Title of Invention	3,4-DI-SUBSTITUTED CYCLOBUTENE-1,2-DIONES AS CXC-CHEMOKINE RECEPTOR LIGANDS
Abstract	The present invention relates to a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, which are useful for the treatment of chemokine-mediated diseases such as acute and chronic inflammatory disorders and cancer.

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This application claims the benefit of US Provisional Application 60/284,026, riled April 16, 2001. -lELD OF THE INVENTION The present invention relates to novel substituted cyclobutenedione ;ompounds, phannaceutical compositions containing the compounds, and the use of he compounds and formulations in treating CXC chemokine-mediated diseases. BACKGROUND OF THE INVENTION Chemokines are chemotactic cytokines that are released by a wide variety of ;ells to attract macrophages, T-cells, eosinophils, basophils, neutrophils and jndothelial cells to sites of inflammation and tumor growth. There are two main ilasses of chemokines, the CXC-chemokines and the CO- chemokines. The class lepends on whether the first two cysteines are separated by a single amino acid CXC-chemokines) or are adjacent (CC-chemokines). The CXC-chemokines include iterleukin-8 (IL-8), neutrophil-activating protein-1 (NAP-1), neutrophil-activating rotein-2 {NAP-2), GROa, GROp, GROy, ENA-78, GCP-2, lP-10, MIG and PF4. CC hemokines include RANTES, MIP -1a, MlP-2p, monocyte chemotactic protein-t VICP-1), MCP-2, MCP-3 and eotaxin. Individual members of the chemokine families re known to be bound by at least one chemokine receptor, with CXC-chemokines enerally bound by members of the CXCR class of receptors, and CC-chemokines by lembers of the CCR class of receptors. For example, IL-8 is bound by the CXCR-1 nd CXCR-2 receptors. Since CXC-chemokines promote the accumulation and activation of sutrophils, these chemokines have been implicated in a wide range of acute and ironic inflammatory disorders including psoriasis and rheumatoid arthritis. Baggiolini t al., FEBS Lett 307, 97 (1992); Miller et al., Crit. Rev. Immunol. 12. 17 (1992); i Oppenheim et al., Annu. Fev. Immunol. 9,617 (1991); Seitz et al., J. Clin. Invest. 87, 463 (1991); Miller et al., Am. Rev. Respir. Dis. 146,427 (1992); Donnely et al.. Lancet 341,643(1993). ELRCXC chemokines including IL-8. GROa, GROp, GROy, NAP-2, and ENA-78 (Strieter et al. 1995 JBC 270 p. 27348-57) have also been Implicated in the induction of tumor angiogenesis (new blood vessel growth). All of these chemokines are believed to exert their actions by binding to the 7 transmembrane G-protein coupled receptor CXCR2 (also known as IL-8RB), while IL-8 also binds CXCR1 (also known as IL-8RA). Thus, their angiogenic activity is due to their binding to and activation of CXCR2, and possible CXCR1 for IL-8, expressed on the surface of vascular endothelial cells (ECs) in surrounding vessels. Many different types of tumors have been shown to produce ELRCXC chemokines and their production has been correlated with a more aggressive phenotype (inoue et al. 2000 Clin Cancer Res 6 p. 2104-2119) and poor prognosis (Yoneda et. al. 1998 J Nat Cancer Inst 90 p. 447-454). Chemokines are potent chemotactic factors and the ELRCXC chemokines have been shown to Induce EC chemotaxis. Thus, these chemokines probably induce chemotaxis of endothelial cells toward their site of production in the tumor. This may be a critical step in the induction of angiogenesis by the tumor. Inhibitors of CXCR2 or dual inhibitors of CXCR2 and CXCR1 will inhibit the angiogenic activity of the ELRCXC chemokines and therefore block the growth of the tumor. This anti-tumor activity has been demonstrated for antibodies to IL-8 (Arenberg et al. 1996 J Clin Invest 97 p. 2792-2802), ENA-78 (Arenberg et al. 1998 J Clin Invest 102 p. 465-72). and GROa (Haghnegahdar et al. J. Leukoc Biology 2000 67 p. 53-62). Many tumor ceils have also been shown to express CXCR2 and thus tumor cells may also stimulate their own growth when they secrete ELRCXC chemokines. Thus, along with decreasing angiogenesis, inhibitors of CXCR2 may directly inhibit the growth of tumor cells. Hence, the CXC-chemoklne receptors represent promising targets for the development of novel anti-inflammatory and anti-tumor agents. There remains a need for compounds that are capable of modulating activity at CXC-chemokine receptors. For example, condittons associated with an increase in S^IL-8 production (which Is responsible for chemntavie of nentmnhii and T_/«OII enhcAte wherein the substituents on the substituted R^ groups are the same or different and independently selected from 1-6 R® groups; R^ and R"* are the same or different and are independently selected from the group consisting of hydrogen, cyano, halogen, alkyl, alkoxy, -OH, unsubstituted or substituted heteroaryl, wherein the substituents on the substituted R^ and Regroups are the same or different and independently selected from 1-6 R^ groups; R^ and R® are the same or different and are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, -CF3, -OCF3, -NO2, -C(0)R^^ -C(0)OR^^ -C(0)NR^^R"*. -S0(t)NR"R^^ -C(0)NR^30R^^ cyano. an unsubstituted or substituted aryl and unsubstituted or substituted heteroaryl group, wherein the substituents on the substituted R^ and R^ groups are the same or different and independently selected from 1-6 R^ groups; R" and R® are the same or different and are independently selected from the group consisting of H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyi, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyi, unsubstituted or substituted cycloalkylalkyi, -COaR^^ -CONR^^R^*, fluoroalkyi, alkynyl, alkynylalkyl, alkenyl, alkenylalkyl and cycloalkenyl, wherein the substituents on the substituted R^ and R° groups are selected from the group consisting of a)H. b) halogen, c)-CF3. d)-COR", R10 and R11 are the same or different and are independently selected from the roup consisting of hydrogen, halogen, -CF3, -OCF3, -NR^^R^"*, MR"C(0)NR"R^\ -OH. -C(0)OR^^ -SH, -SO(t)NR"R^^ -S02R^^ -NHC(0)R^^ ^JHS02NR"R^\ -NHSO2R", -C(0)NR^^R^^ -C(0)NR"0R^"*. 0C(0)R" and cyano; R"*^ is hydrogen, -0C(0)R", or an unsubstituted or substituted aryl, nsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyi, nsubstituted or substituted cycloalkyl. unsubstituted or substituted alkyl, nsubstituted or substituted cydoalkylalkyl or unsubstituted or substituted eteroarylalkyi group, wherein the substituents on the substituted R^^ groups are the same or different nd independently selected from 1-6 R^ groups; R" and R^*are the same or different and are independently selected from the roup consisting of H, unsubstituted or substituted alkyl, unsubstituted or substituted ryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyi. nsubstituted or substituted heteroarylalkyi, unsubstituted or substituted cycloalkyl, nsubstituted or substituted cydoalkylalkyl, and unsubstituted or substituted joroalkyl, or R" and R^* can be taken together when both are attached to a nitrogen atom I form an unsubstituted or substituted 3 to 7 membered heterocylic ring containing ie to two heteroatoms selected from oxygen, sulfur and nitrogen, wherein the substitutents on the substituted R" and R^* groups are the same • different and independently selected from 1-6 of H, alkyl, aryl, arylalkyi, fluroalkyi, ^cloalkyl, cydoalkylalkyl, heteroaryl, heteroarylalkyi, amino, -C(0)OR^^. :(0)NR""^R^®. -S(0)tNR^^R^^ -C(0)R^^ -S02R^^ -NHC(0)NR^^R^"* and halogen; R^^ and R^® are the same or different and are independer^tly selected from the Toup consisting of H, alkyl, aryl, arylalkyi, cycloalkyl and heteroaryl; R^^is-S02 .. ,.-. --. ... R^ is alkyl, cycloalkyl. -CN. -NO2. or -SOzR^^ R^^ are the same or different and are independently selected from the group consisting of unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl and unsubstituted or substituted cycloallcyl; wherein the substituents on the substituted R^^ groups are the same or different and independently selected from 1-6 R® groups; and t is 0,1 or 2. DETAILED DESCRIPTION OF THE INVENTION This invention provides compounds of the formula (I): or a pharmaceutically acceptable salt or solvate thereof wherein the substituents are as defined In the Summary of the Invention. Another aspect of the present invention is a pharmaceutical composition comprising the compound of formula (I) in combination or association with a phamiaceutically acceptable earner or diluent. Another aspect of tiie present invention is a method of treating an a-chemokine mediated disease in a mammal which comprises administering to a patient in need thereof of a therapeutically effective amount of the compound of formula (I), or a phamiaceutically acceptable salt or solvate thereof. Examples of chenrKskine mediated diseases include psoriasis, atopic dermatitis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease, Crohn"s disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, cardiac and renal reperfusion injury, glomerulo-nephritis or thrombosis, alzheimer"s disease, graft vs. host reaction, allograft rejections and malaria. Arwther aspect of the present invention is a method of treating cancer, comprising administering to a patient in need thereof, concurrently or sequentially, a therapeutically effective amount of (a) a compound of formula (I), and (b) a microtubule affecting agent or antineoplastic agent or anti-angiogenesis agent or VEGF receptor kinase inhibitor or antibodies against the VEGF receptor or interferon, and/or c) radiation. In further embodiments, a compound of formula (1) is combined with one of the following antineoplastic agents: gemcitabine, paclitaxel (Taxol®), 5-Fluorouracil (5-FU), cyclophosphamide (Cytoxan®), temozolomide, taxotere or Vincristine. In another embodiment, the present invention provides a method of treating cancer, comprising administering, concurrently or sequentially, an effective amount of (a) a compound of fomriula (I), and (b) a microtubule affecting agent (e.g., paclitaxel). Unless indicated otherwise, the following definitions apply throughout the present specification and claims. These definitions apply regardless of whether a term is used by itself or in combination with other terms. Hence the definition of "alkyl" applies to "alkyl" as well as to the "alkyl" portions of "alkoxy", etc. When any variable (e.g., aryl, R2) occurs more than one time in any constituent, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. "Patient" includes both human and other mammals. "Mammal" means humans and other animals. Preferably, mammal means humans. "Alkyl" means a straight or branched saturated hydrocarbon chain having the designated number of carbon atoms. Where the number of carbon atoms is not specified, 1 to 20 carbons are intended. Preferred alkyl groups contain 1 to 12 carbon atoms in the chain. More preferred alkyl groups contain 1 to 6 carbon atoms in the chain. "Alkoxy" means an alkyl-O group in which alkyl is as previously defined. Non-limiting examples of alkoxy groups include methoxy, ethoxy. n-propoxy, iso-propoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen. "Alkenyi" means an aliphatic hydrocartx}n group containing at least one carbon-cart)on double bond and which may be straight or branched. Where the number of cart)on atoms is not specified, 2 to 20 cartxsns are intended. Preferred alkenyl groups have 2 to 12 carbon atoms in the chain; and more preteraoiy zto\5 carbon atoms in the chain. Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl. "Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched. Where the number of carbon atoms is not specified, 2 to 15 carbons are intended. Preferred alkynyl groups have 2 to 12 carbon atoms in the chain; and more preferably 2 to 4 carbon atoms in the chain. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl. "Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. Non-limiting examples of suitable aryl groups include phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl, fluorenyl and the like. "Arylalkyl" means an aryl-alkyi group in which the aryl and alky) groups are as defined. Non-limiting examples of suitable arylalkyl groups include benzyl, phenethyl and naphthleneylmethyl. The bond to the parent moiety is through the alkyl group. "Cycloalkyl" means a non-aromatic ring system having 3 to 10 carbj3n atoms and one to three rings, preferably 5 to 10 carbon atoms. Preferred cycloalkyl rings contain 5 to 7 ring atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cydohexyl, cycloheptyl, nortxjmyl, adamantyl and the like. "CycloalkylalkyI" means a cycloalkyl group attached to the parent moiety through an alkyl group. Non -limiting examples include cyclopropylmethyl, cyclohexylmethyl and the like. "Cycloalkenyl" means a non-aromatic mono or multicyclic ring system comprising 3 to 10 carbon atoms, preferably 5 to 10 carbon atoms which contains at least one caribon-carbon double bond. Preferred cycloalkenyl rings contain 5 to 7 ring atoms. Non-limiting examples of cycloalkyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl. norbornenyl and the like. "Cycloalkenyl" means a non-aromatic mono or multicyclic ring system comprising 3 to 10 carbon atoms, preferably 5 to 10 carbon atoms which contains at least one carbon-carbon double t)ond. Preferred cycloalkenyl rings contain 5 to 7 ring atoms. Non-limiting examples of cycloalkyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, norbomenyl and the like. "Halo" means fluoro, chloro, bromo, or iodo groups. Preferred are fluoro, chloro or bromo, and more preferred are fluoro and chloro. "Halogen" means fluorine, chlorine, bromine, or iodine. Prefen^ed are fluorine, chlorine or bromine, and more preferred are fluorine and chlorine. "Haloalkyl" means an alkyl group as defined above wherein one or more hydrogen atoms on the alkyl is replaced by a halo group defined above. "Heterocyclyl" or "heterocyclic" means a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to 10 ring atoms, preferably 5 to 10 ring atoms, in which one or more of the atoms in the ring system is an element other than cartaon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain 5 to 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide. S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, moipholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. The term heterocyclic acidic functional group is intended to include groups such as, pyrrole, Imidazole, triazole, tetrazole, and the like. "Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising 5 to 14 ring atoms, preferably 5 to 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain 5 to 6 ring atoms. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the conesponding N-oxIde. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl. thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazoiyi, 1,2,4-thladiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazlnyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]Uiiazolyl, benzofurazanyl, indotyt, a2:aindolyt, benzimidazolyl. benzothienyl, quinolinyl. imidazoiyi, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like. "Heteroarylalkyl" means a heteroaryl-alkyi group where the bond to the parent moiety is through an alky! group. N-oxides can form on a tertiary nitrogen present in an R substituent, or on =N-in a heteroaryl ring substituent and are included In the compounds of formula I, The term "prodrug," as used herein, represents compounds which are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-dnjgs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Dmg Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Also, "Bn" represents benzyl. R" and R^"* when taken together with the nitrogen they are attached to in the groups -NR^^R^\ -C(0)NR^^R^*, -S02NR^^R^^ -OC(0)NR^^R^^ -CONR^^R^^ -NR"C(0)NR"R^*, -S0,NR"R^\ -NHSOJNR^^R^* preferably form an unsubstituted or substituted 3 to 7 membered, saturated heterocyclic ring optionally containing one or two additional heteroatoms each independently selected from O, 8 or NR^° wherein R^° is selected from H, alkyl, aryl, heteroaryl, -C(0)R^^. -S02R^^ and -C(0)NR^^R^°, wherein R^® and R^° are the same or different and each is independently selected from alkyl, aryl and heteroaryl, wherein the substituents on the substituted cyclized R^^ and R^"* groups are the same or different and independently selected from 1 to 3 of alkyl, aryl, hydroxy, hydroxyalkyi, alkoxy. alkoxyalkyl, arylalkyi, fluoroalkyl, cycloalkyi, cycloalkylalkyl. heteroaryl. heteroarylalkyl, amino. -C(0)OR^^, -C(0)NR^^R^^. - -SOtNR^^R^^ -C{0)R^^ -S02R^^ -NHC(0)NR^^R^® and halogen, and wherein R^^ and R^^ are the same or different and are independently selected from the group consisting of H, alkyl, aryl, arylalkyi, cycloalkyi and heteroaryl. In a prefenred group of compounds of fomnula (I), aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylaikyl. unsubstituted or substituted heteroaryialkyt. unsubstituted or substituted cyctoalkyi, unsubstituted or substituted cycloalkylalkyi, -COaR^^. -CONR^^R^"*. fluoroalkyl, alkynyl, alkenyl, and cydoatkenyl, wherein said substituents on said R^ and R^ substituted groups are selected from the group consisting of: a) cyano, b) -C02R^^ c) -C(0)NR"R^^ d) -S02NR^^R^\ e)-N02. f) -CF3. g)-OR". h)-NR"R^*. i) -0(C=0)R". j)-0(C=0)NR"R^*.and k) halogen; and B is selected fn^m ttie group consisting of: iviure preieraoiy, R^ and R® are the same or different and are independently selected from H, alkyl, fluoroalkyl such as, -CF3 and -CF2CH3; cycloalkyi and cycloalkylalkyi such as, for example, methyl, ethyl, t-butyl, isopropyl, cyclopropyl, cyclopropylmethyl and cyclohexyl, and R® is the same or different and is 1-3 moieties selected from the group consisting of H, halogen, alkyl, cycloalkyi, -CF3, cyano, -OCH3, and -NO2; wherein R2 is H. OH. -NHC(0)R" or -NHSO2R"; R3 Is -S02NR"R^^ -NO2. cyano. -C(0) NR^R""*. -SOZR"^; or -C(0)0R"; R* is H, -NO2, cyano, -CH3. halogen, or -CF3; R* is H, -CF3, -NO2, halogen or cyano; R^isH.alkylor-CFs; K" and K" are the same or different and are independently selected from the group consisting of hydrogen, halogen, -CF3, -NR"R^^, •NR^^C{0)NR"R^*, -C(0)0R^^, -SH, -SO(t)NR^^R^^-S02R^^ -NHC(0)R^^ NHS02NR^^R^^ -NHS02R^^ -C(0)NR"R^\ -C{0)NR"OR^^ -OC(0)R^^ COR", -OR", and cyano; R" and R^* are the same or different and are Independently selected from nethyl, ethyl and isopropyl; or R" and R^"* when taken together with the nitrogen they are attached to in the iroups -NR^^R^^. -C(0)NR"R^^, -SOZNR^R^*, -0C(0)NR^^R^^, -CONR^R^^, NR"C(0)NR"R^^. -SOiNR^R^"^, -NHS02NR"R^"* preferably form an unsubstituted or ubstituted 3 to 7 membered, saturated heterocyclic ring optionally containing one dditional heteroatom selected from O, S or NR^° wherein R^® is selected from H, Ikyl. aryl. heteroaryl. -C(0)R^^ -SOaR^® and -C(0)NR"R2°. wherein R^^ and R^" are le same or different and each is independently selected from alkyl, aryl and eteroaryl, wherein the substituents on the substituted cydized R" and R^^ groups re the same or different and independently selected from 1 to 3 of alkyl, aryl, /droxy, hydroxyalkyi, alkoxy, alkoxyalkyl, arylalkyi, fluoroalkyl, cycloaikyi, ^cloalkylalkyl, heteroaryl, heteroarylalkyl. amino, -C{0)OR^^, -C{0)NR^^R^®, SOtNR^^R^^ -C(0)R^^ -S02R^^ -NHC(0)NR^^R^® and halogen, and wherein R^^ and ^® are the same or different and are independently selected from the group )nsisting of H, alkyl, aryl, arylalkyi, cycloaikyi and heteroaryl; wherein, R^ is H, -CF3, -CF2CH3, methyl, ethyl, isopropyl, cyclopropyl or t-butyl; R° is H; R^ is H, F. CI, Br. alkyl or -CF3. and Bis: wherein: R2 is H. OH, -NHC{0)R" or -NHSO2R"; R^is -S02NR"R^\ -NO2, cyano, -C(0) NR^^R"^ . -SOzR^^; or-C(0)OR^^ R* is H, -NO2, cyano. -CH3 or -CF3; R^ is H. -CF3. -NO2, halogen or cyano; and R^sH. alkyl or-CF3; R^^ is H, halogen or alkyl; and R^^ and R^* are the same or different and are independently methyl, ethyl or isopropyl; or R" and R^^ when taken together with the nitrogen they are attached to In the groups -NR"R^^. -C(0)NR"R^*. -S02NR"R^*. -0C(0)NR"R^\ -CONR^^R^"^, -NR"C(0)NR"R^^ -SCNR^R^"^, -NHSOaNR^R^* preferably fomn an unsubstituted or substituted 3 to 7 membered, saturated heterocyclic ring optionally containing one additional heteroatom selected from O, S or NR"** wherein R^® is selected from H, alkyl, aryl. heteroaryl. -C(0)R". -S02R^^ and -C(0)NR^^R^. wherein R^^ and R^ are the same w. w....v^,v,..v u..^ wawn lo inucpcuuciiuy seit^uiea rrom aiKyi, aryi ana heteroaryl, wherein the substituents on the substituted cyclized R^^ and R^"^ groups are the same or different and independently selected from 1 to 3 of alkyl, aryl, hydroxy, hydroxyalkyi, alkoxy, alkoxyalkyl, arylalkyi, fluoroalkyl, cycloalkyi, cycloalkylalkyl. heteroaryl. heteroarylalkyl. amino, -C(0)OR^^. -C(0)NR^^R^^ -SOtNR^^R^^, -C(0)R^^ -S02R^^ -NHC(0)NR^=R^^ and halogen, and wherein R^^ and R^^ are the same or different and are independently selected from the group consisting of H, alkyl, aryl, arylalkyi, cycloalkyi and heteroaryl; VVI f\^l X^ll I. R2 is H, OH. -NHC(0)R^^ or-NHSOaR"; R^ is -S02NR"R^\ -C(0)NR"R^^, -SOZR^^ -NO2 or cyano; R^ is H, -NO2. -CF3.