| Title of Invention | AMINOGUANIDINES AND ALKOXYGUANIDINES AS PROTEASE INHIBITORS |
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| Abstract | Aminoguanidine and alkoxyguanidine compounds, including compounds or the formula: wherein X is O or NR9 and R1-R4, R6-R9, R11, R12, Ra, Rb, Rc, Y, Z, n and m are set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof, that inhibit proteolytic enzymes such as thrombin are described. Also described are methods for preparing the compounds of Formula . The novel compounds of the present invention are potent inhibitors of proteases, especially trypsin-like serine proteases, such as chymotrypsin, trypsin, thrombin, plasmin and factor Xa. Certain of the compounds exhibit antithronibolic activity via direct, selective inhibition of thrombin, or are intermediates useful for forming compounds having antithrombotic activity. The invention includes a composition for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutioally acceptable carrier. Other uses of compounds of the invention are as anticoagulants cither embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents. |
| Full Text | 1A Background of the Invention Field of the linvention The present invention relates to novel compounds that function as enzyme inhibitors, and particularly to a new class of non-peptidic inhibitors of prolcolytic enzymes. Related Art Proteases are enzymes that cleave proteins at single, specific peptide bonds. Proteases can be classified into four generic classes: serine, thiol or cysteinyl, acid or aspartyl, and mclalloproleases (Cuypcrs el ai, J. Dial Client. 257:7086 (1982)). Proteases arc essential to a variety of biological activities, such as digestion, formation and dissolution of blood clots', rcproduclion and the immune reliction to foreign cells and organisms. Aberrant ptolcoiysis is associated with a number of disease stales in man and other mammals. . The human neutrophil proteases, elastase and cathepsin G, have been implicated as contributing to disease states marked by tissue destruction. These disease states include emphysema, rheumatoid arthritis, corneal ulcers and glomerular nephritis. (Barret, in Enzyme Inhibitors as Drugs, Sandier, ed., University Park Press, Baltimore, (1980)). Additional proteases such as plasmin, C-l esterase, C-3 converlase, urokinase, plasminogcn activator, acrosin, and kallikreins play key roles in normal biological functions of mammals. In many instances, it is beneficial to disrupt the function of one or more proteolytic enzymes in the course of therapeutically treating a mammal. Serine proteases include such enzymes as elaslase (human leukocyte), cathepsin G, plasmin, C-I esterase, C-3 convcrtase, urokinase, plasininogen activator, acrosin, chymolrypsin, trypsin, thrombin, factor Xa and kallikreins. Human leukocyte elastase is released by polymorphomiclcar leukocytes at sites of inflammation and thus is a contributing cause for a number of disease siales. Cathepsin G is another human neulrophil serine protease. Compounds with the ability to inhibit the activity -2- of these enzymes are expected to haVe an miti-inllammjilory effect useful in the treiitment of gout, rheumatoid arthritis and other inflammatory diseases, and in the treatment of emphysema. Cliymotrypsin and tcypsin ore digestive enzymes, inhibitors of these enzymes are useful in treating pancreatitis. Inhibitors of urokinase and piasminogen activator are useful in treating excessive cell growth disease slates, such as benign proslntic hypertrophy, prostatic carcinoma and psoriasis. The serine protease thrombin occupies a central role in hemostasis and thrombosis, and as a multi facto rial protein, induces a number of effects on platelets, endolhelial cells, smooth muscle cells, leukocytes, the heart, and neurons (Tapparelli et oi, Trends in Pharmacological Sciences 14:366-376 (1993); Lcikovils and Topol, Circulation 90(3):1522-1536 (1994); Marker, Blood Coagulation and Fibrinolysis 5 (Suppl /):S47'-S58 (1994)). Activation of the coagulation cascade through cither the intrinsic pathway (contact activation) or the extrinsic pathway (activation by exposure of plasma to a non-endothelial surface, damage lo vessel walls or tissue factor release) lends lo a series of biochemical events thai converge on thrombin. Thrombin cleaves fibrinogen ultimately leading to a hemostatic plug (clot formation), potently activates platelets through a unique proteolylic clcnvnge of the cell surface thrombin receptor (Coughlin, Seminars in linmatology 3/(4):270-277 (1994)), and nulonmplifies its own production through a feedback mechanism. Thus, inhibitors of thrombin function have therapeutic potential in a host of cardiovascular and non-cardiovascular diseases, including: myoeardial infarction; unstable anginn; stroke; restenosis; deep vein thrombosis; disseminated intravascular coagulation caused by Irauma, sepsis or tumor metastasis; hemodialysis; cardiopulmonary bypass surgery; adult respiratory distress syndrome; endotoxic shock; rheumatoid arthritis; ulcerative colitis; induration; metastasis; hypercoagulability during chemotherapy; Alzheimer's disease; Down's syndrome; fibrin formation in the eye; and.'wound healing. Oilier uses include the use of said thrombin inhibitors as anticoagulants cither embedded in or physically linked lo materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stems. Factor Xa is another, serine protease in the coagulation pathway. Factor Xa associates with factor Va and calcium on a phospholipid membrane thereby forming a prothrombinase -3- complex. This prothiombinase complex then converts prothrombin to thrombin (Claeson, Blood Coagulation and Fibhnolysis 5:41]-436 (1994); Marker, Blood Coagulation and Fibrinolysis 5 (Suppl /):S47-S58 (1994)). Inhibitors of factor Xa arc tliought to offer an advantage over agents that directly inhibit thrombin since direct ihrombin inhibitors still permit significant new thrombin generation (Lcfkovils and Topol, Circulation .9(7(3): 1522-1536 (1994); Harker, Blood Coagulation and Fibrinolysis 5 (Suppl J):S41-S58 (1994)). A need continues to exist for non-peptidic compounds that are potent and selective protease inhibitors, and which possess greater bioavailability and fewer side-effects than currently available protease inhibitors. Accordingly, new classes of potent protease inhibitors, characterized by potent inhibitory capacity and low mammalian toxicity, are potentially valuable therapeutic agents for a variety of conditions, including treatment of a number of mammalian protcolytic disease states. Ozawa, I-I. el af., Yakugaku Zosshi, 95(8).966-74 (1975) describe a number ofben/yl-and bcnzylidinc aminoguanidinc and atnidinohydnizonc compounds. For example, the following sails are described: The compounds were tested lor their elTect on blood pressure in rats, Augstein, J. el ai," .j Med. Chem., 10(3):391-400 (1967) discloses a series of aryloxyalkylamino-guanidines of (he formula: -4- In some compounds R, is nicthoxy, while R2 is hydrogen and R3 and R, arc cither hydrogen or melhyl. Several such aminoguanidines containing chloro and methyl substituenls in the aromatic ring were shown to possess adrencrgic neuron blocking properties and to inhibit dopamine p-oxidase in vitro. The synthesis and testing of aminoguanidines containing one or more mclhoxy substitucnts in the aromatic ring is also disclosed. Summary of the Invention The present invention is directed to novel compounds having Formula / (below). Also provided are processes for preparing compounds of Formula /. The novel compounds of the present invention are potent inhibitors of proteases, especially trypsin-like serine proteases, such as chymotrypsin, trypsin, thrombin, plasmin and factor Xa. Certain of the compounds exhibit antithrombotic activity via direct, selective inhibition of thrombin, or are intermediates useful for forming compounds having antilhrombolic activity. The invention includes a composition for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting cmbolus formation in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. These compositions may optionally include anticoagulants, antiplatelet agents, and ihrombolytic agents. The compositions can be added to blood, blood products, or mammalian organs in order to effect the desired inhibitions. Also provided are methods of inhibiting or treating aberrant proteolysis in a mammal, and methods for treating myocardial infarction; unstable angina; stroke; reslenosis; deep vein thrombosis; disseminated intravascular coagulation caused by trauma, sepsis or tumor metastasis; hcmodialysis; cardiopulmonary bypass surgery; adult respiratory distress syndrome; endotoxic shock; rheumatoid arthritis; ulcerative colitis; induration; metastasis; hypcrcoagulabilily during chemotherapy; Alzheimer's disease; Down's syndrome; fibrin formation in the eye; and wound healing. Other uses of compounds of the invention are as anticoagulants either embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents. -5- The invention also includes a method for reducing the thrombogenicily of a surface in a mammal by attaching to the surface, either covalently or noncovalently, a compound of the invention. Detailed Description of the Preferred Embodiments Compounds of the present invention include compounds of Formula /: or a solvate, hydrate or pharmaccutically acceptable salt thereof; wherein: Rl is one of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl or heteroaryl, any of which may be optionally substituted; Z is one of-NR10SO2- -SO2NR10-, -NR'°C(RyRz)- -C(RJ"R Ry and Rz are eacli independently one of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxy; R2, R3 and R4 are each independently one of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nilro, carboxamido, -CO2RX, -CH2ORX or~ORx, or when present on adjacent carbon atoms, R2 and R1 may also be taken together to form one of -CH=CH-CH=CH- or -(CH2)q-, where q is from 2 to 6, and R4 is defined as above; Rx, in each instance, is independently one of hydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl groups may optionally have one or more unsaturations; Y is one of-O-, -NR10-, -S-, -CHR10- or a covalent bond; X is oxygen orNR9; -6- R9 is one of hydrogen, alkyl, cycloalkyl or aryl, wherein said alkyl, eycloalkyl or ary] can be optionally substituted with amino, monoalkylamino, dialkylamino, alkoxy, hydroxy, carboxy, aikoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, aryl, hclcroaryl, acyiamino, cyano or trifluoromethyl; R6 is one of hydrogen, alkyi, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaniino(C2.1o)a!kyl, dialkylammo(C2,10)alkyl or caiboxyalkyl, or alternatively. R' and R12 taken togetlicr to form -(CM2)W-, where w is 1-5; R7 is one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, diaikylaminoalkyl, carboxyalkyi, hydroxy, alkoxy, aralkoxy, aryloxy, heteroaryloxy, or mono- or di- alkylamino, provided that n is other than zero when R7 is hydroxy, alkoxy, aralkoxy, aryloxy, heteroaryloxy, or mono- or di- alkylamino R8, R11 and R12 are each independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, diaikylaminoalkyl of carboxyalkyi; or R7 and R8 arc taken together to form -(CI I2)y-, where y is zero (a bond), 1 or 2, while R" and R12 are defined as above; or R; and R12 arc taken together to form -(CH2)q-, wlicrc q is zero (a bond), or 1 to 8, while RH and R" are defined as above; or R" and R" an taken together to form -(CH2)r~, where r is 2-8, while R7 and R12 are defined as above; R10, in each instance, is independently one of hydrogen, alkyl, aralkyl, aryl, hydroxy(C2_|0)a!kyl, amino(C2.l0)aIkyl, nionoalkyIamino(C_vl0)alkyl, dialkylamhio(C2.n,)alkyl or carboxyalkyi; R;1, Rh and Rc are independently hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or-CO:Rw; Rw is alkyl, cycloalkyl, phenyl, benzyl, -7- where Rd and Rc are independently hydrogen, C,-6 alkyl, C2-6 alkenyl or phenyl, R1is hydrogen, C,-6 alkyl, C2-6 alkenyl or phenyl, RB is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, and Rh is aralkyl or C1-6 alkyl; n is from zero to 8; and m is from zero to 4. A preferred group of compounds falling within Ihu scope of the present invenlion include compounds of Formula / wherein: R1 is one of Q6-l0 aryl, pyridinyl, thiophenyl (i.e., thiophene), quinazolinyl, quinolinyl ortetrahydroquinolinyl, any of which is optionally substituted by one or two of hydroxy, nitro, Irifluoromethyl, halogen, C1-6 alkyl, C6-10 aryl, C1-6 alkoxy, C6-I0 ar(C1-.6)alkoxy, C1-6 aminoalkyl, C1_6 aminoalkoxy, amino, mono(CM)alkylamino, di(CM)alkylamino, C2^ alkoxycarbonylamino, C2-6 alkoxycarbonyl, enrboxy, C1-6 hydroxyalkyl, C3.6 hydroxyalkoxy, (C1-6)aIkoxy(C2-6)alkoxy, mono- and di- CM alkylamino(C2-6)alkoxy, C 2.t0 mono(carboxyalkyl)amino, di(C2_l0 carboxya!kyl)amino, C6-l4 ar(C1-6) alkoxycarbonyl, C2.6 alkynylcarbonyl, C,.6 alkylsulfonyl, C2-6 alkenylsulfonyl, C2_6 alkynylsullbnyl, C6.10 arylsulfonyl, C6-10 ar(C1-6) alkylsulfonyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonamido, C6.,0 arylsulfonamido, C6-10ar(C1.6) alkylsulfonamido, amidino, guanidino, C1-6 alkyliminoamino, formyliminoamino, C2.6 carboxyalkoxy, C2.6 carboxyalkyl, carboxyalkylaniino, cyano, trifluoromelhoxy, pcrfluoroclhoxy and R13R''NSO2-; R13 and R14 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycle. heterocycloalkyl. carboxyalkyl, alkoxycarbonylalkyl, cyano(C2.|0)alkyl, hydroxy(C2.10)alkyI, alkoxytQ.^Jalkyl, inono-and di-aIkyIamino(C2.10)alkyl, or R13 and R14 can be taken together with the nitrogen atom to which they are attached to form a three to seven membered ring, optionally containing one or more heteroatoms in addition to said nitrogen, such as oxygen, sulfur, or nilrogen (NR15), said ring being preferably saturated, and said ring having one or two optional substituents selected from the group consisting of hydroxy, acyloxy, alkoxy, aryloxy, amino, mono- and di- alkylamino, acylaiuino. alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycle, heterocycloalkyl, carboxyalkyl, alkoxycarbonylalkyl, cy;mo(C2-10)alkyI, hydroxy(C2-m)alkyl.alkoxy(C2-0)alkyl,mono-and di-alkylamino(C2-10)aikyl, carbox.y. alkoxycarbonyl. carboxamido, formyl, alkanoyl, aroyl, aralkanoyl. sulfonyl, alkylsulfonyl, alkoxysulfonyl, sulfonamido, -8- phosphonyl, phosphoramido, and phosphinyl, and wherein R15 is selected from the group consisting of hydrogen, alkyl, cycloalkyl alkenyl, alkynyL aryl, aralkyl, heterocyele, hclerocycloalkyl, carboxyalkyl, alkoxycarbonylalkyl, cyano(C2-10)alkyL hydroxy(C2_10)alkyl, alkoxy(C2-10)alkyl, mono- and di-alkylamino(C2-10)alkyl, carboxy, alkoxy earbony!, carboxamido, funny 1, alkanoyl, nioyl, aralkanoyl, sullonyi, alkylsulfonyl, alkoxysulfonyl, sulfonamido, phosphonyl, phosphoramido, and phosphinyl; Z is one of-SO2O-, -SO2NR10- -C(RyR7)O- or -OC(RyRz)-, where Ry and Rz are each hydrogen; R2, R3 and R4 are independently one of hydrogen, CM alkyl, C3-8 cycloalkyl, phenyl, benzyl, trifluoromethyl, halogen, hydroxy(CM)alkyl, cyano, nitro, carboxamido, carboxy, CM alkoxycarbonyl, CM alkoxymethyl or CM alkoxy; or alternatively, R2 and R3 when present on adjacent carbon atoms, may also be taken together to form one of -CM -CH-CII =CI I- or ~(CI I,),,-, where q is from 2 to 6, and R4 is as defined above; Y is one of-O~, -S-, -NR"1-, or a covalcnt bond; R\ R1' and Rc arc each one of hydrogen, CM alkyl, hydroxy, C,_j alkoxy, phenoxy, CM alkyloxycarbonyl, benzyloxycarbonyl. cyano. where Rh is benzyl, methyl, ethyl, isopropyl, .vcc-butyl or /-butyl, and where Rris hydrogen or C1-6 alkyl; R6 is one of hydrogen, C1-6 alkyl, C6-1O ar(C1-6)alkyI, C6-1o aryl, C2-10 hydroxyalkyl, C2-1o aminoalkyl, mono(C1-4)alkylamino(C2-8)alkyl, di(C1-4)alkylamino(C2-8)alkyl or C2-10 carboxyalkyl; R7, R8, R11 and Rl2 are independently one of hydrogen. C1-6 alkyl, C2-10 carboxyalkyl or C2-10 hydroxyalkyl, or R7 and R8 are taken together to form -(CH2)y- where y is zero, 1 or 2, while R11 and R12 are defined as above; or R7 and R12 arc taken together to form -(CH2) -, where q is zero (a bond), or 1, 2 or 3, while R8 and R11 are defined as above; or -9- R8 and R" arc taken together to form -(Cl l2)-, where r is 2, 3, or 4. while R7 and R'2 are defined as above; R9 is hydrogen, or C1-10 alkyl, optionally substituted with amino, mono(C1-4)alkylamino, C1-6 alkoxy, hydroxy, carboxy, phenyl, C1-4 alkyloxycarbonyl, C6-lo ar(C1-4)alkoxycarbonyl, C1-6 acylamino, cyano or Irifluoromethyl; R10, in each instance, is independently hydrogen, C1-6 alky], benzyl, phenyl, C2-10 hydroxyalkyl, C2-10 aminoalkyl, CM monoaIkyIamino(C2.R)alkyl, C,.4 dialkylamino(C2.8)alkyl or C2.10 carboxyalkyl; n is from zero to 8; and m is from zero to 4. In this preferred embodiment, R1 can be one of C6.]0 aryl, pyridinyl, thiophenyl (i.e., thiophene), quinazolinyl, quinolinyl or tetrahydroquinolinyl, any of which is optionally substituted by one or two of hydroxy, nitro, trifluoromethyl, halogen, C,.6 alkyl, C,.A alkoxy, C,_6 aminoalkyl, C,.6 aminoalkoxy, amino, mono(CM)alkylamino, di(C,.4)alky]amino, C:.(, alkoxycaibonylamino, C2.6 alkoxycarbonyl, carboxy, C,.6 liydroxyalkyl. CM, hydroxyalkoxy, Cj.,,, niono(c:irhoxyalkyl)amii)ot bis(C% l0 carluiNyalkyDamiuo. (',,.,,, ar(C,.6) alkoxycarbonyl, C2.f, alkynylcarbonyl, C,.f, alkyisulfonyl, C2.6 alkenylsulfonyl, C2.6 alkynylsulfonyl, C,.6 alkylsulfinyl, C,.f, alkylsulfonamido, amidino. guanidino, C,.6 alkyliminoamino, formyliminoamino, C2.6 carboxyalkoxy, C2.fi carboxyalkyl, carboxyalkylamino, cyano, trifluoromelhoxy, and perfluoroelhoxy. An especially preferred group of compounds include compounds of Formula / wherein: R1 is one of phenyl, naphthyl, pyridyl, thiophenyl, quinolinyl or isoquinolinyl, optionally substituted by one or two of chloro, methoxy, methyl, trifluoromcthyl, cyano, nilro, amino or dimcthylamino; Z is one of-SO2O- -SO-.NR10-. -C1I,O- or -OCII2-; R2 and R3 are hydrogen or CM alkyl, or R2 and R3 may also be taken together to form -CM-CM-Cl 1-CII-; R4 is one of hydrogen, methyl, methoxy or iriiluoromcthyl; Y is one of O, NR10 or a covalent bond; -]0-Ra, R1' and Rc are hydrogen, hydroxy, where Rh is benzyl or /-butyl, and where R1 is hydrogen or methyl; R6 is hydrogen, CM alkyj, C2.4 hydroxyaikyl, C2.4 carboxyalkyl, C2.4 aminoalkyl, dimethylamino(C2.8)alkyl, or methylamino(C2.g)alkyl; R7, R8, R" and R13 are independently one of hydrogen, C,_6 alkyl, C3.10 hydroxyaikyl or C,.]o carboxyalkyl, or R7 and RR arc taken together to form -(CM2)y- where y is zero, 1 or 2, while R11 and R12 are defined as above; or R7 and R12 are taken together to form -(CI I2),~, where q is zero (a bond), or 1. 2 or 3, while RK and R" are defined as above; or R* and R" arc taken together to form -(CI I2)r~, where r is 2, 3 or 4, while R7 and R12 arc defined as above; R9 is hydrogen or CM alkyl; R10, in each instance, is independently hydrogen, CM alkyl, C2_A hydroxyaikyl, C^ carboxyalkyl, C2.4 aminoalkyl, dimethylamino(C2.R)aJkyl, methylamino(C2.s)alky!; n is from zero to 4; and m is zero, 1, 2 or 3. Another especially preferred group of compounds include compounds ofl'onnula / wherein: R1 is phenyl, substituted by one of alkylsulfonyl, arylsulfonyl and R13RHNSO2-, where R13 and Rt4 are independently selected from the group consisting of hydrogen, Cs.6 alkyl, C3.7 cycloalkyh C2.fl alkenyl, C2.6 alkynyl, C6.10 aryl, C6.10 ar(CM)aIkyl, pyridyl, pyridyKC^Jalkyl. carboxyfC^^alkyl, Cj.4 alkoxycarbonyKC,..,);!^)'!, cyano(C2.,,)alkyl, hydroxytC2.ft)alkyl, C,.,, alkoxy(C2.6)alkyl, mono- and di-(CM)alkylamino(C2.6)alkyl, or R!3 and R14 can be taken together with the nitrogen atom to which they are attached to form a hetorocyclic ting seJedcd from the group consisting of N-morpholinosullonyl, N-pipcrazinylr-ulfonyl (optionally N' substituted with C,.6 alkyl, C,.f, hydroxyaikyl, Cfi.l0 aryl, C6.,0 aryl(C,.6)a!ky!, C,.6 alkylsulfonyl, Cr,.lu arylsulfonyl, CJJf> -11- alkylcarbonyl, morpholino or C(,.l0 arylearbonyl), N-pyrrolylsuUbnyl, N-piperidinyisulfbnyl, N-pyrrolidinylsulfonyl, N-dihydropyridylsulibnyl, N-indolylsulfonyl, wherein said helerocyclic ring can be optionally substituted with one or two of hydroxy, Cx_8 alkanoyloxy. C,_6 alkoxy, C6.10 aryloxy, amino, mono-and di- C,_r, alkylamino, C,.H alkanoylamino, CM alkyl, C,.7 cycloalkyl, Cf,.U( aryl, Cft.,0 ar(CM)alkyi, hctcrocycie, hetcrocycloalkyi, carboxy(G,.6)alkyl, CM alkoxycarbonyi(C,.4)alkyl, cy;ino(C.\.Jalkyl, hydroxy(C2.(1)alkyl, C,,,, alkoxy(C2.fi)alkyI, mono- and di-(CM)alkyiamino(C3.6)alky], carboxy, C,.,, alkoxycarbonyl, carboxamido, formyl, C,.6 alkanoyl, CM0 aroyl, C6.l0 ar(CM)aIkanoyl, sulibnyl, C,.6 alkylsulfonyl, C,.6 alkoxysulfonyl, sulfonamido, phosphonyl, phosphoramido. or phosphinyl; Z is one of-SO3O-, -SO2NR10-, -CH2O- or -OCH2-; Rz and R3 are hydrogen or CM alkyl, or R2 and R3 may also be taken together to form-CII=Cll-CII=CII-; R4 is one of hydrogen, methyl, methoxy or trifluoromclhyl; Y is one of O, NR10 or a covalent bond; R°, R1' and Rc arc hydrogen, hydroxy. where Rh is benzyl or /-butyl, and where Rf is hydrogen or methyl; R6 is hydrogen, C,.,, alky!, C2.4 hydroxyaikyl, C2.4 earboxyalkyl. C2.., aminoalkyl, dimethylamino(C2.E)alkyl, or melhylamino(C2.8)alkyl; R7, R8, R" and l^12 arc independently one of hydrogen, C,_6 alkyl, C2.10 hydroxyalkyl or C2.10 carboxyalkyl, or R7 and RR are taken together to form -(CH2)y- where y is zero, I or 2, while RH and R12 are defined as above; or R7 and R12 are taken together to form -(CH2) -, where q is zero (a bond), or 1. 2 or 3. while Rs and R1' arc defined as above; or R8 and R11 are taken together to form -(CH2)r-7 where r is 2, 3 or 4,- while R7 and R12 arc defined as above; -12- R" is hydrogen or CM alkyl; R10, in each instance, is independently hydrogen, C,.., alkyl, C2.4 hydroxyalkyl. C3.,, carboxyalkyl, C2.4 aniinoalkyl, dimethykimino(C\.K)alkyl, methylamino(C2.8)aIkyl; n is from zero to 4; and m is zero, 1, 2 or 3. The moiety -Z-R1 oi* Formula / is attached to the benzene ring in a position ortho-, meta- or para- to Y, with the mcta- position being preferred. Preferred compounds of the present invention are those of Formula /wherein Y is one of divalent oxygen (-O-), -NR'°- or a covalent bond, most preferably -O- and Z is one of -SO2NRt0-, - SO2O- or - CH:O-, most preferably -SO2O-. Preferred compounds of the present invention are those of Formula / wherein R1 is one of C,.,2 alkyl, especially C3.K alkyl, C4.7 cycloalkyl, C2_R alkenyl, C2.K alkynyl or C6.,4 aryl, especially C6.10aryl, any of which is optionally substituted. Substiluents that can be optionally present on the R1 moieties include one or more, preferably one or two, of hydroxy, nilro, irifluoroinethyl, halogen, alkoxy, aralkoxy, aminualkoxy, aniinoalkyl, hydroxyalkyl, hydroxyalkoxy, alkoxyalkoxy. mono- and di-alkylaminoalkoxy, cyano. aryl. amino, inonoalkylamino, dialkylamino, caiboxy, carboxyalkyl, eaiboxyalkoxy, mono(hydroxyalkyl)amino, bis(hydroxyalkyl)amino. mono(earboxyalkyl)amino, bis(carboxyalkyl)amino, alkoxycarbonylamino, alkoxycarbonyl, aralkoxycarbonyl, aikenylcarbonyl, alkynylcarbonyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, aralkylsulfonyl, alkylsulfinyl, alkylsulfonamido, arylsulfonamido, aralkylsulfonamido, amidino, guanidino, alkyliminoamino, formyliminoamino, trifluoromethoxy, perfluoroethoxy or an aminosulfonyl group R13RHNSO2-, where Rt3 and RH are as defined above. A further substituent on aryl. cycloalkyl, alkenyl, alkynyl and aralkyl moieties of R1 includes one or more, preferably one or two, alkyl moieties. Preferred values of optional subslituents on R1 include hydroxy, nilro, trifluoromethyl, halogen, C,.6 alkyl, C,,,-, alkoxy, C,.6 aminoalkyl, C6.ll( aryl, Q-io o'ir(C,.r,);ilkoxy, biphenyl(CV(,);ilkoxy t',.(. aininoalkoxy,.amino. mono(C,..i)alkylamino, di(CM)alkylamino, C2.fi alkoxycarbonylamino, C2.6 alkoxycarbonyl, carboxy, C,.6 hydroxyalkyl, C2.|0 mono(carboxyalkyl)amino, bis(C2.10 carboxyalkyl)amino, C6.H ar(C,.6)alkoxycarbonyl, C2.6 alkynylcarbonyl, C,.6 alkylsulfonyl, C6.10 arylsulfonyl, C2.6 alkenylsulfonyl, C2.6 alkynylsulfonyl. C,.6 alkylsulfinyl, C,.fi alkylsulfonamido, -13- amidino, guanidino, C,.6 alkyliminoamino, fonnyliminoamino, C2.6 carboxyalkoxy, carboxyalkylamino, cyano, trifluoromethoxy, and perfluoroethoxy. Additional preferred values of optional substituents on R1 include C(.6 alkylsulfonyl, C6.m arylsulfonyl, C(,.1O ar(C,.(1) alkylsulfonyl, C6.,,, arylsulfonamido, C6.|,, nr(C,.fi) alkylsulfonnmido, M-morpholinosuIlbnyl, and RnRI'1NSO?-, where R1"1 and R14 are independently selected from the group consisting of hydrogen, C,.6 alkyl, C3.7 cycloalkyl, C2_6 alkenyl, C2.6 alkynyl, Cfi.1{, aryl, CM0 ar(CM)nlkyl, pyridyl, pyridyl(C1.4)alkyl, carboxy(C,,6)alkyl, CM alkoxycarbonyl(C,..,)aIkyl, cyano(C2.6)alkyl, hydroxy(C3.6)a!kyl, C|.4 alkoxy(C2.6)aIkyl, mono- and di-(Cl.4)alkylamino(C2.6)alkyl, or R13 and R14 can be taken together with the nitrogen atom to which they are attached to form a heterocyclic ring selected from the group consisting of N-morpholinosulfonyl,, N-piperazinylsuIfonyl (optionally N' substituted with C,.6 alkyl, C,.6 hydroxyalkyl, C6.1U aryl, Cfi,,0 aryl(C|.6)alkyl, C,.f, alkylsulfonyl, Cfi.|,, arylsulfonyl. C,.fi alkylcarbonyl. morpholino or Cf,.I0 arylcaihouyl), N-pvniil)lsu!ronyl, N-pipciidinylsuli'onyl, N-pyrrolidinylsulfonyl, N-dihydropyridylsulfonyl, N-indolylsulfonyl, wherein said heterocyclic ring can be optionally substituted with one or two of hydroxy. C,.K alkanoyloxy, C,.6 alkoxy, C6.l0 aryloxy, amino, mono- and di- C,.fi alkylamino, C,.8 alkanoylamino, CM alkyl, C3.7 cycloalkyl, C,,.1(, aryl, C6.U) ar(C,..,)alkyl, hcterocyclc, heterocycloalkyl, carboxy(C,.6)alkyl, C|.4 aikoxycarbonyl(C,.4)alkyl, cyano(C2.6)alkyl, hydroxy(C2.,.,)aIkyl, CM aikoxy(C,.,,);ilkyl, mono- nnd di-(C|..,)alkylamino(C:.,,)alkyl, carboxy, C,.6 alkoxycarbonyl, carboxamido. formyl, Cu, alkanoyl, C6.l() aroyl, C6.lo ar(CM)a!kanoyl, sulfonyl, C,.6 alkylsulfonyl, C,.6 alkoxysulfonyl, sulfonamido, phosphonyi, phosphoramido, or phosphinyl. An additional preferred group of compounds are those compounds of Formula I wherein R1 is heteroaryl or substituted hcicroaryl. Preferred Rl hctcroaryl groups include pyridyl, pyrazolyl, thiophenyl, chromenyl, benzoxazolyl, benzthiadiazolyl, quinazolinyl, quinolinyl, isoquinolinyl and ictrahydroL[Liinolinyl. with lhio|ihcuyl, quin;i/.olinyl. quinolinyl and letrahydroquinolinyl being more preferred and thiophenyl, isoquinolinyl and quinolinyl especially preferred. Preferred compounds when R1 is substituted heteroaryl include those compounds having one of the hctcroaryl groups mentioned as preferred that have one or more, preferably one or two, substituents that are listed in the -14- prcccding paragraph. Preferred subsliliients when R1 is substituted heleronryl include one or more substituents, preferably 1 to 3 subslitucnts, independently selected from halogen, C,_6 alkyl, C,.6 alkoxy, amidino, guanidino, carboxyalkoxy, carboxyalkylamino, amino, mono(C1.f,)alkylamino and/or di(C,.6)alky]amino. Useful values of R1 include phenyl, chlorophcnyl, iodophenyl, dichlorophcnyi, bromopbenyl, trifluoromethylpbenyl, metbylsulfonylphenyl, di(trifluoromethyl)phenyl, methylphenyl, f-butylphenyl, inethoxyphenyl, dimctboxyphenyl, bydroxyphenyl, carboxyphenyl, aminophenyl, methylaininophenyl, /7-bulyIaminophenyl, amidinophenyl, guanidinophenyl, formyliminoaminopbenyl, acctiniidoylaminophenyl, methoxycarbonylphenyl, clhoxycarbonylphenyl, carboxymethoxyphenyl, naphthyl, hydroxynaphthyl, cyclohexyl, cyelopentyl, 2-propylbutyl, 5-chloro-2-methoxyphenyl, 2-cyanophenyl, 2-(jV-hydroxy)aminophenyl, 2-(4-biphenylmethoxy)phenyl, 2-(3-biphenylmethoxy)phenyl, benzyl, 3-(6-(2,3-dihydro-l,l-dioxobenzo[b]thiophene)phenyl, 2-(phcnylsulfonyl)phenyl, 2,4-bis(methylsulfonyl)phenyl, and 2-chloro-4-melhylsulfonylphenyl. Additional useful values include 8-quinolinyl, 5-methyl-8-quinolinyl, 4-benzo-2,l,3-lhiadiazolyl, 5-ehloro-2-lhiophenyl, 5-ehloro-l,3-diniclhyl-4-pyrazolyl, pyridyl, isoquinolinyl, and tctrahydioquinolinyl. Useful values of R\ when W is piienyl substituted by R'-RI4NSO,- include 2-{N-methylphenethylaminosulfonyl)phenyl, bis(2-methoxyethyl)aminosulfonylphenyl? 2-N-nicthyl-(3,4-diineliioxyphenyl)etliylaniinosulfonylplienyl, A'-mcthyl-A;-ethoxycarbonylmethyl)aminosuIfonyIphenyK 2-(Ar-methyl-A^-(2-(2-pyridyl)ethyl)-aminosulfonyl)phenyl, 2-(A^propyl-A'-(2-(2-pyridyI)ethyl)aminosulfonyl)phenyl. 2-(A^-ethyl-A^-(4-pyndylmethyl)aminosulfonyl)phenyl, 2-(A^-methyl-A^(4-methoxyphenyl)-aminosulfonyl)phenyl, 2-(Ar-methyl-A^-(4-methoxycarbonylphenyl)aminosulfonyl)phenyl; 2-(Ar-(2-cyanoethyl)-A;-(3-pyridylmetiiyl)aminosuifonyl)phenyI, 2~(N,N-b\s-(2-cyanoelhylJaininosulibiiyOplR-nyl, 2-(A/-(2-etliuxycarboiiyIelhyl)-A'-beiv/.yl-aminosulfonyl)phenyl, 2-tA^-mcthyl-A/-(2-(4-pyridyl)cthyf)aminosulfonyl)phenyl, 2-(A'-(elhoxyearbonylniethyl)-A/-(2-pyridyIniellnrl)aminosulfonyl) phenyl, 2-(MA'-,bis-(ethoxycarbonylmelhyl)aminosulfonyl)plienyl, 2-(jV,ALbis-(carboxymethyl)aniinosulfonyl)phcnyl, 2-(/Y-mcthyl-Ar-(4-carboxyphenyl)- -15- aminosuironyl)phenyl, 2-(M-(2-carboxyethyI)-^-bcnzylaminosu]fonyl)phciiyl, 2-(A^-(2-cyanoelhyl)-A'-(2-furanylmethyI)aminosulfonyl)phenyK2-(A;-ethyl-A/-(l-ben7.y]-3-pyrrolidinyl)aminosiilfonyl)phcnyl, 2-(A'-benzyl-A/-(2-(A',A'-dimelhylarnino)-elhyl)aminosulfonyl)phenyl, 2-(A'-methyl-A/-(l-melhy}-4-piperidinyl)-aminosulibuyl)pheiiyl, 2-(A/Huelhyl-A43-pyri(iylmethyl)anunosuilbnyl)phenyl, 2-{N-ethyl-A'-(2-(A^A^-dimethyIainino)etbyl)amino5ulfonyl)phenyl, 2-(2-(4-morpholinyl)-ethylaminosulfonyl)phenyl, 2-(AMiicthyl-A42-(A',ALdimethylamino)ethyl)amino su1fonyl)phcnyl, A^-clhyl-3,4-(mclhylcncdioxy)nnilinosulfonylphcnyl, 2-(A/-mcthyI-A'-(3-(A^A^dimethylamino)propyl)aminosulfonyl)phcnyl, and 2-(4-pyridylmclhyl-amino-sulfonyl)phenyl. Further useful values ofR1, when I^1 is plicnyl substituted by Rt?RMNSO2- include 2-morpholinylsulfonylphenyl, 2-(acetylpipcrazinylsulfonyl)phenyl, 2-(4-cihyloxycarbonyl)pipcridinylsuHbnyI, 2-(4-c;irboxyl)pipcridinylsuironylpIicnyl, 3-clhoxycarbonyl-l-pipcridinosuironyl)phcnyl. 3-earbo\ypiperidinosulfonyl)phcnyl, 2-metlioxyearbonyl-1 -pyrrolidiiiosullbnyOphc-nyl. 2-(.';nln)xy-i-pyiT The groups R?, R3 and R4 in Formula / substilute for any remaining hydrogen atoms on the benzene ring after allowing for attachment of the moiety -Z-R1. Preferred compounds are those where R3, R3 and R4 arc independently hydrogen, C,.4 alkyl, C4.7 cycloalkyl, C6.,,, aryl, especially C6.I0 aryK C6_K) ar(C,.4)alkyl) trifluoromethyl, halogen, hydroxyalkyl, cyano, nilro, carboxamide, carboxy, alkoxycaibonyl. carboxymclhyl. alkoxycarbony]methyl, or cycloalkyloxycarbonyl. -16- Allenmlivcly, R2 ;IIKI R3, when attached lo adjacent carbon atoms on the, benzene ring, are one of-CH=CH-CH=CH-or-(CH^-. where q is from 2 to 6, thereby forming a fused ring. Preferred values of R2 together with I.I3 include -CH=CH-CH-CH- -CH2-CH2-CH2- and -CH2-CH2-CH2-CH2-. When R2 and R3 together form a fused ring, R'1 is preferably hydrogen. Useful values of R2, R3 and R4 include hydrogen, methyl, ethyl, chloro, bromo, trifluoromelhyl, hydioxymcihyl, methoxy, cthoxy. carboxamidc. nitro. phcnyl, cyclo-propyl, hydroxy, isopropyl, methoxycarbonyl, elhoxycarbonyl and benzyl. Useful values of R2, R3 and R4 also include R2 and \V together forming -CINCH-CllOlI-or -CH2-CH2-CH2- and R1 being hydrogen. Preferred compounds are those of Formula /, where R6 is hydrogen or Cu, alkyl. Preferred compounds are those of Formula /, where R7, R8. R" and R1" are independently one of hydrogen, C,.6 alkyl, C6.10 ar(C,.6)alkyl, C6_,0 aryl, C2.l0 hydroxyalkyl or C2.7 carboxyalkyl. Useful values of R7, RR, R" and R12 include liydrogen, methyl, ethyl, propyl, w-butyl, benzyl, phenylethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-carboxymelliyl, 3-carboxyethyi and 4-earboxypropyl. Additional prelened compounds are those wherein R7 and RH are tnken together to form -(CI U) - where y is most preferably 2. Another group of preferred compounds are those where RB nnd R" are taken together to form -(CI I2)r- where r is most preferably 2. Preferred compounds are those of Formula /, wherein R9 is hydrogen or C,.f, alkyl. optionally substituted by one, two or three, preferably one, of amino, monoalkylamino, dialkylamino, alkoxy, hydroxy, alkoxycarbonyl. aryloxycarbonyl, aralkoxycarbonyl, carboalkoxy, phenyl, cyano, trifluoromelhyl, acclylamino, pyridyl, thiopheayl, furyl, pyrrolyl or imidazolyl. Suitable values of R" include hydrogen, methyl, ethyl, propyl, ;;-butyl, beiv/.yi, phenethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl. earboxymethyl and carhoxyelhyl. Preferred values of R10 in Formula / include hydrogen. C,.6 alkyl. C6.l0 ar(C,.5)alkyl, C6.i0 aryl, C2.,o hydroxyalkyl C2.10 aminoalkyl. C3.7 carboxyalkyl, mono(C,.., alkyl)amino(CU8)alky], and di(C,.4 alkyl)amino (C,.s)aikyl. Suitable values of R'° include methyl, ethyl, propyl, //-butyl, benzyl, phenylethyl, 2-hydroxyethyl. 3-hydroxypropyl, 4- -17- hydroxybutyl, 2-aminocthyl, 2-carboxyincthyl, 3-carboxyelhyI, 4-carboxypropyI and 2-(dimethylamino)ethyl. Preferred values of R\ Rb and Rc in Formula / arc hydrogen, hydroxy, C,.6alkyl, C,_6 alkoxy, cyano or-CO2Rw, where Rw, in each instance, is preferably one of C,_,alkyl, C4.7cycloalkyl or benzyloxycarbonyl. Suitable values of R\ R1' and W include hydrogen, methyl, ethyl, propyl, H-butyl, hydroxy, mcthoxy, ethoxy, cyano, -CO2CH3, -CO2CI-I2CM3 and -CO2CII2CII2CH3. In the most preferred embodiments, \V\ Kh and Rc are each hydrogen. Also preferred at R\ Rb and Rc is the group -CO2RW, where Rw is one of where Rli-\<.b are defined as above. when k r and rc where is one oi of these moieties the resulting compounds prodrugs that possess desirable formulation bioavailability characteristics. a preferred value for each rd rb hydrogen rf methyl values rh include benzyl fe> Preferred values of n in Formula I include from zero to 6, more preferably from zero to 4, and most preferably zero, 1 or 2. Preferred values of m include from zero to 4, more preferably zero, I, 2 or 3. Compounds having the following formulae (Formula IIA and Formula///?) have been discovered to have exceptional potency as inhibitors of serine proteases: -18- or a solvate, hydrate, pharmaceutically acceptable salt or prodrug thereof, wherein: R21 is one of phenyl, naphthyl, thiophenyl, qiiinolinyl or isoquinolinyl, optionally substituted by one or two substitucnts independently selected from the group consisting of halogen, CM alkyl, C|.4 alkoxy, methoxy, tniluoromelhyl, cyano, nilro, amino or dimcthylamino; and when R21 is phenyl, said phenyl can be optionally orllio- substituted by CM, alkylsLillbnyl, C,,.,,, arylsulfonyl, C,,.ln ;u(C'M,) alkylsulfonyl, ("".," nrylsulfoniimido, C6.J0 ar(C,_6) alkylsulfonamido, A'-morphoIinosulfonyl, or R:2R23NSO2-, where R22 and R2i are independently selected from the group consisting of hydrogen, CUil alkyl, C3.7 cycloalkyl, C2.6 alkenyl, C2.6 alkynyl, C6.l0 aryl, C6.10 ar(C,.4)alkyl, pyridyl, pyridyl(C,.4)alkyl, carboxy(C,.6)aIkyl, C,.j alkoxycarbonyl(C,.4)alkyl, cyano(C3.ft)alkyl, hydroxy(C2.6)alkyl, CM alkoxy(C2.6)alkyl, mono- and di-(C,.4)alkylamino(C2.6)alkyI, or R22 and R23 can be taken together with the nitrogen atom to which they are attached to form a helerocyclic ring selected from the group consisting of N-morpholinosulfonyl, N-piperazinylsulfonyl (optionally N' substituted with C,.6 alkyl, C,.fj hydroxyalkyl, C6.)0 aryl, C6.10 aryl(C,^)alkyI, C,.6 alkylsulibnyl, Ch.lo arylsulfonyl, C,.6 alkylcarbonyl, morpholino or C6.10 arylcarbonyl), N-pyrrolylsulfonyl, N-pipcridinylsulfonyl, N-pyrrolidinylsuIfonyl, N-dihydropyridylsulfonyl, N-indolylsulfonyl, wherein said heterocyclic ring can be optionally substituted with one or two of hydroxy, C,.8 alkanoyloxy, C,.fi alkoxy, Cfi.in aryloxy, amino, mono- and di- C,.6 alkylamino. Ct.R alkanoylamino, CM alkyl, C3.7 cycloalkyl, C6.10 aryl, C6.10 ar{C,.4)alk>i, heterocycle, hctcrocycloalkyl, carboxy(C|.6)alkyl, C,.4 alkoxycarbonyl(C,..,)alky], cyano(C3.6)alkyl, -19- hydroxy(C-M,)a!kyl, C,.., alkoxy(Cw)aiky], mono- and di-(C, Jalkylamino(C2.,,)alkyl, carboxy, C,.6 alkoxycarbonyl, earboxamido, formyl, C,.6 alkanoyl, C6.10 aroyl, C6.E0 ar(CM)aIkanoyl, sulfonyl, C,.6 alkylsulfonyl, C,.6 alkoxysulfonyl, sulfonamido, phosphcnyl, phosphoramido, or phosphinyl; R2^ is hydrogen or CM alkyl; Y1 is one of O, NR10, where R!0 is defined as above, or a covalent bond; a and b are 0. 1 or 2, preferably 1; X'isOorNR29;and R29 is hydrogen or CM alkyl. Preferred and suitable values of R21 are the same as those described above for R1; Y' is preferably O; a is preferably one; and X' is preferably O or Nil. Specific compounds within the scope of the invention include the following: 3-[3-(2-chlorophenylsulfonyloxy)-5-methy]phenoxy]propoxyguanidine; 3-[3-(2-nictlioxyphenylsulfonyloNy)-5-meth\ lphcnoxy]propoxygiKiiiidinc; 3-[5-nicthyl-3-(quijiolinyi-8-si]ironyloxy)|)lienoxy]pro[)o\yguanidinc hydrochloridc; 3-[3-(5-chloro-2-incthoxyplicnyIsuiroiiylo\y)"!:i-iiic(hylplicfi(ixy|p(0|ioxygiKi!iidiiic liydrochlondc; 3-[3-(5-chU)ri)lhiophciiyl-2-suironyU"xy)-5-iiii.ili)'tjihcnoxyjpropi)xygu;mitline hydrochli>riilc; 3-[3-(2-cyanopheny!sulfoiiyloxy)-5-mcthy!phcnoxy]propoxygu;inidinc hydrochloridc; 3-[3-(5-isoc|iiinoIinylsuHbiiyloxy)-5-inclhyl|ilicnoxy]piopoxyguiu!iiliiic liydroclili)ridc: 3-[5-methyl-3-[2-(metliyIsulfonyl)plicnylsulfonyloxyjplienoxy]propoxyguanidine hydrochloride 3-[5-n]clhyl-3-(l,2,3,4-tetnihy(iroquiiiolinyl-8-SMlfonyloxy)pliciioxy]propoxyguaiiidine acetate; 3-[5-hydroxyinethyl-3-(quinolinyI-8-sulfonyioxy)phenoxy]propoxyguanidineacetic acid salt; l-[[5-methyl-3-(2-niethylsu!fonylphenylsulfonyloxy)phenoxy]methyl]cyclopropylmethoxy guanidinc hydrochloridc; l-[[5-methyl-3-(2-cyanophenylsuIfonyloxy)p]ienoxy]methyI]cyclopropyImethoxyguanidine acetate; l-[[5-n]Cli)yl-3-(quinoliMvl-8-suironyloxy)phcnoxy]nicthvl]cycloprop>rlniethoxyguanidine acetate; 3-[5-methyU3-(2-iiiorpholiiiylsuHbnylp]ienylsulfony!oxy)phenoxy]propoxyguanidine hydrochloride; 3-[5-mcthyI-3-(2-(acety1pipcra7jnyIsuironvl)phcnylsulfbnyioxy)phcnoxy]propoxyguanidiiic hydrochloride; -20- 3-[5-mcthy]-3-(2-(//-inethylphcnelhylaminosulfonyl)plieiiylsuironyloxy)pheiioxy]propoxy guanidine hydrochloride; 3-[5-niel!ioxy-3-(2-incl]iylsulfonylphcnylsiilfonyloxy)pliciioxy]|iiopoxyguanidiiic hydrochloride; 3-[5-ctliyI-3-(2-methylsLilfonylplicnylsulfoiiyloxy)phcnoxyjpropoxyguaiiidine hydrochloride; 3-[5-iiiclliyl-3-(2-(phcnylsiilfonyl)piiciiylsii!fonyloxy)plicnoxy]propoxyguniiidiiic hydrochloride; 3-[5-incthyl-3--(2-(4-elhykixyc;ii-bonyl)pipcridii)yistilibi]ylj)iicnylsulfbnyloxy)phciioxy]propoxy guanidine hydrochloride; 2-[5-methyl-3-(2-(mcthylsulfonyl)phenylsuIfonyioxy)phenoxy]ethoxyguanidine; 2-Iiydroxy-3-[5-inelhyl-3-(2-methyIsulfonyl)phcnylsuironyloxyphcnoxy]propoxyguanidine; 3-[3-(2, hydrochloride; 3-[5-nielliyl-3-(3-mcthylsulfonyI)phcnylsiilfoiiyloxyphcnoxy]propox)'gunnidinc hydrochloride; 3-[3-((2-chioro-4-mclhyliiulIi)iiyl)plicnylsuironylox\ ')-5-mclliylphcMoxyJpropoxygiiiinidinc hydrochloride; 3-(6-(2,3-dihydro-lJ-dioxobeii/.olb]lhio|iliene)plicMvlsiiironyloxy)-5-inclhylpI)enoxypropoxy] guanidinc lrifluoroacclate; 3-[5Hrtcniyl-3-(2-(4-cfirboxyl)pipcriciinylsuironylphcnylsiilfoiiyloxy)plicnoxy]pi'Opoxyguanidinc; 3-[5-inethyl-3-(3-meliiylquiiioliny!-8-sulfonyloxy)p!icnoxy]propoxygiianidine diacclalc; 3-[5-mcthyl-3-[2-(A^-hydroxy)aniinoplienylsulfonylox>]phenoxy]propoxygunnidine hydrocliloritlc; 3-[5-inclhyl-3-[2-aniinopliciiylsuIfoiiyloxy]plicnoxy]propoxygiuinidiiic hydrochloride; 3-[3-(2-(4-biphciiyiiiicllioxy)pi)eiiy!suirony!oxy)-5-!iic(hylphcnoxy]propoxygLiai]idinc; 3-[3-(2-(3-biphcnyImcthoxy)phenylsuironyloxy)-5-mclhyIphenoxy]propoxyguanidine hydrochloride; l-[(3-benzyloxy-5-mctliylplienoxy)mcthyl]-l.i-cyclopropyietlioxyguanidine; 3-[5-methyl-3-bis(2-methoxyethyl)aminosiilfonylphenylsulfonyloxy)phenoxy]propoxyguanidine liydrochioridc; 3-[5-mcthyl-3-(A'-cthyl-3,4-(niclhyleiiedioxy)niiilitiosulibiiylphcnylsuironyloxy)plienoxy] propoxyguanidiiic hydrochloride; 3-[5-niclhyl-3-(2-A'-nic(hyl-(3/-diino(lKixyphLM"yl)cthy|jiminosinibi)ylp!icnyIsuironyloxy) phenoxyjpropoxyguanidine hydrocliloride; 3-[5-]nclliyl-3-((3-cthoxyc:irbonyI-l-pipcridinosiillt)Myl)phcn)ilsuironyloxy)phciioxy]propoxy guanidine hydrochloride; -21- 3-[5-iiiclhyl-3-((3-c"rbnxypipcridinosuiroi]yl)phcnylsulfonyIoxy)phcnoxy]propoxyguanidinc hydrochloridc; 3-[5-nicthyl-3-((2-niclhoxycarboiiyll-pyiTolidiiKiSMiroiiyl)plicn}Isuiroiiyloxy)phcnoxyJpropoxy guanidine liydrochloride; 3-[5-nielliyl-3-((2-cnrboxy-l-pyrrolidinosiilfonyl)plicnylsiiIfonyloxy)pl]ciioxy]propoxyguanidiric hydrochloridc; 3-[5-methyl-3-(A'-nielhyl-A'-cthoxycarbonyInicthyl)aininosuironylphenylsLilfoiiyloxy)pherioxy] propoxyguanidiiic hydrochloridc; 3-[5-mcthyl-3-(A'-mclhyi-A'-clhoxycarbony!mclhyl)ain inosulfonylphcnyl.su I fonyloxy)phcnoxy] propoxyguanidinc hydrochloridc; 3-[5-methyI-3-(2-(4-metliylsulfonyIpipcrazin-]-y!sulfonyl)pIienyIsulfonyloxy)phenoxy] propoxyguanidine liydrochloride; 3-[5-niclhy!-3-{2-(4-(2-pyriniidinyl)pi|)crnzin-l-ylsuironyl)phcnylsuironyloxy)phciioxy] propoxyguanidine iiydrochloride; 3-[5-mclhyi-3-(2-(A/-n]clhyl-A/-(2-(2-pyridyi)clhyl);uninosuironyl)phcnylsuironyioNy)phcnoxy] propoxyguanidiiic dihydrochloridc; 3-|5-inclhyl-3-(2-(A/-prop)'I-Af-(2-(2-p\'ritIsl)clliyl);miinosiiHoiiyr)pltcnyisiiirony!oxy) phcnoxyjpropoxyguaniclinc dihydrochloridc; 3-[5-methyl-3-(2--(Af-clhy!-A'-(4-pyridy!mcthyl)aminosu!fonyI)plicnylsuironyloxy)phenoxy] propoxyguanidine dihydrochloridc; 3-[5-methyl-3-(2-(A'-niethyl-A7-(4-niethoxyphenyI)nniinosu]ronyl)phenylsulfonyloxy) phenoxy]propoxyguanidine liydrochloride; 3-[5-inclhyl-:J-(2-(4-cihylpipcia/jn-l-ylsuironyl)phcuylsuironyloxy)phcnoxyJpropox\giKinidinc dihydrochloridc; 3-[5-nictliyl-3-(2-(Minclliyl-A/-(4-inclhoxycarboiiy!phcnyl)aiiiii]osulibnyl)pl]CiiylsuMbnyloxy) phenoxyjpropoxyguanidine liydrochloride; 3-[5-inclhyl-3-(2-(A/-(2-cyniH)clliyl)-A/-(3-pyri(iyhnclh\l);iiniiH>suiroiiyl)phcnylsiiiro[iyloxy) phcnoxy]propoxyguauidinc dihydrochloridc; 3-[5-mcthyl-3-(2-(A/,A/-bis-(2-cyanoclhyl)aniiiiosuironyl)p!ienylsulfonyloxy)phcnoxy] propoxyguanidinc hychocliloridc; 3-[5-methyl-3-(2-(A7-(2-ellioxycarbonyIethyl)-A;-bciizylaminosuironyl)phenylsulfonyloxy)-phenoxy] propoxyguanidinc hydrochloridc; 3-[5-melliyl-3-(2-(4-(pipcridin-]-yl)pipcridin-I-ylsulfonyI)phenylsuIfonyloxy)phcnoxy3 propoxyguanidinc diliydrochUiridc; -22- 3-[5-nielhyl-3-(2-(A'-methyl-yV-(2-(4-pyridyl)cthyl)aininosulfonyl)plicnyIsulfonyloxy)phciioxy] propoxy guanidine dihydrochloride; 3-[5-inclliyl-3-(2-(A'-(ctlioxyciirhoiiylnictliyl)-A'-(2-pyridyliiiclliyI);iminosiiironyl) phenylsullbnyloxyjphenoxyjpropoxygunnidinc dihytlrochloridc; 3-[5-inclliyl-3-(2-(A',A'-his(clho,\yc;irl)[)iiy!ini:lli)'l):nni[insii!roiiyl)phcnylsi]iroiiy!oxy) phenoxyjpropoxyguanidinc hydrochloride; 3-[5-mclhyl-3-(2-(4-(cthoxycarbonylincthyl)pipera7.in-l-ylsuironyl)pIicnyIsulfonyloxy)phenoxy] propoxyguaiiidinc dihydrochloride; 3-[5-melhyI-3-(2-(7V.A'-bis(carboxymethyl)a!ninosuIfonyl)pIienylsiilfonyloxy)phenoxy] propoxyguan id ine; 3-[5-mcthyl-3-(2-(A/-uiclhyl-A/-(4-carboxyphenyl)nniinosuifonyl)plicnylsulfonyIoxy)phcnoxy] propoxyguan id inc; 3-[5-melliyi-3-(2-(A/-(2-carboxycthyl)-A;-bcnzyianiinosulfonyl)pliciiylsulfohyloxy)plienoxy] propoxyguan td i tie; 3-[5-nictIiyl-3-(2-(4-(carboxyinclhyl)pipcni7.in-I-ylsu!Ibiiyi)p!]onylsti!ronyl(i\y)- phenoxyjpropoxy guanidine; 3-r5-mcthyl-3-(2-(4-(2-pyridyl)pipcrn7jn)lsuiro[iyI)plicnylsulfonyloxy)plicnoxy]- propoxyguiinidinc hydrocliloriiL'; 3-[5-mcthyI-3-(2-(4-phcny!pipcraziiiylsiiironyI)phcnylsiiironyloxy)phcnoxy]propox> guanidine hydrochloride; 3-[5-inclhyl-3-(2-(4-beiizylpipcra7.inylsiilfonyl)phcn\ 1 still onylo\y')plicnoxy]piopo\yguan id inc liydmchloride; 3-[5-mclhyl-3-(2-(4-(2-mctlioxyphcnyl)pipcraziiiylsuiron\i)plieiiyIsulfon>'loxy)plicnoxy] propoxyguan id ine hydrochloride; 3-[5-mclhyl-3-(2-(A'-(2-cyiiiiociliyl)-A/-(2-fiiraiiylinclliyl)aminosulfoiiyl)pIicnylsiilfony!oxy) phenoxyjpropoxyguanidine; 3-[5HiicthylO-(2-(4-mcthylpipcrazinylsiilfonyl)phcnylsuironyloxy)phcnoxy]propoxygiianidinc liydrochloHdc; 3-[5-inclhyl-3-(2-(A' sulfonyloxy)piieiioxyjpropoxygu;midine dihydrochlnridc; 345-methyl-3-(2-(A/-benzyl-AK2-(A'1A'-diniclhylauiino)c(liy!)nminosiiifonyl)plicny!sulfonyloxy) phenoxyjpropoxyguan id inc dihydrochloiiilc; 3-[5-melhyl-3-(2-(A'-methy!-A'-(]-mcthyl-4-piperidinyl)aminosi]|fonyl)phenylsulfonyloxy) phenoxyjpropoxyguanidinc di!i)drochloride; -23- 3-l5-inc(hyl-3-(2-(A'-niclliyl-/V-(3-pyriciylincMhyl);nuinosM!ronyl)|ilicii)'lsu[ronyloxy)piicno.\yj propoxyguanidine dihydrochloride; 3-[5-niclliyl-3-(2-(A^-ethyl-A^-(2-(A;,A^-diinelhylnniiiio)c1hyl)aminosiiiroiiyl)plienylsuironyloxy) phenoxyjpropoxyguanidine diiiydrochloride; 3-[5-mcthyl-3-(2-(2-(4-niorpliolinyl)c(liylnmiiiosiiironyl)phoiiylsulfonyloxy)p!icnoxy] propoxyguanidinc dihydrochloride; 3-[5-melhyi-3-(2-(A'-methyl-A'-(2-(A',A'-dimethylamino)elhyl)aniino sulfonyl)phenylsulfonyloxy) phcnoxy]propoxyguanidinc hydrochloridc; 3-[5-mctIiyl-3-(2-('1-Cpyrrolidin-l-yl)pipcridiii-]-yisuiroiiyl)phcnyl.suiroiiyloNy)phcnoxy] propoxyguanidine; 3-[5-niclhyI-3-(2-(4-clhoxycarbonyl-l-pipcra/.inylsuiibnyl)phcnylsuironyIoxy)phciio\y] propoxyguanidine hydrochloride; 3-f5-me(hyl-3-(2-(A'-nic(hyl-A'-(3-(/V,A'-dinietliylainino)propyi)nniinosLiironyl)phenyI- sulfonyloxy)phcnoxy] propoxyguanidine; 3-[5-inelhyI-3-(2-('1-pyridylniclhyl;iininosi]irnnyl)plRinylsuironylo.