3H), 1.94-1.97 (m, 3H),
1.66-1.73 (m, 2H), 1.29-1.37 (m, 4H). ESI-MS (m/z): Calcd. for
C33H37N7O6S3: 724.2 (M+1); found: 724.2.
Example 284
4-(4-Amino-3-bromo-beozenesuIfonyl)-5-methylsulfanyl-tbJophene-2-
carboxamidine
The reaction conditions in Example 12: step /were followed using 4-
(4-amino-3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic
acid amide {{Example 319: step d) 50 mg, 0.12 mmol) and dimethylaluminum
amide reagent (5 mL). Analogous workup and HPLC puriiication yielded the
title compound as an off-white solid (26 mg, 34%). 1H-NMR (CD3OD): d
8.23 (s, 1H), 7.96 (d, 1H, J= 2.1 Hz), 7.67 (dd. 1H, J = 2.1, 8.6 Hzi. 6.S5 (d.
1H, J = 8.6 Hz), 2.71 (s, 3H). ES1-MS (m/z): Calcd. for CnH^BrNjChS?
(M+H): 405.9; found: 405.9, 407.9 (m+2).
Example 285
[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2,6-dimethyl-
biphenyl-4-yloxymethyl]-phosphonicacid
To a flask containing {[4-(4'-hydroxy-2',6'-dimethyl-biphenyl-3-
sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-
butyl ester ((Example 224: step b) 233 mg, 0.42 mmol), Cs2CO3 (137 mg, 0.42
mmol), DMF (2 mL), and trifluoro-methcinesulfonic acid diethoxy-
phosphorylmethyl ester (200 mg, 0.67 mmol, (Xu, Y. et al. J. Org. Chem. 61,
7697 (1996); Phillion, D. et al. Tetrahedron Lett. 27, 1477 (1986)) were added
and heated to 50 C. This mixture was heated and stirred for 18 h under an Ar
atmosphere. DMF was removed under vacuum and the residue was taken in
EtOAc and washed with waiter and saturated NaCl. The EtOAc layer was
separated dried over Na2SO4 and evaporated under vacuum to give an oil. This
was purified by preparative thin-layer chromatography (EtOAc/Hexane) to
give 94 mg (33 %) of {3'-[5--(tert-butoxycarbonylamino-imino-methyl)-2-
methylsuIfanyl-thiophene-3-sulfonyl]-2,6-dimethyl-biphenyl-4-yloxymethyl}-
phosphonic acid diethyl ester as a white solid. This solid was dissolved in
dichloromethane (2 mL), and cooled in an ice bath. To this iodotrimethylsilane
(Aldrich Chemical Company, 60 (aL) was added and the mixture was stirred
for lh at which time the dicbJoromethane was removed and the residue was
taken in MeOH and treated with 6N HC1. This mixture was stirred for 3 h and
the solvents were removed under high vacuum. To this residue a 50% solution
of TFA in dichloromethane was added and the mixture was stirred for 1 h.
TFA and dichloromethane were removed under vacuum and the residue was
purified by preparative HPLC (Rev. Phase acetonitrile/water) which yielded
the title compound as a white solid (30 me, 33%). 1H-NMR (CD3OD): d 7.8-
7.7 (m, 2H), 7.62 (s, 1H), 7.5-7.3 (m, 2H), 6.7 (s, 2H), 3.77 (d, 2H, J - 9.8
Hz), 2.44 (s, 3H), 1.74 (s, 6 H). ESI-MS (m/z): Calcd. for C21H23N2O6PS3:
527.1 (M+H); found: 527.1.
Example 286
5-Methylsulfanyl-4-(3-piperidin-l-yl-benzenesulfonyl)-thiophene-2-
carboxamidine
a) 4-Brom o-5-nitro-th ioph en e-2-carbaldehyde
A solution of potassium nitrate (110 g, 1.09 mol) in H2SO4 (550 mL,
cone.) was added to a solution of 4-bromo-thiophene-2-carbaldehyde (207.6 g,
1.08 mol) in H2SO4 (1.1 L, cone.) at CH2C12 (5 mL, anhydrous) at 0 °C over a
45 minute period. The reaction mixture was stirred 0 °C for 2 hrs, then stirred
overnight at rt. The reaction mixture was poured over ice, filtered, and
washed with water and hexanes. The yellow solid was dried overnight to
afford the title compound (251.4 g, 98.6%). 1H-NMR. (DMSO-d6): d 9.90 (s,
1H), 8.56 (s, 1H).
b) 4-Bromo-5-nitro-tlii.ophene-2-carbaldehyde oxime
Hydroxylamine hydrochloride (85 g, 1.2 mol) was added to a solution
of 4-bromo-5-nitro-thiophene-2-carbaldehyde (234 mg, 0.529 mmol, Example
286: step a) in EtOH (7.5 mL 200 proof - anhydrous) :pyndmt: (lOOmL,
anhydrous) at rt over 5 min. The reaction mature was heated to reflux
overnight, then cooled to rt. The solvents were removed in vacuo resulting in
a solid residue that was washed with water and filtered. The solid was dried
overnight under high vacuum to afford the title compound as a yellow solid
(225 g, SS%). The solid was; used for the next step without further
characterization.
c) 4-Bromo-5-nitro-thiophene-2-carbonitrile
A mixture of 4-bromo-5-nitro-thiophene-2-carbaldehyde oxime (216 g,
0.86 mol, Example 286: step b) and acetic anhydride (1 L, 10.6 mol) was
heated to reflux for 4 hrs. The reaction mixture was cooled to rt and the
solvents were removed in vacuo. The crude reaction mixture was diluted in
methylene chloride and washed with water. The organic layer was dried over
magnesium sulfate and concentrated in vacuo resulting in a residue, which was
stirred in diethyl ether/hexanes and filtered to afford the title compound as a
yellow solid (170.2 g, 85%). 1H-NMR (DMSO-d0): d S.25 (a, 1H).
d) 4-(3-Bromo-phenylsulfanyl)-S-nitro-thiophene-2-carbonitrile
Triethylamine (104 ml,, 0.7:5 mol) was slowly added to a solution of 4-
bromo-5-niiTD-thiophene-2-carbonitrile (165 g, 0.708 mol, Example 286: step
c) and 3-bromo-benzenethiol (78 ml, 0.76 mmol) in THF (1.2 L) at rt for 2
days. The solvents were removed in vacuo and the resulting residue was
diluted in EtOAc, washed with saturated Na2CO3 solution, and dned over
magnesium sulfate. The solvents were removed in vacuo and the residue was
stirred in diethyl ether rhexanes (1:5) and filtered to afford the title compound
as a yellow solid (232.7 g, 96%). ]H-NMR (DMSO-de): d 7.88-7.92 (m, 1H),
7.65-7.81 (m, 2H), 7.48-7.54 (m, 1H), 7.22 (s, 1H).
e) 4-(3-Bromo-benzenesulfonyl)-5-nitro-thiophene-2-carbonitnlc
A solution of mCPBA (26.3 g, 11.7 mol, 77%) in 1,2-dichloroethane
was added to a solution of 4-(3-bromo-phenylsulfanyl)-5-nitro-thiophene-2-
carbonitnle (10 g, 29.3 mmol, Example 286: step d) in 1,2-dichloroethane
(200 mL) at rt over 30 min. The reaction mixture was heated to reflux for 2.5
hrs then cooled to rt. The reaction mixture was washed with 0.5 N NaOH and
water and the organic layers were dried over magnesium sulfate. The solvents
were removed in vctciio. The residue was stirred in diethyl ether, filtered, and
dried under high vacuum to afford the title compound as a yellow solid (6.9 g,
63%). ]H-NMR (DMSO-d6): d S.53 (s, 1H), 8.14-8.16 (m, 1H), 7.98-8.05 (m,
2H), 7.62-7.67 (m, 1H).
f) 4-(i-Bromo-benzenesulfonyl)-5-methyl$ulfanyl-thiophene-2-
carbonitvile
A solution of sodium thiomethoxide (1,87 g, 26.8 mmol) in EtOH
(26.8 mL, anhydrous) was added to a suspension of 4-(3-bromo-
benzenesulfonyl)-5-nitro-thiophene-2-carbonitrile (10 g, 26.8 mmol, Example
286: step e) in THF (67 mL, anhydrous) portionwise at -78 °C. The
temperature of the reaction was maintained at -78 °C with stirring for 1 hour.
The reaction was quenched with acetic acid (2 mL, 34.9 mmol) at-78 °C
followed by warming the reaction mixture to rt and then filtered. The yellow
solids were washed with diethyl ether and saved. The filtrate was
concentrated in vacuo resulting in a residue that was suspended in diethyl
ether and stirred at rt overnight. The solids were: filtered from the suspension.
The combined yellow solids were dried under high vacuum to afford the title
compound (8.77 g, 87.4 %). 1H-NMR (DMSO-dg): d 8.45 (s, IB), 7.97-8.16
(m, 3H), 7.62-7.67 (m, 1H), 2.71 (s, 3H).
g) 5-Methylsulfanyl-4-(3-piperidw-l-yl-benzenesulfonyl)-thiophene-2-
carbonitrile
A mixture of 4-(3-Bromo-benzenesulfonyl)-5-methylsulfanyl-
thiophene-2-carbonitrile {Example 286: step f , 200 mg, 0.534 mmol),
pipendine (56 mg, 0.64 mmol), Pd(OAc)2 (24 mg, 0.11 mmol), BINAP (100
mg, 0.16 mmol) and CS2CO3 in 2 111L of toluene under At was stirred at 150 °C
for 16 h, then cooled to RT. The mixture was purified directly by PTLC (30%
EtO Ac/hex an e) to give 20 mg of product as a light yellow oil: 1H-NMR
(CDCI3; 400 MHz) 5 7.68 (m, 1H), 7.67 (s, 1H), 7.54-7.52 (m, 1H), 7.39-7.32
(m, 2H), 3.16-3.12 (m, 4H), 2.45 (s, 3H), 1.64-1.59 (m, 4H), 1.55-1.50 (m,
2H). Mass spectrum (ESI, m/z): Calcd. for C17H1BN2O7S3, 379.1 (M+H),
found 379.3.
h) {Imino-[5-methylsulfanyl-4-(3-piperidin-l-yl-benzene.sulfonyt)-
thiophen-2yl]-methyl}-carbamic acid tert-bntyl ester
To a solution of carbamic acid tert-butyl ester (8 mg, 0.069 mmol,
Aldrich Chemical Company) in 1 mL of THF at -78 °C was added 35 uL of n-
BuLi under Ar. The mixture was stirred at -78 °C for 15 min. A solution of
5-methylsulfanyl-4-(3-piperidin-l-yl-benzenesulfonyl)-thiophene-2-
carbonitrile (20 mg, 0.053 mmol, Example 286: step g) in 1 mL of THF was
added. The resulting mixture was stirred at RT for 5 h, then at 50 °C
overnight. Cooled to RT, the mixture was purified directly by PTLC (20%
EtOAc/hexane) to give 10 mg (3S%) of product as colorless oil: 1H-NMR
(CDCb; 400 MHz) 5 8.42 (s, IB), 7.74 (dd, 1H, J - 1.6, 1.6 Hz), 7.67 (s, 1H),
7.62 (ddd, 1H, J = 7.5, 1.6, 1.6 Hz), 7.57 (d, 1H, J = 7.5, 1.6, 1.6 Hz), 7.52 (dd,
1H, J = 7.5, 7.5), 3.42-3.40 (m, 4H), 2.54 (s, 3H), 1.64 (br s, 6H), 1.61 (s, 9H).
Mass spectrum (ESI, m/z): Calcd. for C22H29N3O4S3, 496.1 (M+H), found
495.9.
i) 5-Methylsulfanyl-4-(3-piperidin-l-yl-benzenesulfonyl)-thwphene-2-
carboxamidine
To a solution of 5-methylsulfanyl-4-(3-pipendin-l-yl-
benzenesu]fony])-thiophene-2-carboxamidine (10 mg, 0.020 mmol, Example
286: step h) in 1 mL of CH2C12 under Ax at 0 °C was added 5 drops (- 200 ul)
of TFA. The mixture was stirred at 0 °C for 1 h. Removal of the solvent
under reduced pressure followed by flash chromatography of the residue on
silica gel (5% MeOH/ CH2Cl2) gave 7.5 mg (77%) of product as colorless oil:
!H-NMR (CD3OD, 400 MHz) 6 8.25 (s, 1H), 7.76 (dd, 1H, J = 1.6, 1.6 Hz),
7.62 (ddd, 1H, J = 7.5, 1.6, 1.6 Hz), 7.56 (ddd, 1H, J = 7.5, 1.6, 1.6 Hz), 7.51
(dd, 1H, J = 7.5, 7.5), 3.31-3.30 (m, 4H), 2.54 (s, 3H), 1.57-1.56 (m, 6H).
Mass spectrum (ESI, m/z): Calcd. for Ci7H2iN3O2S3, 396.1 (M+H), found
396.2.
Example 287
5-Methylsulfanyl-4-{3-[5-methyl-l-(2-trimethylsilanyl-ethoxymethyl)1H-
benzoimidazol-4-yl]-benzenesulfonyl}-thiophen-2-carboxamidine
a) 4-Iodo-5-methy!-lH"benzoimidazole
A solution of 5-methyMH-benzoimidazole (132 mg, 10 nimol) and
NIS (248 mg, 1.10 mmol) in 1 mL of TFA was reflux for 1 hr and then cooled
to RT. Treated with 30 mL of EtOAc, the mixture was neutralized with sat.
NaHCO3 solution. The organic layer was washed with H2O (10 mL), brine
(10 mL) and dried (Na2SC)4). Removal of the solvent under reduced pressure
followed by flash chxomatography of the residue on silica gel (5 %
MeOH/CH2Cl2) gave 78 mg (30%) of product as a white solid: 1H-NMR
(CDCl3; 400 MHz) 5 8.07 (d, 1H), 7.57 (br s, 1H), 7.22 (d, 1H, J = 8.4 Hz),
2.59 (s, 3H). Mass spectrum (ESI. m/z): Calcd. for C8H-.rN2, 259.0 (M+H),
found 259.2.
b) 4-Iodo-5-methyl-l-(2-tritnethylsilanyl-ethoxymethyl)1H-
benzoimidazole
To a solution of 4-Iodo-5-methyl1H-benzoimidazole (100 mg. 0.39
mmol, Example 287: step a) and SEMC1 (71 mg 0.43 mmol) in 2 mL of DMF
under Ar was added Nat! (llmg. 0.43 mmol). The mixture was stirred at RT
for 4 h and purified directly by PTLC (25% EtOAc/hexane) to give 122 mg
(81 %) of product as a colorless oil: 1H-NMR (CDCl3; 400 MHz) 5 7.95 (s,
1H), 7.37 (d, 1H, J = 8.4 Hz), 7.21 (d, 1H, J = 8.4 Hz), 5.48 (s, 2H). 3.47 (t,
2H, J = 8.3 Hz), 2.59 (s, 3H), 0.S9 (t, 2H, J = 8.3 Hz), -0.06 (s, 9H). Mass
spectrum (ESI, m/z): Calcd. for Ci4H2iIN2OSi, 389.1 (M+H), found 3S9.0.
c) [Iiuino-(5-methylsnlfanyl-4-{3-[5-methyl-l-(2-trimethylsilanyl-
ethoxymethyl)1H-benzoimidazol-4-yl]-betizeiiesulfonyl}-thioplien-2-yl)-
m ethyl]-carbamic acid tert-lmtyl ester
A mixture of {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester.
(20 mg, 0.044 mmol, Example 140: step a), 4-Iodo-5-methyl-1 -(2-
trimethylsilanyl-ethoxymethyl)1H-benzoimidazoIe (21 mg, 0.054 mmol.
Example 287: step b) and Pd(PPh3)4 in 1.2 ml of 1:1:2 EOH/2M
Na2C03/toluene was stirred at 90 °C for 5 h, the cooled to RT. Treated with 3
mL of H2O, the mixture was extracted with EtOAc (3X5 mL)/ Removal of
the solvent under reduced pressure followed by flash chromatography of the
residue on silica gel (30% EtOAc/hexane) gave 21 mg (71%) of product as a
light yellow solid: 1H-NMR (CDCl3; 400 MHz) 8 8.42 (s, 1H). 8.08 (s, 1H),
8.05 (s, 1H), 8.01 (ddd, 1H, J = 7.2, 1.8, 1.7 Hz), 7.71-7.67 (m, 2H), 7.57 (d,
1H, J = 8.4 Hz), 7.39 (d, 1H, J = 8.7 Hz), 5.64 (s, 2H), 3.57 (t, 2H, J = 8.3 Hz),
2.61 (s, 3H), 2.33 (s, 3H), 1.51 (s, 9H), 0.95 (t, 2H, J = 8.3), -0.03 (s, 9H). ).
Mass spectrum (ESI, m/z): Calcd. for C3,H4oN405S3Si, 673.2, (M+H), found
672.9.
d) 5-Methylsulfanyl-4-{3-[5-methyl-l-(2-trimethylsilanyl-
ethoxymethyl)1H-benzoimidazol-4-yl]-benzenesulfonyl}-thiophen-2-
carboxam idin e
To a solution of [Iraino-(5-methylsulfanyl-4-{3-[5-methyl-l-(2-
trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-4-yl]-benzenesulfonyl} -
thiophen-2-yl)-methyl]-carbamic acid tert-butyl ester (7 mg, 0.01 mmol.
Example 287: step c) in 0.7 mL of CH2C12 was added 0.3 mL of T.FA. The
resulting solution was stirred at RT for 1 h. Removal of the solvent under
reduced pressure followed by flash chromatography of the residue on silica gel
(5 - 10% MeOH/ CH2Cl2) gave 6 mg (S4%) of product as colorless oil: 1H-
NMR (CD3OD; 400 MHz) 5 8.84 (s, 1H). 8.32 (s, 1H), 8.14 (ddd, 1H, J = 7.6,
1.6, 1.6 Hz). 8.08 (s, 1H), 7.83-7.77 (m, 3H), 7.52 (d, 1H, J = 8.4 Hz), 5.79 (s,
2H), 3.65 (t 2H, J = 8.0 Hz), 2.72 (s, 3H), 2.29 (s, 3H), 0.93 (t, 2H, J - 8.0
Hz), -0.04 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C26H32N4O3S3Si,
573.1, (M+H), found 573.0.
Example 288
4-[3-(5-Methyl1H-benzoiinidazol-4-yl)-benzenesulfonyl]-5-raethyJsu]fanyl-
thiophene-2-carboxamidine
A solution of [Imino-(5-methylsulfanyl-4-{3-[5-methyl-l-(2-
trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-4-yl]-benzenesulfonyl} -
thiophen-2-yl)-methyl]-carbamic acid tert-butyl ester (14 mg, 0.021 mmol,
Example 287: step c) in 1 mL of TFA was heated at 50 °C for 2 h under Ar,
cooled to RT. Removal of the solvent under reduced pressure foliowed by
flash chromatography of the residue on silica gel (10 - 15% MeOH/ CH2C12)
gave 14 mg (100%) of product as colorless oil: 1H-NMR (CD3OD; 400 MHz)
5 9.28 (s, 1H). 8.35 (s, 1H), 8.20 (d, 1H, J = 7.6 Hz). 8.11 (s, 1H), 7.86 (dd,