-CH3 or cyano, R^ is H, halogen, -NO2. cyano or -CF3; R®isH,-CF3 or alkyl, R^s R" is H; R^ Is H, F, CI, Br, alkyl. cycloalkyi or -CF3; R^^ Is H, halogen or alkyl; and R" and R^^ are independently methyl or ethyl. Most preferably, A is selected from the group consisting of R2 is -OH; R^ is -S02NR"R^^ or -CONR^R^^; R^isH.-CHaOr-CFa: R^ is H or cyano; R^isH.-CHaor-CFa; R^^ is H. and R^^ and R^"* are methyl. Representative embodiments of this invention are described below. The ibodiments have been numbered for purposes of reference thereto. Embodiment No. 1 is directed to the methods of treatment described above ng formula I, except the compounds used are those of formula lA: I their pharmaceutically acceptable salts (e.g., sodium or calcium salt) and solvates ■eof. wherein: A is selected from the group consisting of: C(0)NH0R". -C{0)NR^^0H, - S(02)OH. -OC(0)R", an unsubstituted heterocyclic jcidic functional group, and a substituted heterocyclic acidic functional group; wherein here are 1 to 6 substituents on said substituted heterocyclic acidic ftjnctional group jach substituent being independently selected from the group consisting of: R® jroups; each R^ and R"* is independently selected from the group consisting of: lydrogen, cyano, halogen, alkyl, alkoxy, -OH, -CF3, -OCF3, -NO2, -C(0)R^^ C(0)OR^^ -C(0)NHR", -C(0)NR^^R^\ -SO(t)NR^^R^*, -SO(t)R^^-C(0)NR^20R^*. jnsubstltuted or substituted aryl, unsubstituted or substituted heteroaryl, vherein there are 1 to 6 substituents on said substituted aryl group and each ►ubstitutent is independently selected from the group consisting of: R^ groups; and vherein there are 1 to 6 substituents on said substituted heteroaryl group and each lubstitutent is independently selected from the group consisting of: R^ groups; each R^ and R^ are the same or different and are independently selected from he gn^up consisting of hydrogen, halogen, alkyl, alkoxy, -CF3, -OCF3, NO2. -C(0)R", -C(0)OR^^ -C(0)NR"R^\ -SO(t)NR^^R^^ -C(0)NR^^0R^^ cyano. insubstituted or substituted aryl, and unsubstituted or substituted heteroaryl group; vherein there are 1 to 6 substituents on said substituted aryl group and each iubstitutent is independently selected from the group consisting of: R^ groups; and /herein there are 1 to 6 substituents on said substituted heteroaryl group and each iubstitutent is independently selected from the group consisting of: R® groups; each R^ and R® is independently selected from the group consisting of: H, insubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or ubstituted heteroaryl. unsubstituted or substituted arylalkyl, unsubstituted or ubstituted heteroarylalkyl, unsubstituted or substituted cycloalkyl. unsubstituted or ubstituted cycloalkylalkyl. -CO2R". -CONR^^R^"*. alkynyl, alkenyl, and cycloalkenyl; ind wherein there are one or more (e.g., 1 to 6) substituents on said substituted R"^ p) alkyl substituted with one or more (e.g., one) -OH groups (e.g.. (CH2)qOH, wherein q is 1-6, usually 1 to 2, and preferably 1), q) alkyl substituted with one or more (e.g., one) -NR^^R^* group e.g., -(CH2)qNR"R^"*, wherein q is 1-6, usually 1 to 2, and preferably 1), and r) -N(R^^)S02R^"* (e.g., R" is H and R^* is alkyl. such as methyl); each R^° and R^^ is Independently selected from the group consisting of lydrogen. alkyl (e.g.. Ci to Ce, such as methyl), halogen, -CF3, -OCF3, -NR"R^*, NR"C(0)NR"R^^ -OH, -C(0)0R". -SH. -S0(,)NR^^R^*. -SO2R". -NHC(0)R", NHS02NR^^R^\ -NHS02R^^ -C(0)NR"R^*, -C(0)NR"0R^^, -OC(0)R^^ and cyano; R^^ is selected from the group consisting of: hydrogen, -C(0)OR""^, insubstltuted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted >r substituted aryialkyi, unsubstituted or substituted cycloaikyi, unsubstituted or lubstituted alkyl, unsubstituted or substituted cycloalkyialkyi, and unsubstituted or lubstituted heteroarylalkyi group; wherein there are 1 to 6 substituents on the ubstltuted R^^ groups and each substituent is independently selected from the group insisting of: R^ groups; each R" and R^*is independently selected from the group consisting of: H, insubstltuted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted aryialkyt. unsubstituted or substituted heteroarylalkyi. unsubstituted or substituted cycloaikyi, unsubstituted or lubstituted cydoalkylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted fluoroalkyl, and unsubstituted or substituted heterocycloalkylalkyi (wherein "heterocyioalkyr means heterocyclic); wherein there are 1 to 6 substituents on said substituted R^^ and R^"* groups and each substituent is independently selected from the group consisting of: alkyl, -CF3, -OH, alkoxy, aryl, arylalkyi, fluroalkyl, cycloalkyi, cycloalkylalkyl. heteroaryl, heteroarylalkyi, -N(R^°)2, -C(O)0R^^ -C(0)NR^^R^^ -S(0)tNR^^R^^ -C(0)R^^ -SOzR^^ provided that R^^ is not H, halogen, and -NHC(0)NR^^R^^; or R^^ and R^* taken together with the nitrogen they are attached to in the groups -NR"R^^ -C(0)NR^^R^^ -SOzNR^ V^ -OC{0)NR^^R^*. -CONR^^R^^ -NR"C(0)NR"R^^ -SOtNR^^R^^. -NHSOzNR^R^"" form an unsubstituted or substituted saturated heterocyclic ring (preferably a 3 to 7 membered heterocyclic ring), said ring optionally containing one additional heteroatom selected from the group consisting of: O, S and NR^^; wherein there are 1 to 3 substituents on the substituted cycllzed R" and R^^ groups (i.e., there is 1 to 3 substituents on the ring formed when the R^^ and R^* groups are taken together with the nitrogen to which they are bound) and each substituent is independently selected from the group consisting of: alkyl, aryl, hydroxy, hydroxyalkyi, alkoxy, alkoxyalkyl, arylalkyi, fluoroalkyl, cycloalkyi, cycloalkylalkyl, heteroaryl, heteroarylalkyi, amino, -C(0)OR^^ -C(0)NR^^R^^ -SOiNR^^R^^, -C(0)R^^ -SOzR^^ provided that R^^ is not H. -NHC(0)NR^^R^^. -NHC(0)OR^^ halogen, and a heterocylcoalkenyl group (i.e.. a heterocyclic group that has at least one, and preferably one, double t)ond in a ring, e.g.. each R^^ and R*^ Is independently selected from the group consisting of: H, alkyl, aryl, arylalkyi, cycloalkyi and heteroaryl; R^^ is selected from the group consisting of: -SOaalkyI, -S02aryl. -S02cycloalkyl, and -S02heteroaryl; R^® is selected from the group consisting of: H, alkyl. aryl. heteroaryl, -C(0)R^^, -SOzR^^ and -C(0)NR^®R^; each R^® and R""" Is Independently selected from the group consisting ot: alkyl, aryl and heteroaryl; R^° Is selected from the group consisting of: alkyl, cycloalkyl, -CN, -NO2, or -SOaR^^ provided that R^^ Is not H; each R^^ Is independently selected from the group consisting of: unsubstltuted or substituted alkyl, unsubstltuted or substituted aryl, unsubstltuted or substituted heteroaryl and unsubstltuted or substituted cycloalkyl; wherein there are 1 to 6 substituents on said substituted R^^ groups and each substituent is independently selected from the group consisting of: R^ groups; each R"^^ is independently selected from the group consisting of: H, alkyl and cycloalkyl; and t is 0, 1 or 2. In Embodiment No. 1, at least one (e.g.. 1 to 3, and usually one) compound of fomnula lA are used. Embodiment No. 2 is directed to the use of at least one (e.g., 1 to 3, and usually 1) compound of formula lA for the manufacture of a medicament for the treatment of the diseases described above in the methods of treatment using formula I. Embodiment No. 3 is directed to compounds of formula lA wherein B is selected from the group consisting of: wherein R^ is selected from the group consisting of: -C(0)NR""^R^"*, R^, R^^, and R^* are as defined for compounds of formula I or lA, and all other substituents are as defined in formula I or lA. Embodiment No. 111s directed to compounds of formula lA wherein B is: R^ is -OH, R^^ and R^* are as defined for compounds of formula I or lA, and all other substituents are as defined in formula I or lA. Embodiment No. 12 is directed to compounds of formula lA wherein B is: R^ is as defined for compounds of formula I or lA, R^^ and R^^ are the same or different alkyl group, and alt other substituents areas defined for compounds of formula I or lA. Embodiment No. 13 is directed to compounds of formula lA wherein B is: R^ is -OH, R^^ and R^* are the same or different alkyl group, and all other substituents areas defined for compounds of formula I or lA. Embodiment No. 14 is directed to compounds of fomnula lA wherein B is is as described in Emtx)diment No. 8, R* is H, R^ is H, R^ is H, and all other substituents areas defined for compounds of formula I or lA. Embodiment No. 15 is directed to compounds of formula lA wherein B is is as described in Embodiment No. 9, R^ is H, R^ is H, R® is H, and all other substituents areas defined for compounds of formula I or lA. Embodiment No. 16 is directed to compounds of formula lA wherein B is as described in Embodiments Nos. 6, 7,10 and 11, except that R^^ and R^* are each methyl, and all other substituents are as defined in formula i or lA. and ail substituents are as defined in foimula I or lA. Embodiment No. 30 is directed to compounds of formula lA wherein B is as described in any one of the Embodiment Nos. 3 to 29, and A is as defined In all of the preferred descriptions above for A in formula I, or A is as described for fomiula lA. Embodiment No. 31 is directed to compounds of formula lA wherein B is as described in any one of the Embodiment Nos. 3 to 29, and A is: wherein the furan ring is unsubstituted or substitued as described in the definition of A for formula I or lA. and all other substitutents are as defined for formula lA. Embodiment No. 32 Is directed to compounds of formula lA wherein B is described in any one of the Embodiment Nos. 3 to 29, and A is wherein the fliran ring is substituted and all other substituents are as defined for fomiula I or lA. Embodiment No. 33 is directed to compounds of formula lA wherein B is as described In any one of the Embodiment Nos. 3 to 29,and A is wherein the furan ring is substituted with at least one (e.g., 1 to 3, or 1 to 2) aikyi group and ail other substituents are as defined for fomiuia I or lA. Emtwdiment No. 34 is directed to compounds of formula lA wherein B is as described in any one of the Embodiment Nos. 3 to 29, A Is wherein the fliran ring is substituted with one alkyl group and all other substituents are as defined for formula I or lA. Embodiment No. 35 is directed to compounds of formula lA wherein B is as described in any one of the Embodiment Nos. 3 to 29, and A is wherein the furan ring is substituted with one Ci to C3 alkyl group (e.g., methyl or isopropyl), and all other substituents are as defined for formula I or lA. Embodiment No. 36 is directed to compounds of formula lA wherein B is as described in any one of the Emfc>odiment Nos. 3 to 29, and A is as defined in any one of the Emfc>odiment Nos.31 to 35. except that R^ and R^ are the same or different and each is selected from the group consisting of: H and alkyl. Embodiment No. 37 is directed to compounds of formula lA wherein B is as described in any one of the Embodiment Nos. 3 to 29, and A is as defined in any one of the Embodiment Nos. 31 to 35, except that R^ is H, and R° is alkyl (e.g., ethyl or t-butyl). Embodiment No. 38 is directed to any one of the Embodiment Nos. 3 to 37 iwherein the compound of formula lA is a pharmaceutically acceptable salt. Embodiment No. 39 is directed to any one of the Embodiment Nos. 3 to 37 /vherein the compound of fomfiula lA is a sodium salt. Embodiment No. 40 Is directed to any one of the Embodiment Nos. 3 to 37 vherein the compound of formula lA is a calcium salt. —■■•■"w^.i..wi■> • iw. 1 I iw VIII^uiwu ivr u 1^1 laiiiiciv one of the representative compounds of this invention. Embodiment No. 42 is directed to a sodium salt of any one of the representative compounds of this invention. Embodiment No. 43 is directed to a calcium salt of any one of the representative compounds of this invention. Embodiment No. 44 is directed to a pharmaceutical composition comprising at least one (e.g., 1 to 3, usually 1) compound of formula lA as described in any one of the Embodiment Nos. 3 to 43 in combination with a pharmaceutically acceptable canrier. Embodiment No. 45 is directed to a method of treating any one of the diseases described above comprising administering to a patient in need of such treatment an effective amount (e.g., a therapeutically effective amount) of a compound of formula lA as described in any one of the Embodiment Nos. 3 to 43. The diseases referred to in this embodiment are those described in the methods of treatment using compounds of formula I. Embodiment No. 46 is directed to the use of a compound of formula lA as described in any one of the Embodiment Nos. 3 to 43 for the manufacture of a medicament for the treatment any one of the diseases described above. The diseases referred in this embodiment are those described in the methods of treatment using compounds of formula I. an such stereorsomers both in pare form and in aomxiu incruaaing racemic mixtures. Isomers can be prepared using conventional methods. Certain compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts fomned with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like. Certain basic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention. All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention. Compounds of formula I or lA can exist in unsolvated and solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to the unsolvated forms for the purposes of this invention. In a preferred embodiment, a compound of formula (1) or lA is combined with one of the following antineoplastic agents: gemcitabine, paclitaxel (TaxoKD), 5-Fluorourcii (5-FU), cyclophosphamide (Cytoxan®), temozolomide, or Vincristine. In another prefeired embodiment, the present invention provides a method of treating cancer, comprising administering, concurrently or sequentially, and effective amount of a compound of formula (1) or lA and a microtubule affecting agent e.g., paclitaxel. For preparing phamnaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable camers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found m A. Gennaro (ed.), Remington"s Pharmaceutical Sciences, 18*^ Edition, (1990), Mack Publishing Co., Easton, Pennsylvania. Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable earner, such as an inert compressed gas, e.g. nitrogen. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. The compounds of the invention may also be deliverable transdermally. The transdermal composition can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose. Preferably the compound Is administered orally. Preferably, the pharmaceutical preparation is in a unit dosage fomri. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 1000 mg, preferably from about 0.01 mg to about 750 mg, more preferably from about 0.01 mg to about 500 mg, and most preferably from about 0.01 mg to about 250 mg, according to the particular appjication. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total dosage may be divided and administered in portions during the day as required. The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 0.04 mg/day to about 4000 mg/day, in two to four divided doses. Another aspect of the invention is a method treating cancer, comprising administering to a patient in need thereof, concurrently or sequentially, a therapeutically effective amount of (a) a compound of formula (I) or lA and (b) an atineoplastic agent, microtubule affecting agent or anti-angiogenesis agent. Classes of compounds that can be used as the chemotherapeutic agent (antineoplastic agent) include: alkylating agents, antimetabolites, natural products and their derivatives, hormones and steroids (including synthetic analogs), and synthetics. Examples of compounds within these classes are given below. Alkylating agents (including nitrogen mustards, etiiylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes): Uracil mustard, Chlormethine, Cyclophosphamide (Cytoxan®), Ifosfamide, Melphalan, Chlorambucil, Pipobroman. Triethyiene-melamlne, Triethylenethlophosphoramine, Busulfan, Camiustine, Lomustine, Streptozocin, Dacarbazine, and Temozolomide. Antimetabolites (including folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors): Methotrexate, 5-Fluorouracil, Floxuridine, Cytarablne, 6-Mercaptopurine, 6-Thloguanine, Fludarabine phosphate, Pentostatine, and Gemcitabine. Natural products and their derivatives (including vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins): Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, idarubicin, paclitaxel (paciitaxel is commercially available as Taxol® and is described In more detail below in the subsection entitled "Microtubule Affecting Agents"), Mithramycin, Deoxyco-formycin, Mitomycin-C, L-Asparaginase, Interferons (especially IFN-a), Etoposide, and Teniposide. Hormones and steroids (including synthetic analogs): 17a-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Tamoxifen, Methylprednisolone, Methyl-testosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremlfene, Zoladex. Synthetics (including inorganic complexes such as platinum coordination complexes): Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane. Mitoxantrone, Levamisole, and Hexamethylmelamine. Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the "Physicians" Desk Reference" (PDR), e.g., 2002 edition (Medical Economics Company, Montvale, NJ 07645-1742, USA); the disclosure of which is incorporated herein by reference thereto. As used herein, a microtubule affecting agent is a compound that interferes with cellular mitosis, i.e.. having an anti-mitotic effect, by affecting microtubule formation and/or action. Such agents can be, for instance, nnicrotubule stabilizing agents or agents that disrupt microtubule formation. Microtubule affecting agents useful in the invention are well known to those of skill In the art and Include, but are not limited to allocolchicine (NSC 406042), Haiichondrin B (NSC 609395), colchicine (NSC 757). colchicine derivatives (e.g., NSC 33410). dolastatin 10 (NSC 376128). maytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel (Taxol®, NSC 125973), Taxol® derivatives (e.g., derivatives (e.g., NSC 608832), thiocoichicine (NSC 361792), trityl cysteine (NSC 83265), vinblastine sulfate (NSC 49842), vincristine sulfate (NSC 67574), epothilone A, epothilone, and discodermolide (see Sen/ice, (1996) Science, 274:2009) estramustine, nocodazole, MAP4, and the like. Examples of such agents are also described in the scientific and patent literature, see, e.g., Bulinski (1997) J. Cell Sci. 110:3055-3064; Panda (1997) Proc. Natl. Acad. Sci. USA 94:10560-10564; Muhlradt (1997) Cancer Res. 57:3344-3346; Nicolaou (1997) Nature 387:268-272; Vasquez (1997) Mol. Biol. Cell. 8:973-985; Panda (1996) J. Biol. Chem. 271:29807-29812. Particularly preferred agents are compounds with paditaxel-like activity. These include, but are not limited to paclitaxel and paclitaxel derivatives (paditaxel-like compounds) and analogues. Paclitaxel and its derivatives are available commercially. In addition, methods of making paclitaxel and paclitaxel derivatives and analogues are well known to those of skill in the art (see, e.g., U.S. Patent Nos: 5,569,729; 5.565,478; 5.530,020; 5,527,924; 5,508,447; 5,489,589; 5,488,116; 5,484,809; 5,478,854; 5,478,736; 5,475,120; 5,468,769; 5,461,169; 5.440.057; 5,422,364; 5,411.984; 5,405.972; and 5.296,506). More specifically, the term "paclitaxel" as used herein refers to the drug commercially available as Taxol® (NSC number 125973). Taxol® inhibits eukaryotic cell replication by enhancing polymerization of tubulin moieties into stabilized microtubule bundles that are unable to reorganize into the proper structures for mitosis. Of the many available chemotherapeutic drugs, paclitaxel has generated interest because of its efficacy in clinical trials against drug-refractory tumors, including ovarian and mammary gland tumors (Hawkins (1992) Oncology, 6: 17-23, Honwitz (1992) Trends Pharmacol. Sci. 13:134-146, Rowinsky (1990) J. Natl. Cane. Inst. 82:1247-1259). ■ Additional microtubule affecting agents can be assessed using one of many such assays known In the art, e.g., a semiautomated assay which measures the tubulin-polymerizing activity of paclitaxel analogs in combination with a cellular assay to measure the potential of these compounds to block cells in mitosis (see Lopes (1997) Cancer Chemother. Pharmacol. 