\y)- phcnoxyjpropoxyguanidinc; A/-niclhyl-A'-{3-|5-incthyl-3-f2-(inethylsu!I'on>l)phcnylsuironvk)xy)phciK)xyJpiopoxy}gu;]uidiiic hydrochloridc; 3-[3-melhyl-5-(W-nicU)yl-2-(nicthy!suironyl)phcnylsuironyIaniino)phcnoxy]propoxygiinnidine liydiochloridc; 3-[3-(2-chldrophenylsulfonyloxy)-5-methylpiicnoxy]-propylaminoguanidinedincelate; 13-[5-iiiclhyi-3-(2-trinuoroinclhylplicnyls(iHunylox)')phciioxy]-piopylaininoJgu;niidinc hydrochloridc; t3-[3-(5-chlorotliiophenyl-2-sulfonyIoxy)-5-methylphenoxy]propylamino]guanidine acetate; [3-[3-(2-inclhoNyplienylsu!roiiyIoxy)-5-niclhylplicnoxyJ-piopylaiuino]gu;inidine dincclatc; [3-[3-(2-cyanophcnylsuironyIoxy)-5-mctliylphenoxy]propylamino]guanidine acetate; as well as plKiniuiccuticnlly ;iccoptahlc salts thcrcol', lor cxiunplc the hydrochloride and acctalc salts thereof. Structures for these compounds are provided in the pages prior to the claims. Alternative embodiments of the present invention include compounds of Formula/ in which two "R" groups together form a saturated or unsaturated hydrocarbon bridge, thus forming an additional cyclic moiety in the resulting compounds. Alternative embodiments include compounds of Formula /wherein Z. R'-R\ Y, m and n arc as defined above; and: -24- A. R7 and R12 arc taken together to form -(CI \2)o-. where o is 1, 2 or 3; R" is hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl; R8 is hydrogen and R6, R\ Rb and Rc are defined as above; or B. R" is hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl; R7 is hydrogen; R8 and R12 are taken together to form --(CH2)-(CH2)-(CH2)p-, where p is 1, 2 or 3; and R6, Ra, Rb and Rc are defined as above; or C. R6 and Rb are taken together to form - (CH2)-(CH2)r- or -CH-N-CM-NH-, where r is 1, 2 or 3; Rn is hydrogen or hydroxy; R1' is hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbamoyloxy, cyano or -CO2RW-, where Rw is as defined above; R7, R\ R" and R12 are each independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl, or R7 and R* are taken together to form -(CI I2)-. where y is zero. 1 or 2; or D. Ra and Rc are taken together to form -CH2-(CH2)5-, where s is 1 or 2; Rfi is hydrogen, alkyl, alkoxy. aryloxy, aralkoxy, alkoxycarbonyloxy. cyano or -CO2RW-, where Rw is as defined above; and R7, RR, R" and R12 are each independently one of hydrogen, alkyl. aralkyl, aryl, hydroxyalkyl or carboxyalkyl, or R7 and R" are taken togelher to form -(CH2)y-, where y is zero, 1 or 2. Thus, compounds having formulae ///, II', Kand VI are contemplated: -25- wherein R'-R4, Z, Y, Rfi-R12, Ra-Rc, JI? m, o, p, r and s are defined as above. Preferred values for each of these variables arc the same as described above for Formula /. Specific compounds within the scope ofthese formulae include:. -26- It is also lo be understood that the present invention is considered to include stereoisomers as well as optical isomers, e.g. mixtures of enanlioincrs as well as individual enantiomers and diastercomcrs, which arise as a consequence of structural asymmetry in selected compounds of the present series. The compounds of Formula 7 may also be solvated, especially hydraled. Hydration may occur during manufacturing of the compounds or compositions comprising the compounds, or the hydration may occur over lime due to the hygroscopic nature of the compounds. Certain compounds within the scope of Formula / are derivatives referred to as prodrugs. The expression "prodrug" denotes a derivative of a known direct acting drug, which derivative lias enhanced delivery characteristics and therapeutic value as compared to the drug, and is transformed into the active drug by an enzymatic or chemical process; see Notari, R.E., "Theory and Practice of Prodrug Kinetics," Mctluuis in Enzymolog\\ 772:309-323 (1985); Bodor, N., "Novel Approaches in Prodrug Design," Drugs of the Future, 6(3): 165-182 (1981); and Bundgaard, H., "Design of Prodrugs: Bioreversible-Derivatives for Various Functional Groups and Chemical Entities," in Design of Prodrugs (H. Bundgaard, ed.), Elscvicr, New York (1985)! Useful prodrugs are those where R°, R" and/or Rc arc -CO:R", -77- whcrc Rwis defined above. See, U.S. Patent No. 5.466,811 and Saulnicr et "/., Bioorg. Pled Chem. Lett. 4:1985-1990 (1994). The term "alkyl" as employed herein by ilsclf 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, /-butyl, isobutyl, penlyl, hexyl, isohcxyl, heplyl, 4,4-dimcthylpeiityl, oetyl, 2,2,4~tnmelhylpentyl, 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, including, but not limited to. elhenyl, 1-propenyl, 2-propenyl, 2-melhyl-l-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 from 2 to 4 carbon atoms in length. The term "alkynyl" 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 triple bond between two of the carbon atoms in the chain, including, but not limited to, acetylene, l-propylcne, 2-propyIenc, and the like. Preferably, the alkynyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8 carbon atoms in length, most preferably from 2 to 4 carbon atoms in length. In all instances herein where there is an alkenyl or alkynyl moiety as a subslituenl group, the unsaturated linkage, i.e., the vinylcne or acetylene linkage is preferably not directly attached to a nitrogen, oxygen or sulfur moiety. The term "alkoxy" is used herein to mean 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, cthoxy. //-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 "aryl" as employed herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 12 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl. The term "heteroaryl" as employed herein refers to groups having 5 to 14 ring atoms; 6, 10 or 14 TC 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: thicnyl. -28- bcnzo[b]thicnyl, naphtho[2,3-b](hicnyl, thianlhrenyl, Airyl, pyranyl, isoben/.ofuranyl, benzoxazolyl, chromenyl, xanlhenyl, phenoxathiinyl, 2//-pyrrolyl, pyrrolyK imidazolyl, pyra/olyl, pyridyl, pyra/.inyl, pyriinidinyl, pyridaztnyl, indoli/.iny], isoindolyl, 3/Aindolyl, indolyl, indazolyl, purinyi, 4//-quinolizinyl, isoquinolyl, guinolyl, phlhalazinyl, naphlhyridinyl, quinazolinyl, cinnolinyl, pteridinyl, 4a//-carbazolyl, carbazolyl, (3-carbolinyl, phenanlhridinyl, acridinyl, perimidinyl, phenantlirolinyl, phenazinyl, isolhiazolyl, phenothiazinyl, isoxazolyl, furazanyl and phenoxazinyl groups). The term "aralkyl" or "arylalkyl" as employed herein by itself or as part of another group refers to CM)alkyl groups as discussed above having an aryl substilucnt, such as benzyl, phenylelhyl or 2-naphthylmethyI. 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 cyelopropyl, cyclobutyl, cyclopentyl, cyclohcxyl, cycloheplyl, cyclooetyl and cyclononyl. The terms "alkoxy" refers to any of the above alkyl groups linked to an oxygen atom. The term "halogen" or "halo"as employed herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine whh 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 "hydroxyalkyl" as employed herein refers to any of the above alkyl groups substituted by one or more hydroxyl moieties. The term "carboxyalkyl" as employed herein refers to any of the above alkyl groups substituted by one or more carboxylie acid moieties. The term "helerocyclic" is used herein to mean a saturated or wholly or partially unsaturated 3-7 membered monocyclic. or 7-3 0 membercd bicyclic ring system, which consists of carbon atoms and from one to four hcteroaloms 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 quatcrnized. and including any bicyclic -29- group in whicli any of the above-defined hctcrocyclic rings is fused to a benzene ring, and wherein the helerocyclic ring can be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Especially useful arc rings containing one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur combined with one of two nitrogen atoms. Examples of such hctcrocyclic groups include piperidinyl, pipcrn/.inyl, 2-oNopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidnzolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isolhiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, fury), tclrahydrofuryl. tctrahydropyranyl, thienyl, benzotiiicnyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sullbnc, and oxadiazolyl. Morpholino is Ihe same as morpholinyl. The term "helcixialom" is used herein to mean an oxygen alom ("()"), a sulfur atom ("S") or a nitrogen atom ("N"). It will be recognized that when the hcleroatom is nitrogen, it may form an NRyR' moiety, wherein It? and R' are, independently from one another, hydrogen or C, to C8 alkyl, or together with the nitrogen to which they are bound, form a saturated or unsaturated 5-, 6-, or 7-membered ring. wherein R6, Ra, Rb and Rc are defined as above, with a carbonyl-containing compound of the formula Another aspect of the present invention is a process for preparing an aminoguanidine compound of Formula /, comprising reading an aminogunnidine of the formula -30- whcrcin \V-R\ Z, Y, n, m, R7, R\ R" and R12 arc defined as above to form an amidinohydrazone, and thereafter selectively reducing the hydrazone carbon to nitrogen double bond of the amidinohydrazone. The aminoguanidine is typically provided as a salt, preferably the nitrate salt. The first step proceeds at ambient temperature using alcohol as a solvent. Ati acid, such as 4N i 1C1 in dioxane is added to the reaction mixture. The reaction is more fully described herein. Another aspect of the present invention is a process for preparing a hydroxyguanidine compound of Formula /, comprising reacting an alkoxyaminc compound of the formula wherein \V-R'\ Z. Y, n. m, R7, R\ R" and R': are defined as above with a guanidiuylnting reagent. Preferred guauidinylating reagents include: aminoiminosullbnic acid, optionally substituted l//-pyrazole-1-carboxamidines, or KN'-bis(tcrt-butoxycarbonyl) S-methyl isothiourea. The invention is also directed to alkoxyainine intennediates that are useful for forming the protease inhibiting compounds of Formula /. These intermediates are represented by Formula IX: wherein R'-R4, Z, Y, n, m, R\ R8, Rh and R12 are defined as above for Formula /. Schemes ///, //;, and Ic outline the synthetic steps to produce compounds ol'lhe present invention where R'-Z is R'-C(RyR'):O- or R!-SO,O-. Scheme la illustrates but is not limited to the preparation of the compounds of Examples 1-8, 10-18, 21-22, 28-33. and 82-86. -32- Phenols I (where Pa = H) arc converted to monosulfonales 2 by treatment with appropriate sulfonyl chlorides. Preferred conditions include treating phenol 1 with a sulfonyl chloride in a biphasic system composed ofan organic solvent, such as an ether, and an aqueous phase saturated with NaHCO3. Alternatively, the reaction may be effected first by deprolonaling I with one equivalent ofa strong base, most preferably Nail, in ;i polar organic solvent, such as Af.^V-dimethylformamide or letrahydrofuran,. followed by treating the deprotonated phenol with the sulfonyl chloride. Still alternatively, phenol 1, in a typical organic solvent, such as dichloromethane, may be converted to 2 by treating the phenol with sulfonyl chloride in the presence ofan amine base, such as 4-methylmorpholine. Phenols 1 may be monoprotecled (Pa is a protecting group) with a variety of protecting groups known in the art. such as esters and benzyl ethers (Greene, T.W. and Wuls, P.G.M., Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, Inc. New York (1991)). Deprotection of the hydroxy groups is routinely accomplished using the reaction conditions well known in the art. l;or example, dcproteclion of benzyl ethers may be effected through catalytic hydrogenation using palladium on carbon as a catalyst in solvents such as cthanol or tetrahydrofuran. Deprotcction ofan acetate is accomplished by basic hydrolysis, most preferably with sodium hydroxide in aqueous letrahydrofuran. Phenols 2 are coupled to 3 (for I. - Oil) using a Mitsunobu coupling procedure (Mitsunobu, O., Synthesis 1 (1981)), where P1' of 3 may be a suitable alcohol protecting group. Alternatively, suitable diols (Ph = I-I) may be used in the Mitsunobu reaction. Preferred coupling conditions include using a trialkylphosphinc or triarylphosphinc, such as Iriphenylphosphine or trwj-bulylphosphine, in a suitable solvent, such as telrahydrofuran or dichloromethane, and an azodicarbonyl reagent, such as diethyl azodicarboxylate or l,l'-(azodicarbonyl)dipiperidine. Typical Pb (where Pb is an alcohol protecting group) is well known in the art, such as esters and benzyl ethers (Greene, T.W. and Wuls, P.G.M., supra). Alternatively, where L is a reactive leaving group such as lialide or sulfonate, phenol 2 may be treated with a base, such as sodium hydride, in a solvent, such as 7V,A^-dimclhylformamide, and then treated with 3. Removal of P'1 is routinely accomplished using the reaction conditions well known in the art. For example, dcprolcction of benzyl ethers may be effected through catalytic hydrogenation using palladium on carbon as a catalyst in solvents such as cthanol or letrahydrofuran. Dcprolcction of an acetate is -33 - accomplished by basic hydrolysis, most preferably with sodium hydroxide in aqueous iclrahydrofuran. Alternatively still, alcohol 4 can be obtained by reduction of the appropriate aldehyde or kctone 7 (obtained from 2 as described below) with a suitable reducing agent, such as sodium or lithium borohydride (Wallbridge, J. Prog. Jnorg. Chem 77:99-231 (1970)). Alcohol 4 is converted to 9 employing a Mitsunobu reaction with an //-hydroxycyclic imide derivative such as AMiydroxyphthalimide. Unveiling of the phthalimidc protecting group is accomplished using standard conditions well known in the art (Greene, T.W. and Wuts, P.G.M., supra), for example, sodium borohydride in a mixture of an appropriate alcohol (e.g. ethanol or 2-propanoI)/ water followed by acidification. Alternatively, removal of the protecting group may be accomplished using hydrazine or methylamine. Guanidinylation of the resulting alkoxyamine to 10 is achieved using standard reagents such as aminoiminosulfonic acid (Miller, A. B. and Bischoff, J. .1. Synthesis 777 (1986)), or 17/-pyra/ole-l-c;uboxnmidine hydrochloiide (Bcrnatowicz, M. S. ct. til. J, Org. Chem 57(8):2497 (1992)), or with substituted guanidinylating reagents such as /V,7\/'-bis(/c77-butoxycatbonyl)- S-mclhylisothioutca (Bergeron, R.J. and McManis. J.S. .7. Org. Chem. 52:1700 (1987)) or N-R\ N-R\ A'-Rc-l//-pyrazole-l-carboxamidine, where Ra, Rb and Rc are defined as above for Formula /. Useful l//-pyrazole-l-carboxamidines include Af,Ar-bis(ft'/7-butoxycarbonyl)-l//-pyrazolc-l-carboxamidine and 7V,7V'-bis(benzyloxycarbonyl)-l/V-pyrazole-l-carboxamidine (all of which can be prepared according to Bernatowicz, M.S. et. a!., Tetrahedron Letters J-/:3389 (1993)). Conversion of alcohol 4 to the corresponding aldehyde or kctone 7 is accomplished using routine procedures for the oxidation of alcohols (see for example Corey, I7.A, Sundberg, R.J. Advanced Organic Chemistry, Part B: Reactions and Synthesis, 3rd edition, Plenum Press, New York (1990)) such as the Swcrn oxidation (Mancuso, A.J. et al. Journal of Organic Chemistry 3329 (1976)) pyridinium chlorochromate (Corey, E.J. and Suggs, J.W. Tetrahedron Letters 2647 (1975)) pyridinium dichromatc (Corey, E.J. and Schmidt, G. Tetrahedron Letters 399 (1979)), or sulfur trioxide pyridine complex / dimethylsulfoxide {Tetrahedron Letters 2S:\(M (1987)). Still alternatively, 2 may be coupled directly to 5 where L - OH or a reactive leaving group sucii as halide, alky! sulfonate, or aryl sulfonatc. ¦ In the case of L - OH, the -34- Mitsunobu coupling procedure may be used. In cases where L is a reactive leaving group such as halidc or sulfonatc, phenol 2 may be treated with a base, such as sodium hydride, in a solvent, such as MM-dimelhylformamidc, and then treated with 5. Alternatively., phenol 2 may be converted to 7 by the Mitsunobu reaction using 6 wherein L = OH and Pc is an aldehyde or ketone protecting group which is well known in the art (Greene, T.W. nnd Wuls, P.CM., supra), for example, a dimethyl ketal or acetal, 1,3-dioxolane group, or 1,3-dioxane group. Alternatively, where L of 6 is a reactive leaving group such as halide or sulfonale> phenol 2 may be treated with a base, such as sodium hydride in a solvent such as A'.A'-dimcthylformamide, and then treated with 6. Pc may then be removed to afford 7 using standard conditions well known in the art, for example, /7-toluencsulfonic acid in acetone (Greene, T.W. and Wuls, l'.G.M., supra). Compound 7 is then converted to nmidinohydrnzonc 8 using standard conditions, for example, treatment with an aminoguanidine, such, as aminoguanidinc or 2-hydrazinoimidazoline, optionally in the presence of an acid such as nitric acid, hydrogen chloride, or hydrogen bromide, in an appropriate solvent, for example, cthanol or methanol, which, in addition, may contain other solvents such as diehloromethane or tctrahydrofuran. Conversion of S to 11 is accomplished under reducing conditions well known in the art, for example, lithium borohydride in an appropriate solvent such as tetrahydrofuran or methanol at various temperatures up to reflux. As an alternative method, catalytic hydrogenntion with palladium on carbon catalyst can be employed. When Rn, Rb and/or Rc arc a protecting group, for example l-butyloxycarbonyl (Boc), these protecting groups can be optionally removed by treatment with acid, usually trifluoroacetic acid in a suitable solvent such as dichloromelhane or water, or by HC1 gas dissolved in a suitable solvent, such as 1,4-dioxane. -35 -Scheme lb A variation of Scheme la (Scheme lb) involves the use of monoprotecled phenols in the synthesis of Examples 19-20, 23-26, and 80. Phenols 1 are monoprotected (Pa is a protecting group) with a variety of protecting groups known in the nit such as esters, and benzyl ethers (Greene, T.W. & Wuts, P.G.M., supra). Monoprotected phenols 1 are coupled to 3 as described for Scheme la, Oeprotection and another Mhsunobu coupling with an ;V-hydroxy imide derivative, such as AMiydroxyphthalimide, as described for Scheme fa, gives the alkoxyphthalimidcs 16. The removal of ihe pbthatimide group, as described for Scheme la, produces the alkoxyamine. The alkoxyamines are subsequently converted to the optionally protected alkoxyguanidines, using the standard guanidinylation reagents, sucli as aminoiminosulfonic acid (Miller, A. H. & Bischoff, J. J., supra) or l/f-pyrazole-l-carboxamidinc hydmchloride (Bernalowicz, M.S. ci. a!., supra), or with substituted guanidinylating reagents such as A:,A'-bis(/e/7-butoxycarbonyl)-S-methylisolhiourea (Bergeron, R.J. & McManis, J.S., supra) or A'-R", N-Rh, A'-R'-l/Z-pyrazoie-l-caiboxamidine including Af,A/'-bis(/e/7-butoxycarbonyl)-l/"/-pyrazole-I-carboxamidine and N,N'-bis(benzyloxycarbonyl)-l/-/-pyrazolc-l-carboxamidine (all of which can be prepared according to (Bcrnatowicz, M.S. et. at., supra) where R", Rb and Rc arc as defined above. -36- Tlic phenolic protecting group, P\ may be removed to give 17 and the resultant phenolic group reacted with sulfonyl chlorides. Optionally, the protected alkoxyguanidines may he alkylated on the unprotected nitrogen of the guanidine using a Milsunobu coupling with an alcohol R6OH (e.g., melhano! gives the TV-methyl alkoxyguanidinc derivative). Finally, the guanidine protecting groups, Ra, Rb, and Rc, may be removed as outlined for Scheme la. Scheme Ic -37- Schcme Ic outlines the synthesis of the 1,2-benzcncdisulfo derivatives described in Examples 34-79. In particular, Examples 34-68 were synthesized by the reaction of ],2-bcnzencdisulfonic anhydride 18 (Koeberg-Telder ei al, J. Chem. Soc. Perkin 1198 (1973)) with secondary amines, R13RMNI1, in (he presence of a base such as a tcrliary amine where R'3 and R14 are as defined above, provided that they are both other than hydrogen. The resultant monosulfonie acid salt is converted to the sulfonyl chloride.in situ by reaction with 1 equivalent of oxalyl chloride. The resultant sulfonyl chloride is reacted in situ with the phenol 17. The optional guanidine protecting groups, R\ Rh, and Rc, may be removed as outlined for Scheme la to give 19. The Examples of 68-79 were alternatively synthesized by the reaction of the bcnzcncdisulfonic anhydride 18 with the O-phlhalimide 16 (I'-1 = Ii). The resultant monosulfonic acid salt is converted in situ to the sulfonyl chloride with i equivalent of oxalyl chloride. The resultant sulfonyl chloride is reacted with amines, especially primary and diamincs, to produce sulfonamidcs. The O-aminc is next deprolectcd and guanidinylatcd by the means outlined for Scheme la. Finally, the optional guanidine protecting groups, Rn, Rh, and Rc, may be removed as outlined for Scheme la to give 19. -38-Scheme lla -39- Sclicmes I/a and lib outline the syntheses of primary and secondary sulfonamidophenoxy derivatives and carboxamido derivatives, where R'-Z- is R'-SO2NR'°-orR'-CONR10-. Sclieme //// outlines the synthesis of intermediate l,.V;iiiiinophcnols wliich are further converted to sulfonamidophenoxy derivatives where R'-Z is R'-SO2NR10- and R10 is preferably an alkyl group, as exemplified by Example 81, or are alternatively converted to carboxamidophenoxy derivatives where R'-Z is R'-CONR10-. Phenols 1 are reacted with 2-bromo-2-methyl propanamide in the presence of a base, such as sodium hydride, to give the aryloxyamides 20. The aryloxyamides 20 are treated with sodium hydride in a high boiling solvent, such as 1,3-dimelhyl-3,4,5,6-tctrahydro-2(UI)-pyrimidinone, at an elevated temperature (e.g., 100 °C for 3 h) and undergo the Smiles rearrangement to the anilidcs 21 (Cotls & Southcott,./. Chem. Soc. FT I 767 (1990)). The anilidcs 21 are hydrolyzed using strong base and elevated temperature (e.g., ION sodium hydroxide at reflux) for extended times (e.g., 2 days) in order to provide the corresponding anilines 22. The anilines 22 are converted to sulfonamides 23 by the reaction with sullbnyl chlorides in the presence ol'a suitable base, such as a tertiary amine. The sulfonamidcs 23 arc reacted with base (e.g., cesium carbonate) and R|(ll, where L is a reactive leaving group, such as halidc or sulfonale. Alternatively, the anilines 22 are converted to carboxamides by the reaction with acyl chlorides (R'COCl) in the presence of a suitable base such as a tertiary amine. Still alternatively, the carboxamides may be produced by the reaction of anilines 22 with carboxylic acids (R'COOIl) by any of the known peptidc coupling reagents, such as 1.3-dicyclohexylcarbodiimide or Castro's reagent (BOP) (Castro B., et al., Tetrahedron Lett, 1219 (1975)). The phenolic protecting group, P\ is then removed and the resultant phenols 24 are coupled with 3 as described for Scheme la. After removal of the alcohol protecting group, Pb, the alcohol is coupled to AMiydroxy imides, such as AMiydroxyphthalimide, as described for Scheme ///. The removal of the phlhnlimidc group, as described for Scheme la, produces the alkoxyammc. The alkoxyamiues are subsequently converted to the optionally protected alkoxyguanidines, using the standard guanidinykition reagents outlined for Scheme la. Finally, the guanidine protecting groups. Ra, Rb, and Rc, may be optionally removed as outlined for Scheme la to produce the target 27. -40- Schcme lib An alternative method to synthesize sulfonamidcs, especially unalkylaled sulfonamides (where R10 = H) is shown in Scheme lib. Nilrophenol 28 is coupled to 3 by standard techniques. Preferably, the reaction is effected by the Mitsunobu reaction (where L is OH). Alternatively, the nitrophenol is treated with a base, such as NaH, in a suitable solvent such as A^/V-dimcthylformamidc or tetrahydrofuran, followed by the addition of 3 (where L is a reactive group, such as Cl, 13r. I or sulfonatc). After I)l> group removal, the alcohol 29 undergoes a Mitsunobu coupling with an A'-hydroxy iniide, such as N-hydroxyphthalimide, as described in Scheme la. The nitro group of 30 is thereafter reduced, for example, by catalytic reduction using palladium on carbon in a suitable solvent such as elhanol or tetrahydrofuran. The resulting product is treated with an appropriate sulfonyl chloride (R'SO2C1) to provide the sulfonamide 31. At this point, the sulfonamide group may be optionally alkylatcd as described in Scheme lla. Alternatively, the resulting product from nitro reduction is treated with an appropriate acyl chloride (R'COCI) to provide the corresponding carboxamide 31. Still alternatively, the carboxamides 31 may be produced by the reaction of the product from nitro reduction with carboxylic acids (R'COOH) by any of the known peptidc coupling reagents, such as 1,3-dicyclohcxylcarbodiimide or Castro's -41 - reagent (BOP). Removal of the O-amine protecting group and gunnidinylation of the O-aminc are accomplished by methods described in Scheme la. Finally, (he O-guanidinc protecting groups, Ra, Rb, and Rc, may be removed as outlined in Scheme la to give the target 32. Scheme lie The compounds oflhe present invention where K'-Z is R'-Ol l(RyR')NUItl- can be synthesized by the steps outlined in Scheme lie. Aniline 22 is converted to 33, where Rx is H, by reductive aminalion with a suitable carbonyl component, R'CORy. The preferred reducing agent is tetramethylammonium triacetoxyborohydride. Alternatively, sodium Iriacctoxyborohydridc or sodium cyanohydride may be used. Still alternatively, reductive amination may be carried out by forming an imine (Schiff base) between (he amine and the carbonyl component using a catalytic amount of acid such as p-toluencsulfonic acid. -42- followed by reduction with sodium borohydride. Still alternatively, the imine may be reduced using catalytic hydrogenalion using a catalyst such as palladium on carbon in standard solvent such as clhanol. As an alternate to a reductive animation, aniline 22 may be reacted with R'O^R^L, where L is a reactive leaving group, sucJi as balide or suJfoivite. The remaining conversion of 33 to 37, which comprises of Pn removal, coupling to 3, Ph removal and coupling to a jV-hydroxy imide, dcpmtecu'on of O-amine, guanidinylalion and optional deprotection of the guanidine group, is similar to those steps detailed for the conversion of 23 to 27 in Scheme 11a. Scheme I/I Additionally, compounds of the present invention where Y is NR10 and R'-Z is Rl-SO2NR10- or R'-CONR1"- can be prepared by Scheme ///. Nitroanilinc 38 is converted to a sulfonariiidc by treatment with an appropriate sullbnyl chloride R'SO2CI in the presence of a weak base, such as a tertiary ;imine. The resulting sullonnmideorcarboxaniide nitrogen can be alkylated with a suitable alkylating agent R10L as described in Scheme Ha to provide intermediate 39. Alternatively, 38 is treated with an appropriate aeyl chloride (R'COCI) to provide the corresponding carboxamide 39. Still alternatively, the catboxamides 39 may be produced by the reaction of 38 with carboxylic acids (R'COOH) by any of the known -43- pcptidc coupling reagents, such as 1,3-dicycIohexyIcarbodiimide or Castro's reagent (BOP). After reduction of the nitro group, as described in Scheme lib, the resulting aniline is coupled with aldehyde 40 preferably under reductive animation conditions to give 41. The preferred reducing agent is tctramethylammonium triacetoxyborohydride. Alternatively, sodium triacetoxyborohydride or sodium cyanohydride may be used. Still alternatively, reductive animation may be carried out by forming an iminc(SchilTbase) between theaminc and the carbonyl component using a catalytic amount of acid such as p-toluenesulfonic acid, followed by reduction with sodium borohydridc. Slill alternatively, the imine may be reduced using catalytic hydrogenation using a catalyst such as palladium on carbon in standard solvent sucli as ethanol. Finally, the O-guanidine protecting groups, Ra, Rb, and Rc, of 41 may be removed as outlined in Scheme la to give 42. Scheme IV As an alternative scheme to produce the O-phthalamidc-conlaining intermediates 9, 16, 26, 31, and 36, the respective phenols 2, 1, 24, 28, and 34 may be reacted under basic conditions with reagent 43 which contains a leaving group L. This scheme is limited to -44- producing compounds where R12 is hydrogen. Reagent 43 is produced by rending a compound having two leaving groups, L, ami 1/ under basic conditions with N-hydroxyphlhalimide (Khadilkar and Samant, Indian./. Chcm. Sec. B 1137 (1993)). Compounds wherein Ra and Rc together form a cyclic group, such as an imidazolinc, can be syntliesized by employing an hnidazoline in place of the aniinoguanidine in the above Schemes. Compounds wherein R7 and R!2 or R8 and R12 together form a melhylene linkage can be synthesized by substituting a cyclic ketone having a reactive group I, that is attached directly or indirectly to the carbocyclic ring. Examples of suitable reagents include 2-hydroxycyclopentanone, 3-hydroxycyclopentanone, 2-hydroxycyclohcxanone and 3-hydroxycyclohexanone. Compounds VI wherein Rfi and R'1 are taken together with the nitrogens to which they are attached to form a ring structure are prepared by substituting a heterocyclic amine 12 (below) for the aniinoguanidine in the above Schemes. Compounds ^wherein Rq and R1' are taken together with the nitrogen atoms to which they are attached to form an imidazoline moiety are prepared by substituting a 2-hydrazinoimidazoline 13 (above) for the aminoguanidines in the above Schemes. for medicinal use, the pharmaccutically acceptable acid addition salts, those salts in which the anion docs not contribute significantly to toxicity or pharmacological activity of tlic organic cation, are preferred. The acid addition salts are obtained cither by reaction of an organic base of formula / with an organic or inorganic acid, prelembly 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 arc hydrohalide - 45 - acids such iislICI, I Mr, III; sulfuric acid; phosphoric acid and (lie tike. Preferred acids for forming acid addition salts include HC1 and acetic acid. The compounds of the present invention represent a novel class of potent inhibitors of mclallo, acid, thiol and serine proteases. P.xamplcs of (he serine proteases inhibited by compounds within the scope of the invention include leukocyte netitrophil elastase. a protcolylic enzyme implicated in the pathogenesis o('emphysema; chymolrypsin and trypsin, digestive enzymes; pancreatic elastase, and cathepsin G, a chymotrypsin-like protease also associated with leukocytes; thronibin and factor Xa, protcolytic enzymes in the blood coagulation pathway. Inhibition of thermolysin, a metalloprotease, and pepsin, an acid protease, are also contemplated uses of compounds of the present invention. The compounds of the present invention are preferably employed to inhibit trypsin-like proteases. An end use application of the compounds that inhibit chymotrypsin and trypsin is in the treatment of pancreatitis. For their end-usc application, the potency and other biochemical parameters of (he enzyme-inhibiting characteristics of the compounds of (he present invention is readily ascertained by standard biochemical techniques well known in the art. Actual dose ranges for their specific end-use application will, of course, depend upon the nature and severity of the disease state of the patient or animal to be treated, as determined by the attending diagnostician. It is expected that a useful dose range will be about 0.01 to 10 nig per kg per day for an effective therapeutic effect. Compounds oflhc present invention that arc distinguished by their ability to inhibit either factor Xa or thrombin may be employed for a number of therapeutic purposes. As factor Xa or thrombin inhibitors, compounds of the present invention inhibit thrombin production. Therefore, these compounds are useful for the treatment or prophylaxis of slates characterized by abnormal venous or arterial thrombosis involving either thrombin production or action. These states include, but arc not limited to, deep vein thrombosis; disseminated intravascuiar coagulopaihy which occurs during seplic shock, viral infections and cancer; myoeardial infarction; stroke; coronary artery bypass; fibrin formation in the eye; hip replacement; and thrombus formation resulting from either Ihrombolytic therapy or percutaneous transluminal coronary angioplasty (1'CTA). Other uses include the use of said thrombin inhibitors as anticoagulants either embedded in or physically linked to materials used in the manufacture of devices used in -46- blood collection, hlood circulation, and blood storage, such us calhelers, blood dialysis machines, blood collection syringes and tubes, blood lines and stouts. The compounds oflhe present invention may also be used as an anticoagulant in extracorporeal blood circuits. Metal stcnts have been shown to reduce reslenosis, but are throtnbogenic. A strategy for reducing the thrombogenicity of stents is to coat, embed, adsord or covalently attach a thrombin-inhibiting agent to the stcnt surface. The compounds of the present invention can be employed for this purpose. Compounds oflhe invention can be attached to, or embedded within soluble and/or biodcgradcable polymers as and thereafter coated onto stcnt mafcrials. Such polymers can include polyvinylpyrrolidonc, polyhydroxy-propylmcthacrylamidc-phcnol, polyhydroxycthyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacelals, polydihydropyrans, polycyanoacrylalcs and cross linked or amphipathic block copolymers of hydrogels. See European Application 761 251, European Application 604,022, Canadian Patent 2,164,684 and PCT Published Applications WO 96/11668, WO 96/32143 and WO 96/38136. By virtue oflhe effects of both factor Xa and thrombin on a host of cell types, such as smooth muscle cells, endothelial cells and neutrophils, the compounds of the present invention find additional use in the treatment or prophylaxis of adult respiratory distress syndrome; inflammatory responses; wound healing; repcrfusion damage; atherosclerosis; and restenosis following an injury such as balloon angioplasty, atherectomy, and arterial stent placement. The compounds of the present invention may be useful in treating neoplasia and metastasis as well as neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. When employed as thrombin or factor Xa 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 nig/kg, preferably between 0.1 to 10 mg/kg body weight, on a regimen in single or 2-4 divided daily doses. When employed as inhibitors of thrombin, the compounds oflhe present invention may be used in combination with thrombolytic agents such as tissue plasminogen activator, streptokinase, and urokinase. Additionally, the compounds of the present invention may be -47- uscd in coinbinalion with other anlithrombolic or anticoagulant drugs such as. but not limited to, fibrinogcn antagonists and thromboxanc receptor antagonists. Human leucocyte elastase is released by polymorphonuclear leukocytes at sites of inflammation and thus is a contributing cause for a number of disease stales. Compounds of the present invention are expected to have an anti-inflammatory effect useful in the treatment of gout, rheumatoid arthritis and other inflammatory diseases, and in the treatment of emphysema. The leucocyte elastase inhibitory properties of compounds of the present invention arc determined by the method described below. Cathepsin G lias also been implicated in the disease states of arthritis, gout and emphysema, and in addition, glomerulonephritis and lung infestations caused by infections in the lung. In their end-use application the enzyme inhibitory properties of the compounds of Formula / is readily ascertained by standard biochemical techniques that are well-known in the art. The Cathepsin G inhibitory properties of compounds within the scope of the present invention are determined by the following method. A preparation of partially purified human Cathepsin G is obtained by the procedure of Uaugh cf a/., Biochemistry 15: 836 (1979). Leukocyte granules are a major source for the preparation of leukocyte elastase and cathepsin G (chymotrypsin-like activity). Leukocytes are lyscd and granules arc isolated. The leukocyte granules are extracted with 0.20 M sodium acetate, pH 4.0, and extracts are dialyzed against 0.05 M Tris buffer, pH 8.0 containing 0.05 M NaCl overnight at 4°C. A protein fraction precipitates during dialysis and is isolated by centrifugation. This fraction contains most of the chymotrypsin-like activity of leukocyte granules. Specific substrates are prepared for each enzyme, namely N-Suc-Ala-Ala-Pro-Val-p-nilroanilide and Suc-Ala-Ala-Pro-Phe-/>nitroanilide. The latter is not hydrolyzed by leukocyte elastase. Enzyme preparations are assayed in 2.00 mL of 0.10 M Ilcpcs buffer, pi 1 7.5, containing 0.50 M NaCl, 10% dimelhylsulfoxide and 0.0020 M Suc-Ala-Ala-Pro-Phe-p-nitroanilide as a substrate. Hydrolysis of the p-nitroanilidc substrate is monitored at 405 mn and at 25°C. Useful dose range for the application of compounds of the present invention as neutrophil elastase inhibitors and as Cathepsin G inhibitors depend upon the nature and severity of the disease state, as determined by the attending diagnostician, with a range of 0.01 to 10 ing/kg body weight, per day, being useful for the aforementioned disease states. Compounds of the present invention that inhibit urokinase or plasminogen activator arc potentially useful in treating excessive cell growth disease state. As such compounds -48- of the present invention may also be useful in the treatment of benign proslalic hypertrophy and proslatic carcinoma, the treatment of psoriasis, and as abortifacients. For their end-use application, the potency and other biochemical parameters of the enzyme inhibiting characteristics of compounds of the present invention arc readily ascertained by standard biochemical techniques well known in the art. Actual dose ranges for this application will depend upon the nature and severity of the disease stale of the patient or animal to be treated as determined by the attending diagnostician. It is to be expected that a general dose range will be about 0.01 to 10 mg per kg per day for an effective therapeutic effect. Additional uses for compounds of the present invention include analysis of commercial reagent enzymes for active site concentration. For example, chymotrypsin is supplied as a standard reagent for use in clinical quantitation of chymolrypsin activity in pancreaticjuices and feces. Such assays are diagnostic for gastrointestinal and pancreatic disorders. Pancreatic clastase is also supplied commercially as a reagent for quanlilation of ct|-antitrypsin in plasma. Plasma a,-antitrypsin increases in concentration during the course of several inflammatory diseases, and a,-nntitryp$in deficiencies are associated with increased incidence of lung disease. Compounds of the present invention can be used to enhance the accuracy and rcproducibilily of these assays by tilrametric standardization of the commercial elastase supplied as a reagent. See, U.S. Patent No. 4,499,082. Protease activity in certain protein extracts during purification of particular proteins is a recurring problem which can complicate and compromise the results of protein isolation procedures. Certain proteases present in such extracts can be inhibited during purification steps by compounds of the present invention, which bind tightly to various protcolytic enzymes. 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, intrapcritoneal, transdermai. 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. -49- 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 phnnnaeeutieally 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 arc, in particular, fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, iricalcium 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, hytlroxypropylmelliyleeUiiIose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents can be added, such as, the above-mentioned starches and also earboxymethyl-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 stcarate 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, acetylcelluiose phthalale or hydroxypropylmcthyl-cclluiose phthalatc, 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, -50- glyccrol or sorbitol. The push-fit capsules can contain (he active compounds in (tic form of granules thai may be mixed with fillers such as lactose, binders such its si arches, 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 tin's 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 (lie viscosity of the suspension, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers. The following examples arc 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. Example 1 3-l3-(2'Chtorophenylsiilfonyloxy)-5-t}tctIiyIphc!to.\ylpropo\y^fi(uutIwc a) 3-(2-CIilorophciiyIsuHoiiyIoxy)-5-mclhyIphcnol: Orcinol monohydratc (1.42 g, 10 mmol) and 2-chloroben/.cnesulfonyl chloride (2.43 g. 1 1 nimol) were mixed in saturated NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at room temperature for 2 days. The reaction mixture was quenched with 50 ml. o! water and extracted into ethyl acetate (3x50 mL). The organic phase was washed with brine (2 x 50 mL) and dried over Na2SO4. After removing the solvent in vacua, the residue was -5] - purified by Hash column cinematography (2% ethyl acetate in dichloromelliarie) to give the title compound as a pale-yellow liquid (2.15 g, 71%). 'H-NMR (300 MHz, CDCh.) 6 2.22 (s, 3H), 5.24 (s, IH), 6.43 (s, IH), 6.52 (s, 2H), 7,38 (m, 1H), 7.60 (m, 2H), and 7.96 (dd, 1H, .1 = 3.9,0.6 Hz). b) l-(2-C[il"r("phcuyIsiiironyIoxy)-3-(3-htii7.yIoxy)propu\y-5-nic(IiyH)cnz:cnc: Diethyl azodicarboxylale (230 uL, 1.46 mmot) was added siowiy to a solution of 3-(2- chlorophenylsulfonyloxy)-5-methyIphenoI (253 mg, 0.866 mmol), as prepared in the preceding step, 3-benzyloxypropanol (363 mg, 1.24 mmol), and (riphcnylphospliine (385 mg, 1.47 mmol) in dichloromethane (7 mL) at 0 "C. The cold bath was removed, and the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was quenched with water (10 mL) and extracted into diethyl ether (3 x 20 mL), The combined organic extracts were dried (MgSOJ and the product purified by flash chromatography (2 : 1 to 100 : 0 dichloromethane / petroleum ether) to afford the title compound (328.5 mg, 85% yield) as a colorless oil. '11-NMR (.100 Ml I*. CDC1,) 8 7.95 (dd, 1II, .1 = 7.9. 1.7 Hz), 7.52 - 7.62 (m, 211). 7.28 - 7.38 (m, 611), 6.5S (br s, 1H), 6.54 (br s. 111), 6.48 (t. 1H, .1=1.1 11/.), 4.51 fs, 211), 3,95 (i, 311, J = 6.2 11/,), 3.62 (t, 211, J =6.1 Hz). 2.24 (s, 311), and 2.01 (pentet, 2H, J = 6.2 Hz). Mass spectrum (K4ALD1-TOF, o>cyano-4-hydroxycinnamic acid matrix) calcd. for CJJHJJCIOJS: 469.1 (M + Na). Found: 469.1. c) 3-i3-(2-Chloroplicnylsulfonyloxy)-5-iucthylphcnoxy)propaiiol: A mixture of l-(2- chlorophenyIsulfonyloxy)-3-(3-benzyloxy)propoxy-5-methylbenzene (328.5 mg, 0.736 mmol), as prepared in the preceding step, 66 mg of 10% palladium on carbon, and 180 uL (0.72 mmol) of 4 N HC1 / dioxane in 5 mL of telrahydrofuran was hydrogenated (atmospheric pressure) at ambient temperature (or 1 h. The reaction mixture was filtered through Celite 545 and then concentrated. Purification by flash chromatography using eluliou.s of 2 - 10% diclhyl ether/ dichloromelhaue gave 217 mg (83% yield) of the title compound as an oil. M-l-NMR (300 MHz, CDCI,) 5 7.97 (dd, 111, J = 7.8, 1.4 11/.), 7.56 - 7.65 (m, 2H), 7.36 - 7.4! (m, 1 H), 6.60 (br s, IH), 6.54 (br s, IH), 6.50 (t, IH, J = 2 Hz), 4.03 (t, 2H, J = 4.7 Hz), 3.92 (s, 1H)3 3.82 (q. 211, J = 6.7 Hz), 2.24 (s, 3H), and 1.99 (pentet, 2H, -I = 6 Hz). d) 7V-l3-l3-(2-ChloropliciiyIsulfoMyloxy)-5-ine(hylphL"in)xyjprupoxy]ph1hjiliniidt': Dielhyt ;v/odicarboxyla(e (4.0 mL, 0.024 mo!) was added dropwisc to a solution of 3-p-(2- chlorophenylsulfonyloxy)-5-methy[plicnoxyJpropanoI (8.5 g, 0.024 mol), ;is prepared in the -52- prcccding slcp, triphcnylphosphinc (6.26 g, 0.024 niol), and /V-hydroxyphllmlimide (4.01 g, 0.024 mo!) in anhydrous Ictrahydrofurnn (240 niL). The solution was allowed to stir at ambient temperature overnight. The tetrahydrofuran was evaporated, and the residue was purified by silica gel chromatography. Elulion was carried out using a gradient of 50% dichloromethane in hexane to 100% dichloromethane. The appropriate fractions were combined, evaporated to dryness, and placed under high vacuum to give 6.5 g (54% yield) of an oil. Mass spectrum (MALDI-TOF, cc-cyano-4-hydroxycinnamic acid matrix) calcd. forC24H20C]NO7S: 524.1 (M + Na). Found: 524.2. c) 3-I3-(2-CliloropIicnylsulfonyloxy)-5-iiiciliylphcnoxy]propoxynininc: A suspension of yV-[3-[3-(2-chlorophenylsulfonyloxy)-5-mclhylphcnoxy]propoxy]phlhalimidc (6.5 g, 0.013 mol), as prepared in the preceding step, in 2-propanol / water (6:1; 690 mL) was treated with sodium borohydride (2.46 g, 0.065 mol). The reaction mixture was stirred at ambient temperature for 2 days. The reaction mixture was quenched with 2N hydrochloric acid, and the mixture was warmed at 50°C for 2 hours. The reaction mixture was cooled in an ice : water bath and adjusted to pi I 8.0 with 2 N sodium hydroxide. The 2-propanol was evaporated on a rotary evaporator, and the residual aqueous solution was extracted with ethyl acetate (3 x 75 ml-). The combined ethyl acetate extracts were washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The material was purified by silica gel chromatograpliy by elulion with a gradient of 50% dieliloionielluine/ hcxane to 100% dichloromethane, followed by 90% dichloromethane / 10% acetonitrile. The appropriate fractions were combined and evaporated to an oil, which crystallized under high vacuum to give 4.1 g (85% yield) of the title compound. 'H-NMR (300 MHz, CDC13) 5 7.97 (dd, J = 7.9, 1.5 Hz, 1H), 7.55 - 7.65 (m, 2H). 7.37 (td; J = 7.8, 1.6 Hz, .1H), 6.59 (br s, 1H), 6.53 (m, IH), 6.49 (t, J = 2.2 Hz, 1H), 5.39 (br d, 2H), 3.92 (t, J = 6.3 Hz, 2H), 3.79 (t, J = 6.2 Hz, 2H), 2.24 (s. 3H), and 2.00 (pentet, .1 = 6.2 1 Iz. 211). Mass spectrum (MALOI-TOI\ 0 3-[3-(2-Clilorophcnylsnlfonyloxy)-5-iiiethyIphtiiioxy|propoxyguaiiii!inc: A solution of 3-[3-(2-chlorophenylsulfonyloxy)-5-methylphenoxy]propoxyaniine (0.43 g, 0.0012 mol), as prepared in the preceding step, in anhydrous /V,/V-dimclhylformamide (15 mL) was treated with 1 //-pyrazole-l -carboxamidine hydrochloride (0.34 g, 0.0034 mol). The reaction mixture was stirred overnight at ambient temperature. An additional 100 mg of MI- - 53 - pyrazo!e-l-carboxainidine hydiochloride was added, and liie reaction mixture was stirred al ambient temperature overnight. The reaction mixture was evaporated to dryncss under high vacuum. The residue was treated with acetonitrile, and the resulting crystalline material was collected by filtration and discarded. The filtrate was evaporated to dryncss and partitioned between ether and water. The aqueous layer was washed with ether (4 x 25 ml). The aqueous layer was separated and basified with 2N sodium hydroxide, and the resultant aqueous layer was extracted with ethyl acetate (4 x 50 mL). The combined ethyl acetate extracts were washed with brine, dried, and evaporated to give 0.46 g of the title compound as an oil. 'H-NMR (300 MHz, CDC13) 5 7.94 (d, J = 7.6 Hz, 1H), 7.54 - 7.62 (m, 2H), 7.34-7.40 (m, 1H), 6.57 (br s, HI), 6.48 (m, 211), 5.75 (br m, 211), 3.96 (t, J - 6.2 Hz, 4H), 2.21 (s, 311), and 2.05 (pcnlct, J = 6.2 Hz. 2H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for Cl7H20CIN3O5S: 414.1 (M + H). Found: 414.2. Example 2 . 3-f3-(2-MethoxyphenyIsuffonylo.xy)~5-niethytpheno\ylprop0xyguaiti(Iiiie a) 3-(5-Cliloro-2-nicthoxyphcnylsulfonyloxy)-5-nicthylphciiol: Saturated aqueous NaHCO3 (70 mL) was added to a solution of 5-chloro-2-melhoxybenzenesulfonyl chloride (3.83 g, 15.9 mmol) and orcinol monohydrate (3.39 g, 23.9 mmol) in diw/-bulyl ether (53 mL) and letrahydrofuran (17 mL). The biphasic solution was mixed vigorously at 50°C for 7 h tlicn at ambient temperature overnight. The reaction mixture was combined with that from a previous reaction (which used 4.53 g 18.8 mmol of 5-chloro-2-methoxybenzenesulfonyl chloride), the layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with brine (250 mL), dried overNa3SO4, filtered, and evaporated to give 18.25 g of a clear brown oil. The product was purified by Hash column chromatography (1% to 4% ethyl acctctc in dichloromclhanc) to give the title compound (9.8(1 g, 86%) as a pale yellow oil which crystallized upon standing. 