1H, J = 7.7, 7.7), 7.80 (m, 2H), 7.63 (d, 1H, J = 8,6 Hz), 2.72 (s, 3H). 2.30 (s,
3H). Mass spectrum (ESI, m/z): Calcd. for C20H18N4O2S3, 443.1.00 (M+H).
found 443.1.
Example 289
4-[3-(3-Methyl-5-nitro-pyridin-2-yl)-benzenesulforiyl]-5-methylsulfanyl-
thiophene-2-carboxamidine. TFA salt
a) (lmino-{4-[3-(3-methyl-5-nitro-pyridin-2-yl)-benzenesulfonyl]-5-
methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester
A solution of {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5-
methylsulfanyl-thiophen-2-y]]-imJno-methyl}-carbamic acid tert-butyl ester
(0.05S mmol, 40 mg, Example 140: step a), 2-iodo-3-methyl-5-nitropyridine
(0.08 mmol, 21.1 mg), Cul (0.01 mmol, 2.2 mg) and (Ph3P)4Pd (0.006 mmol)
in DMF (0.6 mL) was heated at 100° under Ar for 3 hr. The reaction mixture
was allowed to cool to RT and poured in to water ( 20 mL). The product was
extracted with CH2Cl2 (3x10 mL). CH2Cl2 extracts were combined, dried
(Na2SO4) and concentrated in vaccuo. The resulting residue was purified on
silica (30% EtOAc:Hexane) to obtain (Imino-{4-[3-(3-methyl-5-nitro-pyridin-
2-yl)-benzenesulfonyl]-5-me1:hylsulfanyl-thiophen-2-yl}-methyl)-carbamic
acid tert-butyl ester. Yield: 48%; !H NMR (CDCl3) 5 9.36 (br, 1H), 8.37 and
8.25 ( s, 1H each), 8.1 and 7.8 (d, J=2.4 Hz, 1H each), 7.93 ( s, 1H), 7.74 (t,
J=6.8 Hz, 1H), 2.7 and 2.5 (s, 3H each), 1.35 (s, 9H)
b) 4-[3-(3-Methyl-5-nitro-pyridin-2-yl)-benzenesulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine. TFA salt
(Imino-{4-[3-(3-methyl-5-:aitro-pyridin-2-yl)-benzenesulfonyl]-5-
methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester ( 20 mg,
Example 289: step a) was theao dissolved in 1:1 mixture of CH2Cl2 and TFA (1
mL). The resulting solution was stirred at RT for 1 hr. and concentrated in
vaccuo to obtain a yellow oil which was dried in a high vaccum. Ether (10
mL) was then added and the precipitate formed was collected by suction
filtration to yield 4-[3-(3-Methyl-5-nitro-pyridin-2-yl)-benzenesulfon>'l]-5-
methylsulfanyl-thiophene-2-carboxamidine. TFA salt.
Yield: 78%; 1H NMR (DMSO) 5 9.36 (br, 2H), 9.31 (d. J=2.4 Hz. 1H),
8.75 (brs, s), 8.65 ( d, J=2.4 Hz, 1H), 8.45 (s, 1H), 8.20 (m, 1H), 8.1? and
8.06 ( d, J= 6.6 Hz, 1H each), 7.84 (t, J=6.7Hz, 1H), 2.7 and 2.4 (s, 3H each);
MS 448,03 (MT) calculated for C18H16N4O4S3; found 449.1 (M++l)
Example 290
4-[3-(5-Amino-3methyl-pyridir!-2-yl)-benzenesulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine. TFA salt
A solution of {[4-(3-dihydroxyboranyl-benzenesuIfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(0.058 mmol, 40 mg, Example 140: step a), 2-iodo-3-methyl-5-nitropyridine
(0.08 mmol, 21.1 mg), Cul (0.01 mmol, 2.2 mg) and (Ph3P)4Pd (0.006 mmol)
in DMF (0.6 mL) was heated at 100° under Ar for 3 hr. The reaction mixture
was allowed to cool to RT and poured in to water (20 mL). The product was
extracted with CH2C12 (3x10 mL). CH2C12 extracts were combined, dried
(Na2SO4) and concentrated in vaccuo. The resulting residue was purified on
silica (30% EtOAc:Hexane) to obtain the expected coupling product. The
product (54.8 mg, 0.1 mmol) was suspended in EtOH:water (2:1, 10 mL) and
NH4Cl (53.5 mg, 1 mmol) and Fe powder ( 28 mg, 0.5 mmol) were added. The
resulting mixture was heated at reflux for 2 lir. The reaction mixture was
cooled to RT and poured in to Std. Na2CO3 solution and the product was
extracted with CH2C12 (3 x10 mL). CH2C12 extracts were combined, dried
(Na2SO4) and concentrated in vaccuo to obtain a brownish yellow oil. This
compound ( 29 mg) was then dissolved in 1:1 mixture of CH2C12 and TFA (1
mL). The resulting solution was stirred at RT for 1 hr. and concentrated in
vaccuo to obtain a yellow oil which was dried in a high vaccum. Ether ( 10
mL) was then added and the precipitate formed was collected by suction
filtration to yield the title compound.
Yield: 2S%; 1H NMR (DMSO) 8 9.37 (br, 2H). 9.07 (br, 2H), 8.4 ( s,
1H), 8.05 (s, 1H), 7.9 (d, J=2.6 Hz, 1H), 7.85 (m, 2H),7.74 (t, J= 6.7 Hz. 1H),
7.1 ( s, 1H), 2.6 and 2.2 (s, 3H each); MS 418.06 (M+) calculated for
C18H16N4O2S3; found 419.1 (b/t+l)
Example 291
4-[3-(3-Methyl-pyrazin-2-yl)-beii2;enesulfonyl]-5-methylsulfanyl-thiophene-2-
carboxamidine TFA salt
a) (ImiHO-{4-{3-(3-methyl-pyrazine-2-yl}-benzeuesulfaiiyl-thiophene-2-
yl}-ittethyl)-carbatnic acid tert-butyl ester
To a flask containing {lmino-[5-methylsulfanyl-4-(3-tributylstannanyl-
benzenesulfonyl)-thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester (22.3
mg, 0.031 mmol, Example 152: step a), methyl-iodopyrazine (8.3 mg, 0.038
mmol), Pd(PPh3)4 (10 mol%, 3.6 mg), and Cul (20 mol%, 1.2 mg) was added
0.5 mL of DMF. The flask was purged with Ar, and then heated to 100 °C for
16 h in an oil bath. The result was concentrated in vacuo and purified by
preparative TLC (80 % EtOAc-Hexanes) to give the 7.2 mg (46%) of the
product as a yellow solid contaminated with a small amount of tin. Mass
spectrum. (ESI, m/z) calcd. for C22H24N4O4S3, 505.1 (M+H), found 405.1
(M+H-BOC). 1H NMR (CDCl3, 400 MHz): d 1.53 (s, 9H), 2.60 (s, 3H)? 2.65
(s, 3H), 7.70 (t, 1H, J=S.8 Hz), 7.87-7.89 (m, 2H), 8.10 (d, 1H, J=8.8 Hz), 8.25
(s, 1H), S.53 (m, 2H);
b) 4-[3-(3-Methyl-pyrazin-2-yl)-benzenesulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine TFA salt
To a solution of 7 mg of (Imino-{4-{3-(3-methyl-pyrazine-2-yl)-
benzenesulfanyl-thiophene-2-yl}-methyl)-carbamic acid tert-butyl ester
(Example 291: step a) in 0.3 mL of CH2C12 at 0°C was added 0.3 mL of TFA
containing 10 µL H2O. The reaction was allowed to warm to ambient
temperature. After 1 h, the solution was concentrated in vacuo with azeotropic
removal using toluene (2x5 mL). The orange-brown solid was treated with 0.2
mL hexanes/0.5 mL CHCI3 and finely divided using somcation. The
supernatant was removed via pipette. The solids were dried giving 4.8 mg
(71%) of 4-[3-(3-Methyl-pyrazin-2-yl)-benzen.esulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine TFA salt as a yellow film.
Mass spectrum (ESI, m/z) calcd. for C17H16N4O2S3, 404.5. (M+H),
found 405.1 ; 1H NMR (CD3OD, 400 MHz): d 2.62 (s3 3H), 2.74 (s, 3H), 7.79
(t, 1H, J=8.9 Hz), 7.99- 8.01 (m, 1H), 8.17-8.19 (m, 1H), 8.29 (t, 1H, J=1.7
Hz), 8.35 (s, 1H), 8.56-8.58 (m, 2H);
Example 292
4-[3-(4-Piperazin-l -yl)-be.nzenesulfonyl] -5-methylsulfanyl -thiophene-2-
carboxamidine
a) 4-[3-(4-Methyl-piperazin -1 -yl) -benzen esulfonylJ-5-m ethylsufanyl-
thiophene-2-carbonitvile
To a flask containing 0.15 g (0.4 nunol) of 4-(3-bromo-
beiizenesulfonyl)-5-methylsulfanyl-thiophene-2-carbonitrile {Example 286:
step j), 44.1 jiL (0.4 mmol) of N-methylpipirazine, 4.5 mg (0.02 mmol) of
Pd(OAc)2, 24.8 mg (.04 mmol) of BINAP, and 195 mg (0.6 mmol) of CsCO3
was added 2.5 mL of toluene. The flask was purged with Ar, and heated to 100
°C for 16 h. The reaction was then concentrated in vacuo and purified by
preparative TLC (50%-EtOAc-Hexane), isolating the low Rf material, which
was subjected to preparative TLC again (10% MeO'H- CHCI3) to give 15.5 mg
(10% yield) of 4-[3-(4-methyl-piperazin-l-yl)-benzenesulfonyl]-5-
methylsufanyl-thiophene-2-ca.rbonitrile in greater than 98% purity.
Mass spectrum (ESI, rn/z) calcd. for C17H19N3O2S3, 394.06 (M+H),
found 394.1 ; 1H NMR (CDCl3, 400 MHz): d 2.36 (s, 3H), 2.57-2.59 (m, 4H),
2.62 (s, 3H), 3.29 (m, 4H), 7.11-7.13 (m, 1H), 7.38-7.40 (m, 2H), 7.49 (d, 1H,
J=1.2Hz),7.84(s,lH);
b) 4-[3-(4-Methyl-piperazin-l-yl)-benzenesulfonyl]-5-methylsuIfanyl-
thiophene-2-carboximidic acid methyl ester
To a flask containing 15 mg (0.03 mmol) of 4-[3-(4-methyl-piperazin-
l-yl)-benzenesulfonyl]-5-methj'lsufanyl-thiophene-2-carbonitrile (Example
292: step a) was added 1 ml. of MeOH and the resultant solution was treated
with 1 mL 2M NaOMe in MeOH (2 mmol) at room temperature. The reaction
was heated to 50 °C for 2 h. At this time it was cooled to room temperature
and 2 drops of H2O was added. Concentration of the mixture in vacuo
followed by purification by preparative TLC (5% Me()H-CHCl3) yielded 12
mg (74%) of 4-[3-(4-methyl-piperazin-l-yl)-benzenesulfonyl]-5-
methylsulfanyl-thiophene-2-carboximidic acid methyl ester as a yellow solid.
Mass spectrum (ESI, m/z) calcd. for C1SH23N3O3S3, 426.09 (M+H),
found 426.2; 1H NMR (CDC]3, 400 MHz): d 2.36 (s, 3H), 2.56-2.5S (m5 7 H),
3.27-3.30 (m, 4H), 3.88 (s, 3H), 7.09-7.11 (m, 1 H), 7.35-7.43 (m, 2H), 7.54
(s, 1H), 7.57 (s, 1H), 7.71 (s, 1H);
c) 4-[3-(4-Piperazin-l-yl)-benzenesnlfonyl] -5-methylsulfanyl -
thiophene-2-carboxamidine
4-[3-(4-Methyl-piperazin-l-yl)-benzenesulfonyl]-5-methylsulfanyl-
thiophene-2-carboximidic acid methyl ester (10 mg, 0.023 mmol. Example
292: step b)\ NH4OAc (10 mg, 0.6 mmol) and 1 mL of 2M NH3 in MeOH
were heated in a sealed tube at 60 °C for 3 h. The reaction was then
concentrated in vacuo and purified by preparative TLC (10% MeOH-CHCl3-
sat'dNH3) to give 8.7 mg (94%) of 4-[3-(4-Piperazin-l-yl)-benzenesulfonyl] -
5-methylsulfanyl -thiophene-2-carboxamidine as a yellow solid.
Mass spectrum (ESI, m/z) calcd. for C18H23N3O3S3, 411.09 (M+H),
found 411.2. 1H NMR (CD3OD, 400 MHz): d 2.36 (s, 3H), 2.61-2.64 (m, 4H),
2.67 (s, 3H), 3.28-3.31 (m, 4H), 7.24-7.27 (m, 1H), 7.42-7.44 (m, 2H), 7.54
(d, lH,J=1.3Hz), 8.00 (s, 1H);
Example 293
4-[3-(4-Methyl-pyrimidin-5-yl)-beiizenesulfonyl]-5-methylsulfanyl-thiophene-
2-carboxamidine
a) (Intino-{4-[3-(4-methyl-pyrimidin-5-yl)-benzenesulfonyl]-5-
methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester
To a flask with a reflux condenser under argon was added 5-Bromo-4-
methyl-pyrimidine (9 mg, 0.044 rnmol), prepared according to the procedure
of Yamanaka, Sakamoto, Nishimura, and Sagi, Chem. Pharm. Bull. 35(8),
3119-3126 (1987) . {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(20 mg, 0.044 mmol, Example 140: step a), Na2CO3 (2M, 0.220 mL, 0.44
mmol), Pd(PPh3)4 (S mg, 0.007 mmol), ethanol (0.220 mL) and toluene (0.440
mL). PdCl2(PPh3)2 (42 mg, 0.06 mmol), dioxane (4 mL), and triethylamine
(420 µL, 3 mmol) and the mixture was stirred for 2 h 15 min at 90 °C. After
cooling to rt, EtOAc (2 mL) and NaHCO3 (saturated, 2 mL) were added and
the layers were separated. The organic layer concentrated in vacuo followed
by purification of the crude material by preparative TLC (5% methanol in
dichloromethane) to yield the title compound (19 ltng, 87%) as a white solid.
1H-NMR (CDCl3): d 9.12 (s, 1H), 8.54 (s, 1H), 8.10-7.29 (m, 7H), 2.59 (s,
3H), 2.50 (s, 3H), 1.51 (s, 9.H). ESI-MS (m/z): Calcd. for C22H24N4O4S3:
504.1 (M-BOQ+H; found: 405.1.
b) 4-[3-(4-Methyl-pyrimidni-5-yl)-benzenesulfonylJ-5-methylsulfa>iyl-
thiophcne-2-carboxamidine
The (imino-{4-[3-(4-methyl-pyrimidin-5-yl)-betizenesulfonyl]-5-
methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-buty] ester
{{Example 293: step a) 15 nig, 0.03 mmol) was dissolved in dichloromethane
(1 tnL), water (1 drop) was added, followed by trifluoroacetic acid (1 mL).
The solution was stirred for 1 h 40 min at rt. The solvents were removed in
vacuo, the residue was co-evaporated with dichloromethane and methanol,
then purified by preparative TLC (10% methanol in dichloromethane) which
yielded the title compound as a pale yellow glass (4 nig, 32%). 1H-NMR
(CD3OD): d 9.05 (s, 1H), 8.61 (s, 1H), 8.13-8.08 (m, 2H), S.04 (s, 1H), 7.78-
7.76 (m, 2H), 2.66 (s, 3H), 2.49 (s, 3H). ESI-MS (m/z): Calcd. for
C17H16N4O2S3: 404.5 (M+H); found: 405.1.
Example 294
4-{4',6t-Bis-[3-(3-methanesulfonyl-propyl)-ureido]-2'-methyl-biphenyl-3-
sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
a) 4-Bromo-5-methyl-3-nitrobenzoic acid methyl ester
4-Bromo-3-methylbenzoic acid methyl ester (10.13 g, 44 mmol) was
dissolved in a mixture of H2SO4 120 mL and TFA (15 mL) at room
temperature. The solution was cooled on an ice bath and KNO3 (4.65 g, 46
mmol) was added portionwise over 30 min. The mixture was stirred at
ambient temperature for 4 hours during which it warmed to rt. TLC analysis
(after mini aqueous workup) showed total disappearance of starting material
(30% EtOAc/Hex). The solution was poured onto ice and the aqueous slurry
was extracted with EtOAc (3 x 150 mL). The organic layer was washed with
5% Na2CO3 (3 x 75 mL), NaHCO3 (3 x 50 mL), water (2 x 100 mL), brine
(100 mL), then was dried over sodium sulfate. Concentration of the solution
yielded a yellowish solid/gel substance (11.6 g) which was one spot by TLC.
1H NMR analysis shows two (major) products in ~2:1 ratio, corresponding to
the o- and m- nitrobenzoate derivatives.. The material was carried onto the
next step without further purification.
b) 4-Bromo-5-methyl-3-nitrobenzoic acid
4-Bromo-5-methyl-3-nitrobenzoic acid methyl ester ((Example 294:
step a (11.6 g, 42.3 mrnol) was dissolved in MeOH (400 mL) at rt and 2N
NaOH (43 mL) was added dropwise over 30 rnin via addition funnel. The
solution was stirred for 12 hr during which, precipitate appeared, and sm
disappeared (TLC shows only baseline spot in 30% EtOAc). The pH was
adjusted to -2 with cone HC1 and the methanol was removed in vacua. EtOAc
(300 mL) was added to the aqueous slurry and the layers were separated. The
aqueous layer was extracted with EtOAc (2 x 50 mL) and then discarded.
TLC analysis of the combined organic extracts ishowed two products (40%
EtOAc in Hexanes, 4% AcOH). The combined organic extracts were washed
with a 3:1 solution of 0.5N NaH2PO4/0.5N NaOAc (-30 x 50 mL portions)
until removal of the o-nitrobenzoic acid (lower spot on TLC, 40% EtOAc in
Ilex, 4% AcOH) was complete. The organic layer was then washed with brine
and dried over sodium sulfate. Concentration of the solution yielded 5.4 g
(47%) of a white solid. 1H NMR (CD3OD) 8 8.10 (m, 2H), 2.54 (s, 3H).
c) (4-Bromo-3-methyl-5-nitro-phenyl)-carbamic acid 2-trimethylsilanyl-
ethyl ester
Diphenylphosphorylazide (4.31 mL, 20 mmol)was added to a stirred
solution of 4-bromo-3-methyl-5-nitro-benzoic acid (Example 294: step b (5.2
g, 20 mmol)) and diisopropylethylamine (3.66 mL, 21 mmol) in 1,4-dioxane
(SO mL) at rt. After 30 minutes at rt, the reaction was heated to 90 °C for 5