41:37-47). Generally, activity of a test compound is determined by contacting a cell with that compound and determining whether or not the cell cycle is disrupted, in particular, through the Inhibition of a mitotic event. Such inhibition may be mediated by disruption of the mitotic apparatus, e.g., disruption of normal spindle formation. Cells in which mitosis is interrupted may be characterized by altered morphology (e.g., microtubule compaction, increased chromosome number, etc.). In a preferred embodiment, compounds with possible tubulin polymerization activity are screened in vitro. In a preferred embodiment, the compounds are screened against cultured WR21 cells (derived from line 69-2 wap-ras mice) for inhibition of proliferation and/or for altered cellular morphology, in particular for microtubule compaction. In vivo screening of positive-testing compounds can then be performed using nude mice bearing the WR21 tumor cells. Detailed protocols for this screening method are described by Porter (1995) Lab. Anim. ScL, 45(2):145-150. Other methods of screening compounds for desired activity are well known to those of skill in the art. Typically such assays involve assays for inhibition of microtubule assembly and/or disassembly. Assays for microtubule assembly are described, for example, by Gaskin et al. (1974) J. Molec. Biol., 89: 737-758. U.S. Patent No. 5,569,720 also provides in vitro and in vivo assays for compounds with paclitaxel-like activity. Methods for the safe and effective administration of the above-mentioned microtubule affecting agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the "Physicians" Desk Reference" (PDR), e.g., 1996 edition (Medical Economics Company, Montvale, NJ 07645-1742, USA); the disclosure of which is incorporated herein by reference thereto. The amount and frequency of administration of the compounds of formula (I) or lA and the chemotherapeutic agents and/or radiation therapy will be regulated according to the judgment of the attending clinician (physician) considering such factors as age, condition and size of the patient as well as severity of the disease being treated. A dosage regimen of the compound of formula (I) or lA can be oral administration of from 10 mg to 2000 mg/day, preferably 10 to 1000 mg/day, more preferably 50 to 600 mg/day, in two to four (preferably two) divided doses, to block tumor growth. Intermlttant therapy (e.g., one week out of three weeks or three out of four weeks) may also be used. The chemotherapeutic agent and/or radiation therapy can be administered according to therapeutic protocols well known in the art. It will be apparent to those skilled In the art that the administration of the chemotherapeutic agent and/or radiation therapy can be varied depending on the disease being treated and the known effects of the chemotherapeutic agent and/or radiation therapy on that disease. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered therapeutic agents (i.e., antineoplastic agent or radiation) on the patient, and in view of the observed responses of the disease to the administered therapeutic agents. In the methods of this invention, a compound of formula (I) or lA is administered concurrently or sequentially with a chemotherapeutic agent and/or radiation. Thus, it is not necessary that, for example, the chemotherapeutic agent and the compound of formula (I) or lA, or the radiation and the compound of formula (I) or lA, should be administered simultaneously or essentially simultaneously. The advantage of a simultaneous or essentially simultaneous administration is well within the detemnination of the skilled clinician. Also, in general, the compound of formula (I) or lA and the chemotherapeutic agent do not have to be administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, have to be administered by different routes. For example, the compound of formula (I) or lA may be administered orally to generate and maintain good blood levels thereof, while the chemotherapeutic agent may be administered intravenously. The determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician. The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician . The particular choice of a compound of formula (I) or lA, and chemo-therapeutic agent and/or radiation will depend upon the diagnosis of the attending physicians and their judgement of the condition of the patient and the appropriate treatment protocol. The compound of formula (I) or lA, and chemotherapeutic agent and/or radiation may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the proliferative disease, the condition of the patient, and the actual choice of chemotherapeutic agent and/or radiation to be administered in conjunction (i.e., within a single treatment protocol) with the compound of formula (I) or lA . If the compound of formula (I) or lA, and the chemotherapeutic agent and/or radiation are not administered simultaneously or essentially simultaneously, then the Initial order of administration of the compound of formula (I) and lA, and the chemotherapeutic agent and/or radiation, may not be important. Thus, the compound of fonmula (I) or lA may be administered first, followed by the administration of the chemotherapeutic agent and/or radiation; or the chemo-therapeutic agent and/or radiation may be administered first, followed by the administration of the compound of formula (I) or lA. This altemate administration may be repeated during a single treatment protocol. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the disease being treated and the condition of the patient. For example, the chemotherapeutic agent and/or radiation may be administered first, especially If it is a cytotoxic agent, and then the treatment continued with the administration of the compound of formula (I) or lA followed, where determined advantageous, by the administration of the chemotherapeutic agent and/or radiation, and so on until the treatment protocol Is complete. Thus, in accordance with experience and knowledge, the practicing physidan can modify each protocol for the administration of a component (therapeutic agent-i.e., the compound of formula (I) or lA. chemotherapeutic agent or radiation) of the treatment according to the individual patient"s needs, as the treatment proceeds. The attending clinician, in judging whether treatment is effective at the dosage administered, will consider the general well-being of the patient as well as more definite signs such as relief of disease-related symptoms, inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radio-logical studies, e.g., CAT or MRI scan, and successive measurements can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment. BIOLOGICAL EXAMPLES The compounds of the present invention are useful in the treatment of CXC-chemokine mediated conditions and diseases. This utility is manifested in their ability to inhibit IL-8 and GRO-a chemokine as demonstrated by the following in vitro assays. Receptor Binding Assays: CXCR1 SPA Assay For each well of a 96 well plate, a reaction mixture of 10 ng hCXCR1-CH0 overexpressing membranes (Biosignal) and 200 jag/well WGA-SPA beads (Amersham) in 100 ^1 was prepared in CXCR1 assay buffer (25 mM HEPES, pH 7.8, 2 mM CaCb, 1mM MgClz. 125 mM NaCI, 0.1% BSA) (Sigma). A 0.4 nM stock of ligand, [125IJ-IL-8 (NEN) was prepared in the CXCR1 assay buffer. 20X stock solutions of test compounds were prepared in DMSO (Sigma). A 6 X stock solution of IL-8 (R&D) was prepared in CXCR2 assay buffer. The above solutions were added to a 96-weH assay plate (PerkinElmer) as follows: 10 ^1 test compound or DMSO, 40 ^1 CXCR1 assay buffer or IL-8 stock, 100 \i\ of reaction mixture, 50 |xl of ligand stock (Final [Ligand] = 0.1 nM). The assay plates were shaken for 5 minutes on plate shaker, then Incubated for 8 hours before cpm/well were determined in Microbeta Trilux counter (PerkinElmer). % Inhibition of Total binding-NSB (250 nM IL-8) was determined for 1050 values. Compounds of this invention had an IC50 of CXCR2 SPA Assay For each well of a 96 well plate, a reaction mixture of 4 jig hCXCR2-CH0 overexpressing membranes (Biosignal) and 200 jig/well WGA-SPA beads (Amersham) in 100 ^il was prepared in CXCR2 assay buffer (25 mM HEPES, pH lA, 2 mM CaCl2,1mM MgCb). A 0.4 nM stock of ligand, [125IJ-IL-8 (NEN), was prepared in the CXCR2 assay buffer. 20X stock solutions of test compounds were prepared in DMSO (Sigma). A 6 X stock solution of GRO-a (R&D) was prepared in CXCR2 assay buffer. The above solutions were added to a 96-well assay plate (PerkinElmer or Coming) as follows: 10 jal test compound or DMSO, 40 ul CXGR2 assay buffer or GRO- a stock, 100 ^il of reaction mixture, 50 ^1 of ligand stock (Final [Ligand] = 0.1 nM). When 40 X stock solutions of test compounds in DMSO were prepared, then the above protocol was used except instead 5 \i\ test compound or DMSO and 45 ^1 CXCR2 assay buffer were used. The assay plates were shaken for 5 minutes on a plate shaker, then incubated for 2-8 hours before cpm/well were determined in Microbeta Trilux counter (PerkinElmer). % Inhibition of total binding minus non-specific binding (250 nM Gro-a or 50 ^M antagonist) was determined and IC50 values calculated. Compounds of this invention had an IC50 of Calcium Fluorescence Assay fFLIPR> HEK 293 cells stably transfected with hCXCR2 and Gai/q were plated at 10,000 cells per well in a Poly-D-Lysine Black/Clear plate (Becton Dickinson) and incubated 48 hours at 5% CO2, 37°C. The cultures were then incubated with 4 mM fluo-4, AM (Molecular Probes) in Dye Loading Buffer (1% FBS, HBSS w. Ca & Mg. 20 mM HEPES (Ceilgro), 2.5 mM Probenlcid (Sigma) for 1 hour. The cultures were washed with wash buffer (HBSS w Ca, & Mg, 20 mM HEPES, Probenicid (2.5 mM)) three times, then 100 ^tl/well wash buffer was added. During incubation, compounds were prepared as 4X stocks in 0.4% DMSO (Sigma) and wash buffer and added to their respective wells in the first addition plate. IL-8 or GROna (R&D Systems) concentrations were prepared 4X in wash buffer + 0.1% BSA and added to their respective wells in second addition plate. Culture plate and both addition plates were then placed in the FLIPR imaging system to detennine change in calcium fluorescence upon addition of compound and then ligand. Briefly, 50 ^1 of compound solutions or DMSO solution was added to respective wells and change in calcium fluorescence measured by the FLIPR for 1 minute. After a 3 minute incubation within the instrument, 50 jii of ligand was then added and the change in calcium fluorescence measured by the FLIPR instrument for I minute. The area under each stimulation curve was determined and values used to detenmine % Stimulation by compound (agonist) and % Inhibition of Total Calcium response to ligand (0.3 nM IL-8 or GRO-a) for IC50 values of the test compounds. Chemotaxis assavs for 293-CXCR2 A chemotaxis assay is setup using Fluorblok inserts (Falcon) for 293-CXCR2 cells (HEK-293 cells overexpressing human CXCR2). The standard protocol used at present is as follows: 1. Inserts are coated with collagenlV (2ug/ml) for 2 hrs at 37°C. 2. The collagen is removed and inserts are allowed to air dry overnight. 3. Cells are labeled with 10uM calcein AM (Molecular Probes) for 2 hrs. Labeling is done In complete media with 2% FBS. 4. Dilutions of compound are made in minimal media (0.1% BSA) and placed Inside the Insert which is positioned inside the well of a 24 well plate. Within the well is IL-8 at a concentration of 0.25nM in minimal media. Cells are washed and resuspended In minimal media and placed Inside the insert at a concentration of 50,000 cells per insert 5. Plate Is incubated for 2hrs and Inserts are removed and placed in a new 24 well. Fluorescence Is detected at excitation=485 nM and emlssion=530 nM. Cvtotoxicitv Assavs A cytotoxicity assay for CXCR2 compounds is conducted on 293-CXCR2 cells. Concentrations of compounds are tested for toxicity at high concentrations to determine If they may be used for further evaluation in binding and cell based assays. The protocol Is as follows: 1, 293-CXCR2 cells are plated ovemight at a concentration of 5000 cells per well in complete media. 2. Dilutions of compound are made in minimal media w/0.1% BSA. Complete media is poured off and the dilutions of compound are added. Plates are Incubated for 4. 24 and 48hrs. Cells are labeled with 10uM calcein AM for 15 minutes to detemnine cell viability. Detection method is the same as above. Soft Agar Assay 10,000 SKMEL-5 cells/well are placed in a mixture of 1.2% agar and complete media with various dilutions of compound. Final concentration of agar is 0.6%. After 21 days viable cell colonies are stained with a solution of MTT (Img/ml in PBS). Plates are then scanned to determine colony number and size. IC50 is determined by comparing total area vs. compound concentration. Compounds of formula (I) or lA may be produced by processes known to those skilled in the art in the following reaction schemes and in the preparations and examples below. A general procedure for the preparation of compounds of formula I or lA is as follows: hydrogen atmosphere in the presence of a suitable catalyst. The remaining partner required for the synthesis of the final target is prepared by condensing an aryl amine with the commercially available diethyisquarate to give the aminoethoxysquarate product. Subsequent condensation of this intermediate with the aminobenzamide prepared earlier provides the desired chemokine antagonist (Scheme 1). Scheme 2 Alternatively, the aminobenzamide of Scheme 1 is first condensed with commercially available diethyisquarate to give an alternate monoethoxy intermediate. Condensation of this Intermediate with an amine gives the desired chemokine antagonist. Scheme 3 Scheme 4 ^X^^.-A "- 1 Rg Scheme 4 ^X^^.-A "- 1 Rg Scheme 3 Benztriazole compounds of Formula (I) or lA are prepared by stirring nitrophenylenediamines with sodium nitrite in acetic acid at 60°C to afford the nitrobenzotriazole intermediate (Scheme 3). Reduction of the nitro group in the presence of palladium catalyst and hydrogen atmosphere provides the amine compound. Subsequent condensation of this intermediate with the aminooethoxysquarate prepared eariier (Scheme 1) provides the desired chemokine antagonist. Scheme 4 Condensation of nitrophenylenediamines with anhydrides or activated acids at reflux (Scheme 4) affords benzimidazole intermediates which after reduction with hydrogen gas and palladium catalyst and condensation with the aminoethoxysquarate previously prepared (Scheme 1) affords benzimidazole chemokine antagonists. Scheme 5 R5 R4N^ ^Re R4\^--"^^^R6 Rio^ "^NOz Rio^^^T^NHz B ^tr EtO^^N A R5 " R ^yv^M^^N"^ ^"°^T W H N-NH C Scheme 6 R5 |5 R4\^.A^R6 R4^.^"^^R6 RI0- >-NH >-NH ?= R O O "" /—NH R9 ^ Scheme 5 R5 R4N^ ^Re R4\^--"^^^R6 Rio^ "^NOz Rio^^^T^NHz EtO^^N A R5 " R.yj^« °Yf° - ^"°^T W H N-NH C Scheme 6 R5 |5 RI0- >-NH >-NH R( A "^^ B W ?= R O O "" /—NH R9 ^ Scheme 5 Indazole structures of Formula (I) or lA can be prepared according to Scheme 5 by reduction of nitroindazole A (J. Am. Chem Soc. 1943, 65,1804-1805) to give aminoindazoJe B and subsequent condensation with the aminoethoxysquarate prepared earlier (Scheme 1). Scheme 6 Indole structures of Formula (I) or lA can be prepared according to Scheme 6 3y reduction of nitroindole A (J. Med. Chem. 1995. 38.1942-1954) to give aminoindole B and subsequent condensation with the aminoethoxysquarate prepared earlier (Scheme 1). The invention disclosed herein is exemplified by the following preparations and examples which should not be construed to limit the scope of the disclosure. Altemative mechanistic pathways and analogous structures may be apparent to those skilled in the art. PREPARATIVE EXAMPLE 1 3-Nitrosalicylic acid (500 mg, 2.7 mmol). DCC (563 mg) and ethyl acetate (10 iL) were combined and stin-ed for 10 min. (R) -(-)-2-pyrroHdinemethanol (0.27 mL) ras added and the resulting suspension was stirred at room temperature ovemight. he solid was filtered and the filtrate washed with 1N NaOH. The aqueous phase was cidified and extracted with EtOAc. The resulting organic phase was dried over mhydrous MgS04, filtered and concentrated in vacuo. Purification of the residue by (reparative plate chromatography (silica gel, 5% MeOH/CH2Cl2 saturated with AcOH) lave the product (338 mg, 46%, MH* = 267). SxepM 3-Nitrosalicylic acid (9.2 g), bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP, 23 g) and N,N-diisopropylethylamine (DIEA, 26 mL) in anhydrous CH2CI2 (125 mL) were combined and stin-ed at 25°C for 30 min. ( R) -(+)-3-pyrrolidlnol (8.7 g) in CH2CI2 (25 mL) was added over 25 min and the resulting suspension was stirred at room temperature ovemight. The mixture was extracted with 1M NaC" """^ """* **"* "■^^nJ"* i^in-»o« ,t,r,t> riior aciditied with 1M HCI (aq), extracted with EtOAc, dried over anhydrous NaaSOA, filtered and concentrated in vacuo to afford the crude product (7 g) which was used without further purification. SteoB The crude product from Step A above was stirred with 10% Pd/C (0.7 g) in MeOH (100 mL) under a hydrogen gas atmosphere overnight The reaction mixture was filtered through celite, the filtrate concentrated in vacuo, and the resulting residue purified by column chromatography (silica gel, 10% MeOH/CHaCb saturated with NH4OH) to give the product (2.5 g, 41%. MH+=223). To N-BOC-3-(amino)piperidine (0.5 g) dissolved in CH2CI2 (10 mL) was added benzylisocyanate (3 mmol). After stirring for 2 hrs, amine scavenger resin (1.9 mmol) was added and the mixture was stirred overnight, filtered, the resin back-washed with CH2CI2 and methanol, and the organics concentrated in vacuo. Stirring of the crude material in 4N HCI/dioxane (40 mL) for 2.5 hrs before concentrating in vacuo gave the title compound (41%, MH+=369). PREPARATIVE EXAMPLE 2.2 - 2.6 Following the procedures set forth in Preparative Example 2.1 but using the Isocyanate (or chloroformate) indicated in the Table below, the amines were obtained and used without further purification. To N-BOC-3-(amino)piperidine (5 mmol) dissolved in CH2CI2 (30 mL) was added trifluoromethanesulfonic anhydride (5 mmol) and the mixture was stin-ed overnight. The mixture was concentrated in vacuo, diluted with CH2CI2 (10 mL) and treated witii trifluoroacetic acid (10 mL). After stirring for 2 hr, the mixture was concentrated in vacuo to give the title compound (43%, MH+=233.1). tep A 3-NJtrosalicylic acid (5 mmol) and N-hydroxysuccinimide (5 mmol) were added > a solution of 2% DMF/CH2CI2. followed by DCC (5 mmol). After stining for 2 hr, the uxture was filtered and concentrated in vacuo and the residue used directly in Step tepB The product from Step A above was suspended in DMF and to this was added rarpholino-2-carboxylic acid HCI (5 mmol) in CH2CI2 (10 mL)/DMF (5 mL) and iisopropylethylamlne (10 mmol). The mixture was stirred ovemight, filtered, basified rjth IN NaOH (50 mL), washed with CH2CI2, acidified with 5N HCI and extracted with tOAc. The organic phase was dried over Na2S04, filtered and concentrated in vacuo ) give the desired compound which was used directly in Step C (MH+=296). Following a similar procedure as in Preparative Example 2 Step B, but using the product from Step B above, the title compound was obtained (23%, MH+=267). Step A 2-Piperazinecartx)xyiic acid and 2-chloro-1,3-pyrimldine were stirred with triethylamine and MeOH. After stirring overnight at reflux, the mixture was filtered and concentrated in vacuo to give the desired compound which was used directly in Step B (MH+ = 209). SteoB Following a similar procedure as Preparative Example 2.8, Step B except using the product from Preparative Example 2.9 Step A above, the desired compound was obtained (41%, MH+ = 374). SteoC Following a similar procedure as in Preparative Example 2, Step B, but using the product from Step B above, the desired compound was obtained (99%, MH+=344). step A Following a similar procedure as Preparative Example 2.8, Step A except using 3-nitrobenzoic acid, the desired compound was obtained and used directly in Step B. SteoB Following a similar procedure as Preparative Example 2.8, Step B except using the products from Preparative Example 2.9, Step A and Preparative Example 2.10, Step A, the desired compound was obtained (86%). SteoC Following a similar procedure as in Preparative Example 2, Step B, but using the product from Step B above, the desired compound was obtained (67%, MH+=331). step A N-Benzylpiperidone (2 g, HCI salt, hydrate) was stirred with THF (20 mL), concentrated to dryness, and placed under high vac. The residue was diluted In THF (20 mL), and methyllithlum was added (2.5 eq of 1.6A/ in Et20) via syringe. After stirring for 3 hr, the mixture was concentrated in vacuo, diluted with water, extracted with CH2CI2, and dried over Na2S04. Filtration and concentrating in vacuo gave the desired product (50%, MH+ = 205). StepB Following a similar procedure as In Preparative Example 2, Step B, but using the product from Step A atiove, the title compound was obtained (95%. MH+=116). Step A To N-benzyl-N-methylamine (20 mmol) dissolved In acetone (50 mL) was added concentrated HCI (20 mmol), p?"