'H-NMR (300 Ml I/, CDC13) ( 7.81 (d, 111, J = 2.6 Hz), 7.55 (dd, 1H, J = 8.9, 2,6 Hz), 7.02 (d, 1H, J = 8.9 Hz), 6.53 (m, 2I-I), 6.41 (t. III, .1 = 2.2 Hz), 3.99 (s, 311), 2.24 (s, 311). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for CHHI3C1O5S: 351.0(M + Na). Found: 351.1. -54- b) 3-(2-IMcllioxyplicnylsuironyIoxy)-5-mcHiyl|)licnol: 4-Mcthylmorpholinc (3.2 niL, 29.1 mmol) was added to a mixture of 3-(5-chloro-2-methoxyphcnylsulfbnyloxy)-5-methylphenol (8.82 g, 26.8 mmol, prepared in the preceding step) and 10% palladium on carbon (2.23 g) in dcoxygenatcd mclhnnol (15 inL). The mixture was stirred al ambient temperature under hydrogen (balloon) for 3 h, then filtered through Cclitc (draibmaceous earth) with mcthanoi. Solvent was removed in vacua and crude product was purified by flash column chromatography (CH2C12 to 5% ethyl acetate in dichloromethane) to give the title compound (4.97 g, 63%) as a colorless syrup. 'H-NMR (300 MHz, DMSO-d6) ( 9.71 (s, lH),7.76(ddd, 1H, J = 8.4, 7.4, 1.7 Hz), 7.69 (dd, 1H, J = 7.9, 1.7 Hz), 7.38 (d, 1H,J = 8.4 Hz), 7.09 (dt, 1H, J = 7.9, 1.0 Hz), 6.48 (br s, 1H), 6.33 (br s, 1H), 6.26 (l, 1H, J - 2.2 Hz), 4.00 (s, 3H), 2.15 (s, 3H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for Ci4Ht4O5S: 317.0 (M + Na). Found: 316.9. c) 3-|3-(2-McthoxyplicnyLsulfonyloxy)-5-mcthylpheiioxy]pn"pnnoI: Tri-/i- butylphosphine (8.4 inL, 34 mmol) was added dropwise over 5 min to 3-(2-mcthoxyphenyisuironyloxy)-5-methylphenol (4.97 g, 16.9 mmol, prepared in the preceding step), l,3-propanedioi(12 mL, 170 mmol) and l.r-(azodicarbony!)dipiperidinc(8.54 g, 33.8 mmol) in anhydrous tetrahydrofuran (75 mL) at 0°C under a nitrogen atmosphere. Dichloromethane (75 mL) was added mid-way through the tri-H-butylphosphine addition to aid stirring. The slurry was stirred at ambient temperature for 1 h, then the mixture was cooled to 0°C and additional 1,1 '-(azodicarbonyl)dipiperidinc (4.27 g, 16.9 mmol) and \n~n-butylphosphine (4.2 mL. 16.9 mmol) were added. The reaction was stirred overnight at ambient temperature. Dielhyl ether (200 mL) was added and the mixture was filtered. The filtrate was concentrated in vacno, and the residue was purified by flash column chromatography (25% ethyl acetate in hexane to 60% ethyl acetate in hexane, then 2% acetone in dichloromethane to 7% acetone in dichloromethane in two separate chromatographie separations) to give the title compound (3.79 g, 64%) as a gold oil. 'II-NMR(300 MHz, COC13) 67.82 (dd, 1H, J - 7.9, 1.7 Hz), 7.61 (ddd, 1H, J = 8.4, 7.5, 1.8 Hz), 7.08(d, III, J = 8.4 11/.), 7.01 (ddd. Ill, .1 - 7.9, 7.5, 1 I Iz), 6.5S (br s, 111). 6.51 (br s, 111), 6.46 (t, 1H, .1-2.1 Hz), 4.02 (s. 31-1), 4.00 (t, 211, j = 6.0 Hz), 3.81 (dt. 2H. J = 5.7. 5.3 Hz), 2.24 (s, 311), 1.98 (pentet, 211, .1 = 6.0 11/.), 1.72 (t, 111. .1 = 5.0 Hz). Mass spectrum (MALDI-TOF, (a-cyano-4-hydroxycinnamic acid matrix) calcd. for C|7H20O6S: 375.1 (M + Na). Found: 375.1. -55 - (1) A'-|3-|3-(2-MvlIioxypliciiylsiill(>iiyl"xy)-5-nu>(hylphoiifi\y||)i-o|)o\ylpli(Ii:ilimi(le: Dielhyl a?.odicarboxylale (67 (L, 0.40 mmol) was added dropwisc over 5.5 min to 3-|3-(2-niclhoxyphcnylsuironyloxy)-5-mclhylphcnoxyJpropanol (118 mg, 0.33 mmol, prepared in llie preceding slop), triphenylphosphine (106 mg, 0.40 mmol), and A'-hydroxyphlhalhnide (55 mg, 0.33 mmol) in anhydrous tetrahydrofuran (3 mL) at 0°C under a nitrogen atmosphere. The solution was stirred at 0°C for an additional 20 min then at ambient temperature overnight. The reaction mixture was concentrated, and the residue was purified by flash column chromatography (dichloromcthanc) to give the title compound (116 mg, 69%) as a colorless resin. 'H-NMR (300 MiIz, CDC13) ( 7.88-7.73 (m, 511), 7.61 (ddd, 111, J = 8.4, 7.4, 1.7 Hz), 7.10 (d, 1H, J = 8.4 Hz), 7.01 (dt, 1H, J = 7.7, 0.9 Hz), 6.60 (br s, 1H), 6.56, (br s, 1H), 6.42 (i, 1H, J - 2.2 Hz), 4.36 (t, 2H, J = 6.2 Hz), 4.09 (t, 2H, J = 6.2 Hz), 4.04 (s, 3H), 2.25 (s, 3H), 2.18 (pentet, 2H, J = 6.2 Hz). Mass spectrum (M ALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C35H23NO8S: 520.1 (M + Na). Found: 520.2. e) 3-{3-(2-Mothoxy|)liciiylsiiirniiyloxy)-5-mi>Iliylj)lu>iioxy]propo\y:iiiiiiu>: A mixture of sodium borohydride (45 mg, 1.1 mmol) and A^[3-[3-(2-nicthoxyplicnylsuIfonyloxy)-5- mclhylphenoxyjpropoxyjphthalimide (113 ing, 0.23 mmol, prepared in the preceding .step) in 2-propanoI (12 mL) and water (2 mL) was stirred overnight at ambient temperature. The reaction mixlure was adjusted to pi I 1 with aqueous 1IC1 (3.5 nil,, 2N). and the solution was stirred at 50°C for 2 h. The solution was cooled to 0°C and adjusted to pH 12 with 2N NaOH. The solution was stirred at ambient temperature for 2 h, then 2-propanol was removed by rotary evaporation. The resulting mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were washed with brine (40 mL), dried over Na2SO4, filtered, and evaporated to give the title compound (79 mg, 95%) as a colorless oil. 'H-NMR (300 MHz, CDCI3)( 7.82 (dd, II I, .1 = 7.9, 1.7 Hz), 7.61 (ddd, 11], J - 8.4, 7.5, 1.8 Hz), 7.08 (dd, 111, J = 8.4, 0.8 Hz), 7.00 (ddd. 111, .1 - 8, 7.5, 1 1 Iz), 6.58 (br s, 111), 6.50 (br s, 1H), 6.45 (t, 1H, J = 2.1 Hz), 5.38 (br s, 2H), 4.02 (s, 3 H),'3.92 (t, 2H, J = 0.3 Hz), 3.79 (t, 211, J - 6.2 I Iz), 2.23 (s, 311), 2.00 (penlel, 211, .1 - 6.2 11/.)- Mass spectrum (M ALDI- TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C1?H21NO6S: 390.1 (M + Na). Found: 390.1. f) 3-[3-(2-McilioxyphcH>isH[fony1oxy)-5-mc(liylphcn(>xyipr"poxyRiianulinc: A solution of 3-|"3-(2-nic(hoxypliei"ylsiiH(myl(txy)-5-niLMhyipliLMioxyjproptv\ynmine (74 mg, 0.20 -56- mmol, prepared in the preceding step) and I//-pyrazole-l-earboxamidinc liydrochloride (60 mg, 0.41 inmol) in anhydrous A'.A'-diinelhyUbnnaiiiide (2 mL) was slirred at ambient temperature overnight. Additional l//-pyrazole-l-carboxamidine hydrochloride (30 mg, 0.20 mmol) was added, and the reaction was stirred at ambient temperature for 3 days. N,N-Diinelhylformamidc was removed in vaaio. then the residue was treated with ncetonilrile. The mixture was filtered lo remove excess 1 //-pyrazolc-1 -carboxamidinc hydrochloride, and the illtratcj was concentrated in vacua. The residual oil was partitioned between dicthy! ether (10 niL) and water (10 mL). The aqueous layer was washed with dicthyl ether (2x10 mL), adjusted to pH 8 with 2N NaOH, and extracted with ethyl acetate (2x10 mL). The ethyl acetate extracts were washed with pH 7 buffer (2x15 mL) and brine (15 mL), dried over Na2SO4, filtered, and evaporated to give the title compound (64 mg, 78%) as a colorless oil. 'H-NMR (300 MHz, DMSO-d6) 6 7.76 (ddd, 1H, J = 8.4, 7.4, 1.8 I Iz), 7.69 (dd, 1H, J = 7.9, 1.6 Hz), 7.37 (d, 1II, J - 7.7 1 Iz), 7.09 (dt, 111, J - 7.9, 1.0 1 lz), 6.69 (s, 111), 6.47 (s, 1H), 6.33 (t, 1H, .1 - 2.1 Hz), 4.00 (s, 3H), 3.92 (t, 2H, J - 6.5 Hz), 3.70 (t, 2H, J - 6.1 Hz), 2.20 (s, 311), 1.88 (pentel, 211, .1 = 6.3 I Iz). Mnss spectrum (MALI)I-TOF, a-eyano-4-hydroxycinnamic acid matrix) calcd. for C,RH23N3O6S: 410.1 (M + H), 432.1 (M + Na). Found: 410.1,432.6. Example 3 3-[5-Methyl-3'(quinoHnyl-8-sulfonyloxy)phenoxy]propoxyguanidme hydrochloride a) -Mc(hyI-3-((niinoIiiiyI-8-suIi g, 28 mmol) and 8-quinoHnesulfonyl chloride (6.1 g, 26.7 mmol) in diethyl ether (120 mL) and saturated sodium bicarbonate (120 mL) was vigorously slirred at ambient temperature for 4 days. The reaction mixture was extracted into ethyl acetate, dried (MgSO4), and concentrated. Crystallization from diethyl ether / ethyl acetate / hexane gave 4.48 g (50%) of the title compound as a tan powder. 'Il-NMR (300 MHz, DMSO-d6) o 9.62 (br s, 1H), 9.23 (dd, 1H, J = 4, 2 Hz), 8.63 (dd, 1 H. J - 8, 2 Hz). 8.45 (dd, 1H, J = 8. 2 Hz), 8.36 (1H, J = 8, 2 Hz), 7.74 -7.83 (m, 211), 6.44 (brs, III). 6.29 (brs, ill), 6.10 (I, 111, J = 2 Hz), 2.09 (s, 3H). Mass spectrum (MALDI-TOF, cx-cyano-4-hydroxycinnamic acid matrix) calcd. for C,6H13NO4S: 316.1(M -HI), 338:0 (M i-Na). Found 316:0, 338.1. b) 3-[5-Mctliyl-3-(quinoliiiyl-8-sulfonyloxy)phciioxy]propanol: To 5-melhyI-3- (quinoIinyi-8-sulfonyloxy)phcnoI (3.0 g, 9.0 mmol), as prepared in the preceding step, 1.3- -57- propancdiol (4 mL, 55.2 mmol), and l,r-(azodicarbonyl)dipiperidinc (3.42 g, 13.6 nimol) at 0 °C in telrahydrofuran (60 mL) was added slowly tri-H-butylphosphine (336 mL, 13.5 mmol). The cold bath was removed, and the reaction mixture was stirred at ambient lenipenUure overnight. TLC analysis showed starling material. To the reaction mixture was added sequentially l,l'-(azodicarbonyl)dipipcridine (1.9 g) and trir//-butylphosphine (1.7 mL). The reaction mixture was stirred at ambient temperature for 2 h. The reaction mixture was then diluted with diethyi ether and (he resulting suspension filtered. The filtrate was concentrated and purified directly by flash chromatography using elutions of dichloro me thane / ethyl acetate (3 : 1 then 2 : 3) to give 3.19 g (95% yield) of the title compound as an oil. 'II-NMR (300 MHz, CDC13)5 9.27 (dd, 1H, J = 4, 2 Hz), 8.41 (dd, 1H, J = 7,2Hz),8.31 (dd, 111, J = 8, 2 Hz), 8.14 (dd, 1HJ = 7,2 Hz), 7.61 - 7.65 (m, 211), 6.54 (brs, III), 6.49 (bis, 111), 6.42 (t. III, J - 2 11/.), 3.92 (t. 21 i, J = 6 11/.). 3.77 (t, 211), 2.17 (s, 311). Mass spectrum (MALDI-TOF, ct-cyano-4-hydioxycinnamic acid matrix) calcd. for C,9M,VNO3S: 374.1 (M-MI), 396.1 (M+Na). Found: 374.0,396.2. c) yV-|3-l5-Mc(hyl-3-(quiiioIin>i-8-sulfonylu\y)phciio\y]prupo\yJphtli:iIiiui(lc: Dicthyl azodicarboxylate (136 uL, 0.81 mmol) was added dropwise over 7 min to 3-[5-methyl-3- (quinolinyl-8-sulfonyloxy)phcnoxy]propanol (252 nig, 0.68 mmol, prepared in the preceding step), jV-hydroxyphthalimide (111 nig, 0.68 mmol), and triphenylphosphine (213 mg, 0.81 mmol) in anhydrous telrahydrofuran (6 mL) at 0°C under a nitrogen atmosphere. The solution was stirred at 0°C for 1 h then at ambient temperature for 3 days. Solvent was removed in vacua, and the crude product was purified by flash column ehromatography (100% dichloromethane to 1% acetone in dichloromethane) to give the title compound (332 mg, 92%) as a colorless foam. 'H-NMR (300 MHz, CDC1,) 5 9.28 (dd, 1H,J = 4.2, 1.8 Hz), 8.43 (dd, 1H, J = 7.4, 1.4 Hz), 8.30 (dd, 1H, J - 8.4, 1.7 Hz), 8.14 (dd, 1H, J = 8.3, 1.3 Hz), 7.85-7.75 (m, 4H), 7.63 (d, 1H, J - 8.3 Hz), 7.61 (dd, 1H, J *= 8.2, 3.2 Hz), 6.56 (br s, 1H), 6.53 (brs, HI), 6.36 (br s, 111), 4.31 (I. 211, J - 6.2 Hz), 3.98 (J, 211, J = 6.2 11/), 2.19 (s, 3H), 2.11 (pentet, 211, J - 6.2 Hz). Mass spectrum (MALDI-TOF, ct-cyano-4- hydroxycinnamie acid matrix) calcd. for C27H:,N2O7S: 519.1 (M + 11), 541.1 (M + Na). Found: 518,7,540.8. d) 3-[5-Mvtliyl-3-(t]i]HiolinyI-8-suliunyl(>xy)plicn(K\yJprop(>xy;iniinc: Sodium borohydride (107 mg, 2.8 mmol) was added to A^[3-[5-methyl-3-(quinoIinyl-8- sulfonyloxy)phenoxy]propoxy]phthalimide (292 mg. 0.56 mmol, prepared in the preceding -58- step) in2-propanol (10 mL), letrahydrofuran (1.7 mL) and water (1.7 mL). Hydrogen gas was evolved for 40 min. The mixture was stirred overnight at ambient temperature. Aqueous HC1 (8.4 mL, 2N) was added dropwise (hydrogen was evolved), and the solution was heated at 50°C for 2 h. The solution was eooled to 0°C and adjusted to pH 10 with 2N NaOH. Organic solvent was removed in vacuo, and the residual mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and evaporated to give a pale gold oil. Crude product was purified by flash column chromatography (60 : 40 to 80 : 20 ethyl acetate / hexane) to give the title compound (166 mg, 76%). 'I-l-NMR (300 Ml Iz, CDC13) ( 9.27 (dd, 111, J - 4.3, 1.8 Hz), 8.42 (dd, 1H, .1 = 7.4, 1.5 Hz), 8.30 (dd, 111, J = 8.3, 1.8 Hz), 8,14 (dd, HI, J = 8.2, 1.5 Hz), 7.63 (d, 111, J - 8.2 Hz), 7.61 (dd, HI, J = 8.3, 3.5 Hz), 6.53 (br s, III), 6.47 (br s, 1H), 6.41 (t, 1H,J = 2I]//), 5.37 (brs, 2 11), 3.83 (1,211.1-6.3 Hz), 3.75 (t, 2 II, J-6.2 Hz), 2.17 (s, 3 H), 1.94 (pentet, 211, J - 6.2 Hz). Mass spectrum (MALD1-TOI\ a-cyano-4-hydroxycinnamic acid matrix) calcd. for Cl9H20N2O5S: 389.1 (M + H), 411.1 (M + Na). round: 38X.7, 410.9. e)3-[5-Mcthyl-3-(qiiinolinyl-8-sulfoii)ioxy)phcnoxy]propoxyguanidincliydrochIoride: A solution oi"3-[5-mcll)yl-3-(quiiiolii]yl-8-sullbnvl(ixy)pheno\y Ipropoxyamine (102 nig, 0.42 mmol, prepared in the preceding step) and 1 //-pyrazolc-1-carboxamidine hydrochloride (184 mg, 1.25 mmol) in anhydrous TV.N-dimcthylformamidc (2.0 mL) was stirred at ambient temperature under nitrogen for 18 h. Additional l//-pyrazole-l-carboxamidine hydrochloride (61.4 mg, 0.42 mmol) was added, and stirring was continued overnight. N,N-Dimethylformamide was removed in vacuo, then acetonitrile (5 mL) was added, and the solution was cooled to 0cC to crystallize excess l//-pyrazole-l-carboxamidine hydrochloride. The mixture was filtered and the filtrate was concentrated ;'// vacua to give a pale gold-brown oil. Crude product was dissolved in water (15 mL) and extracted with dicthyl ether (2 x 15 mL). The aqueous layer was neutralized (pi I 7) with 2N NaOM and extracted with ethyl acetate (2x15 mL). The combined ethyl acetate extracts were washed with pi I 7 buffer (2 x 15 mL) and brine (15 mL), dried over Na^SO.,, filtered, and evaporated to give the free base of the title compound (147 mg, 82%) as a colorless oil. The title compound was made by adding a solution of the free base, 3-[5-methyl-3-(quinolinyl-8-sulfony!oxy)phenoxy]propoxyguanidine, (143 mg, 0.33 mmol, prepared above) inelhanol (1 mL) to ethanolic MCI (1.06 mL, 1.1 M, 1.2 mmol) in anhydrous dielhyl -59- ctber (100 mL). Filtration under nitrogen gave the title compound (120 nig, 77%) as a hygroscopic yellow solid. 'II-NMK (300 MHz, DMSO-d(1) 6 9.23 (dd. IIK J - 4.2, 1 .S 1!/), 8.64 (dd, 1H, J = 8.4, 1.8 Hz), 8.47 (dd, 1H, J - 8.3, 1.4 Hz), 8.38 (dd, 1H, J = 7.4, 1.4 Hz), 7.81 (dd, 1H, J - 8, 4.2 Hz), 7.80 (d, 1H, J - 8 Hz), 6.66 (br s, III), 6.40 (br s, 1H), 6.34 (t, 1H, J = 2.2 Hz), 3.87 (q, 4H, J = 6 Hz), 2.14 (s, 3H), 1.95 (pentet, 2H, J = 6 Hz). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C2(}H22N4O5S: 431.1 (M + H). Found: 430.9. Example 4 3-[3-(5-Ch!oro-2-methoxyphenylsulfonyloxy)-5-methyIphenoxy] propoxyguanidine hydrochlor'ule a) 3-[3-(5-Chloro-2-nicthoxyphcnylsulfonyloxy)-5-mcthylphcnoxy]propanoI: Tri->7- butylphosphine (7.6 mL, 30.4 mmol) was added dropwisc over 20 min to 3-(5-chloro-2- methoxyphenylsulfonyIoxy)-5-methylphenol (5.00 g, 15.2 mmol, prepared in step a of Ilxamplc 2), 1,3-propanediol (3.3 nil,, 45.0 mmol) and l,r-(a/.odicaiboiiyl)dipipcridine (7.68 g, 30.4 mmol) in anhydrous tctrahydrofuran (80 mL) at 0°C under a nitrogen atmosphere. Dichloroniethane (150 mL) was added mid-way through the \x\~n- butylphosphine addition to aid stirring. The slurry was stirred for an additional 5 min at 0°C then at ambient temperature for 3 h. Dicthyl ether (400 mL) was added, and the mixture was stirred for 10 min then filtered. The filtrate was concentrated and the product was purified by flash column chromatography (25% to 60% ethyl acetate in hexane) to give the title compound^(4.07 g, 69%) as a gold oil. 'H-NMR (300 MHz, CDC13) ( 7.82 (d, 1H, J - 2.8 Hz), 7.56 (dd, 1H, J - 8.9, 2.6 Hz), 7.03 (d, 1H, J = 8.9 Hz), 6.62 (br s, 1H), 6.52 (br s, 1H), 6.47 (t, 1H, J = 2.3 Hz), 4.03 (t, 2H, J = 6 Hz), 4.01 (s, 3H), 3-85-3.80 (m, 2H), 2.26 (s, 3H), 2.00 (pentet, 2H, J = 6 Hz), 1.64 (t, 1H, J = 5 Hz). Mass spectrum (MALDI-TOF, a-cyano- 4-hydroxycinnamic acid matrix) calcd. for C,7! 1I()C1O(1S: 409.0 (M .+ Na). Found: 409.0. b) TV-Tp-IS^S-Chloro^-mcthoxyphenylsulfonyloxj^-S-niethylphcnDxylpropoxy] plilhnliinidc: Dielhyl azodicarboxylate (0.16 niL, 0.95 mmol) was added dropwise over 6 min to 3-[3-(5-chloro-2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propanol (0.31 g, 0.79 mmol, prepared in the preceding step), triphcnylphosphine (0.25 g, 0.93 mmol), and AMiydroxyphthalimide (0.13 g, 0.80 mmol) in anhydrous tctrahydrofuran (7.9 mL) at 0°C under a nitrogen atmosphere. The solution was stirred at ()°C for an additional 15 min then -60- al ambient temperature overnight. The reaction mixture was concentrated, and the crude product was purified by Hash column chromalography (1% acetone in dichloromethane) to give the title compound (0.417 g, 99%) as a colorless foam. 'H-NMR (300 MHz, CDCI3) 6 7.88-7.75 (m, 5H), 7.56 (dd, III, J = 8.9, 2.7 11?.). 7.05 (d, III, J = 8.9 Hz), 6.64 (br s, 1H), 6.57 (brs, II I), 6.43(1, HI, J = 2 Hz), 4.37 (t, 211, J - 6.1 Hz), 4.12 (I, 211, J = 6.2 Hz), 4.03 (s, 3H), 2.28 (s, 3H), 2.19 (pentet, 2H, J = 6.1 Hz). Mass spectrum (MALD1-TOF, genlisic acid matrix) calcd. for C25H22C1NO8S: 554.1 (M + Na). Found: 553.7. c) 3-[3-(5-Chloro-2-mc(hoxyplicnylsulfonyIoxy)-5-niethylphcnovy]propoxyamine: Sodium borohydride (145 mg, 3.84 mniol) was added to a solution of A?-[3-[3-(5-chloro-2-mcthoxyphenylsulfonyloxy)-5-mcthylphcnoxy]propoxy]phthalimidc (407 mg, 0.76 mmol, prepared in the preceding step) in 2-propanol (25 mL), letrahydrofuran (5 mL), and water (4 mL). Hydrogen was evolved for 20 min. The mixture was stirred overnight at ambient temperature. Aqueous HCl (11.4 mL, 2N, 22.8 mmol) was added dropwise; hydrogen was evolved. The solution was stirred at 50°C for 2 h. cooled to 0°C, and adjusted to pi I 10 with 2N NaOH. Organic solvent was removed by rotary evaporation at ambient temperature, and the resulting mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were washed with brine (50 mL), dried overNa2SO4, filtered, and evaporated to give 365 mg of a colorless oil. Crude product was purified by flash column chromatography (50% ethyl acetate in hcxane to 100% ethyl acetate) to give the title compound (265 mg, 86%) as a colorless oil. 'II-NMR (300 MHz, CDC13) ( 7.82 (d, 1H, J = 2.6 I Iz), 7.56 (dd, 111, J = 8.9, 2.6 Hz), 7.03 (d, HI, J = 8.9 Hz), 6.60 (br s. Ill), 6.51 (br s, 1H), 6.46 (t, 1H, J = 2.2 Hz), 5.39 (br s, 2H), 4.01 (s, 3H), 3.95 (t, 2H, J = 6.3 Hz), 3.80 (t, 2H, J = 6.2 Hz), 2.26 (s, 3H), 2.02 (pentet, 211, J = 6.2). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C17H20ClNO6S: 402.1 (M + H), 424.1 (M + Na). Found: 401.6,423.9. d) 3-|3-(5-Cliloro-2-incMi(>xyphenylsuironylgiiiiiiiilinc hydrochloridc: A mixture of 3-[3-(5-chloro-2-methoxyphenylsulfonyloxy)-5-melhylphenoxyjpropoxyaminc (265 mg, 0.66 mmol, prepared in the preceding step) and \H-pyrazole-I-carboxamidine hydrochloridc (196 mg, 1.33' mmol) in anhydrous N.N-dimcthylformaniidc (3 mL) was stirred at ambient temperature for 2.5 h. Additional 1/-/-pyrazole-1-carboxamidine hydrochloride (97 mg, 0.66 mmol) was added and the reaction was stirred at ambient temperature for 3 days. A'.A'-Dimethylformamide was removed in -61 - vacuo, then acetonitrile (1 mL) was added to precipitate excess l//-pyrazole-l-carboxamidine hydrochloride. The mixture was filtered and the filtrate was concentrated in vacuo. The residual oil was partitioned between diethyl ether (20 mL) and water (20 mL). The aqueous layer was washed with diclhyl ether (2 x 20 mL). The aqueous layer was neutralized (pH 7) with 2N NaOH and extracted with ethyl acetate (2 x 30 mL). The ethyl acclatc extracts were washed with pi I 7 buffer (2 x 20 mL) and brine (30 mL), dried over Na2SO4, filtered, and evaporated to give the free base of the title compound (281 mg, 96%) as a colorless oil. Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C18H22CIN3O6S: 444.1 (M + H), 466.1 (M + Na). Found 444.6, 466.7. The hydrochloride salt of the title compound was made by adding a solution of the free base, 3-[3-(5-chloro-2-methoxyphenylsulfonyloxy)-5- methylphenoxyjpropoxyguanidine, (261 mg, 0.59 mmol) in 2-propanol (6 mL) to diethyl ether (100 mL) containing HC1 in ethanol (1.1 mL of a 1.1 M solution, 1.2 mmol). Solvent was removed in vacua to give the title compound (285 mg) as a colorless oil. 'H-NMR (300 MHz, DMSO-d6) ( 7.86 (dd, 111, J = 9.0, 2.7 Hz), 7.65 (d, 1H, J = 2.7 Hz), 7.44 (d, 1H, J = 9.0 Hz), 6.74 (br s, 1H), 6.49 (br s, 1H), 6.43 (br s, 1H), 4.01 (s, 3H), 4.00 (t, 2H, J - 6.4 Hz), 3.91 (t, 2H, J - 6.3 Hz), 2.23 (s, 311), 2.02 (pcnlet, 211, J = 6.3 Hz). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C,8H22C1N3O6S: 444.1 (M + H). Found 443.5. Example 5 3-[3-(5-Chlorothiophenyl-2-sulfonyloxy)-5-methylphetwxyj propoxygttanidine hydrochloride a) 3-(5-Chlorothiophcnyl-2-sulfonyloxy)-5-methy]plienol: A mixture of orcinol monohydrate (5.0 g, 35.2 mmol), and 5-chlorothiophene-2-sulfonyl chloride (7.64 g, 35.2 mmol) in 50 mL of saturated sodium bicarbonate, 50 mL of diethyl ether, and 15 mL of tetrahydrofuran was stirred at 60°C for 2 h and then at 40°C overnight. The reaction mixture was extracted into diethyl ether, dried (MgSO4), and passed through a thick pad of silica gel (ca. 500 mL) using elutions of dichloromelhanc and then 3% diethyl ether / dichloromcthanc to provide 5.49 g (51%) of the title compound as a pale orange oil. 'H-NMR (300 MHz, CDCI3) 5 7.40 (d, 1H, J = 4 Hz), 6.94 (d, 1H, J = 4 Hz), 6.59 (br s, 1H), -62- 6.49 (br s, HI), 6.40 (I, 111, J - 2 I !z), 5.38 (s, 111), 2.26 (s, 311). Mass spectrum (MALD1-TOF gentisic acid matrix) calcd. ibr C,,n c) A'-[3-[3-(5-Clilorotliiopht'nyl-2-sulfoiiylnxy)-5-inciliyIplicnoxy|pi'op"xy| phthalimide: Diethyl azodicarboxylate (115 uL, 0.68 mmol) was added dropwise over 8.5 min to 3-[3-(5-ch!orothiopheiiyl-2-suironyloxy)-5-inclhylphenoxy]propanol (207 mg, 0.57 mmol, prepared in the preceding step), triphenylphosphine (180 mg, 0.68 mmol), and N-hydroxyphthalimide (93 mg, 0.57 mmol) in anhydrous tetrahydrofuran (5.1 mL) at 0°C under a nitrogen atmosphere. The solution was stirred at 0°C for an additional 30 min. The reaction mixture was concentrated and the residue purified by flash column chrornatography (dichloromethane) to give the title compound (272 mg, 94%) as a colorless resin. 'H-NMR (300 MHz, CDC13) 6 7.86-7.75 (m, 4H), 7.42 (d, 1H, J = 4.1 Hz), 6.96 (d, 1H, J - 4.1 Hz), 6.69 (brs, 111), 6.52 (brs. Ill), 6.44 (br s, III), 4.39 (t, 211, J - 6.1 I !z), 4.16 (t, 211, J - 6.1 Hz), 2.29 (s, 3H), 2.21 (pentet, 2H, J = 6.1 Hz). Mass spectrum (MALDI-TOF, oc-cyano-4-hydroxyciunamicacid matrix) calcd. Tor C22U|KC1NO7S2: 530.0 (M -I- Na). Found: 529.5. -63- d) 3-|3-(5-Ch!oroUiiophcnyI-2-siilfoiiyloxy)-S-iiiclliylplicnoxyJpn)|)oxyaminc: Sodium borohydride (85 mg, 2.2 mmol) was added to a solution of M[3-[3-(5-chlorolhiophenyl-2-sulfonyIoxy)-5-methylphcnoxy]propoxy]phthalimidc (227 mg, 0.45 mmol, prepared in the preceding step) in 2-propanol (23.2 ml.), tetrahydrofuran (5.8 mL), and water (3.9 ml). Hydrogen gas was evolved. The mixture was stirred overnight at ambient temperature. The reaction mixture was carefully acidified with aqueous 11C1 (6.6 mL, 2N), and the solution was stirred at 50°C for 2 h. The solution was cooled to 0°C and neutralized (pH 7) with 2N NaOH. Organic solvent was removed by rotary evaporation, and the resulting mixture was extracted with ethyl acetate (2x15 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered, and evaporated. The residue was purified by flash column chromatography (25% ethyl acetate in hexane) to give the title compound (141 mg, 84%) as a colorless oil. 'H-NMR (300 MHz, CDC13) 6 7.40 (d. 1H, .1 = 4.0 Hz), 6.95 (d, IH, J = 4.0 Hz), 6.65 (br s, 1H), 6.48 (br s, 1H), 6.43 (t, 1H, J = 2.2 Hz), 5.39 (br s, 2H), 3.96 (t, 2H, J = 6.3 Hz), 3.81 (t, 2H, J = 6.1 Hz), 2.28 (s, 3H), 2.03 (pentet, 2H, J = 6.2 Hz). Mass spectrum (MALDI-TO17, a-cyano-4-hydroxycinnnmic acid matrix) calcd. for CI4H16C1NO5S2: 378.0 (M + H), 400.0 (M + Na). Found: 377.6,399.5. c) 3-I3-(5-Chlorothioplicnyl-2-sulfoiiyIoxy)-5-mctliyIphcnoxy|propoxyguaiiidinc hydrochloride: A solution of 3-[3-(5-chIorothiophenyl-2-sulfonyloxy)-5-metbylphenoxy] propoxyaminc (129 mg, 0.34 mmol, prepared in the preceding step) and I//-pyrazole-1-carboxamidine hydrochloride (103 mg, 0.70 mmol) in anhydrous TV, Af-dimethylformamide (1.5 mL) was stirred at ambient temperature overnight. Additional l//-pyrazole-l-carboxamidine hydrochloride (103 mg, 0.70 mmol) was added, and the reaction was again stirred at ambient temperature overnight. A',A'-Dimethylformamide was removed in vacito, and the residue was treated with acetonitrile (3 mL). The mixture was filtered to remove excess 1/f-pyrazole-l-carboxamidine hydrochloride. and the filtrate was concentrated. The residual oil was partitioned between diclhyl ether (15 mL) and water (10 mL). The aqueous layer was washed with dielhyl ether (2x15 mL), basified (pH 8) with 2N NaOH, and extracted with ethyl acetate (2 x 20 mL). The ethyl acetate extracts were washed with pi I 7 buffer (2 x 25 mL) and brine (25 mL), dried over Na2SO4, filtered, and evaporated to give the free base of the title compound (129 mg, 90%) as a colorless oil. The hydrochloride salt of the title compound was made by adding a solution of the free base, 3-[3-(5-chlorothiophenyl-2-suIfonyloxy)-5-mcthylphcnoxy]propoxyguanidine, -64- (114 mg, 0.27 mmol, prepared above) in a minimum volume of letiahydiofunm to anhydrous diclhyl ether (100 mL) containing IIC1 in etlianol (0.75 mL, 1.1 M, 0.82 mmol). Solvent was removed in vacito to give 130 mg of the title compound as a pale yellow oil. 'H-NMR (300 MHz, DMSO-d6) 6 7.76 (d, 2H, J = 4.2 Hz), 7.41 (d, 2H, J = 4.2 Hz), 6.80 (br s, 1H), 6.55 (br s, 1H), 6.49 (t, 1H, J - 2.2 Hz), 4.02 (t. 2H, J = 6.3 Hz), 3.92 (t, 2H, J = 6.3 Hz), 2.26 (s, 311), 2.03 (pcnlel, 211, J = 6.3 llz). Mass .spectrum (MALD1-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C|5Hi8ClN3O5S2: 420.0 (M + H). Pound: 419.9. Example 6 3-[3-(2-Cyanophenylsulfonyloxy)-5-metltylpheiwxy}propoxyguanidine hydrochtoride a) 3-(2-CyanophcnylsulfonyIoxy)-5-mctliylphcno): Orcinol monohydrate (1.42 g, 10.0 mmol) and 2-cyanobenzenesulfonyl chloride (2.02 g, 10.0 mmol) were mixed in saturated NaHCO-, (30 mL) and diethyl ether (30 mL)- 1 he biphnsic mixture was stirred vigorously al room temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3 x 50 mL). The organic phase was washed with brine (2 x 50 mL) and dried over Na2SO4. After removing the solvent in vacua, the residue was purified by flash column chromalography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a white solid (1.65 g, 57%). 'H-NMR (300 MHz, CDCI3) 6 8.07 (m, 1H), 7.94 (m, 1H), 7.75-7.80 (m, 2H), 6.57 (s, 1H), 6.53 (s, 1H), 6.49 (s, 1H), 5.69 (brs, ill), 2.22 (s, 311). b) 3-|3-(2-Cyanopheny]sulfonyloxy)-5-nicthvIphenoxy]propanol: To a solution of 3-(2- cyanophenylsulfonyloxy)-5-methylphcnol (580 mg, 2.0 mmol), as prepared in the preceding step, tri-/7-butylphosphine (607 mg, 3.0 mmol), and 1,3-propanediol (760 mg, 10 mmol) in tctrahydrofuran (20 mL) was added l,r-(nzodicarbonyl)dipcridinc(757 mg, 3.0 mmol). The mixture was stirred at room temperature overnight. Hexanc (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column cliromatography (10% ethyl acetate in dichloromethane) to give the title, compound as a colorless oil (560 mg, 80 %). 'H-NMR (300MHz,CDC!3)6 8.11 (m. III), 7.94 (m, IH), 7.77-7.82 (m, 2H), 6.65 (s, lH),6.59(s, 1H), 6.57 (s, 1H), 4.05 (t, J - 6.0 Hz, 211), 3.82 (t, J - 6.0 Hz, 2H), 2.26 (s, 311), 2.00 (m. 2!1), 1.76 (brs. 111). -65- c) 7V-|3-[3-(2-Cy:nioplicnylsuin>iiylo\y)-5-uic(liylplivnoxy|pi'6po\y]|)hth;iliiiiiilc: To a solution of 3-[3-(2-cyanophcnylsiilfonyloxy)-5-mcthylphcnoxy]pi"opaiiol (1.04 g, 3.0 mmol), as prepared in the preceding step, triphcnylphosphine (1.05 g, 4.0 mmol), and A'-hydroxyphlruilimidc (490 nig, 3.0 nimol) at 0 "C in tetnihydroiiiran (20 nil.) was added diethyl azodicarboxylate (700 mg, 4.0 mmol). The reaction mixture was stirred overnight. Water (50 mL) was added, the reaction mixture was extracted into ethyl acetate (3 x 50 mL). The ethyl acetate solution was washed with brine (2 x 50 mL) and dried over Na2SO4. After removing the solvent, the residue was purified by flash column chromatography (2 : 1 dichloromethane / hexane to dichloromethane) to give the title compound as a colorless foam (1.12 g, 76%). 'H-NMR (300 MHz, COCK) 6 8.09 (m, 1H), 7.97 (m, 1H), 7.84 (m, 2H), 7.78 (m, 4H), 6.67 (s, 1H), 6.60 (sf 111), 6.50 (s, 1H), 4.37 (t, J = 6.1 Hz, 2H), 4.13 (t, J = 6.1 Hz, 2U), 2.27 (s, 311), 2.19 (m. 211). d) 3-|3-(2-Cy:inophcnylsulfonyloxy)-5-iiictliylphcnoxy]propoxyaiiiiiic: To a solution of//-[3-[3-(2-cyanophenylsulfonyloxy)~5-methylphcnoxy]propoxy]phthalimide (600 mg, 1.2 mmol), as prepared in the preceding step, in 40 mL of cthanol / tetrahydrofuran / water (2:1:1) was added sodium borohydridc (230 mg. 6.0 mmol). The reaction mixture was stirred at ambient temperature overnight. The mixture was acidified (pll 1-2) and heated to 50 °C for 2 hours. After cooling to room temperature, the solution was adjusted to pH 8-9 with 2N NaOH. The mixture was extracted into ethyl acetate (3 x 50 mL), and the organic phase was washed with brine (50 mL) and dried over Na2SO4. After removing the solvent, the residue was purified by flash column chromatography (dichloromethane to 2% melhanol in dichloromethane) to give the title compound as a colorless oil (370 mg, 85%). 'H-NMR (300MHz,CDCl3)6 8.06(ni, lH).7.93(m, 111), 7.76 (m, 211). 6.61 (s, 1M). 6.53 (s, 2H). 5.36 (br s, 2H), 3.94 (t, J = 6.3 Hz, 2H), 3.78 (t, J - 6.2 Hz, 2H), 2.23 (s, 3H), 1.99 (m, 2H). c) 3-[3-(2-Cyanophenylsulfonyloxy)-5-mcihylphcnoxy]propoxyguanidine hydrnchloridc: To a solution of 3-[3-(2-cyanophenylsulfonyloxy)-5-mcthylphcnoxy] propoxyaminc (362 mg, 1.0 mmol), as prepared in the preceding step, in N,N-dimcthylformnmidu (10 mL) was added 1 //-pyrazole-cnrbo.xamidine hydrochloridc (590 mg, 4.0 mmol). The reaction mixture was stirred at ambient temperature for two days. N,N-Dimcthylfornuimide was removed under high vacuum. Acelonitrile (10 mL) was added, the solid was removed by filtration, the filtrate was concentrated in vacua, and the residue was dried under high vacuum. The residue was partitioned between water (30 mL plus 2 mL -66- brine) and dicthyl elhcr (20 niL). Tlie water solution was extracted with diethyl ether (20 mL), and the combined diethyl ether extracts were extracted with acidic water (pH 5). 'Hie combined water solutions were adjusted to pH 8-9 by using 2N NaOH and extracted with ethyl acetate (3 x 50 mL). The ethyl acetate solution was washed with pM 7 buffer solution (2 x 30 mL) and brine (30 mL) and dried over Na2SO4. After removing the solvent, 0.6N IIC! melhanol (10 mL) was added, and the solution was conccnlralcd to give the title compound as a colorless oil (340 mg, 77%). 'H-NMR (300 MHz, DMSO-d6) o 8.30 (d, J = 7.5 Hz, HI), 8.09 (I, J = 7.5 11/, 111), 8.04 (m, 211), 7.72 (br s, 511;, 6.79 (s. 111), 6.49 (s, 1H), 6.47 (s, 1H), 3.99 (t, J = 6.2 Hz, 2H), 3.90 (i, J - 6.3 Hz, 2H), 2.22 (s, 3H), 2.01 (m, 2H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C,8H20N4O5S: 405.1 (M + H), 427.1 (M + Na). Found: 405.1,427.0. Example 7 3-l3-(5-Iso(iuitio!iiiylsulf0nylo.\y)-5-ntethyIphi'iio.xy}pro[)o.\yguaiti(lint' hydrochloride a) 5-Isoquinoliitesiiironyl chloride: A mixture of 5-isoquinolinesulIbnic acid (4.18 g, 20 mmol), and phosphorus pcnlachloridc (6.24 g, 30 mmol) in phosphorus oxychloride (20 mL) was healed at 120 °C for two days. The reaction mixture was cooled to room temperature and diluted with dry chloroform (60 mL). The white precipitate was collected, washed with dry chloroform, and dried under high vacuum to give the title compound as a white solid (4.40 g, 83%) which was used for next step without further purification. 'H-NMR (300 MIIz,CDCl3)S9.95(s, 111), 9.16 (d, J = 6.8 Hz. Ill), 8.74 (d, J = 6.8 I Iz, III), 8.52 (t, J " 7.0 Hz, 2H), 7.99 (t, J = 7.3 Hz, 1H). b) 3-(5-IsoquinolinylsuIfonyloxy)-5-niethyIpliciiol: Orcinol monohydrate (1.42 g, 10.0 mmol) and 5-isoquinolincsulfonyl chloride (2.64 g, 10.0 mmol), as prepared in the preceding step, were mixed in saturated NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at room temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3 x 50 mL). The organic phase was washed with brine (2 x 50 mL) and dried over Na2SO4. After removing the solvent in vacua, the residue was triturated with ether/hexane to give the title compound as a pale yellow solid (1.15 g, 37%). '11-NMR (300 Ml 1?, CI)C13) 5 9.67 (s, 111). 9.60 (s. 1H), 8.86 (d, J = 6.1 Hz, 1H), 8.63 (d, J - 8.2 Hz, III), 8.37 (t, J - 6.1 Hz. 2H), 7.86 (t, J - 7.8 Hz, 1H), 6.46 (s, 1H), 6.23 (s, 1H), 5.97(3, 111), 2.08 (s,3H). -67- c) 3-|3-(5-Iso(juiiiolinylsiiIfoiiyIoxy)-S-inctliylphciioxy]piopanoI: To a solution of 3-(5- isoquinolinylsullbnyloxy)-5-mc(hylpheuoI (630 nig, 2.0 mmol), as prepared in (lie preceding slep, Irwj-butylphosphine (607 ing, 3.0 minol), and 1,3-propanediol (760 mg, 10 mmoi) in lelrahydrofuran (20 mL) wns added 1 ,l"-(azodic;arbonyl)dipiperidinc (757 nig, 3.0 mmol). The mixture was stirred at room temperature overnight. Hexane (30 mL) was added to the mixture, and ihe precipitates were removed by filtration. The filtrate was evaporated in vacuo, the residue was purified by flash column chromatography (4:1 ethyl acetate/ CH2C12) to give the title compound as a colorless oil (620 mg, 82%). 'H-NMR (300 MHz. CDCI3) 5 9.41 (s, 111), 8.80 (d. J = 6.1 Hz, 111). 8.54 (d. J = 6.1 Hz, 111), 8.33 (d. J = 7.2 Hz, 1H), 8.29 (d, J = 7.6 Hz, 1H), 7.67 (t, J = 7,7 Hz, 1H), 6.56 (s, 1H), 6.29 (s, 1H), 6.24 (s, 1H), 3.89 (t, J = 6.) Hz, 211), 3.75 (I, .1 = 6.0 Hz, 211), 2.16 (s, 31-1), 2.05 (ni, 2H), 1.90 (br s, 1H). d) 7V-[3-|3-(5-Iso(]iiiti()Iiiiylsuiroi]yl(>xy)-5-nicthy]plicnoxy]propoxy]|ihtliiiliniu]c: To a solution of 3-[3-(5-isoquinolinylsulfonyloxy)-5-nielhy!phenoxy]propanol (560 nig, 1.5 mmol), as prepared in the preceding step, triphenylphosphine (520 mg, 2.0 mmol), and JV- hydroxyphlhalimidc (245 mg, J.5 mmol) in letrahydrofuraii (15 mL) at 0 "C was added dicthyl azodicarboxylate (350 mg, 2.0 mmol). The reaction mixture was stirred at room temperature overnight. Water (50 mL) was added, and the reaction mixture was extracted into ethyl acetate (3 x 50 mL). The ethyl acetate solution was washed with brine (2 x 50 mL) and dried over Na2SQ,. After removing the solvent, the residue was purified by Hash column chromatography (4 : 1 dichloromethane / ethyl acetate) to give the title compound as a colorless foam (580 mg, 75%). 'H-NMR (300 MHz, CDC!3) 6 9.42 (s, 1H), 8.81 (d, J = 6.1 Hz, 1H), 8.56 (d, J = 6.1 Hz, 1H), 8.34 (d, J - 7.1 Hz, 1H), 8.31 (d, J = 7.2 Hz, 1H), 7.84 (m, 2H), 7.77 (m, 2H), 7.68 (t, J = 7.7 Hz, 1H), 6.59 (s, 1H), 6.33 (s, 1H), 6:21 (s, 1H), 4.31 (t,J = 6.1 Hz,2H),4.00(t,J = 6.1 Hz, 2H). 2.17 (s, 3H), 2.11 (m, 2H). c) 3-J3-(5-ls -68- Na2SO4. After removing the solvent, the residue was purified by flash column chromatography (ethyl acetate) to give the title compound as a colorless oil (110 mg, 26%). 'H-NMR (300 MHz, CDCI3) 6 9.42 (s, IH), 8.81 (d, J = 6.1 Hz, IH), 8.54 (d, J = 6.1 Hz, 111), 8.33 (m, 211), 7.67(1, .1 - 7.S Hz, 111), 6.55 (s, HI), 6.28 (s, III), 6.23 (s. III), 3.81 ((, J = 6.3 Hz, 2H), 3.74 (t, J - 6.1 Hz. 211), 2.15 (s, 3H), 1.94 (m, 2H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C1,,11:,,N2O5S: 389.1 (M + H), 411.1 (M+Na). Found: 389.3,411.1. f) 3~[3-(5-Isoquinoliiiylsulfoiiyloxy)-5-mctliylphciioxy]propoxyguunidiiic hydrochloride: To a solution of 3-[3-(5-isoquinolinylsulfonyloxy)-5-methylphenoxy] propoxyamine (100 mg, 0.25 mniol), as prepared in the preceding step, in N,N-dimethylformamide (4 ml) was added l//-pyrazole-carboxamidine hydrochloride (150 mg, 1.0 nimol). The reaction mixture was stirred at ambient temperature for two days. N,N-Dimethylformamide was removed under high vacuum. Acctonilrilc (5 mL) was added and the solid was removed by filtration. Hie filtrate was concentrated in vacua and the residue was dried under high vacuum. 1 he residue was partitioned between water (20 mL plus 2 mL brine) and diethy! ether (10 mL). The water solution was extracted with diethyl ether (10 mL). The combined diethyl ether extracts were extracted wilh pi I 5 water. The combined water solution was basified (pH 8-9) by using 2 N NaOH and extracted with ethyl acetate (3 x 30 mL). The ethyl acetate solution was washed with p'1-1 7 buffer solution (2 x 20 mL) and brine (20 mL) then dried over Na2SOj. After removing the solvent, 0.6 N HC1 mcthanol (3 mL) was added, and the solution was concentrated to give the title compound as colorless foam (95 nig, 81%). 'H-NMR (300 MHz, DMSO-d6) 6 11.16(brs, IH), 9.75 (s, IH), 8.89 (d, J = 6.3 Hz, IH), 8.73 (dt J - 8.3 Hz, 1H), 8.46 (m, 4H), 7.93 (t. J = 7.9 Hz, IH), 7.72 (br s, 4H), 6.71 (s, IH), 6.33 (s, IH), 6.27 (s, IH), 3.88 (m, 411), 2.13 (s, 3H), 1.94 (m, 2H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycmnamic acid nia(rix) calcd. for C20Hj2H,OsS: 431.1 (M + 11). 453.1 (M + Na). Found: 431.2, 453.3. ^ -69- Examplc 8 3-[5-MethyI-3-{2-(methylsulfony!)phenytsulfonyloxyJpUenoxyJ propoxyguanid'uie hydrochloride a) 5-Mctliyl-3-l2-(inc(liyIsuIfoiiyl)phcnylsulfonyloxy]phenol: A mixture of orcinol monohydrate (1.68 g, 12 mmol) and 2-methyIsulfonylbenzenesuIfonyl chloride (3.0 g, 11.8 lnmol) in saturated Nal ICO, (25 in!,) and dichloroniethniie (25 mL) was stirred vigorously at room temperature for one week. The reaction mixture was diluted with 50 mL of water and extracted into dichloromclhanc (3 x 50 mL). The organic phase was washed with brine (2 x 50 mL) and dried over Na2SO4. After removing the solvent in vacua, the residue was treated with dichloromethanc and ether to initiate crystallization. The mixture was filtered to provide 1.05 g (26% yield) of a white solid. 'H-NMR (300 MHz, CDC13) 5 2.22 (s, 3H), 3.45 (s, 3H), 5.20 (s, 1H), 6.51 (t, 1H), 6.54 (s. H). 6.61 (s, 1H),7.74(td, 1H, .1 = 7.7, 1.4 Hz), 7.87 (td, 1I-I, J = 7.7, 1.3 Hz), 8.12 (dd, 1H, J - 7.8, 0.7 Hz), and 8.44 (dd, 1H, J = 7.8, 0.5 Hz). b) 3-|5-MctIiyl-3"[2-(iiKiUiylsiiHoiiyl)plR'nyl.siilf(niy!(ixy|plicnoxy|pn>p:inol: Dielhyl azodicarboxylate (0.46 mL, 2.9 mmol) was added slowly to a solution of 1.0 g (2.9 mmol) of 5-methyl-3-[2-(melhylsuifonyl)pIicnylsulfonylo\yJphenoL as prepared in the preceding step, 0.21 mL (2.9 mmol) of 1,3-propanediol, and 760 mg (2.9 mmol) of triphenylphosphine in tetrahydrofuran (25 mL). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated to dry ness. The residue was triturated with hexane under sonication and decanted (4 times). The residue was dissolved in dichloromclhanc and diluted with hexane to produce a crystalline material, which was discarded. The filtrate was diluted with hexane to give an oil and the solvent was decanted. The oil was dissolved in a minimum of methanol and diluted with water to initiate crystallization. The solid was collected by filtration to afford the title compound 1.16 g (quantitative yield). 'H-NMR (300 Ml 1/. CDCI3) 5 8.45 (dd. 1IU-7.8, 1.3 I Iz). 8.12 (dd, 1H,J = 7.8, 1.2 Hz), 7.88 (td, 1H, J - 7.7, 1.3 Hz), 7.74 (td, 1H,J = 7.7, 1.3 Hz), 6.61-6.56 (m, 3H), 4.00 (t, 2H, J = 6 Hz), 3.81 (t, 3M, J = 5.9 Hz), 3.45 (s, 3H), 2.24 (s. 3H), and 1.97 (pentet, 2H, J = 6.2 Hz). Mass spectrum (MALDI-TOF, ct-cyano-4-hydroxycinnamic acid matrix) calcd. for Cl7H20O,S2: 423.1 (M + Na). Found: 423.1. c) N-|3-|5-MctIiyl-3-|2-(nicthylsulfonyl)phcnylsiilfonyloxy]phcnoxy]propoxy] phthnliniidc: The dicthyl azodicarboxylate (3.5 mL, 0.022 mol) was added dropwisc to a -70- solution of 3-[5-methyi-3-[2~(methylsuIfonyI)phenylsulfonyloxy]phenoxy]propanol (7.4 g, 0.018 mol), as prepared in the preceding step, triphenylphosphine (5.82 g, 0.01 8 mol), and AMiydroxyphthalimide (3.11 g, 0.018 mol) in anhydrous lelrahydrofuran (120 mL). The solution was allowed to stir at ambient temperature over a weekend. The lelrahydroi'uran was evaporated. The residue was dissolved in aceionitrile (minimum) and diluted with hexaue to produce a crystalline product which was collected by nitration and discarded. The filtrate was evaporated to dryness and purified by silica gel chromatography using dichloromethane as an elution solvent. The appropriate fractions were combined, evaporated to dryness, and placed under high vacuum to give 7.3 g (74% yield) of a colorless foam. 'H-NMR (300 MHz, CDC13) o 8.45 (dd, HI, .1 - 7.8, 1.3 Hz), 8.12 (dd, 1H, J = 7.8, 1.2 Hz), 7.82-7.91 (m, 3H), 7.73-7.79 (m, 311), 6.61-6.63 (m, 211), 6.55 (t, 1H, J = 2.1 Hz), 4.36 (t, 211, J = 6.2 H/.), 4.10 (m, 211), 3.45 (s, 311), 2.24 (s, 311). 2.13-2.23 (pentel, 2H, J -6.2 IIz). Mass spectrum (MALDI-TOF, a-eyano-4-hydroxycinnamic acid matrix) calcd. forC2SH23NO9S2: 568.1 (M + Na). Found: 568.0. d) 3-|5-IVIeiliyI-3-|2-(nK'(liyIsulf()iiyI)plK>iivlsuMonyl"xy|pIicii()xy]pio|>("xy;iiiiii"e: A solution of Ar-[3-[5-melhyl-3-[2-(mclhylsulfonyl)phenylsuIfonyloxy]phenoxy]propoxy] phlhalimide (7.22 g, 0.013 mol), as prepared in the preceding step, in isopropanol:tctrahydrofuran:walcr (5:1:1; 700 mL) was treated with sodium borohydride (2.5 g, 0.066 mol). The reaction mixture was allowed to stir at ambient temperature overnight. The reaction mixture was quenched with 2N hydrochloric acid and the mixture was warmed at 50°C for 2.5 hours. The reaction mixture was cooled in an ice:watcr bath and adjusted to pH 8.0 with 2N sodium hydroxide. The isopropanol was evaporated on a rotary evaporator and the residual aqueous solution was extracted with ethyl acetate (3 x 75 mL). The combined ethyl acetate extracts were washed with brine, dried over anhydrous sodium sulfate, and evaporated to dryness. The material was purified by silica gel chromalography by elution with 60% ethyl acetate/ hexanc, followed by 75%> ethyl acetate/ hexane. The appropriate fractions were combined and evaporated to 2.8 g (52% yield) of a while solid. 'H-NMR (300 Ml I/, CDCI0 o 8.45 (dd, .1-7.9. 1.2 Hz, 111), 8.11 (dd, .1-7.8, 1.3 Hz, 1H), 7.87 (td, J - 7.7, 1.3 Hz, 1H), 7.74 (td, J = 7.8, 1.3 Hz, 1H), 6.56-6.60 (m, 3H), 5.39 (m, 2H), 3.92 (t, J = 6.3 Hz, 211), 3.79 (t, J - 6.1 Hz, 2H), 3.45 (s, 3H), 2.23 (s, 3H), and 1.99 (pentet, J = 6.2 Hz, 2H). Mass spectrum (MALDI-TOF, ot-cyano-4-hydroxycinnamic acid matrix) calcd. for CI7H2!NO7S2: 438.1 (M + Na). Found: 438.2. -71 - c) 3-j5-Mcthyl-3-|2-(mc(hylsulf(niyl)phcnylsulfonyloxy|pIicnoxy]pr(>poxygu:inidine hydrochloridc: A solution of 3-|5-mcthyl-3-|2-(mcthylsulfonyl)phcnylsulfonyloxy] phenoxyjpropoxyamine (2.75 g, 0.0066 mol), as prepared in the preceding step, in anhydrous A^TV-dimethylformamide (100 mL) was treated with l//-pyrazole-l- carboxamidine hydrochloride (2.93 g, 0.02 mol). The reaction mixture was allowed to stir overnight at ambient temperature. The reaction mixture was evaporated to dryness under high vacuum. The residue was treated with acetonitrile and the resulting crystalline material was collected by filtration and discarded. The filtrate was evaporated lo dryness and applied to a silica gel column. The column was cluted with 5% methanol in acclonilrile, which resulted in mixed product fractions. These fractions were combined and evaporated to dryness. The residue was dissolved in water and the solution was adjusted to pH 3-4 with methanolic HC1. This solution was washed with ether and ethyl acetate. The aqueous solution was treated with solid sodium chloride and extracted with ethyl acetate and dichloromethane. Both the ethyl acetate and the dichloromethane extracts were separately washed with brine and dried (Na,SO,). The organic extracts were conihined and evaporated to dryness. The residue was triturated with both hexnne and ether under sonication and decanted. The residue was placed under high vacuum with snnicaliim lor 2 h lo give 2.67 g (82% yield) of a white powder. 'H-NMR (300 MHz, CDC13) 5 8.42 (dd, J - 7.8, 1.3 Hz, 1H), 8.10 (dd,J = 7.8, 1.3 Hz, 111), 7.90 (td, .1 = 7.7, 1.3 1 lz. Hi), 7.77 (id, J - 7.7, 1.3 Hz, 1H), 7.27 (broad), 6.57 (m, 2H), 6.52 (br t, III), 4.04 (t, J - 6.1 Hz, 2H), 3.94 (t, J = 5.6 Hz, 2H), 3.43 (s, 3H), 2.21 (s, 3H), and 2.06 (pentet, J = 5.6 Hz, 2H). Mass spectrum (MALDI- TOF, ot-cyano-4-hydroxycinnamic acid matrix) calcd. for C^H^N^S,: 458.1 (M -I-11). Found: 457.9. HPLC (C18, 5yi, 4.6 x 100mm, Gradient: 5->100% B in 15 min; A =0.1% TFA/H2O; B=0.1%TFA/CH3CN, 20 uL inj, 15 min run time, Del: 215nm, FR:1 mL/min) 98% @ 8.74 min. Example 9 3~/S-Me/hy/-3-(It2f3f4^fetrn/iyt/roqiiinolinyl-S-sutfonyloxy)p/ienoxy/ propoxyguanidine acetate A solution of 3-[5-methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]propoxyguanidine hydrochloride (0.317 g, 0.68 mmol), as prepared in Example 3, in melhanol (32 mL) was evacuated, flushed with nitrogen, then treated with 10% palladium on carbon (115 mg). "Hie -72- reaction was then placed under a hydrogen-filled balloon. After 8 hours, a 52 mg-portion of 10% palladium on carbon was added and the reaction was again placed under a hydrogen-filled balloon. After stirring overnight, the reaction mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was triturated with hexane twice. The residue was taken up in a minimum amount of acetonitrile, filtered through a PTFE filter (0.45 u), and evaporated to dryness. The residue was purified on a Waters Scp-Pak silica gel column (5 g silica) by elution with a mixture of 40% dichloromethane:methanol:acetic acid (400/100/10) in dichloromclhanc. The appropriate fractions were combined and evaporated to dryness. The residue was triturated with hexane twice and then placed under high vacuum. The residue was treated with 50% aqueous acetonitrile and lyophilized overnight to give the title compound as a hydroscopic solid (0.248 g, 74% yield). 'H-NMR (300 MHz, CDC13) 5 7.28 (d, J - 8.0 Hz, IH), 7.08 (d, J - 7.1 Hz, 1H), 6.54 (s, 1H), 6.36-6.45 (m, 3H), 6.01 (broad s, 1H), 4.04 (m, 2H), 3.91 (m, 2H), 3.67 (m, 2H), 2.75 (t, J = 6.1 Hz, 2H), 2.18 (s, 3H), 2.03 (m, 2H), 1.87 (pentct. J = 5.4 Hz. 2H). Mass spectrum (MALDI-TO1\ u-cyano-4-hydroxycinnainic acid matrix) ailed, for Cwl 1:(,N.,()5S: 435.2 (M -i- II). Toiind: 434.9. IIPLC (C18, 5p, 4.6 x 100mm, Gradient: 5->100% B in 15 min; A =0.1% TPA/II,O; B=0.1%TFA/Cll.,CN. 20 pL inj. 15 min run lime, Del: 215nm, FR:i niL/min) 98.8% @ 10.0 min. Example 10 3-l5-I1ytlnh\yntethyl-3-((iiiinortnyl-8-sulfonyloxy)plu>twxylpropoxy acetic acid salt a) 5-Mctlioxycarboiiyl-3-(quinolinyl-8-sulfonyloxy)phciiol: A mixture of methyl 1,3-dihydroxyben/.oatc (2.56 g, 0.015 mol) and 8-quinolinesulfonyl chloride (3.46 g. 0.015 mol) in dichloromethane (100 mL) and saturated sodium bicarbonate (100 mL) was stirred at room temperature for 5 days. The reaction mixture was diluted with water and dichloromethane. The dichloromethane was separated and the aqueous layer was extracted with dichloromethane (2 x 25 ml.,). The dichloromethane extracts were combined, washed with water and brine, dried over sodium sulfate and evaporated to dryness. The residue was treated with methanol and filtered to remove insoluble material. The filtrate was evaporated to dryness to give the title compound as a pale yellow foam (4.34 g, 80% yield) which was used without further purification. -73- b) 3-[5- Methoxycarbonyl -3-(quinolinyl-8-sulfoiiyloxy)phenoxy]propanol: A mixture of 5-methoxycarbonyl -3-(quinolinyl-8-sulfonyloxy)phenol (4.34 g, 0.012 mol), as prepared in the preceding step, 3-bromo-l-propanol, and cesium carbonate (3.91 g, 0.012 mol) in acclonitrilc (40 mL) was warmed at 50" C overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was separated and extracted with ethyl acetate (2 x 25 ml,). The ethyl acetate layers were combined, washed with brine, dried, and evaporated to dryncss. The residue was purified on a silica gel column (80 g) by clution ¦with 10-20% ethyl acetate in dichloromethane. The appropriate fractions were collected, evaporated to dryness, and placed under high vacuum to give the title compound as a white solid (2.83 g, 57% yield). 