min. Trimethylsilylethanol (5.73 mL, 40 mmol) was added and the solution
was stirred for 16 h at 95 °C. The solvents were removed in vacua and the
residue was partitioned between EtOAc (100 mL) and water (30 mL). The
organic layer was further extracted with aq citric acid (3 x 30 mL), NaHCO3,
(2 x 30 mL) and bnne (50 mL). Purification by column chromatography (9:1
Hex/EtOAc) yielded the title compound as a yellow solid. 'H NMR (CDCl3)
S 7.73 (d, 1H, J=2.4 Hz), 7.41 (br dr 1H, J=1.7 Hz), 7.01 (s, 1H), 4.24 (m.
2H), 2.43 (s, 3H), 1.02 (m, 2H), 0.04 (s, 9H).
d) (3-Amiiio-4-bronio-5-methyl-phenyl)-carbamic acid 2-
trim ethyl silanyl-ethyl ester
lion powder (6.1 g, 109 mmol) was added to a suspension of (4-
bromo-3-methyl-5-nitro-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester
{Example 294: step c (4.1 g, 10.9 mmol)) and NH4C1 (5.84 g, 109 mmol) in
EtOH (27 mL) and water (54 mL). The reaction was heated at 85 °C for 14 h.
The cooled mixture was filtered through celite arid the solids were washed
with 1:1 EtOAc/MeOH (200 mL). The filtrate was concentrated in vacuo and
the residue was partitioned between EtOAc (100 mL) and H2O (30 mL). The
organic solution was washed with water (30 mL), and brine (50 mL). Drying
and concentration of the solution yielded the title compound (3.24g, 86%) as a
brown solid which was used without further purification. 1H NMR (CDCl3)
5 6.96 (s, 1H), 6.54 (s, 1H), 6.39 (s, 1H), 4.26 (m, 2H), 4.16 (s, 2H), 2.35 (s,
3H), 1.06 (m, 2H), 0.08 (s, 9H).
e) [3-Amino-5-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
phenyl]-carbamic acid 2-trimethylsilanyl-ethyl ester
Palladium acetate (106 mg, 0.47 mmol), 2-
(dicyclohexylphosphino)biphenyl (658 mg, 1.88 mmol), (3-amino-4-bromo-5-
methyl-phenyl)-carbamic acid 2-trimethylsilanyl-ethyl ester {Example 294:
step d (3.24 g, 9.38 mmol)) were combined in a flask and placed under an
argon atmosphere. p-Dioxane (40 mL) was added, followed by triethylamine
(5.23 mL, 38 mmol) and pinacolborane (4.08 mL, 28 mmol). The solution
was stirred at 80 °C for lh during which a precipitate appeared. The solvent
was removed in vacuo and the residue was partitioned between EtOAc (100
mL) and aq. NH4Cl (50 ml,). The organic layer was further extracted with
NH4C1 (2 x 30 mL), NaHCO3 (30 mL), and brine (50 rnL). The organic layer
was dried (MgSO4), concentrated in vacuo, and the; residue was purified by
SiO2 flash column chromatography (8:2 Hex/EtOAc) to afford the product
(2.44 g, 66%) as a brown solid. 1H NMR (CDCl3) 5 6.77 (s, 1H), 6.38 (s,
1H), 6.2S (d, 1H, J= 1.9 Hz), 4.91 (s, 2H), 4.23 (m, 2H), 2.42 (s, 3H), 1.32 (s,
12H), 1.03 (m,2H), 0.05 (s,9H).
f) {6Amino-3'-[5-(tcrt-butoxycarbonylamin o-imino-methyl)-2-
methylsulfanyl-thiophene-3-mlfonyl]-2-methyl-biphetiyl-4-yl}-carbiiinic acid
2-trim ethylsilanyl-ethyl ester
A flask with a stirbar was charged with [3-amino-5-methyl-4-(4,4,5,5-
tetramethyl-[ 1,3.2]dioxaborolan-2-y])-phenyl]-carbamic acid 2-
trimethylsilanyl-ethyl ester ((Example 294: step e) 2.34 g, 5.96 mmol), {[4-(3-
bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl] -imino-methyl} -
carbamic acid f erf-butyl ester {(Example 27: step c) 2.93 g, 5.96 mmol),
aqueous Na2CO3 (2M, 11.9 mL, 23.8 mmol), ethanol (12 mL) and toluene (24
mL). The solution was sparged with argon for 10 min and Pd(PPh3)4 (689 mg,
0.6 mmol) was added. The biphasic solution was vigorously stirred under
inert atmosphere at 80 °C for 16 h, then was cooled to rt. EtOAc (80 mL) and
water (20 mL) were added and the layers were separated. The organic layer
was washed with saturated NaHCO3 (2 x 20 mL), brine (20 mL) and was dried
over sodium sulfate. Removal of the solvents in vacuo followed by column
chromatography (85:15 DCM/EtOAc) of the residue yielded the title
compound (2.24 g, 55%) as a light brown solid. 1H-NMR (CDCl3): § 7.98
(ddd, 1H, J= 1.3, 1.9, 7.8 Hz), 7.89 (m, 2H), 7.61 (t, 1H, J = 7.7 Hz), 7.5 (dt,
1H, J= 1.3, 7.7 Hz), 6.88 (s, 1H), 6.55 (d, 1H, J= 1.7 Hz), 6.47 (s, 1H), 4.26
(m, 2H), 3.42 (s, 2H), 2.56 (s, 3H), 1.9 (s, 3H), 1.52 (s, 9H), 1.06 (m, 2H),
0.08 (s, 9H).
g) {[4-(4', 6'-Diamino-2'-methyl-biphenyl-3-sulfonyl)-5-methyhulfanyl-
thiopheti-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
A solution of tetrabutylammonium fluoride (1M in THF, 1 mL, 1
mmol) was added to a solution of {6-amino-3'-[5-(rerr-butoxycarbonylamino-
imino-methyl)-2-methylsulfanyl-tbiophene-3-sulfonyl]-2-methyl-biphenyl-4-
yl}-carbamic acid 2-trimethylsilanyl-ethy] ester {{Example 294: step 1) S6 mg,
0.11 mmol) in THF (1 mL). The solution was heated at 50 °C for 12 h, then
the solution was partitioned between EtOAc (50 mL) and water (20 mL). The
layers were separated and the organic layer was further extracted with water (5
x 10 mL) and brine (20 mL). The solution was dried over sodium sulfate and
concentrated in vacuo to yield the title compound (71 mg, 84%) which was
used without further purification. ESI-MS (m/z): Calcd. for C24H2SN4O4S3
(M+H): 533.1; found: 532.7.
h) 4-{4',6'-Bis-[3-(3-methanesulfonyl-propyl)-ureido]-2'-methyl-
biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophene-2-carboxamidine
triflnoroacetate
The procedure in Example 296 was followed using {[4-(4',6-diamino-
2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-
methyl}-carbamic acid tert-butyl ester (71 mg, 0.13 mmol),
diphenylphosphoryl azide (250 µL, 1 mmol), 4-methanesulfonyl-butyric acid
(166 mg, 1 mmol), and DIEA (183 µL, 1.05 mmol) in dioxane (4 mL).
Analogous treatment of the crude intermediate with TFA/DCM and HPLC
purification yielded the product (8 mg, 7%). 1H-NMR (CD3OD): d 8.30 (s,
1H), 8.04 (ddd, 1H, J= 1.1, 2.1, 8.1 Hz), 7.90 (t, 1H, J= 1.6 Hz), 7.73 (t, 1H,
J= 7.9 Hz), 7.58 (m, 1H), 7.49 (m, 1H), 7.23 (dd;, 1H, J= 0.6, 2.1 Hz), 3.38 (t,
2H, J= 6.8 Hz), 3.20 (m, 4H), 3.0 (m, 2H), 3.01 (s, 3H), 2.97 (s, 3H), 2.74 (s,
3H), 2.05 (m, 2H), 2.02 (s, 3H), 1.87 (m, 2H). ESI-MS (m/z): Calcd. for
C27H32N4O4S3 (M+H): 759.1; found: 759.1, 781.1 (M+Na).
Example 295
ll-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-
guanidino-6-methyl-biphenyl-2-ylcarbamoyl]-undecanoic acid bis-
trifluoroacetate
a) 8-Methyl-1H-benzo[d][l,3]oxazin e-2,4-dione
To a solution of 2-ammo-3-methylbenzoic acid (9.07 g, 60 mmol) in
THF (60 mL) was added simultaneously diisopropylethylamine (20.9 mL) and
a solution of triphosgene (5.94 g, 20 mmol) in dichloromethane (60 mL) over
30 minutes period. After the addition was completed, the mixture stirred at
ambient temperature for 16 hours. Solid was filtered and washed with ether (2
x 100 mL) and H2O (3 x 50 mL), and dried in high vacuum to afford the title
compound (10.02 g, 94 % yield) as a white solid. 1H NMR (DMSO)
5 11.02 (s, 1H), 7.76 (d, 1H, J=7.7 Hz), 7.57 (d, 1H, .7=7.5 Hz), 7.17-7.13 (m,
1H), 2.32 (s, 3H).
b) 8-Methyl-6-nitro-1H-benzo[d][l,3]oxazine-2,4-dione
To a flask charged with 8-methyl1H-benzo[d][l,3]oxazine-2.4-dione
((Example 295: step a) 9.27 g, 52.4 mmol) in an ice-water bath was added
concentrated H2SO4 (90 mL) over 5 minutes period. After stirring for 10
minutes, fuming HNO3 (2.9 mL) was added over 15 minutes. The reaction
mixture was stirred for further 30 minutes in the ice-water bath, 30 minutes at
ambient temperature, then slowly poured into ice with stirring. The solid was
collected, washed with H2O (3 x 50 mL), and dried in high vacuum to give the
title compound (10.4 g, 89% yield) as a yellow solid. 1H NMR (DMSO)
6 11.65 (br s, 1H), 8.46-8.43 (m, 2H), 2.44 (s, 3H).
c) 2-Amino-3-methyl-5-nitro-benzoic acid methyl ester
To a suspension of S--memyl-6-rutro1H-benzo[d][l,3]oxazine-2,4-
dione ((Example 295: step b) 1.04 g, 4.68 mmol) in methanol (30 mL) was
added a solution of sodium methoxide (0.5 M, 0.94 mL. 4.7 mmol) in
methanol. The mixture was stirred at ambient temperature for 1 hour and
neutralized by addition of saturated NH4Cl. Methanol was removed under
reduced pressure and the resulting mixture was filtered. The solids were
washed with H2O (twice), dried in high vacuum to give the product (0.97 g,
99% yield) as a yellow solid. 1H NMR (DMSO) 5 8.48 (d, 1H, .7=2.7 Hz),
8.02-S.01 (m, 1H), 7.75 (br s, 2H), 3.86 (s, 3H), 2.20 (s, 3H).
d) 2-Bromo-3-methyl-5-nitro-benzoic acid methyl ester
To a flask charged with copper (II) bromide (7.40 g, 33.1 mmol) was
added a solution of t-butyl nitrite (4.50 mL, 37.9 mmol) in MeCN (30 mL) at
ambient temperature. After stirring for 5 minutes, a suspension of 2-amino-3-
methyl-5-nitro-benzoic acid methyl ester ((Example 295: step c) 4.97 g, 23.7
mmol) in MeCN (50 mL) was added. The mixture was stirred at ambient
temperature for 15 minutes, 65 °C for 20 minutes, then cooled back to ambient
temperature. The reaction was filtered and the filtrate was concentrated to
give a dark brown solid. The solid was triturated with hexane , filtered off,
and washed with hexane (4 x 50 mL). All hexane layers were combined and
concentrated to give the title product (5.7 g, 88 % yield) as a pale yellow solid.
1H NMR (CDCl3) 5 8.35 (d, 1H, .7=2.5 Hz), 8.21 (d, 1H, J=2.9 Hz), 3.99 (s,
3H), 2.59 (s, 3H).
e) 2-Bromo-3-methyl-5-nitro-benzoic acid
To a solution of 2-bromo-3-methyl-5-nitro-benzoic acid methyl ester
((Example 295: step d) 5.04 g) in ethanol (50 mL) was added a solution of aq
NaOH (4M, 1.62 g, 40.5 mmol) and stirred at ambient temperature for 16 h.
The resulting red colored solution was concentrated to dryness, dissolved in a
minimum amount of H?O, and acidified with 1 N HC1 to pH 3-4. The solid
was filtered, washed with H2O (3 x 50 mL) dried under high vacuum to afford
the title compound (4.5 g, 94 % yield) as a pale yellow solid. 1H NMR
(DMSO) 8 8.36-S.35 (m, 1H), 8.24-S.23 (m, 1H), 2.53 (s, 3H).
f) (2-Bromo-3-methyl-5-nitro-phenyl)-carbamic acid tert-butyl ester
Diphenylphosphorylazide (453 µL, 2.1 mmol) was added to a stirred
solution of 2-bromo-3-methyl-5-nitro-benzoic acid ((Example 295: step e) 520
mg, 2 mmol) and triethylamine (1.4 mL, 2.1 mmol) in terf-butanol (25 ml.) at
rt. After 15 minutes, the reaction was heated to 80 °C for 16 h. EtOAc (100
mL) was added and the solution was extracted with solutions of citric acid (3 x
30 mL), NaHCO3,(2 x 30 mL) and brine (50 mL). Purification by column
chromatography yielded the title compound as a white solid. 1H NMR
(CDCl3) 8 8.93 (d, 1H, J= 2.6 Hz), 7.77 (app dd, 1H,J= 0.7, 2.8 Hz), 7.26
(br s, 1H), 2.51 (s, 3H), 1.55 (s, 9H).
g) 2-Bromo-3-methyl-5-nitro-phenylamine
2-Bromo-3-methyl-5-nitro-phenyl)-carbamic acid to-f-butyl ester
((Example 295: step d) 435 mg, 1.32 mmol) was dissolved in 10 mL of a 1:1
mixture of trifluoroacetic acid and DCM (10 mL total). After stirring for 1 h,
the solvent was removed in vacito and the yellow solid residue (306 mg) was
used without further purification. 1H NMR (CDCl3) 5 7.46 (d, 1H, J = 2.8
Hz), 7.42 (d, lHJ= 2.8Hz), 6.62 (br s, 2H), 2.42 (s, 3H).
h) {[4-(6'-Amino-2'-methyl-4'-nitro-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thioplien-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
A flask with a stirbar was charged with {[4-(3-dihydroxyboranyl-
benzenesulfonyl)-5-metIiy]sulfanyJ-thiophen-2-yl]-imino-methyl}-carbamic
acid tert-butyl ester ((Example 140: step a (752 mg, 1.65 mmol), 2-bromo-3-
methyl-5-nitro-phenylamine ((Example 295: step g) 306 mg, 1.32 mmol),
aqueous Na2CO3 (2M, 4 mL, 8 mmol), ethanol (4 mL) and toluene (8 mL).
The solution was sparged with argon for 10 min and Pd(PPh3)4 (294 mg, 0.25
mnio]) was added. The biphasic solution was vigorously stirred under inert
atmosphere at 80 °C for 16 h, then was cooled to rt. EtOAc (40 mL) and
water (20 mL) were added and the layers were separated. The organic layer
was washed with saturated NaHCO3 (2 x 20 mL), brine (20 mL) and was dried
over sodium sulfate. Removal of the solvents in vacua followed by column
chromatography (10-40% EtOAc in hexanes) of the residue yielded the title
compound (245 mg, 33%) as a yellow solid. 1H-NMR (CDCl3): d 8.03 (ddd,
1H, J= 1.2, 2.1, 8.1 Hz), 7.91 (s, 1H), 7.90 (t, 1H, J= 1.6 Hz), 7.69 (t, 1H, J
= 7.9 Hz), 7.53 (app dd, 1H, .J= 0.7, 2.3 Hz), 7.50 (dt, 1H, J= 1.4, 7.7 Hz),
7.44 (app dd, 1H, J = 0.5, 2.3 Hz), 3.70 (s, 2H), 2.59 (s, 3H), 2.00 (s, 3H), 1.51
(s, 9H).
i) ll-{4-Amino-3f-[5-(teirt-butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylcarbamoyl}-
undecanoic acid methyl ester
Triethylamine (139 µL, 1 mmol) was added to a solution of {[4-(6"-
amino-2'-methyl-4'-nitro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-
yl]-imino -methyl) -carbamic acid tert-butyl ester ((Example 295: step h) 118
mg, 0.21 mmol) in DCM (10 mL). 11-chlorocaJ-bonyl-undecanoic acid ethyl
ester (73 mg, 0.26 mmol) was added dropwise over 5 min. After 30 minutes
of stirring, the reaction was not complete. Additional portions of acid chloride
(3 x leq) were added in a similar manner, until the reaction was complete.
Addition of EtOAc (40 mL) followed by aqueous workup with NaHCCh (2 x
20 mL) and brine (30 mL) yielded the crude amide (206 mg) as a glass. The
residue was dissolved in EtOH (5 mL) and 4M aq NH4C1 (1 mL) was added.
Iron powder (165 mg, 3 mmol) was added and the reaction was heated at 75°C
for lh. The cooled mixture was filtered through a 0.22 urn filter and solids
washed with 5 mL portions of MeOH and EtOAc. Additional EtOAc (80 mL)
was added and the organic solution was washed with citric acid (2 x 20 mL).
NaHCO3 (2 x 30 mL), water (30 mL), and brine (50 mL). Drying and
concentration of the solution yielded the title compound (165 mg) which was
used without further purification.
j) 11-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophette-3-sulfonyl]-4-(N,N-bis-(tert-
Butoxycarbonylamino))giianidino-6-methyl-biphenyl-2-ylcarbamoyl}-
undecanoic acid
Sodium hydroxide (1M, 1 mL) was added to a solution of 11-{4-
amino-3'- [ 5 -(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfaii yl-
thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylcarbamoyl}-undecanoic acid
methyl ester ({Example 295: step i) 122 mg, 0.16 mmol) in MeOH (10 mL).
The solution was stirred for 18 h at rt, the solution was quenched with AcOH