~"*">"~""«"«"»»""" mL). After stirring at reflux overnight, the mixture was concentrated in vacuo, diluted with water, basified to pH 14 and extracted with ether. The organic phase was dried over Na2S04, filtered and concentrated in vacuo to give the desired product (98%) which was used directly in Step B. SteoB The product from Step A above (500 mg) was dissolved in MeOH (20 mL) and to this was added NaBH4 (50 mg). After stirring for 10 min, the solution was concentrated in vacuo to give the desired compound which was used directly in Step C without purification. StepC .^ Tlie product fronrj,Step B above was diluted with MeOH (20 mL) and to this was added AcOH (0.1 mL), a catalytic amount of Pd/C (10%) and the mixture stinred under H2 atmosphere (balloon) overnight. The mixture was filtered, 4N HCI in dioxane (1 mL) was added, and the mixture was concentrated in vacuo to give the desired compound that was used directly without purification. Step A Following a similar procedure as Preparative Example 2, Step A except using methvl alvcinate. the desired ester was obtained. The mixture was poured into 200 NaCI was added until saturation. After several hours, the resulting precipitate was filtered and washed with cold water to give the desired product (42%). StepB Following a similar procedure as in Preparative Example 2 Step B, but using the product from Step A at>ove, the title compound was obtained (95%). Step A Following a similar procedure as in Preparative Example 2.13, Step A except using methyl N-methylglycinate, the desired product was obtained (18%). SteoB Following a similar procedure as in Preparative Example 2. Step B, but using the product from Step A above, the title compound was obtained (95%, MH+ = 225). lilt:uyuuuuitjiitiuiurit:; iniermedlatefrom Preparative Example 87 (200mg), DIEA (100ul), 3-aminosaiicylic acid (120mg) and EtOH {4ml) were combined and heated to reflux overnight to give the title compound (90%, MH+=367). The above n-oxide (2g) was combined with H2NMe/H20 (15cm^) and heated to 140°C ovemight. Potassium carbonate (1.3g) added and the mixture concentrated in vacuo. Extraction with EtOH and concentration of the filtrate in vacuo gave 1.56g of crude amine (MH+=125). PREPARATIVE EXAMPLE 3-10.50 Following the procedures set forth in Preparative Examples 1-2 but using the carboxylic acid, amine, and coupling agent [DCC (Prep. Ex. 1) or PyBrop (Prep. Ex. 2)] listed in the Table below, the indicated amide products were obtained and used without further purification. To the material from step A diluted in dichloromethane (50 mL) and cooled to " C was added dimethyl amine In THF {2N solution, 24.6 mL) and triethylamine (4 q.). After stirring for 24 hours at room temperature the mixture was concentrated in 3CU0, diluted with 1M sodium hydroxide (30 mL) and after a half hour was washed ith dichloromethane. The aqueous phase was acidified with 6M HCI (aq), extracted ith dichloromethane and the organic phase was washed with water, dried over 82804 and concentrated to give the title compound (3.2 g, 93%). A mixture of the product from step B above (6 g), 10% Pd/C (0.6 g), and EtOH ) mL) was stinred In a parr shaker under hydrogen (40 psi) at room temperature for lays. Filtration through celite and concentration in vacuo afforded the title product 1g,99%.MH* = 181). step A Following a similar procedure as in Preparative Example 1 except using dimethylamine (2M In THF, 33 mL) and 5-methylsallcylic acid (5 g), the desired product was prepared (6,5 g). StepB Nitric acid (0.8 mL) in H2SO4 was added to a cooled (-20°C) suspension of the product from Step A above (3 g) In H2SO4 (25 mL). The mixture was treated with 50% NaOH (aq) dropwise, extracted with CH2CI2, dried over anhydrous MgS04, filtered and concentrated in vacuo to give the product as a crude solid (2.1 g, 44%, MH* = 225). StepC The product was prepared in the same manner as described in Step B of Preparative Example 2 (0.7 g, 99%. MH"^ = 195). >tep A The above amine was reacted with the acid using the procedure set forth in "reparative Example 2, Step A to yield the desired amide (54%). teoB Na2S204 (1.22g) was dissolved in water (4ml) followed by the addition of H3/H2O (SOOul). The solution ws then added to the product from Step A (200 mg) in dioxane (4ml) and stirred for 30min. The crude material was purified via flash column chromatography (CH2Cl2/MeOH, 20:1) to give 100mg of product (56%, MH+=251). Following the procedures set forth in Preparative Example 11.1, Steps A and B, but using N-methylmethoxylamine, the title compound was obtained (86%, MH+=181). Step A Following the procedure set forth in Preparative Example 1, but using N-hydroxysuccinimide and 2% DMF in CH2CI2. the desired amide was obtained (33%, MH+=297). SteoB Following the procedure set forth in Preparative Example 2. Step B, the amine was prepared (99%. MH+=267). PREPARATIVE EXAMPLE 11.11 - Following the procedures set forth in Preparative Examples 11.11 but using the carboxylic acid, amine, and coupling agent DCC indicated, the indicated amide products were obtained and used without further purification. A Following a similar procedure as described in Preparative Example 2 Step A )t using dimethylamine in place of R-(+)-3-pyrrolidinol, the desired product was ired. B The product from step A atxjve (8 g) was combined with iodine (9.7 g), silver B (11.9 g), EtOH (200 mL) and water (20 mL) and stin-ed overnight. Filtration, sntration of the filtrate, re-dissolution in CH2CI2 and washing with 1M HCI (aq) an organic solution which was dried over anhydrous MgS04, filtered and sntrated in vacuo to afford the product (7.3 g. 57%, MH* = 337). The product from Step B above (3.1 g) was combined with DMF(50 mL) and 1.6 mL). NaH (60% in mineral oil, 0.4 g) was added portionwise and the mixture was stirred overnight. Concentration in vacuo afforded a residue which was diluted with CH2CI2. washed with 1/W NaOH (aq), dried over anhydrous MgS04, filtered and concentrated in vacuo. Purification through a silica gel column (EtOAc/Hex, 1:1) gave the desired compound (1.3 g, 41 %, MH^ = 351). I SteoD The product from Step D above (200 mg), Zn(CN)2 (132 mg), Pd(PPh3)4 (130 mg) and DMF (5 mL) were heated at 80°C for 48 hrs, then cooled to room temperature and diluted with EtOAc and 2M NH4OH. After shaking well, the organic extract was dried over anhydrous MgS04. filtered, concentrated in vacuo and purified by preparative plate chromatography (Silica. EtOAc/Hex, 1:1) to give the desired compound (62 mg, 44%. MH* = 250). StepE BBra (1.3 mL. 1M in CH2CI2) was added to a CH2CI2 solution (5 mL) of the product from step D above (160 mg) and stirred for 30 min. The mixture was diluted with water, extracted with CH2CI2, dried over anhydrous MgS04, filtered, and concentrated in vacuo to give the desired compound (158 mg, MH* = 236). SteoF A mixture of the product fix>m step E above (160 mg), platinum oxide (83%, 19 mg), and EtOH (20 mL) was stin-ed under hydrogen (25-40 psi) for 1.5 hr. Filtration through celite and concentration in vacuo afforded the product (165 mg, MH* = 206). step A Following a similar procedure as in Preparative Example 2, Step A except using 3-(methylanninomethyl)pyridine and 3-nitrosalicyiic acid, the desired connpound was prepared (41%). StepB The compound from Step A above (0.3 g) was diluted with chloroform (15 mL) and stirred with mCPBA (0.4 g) for 2 hr. Purification by column chromatography (silica, 10% MeOH/CHaCb) gave the pyridyl N-oxide (0.32 g, 100%, MH* = 303.9). SteoC Following a similar procedure as in Preparative Example 11.1, Step B, but using the product from Step B above, the desired compound was obtained (15%, MH+=274). I- StepA 3-Nitrosalicylic acid (4 g) in MeOH (100 mL) and concentrated H2SO4 (1 mL) were stirred at reflux ovemight, concentrated in vacuo, diluted with CH2CI2, and dried over Na2S04. Purification by column chromatography (silica, 5% MeOH/CH2Cl2) gave the methyl ester (2.8 g, 65%). StepB Following a similar procedure as in Preparative Example 2, Step B, but using the product from Step A above, the desired compound was obtained (95%, MH+=167.9). To morpholine-2-carboxilic acid (200mg) in EtOH (40mL) at 0°C was added cetyl chloride (3mL) and the mixture was stirred at reflux overnight. Concentration in acuo, dilution with CH2CI2 and washing with NaHCOa (aq) gave the title compound J9%.MH*= 160.1). To N-Boc morpholine-2-carboxylic acid (2g) in THF (5ml) at 0°C was added a Diution of borane.THF complex {1N, 10.38ml) and the mixture was stin-ed for SOmin 10°C, and for 2hr at room temperature. Water (200ml) was added to the reaction nd the mixture extracted with CH2CI2, dried with Na2S04, and concentrated in vacuo > give 490mg of product (26%). The product was then stirred in 4N HCI/dioxane to ive the amine salt. step A Following a similar procedure as in Preparative Example 1 except using dimethylamine (2A/f in THF, 50 mL) and 4-methylsalicylic acid (15 g), the desired compound was prepared (6.3 g. 35%). StepB The product from step A above (1.5 g) was combined with iodine (2.1 g), NaHCOa (1-1 g). EtOH (40 mL) and water (10 mL) and stin-ed overnight Filtration, concentration of the filtrate, re-dissolution in CH2CI2 and washing with 1M HCI (aq) gave an organic solution which was dried over anhydrous MgS04, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 0.5-0.7% MeOH/CHaCIa) gave the product (0.5 g. 20%, MH* = 306). SteoC Nitric acid (3.8 mL) in AcOH (10 mL) was added to the product from Step B above (0.8 g) and the mixture was stirred for 40 min. The mixture was diluted with water and extracted with CH2CI2, dried over anhydrous MgS04, filtered and concentrated in vacuo to give the product as an orange solid (0.8 g, 92%, MH* = 351). A mixture of the product from step C above (800 mg), 10% Pd/C (100 mg), and EtOH/MeOH (40 mL) was stirred in a pan- shaker under hydrogen (45 psi) for 1.5 hr. Filtration through cellte and concentration in vacuo afforded the title product after purification by preparative plate chromatography (Silica, 10% MeOH/CH2Cl2, saturated with NH4OH) to give the product (92 mg. 22%, MH* = 195). SteoA Following a similar procedure as in Preparative Example 2, Step A except using dimethylamine (2M in THF, 23 ml) and 5-bromosalicylic acid (5g), the desired compound was prepared (4.2g, 75%, MH+=244). StepB Nitric acid (10ml) in AcOH (100ml) was added to the product from Step A above (2g) and the mixture was stirred for 20 min. The mixture was diluted with water and extracted with CH2CI2, dried over anhydrous MgS04, filtered and concentrated in vacuo to give the product as a yellow solid (1.9g. 80%, MH+=289). SteoC The product from Step B above (1.9g) was partially dissolved in EtOH(50mI). Cone HCI in EtOH (5ml in 40ml). followed by SnCl2.2H20 (5.74g) was added and stirred at room temperature ovemight. The crude reaction was concentrated in vacuo, diluted with CH2CI2 and washed with NaHCOa, dried over anhydrous IVlgS04, filtered and concentrated in vacuo to give the product as a solid (185mg, 9%, MH+=259). SteoA Following a similar procedure as in Preparative Example 2, Step A, except using dimethylamine (2M in THF, 29 ml) and 5-chlorosalicylic acid (5g), the desired compound was prepared (4.5g, 78%, MH+=200). SteoB Nitric acid (10ml) in AcOH (100ml) was added to the product from Step A above (2g) and the mixture was stirred for 20 min. The mixture was diluted with water and extracted with CH2CI2, dried over anhydrous MgS04, filtered and concentrated in vacuo to give the product as a solid (2.2g, 88%. MH+=245). SteoC The product from Step B above (2.2g) was partially dissolved in EtOH(50ml). Cone HCI in EtOH (5ml in 40ml), followed by SnCl2.2H20 (7.01 g) was added and stirred at room temperature overnight The crude reaction was concentrated in vacuo, diluted with CH2Ci2and neutralized with NaOH. The entire emulsion was filtered though celite, the layers were separated and the organic layer was dried over tepA 3-Nitrosalicylic acid {10g), PyBroP (20.52g). and DIEA (28ml) in anhydrous H2CI2 (200ml) were combined and stirred at room temperature for 10 min. methylamlne (2M in THF, 55ml) was added and let the reaction stir over the 3ekend. The mixture was extracted with 1N NaOH (aq) and the organic phase was scarded. The aqueous phase was acidified with 1N HCI (aq), extracted with CH2CI2, led over anhydrous MgS04, filtered and concentrated in vacuo. The oil was taken I in ether and a solid crashed out, triterated in ether to give 4.45g of a solid (39%, H+=211). 3DB The product from Step A (2.99g), K2CO3 (9.82g), and iodomethane (8.84ml) sre combined in acetone and heated to reflux overnight The reaction was filtered d concentrated in vacuo. The oil was taken up in CH2CI2 and washed with 1N NaOH, dried over anhydrous MgS04, filtered and concentrated in vacuo to give 3.3g of an oil (99%. MH+=225). SteoC The crude product from Step B (3.3g) was stirred with 10% Pd/C (350mg) in EtOH (50ml) under a hydrogen gas atmosphere at 20psi overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to give 2.34 g of a solid (85%, MH+=195). SteoD The product from Step C (469mg) was dissolved in AcOH (6ml). 1.95M Br2 in AcOH (1.23ml) was added dropwise to the reaction and the mixture was stirred at room temperature for 1 hour. 50% NaOH was added to the reaction at 0°C and the mixture was extracted with CH2CI2. dried over anhydrous MgS04, filtered and concentrated in vacuo. The crude mixture was purified by preparative plate chromatography (Silica, 5% MeOH/ CH2CI2) to give the desired product (298mg. 23%, MH+=273). SteoE BBra (2.14ml, 1M In CH2CI2) was added to a CH2CI2 solution (8ml) of the product from Step D above (290mg) and stirred overnight. A solid formed and was filtered, taken up in MeOH/ CH2Cl2and purified by preparative plate chromatography (Silica. 5% MeOH/ CH2CI2) to give the desired product (137mg. 49%, MH+=259). step A To the product from Preparative Example 13.3 Step D (200mg) was added phenylboronic acid (98mg), PdCl2(PPh3)2 (51 mg), and NaaCOs (155mg) in THF/H2O (4ml/1ml). The solution was heated at 80°C overnight. EtOAc was added to reaction and washed with IN NaOH. The organic layer was dried over anhydrous MgS04, filtered and concentrated in vacuo. The cnjde mixture was purified by preparative plate chromatography (5% MeOH/ CH2CI2) to give 128mg of an oil (65%, MH+=271). SteoB Following a similar procedure as in Preparative Example 13.3 Step E and using the product from Step A above, the desired compound was prepared (0.1 g, 69%, MH+=257.1). PREPARATIVE EXAMPLE 13.5-13.7 Following the procedures set forth in Preparative Example13.4 but using the boronic acid fi"om the Preparative Example indicated in the Table below, the amine products were obtained. 2-Cyanophenol (500mg), sodium azide (819mg), and triethylamine hydrochloride (1.73g) were combined in anhydrous toluene and heated to 99°C overnight. After the reaction cooled down, product was extracted with H2O. Aqueous layer was acidified with cone. HCI dropwise giving a precipitate, which was filtered io give the product (597mg, 87%, MH+=163). StepB Nitric acid (0.034ml) in AcOH (5ml) was added to the product from Step A above (100mg) in AcOH and the mixture was allowed to stir for Ihr. CH2CI2 and H2O were added to reaction. The organic layer was dried over anhydrous MgS04, filtered and concentrated in vacuo to give an oil. Trituration in ether gave the product as a solid (12mg. 9%. MH+=208). StgpQ The product from step C (56mg) was stirred with 10% Pd/C (20mg) in EtOH/MeOH (15ml) under a hydrogen gas atmosphere overnight. The reaction mixture was filtered through celite, the filtrate was concentrated in vacuo to give 29mg of a solid (62%. MH+=178). The amine was prepared following the procedure disclosed in WO Patent Application 01/68570. The amine was prepared following the procedure disclosed in WO Patent Application 01/68570. Step A Following the procedure described in Preparative Example 88.2, Step A, the ketone was prepared (6.4g, 36%). StepB To a solution of ketone (1g) and 2-R-methylbenzylamine (0.73ml) in anhydrous toluene (20ml) was added 1N TiCU in toluene (3ml) at room temperature for 1.5hrs. The precipitate was filtered and the filtrate was concentrated in vacuo and purified via flash column chromatography (Hex/EtOAc, 18/1) to give BOOmg of product (71%). SteoC The imine from above (760mg) and DBU (800ul) were stirred without solvent for 4hr. The crude reaction was concentrated in vacuo and purified via flash column chromatography (Hex/EtOAc, 8/1) to give BOOmg of product (79%). The imine from Step C (560mg) was dissolved in ether (8ml). 3N HCI (5ml) added and let stir at room temperature overnight. The ether layer was separated and concentrated in vacuo to give 400mg of the amine hydrochloride product (93%). The title compound was prepared similarly as In Preparative Example 13.11, but using the 2-S-methylbenzylamine instead of 2-R-methylbenzylamine (69%). Step A At room temperature, CsF (SOmg) was added to a mixture of furfuraldehyde (1.3ml) and TMS-CF3 (2.5g) and stirred at room temperature (24 h) and refluxed for another 12h. 3N HCI (40ml) was added and after 4hr, the mixture was extracted with ether, washed with brine, dried over MgS04, and concentrated in vacuo to give the product (2.6g. 100%). StepB 1, To a solution of alcohol from above (2.6g) in CH2CI2 at room temperature was added Dess-Martin reagent (10g) portionwise and 1 drop of water. After stirring for 3hr at room temperature, 10% Na2S203 (60ml) was added and after stirring overnight, the solid was filtered off and the filtrate was extracted with CH2CI2. The organic layer was washed with saturated sodium bicarbonate, dried with MgSC4, filtered and concentrated in vacuo. Ether/hexane (1:2; 30ml) was added to the residue, filtered, and filtrate concentrated in vacuo to give the product (2g, 78%). StepC Following the procedures described in Preparative Example 13.11, Steps B, C and D, the amine salt was prepared. PREPARATIVE EXAMPLES 13.15-13.17 Following the procedure set forth in Preparative Example 13.13, but using the prepared or commercially available aldehydes, the optically pure amine products in the Table below were obtained. step A Methyl-3-hydroxy-4-bromo-2-thiophenecarboxylate (10.0 g, 42.2 mmol) was dissolved in 250 mL of acetone. Potassium cartxjnate (30.0 g, 217.4 mmol) was added followed by a solution of iodomethane (14.5 mL, 233.0 mmol). The mixture was heated to reflux and continued for 6 h. After cooled to room temperature, the mixture was filtered, the solid material was rinsed with acetone (-200 mL). The filtrate and rinsing were concentrated under reduced pressure to a solid, further dried on liigh vacuum, yielding 13.7 g (100%) of metliyl-3-metlioxy-4-bromo-2-thiophenecait)oxylate (MH* = 251.0). SteoB Methyl-3-methoxy-4-bromo-2-tliiophenecarboxylate (13.7 g), available from step A, was dissolved in 75 mL of THF, and added with a 1.0 IVI sodium hydroxide aqueous solution (65 mL, 65.0 mmol). The mixture was stirred at room temperature for 24 h. A 1.0 M hydrogen chloride aqueous solution was added dropwise to the mixture until pH was approximately 2. The acidic mixture was extracted with CH2CI2 (100 mL x 2, 50 mL). The combined organic extracts were washed with brine (40 mL), dried with Na2S04, and concentrated under reduced pressure to a solid, 10.0 g (100%, over two steps) of 3-methoxy-4-bromo-2-thiophenecarboxylic acid (MH* = 237.0). StepC To a stirred solution of 3-methoxy-4-bromo-2-thlophenecarboxyllc acid (6.5 g, 27.4 mmol) in 140 mL of CH2CI2, obtained from step B. was added bromo-tripyrroiidlnophosphonlum hexafluorophosphate (PyBrop, 12.8 g, 27.5 mmol), a 2.0 M solution of dimethyl amine in THF (34.5mL, 69.0 mnral), and diisopropylethyl amine (12.0 mL, 68.7 mmol). After 3 d, the mixture was diluted with 100 mL of CH2CI2, and washed with a 1.0 M sodium hydroxide aqueous solution (30 mL x 3) and brine (30 mL). The organic solution was dried with NaaSOA, filtered, and concentrated to an oil. This crude oil product was purified by flash column chromatography, eluting with CH2Cl2-hexanes (1:1, v/v). Removal of solvents afforded a solid, further dried on high vacuum, yielding 6.76 g (93 %) of N, A/"-dimethyl-3-methoxy-4-bromo-2-thiophenecarboxamide (MH* = 265.0, M+2 = 266.1). SteoD An oven dried three-neck round bottom flask was equipped with a refluxing condenser, charged sequentially with palladium acetate (95 mg, 0.42 mmol), (R)-BINAP (353 mg, 0.57 mmol). cesium carbonate (9.2 g, 28.33 mmol), and N, N-dimethyl-3-methoxy-4-bromo-2-thiophenecarboxamide (3.74 g, 14.2 mmol, from step C). The solid mixture was flushed with nitrogen. Toluene (95 mL) was added to the solid mixture followed by benzophenone imine ^i.o mL, ^^^ .5 mmol). The mixture was heated to reflux and continued for 10 h. A second batch of