'H-NMR (300 MHz, CDCI3) 5 9.25 (dd, 1H, J - 4.2, 1.8 Hz), 8.43 (dd, 1H,J = 7.4, 1.4 Hz), 8.31 (dd, 1H,J = 8.4, 1.7 Hz), 8.16 (dd, 1H,J = 8.2, 1.4 Hz), 7.60-7.66 (m,2H), 7.41 (m, lH),7.30(m, 1H), 6.91 (t, 1H,J = 2.3 Hz), 4.03 (t, 2H, .1 = 6.0 Hz), 3.83 (s, 311), 3.80 (t, 211, J = 6.0 Hz), 1.98 (pentct, 211, J - 6.0 Hz). Mass spectrum (MALDI-TOF, ct-cyano-4-hydroxycinnamic acid matrix) calcd. for C20H19NO7S: 418.1 (M + H). Pound: 417.9. c) yV-[3-15-Mc(lioxycMrbonyl-3-(qui noli nyU8-s ul fonyloxy)phcnoxy]propox3r] phUialimidc: A solution of 3-[5-methoxycarbonyl-3-(quinolinyl-8-sullbnyloxy) phenoxy]propanol (2.83 g, 0.0068 mol), as prepared in the preceding step, triphenylphosphine(2.1 g, 0.008 mol), and AMiydroxyphlhalimide (1.11 g, 0.0068 mol) in anhydrous tetrahydrofuran (50 mL) was treated with diethyl azodicarboxylate (1.26 mL, 0.008 mol) dropwisc. The reaction mixture was allowed to stir at ambient temperature overnight. The tetrahydrofuran was evaporated and the residue was treated with acctonitrilc/hcxanc to produce a crystalline crop which was removed by filtration and discarded. The filtrate produced a granular crystalline material which was collected by filtration and discarded. The filtrate was evaporated to dryncss and the residue was treated with ethyl acclate/hcxane to produce the title compound as a crystalline material in two crops (3.53 g, 92% yield). 'H-NMR (300 MHz, CUC13) indicated 88% title compound and 12% triphcnylphosphinc oxide: 5 9.28 (dd. 111, J = 4.2, 1.7 IIz), 8.43 (dd, 11!, .1 - 7.4, 1.4 Hz), 8.31 (dd, 1H, .1 = 8.4, 1.8 Hz), 8.16 (dd, 111. .1 = 8.2, 1.4 Hz). 7.75-7.88 (m, 4H), 7.60-7.71 (m, 211), 7.43 (m. 111), 7.33 (m. 111), 6.88.(1, 11U = 2.3 Ilz). 4.35 (t. 211, J = 6.1 Hz), 4.13 (t,2H, J = 6.1), 3.84 (s, 3H), 2.18 (pentct, 2H, J - 6.1 Hz). Mass spectrum (MALDI- -74- TOF, a-cyano-4-hydroxyctnnamie acid matrix) caled. for C-,KI13:!N;O,,S: 563.1 (M -i- II). Found: 563.1. d) 3-|5-HydroAymethyJ-3-(quinolinyI-8-sulfonyloxy)phenoxy]propoxyaiiiiHe: A suspension of Ar-[3-[5-melhoxycarbonyl-3-(quinoliny]-8-sulfonyloxy)phc[ioxy] propoxyjphthalimide (3.52 g, 0.0063 mol), as prepared in the preceding step, in cthanol/tctrahydroruran/\vatcr(48:48:24 mL each) was treated with sodium borohydride (1.2 g) and the reaction was stirred at ambient temperature overnight. The reaction mixture was quenched with 2N MCI and warmed at 50° C for 2.5 h while maintaining a pi I of 2.0. The solvents were evaporated and the concentrate was cooled in an ice bath, adjusted to pH = 10 with 2N NaOH, and extracted with ethyl acetate (4 x 25 mL). The ethyl acetate extracts were combined, washed with brine, dried, and evaporated. The residue was dissolved in ethyl acetate and extracted with 10% citric acid (3 x 25 mL). The citric acid extracts were combined and washed with ethyl acetate (1 x 20 mL). The citric acid layer was adjusted to pH = 10 with 2N NaOII and extracted with ethyl acctale ( 3 x 25 mL). The ethyl acetate extracts were combined, washed with brine, dried, and evaporated to dryness. The residue was placed under high vacuum overnight to give the title compound (1.2 g, 54% yield). Mass .spectrum (MALDl-TOl", u-cyano~i-hydroxycinnamic acid matrix) calcd. Tor C19H20N2O6S: 405.1 acid salt: A solution of 3-[5-hydroxymethyl-3-(quinolinyl-8-suIfonyloxy)phenoxy] propoxyamine (1.2 g, 0.003 mol), as prepared in the preceding step, in N,N- dimethyiformamidc (25 mL) was treated with l/-/-pyrazole-l-carboxamidine hydrochloride (1.3 g, 0.009 mol) and (he read ion mixture was stirred al ambient temperature overnight. The AfjV-dimcthyifornuimide was evaporated under high vacuum. The residue was triturated with hot acetonitrite and filtered. The filtrate was evaporated to dryness. The residue was dissolved in water, acidified to pit 3-4 with metlumolic HC1, and washed with diethyl ether. The aqueous layer was adjusted to pll 9-10 with 2N NaOH and extracted with ethyl acetate (3 x 25 mL). The ethyl acetate extracts were combined, washed with pi I 7 buffer and brine, dried, and evaporated to dryness. The residue was redissolved in ethyl acetate and washed with pi 1 7 buffer and brine, dried, and evaporated. The residue was purified on a silica ge! column (10 g) by elution with a 1:1 mixture of dichloromcthane and a solution of dichloromelhane/methanol/acctic acid (400/100/10), followed by a 1:3 mixture of the same -75- composition. The appropriate fractions were combined and evaporated. The residue was treated with acelonitrile and water and lyophili/.ed overnight to give the title compound (0.8 g, 60% yield). 'H-NMR (300 MHz, CDCl3/DMSO-d6) 5 9.25 (dd, 1H, J = 4.2, 1.8 Hz), 8.38 (td, 2H, J = 7.5, 1.4 Hz), 8.20 (dd, 1H, J = 8.3, 1.4 Hz), 7.62-7.68 (m, 2H), 6.79 (s, 1H), 6.64 (s, 1H), 6.41 (t, 1H, J = 2.3 Hz), 4.45 (s, 2H), 3.88 (m, 4H), 1.93-2.02 (in, 5H). Mass spectrum (MALDI-T017, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C2,,l I^N^O^S: 447.1 (M + H). Found: 447.0. HFLC (C18, 5u, 4.6 x 100mm, Gradient: 5->100% B in 15 min; A =0.1% TFA/112O; B-0.1% TFA/CI 1,CN, 20 fiL inj. 15 min run time, Del: 215nm, FR:1 mL/min) 95.8% @ 11.5 min. Example 11 {l-(l5-Methyl-3-(2-methylsulfohytphenylsulfonytoxy)phenoxy]methyl] cyclopropylmethoxy} guanidine hydrochloride a) 1,1-DiIiydroxymcthylcycIopropanc: To a solution of BH3.THF (1.0 M, 100 mL, 100 mmol) was added ethyl 1,1-cyclopropanedicarboxylate (9.3 mL, 50 nimol) at room temperature dropwisc. The mixture was stirred ut 50 °C overnight, quenched with melhano! (100 mL) carefully at 0 "C and stirred at room temperature lor 1 h. The reaction mixture was concentrated in vacua. The residue was co-cvaporatcd with mcthanol several times (4 x 50 mL) to give the title compound as colorless oil (5.3 g) which was directly used in the next step without further purification. b) (l-[5-Mcthyl-3-(2-nictliylstilfoiivlpIicnylsulfonyloxy)plicno\y] methyl] cyclopropylmcthanol: To a solution of 3-(2-methylsulfonylphenylsulfonyIoxy)-5- methylphenol (6.85 g, 20.0 mmol), as prepared in step a of Example 8, tri-yV-butylphosphine (6.1 g, 30 mmol) and 1,1-dihydioxylmclhylcyelopropane (5.1 g, 50 mmol), as prepared in the preceding step, in tctrahydrofuran (200 mL) was added 1 ,r-(azodicarbonyl)dipiperidine (7.6 g, 30 mmol). The mixture was stirred at room temperature overnight, hexane (300 mL) was added to the mixture and the precipitates were removed by filtration. The filtrate was evaporated in vacua, the residue was purified by flash column chromatography (1 : 1 to 2 : 1 ethyl acetate/ hexane) and by crystallization from ethyl acetate/ hexane (1 : 5) to give the title compound as white solid (4.9 g. 57%). 'H-NMR (300 MHz. CDC13) 6 8.45 (d. J = 7.8 Hz, 11-1), 8.13 (d, J = 7.91 iz, III), 7.88 (t, J = 7.7 Hz, III), 7.75 (I, J = 7.7 Hz; 1H), 6.77 (br s, 3H), 3.82 (s, 2H), 3.59 (d. J = 5.5 I Iz, 211), 3.45 (s. 311), 2.23 (s, 3H), 0.61 (s, 4H). -76- c) A/-(l-||5--[Vlc(liyI-3-(2-nH(liylsuH(niy!|)!u'nylsiilfoiiyl()xy)phiiioxyInH'lhyl| cyclopiopylinelhoxyjplithalimide: To a solution of [l-[5-methyl-3-(2- methylsulfonylphenylsulfonyloxy)phenoxy]methyl]cyclopropylmethanol(4.7g, 1 l.Ommol), as prepared in the preceding step, triphcnylphosphinc (3.4 g, 13.0 mmol), A^- hydroxyphlhalimicle (2.1 g, 13.0 mmol) in tetrahydrofuran (80 mL) was added diethyl azodicarboxylate (2.3 g, 13.0 mmol) al 0 "C. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacua and ethyl acetate (100 mL) was added to the residue. The solid was collected, washed with ethyl acetate and dried in high vacuum to give the title compound as while solid (5.5 g, 87%). 'H-NMR (300 MHz, CDC13) 6 8.37 (d, J = 7.8 Hz, 1H), 8.15 (d, J = 7.8 Hz, 1H), 8.10 (t, J - 7.7 Hz, 1H), 7.97 (t,J = 7.7 Hz, 111), 7.86 (s, 411), 6.77 (s, 111), 6.54 (s, 111), 6.51 (s, 111), 4.11 (s, 2H), 3.97 (s, 2H), 3.48 (s, 3H), 2.22 (s, 3H), 0.61-0.66 (m, 4H). d) N-{l-[[5-Mcthyl-3-(2-niethylsulfonylphenylsulfonyloxy)phcnoxy] methyl] cyclopropylmclhoxy}aniinc: To a solution of A/-{l-[[5-mcthyl-3-(2- mcthylsuilbny!phcnylsulfbnyi(i\y)pheiK)NyIniethyl|eyclopropylnietlH)xy}phlhaliniide (5.4 g, 9.5 mmol), as prepared in the preceding step, in cthanol (100 mL)/tctrahydrofuran (100 mL)/water (50 mL) was added sodium borohydridc (1.15 g, 30.0 mmol). The reaction mixture was stirred at ambient temperature overnight. 2N HC1 was added to adjust the pH to 1-2, the mixture was heated to 50 °C for 2 hours. The reaction mixture was concentrated to about 100 mL, water (50 mL) was added and the mixture was neutralized to pH 8-9 with 2N NaOl I. The mixture was extracted into ethyl acetate (3 x 100 mL) and the organic phase was washed with brine (2 x 100 mL) and then dried over Na2SO4. After removing the solvent, the residue was purified by flash column chromatpgraphy (4 : 1 ethyl acctatc/hcxane) to give the title compound as a white solid (3.6 g. 86%). ':! I-NMR (300 MHz, CDCy 6 8.45 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.88 (t, J = 7.7 Hz, 1H), 7.74 (t, J = 7.7 Hz, III), 6.61 (s, III), 6.58 (s, 211), 5.44 (br s, 2H),3.76 (s, 2H), 3.63 (s, 2H), 3.45 (s, 3H), 2.23 (s, 311), 0.57-0.65 (m, 411). c) {1-(I5-Mcthyl-3-(2-nic(hylsulfnnylphcny]sulfunyloxy)phcnoxy] methyl] cyclopropylmcthoxy} gunnidinc hydrochloridc: To a solution of A'-{ l-[[5-methyl-3-(2-mclhylsuironylphcnylsiillonyloxy)phcnoxy|mclhyl]cyclopropylmcthoxy Jimiinc (3.5 g. 8.0 mmol), as prepared in the preceding step, in A'.A'-dimcthylforniamide (30 mL) was added 1/7-pyrazolc-carboxainidine hydrochloridc (3.7 g. 25.0 mmol). The reaction mixture was -77- stirrcd at ambient temperature overnight. /Y.A'-Dimethylformamidc was removed under high vacuum. Acclonilrile (50 ml.) \v;is added and the solid was removed by filtration. The filtrate was concentrated in vacuo and the residue was dried under high vacuum. The residue was partitioned between water (100 mL plus 5 ml brine) and diclhyl ether (50 mL). The water solution was extracted with diethyl ether (50 mL). The combined diethyl ether solution was extracted with pi I 5 water (30 mL)- 'he combined water solution was adjusted to pH 8-9 by using 2N NaOH and extracted into ethyl acetate (3 x 100 mL). The ethyl acetate solution was washed with pH 7 buffer solution (5 x 60 mL) and brine (50 mL) and dried overNa2SO4. Alter removing the solvent. 0.6N HC1 methanol (50 mL) was added and the solution was concentrated. The residual oil was crystallized from methanol/ethyl acetate (I : 50) to give the title compound as white solid (3.6 g, 86%). 'H-NMR (300 MHz, DMSO-d6)8 11.07 (brs, 1H), 8.37 (d, J = 7.8 H?, 1H), 8.09-8.14 (m, 2H), 7.97 (U = 7.7 I Iz, 1H), 7.65 (br s, 4H), 6.76 (s, 1H), 6.52 (s, 1H), 6.51 (s, III), 3.86 (s, 2H), 3.78 (s, 2H), 3.48 (s, 3H), 2.21 (s, 3H), 0.69 (m, 2H), 0.62 (m, 2H). Mass spectrum (MALDI-TOF, ct-cyano-4-hydroxycinnamic acid matrix) calcd. for C2()!I25N3O7S2: 484.1 (M + II), 506.1 (M + Na). Found: 484.0, 506.0. Example 12 {J-ll5'Meihyl-3-(2-cyiuu)pfieifylsiilfoiiYlt>\y)phcito\yJnie(hyIlcyclopropytinetho\y} guanidinc acetate a) l-[[3-(2-Cyanop]icnylsuIfonyloxy)-5-mc(hylplicnoxy]nicthyI]cyclopropylincthaiiol: The title compound was prepared in 62% yield from 3-(2-cyanophenylsulfonyloxy)-5-methylphenol, as prepared in step a of Example 6, in a manner analogous to step b of Example 11. 'H-NMR (300 MHz, CDC13) 6 8.09 (m, lH).7.93(m, 1H), 7.80 (m, 2H), 6.66 (s, 1H), 6.60 (s, 1H), 6.56 (s, 1H), 3.86 (s, 211), 3.60 (sf 2H), 2.26 (s, 3H), 1.85 (br s, 1H), 0.62 (s, 411). b) {l-|[3-(2-Cy;ui()pIieiiylsiilionyl()xy)-5-inethylplienoxy]e(hyl]yclopropoxy} |)ih;ilimi(|c: The title compound was prepared in 94% yield from l-|[3-(2- cyanophenylsuifonyloxy)-5-melhylphcnoxyjmelhyl]cyclopropylmethanol, as prepared in the preceding step, in a manner analogous to step c of Example 11. 'II-NMR (300 MHz, CDCl3)(8.10(m, 1H), 7.95(m, 1H), 7.78 (m, 611), 6.70 (s, IH), 6.60 (s, lH).6.52(s, 1H), 4.18 (s, 2H), 4.01 (ss 2H). 2.28 (s, 3H). 0.70 (m. 4M). -78- c) {J-[f3-(2-Cyano|)hciiylsulfonyIo\y)-5-iiiclliyIphcnoxy]methyl] cyclopropylmcthoxy) ammc: The tide compound was prepared in 60% yield from A'-{l-|[3-(2- cyanophcnylsulfonyloxy)-5-melhylphcnoxy]mcthyl]cyclopropoxy}phthalimide, as prepared in the preceding slop, in a manner analogous to step d of Example 1 1. 'Il-NMR (300 MHz, CDC13)(8.11 (m, lH),7.97(m, 1H), 7.79 (m, 2H). 6.66 (s, lH),6.58(s, lH),6.56(s, 1H), 5.30 (br s, 21 i), 3.80 (s, 211), 3.64 (s. 211), 2.26 (s, 311), 0.63 (m, 411). d) {l-[[5-Mcthyl-3-(2-cyanophcnyIsu]fonyloxy)phcno\y]mcthylJcyclopropylmctlioxy} guanidinc acetate: The title compound was prepared in 79% yield from {l-[[3-(2- cyanophenylsulfonyIoxy)-5-methyIphenoxy]mcthyl]cyclopropylmethoxy}aminc.asprepared in the preceding step, in a manner analogous to step e of Example 11. Flash column chromatography (100 : 10 : 1 dichloromclhane : methanol : acetic acid) gave the title compound as an acetic acid salt. 'H-NMR (300 MHz. DMSO-d,,) 6 8.29 (d. .1 = 7.0 Hz, 1H), 8.02 (d,J = 7.2 JIz, III), 7.98 (me 211), 6.77 (s. Ill), 6.47 (s, 111), 6.42 (sf 111), 5.02 (br s, 4H), 3.80 (s,2H), 3.56 (s, 211), 2.21 (s, 311). 1.89 (s, 3H), 0.55 (s, 2H), 0.52 (s, 2H). Mass spectrum (MALDI-TOI7. a-cyano-4-liydroxycinnamic acid matrix) calcd. for C\()l I22N4O5S: 431.1 (M + H), 453.1 (M + Na). Found: 430.9,452.8. Example 13 {l-ll5-Methyl-^-((iuinolhtyl-H-stilfoiiyl(X\y)p}untoxyjnic(hyllcyclopropyliiwthoxy} guanidinc acetate a) l-[[5-IVlctliyl-3-(quiiiolinyI-8-suIfonyloxy)plicnoxy] methyl ]cyclopropyliiicthanol: The title compound was prepared in 73% yield from 5-niclhyl-3-(quinolinyl-8-sulfonyloxy)phenol, as prepared in step a of Example 3, in a manner analogous to step b of Example l'l. 'H-NMR (300 MHz, CDC13) ( 9.26 (d, J - 4.2 Hz, HI), 8.42 (d, J = 7.4 Hz, 1H), 8.30 (d, J = 7.4 Hz, 1H), 8.14 (d, J - 7.3 Hz, 1H), 7.64 (s, IH), 7.61 (t, J = 4.2 Hz, 1H), 6.55 (s, IH), 6.46 (s. 211), 3.73 (s, 211), 3.55 (s. 211), 2.16 (s, 3H), 1.66 (bis, 111), 0.58 (m, 41-1). b) yV-{l-|[5-lVIcMliylO-(qiiiii"linyl-S-sulfoiiyl(?xy)phciinxyliiiclhyl|cycIopropoxy} phlhaliniidc: The title compound was prepared in 8°% yield from l-|[5-methyl-3- (quinolinyI-8-sulfonyloxy)phenoxy]melhyl)cycIopropyl methanol, as prepared in the preceding step, in a manner analogous to step c of Example 11. 'H-NMR (300 MHz, CDC13) o 9.29 (d, J - 4.3 Hz, III). 8.43 (d. J - 7.4 Hz, 111), 8.30 (d, J - 7.4 Hz. IH), 8.14 -79- (d, J = 7.2 1 ]/., 111), 7.K2 (111. 2! I), 7.75 (m, 211). 7.62 (m, 211), 6.59 (s, 111), 6.50 (s. 111), 6.42 (s, IH), 4.13 (s, 211), 3.88 (s, 211), 2.18 (s, 311), 0.64 (s, 4H). c) {l-[[5-Mcthyl-3-(quinolinyl-8-suIfonyloxy)phcnoxy]methyl] cyclopropylmethoxy} aminc: The lillc compound was prepared in 79% yield from A'-{ 1 -j[5-nicthyl-3-(quinolinyl- 8-sulfonyloxy) phenoxy]methyl]cyclopropoxy}phthalimidc, as prepared in the preceding step, in a manner analogous to step d of 1-xample 11. 'l 1-NMlt (300 MHz, CDCI3) 6 9.23 (d, J = 4.2 Hz, IH), 8.63 (d, J = 7.4 Hz, IH). 8.46 (d, J - 7.3 Hz, IH), 8.38 (d, J = 7.3 Hz, 1H), 7.78 (m, 211), 6.64 (s, 1II), 6.38 (s, 111). 6.27 (s. 111), 5.93 (br s7 211), 3.59 (s, 2H), 3.42 (s, 2H), 2.12 (s, 3H), 0.47 (m, 4H). d) {l-[I5-Mcthyl-3-(quinolin}i-8-sulfonyloxy)phcnuxy]mcthyl]cyclopropylmctlioxy} guanidinc acetate: The title compound was prepared in 83% yield from {l-[[5-methyl-3-(quinolinyl-8-sulfonyloxy)phenoxy]methyl]cyclopropylmethoxy}amine, as prepared in the preceding step, in a manner analogous to step e of Example 11. Flash column chromalography (100 : 10 : 1 dichloromcthanc : mcthanol : acetic acid) gave the title compound as the acetic acid salt. 'I I-NMR (300 Mil/., DMSO-d,,) o 9.23 (d. J - 4.3 11/., 111), 8.63 (d,J = 8.3 Hz, IH), 8.45 (d, J = 8.3 I Iz. Ill), 8.38 (d, .1 - 7.4 Hz, III), 7.78 (m, 211), 6.63 (s. 111), 6.3K (s. 111), 6.27 (s, ill), 5.25 (Ins.'Ill), 3.05 (s, 211). 3.53 (s. 211), 2.12 (s, 3H), 1.89 (s, 3H), 0.55 (br s, 2H), 0.44 (br s, 2H). Mass spectrum (MALDI-TOF, a-cyano- 4-hydroxycinnamic acid matrix) calcd. for C22H24N4O5S: 457.2 (M + H), 479.1 (M + Na). Found: 457.2, 479.0. Example 14 {3-l5-Methyl-3-(2-niori)hoIitiylstilfoiiylpln'tiylsulfonyIoxy)phe!U)xyl[nopoxy} gitanitline hydrochloritle a) l-(Morpl]oUnylsulfoiiyl)-2-nitroben7.cnc: To a solution of morpholine (1.91 g, 22 mmol) and tricthylaminc (2.2 g, 22 mmol) in dichloromclliane (100 mt) at 0°C was added 2-nitrobcnzencsulfonyl chloride (4.42 g, 20 mmol). The mixture was stirred for 4 h and then additional dichloromethanc (100 ml) was added. The dichloromethane solution was washed with saturated NaHCO3 (2 x 50 rriL), 10% HC1 (2 x 50 mL) and brine (50 mL) and dried over Na2SO,|. Evaporating the solvent in vacua yavc the title compound as a yellow solid (5.3 g, 97%). '1I-NMK (300 MHz, CDC1,) 6 7.97 (d, J = 7.3 Hz, III). 7.62-7.77 (m, 3H), 3.75 (t, J - 4.7 I Iz, 411), 3.30 (iv J - 4.8 1 Iz, 411). -80- I)) 2-(MorplioliiiyIsiiH(inyl)aniliiic: A mixture of I -(mo!pholinylsullbnyl)-2-iiitmlx'n/.eiie (5.18 g, 19 inniol), ;is prepared in ihc preceding slop, ami 10% palladium on carbon (520 mg) in elhanol (80 mL) and tetrahydrofuran (80 mL) was stirred under hydrogen (balloon) for 5 h. The catalyst was removed by filtration through Celite. The filtrate was concentrated i to give the title compound as a yellow solid (4.50 g. 98%) which was directly used for the next step without further purification. c) 2-(MorpholinylsuIfonyl)phenyIsulfonyl chloride: The title compound was prepared in 47% yield from 2-(morpholinylsulfonyl)aniline, as prepared in the preceding step, in a manner analogous to step a of Example 19. 'I I-NMR (300 MHz, CDC13) 6 8.43 (d, J - 7.4 Hz, 1H), 8.24 (d, J - 7.4 Hz, 111), 7.88 (m, 2H). 3.74 (t, J = 4.7 Hz, 4H), 3.36 (t, J = 4.7 Hz, 4H). d) 5-Mcthyl-3-I2-(iiiorpliolinylsuironyl)i)hcny1.sulfonyIoxy]phciiol: The title compound was prepared in 60% yield from 2-(morpholinylsulfonyl)phenylsulfonyl chloride, as prepared in the preceding step, in a manner analogous to step a of Example 1. 'H-NMR (3OOMIIz,CDCI3)( 8.25 (d, J = 7.8 Hz, III), 8.21 (d, J = 7.8 Hz. Ill), 7.80 (U = 6.3 Hz, 1H), 7.70 (l, J = 6.4 Hz, 1H), 6.60 (s. III), 6.54 (s. 1H), 6.49 (s, 1H), 3.73 (I, J = 4.7 Hz, 411), 3.36 (t, J - 4.7 I Iz, 411), 2.24 (s. 311). c) 3-{5-MctliyI-3-[(2-niorplioIinylsulfoiiyl)p!icnylsulfonyloxy|phenoxy}propanol: The title compound was prepared in 83% yield from 5-mclhyl-3-[2-(morpholinylsulfonyl)phenylsulfonyloxy]phenol, as prepared in the preceding step, in a manner analogous to step b of Example 10. 'I I-NMR (300 MHz, CDCI3) o 8.25 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 7.8 Hz, 114), 7.81 (t, J -7.7 Hz, 111). 7.70 (I, J - 7.6 Hz, HI), 6.60 (s, 2H), 6.56 (s, 1H), 4.36 (t, J = 6,7 Hz, 2H). 4.11 (t, J = 7.0 Hz, 2H), 3.75 (t, J. = 4.7 Hz, 4H), 3.35 (t, J = 4.7 Hz, 4H), 2.24 (s, 3H) 2.05 (t, J = 7.0 Hz, 2H). f) yV-{3-15-Mcthyl-|3-(2-iiiorplioIinyIsu1fnnyl) phenylsuHoiiyloxy|phenoxy]propoxy} phlliuliinidc: The title compound was prepared in 83% yield from 3-{5-methyl-3-|(2-morpholinylsullbnyl)pheiwlsulfonyloxyjphcnoxy}propanol, as prepared in the preceding step, in a manner analogous to step d of Example 1. M I-NMR (300 Mil/.. CIH.1,) 6 8.26 (d, J = 7.8 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H), 7.68-7.86 (m, 6H), 6.63 (s, 1H), 6.59 (s, 1H), 6.51 (s, 1H), 4.36 (t, J - 6.7 Hz, 2H), 4.11 (t, J = 7.0 Hz, 2H)f 3.72 (t, J = 4.7 Hz, 4H), 3.36 (t. J - 4.7 Hz, 411), 2.25 (s, 3H), 2.18 (t, J = 6.4 I Iz. 2H). -81 - g) 3-[5-MctIiyI-(3-(2-morpholiiiylsiilF[>nyl)phciiylsi]ironyloxy]plicnoxy]propoxy;iniinc: The title compound was prepared in 95% yield from A^-{3-[5-mcthyi-|'3-(2- morpholinylsulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phlhalimide. as prepared in the preceding step, inn manner analogous to step e of Example 1. Ml-NMR (300 MHz, CDC!,) ( 8.26 (d, J - 7.9 Hz, 1H), 8.20 (d. J - 7.8 Hz, I H), 7.81 (t, J = 7.7 Hz/1H), 7.70 (t, J = 7.7 Hz, lH),6.59(s, III), 6.57 (s, 111), 6.54 (s, III). 3.93 (t; J - 6.3 Hz, 211), 3.79 (t. J - 6.2 Ilz, 2H), 3.73 (t, J = 4.7 Hz, 411), 3.36 (t, J = 4.7 I Iz, 411), 2.25 (s, 3H), 2.00 (t, .1 = 6.3 Hz, 211). h) {3-[5-MctIiyI-3-(2-niorpliolinylsiiIfonyIphciiyIsiilfonyIoxy)phciioxy|propuxy} guanidinc hydrochloridc: The title compound was prepared in 95% yield from 3-[5-methyl-[3-(2-morpholinylsulfonyl)phenylsulfonyloxy]phenoxy]propoxyamine, as prepared in the preceding step, in a manner analogous to step f of Example 1. 'H-NMR (300 MHz, DMSO-d6) 6 8.21 (t, J = 8.0 Hz, 2H), 8.04 (i, J = 7.8 Hz, 1H), 7.92 (t, J = 7.8 Hz, 1H), 7.71 (br s, 4H)t 6.75 (s, 111). 6.53 (s, 111), 6.49 (s, 111), 3.99 (I. J = 6.3 I Iz, 211), 3.90 (t, J - 6.4 Hz, 2H), 3.62 (t, J - 4.7 1 Iz, 411), 3.25 (t, .1 - 4.7 I Iz. 4H), 2.22 (s. 311), 2.02 (t. J - 6.3 Hz, 211). Mass spectrum (MAI,I)1-TO1\ a-cyano-4-hydroxycinnamic acid matrix) calcd. for C2IH28N4O8S2: 529.1 (M + H), 551.1 (M +Na). Found: 528.9, 550.8. Example 15 {3-/5-Methyl-3-(2-(acety/pipcrazimisulfon\i)phenyIsiil/onyIo.\y) pheitoxylpropo.\y}gii(uii(linehydrochloridc a) l-(Acctylpipcr"7jnyIsuIfonyl)-2-nitrohcn7.cnc: The title compound was prepared in 87% yield from acetylpiperazine in a manner analogous to step a of Eg. 14. ll I-NMR (300 MHz, CDCI3) 6 7.99 (d, J - 6.8 Hz, 1H). 7.74 (m. 2H), 7.64 (d, J = 6.8 Hz. 1H), 3.70 (t, J-5.1 H/,211), 3.57 (I. J -5.0 11/., 2! I), 3.35 (t..I 5.0 11/,. 211), 3.27 (t, J - 5.1 Hz, 211), 2.10 (s,3H). b) 2-(Accty]pipcrazinylsulfonyl)anilinc: The title compound was prepared in 80% yield from l-(acetyipipcrazinylsulfonyl)-2-niliobcn/.enc, as prepared in the preceding step, in a manner analogous to step b of Example 14. This compound was directly used for next step without further purification. c) 2-(Acctylpiper:!/.inylsuIf preceding step, in a\nanncr analogous to step a of Example 19. 'H-NMR (300 MHz, -82- CDCjj) 6 8.42 (d, J - 7.2 Hz, HI), 8.27 (d, J = 7.3 Hz, 111), 7.89 (m, 2H), 3.27-3.68 (m, 8M), 2.10 (s, 311). d) 5-Mcthyl-3-|2-(acclyl|)cpipcrnziny!sulfonyl)phc(iylsuironyloxy]phcnoI: The title compound was prepared in 44% yield from 2-(acelylpiperazinylsii!fonyl)phenylsulfonyl chloride, as prepared in the preceding step, in a manner analogous to step a of Eg.l. 'H-NMR (300 MHz, CDCI3) 6 8.26 (d, J - 7.8 11/., II1). 8.17 (d, J - 7.8 Hz, 111), 7.81 (I, J = 7.7 Hz, 1H), 7.70(t, J = 7.6 Hz, 1H), 7.16 (s, 1HJ, 6.55 (s, 1H), 6.51 (s, 1H), 6.45 (s, HI), 3.68 (t, J = 4.8 Hz, 2H), 3.55 (m, 2M), 3.46 (m, 2H), 3.29 (t, .1 = 4.9 Hz, 2H), 2.21 (s, 3H), 2.09 (s, 311). c) 3-{5-Mcthyl-3-|2-(acclylpipcnr/Jnylsulf The title compound was prepared in 76% yield ironi 5-mcthyl-3-[2-(acetylpepiperazinylsL,Hbnyl)phenylsu!fonyloxyjphenol, as prepared in the preceding step, in a manner analogous to step b of Example 10. 'H-NMR (300 MHz, CDC!3) 6 8.29 (d, J = 7.8Hz, lH),8.19(d,J = 7.8Hz, IH). 7.82 (t,J = 7.7 Hz, 1H), 7.71 (t, J = 7.7 Hz, IH), 6.61 (s, 111), 6.56 (s, 111), 6.53 (s, 111), 4.00 (t, .1 - 6.0 1I/., 211), 3.78 (m, 211), 3.65 (in, 211), 3.61 (m, 211), 3.54 (m, 211), 3.30 (m. 211). 2.24 (s, 311). 2.08 (s. 311), 1.97 (t, J - 6.0 I Iz, 211). 1) Ar-p-|5-/\1clliyl-3-|2-(iicc(ylj>i["cra/.inyIsitir propoxyjphthalimide: The title compound was prepared in 89% yield from 3-{5-melhyl-3- [2-(acctylpipera/JnylsLilfbnyl)pheny!su!ibnylo\y]phcnoxy}piopanol, as prepared in the preceding step, in a manner analogous to step d of Example 1. 'H-NMR (300 MHz, CDCij) 5 8.31 (d, J - 7.8 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H). 7.44-7.86 (m, 6H), 6.63 (s, 1H), 6.57 (s, IH), 6.49 (s, 11-1), 4.36 (t, J = 6.1 Hz, 211), 4.10 (t, J = 6.0 Hz, 211), 3.67 (m, 2H), 3.54 (m, 2H), 3.48 (m, 2M), 3.28 (m, 2H), 2.25 (s, 3M), 2.18 (t. J -6.1 Hz. 211), 2.08 (s, 3H). g) 3-[S-Mct]iyI-3-[2-(acctylpipcraziiiy]$uIfonyl)phcnyIsiilfoiiyIoxy|plicnoxyj. propoxyaniinc: The title compound was prepared in 73% yield from Af-{3-[5-methyl-3-|2-(acctylpiperazinyl.suirunyOphenylsulfbnyloxylphenoxyJpmpoxyJplithaliniide, as prepared in the preceding step, in a manner analogous to step e of Example 1. 'H-NMR (300 MHz, CDCI3) 6 8.29 (d, .1 - 7.9 Hz, 111), 8.18 (d, .1 = 7.8 Hz, 111). 7.82 (t, J = 7.8 1 Iz, 111), 7.70 (t, J - 7.8 Hz, IH), 6.60 (s, 1H), 6.54 (s, 1H), 6.52 (s, IH). 3.92 (t, J = 6.3 Hz, 2H), 3.79 (t, J - 6.2 Hz, 2H), 3.67 (t, J - 5.5 I Iz. 211), 3.55 (t, J = 6.0 Hz, 211), 3.48 (t, J = 5.8 Hz, 2H), 3.30 (t, J = 5.6 Hz, 211), 2.24 (s, 311). 2.08 (s. 3H). 2.00 (t, .1 - 6.2 Hz. 2H). -83 - h) {3-|5-Mcthyl-3-[2-(acctyIpipcrazinyIsulfony])phcnyIsu]fonyloxy]phcnoxy]propoxy} gminidinc hydrochloiide: The title compound was prepared in 84% yield from 3-|5-methyl-3-[2-(acelylpiperazinylsulfonyI)phcnylsulfonyloxy]phenoxy]propoxyamine, as prepared in llic preceding step, in u manner analogous lo step f ofl:Anmpie I. 'l I-NMR (300 MHz,DMSO-d6)6 11.11 (bfs, III). 8.19 (t, J = 7.9 Hz, 2H), 8.03 (t, J = 7.7 Hz, 1H), 7.91 (t,J = 7.7Hz, 1H), 7.71 (br s, 411), 6.75 (s. III), 6.53 (s, HI), 6.49 (s, III), 3.99 (t, J =* 6.2 Hz, 2H), 3.90 (t, J = 6.3 Hz, 2H), 3.50 (m, 4H), 3.32 (m, 2H), 3.24 (m, 2H), 2.22 (s, 3H), 2.04 (t, J - 6.2 Hz, 2H), 1.99 (s, 3H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C23H31N5O8S2: 570.2 (M + H), 592.2 (M + Na). Found: 570.2,592.2. Example 16 {3-l5~Methy!-3-(2-(N-tiiethylpheiiet!tylattiinosii[foiiyl)i)IieftylsuIfoiiyIoxy)p!ieno\yl propoxyjgitanidine hydrochloride a) l-(yV-Mclhylphcnclhyl:iininosuironyl)-2-iii(robcn/cne: Hie title compound was prepared in 94% yield from N-methylphenethylamine in a manner analogous to step a of Example 14. 'II-NMR (300 MHz, CDC1,) 6 7.93 (d, .1 = 7.7 Hz, 111), 7.56-7.68 (m, 311), 7.18-7.31 (m, 5H), 3.47 (t, J = 7.8 Hz, 2H), 2.92 (s, 3H), 2.90 (t, J - 7.6 Hz, 2H). b) 2-(yV-Mctliylphcnc(hylaniinosulfonyl)aniline: The title compound was prepared in 95% yield from l-(A/-methylphcnethylaminosullbnyl)-2-nitrobenzcne, as prepared in the preceding step, in a manner analogous to step b of Example 14. This compound was directly used for next step without further purification. c) 2-(7V-MetliyIphcncthylaminosulfonyl)phcnylsulfonyl chloride: The title compound was prepared in 40% yield from 2-(A'-mcthylphcnethylaminosulfonyl)anilinc, as prepared in the preceding step, in a manner analogous to step a of Example 19. 'H-NMR (300 MHz, CDC13) 6 7.93 (d,J = 7.7 11/, III), 8.10 (d, J - 7.6 IIz, HI), 7.77 (I. .1 = 7.6 Hz. 211), 7.I8- 7.31 (m, 5H), 3.50 (t, J - 7.8 I Iz, 211), 2.94 (s. 311), 2.90 (t, .1 - 7.6 Hz, 211). d) 5-McUiyl-3-[2-(/V-niclliylphcnc(hylaniinosiilfoiiyl)phcnylsiilf">nyloxylphciiol: The title compound was prepared in 24% yield from 2-(A'-methylphenethylaminosulfonyl) phenylsulfonyl chloride, as prepared in the preceding step, in a manner analogous to step a of Eg. 1. 'H-NMR (300 MHz, CDC13) 6 8.18 (d, J = 7.8 Hz, 1H), 8.12 (d. J = 7.8 Hz, 1H), 7.73 (t, J = 7.7 Hz, 1H), 7.63 (t. J = 7.7 Hz, IB), 7.17-7.2? (m, 5H), 6.59 (s. 1H), 6.53 (s, -84- 1M), 6.49 (s. III), 3.56 (t, J - 7.8 Hz, 211), 2.96 (s, 311). 2.92 (t, J - 7.7 Hz, 2H), 2.22 (s, 3H). e) 3-{5-Mcthyl-3-|2-(7V-mcthylplicncthylaminosiiIfonyl) phenylsulfonyloxy] phcnoxy} propanol: The title compound was prepared in 73% yield from 5-mcthyl-3-[2-(A'- methylphenethylaminosulfonyl)phenylsulfonyloxy]phenol, as prepared in the preceding step, in a manner analogous to step b ofF.xample 10. 'Il-NMR (300 Ml Iz, COC13) 6 8.20 (d, J = 7.9 Hz, 1H), 8.13 (d, J - 7.8 Hz, 111), 7.74 (t, J - 7.7 Hz, 1H), 7.63 (t, J - 7.7 Hz, 1H), 7.17-7.29 (m, 511), 6.59 (s, 111), 6.57 (s, III), 6.53 (s. 111), 3.99 (t, J - 6.0 1 Iz, 2IJI), 3.80 (t, J = 5.9 Hz, 2H), 3.55 (t, J - 7.8 Hz, 211), 2.97 (s, 3H), 2.92 (t, J = 7.7 Hz, 2H), 2.22 (s, 3H), 1.96 (t,J-6.0 Hz, 211). f) 7V-{3-[S-Mcthyl-3-[2-yV-nicthylphcnctIiyIaininosulfonyl)phcnylsulfonyloxy] phenoxyjpropoxy} phthalimidc: The title compound was prepared in 63% yield from 3- {5-mclhyl-3-|_2-(N-niclhylphcncthylaminosul Tony l)phcnylsulibnyloxy]phcnoxy} propanol, as prepared in the preceding step, in a manner analogous to step d of Example 1. 'H-NMR (300 MHz, COC13) 6 8.22 (d, .1 = 7.8 Hz, 111). 8.13 (d, .1 - 7.8 11/, 111), 7.83 (m, 211), 7.74 (m, 311), 7.63 (I. .1 = 7.7 1 Iz, 111), 7.17-7.29 (m, 511), 6.62 (s. 111), 6.59 (s, 111). 6.52 (s. 111). 4.35 (I, J - 6.0 I Iz, 211), 4.08 (t, J = 6.1 I Iz, 211), 3.57 (t, J = 7.8 I Iz. 211), 2.97 (s, 311), 2.92 (t, J = 7.7 Hz, 2H), 2.24 (s, 311), 2.17 (t, J = 6.0 Hz, 2H). g) 3-I5-Methyl-|3-(2-/V-nic(hylphciicthylaininosulfoiiyl) phcnylsulfonyloxy] phcnoxy 1 propoxyaminc: The title compound was prepared in 90% yield from A^-{3-[5-melhyl-3-[2- (A^-mcthyIphenethylaminosulfonyl)phcnylsuironyloxy]phenoxy]propoxy}phthalimide, as prepared in the preceding step, in a manner analogous to step c of Example 1. 'H-NMR (300 MHz, CDCI3) 6 8.21 (d, J = 7.9 Hz, HI). 8.13 (d, J = 7.9 Hz, 1H), 7.74 (t, .1 - 7.8 Hz, 2H), 7.62 (t, J = 7.7 Hz, 1H), 7.17-7.29 (m, 511), 6.58 (s, 211), 6.55 (s, 1H), 3.91 (t, .1 - 6.2 Hz, 2M), 3.80 (t, J - 6.1 Hz, 2H), 3.57 (t, J - 7.8 Hz, 2H), 2.97 (s. 3H), 2.92 (t, J - 7.7 Hz, 211), 2.23 (s, 311), 1.99 (t, J - 6.2 1 Iz, 211). h) {3-I5-Mctliyl-3-(2-(iV-mcthy!phciicthylaniinosulfoiiji)phcnyIsulfonyloxy)phciioxy] propoxyjguanidinc hydrochloridc: The title compound was prepared in 84% yield from 3-[5-melhyl-3-[2-(yV-methylphenethylaminosuifonyl)phenylsulfonyIoxy] phcuoxyjpropoxyaminc, as prepared in the preceding step, in a manner analogous to step f of Example 1. 'H-NMR (300 MHz. DMSO-d6) 6 11.01 (br s, 1H), 8.14 (d, J - 7.9 Hz, IH), 8.07 (d, .1 = 7.9 llz. III), 7.97 (t, J = 7.8 Hz. 211). 7.86 (t, J = 7.7 Hz, H I), 7.63 (br s. 411), -85- 7.17-7.29 (m,5H), 6.74 (s, lH),6.54(s, 1H), 6.51 (s, 1H), 3.98 (t, J = 6.2 Hz, 2H), 3.90 (t, J = 6.1 Hz,!2M), 3.53 (t, .1 = 7.8 Hz, 21I), 2.94 (s. 311), 2.87 (t, J = 7.7 Hz, 211), 2,21 (s, 3H), 2.01 (t, J = 6.2 Hz/2H). Mass spectrum (MALDI-TOF, ct-cyano-4-hydroxycinnamic acid matrix) calcd. for C23H3]N5O8S2: 577.2 (M + H), 599.2 (M + Na). Pound: 577.1; 599.0. Example 17 {3-[5-Metltoxy-3-(2-methylsnlfoiiyIp!tetiylsulfonyl prepared in 80% yield from 2-methylsulfonylbenzenesulfonyl chloride and 5- methoxyresorcinol in a manner analogous to step a of Example 1. 'H-NMR (300 MHz, CDC13) 5 8.42 (d, J - 7.8 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.88 (U J = 7.8 Hz, 1H), 7.75 (t,J-7.7Hz, III), 6.36 (s, 1H),6.31 (s, III), 6.28 (s, 1H), 3.68 (s, 311), 3.45 (s, 3H). b) 3-{5-Metlioxy-3-[2-(nictliylsulfonyl)pIienyIsulfonyloxy]phcnoxy}prop:uioI: The title compound, was prepared in 72% yield IVoin 5-niclhoxy-3-|2- (mcthylsulfonyl)phenylsulfonyloxyjphenol. as prepared in the preceding step, in a manner analogous to step h of Example 10. '11-NMR (300 MI Iz, CDCIO 6 K.44 (d, J - 7.8 11/., Ill), 8.14 (d, J = 7.8 Hz, 1H), 7.88 (t, J = 7.7 Hz, 1H), 7.75 (t, J - 7.7 Hz, 1H), 6.40 (s, .1H), 6.38 (s, 1H), 6.33 (s, 1M), 4.13 (t, J - 6.3 Hz, 211), 3.99 (t, J = 6.0 Hz. 2H), 3.69 (s, 3H), 3.45 (sf 3H), 1.97(t,J = 6.0Hz, 2H), 1.67 (brs. 1H). c) Ar-{3-[5-Methoxy-3-|2-(mcthylsulfonyI)plienylsuIfonyIoxy]plienoxy]propoxy} plUluiIiniide: The title compound was prepared in 88% yield from 3-{5-metho\y-3-[2- (methylsulfonyl)phcnylsul{bnyloxy]phcnoxy}propanol, as prepared in the preceding step, in a manner analogous to step d of Example 1. '11-NMR (300 MHz, CDC13) 6 8.45 (d, J = 7.8 Hz, 1H), 8.14 (d, J - 7.8 Hz, 1H). 7.74-7.89 (m, 6H), 6.37 (s, 3H), 4.46 (I, J:= 6.2 Hz, 211), 4.10 (t, J- 6.1 Ilz, 211), 3.69 (s, 311), 3.45 (s, 311), 2.18 (t, .1 = 6.1 Hz, 211). d)3-[5-Methoxy-3-[2-(nicthyIsulfonyl)phcnyIsulfoiiyl(>xy]phenoxyJpropoxyamine: The title compound was prepared in 79% yield from A'-{3-[5-mcthoxy-3-[2- (methylsulfonyl)phenylsulfonyloxy]phenoxy]propoxy}phthalimide, as prepared in the preceding step, in a manner analogous to step e of Example 1. 'H-NMR (300 MHz, CDCI3) 6 8.45 (d, J = 7.8 Hz, HI), 8.13 (d, J = 7.8 Hz, III), 7.88 (t, J - 7.7 Hz, 1H), 7.75 (t, .1 - 7.7 -86- Hz, 1H), 6.38 (s, IH), 6.36 (s, 1H), 6.32 (s. III). 5.40 (br s, 2H), 3.92 (t, J = 6.3 Hz, 2H), 3.78 (I, J = 6.1 Hz, 2H), 3.69 (s, 3H), 3.45 (s. 3J1). ] .99 (t, J = 6.2 Hz, 2H). c) {3-[S-Mcthoxy-3-(2-incthyIsulfonylphcnylsulfoiiyloxy)phenoxy]propoxy}guanidinc liydrvclilot'itlc: The title compound was prepared in 71% yield from 3-[5-mcfhoxy-3-[2-(melhylsulfonyl)phcnylsulfonyloxy]phcnoxy]propoxyaminc, as prepared in the preceding step, in a manner analogous to slop f oITixample I, '1 1-NMR (300 MM/.. DMSO-d6) 5 11.14 (br s, 1H), 8.37 (d, J = 7.8 Hz, 1H), 8.13 (m, 2H), 7.97 (t, J = 7.7 Hz, 1H), 7.71 (br s, 4H), 6.48 (s, 111). 6.3! (s, 1 f J), 6.26 (s. 111), 3.99 (I, J - 6.2 1 Iz, 211), 3.90 (I, J = 6.3 I Iz, 211), 3.66 (s, 3H), 3.47 (s, 3H), 2.01 (t, J = 6.2 Hz, 2H). Mass spectrum (MALDI-TOF, cc-cyano-4-hydroxycimiamic acid matrix) calcd. for C^H^O^: 474.1 (M + H), 496.1 (M + Na). Found: 474.0, 496.0. Example 18 {3-l5-EtIiyI-3-(2-ntethylsiitfonylpheity]siiifonyIoxy)pltcn0xy]propo.\y} gtutititlitie hythochloridc a) 5-Ktliyl-3-|2-(nictliylsulf(myl)phcnyl-sulfonyloxy|i>ln;in>l: The title compound was prepared in 89% yield Ironi 2-methylsiilfonylben/.encsii1[bnyl chloride and 5-ethylresorcinol in a manner analogous to step a of Eg. 1. 'I I-NMR (300 MHz, CDC13) 6 8.43 (d, J = 7.8 Hz, ]H), 8.09 (d, .1 - 7.8 Hz, 1H), 7.87 (t, J = 7.8 Hz, 1H), 7.73 (t, J = 7.7 Hz, IH), 6.56 (s, 2H), 6.52 (s, IH), 5.59 (br s, IH), 3.45 (s, 311), 2.49 (q, J = 7.6 Hz, 2H), 1.09 (t, J = 7.6 Hz, 3H). b) 3-{5-Etliyl-3-|2-(nK-niylsulfunvl)phcnyisiilf(Miyl(>xyjplKn("xy}iiip:inoI: The title conipoiMidwasprepaivd ill 82% yield fr()in5-ethyl-3-12-(iuelhylsiiI[bnyl)phcnyisLilfoiiyloxyj phenol, as prepared in the preceding step, in a manner analogous to step b of Example 10. '1 I-NMR (300 MHz, UXJlj) 6 8.45 (d. J - 7.K 11/.. ! FI), 8.10 (d, J = 7.8 1 [/., i i 1), 7.88 (t, .1 = 7.7 Hz, IH), 7.73 (t, J = 7.8 Hz, IH), 6.62 Hz, 3H). ^ -87- c) A'-{3-|5-|i; h) {3-[5-Ethyl-3-(2-inethylsulfonylphcnylsulfonyloxy)phcnoxy]propoxy}guanidinc liydrochloridc: The title compound was prepared in 82% yield from 3-|5-ethyl-3-|2-(methylsulfonyl)phcnylsulfonyloxyjphenoxyjpropoxyamine, as prepared in the preceding Step, in a manner analogous to slop f'of l'\ainple 1. 'i I-NMR (300 MHz, l)MS()-d(,)o 11.17 (brs, IH), 8.37 (d, J = 7.8 Hz, IH), 8.08 (in, 2H)S 7.95 (t. J - 7.6 Hz, IH), 7.73 (br s, 4H), 6.77 (s, 1H), 6.54 (s, 11 i), 6.48 (s, 1II), 4.00 (t, J - 6.2 Hz, 211), 3.91 (t, J = 6.3 Hz, 211), 3.47 (s, 3H), 2.50 (q, J - 7.6 Hz, 2H), 1.02 (t, J = 7.6 Hz, 3H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C,,>H2,N,O7S2: 472.1 (M + H), 494.1 (M + Na), 510.1 (M + K). Found: 472.0, 493.9, 509.9. Example 19 {3-l5-Methyf-3-(2-(phenylsiiIfnyl)pluniy!sulfonyIoxy)plHnwxy]propoxy} guanidine hydrochtoride a) 2-(PlienyIsulfonyI)bciizeiicsuIfonyI chloride: To a solution of 2-(phenylsulfonyl)aniiinc (2.33 g, 10 mmol) in 30% aqueous hydrochloric acid (4 mL) was added 40 % aqueous sodium nitrite (4 ml.) at 0-5 PC. After 15 minute, to the diazo solution were added 30% aqueous hydrochloric acid (10 mL), copper sulfate (50 mg) and 40% aqueous sodium bisulfite (10 mL) at 5-lO°C. The mixture was stirred for 30 minutes and additional water (30 mL) was added. The mixture was extracted inlo-dichloromelhanc (3 -88- x 40 mL) and the dichloromclhane solution was washed with brine (40 mL) and dried over Na2SO4. Aflcr removing the solvent in vactto. the residue was purified by Hash column chromatography (dichloromethane) to give the title compound as a white solid (2.1 g, 66%). 'I I-NMR (300 Ml I/,, CDCI3) 5 8.62 (d, J - 7.8 11/., 111), 8.34 (d, J - 7.9 11/., 111), 7.85-7.98 (m, 4H), 7.48-7.63 (m, 3H). b) yv,yV'-(Bis-/L'/-/-l)iityl phcnylsulfonyloxy)plicnoxy]propoxy}guanidinc: To a solution of (A'.W-bis-te/V-butyloxycarbony!)-{3-[(3-hydroxy-5-methyI)phcnoxy)propoxy}guanidine (88 mg, 0.2 mmol), as prepared in step f of Example 20, and triethylamine (0.2 mL) in dichloromethane (10 mL) was added 2-(phcnylsulfonyl)bcnzcncsuIfonyl chloride (64 mg, 0.2 mmol), as prepared in the preceding step. The mixture was stirred at ambient temperature for 2 h. Additional dichloromethane (50 mL) was added. The dichloromethane solution was washed with 10% citric acid (2 x30 mL) and brine (30 mL) and dried overNa2SO4. Aflcr removing the solvent, the residue was purified on a Waters Sep-Pak (10 g silica, dichloromethane) to give the title compound as a colorless foam (109 mg, 75%).' 'll-NMR (300 MHz, COC13) 6 9.08 (s, 1H), 8.64 (d, J = 7.9 Hz, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.97 (d, J = 7.9 Hz, 2H), 7.89(1, .1-7.8 Hz, III), 7.71 (1, .)-7.8llz, 211). 7.5(> (d, .1 - 7.2 I lz, 111). 7.49 (t, .1 > 7.1 11/., 2H), 6.59 (s, 1H), 6.57 (s. 111), 6.53 (s, 111). 3.19 (t, J = 6.2 Hz, 2H), 3.94 (t, J - 6.2 Hz, 211), 2.91 (s, 311), 2.23 (s, 311), 2.11 (1. .1 - 6.2 11/.. 211), 1.49 (s, 1811). c) {3-|5-Mc(hyI-3-(2-(p!iciiylsiiironyl)piKMiylsulfonyloxy)phciioxy|propoxy)Riia"iiIi"c hydrocliloridc: To a solution of A;.A^-(bis-rc/7-butyloxycarbonyl)-{3-[5-mclhyl-3-(2-phenylsulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidine (108 nig, 0.15 mmol), as prepared in the preceding step, in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at ambient temperature for 3 h and then the solvent was evaporated in vacua. The residue was dissolved in dichloromethane (50 mL), washed with 2 N K2CO3 (2 x 30 mL) and dried over Na:SO4. After the solvent was evaporated, the residue was converted to the HC1 salt with mcthanolic HC1 mid purified on a Waters Sep-Pak (5 g silica, 10 % melhnnol in diehloromelluine) to give the title compound as a colorless foam (78 mg, 93%). 'H-NMR (300 MHz, DMSO-d6) 6 11.05 (br s, 1H), 8.62 (d, J - 7.9 Hz, HI), 8.13 (m, 211), 7.98 (d, J = 8.1 11/, 111), 7.93 (m. 211), 7.69 (d, J = 7.6 Hz, 111). 7.60(1, J = 7.8 Hz, 2H), 7.20 (br s, 4H), 6.74 (s, 1H), 6.47 (s, 1H), 6.45 (s. 1H), 3.98 (t, J = 6,3 Hz, 2H), 3.88(t, J - 6.3 Hz, 2H). 2.91 (s, 3H), 2.21 (s, 3H). 2.00 (t, J = 6.3 Hz, 2H). Mass -89- specirum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C23H25N3O7S2: 520.1 (M + 11), 542.1 (M + Na). Found: 520.3. 542.2. Example 20 {3-l5-Methyl-3-(2-(4-ctliyIoxycorbonyl)pipcri(i'uiylsulfonylpUenylsitlfonyloxy) p/tenoxy/propoxy/guanidine hydrochloride a) 3-BcnzyIoxy-5-mctliyIphenoI: Orcinol monohydrate (7.10 g, 50 mmol) in N,N-dimethylformamide (20 mL) was added dropwise to a mixture of NaH (95%, 2.4 g, 100 mmol) in fyW-dimelhylformamide (60 mL) and the mixture was stirred at room temperature for 20 min. Benzyl bromide (8.55 g, 50 mmol) in A^A'-di methyl form amide (20 mL) was added dropwise to the mixture and stirred at room temperature for 2 hours. Water (100 mL) was added slowly to the reaction mixture. The reliction mixture was extracted with ethyl acetate (3x100 mL) and then the organic phase was washed with brine (2x50 mL) and dried over Na2SO4. After the solvent was evaporated, the residue was purified by flash column chromatography (silica gel, 3 : 1 hexane : ethyl acetate) to give the title compound as a yellow oil (5.20 g, 48%). 'H-NMR (300 MHz, CDC!3) 5 7.39 (m, 5H), 6.40 (s, 1H), 6.29 (t, .1 = 5.3 11/., Ill),), 6.26 (s. 111), 5.25 (s, 111), 4.99 (s, 211), 2.26 (s, 311). h) 3-[(3-IJcnzyIoxy-5-niethy1)phcnoxy]prop:inol: 3-BenzyIoxy-5-methyIphenol (5.20 g, 24 mmol), as prepared in the preceding step, was stirred with 3-bromopropanol (3.6 g, 26 mmol) and Cs2CO3 (8.2 g, 25 mmol) in acctonitrile (80 mL) at 50 "C overnight. After cooling to room temperature, the solid was removed by nitration. The filtrate was concentrated in vacua and the residue was purified by flash column chromatography (1:2 to 1:1 ethyl acetate : hexane) to give the title compound as a yellow oil (4.3 g, 66%). 'H-NMR (300 MHz, CDC13) 6 7.38 (m, 511). 6.41 (s. Ill), 6.36 (s, 211). 5.01 (s, 211), 4.07 (t, J = 6.3 Hz, 2H), 3.83 (t, J = 6.0 Hz, 2H), 2.29 (s. 3H), 2.05 (m, 2H). c) A^-{3-|(3-Hcn/.yloxy-5-iiuiihyl)phennxy]pn)poxy}p!i(IiiiIiiiii(k>: To a solution of 3-|(3-bcnzyloxy-,5-methyl)phenoxy|propanol (4.2 g. 15.0 mmol), as prepared in the preceding step, triphcnylphosphinc (4.5 g, 17.0 mmol) and A'-hydroxyphthalimide (2.8 g, 17.0 iiiino!) in tetraliydrofuran (100 mL) was added dicthyl azodicarboxylale (3.0 g, 17.0 mmol) at 0°C. The reaction mixture was stirred al ambient temperature overnight. The reaction mixture was concentrated in vacua and ethyl acetate (100 mL) was added to the residue. The solid was removed by filtration and the filtrate was concentrated in vocno. The residue was -90- purified by flash column chromatography (dicliloromcthanc) lo give the title compound as a pale yellow oil (5.0 g, 89 %). 'H-NMR (300 MI Iz. CDG13) 6 7.82 (d, J - 8.2 Hz, 211), 7.74 (d, J = 8.3 Hz, 2H), 7.38 (m, 5H), 6.41 (s, 1H), 6.39 (s, 1H), 6.38 (s, 1H), 5.02 (s, 2H), 4.40 (t, J - 6.3 Hz, 2H), 4.19 (t, J - 6.1 Hz, 2H), 2.29 (s, 3H), 2.23 (t, J - 6.2 Hz, 2H). d) {3-|(3-Bciizyloxy-5-nic1hyl)pliciioxy{propoxy}"miiic: 7V-{3-[(3-Benzyloxy-5- mcthyl)phenoxy]propoxy}phthalimidc (2.25 g, 6.0 mmol), as prepared in the preceding slep, was stirred with 40% aqueous meihylamine (4.8 mL, 60 mmol) in ethanol (60 mL) and tetrahydrofuran (20 mL) for 1 h. The reaction mixture was concentrated in vacua to give a white solid. Flash column chromatography (20% ethyl acetate in dichloromethane) gave the title product as a colorless oil (1.40 g, 82%). 'H-NMR (300 MHz, CDC13) 6 7.40 (m, 5H), 6.41 (s, 1H), 6.36 (s, 2H), 5.35 (br s, 2H), 5.00 (s, 2H), 4.00 (t, J = 6.3 Hz, 2H), 3.83 (t, J = 6.2 Hz, 2H), 2.29 (s, 3H), 2.04 (t, J - 6.3 Hz, 2H). e) (yV,7Vf-Bis-i'cr/-butyIoxyc:irbonyl)-{3-((bcnzjioxy-5-niclhy1)phciH)xy]propoxy} guanidinc: To a solution of 3-[(3-benzyloxy-5-mcthyl)phenoxy]propoxyamine(1.75 g, 6.0 mmol), as prepared in the preceding step, in A',A'-dimcthyIfonn;imide (20 mL) was added (A/,A^'-bis-/c/7-butyloxycaibonyl)-l//-pyraz(>le-carboxamidine (2.2 g, 7.0 mmol). The mixture was stirred al ambient temperature overnight. The solvent was evaporated tinder high vacuum and the residue (3.8 g) was directly used in the next step without purification. f) (7V,7Vf-Bis-/c'/Y-butyIoxycarbonyI)-{3~l(3-hydroxy-5-nicthyl)phcnoxy)propoxy} guanidinc: A mixture of (A^A'-bis-/e/y-butyloxycarbonyl)-{3-l(benzyIoxy-5-methyl) phcnoxy]propoxy}guanidine (3.8 g). as prepared in the preceding step, and 10% palladium on carbon (400 ing) in clhanol (30 mL) and TUT (30 mL) was stirred under hydrogen (balloon) overnight. The catalyst was removed by filtration through Cclite and the filtrate was concentrated in vacua. The residue was purified by Hash column chromatography (3:1 ether:hexane) to give the title compound as a white foam (2.45 g, 93%). 'H-NMR (300 MHz, CDC13) 6 9.09 (s, UI),7.74(brs, III), 6.33 (s, HI), 6.29 (s, 111), 6.27 (s. 111), 4.20 (t, J = 5.9 Hz, 2H), 4.03 (t, J - 6.1 Hz, 2H), 2.25 (s, 3H), 2.15 (pentet, J - 5.9 Hz, 2H), 1.49 (s, 1811). -91 - g) 1,2-Bcnzcncdisuifonic anhydride: A mixture of 1.2-benzcnedisuJfonic acid dipotassium suit (20 g, 0.064 mol) in fuming sulfuric acid (100 mL) was heated at 70-75°C overnight. The reaction mixture was slowly poured onto ice and the precipitate was quickly collected by filtration. The solid was treated with benzene (500 mL) and dried over anhydrous sodium sulfale. The solvent was filtered and evaporated to give the title compound as a crystalline solid (7.0 g, 50% yield), nip 182-3"C. 'll-NMR (300 MHz, CDC13) 6 8.02-8.09 (m,4H). h) Ar,/V-(Bis-/^/'/-but>'Ioxycarbonyl)-{3-|5-mcthyl-3-(2-(4-ctIiyloxycarbonyl) pipcridinylsulfonylphcnylsulfonyloxy)phcnoxy]propoxy}guanidinc: To a solution of 1,2-benzenedisulfonic anhydride (440 mg, 2.0 mmol), as prepared in preceding step, and N,N-diisopropylelhylamine (360 uL, 2.0 mmol) in dichloromclhane (20 mL) was added ethyl isonipecotale (315 ing, 2.0 mmol). After stirring the mixture for 4 h at ambient temperature, oxalyl chloride (160 uL, 2.0 mmol) and 5 drops of A',A'-dimethylformamide were added. The mixture was stirred for another 4 h. (;V, A'-I3is-ter/-butyloxycarbony1)-{3-|(3-hydioxy-5-H)clhyl)phcnoxy)piopoxy)i;,ii;iiiidinc (700 ing, 1.6 mmol), as prepared in step f, and A^/V-diisopropylcthylamine (360 (L, 2.0 mmol) were added to the mixture. The mixture was stirred at ambient temperature overnight and then additional diehloronielhane (100 mL) was added. The solution was washed with 10% citric acid (3 x 50 mL) and brine (50 mL), and dried ovcrNa,SO4. After the solvent was evaporated in vacua, the residue was purified by flash column chromatography (diehloromethane to 10% ethyl acetate in diehloromethane) to give the title compound as a colorless foam (1.04 g, 81%). 'll-NMR (300 MHz, CDCJ3) 6 9.08 (s, 111), 8.28 (d, J - 7.9 Hz, HI), 8.15 (d, J = 7.8 Hz, 1H), 7.78 (t, J - 7.7 Hz, 1H), 7.68 (t, J - 7.8 Hz, 111). 7.66 (t. J- = 7.7 Hz, 1H), 6.58 (s, 1H), 6.56 (s, 1H), 6.50 (s, 1H), 4.18 (t, J = 6.2 Hz, 211). 4.12 (q, J = 7.1 Hz, 2H), 3.94 (t, J = 6.2 Hz, 2H), 3.84 (m, 2H), 2.97 (t, J- 10.3 Hz, 2H), 2.41 (m, 1H), 2.23 (s, 3H), 2.10 (t, J - 6.2 Hz, 2H), 1.95 (m, 211), 1.79(m,2H), 1.49 (s. 1811). 1.23 (t. J -7.1 Hz, 311). i) (3-[5-TVIcthyl-3-(2-(4-clliyIoxyc:irbonyl)pipcridinyIsulfonylphcnylsulfony1oxy) phcnoxy]propoxy}Kiiiiiiidinc bydrocliliiride: To a solution of N,N'-{b'\s-lcr(-butyloxycarbonyl)-{3-[5-mcthyl-3-(2-(4-cthyloxycarbonyl)piperidinyl sulfonylphenylsuHbnyloxy)phcnoNy]propoxy}guanidinc (270 nig, 0.34 mmol), as prepared in the preceding step, in diehloromethanc (10 111L) was added triiluoroacctic acid (4.0 mL). The mixture was stirred at ambient temperature for 3 h and the solvent was evaporated in -92- vacuo. The residue was dissolved in ciiehloromethane (50 mL), washed with 2 N K2CO3 (2 x 30 mL) and dried over Na2SO4. After the solvent was evaporated, the residue was purified by flash column chromatography (10% methanol in dichloromethane) and converted to the HCI salt (1 eq. mcthanolic HCI and concentration) to give the title compound as a colorless foam (175 mg, 85%). 