(500 fiL), and the solvent was removed in vacuo. The residue was dissolved
in MeOH (10 mL), AcOH (500 µL), and N,N-bis(tert-butoxycarbonyl)-S-
methyl-isothiourea (145 mg, 0.5 mmol) was added. The solution was stirred
at 40 °C for 16 h and the solvent removed in vacuo. The residue was
partitioned between EtOAc (50 mL) and water (20 mL) and the organic layer
was washed with brine (20 mL). Drying and concentration of the solution
yielded a residue which was purified by SiO2 flash column chromatography
(6:4 Hex/EtOAc, then 25:75:5 Hex/EtOAc/MeOH). The residue was further
purified by RP-HPLC (C-18 column, CH3CN/H2O) to yield 115 mg of
product). 1H-NMR (CD3OD): d 8.16 (s, 1H), 8.01 (ddd, 1H, J= 1.2, 1.9, 7.9
Hz), 7.87 (t, 1H, J= 1.6 Hz), 7.65 (t, 1H, J= 7.9 Hz), 7.53 (m, 1H), 7.50 (dt,
1H, J= 1.4, 7.7 Hz), 7.39 (m, 1H), 2.66 (s, 3H), 2.29 (t, 2H, 7= 7.4 Hz), 2.05
(s, 3H), 1.93 (m, 2H), 1.61 (m, 2H), 1.53 (s, 18H), 1.49 (s, 9H), 1.0-1.40 (m,
12H), 0.94 (m, 2H).
k) ll-[3'-(5-Carbamimid.oyl-2-methylsulfanyl-thiophene-3-sulfonyl)-4-
guanidino-6-methyl-biphenyl-2-ylcarbamoyl]-undecanoic acid bis
trifluoroacetate
The procedure in Example 260: step b was followed using 11 -{3'-[5-
(/e7-/-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-
sulfonyl]-4-(N,N-bis-(te7-r-butoxycarbonylamino))guanidino-6-methyl-
biphenyl-2-ylcarbamoyl}-undecanoic acid ((Example 295: step j) 15 mg,
0.015 mmol) and 1:1 TFA/DCM (10 mL). Purification by HPLC yielded the
product (8.2 mg, 55%) as an opaque glass. 1H NMR (CD3CN/D2O): 6 8.16 (s,
1H), 7.79 (ddd, J= 1.2, 2.1, 7.9 Hz), 7.82 (m, 1H), 7.67 (t, 1H, 7= 7.9 Hz),
7.49 (m, 1H), 7.18 (m, 1H), 7.14 (m, 1H), 2.65 (s, 3H), 2.26 (t, 2H, J= 7.4
Hz), 2.02 (s, 3H), 1.85 (m, 2H), 1.55 (m, 1H), 0.9-1.3 (m, 12H), 0.80 (m, 2H).
ESI-MS (m/z): Calcd. for C32H42N6O5S3 (M+H): 687.2; found: 687.2.
Example 296
4-{4'-[3-(3-Methanesulfonyl-propyl)-ureido]-2'-methyl-biphenyl-3-sulfonyl}-
5-methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
Diphenylphosphoryl azide (250 µL, 1 mmol) was added to a solution
of 4-methanesulfonyl-butyric acid ((Example 209: part a) 166 mg, 1 mmol)
and DIEA (183 µL, 1.05 mmol) in dioxane (4 mL). The solution was stirred
at rt for 15 min, then stirred at 90 °C for 3 h. The solution was cooled, then an
aliquot (250 u.L) was added to a solution of {[4-(4'-amino-2'-methyl-biphenyl-
3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid
tert-butyl ester {(Example 220: step b) 76 nig) in DCM (2 mL). The reaction
was stirred overnight and the solvent was removed in vacua. The residue was
partially purified by SiCb flash column chromatography. The impure urea was
treated with 1:1 TFA/DCM as described in Example 1: step d and was purified
by HPLC to yield the title compound (31 mg, 19%). 1H-NMR (CD?OD):
d S.32 (s, 1H), 8.0 (m, 1H), 7.97 (:m, 1H), 7.67 (m, 2H), 7.33 (m, 2H), 7.13 (d,
1H, J= 8.1 Hz). 3.37 (t 2H, 7= 6.8 Hz), 3.20 (m, 2H), 3.0 (s, 3H). 2.73 (s,
3H), 2.22 (s, 3H), 2.05 (m, 2H). ES1-MS (m/z): Calcd. for C24H28N4O5S4
(M+H): 581.1; found: 581.1.
Example 297
4-[2'-Methyl-6'-(4-methyl-pipera2in-l-yhnethyl)-biphenyl-3-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidinebis-trifluoroacetate
Methanesulfonyl chloride (100 µL) was added over 1 min to a 0 °C
solution of {[4-(6'-hydroxymethyl-2'-metiiyl-biphenyl-3-sulfonyl)-5-
methylsulfiinyl-thiophen-2-yl]-immo-methyl}-carbaimic acid tert-butyl ester
((Example 5: step c) (30 mg, 0.06 inmol) and diisopropylethylamine (0.25 ml)
in DCM (10 mL). The solution was stirred for 1 h at 0 °C and warmed to rt.
1-Methylpiperazine was added (0.25 mL) and the solution was stirred for 3 h
at rt. The volatile components were removed in vacuo and the residue was
treated with 1:1 TFA/DCM (10 mL) for 2 h at rt. The solvent was removed in
vacuo the residue was purified via preparative HPLC (C18 -column, 10-70%
CH3CN over 30 min) which yielded the title compound as a opaque glass (8.2
mg). 1H-NMR (CD3OD): d 8.38 (s, 1H), 8.02 (ddd, 2H, .J= 1.2, 1.9, 7.9 Hz),
7.98 (t, 1H, J= 1.6 Hz), 7.72 (t, 1H. J= 7.9 Hz), 7.57 (dt, IK, J= 1.4, 7.7 Hz),
7.26-7.35 (m, 3H), 3.39 (d, III, J= 12.9 Hz), 3.21 (d, 1H, J= 12.9 Hz). 3.20
(br s, 4H), 2.87 (s, 3H), 2.75 (s. 3H), 2.50 (br s, 4H), 1.98 (s, 3H). ESI-MS
(m/z): Calcd. for C25H30N4O2S3 (M+H): 515.2; found: 515.2
Example 298
4-(2>-Methyl-6'-morpholin-4-y]methyl-biphenyl-3-sulfbnyl)-5-methylsulfanyl-
thiop'hene-2-carboxamidine
Methanesulfonyl chloride (100 µL) was added over 1 min to a 0 °C
solution of {[4-(6'-hydroxymethyl-2'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
(Example 5: step c) (30 mg)) and diisopropylethylamine (0.25 mL) in DCM
(10 mL). The solution was stirred for 1 h at 0 °C and warmed to it. 4-
Methylmorpholine (0.5 mL) was added and the solution was stirred for 3 h at
rt. The volatile components were removed in vacua and the residue was
treated with 1:1 TFA/DCM (10 mL) for 2 h at rt. The solvent was removed in
vacuo and the residue was purified by preparative HPLC (C18-column, 10-
70% CH3CN over 30 min) which yielded the title; compound as a opaque glass
(6.8 mg). 1H-NMR (CD3OD): d 8.40 (s, 1H), 8.13 (ddd, 1H, J= 1.2, 1.9, 7.9
Hz), 7.97 (t, 1H, 7- 1.6 Hz), 7.82 (t, 1H, J= 7.9 Hz), 7.61 (m, 2H), 7.49 (m,
2H), 4.15 (d, 1H, J= 13.5 Hz), 4.07 (d, 1H, J= 13.5 Hz), 3.82 (br s, 4H), 2.75
(s, 3H), 2.18 (s, 2H), 2.03 (s, 3H), 1.31 (s, 2H). ESI-MS (m/z): Calcd. for
C24H27N3O3S3 (M+H): 502.1; found: 502.1.
Example 299
[3'-(5-Carbamimidoyl-2-methy]sulfany]-thiophene-3-sulfon)'])-6-mcthy]-
biphenyl-2-ylmethoxy]-acetic acid trifluoroacetate
a) (2-Iodo-3-methyl-benzyloxy)-acetic acid ten-butyl ester
Sodium hydride (53 mg, 2.2 mmol) was added to a 0 °C solution of 2-
iodo-3-methyl-phenyl-methanol ((Example 5: step a) 492 mg, 2 mmol) in
DMF (20 mL). The solution was stirred at 0 °C for 30 min and tert-buiyl
bromoacetate (0.4 mL, 2.5 mrnol) was added. The solution was warmed to rt
over 15 min and stirred for 3 h at rt. EtOAc (80 mL) and water (40 mL) were
added, the layers were separated, and the organic layer was washed with water
(6 x 20 mL), brine (30 mL), amd was dried over sodium sulfate. Concentration
of the solution followed by SiO2 flash column chromatography (5-10% EtOAc
in hexanes) yielded the title compound (0.571 g, 79%) as an oil. 1H-NMR
(CDCl3): d 7.36 (dd, 1H, J= 1.4, 7.4 Hz), 7.30 (t, 1H, 7.4 Hz), 7.24 (dd, 1H, J
= 1.4, 7.4 Hz), 4.72 (s, 2H), 4.15 (s, 2H), 2.53 (s, 3H), 1.56 (s, 9H).
b) [3-Methyl-2-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-
benzyloxyj-acetic acid tert-butyl ester
The procedure used in Example 3: step b v/as followed using (2-iodo-
3-methyl-benzyloxy)-acetic acid tert-butyl ester ((Example 299: step a) 571
mg, 1.6 mmol), PdCl2(PPh3)2 (55 mg, 0.08 mmol), triethylamine (1.25 mL, 9.4
mmol), and 4,4,5,5-tetramethyl-[l.,3,2]dioxaborolane (0.91 mL, 6.4 mmol) in
dioxane (5 mL) at a reaction temperature of 80 °C. Analogous aqueous
workup and purification by SiO2 flash column cfaromatography yielded the
title compound contaminated with the product resulting from halide reduction
(542 mg, 95%). The material was used without further purification. 1H-NMR
v: 6 7.20 (t, 1H, 7.4 Hz), 7.11 (d, 1H, J= 7.4 Hz), 7.07 (d, 1H, J= 7.4
Hz), 4.72 (s, 2H), 3.86 (s, 2H), 2.43 (s, 3H), 1.46 (s, 9H). 1.39 (s, 12H).
c) [3'-(5-Carbamimidoyl-2-methylsulfaityl-thiophene-3-sulfonyl)-6-
methyl-biphenylylmethoxyj-acetic acid trifluoroacetate
The procedure used in Example 1: step c was followed using {[4-(3-
bromo-benzenesu]fonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-
carbamic acid tert-bnty\ ester ((Example 27: step c) 123 mg, 0.25 mmol), [3-
methyl-2-(4,475,5-tetramethy]-[l,3,2]dioxaboroIan-2-yl)-benzyloxy]-acetic
acid tert-butyl ester ((Example 299: step c) 270 mg, 0.75 mmol), Na2CO3 (2M,
1.5 mL, 3 mmol), Pd(PPh3)4 (66 mg, 0.06 mmol), ethanol (1.5 mL) and
toluene (3 mL). Analogous aqueous workup yielded 417 mg of crude material
which was treated with 1:1 TFA/DCM as described in Example 1: step d.
Analogous purification by C18-HPLC yielded the title compound (26.8 mg,
22%) as a white solid. 1H-NMR (CD3OD): d 8.35 (s, 1H), 8.07 (ddd, 1H, J =
1.2, 1.9, 7.9 Hz), 7.86 (t, 1H, J== 1.6 Hz), 7.71 (t, 1H, J== 7.9 Hz), 7.10-7.43
(m, 3H), 4.25 (m, 2H), 4.07 (br s, 1H), 3.78 (br s, 1H), 2.73 (s, 3H), 2.35 (s,
3H), 2.02 (s, 3H). ESI-MS (m/z): Calcd. for C22H22N2O5S3 (M+H): 490.1;
found: 490.1.
Example 300
[3'-(5-Carbamimidoyl-2-rnethylsulfanyl-thiophene-3-sulfonyl)-6-methyl-
biphenyl-3-ylmethoxy]-acetic acid
a) (3-Iodo-4-methyl-benzyloxy)-acetic acid tert-butyl ester
The procedure used in Example 299: step a was followed using sodium
hydride (53 mg, 2.2 mmol), 3-iodo-4-methyl-benzyl alcohol (992 rag, 4
mmol), tot-butyl bromoacetate (0.4 mL, 2.5 mraol) in DMF (10 mL).
Analogous aqueous workup and purification by SiO2 flash column
chxomatogiaphy yielded the title compound (1.30 g, 89%) as an oil. lH-NMR
(CDCl3): d 7.84 (d, 1H, J= 1.4 Hz), 7.27 (d. 1H, J= 1.4 Hz), 7.23 (d. 1H, J =
1.1 Hz), 4.55 (s, 2H), 3.99 (s, 2H), 2.44 (s, 3H), 1.51 (s, 9H).
b) [4-Methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-
benzyloxyj-acetic acid tert-butyl ester
The procedure used in Example 3: step h was followed using (3-iodo-
4-methyl-benzyloxy)-acetic acid terr-butyl ester ((Example 300: step a) 600
mg, 1.65 mmol), PdCl2(PPh3);. (58 mg, 0.08 mmol), triethylamine (1.25 mL,
9.4 mmol), and 4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (0.91 mL, 6.4 mmol)
in dioxane (5 mL). Analogous aqueous workup and purification by SiO2 flash
column chromatography yielded the title compound contaminated with the
product resulting from halide reduction (569 mg, 95%). The material was used
without further purification. 1H-NMR (CDCl3): d 7.73 (d, 1H, J = 1.9 Hz),
7.38 (dd, 1H, J= 2.1, 7.9 Hz), 7.18 (d, 1H, J = 7.9 Hz), 4.61 (s, 2H), 3.97 (s,
2H), 2.55 (s, 3H), 1.50 (s, 9H), 1.37 (s, 9H).
c) [3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-
tnethyl-biph enyl-2-ylmethoxy]-acetic acid trifluoroacetate
The procedure used in Example 1: step c was followed using {[4-(3-
bromo-beiizenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-
carbamic acid tert-butyl ester ((Example 27: step c) (239 mg, 0.24 mmol)), [4-
methyl-3-(4,4,5,5-tetramethyl-[l,,3,2]dioxaborolan-2-yl)-benzyloxy]-acetic
acid tert-butyl ester ((Example 300: step c) 530 mg, 1.46 mmol), Na2CO3 (2M,
3 mL, 6 mmol), Pd(PPh3)4 (70 mg, 0.06 mmol), ethanol (3 mL) and toluene (6
mL). Analogous aqueous workup yielded 629 mg of crude material which
was treated with 1:1 TFA/DCM as described in Example 1: step d. Analogous
purification by C18-HPLC yielded the title compound (47 mg, 38%) as a white
solid. RP-HPLC (5 to 100% ACN over 8 min) analytical purity = 200%. ESI-
MS (m/z): Calcd. for C22H22N2O5S3 (M+H): 491.1; found: 491.1.
Example 301
3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-inethyl-
biphenyl-3-carboxyiic acid (3-morpholin-4-yl-propyl)-amide bus
trifluoroacetamide
a) 3-Iodo-4-methyl-N-(3-morpholin-4-yl-propyl)-benzatnide
Thionyl chloride (5.6 mL) was added over 1 min to a 0 °C solution of
3-iodo-4-methyl benzoic acid (5 g, 19.1 mmol) in THF (30 mL). The solution
was stirred for 24 h at rt and the volatile components were removed in vacuo.
A portion of the crude acid chloride (1 g, 3.57 mmol) was dissolved in DCM
(10 mL) and was cooled to 0 °C. Diisopropylethylamine (0.78 mL, 4.46
mmol) was added followed by 3-morpholin-4-yl-propylamine (0.52 mL, 3.56
mmol) and the reaction was stiixed for 1 h at rt. EtOAc (80 mL) and aq.
NH4Cl (20 mL) was added and 1he layers were separated. The organic layer
was washed with aq NH4C1 (2 x 10 mL), NaOH (IN, 3 x 20 mL), water (20
mL), brine (50 mL) and was dried over sodium sulfate. Concentration of the
solution and SiC»2 flash column chromatography of the residue (0-10% MeOH
in DCM) yielded the product (695 mg, 50%) as a yellow glass.
b) 4-Methyl-N-(3-morpholin-4-yl-propyl)-3-(4A,5,5-tetramcthy1-
[l,3,2]dioxaborolau-2-yl)-benzainide
The procedure used in Example 3: step b was followed using 3-iodo-4-
methyl-N-(3-morpholin-4-yl-propyl)-benzamide ((Example 301: step a) 695
mg, 1.79 mmol), PdCl2(PPh3)2 (63 mg, 0.09 mmol), triethylamine (1.25 mL,
9.4 mmol), and 4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (0.91 mL, 6.4 mmol)
in dioxane (5 mL). Analogous aqueous workup and purification by SiO? flash
column chromatography (0-10% MeOH in DCM) yielded the title compound
contaminated with the product resulting from halide reduction (653 mg, 94%).
The material was used without further purification.
c) 3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-
methyl-biphenyl-3-carboxylic acid (3-morpholin-4-yl-propyl)-amide bis
trifluoroacetam ide
The procedure used In Example 1: step c was followed using {[4-(3-
bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-
carbamic acid tert-butyl ester ((Example 27: step c) (237 mg, 0.24 mmol)), 4-
methyl-N-(3-morpholin-4-yl--propyl)-3-(4,4,5,5-tetramethyl-
[l,3,2]dioxaborolan-2-yl)-benzamide ((Example 301: step b) 563 mg, 1.45
mmol), Na2CO3 (2M, 3 mL, 6 mmol), Pd(PPh3)4 (67 mg, 0.06 mmol), ethanol
(3 mL) and toluene (6 mL). Analogous aqueous workup followed by SiO2
flash column chromatography (0-10% MeOH in DCM) yielded 605 mg of
material which was treated with 1:1 TFA/DCM as described in Example 1:
step d. Analogous purification by C18-HPLC yielded the title compound (92
mg, 48%) as a white solid. RP-HPLC (5 to 100% ACN over 8 min) analytical
purity = 100%. ESI-MS (m/z): Calcd. for C27H32N4O4S3 (M+H): 573.2;
found: 573.2.
Example 302
3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-
biphenyl-2-carboxylic acid (3-morpholm-4-yl-propyl)-amide bis
trifluoroacetamide
a) 2-lodo-3-methyl-N-(3-morpholin-4-yl-propyl)-benzamide
The procedure and scale used in Example 301: step a was followed
using 2-iodo-3-methyl benzoic acid. Concentration of the solution and SiCh
flash column chromatography of the residue (0-10% MeOH in DCM) yielded
the product (878 mg, 63%) as a yellow glass.