palladium acetate (95 mg. 0.42 mmol) and (R)-BINAP (353 mg. 0.57 mmol) in 5 mL of toluene was added. Refluxing was continued for 14 h. The third batch of palladium acetate (30 mg, 0.13 mmol) and (R)-BINAP (88 mg, 0.14 mmol) was added, and reaction continued at 110°C for 24 h. The mixture was cooled to room temperature, diluted with ether (50 mL), filtered through a layer of Celite, rinsing with ether. The filtrate and rinsing were concentrated under reduced pressure to an oil, which was purified twice by flash column chromatography using CH2CI2 and CH2Cl2-MeOH (200:1) as eluents. Removal of solvents afforded 4.1 g (79 %) of the amido-thiophene diphenylimine product as a solid (MH* = 365.1). StepE To a stirred solution of thiophene imine (5.09 g, 13.97 mmol), obtained from step D, in 140 mL of CH2CI2 at-78°C was added dropwise a 1.0 M solution of boron tribromide in CH2CI2. The mixture was stirred for 3 h while the temperature of the cooling bath was increased slowly from -78°C to -15°C. 100 mL of H2O was added, the mixture was stirred at room temperature for 30 min, then the two layers were separated. The organic layer (as A) was extracted with H2O (30 mL x 2). The aqueous layer and aqueous extracts were combined, washed with CH2CI2 (30 mL), and adjusted to pH - 8 using a saturated NaHCOa aqueous solution. The neutralized aqueous solution was extracted with CH2CI2 (100 mL x 3), the extracts were washed with brine, dried with Na2S04. and concentrated under reduced pressure to a light yellow solid, 1.49 g of N, N"-dimethyl-3-hydroxy-4-amino-2-thiophenecarboxamide (first crop). The previous separated organic layer A and organic washing were combined, stirred with 30 mL of a 1.0 M HCI aqueous solution for 1 h. The two layers were separated, the aqueous layer was washed with CH2CI2 (30 mL) and adjusted to pH ~8 using a saturated NaHCOa aqueous solution, and the separated organic layer and organic washing were combined as organic layer B. The neutralized aqueous solution was extracted with CH2CI2 (30 mL x 4), the extracts were washed with brine, dried by Na2S04, and concentrated under reduced pressure to give 0.48g of a solid as the second crop of the titled product. Organic layer B from above was washed with brine, and concentrated to an oil, which was separated by preparative TLC (CH2CI2-MeOH = 50:1) to afford 0.45 g of a solid as the third crop of the titled product. The overall yield of the product, N, N"- dlmethyl-3-hydroxy-4-amino-2- thiophenecarboxamlde, is 2.32 g (89%) (MH* = 187.0). tepA To the product from Preparative Example 13.19 Step D (1.56g) in CH2CI2 5ml) was added potassium carbonate (1.8g) followed by dropwise addition of omine (0.45ml). After 5hr of mixing, water (100ml) was added to the reaction and e layers were separated. The aqueous layer was extracted with CH2CI2, which was en washed with brine, saturated sodium bicarbonate, and brine again. The organic /er was dried with Na2S04, and concentrated in vacuo. The residue was purified via ish column chromatography (CH2CI2) to yield 1.6g of product (83%). eoB The product from atjove was reacted in the procedure set forth in Preparative cample 13.19 Step C to give the amine. ep A To the product from Preparative Example 13.20, Step A (300mg) in THF (7ml) -78 °C was added a solution of n-BuLi (1.6M in hexanes, 0.54ml). After 1 hr, jomethane {0.42ml) was added dropwise. After 3 hrs of stirring at -78 °C, the reaction weio wail lieu luruom temperature overnight. Saturated ammonium chloride and water were added to the reaction and extracted with CH2CI2. The organic layer was washed with saturated sodium bicarbonate and brine, dried over Na2S04, and concentrated in vacuo. The crude product was purified by preparative plate chromatography (CH2Cl2-MeOH = 70:1 to 50:1) to afford the product (111mg.43%). StepB The product from above was reacted in the procedure set forth in Preparative Example 13.19, Step E to give the amine. Step A To the product from Preparative Example 13.19 (400mg), Step D in CH2CI2-pyridine (14ml) was added N-chlorosuccinimide (220mg). The mixture was stirred for 5hr and then diluted with CH2CI2 and washed with water, saturated sodium bicartjonate and brine, and concentrated in vacuo. The crude product was purified via preparative plate chromatography (CH2Cl2-MeOH = 50:1) to give 180mg of product (64%). StepB The product from above (274mg) was reacted in the procedure set forth in Preparative Example 13.19, Step E to give the amine (BSmg, 58%). StgpA To a stirred solution of acid (630mg) from Preparative Example 13.19, Step B In CH2Cl2(25ml) was added oxalyl chloride (235ul) followed by a catalytic amount of DMF (iOul). The mixture was stirred for 1hr, then potassium carbonate (1.8g) was added followed by 3-amino-5-methylisoxazoi& (4i^3mg). The reaction stirred overnight and was quenched with water (25ml). Layers were separated and the organic layer was washed with brine, dried over Na2S04, and concentrated in vacuo. The crude product was purified by preparative plate chromatography (CH2CI2) to afford the product (580mg. 78%. MH+=317.319). SteoB The acid from the above (750mg) step was reacted following the procedure set forth In Preparative Example 13.3. Step B to yield 625mg of product (80%, MH+=331). SteoC The product from above was reacted following the procedure set forth in Preparative Example 13.19, Step D to yield 365mg of product (53%) SteoD The product from above was reacted following the procedure set forth in Preparative Example 13.19, Step E to give the amine product (MH+=254). step A To a solution of 2-methylfuran (1g) in ether (30ml) was added n-BuLi (5.32ml) at -78°C. The reaction was warmed to room temperature and then refluxed at 38 °C for 1 hr. The reaction was cooled back down to -78°C where the fury! lithium was quenched with trifjuorobutyraldehyde and let stir at room temperature overnight. Saturated ammonium chloride added and extracted with ether. Purified via flash column chromatography to yield pure product (2g, 80%) StepB The azide was prepared using the procedure from Preparative Example 75.75, Step B and the alcohol (1g) from above and carried on crude to Step C below. SteoC The amine was prepared using the procedure from Preparative Example 75.75, Step C to yield 400mg of an oil (53%). step A Perfluoroiodide (3.6ml) was condensed at -78°C. Ether (125ml) was added followed by the methylllthium.llthiumbromide complex (1.5M in ether, 18.4ml). After 15mln, a solution of 5-methylfuraldehyde (2.5ml) in ether was added dropwise. The reaction was warmed to -45 °C and let stir for 2hr. Saturated ammonium chloride (30ml) and water (30ml) were added and let stir at room temperature for 1hr. The layers were separated and the aqueous layer was extracted with CHaCla. The organic layer was washed with brine, dried with Na2S04. filtered and concentrated in vacuo to give 5.86g of product (100%). SteoB The alcohol from above was reacted to form the azide using the procedure set fortti in Preparative Example 75.75 Step B. SteoC The azide from above was reacted to form the racemic amine using the procedure set forth In Preparative Example 75.75 Step C. step A Following the procedure set forth In Preparative Example 13.26, Step A, the alcohol was prepared (100%). SteoB To a solution of the alcohol (500mg) from step A above in CH2CI2 (20ml) was added N-methyl-morphollne monohydrate (575mg) and a catalytic amount of tetrapropyl ammonium perruthenate (76mg). After 3hr, the mixture was diluted with hexane (10ml) and filtered through a silica pad, rinsing with hexane: CH2CI2 (200ml). The filtrate was concentrated in vacuo to give 350mg of product (70.7%) StepC The ketone (1.19g) from Step B was dissolved In THF (9.5ml) and cooled to 0 *"C, A solution of S-methyl oxazoborolidine (1M in toluene, 1 ml) followed by a solution of borane complexed with dimethylsulflde (9.5ml, 2M in THF) was added to the solution. The mixture was stirred at 0 °C for 30min and continued at room temperature for 5hr. The mixture was cooled back down to 0 °C and methanol (15ml) was added dropwise to the mixture. After 30min, the mixture was concentrated in vacuo to give an oily residue. The residue was dissolved in CH2CI2 and washed with 1N HCI, water, and brine. Dried with Na2S04, filtered and concentrated in vacuo. The crude material was purified via flash column chromatography (Hex/ CH2CI2, 1:1) to afford 1.14gofanoil(67%). StepD The alcohol (1.14g) from above was reacted to form the azide using the procedure set forth in Preparative Example 75.75 Step B. StepE The azide (1.11g) from above was stirred with 10% Pd/C (280mg) in EtOH (40ml) under a hydrogen gas atmosphere ovemight. The reaction was filtered through cellte, the filtrate was concentrated in vacuo to give 700mg of product (70%). Step A To a stirred solution of 1-(2-thienyl)-1-propanone (3g) in acetic anhydride (6ml) at 0°C was added dropwise a solution of fuming nitric acid in acetic acid (2ml in 10ml). After 30min, the reaction was warmed to room temperature and let stir for 5hrs where a solid precipitated out. Ice was added to the reaction and the solid was filtered. The solid was purified by flash column chromatography (Hex/ CH2CI2, 3:1 and 2:1) to yield 800mg of desired product (20%). SteoB The above nitro-thiophene compound (278mg) was reduced using the procedure set forth in Preparative Example 2, Step B to give 54mg of product (23%). The above amine (395mg), TEA (1ml) and methanesulfonylchloride (0.5ml) were combined in CH2CI2 (35ml) and stinred at room temperature for 1hr. The reaction was quenched with saturated sodium bicarbonate (15ml). The organic layer was washed with brine, dried over Na2S04, filtered and concentrated in vacuo to afford product (854mg, 100%). StepD To the above product (854mg) in THF (25ml) was added dropwise a solution of tetrabutylammonium fluoride (1M in THF, 2.8ml). The mixture was stirred overnight, then diluted with CH2CI2 (30ml), washed with amnnonium chloride and brine, dried over over Na2S04, filtered and concentrated in vacuo to afford product (2.36g, >100%). SteoE The ketone (2.36g) above was reacted via the procedure set forth in Preparative Example 88.2, Step B to yield 547mg of product (86.6%). SteoF To the product from step E (310mg) in dimethoxyethane (12ml) was added dropwise a solution of LAH (1M in ether, 3.8ml). The mixture was heated to reflux overnight. The reaction was cooled to room temperature, Si02 was added as well as water (1ml) dropwise and let stir for 15min. The mixture was filtered and the filtrate was concentratred in vacuo. The crude product was purified by preparative plate chromatography (MeOH/ CH2CI2.15:1) to give the amine product (40mg, 14%). step A 3-Nitro-1,2-phenylenediamine(10 g), sodium nitrite (5.4 g) and acetic acid (20 mL) were heated at BO"C overnight, then concentrated in vacuo, diluted with water and extracted with EtOAc. The product precipitated from the organic phase (5.7 g) as a solid and used directly in step B. StepB The product from Step A above (2.8 g) was stin-ed with 10% Pd/C (0.3 g) in MeOH (75 mL) under a hydrogen gas atmosphere overnight. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo, to give the product (2.2g.MH+=135). N-methyl-4-bromopyrazole-3-carboxylic acid was prepared according to kno ds, see: Yu. A. M.; Andreeva. M. A.; Perevalov, V. P.; Stepanov, V. I.; /skaya, V. A.; and Seraya, V. I. in Zh. Obs. Khim. (Journal of General stry of the USSR) 1982. 52, 2592. and refs cited therein. To a solution of N-methyl-4-bromopyrazole-3-carboxylic acid (2.0 g), availab :ep A, in 65 mL of anhydrous DMF was added bromotripyrrolidinophosphonii lorophosphate (RyBrop, 4.60 g), dimethyl amine (10 mL, 2.0 M in THF) and opylethyl amine (5.2 mL) at 25 °C. The mixture was stirred for 26 h, and rtrated under reduced pressure to an oily residue. This residue was treated 1.0 M NaOH aqueous solution, and extracted with ethyl acetate (50 mL x 4). janic extracts were combined, washed with brine, and dried with anhydrous 4. Removal of solvents yielded an oil, which was purified by preparative thin firomatography, eluting with CH2ClrMeOH (20:1), to give 1.09 g of the amid( t (48%. MH* = 232.0). To a solution of the amide (0.67 g), obtained from step B. in 8 mL of trated sulfuric acid at 0 °C was added potassium nitrate (1.16 g) in small s. The cooling bath was renvived and the mixture was heat*aH at ■^^n°r. f«r R h. After cooling to 25 °C, the mixture was poured into 80 mL of H2O, and an additional 20 mL of H2O was used as a rinse. The aqueous mixture was extracted with CH2CI2 (100 mL x 4). The combined extracts were washed with brine (50 mL), sat. NaHCOa aqueous solution (50 mL), brine (50 mL), and dried with Na2S04. Evaporation of solvent gave an oil, which solidified on standing. The crude product was purified by flash column chromatography, eluting with CH2Cl2-MeOH (1:0, 50:1 and 40:1). Removal of solvents afforded 0.521 g (65%) of the product as a solid (MH* = 277.1) StepD The product (61 mg) obtained from step C was dissolved in 3 mL of THF. To this solution at - 78 °C was added dropwise along the inside wall of the flask a 1.6 M solution of n-butyl lithium in hexane. After 45 min, a solution of methyl borate (0.1 mL) in THF (1.0 mL) was added. After 1.5 h, a solution of acetic acid in THF (0.25 mL, 1:10 v/v) was added to the cold mixture. Stirring was continued for 10 min, and a 30 wt % aqueous hydrogen peroxide solution (0.1 mL ) was added. An additional portion of hydrogen peroxide aqueous solution (0.05 mL) was added 20 min later. The cooling bath was removed, and the mixture was stirred at 25 °C for 36 h. The mixture was poured into 30 mL of H2O, and the aqueous mixture was extracted with ethyl acetate (30 mL x 4). The extracts were combined, washed with brine (10 mL), 5% NaHCOa aqueous solution (10 mL) and brine (10 mL). The organic layer was dried with Na2S04 and concentrated under reduced pressure to a residue, which was then purified by preparative thin layer chromatography eluting with CH2ClrMeOH (20:1) to give the hydroxylated product (5 mg, 10%, MH" = 215.3). SteoE By treating the hydroxylated product of Step E with H2 under the conditions of 10% palladium on carbon in ethanol, one would obtain the desired hydroxyl-amino compound. step A Following a similar procedure used in Preparative Example 13, Step C except using the known compound, 4-methyl-pyrimidin-5-ol, the product can be prepared. StepB Following a similar oxidation procedure used in Preparative Example 15, Step A except using the compound from Step A above, the product can be prepared. StepC Following a similar procedure used in Preparative Example 11, Step A except using the compound from Step B above, the product can be prepared. StepD Following a similar procedure used in Preparative Example 12, Step F except using the compound from Step C above, the product can be prepared. step A Following a similar procedure used in Preparative Example 11, Step A except using the known 4-hydroxynicotinic acid, the product can be prepared. SteoB Following a similar procedure used in Preparative Example 13, Step C except using the compound from Step A above, the product can be prepared. StepC Following a similar procedure used in Preparative Example 12, Step F except using the compound from Step C above, the product can be prepared. step A Following a similar procedure used in Preparative Example 13, Step C except using the compound from Step A above, the product can be prepared. SteoB Stirring the compound from Step A above, a suitable R or Pd catalyst and EtOH under hydrogen atmosphere (1-4 atm) the product can be prepared. The product from Preparative Example 3 (14.6 g) dissolved In absolute EtOH (100 mL) was added dropwise over 4 hours to a stirred ethanolic (100 mL) solution of diethytsquarate (19 mL, 128 mmol). After 5 days, the reaction mixture was concentrated in vacuo, &id the resulting residue purified by column chromatography (silica yel, 0-5% MeOH/CH2Cl2) gave the product (65%, MH* = 305, mp = 178.6°C). The amine from Prepartive Example 3 (5g) and dimethylsquarate (3.95g) in i/leOH were stirred overnight. The precipitated product was filtered to give 6.32g of Jolld(78%, MH+=291.1) PREPARATIVE EXAMPLE 20-23.14 Following the procedures set forth in Preparative Example 19 but using the imine from the Preparative Example indicated in the Table below, the ".yclobutenedione intermediates were obtained. reaction to be complete). The resulting mixture was washed sequentially with 10% citric acid (3 x 20 mL), sat. aq. NaHCOa (3 x 20 mL), and brine (3 x 20 mL). The organic layer was dried {Na2S04), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with CH2Cl2/MeOH (40:1) to afford 1.0 g (63% yield) of a solid. SteoB To a round bottom charged with the A/-protected amide (1.0 g, 4.35 mmol) (from Step A) was added 4N HCI/dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. The mixture was diluted with EtaO (20 mL) and concentrated under reduced pressure. The crude product was treated with Et20 (2 x 20 mL) and concentrated under reduced pressure to afford 0.72 g (-100 % yield) of crude product as the HCI salt. This material was taken on without further purification or characterization. PREPARATIVE EXAMPLES 25-33.1 Following the procedure set forth in Preparative Example 24 but using the commercially available A/-protected amino acids and amines in the Table below, the amine hydrochloride products were obtained. step A BOC-valine (45mg) and PS-carbodiimide (200mg) were suspended in CH2CI2 (4ml). After addition of the CH2Cl2-amine solution (0.138N, 1ml), the mixture was shaken overnight. The solution was filtered and the resin was washed.,,vvith more CH2CI2, and the filtrate was concentrated in vacuo to yield the product, which was carried on directly in Step B. StepB The crude material from Step A was dissolved in 4N HCI/dioxane (2.5ml) and stirred for 2h. The reaction was concentrated in vacuo to yield the desired amine hydrochloride, which was used directly In the next step. PREPARATIVE EXAMPLES 33.3-33.47 Following the procedure set fortii in Example 33.2 but using tiie commercially available N-protected amino acids in the Table below, the amine hydrochloride products were obtained. jenzaldehyde (2.0 g. 14.2 mmol) in THF (5 mL) at 0 "C was added LiN(TMS)2 (17.0 ml, 1.0 M in THF) dropwise and the resulting solution was stin^ed for 20 min. EtMgBr (6.0 mL, 3.0 M in Et20) was added dropwise and the mixture was refluxed for 24 h. The mixture was cooled to room temperature, poured into saturated aqueous NH4CI (50 mL), and then extracted with CH2CI2 (3 X 50 volumes). The organic layers were combined, concentrated under reduced pressure. The crude residue was stin-ed with 3 M HCI (25 mL) for 30 min and the aqueous layer was extracted with CH2CI2 (3x15 mL) and the organic layers were discarded. The aqueous layer was cooled to 0 °C and treated with solid NaOH pellets until pH = 10 was attained. The aqueous layer was extracted with CH2CI2 (3x15 mL) and the organic layers were combined. The organic layer was washed with brine (1 x 25 mL), dried (Na2S04), and concentrated under reduced pressure to afford 1.6 g (66% yield) of the crude amine as an oil (MH* 170). This material was determined to be >90% pure and was used without further purification. The aldehyde (3.5g) and cone. HCI (20ml) were combined and stirred overnight at 40°C. The reaction mixture was poured into cold water and extracted with ether, washed with satd. NaHCOsand brine, dried over anhydrous MgS04, filtered and concentrated in vacuo to give 1.76g of product (55%) Chlorine was bubbled into 100ml of CH2CI2 at 10°C. The aldehyde (3.73ml) was charged with 50ml of CHCI3 and then cooled to 0*"C. AICI3 was added portionwise, followed by the chlorine solution and let stir at room temperature overnight. The reaction was poured into 150ml of ice and SOml of 3N HCl and stirred for 30min. Organic layer was washed with brine, dried with Na2S04, and concentrated in vacuo. The crude product was purified via flash column chromatography (Hex/EtOAc 40/1) to yield 1.5g of pure product. Step A The ketone (3.25g) was reacted following the procedure set forth in Preparative Example 88.2, Step B to give the oxime (3.5g, 99%). SteoB The product from step A (1.2g) was stin-ed with AcOH (3ml) and Pd/C (10%, 300mg) in EtOH (40ml) under a hydrogen atmosphere ovemight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The crude material dissolved in ether and washed with 2N NaOH, organic washed with brine, dried with Na2S04, and concentrated in vacuo to give product (960mg, 86%). To a suspension of NaH (1.45g) In DMF (25ml) under a nitrogen atmosphere was added p-bromophenol (5g) at 0°C. After stirring for 20min. BrCH2CH(OEt)2 (5.3ml) was added and the reaction was heated to reflux ovemight. The solution was was washed with 1N NaOH and brine, dried witii MgS04, filtered and concentrated in vacuo to give 8.4g of crude product (100%) StepB To a solution of the product from Step A (8.4g) in benzene {50mi) was added polyphosphoric acid (10g). The mixture was heated at reflux for 4 hrs. The reaction was cooled to 0°C and poured into ice water (80ml) and extracted with ether. The ether layer was washed with saturated sodium bicarbonate and brine, dried with MgS04, filtered and concentrated in vacuo to give 4.9g of crude product (85%) StepC To a solution of the product from Step B (2g) in ether (20ml) at -78°C was added t-BuLi dropwise. After stirring for20min, DMF (950mg) was added dropwise and the mixture was stirred at -25°C for 3hrs and then warmed to room temperature overnight. Saturated ammonium chloride was added and the solution was extracted with ether. The ether layer was washed with brine, dried with MgS04. filtered and concentrated in vacuo to give 980mg of crude product (67%). StepP To a solution of aldehyde (400g) in ether (lOml) was added LiN(TMS)2 (1M In THF, 3.3ml) at 0°C dropwise. The solution was stin-ed at O^C for 30min and EtMgBr (3M in THF. 1.83ml) was added dropwise. The reaction was refluxed overnight, cooed to 0°C, quenched with saturated ammonium chloride and extracted with ether. The ether was stirred with 3N HCI (20ml), then the aqueous layer was basified with NaOH pellets and extracted with ether. The ether layer was washed with brine, dried with MgS04. filtered and concentrated in vacuo to give 220mg of product (46%). Following the procedures set forth in Preparative Example 34.4 Steps A through D, but using m-bromophenoi (8g), both amines were formed and separated by preparative plate chromatography (63-65%. MH+=175). To a solution of 3-methyl-thiophene (5g) in ether (50ml) was added dropwise a solution of n-BuLi (1.6M in hexane, 32ml). The mixture was stirred for 1.5hr at room temperature. DMF (5.1ml) was then added and let stir overnight. The mixture was poured into saturated ammonium chloride and extracted with ether. The ether layer was washed with brine, dried with Na2S04, and concentrated in vacuo. The crude product was purified via flash column chromatography (EtOAc/Hex 20:1) to afford 5.27gofanoil(84%). >tepA To a solution of 4-bromo-2-furaldehyde (4g) in MeOH (75ml) was added rimethyl- orthoformate (3.8ml). A catalytic amount of p-toluene sulfonic acid (195mg) md the mixture was heated to reflux for 3.5hr. The reaction was cooled down and >otassium carbonate was added. The mixture was filtered through a silica gel pad. ^he filtrate was concentrated in vacuo, dissolved in CH2CI2 and filtered. The filtrate vas again concentrated in vacuo to give 4.03g of product (80%). ateoB To a solution of the product from Step A (2.02g) in THF (80ml) at -78°C was Jdded dropwise a solution of n-BuLi (2.5M in hexanes, 4.4ml) and stirred for 1.5hr. A solution of iodomethane (1.7ml) was added and let stir for 2.5hrs at -60°C. The xx)ling bath was removed and saturated ammonium chloride was added and let stir or 10min. The layers were separated and the organic layer was washed with brine, Iried with Na2S04, and concentrated in vacuo to afford 1.34g of crude product. 