'H-NMR(300 MHz, DMSO-d6) 6 8.20 (d, J = 7.9 Hz, IH), 8.15 (d, J-7.9 Hz, HI), 8.01 (t, .1 = 7.7 Hz. HI), 7.88 (U = 7.7 Hz, III), 6.73 (s. III), 6.51 (s. 111), 6.41 (s, IH), 6.25 (br s, 4H), 4.05 (q, J = 7.1 1 Iz, 2H), 3.93 (t, J = 6.4 Hz, 2H), 3.76 (m, 2H), 3.71 (t, J = 6.1 Hz, 211), 2.93 (t, J = 10.2 Hz, 211), 2.50 (m, IH), 2.21 (s, 3H), 1.88 (m, 4H), 1.55 (m, 2H), 1.16 (t, J =7.1 Hz, 3H). Mass spectrum (MALD1-TOF, cc-cyano-4-hydroxycinnamic acid matrix) calcd. for C35H1.,N,O,>S2: 599.2 (M + 11), 621.2 (M + Na). Found: 599.2, 621.3. Example 21 2-[5-Methyl-3-(2-(niethytettIfonyl)pUenyIsiilfony!oxy)phi:noxy}eflwxygu(inidine a) 2-|5-Me(hyl-3-(2-(inclhyIsulfonyl)pheiivlsulfonyIi"xy)pheiioxy|etlu>x5 (ohiciic: A solution of 5-mcthyl-3-|2-(mclhylsullbnyl)phenylsulfonyIoxylphcnol (505 mg, 1.47 ininol), as prepared in step a of Example 8, 2-bcnzyloxyethnnol (209 |iL, 1.47 mmol), 1.1'-(azodicarbonyl)dipiperidine (444 mg, 1.76 mmol) and anhydrous tetrahydrofuran (10 mL) was cooled to 0°C under nitrogen! Neat tri-A'-butylphosphinc (0.44 mL. 1.77 mmol) was added over 3.5 minutes. The solution was stirred at 0°C for 1 hour and then at ambient temperature overnight. Diethyl ether was added and the mixture was filtered. The solid was discarded and the filtrate was concentrated in vacua,. The product was purified by flash column ehromatography through 40 g of silica gel using 0% to 0.5% diethyl ether in dichlorometluine to give the title compound (495 mg. 71%) as a colorless solid. 'll-NMR (300MHz,CDCl3)5 8.44(dd. 1H,J = 7.9, 1.3 Hz), 8.10 (dd. IH. .1 = 7.9, 1.3 Hz). 7.85 (td, 111, J = 7.7, 1.4 I Iz), 7.71 (td, 111, J = 7.7. 1.4 11/). 7.28 - 7.37 (m. 511). 6.5S - 6.63 (m, 3H), 4.60 (s, 2H), 4.02 (m, IH), 3.76 (m, IH). 3.45 (s; 3H)? 2.23 (s, 3H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C23H24O7S2: 499.1 (M + Na). Found: 498.7. -93- ¦ IJ) 2-|5-Mcl!iyl-3-(2-(mclhyIsiiironyl)phciiylsiilf"iiyloxy)|)hciiosy]ctlisiiii"l: A mixture "r2H>incthylO-(2-(ii]clhylsu]rony!)phcny]siiirony]oxy)pliLMi()xyJct!H>xytulucnc(4K()nig, 1.01 mmol), as prepared in the preceding step, 10% palladium on activated carbon (48.2 nig), ethanol (2 ml) and tetrahydrofuran (9 ml.) \v;is stirred at ambient temperature under hydrogen (balloon) for 45 minutes. The mixture was filtered through Celite and the filtrate was concentrated to give the title compound (404 nig, quantitative) as a colorless gum. 'H-NMR (300 MHz, CDC13) 5 8.45 (dd, 1H, J = 7.8, 1.4 Hz), 8.13 (dd, 1H, J = 7.8, 1.4 Hz), 7.88 (td, 1H, J - 7.7, 1.4 Hz), 7.75 (td, 1H, J = 7.7, 1.4 Hz), 6.60 - 6.66 (m, 3H), 3.77 - 3.98 (m, 4H), 2.25 (s, 3H), 1.95 (t, 1H, J = 6 Hz). Mass spectrum (MALDI-TOF, ct-cyano-4-hydroxycinnamic acid matrix) calcd. for C,fiII,8O7S2: 409.0 (M + Na). Found: 408.7. c) 2-|5-MctIiyl-3-(2-(iiictliylsuiruiiyI)phcnylsu]foiiyloxy)plicno\yJvthoxygiiani(linc: The title compound was prepared from 2-[5-methyl-3-(2-(rnethylsulfonyl) phenylsulfonyloxy)phenoxyjethanol (as prepared in the preceding step) in a manner analogous to steps c, d, and c of Example 10. Mass spectrum (MALDI-TOF, ct-cyano-4-hydroxycinnamic acid matrix) calcd. for CI7I!:1N3O7S2: 444.1 (M +II), 466.1 (M+Na). Found: 444.5,466.3. Example 22 2-Hydroxy-3-l5-methyl-3-(2-ine1hylsuIfotiyl) phenylsii/fonytoxyphenoxyj propoxyguanidinc a) 2-UcnzyIoxy-3I5-nicthyI-3-(2-mclhylsu]foiiyl)plicny1siilfoiiyloxyphciioxy)propanol: A solution of 5-nielhy!-3"[2-(mcthylsulibnyl)phcnylsunonyloxy]phcnol (2.00 g, 5.85 mmol), as prepared in step a of Example 8, 2-benzyloxy-U-propanediol (2.0 g, 11.0 mmol), and tri-TV-butylphosphine (2.38 g, 9.44 mmol) in tetrahydrofuran (100 mL) at 0°C was treated with dropwise addition of l,r-(azodicarbonyl)dipiperidine (2.38 g, 9.44 mmol) in tctrahydrofuran (20 mL). The reaction mixture was stirred to ambient temperature overnight. The reaction mixture WHS diluted with diethyl ether and filtered. The filtrate was concentrated and purified by Hash chromatography using elutions of 5 - 10% diethyl cther/melhylene chloride to give 1.11 g (38%) of the title compound as colorless oil. Ml-NMR (300 MHz, CDC13) 5 8.45 (dd, 1H, J = 7, 1 Hz), 8.12 (d, 1H, J = 7, 1 Hz), 7.85 (td, 1HJ-7, 1 Hz), 7.72 (Id, 111, J-7, 1 Hz). 7.2S - 7.39 (m, 511), 6.60 - 6.63 (m, 311). 4.74 (d, 1H, J = 12 Hz), 4.64 (d, 1H, J = 12 Hz), 3.99 (m, 2H)S 3.67 - 3.86 (m, 3H), 3.45 (s, 3H), -94- 2.24 (s, 3H). Mass spcclrum (MALDI-TOF, a-cyano-4-hydroxyeinnamic acid matrix) calcd. for C2,i!2(,OHS2: 529.1 (M H-Na). Found: 529.1. b) 2-Hydroxy-3-[5-mcthyl-3-(2-mcthyIsulfonyl)phcnylsulfonyIoxyphcnoxy]propanol: A mixture of 2-bcn/.yIoxy-3-[5-nicthyl-3-(2-niclhyisiiironyl)phcnyJsuironyloxy phenoxyjpropanol (627 mg,f1.24 mmol), as prepared in the preceding step, 10% palladium on activated carbon (97.9 nig) and deoxygenated cthanol (20 mL) was stirred at ambient temperature under hydrogen (balloon) for two hours. The mixture was filtered through Celite 545 and the filtrate was evaporated. The product was purified by flash column chromatography through 50 g of silica gel using 10% hexane in ethyl acetate to give the title compound (342 mg, 66%) as a colorless resin. 'M-NMR (300 MHz, CDC13) 5 8.45 (dd, 1H, J = 7.8, 1.41 Iz), 8.13 (dd, III, J = 7.8. 1.4 Hz), 7.88 (td, 111, .1 = 7.7, 1.4 11/.), 7.75 (id, HI, J = 7.7, 1.4 Hz), 7.26 (br s, 21-1), 6.65 (br s, 1H). 4.03 (complex m, 1I-I), 3.89 - 3.97 (mi, 211), 3.80 (dd, 1H, J = 11.4, 3.9 1 Iz), 3.70 (dd, 1H, J - 11.4, 5.5 1 Iz), 3.45 (s, 311), 2.25 (s; 3H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for CI7II20O8S: 439.0 (M + Na). Found: 438.8. c) 7V-|2-Hytlroxy-3-|5-niethyI-3-(2-nicthylsulfonyl)phcnylsuIfonyIoxyphcnoxy] propoxylpiithaliiuulv: A solution of 2-hydroxy-3-|5-mothyl-3-(2-metliylsullbnyl) phenylsulfonyloxyphenoxyjpropanol (461 mg, 1.11 mmol, as prepared in the preceding step), AMiydroxyphthalimide (186 mg, 1.14 mmol), l,l'-(azodicarbonyl)dipipcndine (425 mg, 1.68 mmol) and anhydrous tetrahydrofurun (14.7 ml,) was cooled to 0°C, and neat tri-7V-butylphosphine(419 fiL, 1.68 mmol) was added dropwisc over 3 minutes, 'flic reaction was stirred at 0°C for 5 minutes and then at ambient temperature for 3 days. The product was purified by flash column chromalography through 75 g of silica gel using 60:40 ethyl acctate/hexane to give the title compound (209 mg, 33%) as a white foam. Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C25H23NO10S: 584.1 (M + Na), 600.0 (M + K). Found: 583,9, 599.S. d ) 2-Ilydroxy-3-I5-mclhyl-3*(2-iiicthyIsulfoiiy1)phcnyIsiiiroiiyloxypIicnoxy] propoxyguniiiriinc: The title compound was prepared from A'-|2-hydro\y-3-|5-methyl-3-(2-methylsulfonyl)phcnylsuIfonyloxyphenoxy]propoxy]phthalimide (as prepared in the preceding step) in a manner analogous to steps d and c of F,xample 68. Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C,SH23N3O8S2: 474.1 (M + H), 496.1 (M+Na). Found: 473.9,496.1. -95- Example 23 3-l3-(2,4-Bis(meihylsulfony!)phenyIsulfonyloxy)-5-methylpheuo.xyJ propoxyguaitidine hydrochloride a) 2,4-Bis(mcthyIsiilfonyl)hcnzcnc.siilfmiyl chloride: The tide compound was prepared in 24% yield from 2,4-bis(melhylsuIfonyI)aniIinc in a manner analogous to step a of Example 26. '11-NMR (300 MHz, CDCI,) 6 8.91 (d. 111. J- 1.9 11/,), 8.60 (d, III, J = 8.2 Hz), 8.47 (dd, 1H, J = 8.2, 1.9 Hz), 3.46 (s, 311), 3.21 (s, 3H). b ) 3-[3-(2T4-IJis(nie(liyIsi!lfonyl)phcHyIsiilfonyIoxy)-5-methyI|)liciioxy] propoxyguanidiiic hydrochloride: The title compound was prepared from 2,4-bis (methylsulfonyl)benzenesulfonyl chloride (as prepared in the preceding step) in a manner analogous to step b of Example 26 and then step g of Example 29. Mass spectrum (MALDI-TOF, cc-cyano-4-hydroxycinnamic acid matrix) calcd. for C19H2?N3O9S_,: 536.1 (M + H), 558.1 (M + Na). Found: 536.2,558.2. Example 24 3~l5-Met!tyl-3-(3-methyIsu!fonyl)pheitylsulfottylo.xypheiw.xyJ propoxygttanidine hydrochloride a) 3-MclhylsulfoiiylbenzciicsuIfonyl chloride: The title compound was prepared in 64% yield from 3-methylsulfonylaniline hydrochloride in a manner analogous to step a of Example 26. 'H-NMR (300 MHz, CDC13) 5 8.62 (i, 1H, J = 2 Hz), 8.35 (m, lH),8.32(m, IH), 7.90 (t, 1H, .1 = 8 Hz), 3.16 (s. 3H). b) 3-|5-Mciliyl-3-(3-iiictliylsulfoiiyl)p1iciiylsiilfonyloxypIiciioxyl|>ropoxygii:iiiidinc hydrochloride: The title compound was prepared from 3-melhylsuIfonylbenzenesulfonyl chloride (as jireparcd in the preceding step) in a manner aiKilogous let step h ol'l-xample 26 and then step g of Example 29. Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C1BH23N3O7S2: 458.1 (M + II). Found: 458.7. L$ - 96 - Example 25 3-l3-((2-Chioro-4-iiietIiyIsulfoiiy!)p!ienylsulfonyloxy)-5-methylphenoxy] propoxyguaitidine liydrochloride a) 2-ChIoro-4-nicihyIsulf a of Example 26. 'lI-NMR (300 MI!/., CDC!,) 8 8.37 (il. HI, .1 = 8.4 Hz), 8.22 (d, IH, J = 1.8 Hz), 8.06 (dd, 1H, J = 8.4, 1.8 Hz), 3.15 (s, 3H). b) 3-|3-((2-ChIoio-4-niethylsiilfonyJ)pIicnylsiiIfnnyIoxy)-5-n]ctliylphcnoxy] propoxyguanidine hydrochloridc: The title compound was prepared from 2-chloro-4- methylsulfonylbenzenesulfonyl chloride (as prepared in the preceding step) in a manner analogous to step b of Example 26 and then step g of Example 29. Mass spectrum (MALDI- TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd for CI8H22C1N3O7S2: 492.1 (M + H). Found: 492.2. Example 26 (3-((>-(2,3-Dihy(lr()-l,1~(lioxohi'iizojbl(hiophciie)i)lic}iylsulfony!o.\y)-5- ¦ methyfphcnoxy)propo.\y]gutuiidinv triJJ/ioroacc/atc a) I,l-l)iox(>l)enz(>|b)ihioplicne-6-sulioiiyl chloride: A mixture of 6-amino-l,l-dioxobenzo[b]thiophene (253 mg, 1.39 mmol) and 30% aqueous HC1 (1.53 mL) was cooled to 0°C in an open flask, and then 40% aqueous sodium nitrite (754 \xL) was added dropwise over 2.25 minutes. The mixture was stirred at 0°C for 15 minutes, and then 30% aqueous HC1 (768 nL) and solid CuSO, (20.4 mg, 0.128 mmol) were added. To this mixture was added 40% aqueous NaHSO3 (2.39 mL) dropwise over 6 minutes, and the reaction was siirrred at 0"C for 2.5 hours. The reaction was diluled wilh water (50 ml,) and extracted with dichloromcthanc (2 x 50 mL). The combined organic layers were washed with brine (75 ml,), dried over Ni^SO.,, filtered and evaporated. The product was purified by flash column chromalography through 20 g of silica gel using CH:CI2 to give the title compound (171 mg, 46%) as a pale yellow solid. '] I-NMR (300 Ml W,. CDC1,) ft 8.35 (m, IH), 8.26 (dd, IH, J = 8.0, 1.8 Hz), 7.65 (d, 1H, J = 8.0 Hz), 7.34 (dd, IH, J - 7.0, 1.0 Hz), 7.02 (d, lH,J = 7.0Hz). -97- b ) yV,/V'-nis-/i'/-/-l)iilyloxyc:irl"iMiyl-|(3-(6-(l,I-di"xohcn/.oIli|fliio|)licnc)- phciiylsuironyloxy)-5-niclIiylpliciifixy)pn)|)oxylKu:iiiidiiiv: A solution of(A',A/'-bis-/c>/7- butyIoxycarbonyl)-[3-((3-hydroxy-5-methyI)phcnoxy)propoxy]guanidine (60.0 mg, 0.137 mmol, as prepared in step f of Example 20),CII_>C], (660 (il/), A',A;-diisopropylethylaminc (36 jiL, 0.207 mmol), and l,l-dioxobenzo[b]thiophene-6-sulfonyl chloride (36.1 mg, 0.136 mmol, as prepared in the preceding slcp) was stirred overnight at ambient temperature. The reaction mixture was concentrated in vacua, and the residual gold oil was partitioned between dilute aqueous TIC1 (10 mL, pi 1 2) and dicthyl ether (10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO^, filtered and evaporated. The product was purified by column chromatography through 4.6 g of silica gel using 60:40 dicthyl ethcr/hexane to give the title compound (78.7 mg, 86%) as a white semisolid. 'H-NMIl (300 MHz, CDCI3) 5 8.13 (s, 1H), 8.05 (dd, IH, J = 7.9, 1.6 Hz), 7.57 (d, 1H, J = 7.9 Hz), 7.34 (dd, IH, J = 7.0, 0.7 Hz), 6.95 (d, IH, .1 = 7.0 Hz), 6.64 (s, IH), 6.46 (s, IH), 6.30 (t, IH, J -2.2 Hz), 4.18 (t, 2H, J - 6.2 Hz), 3.96 (t, 2H, J - 6.2 Hz), 2.27 (s, 3H), 2.11 (pentet, 2H, J = 6.2 Hz), 1.50 (s. 911), 1.49 -98- d) (3-(6-(2,3-Oiliydro-l,l-dioxobcnzo|b]tliiop)icnc)plicny]sulfonyloxy)-5- iiu(livl|)!icini\y)|)i (i|)(t\y]^u:iiii(liiHlrillinn Example 2 7 {3-l5-Metliyl-3-(2-(4-caiboxyl)piperi To a solution of {3-l5-mc(hyI-3-(2-(4-ethyloxyearbonyl) piperidinylsulfonylphcnylsulfonyloxy)phenoxy]propoxy}guanidiiie hydrochloride (90 mg, 0.15 mmol), as prepared in step h of Hxample 20. in mcthanol (4.0 mL) was added 2N NaOH (0.2 mL, 0.4 mmol). The mixture was stirred at ambient temperature for 2 h. The mixture was diluted with water (20 mL), acidified to pH 7 with 2N HCI, and extracted with ethyl acetate (3 x 20 mL). The ethyl acetate solution was washed with brine (20 mL) and dried over Na2SO4. After the solvent was evaporated, the residue was purified on a Waters Sep-Pak (10 g silica, 15% methanol in dichloromethane) to give the title compound as a white solid (50 mg, 58%). 'H-NMR (300 MHz. DMSO-d6) 6 8.15 (m, 2H), 8.01 (t, J - 7.8 11/., Ill), 7.88 (U- 7.7 11/, III), 6.72 (s. 111), 6.53 (s. III), 6.40 (s. Ill), 5.33 (brs, 411). 3.93 (t, .1 = 6.4 Hz, 211), 3.72 (U = 6.2 Hz. 211), 3.65 (m. 211). 2.93 (1. J - 10.0 Hz, 2H), 2.34 (m, HI), 2.22 (s. 31!), I}){) (t, J ¦ 0.2 11/, 211). 1,80 (in, 211). 1.53 (in, 211), Mass spectrum (MALDI-TOF, cc-cyano-4-hydroxycinnamic acid matrix) calcd. for C23H30NjO9S2: 571.2 (M + H), 593.1 (M+Na). Found: 571.2. 593.1. -99-Examplc 28 3-l5-Methyl-3-(3~methyIquinormyl-8-sitlfonyloxy)plieiw.\yJ propoxyguanidine diacctate a) 3-Mctlivl- atO°C was added slowly 3-inethylquinoIine (5.2 g, 36 niniol). The bath was removed and stirring was continued at 100°C overnight. The reaction mixture was cooled to ambient temperature and then treated with 3.3 mL (45 mmol) of thionyl chloride. The reaction mixture was heated at 70°C for 1 h, cooled to 0°C and carefully quenched with ice (very vigorous reaction). The reaction mixture was diluted with 100 mL of water and extracted into dichloromethane (100 mL). The organic phase was washed with water, dried (MgSO4) and concentrated. The residue was triturated with dichloromcthanc/diethyl ether to provide 1.58 g (18%) ofthe title compound as a tan solid. 'II-NMR (300 Ml Iz, DMSO-d6) 5 9.17 - 9.29 (m, 2H), 8.32 - 8.38 (m, 2H), 7.96 (dd, 1H, J = 7 Hz), and 2.51 (t, 3H, J = 2 Hz). b) S-Motliyl-^-t^-nH'lhyhiiiinnlinvl-H-suironyloxyJplit'iiol: A mixture of orcinol monohydrate (2.8 g-, 19.7 mmol) and 3-mclhyl-8-quinolincsuIlbnyI chloride (3.68 g, 15.2 mmol), as prepared by the preceding procedure, in dicthyl ether (70 ml), telrahydrofuran (20 mL), and saturated sodium bicarbonate (100 mL) was vigorously stirred at ambient temperature for 12 h. The reaction mixture was extracted into 15% telrahydrofuran / 85% dichloromethane, dried (MgSO4), and purified by Hash chromatography using clulions of dichloromethane / diethyl ether (95 : 5 to 92 : 8) to give 1.57 g (31% yield) ofthe title compound as a colorless solid, 'l I-NMR (300 Mil/. DMSO-d,,) 5 9.62 (s, 111), 9.09 (d, 111, J = 1.2 Hz), 8.38 - 8.34 (m, 2H), 8.27 {^ 111, .1= 7, 1 Hz), 7.72 (U 1 H, J = 8 Hz), 6.43 (in, 1H), 6.29 (m, HI), 6.09 (t, 1H, .1 = 2 Hz), 2.58 (s, 311), 2.09 (s, 3H). Mass spectrum (MALD1-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C]7H15NO^S: 330.1 (M + H), 352.1 (M-i-Na). Found 329.8, 351.9. c) 3-[5-Mc(hyl-3-(3-mcthyU|uinolinyI-8-suiroiiyloxy)phciioxy]propHiiol: A mixture of 5-inelliyl-3-(incthyU|iiiin>rMiyl-S-sulfony!(>xy)pheiH)l (1.73 g, 5.26 mmol), as prepared in the preceding step, 3.2 mL (6.4 mmol) of 2 N NaOH, and 540 uL (5.79 mmol) of 3- bromopropanol in 20 mL of telrahydrofuran was stirred at 50°C overnighl. The reaction mixture was diluted with water (70 mL). extracted into a 1:1 mixture of ethyl acetate / diethyl ether, dried (MgSOJ, and concentrated. The residue was crystallized from melhanol - 100- /dicthyl ether/hcxanelo give 1.50 g (74%) ofthc title compound as a colorless powder. ¦H-NMR (300 MHz, DMSO-dJ 5 9.09 (d. 111. J = 2 I Iz), 8.26 - 8.39 (m, 31I), 7.72 (i, 1H, J = 7 Hz), 6.63 (s, lH),6.40(s, IH), 6.22 (s, 1H), 4.51 (t, IH, J = 5 Hz), 3.78 (t, 2H, J = 7 Hz), 3.43 (q, 2H, J = 6 Hz), 2.58 (s, 3H), 2.14 (s, 311), 3.80 (pentet, 211, J = 7 Hz). Mass spectrum (MALDI-TOF, ot-cyano-4-hydro.xycinnamic acid matrix) calcd. for C2,,I I21NO5S: 388.1 (M -MI), 410.1 (M-i-Na). Found: 3X8.0,409.9. d) A'-IS-IS-Methyl-S^-methylquinoIinyl-S-suIfonyloxyJphenoxylpropoxy] plitlinliniidc: Dicthyl azodicarboxylatc (830 uL, 5.3 inmol) was added slowly to 3-["5-methyl-3-(3-methylquinolinyl-8-sulfonyloxy)phenoxy]propanol (1.5 g, 3.88 mmol), as prepared in the preceding step, AMiydroxyphthalimide (710 mg, 4.36 mmol), and Iriphenylphosphine (1.3 g, 4.96 mmol) in anhydrous tctrahydrofuran (70 niL) at 0°C under a nitrogen almosphcrc. The .solution was stirred at ambient temperature for 90 min. The reaction mixture was diluted with dicthyl ether (200 niL), washed with water (2 x 150 niL), dried (MgSOd), and concentrated. The residue was dissolved in dichloromcthanc and passed through a thick pad ol'siliea gel (100:0 to 95 : 5 diehloromethane /dielhyl elher) to give the title compound (2.0 g, 82%) as a colorless solid. "11-NMR (300 MHz, DMSO-dJ 6 9.11 (s, IH), 8.28 -8.38 (m, 311), 7.72 (t, III, J = 8 Hz), 6.67 (s. III), 6.43 (s, HI), 6.29 (s, IH), 4.21 (t, 2H, J = 7 Hz), 3.96 (t, 2H, J = 7 Hz), 2.50 (s, 3H), 2.15 (s, 3H), 1.99 (pentet, 2H, J = 6 Hz). Mass spectrum (MALDI-TOF, cc-cyano-4-hydroxycinnamic acid matrix) calcd. for C28H24N2O7S: 533.1 (M + H), 555.1 (M + Na). Found: 532.9,554.9. c) 3-|5-Mc(liyl-3-((|iiiiio]iiiyl-8-siilfnnyloxy)phcii"xy]propoxyiiminc: Sodium borohydridc (388 mg, 10.3 mmol) was added to A'-[3-[5-mcthyl-3-(3-nicthylquinolinyl-8-sulfonyloxy)phcnoxy]propoxy]phthalimide (2.0 g, 3.17 mmol), as prepared in the preceding step, in clhnnol (30 ml.), letrnhydroiuran (30 mL) and water (10 mL). I lydlogen gas was evolved for 40 min. The mixture was stirred overnight at ambient temperature. Aqueous I-1C1 (10 niL, 2N) was added dropwise (hydrogen was evolved), and the solution was heated at 50°C for 40 min. The reaction mixture was concentrated to ca. '/-, volume. The reaction mixture was adjusted to pi I 10 with 2N NaOIl. diluted with water and extracted into dichloromethane. The organic extracts were washed with water, dried (K:CO3), and purified by flash chronintography (85 : 15 to 67 : 33 diethyl ether/ dichloromethane) to give 1.14 g of the title compound as an oil. 'H-NMR (300 Ml Iz, CDC13) 6 9.11 (d, 111, J = 2 I Iz). 8.33 (dd, HI, J = 7, 2 11/.). 8.04 - 8.07 (m, 211), 7.56 (t. 211, J = 8 1 Iz). 6.53 (s, 111), 6.46 (s. 1H), - 101 - 6.41 (s. 111), 3.84 ((, 211, J = 6 Hz), 3.75 (I, 211, J =¦¦ 6 llz). 2.61 (s, 311, 2.17 (s, 311), 1.95 (penlet, 211, J " 6 Hz). Mass spectrum (MAL1M-TOF, 3-l5-Meihyl~3-l2-(N~hydroxy)amhu)phiniylsirifonylo\yJplunu}xyJpropoxy£uaiiidinc hydrochioride a) 2-(2~NitrophenylsuIfonyIoxy)phcnol: A mixture of orcinol monohydrate (4.32 g, 30.2 mmol) and 2-niiiobcnzenesulfonyl chloride (6.65 g, 30.0 mmol) in dietliyl ether (100 mL) and saturated NaHCO3 (100 mL) was stirred at ambient temperature for 36 li. The reaction mixture was diluted with water (100 ml.) and extracted into 10% tetrahydrofuran / ethyl acetate, dried (MgSO4), and concentrated. The residue was diluted with diethyl ether (150 mL) and the resulting disullbnated product (1.6 g) removed by filtration. The filtrate was concentrated and purified by flash chromatography (3 : 97 to 10 : 90 diethyl ether / dichloromethanc) to give 5.67 g (61%) of the title compound as an oil. 'H-NMR (300 MHz, CDC13) 6 7.99 (dd. 1II, J - 7, 2 I Iz), 7.79 - 7.86 (m. 211), 7.65 - 7.73 (m, 111). 6.60 -6.61 (m, 1H), 6.58 - 6.59 (m, 111), 6.50 - 6.51 (m. 111), 5.32 (s. 1H), 2.25 (s. 311). - 102- b) 3-|3-(2-Nihopliciiylsiilfonyl (m, 7H), 6.67 (s, IH), 6.64 (m, IH), 6.55 (t, 1 IL J - 2 Hz), 4.36 (L 2H, J = 6 Hz), 4.12 (t, 211, .1^611/.), 2.2S (s, 311). 2.18 fpcnlcl. 211. .1 -6 11/.). Mass spectrum (MALOl-TOF. "-cyano-4-hydroxycinnamic acid) calcd. for C24M20N2O9S: 535.1 (M + Na). Found: 535.0. d) 3-|3-(2-Nilr"plicnylsulfonyloxy)-5-nic(liylplicii"xy]propoxyaiiihic: A solution of//-[3-[3-(2-nitrophcnylsulfonyloxy)-5-mcthylphenoxy]propoxy]-phthalimide (2.33 g? 4.55 mmol), as prepared in the preceding step, in tetrahydrofuran (30 mL) and ethanol (30 mL) was treated with sodium borohydride (524 mg, 13.9 mmol). The reaction mixture was stirred at room temperature overnight, quenched carefully with 2N HC1 (14 mL) and heated at 50 °C for 90 min. The reaction mixture was then concentrated to '/, volume, basificd with 2N NaOI 1, diluted with water, and extracted into ethyl acetate. The organic phase was dried (K2CO-,)and purified by flash clmmiatography (1 : 4 to 1 : 2 diethyl ether/dichloromethane to give 1.12 g (64%) of the title compound as a pale yellow oil. 'H-NMR (300 MHz, CDC13) 5 7.98-8.01 (m. 111), 7.79 - 7.87 (m, 211), 7.66 - 7.74 (m. 111), 6.64 (in. 111). 6.60 (s. Ml), 6.57 (t, IH, J = 2 Hz); 3.96 (t, 2H. J - 6 Hz). 3.80 (t. 211, J = 6 Hz), 2.27 (s, 3H), 2.02 - 103- (pcntet, 2H, J = 6 1Iz). Mass spcclruni (MALD1-TOF, ct-cyano-4-hydroxycinnamic acid) calcd. for CI61!18N2O7S: 405.1 (M + Na). Found: 405.2. c ) yV,Nt-(Bis-/c'r/-butyloxyc:irhonyl)-[3-[3-(2-nilr6phcnylsulfonyloxy)-5- inclIiyIplK'ii(i\y]pr("|H>\y|^ii:iiii - 104 - g) 3-|5-Mt'lliyl-3-|2-(7V-hy(lr()xy):iniin()plionylsull(m> loxyjplicnnxylprnpoxy^iinnitliiic hydrochloridc: A solution of 7V,A/'-(bis-/6'/Y-butyloxycaibonyl)-[3-[3-(2-(A/-hydro\y) aminophenyI-suIfonyloxy)-5-methylphenoxy]propoxy]guanidine (85 mg, 0.14 mmol) in dichloromethane (1 nil,) was 1 rented wilh I ICI (4N in dioxanc). The reaction mixture was stirred at ambient temperature for 1 h. Additional I ICI (300uL) was added and stirring was continued Tor 1 h. Another 3 nil, ol"4N I ICI was added. The reaction mixture was stirred for 2 h. The reaction mixture was concentrated and suspended in a mixture of dicthyl ether / dichloromcthane / hcxanc. The solvent was removed in vacua and the concentration from diethyl ether / dichloromelhane / hexane was repeated several times to give 74 mg of the title compound as an orange solid. 'H-NMR (300 MHz, CD3OD) 5 7.58 (td, IHS J = 7, 1 Hz), 7.40 - 7.50 (m, 2H), 6.80 - 6.85 (m, 1H), 6.65 (s, IH), 6.44 (s, 1H), 6.42 (s, 2H), 3.95 - 4.15 (m, 4H), 2.19 (s, 3H), 2.05 - 2.17 (m, 2H). Mass spectrum (MALDI-TOF, ot-cyano-4-hydroxycinnamic acid matrix) calcd. for C|7H23N4O6S: 411.1 (M + H). Found: 411.0. Example 30 3-l5-Metliyt-3-[2-innino[)Itenytsulfnyloxylpltcnoxylpropo.xyj>ii(iiiiiIine hydrochloridc A solution of A;,A/'-(i)is-/Li/7-biityIo.\yc;nbonyl)-[3-[3-l2-(A/-hytiioxy)aininopIienyl-sulfonyloxy)-5-methylphenoxy]propoxy]guanidine (289 mg), as prepared in step f of the preceding Example, in tetrahydrofuran (2 inL) containing 10% palladium on carbon was hydrogenated at atmospheric pressure for 20 h. The reaction mixture was filtered and concentrated. The residue was treated with I ICI (1.5 mL; 4N in dioxanc). After stirring for 4 h, the reaction mixture was concentrated from dichloromethane/methanol/diethyl ethcr/hcxane to give 52 nig (26% yield) of impure title compound. Mass spectrum (MAI.DI-TOF, a-cyuno-4-hydroxycimiamic acid matrix) ealed. for Cnll22N4OsS: 395.1 (M + H). Found: 395.2. * -105- Exmnplc 31 3-l3-(2-(4-}tiphenyhnetho\y)phenylsulfonyloxy)~5-niL>thylpIunu)\yJpropo\y" a) 4-(Rromoiiic(!iyl)liiphcnyl: A mixture of 4-phcnyllolucne (4.83 g, 28.7 mmol), N- bromosuccinimide (5.64 g, 31.7 mmol), benzoyl peroxide (catalytic), and anhydrous carbon tetrachloride (35 ml) was refluxed for 24 hours. The mixture was cooled lo room temperature and filtered to give a mixture (7.32 g) of 4-(dibromomcthyl)biphcnyl, 4- (bromomethyl)biphenyl, and 4-phenyltoluene (14 : 82 : 4 molar ratio by 'H-NMR). The product was used without further purification in the next step. 'H-NMR of the title compound (300 MHz, CDC13) 5 7.56 - 7.60 (m, 4H), 7.33 - 7.48 (m, 5H), 4.55 (s, 2H). Partial 'H-NMR of 4-(dibromomelhyl)biphcnyl (300 MHz, CDC13) 5 6.71 (s. 111). b) l-(4-Biphenylmcthoxy)-2-iodobcnzcnc: A mixture of 2-iodopbenol (6.35 g, 28.8 mmol), acetonilrilc (150 nil,), cesium carbonate (11.25 g, 34.5 mmol) and 4- (bromomcthyl)biphcnyl (7.26 g, mixture of 4-(dibromomcthyl)biphenyI, 4- (bromomethyl)biphcnyl and 4-phcnyltoluene, 14:82:4 molar ratio, as prepared in the preceding step) was stirred at ambient temperature for 1 hour and then concentrated in vacua. The residual solid was partitioned between water (200 ml) and ethyl acetate (250 mL). The organic layer was washed with aqueous NaOH (0.1N, 2 x 200 mL) and brine (200 mL), dried over MgSO4, filtered and evaporated. The product was purified by flash column chromatography through 200 g of silica gel using 0% to 10% dichloromclhane in hexane to give the title compound (8.38 g, 76% from 4-phcnylloluene) as a white solid. '.H-NMR (300 MHz, CDC13) 5 7.81 (dd, 111, J = 7.8, 1.5 11/). 7.56 - 7.64 (m, 611), 7.26 - 7.47 (m, 411). 6.89 (dd, 1H, J = 8.2, 1.2 Hz), 6.74 (td, 1H, J - 7.6. 1.2 Hz), 5.20 (s, 2H). c) 2-(4-IJiphcnyIiiiclhoxy)bcnzcncsu]fonyl chloride: A solution l-(4-btphcnylmethoxy)- 2-iodobenzene (6.04 g, 15.6 mmol, as prepared in the preceding step) in 40 mL of anhydrous THF was added over 45 minutes to a cooled (-78CC) solution of Ar-butyl)ithium (0.89M in hexanes, 14.0 mL, 12.5 mmol) in 75 mL of anhydrous fill'. Additional A'-butyllithium (13 mL, 11.6 mmol) was added to drive the reaction to completion. The reaction was stirred at -78°C for 3 hours, and then a cooled (0"C) solution ofSO2 (18 g, 280 mmol) in 55 mL anhydrous tetrahydrofuran was added over 15 minutes. The solution was allowed to warm from -78°C to 0°C and then stirred at 0°C for 30 minutes. Sulfuryl chloride (1.0M in dichloromethane, 72 mL, 72 mmol) was added to the cooled (0°C) reaction mixture over 45 minutes. The solution was stirred at 0°C for 45 minutes and then at ambient temperature - 106- overnight. The reaction was again cooled to 0°C and sulfuryl chloride (1.0M in dichloromethane, 47 niL, 47 mmol) was added over 30 minutes. The solution was stirred at 0°C for 30 minutes and then at ambient temperature for 1 hour. THP was removed by rotary evaporation, and the residual solution was poured into 1 liter of water and 600 mL of dicthyl ether and separated. The organic layer was washed with water (2 x 1 L) and brine (600 mL), dried over MgSO4, filtered, and evaporated. The product was chromatographed through 800 g of silica gel using 20% lo 35% CH2C12 in hexane. The resulting solid was triturated with hcxanc and filtered to give the title compound (2.23 g, 40%) as a fluffy white solid. 'H-NMR (300 MHz, CDC13) 5 8.16 (dd, 1H, J = 8.0, 1.7 Hz), 7.74 - 7.84 (m, 7H), 7.48 - 7.63 (m, 3H), 7.33 (d, 1H, J = 8.5 Hz), 7.27 (t, 1H, J = 7.7 Hz), 5.56 (s, 2H). d) [3-(2-(4-Biphcnylmethoxy)pIicnylsuironyluxy)-5-inctliylplicnyl]ncct:itc: 2-(4-Biphenylmelhoxy) enzenesulfonyl chloride (399 mg, 1.11 mmol, as prepared in the preceding step) was added to a solution of orcinol monoacctale (185 mg, 1.11 mmol), N,N-diisopropylethylamine (272 uX, 1.56 mmol) and dichloromethane (5.6 mL). After stirring overnight at ambient temperature, the solution was concentrated /'/; vucuo. The residual oil was partitioned between ethyl acetate (45 mL) and dilute aqueous HC1 (0.02N, 45 mL). The organic layer was washed with brine (45 mL), dried over Na2$O.,, filtered and evaporated to give the title compound (534 mg, 98%) as a white solid. 'H-NMR (300 MHz, CDC1,) 5 7.89 (dd, 1H, J = 7.9, 1.7 Hz), 7.57 - 7.64 (m, 7H), 7.32 - 7.47 (m, 3H), 7.15 (d, 1H, J - 8.4 Hz), 7.05 (t, 1H, J = 7.7 Hz), 6.79 (m, 1H), 6.75 (br s, 1H), 6.66 (m, 1H), 5.33 (s, 2H), 2.20 (s, 3H), 2.15 (s, 311). Mass spectrum (MALDI-TOF, gentisic acid matrix) caled. for G28H24O6S: 511.1 (M + Na). Found: 511.0. c)-3-(2-(4-Biphcnyhnc(hoxy)phenylsulfonyloxy)-5-mcthylphcnol: A mixture of [3-(2-(4-biphenylmethoxy)phenylsullbnyIoxy)-5-methylphenylJacelale (503 mg, 1.03 mmol, as prepared in the preceding step), methanol (10 mL), telrahydrofuran (5 mL) and aqueous NaOH (2N, 0.52 mL) was stirred at ambient temperature for 20 minutes and then concentrated in vacua. The residue was partitioned between dilute aqueous HC1 and ethyl acetate. The organic layer was washed with brine, dried over Na:SO.,, filtered and evaporated to give the title compound (468 mg. quantitative yield) as a colorless foam. 'H-NMR (300 MHz, CDC1,) o 7.90 (dd. 1II. J - 7.9. 1.7 Hz), 7.57 - 7.63 (m, 711), 7.33 - 7.47 (m, 3H), 7.16 (d, 111, .1 = 8.2 Hz), 7.05 (t, 1IL J - 7.6 Hz), 6.49 (br s, 1 H), 6.47 (br s, 1H), - 107- 6.30 (I, III, J = 2.1 Hz), 5.35 (s, 211), 2.15 (s, 311). Mass spectrum (MALDl-TOF. gcnlisic acid matrix) calcd. lor C26I!22O5S:. 469.1 (M i Na). Found: 469.2. f ) 3 - f 3 - (2 - (4 - B i p h c n y I m c t h o x y) p 1i c n y 1 s u I f o n y 1 o x y) - 5 - nictliylpliciin.xylpropoxy^unniriinc: The lillc compound was prepared from 3-(2-(4-bipliciiyImcllioxy)phciiylsuironyloxy)-5-mcthylphenol (as prepared in the preceding step) in a manner analogous l steps b. c, d and c of Example 10. Mass spectrum (MALI)I-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C30H31N3O6S: 562.2 (M + H). Found: 562.0. Example 32 3-l3-(2~(3-Bij)ltetiylmethoxy)pheitylsuljoityloxy)-5-methylphenoxyj propoxygiianidinc hydrochloride :i) 3-(BroinoinclliyI)hiplicnyl: The title compound was prepared as a mixture of 3-(dibromomethyl)biphenyl, 3-(bromomethyl)biphenyl and 3-phenylloluene in a 22 : 69 : 9 molar ratio (7.77g from 29.4 mmol of 3-phcnyltolticnc) in a manner analogous to step a of Example 31. The compound was used without purification in the next step. 'H-NMR of the title compound (300 MI 1/., CDC1,) o 7.33 - 7.62 (m, 9! 1), 4.56 (s. 211). b) l-(3-Biphenyliiie(lioxy)-2-iodobenzcnc: The title compound was prepared in 68% yield (over two steps) in a manner analogous to step b of Example 31. '1I-NMR (300 MHz, CDC13) 5 7.81 (dd, 1II, J = 7.8. 1.6 I Iz), 7.77 (br s. 111), 7.26 - 7.65 (m. 9H), 6.90 (dd, 1H, J-8.2, 1.3 Hz), 6.74 (td, 11I, J - 7.6, 1.3 Hz). 5.22 (s. 211). c) 2-(3-Uiphcnylmcthoxy)bcnzcncsiilfonyl chloride: The title compound, a light yellow oil, was prepared in 23% yield in a manner analogous to step c of Example 31. 'H-NMR (300 MHz, CDCl3)o" 8.01 (dd, III, J = 8.0, 1.7 Hz), 7.81 (br s, 111), 7.33 - 7.68 (m, 911), 7.17 (d, 1H, J - 8.4 Hz), 7.11 (t, 1H, J = 7.7 Hz), 5.42 (s, 2H). d) (3-(2-(3-Hipliciiyliiicthoxy)phciiyl.siilf(>nyloxy)-5-iiic(hylphenyl|.icc(a(c: The title compound was prepared in 71% yield from 2-(3-biphenylmelhoxy)bcnzencsulfonyl chloride in a manner analogous to step d of Example 31. 'H-NMR (300 Mil/, CDC\?) ft 7.89 (dd, 1H, J = 7.9, 1.7 Hz), 7.81 (br s, 1H), 7.3 1 - 7.63 (m, 9H), 7.14 (d. 1 H; J = 8.4 Hz), 7.05 (t, 1H, .1 = 7.6 Hz), 6.76 (br s. III). 6.72 (br s. III). 6.64 (t. Ill, J = 2.2 Hz). 5.35 (s. 2H). 2.18 (s, 3H), 2.14 (s, 3H). Mass spectrum (MALDI-TOF. genlisic acid matrix) calcd. for C2BH24O6S: 511.1 (M-t-Na). Found: 510.9. - 108- c) 3-(2-(3-ItipIiviiyliiK>(lioxy)phciiylsiilfonyloxy)-5-nic(liyli)liciinl: The title compound was prepared in quantitative yield from L3-(2-(3-biphcnylmethoxy)phcnyIsullbnyloxy)-5-methylphenyljacetate in a manner analogous to step e of Example 31. 'H-NMR (300 MHz, CDC13) 5 7.91 (dd, 1IL J = 7.9, 1.7 Hz), 7.85 (br s. 111), 7.32 - 7.63 (m, 9H), 7.16 (d, 1H, J - 8.3 Hz), 7.05 (t, 1H, J = 7.8 Hz), 6.48 (br s, 1H), 6.43 (br $, 1H), 6.25 (t, 1H, J = 2.2 Hz), 5.36 (s, 21!), 2.11 (s, 311). Mass spectrum (MAI,D1-TO1\ a-cyano-4-hydroxycinnamic acid matrix) calcd. for C26H22O5S: 469.1 (M + Na). Found: 469.1. f ) 3 - | 3 - ( 2 - (3 - IS i p li c n > I in c I li o x y ) p !i c n y I s u 1 f o II y I o x y ) - 5 - mctliylphenoxyjpropoxyguanidinc hydrochloridc: The title compound was prepared from 3-(2-(3-biphenyImcthoxy) phenylsu!fonyIoxy)-5-methylphenol (as prepared in the preceding step) in a manner analogous to steps b, c, d and e of Example 10. Mass spectrum (MALDI-TOF, ct-cyano-4-hydroxycinnamic acid matrix) calcd. for C30H3,N3O6S: 562.2 (M + H), 584.2 (M + Na). Found: 561.9,584.0. Example 33 l-l(3~Jhm7yJo\y-5-me{hyIphinio\y)nic{ltyij-lJ-iycloivoi)yle(ho\y^ii(uu(liiu' :|) |-|(3-IJL'ir/.yl"xy-5-mt'lliylplH'iinxy)itu'(liyl|-l,l-cyclopr"pyk1iIiaiiol: The title compound was prepared in 72% yield from 3-benzyloxy-5-melhylphenol. as prepared in step a of Example 20, in a manner analogous to step b of Example 11. 'H-NMR (300 MHz, CDC13) 5 7.34-7.44 (m, 5H), 6.43 (s, 1H), 6.37 (s. 1H), 6.36 (s, 1H), 5.02 (s, 2H), 3.89 (s, 2H), 3.63 (s, 2H), 2.29 (s, 311), 0.63 (s, 41 J). b) N-{l-|(3-Bcnzyloxy-5-iiieihylphenoxy)mcthyll-l,l*cyc1opropy]cthoxy}phthalimide: The title compound was prepared in 72% yield from l-f(3-bcnzyloxy-5-methylphenoxy)methylJ-Kl-cyclopropylcthanol, as prepared in the preceding step, in a manner analogous to step a of Example 11. '11-NMR (300 MHz. CDCI3) 5 7.81 (in. 211). 7.73 (m, 2H), 7.31-7.45 (m, 51-I), 6.44 (s, HI). 6.43 (s, III), 6.41 (s, HI), 5.03 (s, 211), 4.23 (S, 2H), 4.09 (s, 21 i), 2.29 (s, 311), 0.71 (m. 411). - 109 - c) l-[(3-Bcnzyloxy-5-nictliylphcnoxy)nicthyl]-l,l-cyclopropylcthoxynniine: A solution ofA^-{l-[(3-bcnzyloxy-5-metliylphcnoxy)mcthyl]-l,l-cyclopropylclhoxy}phthalimide(4I9 mg, 0.945 mmol, as prepared in the preceding step), telrahydrofuran (3.5 mL), ethanol (25 mL), and 40% aqueous mcthylaminc (0.81 mL, 9.45 mmol) was stirred at ambient temperature for 1 hour and then concentrated in vacua. After stirring the residue with 15 ml, of 8:2 clhyl acclalc/hexane, the mixture w;is filtered ;tnd the filtrate \v:is concentrated. The product was purified by Hash column chromalography (1:1 ethyl acctate/liexane) to give the title compound (271 mg, 92%) as a colorless liquid. 'H-NMR (300 MHz, CDC13) 5 7.32 - 7.45 (m, 5H), 6.41 (br s, 1H), 6.39 (t, 1H, J = 2.2 Hz), 6.37 (br s, 1H), 5.44 (br s, 1H), 5.02 (s, 2H), 3.84 (s, 2H), 3.69 (s, 2H), 2.29 (s, 3H), 0.64 (s, 4H). Mass spectrum (MALD1-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C19H23NO3: 314.2 (M +1 H), 336.2 (M + Na). Found: 314.3.336.3. d) l-|(3-HcMi/ylo\y-5-invtIiylphLMioxy)iiicniyl]-l,l-cyclopropylc(hoxygii:iiiidiiic: A solution of l-[(3-benzyloxy-5-mcthylphcnoNy)methyl]-l,l-cyclopropylclIioxyamine (245 mg, 0.782 mmol), as prepared in the preceding step, 1 //-pyrazole-l -carboxamidine hydrochloride (22S mg, 1.56 mmol) and A'.A'-dimelhylfonvKimide (5 ml.) was stirred overnight at ambient temperature. The reaction mixture was concentrated in vacua, and the residual colorless oil was dissolved in acetonilrile (5 mL). The mixture was filtered, the collected solid was discarded, and the filtrate was concentrated. The crude product was partitioned between dilute aqueous HC1 (15 mL, pH 2) and diethyl ether (10 mL). The aqueous layer was extracted again with diclhyl ether (10 mL), and the ether layers were discarded. The aqueous layer was neutralized (pi I 6-7) with 2N aqueous NaOll and extracted with ethyl acetate (2 x 25 mL). The combined ethyl acetate layers were washed with brine, dried over Na,SO,,, filtered and evaporated. The product was purified by Hash column chromatography (7% to 10% methanol in dichloromethane) to give the title compound (123 mg, 44%) as a while solid. 'll-NMR (300 MHz. CD,OD) 6 7.26 - 7.43 (m, 5H), 6.41 (br s, III), 6.35 (br s, 1 H), 5.01 (s, 211), 3.89 (s, 2H), 3.77 (s, 2H), 2.25 (s, 3H), 0.64 (s, 411). Mass spectrum (MAL1)1-TOI\ a-cyano-4-hydroxycinnamic acid matrix) calcd. for C20H25N3O3: 356.2 (M + H), 378.2 (M + Na). Found: 356.1.378.1. -110-Example 34 {3-l5~Mcthyl~3-hi\(2-mctlio\ycthyl)aniinosulfony!phciiylsulJonylo\y)f)hc propoxy/guanidine hydrochhride a ) N,NM"is-/t'/7-butyloxycarbonyl)-{3-(5-inctliyl-3-bis(2-niothoxy(.'(hyl) aiiiiiiosuir"iiyl|>licnylsulfoiiylo.\y)plicnoxy]pnipo.\ygu;uiiiiiiic: The title compound was prepared in 29% yield from bis(2-mclhoxyclhyl)aminc in a manner analogous to step h of Example 20. 'H-NMR (300 MHz, CDC13) 5 9.05 (s, 1H), 8.28 (dd, J - 4.9, 13 Hz, IH), 8.10 b) {3-|5-MctliyI-3-bis(2-mctlioxycthyl):iininosulfoiiylphcnyIsuiroiiylo\y)pliciioxy] propoxy}giuinidinc hydrochloridc: The title compound was prepared in 87% yield from yV,VV'-(bis-/(;/7-biityl()xyciirbonyl)-{3-[5-nictliyl-3-bis(2-methoxyethyl)aniinosiiiroiiyl phenylsulfonyloxy)phenoxy]propoxy}guanidine, as prepared in the preceding step, in a manner analogous to step i of Example 20. 'H-NMR (300 Mil/, CDC I.,) o" 8.24 (d. .1 = 6.6 Hz, IH), 8.18 (d, J - 7.6 Hz, IH), 7.69-7.79 (m. 2H), 6.64 (br s, 1 H), 6.59 (br s, 2H), 4.08 (m, 2H), 4.00 (m, 211), 3.65 (br s, 4I-I), 3.52 (br s, 4H), 3.27 (s, 6!l), 2.25 (s, 311), 2.09 (m, 2H). Mass spectrum (MALD1-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C23H34N4O9S2: 575.2 (M + H), 597.2 (M + Na). Found: 575.1, 597.3. Example 35 {3-l5-I\tetliyl-3-(N-ethyl-3,4-(methylenedio.\y) anUmosulfonylpheiiylsulfonyIoxy)phenoxyJpropoxy}guaitidine hydrochhride a) yV,/V'-(l?is-/err-bulyIoxycarl>onyl)-{3-15-mciliyl-3-(Ar-c*Iiyl-3,4-(inc(hylcncdioxy) anilinosulfonylphcnylsulfonyloxy)phcnoxy]propoxy}guanidine: The title compound was prepared in 35% yield from A'-cthyl-3.4-(mcthylencdioxy)aniline in a manner analogous to step h of Example 20. 'H-NMR (300 MHz. CDC13) 5 9.07 (s. Ill), 8.09-8.14 (m. Ill), 7.83-7.88 (m, IH), 7.71 (s, 111), 7.52-7.61 (m, 211), 6.71 (d. .1 - 1.8 IIz. Ill), 6.56-6.66 (m, 511). 5.95 (s, 2M), 4.12 (q, .1 = 7.0 IIz, 411). 3.94 (q. .1 - 6.9 Hz. 411), 2.26 (s, 311), 2.09 (pentet, 2H, J = 6Hz), K49 (s, 1811), 1.16 (t. J = 7.1 Hz. 311). - Ill - b) {3-[5-Mcthyl-3-(Af-cth)i-3,4-(inctli)icnctlioxy)anilinosiilfonylplicnylsulfonyloxy) plicu("xy||>r 3.85-4.07 (m, 6H), 2.23 (s, 3H), 2.08 (m, 2H), 1.14 (t, J = 7.1 Hz, 3H). Mass spectrum (MALD1-TOI7, rx-cyano-4-hydroxycinnamic acid matrix) calcd. for C26H30N4OyS2: 607.2 (M + H), 629.1 (M + Na). Found: 607.0, 629.1. Example 36 {3-(5-Methyl-3~(2-N-methyI-(3y4- b) {3-15-Mcthyl-3-(2-A'-iiictliyl-(3,4-(Iiine(h()xyp!icny])c(hylainiiiosuI(oii)lphL'iiyl 'sulfonyloxy)|}|]ciioxy|propoxy}f>uiiiiidiiic hydrochloridc: The title compound was 'prepared in 63% yield from A',A/'-(bis-/c'/7-bulyIoxyeaibonyl)-{3-l5-mcthyI-3-(2-A^methyl-(3,4-dimclhoxyphcnyl)elliylaniinosulfbnylplicnylsuironyloxy)phenoxy|pmpoxy}gunnidinc, as prepared in the preceding step, in a manner analogous to step i of lixamplc 20. 'l I-NMR (300 MHz, CDC13) 8 10.85 (s, 1H), 8.11 (m, 2H), 7.75 (t, J = 7.0 Hz, 1H), 7.66 (t, J = 7.5 Hz, IH), 6.53-6.76 (m, 611), 4.06 (t, J - 5.4 I Iz, 211), 3.96 (t, J = 5.5 IIz, 2H). 3.83 (s, 6H), 3.55 (t, J = 7.5 Hz, 2H), 2.97 (s, 3H), 2.84 (t, J = 7.0 Hz, 2H), 2.23 (s, 3H), 2.06 (m, 2H). Mass spectrum {MA1.D1-TOI7, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C^H^N.O.S,: 637.2 (M + 11), 659.2 (M + Na). Found: 637.3, 659.5. - 112- Example 3 7 {3~l5-MetItyI-3-((3-e1hoxycarbonyI-I-piperidinosulfonyl)phenylsulfonyloxy)phenoxyjpropoxy}guanidhie hydrochloride a) Ar,N'-(I}is-/6'/-/rl>utyloxycaii}niiyl)-{3-(5-incihyI-3-((3-ctIio\ycaii>onyl-l- pipcridinosu]fonyl)phcnylsulfonyloxy)phcnoxy]propoxy}guanidinc: Thetitlecompound was prepared in 51% yield from ethyl nipeeotate in a manner analogous to step li of Example 20. Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnaniic acid matrix) calcd. for C35H50N4Ol3S2: 599.3 (M -2 /-BOC + 3H). Found: 599.5. b) {3-[5-Mc(liyl-3-((3-ctlioxyc;"rbonyl-l-pipcridinosulfonyI)phcnyIsulfonyloxy) phcnoxy]propoxy}guanidine hydrochloride: The title compound was prepared in 63% yield from ^^'-(bis-Ze/V-butyloxycarbonylJ-IS-tS-methy'l-S-CCS-elhoxycarbonyl-l- piperidinosulfonyl)phenylsulfonyloxy)phenoxy] propoxyjguanidine, as prepared in the preceding step, in a manner analogous to step i ol'UNample 20. Ml-NMR (300 Mil/,, CDCI3) 5 10.84 (s, 1H), 8.22 (dd, J = 7.9, 1.3 Hz, 111). 8.15 (dd, J = 7.9, 1.3 Hz, III), 7.80 (td, J = 7.7, 1.3 llz. 111), 7.6X (id, J *= 7.7, 1.3 11/, 111). 6.57 (m. 111), 6.51 (in. 211). 4.03-4.12 (m, 4H), 3.90-3.97 (m, 311). 3.75 (m, 111), 2.97-3.05 (m, li 1), 2.83-2.90 (m, 1H), 2.57-2.66 (m, 1H), 2.22 (s, 311), 2.02-2.14 (m, 311), 1.48-1.79 (m, 311), 1.21 (1,¦ J -7.0 llz, 311). Mass spectrum (MALDI-TOF. a-cyano-4-hydroxycinnamic acid matrix) calcd. for C25H3^N4O9S2: 599.2 (M + H), 621.2 (M I- Na). Found: 599.0. 620.9. Example 38 {3-{5~Meihyl-3-((3~carboxypiperidinositlf(>nyl)phettylstilfanyloxy)phenoxy]propoxy} gtianidine hydrochloride A solution of {3-[5-inelhyl-3-((3-ethoxycaibonyl-l-pipeiidinosulfonyl)phenyl sulfonyloxy)phenoxy]propoxy}guanidine hydrochloride (0.056 g, 0.09 mmol), as prepared in the preceding step, in mclhano! (3 ml,) and 0.25N NaOI I (1.5 mL) was stirred at ambient temperature for 2 h. The mcthanol was evaporated. The concentrate was diluted with water, washed with dichloromcthane and adjusted to pi I 7 with 10% MCI. The aqueous layer was extracted with ethyl acetate (4 x 10 mL). The ethyl acetate extracts were combined, washed with brine, dried (Na?SOj), and evaporated to dryncss to give the title compound as a white solid (0.035 g, 69% yield). Ml-NMR (300 MHz. CDC13/ DMSO-d6) 5 8.07 (dd, J = 7.9, 1.1 Hz, 1H), 8.00 (dd,J = 7.9, 1.3 II?.. Ill), 7.81 (td, J = 7.7, 1.4 Hz, III). 7.65 (td. J = 7.7, 1.2 - 113- Hz, IN), 6.79 (s, III), 6.60 (s, 1M), 6.30 (I. J = 2.0 Hz, 111). 3.92-4.02 (m, 511). 3.73-3.84 (m, 111), 2.94-3.04 (in. 211), 2.40-2.47 (in, 111), 2.33 (s, 311), 1.85-2.16 (in, 411), 1.51-1.73 (m, 2H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) caicd. for C23H30K,O Example 39 {3-(5-MethyI-3-((2-mcthoxycarbonyll-pyrrolidinosulfonyI) phenylsulfony!oxy)phenoxy]propoxy}gu(widine hydrochloride a) 7V,A"-(Bis-/t'//-bu(yloxycarbonyl)-{3-[5-mcthyl-3-((2-incthoxyciuboiiyl-l- pyrrolidinosulfonyl)phcnylsulfonyloxy)plicnoxy]propoxy}guanidinc: The title compound was prepared in 35% yield from L-pioline mcliiyl ester hydrochloride in a manner analogous to step h of Example 20. 'H-NMR (300 MHz, CDC13) 5 9.05 (s, 1H), 8.36 (dd,J = 7.9, 1.3 Hz, HI), 8.11 (dd, J = 7.9, 1.3 Hz, 1H), 7.76 (Id, J - 7.6, 1.3 Hz, IH), 7.60- 7.68 (m, 2H), 6.51-6.56 (m, 3H), 4.79 (dd, J = 8.3, 2.8 Hz, 1H), 4.15 (t, J - 6.2 Hz. 2H), 3.91 (Id, J = 6.2, 1.3 11/, 211), 3.62 (s, 311), 2.2-2.30 (m, 411), 1 .'M-2.17 (in, 711). 1.47 (s, 18H), 1.24 (t, J = 7.1 Hz, 211). b) {3-|5-Mf(liyl-3-((2-iiH'lhoxyt:u 'Imnyl-l-pyi on"lidinnsiiir"inyl)plii*nylsiiirniijinxy) plicnoxy]propoxy}guanidinc hydrochloride: The title compound was prepared in 45% yield from A/,W-(bis-/e/7-butyIoxycarbonyl)-{3-[5-methyl-3-((2-mcthoxycarbonyl-l- pyrrolidinosulfonyl)phenylsulfony)oxy) phenoxy]propoxy}guanidine, as prepared in the preceding step, in a manner analogous step i of Example 20. 'H-NMR (300 MHz, CDC13) 5 8.35(dd,J-7.9, 1.3 Hz, 111), 8.19 (dd, J = 7.9, 1.3 Hz, 1H), 7.84 (Id, J = 7.7, 1.3 Hz, IH), 7.71 (td, J = 7.7, 1.3 Hz, IH), 6.57-6.66 (m, IH), 4.78 (dd, J = 8.3, 2.6 Hz, IH), 4.08 (t, J = 5.8 11/, 211), 3.99 (I, .1 5.8 11/., 211), 3.00-3.66 (in, 411). 3.42 (in, 111). 2.25 (s. 311), 1.91 -2.20 (m, 4H). Mass spectrum (MALOl-TOF. a-cyano-4-hydroxycinnamic acid matrix) calcd. forC23ll3))N,Ol)S:: 571.2 (M -Ml). 593.1 (M -f Na). Found: 571.0. 593.3. Example 40 {3-(5-MethyI-3-((2-carboxy-l-pynolidinositifonyl) phcnylsulfonyloxy)phenoxy]propnxy}gtiaiiidine hydrochloride A solution of {3-[5-inelhyl-3-((2-carboxy-l-pyrrolidinosulibnyl)phcnylsulfonyloxy) phenoxy]propoxy}guanidinc hydrochloride (0.037 g, 0.065 mmol). as prepared in the - 114- preceding step, in melhanol (3 mL) and 0.25N NaOH (1.0 mL) was stirred at ambient temperature lor 2 h. The mcthanol was cvapmalal. The eoncenlnile was diluted willi water, washed with dichloromethane, and adjusted to pi I 7 with 10% MCI. The aqueous was extracted wilh ethyl acelale (4 x 10 ml,). The ethyl acetate extracts were combined, washed with brine, dried, and evaporated to dryness to give the title compound as a white solid (0.015 g, 43% yield). 'I I-NMR (300 MM/., CDCV DMSO-dJ 6 8.41 (d. J - 7.0 11/., 111), 8.05 (dd,J = 7.8, 1.0 Hz, 1H), 7.79 (td,J = 7.7, 1.2 Hz, lH),7.64(t, lH),6.72(s, 1H),6.6O (s, 1H), 6.49 (s, 1H), 4.60 (dd, J - 7.7, 2.9 Hz, III), 3.88-4.03 (m, 4H), 3.54-3.67 (m, 2H), 2.30 (s, 3H), 1.94-2.27 (m, 6H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C22H2gN4O9S2: 557.1 (M + H), 579.1 (M + Na). Found: 557.0, 579.0. Example 41 {3-l5-Mefhyl-3-(N-metltyl-N-etItoxycarb(Miy!niefhyl)aniinosulfonylpltenylsulfonyloxy) plienoxyjp/vpoxy/guanicline hydrochloride a) 7V,Af'-(nis-/(.'/7-l)iityloxyearl)nnyl)-{3-|5-int.'thyl-3-(A/-inclhyUA'- cihoxycarbonyliiictliyl):iininusulf(MiylphcnylsiiironyIoxy)phciioxyJpropu\y}gii"iiidinc: The title compound was prepared in 67% yield from sarcosine ethyl ester hydrochloride in a manner analogous to step h of Example 20. 'M-NMR (300 MHz, CDClj) 5 9.08 (s, 1M), 8.37 (dd, .1 = 7.9, 1.3 11/, 111), 8.14 (dd, J - 7.9. 1.3 llz. Ml), 7.81 (dt, J - 7.7. 1.4 llz. 111), 7.64-7.73 (m, 21-1), 6.51-6.59 (m, 311), 4.09-4.20 (m, 4H), 3.94 (t, J - 6.2 llz, 21-1), 2.99 (s, 3H), 2.26 (s,3H), 2.06-2.15 (m,2H), 1.49 (s. 18H). 1.20-1.28 (m,5H). 1>) {3 -1 5 - M e t li y I' - 3 - (N - in c t h y 1 - TV - e t h o x y c n r b o n y Im c t h y I) aminosulfonylphenylsulfonyloxy) phenoxy | propoxyjguanidinc hydrochloride: Hie title compound was prepared in 72% yield from A',A'-(Bis-/e/7-butyloxycarbonyl)-{3-[5-methyl-3 - (N- m e t h y 1 - A^- e t h o x y c a r b o n y 1 m e t h y 1) a m i n o s u 1 f o n y I p h e n y 1 s u 1 f o n y I o x y) plicnoxy]propoxy}jiuaniditK\ as jTrcparcd in the preceding step, in a manner analogous to step i of Example 20. 'I I-NMR (300 MHz. CDC13) 5 8.34 (dd. J = 7.9, 1.3 Hz, 1H), 8.18 (dd, .1 = 7.9, 1.3 Hz, 111). 7.S5 (Id, .1 -7.7, 1.3 11/., III). 7.71 (Id. .1 -7.7. 1.3 llz. 111). 6.64 (s, 1H), 6.59 (s, 1H), 6.54 (t, J - 2.0 Hz, 1H)S 4.27 (s, 2H), 4.06-4.17 (m, 4H)f 3.98 (tf J = 5.7 Hz, 2M), 2.99 (s, 311). 2.25 (s. 311). 2.06-2.17 (m. 211). 1.22 (t, J - 7.2 Hz, 311). Mass spectrum (MALDl-TOF, ct-cyano-4-hydroxycinnamic acid matrix) calcd. for C22H30N4O9S2: 559.2 (M + H), 581.1 (M + Na). Found: 559.2, 581.2. - 115- Exmnple 42 {3-lS-MetItyl-3'(N-iitethyl-N-ethoxycarhoiiyhnethyl)anmwsitlfonylph^ phenoxyjpropoxyfguanidine hydrochloride A solution of {3-i5-mclhyl-3-(A^-niclliyl-A/-cthoxyc;irbonylmclhyI) aminosulfonylphenylsulfonyloxy)phenoxy]propoxy}guanidinchydrochloride(0.076g,0.136 mmol), as prepared in (he preceding step, in niethanol (3 mL) and 0.25N NaOIl (1.5 mL) was stirred at ambient temperature for 2 h. The methanol was evaporated. The concentrate was diluted with water, washed with dichloromethane, and adjusted to pH 7 with 10% HC1. The aqueous was.,extracted with ethyl acetate (4 x 10 mL). The ethyl acetate extracts were combined, washed with brine, dried, and evaporated to dryness to give the title compound as a white solid (0.055 g, 76% yield). 'H-NMR (300 MHz, DMSO-d6) 5 8.26 (dd, J - 7.9, 1.3 Hz, 1H), 8.11 (dd, J = 7.9; 1.3 Hz, 1H), 7.99 (td. J = 7.7, 1.2 Hz, 1H), 7.85 (id. J = 7.7, 1.2 llz, III), 6.74(m, 1 II), 6.47-6.56(m, 211), 4.13 (s, 211), 3.97 (t, .I = 6.2 11/., 211), 3.89 (t, J = 6.2 Hz, 2H), 3.34 (s, 3H), 2.22 (s, 3M), 1.96-2.02 (m, 2H). Mass spectrum (MALDI-TOF, (x-cyano-4-1iydroxycinnaniic acid matrix) cnlcd. for C\()IL,,N.,O,,S;: 531.1 (M + ! 1). 553.1 (M+Na). Found: 531.3,553.3. Example 43 3-l5-Mefhylr3-(2-(4-methylsiilfoiiyIi)iperaziit-I-ylsiilfonyl)i)henylsulfofiyloxy) phenoxy] propoxyjguanidine hydrochloride a) Ar,/V-(I}is-/er/-butyloxycarbonyl)-{3-|5-incthyl-3-(2-(4-mcthylsulfoiiylpipcrazi/i-1-y)sulfoiiy|)phcii) Isulloii} lox))plKiinxyj|>rnpnxy}^iiaiiiilino: lo a solution ol 1,2-benzenedisulfonic anhydride (440 mg, 2.0 mmol), as prepared in step g of Example 20, and TV.A'-diisopropyiclhylaminc (720 (L, 4.0 mmol) in dichlorometluinc (20 mL) was added (A;-melhylsulfonyl)p[perazine hydrochloride (400 mg, 2.0 mmol). After stirring the mixture for 4 h at ambient temperature, oxalyl chloride (160 (L, 2.0 mmol) and 5 drops of N,N-dimclhylformamidc were added. The mixture was stirred for another 4 h. (A^A^-bis-Zcr/-bulyloxycarbonyl)-{3-|(3-liydi"oxy-5-mcthyl)phcnoxy)propoxy}guanidinc (560 mg. 1.4 mmol), as prepared in step f of Example 20. and A'.A'-diisopropylcthylainine (360 (L, 2.0 mmol) were added to the mixture. The mixture was stirred at ambient temperature overnight. Additional dichloromeihanc (100 mL) was added and the solution vas washed with 10% citric acid (3 x 50 mL), brine (50 mL). and dried over Na2SO.