b) 3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-
methyl-biphenyl-2-carboxylic acid (3-morpholin-4-yl-propyl)-amide bis
trifluoroacetamide
The procedure used in Example 295: step h was followed using 2-iodo-
3-raethyl-N-(3-morpholin-4-yl-propyl)-benzamide ((Example 302: step a) 150
mg, 0.39 mmol), {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5-
methylsulfanyl-thiophen-2-yt]-irnino-methyl]-cai:bamic acid ten-butyl ester
((Example 140: step a (25 mg, 0.0S mmol), Na2CO3 (2M, 1 mL, 2 mmol),
Pd(PPh3)4 (30 mg, 0.03 mmol), ethanol (1 mL) and toluene (2 mL).
Analogous aqueous workup followed by SiO2 flash column chromatography
(0-10% MeOH in DCM) yielded 60 mg of material which was treated with 1:1
TFA/DCM as described in Example 1: step d. Analogous purification by Cig-
HPLC yielded the title compound (22 mg, 55%) as a white solid.1H-NMR
(CD3OD): d 8.35 (s, 1H), 8.05 (ddd, 1H, J= 1.2, 1.9, 7.9 Hz), 7.96 (t, 1H, J =
1.6 Hz), 7.72 (t, 1H, J = 7.9 Hz), 7.66 (dt, 1H, 1.4, 7.7 Hz), 7.46 (m, 1H), 7.40
(m, 1H), 4.06 (m, 2H), 3.73 (m, 2H), 3.35 (m, 2H), 3.20 (m. 2H), 3.08 (ra,
2H), 2.94 (m, 2H), 2.73 (s, 3H), 2.09 (s, 3H), 1.75 (m, 2H). ESI-MS (ra/z):
Calcd. for C27H32N4O4S3 (M+H): 573.2; found: 573.2.
Example 303
4-[3-(6-Formyl-pyridin-2-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophene-2-
carboxamidine
a) 2-Bromo-6-dimethoxymethyl-pyridine
The procedure in Example 6: step b was followed using 6-bromo-
pyridine-2-carbaldehyde (600 mg, 3.23 mmol), trimethyl orthoformate (8 mL),
and toluenesulfonic acid (100 mg) in MeOH (50 mL). Analogous aqueous
workup yielded the product (743 mg) which was used without further
purification.
b) 4-[3-(6-Formyl-pyridin-2-yl)-benzenesulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine
To a slurry of Rieke Zinc (370 mg, 5.64 mmol) in THF (7.4 mL) was
added a solution of 2-bromo-6-dimeth.oxymethyl-pyrid.ine (400 mg, 1.7 mmol)
in THF (2.6 mL). The suspension was heated to 65 °C for 2h and the solution
was filtered through a 0.23 (am syringe filter into a THF solution of {[4-(3-
bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-
carbamic acid /e/t-butyl ester ((Example 27: step c) (2.50 mg, 0.5 mmol)) and
Pd(PPh3)4 (0.112 mg, 0.1 mmol).The reaction was heated at 80 °C for 30 min,
cooled, and was poured into aqueous NaHCO3. EtOAc (70 mL) was added
and the layers were separated. The organic layer was washed with NH4Cl (2 x
20 mL), NaHCCh (20 mL) and brine (30 mL) and was dried over sodium
sulfate. Concentration of the solution followed by SiO2 flash column
chromatography of the residue yielded 200 mg of the title compound which
was contaminated with 2-dimethoxyrnethyl-pyridine. The material was
treated with 1:1 TFA/DCM as described in Example 1: step d. Analogous
purification by C18-HPLC yielded the title compound (118 mg, 38%) as a
white solid. 1H-NMR (CD3OD) (aldehyde exists m hydrated form (acetal)) 5
8.60 (m, 2H), 8.44 (s, 1H), 8.33 (d, 1H, J= 7.9), 8.27 (d, 1H, J= 7.7)., 8.23 (d,
1H, 7= 7.7), 8.12 (d, 1H, J= 7.9), 7.9 (t, 1H, J = 7.7), 5.82 (s, 1H), 2.74 (s,
3H). ESI-MS (m/z) (sample in MeOH): Calccl. for C18H15N3O3S3 (M+H):
418.0; found: 449.9 (MeOH adduct).
Example 304
4-[3-(6-Methyl-benzo[l,3]dioxol-5-yl)-benzenesulfonyl]-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate
a) 5-bromo-6-methyl-benzo[l,3]dioxole
Bromine (3.36 g, 21 mmol) was added to a solution of piperonal
alcohol (3.0 g, 20 mmol) in chloroform (15 mL). The solution was heated to
60 °C for 12 h. After cooling, DCM (60 mL) was added and the solution was
extracted with aq NaHCO3 (2 x 20 mL), brine (20 mL), and was dried over
sodium sulfate. After concentration, the residue 5-bromo-6-bromomethyl-
benzo[l,3]dioxole (5.8Sg, 100%), solidified upon standing. A portion of the
crude solid (2.44g, 8.33 mmol) was dissolved in THF and cooled to -78 °C.
Lithium aluminum hydride (348 mg, 9.16 mmol) was added and the solution
was stirred for 3 h. An additional portion of LAH (80 mg, 2.03 minol) was
added and the reaction was stirred an additional hour EtOAc was added
carefully to quench the excess LAH, followed by addition of MeOH (20 mL).
The salts were filtered and the filtrate was concentrated in vacuo, to yield the
title compound (1.76 g, 99%) which was used without further purification.
1H-NMR (CDCl3): 6 7.01 (s, 1H), 6.73 (s, 1H), 5.95 (s. 2H), 2.32 (s, 3H).
b) 4-[3-(6-Methyl-benzo[l,3]dioxol-5-yl)-benzenesulfonyl]-5-
m ethylsulfanyl-th ioph en e-2-carboxam idin e trifluoroacetate
Butyllithium (2.5 M, 2.4 mL, 6 mmol) was added dropwise to a -78 °C
solution of 5-bromo-6-methyl-benzo[l,3]dioxole ({Example 304: step a) 64S
mg, 3 mmol) in Et20 (12 mL). The solution was stirred for 4 h maintaining
the temperature between -20 and -40 °C. The solution was cooled to -78 °C
and trimethylborate (5 mL, 44 mmol) was quickly added in one portion. The
solution was warmed to rt over 15 min and stirred for 1 h at rt (appearance of
gelatin-like ppt). The volatile components were removed in vacuo to give the
crude arylboronic acid as a yellow solid. A portion of the crude arylboronic
acid (99 mg, 0.4 mmol) was combined with {[4-(3-bromo-benzenesulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester
((Example 27: step c) (50 mg, 0.1 mmol)), aq Na2CO3 (2M, 0.8 mL, 1.6
mmol), ethanol (0.8 mL), and toluene (1.6 mL). The procedure used in
Example 1: step c was followed, and analogous workup yielded the product
which was purified by preparative TLC. The purified material was treated
with 1:1 TFA/DCM as described in Example 1: step d. Analogous
purification by Cis-HPLC yielded the title compound (25 mg, 45%) as a white
solid. 1H-NMR (CD3OD): d 8.32 (s, 1H), 7.99 (m, 1H), 7.93 (m, 1H), 7.64
(m, 2H), 6.79 (s, 1H), 6.68 (s, 1H), 2.72 (s, 3H), 2.12 (s, 3H),. ESI-MS (m/z):
Calcd. for C20H18N2O4S3 (M+H): 447.0; found: 447.2.
Example 305-306
4-[7-Bromo-3-(3-methyl-but-2-enyl)-3H-benzoimidazole-5-sulfony]J-5-
methylsulfanyl-thiophene-2-carboxaniidine bis-trifluoroacetate
4-[7-Bromo-l-(3-methyl-but-2-enyl)1H-benzoimidazole-5-sulfonyl]-5-
methylsulfanyl-tkiophene-2-carboxamidinebis-lnfluoroacetate
A mixture of {[4-(7-bromo1H-benzoimidazole-5-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-immo-methyl}-carbamic acid tert-butyl ester
{(Example 187-188; step c) 30 mg, 0.061 mmol), K2CO3 (10 rag, 0.072
mmol), and]-bromo-3-methyi-but-2-ene (60 µL, 0.5 mmol) were stirred in
DMF (2.5 mL for 16 h at rt. EtOAc (50 mL) was added and the organic
solution was washed with water (8 x 20 mL) and brine (20 mL) and was dried
over sodium sulfate. Removal of the solvent in vacuo yielded 22 mg of
material which was treated with 1:1 TFA/DCM as described in Example 1:
step d. Analogous purification by C18-HPLC (10-55% CH3CN over 30 min)
yielded the title compounds as white solids.
4-[7-Bromo-3-(3-methyl-but-2-enyl)-3H-benzoimidazole-5-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine bis-trifluoroacetate. lH-NMR
(CDCl3): d 8.55 (s, 1H), S.34 (s; 1H), 8.27 (m, 1H), 8.06 (m, 1H), 5.44 (m,
1H), 5.01 (m, 2H), 2.72 (s, 3H), 1.96 (s, 3H), 1.83 (s, 3H). ESI-MS (m/z):
Calcd. for Ci8Hi9BrN4O2S3 (M+H): 499.0; found: 498.9, 500.9 (m+2).
4-[7-Bromo-l-(3-methyl-bui-2-enyl)1H-benzoimidazole-5-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine bis-trifluoroacetate. H-NMR
(CDCl3): S 8.50 (br s, 1H), 8.37 (br s, 1H), 8.32 (s, 1H), 8.09 (s, 1H), 5.43 (m,
1H), 5.27 (m, 2H), 2.72 (s, 3H). 1.85 (s, 3H), 1.77 (s, 3H). ESI-MS (m/z):
Calcd. for QgH^BrN^Ss (M+H): 499.0; found: 498.9, 500.9 (m+2).
Example 307-308
4-(3-Benzyl-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine bis-trifluoroacetate
4-(l-Benzyl1H-benzoimidazole-5-suIfonyl)-5-methylsulfanyl-thiopliene-2-
carboxamidine bis-trifluoroacetate
The procedure in Example 318: step e was followed using 4-(4-amino-
3-nitro-ben2;enesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid
methyl ester ((Example 264: step a) 40 rag, 0.1 mmol) to yield the
benzimidazole intermediate which was used without further purification. ESI-
MS (m/z): Calcd. for C14H12N2O4S3: (M+H): 369.00; found: 369.1.
The procedure in Example 305/306 was followed using 4-(3H-
beiizoimidazole-5-sulfonyl)-5-methylsulfanyl-tbiophene-2-carboxylic acid
methyl ester ((Example 187-188: step c) 20 mg, 0.037 mmol), K2CO3 (25 mg,
0.18 nimol)., and benzyl bromide (30 mg, 0.175 mmol) in DMF (2.5 mL).
After analogous workup, the isomeric mixture of compounds was treated with
dimethylaluminum amide reagent (5 mL) following the procedure in Example
12: step f. Analogous workup and purification by HPLC yielded the title
compounds each as a white solid.
3-benzyl isomer: 1H-NMR (CD3OD): d 8.80 (br s, 1H), 8.26 (s, 1H), 8.20 (br
s, 1H): 7.88 (s, 2H), 7.36 (m, 5H), 5.66 (s, 2H), 2.56 (s, 3H). ESI-MS (m/z):
Calcd. for C20H1SN4O2S3 (M+H): 443.0; found: 443.1.
1-benzyl isomer: 1H-NMR (CD3OD): d S.62 (br s, 1H), 8.44 (s, 1H)5 8.32 (br
s, 1H), 7.94 (dd, 1H, J= 1.6, 8.8 Hz), 7.88 (s, 2H), 7.70 (d, 1H, J= 8.8 Hz),
7.34 (m, 5H), 5.58 (s, 2H), 2.72 (s, 3H). ESI-MS (m/z): Calcd. for
C2oHiSN.iO;)S3 (M+H): 443.0; found: 443.1.
Example 309
4-[7-Bromo-lR-(l-phenyl-ethyl)1H-benzoimidazole-5-sulfonyr]-5-
methylsulfanyl-thiophene-2-carboxarnidine bis-trifluoracetate
The procedures used in Example 318: parts d-f were followed using
with 4-(3-bromo-4-chloro-5-nitro-benzenesulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester ((Example 318: part c) 35 mg, 0.072
mmol), 1R-phenyl-ethylaimine (50 rag), and DD5A. (100 µL). All other reagent
amounts, reaction conditions;, and purifications were identical to Example 318
d-f. 1H-NMR (CD3OD): d 8.86 (s, 1H), 8.23 (s, 1H), 8.01 (d, 1H, J= 1.4 Hz),
7.96 (d, 1H, J= 1.4 Hz), 7.35 (m, 5H), 5.95 (q, 1H, J= 7.2 Hz), 2.56 (s, 3H),
2.07 (d, 3H, J= 7.2 Hz). ESI-MS (m/z): Calcd. for CaiHigBrN^Sj (M+H):
535.0; found: 534.9, 536.9 (m+2).
Example 310
4-[7-Bromo-1S-(1-phenyl-ethyl)-1H-benzoimidazole-5-sulfonyl] -5-
methylsulfanyl-thiopbene-2-carboxamidine bis-trifluoracetate
The procedures used in Example 318: parts d-f were followed using
with 4-(3-bromo-4-chloro-5-nitro-benzenesulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester ((Example 318: part c) 35 mg. 0.072
mmol), 1S-phenyl-ethylamine (50 mg), and DIEA (100 µL). All other reagent
amounts, reaction conditions, and purifications were identical to Example 318
d-f. 1H-NMR (CD3OD): d 8.86 (s, 1H), 8.23 (s, 1H), 8.01 (d, 1H, J= 1.4 Hz),
7.96 (d, 1H,J= 1.4 Hz), 7.35 (m, 5H), 5.95 (q, 1H, J= 7.2 Hz), 2.56 (s, 3H),
2.07 (d, 3H,J= 7.2 Hz). ESI-MS (m/z): Calcd. for C21H19BrN4O2S3 (M+H):
535.0; found: 534.9, 536.9 (m+2).
Example 311
6-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-methyl-
biphenyl-4-yl]-ureido}-hexanoic acid ethyl ester triiluoroacetate
a) 6-(3-{3'-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-
methylsulfanyl-thiophene-3-sulfonyl]-2-methyl-biphenyl-4-yl}-ureido)-
hexanoic acid ethyl ester
Diisopropylethylamine (35 µL, 0.2 mrnol), 6-isocyanato-hexanoic acid
ethyl ester (40 µL, 0.2 mmol), and {[4-(4'-amino-2'-methyl-bi.phenyl-3-
sulfonyl)-5-methylsulfanyl-tkiophen-2-yl]-imino-inethyl}-carbamic acid tert-
butyl ester ((Example 220: step b) 20 mg, 0.04 mmol) were stirred for 24 h in
DCM (1 mL). The solution was partitioned between EtOAc (40 mL) and 0.1
N HC1 (10 mL) and was washed with additional 0.1N HC1 (2 x 10 mL),
NaHCO3 (10 mL), and brine; (20 mL). The solution was dried, concentrated in
vacuo, and purified by SiO2 preparative TLC to yield the product (12 mg,
43%). 1H-NMR (CDCl3): d 8.06 (s, 1H), 7.94 (m, 1H), 7.81 (m, 1H), 7.46 (m,
2H), 7.23 (br t, 1H, J= 5.4 Hz), 7.15 (m, 1H), 7.07 (m, 2H), 6.97 (m, 1H),
5.32 (br t, 1H), 4.15 (q, 2H, J= 7.2 Hz), 2.40 (s, 3H), 2.30 (t, 2H, J = 7.3 Hz),
2.11 (s, 3H), 1.54-1-70 (m, 4H), 1.51 (s, 9H) 1.35 (m, 2H), 1.25 (t, 3H, J= 7.3
Hz).
b) 6-{3-[3'-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-
2-methyl-biphenyl-4-yl]-ureido}-hexanoic acid ethyl ester trifluoroacetate
Following the procedure in Example 1: step d, 6-(3-{3'-[5-(ie/7-
butoxycarbonylamino-iinino-methyl)-2-methylsulfanyl-thiophene-3-sulfonylj-
2-methy]-biphenyl-4-yl}-ureido)-hexanoic acid ethyl ester ((Example 311:
step a) 12 mg) was treated with 1:1 TFA/DCM. Purification by HPLC yielded
the product (8.3 mg) as a white solid. 1H-NMR (CD3OD): d 8.31 (s, 1H), 7.97
(m, 1H), 7.94 (m, 1H), 7.65 (m, 2H), 7.29 (m, 2H), 7.09 (m, 1H), 4.10 (q, 2H.
7.2Hz), 3.20 (t, 2H, 7.0 Hz), 2.71 (s, 3H), 2.33 (t, 2H, J = 7.3 Hz). 2.19 (s.
3H), 1.65 (m, 2H), 1.55 (m, 2H), 1.40 (m, 2H), 1.23 (t, 3H, J= 7.2 Hz). ESI-
MS (m/z): Calcd. for C28H24N4O5S3 (M+H): 603.2; found: 603.2.
Example 312
6-{3-[3l-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-2-methyi-
biphenyl-4-yl]-ureido}-hexanoic acid trifluoroacetate
Aqueous sodium hydroxide (1M, 0.75 µL), was added to a solution of
6-(3-{3'-[5-(tert-butoxycarbonylarnino-imino-methyl)-2-methylsulfai!yl-
thiophene-3-sulfonyl]-2-methyl-biphenyl-4-yl} -ureido)-hexanoic acid ethyl
ester {Example 311: step a) 52 mg, 0.07 mmol) in MeOH. The solution was
stirred for 6 h at rt, AcOH was added (100 µL) and the solvent was removed in
vacuo. The residue was treated with 1:1 TFA/DCM as in Example 1.step d
and analogously purified via RP-HPLC to yield a white solid (26 mg, 54%).
1H-NMR (CD3OD): 6 8.34 (s, 1H), 8.00 (m, 1H), 7.95 (m, 1H), 7.67 (m, 2H),
7.32 (m, 2H), 7.11 (d, 1H, J= 8.4 Hz), 3.24 (t, 2H, 7.0 Hz), 2.74 (s, 3H), 2.34
(t, 2H, J= 7.3 Hz), 2.22 (s, 3H), 1.68 (m, 2H), 1.59 (m, 2H). 1.44 (m, 2H).
ESI-MS (m/z): Calcd. for C26H30N4O5S3 (M+H): 575.1; found: 575.1.
Example 313
6-{3-[3"-(5-Carbamimidoyl-2-methylsulfanyl-thiophene-3-sulfonyl)-6-methyl-
biphenyl-2-yl]-ureido}-hexanoic acid ethyl ester trifluoroacetate
The procedure used In Example 311: step a was followed using {[4-
(6'-amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen--2-yl]-
imino-methyl}-carbamic acid tert-butyl ester ((Example 25: step c) 60 mg,
0.12 mmol), 6-isocyanato-hexanoic acid ethyl ester (28 mg, 0.15 mmol), and
DIEA (89 µL, 0.5 mmol). After analogous workup and purification, the crude