3tepC The product from Step B (1.43g) was dissolved in acetone (50ml) and treated vith a catalytic amount of p-toluene sulfonic acid (80mg). The mixture was heated to eflux for 2hr. The reaction was cooled down and solid potassium carbonate was idded. The mixture was filtered through a silica gel pad and the filtrate was »ncentrated in vacuo to give 1.246g of crude product. step A To a stirred solution of potassium t-butoxide (2.5g) in HMPA (20ml) was added 2-nitropropane (2ml) dropwise. After 5min, a solution of methyl-5-nitro-2-furoate (3.2g) in HMPA (8ml) was added to the mixture and stin-ed for 16hr. Water was added and the aqueous mixture was extracted with EtOAc. The EtOAc layer was washed with water, dried with MgS04, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography (Hex/EtOAc, 6:1) to yield 3.6g of product (90%). StepB To a solution of the product from Step A (3.6g) in toluene (16ml) was added tributyltin hydride (5.4ml) followed by AIBN (555mg). The mixture was heated to 85°C for 3.5hr. After cooling, the mixture was separated by flash column chromatography (Hex/EtOAc, 7:1) to afford 2.06g of product (73%). SteoC To a solution of product from Step B (2.05g) in THF (60ml) at 0°C was added a solution of l_AH (1M in ether, 12.8ml). The reaction was stirred at room temperature for 30min. Water and 1M NaOH was added until a precipitate formed, diluted with EtOAc, stirred for 30min and then filtered through a celite pad. The organic filtrate was concentrated in vacuo to give 1.56g of product (93%). To a solution of product from Step C (2.15g) in CH2CI2 (100ml) was added Dess-Martin oxidant (7.26g) in CH2CI2 (45ml) and stirred for 30min. The mixture was diluted with etfier (200ml). The organic layer was washed with 1N NaOH, water and brine, dried with MgS04, filtered and concentrated in vacuo to give oil and solid. The material was extracted with ether and filtered. Some solid crystallized out from the filtrate, filtered again, and the filtrate was concentrated in vacuo to give 2.19g of product. PREPARATIVE EXAMPLE 34.9 Step A To a solution of carlxaxylic acid (5g) in CH2CI2 (400ml) at 0°C was added N(OCH3)CH3.HCI (11.5g), DEC (15.1g), HOBt (5.3g) and NMM (43ml) and stirred for 14hr. The mixture was diluted with CH2CI2 (100ml) and the organic layer was washed with 10% HCI, saturated sodium bicartxjnate and brine, dried with Na2S04, and concentrated in vacuo to afford 5.74g of caide product (85%). StepB To a solution of iodoethane (0.56ml) in ether (5ml) at -78°C was added a solution of t-BuLi (1.7M in pentane, 8.3ml) dropwise. The mixture was warmed to room temperature for Ihr and transfen-ed to a 100ml round bottom charged with the product from Step A (1 g) in THF (12ml) at -78°C. The mixture was stin-ed at -78°C for 1 hr and at 0°C for an additional 2hr. 1M HCI was added dropwise followed by CH2CI2. The layers were separated and the organic layer was washed with brine, dried with Na2S04, and concentrated in vacuo to afford 620mg of product (76%). To a solution of the product from Step B (620mg) in THF/MeOH (10:1) at 0°C was added NaBH4 (250nng) in one portion. The mixture was stirred overnight at 0°C, concentrated in vacuo and the crude material was dissolved in CH2CI2 and washed with 1N NaOH and brine, dried with Na2S04, and concentrated in vacuo to afford 510mg of product. StgpD The above material was reacted in the procedures set forth in Preparative Example 75.75 Steps B and C to yield 170mg of amine product (28%). ,The aljove amine was made analogous to the procedures set forth in Patent W096/22997 p.56. but using ethylglycine instead of benzylglycine in the DCC coupling. step A To the nitro compound (3.14g) and cyciohexylmethanol (1.14g) jn THF (50ml) was added PPH3 (4.72g) and cooled to 0°C. Diisopropylazadicarboxylate (3.15ml) was added dropwise and let stir overnight. The reaction was concentrated in vacuo and purified via flash column chromatography (Hex/EtOAc, 30:1) to give product (3.3g), which was carried on directly to the next step. SteoB To the product from step A (3.3g) in EtOH (50ml) was added 10% Pd/C (1.7g) under a hydrogen atmosphere at 55psi and let stir overnight. The reaction was filtered through celite and concentrated in vacuo to give 3.2g of product. Step A A solution of acid (2g) in ether (20ml) was added dropwise to a suspension of LiAIH4 (350mg) in ether (15ml) at 0°C. The solution was refluxed for 3hr and stirred at room temperature ovenright. 5% KOH was added and reaction was filtered, extracted with ether, dried with MgS04, filtered and concentrated in vacuo to give the product (1.46g,79%,MH+=166). SteoB To a solution of alcohol from above (1.46g) in CH2CI2 at room temperature was added Dess-Martin reagent (5.6g) portionwise and one drop of water and let stir over the weekend at room temperature. 10% NaaSaOa was added and stin-ed for 20min, extracted with CH2CI2. washed with saturated sodium bicart)onate, dried with NaaSOA, and concentrated in vacuo to afford l.lg of product (76%). The above compound was prepared in the procedure set forth in EP Patent 0 i5153A1. The aldehyde (500mg) from above was reacted following the procedure set forth in the Preparative Example 13.4. Step A to yield 372mg of product (76%). PREPARATIVE EXAMPLES 35-51.20 Following the procedure set forth in Preparative Example 34 but using the commercially available aldehydes and Grignard reagents listed in the Table below, the amine products below were obtained. step A A mixture of 2-(trifluoroacetyl)thiophene (2 mL, 15.6 mmol), hydroxylamine hydrochloride (2.2 g, 2 eq), diisopropylethylamine (5.5 mL, 2 eq) and MeOH (50 mL) was stirred at reflux for 48-72 hrs, then concentrated in vacuo. The residue was diluted with EtOAc, washed with 10% KH2PO4 and dried over Na2S04 (anhydrous). Filtration and concentration afforded the desired oxime (2.9 g, 96%) which was used directly in Step B without further purification. SteoB To a mixture of the product from Step A above in TFA (20 mL) was added Zn powder (3 g, 3 eq) portionwise over 30 min and stirred at room temperature overnight. The solid was filtered and the mixture reduced in vacuo. Aqueous NaOH (2 M) was added and the mixture was extracted several times with CH2CI2. The organic phase was dried over anhydrous NaaSOA, filtered and concentrated to afford the desired product (1.4 g, 50%). To a cooled (O-S^C) suspension of L-a-(2-thienyl)glycine (0.5 g) and LiBH* {2M in THF. 3.8 mL) in anhydrous THF (10 mL) was slowly added a THF (5 mL) solution of iodine (0.8 g). After stirring at room temperature for 15 min, the mixture was stirred at relux overnight. After cooling to room temperature, MeOH was added dropwise until gas evolution ceased and after 30 min, the mixture was evaporated. The oily residue was stinred in 20 mL KOH for 4 hrs, diluted with brine and extracted with EtOAc. The organic phase was dried over anhydrous MgS04, filtered and concentrated in vacuo to afford a crude mixture. Purification by flash column chromatography (50% EtOAc/ CH2CI2. silica) afforded the product (0.3 g. 63%, MH* = 144). CeCl3-7H20 was dried at 140-150°C for 22 hr. To this solid was added THF (80 mL. anhydrous) and after stirring for 2 hr, the suspension was cooled to -78°C and to It was added methyl lithium over 30 min. After stirring for an additional 30 min 2-thiophenecart)onltrile dissolved in anhydrous THF (4.5 mL) was added and the resulting mixture stirred for an additional 4.5 hr at -yB"C. Concentrated aqueous NH3 (25 mL) was added and the mixture was warmed to room temperature and filtered through celite. The filtrate was extracted with dichloromethane, dried over anhydrous Na2S04. filtered and concentrated in vacuo to afford a crude mixture. Purification by flash column chromatography (5% MeOH, CH2CI2, silica) afforded the desired product (1.2 g. 62%). PREPARATIVE EXAMPLE 64 Step A To a solution of (D)-valinol (4.16 g. 40.3 mmol) in CH2CI2 (60 mL) at 0 °C was added MgS04 (20 g) followed by dropwise addition of 3-fluorobenzaldehyde (5.0 g, 40.3 mmol). The heterogenous solution was stin-ed at 0°C for 2h and was allowed to warm to room temperature and stir ovemight (14h). The mixture was filtered and the drying agent was washed with CH2CI2 (2x10 mL). The filtrate was concentrated under reduced pressure to afford 8.4 g (100%) of an oil which was taken onto the next step without further purification. SteoB To a solution of the imine (8.4 g, 40.2 mmol) from Step A in CH2CI2 (60 mL) at room temperature was added EtaN (6.2 mL, 44.5 mmol) followed by dropwise addition of TMSCI (5.7 mL, 44.5 mmol). The mixture was stirred for 6h at room temperature whereupon the ppt that had formed was filtered off and washed with CH2CI2 (2x10 mL). The combined filtrate was concentrated under reduced pressure and was taken up in Et20/hexane (1:1/150 mL). The precipitate was filtered off and the filtrate was concentrated under reduced pressure to afford 10.1 g (89%) of the protected Imine as To a solution of EtI (4.0 g, 25.6 mmol) in EtaO (40 mL) at -78 "C was added t-BuLI (30.1 mL, 51.2 mmol, 1.7 M in pentane) and the mixture was stin-ed for 10 min. The mixture was warmed to room temperature, stirred for 1 h, and was recooled to -40 "C. A solution of the imine (6.0 g, 21.4 mmol) from Step B in EtaO (30 mL) was added dropwise via addition funnel to afford a bright orange mixture. The reaction mixture was stirred for 1.5 h at -40 °C then 3M HCI (50 mL) was added and the mixture was allowed to warm to room temperature. Water (50 mL) was added and the layers were separated. The aqueous layer was extracted with Et20 (2 x 30 mL) and the organic layers were combined and discarded. The aqueous layer was cooled to 0 °C and carefully treated with solid NaOH pellets until pH = 12 was attained. The aqueous layer was extracted with Et20 (3 x 30 mL) and the combined layers were washed with brine (1 x 30 mL). The organic layer was dried (Na2S04). filtered, and concentrated under reduced pressure to afford 4.8 g (94% yield) of the amine as an oil. This material was taken on cnjde to the next step without further purification. SteoD To a solution of amine (4.5 g, 18.8 mmol) from Step C in MeOH (80 mL) at room temperature was added MeNHa (25 mL, 40% in water) followed by addition of a solution of H5IO5 (14.0 g, 61.4 mmol) in H2O (25 mL). The heterogenous mixture was stin-ed for 1.5 h (until the reaction was complete by TLC) and the precipitate was filtered off. The resulting filtrate was diluted with water (50 mL) and the mixture was extracted with Et20 (4 x 60 mL). The combined organic layers were concentrated to a volume of-30 mL whereupon 3M HCI (75 mL) was added. The mixture was stin-ed ovemight (12h at room temperature) after which the mixture was concentrated to remove the volatiles. The aqueous layer was extracted with Et20 (3 x 40 mL) and the organic layers were discarded. The aqueous layer was cooled to 0 "C and was carefully treated with solid NaOH pellets until pH -12 was reached. The aqueous layer was extracted with Et20 (3 x 60 mL) and the combined organic layers were dried (MgS04). The organic layer was concentrated under reduced pressure to afford 2.8 g (97% yield) of the desired amine as an oil [MH* 154]. This compound was proven to be >85% pure by ^H NMR and was used crude In the subsequent coupling step. step A To a solution of aldehyde (2.5g) in ether (50ml) at 0°C was added EtMgBr 4.56ml) dropwise. The heterogenous mixture was stin-ed for 2hr at 0°C and then (oured into a t)eaker of saturated ammonium chloride (25ml), ice and CH2CI2 (30ml). Vflerthe biphasic mixture stirred for 10min, the organic layer was separated, washed /ith brine, dried over NaaSOA, filtered, and concentrated in vacuo to afford the product 2.41 g. 95%) ;tepB To a solution of alcohol from Step A above (1g) in toluene at room temperature ras added DPPA. The mixture was cooled to 0°C and DBU was added and let stir for 2hr at room temperature. The layers were separated and the organic layer was fashed with water, 1N HCI and dried over NaaSOA, filtered, and concentrated in acuo. Purified by preparative plate chromatography (hexane/EtOAc 20/1) to give the roduct (840mg, 75%). StepC To a solution of azide (730mg) from Step B above in THF (7ml) was added PPha (1g). The heterogenous solution was stirred for 12hr, whereupon water {1.5ml) was added. The mixture was refluxed overnight, cooled to room temperature and concentrated in vacuo. Ether and 1N HCI were added to the residue. The aqueous layer was cooled to 0°C, basified with NaOH pellets and extracted with ether. The ether layer was dried over MgS04, filtered, and concentrated in vacuo to afford the product (405mg. 62%). SteoD To a solution of azide in THF at -10°C was added LiAIH4 portionwise. The heterogenous solution was stirred at room temperature for 1hr and then refluxed for 4hr. The solution was cooled to O^C and water, 2M NaOH and ether were added to the reaction. The mixture was filtered through a celite pad. The filtrate was treated with 3N HCI., The aqueous layer was cooled to 0°C, basified with NaOH pellots and extracted with ether. The ether layer was dried over MgS04. filtered, and concentrated in vacuo to afford the product. PREPARATIVE EXAMPLE 75.76-75.90 Following a similar procedure set forth in Preparative Example 75.75, and using the reduction procedure Indicated, the following amines were obtained. step A To a solution of amine from Preparative Example 75.90 (2.22g) in CH2CI2 (50ml) at 0°C was added TEA (3.03ml) followed by BOC2O (2.85g). The heterogenous mixture was allowed to stir at room temperature ovemight. 10% Citric acid was added to the reaction and the layers were separated. The organic layer was washed with saturated sodium bicarbonate, brine and dried with NaaSOA, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography (Hex/EtOAc 10:1) to afford 2.7g of an oil (81%). SteoB Following the procedure from Preparative Example 13.4, Step A, but using the product from Step A above (450mg) and 3-thiophene boronic acid (284mg), the product was prepared (325mg, 71%). SteoC To the product from Step B (325g) was added 4M HCI in dioxane (1.31 mi) and let stir for Ihr. The reaction was concentrated in vacuo and taken up in CH2CI2 and concentrated in vacuo again. This procedure was repeated 5 times to afford a semisolid (89%). To a solution of ketone from Step A above (500mg) in THF (5ml) at 0°C was added S-2-methyl-CBS-oxazaborolidine (0.98ml) dropwise followed by BH3.Me2S (1.48ml). The mixture was stirred at 0°C for 2hr and was allowed to warm to room temperature and stir overnight. The mixture was cooled to 0°C and treated with MeOH (10ml). After stirring for 20min, the reaction was concentrated in vacuo. The residue was dissolved In CH2CI2 and washed with 1M HCI, saturated sodium bicarbonate, water and brine, dried over Na2S04, filtered, and concentrated in vacuo. The crude material was purified by preparative plate chromatography (Hex/EtOAc 4:1) to afford 650mg of an oil (89%). StepC The chiral alcohol from Step B atxjve was reacted via the Preparative Example 75.75 Step B to give the azide. StepD The azide from Step C atxjve was reacted via the Preparative Example 75.75 Step C to give the amine product. PREPARATIVE EXAMPLE 76.11 The desired compound was prepared as in Preparative Example 76.10, but using the R-2-methyl-CBS-oxazaborolidine in step B. To a solution of carboxylic acid (1.5 g, 7.89 mmol) in HaO/acetone (1 -.10/12 mL total) at CC was added EtaN (1.43 mL, 10.3 mmol) followed by addition of ethyl chlorofonnate (0.83 mL, 8.68 mmol). The resulting mixture was stin-ed for 30 min after which a solution of NaNa (0.77g, 11.8 mmol) in H2O (2 mL) was added dropwise. The resultant heterogenous mixture was stin-ed for 1 h at 0°C, then cold water (5 mL) and EtaO (10 mL) were added. The layers were separated and the aqueous layer was extracted with EtaO (2x10 mL). The organic layers were combined, toluene (20 mL) was added, and the organic layers were dried (MgS04) and concentrated under reduced pressure to a volume of 20 mL. NBuOH (5 mL) was added and the mixture was refluxed for 12h. The mixture was concentrated under reduced pressure and the crude residue was taken up in 3M HCI (30 mL) and was heated at reflux for 12h. The mixture was cooled to room temperature and extracted with EtaO (3x15 mL). The aqueous layer was cooled to 0 °C and solid NaOH pellets were added until pH -12 was reached. The aqueous layer was extracted with Et20 (3 x 30 mL) and the combined organic layers were dried (MgS04) and concentrated under reduced pressure to afford 0.78 g (61% yield) of an oil [MH* 162]. This material was used without further purification. step A 2-Methylthiophene (3g) was dissolved in THF and cooled to -40°C. N-butyllithium (2.5M in hexane,12.24ml) added dropwise and let stir at -40°C for 30min. CuBr.