+ Alter the solvent was evaporated n vacua, the residue was purified by Hash column chromatography - 116- (dichloromethanc to 5% ethyl acetate in diehloromcllumc) to give the title compound as a colorless foam (1.0 g, 89%). 'H-NMR (300 MHz, CDCI3) 5 9.08 (s. 111), 8.31 (d, .1 = 7.9 Hz, 1H), 8.18 (d, J -7.9 Hz, 1H), 7.82 (t,.! = 7.8 Hz, 1H), 7.72 (t, J - 7.7 Hz, 2H), 6.60 (s, 1H), 6.54 (s, 1H), 6.48 (s, 1H), 4.18 (t, J = 6.1 Hz, 211), 3.95 (t, J = 6.2 IIz, 211), 3.52 (m, 4M), 3.31 (m, 4H), 2.78 (s, 3H), 2.24 (s, 3H), 2.11 (t, J = 6.2 Hz, 2H), 1.49 (s, ] 8H). h) 3-|5-McUiyl-3-(2--(4-iiiclhylsiiirii3ipipcra/.iii-l-yIsiiHnn}i)phciiylsiiUoii)ioxy) phcnoxy]propoxy}guani(Iinc hydrochloridc: To a solution of N,N'-(his-tert~ butyloxycarbonyl)-{3-|'5-methyl-3-(2-(4-methylsulfonylpiperazin-l -ylsulfonyl) phenylsulfonyld'xy)phcnoxy]propoxy}guanidinc (725 mg. 0.9 mmol), as prepared in the preceding step, in dichloromethane (20 mL) was added trifluoroacetic acid (5 ml). The mixture was stirred at ambient temperature for 3 h, the solvent was evaporated in vacua. The residue was dissblved in dichloromethane (100 mL), washed with 2N K2CO3 (2 x 50 mL) and dried over Na2SO4. Alter evaporated the solvent, the residue was converted to the 11CI $alt (1 eq. methanolic HC1 and concentration) and purified by flash column chromatography (10 % mclhanolin dichloromethane) to give the title compound as a colorless foam (530 mg,91%). lll-NMR(300MMz,DMSO-d(,)cS 10.97 (br s. Ill), 8.22 (d, .1 - 7.9 Hz, 111). 8.17 (d, J = 7.9 11/., Ill), 8.03(1, .1 = 7.7 11/,, 111), 7.91 (t, J - 7.7 11/.. 211), 7.23 (hr s, 411), 6.75 (s, 1H), 6.52 (s, 1H), 6.49 (s, 1H), 3.98 (U J = 6.3 Hz, 2H), 3.88 (t, J = 6.3 Hz, 2H), 3.42 (m, 4H), 3.20 (m, 411), 2.91 (s, 311), 2.22 (s, 311), 2.00 (pentet, .1 = 6.3 Hz, 211). Mass spectrum (MALDI-TOF, ri-cyano-4-hydroxycinnamic acid matrix) calcd. forC^I^NjC^S;,: 606.1 (M + H), 628.1 (M + Na). Found: 605.9, 628.1. i Example 44 {3-l5-Metliyl-3-(2-(4-(2-pyrimidhtyl)piperazin-l-ylsulfonyl)pheuytsulf i WiTV-diisopropytethylamine (90 (L, 0.5 mmol) in dichloromethane (10 mL) was added 2-(l-piperazinyl)pyrimidinc (82 mg, 0.5 mmol). After stirring the mixture for 4 h at ambient temperature, oxalyl chloride (40 (L. 0.5 mmol) and 2 drops of A'.A'-dimcthylformamide were added. The mixture was stirred for another 4 h. (A7,/V'-Bis-/(77-lHityUixycarbonyl)-{3-|(3- -117- hydroxy-5-methyI)phcnoxy)propoxy}guanidine (180 ing, 0.4 nunol), ns prepared in slop f of Ilxamplc 20, and A'.A'-diisopropylethylamine (ISO (L, 1.0 nnnol) were added to (he mixture. The mixture was stirred at ambient temperature overnight. Additional dichloromcthanc (50 mL) was added, washed with 10% citric acid (3 x 20 ml,) and brine (20 mL), and dried over Na2SO4. After the solvent was evaporated//? vacua, the residue was purified on a Waters Scp-Pak ( 5 g silica, 3 :1 hcxanc : ethyl acetate) to give the title compound as a colorless foam (185 mg, 64%). 'H-NMR (300 MHz, CDC13) 5 9.08 (s, 1H), 8.29 (d, J = 4.8 Hz, 1H),8.17 (d, J = 8.0 Hz, 1H), 7.81 (t, J = 7.7 Hz, 1H), 7.70 (m, 2H), 6.59 (s, 1H), 6.57 (s, 1H), 6.52 (s, 1H), 6.49 (s, III), 4.18 (t, J = 6.2 Hz, 2H), 3.93 (m, 6H), 3.43 (m, 4H), 2.24 (s, 3H), 2.10 (pentet, J = 6.2 Hz. 211), 1.49 (ss 18H). b) 3-|5-Mctliy]-3-(2-(4-(2-pyrimidiiiyl)pipcnizin-l-yIsiiiruiiyl)pliciiyIsuironyIfi\y) phcnoxylpropoxygunnidinc liydrochloridc: To a solution of A/,7V'-(bis~/e/V-butyloxycarbonyl)-{3-[5-methyl-3-(2-(4-(2-pyrimidinyl)pipcrazin-)-ylsulfony!)phenyl sulfonyloxy)phenoxy]propoxy}guanidine (170 mg, 0.235 mmol), as prepared in the preceding step, in dichloromclhane (6 ml,) was added trifluoroacctic acid (3 mL). The mixture was stirred at ambient temperature for 2 h. the solvent was evaporated //; vacuo. The residue was dissolved in dichloiomethane (50 ml.), washed with 2N KX'O-, (2 x 30 mL) and dried overNa2SO^ After evaporated the solvent, the residue was converted to the HCI salt by HCI mcthanol to give the title compound as a colorless foam (140 mg. 93%). 'H-NMR (300 MHz, DMSO:-d6) 5 11.09 (s, III), 8.38 (d, J = 5.0 Hz, 2H), 8.16-8.24 (m, 2H), 8.01 (t, J = 7.7 Hz, 1H), 7:90 (t, J - 7.7 Hz, 2I-I), 7.69 (br s, 4H), 6.74 (s, 1H), 6.68 (t, J - 4.8 Hz, 1H), 6.54 (s, 1H), 6.51 (s, 1H), 3.99 (t, J = 6.2 Hz, 2H), 3.90 (t, J - 6.3 Hz, 2H), 3.83 (m, 4H), 3.36 (m, 4H), 2.22 (s, 3H), 2.01 (pentet, J - 6.3 Hz, 2H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxyeinnamic'acid matrix), calcd. for C25ll3,N7O7S2: 606.2 (M + 11), 628.2 (M +Na). Found: 606.0, 627.9. - 118-Examplc 45 3~l5-Methyt-3-(2-(N-methyl-N-(2-(2-pYri(lyI)ethyI)aniinosulfoiiyl)[)ltL>ny pftenoxyfpropoxygua/tidine dihydrochtoride a^A^Bis-fcrZ-lMityluxycartM^^^ aniinosulfonyl)plicnylsulfoiiyloxy)phcnoxyjpropo\y}guanidinc: The title compound was i prepared in 67% yield from 2-(2-mcmylaminocthyl)pyridine in a manner analogous to step h of Example 20. 'H-NMR (300 MHz, CDC13) 5 9.08 (s, 1H), 8.44 (d, J = 4.9 Hz, 1H), 8.21 (d, J - 7.9 Hz, 1H), 8.10 (d, J = 7.9 Hz, 1H), 7.77 (d, J - 7.7 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.11 (m, 1H), 6.58 (s, 1H), 6.56 (s, 1H), 6.50 (s, 1H), 4.17 (1, J = 6.2 Hz, 211), 3.92 (t, J = 6.1 Hz, 2H), 3.75 (I, J - 7.4 I Jz, 211), 3.1 1 (l, J = 7.5 I Iz, 211). 2.96 (s, 311), 2.22 (s, 311). 2.09 (pcnlcl, J = 6.2 Hz,2H), 1.49 (s, 18H). b) 3-|5-Mcl]iyl-3-(2-(A^-mcthy1-^-(2-(2-pyridyI)clhyl)siiiiiiiosiilloiiyI) phenylsulfonyloxy) phenoxyjpropoxyguanidinc dihydrochloridc: The title compound was prepared in 89% yield from A7,N'-(bis-^c/7-biilyloxycarboiiyl)-{3-[5-mcthyl-3-(2-(A^- j methyl-//-(2-(2-py ridy l)cthy 1 )am i nosul fony I )pheny 1 sul fony 1 oxy) phcnoxy]propoxy}guanidine, as prepared in the preceding step, in a manner analogous to step i of Example 20. 'II-NMR (300 Ml Iz. DMSO-d6) 6 11.14 (br s, 2H), 8.58 (d, J = 4.5 Hz, 1H), 8.10 (d, J - 7.8 I Iz, HI), 8.06 (d. .1 - 7.8 Hz, III). 7.98 (t. .1 - 7.7 Hz, 2H), 7.57 (t, J = 7.6 Hz, 111), 7.71 (br s, 411), 7.56 (br s. Ill), 7.47 (m, 111), 6.74 (s. 111), 6.51 (s, 111), 6.46 (s, 1H), 3.97 (t, .1 = 6.2 Hz, 2H), 3.90 (t. J - 6.2 Hz, 2H), 3.74 (t, J - 7.3 Hz, 2H), 3.17 (U = 7.I Hz, 211), 2.98 (s, 311), 2.21 (s. 311). 2.01 (pcnlct, J = 6.2 Hz, 211). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C25H3[N5O7Sj: 578.2 (M i: + H), 600.2 (M + Na). Found: 578.2, 600.0. K^ - 110- Exumple 46 3-l5-Methyl-3-(2-(N-propyl-N-(2-(2-pyridyl)ethy!)iiminosuljony0 phenoxy/propoxyguaitidine dihydrochloride :i)A^f-(B>s-/tTM>Hlyloxyc;u-l>oiiy0^ aminosuir"nyl)plicnylsuli'onyloxy)plicnoxy]pn>poxy}gu;inidinc The title compound was prepared in 53% yield from 2-|2-(A/-propylaniino)etliylJpyridinc in a manner analogous lo step h of Example 20. 'H-NMR(300 MHz, CDC13) 5 9.08 (s, 1H), 8.43 (dj = 4.9Hz, 1H), 8.22 (d, J = 7.9 Hz, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.75 (m, 3H), 7.61 (t, J - 7.7 Hz, 1H), 7.32 (m, 2H), 7.20 (m, 2H), 6.56 (s, 2H), 6.51 (s, 1H), 4.17 (t, J = 6.2 Hz, 2H), 3.92 (t, J -6.1 Hz, 2H), 3.82 (t, J - 7.4 Hz, 2H), 3.39 (t, J = 7.5 Hz, 2H), 3.15 (t, J = 6.6 Hz, 2H), 2.15 (s,3H),2.09(l,J = 6.1 Hz,2H), 1.61 (m, 211), 1.49 (s, 18H), 0.84 (pentel, J - 7.4 Hz, 3H). b)3-I5-IVJcthyl-3-(2-(/V-propyl-A^-(2-(2-pyrit]y1)ethyl)aminosulfonyl)phcnylsuIfonyloxy) phcnoxy]propoxyguiinidiiic dihydrocliloridc: The title compound was prepared in 89% yield from A/,W-(bis-/t?/7-butylo\ycarhonyl)-{3-[5-mcthyl-3-(2-(A?-propyl-A'-(2-(2-pyridyl)ethyl)auiiiu)siillbnyl)plienylsullbnyloxy) phenoxy|piopoxy }guanidine, as prepared in the preceding step, in a manner analogous to step i of Example 20. 'J-I-NMR (300 MHz, DMSO-d6)o" 11.08(brs, 211), 8.43 (d, .1 -4.0 !lz. Ill), 8.11 (d. J -7/) Hz. 111). 8.09 (d, J - 7.7 Hz, 1H), 7.95 (t, J = 7.7 Hz, 1H), 7.84 (t, J = 7.7 Hz, 1H), 7.68 (br s, 5H), 7.27 (m, 2H), 6.73 (s, 1H), 6.53 (s, 1H), 6.49 (s. \\\), 3.97 (t, J = 6.2 Hz, 2H), 3.89 (t, .1 = 6.3 Hz, 2H), 3.71 (t, J = 7.8 Hz, 2H), 3.34 (t, J - 7.5 1 Iz. 2H), 3.01 (i, J - 7.6 llz. 2H). 2.20 (s, 311), 2.00 (pcnlet, J - 6.2 llz, 211), 1.52 (m. 211), 0.77 (t. J - 7.4 Hz. 3H). Mass spectrum (MALD1-TOF, a-cyano-4-hydroxyeinnamic acid matrix) calcd. for C271 l.i5NsO7S2: 006.2 (M + H), 628.2 (M + Na). Found: 606.2, 628.3. I Example 47 3-l5-Methyl-3-(2-(N-ethyl-N-(4-pyridylmethyl)anunosirffonyl)phenylsi^^ plienoxylpropoxyguaHtdine di/tydroc/iloridc a) N,-N'-("is-/c'r/-bntyloxyciirboi"yl)-(3-|5-!"c(hyl-3-(2-(Ar-clhyl-Ar-(4-pyriilylnicthyl) aminosulfonyl)plienylsulfoiiyloxy)plicnoxylpropoxy}guanidiiie: The title compound was prepared in 48%) yield from 4-(A/-cthyl)aminnmethylpyridinc in a manner analogous to step h of Example 20. '11-NMR (300 Mil/. CIX'l,) 5 9.08 (s. 111)- 8.56 (d, J = 4.7 I Iz, 211). 8.37 (d, J - 7.8 Hz, HI), 8.16 (d, J - 7.8 llz. 111), 7.77 (t, J - 7.7 Hz, 1H), 7.68 (d, J = 7.8 Hz, 2I-I), 7.28 (m, 211), 6.58 (s, 211), 6.53 (s. III). 4.70 (s, 211), 4.17 (t, J - 6.2 Hz, 2H), 3.93 (t, - 120- J - 6.1 1Iz, 211). 3.32 ((, J - 7.4 1I/,, 211), 2.23 (s, 311). 2.09 (penlct, .1 = 6.1 J Iz, 211), I .49 (s, 1811X0.94(1, .1 = 7.2 Hz, 311). b) {3-[5-Mct1iyl-3-(2-(7V-ctIiyl-7V-(4-pyriclylnicthyl)aminosulforiyl)plicnylsulfonyloxy) phcnoxy]propoxy}guanidinc dihydrochloridc; The title compound was prepared in 84% yield from A',A^'-(Bis^c/7-butyloxycarbonyl)-{3-[5-methyl-3-(2-(A^-elhyl-A(-(4-pyrkiylmcthyl)amim)siil(bnyl)phcnylsulfonyloxy) phcnoxy|propoxy}guanidinc, as prepared in the preceding step, in a manner analogous to step i of Example 20. 'H-NMR (300 MHz, DMSO-dti) ft 8.54 (d, .1 - 4.5 Ilz, 211), 8.23 (d, .1 = 7.9 11/, 1II). 8.17 (d, .1 - 7.8 1 Iz, 111), 8.01 (t, J = 7.7 Hz, 1H), 7.89 (t, J = 7.7 Hz, 1H), 7.42 (br s, 4H), 7.34 (d, J = 5.8 Hz, 2H), 6.74 (s, 1H), 6.54 (s, 1H), 6.50 (s, 1H), 4.67 (s, 2H), 3.97 (t, J - 6.3 Hz, 2H), 3.87 (t, J = 6.3 Hz, 2H), 3.36 (t, J = 7.1 Hz, 2H), 2,21 (s, 3H), 2.00 (penlct, J = 6.1 Hz, 2H), 0.92 (t, J = 7.1 Hz, 3H). Mass spectrum (MALDI-TOF, ct-cyano-4-hydroxycinnamic acid matrix) calcd. for C25H3IN5O7S2: 578.2 (M + H), 600.2 (M + Na), 616.1 (M + K). Found: 578.1, 599.9, 616.0. Example 48 3-(5-MetIiyl-3-(2-(N-iitethyt~N-(4-niL'tlioxyi)heiiyl){tniinosulfo!tyl)i)!iettyIsulfonyloxy) phenoxy]propoxyf*uanidine hydrocltloridc a)7VA4Bis-/L'/-/-lHityloxycarbonyl)-{3-[5-mctliy]-3-(2-(A'-iiicthyl-yV-(4-nictlioxyphcnyl) aminosu1fonyl)phcnylsulfunyloxy)phciioxy]propoxy}gunnidiiic: The title compound was prepared in 80% yield from A^-methyl-p-anisidine in a manner analogous to step h of Example 20. 'H-NMR (300 MHz, CDC1,) 5 9.08 (s. 111). 8.15 (d, .1 - 7.6 Hz. lll),7.78(d. J = 7.6 Hz, 1H), 7,71 (br s, 1H), 7.57 (t, J - 7.7 Hz, 211), 7.11 (d, J = 8.9 Hz, 2H), 6.77 (d, J = 8.9 Hz, 211), 6.61 (s, 111), 6.58 (s, 211). 4.18 (t, J - 6.1 Hz, 2H), 3.94 (lp J = 6.2 Hz, 2H), 3.77 (s, 311), 3.44 (s, 311), 2.23 (s, 311), 2.09 (pentet, J -6.1 I Iz, 211), 1.49 (s, 1811). b)3-|5-Mcthyl-3-(2-(/V-mc(liyl-/V-(4-mcthoxypbcnyl)aminosiilfonyl)plicnyIsiilfoiiyloxy) phciioxylpropoxy^uaiiidine bydrocliloridc: Tlie title compouiid was prepared in 92% yield from yV,A'-(Bis-/c/7-butyIoxycarbonyl)-{3-[5-methyl-3-(2-(/V-methyl-A^-(4-mctlioxyphcnyl)amhiosullbnyl)plienylsulfonyloxy)phcnoxy]propoxy}giianidinc,asprcparcd in the preceding step, in a manner analogous to step i of Example 20. 'H-NMR (300 MHz, DMSO-d6)5 11.04 (s. 111), 8.16 (d. .1-6.7 Hz, III). 7.88 (m, 31.1). 7.66 (br s, 4H). 7.16 (d. J = 8.9 Hz, 211), 6.88 (d, .1 -8.9 I lz. 211). 6.673 (s. Ill), 6.48 (s, 2! 1). 3.97 (t. J = 6.2 Hz, 211), 3.90 (t, J - 6.3 !lz, 211), 3.72 (s, 311). 3.35 (s. 311). 2.19 (s, 3H). 2.01 (pentet, .1 = 6.3 - 121 - Hz, 21-1). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C,5M3,,N4O8S2: 579.2 (M + f I), 601.1 (M -t- Na). 617.1 (M -(o K). Found: 579.1, 601.3, 6) 7.2. Example 49 3-l5-MrihyI-3-(2-(4-e1hyIpiiH>ntzin-i-y!sulfoityt) pht!nylsu!joityloxy)phenoxyjpropo.\y}>uanitliiiif tiihydiochlorhle a) Ar,Ar'-(Bis-/er/-butyloxycarbonyI)-{3-[5-nicthyl-3-(2-(4-cthylpiperazin-l-ylsulfonyl) phcny)sulfonyloxy)plienoxy]propoxy}gti:inidine: The title compound was prepared in [23% yield from /V-cthylpipcrazine in a manner analogous to step h of Example 20. 'H-NMR (300 MHz, CDC13) 5 9.08 (s, 1II), 8.20 (I, J = 8.2 I Iz, 2M), 7.80 (t, J = 7.8 Hz, 1H), 7.69 (m, 2H), 6.57 (s, 2H), 6.51 (s, 1H), 4.18 (t, J = 6.2 Hz, 211), 3.94 (1, J - 6.2 Hz, 211), 3.40 (t, J = 4.8 I Iz, 411), 2.51 (t, .1 - 4.8 I Iz, 411). 2.43 (q. J - 7.2 1 Iz, 211), 2.23 (s, 311). 2.10 (pentet, J = 6.2 Hz, 2H), 1.49 (s, 18H), 1.05 (t, J = 7.2 Hz, 3H). ib) 3-15-McthyI-3-(2-(4-cthyIpipcrazin-l-ylsulfonyl)phenyIsuIfonyloxy)plienoxy] Ipropoxyguiiiiidiiic dihydrochloridc: The title compound was prepared in 80% yield from |W,A'r-(Bis-^er/-bulyloxycai'bonyl)-{3-i5-methyl-3-(2-(4-cthylpipcnizin-I-yIsu|[bnyl) plicnylsulfonyloxy)p]>cnoxyjpropoxy}guiinidi!ie. as prepared in the preceding step, in a manner analogous to slcp i of Example 20. 'H-NMR (300 MHz, DMSO-d6) 5 11.06 (br s, 111), 10.89(brs, 111), 8.29 (d, .1 = 7.9 11/., HI). 8.19 (dj = 7.9 11/, HI), 8.07 (t, J = 7.8 11/, 1H), 7.94 (t, J = 7!7 Hz, 1H), 7.66 (br s, 4H), 6.76 (s, 111), 6.51 (s, 111), 6.48 (s, 111), 3.99 (1, J - 6.2 I Iz, 211), 3.90 (t, J = 6.3 Mz, 211). 3.52 (br s, 2H), 3.33. (br s. 4H), 3.26 (br s, 2H), 3.13 (br s, 2H), 2.22 (s, 3H), 2,02 (pentel, J = 6.2 Hz, 211), 1.21 (t, J = 7.2 Hz, 311). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C23H33N5O7S2: 556.2 (M + H), 578.2-(M + Na), 594.1 (M + K). Found: 555.9, 577.9, 593.7. * 1 -122- Example 50 3-[5-McthyI-3-(2-(N-methyt-N-(4-methoxycarbonyIphenyI)antinosuIfoHyl) pheiiylsulfonyloxy)phenoxyjpiopoxyguanid'me hydtochloride a) A',A/'-(Bis-/t'/7-bii(yloxyc;Ml>ony])-{3-|5-inc(hyi-3-(2-(A/-nio(!iyl-Af-(4- mctlioxyc"rbonylphciiyl)aniino5ulfon)i)|)liciiylsiilf'ui]yloxy)phciio\yjpropoxy} Ktiaiiidiiu': The title conipotnul \v;is prepared in S()% yield from methyl 4-mcthylaminobcnzoalc in a manner analogous to slcp h ol" Example 20. 'H-NMR (300 MHz, CDC13) 5 9.11 (s, 1H), 8.14 (d, J = 9.0 Hz, 1H), 7.94 (d, J = 8.8 Hz, 2H), 7.86 (d, J - 9.1 Hz, 1H), 7.60 (m, 2H), 7.34 (d, J = 8.8 Hz, 2H), 6.58 (s, 1H), 6.54 (s, 1H), 6.51 (s, IH), 4.18 (t, J = 6.1 Hz, 2H), 3.93 (t, J = 6.1 Hz, 2H), 3.89 (s, 3H), 3.51 (s, 3H), 2.22 (s, 3H), 2.10 (pcnlcl, J = 6.0 Ilz, 211), 1.49 (s, 1811). b) {3-|5-MethyU3-(2-(Ar-nicihyI-Af-(4-iiK'thoxyc:iibonylphcnyl)aininosu!foiiyl) j>hc'nylsuironylnx))))l)Liu>\y|prnpnx) jj;ii;tuiiliiK' liydrochloridc: The lillc compound was prepared in 92% yield from A^A^'-(Bis-/e/7-butyloxycarbonyl)-{3-[5-methyl-3-(2-(A'-methyl-^-(4Tniellioxycjirbonylphcnyl):uninosuironyl)phcnylsiilfonyloxy)phcnoxy]propoxy} guanidinc, as prepared in the preceding step, in a manner analogous to step i of Example 20. 'H-NMR (300 MHz, OMSO-d6) 6 11.07 (br s. 111), 8.17 (d, .1 = 7.5 1 Iz, 111), 7.88-7.99 (m. 5H), 7.67 (br s, 4H), 7.43 (d, J = 7.7 Hz, 2H), 6.74 (s, 1H), 6.45 (s, 2H), 3.98 (ts J = 6.2 Hz, 2H), 3.90 (t, J - 6.3 Hz, 211), 3.83 (s, 311), 3.46 (s. 3H), 2.19 (s, 3H), 2.02 (pentel, .1 - 6.2 Hz, 211). Mass spectrum (MALDI-TOF, a-cyano-4-bydroxycinnamic acid matrix) calcd. for C26H30N4O9S2: 607.2 (M + II), 629.1 (M + Na). Found: 606.9, 628.8. Example 51 3-[5-Methyl-3-(2-(N-(2-cy pyridylnic(hyl)aiiiiiiosiilfniiyl)plH'n} Isulfonylox^OplH'iinxylpropoxyJgiiiuiidint1: The title compound was prepared in 66% yield from 3-(3-pyridyImcthylamino)propionitrilc in a manner analogous to step h of Example 20. Ml-NMR (300 MI Iz. CDC!3),5 9.08 (s. i J I), 8.56 (brs, 111), 8.50 (br s, 1H). 8.35 (d, J - 7.7 Hz, 1H). 8.18 (d. J = 7.8 Hz. 1H). 7.81 (t, J-7.7 Hz, 111), 7.72 (111,311), 7.29 (t. J = 7.7 Hz, 111), 6.60 (s, 111), 6.57 (s, HI), 6.52 (s, 1H), 4.70 (s, 2H), 4.17 (t,.! - 6.2 Hz. 211). 3.94 (t. J = 6.2 Hz. 2H), 3.65 (t. J = 7.0 Hz, 2H), 2.50 (l, J = 7.0 J Iz, 211), 2.24 (s. 311). 2.12 (pentet. J = 6.3 Hz, 211), 1.49 (s, 1811). - 123- b) 3-|5-McUiyl-3-(2-(yV-(2-cy:inoclliyl)-Ar-(3-pynd)1iiic(liyl)iiiiiiiiosiilfouy0 phcnylsulfonyloxy)phcnoxy]propoxyguanidinc d.ihydrocbloridc: The title compound was prepared in 91% yield from A^Ar'-(bis-/e/7-butyloxycarbonyl)-{3-[5-methyl-3-(2-(A^-(2-cyanocthyl)-N-(3-pyridylmcthyl)aminosuironyl)plicnylsulfonyloxy)phcnoxyl propoxyjguanidine, as prepared in the preceding step, in a manner analogous to step i of Example 20. 'l I-NMK (300 Ml I/., DMSO-d,,) fi 1 1.()") (s,-!l I). K.70 Example 52 3-f5-Met/iyl-3-(2-(/VfN-bis-(2-tyanoethyl)amiiiosulfoHyl)p/iL'ny propoxyxnottit/ine hydrochloride a) 7V,/V'-(I$is-fc7Y-butyloxyc;ii^ aminosutfonyl)pliciiylsulfonyloxy)phciio\y]propoxy}gunnidinc: The title compound was prepared in 46% yield from 3,3'-iminodipropionitrile in a manner analogous to step h of Example 20. 'H-NMR.(300 MHz, CDC13) 5 9.08 (s, 111), 8.39 (d, J = 7.9 Hz, 111), 8.19 (d, J = 7.8 Hz, 1H), 7.88 (t, J - 7.7 Hz, III). 7.76 (t, J - 7.7 Hz. Ill), 7.70 (s, 1H), 6.60 (s. 1H), 6.55 (s, 111), 6.49 (s, 111), 4.17 (I, J = 6.2 Hz, 211), 3.94(1, J = 6.2 Mz, 211), 3.7S (t, J = 6.8 Hz, 4H), 2.73 (t, J - 6.8 Hz, 41-1), 2.24 (s, 311), 2.10 (pentet, J - 6.2 Hz, 2H), 1.49 (s, 18H). b) 3-|5-Mcthyl-3-(2-(A^,A'-bis-(2-cyaiinc(hyI)amiiiosulfonyl)plic.inylsulfonyloxy) phenoxy) propoxyguanidine hydrochloride: The title compound was prepared in 85% yield from MA/'-(bis-/c77-butyloxycarbonyl)-N"~{3-[5-mcthyl-3-(2-(A',vV-bis-(2- cyanoethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy] propoxy}guanidine, as prepared in the preceding step, in a manner analogous to step i of Example 20. 'H-NMR (300 MHz, DMSO-d6) 5 11.05 (br s, 1H), 8.25 (d, J = 7.9 Hz. Ill), 8.14 (d, J = 7.8 Hz, 1H), 8.01 (t, J = 7.7 Hz, 11-1), 7.90 (t, .1 = 7.7 Ilz, 111), 7.66 (br s. 411), 6.74 (s, HI), 6.54 (s, 111). 6.51 (s. 1H), 3.99 (l,;J - 6.2 Hz, 211), 3.91 (I, J - 6.3 Hz, 211), 3.71 (t, J = 6.8 Hz, 411). 2.S4 (t, J - 6.8 Hz, 4H),,2.22 (s, 311), 2.02 (pentet, J - 6.2 IIz, 211). Mass spectrum (MALDI-TO17, a- - 124 - cyano-4-hydroxycmnnmic acid matrix) c;ilcd. for C\,l i:xN(,()7S:.. 565.2 (M -i- ] 1), 587.1 (M + Nii); round: 565.2,587.0. Example 53 3-[5-Methyl-3- (2- (N- (2-elh oxycarb ony >tethy /) -N-ben z) -laininosulfon) I) phenylsulfonyIoxy)pJienoxy]propoxyguaitidine hydrochtoride n) ^N4ins-/r//-l)iHyloxyc;ir]H)iiv!)-{3-|5-iiicn)yl-3-(2-(A'-(2-i(hoxye;irltonyk(liyl)-A/-bcn/.yhiniiiiosuironyI)p]icnyLsuiroiiylo\y)phcno\y]propo\y}giianidinc: The title compound was prepared in 74% yield from W-benzyl-3-aminopropionic acid ethyl ester in a manner analogous to step h of Example 20. 'II-NMR (300 MHz, CDC13) 5 9.02 (s, 1H), 8.76 (s, 1H), 8.16 (t, J = 8.1 Hz, 2H), 7.98 (t, J = 7.7 Hz, IH), 7.88 (t, J - 7.8 Hz, 1H), 7.34 (m, 5H), 6.74 (s, IH), 6.54 (s, IH), 6.47 (s, 1H), 4.63 (s, 2H), 3.91 (m, 6H), 3.53 (t, J - 7.2 Hz, 2H), 2.37 (t,J = 7.3 Hz, 411), 2.21 (s, 311), 1.96 (pentet, J = 6.2 Hz, 211), 1.39 (s, 1SH), 1.09 (t,J = 7.1 Hz, 3H). b) 3-|5-Mc(liyl-3-(2-(Af-(2-cUioxycjirbonylclliyI)-A'-l>cii/.ylaiiiiiH"snironyl) plicnylsulfoiiyloxy)plicnoxy]pn"poxymiani(line hydrochloridc: The title compound was prepared in 92% yield from N,A/l-(his-^7Y-butyloxyciirlH>nyl)-{3-|5-nicthyl-3-(2-(A/-(2-ethoxycarbonylcthyl)-A;-bcnzylaminosulfonyl)pbcnylsulfonyloxy)phenoxy]propoxy} guanidine, as prepared in the preceding step, in a manner analogous to step i of Example 20. 'H-NMR(300 MHz, DMSO-d6) 5 11.10 (br s, III), 8.18 (t, J = 8.8 Hz, 2H), 7.99 (t, J = 7.7 Hz, IH), 7.89 (t, J - 7.8 Hz, IH), 7.69 (br s, 4H), 7.34 (m, 5H), 6.75 (s, IH), 6.54 (s, IH), 6.52 (s, IH), 4.63 (s, 2H), 3.98 (t, J = 6.2 Hz. 211), 3.91 (q, J = 7.0 Hz, 4H), 3.53 (t, J = 7.3 Hz, 2H), 2.38 (t, J = 7.3 Hz, 4H), 2.21 (s, 3H), 2.01 (pentet, J = 6.2 Hz, 2H), 1.09 (I, J - 7.1 11/., 311). Mass specliiini (MALD1-TOF, a-cynno-4-liydroxycinniiniic acid matrix) calcd. for CMH36N4O9S2: 649.2 (M + H), 671.2 (M + Na); Found: 649.0, 671.0. "t -125- Example 54 3-l5-i\h>thyI-3-(2-(4-(piperi(!in-l-yI)i)ii>eridin-l-ylsulfonyl)phenyIsHlfoiiyloxy)phenoxyJpropoxyguaniduie dihydrochloride a) /V,VVXIHs-/m-bii ylsuirunyl)phciiylsu]roiiyloxy)phcnoxy]propoxy}guanidinc: The title compound was prepared in 37% yield from 4-piperidinopiperidine in a manner analogous to step h of Example20. 'H-NMR (300 MHz, CDC13) 5 9.08 (s, 1H), 8.31 (d,J = 7.9Hz, 111), 8.15 (d, J - 7.9 Hz, IH), 7.82 (t, J - 7.7 Hz, 111), 7.70 (m, 211), 6.60 (s, 1H), 6.52 (s, 1H). 6.47 (s, 1H), 4.17 (i, J = 6.2 Hz, 2H), 4.07 (m, 2H), 3.94 (t, J = 6.2 Hz, 2H), 2.88 (m, 3H), 2.27 (in, 2H), 2.24 (s, 3H), 2.10 (pentet, .1 - 6.2 1Iz. 211), 1.51 -1.96 (m, 1 OH), 1 -49 (s, 18H). 1.25 (m, 2H). b) 3-[5-Mcthyl-3-(2-(4-(pipcridinyl-yJ)pipcndin-l-ylsuIfonyl)pbciiylsulfonyloxy) phcnoxy]propoxygu:inidinc dihydrocliloridc: The title compound was prepared in 8S% yield from TV, A^-(Bis-^e/V-butyloxycarbonyl)-{3-[5-methyl-3-(2-(4-(piperidin-l-yl)piperidin- l-ylsulfonyl)phcnylsulfonyloxy) phcnoxy]propoxy}guanidine, as prepared in the preceding step, in a manner analogous to slcp i of Example 20. 'H-NMR (300 MHz, DMSG-d6) 5 M.10(brs, 111), 10.29 (hr s, 111), 8.24 (d. J ¦- 7.9 11/., II I). 8.17 (d, J - 7.9 il/, 111), S.03 (t, J = 7.7 Hz, 111), 7.91 (I, J - 7.7 1 lz, 111), 7.68 (br s, 4H), 6.75 (s. 1H), 6.52 (s, 1H). 6.48 (s, 1H), 3.98 (t, J = 6.2 Hz, 4H), 3.90 (t, .1 - 6.3 Hz, 2H), 3.35 (m, 5H), 2.88 (m, 4I-I), 2.22 (s, 3H), 2.16 (m, 211), 2.02 (pentet, J - 6.3 Hz, 211), 1.67-1.79 (m, 611). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C27H39N5O7S3: 610.2 (M + H), 632.2 (M + Na), 648.2 (M + K); round: 610.1, 632.0, 648.1. Example 55 {3-[5-Methyt-3-(2-(N-ntethyl-N-(2~(4-pyridyI)ethyl)aminosu^^^ phenaxyjpropoxyiguanidhte dihydrochloride a)/V,Ar-(lHs-frT/-lMi(yloxycart>onyl)-{3H^ aniinosulfoiiyl)pliciiylsiilfonyloxy)plicii()xyjpi'opoxy}guanidinc: The title compound was prepared in 15% yield from 4-[(2-methylamino)cthyl]pyridine in a manner analogous to step h of Eg. 20. 'H-NMR (300 MHz, CDC13) 5 9.08 (s, 1H), 8.55 (d, J = 5.1 Hz, 2H), 8.24 (d, J = 7.7 Hz, 1H), 8.12 (d, J = 7.8 Hz, 111). 7.69 (m, 3H), 7.30 (in, 2H), 6.58 (s, 1H), 6.54 (s, 1H), 6.48 (s, 1H), 4.18 (t, .1 = 6.2 Hz. 211). 3.92\\, J = 6.2 Hz, 2H), 3.65 (t, J = 7.3 Hz, 2H), - 126- 3.05 (I, J = 7/1 11/. 211), 2.90 (s, 311). 2.23 (s, 311), 2.08 (pentet, .1 -6.2 11/, 211), 1/19 (s, 1811). b) {3-|5-Mc(hyl-3-(2-(A^methyl-7V-(2-(4-pyridyl)c(hyl)nniinosulfonyl) phcnylsiilfonyloxy) phcnoxy]propoxy}giianidinc.dihydrochloridc: The title compound was prepared in 83% yield from A^,A^-(bis-/e/7-butyloxycarbonyl)-{3-[5-methyl-3-(2-(A^-methyl-A^-(2-(4-pyridyl)cthyl)aminosulfonyl)phcny]suUbnyloxy)phenoxy]propoxy} guanidine, as prepared in the preceding step, in a manner analogous to step i of Example 20. 'H-NMR (300 MHz, CDC13/CD3OD) 8 8.72 (br s, 2H), 8.15 (t, J = 7.8 Hz, 2H), 7.65-7.95 (m, 3H), 7.74 (t, J = 7.4 Hz, 1H), 6.64 (s, 111), 6.60 (s, 1H), 6.45 (s, IH), 4.03 (br s, 2H), 3.94 (br s, 2H), 3.83 (br s, 211), 3.39 (m, 211), 2.98 (s, 3H), 2.27 (s, 3H), 2.07 (in, 2H). Mass Spectrum (MALDI-TOF, cc-cyano-4-hydroxycinnamic acid matrix) calcd. for C25I i3|N5O7S2: 578.2 (M + 11), 600.2 (M + Na); Found: 578,0. 599.9. Example 56 3-[5-Methyt-3-(2-(N-(ethoxycurhoitytnicthyl)-N-(2-iJyriiiylnu'fhyl)(iniino\u[fony!) pltcnylsulfonyloxyjplienoxyjpropoxygitanidine dihydrochloridc a) 7V,/V4IHs-fcTM>ij(yloxyciiri>onyO (2-pyridylmcthyl)aniinosulfonyl)phcnyIsulfonyloxy)phciioxylpropoxy}guanidinc: The litlc compound was prepared in 38% yield from A'-(pyridylmethyl)glycinc ethyl ester in a manner analogous to step h of Example 20. 'II-NMR (300 MHz, CDC13) 5 9.05 (s. Ill), 8.47 (d, J - 4.0 Hz, 1H), 8.37 (d, J = 7.8 Hz, IH). 8.14 (d, J - 7.9 Hz, IH), 7.75 (t, J = 7.7 Hz, 1H), 7.63 (m, 3H), 7.40 (t, J = 7.9 11/, 111), 6.57 (s, 211), 6.53 (s, 111), 4.73 (s, 311), 4.31 (s, 3H), 4.16 (t, J = 6.2 Hz, 2H), 4.02 (q, J - 7.1 Hz, 2H), 3.92 (t, J = 6.1 Hz, 2H), 2.21 (s, 3H), 2.07(pentet,J = 6.2Hz,2H), 1.49 (s, 1811). 1.15 (t, J - 7.1 IIz,3H). b) 3-I5-Mcthyl-3-(2-(yV-(cthoxycarhonylnicthyl)-7V-(2-pyridyIinct!iyl)aminosulfonyl) plicnylsiiiroiiyloxj^pIivitnxylprupoxy^iiaiiidiiK1 dihydrochloride: The title compound was prepared in 90% yield from A/,Af'-(Bis-/t'/7-butyloxycarbonyl)-{3-[5-mclliyl-3-(2-(A'- (clhoxycarbonyliiiL>lhyl)-Ar-(2-pyridylim:lliyl)aininosuironyl)phcnyIsuIfoiiyloxy) phenoxy]propoxy}guanidine, as prepared in the preceding step, in a manner analogous to step i of Example 20. 'H-NMR (300 MHz, DMSO-d6) 5 8.54 (d, J - 4.4 Hz. IH), 8.39 (d, J = 7.8 Hz, IH), 8.14 (d, J = 7.8 Hz, 1H), 7.97 (t; J = 7.7 Hz, IH), 7.87 (t. J - 7.8 Hz. 2H), 7.67 (br s,;411), 7.43 (t, J =* 7.7 Hz, 211), 6.75 (s. 1H), 6.53 (s, 1H), 6.50 (s, 1H), 4.76 (s, 3H), - 127- 4.36 (s, 3H), 3.97 (q, J = 7.1 Hz, 2H), 3.90 (l, i - 6.5 Hz, 411), 2.22 (s, 311), 2.02 (penlet, J = 6.4 Hz, 211), 1.06 (l, .1 = 7.1 11/., 311). Mass speed urn (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C^II^NjO^S,: 636.2 (M + H), 658.2 (M + Na); Found: 636.0, 658.0. Example 57 3-I5-Me1hyl-3-(2-(NfN-bis(ethoxycarbonylme(hyl)ambtosiilfonyl)phenylstilfonyloxy) phenoxyjpropoxyguanidinc hydrocftloride a)Ar,A7-(I3iWe/-M)utyIoxycarbonyl)-{3-l5-mcthyl-3-(2-(Ar,A'-bis{cthox)'cijrbo[iylinctIiyi) aminosulfonyl)plicnylsulfonyloxy)phcnoxy]propoxy}guanidinc: The title compound was prepared in 76% yield from dicthyl iminodiacctaic in a manner analogous to step h of Eg. 20. 'H-NMR (300 MHz, CDC1,) 5 9.07 (s, 1H), 8.35 (d, J = 7.9 Hz, 1H), 8.15 (d, J - 7.8 Hz, 1H), 7.79 (l, J = 7.7 i)/., 111), 7.69 (d, J - 7.9 11/.. 111), 7.66 (t, ,1 - 7.7 11/., 111), 6.57 (s, 211), 6.52 (s, HI), 4.35 (s, 411), 4.18 (t, J = 6.2 Hz, 211), 4.12 (q, J = 7.1 Hz, 411), 3.94 (t, J - 6.2 Hz,2H),2.23(s, 311), 2.10 (pcntct,J = 6.2 Hz. 211), 1.49 (s, 1811). 1.21 (t, .1 = 7.1 Hz. 611)-b)3-I5-Mcfhyl-3-(2-(A;,A'-bis(ctlioxyciubony1nietliyl)anuiiosulf()iiyl)phcnylsulfonyloxy) phcnoxyjpropoxyguuiiidine hydrochloridc: llic title compound was prepared in 74% yield from A^ Ar'-(bis-^/7-butyloxycarbonyl)-{3-[5-meihyl-3-(2-(//1//~bis (clhoxycarbonylmcthyl)aminosulfonyl)plKnylsulfonyloxy)phcnoxylpropoxy}giianidine, as prepared in the preceding step, in a manner analogous to step i of Example 20. 'H-NMR (300 MHz, DMSO-dfi) 6 8.41 (d, J - 7.9 I Iz. 111). 8.13 (d, J = 7.8 Hz, 111), 7.98 (t, J = 7.7 Hz, 1H), 7.88 (d, J - 7.8 I Iz, HI), 7.65 (br s. 411), 6.75 (s, 111), 6.52 (s, 111), 6.49 (s, 111). 4.30 (s, 411), 4.99 (q, J - 7.1 Hz, 611), 3.91 (t, .1 = 6.3 \\z, 211), 2.22 (s, 311), 2.02 (pentet, J = 6.2 Hz, 2H), 1.10 (t, J = 7.1 Hz, 6H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C251 l^NPuS,: 631.2 (M + H), 653.2 (M + Na); Found; 630.9, 653.1. * - 128- Example 58 3-[5-Me1hyl-3-(2-(4-(ethoxycarhonyImetliyI)piperaz'uiy}-yIsuIfotiyl) phenylstilfonyloxy)phenoxyjpropoxyguanidine dihydrochloride a) Ar,Af-(Bis-rc'/-M)iityloxyc:iihoiiyl)-{3-|5-nic(liyl-3-(2-(4-(elhoxyc:ul)Oiiylnic(hyI) pipc'raziii-l-ylsulioiiyl)phcnylsiilfonyloxy)phcnoxy]propoxy}guanidinc: The title compound was prepared in 74% yield from 1 -{cthoxycarbonylmetliyl)pipcra7.inc in a manner analogous to step h of Example 20. 'H-NMR (300 MHz, CDU3) 6 9.08 (s, 111), 8.23 (d, J = 7.9 Hz, 1H), 8.19 (d, J = 7.9 I Iz, 1H), 7.80 (t, J = 7.7 Hz, 1H), 7.71 (s, 1) I), 7.68 (t, J = 7.8 Hz, 1H), 6.59 (s, 1H), 6.56 (s, 1H), 6.51 (s, III), 4.17 (m, 4H), 3.94 (t, J - 6.2 Hz, 2H), 3.47 (t, J = 4.6 Hz, 4H), 3.25 (s, 2H), 2.72 (m, 4H), 2.23 (s, 3H), 2.10 (pcnlet, J = 6.2 Hz, 2H), 1.49 (s, 18H), 1.26 (t, J = 7.2 Hz, 3H). b) 3-[5-Mctliyl-3-(2-(4-(cthoxycarbonylmcthyl)pipcrazin-l-yIsulfonyI) hciiylsulfonyloxy) phciioxy]propoxyyuanidinc dihydroehlotidc: The title compound was prepared in 82% yield from MA/'-(bis-/c/7-butyloxycarbonyl)-{3-[5-methyl-3-(2-(4- (clhoxycarbonylmelhyl) pipcrazin-l-ylsiiHunyl)phcnylsiilfbnyloxy)phcnoNyJprt)poxy} guanidine, as prepared in the preceding step, in a manner analogous to step i of Example 20. 'H-NMR (300 Ml Iz, DMSO-d6) 5 11.15 (s, 111), 8.27 (d, J = 7.8 11/,, 111), 8.1 8 (d. .1 = 7.8 Hz, 1H), 8.07 (t, J = 7.7 Hz, 1H), 7.94 (t, J = 7.8 Hz, 1H), 7.71 (br s, 4H), 6.75 (s, 1H), 6.51 (s, 1H), 6.47 (s, HI), 4.18 (q, J = 7.1 Hz. 2H). 3.98 (t, J = 6.2 Hz, 211). 3.90 (l. J - 6.3 Hz, 2H), 3.56 (br s, 6H), 3.20 (br s, 4H), 2.22 (s, 3H), 2.02 (pentet, J = 6.2 Hz, 211), 1.22 (t, J = 7.2 Hz, 31-1). Mass spectrum (MALDI-TOF, cc-cyano-4-hydroxycinnamic acid matrix) calcd. for Ca5H35N5O9S2: 614.2 (M + H), 636.2 (M + Na), 652.2 (M + K). Found: 614.1, 636.0,652.1. Example 59 3-l5~Metfiyl-3-(2-(N,N-bis(c(irboxynicthyt)(im'uiosutjonyl)plu^iylsulfonyloxy) phenoxyjpropoxygttamdine i. The title compound was prepared in 87% yield from 3-j5-mcthyl-3-(2-(A',A^- bis(ethoxycarbonylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine liydrochloride, as prepared in step b of Example 57, in a manner analogous to Example 27. 'H-NMR (300 MHz, DMSO-d6) 5 8.29 (d, J = 7.0 Hz, 1H), 8.10 (d, .1-7.6 l-iz; 1H), 7.97 (t, J = 7.6 Hz, 1H), 7.84 (t, J = 7.6 I Iz, 111). 7.63 (br s, 4H); 6.72 (s, 1H), 6.58 (s. 1H), 6.49 (s, 1H), 4.13 (s, 4H)3 3.97 (t, J = 6.3 llz, 211). 3.90 (I, J = 6.3 Hz, 211), 2.23 (s. 311), 2.03 -129- (pcntcl, .1 = 6.2 11/., 211). Mass spectrum (MAU)l-'l OF, a-cyano-4-hydroxycinnamic acid matrix) calcd. lor C^II^N/),^-,: 575.1 (Ml II), 597.1 (M -I- Na),613.1 (Ml- K). round: 575.1,597.0,613.1. Example 60 3-l5-Methyl-3-(2~(N-mcthyl-N-(4-carboxyphcny!)amutostiIfonyI)p!ieityIsulfonyIoxy) phetwxyjpropoxyguanidine The title compound was prepared in 84% yield from 3-[5-methyl-3-(2-(A/-methyl-A'-(4-methoxycarboiiylphcnyl)aminosuironyl)phenylsuironyloxy)phenoxy]propoxyguanidine hydrochloridc, as prepared in step b of Example 50, in a manner analogous to Example 27. '11-NMR (300 Ml 1/., DMSO-d,) ft 8.17 (d, J - 7.4 11/, 111), 7.97 (1, J - 7.6 11/., 111), 7.90 (in, 4H), 7.61 (br s, 4H), 7.40 (d, J = 7.7 Hz, 2H), 6.74 (s, 1H), 6.45 (s, 2H), 3.98 (t, J = 6.2 Hz, 2H), 3.90 (t, J = 6.3 Hz, 2H), 3.46 (s, 3H), 2.19 (s, 3H), 2.01 (pentet, J = 6.2 Hz, 2H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C25H28N4O9S2: 593.1 (M + H), 615.1 (M + Na), 631.1 (M + K). Found: 593.1, 615.0, 630.9. Example 61 3-15-Methyt~3-(2-(N-(2-carboxyethy{)-N-benzyIamwosu!foiiyl)phenylstilfonyloxy) phcnoxyjpropoxyguaniditie The title compound was prepared in 97% yield from 3-[5-methyl-3-(2-(Ar-(2-ethoxycarbonylethyl)-JV-benzylaminosulfonyI)phenylsulfonyloxy)phenoxy] propoxyguanidinc hydrochloridc as prepared in step b of Example 53, in a manner analogous to Example 27. 'H-NMR (300 MHz, DMSO-d6) 5 8.19 (t, J = 7.9 Hz, 2H), 7.99 (t, J = 7.7 I Iz, 111), 7.88 (t, .1 = 7.8 1 Iz. 111), 7.56 (br s. 411). 7.34 (m, 511). 6.74 (s. 111), 6.54 (s, 1H), 6.51 (s, III), 4.63 (s, 211), 3.97 (t, J = 6.2 Hz, 21-1), 3.89 (t, J = 6.1 Hz, 2H), 3.51 (t, J = 7.4 Hz, 2H), 2.28 (t, J = 7.5 I Iz, 411), 2.22 (s. 311), 1.99 (pcnlcl, ,1 = 6.1 Hz, 211). Mass spectrum (MALDl-TOF, a-cyano-4-hydioxycinnamic acid matrix) calcd. for C,71 I^.N^O^ST: 621.2 (M + H), 643.2 (M + Na). Found: 621.0,642.9. - 130 - Example 62 {3-l5-Methyl-3-(2-(4-(carboxymethyl)piperuzhtN-}-ylsulfoiiy!)phenylsulfonyloxy) phenoxyjpropoxy}guanidine The title compound was prepared in 85% yield from {3-[5-mcthyl-3-(2-(4-(clhoxyearbouylme(hyl)piperazin-] -ylsulfonyl)plicny lsulfonyloxy)phenoxy] propoxyjguanidine dihydroeliloridc, as prepared in step b of F.xampie 58, in a manner analogous to Example 27. 'H-NMR (300 MHz, DMSO-d6) 5 11.12 (s, -I H), 8.27 (d, J = 7.9 Hz, 1H), 8.18 (d, J - 7.9 Hz, III), 8.08 (t, J = 7.7 Ib, 1H), 7!94 (t, .1 = 7.7 Hz, 111). 7.69 (br s, 4H), 6.76 (s, 1H), 6.51 (s, 1H), 6.47 (s, III), 3.99 (t, J = 6.2 Hz, 2H), 3.90 (U J - 6.3 Hz, 2H), 3.43 (br s, 6H), 3.25 (br s, 4H), 2.22 (s, 3H), 2.02 (penlet, J = 6.2 Hz, 2H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamie acid matrix) calcd. forC23H31N;;O9S2: 586.2 (M + H), 608.1 (M + Na). Found: 586.2, 608.0. Example 63 3-f5-inc'tliyl-3-(2-(4-(2-pyri(lyI)pipcr(izinyf\tilf()nyf)pf!cnyfsiilfotiylox^^^^ propoxyguanidine Uydrochloride a) 7V,yVf-Bis-(/c>/'/-l>utoxycjirl)oiiy)-3-|5-niethyl-3-(2-(4-{2-pyridyl)pipcr:i7.inylsulfoiiyl) plicnylsulfonyloxy)phcnoxy]propoxygii:imdiiic: The title compound was prepared in 67% yield from l-(2-pyridyl)piperazine, in a manner analogous to step h of Eg. 20. !H NMR (300 MHz, CDClj) 5 9.08 (s, 1H), 8.28 (dd, III, J - 7.93 1.3 Hz), 8.16 (m, 2H), 7.81 (td, 1H, J = 7.7, 1.4 Hz), 7.68 (m, 2H), 7.48 (m, 1H), 6.61 (m, 4H), 6.51 (t, 1H, J = 2.1 Hz), 4.18 (m, 211), 3.94 (I, 211, J = 6.2 Hz), 3.63 (m, 411), 3.48 (m. 411), 2.23 (s, 311), 2.10 (ni, 211), 1.49 (s, 18H). b) 3-|5-nictliyl-3-(2-(4-(2-pyridyl)pipcra7inylsulfoiiyl) plienylsulfonyloxy)plicnoxy| propoxyguanidinc hydrochloridc: The title compound was prepared in quantitative yield from A/",^'-bis-(/e/7-butoxycarbony)-3-[5'mcthyl-3-(2-(4-(2-pyridyl)piperazinylsulfonyl) phenylsulfonyloxy)phcnoxy]propoxyguanidine, as prepared in the previous step, in a manner analogous lo step i of lixamplc 20 (without chromatographic purification)- 'II NMR (300 MHz, CDC13/CD3OD)5 8.33 (d, 111, J = 6.9 Hz), 8.20 (dd, 1HJ-7.8, 1.1 Hz), 8.11 (dd, 1H, J - 6.0, 1.5 Hz), 7.90 (m, 2H), 7.78 (m. 1H), 7.06 (d, 1H, J - 8.9 Hz). 6.93 (t, 1 H. J = 6.6 llz), 6.63 (ni, 211), 6.50 (t, 111, J = 2.1 1 Iz). 4.06 (I, 211, J = 6.0 Hz), 4.01 (1,211, .1 = 5.9 Hz), 3.89 (m, 4H), 3.60 (m, 4H), 2.28 (s, 311), 2.10 (pentet, 2H, J = 5.9 Hz). Mass spectrum - 131 - (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C26H32N6O7S2: 605.2 (M+H), 627.2 (M+Na). Found: 605.0,627.1. Example 64 3~J5-mcthyI-3-(2-(4-phenylpiperazi'iyhuffony!)phenylsulfonyhxy)pftenoxy] propoxygtiaitiditie hydrochloride a) Af,7V'-Bis-(/t'//-l)ii(oxyc;irbony)-3-|5-incthyl-3-(2-(4-plicnylpi[>craziiiylsulionyl) phcnylsulfonyloxy)phciioxy]propoxyguaiiidinc: The title compound was prepared in 40% yield from 1-phenylpiperazinc, in a manner analogous to step h of Example 20. 'H NMR (300 MHz, CDC13) 8 9.08 (s, 1H), 8.28 (dd, 1H, J = 7.9, 1.3 Hz), 8.19 (dd, 1H, J = 7.9, 1.4 Hz), 7.81 (td, 111, J - 7.7, 1.4 Hz), 7.69 (m, 211), 7.27 (in, 411), 6.89 (in, 3H), 6.58 (br s, 2H), 6.52 (t, 1H, J = 2.1 Hz), 4.18 (t, 2H, J - 6.2 Hz), 3.94 (t, 2H, J = 6.2 Hz), 3.53 (m, 4H), 3.24 (111,411), 2.24 (s, 311), 2.10 (m, 211). 1.49 (s, 1811). b) 3-[5-mcthy1-3-(2-(4-plicnylpipcrnzinyIsulfonyl)phcnyIsulfonyloxy)phcnoxy] propoxy^n:iiiidiiiu hydrocliloridc: The title compound was prepared in quanlitalive yield from N,A^-bis-(/c/7-butoxycarbony)-3-(5-incihyl-3-(2-(4-phcnylpiperazinylsulfonyl) phcnylsullbnyloxyiplu'iioxyl propoxy^iianidine, as prepared in ihe previous step, in a manner analogous to step i of Example 20 (without chromalographic purification). 'H NMR (300 MHz, CDCI3/CD3OD) 8 8.34 (d. III. J = 7.3 Hz), 8.21 (d, HI, J = 7.6 Hz), 7.94 (m, 1H), 7.83 (1, III, J = 7.4 Hz), 7.74 (d, 211, J = 7.7 Hz), 7.50 (m, 3H), 6.64 (s, 111), 6.57 (s, 1H), 6.53 (s, IH), 4.03 (m, 18H). 3.67 (m, 411), 2.26 (s, 3H), 2.12 (m, 2H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C27HBN5O7S2: 604.2 (MH-II), 626.2 (M-f-Nn). Found: 604.2,626.3. Example 65 3~/5-ini'fhyf-3-(2-(4-ht>tiTy/pipi'nizinyl,\ijIf(>nyl)phi'nyIsn(/bfiyIoxy)/>hi'niK\y/ propoxyguanidinc hydrochloride a) 7V,yV-Ilis-(/t'/7-biitoxycarb(>ny)-3-|5-nictliyl-3-(2-(4-bcnzylpipcraziiiylsiilfonyl) phcnylsulfonyloxy)plicnoxy|propoxyguanidinc: The title compound was prepared in 75% yield from 1-bcnzylpiperazinc. in a manner analogous to step h of Example 20. lH NMR(300MHz,CDCl3)5 9.08(s, HI). 8.21 (m, III), 8.17 (eld, 1H.J = 6.6, 1.4 Hz), 7.78 (td, 1H, J = 7.7, 1.5 Hz). 7.70 (s, IH), 7.66 (td. 1H, J = 7.7. 1.4 Hz), 7.28 (m, 5H), 6.57 (m, -132- 2H), 6.51 (t, 1H, J - 2.1 Hz), 4.18 (t, 2I-I, J = 6.2 Hz), 3.94 (t, 2H, J = 6.2 Hz), 3.52 (br s, 2H), 3.40 (br s, 4H), 2.53 (br s, 4M), 2.23 (s, 3H), 2.08 (m, 2H), 1.49 (s, 1SH). b) 3-[5-mcthyI-3-(2-(4-bciizylpipcrazinylsulfonyl)phenylsulfoiiyloxy)phenoxy] propuxygicmidiiic liy 3-}5-nieihy!-3'(2-(4-{2-mclhoxyphcnyI)pipcruzinyLsuifony!)plienyhulfonyi(K\v) phciio.xyjpropoxyguanidine hydrochloride a) /V,/V'-IJis-(/'iitoxyc:irl)oiiy)--l-15-iiH-Uiyl-3-(2-(4-(2-.iiicllioxyplitinvl) pipcrazinylsulfonyl)phcnylsulfonyloxy)plictioxy|propoxygu:iiiidinc: The title compound was prepared in 79% yield from l-(2-mclhoxyphcny])piperazinc, in a manner analogous to step h of Example 20. '11 NMK (300 MI Iz. C1)C13) 5 9.09 (s, 111), 8.24 (dd, 111,.! = 7.9, 1.3 llz), 8,21 (dd, III, J - 8.0. 1.4 Jl/,)s 7.81 (id. 111, J - 7.7. 1.4 11/.), 7.69 (m. 211). 7.02 (m. 1H), 6.90 (in, 311), 6.59 (m, 211), 6.53 (t, 11IJ = 2.1 llz), 4.18 (t, 211, J = 6.2 llz), 3.95 (I, 211, J =6.2 11z); 3.83 (s, 310.3.55 (m, 411). 3.13 (br t. 411, J = 4.8 Hz). 2.24 (s, 311), 2.10 (pentet, 2H, J = 6.2 Hz), 1 -49 (s, 1811). b) 3-[5-methyl-3-(2-(4-(2-nietlioxyplicnyl)pipcriizinylsiilfonyl) phcnylsulfonyloxy) phenoxyjpropoxyguanidinc hydroclilnride: lhe title compound was prepared in 33% yield from A;,A'-bi.s-(/t'/7-bu!oxyenrbony)-3-|5-niethyl-3-{2-(4-(2-methoxyphenyl) pipcra/.inylsuUbnyi)phenylsu|[bnyloxy)plieiioxy|pi'opoxygu;>nidine. as prepared in the previous slcp, in a manner analogous to step i of Example 20 (without HCl-methanol acidification). 'II NMR (300 MHz, CDC1,) o 8.21 (m. 211). 7.81 (l. III..1 = 7.5 llz), 7.69 (t. IH, J = 7.5 Hz), 7.00 (m, JH), 6.89 (m, 311). 6.58 (s, 2H), 6.53 (s, JH)f 3.95 (nn 4H)f 3.82 (s, 3H), 3.53 (m, 411), 3.11 (m, 4H), 2.22 (s. 311), 2.03 (m, 2H). Mass spectrum (MALDI- - 133- TOF, a-cyano-4-liydroxycinnamic acid matrix) calcd. for C2RH35N.;OKS:: 634.2 (M+H), 656.2 (M+Na). Found: 634.2,656.3. Example 6 7 3-l5-methyl-3-(2-(N-(2-cyanoethyl)-N-(2-furanytme(hy!) aminosulfonyl) phenylsulfonyloxy)phcnoxy]propoxyguamdhte a) 7V,A"-Bis-(^r/-butoxycnrbony)-3-|5-mcthyI-3-(2-(7V-(2-cyanocthyl)-A'-(2- furanylmcthyl) ;niiiiiosulfonyl)plienylsulfonyl"xy)plicnoxy]prop"xyj"iianidinc: The title compound was'prepared in 49% yield from 3-(furfurylamino)propionitrile, in a manner analogous to step h of Example 20. 'H NMR (300 MHz, CDC13) 6 9.08 (s, 1H), 8.29 (dd, 1H,J = 7.9, 1.4 IJz), 8.16 (dd, III, .1 = 7.8, 1.5 llz), 7.79 (m, III), 7.70 (m, 211), 7.33 (t, 1H, J = 1.3 Hz), 6.60 (m, 1H), 6.57 (m, 1H), 6.52 (t, 1H, J = 2.1 Hz), 6.32 (m, 2H), 4.65 (s, 2H), 4.18 (t, 2H, J - 6.2 Hz), 3.94 (t, 211, J - 6.2 Hz), 3.65 (m, 211), 2.55 (m, 211), 2.24 (s, 3H), 2.10 (pcntct, 2H, J - 6.2 Hz ), 1.49 (s. 1811). b) 3-|5-iiH-lhyl-3-(2-(/V-(2-iT:iiioi"Hiyl)-/V-(2-fiiranyliiitiliyl);iniiiiosii1fniiyl) phcnylsulfonyloxy)phen()xy|propoxy^uanidine: The title compound was prepared in 42% yield from N.W'-bis-(/('/'/-bul()xyc;irh()iiy)-3-|5-inClhyl-3-(2-(A;-(P.-cy;iht)L-lliyl)-A^-(2- furanylmethyl)aminosulfonyl)phenylsulfonyloxy) phenoxyjpropoxyguanidine, as prepared in the previous step, in a manner analogous to step i of Example 20 (without HCl-methanol acidification). 'H NMR (300 MHz, CDCI3) 5 8.23 (dd, 1H, J = 7.9. 1.3 Hz), 8.14 (dd, 1H, j^7.95 1.4 Hz), 7.76 (td, 1H.J = 7.7, 1.4 Hz). 7.67 (id. 1H, .1 = 7.7, 1.3 Hz), 7.29 (t, 1H.J = 1.3 Hz), 6.56 (in, 211), 6.51 (m, Ml), 6.28 (m. 211). 4.61 (sf 2H), 3.91 (m, 411), 3.62 (t, 21K J = 7.1 Hz), 2.53 (1, 2H, J = 7.1 Hz). 2.20 (s. 311). 2.00 (pcntct, 211, .1 = 6.1 Hz). Mass spectrum (MALDI-TOI\ Example 68 3-l5-Mcthyl-3-(2-(4'nii't!iylpiiyc}(iz'niylsulJoiiyl)phciiylsiilJotiylo.\y)i)hcno\yJ propoxyguanidine hydrocfiloride a) 7V-3-|(3-nydroxy-5-iiic(hyl)phcnoxy]propoxyphtliaIimi(lc: A mixture of W-3-|(3-benzyloxy-5-mclhyl)plicnoxyJpropoxyiilitlut]imidc (9.19 g, 22.0 mniol). as prepared in step c of Example 20, and 10% palladium on carbon (516 nig) in letrahydrofuran (100 mL) and - 134- cthanol (100 mL) was stirred at room temperature under hydrogen (balloon) for 3 hours. The catalyst was removed by filtration over Cclitc, the filtrate was concentrated and the remaining solid was purified by trituration with cold methanol giving the title compound as a pale yellow solid (5.72 g, 79%). \l I NMR (300 Ml Iz, CUC13/CD3OD) 6 7.83 (m, 211), 7.77 (m, 2H), 6.26 (m, 3H), 4.40 (t, 2H, .1 = 6.3 Hz), 4.17 (t, 2H, J = 6.2 Hz), 2.23 (m, 5H). b) 3-I5-lVIctliyl-3-(2-clilorosiiiroiiyl)pliciiyIsiilfoiiyIo\y)pliciioxy] propoxyphthnliniUlc: A mixture of 1,2-benzenedisulfonic anhydride (1.74 g, 7.91 mmol), as prepared in step g of Example 20, yV-3-|(3-hydroxy-5-mcthyl)phcnoxy] propoxyphthahmidc (2.59 g, 7.92 mmol), as prepared in the previous step, and A^TV-diisopropylethylamine (1.40 mL, 8.05 mmol) in anhydrous dichloromethane (100 mL) was stirred at room temperature under nitrogen (balloon) for 18 hours. Oxalyl chloride (1.40 mL, 16.0 mmol) and A'.A'-dimethylformamide (0.02 mL) were added and the reaction stirred another 4 hours at room temperature. The solution was concentrated and the residue was purified by flash chromatography (dichloromethane) giving the title compound as a white solid (3.31 g, 74%). lH NMR (300 MHz,CDCI3)5 8.48(dd, HI, J = 7.6. 1.7 11/.), 8.25 (dd, 1II,J.= 7.5, 1.8 Hz). 7.90 (m, 411), 7.77 (m, 211), 6.66 (m. 111), 6.62 (br s, ! 11), 6,53 (I. 111, .1 - 2.2 11/.), 4.37 (I, 211. J = 6.1 11/.). 4.13 (I, 211, .1 - 6.1 llz), 2.27 (s, 311), 2.19 (pentet, 211, .1 - 6.1 Hz). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C27H33N5O7S2: 588.0 (M+Na). Found: 588.2. c) 3-[5-Mc(hyl-3-(2-(4-mcthylpipcra/inylsulfonyl)phenylsulfonyIoxy)phcnoxy] propoxyplit1i:i1imi(lc: A mixture or3-|5-mcthyl-3-(2-ehlor(isuironyl)phenylsul(bnyloxy) phenoxy]propoxyphthalimide (181 mg, 0.32 mmol), as prepared in the previous step, 1-niclhylpipcra/.ine (34 nig, 0.34 mmol). and A'.yV-diisopropyk'thylaniine (0.06 ml,. 0.35 mmol) in anhydrous Cl I2C12 (10 mL) was stirred at room temperature under nitrogen (balloon) for 4 hours. The solution was concentrated and the residue was purified by flash chronintography (2.5% to 5% mclhanol in dichloromethane) giving the title compound as awhile solid (161 mg, 80%). 'H NMR (300 Ml Iz, CDC13) 8 8.24 (dd, ,1H, J - 7.9, 1.3 Hz), .8.19 (dd, 1H, J = 7.9, 1.4 Hz), 7.84 (m, 2H), 7.77 (m, 3H), 7.68 (Id, 1H, J = 7.7, 1.3 Hz), 6.62 (br s, 1H), 6.59 (br s, 1H), 6.51 (t, 1H, J - 2.2 Hz), 4.36 (t, 2H, .1 = 6.2 Hz), 4.10 (t, 2H, J = 6.1 Hz), 3.40 (m, 4H), 2.47 (br t, 411, J = 4.9 1 Iz), 2.28 (s, 311), 2.25 (s. 3H), 2.18 (pentet, 2H,J = 6.1 Hz). - 135- d) 3-|S-Mblliyl-3-(2-(4-iiivtliylpipLM-n/.iiiylsiillony1)|)lu propoxyaniinc: A mixture 3-|5-niclhyl-3-(2-(4-nicthyIpipcra/.inylsullbnyl) phenylsulfonyloxy) phenoxyjpropoxyphthalimide (156 mg, 0.25 mmol), as prepared in the previous step, and 40% aqueous mclhylainine (1.50 nil,, 21.5 mmol) in tclrahydrol'uran (5 mL) and ethanol (5 ml) was stirred at room temperature for 4 hours. The solution was concentrated and the residue was purified by flash chromatography (10% methanol in dichloromethane) giving a slurry that was twice dissolved in diethyl ether, filtered, and concentrated giving the title compound as a clear oil (113 mg, 91%). 'H NMR (300 MHz, CDCI3/CD3OD) 5 8.22 (dd, 1H, J = 7.9, 1.3 Hz), 8.18 (dd, 1R J = 7.9, 1.4 Hz), 7.83 (td, 1H, J = 7.7, 1.4 Hz), 7.70 (id, 1II, J - 7.7, 1.3 1 Iz), 6.60 (br s, 111), 6.56 (br s, 111), 6.53 (t, 111, J-2.1 Hz), 3.93 ((,211, .1 = 6.3 Hz), 3.80 (t, 211, J - 6.2 Hz), 3.4! (m, 511), 2.50 (br t, 411, J = 4.9 Hz), 2.30 (s, 311), 2.24 (s, 3H), 2.00 (pcnlct, 211, J = 6.2 Hz). c) 3-[S-Mcthy]-3-(2-(4-nicthylpipci'Hzinylsulfuiiyl)phcnyIsulfonylo\y)phcnux3'] propoxyguanidinc hydrochJoride: A mixture of 3-[5-methyl-3-(2-(4- mcthylpipcrazinylsulfonyl)phcnylsulfonyloxy) phenoxyjpropoxyaminc (1 13 nig, 0.23 mmol), as prepared in the previous step, and l//-pyrazole-l-carboxamidine hydrochloride (62 nig, 0.42 nnnol) in anhydrous A7,A'-diiiK'lliyllornmmid.c (10 ml.) was slinvd al room temperature under nitrogen (balloon) for 18 hours. The solution was concentrated under high vacuum with heating and the residue was purified by flash chromalogrnphy (10% to 20% methanol in dichloromelhanc), then dissolved in dichloromethane, tillered and concentrated to give the title compound (105 mg, 80%) as a white solid. 'H NMR (300 MHz, CDCI3)6 8.20(rn,2H), 7.83 (td, 111, J = 7.7, 1.3 Hz), 7.70 (td, 1JU-7.7, 1.2 Hz), 6.59 (m, 2H), 6.52 (m. 1H), 6.28 (m. 3H). 4.04 (t. 2H, J = 5.8 Hz), 3.96 (t, 2H, J - 5.8 Hz), 3.43 (m, 411), 2.33 (s, 311), 2.23 (s, 311), 2.00 (m, 211). Mass spectrum (MALD1-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C23H3|Np^ 542.2 (M+H), 564.2 (M-i-Nn). round: 542.3, 564.3. ^ - 136- Example 69 {3-l5-MethyI-3-(2-(N-ethyl-N-(l-bcnzyI-3-pynoli(linyl)lwthio sulfonyfyphenylsulfonyloxy) p/tenoxy/propoxy/guanidine dihydrochloride a) N-{3-|5-Mc(liyl-3-[(2-(Ar-cniyl-yV-(]-bciiz>10-pyiTo1idiiiyI):iniinosulfoiiyl) phcnylsulfonyloxy]phciioxy|propoxy}phtha!imide: The title compound was prepared in 98% yield from l-benzyl-3-(ethylamino)pynolidine in a manner analogous to step e of Example 68. "H-NMR (300 MHz, CDC13)5 8.36 (brs, 11-1), 8.13 (d, J = 7.7 Hz, HI), 7.75- 7.86 (m, 5H), 7.68 (t, J = 7.8 Hz, 1H), 7.34-7.57 (m, 5H), 6.62 (s, 1H), 6.56 (s, 1H), 6.51 (s, 1H), 4.36 (l,J = 6.1 Hz, 2H),4.10(m,4H), 3.50-4.16 (m,4H), 2.31 (m, III), 2.24 (s, 3H), 2.17 (pentet, J = 6.1 Hz, 2H), 1.62(m,4H), 1.26 (t, J = 7.1 Hz, 3H). b) 7V-{3-|5-Mctliyl-3-[(2-(A;-c(hyl-A;-(l-bcnzyl-3-pyrrolidinyl)aminosulfonyl) phenylsulfonyloxy|phcnoxy]propoxy}aminc: The title compound was prepared in 83% yield from N-{3-[5-inetliyl-3-|(2-(A/-L'iliyl-A'-(I-ben/yl-3-pyiTolidinyl)iiniinosullonyl) phenylsu!fonyloxy]phenoxy]propoxy}amine, as prepared in the preceding step, in a manner analogous to step d of F.xample 6K. Ml-NMR (300 Mil/.. CHOI,) 8 8.2f> (d, .1 ^ 7.9 11/, 111). 8.12 (d, J = 7.9 I Iz, 1H), 7.73 (I, J = 7.7 I Iz. 111), 7.61 (I, J - 7.7 I lz, 1 i-1). 7.26 (in, 511). 6.57 (s, 311), 5.37 (brs, 211), 4.56 (br s. III), 3.91 (t, J - 6.3 Hz, 211), 3.78 (t, J = 6.2 Hz, 211), 3.57 (m,4H), 2.80 (m, lH),2.69(m, H-I),2.50(m, 1H), 2.22 (s, 3H), 1.96 (pentet, J - 6.2 Hz, 2M), 1.85 (m, 111), 1.62 (br s, 2H), 1.22 (t. J = 7.1 Hz, 311). . c) A^-{3-I5-Mctliyl-3-l(2-(Af-c(hyl-A'-(l-bcnzyl-3-pyrrolidinyl)amiiiosulfonyl) phcnylsulfnnyloxy|phcnoxy]propoxy}guanidinc dihydrochloride: The title compound was prepared in K3% yield from A;-}3-|?-melhyl-3-K2-(A'-elhyl-A'-(l-ben/.yl-3- pyrrolidinyl)aminosulfonyl)plicnylsulfonyloxy|phcnoxy]propoxy}pblhalimidc. as prepared in the preceding step, in a manner analogous to step f of l-xample 1. 'll-NMR (300 Mllz, DMSO-d6)5 11.15 (br s,2H), 8.18 (d,J = 7.8 Hz, 111), 8.14 (d,J - 7.8 Hz, Hi), 8.00 (t, J = 7.6 Hz, IH), 7.88 (t, J - 7.7 Hz, 111). 7.68 (br s. 411), 7.38 (m. 511), 6.74 (s, 111). 6.52 (s, 1H), 6.48 (s, 1H), 4.66 (br s, 1H), 4.04 (m. 111). 3.97 (t, J = 6.3 Hz, 2H).. 3.89 (I, J - 6.3 Hz, 211), 3.50 (in, 211), 2.75-3.20 (m, 511), 2.21 (s, 311), 2.13 (m. 211), 2.01 (pentet. J - 6.2 Hz, 2H), 1.10 (t, J = 6.9 Hz, 311). Mass spectrum (MALD1-TO1\ tx-cyano-4-hydroxycinnamic acid matrix) calcd. for C,0I I19N5O7S2: 646.2 (M + H). Found: 646.0. - 137 - Example 70 3-l5-Methyl-3-(2-(N-beinyI-N-(2-(N,N-i1imethyIam'uw)ethyI)itnunosulfonyty phcnylsii/fonyhxyjpheiwxyfpropoxyguanidine dihydrochloride a) ^{3H5-Mctliyl-3^(2-(A'-bcnzyl-A'-(2-(A',A^-dinicIhyl:iniiiH>)e(liyI)aniiiiosulfony]) phenylsulfonyloxy]phcnoxy]propoxy}phthnliniidc: The title compound was prepared in 100% yield from AMicnzyl-ZV.A'-dimethylcthylencdiamine in a manner analogous to step c of Example 68. 