material was treated with 1:1 TFA/DCM as in Example 1: step d. Analogous
HPLC purification yielded the product (20 mg, 24%) as a white solid. 1H-
NMR (CD3OD): d 8.31 (s, 1H), 8.06 (ddd, 1H, J - 1.2, 1.9, 7.9 Hz), 7.90 (t,
1H, J= 1.6 Hz), 7.72 (t, 1H,J= 7.9 Hz), 7.13 (m, 1H), 4.11 (q, 2H, 7.2Hz),
2.99 (m, 2H), 2.73 (s, 3H), 2.29 (t, 2H,J= 7.4 Hz), 2.01 (s, 3H), 1.65 (m, 2H),
1.55 (m, 2H), 1.35 (m, 2H), 1.23 (t, 3H, J= 7.2 Hz). ESI-MS (m/z): Calcd.
for C28H34N4O5S3 (M+H): 603.2; found: 603.2.
Example 314
4-(4'-Guanidino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-
2-carboxamidine bis-trifiuoroacetate
DIEA (89 (µL, 0.5 mmol) was added to solution of {[4-(4'-amino-2'-
methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-
carbamic acid tert-butyl ester ((Example 220: step b) 26 mg, 0.05 mmol), 1,3-
bis-(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (29 mg, 0.1 mmol) and
HgCl2 (27 mg, 0.1 mmol) in DMF (2 mL). The solution became hazy after
stirring for 5 min at rt. The solution was stirred for 24 h at rt and then was
partitioned between EtOAc (40 mL) and water (20 mL). The layers were
separated and the organic layer was extracted with citric acid (2x10 mL),
NaHCO3 (20 mL), water (6 x 10 mL), and brine (20 mL). After drying
(Na2SO4) and concentration in vacuo the residue was purified by preparative
TLC. The protected guanidine was treated 1:1 TFA/DCM as in Example 1:
step d. Analogous HPLC purification yielded the; product (8 mg, 24%) as a
white solid. 1H-NMR (CD3OD): d 8.35 (s, 1H), 8.04 (m, 2H), 7.71 (m, 2H),
7.35 (d, 1H, J= 8.1 Hz), 7.28 (d, 1H, J= 2.3 Hz), 7.23 (dd, 1H, J= 2.3, 8.1
Hz), 2.74 (s, 3H), 2.28 (s, 3H). ESI-MS (m/z): Calcd. for C20H21N5O2S3
(M+H): 460.1; found: 460.2, 230.1 (m/2).
Example 315
4-[2'-Methyl-4'-(N'-methoxyl-guanidino)-bipheny3-3-sulfonyl]-5-
rnethylsulfanyl-thiophene-2-carboxamidmebis-trifluoroacetate
a) {Imino-[4-(4'-isothiocyanato-2'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophen-2-yl]-methyl}-carbamic acid tert-butyl ester
A solution of l,l'-thiocarbonyldi-2(lH)-pyridone in DCM (0.25 M,
300 µL, 0.075 mmol) was added to {[4-(4'-amino-2'-methyl-biphenyl-3-
sulfonyl)-5-methylsulfanyl-tbiophen-2-yl]-imino-methyl}-carbamic acid tert-
butyl ester ((Example 220: step h) 26 mg, 0.05 mmol) at it. The orange color
of the thiourea dissipated as the reagent was added, and a new higher spot
appeared on TLC. The solvent was removed in vacuo and the residue was
purified by preparative TLC to yield 23 mg of product. 1H-NMR (CDCl3): d
8.01 (br s, 1H), 7.96 (d, 1H, J= 7.4 Hz), 7.87 (s, 1H), 7.53 (m, 2H), 7.10 (d,
1H, J= 7.9 Hz), 6.93 (br s, Hi), 6.87 (d, 1H, J= 7.9 Hz), 2.51 (s, 3H), 2.2 7 (s,
3H), 1.50 (s, 9H).
b) 4-[2'-Methyl-4'-(N'-methoxyl-guanidino)-biphenyl-3-sulfonyl]-5-
methylsulfanyl-thiophene-2-carboxamidine bis-trifluoroacetate
Methoxylamine hydrochloride (30 mg, 0.36 mmol), {imino-[4-(4'-
isotliiocyanato-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-
yl]-methyl}-carbamic acid tert-butyl ester (Example 315: step a), 21 mg,
0.038 mmol), and triethylamine (100 µL) were stirred in DCM (2 mL)/CH3CN
(lmL), was stirred for 1 h at rt. The solution was partitioned between EtOAc
(40 m.L) and water (20 rnL) and the layers were separated. The organic layer
was extracted with citric acid (3 x 10 mL), NaHCO3 (20 mL), and brine (20
mL). After drying (Na2SO4) and concentration in vacua, the residue was
purified by preparative TLC. The purified material was dissolved in ammonia
in MeOH (2M, 10 mL) and mercuric oxide (100 mg) was added. The mixture
was stirred overnight at rt and at 40 °C for 3 h. The solution was filtered and
the filtrate was concentrated in vacuo. The residue purified by preparative
TLC and the product was treated with 1:1 TFA/DCM as in Example 1: step d.
Purification by HPLC yielded the product (6 mg, 23%) as a white solid. 1H-
NMR (CD3OD): 6 8.36 (s, 1H), 8.05 (m, 2H), 7.72 (m, 2H), 7.30 (m, 1H),
7.25 (ddd, 1H, J= 0.45, 2.3, 8.1 Hz), 7.36 (d, 1H, J= 8.1 Hz), 3.84 (s, 3H),
2.74 (s, 3H), 2.29 (s, 3H). ESI-MS (m/z): Calcd. for C21H23N5O3S3 (M+H):
490.1; found: 490.1.
Example 316
4-[7-Bromo-3-(3,5-dimethyl-isoxazol-4-ylmethyl)-3H-benzoimidazole-5-
sulfonyl]-5-methylsulfainyl-thiophene-2-carboxamidine bis-trifluoroacetate
Example 317
4-[7-Bromo-l-(3;5-dimethyl-isoxazol-4-ylmethyl)1H-benzoimidazole-5-
sulfonyl]-5-methylsulfainyl-thiophene-2-carboxamidine bis-trifluoroacetate
The procedure in Example 305-306 was followed using {[4-(7-bromo-
1 H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imi no-
methyl}-carbamic acid tert-butyl ester ((Example 187-188: step c) 20 mg,
0.037 mmol), K2CO3 (25 mg, 0.18 mmol), and 4-chloromethyl-3.5-dimethyl-
isoxazole (25 µL, 0.15 mmol) in DMF (2.5 mL). The title compounds were
isolated as white solids.
Example 316: 1H-NMR (CDCl3): d 8.69 (s, 1H), 8.33 (s, 1H), 8.10 (d, 1H, J =
1.6 Hz), 7.98 (d, 1H, J = 1.6 Hz), 5.52 (s, 2H), 2.67 (s, 3H), 2.55 (s, 3H), 2.02
(s, 3H). ESI-MS (m/z): Called, for C19H18BrN5O3S3 (M+H): 540.0; found:
540.0, 542.0 (m+2).
Example 317: :H-NMR (CDCl3): d 8.43 (br s, 1H), 8.40 (d, 1H, J= 1.6 Hz),
8.35 (s, 1H), 8.13 (d, 1H,J= 1.6 Hz), 5.73 (s, 2H), 5.27 (m, 2H), 2.73 (s, 3H),
2.19 (s, 3H), 2.03 (s, 3H). ESI-MS (m/z): Calcd. for C19H18BrN5O3S3 (M+H):
540.0; found: 540.0, 542.0 (m+2).
Example 318
4-(7-Bromo-l-phenyl1H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxamidme trifluoroacetate
a) 4-Amino-3-bromo-5-nitro-benzenesulfonyl chloride
4-Amino-3-bromo-5-nitrobenzenesulfonamide ((US 3987199) 1 g,
3.17 mmol) was heated at 95 °C for 3 h in chlorosulfonic acid (10 mL). The
solution was cooled then poured onto ice and then filtered. The solid was
redissolved in DCM and dried over sodium sulfate. Removal of the solvent
yielded the product (960 mg) which was used without further purification.
b) 4-(4-Amino-3-bromo-5-nitro-benzenesulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester
Sodium sulfite (643 nig, 5.1 mmol) and NaHCO3 (4S0 mg. 5.7 mmol)
were dissolved in water (20 mL) and 4-amino-3-bromo-5-
nitrobenzenesulfonyl chloride ((Example 318: step b) 940 mg, 3 mmol) was
added. The suspension was stirred for 1 h at rt and 5 mL of EtOH was added
to aid dissolution. The mixture was stirred for 4 h at rt, during which nearly
all of the sulfonyl chloride had dissolved and the major spot on TLC was at
the baseline. The solvent was removed in vacuo and DMF was added (10
mL). The mixture was stirred for 15 min and the inorganic salts were allowed
to settle. The DMF was removed via syringe, the salts were washed with a
second portion of DMF (10 mL), and the combined DMF solution was slowly
added to a 0 °C solution of 4-bromo-5-nitro-thiophene-2-carboxylic acid
methyl ester ((Example 114: step c) 800 mg, 3 mmol) in DMF (20 mL). The
solution was stirred for 0 °C for 1 h then overnight at rt. The DMF was
removed in vacuo and the residue was partitioned between EtOAc (100 mL)
and aq NaHCO3 (30 mL). The layers were separated and the organic layer
was washed with aq NaHCO3 (2 x 20 mL), water (30 mL), and brine (30 mL),
then dried over soldium sulfate. The solution was concentrated and the
residue was dissolved in THF (20 mL) and cooled to -78 °C. A solution of
sodium methoxide in methanol (1M, 3.75 mL, 3.75 mmol) was added
dropwise and the reaction was stirred for 30 min. Acetic acid (500 µL) was
added followed by EtOAc (100 mL). The solution was washed with NaHCO3
(3 x 30 mL,), brine (40 mL), and was dried over sodium sulfate. Concentration
and chromatography of the residue yielded the product (430 mg). 1H-NMR
(CDCl3): 6 8.88 (d, 1H, J= 2.1 Hz), 8.27 (d, 1H, J= 2.1 Hz), 8.06 (s, 1H),
3.93 (s, 3H), 2.67 (s, 3H).
c) 4-(3-Bromo-4-chloro-5-nitro-benzenesulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid methyl ester
To a mixture of CuCl2 (142 mg, 1.06 mmol), and terr-butylnitrite (157
µL, 1.32 mmol) in CH3CN (10 mL) was added a solution of 4-(4-amino-3-
bromo-5-nitro-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic
acid methyl ester {(Example 318: step b) 410 mg, 0.88 mmol) in CEUCN (10
mL), dropwise over 5 min. After 1.5 h, extra CuCl2 (142 mg), and tert-
butylrntrite (157 jaL) were added and the reaction was stirred an additional 1.5
h. The solution was cooled then partitioned between EtOAc (120 mL) and
water (50 mL). The organic layer was washed with water (2 x 20 mL) and
brine (30 mL) then was dried over sodium sulfate. Concentration of the
solution followed by chromatography yielded an impure product (285 mg,
68%) that was used without further purification 1H-NMR (CDCl3): d 8.43 (d,
1H, J=- 2.1 Hz), 8.34 (d, 1H, J= 2.1 Hz), 8.02 (s, 1H), 3.90 (s, 3H), 2.66 (s,
3H).
d) 4-(3-Brom o-5-nitro-4-ph enylam in o-ben zenesnlfonyl)-5-
methylsulfanyl-thiophene-2-carboxylic acid methyl ester
A mixture of aniline (112 mg, 1.35 mmol), 4-(3-bromo-4-chloro-5-
nitro-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl
ester ((Example 318: step c) 53 mg, 0.11 mmol), and sodium acetate (16.5 mg,
0.2 mmol) in dioxane (3 mL) was heated at 80 ° C for 24 h. The mixture was
partitioned between EtOAc (50 mL) and 0.5 N HC1 (10 mL) and the organic
layer was further extracted with 0.5 N HC1 (2 x 10 mL), NaHCO3 (10 mL),
and brine (20 mL). Drying of the solution over sodium sulfate followed by
concentration yielded the product (58 mg) which was used without further
purification. 1H-NMR (CDCl3): d 8.04 (s, 1H), 7.64 (d, 1H, J=2.1 Hz), 7.32
(d, 1H, J= 1.9 Hz), 7.25 (m, 2H), 6.95 (m, 1H), 6.69 (m, 2H), 5.70) (s, 1H),
3.90 (s, 3H), 2.66 (s, 3H).
e) 4-(7-Bromo-l-phenyl1H-benzoimidazole-5-sulfonyl)-5-
methylsnlfanyl-thiophene-2-carboxylic acid methyl ester
Iron powder (110 mg, 2 ramol) was added to a solution of 4-(3-bromo-
5-nitro-4-phenylamino-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid methyl ester {Example 318: step d) in EtOH (4 ml.) and 50%
aqueous AcOH (1 mL). The reaction was stirred for 30 min at 60 °C during
which a new lower spot became evident by TLC analysis. EtOAc (10 mL)
was added and the mixture was filtered through a 0.22 µm polypropylene
syringe filter. Additional EtOAc (30 mL) was added and the solution was
extracted with aq NaHCO3 (3 x 10 mL) and brine (20 mL). The solution was
dried and concentrated in vacuo. One-half of the residue (26 mg) was
suspended in formic acid (3 mL) and was heated at 95 °C for 4 h. The formic
acid was removed in vacuo and the residue was purified by chromatography to
yield the product (23 mg). 1H-NMR (CDCl3): d 8.56 (d, 1H, J= 1.6 Hz), 8.13
(s, 1H), 8.07 (d, 1H, J= 1.6 Hz), 8.04 (s, 1H), 7.55 (m, 3H, 7.41 (m, 2H), 3.87
(s, 3H), 2.61 (s, 3H).
f) 4-(7-Bromo-l-phenyl1H-benzoimidazole,-5-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
The procedure in Example 12: step f was followed using 4-(7-bromo-l-
phenyl-1H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxylic acid methyl ester ((Example 318: step e) 23 mg, 0.044 mmol) and
dimethylaluminum amide reagent (5 mL). Analogous workup and purification
by HPLC yielded the title compound as a white solid (16 mg, 49%). 1H-NMR
(CD3OD): d 8.53 (s, 1H), 8.47 (d, 1R J= 1.6 Hz), 8.37 (s, 1H), 8.10 (d, 1H, J
= 1.6 Hz), 7.53-7.65 (m, 5H), 2.73 (s, 3H). ESI-MS (m/z): Caicd. for
C19H15BrN4O2S3(M+H): 507.0; found: 507.1, 509.1 (m+2).
Example 319
4-(6-Arnino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-
carboxamidine
a) 3-Bromo-4-fluoro-phenylamine
Sodium chlorite (6.78 g, 75 mmol) and 4-fluoro-3-bromobenzaldehyde
(24.63 mmol) were dissolved in 1:1 THF/water (100 rnL) and stirred
vigorously at 50 °C for 5 h. EtOAc (250 mL) and 1N HCl (50 mL) was added
and the layers were separated. The organic layer was washed with water (3 x
50 mL), then was extracted with 0.5M Na2CO3 (10 x 50 mL). The combined
basic aqueous layers were slowly acidified with concentrated HC1 while
stirring, to precipitate the carboxylic acid product. The solid was collected via
filtration and dried under high vacuum overnight (4.93 g, 91%). A portion of
the solid carboxylic acid was dissolved in chloroform (30 mL) and
concentrated sulfuric acid was added. A reflux condenser was attached to the
flask and the solution was heated to 55 °C. Sodium azide (2.36 g, 36.45
mmol) was added in 3 portions over 1 h. After 4 h, additional sulfuric acid (10
mL) and sodium azide (1 g) were added and the reaction was stirred at 55 °C
for 16 h. The mixture was transferred to a large cooled flask and the sulfuric
acid was slowly quenched with 5N sodium hydroxide. The solution was
adjusted to pH-8 and the aqueous solution was extracted with DCM (5 x 30
mL). The organic extracts were dried over sodium, sulfate and concentrated in
vacuo to yield a dark brown oil (2.2 g, 95%) that solidified upon standing.
1H-NMR (CDCl3): d 6.94 (t, 8.4 Hz), 6.88 (dd, 1H, J = 2.8, 5.6 Hz), 6.58 (m,
1H), 3.62 (s, 2H).
b) 3-Bromo-4-fluoro-benzenesulfonyl chloride
Concentrated HC1 (1.93 mL, 23.16 mmol) was added to a solution of
3-bromo-4-fluoro-phenylamme ((Example 265: part a) 2.2 g, 11.58 mmol) in
15 ml, of 2:1 DCM/MeOH. A precipitate appeared and another 9 mL of 2:1
DCM/MeOH was added. The solution was cooled to -5 °C and tert-
butylnitrate (2.71 mL, 23.16 mmol) was added dropwise over 8 mm. After
stirring for 15 min, sulfur dioxide (-5 mL) was condensed into the reaction,
followed by addition of copper (II) chloride (592 mg, 3.47 mmol) (gas
evolution). The solvent was removed in vacuo and the residue was purified by
SiO2 flash column chromatography to yield the title compound (1.9 g, 59%).
1H-NMR (CDCl3): d 8.31 (dd, 1H, J = 2.3, 5.8 Hz), S.04 (ddd, 1H, J = 2.6, 4.1,
8.8 Hz), 7.39 (dd, 1H, J = 7.7, 8.8 Hz).
c) 4-(3-Brom o-4-fluoro-benz,en esulfonyl)-5-methylsulfanyl-thiophene-
2-carboxylic acid methyl ester
3-Bromo-4-fluoro-benzenesulfonyl chloride ((Example 319: part b) 1.9
g, 6.83 mmol) and sodium bicarbonate (1.15 g, 13.66 mmol) was suspended in
16 mL of water at 70 °C. A solution of sodium sulfite (1.64 g, 13 mmol) in 15
mL of water was added in 3 portions over 3 h. The mixture was stirred for 16