(CH3)2S (6.29g) added and let warm to -25°C where the trifluoroaceticanhydride (4.32ml) was added. The reaction was stirred at -15°C over the weekend. The reaction was quenched with saturated ammonium chloride and extracted with EtOAc. The organic layer washed with brine, dried with MgS04, filtered and concentrated in vacuo to give 4.59g of an oil (78%). StepB The product from Step A (4.58g), hydroxylamine hydrochloride (3g), sodium acetate (4.4g), EtOH (75ml) and H2O (7.5ml) were combined and heated to 75°C overnight. The reaction was concentrated in vacuo , taken up 1N HCI, extracted with ether, dried with MgS04, filtered and concentrated in vacuo to give 4.58g of the product (93%. MH+=210). StepC The product from Step B above (4.5g) was dissolved in TFA (40ml) and cooled to 0°C. Zn powder (4.2g) was added portionwise and let reaction warm to nDom temperature and stir overnight. The reaction was concentrated in vacuo, taken up in 1N NaOH. extracted with ether, dried with MgS04, filtered and concentrated in vacuo to give 3.43g of the product (80%). StepD The product from Step C (526mg), 3,4-diethoxy-3-cyclobutene-1,2-dione (0.4ml) and absolute EtOH (10ml) was stirred at room temperature overnight. Purification by preparative plate chromatography (10% EtOAc/Hex) to give 178mg of product (21%. MH+=320). Following a similar procedure as described in Preparative Example 88.2, but instead using 2-methylfuran, the above cyclobutenedione intermediate was prepared. The amine from Preparative Example 75.1 (973mg) and the dimethoxysquarate (870mg) were dissolved in MeOH (20ml) and stin-ed for 3 days. The reaction was concentrated in vacuo and purified via flash column chromatography (MeOH/CH2Cl2, 1%) to yield 325mg of product (19%. MH+=249.8). The amine from Preparative Example 75.9 (323mg) and the dimethoxysquarate (426mg) were dissolved In MeOH (10ml) and stirred over the weekend. The reaction was concentrated in vacuo and purified via flash column chromatography (MeOH/CH2Cl2. 1:20) to yield 407mg of product (57%. MH+=235.8). To a solution of KH (0.45 g, 11.3 mmol) in THF (15 mL) at room temperature was added amine hydrochloride (0.85 g, 5.1 mmol) portionwise to afford a heterogenous reaction mixture. The mixture was allowed to stand overnight (12h) and Mel (0.32 mL, 5.1 mmol) was added dropwise. The mixture was stirred for 6h after which the mixture was carefully poured into cold brine (125 mL). The mixture was extracted with EtaO (3 x 25 mL) and the organic layers were combined. The organic layer was dried (NaaSO*), filtered, and concentrated under reduced pressure to afford the crude product as an oil. This material was carried on crude to the coupling step without ftjrther purification or characterization. To a solution of KH (l.lg) in THF (20ml) at room temperature was added (R)-2-amino-1-butanol 48ml) dropwise to afford a heterogenous mixture. The mixture was allowed to stand overnight (18hr) and then Mel (1.59ml) was added dropwise. The mixture was stirred for 4hr after which brine was added. Extracted with ether, dried with K2CO3, filtered and concentrated in vacuo to afford 1.75g of an oil. To a solution of KH (1.1g) in THF (20ml) at room temperature was added (S)-2-amino-1-butanol 48ml) dropwise to afford a heterogenous mixture. The mixture ivas allowed to stand ovemight (18hr) and then Mel (1.59ml) was added dropwise. rhe mixture was stirred for 4hr after which brine was added. Extracted with ether, Iried with K2CO3, filtered and concentrated in vacuo to afford 1.75g of an oil. The corresponding cis analog was prepared in an analogous fashion utilizing le procedure described in Preparative Example 89. This material was also used rithout further purification. The desired compound was prepared according to methods previously 3scribed In J. Org. Chem. 1987. 52,4437-4444. A Lithium hexamethyldisilylazide (34 mL, ^M in THF) was added dropwise to a -; THF (20 mL) solution of isobutyronitrile (2.8 mL). After 40 min, (propylmethylbromide (5 g) was added and tlie mixture warmed to and stinted at : ovemight. After cooling to 0°C, IM HCI (aq) was added and the mixture was cted with diethyl ether, dried over anhydrous Na2S04. filtered and concentrated in 0 at O^C to give the desired product (4.5 g). B Methyl Lithium (17 mL, 1.4 M in EtaO) was added to the product from Step A e (1.5 g) in EtaO (anhydrous) at 0°C. The mixture was stirred at 0-25°C light, then diluted with 3M HCI (aq), extracted with CH2CI2, dried over anhydrous ;04, filtered, concentrated in vacuo at CC and used directly in Step C. C The product from Step B above was added to a slurry of NaBH4 (1.4 g) in opanol (50 mL) at O"C, then the mixture was stirred at reflux for 8 hr and at room erature for 48 hrs. Water was added and the mixture was stirred for 30 min, then cted with diethyl ether, dried over anhydrous Na2S04, filtered and concentrated in 0. The residue was diluted with CHaC^and extracted with 3M HCI. The organic 3 was discarded and the aqueous phase was basified with NaOH (aq) and cted with CH2CI2. Drying over anhydrous Na2S04, filtering, and concentration in ?gav step A 2-Thiophenecarbonyl chloride (2.0mL, 18.7mmol) was dissolved in lOOmL dichloromethane. After addition of diisopropylethylamine (4.1 mL, 23.4mmol) and Boc-plperazine (3.66g, 19.7mmol), the mixture was stirred for 4h at room temperature. The resulting mixture was put into water (500mL) and acidified with 3N HCI to pH~1. Extraction with dichloromethane (2x100mL) and drying over sodium sulfate resulted in sufficiently pure product that was used in the next step without any further purification. ^H NMR (300MHz, ds-DMSO) 1.60 (s, 9H), 3.29 (dd. 4H), 3.69 (dd. 4H). 7.23 (dd, 1H). 7.49 (d, 1H).7.79(d. 1H). SteoB The crude material from Step A was dissolved in trifluoroacetic acld/dichloromethane (75mL, 4/1). After stirring for 2h, the reaction mixture was put into IN sodium hydroxide (400mL). Extraction with dichloromethane (2x100mL) and drying over sodium sulfate resulted in sufficiently pure product that was used in Step C without any further purification. ^H NMR (300MHz. de-DMSO) 2.81 (dd. 4H), 3.63 (dd, 4H). 7.21 (dd. 1H), 7.46 (d. 1H). 7.82 (d. 1H). StepC The crude material (3.50g, 17.8mmol) from Step B was dissolved in dichloromethane (lOOmL). After addition of diisopropylethylamine (18.7mL, 107mmol), 3-nitrosalicylic acid (3.3g. 18.0mmol), and PyBrOP (10.4g. 22.3mmol), the resulting mixture was stirred over night at room temperature before being put into 1N sodium hydroxide (200mL). Extraction with dichloromethane (2x200mL) removed all PyBrOP by-products. The aqueous phase was acidified with 3N HCI and subsequently extracted with dichloromethane (3x lOOmL). The combined organic phases of the acidic extraction were dried over sodium sulfate, concentrated, and finally purified by column chromatography (dichloromethane/methanol = 10/1) to yield the desired product (2.31g. 34 % over 3 steps). ^H NMR (300MHz, de-DMSO) 3.30-3.90 (m, 8H), 7.10-8.20 (m, double signals due to E/Z-isomers, 6H). 10.82 (s, 1H). SteoD The nitro-compound (2.3g, 6.4mmol) from Step C was dissolved in methanol (50mL) and stirred with 10% Pd/C under a hydrogen gas atmosphere over night. The reaction mixture was filtered through Celite and washed thoroughly with methanol. Finally, the filtrate was concentrated in vacuo and purified by column chromatography (dichloromethane/methanol = 10/1) to yield the desired product (1.78g, 84%). ^H NMR (300MHz. dg-DMSO) 3.30-3.90 (m. 8H), 7.22 (m. 2H). 7.55 (d. 1H), 7.71 (d, 1H), 7.88 (d. 1H). 8.15 (d, 1H), 10.85 (bs, 1H). step A Picolinic acid (3.0g, 24.3mmol) was suspended in SOCI2 (ISmL). After addition of dimethylformamide (5 drops), the reaction mixture was stirred for 4 hours. Evaporation of the solvent yielded the corresponding acid chloride as HCI-salt. Without any further purification, the solid was suspended in 120mL dichloromethane. After addition of diisopropylethylamine (12.7mL, 73mmol) and Boc-piparazine (4.8g, 25.5mmol), the reaction was stirred over night at room temperature. The resulting mixture was put into water (500mL) and extracted with dichloromethane (2x100mL). Drying over sodium sulfate resulted in sufficiently pure product that was used in Step B without any further purification. ^H NMR (300MHz, de-DMSO) 1.63 (s. 9H). 3.21 (dd, 4H), 3.61 (dd, 4H). 7.57 (dd, 1H), 7.63 (d, 1H). 7.98 (dd, 1H), 8.70 (d, 1H). Steps The crude material from Step A was dissolved in trifluoroacetic acid/dichloromethane (75mL, 4/1). After stirring for 2days, the reaction mixture was put into IN sodium hydroxide (400mL). Extraction with dichloromethane (2x100mL) and drying over sodium sulfate resulted in sufficiently pure product that was used in Step C without any ftjrther purification. ^H NMR (300MHz, de-DMSO) 2.77 (dd. 2H), 2.83 (dd. 1H). 3.38 (dd, 2H). 3.64 (dd. 1H). 7.58 (dd, 1H), 7.62 (d, 1H). 8.00 (dd, 1H), 8.67 (d.lH). StepC The crude material (1.35g, 7.06mmol) from Step B was dissolved in dichloromethane (50mL). After addition of diisopropylethylamine (3.7mL, 21.2mmol). 3-nitrosallcylic acid (1.36g, 7.41 mmol), and PyBrOP (3.62g. 7.77mmol), the resulting mixture was stirred over night at room temperature before being put into 1N sodium hydroxide (300mL). Extraction with dichloromethane (2x100mL) removed any PyBrOP products. The aqueous phase was acidified with 3N HOI. Adjustment of the pH with saturated sodium carbonate solution to almost neutral crushed the desired compound out of solution. The aqueous phase was subsequently extracted with dichloromethane (3x lOOmL). The combined organic layers of the neutral extraction were dried over sodium sulfate, concentrated, and finally purified by column chromatography (dichloromethane/methanol = 20/1) to yield the desired product (1.35g, 16% over 3 steps). ■"H NMR (300MHz, ds-DMSO) 3.30-3.95 (m, 8H). 7.22 (m. 1H). 7.61 (m, 1H), 7JZ (d, 2H). 8.03 (m, 1H). 8.17 (m, 1H), 8.69 (m, 1H). 10.82 (s, 1H). 3tepD The nitro-compound (1.35g, 3.79mmol) from Step C was dissolved in methanol 60mL) and stin-ed with 10% Pd/C under a hydrogen gas atmosphere over night. The eaction mixture was filtered through Celite and washed thoroughly with methanol, ■inally, the filtrate was concentrated in vacuo and purified by column chromatography dichloromethane/methanol = 20/1) to yield the desired product (1.1 Og, 89 %). ^H MR (300MHz, de-DMSO) 3.50-3.85 (m, 8H), 6.47 (dd 1H). 6.74 (m, 2H), 7.59 (dd, H), 7.71 (d, 1H), 8.04 (dd, 1H), 8.68 (d, 1H). step A 1-Methyl-2-pyrrolecarboxylic acid (2.5g, 20.0mmol) was dissolved in dichloromethane (50mL). After addition of PyBrOP (16.3g, 35.0mmol), diisopropylethylamine (14.0mL, 73.0mmol) and Boc-piparazine (5.5g, SO.Ommol), tiie reaction was stin-ed over night at room temperature before being put into 1N sodium hydroxide (200mL). Extraction with dichloromethane (2x100mL) removed all PyBrOP by-products. The aqueous phase was acidified with 3N HCI. Adjustment of the pH with saturated sodium cartx>nate solution to almost neutral precipitated the desired compound. The aqueous phase was subsequently extracted with dichloromethane (3x lOOmL). The combined organic phases of the neutral extraction were dried over sodium sulfate. Removal of the solvent resulted in sufficiently pure product that was used in Step B without any further purification. ^H NMR (300MHz, de-DMSO) 1.59 (s, 9H) 3.21 (dd. 4H), 3.61 (dd, 4H). 3.74 (s, 3H). 6.11 (dd, 1H). 6.33 (d, 1H). 7.01 (d. 1H). SteoB The crude material from Step A was dissolved in trifluoroacetic acid/dichloromethane (75mL, 4/1). After stirring for 3h, the reaction mixture was put into IN sodium hydroxide (400mL). Extraction with dichloromethane (3x100mL) and drying over sodium sulfate resulted in sufficiently pure product that was used in Step C without any further purification. ^H NMR (300MHz, de-DMSO) 2.79 (dd. 4H), 3.62 (dd. 4H). 3.76 (s. 3H). 6.11 (dd, 1H), 6.37 (d. 1H), 6.96 (d, 1H). SteoC The crude material (3.15g, 16.3mmol) from Step B was dissolved in dichloromethane (lOOmL). After addition of diisopropylethylamine (8.5mL, 49.0mmol), 3-nitrosalicylic acid (3.13g. 17.1 mmol), and PyBrOP (9.11g. 19.6mmol), the resulting mixture was stirred over night at room temperature before being put into 1N sodium hydroxide (400mL). Extraction with dichloromethane (2x100mL) removed all PyBrOP products. The aqueous phase was then carefully acidified with 3N HCI until the color of the solution changes from orange to yellow and the desired compound crashed out of solutton. The aqueous phase was subsequently extracted with dichloromethane (3x lOOmL). The combined organic layers of the acidic extraction were dried over sodium sulfate and concentrated in vacuo to yield the desired product. ^H NMR (300MHz, de-DMSO) 3.35-3.85 (m, 8H). 3.79 (s, 3H), 6.13 (dd. 1H), 6.45 (d, 1H), 7.01 (s, 1H). 7.22 (dd. 1H), 7.70 (d, 1H). 8.16 (d, 1H), 10.83 (s, 2H). SteoD The crude nitro-compound from Step C was suspended in methanol (60mL) and stinred with 10% Pd/C under a hydrogen gas atmosphere over night. The reaction mixture was filtered through Celite and washed thoroughly with methanol. The filtrate was concentrated in vacuo and purified by column chromatography (dichloromethane/methanol = 10/1) to yield the desired product (2.61 g, 40 % for 4 steps). ^H NMR (300MHz, de-DMSO) 3.45-4.80 (m, 8H). 3.79 (s. 3H). 6.17 (dd, 1H). 6.45 (m. 2H), 6.78 (m, 2H), 7.01 (d, 1H). step A 2-Bromopyricline N-oxide hydrochloride (1.13g, 5.37mmol) and Boc-piperazine (1.50g. 8.06mmol) were heated to 80° C in pyridine (10mL) over night. The reaction nnlxture was put into water (300mL) and then extracted with dichloromethane (2x100mL). The combined organic phases were dried over sodium sulfate, concentrated, and finally purified by column chromatography (dichloromethane/methanol = 10/1) to yield the desired product (500mg, 33 %). ^H NMR (300MHz. d-CDCb) 1.60 (s. 9H). 3.46 (dd. 4H), 3.78 (dd, 4H), 6.99 (m. 2H). 7.37(dd. 1H),8.33(d. 1H). StepB The purified product (500mg, 1.79mmol) was stirred for 30 min with 4N HCI/dioxane (15mL). Evaporation of the solvent yielded the crude amine (465mg) as multiple HCl-salt which was used in Step C without any further purification. ^H NMR (300MHz. dg-DMSO) 3.38 (m. 4H), 4.81 (m, 4H). 7.34 (dd, 1H). 7.55 (d, 1H). 7.86(dd, 1H).8.55(d. 1H). StepC The aude material (370mg, 1.48mmol) from Step B was suspended in dichloromethane (20mL). After addition of diisopropylethylamine (2.6mL. 14.8mmol). 3-nitrosalicylic acid (406mg, 2.22mmol), and PyBrOP (1.21g. 2.59mmol), the mixture was sfirred over night at room temperature before being put into 1N sodium hydroxide (50mL). Extraction with dichloromethane (2x50mL) removed ail PyBrOP products. The aqueous phase was then carefully acidified (pH ~ 4-5) with 3N HCI and extracted with dichloromethane (3x 50mL). The combined organic layers of the acidic extraction were dried over sodium sulfate, concentrated in vacuo and purified by column chromatography (dichloromethane/methanol = 10/1) to yield the desired product (330mg, 65%). LCMS calculated: 344.1, found: (M+1 )* 345.1 StepD Sodium hydrosulfite (1.05g) was dissolved in water (3.0mL) to yield a 1.5N solution. Addition of dioxane (3.0mL) was followed by injection of cone, amnnonium hydroxide (0.60mL, yields a 1 .ON concentration). After addition of the nitro-compound (lOOmg, 0.29mmol), the reaction mixture was stinted forO.Sh. Subsequently, the solvent was removed and the residue suspended in dichloromethane/methanol (10/1). Filtration through Celite removed most of the salts. Final purification by column chromatography (dichloromethane/methanol = 5/1) yielded the desired product (68mg, 75%). LCMS calculated: 314.14. found: (M+1)* 315.1 Step A 4-Bromopyridine hydrochloride (3.0g, 15.4mmol) was dissolved In water (15mL). After addition of N-benzylpiperazine (14.8mL, 85.0mmol) and 500mg copper sulfate, the reaction mixture was heated overnight to 140° C. The resulting product was extracted with ether (5x75mL), dried over sodium sulfate and concentrated. Final purification by column chromatography (dichloromethane/methanol/NH40H = 10/1/0.1) yielded the desired product (2.16g. 55%). ""H NMR (300MHZ, d-CDCIa) 2.68 (dd, 4H), 3.45 (dd. 4H), 6.76 (d. 2H). 7.40 (m, 5H), 8.38 (d. 2H). StepB The benzylamine (2.16g, 8.54mmol) from Step A, ammonium fomiate (2.71g, 43.0mmol) and Pd(C) (10%, 1 .Og) was suspended in methanol (50mL) and refluxed for 3h. The palladium was filtered off and the filtrate was concentrated. The sufficiently pure product was used in Step C without any further purification. ^H NMR (300MHz, d-CDCIa) 2.48 (bs, 1H). 3.13 (dd. 4H), 3.41 (dd, 4H), 7.78 (d, 2H), 8.39 (d, 2H). SteoC The crude material (1.15g, 7.06mmol) from Step B was dissolved in dichloromethane (50mL). After addition of diisopropylethylamine (4.7mL, 42.4mmol), 3-nitrosalicylic acid (1.94g, lO.Smmol), and PyBrOP (5.78g, 12.3mmol), the resulting mixture was stirred over night at room temperature before being put into 1N sodium hydroxide (300mL). Extraction with dichloromethane (2x100mL) removed all PyBrOP products. The aqueous phase was carefully acidified to pH - 5-6 with 3N HCI and extracted with dichloromethane (3x 10OmL). The combined organic layers of the neutral extraction were dried over sodium sulfate, concentrated, and finally purified by column chromatography (dichloromethane/methanol/NH40H = 10/1/0.1) to yield the desired product (850mg, 37% for 2 steps). StepD The nitro-compound (850mg, 2.59mmol) from Step C was dissolved in methanol (40mL) and stirred with 10% Pd/C under a hydrogen gas atmosphere over night. The reaction mixture was filtered through Celite and washed thoroughly with methanol. Finally, the filtrate was concentrated in vacuo and purified by column chromatography (dichloromethane/methanol/ NH4OH = 10/1/0.1) to yield the desired product (650g. 84 %). ^H NMR (300MHz, de-DMSO) 3.40-3.75 (bm. 8H). 6.49 (dd. 1H). 6.76 (m, 2H). 6.93 (d, 2H). 8.28 (d. 2H). Stepi N,N"-Dibenzyl-ethane-1,2-diamine (20mL, 0.0813mol), triethylamine (22.66mL, 0,1626mol) and benzene (lOOmL) were combined in a round bottom flask. A solution of 2.3-dibromo-propionic acid ethyl ester (11.82mL, 0.0813mol) in benzene (50mL) was added dropwise. The solution was refluxed over night and monitored by TLC (20% ethyl acetate/hexane). The reaction was cooled to room temperature, then filtered and washed with benzene. The filtrate was concentrated then purified by column chromatography (15% ethyl acetate/hexane). The product was isolated as an oil (25.42g. 0.0752mol. 92%). MS: calculated: 338.20, found: 339.2 ^H NMR (300 MHz. CDCI3) 1.23 (t. 3H), 2.48 (m, 3H). 2.62 (m, 1H), 2.73 (m. 1H), 3.07 (m. 1H). 3.30 (m. 1H). 3.42 (d. 1H), 3.56 (m, 2H). 3.91 (d, 1H), 4.17 (m. 2H). 7.27 (m, 10H). Step 2 In a Parr shaker vessel, the ester (25.43g, 0.075mol) and methanol (125mL) were combined. The vessel was purged with argon and palladium catalyst (5% on carbon, 2.5g) was added. The system was shaken under an atmosphere of hydrogen overnight. TLC (20% ethyl acetate/hexane) indicated that reaction was complete. The reaction mixture was filtered through a pad of Celite and washed with methanol. The filtrate was concentrated and the product isolated as a solid (11.7g, 0.074mol, 98%). MS: calculated: 158.11, found: 159.2 ^H NMR (300 MHz, CDCI3) 1.27 (t, 3H), 2.70 (m, 4H). 2.96 (m, 1H), 3.13 (dd, 1H), 3.43 (dd. 1H), 4.18 (m, 2H). Plperazine-2-carboxylic acid ethyl ester (3.11g, 0.0197mol), diisopropylethylamlne (5.15mL, 0.0296mol) and methylene chloride (2G0mL) were combined in a round bottom flask. While stirring at room temperature, a solution of N,N-dimethylcarbamoyl chloride (1.81mL, 0.0197mol) in methylene chloride (20mL) was added dropwise. The reactton was stirred for one hour. After this time the reaction was concentrated and carried on to the next step without further purification. (99% yield). MS: calculated: 229.14, found:230.1 ^H NMR (300 MHz, CDCI3) 1.30 (t. 3H), 2.85 (s. 6H), 3.10 (m, 3H). 3.31 (m. 2H). 3.60 (m, 2H). 4.21 (q, 2H). PREPARATIVE EXAMPLE 103-104 Following the procedure described for Example 102, the Products listed in the table below were prepared using the commercially available chloride shown and piperazlne-2-carboxylic acid ethyl ester from Preparative Example 101. ep1 3-Nitrosalicylic acid (3.61g, 0.0197g), DCC (2.03g, 0.0099mol) and ethyl etate (130mL) were combined in a round bottom flask and stirred for 15min. 4-methylcarbamoyl-piperazine-2-carboxyilc acid ethyl ester (4.51 g, 0.0197g) was ded, and the reaction was stirred for 72 hours. The reaction mixture was ncentrated then dissolved in dichloromethane. The organic phase was washed ce with 0.1 N sodium hydroxide. The aqueous phase was back extracted once with jhloromethane. The aqueous phase was acidified and wash three times with ethyl etate. The aqueous phase was concentrated and purified by column romatography (5% methanol/DCM). >: calculated: 394.15, found:395.0 NMR (300 MHz. CDCI3) 1.32 (t, 3H). 2.86 (m. 7H). 3.15 (m, 1H). 3.51 (m, 4H), 4.24 . 3H). 7.15 (m, 1H), 7.66 (m. 1H). 8.20 (m, 1H). 10.86 (bs. 1H). 4-Dimethylcarbamoyl-1-(2-hydroxy-3-nitro-benzoyl)-piperazine-2-carboxyiic acid ethyl ester (0.80g, 0.002mol) and methanol (50mL) were combined in a round bottom flask. The system was purged with argon. To the solution was added 5% palladium on carbon (-lOOmg). The flask was purged with hydrogen and stirred overnight. The reaction was filtered through a pad of celite and washed with methanol. The material was concentrated then purified by column chromatography (6% methanol/DCM). Isolated product (0.74g, 0.002mol, 100%). MS: calculated: 364.17, found:365.1 ^H NMR (300 MHz. CDCI3) 1.27 (t. 3H), 2.85 (m, 8H), 3.18 (1H), 3.45 (m, 3H), 4.19 (m, 3H). 