'H-NMR (300 MHz, CDC1,) 5 8.26 (d, J - 7.8 1 Iz, 1H), 8.18 (d, .1 = 7.8 Hz, 1H), 7.83 (m, 211), 7.76 (m, 311), 7.67 (t, .1 = 7.6 Hz, 1H). 7.32 (m. 5H), 6.62 (s, 2H), 6.55 (s, 1H), 4.63 (s, 2H), 4.35 (t, J - 6.3 Hz, 2H), 4.10 (t, J - 6.1 Hz, 2H), 3.65 (t, J - 6.8 Hz, 2H), 2.55 (t, J - 6.8 Hz, 2H), 2.33 (s, 6H), 2.25 (s, 3H), 2.17 (pentet, J = 6.2 Hz, 2H). b) 7V-{3-[5-Mcthyl-3-[(2-(yV-bcnzyl-7V-(2-(yV,/V-dimctIiylamiiio)ctliyl)aminosulfonyl) phenylsulfonyloxy]phenoxy]propoxy}amine: The title compound was prepared in 95% yield from A'-{3-|5-]nelliyl-3-[(2-(A/-bcnzyl-N-(2-(A/,A^-dimcthylaniino)cthyl)aminosulfonyl) phenylsulfonyloxy]phenoxy] propoxyjphthalimide, as prepared in the preceding step, in a manner analogous to step d of l-xample OK. 'I I-NMR (300 Ml I/, C'DCI,) 511), 6.62 (s, 111), 6.5'Us, 211). 5.37 (br x, 211), 4.6K (s, 211). 3.2 (I. ¦" ' 6.3 11/.. 211), 3.7X (t, J - 6.2 Hz, 2H), 3.38 (t, J = 7.0 Hz, 2H), 2.26 (t, J - 7.1 Hz, 2H), 2.23 (s, 3H), 2.06 (s, 6Y\\ 1.99 (pentet, J = 6.2 Hz, 2H). c) 3-|5-Mcthyl-3-(2-(yV-bcnzyl-7V-(2-(A',A'-tl""cthylaiHino)cthyI)aiiiiiiosulfonyl) phcnylsulfonyloxy)phcnoxy]prppoxyguanidinc dihydrochloride: The title compound was prepared in 76% yield from A'-{3-[5-mcthyl-3-[(2-(A'-bcnzyl-A/~(2HA/JA/- dimcthylamino)c1hyl)aminosiilfbnyl)phcnylsulfonyloxy]phciioxy]propoxy}aminc, as prepared in the preceding step, in a manner analogous to step ToT l:\ample 1. '1 I-NMR (300 MHz, DMSO-dG) 8 11.98 (br s, 2H), 8.18 (d, J = 7.7 Hz, 1H), 8.16 (d, J = 7.7 Hz, 1H), 7.96 (U -7.7 1!/., Ill), 7.S9(l,.I-7.7 11/.. Ill), 7.0*) (brs,'III), 7.3-1 (m, 511), 6.76 (s. 111), 6.55 (s, 1H), 6.51 (s, 111), 4.64 (s, 2H), 3.98 (t. J = 6.2 Hz, 2H), 3.89 (tf J - 6.3 Hz, 2H), 3.69 (t, J - 7.1 Hz, 2H), 2.85 (br s, 2H), 2.51 (s. 611). 2.22 (s, 3H), 2.01 (pentet, J - 6.3 Hz, 2H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxy.cinnamic acid matrix) calcd. for C2KH37N5O7S2: 620.2 (M + H), 642.2 (M + Na). Found: 620.2, 642.1. -138- Example 71 {3-l5-Methy!-3-(2-(N-me1hy!-N-(l-!netltyl-4-pipcridinyI)aminosuIfonyl) phenylsulfonyloxy)p!tenoxylpropo.xy}guaiiidine dihydrochloride :i)AH3-|5-McUiyl-3-|(2-(/V-nictliyl^ sulfony!oxyjplicnoxylpropoxy}plitha)imi()c: The title compound was prepared in 96% yield from l-mclhyl-4-(melhylamino)pipcridine in a manner analogous to step c of Example 68, 'H-NMR (300 MHz, CDC13) 5 8.33 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.83 (m, 3H), 7.78 (m, 2H), 7.69 (t, J = 7.6 Hz, 1H), 6.63 (s, 1H), 6.54 (s, 1H), 6.51 (s, 1H), 4.61 (m, 1H), 4.36 (t, J = 6.1 Hz, 2H), 4.10 (t, J = 6.1 Hz, 2H), 4.39 (m, 2H), 2.92 (I, J = 12.0 Hz, 2H), 2.79 (s, 3H), 2.74 (s, 3H), 2.55 (m, 2H). 2.24 (s. 3H), 2.17 (pentet, J = 6.1 Hz, 2H), I.99(m,2II). b) 7V-{3-|5-Mcthyl-3-I(2-(yV-incthyl-Ar-(l-inc yield from A/-{3-[5-meihyl-3-[(2-(A/-mclhyl-A'-(l-nicthyl-4-piperidinyl)aminosulfonyl) plienylsulfonyloxy]phenoxy]propoxy}ainine, as prepared in the preceding step, in a manner analogous to step d of Example 68. '11-NMR (300 MHz, CDC13) 5 8.30 (d, J = 7.9 Hz, 1H), 8.13 (d, .1-7.01!/, Ill), 7.78 (U'7.Ml/, 111), 7.61 ((, .1 -7.6 11/., Ill), 6.5N {s. III), 6.56 (s, 1H), 6.54 (s, 111), 5.36 (br s, 211), 4.06 (m, 111). 3.91 (l, J - 6.3 Hz, 211), 3.79 (t, J = 6.2 Hz, 2H), 2.90 (m, 211), 2.83 (s, 311), 2.28 (s. 311), 2.23 (s, 311), 2.11 (mf 211), 1.99 (pemet, J = 6.1 Hz,2H), 1.84 (m,2H), 1.68 (m, 211). c) A'-{3-[5-Mc(]iyl-3-[(2-(A;-inctliy!-A'-(l-nictIiy]-4-pipcridiiiy]);iininosiilfonyl) pIicnylsuiruny]oxy|plicnoxy]prupoxy}giKinidinc dihydrochlorklc: 1 he title compound was prepared in 76% yield from Af-{3-[5-methy]-3-[(2-(A/-methyl-A/-(l-melhyl-4-piperidinyl) aminosulfonyl)phcnylsullbnyloxy]phenoxyjpropoxy}phthalimide, as prepared in the preceding step, in a manner analogous to step f of Example 1. 'H-NMR (300 MHz, DMSO- d,,)(SX.25 (d, .1-7.9 11/, 111), S.I 5 (d..I 7.1> 11/, 111). S.02 (t, .1 -7.0 11/, III), 7.8l> (1. .1 - 7.711/, HI), 7.37 (br s, ^H I), 6.75 (s. Ill), 0.53 (s. 111), 6.47 (s. III), 4.07 (m. 111). 3.97 (t. J = 6.3 11/, 211), 3.87 (I, .1 - 6.3 11/. 211). 3.22 (in, 211), 3.17 (s, 311), 2.79 (s, 311), 2.72 (1, J = 12.0 Hz, 2H), 2.22 (s, 3H), 1.99 (pentet, J - 6.3 Hz, 4H), 1.60 (m, 2H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C.jH^N.O^,: 570.2 (M + H), 592!2 (M + Na). Found: 570.1, 592.1. - 139- kWampfe 72 3-l5-Methyl-3-(2-(N-wethyl~N-(3-pyii phcnylsulfonyloxy] phenoxyjpropoxyjplithalimide: The title compound was prepared in 88% yield from 3-(mclliyInmiuomelhyl)pyridinc in a nuinner analogous to step c of Example 68. 'II-NMR (300 MHz, CDCI3) 5 8.56 (m, 211), 8.35 (d, .1 = 7.9 1 Iz, III). 8.21 (d, J = 7.9 Hz, 111), 7.69-7.86 (m, 711), 7.32 (m, 111). 6.64 (s, 111), 6.62 (s. 111), 6.54 (s. 111). ¦ 4.61 (s, 2H),4.36 (i, J - 6.1 Hz, 2H), 4.11 (t, J -6.1 Hz, 2H), 2.77 (s, 3H), 2.26 (s, 3H), 2.18 (pentet,J = 6.1 Hz, 2H). b)3-[5-Methyl-3-[(2-(7V-methyl-7V-(3-pyriilylmethyl)aniinosuIfonyI)phcnylsulfonyloxyl phenoxy]propoxyaininc: The title compound was prepared in 90% yield from A'-{3-[5-methyl-3-|(2-(A^-nicthyl-A'-(3-pyridylmctliyl)anii]iosulfonyl)phcnylsulfon>ioxy]phenoxy] propoxyjphthalimide, as prepared in the preceding step, in a manner analogous to step d of Example 68. '11-NMR (300 MHz, CDC!,) S 8.56 (m, 211), 8.34 (d. .1 = 7.9 11/., 111), 8.20 (d, J = 7.9 Hz, HI), 7.81 (I, J = 7.7 Hz, 211), 7.70 (t. J = 7.7 Hz, 1H), 7.32 (m, 1H), 6.60 (s. 1H), 6.58 (s. 111), 6.57 (s, II I), 4.60 (s, 211). 3.93 (1,.! 6,3 11/, 211), 3.7S (t,.! - 6.1 1 Iz, 211), 2.77 (s, 3H), 2.24 (s, 3H), 2.00 (pentet, J = 6.2 Hz, 2H). c)3-15-Mcthyl-3-|(2-(Ar-nicthyl-Ar-(3-pyritlylinclhyI)aminosuIf"nyl)phenylsu!fonyloxyl phcnoxyjpropoxyguanidinc dihydroehloiidc: The title compound was prepared in 76% yield from 3-[5-mcthyl-3-f(2-(Ar-nKthyl-A^(3-pyridylmethyl)nminosulfonyl) phcnylsulfonyloxy]phenoxy]propoxyamine. as prepared in the preceding step, in a manner analogous to step f of Example 1. "Il-NMR (300 MHz. DN4SO-d(l) 5 8.78 (t, J = 5.2 Hz, 2H), 8.23 (ni, 311), 8.06 (1, J =7.7 1 Iz, 111), 7.94 (t, J -7.7 I Iz, 111), 7.88 (t, J = 7.9 I Iz. 111), 7.71 (br s, 4H), 6.75 (s, 1H), 6.55 (s, 1H), 6.51 (s, 1H), 4.72 (s, 2H), 3.99 (t, J = 6.3 Hz, 2H), 3.90 (t, J - 6.4 llz, 211), 2.88 (s, 311). 2.22 (s, 311). 2.01 (pentet, .1 .= 6.4 Hz. 211). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) catcd. for C2.]H29N5O7S2: 564.2 (MH-H), 586.1 (M+Na). Found: 564.1,586.2. - 140 - Example 73 H5^1ethy^3-(2-(N-t'thyl-N-(2-(N,N'(Iinwthyliunino) e(hyl)anwu)sulf(wyl)pheiiylsuffonyhxy)phenoxyJimipoxygua a) 3-|5-MclIiyl-3-(2-(yV-c(hyl-yV-(2-(A',^-tliincfhylamino) ethyl) siiuiiiosiilfoiiyl) phciiyIsullonyloxy)plKinoxy]propoxy phlhalimide: The title compound was prepared in 100% yield from A^ N-dimclhyl-A'-ethylclhylcncdianiinc in a manner analogous lo step c of Example 68. 'H-NMR (300 MHz, CDC13) 5 8.27 (d, J = 7.9 Hz, 1H), 8.18 (d, J = 7.9 Hz, 1H), 7.75-7.86 (m, 511), 7.69 (t, J = 7.7 Hz, III), 6.61 (s, III), 6.58 (s, 1H), 6.52 (s, 1H), 4.36 (t, J = 6.2 Hz, 2H), 4.10 (t, J = 6.1 Hz, 2H), 3.81 (br s, 2H), 3.45 (q, J = 7.1 Hz, 2H), 3.00 (br s, 2H), 2.59 (s, 6H), 2.24 (s, 3H), 2.17 (pentet, J = 6.1 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H). b) 3-|5-McihyI-3-(2-(A^-e(]iyl-A^-(2-(yV,yV-diiiiclIiylamino) ethyl) aiiiinosulfoiiyl) phenylsulfoiiyloxy)phcnoxy|propoxyaminc: The title compound was prepared in 97% yield from 3-|5-melhyl-3-(2-(A;-ethyl-7V-(2-(A^,A'-dimelhylamino)ethy!)aminosulibnyl) phenylsulfonyloxy)phenoxy]propoxy phthalimide, as prepared in the preceding step, in a manner analogous to slop d of l-xample 6X. M I-NMR (300 Mil/, t'DCI,) o S.32 (d, .1 - 7.9 Hz, 1H), 8.15 (d, J = 7.9 Hz, 1H), 7.76 (t, J = 7.7 Hz, 1H), 7.63 (t, J - 7.7 Hz, 1H), 6.60 (s, 1H), 6.58 (s, 1H), 6.57 (s, 1H), 5.39 (br s, 2H), 3.92 (t. J = 6.3 Hz, 2H), 3.78 (t, J - 6.1 Hz, 2H), 3.49 (m, 4H), 2.46 (t, J - 7.1 Hz, 211), 2.23 (s, 3H), 2.21 (s, 6H), 1.99 (pentel, J - 6.2 Hz,2H), 1.16 (t,J = 7.1 Hz,3H). c) 3-[5-Mcthyl-3-(2-(yV-ciliyl-yV-(2-(A',A'-diincihylainino)cthyl)aniinosulfoiiyl) phcnylsiilfonyIoxy)plienoxy]propnxyRiiani(liiiv dihydiochloride: The title compound wLisprcparcxlin52%yieldiVoiii3-[5Mncthyl-3-(2-(A^ethyl-A42-(A/.A/-diiiiethyiaiiiino)ethyl) aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyamine, as prepared in the preceding step, in a manner analogous to step f of Example 1. 'I I-NMR (300 MI Iz, DMSO-dfl) 5 8.19 (d, J - 7.8 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.03 (t, J - 7.7 Hz, 1H), 7.90 (t, J = 7.7 Hz, 1H), 7.69 (br s, 411), 6.75 (s, 111), 6.53 (s, 111). 6.50 (s. 111), 3.98 (t, J - 6.2 1 Iz, 211), 3.90 (t, J = 6.3 Hz, 211), 3.78 (I, J = 7.0 Hz, 2H). 3.44 (q, .1 -7.1 Hz, 2H), 3.30 (t, J -7.3 Hz, 2H), 2.79 (s, 611), 2.22 (s, 311), 2.02 (pentel, J - 6.3 Hz, 211), 1.09 (t, J = 7.1 Ilz, 311). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C::,H15N5O7S2: 558.2 (M + H), 580.2 (M + Na). Found: 558.3. 580.3. - 141 -Example 74 3-l5-MetItyl-3-(2-(2-(4-inor[)horinyI)ethyhtniiitosulfoi!yl)pheiiylsti!fonyIo.xy) phenoxy fpropoxyguaniditte dihydrochloride a) 3-|5-Mt aminocthyl)morpholinc in a manner analogous to step e of Example 68. 'II-NMR (300 MHz, CDC13) 8 8.37 (d, J = 7.8 Hz, III), 8.08 (d, J = 7.8 Hz, 1H), 7.75-7.86 (m, 5H), 7.70 (t,J-7.7Hz, lH),6.68(s, lH),6.63(s, lH),6.58(s, lH),6.53(s, 1H), 4.36 (t, J = 6.1 Hz, 2H), 4.11 (t, J - 6.1 Hz, 2H), 3.89 (m, 6H), 3.48 (m, 6H), 2.24 (s, 3H), 2.18 (pentet, J = 6.1 Hz,2H). o b) 3-13-Mclliyl'3*(2-(2-(4-morplioIinyl)cthyhiiiiiiiosuiroiiyl) plienylsullonyloxy) phenoxy] propoxyaminc: The title compound was prepared in 96% yield from 3-[5- melliyl~3-(2-(2-(4-nun"pl)o!iiiyl)etliy laminosulfonyl)phenylsullbny lo\y)plienoxyj propoxyphthalimide, as prepared in the preceding step, in a manner analogous to step d of Example 68. 'H-NMR (300 MHz, CDCi,) S 8.36 (d, J = 7.8 Hz, 1H), 8.06 (d, J - 7.8 Hz, 1H), 7.81 (t, J = 7.7 Hz, III), 7.66 (t, J = 7.7 Hz, IH), 6.68 (s, Hi), 6.60 (s, 1H), 6.58 (s, III), 6.56 (s, III), 3.90 (t,J = 6.1 Hz. 211), 3.79 ((, .1 = 6.1 11/.. 211), 3.67 (br s, 411). 3.14 (br s, 2H), 2.36 (m, 6l\), 2.23 (s, 3H), 1.99 (pentet, J - 6.2 Hz, 211). c) 3-[5-Mc(li>i-3-(2-(2-(4-iiinrplioliiiyl)clliyIaniinosiiironyl)phcnylsuironyloxy) plicnoxyj propoxyguunidinc dihydrochloride: The title compound was prepared in 60% yield from 3-[5-methyl-3-(2-(2-(4-morphoIinyl)ethylaminosuIfonyI)phenylsuIfonyIoxy) phenoxy] propoxyaminc, as prepared in the preceding step, in a manner analogous to step f of Example 1. 'H-NMR (300 MHz. DMSO-d,) 5 8.28 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 7.8 Hz, III), 8.05 (i, J - 7.7 Hz, HI), 7.95 (br s, III), 7.90 (t, J = 7.7 Hz, III), 7.72 (br s, 411), 6.76 (s, 1HJ, 6.55 (s, 1H), 6.50 (s, IH), 3.98 (t, J - 6.3 Hz, 2H). 3.91 (t, J = 6.3 Hz, 2H), 3.79 (m, 411), 3.25 (br s, 411), 3.17 (in. 41!), 2.23 (s. 31 i), 2.02 (penlct. J - 6.3 M/,, 211). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for QII-^NJOKS,: 572.2 (M + H), 594.2 (M + Na). Found: 572.3. 594.4. - 142- Example 75 3-/5-Me/hyl-3-(2-(N-ntetft)>l-N-(2-(N,N-dintetftylamino)e^ phetiy!suIfonyloxy)pUenoxy]propoxygu(wid'uie hydrochloride a) 3-|5-MeHiyl-3-(2-(A^-iiictliyl-7V-(2-(A^-cIiincthylainino)ethyl)aniiiiosiilloiiyl) phcny]suircuyloxy)p]icnoxy]propoxyplithaliniidc: The title compound was prepared in 98% yield from A',A/,A/'-irimcthylcthylenediaminc, in a manner analogous to slop c of Example 6S and was used without characterization. b) 3-|5-Mcthyl-3-(2-(A^-incthyl-Ar-(2-(N,Ar-dinicthyIamiiio)cthyl)aminosulfonyl) phcnylsulfonyloxy)phcnoxy]propoxyaminc: The title compound was prepared in 66% yield from 3-[5-melhyl-3-(2-(Af-methyl-A^(2-(A/,A'-dimethylamino)ethyl)aminosulfonyl) phenylsulfonyloxy)phenoxy]propoxyphlhalimide, as prepared in the previous step, in a manner analogous to step d of Example 68, and was used without characterization. c) 3-15-Mcthyl-3-(2-(A'-iiKtliyI-A42-(A/.A'-(linic(hy!aniino)c(hyl)aiiiinosiiir phcnylsu!fonyloxy)phcnoxy]propoxyguanidinc hydrochloride: A mixture of 3-[5- nicth)M-3-(':-(W-inc(iiyl-A/-(2-(A',A/-(linuiIiyIanii!io)cthy])aniinosiHlbnyl)phciiylsuironyloxy) phenoxyjpiopoxyaminc (94 nig, 0.19 inmol) and 1 //-pyrn/.ole-1 -carboxainRliuc hydrochloi'de (57 ing, 0.39 nunol) in A'.A'-diniclhylformamide (8 ml,) was stirred at room "temperaluie for 18 hours then concentrated in vacito. The residue was dissolved in acetonitrile, filtered, and the filtrate concentrated to an oil. This was dissolved in dilute HCI (pH 3), washed with diethyl ether, basified with aqueous NaHCO3, and extracted with CH2C12. The CH2C12 layer was washed with pH 7 buffer and brine, dried over Na2SO4 and filtered. The filtrate was acidified with IlCI-mclhanol and concentrated giving the title compound as a white solid (100 mg, 92%). 'II NMR (300 MHz, CDC13) 5 8.20 (m, 2H), 7.93 (Id, 1UJ-7.7, 1.4 I Iz), 7.78 (id. Ill, J-7.7, 1.2 Hz), 6.62 (m. 211), 6.51 (1, 111, J = 2.2 Hz), 4.05 (t, 2H,) - 6.1 Hz), 3.99 (t, 2H. J = 6.0 Hz), 3.87 (t, 2H, J = 6.9 Hz), 3.44 (t, 211, J - 6.9 11/), 3.01 (s, 3II), 2.96 (s, 6H). 2.27 (s. 3Il), 2.10 (in. 2II). Mass spectrum (MALD1-TOF, cx-cyano-4-hydroxycinnamic acid matrix) calcd. for C23H33N5O7S2: 544.2 (M+H). Found: 544.0. - 143 - Example 76 3-[5-Methyl-3-(2-(4-(pyn'olidin-}-yl)piperidin-l-ylsttlfonyl) pheitylsiilfonyfoxy)p/tenoxyfpropoxygttanidine a) 3-|5-Methyl-3-(2-(4~(pyrrolidiii-l-yl)pipcritIia-l-ylsiiUonyl)pheiiylsuiroiiyl(>xy) phcnoxyjpropoxyphthalimidc: The title compound was.prepared in 99% yield from 4-(l- pyrrolidinyl)pipcridine, in a manner analogous to step c of Example 68, and was used without characterization. b) 3-[5-Mcthyl-3-(2-(4-(pyrrolidin-l-yl)pipcridin-l-ylsulfonyl)phcnyIsulfonyloxy) phcnoxy] propoxyaminc: The title compound was prepared in 66% yield from 3-[5- methyl-3-(2-(4-(pyrrolidin-l-yl)piperidin-l-ylsuIfonyl)phenylsulfonyloxy)phenoxy] propoxyphthalimide, as prepared in the previous step, in a manner analogous to slop d of Example 68, and was used without characterization. c) 3-|5 Mclhyl-3-(2-(4-(pyiro!idin-l~yI)pipcridiH-l-yI.sulf()iiyI)plienylsulfonyloxy) phenoxy] propoxyguanidinc: The title compound was prepared in 76% yield from 3-[5- methyI-3-(2-(4-(pyrroIidin-l-yl)pipcridin-l -ylsulfonyl)phenylsiilfonyloxy)phenoxy] propoxyaminc, as prepared in the previous step, in a manner analogous to step c of Eg. 75 (without acidification wilh I ICl-MeOI 1). Ml NMR (300 MI I/., COCI,) fi 8.25 (dd, 111, J = 7.9, 1.3 Hz), 8.17 (dd, 1H,J = 7.9, 1.4 Hz). 7.78 (td, 1H, J - 7.7, 1.4 Hz), 7.66 (td, 1H,J = 7.7, 1.4 I-]::), 6.59 (in, 211), 6.54 (t. III, J - 2.2 Hz), 3.92 (m, 6H), 2.93 (m, 2H), 2.59 (m, 4H), 2.24 (s, 3H), 1.99 (m, 5H), 1.79 (m, 411), 1.65 (m, 2H). Mass spectrum (MALDI-TOF, ct-cyano-4-hydroxycinnamic acid matrix) calcd. for C26H37N5O7S2: 596.2 (M+H). Found: 595.9. Example 77 3-l5-MethyI-3-(2-(4-ethoxyc(irboiiyl-l-piperazinyhuIfoiiyl) phirnylsiilf0nytaxy)phenoxylpropoxygu(iiti(line hydrochloridc a) 3-[5-Mctliyl-3-(2-(4-vUioxycarl>oiiyI-l-pipora/jnylsiiiroiiyl)phcnylsiiiroiiyloxy) phcnoxy]-propoxyphlliaHinidc: The title compound was prepared in 97% yield from ethyl A^-pipcrazinccarboxylate, in a manner analogous to step c of Example 68. Ml NMR (300 MHz, CDC13) 5 8.29 (dd, 1H, J = 7.9, 1.4 Hz), 8.18 (dd, 1H. J - 7.8, 1.4 Hz), 7.81 (m, 5H), 7.70 (td, IM, J = 7.7, 1.4 Hz), 6.63 (m, III), 6.58 (m, 1H), 6.49 (t, 1I-I, .1 - 2.2 Hz), 4.12 (in, 4H), 3.55 (m, 41-1), 3.36 (br s, 4H), 2.25 (s. 311), 2.18 (pentct, 2H, J = 6.1 Hz), 1.24 (t. 3H, J = 7.1Hz - 144- b) 3-[5-McUiyl-3-(2-(4-ctIioxycarbonyl-1-piperazinylsiilfonyl)pIicnyIsiiIfoiiyloxy) plivnoxylpi-opoxysiiniiie: The lillc compound was prepared in quantitative yield from 3-[5- methyl-3 -¦(2-(4-c(hoxycarbonyl-l-pipcrazinylsuIfony])phenylsulfonyloxy)phenoxy] propoxyphlhalimidc, ;ts prepared in llic previous step, in a manner analogous to slep d of Example 68, and was used without characterization. c) 3-|5-MetliyI-3-(2-(4-clhoxycaib(inyl-l-pipcnr/,iiiylsiiiroiiyI)plu'iiylsiiironyloxy) phenoxyjpropoxyguanidinc hydrochloridc: The title compound was prepared in 78% yield from 3-[5-methyl-3-(2-(4-ethoxycarbonyl-l-piperazinylsulfonyl)phenylsulfonyloxy) phenoxyjpropoxyamine, as prepared in the previous step, in a manner analogous to step c of Example 75. 'II NMR (300 MHz, CDCI3) 6 8.24 (d, 1H, J = 7.6 Hz), 8.18 (d, 1H, J - 7.6 Hz), 7.84 (t, 1H, J - 7.5 I Iz), 7.73 (t, 1J I, J - 7.5 Hz), 6.58 (br s, 2H), 6.50 (s, 1J -I), 4.11 (q, 2H, J = 7.1 Hz), 4.07 (m, 2H), 3.96 (m, 211), 3.55 (m, 4H), 3.34 (m, 4H), 2.23 (s, 3H), 2.08 (m, 211), 1.23 (I, 311, .1 - 7.1 11/.). Mass spectrum (MALDI-TOF, a-cyano-4- hydroxycinnamic acid matrix) calcd. for C^I-T^NsOgS,: 600.2 (M+H), 622.6 (M+Na). Found: 600.3,622.2. Example 78 3-l5-MciItyl~3-(2-(N~methyl-N-(3-(N,N-dimethylamhw)propyl)aminosulfoiiyl) phenylsulfonyloxy)phenoxy]propoxygttanidine a) 3-|5-McUiyl-3-(2-(yV-inc(]iyi-A;-(3-(A/,A^(liiiicUi)!ainiM(i)pn)p)l):iiiiiii("siill(>nyl) phcnylsulfonyloxy)phenoxy|propoxyphthaliniidc: Tlic title compound was prepared in 97% yield from A^A'-trimcthyl-l^-propanediamine, in a manner analogous to step e of Example 68. 'H NMR (300 MHz, CDC13) 5 8.23 (dd, 1H, J = 7.9, 1.3 Hz), 8.16 (dds 1H, J = 7.9, 1.4 Hz), 7.81 (m, 5H), 7.66 (td, 1H, .1-7.7, 1.4 Hz), 6.61 (m, 2H), 6.53 (t, 1H,J = 2.1 Hz), 4.36 (t, 2H, J - 6.2 Hz), 4.10 (t, 2H, J ^ 6.1 Hz), 3.39 (t, 2H, J = 7.3 Hz), 2.95 (s, 311), 2.32 (m, 211), 2.24 (s, 311), 2.21 (s, 611). 2.16 (m. 211). 1.80 (m. 211). b) 3-|5-McthyI-3-(2-(yV-mc(liyI-7V-(3-(A',Ar-dimctliyliiiiiino)propyl)aininosulfonyI) phciiyIsuIf(niyI()xy)pIu'imxy|[>rn]>oxy:iiniiK': The title compound was prepared in quantitative yield from 3-[5-methyl-3-(2-(A/-methyl-AA-(3-(A/.A'-dimethylamino)propyl) aminosulfonyl)pheny!suiibnyloxy)phcnoxy]piopoxyphthalimide, as prepared in the previous step, in a manner analogous to step d of Example 68, and was used without characterization. - 145- c) 3-(S-McthyI-3-(2-(Ar-ine(hyI-Ar-(3-(A'rAr-(!iiiic(liyl;unino)pr"pyI)uiiiinosuiriMiyl) phcny]sulfoiiyluxy)pliciioxy|propoxygiiauidiiic: The lilie compound was prepared in 78% yield from 3-[5-methyl-3-(2-(A'-me(hyi-7V-(3-(MA'-dimclhylamino)propyl) aniinostiHbnyl)phenyIsiiIf()i]yli>.\y)pheiH)xy |propoxyamine, as prepared in (lie previous step, in a manner analogous lo step c of Example 75 (without acidification with MCl-mcthanoJ). lMNMR(300MII/,,CDCI1/CD;)(^^)oK.IK(tld, HU = 5.2, 1.4 ! Iz), 8.15 (dd. 111, J = 5.2, 1.4 Hz), 7.83 (Id, 1H, J = 7.7, 1.4 I Iz), 7.70 (id, II I, J = 7.7, 1.4 Hz), 6.60 (m, 1H), 6.57 (m, 1H), 6.52 (t, 1H, J = 2.2 Hz), 3.95 (t, 2H, J = 6.3 I Iz), 3.92 (t, 2H, J = 6.1 Hz), 3.37 (m, 2H), 2.95 (s, 3H), 2.38 (m, 2H), 2.27 (s, 6H), 2.24 (s, 3H), 2.03 (pentet, 2H, J = 6.2 Hz), 1.81 (pentet, 2H. J = 7.4 Hz). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C23H35N5O7S2: 558.2 (M+H). Found: 558.0. Example 79 3-(5-Methyl-3-(2-(4-pyri a) 3-[5--Mclliyl-3-(2-(4-pyridylnictIiylnminosulfoiiyl)plicnylsulfonyIoxy)phciioxy] prop(>\ypli(li:ilimi(!c: The title compound was prepared in 97% yield from 4-(amiuo- methyl)pyridine, in a manner analogous to step c of Eg. 68. 'H NMR (300 MHz, CDC13) 5 8.46 (dd, 211, J = 4.5, 1.6 Hz), 8.23 (dd, 1H, J = 7.7, 1.5 Hz), 8.04 (dd, IH, J = 7.7, 1.5 Hz), 7.84 (m, 2M), 7.75 (m, 3H), 7.65 (id. 111, J = 7.6, 1.5 Hz), 7.16 (dd, 211, J = 4.5, 1.5 Hz), 6.64 (brs. III), 6.62 (s. Ill), 6.59 (br s. 111). 6.54 (t. Ill, .1 = 2.2 Hz). 4.36 (t, 2H. J = 6.1 Hz), 4.22 (d, 211, .1 - 6.6 1 Iz), 4.10 (I, 211, J - 6.1 I Iz), 2.24 (s, 311), 2.17 (pentet, 211, J = 6.1 Hz). b) 3-[5-MctIiyl-3-(2-(4-pyridyIinclhylamiiiosulfonyl)phcnyIsulfoiiyIoxy)pliciioxy] propoxyaminc: The title compound was prepared in quantitative yield from 3-[5-methyl-3- (2-(4-pyridylmethylaminosuironyi)phenylsulfonyloxy)phcnoxy] propoxyphthalimide, as prepared in the previous step, in a manner analogous to step d of Example 68, and was used without characterization. c) 3-[5-Mctliyl-3-(2-(4-pyridyInicthylainiiiosiilfunyl)plicnylsiilfonyIoxy)phcnoxy] pnipoxy^nanidinc: The title compound was prepared in 78%> yield from 3-[5-mcthyl-3-(2- (4-pyridyImethylaminosulfonyl)phcnylsulfonyloxy)phenoxy] propoxyamine, as prepared in the previous step, in a manner analogous to step c of Example 75 (without acidification with - 146- HCl-me(hap.ol). 'M NMR (300 MHz, CDC13) 8 8.46 (dd, 211, -I - 4.5, 1.6 11/.), 8.21 (dd, 1H, J = 7.8, 1.4 11/), 8.03 (del, III,.I- 7.7, 1.4 11/.), 7.73 (kl, 111, J-7.6, 1.5 11/), 7.64 (id. 111, J = 7.7, 1.4 Hz), 7.15 (m, 2H), 6.60 (br s, 1H), 6.58 (br s, 1H), 6.54 (t, 1H, J = 2.1 Hz), 4.22 (s, 2H), 3.95 (m, 4H), 2.23 (s, 3H), 2.02 (m, 2H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C22H3IN5O7S2: 550.1 (M+H), 572.1 (M+Na). Found: 550.2,572.1. Example 80 N-Methyl-N~{3-[5-methyl-3-(2-(methylstttfonyl) phenylsulfottyloxy)phenoxy]propoxy}guanidine hydrochloride a) Ar,Arr-(Bis-/e/-/-butyloxycarbonyl)-A^f-{3-I5-niciliyl-3-(2-(nicthyIsulfonyI) phcnylsulfonyloxy)phcnoxy]propoxy}guanidinc: The title compound was prepared in 70% yield from 2-melliylsulfonylbcnzcnesulfonyl chloride in a manner analogous to step b of Example 19. 'H-NMR (300 MHz, CDC13) 8 9.08 (s, 1H), 8.45 (d, J = 7.8 Hz, 1H), 8.10 (d, .1-7.8 Hz, Hi). 7.88 (I, .1-7.7 11/, 111), 7.74 (t, .1 - 7.7 11/,, 111). 7.70 (s, 111), 6.5 (s, 2H), 6.54 (s; 1H), 4.18 (t, J -6.2 Hz, 2H), 3.94 (t, J - 6.1 Hz, 2M), 3.45 (s, 3H), 2.23 (s, 3H), 2.10 (pentet, .1 = 6.2 II/..2H), 1.49 (s, 1811). b)yV,/V'-(Bis-/tr/-bu(yIoxycai1)onyI)-A/M-iiicHiyl-^M-{3-[5-nKMhyl-3-(2-(inctIi3Jsu]fonyI) plicnylsulfonyloxy)pliviioxy]propoxy}guaiiidinc: To a solution of Ar,/V-(bis-/e/7-butyloxycaibonyl)-A'"-{3-[5-methyl-3-(2-(methyIsulfonyl)pIienylsulfonyloxy)phenoxy] propoxy}guanidine (220 ing, 0.334 mmol), as prepared in the preceding step, triphenylphosphine (105 ing, 0.4 mmol) and anhydrous mcthanol (13 ing, 17 (L, 0.4 mmol) in tctrahydrofuran (5 mL) was added dicthy! a/.odicarboxylatc (70 ing, 0.4 mmol). The mixture was stirred al ambient for 4 h. After evaporated the solvent /// vacua, the residue was purified on a Waters Sep-Pak (10 g silica, dichloromethane to 2% ethyl acetate in dichloromcthanc) to give the title compound as a colorless oil (100 mg, 45%). 'H-NMR (300 MHz, CDC1,) 5 8.45 (d, J = 7.8 Hz, HI), 8.13 (d, J - 7.8 Hz, 1H), 7.88 (t, .1 = 7.7 Hz, 1H), 7.75 (t, J = 7.7 IIz, 1II), 7.30 (s, 1H), 6.60 (s. 111), 6.59 (s, 1M). 6.58 (s, 1H), 4.17 (t, J =6.1 Hz, 2H), 3.94 (t, J - 6.1 Hz, 2H), 3.45 (s, 3H), 3.09 (s, 3H), 2.24 (s, 3H), 2.10 (penlet, J -6.2 Hz, 2H)S 1.48 (s. 911), 1.44 (s, 9H). c) A^-Mciliy!-yV-{3-|5-iiicthyl-3-(2-(me(hylsnlfonyl)phcnylsulfonyloxy) phenoxyjpropoxy} ^uanidhic hydrochloride:. The title compound was prepared in 89% - 147 - yield from A^,A^'-(bis-^;7-butyloxycarbonyl)-A'"-melhyl-A^"-{3-[5-nicthyl-3-(2- (mclhylsulfoiiyi)phcnyl.sulfouyloxy) phenoxylprupoxy }gu;midine, as prepared in (lie preceding step, in a manner analogous to step i of Example 20. 'H-NMR (300 MHz, DMSO-d6)5 H.00(s, 1H), 8.37 (d, J = 7.8 Hz, 111), 8.13 (d, J = 7.9 Hz, 1H), 8.11 (t, J -7.7 Hz, 1M), 7.96 (t, J - 7.7 Hz, 1H), 7.53 (br s, 311), 6.75 (s, 1H), 6.54 (s, 1H), 6.50 (s, 1H), 3.98 (t, J =6.2 Hz, 2H), 3.87 (l, J - 6.2 Hz, 211), 3.47 (s, 3H), 2.72 (s, 311), 2.22 (s, 3H), 2.00 (pentet, J = 6.3 Hz, 2H). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C^II^O^: 472.1 (M + U), 494.1 (M+Na). Found: 472.1.494.0. Example 81 3-l3-MetItyl-5-(N-methyI'2-(metliylsu!foityl)plieitylsulfoiiyl(iwitto) phenoxyjpropoxyguanidute hydrochloride a) 2-Broino-2-iiic(hylpropan;iinulc: To a vigorously stirred solution of 2-bromo-2- methylpropanoyl bromide (11 mL) in light petroleum ether (250 mL) at 0 ° C was added in portions aqueous ammonia (50 ml.). Stirring was continued for a further 30 min., and the resulting precipitate was collected and washed with water (2 x 50 mL) to give the title compound as a white .solid (14.1 g, 96%) which was directly used for next step without further purification. b) (3-Bciizyloxy-5-mcthyl)pliciioxy-2-iiicthyIpropnnaniidc: 3-BenzyIoxy-5- mcihylphcnol (2.14g, lOmmol), as prepared in step a of Example 20, was stirred in dry 1,4- dioxane (50 mL) with sodium hydride (265 mg, 11 mniol) for 1 h. 2-Bromo-2- methylpropanainidc (1.66 g, 10 mmol), as prepared in step b, was added and the reaction mixture was heated to 80 °C for 6 h. After cooling , the precipitated sodium bromide was filtered off, the filtrate was evaporated //; vacua. The residue was purified by Hash column chromatography (7% ethyl acetate in dichloromethane) to give the title compound as a pale yellow solid (2.50 g, N3%). 'II-NMR (300 MHz, CDC1.0 o* 7.40 (m, 511), 6.61 (br s, 111), 6.54 (s, 111), 6.38 (s, 211), 5.69 (br s. 111). 5.29 (s. 2H), 2.2S (s, 3M), 1.97 (s. 3H). 1.52 (s, 311). c) Ar-l-(3-I)ciizyIoxy-5-mclIiylphcnyl)-2-Iiydroxy-2-inc(liy]propHnamidc: To a solution of 2-(3-benzyloxy-5-methyI)phenoxy-2-methyIpropanamide (1.50 g. 5.0 mmol). as prepared in the preceding step, in l,3-dimethyl-3,4.5,6-tc(rahydro-2(l/-/)-pyrimidinone (DMPU) (2 mL) and A^/V-dimethylformamidc (18 mL) was added sodium hydride (360 mg. 15 mmol). - 148- the mixture was heated to 100 °C for 3 h. The solution was poured into water (200 mL) and extracted wilh clhyl acetate (3 x 100 ml,)- The organic phase \v;is washed with water (3 x 100 mL), dried over Na2SO,,, and concentrated in vacua. The residue was purified by flash column chromatogrnphy (5% ethyl acetate in dichloromclhanc) to give the title compound as a white solid (870 mg; 58%). 'H-NMR (300 MHz, CDC13) 5 8.61 (s, 1H), 7.42 (m, 5H), 7.28 (s, 111), 6.93 (s, ! 11), 6.59 (s, II I), 5.05 (s, 211), 2.30 (s, 311), 2.18 (s, 111), 1.58 (s, 311), 1.56 (s,3H). d) Bcnzyloxy-5-mcthylanilinc: W-l-(3-Benzyloxy-5-methyIphenyI)-2-hydroxy-2-methylpropanamide (600 nig, 2.0 mmol), as prepared in the preceding step, was mixed with ION NaOH (25 mL) and cthanol (10 mL), the mixture was healed to reflux for2 days. After cooling to ambient temperature, the mixture was diluted with water (60 mL) and extracted with dichloromcthane (3 x 60 mL). The dichloromclhanc solution was washed with brine (2 x 50 mL) and dried over Na2SO.,. After (he solvent was evaporated/^ vacua, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a yellow oil (265 mg, 61%). 'l 1-NMR (300 Ml Iz, CDCi,) o 7.37 (in, 511), 6.24 (s. Ill), 6.14 (s, 2H), 5.00 (s, 2H), 3.59 (br s, 21-1), 2.23 (s, 3H). c) 3-Hcnxylo\y-5-mcthyl-l-(2-(iiictliyIsuirnyl)pheiiylsuiroiiylaminobeii/xnc: 2-Methylsulfonylbenzenesulfonyl chloride (765 mg. 3.0 mmol) was added to a solution of 3-bcnzyloxy-5-mcthyJanilinc (640 mg, 3.0 mmol), as prepared in the preceding step. N-niethylmorpholine (0.7 mL) in dichloromclhanc (20 mL). The mixture was stirred at ambient tcmpcraUnc overnight. After adding additional dichloromethane (100 mL), the dichloromethane solution was washed with saturated Nal 1CO3 (2 x 50 mL), 10% MCI (2 x 50 mL), brine (2 x 50 mL), and dried over Na2SO4. After the solvent was evaporated in vacua, the residue was purified by flash column chromatography (3 : 1 dichloromethane : hexane) to give the title compound as white solid (700 mg, 83%). 'H-NMR (300 MHz, CDCIJ 5 8.28 (d, .1 - 7.8 1 Iz, 111), 8.03 (s. 111). 7.90 (d. J = 7.8 I lz, 111). 7.72 (t. J - 7.6 Hz, 1H), 7.61 (t, J = 7.6 Hz, III), 7.38 (m. 511), 6.69 (s, 1H), 6.65 (s, 1H), 6.48 (s, 1H), 4.98 (s, 211), 3.48 (s, 311), 2.18 (s, 311). J)7V-Mcthy]-3-bcnz3'l("xy-5-incthyl-J-(2-(mctliylsu]fon)i)phcnyIsuJfonyIaniinobciizene: 3-Bcnzyfoxy-5-niethyl-N(2-(incthylsulfonyl)phcnylsulfonyIaminobenzene (1.1 g, 2.5 mmol), as prepared in the preceding step, iodomethane (710 mg, 5.0 mmol), and Cs,CO3 (1.65 g, 5.0 mmol) were mixed in acctonitrile (20 mL). The mixture was stirred at ambient - 149 - temperature for 4 h. The solid was removed by filtration, the filtrate was evaporated in in vacua. The residue was dissolved in ethyl acetate (100 ml), washed with saturated NaHCO3 (2 x 50 mL), brine (2 x 50 mL), and dried over Na7SO4. After the solvent was evaporated, the residue was purified by Hash column chromatography (dichloromclhanc) to give the title compound as a yellow gum (1.08 g, 98%). 'll-NMR (300 MHz, CDC13) 8 8.37 (d, J - 7.7 Hz, III), 7.68 (t, .1 = 8.1 11/., 211), 7.51 (t. .1 = 8.2 Hz, 111). 7.37 (m, 511), 6.69 (s, 1H), 6.64 (s, lH),6.58(s, 111), 4.93 (s, 211), 3.45 (s, 311), 3.40 (s, 311), 2.22 (s, 311). g) 3-Mcthyl-5-(7V-mcthyl-2-(incihylsuironyl)p]icnylsuIfonylaniiiio)phciiol: 7V-Methyl-3-benzyloxy-5-methyl-l-(2-(methylsulfonyl)phenylsulfonyIaminobcnzene (1.07 mg, 2.4 mmol) was mixed with 10% palladium on carbon (110 mg) in ethanol (20 mL), the mixture was stirred under hydrogen (balloon) for 2h. The catalyst was removed by filtration through Celite, the filtrate was evaporated in vacuo to give the title compound as a pale yellow oil (680 nig, 80%) which was directly used lor tiic next step without further purification. '11-NMR (300 MHz, CDC13) 5 8.38 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.72 9t, J = 7.711/., HI). 7.57(1,.! = 7.7 11/., 111), 6.55 (s. 211), 6.51 (s. III), 5.16 (s. 111), 3.46 (s, 311), 3.39 (s, 311), 2.20 (s, 311). h) 3-{5-Mc(liyl-3-|Ar-nic(hyl-2-(nic(1iyl.suHniiyI)pliciiylsiilfoiiylaniiiio|phenoxy} propanol: The title compound was prepared in 91% yield from 3-melhyl-5-(A'-methyl-(2-(mcthylsulfonyl)phenylsulfonylamino)phcnol, as prepared in the preceding step, in a manner analogous to step b of Eg. 20. 'H-NMR (300 MHz, CDC13) 5 8.39 (d, J = 7.8 Hz, 111), 7.72 (t, J = 7.7 Hz, 2H), 7.57 (t, J = 7.7 Hz, 1H). 6.62 (s, 1H), 6.56 (s, 2H), 3.99 (t, J = 6.0 Hz, 211), 3.8] (t, J = 6.0 I lz, 211), 3.46 (s, 311), 3.40 (s, 311), 2.22 (s, 311), 1.97 (pallet, .1-6.0 Hz, 2H). i) yV-{3-|S-Mc(liyl-|3-Nt-mciliyl-(2-(niclhylsuIfonyI)p1uMiyIsiilfonyl:imino|phcno\y| propoxyjphthalimidc: The title compound was prepared in 86% yield from 3-{5-methyI-3-[N-mclhyl-(2-(niclliylsullbiiyl)pheiiylsulfoiiylaniino]phcno\y}propauol, as prepared in the preceding step, in a manner analogous to step d of Example 1. 'H-NMR (300 MHz, CDC13) 5 8.39 (d, J - 7.9 Hz, 1H), 7.85 (m, 2H), 7.77 (m. 3H), 7.72 (t, J = 7.7 Hz, 2H), 7.57 (t, J = 7.7 Hz, 1H), 6.62 (s, 111), 6.56 (s, 211). 3.99 (t. J - 6.0 Hz, 211), 3.81 (t. J = 6.0 Hz, 211), 3.46 (s, 3H), 3.40 (s, 311), 2.22 (s, 311), 1.97 (pcnlct, .1 - 6.0 Hz, 2H). j) 3-I5-Methy!-3-[/V-nicthyl-(2-mctliylsulfonyl)phcnylsuIfonyliuiiino]phcnoxy] propoxyaitiinc: The title compound was prepared in 89% yield from N-{3-|5-mclhyl-[3-A'- - 150- melhyl-2-(melhy!sulfonyl)phcnylsulfonylamino]pIicnoxy]propoxy}phlhalimide,asprepared in the preceding step, in a manner analogous to step c a\~ Example 1. 'M-NMR (300 MHz, CDCI3) 6 8.39 (d, J = 7.9 Hz, 1H), 7.71 (t, J - 7.9 Hz, 2H), 7.56 (t, J = 7.8 Hz, 1H), 6.61 (s, 1H), 6.56 (s, III), 6.53 (s, 1H), 5.39 (br s, 2H), 3.91 (t? J - 6.3 Hz, 2H), 3.79 (1, .1 = 6.1 Hz, 2H), 3.46 (s, 3H), 3.40 (s, 3H), 2.12 (s, 3H), 1.99 (pentet, J = 6.2 Hz, 2H). k) 3 13-I\1t(hy|--5-(A'-inotliyl-2-(nH* Example 82 3-l3-(2-Chlorophiniylsulf{myl0xy)-5-me1hylphivuKxylpropyliwihiogiiuniiline tliacefate a) 3-[3-(2-ChIoroplicny]sulfony]oxy)-5-incthyIphcnoxy]propionaldchydc: Sulfur trioxide pyridine complex (847 mg, 5.36 mmol) was added to a solution of 619 mg (1.74 mmol)3-[3-(2-chlorophenylsulfonyloxy)-5-mclhy!phenoxy]propanol, as prepared according to stepc of Example 1,411 LIL (3.23 mmol) of /V.N-diisopropylcthylamine, and 230 uL (3.0 mmol) of dimelhylsulfoxide in dichlorometluinc (10 mL). The reaction mixture was stirred at ambient temperature for 1 h and then quenched with 10% citric acid (20 mL). The reaction mixture was extracted with diclhyl ether (3 x 30 mL), dried (MgSO4), and purified by Hash chromatogrnphy (diclhyl ether / petroleum ether (2 : 1 to 4 : 1)) to afford 289 mg (47% yield) of Ihe tillc compound as a colorless oil. 'II-NMR (300 Mil/., CI)Ci3) 5 9.83 (t, 1H, J = 1.4 Hz), 7.97 (dd, IH), 7.56 - 7.65 (in, 2H), 7.35 - 7.42 (m, 1H), 6.60 (br s, 1H), 6.57 (br s, 1H), 6.49 (br s, 1H), 4.19 (t, 2H, J - 6.1 I Iz), 2.86 (dt, 2H, J - 6, 1.4 Hz), and 2.25 (s, IH). b) 2-[2-|3-(2-Cliloroplicnylstilfoiiylnxy)-5-mclIiylplicnoxy]c(li)'l-l-iuclliylcnc] hydrazinccarboximidaiiiidc hydrochloridc: A solution of 289 mg (0.82 mmol) of 3-[3- (2-chloroplienylsulfonyloxy)-5-mcthylphenoxy]propionaklchydc, as prepared in the -151 - preceding slop, 223 nig (1.62 mmol) of aminogunnidine nitrate, and 200 nL(0.S0 minol)of" 4N MCI / dioxane in 3 ml of cthanol was stirred al ambient temperature overnight. The reaction mixture was treated with 10 mL of water and stirred for 15 min. The reaction mixture was treated with 1.2 mL of 2N sodium hydroxide and then extracted into dichloromelhane (3 x 20 mL). The organic phase was washed with water (3 x 20 mL), dried (K2CO3), and concentrated to give 321 mg of crude product as a free base. The residue was dissolved in dichloromelhane (1 mL), treated with 800 JIL (3.2 mmol) of 4N HCI / dioxane solution. The solvent was removed and the product was triturated from a mixture of dichloromethane / ether / hexane to give 190 mg of the title compound as a colorless solid. 'H-NMR (300 MHz, DMSO-d6) 5 11.58(brs, 1H), 7.95 (dd, 1M, J = 7.9, 1.5 Hz), 7.90- 7.80 (m, 211), 7.52 - 7.6 J (m, 611), 6.77 (s, 111), 6.49 (s, 111), 6.46 (br U11, .1 = 2.2 1 Iz), 4.14 (t, 2H), 2.67 (q, 2H), and 2.21 (s, 3H). Mass spectrum (MALDI-TOF, a-cyano-4- hydroxycinnamic acid matrix) calcd. for C,7I II9C1N4O4S: 411.1 (M + H). Found: 411.1. c) [3-|3-(2-ClilorophciiylsuIf(Miyloxy)-5-nicthyIplicnoxy|propylamino|giKinidine dinccliitc: To 300 mg of 2-[2-[3-(2-chlorophenylsulfonyloxy)-5-nie[hyIphenoxy]cthyl-l-methylene]hydrazinecarboximidamide hydrochloride, as prepared in the preceding step, in telrahydrofuran (2 mL) was added 3 mL of 2N lithium borohydride in tctrahydrofuran. The reaction mixture was stirred overnight, quenched with 2N sodium hydroxide, and extracted into dichloromethane. The organic phase was dried (K2CO3) and concentrated. The residue was dissolved in diehloromcthane and treated with 1 mL of glacial acetic acid. The solution was concentrated in vacua. The residue was purified, together with the crude product obtained from another reaction using 300 mg of 2-[2-[3-(2-chloi1ophcnylsullbnyloxy)-5-methylphenoxy]ethyl-l-methylene]hydrazinecarboximidamide hydrochloride, by flash chromatography using elutions of dichloromelhane / methanol / acetic acid (85 : 9.5 : 1.5 to 78 : 19 : 3) to give 222 mg of the title compound as a gum. 'H-NMR (300 MHz, CD3OD) 5 7.92 (dd, 1H), 7.67 - 7.77 (m, 2H), 7.44 - 7.51 (ddd, 1H), 6.66 - 6.68 (m, 1H), 6.47 - 6.48 (m, 2H), 3.97 (t, 211, J - 6 Hz), 2.94 (L 2H, J = 7 Hz), 2.21 (s, 3H), 1.9! (pentct, 2H), 1.91 (s, 611). Mass spcclruni (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C,7H2IC1N4O4S: 413.3 (M+ 11). Found: 413.1. - 152 - Example 83 3-[5-Methyl-3-(2-trifliwrtmiethylphenyIsulfonyhhxy)phenoxylpropylamitto guanidinc hydrochloride a) 5-MctliyI-3-(2-lrifliion>nictIiylpliciiylsulfoiiyIo\y)plicnol: Orcinol monohydrate (2.84 g, 20.0 mmol) and 2-trifluoromelhylbcnzciicsulfonyl chloride (4.90 g, 20.0 mmol) were mixed in saturated Nal ICO3 (70 mL) and diclhyl ether (70 mL). The biphasic mixture was stirred vigorously at room temperature overnight. The reaction mixture was quenched with water (100 mL) and extracted into ethyl acetate (3 x 80 mL). The organic phase was washed with brine (2 x 50 mL) and dried over Na2SO,,. After removing the solvent in vactto, the residue was purified by flash column chromatography (dichloromethane to 2% ethyl acetate in dichloromethane) to give the title compound as a white solid (3.65 g, 55%). 'H-NMR (300 MHz, CDC13) 5 8.12 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.80 (t, J = 8.2 Hz, III), 7.69 (I, J = 7.8 11/, III), 6.55 (s. III), 6.48 (s, 111), 6.39 (s, III), 5.11 (s, III), 2.23 (s, 3H). h) 3-I5-ML'lliyl-3-(2-trinii(>rnnic(liylplu>iiylsii!roiiyloJ\y)plu>nuxy]prop:uiol: To a solution or5-melhyl-3-(2-{ni1uoiomethylplicnylsullbnyloxy)phenol (665 ing, 2.0 mmol), as prepared in the preceding step, tri-AMuitylphosphinc (607 mg, 3.0 mmol), and 1,3-propanediol (760 mg, 10 mmol) in tetrahydrofuran (20 mL) was added 1,1'-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at room temperature overnight. Hexane (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacua and the residue was purified by flash column chromalography (2 : 1 hexane / elhyl acetate) io give the litle compound as a colorless oil (745 mg, 94%). 'H-NMR (300 MHz, CDC13) 5 8.13 (d, J = 7.2 Hz, 1H), 7.99 (d, J = 7.2 Hz, 111), 7.80 (t, J = 7.6 I Iz, 111). 7.70 (t, J = 7.3 Hz, 111), 6.63 (s, 111), 6.48 (s, 1H), 6.46 (s, 1H), 4.-02 (t, J = 6.0 Hz, 211), 3.81 (m, 2H), 2.25 (s, 311), 1.99 (m, 2H), 1.61 (s, 1H). c) 3-[5-rVlcthyl-3-(2-trinuoromcthyIphcnylsuIfonyIoxy)phcnoxy]propio]ialdchyde: Sulfur trioxide pyridine complex (1.12 mg, 7.0 mmol) was added to a solution of 3-[5-methyl-3-(2-trifluoromethy]phenylsulfonyloxy)phcnoxy]propanol (700 mg, 1.8 mmol), as prepared in the preceding step. A'./V-diisopropylcthylamine (0.7 mL, 5.5 mmol), and dimcthylsulfoxidc (0.4 mL, 5.6 mmol) in CI12C12 (20 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% citric acid (50 mL). The - 153- mixture was extracted into dichloromethane (3 x50 mL), then the dichloromelhane solution was washed with 10% citric acid (40 mL) and dried over Na,SO.,. Aflcr removing the solvent in vacua, the residue was purified by flash column chromatography (CH2C12) to give the title compound as a colorless oil (595 nig, 85%). '11-NMR (300 MHz, CDC13) 5 9.84 (s, 1H), 8.13 (d, J - 7.5 Hz, 1H), 7.99 (d, J - 7.5 Hz, 1H), 7.80 (t, J - 7.6 Hz, 1H), 7.70 (t, J = 7.3 Hz, III), 6.62 (s, 1H), 6.51 (s, III), 6.45 (s, III), 4.21 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 6.0 Hz, 2H), 2.25 (s, 3H). d) 2-[2-[5-McHiyI-3-(2-trifluoron)ctli>ipIiciiyIsu]fonyIoxy)phcnoxy]ctliyI-]-mctIiylcnc] hydrazinccarboximidamidc nitrate: A solution of 3-[5-methyl-3-(2- trifluoromelhylphcnylsulfonyloxy)phcnoxy]propionaldehyde (583 ing, 1.5 inmol), as prepared in the preceding step, and aminoguanidinc nitrate (412 nig, 3.0 mmol) in cthanol (10 mL) was stirred at ambient temperature overnight. Water (50 mL) was added to the reaction mixture. The precipitates were collected, washed with water (2 x 30 mL) and diethyl ether (2 x 30 mL), and dried under high vacuum to give the title compound as a colorless solid (465 nig, 61 %). 'I I-NMR (300 Ml Iz, DMSO-d{,) S 8.19 (d, J = 7.7 I!/., 111), 8.11 (d, J = 7.8 Hz, 1H), 8.06 (t, J = 7.6 Hz, 1H), 7.94 (t, J = 7.6 Hz, 1H), 7.74 (br s, 1H), 7.55 (br s, 411), 4.14 ((, .1 - 6.3 11/.. 211). 2.6S (t, .1 - 9.0 11/, 211), 2.21 (s, 311). Mass spectrum (MALDI-TOIr, a-cyano-4-hydroxycinnamic acid matrix) calcd. for QAJ^HAS: 445.1 (M +II), 467.1 (M + Na). Found: 445.0,466.8. c) [3-l5-Mcthyl-3-(2-tnnuoromcthylphcnyIsulfoiiyIoxy)plicnoxyJpropyIaniino] guanidine liydrochloriric: A mixture of 2-[2-[5-mcthyl-3-(2- trifluoromeLhylphcnylsulfonyloxy)phcnoxyJcthyl-I-mclhylcnc]hydrazinecarboximidamide nitrate (76 nig, 0.15 mmol) and 10% palladium on carbon (10 ing) in cthanof (5 mL) was stirred under hydrogen (balloon) overnight. The catalyst was removed by filtration through Celite. After evaporating the solvent, the residue was dissolved in dichloromethane (50 mL), washed with 2 N NaOi 1 (10 mL) and brine (10 mL). and dried over K,COV After removing the dichloromelhane, the residue was dissolved in HCl-methanol (10 mL) and concentrated. The residue was purilied by flash column chtomalography (10% methanol in dichloromethane) tc give the title product as a colorless foam (38 mg, 47%). 'H-NMR (300 MHz, DMSO-d6) 5 8.90 (s, 1H), 8.19 (d, J = 7.7 Hz, 1H), 8.11 (d, J = 7.8 Hz, 1H), 8.06 (t, J - 7.6 Hz, 1H), 7.94 (t, J = 7.6 Hz. 1H), 6.90-7.70 (m, 4H), 6.76 (s, 1H), 6.41 (s, 2H), 5.29 (br s, IH), 3.99 (t, .1 - 9.0 Hz. 2H), 2.82 (m, 2H), 2.20 (s, 3H)? 1.78 (m, 2H). Mass - 154- spectrum (MALDI-TOF,, ct-cyano-4-hydroxycinnumic acid matrix) calcd. for CjK'^.^HtO.S: 447.1 (M + H). Found: 446.9. Example 84 l3-l3-(5-Ch!orothiophenyl-2-siiljonyloxy)-5-mcthyIphcno\yl p ropy! a minojg nan id in e a cctate a) 3-[3-(5-ChIorotliiop!ieiiyI-2-suIfonyJoxy)-5-methyIphenoxyJpropionaI(Ichy matrix) calctl. for C,4H,JC1OJS2: 383.0 (M+ NJI). Found: 382.9 b) 2-l2-l3-(5-Cli1oioUnt)i>IiciiyI-2-.suif(tttyl(".vy)-5~inclhyJ|)hcnt>xy]ctlivl-l-nicihylcoe] hydrazinccarboximidamide nitrate: A mixture of 3-(3-(5-chloroll)H>phenyl-2- sulfonyloxy)-5-methylphcnoxy]propiona[dchydc (1.60 g, 4.4 mmol) and aminoguanidine nitrate (0.73 g? 0.53 mmol) in elhanol (15 mL) was stirred overnight at ambient temperature. Water (25 mL) was added dropwise over 15 min. The mixture was stirred for 30 min then filtered to give the title compound (1.75 g. 87%) as a white solid. 'H-NMR (300 MHz, DMSO-d6) 5 7.76 (d, 1H, J = 4.2 Hz), 7,55 (t, 1II, J = 5.0 Hz), 7.40 (d, 1H, J = 4.2 Hz), 6.81 (br s, 1H), 6.55 (br s, 1H), 6.52 (I, I N, J - 2.2 I Iz), 4.17 (t, 211. J - 6.4 11/.), 2.70 (dt, 2H, J = 6.4, 5.0 Hz), 2.26 (s, 3H). Mass spectrum (MALDI-TOF, a-cyano-4-bydroxycinnaniic acid matrix) calcd. for C15HI7CIN,O,S,: 417.0 (M + H). Found: 416.5. c) [3-[3-(5-Chlorothiophenyl-2-suIfonyloxy)-5-me(hyIptienoxy]propylamino]gii;*nidiiie acetate: To 2'[2-[3'(5-chlorothiophcnyi-2-sulfonyloxy)-5-me[hylphenoxy]elhyl-l- methylenejhydrazinecarboximidamidc nitrate (137.5 mg, 0.29 nimoi), as prepared in the - 155- preceding step, in letrahydrofuran (1 ml) was added 1 mL of 2M lithium borohydride in tclrahydrofuran. The reaction mixture was stirred for 5 min, basifled with 10% potassium carbonate, extracted into .dichloromethane, dried (K2CO3), and concentrated. The residue was treated with acetic acid (0.4 mL) and concentrated. The residue was chromatographed using a 10 g Waters Sep-Pak silica gel column eluting with dichloromethane/ mclhanol / ncclic acid (89 : 9.8 : 1.2 to 78 : 19 : 3) to give 106 ing of recovered 2-[2-[3-(5-c h 1 o r o t h i o p h e n y 1 - 2 - s u 1 f o n y 1 o x y) - 5 - m e t h y I p h e n o x y ] e t h y 1 - 1 -mcthylene]hydrazinecarboximidamidc acetate and 27 mg of the title compound. Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C15Hl9CiN4O4S2: 419.1 (M + H). Found: 418.8. Example 85 l3-i3-(2-Mcthoxyphenylsulfonyloxy)-5-methylphcnoxyJpropylaminoJ gnanidi/te diacetate ;i) 3-|3-(2-Mi'IIioxypliciiylsiilf'i)iiyl()xy)-5-ino(hylplH'noxy|[>r trioxide pyridine complex ( 1.87 g 11.7 mmol) was added in portions over 15 min to a solution of 3-[3-(2-methoxyphenylsulfonyloxy)-5-melhylphenoxy]propanol (2.07 g. 5.9 mmol, prepared in step c of Example 2). A'.A'-diisopropylelhylaminc (2.15 mL, 12.3 mmol), and anhydrous dimethylsulfoxide (1.25 mL, 17.6 mmol) in anhydrous dichloromethane (14 mL) at 0°C under a nitrogen atmosphere. The solution was stirred at 0°C for 1 h, then the reaction was quenched with 5% aqueous citric acid (50 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (15 mL). The combined organic extracts were washed with 5% aqueous citric acid (50 mL), pH 7 buffer (40 mL) and brine (50 mL), dried over Na.RO,,, filtered, and evaporated. The residual gold oil was purified by flash column chromatography (3 : 2 diethyl ether / hexanc) to give the title compound (1.28 g, 62%) as a colorless oil. 'H-NMR (300 MHz, CDC13) 5 9.82 (t, 1H, J - 1.5 Hz), 7.82 (dd, 1H, J = 7.9, 1.7 Hz), 7.62 (ddd, 1H, J = 8.4, 7.4, 1.8 Hz), 7.09 (dd, 1H, J - 8.4, 0.8 Hz), 7.02 (m, 1H), 6.58 (br s, 111), 6.54 (br s, 1II). 6.45 (t, 1H, J = 2 Hz), 4.18 (t, 2H, J - 6.1 Hz), 4.02 (s, 3H), 2;85 (dt, 211, J - 6.1, 1.5 11/.), 2.24 (s. 311). Mass spectrum (MALDI-TOF, a-cyano- 4-hydroxycinnamic acid matrix) calcd. for C,7II1BO6S: 373.1 (M + Na). Found: 373.0. b) 2-|2-|3-(2-Mc(hoxyphciiylsuiroiiyloxy)-5-iiic(hylpIicnoxy]ciliyl-I-nic(li)'k'Hc] hydrazinccarboxiiniilamidc acetate: A mixture of aminoguanidine hydrochloride (0.811 - 156- g, 7.33 mmol) and 3-[3-(2-mcthoxyphenylsulfonyloxy)-5-methylphenoxy]propionaldehyde (1.28 g, 3.66 mmol, prquirc-d in the preceding step) in ethnnol (30 ml,) wns stirred overnight at ambient temperature. The mixture was concentrated in vacua to approximately 15 mL, then dichloromethane (60 mL) was added to precipitate excess aminoguanidine hydrochloride. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in dichloromethane (30 mL) and extracted with aqueous NaOII (1.85 mL of 2N NaOH in 90 mL water). The aqueous layer was extracted with CH2C12 (2 x 30 mL). The combined organic extracts were washed with water (50 mL) and brine (2 x 50 mL), dried over K2CO3, filtered, and evaporated to give the free base ol the title compound (1.38 g, 93%) as a gold foam. The acetate salt of the title compound was made by adding glacial acetic acid (0.75 mL, 30 mmol) dropwise to the free base, 2-[2-[3-(2-methoxypheny!sulfonyloxy)-5-methylphcnoxy]-cthyl-l-melhylcnc]hydrazinecarboximidamide, (1.03 g, 2.53 mmol, prepared above) in dichloromethane (10 mL). Solvent was removed in vacuo at ambient temperature;. Crude acetate salt \v;is purified by flash column chromalography (20% to 100% of 1:10: 40 acetic acid / mcthanol / dichloromclhane in dichloromethane) to give the title compound (0.91 g, 77%) as a while fo:ini. Ml-NMR (300 MHz, CDCI/) -157- (m, 2H), 7.28 (d, 1H, J = 8 Hz), 7.05 (dt, 1H, J = 7, 1 Hz), 6.65 (br s, 1H), 6.46 (t, 1H, J = 2 Hz), 6.43 (br s, IH), 4.01 (s, 3H), 3.97 (t, 2H, J = 6 Hz), 2.95 (t, 2H, J = 7 Hz), (s, 3H), 1.92 (s, 6H), 1.90 (penlet, 2H, J = 6 Hz). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C1XI I2,,N,,O5S: 409.2 (M + 11), round: 408.8. Example 86 [3-[3-(2-CyanopItenyIsulfonyloxy)-5-methy!phenoxy]propyIaimnoJguanidine acetate a) [3-(2-CyanoplicnyIsuIfonyloxy)-5-i"etliyIphciioxy]propionaldehydc: Sulfur trioxide pyridine complex (480 mg, 3.0 mmol) was added to a solution of 3-[3-(2-cyanophenylsuIfonyloxy)-5-methylphenoxy]propanol (315 mg, 0.9 mmol), as prepared in step b of Example 6, A'.jV-diisopropylethylamine (0.5 mL, 3.9 mmol) and dimethylsulfoxide (0.2 ml, 2.8 mmol) in dichJoromelliane (10 ml). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% citric acid (30 mL). The mixture was extracted into dichloromcthane (3 x40 mL), and the dichloromcthane solution was washed with 10% cilric acid (30 nil.) and dried over Na,S().,. A Her removing (lie solvent in vacua, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a colorless oil (260 nig, 83%). 'H-NMR (300MHz,CDCl3)5 9.84(s, 1H), 8.11 (m. 1H), 7.94(m, 1H), 7.78-7.81 (m, 2H), 6.65 (s, 1H), 6.61 (s. III), 6.57 (s, III), 4.24 (t..! - 6.0 1 Iz. 211), 2.88 (t, .1 - 6.0 11/, 211), 2.27 (s, 3H). b) |2-|3-(2-CyaiiopliciiylsuIfoiiyloxy)-5-iiiclhylpliciioxy|c(Iiyl-l-iiicthylcnc] ydra/inccarboxiniidaniidc liydrochloride: A solution of 3-[3-(2- cyanophenylsuIfonyloxy)-5-methylphcnoxy]propionaldehyde (240 mg, 0.7 mmol), as prepared in the preceding step, and aminoguanidine nitrate (200 mg, 1.5 mmol) in ethanol (8 mL) was stirred at ambient temperature overnight. Water (20 mL) was added to the reaction mixture. The precipitates were collected, washed with water (2x15 mL) and diethyl ether (2 x 20 mL), and dried under high vacuum. The solid was suspended in water (40 mL), treated with 2N sodium hydroxide (1.0 mL). and extracted into dichloromcthane (3 x 50 mL). The organic phase was dried over K2CO3. After removing the solvent, the residue was dissolved in dichloromcthane (1 mL), and the dichloromcthane solution was added to the solution of 1.5 mL of 0.6M HCI melhanol in diethyl ether (50 mL) to give the title compound as a colorless solid (245 mg, 80%). 