h, and the solvent was removed in vacuo. DMF (15 mL) was added, the
mixture was stirred for 15 min, and the inorganic salts were then allowed to
settle. The DMF was removed via syringe, the salts were washed with a
second portion of DMF (10 mL), and the combined DMF solution was slowly
added to a 0 °C solution of 4-bromo-5-nitro-thiophene-2-carboxylic acid
methyl ester ((Example 114, step c) 931 mg, 3.5 mmol) in DMF (15 mL). The
solution was stirred for 0 °C for 1 h. The DMF wa:s removed in vacuo and the
residue was partitioned between EtOAc (100 mL) and aq NaHCO3 (30 mL).
The layers were separated, and the organic layer was washed with aq NaHCO3
(2 x 20 mL), water (30 mL), and brine (30 mL), then dried over sodium
sulfate. The solution was concentrated and the residue (1.42 g) was dissolved
in THF (20 mL) and cooled to —78 °C. A solution of sodium methoxide in
methanol (1M, 5 mL, 5 mmol) was added dropwise and the reaction was
stirred for 30 min at -78 °C. Acetic acid (500 µL) was added followed by
EtOAc (100 mL). The solution was washed with NaHCO3 (3 x 30 mL), bnne
(40 mL), and was dried over sodium sulfate. Concentration and
chromatography of the residue yielded the title compound (502 mg:, 17%) as a
yellow solid. 1H-NMR (CDCl3): 6 8.16 (dd, 1H, J = 2.3, 6.3 Hz), 7.94 (s, 1H),
7.91 (ddcl, 1H, J = 2.6, 4.4, 8.6 Hz), 7.39 (dd, 1H, J = 5.3, 8.6 Hz).
d) 4- (4-A m in o-3-bromo-benzen esulfonyl)-5-methylsulfanyl-thiophene-
2-carboxylic acid amide
The procedure in Example 124: step a was followed using 4-(3-bromo-
4-fluoro-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid
methyl ester ((Example 319: part c) 100 mg, 0.24 mmol). After 24 h, the
ammonia was allowed to evaporate and the solid product was used without
further purification. 1H-NMR (CDCl3): d 7.73 (d, 1H, J = 2.1 Hz), 7.69 (s,
1H), 7.42 (dd, 1H, J = 2.1, 8.6 Hz), 6.57 (d, 1H), 3.14 (s, 2H), 2.36 (s, 3H).
e) 4-(6-Amino-2'-methyl-biphenyl-5-sulfonyl)-5-methylsulfanyl-
thiophene-2-carboxylic acid amide
The procedure used in Example 1: step c was followed using 4-(4-
amino-3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic
acid amide ((Example 319: part d) 44 mg, 0.11 mmol), 2-methylphenylboronic
acid (54 mg, 0.4 mmol), aq Na2CO3 (2M, 800 µL, 1.6 mmol), and Pd(PPh3)4
(29 mg, 0.025 mmol). Analogous workup and purification by preparative
TLC yielded the title compound (24 mg, 56%). 1H-NMR (CDCl3): d 7.97 (s,
1H), 7.76 (dd, 1H, J = 2.3, 8.6 Hz), 7.67 (d, 1H, J = 2.3 Hz), 7.32 (m, 2H),
7.28 (m, 1H), 7.16 (m, 1H), 6.76 (d, 1H, J = 8.6 Hz), 4.11 (s, 2H)f 2.58 (s,
3H)7 2.13 (s, 3H).
f) 4-(6-Amino-2'-methyl-biphenyl-3-sulfonyl)-5-metltylsulfanyl-
thiophene-2-carboxamidine bis-trifluoroacetate
The reaction conditions in Example 12: step f were followed using 4-
(6-amino-2'-methyl-biphenyl-3-sulfonyl)-5-methylsulfany]-thiophene-2-
carboxylic acid amide ((Example 319: part e) 24 mg. 0.06 rnmol) and
dimethylaluminura amide reagent (5 mL). Analogous workup and HPLC
purification yielded the title compound as an off-white solid (8.8 mg, 24 %).
1H-NMR (CD3OD): d 8.24 (s, 1H), 7.72 (dd, 1H, J = 2.3, 8.S Hz), 7.52 (d. 1H,
7= 2.3 Hz), 7.33 (m, 2H), 7.28 (m, 1H), 7.12 (m, 1H), 6.85 (d. 1H. J = 8.8
Hz), 2.71 (s, 3H), 2.10 (s, 3H). ESI-MS (m/z): Calcd. for C10H19N3O2S3
(M+H): 418.1; found: 41 S.I.
Example 320
4-(6'-Methanesulfonylamino-2'-methyl-biphenyl-3-sulfonyl)-:5-
methylsulfanyl-thiophene-2-carboxamidine trifluoroacetate
{[4-(2'-Amino-6'-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-
thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (20 mg, 0.04
mmol, Example 25 : step c) and methane sulphonyl chloride (5 mg, 0.04
mmol) were dissolved into toluene (lmL) and heated to 100 ° C for 48 hours.
The solvents were removed in vacuo resulting in the desired product with loss
of the tert-butyl protection group. The resulting compound was purified as in
Example 1: step d, yielding the title compound as an off-white solid (1.3 mg).
1H-NMR (CD3OD): d 8.29 (s, 1H), 8.07-8.05 (d, 1H, J= 7.21 Hz), 7.90 (m,
1H), 7.72-7.68 (t, 1H, J= 8.14 Hz, J= 7.67 Hz), 7.57-7.55 (d, 1H, J= 7.67
Hz) 7.35 (m, 2H), 7.26 (m, 1H), 2.75 (s, 3H), 2.50 (s, 3H). 1.30 (s, 3H). ESI-
MS (m/z): Calcd. for C20H21N3O3S4: 496.0 (M+1); found: 496.1.
Example 335
Tablet Preparation
Tablets containing 25.0, 50.0, and 100.0 mg, respectively, of an active
compound are prepared as illustrated below:
TABLET FOR DOSES CONTAINING FROM
25-100 MG OF THE ACTIVE COMPOUND
Amount-mg
Active Compound 25.0 50.0 100.00
Microcrystalline cellulose 37.25 100.0 200.0
Modified food corn starch 37.25 4.25 8.5
Magnesium stearate 0.50 0.75 1.5
All of the active compound, cellulose, and a portion of the comstarch
are mixed and granulated to 10% corn starch paste:. The resulting granulation
is sieved, dried and blended with the remainder of the corn starch and the
magnesium stearate. The resulting granulation is then compressed into tablets
containing 25.0, 50.0, and 100.0 mg, respectively, of active ingredient per
tablet.
Example 336
Intravenous Solution Preparation
An intravenous dosage form of the above-indicated active compounds
is prepared as follows:
Active Compound 0.5-10.0 mg
Sodium Citrate 5-50 mg
Citric Acid 1-15 mg
Sodium Chloride 1-8 mg
Water for Injection (USP) q.s. to 1 ml
Utilizing the above quantities, the active compound is dissolved at
room temperature in a previously prepared solution of sodium chloride, citric
acid, and sodium citrate in Water for Injection (LISP, see page 1636 of United
States Pharmacopeia/National Formulary for 1995, published by United States
Pharmacopeial Convention, Inc., Rockville, Maryland (1994).
Example 33 7
In vitro Inhibition of C1s
Reagents: All buffer salts were obtained from Sigma Chemical
Company (St. Louis, MO), and were of the highest purity available. DTNB
was purchased from Pierce (Rockford, IL). Z-Gly-Arg-S-Bzl was purchased
from Enzyme Systems Products (Livermore, CA). Activated human C1s was
purchased from Calbiochem (La Jolla, CA).
K, Determinations: All assays are based on the ability of the test
compound to inhibit the C1s-catalyzed hydrolysis of the substrate Z-Gly-Arg-
S-Bzl, which is observed via a secondary reaction with 5,5'-dithio-bis(2-
nitrobenzoic acid) (DTNB), In a typical K, determination, substrate is
prepared in DMSO, and diluted into an assay buffer consisting of 50 mM
HEPES, 200 mM NaCl, pH 7.5, 0.05% n-octyl-b-D-glucopyranoside.
Substrate solutions were prepared at a concentration of 45 uM (Km = 190 uM)
with DTNB at a concentration of 200 uM in assay buffer. Test compounds are
prepared as a 10 uM solution in DMSO. Dilutions are prepared in DMSO
yielding 7 final concentrations encompassing a 700-fold concentration range.
Purified activated C1s was diluted into assay buffer for a working
concentration of 66 nM.
In a typical Ki determination, into each well of a 96-well plate is
pipetted 280 µL of substrate solution, 10 µL of test compound solution, and
the plate allowed to thermally equilibrate at 37°C for 15 minutes. Reactions
were initiated by the addition of a 10 µL aliquot of the enzyme, and the
absorbance increase at 405 nm is continuously recorded for 15 minutes in a
Molecular Devices plate reader. Final DMSO concentration was 4.3%. Final
reagent concentrations were: [Cls] = 2.3 nM, [Z-Gly-Arg-S-Bzl] = 45 µM,
[DTNB] = 200 µM. The ratio of the velocity (rate of change in absorbance as
a function of time) for a sample containing no test compound is divided by the
velocity of a sample containing test compound, and is plotted as a function of
test compound concentration. The data are fit to a linear regression, and the
value of the slope of the line: calculated. The inverse of the slope is the
experimentally determined Ki value.
Complement Inhibition Data
The following compounds have Ki values in the range of 0.006 to
0.023 micromolar (uM) for C1s: Examples 1-13, 15-20, 24-26, 28-30, 32-35,
37, 41-96, 98-110, 114-119, 121, 135-136, 171, 173, 184, 192, 194-195, 203,
207, 209-211, 219-220, 224, 228, 231, 233, 236-239, 240, 242, 246, 252, 254-
263, 275, 280, 282, 294-296 and 314-315.
The compound of Example 11 has a Ki value of 0.023 µM for C1s.
The compound of Example 61 has a Ki value of 0.006 µM for C1s. The
results indicate that the compounds of the present invention are inhibitors of
complement, specifically C1s.
Having now fully described this invention, it will be understood to
those of ordinary skill in the art that the same can be performed within a wide
and equivalent range of conditions, formulations, and other parameters
without affecting the scope of the invention or any embodiment thereof. All
patents and publications cited herein are fully incorporated by reference herein
in their entirety.
WE CLAIM:
1. Thiophene amidines comprising a compound having the following
formula:
or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein:
Z is-S(O2)-;
R1 is C1-6 alkylthio or methylsulfonyl; and
R5 is phenyl substituted by three substituents;
one of the substituents being C1-4 alkyl or halo;
the second substituent being C1-4 alkyl, C1-4 alkoxy, hydroxyl, amino, nitro,
optionally-substituted ureido, or optionally substituted alkylcarbonylamino;
and the third substituent being either optionally-substituted ureido, or optionally-
substituted guanidino.
2. The compound as claimed in Claim 1 in which R1 is methylthio.
3. The compound as claimed in Claim 2 in which the C1-4 alkyl substituent
on R5 is methyl.
4. A compound as claimed in claim 1, wherein said optionally-substituted
ureido has the formula -N(L1)-C(O)-N(L2)-Y2a-X2-Y2b-Z2, wherein:
L1 and L2 are both hydrogen, or L1 and L2 together represent ethylene or
trimethylene;
Y2a is a direct covalent bond or an a,?-diradical of a C1-10 straight or
branched alkane;
X2 is O or S, or a direct covalent bond;
Y2b is an a,?-diradical of a d-10 straight or branched alkane, optionally
substituted with a carboxy group; and
Z2 is carboxy, (C1-6 alkoxy)carbonyl, phenoxy, carboxyphenoxy, C1-6
alkylsulfonyl, phenyl, benzyloxycarbonylamino, amino, C1-4 alkylamino,
halophenyl, indolyl, diphenylmethyl, phenylsulfonylamino, N'-(carboxy(C1-4)alkyl)
ureido, tetrazolyl, phosphono or phenylamino;
or, Y2a-X2-Y2b-Z2 represents C1-4 alkylsulfonyl or -(CH2CH2-O-)m-(CH2)n-C(O)
OR wherein m is an integer from 2 to 6, n is an integer from 2 to 4, and R is
hydrogen or C1-4 alkyl.
5. A compound as claimed in claim 1, wherein said optionally-substituted
guanidino has the formula -N(L3)-C(=NL4)-N(L5)-Z3, wherein:
L3 is hydrogen or C1-4 alkyl;
L4 and L5 are both hydrogen, or L4 and L5 together represent ethylene; and
Z3 is hydrogen, C1-6 alkyl, phenyl(C1-6)alkyl, carboxy(C1-6)alkyl, C1-4 alkoxy,
(C1-4 alkyl)carbonyl or C1-4 alkylsulfonyl(C1-6)alkyl.
6. A compound as claimed in Claim 1 wherein said optionally-substituted
alkylcarbonylamino has the formula -N(H)-C(O)-C(H)(W1)-Y1a-X1-Y1b-Z1, wherein:
W is hydrogen or amino;
Y1a is a direct covalent bond or an a,?-diradical of a d-10 straight or
branched alkane;
X1 is O or S, or a direct covalent bond;
Y1b is an a.w-diradical of a d-10 straight or branched alkane, optionally
substituted with a carboxy group or an amino group; and
Z1 is carbamoyl, carboxy, d-e alkylsulfonyl, (C1-6 alkoxy)carbonyl, C2-6
alkanoylamino, sulfo, phosphono, phenyl, aminosulfonyl, amino, C1-6
haloalkylsulfonylamino, formylamino, C1-6 alkylamino, d-e alkylaminosulfonyl, C1-6
alkylsulfonylamino or 2-oxo-hexahydro-thieno[3,4-d]imidazol-6-yl-(C1-6 alkyl)
carbonylarnino;
or, W1 is hydrogen and Y1a-X1-Y1b-Z1 represents hydrogen, halo, amino or
tri-(C1-4 alkyl)ammonio;
provided that, if Y1a is a direct covalent bond and X is O or S, then W1 is
hydrogen.
7. A compound as claimed in claim 1, wherein R5 is phenyl substituted at the
2'-position by methyl and at the 4'-position by optionally-substituted guanidino,
and in the 6' position by amino.
8. A compound as claimed in claim 1, wherein R5 is phenyl substituted at the
2'-position by methyl, at the 4-position by optionally-substituted ureido, and at
the 6'-position by amino.
9. A compound as claimed in Claim 1 wherein:
R5 is phenyl substituted by C1-4 alkyl, amino, and guanidino.
10. A compound as claimed in Claim 1 wherein:
R5 is phenyi substituted by C1-4 alkyl, optionally substituted ureido, and optionally
substituted guanidino.
11. A compound as claimed in Claim 10 wherein:
R5 is phenyl substituted by methyl, optionally substituted ureido, and optionally
substituted guanidino.
12. A compound as claimed in Claim 10 wherein:
R5 is phenyl substituted by at the 2'-position with C1-4 alkyl, at the 4' position with
optionally substituted guanidino, and at the 6' position with optionally substituted
ureido.
13. A compound as claimed in Claim 1 wherein:
R5 is phenyl substituted by three groups which are methyl, amino, and guanidino.
14. The compound as claimed in Claim 1 which is 4-(4'-Guanidino-2'-methyl-
6'-nitro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxamidine bis-
trifluoroacetate; or 4-(6'-Amino-4'-guanidino-2'-methyl-biphenyl-3-sulfonyl)-5-
methylsulfanyl-thiophene-2-carboxamidine bis-trifluoroacetate.
15. A compound as claimed in claim 1, wherein R5 is phenyl substituted at
the 2'-position by methyl, at the 4'-position by optionally-substituted guanidino,
and at the 6'-position by optionally-substituted alkylcarbonylamino or optionally-
substituted ureido.
16. The compound as claimed in Claim 1 which is 4-{4'-Guanidino-2'-[3-(4-
methanesulfonyl-butyl)-ureido]-6'-methyl-biphenyl-3-sulfonyl}-5-methylsulfanyl-
thiophene-2-carboxamidine trifluoroacetate.
Disclosed is a method for treating the symptoms of
an acute or chronic disorder mediated by the classical pathway of the
complement cascade, comprising administering to a mammal in need
of such treatment a therapeutically effective amount of a compound
of Formula (I) or a solvate. hydrate or pharmaceutically acceptable
salt thereof: wherein R1, R2, R3, R4 and R7 are defined in the spec-
ification, Z is SO or SO2 and Ar is an aromatic or heteroaromatic
group as defined herein.

Documents:

1730-kolnp-2004-granted-abstract.pdf

1730-kolnp-2004-granted-assignment.pdf

1730-kolnp-2004-granted-claims.pdf

1730-kolnp-2004-granted-correspondence.pdf

1730-kolnp-2004-granted-description (complete).pdf

1730-kolnp-2004-granted-examination report.pdf

1730-kolnp-2004-granted-form 1.pdf

1730-kolnp-2004-granted-form 18.pdf

1730-kolnp-2004-granted-form 3.pdf

1730-kolnp-2004-granted-form 5.pdf

1730-kolnp-2004-granted-gpa.pdf

1730-kolnp-2004-granted-letter patent.pdf

1730-kolnp-2004-granted-reply to examination report.pdf

1730-kolnp-2004-granted-specification.pdf

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Patent Number

223389

Indian Patent Application Number

1730/KOLNP/2004

PG Journal Number

37/2008

Publication Date

12-Sep-2008

Grant Date

10-Sep-2008

Date of Filing

16-Nov-2004

Name of Patentee

3-DIMENSIONAL PHARMACEUTICALS, INC.

Applicant Address

THREE LOWER MAKEFIELD CORPORATE CENTER, 1020 STONY HILL ROAD. SUITE 300, YARDLEY, PA 19067

Inventors:

#	Inventor's Name	Inventor's Address
1	HUFNAGEL HEATHER RAE	64 GLEN MANOR LANE, GLENMOORE, PA 19343
2	TRAVINS JEREMY M	2703 CORNELL COURT, NEWTOWN SQUARE, PA 19073
3	BALLENTINE SHELLEY K	35 MEADOW LANE, LANSDALE, PA 19446
4	WILSON KENNETH T	263 WOODCREST ROAD, WESTGROVE, PA 19390
5	CUMMINGS MAXWELL D	659 WEST VALLEY ROAD, WAYNE, PA 19087
6	PAN WENXI	140 MESSNER LANE, GLENMOORE, PA 19343
7	GUSHUE JOAN	26 CHERRY AVENUE, APT. #2, COLLEGEVILLE, PA 19426
8	MEEGALLA SANATH	3822 HIGHLAND DRIVE, BOOTHWYN, PA 19061
9	WALL MARK	221 GREEN BANK WAY, HARLEYSVILLE, PA 19348
10	CHEN JINSHENG	11 FAIRWIND LANE, EXTON PA 19341
11	RUDOLPH M JONATHAN	3820 WEST BRANDON WAY, DOYLESTOWN, PA 18901
12	SUBASINGHE NALIN	129 LONGFORD ROAD, WEST CHESTER, PA 19380
13	HUANG HUI	628 LANCASTER COURT, BELLE MEAD, NJ 08502
14	KHALIL EHAB	148 MOUNTAINVIEW DRIVE, WEST CHESTER, PA 19380
15	LEONARD KRISTI	134 EAST CHESTNUT STREET, WEST CHESTER, PA 19380
16	ALI FARAH	329 STEEPLECHASE DRIVE, EXTON, PA 19341

PCT International Classification Number

C07D 333/22, 333/12

PCT International Application Number

PCT/US03/16888

PCT International Filing date

2003-05-28

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/383,130	2002-05-28	U.S.A.