'H-NMR (300 MHz, DMSO-d,,) 5 8.28 - 158- (m, 1H), 8.09 (in, 1H), 7.97-8.04 (m, 2H), 7.55 (br s, 5 H), 6.80 (s, 1H), 6.50 (s, 2H), 4.15 (t, J - 6.3 Hz, 2M), 2.68 (in, 211), 2.22 (s, 311). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. for C1SH,9N5O4S: 402.1 (M + H), 424.1 (M + Na), 440.1 (M + K). Found: 402.1,424.1,440.1. c) -[3-(2-Cyanophciiy]suIfonyIoxy)-5-mcthylphcnoxy]propylainino]guanidine acetate: To a suspension of 2-[2-[3-(2-cyiHiophcnylsiilfonyloxy)-5-nicthylpliciioxy]clliyi-J-melhylenc] hydrazinecarboximidamide hydrocliloride (190 mg, 0.4 mmol), prepared in the preceding step, in tetrahydrofuran (5 mL) was added lithiuni borohydride (2M, 3.0 mL, 6.0 mmol). The reaction mixture was stirred at ambient temperature for two days under nitrogen. The solution was acidified (pH 2) with 10% HC1 solution, and the mixture was stirred for 10 minutes. The solution was basified (pH 8-9) with 2N NaOH, and the mixture was extracted with dichloromcthanc (3 x 50 mL). The dichloromclhanc extracts were washed with brine (50 mL) and dried over K2CO3. After removing the solvent, the residue was purified by flash column chromatography (90 : 9 : 1 dichloromethane / methanol / acetic acid) to [',ivc Ihe tilk1 compound as a colorless jium (65 mj>, 35%). 'll-NMR (300 MHz. CDC13) 5 8.30 (br s, 211), 7.94-8.11 (m, 41!), 6.78 (s, 1H), 6.49 (s, 111), 6.43 (s, 1H), 4.09 (t, .) = 8.0 Hz, 211), 2.75 (t, J - 6.7 11/., 211). 2.22 (s, 311), 1.78 (m, 211). Mass spectrum (MALDI-TOF, a-cyano-4-hydroxycinnamic acid matrix) calcd. forCi8H2|N5O4S: 404.1 (M + H). Found: 404.5. Example 8 7 In vitro Inhibition of Purified Enzymes Reagents: All buffer salts were obtained from Sigma Chemical Company (St. Louis, MO), and were of the highest purity available. The enzyme substrates, N-benzoyl-Phc-Val-Arg-/;-nit roan ilide (Sigma B 7 6 3 2 ), N-bcnzoyl-Ilc-Glu-Gly-Arg-/;-nilro.'inilidc hydrocliloride (Sigma B2291), N-/?-Tosyl-Gly-Pro-Lys-/?-nitroanilidc (Sigma T6140), N-succinyl-Ala-Ala-Pro-Phe-/?-nitroanilide (Sigma S7388) and N-CBZ-Val-Gly-Arg-/?-nitroanilide (Sigma C7271) were obtained from Sigma. N-succinyI-Ala-Ala-Pro-Arg-/>nitroanilide (BACHEM L-1720) and N-succinyl-Afa-Ala-Pro-Val-/;-nitroanilide (BACHEM L-1770) were obtained from BACHEM (King of Prussia, PA). Human a-lhroinbin, human factor Xn nnd human plasmin were obtained from Enzyme Hescarch Laboratories (South Bend, Indiana). Bovine cc-cliymoirypsin (Sigma - 159- C4129), bovine trypsin (Sigma T8642) and human kidney cell urokinasc (Sigma U5004) were obtained from Sigma. Human leukocyte cJaslasc was obtained from Elaslin Products (Pacific, MO). Kj Determinations: All assays arc based on the ability of the test compound to inhibit the enzyme catalyzed hydrolysis of a peptide ;;-nitroanilide substrate. In a typical Kf determination, substrate is prepared in DMSO, and diluted into an assay buffer consisting of 50 mM HEPES, 200 mM NaCl, pH 7.5. The final concentrations for each of the substrates is listed below, In general, substrate concentrations are lower than the experimentally determined value for Knr Test compounds arc prepared as a 1.0 nig/ml solution in DMSO. Dilutions are prepared in DMSO yielding 8 final concentrations encompassing a 200 fold concentration range. Enzyme solutions are prepared at the concentrations listed below in assay buffer. In a typical K; determination, into each well of a 96 well plate is pipetted 280 fiL of substrate solution, 10 j.iL of test compound solution, and the plate allowed to thermally equilibrate at 37°C in a Molecular Devices plate reader for > 15 minutes. Reactions were initiated by tiie addition of a 10 LIL aliquot of enzyme and the absorbancc increase at 405 nm is recorded for 15 minutes. Dala corresponding to less than 10% of the total substrate hydrolysis were used in the calculations. 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 Kj value. Thrombin: Thrombin activity was assessed as the ability to hydrolyze the substrate N-succinyl-AIa-Ala-Pro-Arg-/>nitroanilide. Substrate solutions were prepared at a concentration of 32 j.iM (32 U.M"K/H = 180 uM) in assay buffer. Final DMSO concentration was 4.3%. Purified human ix-thrombin was diluted into assay buffer to a concentration of 15 nM. Final reagent concentrations were: [thrombin] = 0.5 nM, [substrate N-succinyl-Ala-Ala-Pro-Arg-p-nilroanilide] = 32 pM. Factor X [FXa]: FXa activity was assessed as the ability to hydrolyze the substrate N-benzoyl-Ile-GIu-Gly-Arg-/?-nitroani]idehydrochloride. Substrate solutions were prepared at a concentration of 51 uM (51" Km = 1.3 mM) in assay buffer. Final DMSO concentration was 4.3%. Purified activated human Factor X was diluted into assay buffer - 160- to a concentration of 300 nM. Final reagent concentrations were: [FXa] = 10 nM, [N-bcnzoyI-Ilc-Glu-Gly-Arg-/>nitroanilide hydrochioridc] = 51 }_iM. Plasmin: Plasmin activity was assessed as the ability to hydrolyze the N-/?-TosyI-Gly-Pro-Lys-y?-nitroanilidc. Substrate solutions were prepared at a concentration of 37 jiM (37 \xM" Km= 243 u.M) in assay buffer. Final DMSO concentration was 4.3%. Purified human plasmin was diluted into assay buffer to a concentration of 240 nM. Final reagent concentrations were: [Plasmin] = 8 nM, [N-/?-Tosyl-Gly-Pro-Lys-/>nitroanilide] = 37 u.M. Chymotrypsin: Chymotrypsin activity was assessed as the ability to hydrolyze N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide. Substrate solutions were prepared at a concentration of 14 u.M (14 j.iM" Km= 62 fiM) in assay buffer. Final DMSO concentration was 4.3%. Purified bovine chymolrypsin was diluted into assay buffer to a concentration of 81 nM. Final reagent concentrations were: [Chymotrypsin] = 2.7 nM, [N-succinyl-Ala-Ala-Pro-Phc-/?-nilroanilidc] ~ 14 \\M. Trypsin: Trypsin activity was assessed as the ability to hydrolyze N-bcnzoyl-Phe-Val-Arg-/?-nitroanilide. Substrate solutions were prepared at a concentration of 13 ^M (13 iiM" Ktl) = 291 tiM) in assay buffer. Final DMSO concentration was 4.3%. Purified bovine trypsin was diluted into assay buffer to a concentration of 120 nM. Final reagent concentrations were: [Trypsin] = 4 nM, [N-bcnzoyl-Phc-VaUAig-/?-nilroanilidc] = 13 nM. KInsdisc: lihistase nctivity was assessed as the ability lo hydrolyze N-succinyl-Ala-A la-Pro-Val-p-nilroanilidc. Substrate solutions were prepared at a concentration of 19 fiM (19 u.M" KIT, = 89 uM) in assay buffer. Final DMSO concentration was 4.3%. Purified human leukocyte elastase was diluted into assay buffer to a concentration of 750 nM. Final reagent concentrations were: [Elastase] = 25 nM, [N-succinyl-Ala-Ala-Pro-Val-p-nitroani!idc] = 19 uM. Urokinsi.sc: Urokinase activity was assessed as the ability to hydrolyze N-CBZ-Val-GIy-Arg-/;-nitroanilide. Substrate solutions were prepared at a concentration of 100 yiM (100 |.iM nitroanilidc] = 100 niM. - 161 - The results of the compounds of Examples 1, 2. 3, 8, 11, 82 and 83 arc shown in the following table. Table 1 The results indicate that the compounds of the present invention tire inhibitors of proteases, including thrombin. In addition, the compounds of F.xnmples 1. 2. 3. K. 11. 82 and 83 are potent and highly selective inhibitors of thrombin. 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 (hereof. MI patents ami publications cited herein are fully incorporated by reference herein in their entirety. - 162-3-[3-(2-ClilorophcnylsiilfonyIoxy)-5-mcthylphenoxylpropoxyguanidine 3-[3-(2-MelhoxyphcnyIsulfonyloxy)-5-methylphenoxy]propoxyguanidine 3-[5-Mclhyl-3-(quinolinyl-8-suironyloxy)phcnoxy]propoxygunnidinc hydrochloride 3-|3-(5-Chloro-2-nicllioxyphcnylsulfonyloxy)-5-nielhylphcnoxy]propoxyguanidine hydrocliloridc 3-[3-(5-IsoquinolinylsuIfonyloxy)-5-mcthylphenoxy]propoxyguanidine hydrochloride - 163- 3-[5-Methyl-3-[2-(metliyIsulfonyI)phenylsulfonyloxy]phenoxy]propoxy guanidine hydrochloride {3-[[5-Mcthyl-3-(2-mcihyIsu]lbiiyiplienylsulibnyloxy) phenoxy]methyl]cyclopropyImethoxy} guanidine hydrochloride {l-[[5-Methyl-3-(2-cyanophenylsulfonyloxy)phenoxy]methyl] cyclopropylmcthoxy} guanidine acetate {3-[5-Mclhyl-3-(2-morpholinylsuIfonylpbenylsuIfonyloxy) phenoxyjpropoxy} guanidine hydrochloride {3-[5-Mclhyl-3-(2-(phcnylsulfony'l)phcnylsuironyloxy) phenoxyjpropoxy}guanidine hydrochloride - 164- {3-[5-Melhyl-3-(2-(4-elhyloxycarbonyl)piperidinylsulfoJiyl phcnylsuirojiyloxy)phcnoxy]propoxy}guanidine hydrochloride {3-[5-Mclhyl-3-(2-(4-carboxyl)pipcridinylsu.lfonyI phenylsulfonyloxy)phenoxy]propoxy}guanidine 3-[5-Melhyl-3-(3-mclhylquinolinyI-8-suIfo"yloxy)phcnoxy]propbxyguanidine dincctalc 3-[5-Methyl-3-(2-(4-mclhylsulfonylpipcrazin-l-ylsulfonyi)phenyl suUbnyloxy)phcnoxy]propuxy}guanidinc hydrochloride - 165 - {3-[5-Mclhyl-3-(2-(4-(2-pyrimidinyl)piperazin-l-yIsulfonyl)phcnyl sulfony]oxy)phcnoxy]propoxyguanidine hydrochloride 3-[5-Mclliyl-3-(2-(A^-cthyUN-(4-pyridylmcthyl)aininosuironyl) phenylsulfonyloxy)phenoxy]propoxyguanidine dihydrochloridc 3-[5-Mcthyl-3-(2-(4-cihylpipcrazin-l-ylsulfonyl)phenylsulfonyloxy)phcnoxy]propoxyguanidiiic dihydrochloridc 3-t5-Methyl-3-(2-(7V-(2-cyanoelhyl)-N-(3-pyridylmethyl)amino sulfonyl)phcnyisulfonyloxy)phenoxy]propoxyguanidine dihydrochloride - 166- 3-[5-Metliyl-3-(2-(7V~(2-ethoxycarbony]ethyJ)-A^-benzylaminosulfonyl) phenylsulfonyloxy)plienoxy]propoxyguanidine hydrochloride 3-[5-Mc(hy]-3-(2-(7^-(clIioxycarbonylmc(hyl)-N-(2-pyndyInictliyl) niinosulfonyj)phenylsulfonyloxy)phenoxy]propoxyguanidine dihydrochloride 3-|5-Mcthyl-3-(2-(4-(cllK)xycarbonyIinclhyl)pipcraziii-l-y]sulfonyl)plii;nyisuironyloxy)plicno.\yjpropox\'gti:uiicliuc dihydrochloride {3-[5-Methyl-3-(2-(4-(carboxymclhyl)pipcrazin-I-ylsulfonyl)phenylsulfonyloxy)phcnoxy]propoxy}guanidine OH 3-[5-melhyl-3-(2-(4-(2-pyridyl)piperazinylsuIfonyl) phcnylsulfonyloxy)phcnoxy]propoxyguanidinc hydrochloridc 3-[5-methyI-3-(2-(4-plienylpiperazinylsulfonyl) phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride 3-[5-methyl-3-(2-(4-bcnzylpiperazinylsulfonyl) phcnyjsulfbnyloxy)p]icnoxy"|propoxygiinnidine hydrochloridc 3-[5-metbyl-3-(2-(4-(2-methoxyphcnyl)piperazinylsulfonyl) plicnylsulfonyloxy)phenoxy]propoxyguanidinc hydrochloridc - 168- 3-[5-methyI-3-(2-(A^-(2-cyanoethyl)-A^-(2-furanylmethyl) aniinoi>LiIfonyi)phcnylsulfonyloxy)phcnoxy]propoxygiianidinc i 3-[5-Methyl-3-(2-(4-methyIpiperazinylsulfonyl) phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride i 3-[5-Mclhyl-3-(2-(A^-bcn/yl-A/-(2-(A^-dimclhylnniino)clhyl)amino sulfonyl)phenylsulfonyloxy)phcnoxyjpi"opoxygiianidine dihydrochloridc 3-[5-Methyl-3-(2-(A^-methyl-A^-(3-pyridylmetliyl)amino sulfonyl)phenylsulfonyloxy)phcnoxy]propoxyguanidine dihydrochloride - 169- 3-[5-Melhyl-3-(2-(2-(4-morpholinyl)ethyIamino sulfonyl)pheny!suIfonyIoxy)phcnoxy]propoxyRuanidinedihydrociiIoride 3-[5-Methyl-3-(2-(4-ethoxycarbonyI-1 -piperazinylsulfonyl) phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride 3-[5-MethyI-3-(2-(4-pyridylmethylaminosulfonyl) phenylsulibnyloxy)phcnoxy]propoxyguanidine - 170 - WE ClLAIM: Aminoguanidine and alkoxyguanidine compounds having the Formula I: or a solvate, hydrate or pharmaceutically acceptable salt thereof; wherein: R.' is one of'C-j.u alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl or hctcroaryl, any of which may be optionally substituted; % is one of-NRl(1SO,- -SO2NR10-, -NR'°C(R3'R7-)-,--C(RyRlt)NR10-, f ' -OSO2-, -SO2O- -OC(irR')--, -C(RyR')O-, -NR'"CO-'or-CONR10-; IV and R;r- arc each independently one of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalky, carboxyaiky!, aminoalkyl, monoaikylaminoalkyK dialkylaminoalkyi or cai'boxy; R3, R' and R'1 are each independently one ofhydrogen, alkyl, cyeloalkyl, aikenyl, alkyny], aryl. aralkyl, hcteroaryl, trifiuoromcthyl, halogen, hydroxyalkyl, cyano, nitro, carboxamido, -CO_,RS, -CIIiOR" or -OR\ oi' when jiresenl on adjacent carbon atoms, R2 and R3 may also be taken together to form one of-CH=CH--CH=CM- or -(Cl I,)q-, where cj is from 2 (o (1, and R'1 is delmed as nbovc; W, in each instance, is independently one ofhydrogen, alkyl or cyeioalkyl wherein said alky] or cycloalkyl groups may oplionaHy have one or more nnsalurations; Y is one of-0-f -NR"S -S-, -CHR10- or a covalent bond; X is oxygen or NR9; R9 is one ofhydrogen, alky!, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl can be optionally substituted with amino, monoalkylamino, dialkylamino, alkoxy, hydroxy, carlx)xy, alko.xycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, aryl, heteroaryl, acylamino, cyano or trifiuoromcthyl; R^ is'out1, of hydi'oycn, alkyl, aralkyl, aryl, hydroxyalky], aminoalkyl, monoalkylaniino(C2.!0)alkyl, dialkylamino(C2.,0}alkyl or carboxyalkyl; - 17] - R7, R8, R" and R12 are each independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoaikylammoalkyl, dialkylaminoalkyl or carboxyalkyl; or R7 and RR arc taken together to form -(CH2)y-, where y is zero (a bond), 1 or 2, while R" and R12 arc denned as above; or R7 and Ri2 are taken together to form -(CH2)q-, wliere q is zero (a bond), or 1 to 8, while R8 and R" are defined as above; or IIs and R11 are taken together to form -(CIJ2)-, where r is 2-S, while R7 and R12 are defined as above; R10, in each instance, is independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoaikylaniino(C2.l0)alkyl, dialky!amino(C2.!0)aikyJ or carboxyalkyl; Rn, R1' and Rc are independently hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkaxy, alkoxycarbonyloxy, cyano or -COZRW; 1 Rw is alkyl, cycioalkyl, phenyl, benzyl, where Rd and Rc arc independently hydrogen. C,.6 alkyl, C2.f, alkenyl or pheny!, Rr is hydrogen, C,.6 alkyl, C2.6 alkenyl or phenyl, Ru is hydrogen, C,.6 alky!. C2.6 alkenyl or phenyl, and Rh is aralkyl or C,.,, alkyl; in is from zero (o 8; and in is from zero to 4. 2. A compound as claimed in claim 1, wherein R1 is one of Cun alky!, C.,.7 cycioalkyl, C2.8 alkbnyl, C2.s alkynyl or C0.14 aryl, any of which is optionally substituted. 3. A compound as claimed in claim 1, wherein R1 is one of C3.s alkyl, C,,.7 cycloalkyi, C2.8 iilkenyl, C2.B alkynyl or C6.H aryl, my ofuhie'h is oj^tionaliy substituted by one or two moieties indcpcndcnlly selected from the group consisting of alkyl, hydroxy, nitro, trinuoidmeihyl. halogen, alkoxy. aminoalkoxy, nmiruulkyl. hydroxyalkyl, hydroxyalkoxy, cyano, aryl, amino. monoarkylamino, dialkylamino, carboxy, - 172- carboxyalkyl, carboxyaikoxy, mono(hydroxyalkyl)amino, bis(hydroxyalkyl)amino, mono[carboxya]kyl)amiuo, bis(carbo.\yalkyl)amino, alkoxycarbonylamino, alkoxycarbonyi, aralkoxycarbonyl, alkenyicarbonyl, alkynylcarbony], alkylsulfonyl, alkcnyl.su! Pony 1, alkynylsulfony!, aryl.sulfonyl, aralkylsulfonyl, alkylsulflnyl, alkylsiilfonamido, aryisulfonamido, aralkylsulfonamido, amidino, guanidino, alkyliminoamino, fonnyliminoamino, trifluoromcthoxy, pcrfluorocthoxy and and R^R^NSCV, where R'3 and R'" ate independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkcnyl, alkyny], aryl, aralkyl, hclerocyclc, hclcrocycloalkyi, carboxyalkyi, alkoxycarbonylalkyl, cyanoalky!, hydroxyalkyl, alkoxyalkyl, mono and di-alkylaminoalkyl, or R'3 and R1'1 can be taken together wilh tlie nitrogen atom to which they arc attached to form a three to seven membcred ring, optionally containing one or more heteroaloms in addition to.said nitrogen, such as oxygen, sulfur, or nitrogen (NR15), said ring being preferably saturated, and said ring having one or two optional subslitucnls, wherein said optional substituents and Ri5 are independently selected from the group consisting of hydrogen, alkyl, cycloaikyl, alkcnyl, alkynyl, aryl, uralkyl, helerocycle, heterocycloaikyl, caibo.\)'a!ky!, alkoxycarbonylatkyl, cyanoalkyl, hydroxyaikyl, alkoxyalkyl, mono- and di-alky!aminoalkyl, carboxy, alkoNycarbonyi, caiboxamtdo, joi-myl, alkanoyl, aroyl, aralkanoy!, siilli>nyl, aikylsullou\'l, alkoxysullonyl, sulfonainido, phosphony!, phosphoramido. or phosphinyl. 4. A compound as claimed in claim 1, wherein R1 is heteroaryl, optionally substituted by one or more of hydroxy, nitro, trifluoromcthy!, halogen, C,.6alkoxy, C,.f,alkyl, ainino, mono(€,.(;)alkylamino, di(CVfl)aIkyIainino, cyano3 amidino, guanidino. carboxyalkoxy, trifliiorpniclhoxy or [lcrlltioroethoxy. 5, A compound as claimed in claim 1, wherein R1 is pyridyl, pyrazolyl, thiophcnyl, chromcjiyl, benzoxa/.olyl, benzihiadia/.oIyL quinazoiinyX quinolinyl, isoquinolinyl or tetrahydlroquinolinyl. any of which is optionally substituted by one or more subslituents independently selected from the group consisting of hydroxy, tiitro. trinuoromcthyl, - 173 - halogen, C^aUcoxy, C^alkyl, ami no, mono(Cu,)n!kylamino, di(C|.(l)alk>'laniino, cyano, amidijno, fj.uamdino, eaiboxyalkoxy, tridvioi-omcthuxy ;ind periluoroclhoxy. 6. A compound as claimed in claim 1, wherein Y is one of - O-, -NR10- or a covalent bond/and R10 in each instance is one of hydrogen, C,_6alkylf benzyl, phenethyl, C2,,0bydroxyalkyi or C2.7cnrboxyalkyl. 7. A compound as claimed in claim 6, wherein Y is -O. 8. A1 compound as claimed in claim 1, wherein Z is -SO.NR10-, -SO:O- or -CH2O-. 9. A compound as claimed in claim 1, wherein Ra, Rb and Rc are hydrogen. 10. A compound as claimed in claim 1, wherein R7 and R* and Rn and R12 are independently hydrogen, C,.(,nlkyl, Cr>.,u;u(C,.6);i1k}rl, Cf,.,()aryl, Oi.1(,hydroxynlky] or C,.1O carboxyalkyl. 11. A compound as claimed in claim 1, wherein R7 and RK are taken together to form -(CH;)V~, and y is 0, 1 or 2. 12. A compound as claimed in claim I, wherein n is from I lo 4. 13. A compound as claimed in claim 1, wherein in is zero, 1, 2 or 3. i 14. A compound as claimed in claim I, wherein in and n are each zero and R7, R8, R" and R1? arc cacti hydrogen. 15. A compound as claimed in claim 1, wherein R: and R4 are hydrogen and R3 is methyll 16. A compound as claimed in claim 1, wherein : - 17-1 - R' Is one of Cc_l0 aryl, pyridinyl, thiophenyl (i.e., thiophene) quinazolinyl, quinolinyl or lelrnhydroquinolinyl, any ofwhieh is optionally substituted by one or two of hydroxy, nilro, Irifluoromclhyl, halogen, C,.fi alkyl, C6_,0 aryl, C,.6 alkoxy, C,_6 aminoalkyl, C,.fi annnoalkoxy, amino, mono(CM)alkylamino, di(CM)a]kylnmino, C2.6 alkoxycarbonybmino, C2.6 alkoxycarbonyl, carboxy, C[_6 hydroxyalkyl,C?.fl hydroxyalkoxy, C2_K, mono(carboxyalkyl)amino, bis(C2.|0 carboxyalkyl)amino, Q.|4 ar(CK() alkoxycaibonyl, C2.c alkynyicarbonyl, C,.6 alkylsulfonyl, C2.6 alkcnylsulfonyl, C2.fi alkynyl.sulfonyl, Q.I0 arylsulfonyl, C6.|0 ar(C,,6) alkylsulfonyl, C,_6 alkylsulfmyl, C,.6 alkylsulfonamido, C6.,o arylsulfonamido, C6.1P ar(Ct.6) alkylsulfonamido, amidino, guanidino, C,.6 alkyliminoamino, formyliminoamino, C2.6 carboxyalkoxy, C?Y, carboxyalkyl, carboxyalkylamino, cyano, trifluoromcllioxy, pcriluoroclhoxy and RI:1RMNSO2-; R'3 and RM are independently selected from the group consistingof hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocycle, heterocycloalkyi, carboxyalkyl, alkoxycarbonylalkyl. cyanoalkyl, hydroxyalkyl, alkoxyalkyl, mono-land di-aikylaininoalkyl, or R13 and R14 can be taken together with the nitrogen jaLom to which (hey are attached to form a three to seven membcred ring, optionally containing one or more heteroatoms in addition to said nitrogen, such as oxygen, sulfur, or nitrogen (NR15), said ring being preferably saturated, and jsaid ring having one or two optional substitucnts, wherein said optional jsubstitucnts and R15 are independently selected from the group consisting of jhydrogen, alkyl, cycloalkyl, alkcnyl, alkynyl, aryl, aralkyl, heterocycle, iheterocycloalkyl, carboxyalkyl, alkoxycarbonylalkyl, cyanoalkyl, hydroxyalkyl, plkoxyalkyl, mono- and di-alkylaminonlkyl, carboxy, alkoxycarbonyl, carboxamido, fonnyl, alkanoyl, aroyl, aralkanoyl, sulfonyl, alkylsulfonyl, iilkoxysulfonyl, sullbnaniido. phosphonyl, pliosphoramido, or phosphinyl; Z is one of-SO2O-, ~SO3NRHI-, -C(RyR')O- or~OC(RvR'0- ^here IV and R7-are cacli hydrogen; R2, \V and R'1 arc independcnlly one of hydrogen, CM alkyl, C3.s cycloalkyl, phenyl, benzyl, trilluoromclhyl, halogen, hydroxy(C,-.4)alkyI, cyano, nilro, carboxamido, carboxy, Ch,, alkoxycarbonyl, C,.4 alkoxynielhyl or C,_., alkoxy; or alternatively, R: and - 175- R3, when present on adjacent carbon atoms, may also be taken together to form one of -CM=CJ-I"CH-Cn-or-(CJI2)ir, where q is from 2 to 6, and ]V is as defined above; \ Y i.s one of-O-, -S-, -NR10-, or a covalent bond; Rn, Rh and Rc are each one of hydrogen, C,.,, alkyl, hydroxy, CM aikoxy, phenoxy, Cu alkyloxycarbonyl, benzyloxycarbonyl, cyano. wliereR1' is benzyl, methyl, cthy], isopropyl, .Tec-butyl or /-butyl, and where Rris hydrogen or C,.fi alkyl; Rfi is one of hydrogen, Cf.(, alkyl, C,,_H, ar(CKf,)aIkyl, C,,.,,, aryl, C,.]0 hydroxyalkyl, C2.!0 nminoalkyl, mono(Cj.ll)alkylamino(C2.(f)alkyl, di(CM)a!k}¦!aminn(Ci,_!{')alkyI or C\.)t) eatboxyalkyl; R', R", R1' and lV2 are independently one of hydrogen, C,^ alkyl. C:.l0 carboxyalkyi or C2.|0 hydroxyalkyl, or R7 and R8 are taken together to form -(CM2)y-where y is zero, 1 or 2. while R" and R12 are defined as abo\re; or R7 and R12 are taken together to form -(CJl^),,-, where q is zero (a bond), or I, 2 or 3, while RR and R" are defined as above; or KK antl R" are taken together to form -(CIl:),-f where r is 2. 3, or 4, while R' and R12 are defined as above; R" is hytlroj'.t-n, or (!, |(J alkyl, dptionally substiluli.-d wi(h ammo, mono(CM)aIkylnmimi, C,.6 aikoxy, hydroxy, carboxy, pbenyl, CU4 alkyloxycnrbonyl, Q.io ar(C,..,)nlkoxycar!.H)nyl, C,.fY acylamino, c)pano or trifliioromctliyl; iR10, in each instance, is independently hydrogen, C,.fl atky.l, benzyl, phenyl, C2.I0 hydroxyalkyl, Q-,.,,, aminoalkyl, C,.j monoa!kylamino(C2_8)alkyl, Cj.., dialkylamino(C2.|i)iilkyl or C2.i0 earboxyalkyl; n i.s from zero (o (S; and m is from zero to 4. 17. A compound as claimed in claim 1, wherein : K1 is tuie of plu'iiyl, tiaphlhyl, pyridyl. Ihiophenyl. quinoliiiyl or isoi|Uinolin\'[. optionally substituted by one or two of cbloru. methoxy, methyl, trinuoromcthyl. cyano, nitro, amino or dimethylamino; - 3 76- Z i.s one of-SO2O-, -SO2NR10-, -CII2O- or -OCH2-; R7 and R? arc hydrogen or-C,.., alkyl, or R7 and R1 may also he (aken together t1 form ^CH ---CH-CJ-I =CH-; RA is one of hydrogen, methyl, melhoxy ov irifluoromcthyl; Y is one of O, Nil'" or a covalcnt bond; R", R1' rind Rc arc liydrogcn, hydroxy. where Rh is benzyl or f-butyl, and where Rf is liydrogcn or methyl; il6 is hydrogen, CM alkyl, C2.4 hydroxyalkyl, C2.q carboxyalkyl, C2.^ aniinoalkyl, dinicthA,'h!initK;(C?^):;!kyl, or n)L'!hy!an)ino{C?.s)a!kyi; ';R7, R!|, R" and R1"1 tire indcpcjKlciilly one ofhytlaJgcn, C,.f, afkyj, C-,_Ui hydrox;ya))cyl or C2.,o earboxj'iilkyl, or R1 and RR are taken together to form -(CH,)V~ where y i.s zero, 1 or 2, while R11 aifd R1? ttiv dc/fnocl as above; or R7 and Ri: are taken together to form -(CI-I3)t)~, where q is zero (a bond), or 1, 2 or 3, while Rs and R" are defined as above; or RK and Rn arc taken (oycfficr (o form -(CM-,),-, where r is 2, 3 or 4, while R7 and R12 arc defined as above; R" i.s hydrogen of C,.., alky!; :Rin, in each in.stancc, is independently hydrogen, C,^ nlkyl, C:.4 hydroxyaikyl, C7.,, carboxyalkyl, C-,.., annmialkyl, dinie(liy!;unino(C?_K)a[kyi, inctliYlaniino(C2.Klalkyl; iii is JVoin zero to 4; and m is zero, 1, 2 or 3. 18. A compound as claimed in claim 1, wherein : ;R[ IS phenyL substituted by CUl alkylsuilonyi, C6.!0 arylsulfonyl or RI;IRI4NSO2-, where Rn and R1'1 are independently selected from the group consisting of hydrogen, C,.,, nlkyl, C.'j.v cyeloalkyl. (.'_V(, alkenyl, (',.,, alkynyl, (\,.UI aryl. C1,,.,,, aiteV^alkyl, pyriilyl, pyridyI(C,.JaIkyl, earboNy(C,.f,)alkyl, C,.., alkoxycarbonyl(.Ci.4)atkylr eyano(,C,..,)a!kyl? hydroxY(C1.,,)alkyl, CM alkoxy(C,..,)alk)-l. mono- and di-CC^Jalkylamino^Ci.Jalkyk or -Ml - R" and RH can lie laken (ogemer with fhe nitrogen atom lo which (hey arc atlached to form a hetcrocyclic ring selected from the group consisting of N-morpholinosuifbnyJ, N-piperazinylsulfonyl (optionally K substituted with C,.G alkyl, C,.fl hydroxyalkyl, Q,l0 aryl, Cfi.,p aryI(C|.fi)aIkyi; C,.6 alkylsulfonyl, C6.ia aryisulfonyi, C,.6 alkylcarbonyl, morpholi'no or Cfl.1(, arylcarbonyl), N-pyrroIyisu!fonyl, N-pipcridrnylsulfonyl, N-pyrrolidinylsuIfonyl, N-dihydropyridylsulfonyl, N-indolylsuifonyl, wherein said i hcterocytlic ring can be optionally substituted with one or two of CM alkyi, C3.7 cycloalkyl, C"f).l0 aryl, C(:.H) ar(C].4)aIkyl} helcmcyclc, IieterocycIoaJkyl, ca[[io.\y(C|.{i)aikyI, CL^alko'xycarbonylCCL^alkyl, cyano(Ci.6)aIkyl, hydroxy(C,.0)alkyI; CU1 alkoxy(C,.4)alkyl: mono- and di-(CM)alkylamino(C,..,)alkyl, carboxy, C|.f, alkoxycarbonyl, carboxamido, fonnyl, C,.f, alkanoyl, C(,.1O aroyl, C6.l0 ai(C,.4)a!kanoy], sulfonylj C,.6 alkylsulfonyl, C,.6 aikoxysulfonyl, sulfonamido, phosphonyl, phosphqramido, or phosphinyl; Z is one of-SO2O-, -SO2NRin- -C!12O- or-OCM2-; lit7 and \l? aic hydrogen or C\.., alkyl, or K? and RJ may also be taken together lo form-CJI-C1I-CI!-Cll- R'1 is one of hydrogen, melhyt, rncthoxy or triduoronielhyl; Y is one of O, Nil10 or a covalcnt bond; R\ II1' and Rc are hydrogen, hydroxy, where Jl'1 is hen/.yl 01 /-bn(y[, and where R* is liyilrogen of methyl; Ra is hydrogen, C,.4 alkyl, C,.,, hydroxjalkyl, C3.4 carboxyaikyl, C2_4 aminoalky], dimethylaniino(C2.K)alkyl, or niethylamino(C':.s)a'kyl; ;R7, Rs, R" and R12 are independently one of hydrogen, Ct.6 alkyl, C2.l0 hydroxyalkyl or C?_U) carboxyalkyl, or R7 and Rs are taken together (o form ~(CM:)V-wherc y is zero, I or 2, while R" and R1- are defined as above; or R7 and R1' are taken touetheV to form ¦¦{('!!,)"¦-, where q is zero (a bond), or 1, 2 or 3, while Rs and k" are - !78- defined as above; or Rs and R1' are taken together to form -(CH2)f-, where r is 2, 3 or 4, while R7 and R12 arc defined as above; R9 is hydrogen or CM alkyl; Rl03 in cacli instance, is independently hydrogen, CM iilkyl. C,.., hydroxyalkyl, C2.4 carboxyalkyl, C:.4 aminoalkyl, dimclhylamino(C2.B)a]kyI, niclhylaniino(C2.s)aiky]; ri is from zero to 4; and m is zero, 1, 2 or 3. 19. A compound as claimed in claim 1, wherein the moiety -Z-R1 is attached to the benzene ring in a position met a- to Y. 20. A compound having (he formula: or a soivhte, hydrate, pkumaceutically acceptable salt orprodrug thereof; wherein R2' is one of phenyl, naphlhyl, thiopheny], quinolinyl or isoquinolinyl, optionally substituted by one or two snbslituenls independently selected JVom the group consisting of halogen, CM alky], C,.-i alkoxy, methoxy, trilluoroinethyl, cyr.no, nilro, amino or dimclhylomino; and when R21 is phenyl, said phenyl can be optionally substituted by C,.6 alkylsulfonyl, Cfi.!0 arylsulfonyl, C6.m ar(C,.6) alkylsulfonyl, C0.l0 arylsulfonamido, Q.j() arfG,^) alkylsulfonaniido, /Y-niorpholinosulfonyl; or R^R^NSO,-. where R" and R23 are independently selected from the group consisting of hydrogen, C5.6 alky], Chl cycloaikyl, C,_.f, alkenyl, C?.fl alkynyi, C,,.1O aryl, Cr,.|(, nitC^.^alkj'l, pyridyl, pyridyl(G,.4)iilkylJcaibnxy(C!.fl)a!kyl, C,.., alko\ycarbony!(C,.;l)alkyl. cyano(C,.4)a]kyI, l)ydroxy(iC,.,,)alky!, C,.,, rilko\y(C|..|)alk>'l, mono- and i.li-(C|..l)alkyUiniino(.C|_,l)alkyl. or R22 and \i2i can be taken together with the nitrogen alum to which they are attached lo form a h - 179 - N-piperazinylsulfuny! (optionally N' substituted with Cu, alky!, C,.6 hydroxyalkyl, C6.m aryl, Q.,,, riryl(C|,,,);i!kyl, Cu, alkyl.sulfonyl. (\,,w -'irylsiiMbnyl, C,.,- alkylearbonyl, morpholino orC6.f0 arylcarbonyl), N-pyrrolylsulfonyl, N-piperidinylsulfonyl, N-pyrrolidinyl.suI fonyl, N-dihydropyridylsuIfonyl, N-inclolylsulfonyl, wherein said heterocyclic ring can be optionally substituted with one or two ofCM alkyj, C3,7 cycloalkyl, C6.l0 aryl, C6,10 ar(CM)alkyI, hetcrocycle, helerocycloalkyl, carboxy(C,.6)alkyl C|.4)alkoxycurbonyl(C|.,|)alkyl, cyano(C|.f,)alky), Jiydroxy(C|.6)alkyl, Cj.,, alkoxyfCj.Jalkyl, mono- and di-(C[^)a!kyIamino(C|.1()alkyI, carboxy, C,.c alkoxyccirbonyl, carboxamido, formyl, C,.fi alkanoyl, C6.l0 aroyl, C6.K, ar(C|.,,)alkanoyl, sulfonyl, C,.o aikylsulfonyl, CNf, nlkoxysulfonyl, sulfonamido, phosphonyl, phospJioramido, or jiliospliiuyl; RZl) is hydrogen or CM alkyl; V' is one of O. NR10 or a covalcnt bond lij'drogcn, CU(, nlkyl, Cf,.H1 ar(C,.f,)nlkyl, Ca.,0 aryl, C2.,o hydroxyalky! Cj.l0 aminoalkyl, C2.7 carboxyalkyl, mono(C,^ a)kyl)araino(C(.R)alky!, and di(CU(( alkyl)amino(,C,.H)alkyl; and a and b arc 0, 1 or 2; X'isOorNR"; JIIKI Rv> i.s hydiugcn or C[.., alkyl. 21. A compound as claimed in claim 20, wherein : R24 i.s mclhyl; Y' is 0; a is one; and X' is 0 orNH. or a solvalc, hydrate, phavnuKcuticaHy acceptable salt or prodrug thereof; wherein 22. A compound having the formula: - IRC) - RZ1 is one ofphenyl, naphthyl, ihiopbcnyl, quinolinyl or isoquinolinyl, optionally substituted by one or two substituents independently selected from the group consisting of halogen, CM alky], CM alkoxy, methoxy, trifluoromelhyl, cyano, nitro, amino or dimetbylamino; and when R21 is phenyl, said phenyl can be optionally substituted by Cx_6 alkylsulfonyl, C6.,o arylsulfonyl, C6.!0 ar(C|.6) alkylsulfonyl, C6.]0 arylsulfonamido, Cfi.j0 ar(C,.fi) alkylsnlfonnniido, A7-morphoIinosulfonyI, or R22R23NSO2-, where R22 and R23 arc independently selected from the group consisting of hydrogen, C,.fi alkyl, C3.7 cycloalkyl, C2.6 alkcnyl, C2.6 alkynyl, C6.,0 aryl, C6,i0 ar(C,.4)alkyl, pyridyl, pyridyl(Cj.4)alkyl, carboxy(C,.6)alkyl, CM alkoxycarbonyl(CM)alkyl, cyano(CM)alkyi, hydroxy(CM)alkyl, CM alkoxy(C!^)alkyi, mono- and di-(C,.4)aIkyIamino(C,_4)alkyI, or R23 and R23 can be taken together with the nitrogen atom to which they are attached lo fomi a helerocyclic ring selected from the group consisting of N-morpholinosulionyl, N-pipcin/inylsulfonyi (optionally N' substituted with C,.fi alkyl, C,.(, hydroxynlkyl, Cf,.,0 aryl, C6.10 aryl(C,.6)a1kyl, CU6 alkylsulfonyl, C6.10 arylsulfonyl, C[.6 alkylcarbonyl, inorpholiiK) or C,,.1(, arylcarbonyl), N-pyrroIylsnlfonyU N-piperidinylsul(onyl, N-pyrrolidinylsulfonyl, N-dihydropyridylsullbnyl, N-indolylsulfonyl, wliLM-cin said heterocyclic ring can be oplionally substituted with one or two of C,.., alkyl, C^.7 cycloalkyl, C6.10 aryl, C6.,o ar(C,.4)alkyl, heterocycle, heteroeyelonlkyl, carbox)'(C,.6)alkyl C1^)alkoxvcarbonyl(C,.4)aIkyl, cyauo(C|.fi)alkyI, hydroxy(C,.6)alkyl, CX.A alkoxy(CM)alkyl, mono- and di-(C|..1)aikylamino(C1..,)alkyl, carboxy, Cj_(, alkoxycarbonyl, carboxamido, formyl, C,_6 aikanoyl, C6.10 aroyl, C6_I0 ar(Cl-1)alkanoyI, suifonyl, C,.6 alkylsulfonyj, C,.,, alko.vysuifonyl, sulfonamido, jilmsphonyl, phosphoramido, or phosphinyl; R2'1 is hydrogtMi ov C,_4 alkyl; X(isOorNRM;and R?1) is hydrogen or C,.., alkyl; Y' is one of O, NR10 or a co^'alent bond hydrogen, C,.6 alkyl, C6.I0 ar^C,.6)alkyl, C6_10 aryl, C2.10hydroxyalkyl C2_10 aminoalkyl, C2.7 carboxyalkyi, mono(C,.j alkyl^rninotC^ValkyL and di(C,.., alkyl):imino(C,.R)alkyl; and bisO, 1 or 2. 23. A compound as claimed in claim 1, which is one of - 181 - 3-[3-(2-chlorophcny!suIfonylox.y)-5-mc(hy!phenoxy]propoxyg.uanidinc; 3-[3-(2imclhoxyj>licnylsulfonyloxy)-5-mcl!\yIphcnoxy]pvoc)Oxygviaiudinc; 3-[5-methyI-3-(quinoiinyl-8-sulfonyloxy)phenoxy]propoxygv\nnidine hydiochloride; 3-[3-{57t:Uloro-2-mcllioxyphenylsuiroiiyioxy)-5-mcthylplicnoxy]i"!vopoxyguanitrinc hydrodiiioridc; 3-[3-(5-isoquinolinylsuironyloxy)--5-me0iylphcnoxy]propoxyguanidine bydrochloridc; 3-[5-me(byl-3-[2-(melhylsulfonyi)phcny]sulfonyloxy]phcnoxy]propoxyguanidine hydrochloridc; l-[j_5-niell)yI-3-(2-inclliylsu]Jbiiylphcny]suironyloxy)plic!ioxyjim:U)y1J cycloprbpylmclhoxyguanidtne hydrochloridc; 3-[5'inct]iyi-3"(2-inoip]K)Iiiiylsu]roiiylpIicnylsi]ironyloxy)jthciioxyJpiopoxyguanidiin: hydrocliloridc; 3-[5-mcthyl-3-(2-(pIicnylsuHbny])p]iGnylsuironyloNy)phcnoxy]propoxyguanidine hydrochloride; 3-[5-mdlliy]-3-(2-(4-c.l]iyloxycarboi]yl)pipciiidinyl siil Tony lplicnylsullbj)yloxy) phcnoxyjpropoxyguanidinc hydrocliloride; 3-J5-nicl(liyl-3-(2-('f-c:irlH)xyl)pipLTidii])"lstilfbnylpln.'iiylsiiUbiiyloxy) phcnoxyjpropoxyguanidinc; 3-[5-me(liy]-3-(3-mt;lIiyIquinolinyl-8-,ciulfbnyloxy)p]ienoxy]propoxyguaiiidinc diacctalc; 3-[5-rnQt]iy]-3-(2-(4-nicth)dsu]ro)iylpipcr:r/Jn-l-ylsuiroiiyl)jihcnylsulfonyloxy)pbcnoxy] propoxyguanidinc hydrochloride; 3-[5-melbyJ-3-(2-(4-(2-py!iinidi[]yl)pipcrazin-]-yl5ulJbny])plionyIsulIbny!oxy)phcnoxy] propoxyguanidinc bydrochloridc; 3-[5-mcthy]-3-(2-(A'-cUiyl-A^-(4-pyridylniclhyl)aniitiosuHbnyl)pficnylsuironyloxy) phenoxyjpropoxyguanidine dihydrochloride; 3-[5-mcthyl-3-(2-(':5~clhyl)npc-ra7.iu-l-ylsu!ronyl)phcnylsul(bnyloxy) phcnoxyjpropoxyguanidinc dihydvocliloride; 3-[5-nicihy)-3-(2-(Af-(2-cyaiioclhy[)-/V-(3-pyridylmclhyl)aininosuHony]) phenylsulfony)oxy)phenoxy]propoxyguanidine dibydrochloride; 3-[5-mctby]-3-(2-(/V-(2-ethoxycarboiiy!ethyl)-A'-bcnzylaniinosulibnyl)pl\ciiyl-sulfonyloxyjphcnoxylpropoxyguanidinc hydrochloride; - 182- 3-[5-methyI-3-(2-(A/'-(cthoxycarbonyimcihyl}-A/-(2-pyfidy!methyl)nminosulfonyI) phcnylsulfonyloxy)phcnQxy]propoxyguanidinc dihydrochloride; 3-[5-mcthy!-3-(2-(4-(clhoxycavbonylmclhyl)piperazin-l- ylsulfonyl)phcnylsulfonyloxy)phcnoxy] propoxyguanidinc dibydrochloride; 3-[5-mcihyl-3-(2-(4-(carboxymcihyl)pipcrazin-l- )'1suiro'nyl)plicnylsulfonyloxy)plicnoxy'tpropoxygiianidinc; 3-|5-n]clliyl-3-(2-(4-(2-pyridyl)pi]icia"/-ii]ylsu)]bnyl)pi)enyIsulibnyluxy) phenoxyjpropoxyguanidihe hydrochloridc; 3-[5-niel]iyl-3-(2-(4-pl]cny]piperazinyl.siilJbiiyI)phcny]suIibnyloxy) plienoxy]])ropoxyguanidine hydrochloridc; 3-f5-mclliy]-3-(2-(4-bcnzylpipcrazinylsuI(bnyl)phcnylsuironyloxy) phcnoxyjpropoxyguanidine hydrochloride; 3-[5-nit;lIiyI-3-(2-(';l-(2-incllioxyjilicny!)pipci;i/.tnyIsu!ibnyl)plii'nylsuirony!oxy)phciH>xy] propoxyguanidine hydrochloride; 3-['5-mGLliy!-3-(2-(A/-(2-cyanocthyl)-A'-(2-fiirnn}inic(hy]);iniii]O.SLiironyl) phcnylsul(bnyloxy)plienoxy]propoxygiianidinc; 3~|5-inGthyl-3-(2-(4-nK-(liy]pi|ic!azinylsuironyl)phcny]suHbnylo\y) phcnoxyjpj-opoxyguanidinc hydrochloridc; 3-r5-mcUiyI-3-(2-(AM]cn7.yl-A/-(2-(A',Ajr-dinicthyIan]ino)ctIiyl)aniinosuironyl) phenylsuHbnyloxy)pheiioxyJpropoxyguaiiidine dihydrochloiide; 3-[5-mcthyl-3-(2-(A7-inothyl-A^3-pyridylinclfiyl)atnino.suiroiiyl)plicnylsiilfoiiyloxy) phcuoxy jpi'ojjoxyguanidinc ilihydrocliloridc; 3-[5-mclhyl-3-(2-(2-(4-niorpliolinyl)clhy!aminosi!lfony!)phonylsuUbnyloxy)phenoxyj propoxyguanidine; dihydrochlovidc; 3-[5-mdthyl-3-(2-(4-elhoxycarbonyl-l-pipcra7Jny1sulfonyl)phenylsulfonyloxy)phenoxy] propoxyguanidine hydrochSoridc; 3-[5-melhyl-3-(2-(4-pyridylmethylaminosnlfonyl)phenylsuifonyloxy) phcnoxy'jpropoxygiKinidinc; or a hydrochloride or acclalc salt thereof. 24 A compound having the Formula /: 183 - or a sol'vatc, hydrate or phannaccutically acceptable salt thereof; wherein: R1 i.g one ofalkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl or heteroaryl, any of which may ho optionally substituted; iZ is one of-NR'"SO2-, -SO2NR10-, -NRIOC(RJ'R'-)-, -C(RyR')NRH1--OSO2", -SO2O-, -0C(RvR7)- -C(R>'R7)0- -NR'°CO- or -CONR10-; !Ry and R7 are each independently one of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxy; ¦R2, R3 and R'1 are each independently one of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, hctcroaryl, ti illuoroniLihyl, halogen, hydroNyalkyl, cyano, nitro, carboxiimido,-COjr, -C1I2ORX or-OR\ or when present on adjaeeht carbon atoms, R2 and R3.may also be taken together to form one of-CH=CH-CH=CH- or -(CH2)q-, where q is from 2 to 6, and R'1 is defined as above; Rx, in each instance, is independently one of hydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl groups may optionally have one or more unsaturalions; Y is one of - O-, -NR10-, -S-, -CIIR10- or a covalent bond; Rw is alkyl, cycloalkyl, phenyl, ben/.yl, - 1S4- v/here R(l and Rc arc independently hydrogen, C,.f, alky], C;.6 aikcuyl or phcnyl, Rris hydrogen, C,^ alkyl, C2,b alkenyl or phenyj, R': is hydrogen, C,.,, alkyl, (.?¦>. A. R7 and IV2 are Uikcn togcllicr lo form -(CJ-1,)(1-, wlicre o is 1, 2 or 3; ' R" is hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl; RK is hydrogen; R°, Rb and Rc are hydrogen, hydroxy. whore Rh is ben/.yl or /-bulyl, and where Rr is hydrogen or methyl; and R6 is hydrogen, C,.4 alkyl, C2.A hydroxyalkyl, C2.4 carboxyalkyl, C2.4 aminoalkyl, diinct!iyl;unino(C2.j)alkyl, or nK'tiiyliunino(C-,.K)ulkyl; or B. R7 is hydrogen, alky!, aralky), aryl, hydroxyalkyl or carboxyalkyl; Rf and R12 arc taken together !o ibrm -Cll,-CH2-(CM2),,-. where p is J, 2 or 3; R7 is hydrogen; and R\ Rh an where Rh is benzyl-or /-butyl, and where Rr is hydrogen or methyl; and R6 is hydrogen, C,.4 alkyl, C,.,, hydroxyalkyl, C2.., carboxyalkyl, C2.4 aminoalkyl, dinicthylaini[io(C2.s)atkyl, or inclhylamino(C%.s)aikyl; or C. R6 and Rh arc taken together to form =CM-N=CH-NH- or -CH,-(CH2)r~, where r is 1,2 or 3; R'1 is hydrogen or hydroxy; Rc is hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycorbamoyloNy, cyano or- -C()_,RW-, where Rw is as defined above; R7 ntul Rs are each independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or.carboxyalkyl, ¦ or R7 and R" arc taken together to form -(CH2)y-, where y is zero. 1 or 2; R11 is - 1 S5 - hydrogen; and R12 is one of hydrogen, alky], cycloalkyl or aryl, wherein said alky], cycloalkyl or aryl can be optionally substituted with amino, monoalkyiamino, dialkylamino, alkoxy, hydroxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbony!, aryl, hetcroaryl, acylamino, cyano or trifluoromcthyl; or D W and Rc arc taken together to form -CIU-(CU?\-, where s is I or 2; and Rr> is hydrogen, alkyl, alkoxy, aryioxy, arafkoxy, alkoxycarbonyloxy, cyano or -COZRW-, where Rw is as defined above; R7 and Rs are each independently one of hydrogen, alkyl, aralkyi, aryl, liydroxyalkyl or carboxyalkyl, or R7 and R* are taken together to form -(CH2)y-, where y is zero, 1 or 2; R1' is hydrogen; and R'3 is one of hydrogen, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl-can be optionally substituted with amino, monoalkylamino, dialkylamino, alkoxy, hydroxy, earboxy, alkosycmbonyl, aryloxycarbonyl, araikoxycarbonyl, aryl, hel(>roaryl, acylaniino, cyano or triiluoroincUiyl. 25. A compound having Jrormnla IX: wherein !Rl is one oi" alkyl, cycloalkyl, nlkenyl, alkynyl, aryl, aralkyi or hctcroaryi, any of which may be optionally substituted; ;Z is one of-NRloSO2- -SO2NRU>- -NR10C(R>'R7)- -C(RVR7)NR10--OSO2-, -SO2O- -OC(RyK7)-, -C(R-VR?)O- -NR'°CO- or -CONR10-; Ry and R7- are each independently one of hydrogen, alkyl, cycloaikyh aryl, aralkyi, hydroxyaikyS, carboxyalkyl, aminoalkyl, tnonoaikylaininoalkyl, dialkylaminoalkyl or carboxy; R3, IV and R'1 arc each iiulepcndcnlly one of hydrogen, alkyl, eycioiilkvl. nlkenyl, alkynyf, aryl, aralkyi, heteroaryl, irinuoroincUiyl/luiloecn, hydroxyalkvl. cyann, m'tro, carboxamido, -CO2RX, -CI !X)RS or-ORx, or when present on adjacent carbon atoms, R2 - 186- and R3 may also be inken together to form one of -C1I~C1I -CH --CU- or -(CIU),,-, where q is from 2 to 6, and R'1 is defined as above; Rx, in each instance, is independently one of hydrogen, alkyl or cycioalkyl wherein said alkyl or cycloalkyl groups may optionally have one or more unsaturnlions; Y is one of-O-, -NR'°-, -S-, -CHR10- or a covalent bond; R7, R8, Rl! and R12 are each independent!)' one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, mononlkylaminoalkyl, dialkyllaminoalkyl or carboxyalkyl; or R7 and Rs ;irc taken together to form -(CH2)y-, where q is zero (a bond), \ or 1, while R1' and Ru are defined ;m above; or R7 and R12 are defined as above; or RK and R!i are taken together lo form -(CI 1?\-, where r is 2-8, while R7 and R12 are denned as above; R10, in eaeli instance, is imlependenliy one oriiydrogen, alkyl, aralkyi, aryl, hydroxyalkyl, aminoalkyl, monoalky]amtno(C2_lo)a]kyl, dialkylamino(C2.,0)a!kyl, carboxyalkyl or alkoxycarbonylalkyl; n is from zero to 8; and m is from zero to 4. 26. A pharmaceutical composition for inhibiting prolcolysis in a mammal, comprising an amount of a compound as claimed in any one of claims 1,16,17,18,20,22 or 23 effective to inhibit protcolysis, and a pliarmnccnlicalty acceptable carrier or diluent. 27. The pharmaceutical composition as claimed in claim 26, comprising an amount of said compound effective \v inhibit a trypsin-like protease. 28. A pharmaceutical composition as claimed in claim 27, for inhibiting proteolysis in a mammal. 29. A pharmaceutical composition as claimed in claim 28, wherein a trypsin-. like protease is inhibited. 30. A pharmaceutical composition as claimed in claim 26, for treating pancreatitis, thrombosis, ischemia, stroke, restenosis, emphysema or inflammation in a mammal. - 187- 31. A pharmaceutical composition as claimed in claim 26, for inhibiting thrombin-induced platelet aggregation and clotting of fibrinogen in plasma. 32. A pharmaceutical composition as claimed in claim 26, for inhibiting thrombin in blood. 33. A pharmaceutical composition as claimed in claim 26, for inhibiting formation of blood platelet aggregates in blood. 34. A pharmaceutical composition as claimed in claim 26, for inhibiting thrombus formation in blood. 35. In a device used in blood collection, blood circulation, and blood storage wherein said device includes an effective amount of a thrombin inhibiting compound or inacromolcciile as an anticoagulant, either embedded in, or physically linked to, one or more materials lliat form the structure ofsnid device, the improvement comprising employing as .said tlirombin inhibitor one or more compounds as claimed in claim 1. 36. The device as claimed in claim 35, wherein said device is a catheter, blood dialysis machine, blood collection syringe, blood collection tube, blood line or CNlracorporeal blood circuit. 37. The device as claimed in claim 35, wherein said device is a ;:tenl that can be surgically inserted into a mammal. 38, A process for preparing an aminoguanidine compound as claimed in claim comprising readme an aminoguanidine of the formula -188- wherein R9, R", Rb and Rc arc'dcfined in claim 1, with a carbonyl-conlaining compound of the formula wherein R'-R\ Z, Y, n, m, R7, R8, RMand R'2 are defined in claim 1 to form an amidinohydra/.one, and thereafter selectively reducing the hydrazonc carbon to nitrogen double bond of the amidinohydrazone. 39. The process as claimed in claim 38, wherein the aminoguanidine of Formula // is provided a.s a hydrodiloride, acetate or nitralc salt. 40. The process as claimed in claim 38, wherein the reaction is conducted at ambient temperature using an alcohol as a solvent. 41. The process as claimed in claim 38, wherein an acid is added to tiie reaction mixture. 42. A process for preparing an nlkoxyguanidine compound as claimed in claim 1, comprising reacting an aikoxyaminc compound of the formula wherein R'-R'1, Z, Y, nr in, R7, Rs, R", R"and U.17 are defined in claim 1, with a guanidinylating reagent. - 1 89 - 43. The process as claimed in claim 42, wherein said guanklinylniing reagent is aininoiniinusuKbnic acid, optionally .sub.slUufcd MI- pyrn?.o!c-l -earhoxamidincs, or N,N'-bis(tert-butoxycarbonyl) S-methyl isoUiiourea. 44. A compound as claimed in Formula I, as defined herein, substantially as herein described, particularly with reference to the foregoing examples. 45. A compound as claimed in Formula II, as defined herein, substantially as herein described, particularly with reference to the foregoing examples. 46. A compound as claimed in Formula IX, as defined herein, substantially as herein described, particularly with reference to the foregoing examples. 47. A pharmaceutical composition, substantially as herein described, particularly with reference to the foregoing examples. 48. Aminoguanidine compounds, substantially as herein described, particularly with reference to the foregoing examples. 49. Alkoxyguanidine compounds, substantially as herein described, particularly with reference to the foregoing examples. Aminoguanidine and alkoxyguanidine compounds, including compounds or the formula: wherein X is O or NR9 and R1-R4, R6-R9, R11, R12, Ra, Rb, Rc, Y, Z, n and m are set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof, that inhibit proteolytic enzymes such as thrombin are described. Also described are methods for preparing the compounds of Formula . The novel compounds of the present invention are potent inhibitors of proteases, especially trypsin-like serine proteases, such as chymotrypsin, trypsin, thrombin, plasmin and factor Xa. Certain of the compounds exhibit antithronibolic activity via direct, selective inhibition of thrombin, or are intermediates useful for forming compounds having antithrombotic activity. The invention includes a composition for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutioally acceptable carrier. Other uses of compounds of the invention are as anticoagulants cither embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents. |
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02234-cal-1997-correspondence.pdf
02234-cal-1997-description(complete).pdf
02234-cal-1997-letters patent.pdf
02234-cal-1997-priority document.pdf
02234-cal-1997-reply f.e.r.pdf
2234-cal-1997-granted-abstract.pdf
2234-cal-1997-granted-claims.pdf
2234-cal-1997-granted-description (complete).pdf
2234-cal-1997-granted-form 2.pdf
2234-cal-1997-granted-specification.pdf
2234-cal-1997-priority document.pdf
| Patent Number | 210290 | ||||||||||||||||||||||||
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| Indian Patent Application Number | 2234/CAL/1997 | ||||||||||||||||||||||||
| PG Journal Number | 39/2007 | ||||||||||||||||||||||||
| Publication Date | 28-Sep-2007 | ||||||||||||||||||||||||
| Grant Date | 26-Sep-2007 | ||||||||||||||||||||||||
| Date of Filing | 26-Nov-1997 | ||||||||||||||||||||||||
| Name of Patentee | 3-DIMENSIONAL PHARMACEUTICALS, INC., A CORPORATION ORGANISED AND EXISTING UNDER THE LAWS OF THE STATE OF DELAWARE | ||||||||||||||||||||||||
| Applicant Address | EAGLEVIEW CORPORATE CENTER, 665, STOCKTON DRIVE, SUITE 104, EXTON, PENNSYLVANIA 19341, UNITED STATES OF AMERICA. | ||||||||||||||||||||||||
Inventors:
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| PCT International Classification Number | A61K 31/365, A 61K 3 | ||||||||||||||||||||||||
| PCT International Application Number | N/A | ||||||||||||||||||||||||
| PCT International Filing date | |||||||||||||||||||||||||
PCT Conventions:
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