3.90 (m, 3H) step3 1-(3-AmJno-2-hydroxy-benzoyl)-4-dimethylcarbamoyl-piperazine-2-carboxylic acid ethyl ester (0.74g, 0.002inol) was suspended in a solution of dioxane (lOmL) and water (10mL). Lithium hydroxide (0.26g, 0.0061 mol) was added and the mixture stirred for two hours. The solution was acidified to pH=6 with 3N HCl then extracted with butanol. The extracts were combined, dried over sodium sulfate and concentrated. MS: calculated: 336.14, found:337.1 ^H NMR (300 MHz, CD3OD) 2.86 (m, 7H). 3.23 (m, 3H), 3.54 (m, 3H). 6.92 (m. 2H), 7.23 (m.1H). PREPARATIVE EXAMPLE 106-107 Following the procedure described for Example 105, the Products listed in the table below were prepared using the amine from the Preparative Example indicated and 3-nitrosalacylic acid. step A 3-Nitrosalicylic acid (1 .Og, 5.5mmol) was dissolved in ethyl acetate (20mL). 1,3-Dicyclohexylcarbodiimide (0.568g, 2.8mmol) was added and the mixture was stin"ed for approximately 10 minutes and cooled to 0°C. During this time a precipitate formed. Azetidine (0.39mL, 5.8mmol) was added and the reaction was stirred overnight and allowed to warm to room temperature. After this time the reaction was cooled to 0°C and filtered. The collected solid was washed with chilled ethyl acetate. The filtrate was concentrated and purified by column chromatography (80% EtOAc/Hex) to give the product (476mg. 39.0%). ^H NMR (300 MHz, CDCI3) 62.40(m. 2H). 4.38(m, 4H), 6.97(m. 1H). 7.62(d. 1H). 8.12(d, 1H). 12.88(m, 1H) ppm. The nitro compound (0.48g, 2.1mmol) from Preparative Example 32 Step A was dissolved in methanol (25ml) and stirred with 10% Pd/C under a hydrogen gas atmosphere overnight. The reaction mixture was filtered through celite, the filtrate concentrated in vacuo to give the product (344mg, 90%). ^H NMR (300 MHz, CDCI3) 52.52(m. 2H). 4.57(bs. 4H), 6.75(m, 1H). 6.90(m, 2H). 12.71(bs, 1H) ppm. In essentially the same manner as described in Preparative Example 108 above, the morpholino-amine product was obtained. Piperazlne (4.9g, 0.057mol) was dissolved in dichloromethane (lOOmL). N,N"-Dimethylcarbamoyl chloride (I.OmL, 0.011mol) was added dropwise to the solution at oom temperature. The reaction was stirred for one hour. After this time 1N )Otassium hydroxide (200mL) was added. The layers were separated and the iqueous layer was extracted three times with dichloromethane. The organic fractions vere combined and dried over sodium sulfate. Filtration and concentration provided he product, without further purification, as an oil (1.16g, 13%). H NMR (CDCI3, 300 MHz) 1.95 (s, 1H), 2.83 (s. 6H), 2.86 (m. 4H). 3.20 (m, 4H). /IS: calculated: 157.12, found: 158.1. Piperazine (4.9g, 0.057mol) was dissolved in 1N HCI (lOOmL). A solution of phenyisulfonylchloride (1.45mL, 0.011mol) in acetonitrile (25mL) was added dropwise to the solution at room temperature. The reaction was stirred for 30 minutes. After this time the reaction was extracted two times with ethyl acetate. The solution was then made basic with 1N potassium hydroxide and extracted three times with dichloromethane. The dichloromethane fractions were combined and dried over magnesium sulfate. Filtration and concentration provided the product, without further purification, as a solid (1.22g, 9.4%). ^H NMR (CDCI3, 300 MHz) 2.94 (m, 8H), 7.56 (m, 3H). 7.76 (m. 2H). MS: calculated: 226.08. found: 227.1. Piperazine (4.9g, 0.057mol) was dissolved in dichloromethane (lOOmL). Methanesulfonyl chloride (0.85mL, 0.011 mol) was added dropwise to the solution at room temperature. The reaction was stirred for 30 minutes. After this time 1N potassium hydroxide (200mL) was added. The layers were separated and the aqueous layer was extracted three times with dichloromethane. The organic fractions were combined and dried over sodium sulfate. Filtration and concentration provided the product, without further purification, as a solid (1.07g, 11 %). ^H NMR (CDCI3. 300 MHz) 1.75 (s. 1H), 2.78 (s, 3H). 2.97 (m, 4H). 3.20 (m. 4H). MS: calculated: 164.06, found: 165.1. step A Boc-Piperazine (3.0g, 0.0161 mol) was dissolved in dichloromethane (1 OOmL). Propylisocyanate (1.51mL, 0.0161 mol) was added to the solution at room temperature. The reaction was stirred for over night. After this time the reaction was diluted with 1N potassium hydroxide (200mL) and extracted six times with dichloromethane. The organic fractions were combined and dried over magnesium sulfate. Filtration and concentration provided the product as a solid. SteoB The product of Step A above, was dissolved in a 30% trifluoroacetic acid/dichloromethane solution and stirred overnight. After this time a IN potassium hydroxide solution (200 mL) was added to the reaction. The aqueous layer was extracted a total of six times with dichloromethane. The organic fractions were combined and dried over sodium sulfate. Filtration and concentration provided the product (1.37g. 50%). ^H NMR (CDCI3. 300 MHz) 0.92 (t, 3H). 1.52 (m, 2H), 2.89 (m, 4H), 3.01 (s. 1H). 3.18 (m, 2H), 3.37 (m. 4H), 4.61 (bs. 1H). MS: calculated: 171.14. found: 172.0. Piperazine (4.9g, 0.0569mol) was dissolved in IN HCI (70mL). A solution of phenylchloroformate (1.43mL, 0.0114mol) in acetonitrile (25mL) was added dropwise to the solution at room temperature. The reaction was stirred for 30 minutes. After this time the reaction was extracted two times with ethyl acetate. The solution was then made basic with 1N potassium hydroxide and extracted three times with dichloromethane. The dichloromethane fractions were combined and dried over magnesium sulfate. Filtration and concentration provided the product, without further purification, as a solid (2.12g, 18%). ^H NMR (CDCI3. 300 MHz) 1.78 (s. 1H), 2.91 (m, 4H). 3.59 (m, 4H). 7.11 (2H), 7.19 (m. 1H).7.36(m. 2H). MS: calculated: 206.24. found: 207.1. PREPARATIVE EXAMPLE 115-117 Following the procedure described for Example 112, the Products listed in the table below were prepared using the commercially available chlorofomnate shown and piperazine. PREPARATIVE EXAMPLE 118 O » K/—\ O 1. Step A ^^"^K.^DL, ^v ;NH * ci-J-Ph —-^ „MO v^y CI Ph 2. StepB HN^ PREPARATIVE EXAMPLE 118 O » K/—\ O 1. Step A ^^"^K.^DL, ^v ;NH * ci-J-Ph —-^ „MO v^y CI Ph 2. StepB HN^ Step A Boc-Piperazine (3.01g, 0.0161 mol) was dissolved in dichloromethane (lOOmL) along with diisopropylethylamine (5.61 mL, 0.0322mol). Benzoylchloride (1.87mL, 0.0161 mol) was added dropwise to the solution at room temperature. The reaction was stirred for several hours. After this time the reaction was concentrated and the product was purified by column chromatography (10% MeOH/DCM). Boc-Protected product was isolated as a solid (5.21g). ^H NMR (CDCI3. 300 MHz) 1.47 (s, 9H). 3.45 (m, 8H), 7.41 (m, 5H). MS: calculated: 290.16, found: 290.8. StepB The product from Step A above, was dissolved in a 50% trifluoroacetic acid/dichloromethane solution and stirred overnight. After this time the reaction was diluted with 1N potassium hydroxide (200mL) and the organic layer was separated. The aqueous phase was then extracted six times with dichloromethane. The organic fractions were combined and dried over magnesium sulfate. Filtration and concentration provided product (2.93g). ^H NMR (CDCI3. 300 MHz) 1.92 (s, IN), 2.87 (m, 4H), 3.52 (m, 4H). 7.39 (s, 5H). MS: calculated: 190.11, found: 191.1. step A Boc-Piperazine (3.0g, 0.0161 mol) was dissolved in dichloromethane (lOOmL) along with dlisopropylethylamine (3.1mL, 0.0177mol). N.N"-dimethyisulfamoyl chloride (1.73mL, 0.0161 mol) was added dropwise to the solution at room temperature. The reaction was stirred for several hours. After this time the reaction was diluted with water (lOOmL). The layers were separated and the aqueous layer was extracted six times with dichloromethane. The organic fractions were combined and dried over magnesium sulfate. Filtration and concentration provided the product, without further purification, as a solid (4.53g). ^H NMR (CDCI3. 300 MHz) 1.47 (s. 9H), 2.84 (s. 6H), 3.21 (m. 4H). 3.48 (m. 4H). MS: calculated: 293.14, found: 194.1 (M-Boc)*. SteoB The product from Step A above, was dissolved in a 30% trifluoroacetic acld/dichloromethane solution and stirred overnight. After this time the reaction was diluted with water and IN potassium hydroxide was used to make the aqueous layer slightly basic. The aqueous layer was extracted a total of seven times with dichloromethane. The organic fractions were combined and dried over sodium sulfate. Filtration and concentration provided the product (2.96g). ^H NMR (CDQa. 300 MHz) 2.03 (s, 1H), 2.83 (s. 6H), 2.92 (m. 4H), 3.23 (m. 4H). MS: calculated: 193.09, found: 194.1. In essentially the same manner as that described in Preparative Example 105, Step 1, using 3-nitrobenzoic acid Instead of 3-nitrosalicylic acid, the methyl ester product was prepared. The methyl ester (1.79g, 6.1mmol) from Step A above, was dissolved in d"loxane/water (20ml_/15mL) at room temperature. Lithium hydroxide (0.258g, 6.2mmol) was added to the solution. After a few hours more lithium hydroxide was added (0.128g, S.Ommol) and the reaction was stirred for another hour. After this time the reaction was concentrated and then taken up in water. The solution was extracted two times with ether. The aqueous phase was then acidified and extracted three times with ethyl acetate. The organic fractions were then dried over sodium sulfate, filtered and concentrated. Product was isolated by column chromatography (95% EtOAc/Hex. 0.05% HOAc) to give the product (1.66 g. 98%) ^H NMR (300 MHz. CDCI3) 1.49(m, 2H). 1.68(m. 1H). 1.82(m. 2H), 2.44(m. 1H) 3.32(m, 1H), 3.58(m. 1H). 5.57(m. 1H). 7.65(m. 1H). 7.80(m. 1H), 8.32(m. 2H). 10.04(bs, IHppm). The nitro compound was dissolved in an excess of methanol (20mL) and covered by a blanket of argon. 5% Palladium on carbon was added (catalytic) and a hydrogen balloon was attached to the flask. The atmosphere of the system was purged under vacuum and replaced with hydrogen. This step was repeated for a total of three times. The reaction was then stin-ed under hydrogen overnight. After this time the balloon was removed and the solution was filtered through celite followed by several rinses with methanol. The filtrate was concentrated and dried on the vacuum line to provide the desired aniline product (1.33 g, 90%). ^H NMR (300 MHz, CDCI3) 1.40(m, 2H). 1.50(m. 1H), 1.68(m. 2H). 2.33(m, 1H) 3.18{m. 1H), 3.62(m. 1H), 5.39(m, 1H), 6.12(bs, 2H), 6.75(m. 2H). 7.12(m, 1H)ppm. Mass Spectra, calculated: 248, found: 249.1 (M+lf step A 3-Nitrosalicylic acid (500 mg, 2.7 mmol). 1,3-dicyclohexylcarbodiimide (DCC) (563 mg) and ethyl acetate (10 mL) were combined and stirred for 10 min. {R)-{-)-2-pyrrolidinemetfianoi (0.27 mL) was added and the resulting suspension was stirred at room temperature overnight. The solid was filtered off and the filtrate was either concentrated down and directly purified or washed with IN NaOH. The aqueous phase was acidified and extracted with EtOAc. The resulting organic phase was dried over anhydrous MgS04, filtered and concentrated in vacuo. Purification of the residue by preparative plate chromatography (silica gel, 5% MeOH/CHaCb saturated with AcOH) gave the desired compound (338 mg. 46%, MH* = 267). SteoB The product from Step A above was sfirred with 10% Pd/C under a hydrogen gas atmosphere ovemight. The reaction mixture was filtered through celite, the filtrate concentrated in vacuo, and the resulting residue purified by column chromatography (silica gel, 4% MeOH/CH2Cl2 saturated with NH4OH) to give the product (129mg, 43%, MH+=237). PREPARATIVE EXAMPLES 125-145 Following the procedure described for Preparative Example 124, but using the commercially available amine or the amine from the Preparafive Example indicated and 3-nrtrosalicylic acid, the products in the table below were obtained. I step A To a solution of tosylaziridine [J. Am. Chem. Soc. 1998. 120, 6844-6845) (0.5 g, 2.1 mmol) and Cu(acac)2 (55 mg, 0.21 mmol) in THF (5 mL) at 0 "C was added PhMgBr (3.5 ml, 3.0 M in THF) diluted with THF (8 mL) dropwise over 20 min. The resulting solution was allowed to gradually warm to rt and was stirred for 12h. Sat. aq. NH4CI (5 mL), was added and the mixture was extracted with Et20 (3x15 mL). The organic layers were combined, washed with brine (1x10 mL), dried (MgS04) and concentrated under reduced pressure. The crude residue was purified by preparative TLC eluting with hexane/EtOAc (4:1) to afford 0.57 g (86% yield) of a solid. The purified tosylamine was taken on directly to the next step. SteoB To a solution of tosylamine (0.55 g, 1.75 mmol) in NH3 (20 mL) at -78 °C was added sodium (0.40 g, 17.4 mmol). The resulting solution was stirred at -78 "C for 2 h whereupon the mixture was treated with solid NH4CI and allowed to warm to rt. Once the NH3 had boiled off, the mixture was partitioned between water (10 mL) and CH2CI2 (10 mL). The layers were separated and the aqueous layer was extracted with CH2CI2 (2 xlO mL). The organic layers were combined,), dried (NaS04), and concentrated under reduced pressure to a volume of -20 mL. 4N HCI in dioxane (5 mL) was added and the mixture was stirred for 5 min. The mixture was concentrated under reduced pressure and the resultant crude residue was recrystallized from EtOH/Et20 to afford 0.30 g (87% yield) of a solid. PREPARATIVE EXAMPLES 147-156.10 Following the procedure set forth in Preparative Example 146 but using the requisite tosylaziridines and Grignard reagents listed in the Table below, the following racemic amine hydrochloride products were obtained. step A To a solution of the amine (118mg) from Preparative Example 148 in CH2CI2 (10ml) was added triethylamine (120ul). R-Mandelic Acid (164mg), DCC (213mg) and DMAP (8.8mg)and let stir for 40hr. The mixture was diluted with CH2CI2 and washed with saturated ammonium chloride, dried over Na2S04, filtered, and concentrated in vacuo. The crude material was purified by preparative plate chromatography (Hex/EtOAc 4:1) to afford both isomers (A. 86mg, 45%) (B, 90mg. 48%). SteoB To isomer B (90mg) from above in dioxane (5ml) was added 6M H2SO4 (5ml). The reaction was heated to 80°C over the weekend. 2M NaOH added to basify the reaction and extracted witti ether. Ether layer washed with brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was stirred in 4N HCI in dioxane for SOmin, concentrated in vacuo and recrystallized in EtOH/ether to afford 55mg of product (98%). To a solution of 1,2-phenylenediame (1.5g) in CH2CI2 (30ml) at 0°C was added TEA (2.91ml), followed by dropwise addition of MeSOaCI (1.07ml). The mixture was allowed to wamn to room temperature and stir overnight. 1M HCI added and the layers were separated. The aqueous layer was adjusted to pH=11 with solid NaOH, extracted with CH2CI2. The basified aqueous layer was then neutralized using 3N HCI and extracted with CH2CI2, dried with Na2S04, filtered, and concentrated in vacuo to give 1.8g of product (71 %). The known acid (410mg) above {J.Med.Chem. 1996, 34,4654.) was reacted following the procedure set forth in Preparative Example 2, Step A to yield 380mg of an oil (80%). StepB The amide (200mg) from above was reacted following the procedure set forth in Preparative Example 2, Step B to yield 170mg of an oil (100%). Step A To a solution of ketone (500mg) in EtOH/water (3:1,4ml) at room temperature was added hydroxylamine hydrochloride (214mg) followed by NaOH to afford a heterogenous mixture. The reaction was not complete so another equivalent of hydroxylamine hydrochloride was added and refluxed overnight. The reaction was cooled to 0°C and treated with 3N HCI and extracted with CH2CI2, washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to give 500mg of product (92%). SteoB To a solution of oxime (3Q0mg) in THF (5ml) at 0°C was added LiAIH* (266mg) portionwise. The heterogenous solution was stirred at room temperature for 14hr and then refluxed for 8hr. The solution was cooled to 0°C and water, 2M NaOH, water and ether were added to the reaction. The mixture was filtered through a celite pad. The filtrate was treated with 3N HCI. The aqueous layer was cooled to 0°C, basified with NaOH pellets and extracted with ether. The ether layer was dried over MgS04, filtered, and concentrated in vacuo to afford the nroduct M4/imn RQ%^ step A Methoxyacetic acid (14 mL) in CH2CI2 (120 mL) and cooled in an ice-water bath vas treated witli DMF (0.9 mL) and oxalyl chloride (21 mL). After stirring at RT Dvernight, the mixture was concentrated in vacuo and redissolved in CH2CI2 (120 mL). M-methyl-N-methoxylamine (20 g) was added and the mixture stirred at RT overnight, -iltration and concentration in vacuo afforded the desired amide (21 g, 89%). StepB To a solution of the above amide (260mg) in THF (5ml) at -78 °C was added a jolution of 2-thienyllithium (1M In THF, 2.15ml). The solution was stirred for 2hr at -78 "C and warmed to -20 "C for an additional 2hr. The reaction was quenched with jaturated ammonium chloride and extracted with CH2CI2. washed with brine, dried jver Na2S04, filtered, and concentrated in vacuo to give 250mg of product (82%). 3tepC The ketone from above (250mg) was reacted via the procedure set forth in =*reparative Example 156.17 Steps A and B to yield 176 mg of the amine (79%). step A To a solution of 3-chlorothiophene (1.16ml) in ether (20ml) at -10 °C was added n-BuLi (2.5M In hexane, 5ml). After solution was stirred at -10°C for 20min, propionaldehyde (0.82ml) in ether (20ml) was added dropwise and let warm to room temperature slowly. The reaction was quenched with saturated ammonium chloride and extracted with CH2CI2, washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to give 1.37g of product (62%). StepB The alcohol from Step A above was reacted via the procedures set forth in Preparative Example 75.75, Steps B and C to give the amine. step A To a solution of magnesium metal {360mg) in THF (15ml) at 0°C was added 2-bromothiophene (1.45ml) in THF (10ml) dropwise over 20min. The solution was wanned to room temperature for 3hr, recooled to 0 °C whereupon a solution of cyclopropylacetonitrile (1g) in ether (30ml) was added dropwise via a syringe and let warm to room temperature and stir overnight. 3M HCI was added and washed with CH2CI2. The aqueous layer was basified with NaOH pellets and extracted with ether, dried with Na2S04, filtered, and concentrated in vacuo to give 625mg of product (68%). SteoB The ketone was reacted via the procedure set forth in Preparative Example 156.17 Step A to give the oxime. StepC The oxime from above was reacted via the procedure set forth in Preparative Example 156.17 Step B to give the amine. step M To a solution of CH3ONHCH3.HCI (780mg) and acid chloride (1g) in CH2CI2 at 0 °C was added dry pyridine (1.35ml) to afford a heterogenous mixture The solution was warmed to room temperature and stirred overnight. 1M HCI was added to the reaction and the organic layer was separated, washed with brine, dried with Na2S04, filtered, and concentrated in vacuo to give 1g of product (85%). StepB To a solution of EtI (614ul) in ether (5ml) at -78°C was added t-BuLi (1.7M In pentane, 9ml) dropwise. The mixture was warmed to room temperature for 1hr, cooled to -78*"C where the amide (1g) from Step A in THF (4ml) was added and allowed to wann to 0°C for 2hr. 1M HCI was added to the reaction and extracted with CH2CI2, washed with brine, dried with Na2S04, filtered, and concentrated in vacuo to give 500mg of product (63%). StepC To a solution of ketone (BOOmg) in THF/water (10:1.20ml) at 0°C was added sodium borohydride (363mg) portionwise. The solution was stirred for 2hr at 0 °C. The mixture was concentrated in vacuo, the residue was dissolved in CH2CI2. washed with 1N NaOH and brine, dried with Na2S04, filtered, and concentrated in vacuo to give 560mg of product (69%). StepP The alcohol from above was reacted via the procedures set forth In Preparative Example 75.75, Steps B and C to give the amine (176mg, 59%). step A Cyclopropylacetonltrile (12 mmol) in Et20 (50 mL) at 0°C was treated with PhMgBr (14 mmol) and the mixture was stinred for 2 hrs at 0°C, then at RT overnight. Hydrochloric acid (3 M) was added, and after stining for an additional 12 hrs, the mixture was extracted with CH2CI2, washed with brine, dried over Na2S04, filtered and concentrated in vacuo to give the desired ketone (1.34 g, 70%). SteoB Following the procedures set forth in Preparative Example 156.20 Steps B and C, the amine was prepared. The above amine was prepared using the procedures set forth In WO Patent Publication 98/11064. step A By taking the known carboxylic acid [J. Med. Chem. 1996, 39,4654-4666] and subjecting it to tfie conditions outlined in Preparative Example 112, the product can be prepared. SteoB Following a similar procedure used in Preparative Example 2, Step A, except using dimethylamine and the compound from Step A above, the product can be prepared. SteoC Following a similar procedure used in Preparative Example 2, Step B. except using the compound from Step B above, the product can be prepared. Following a similar procedure used in Preparative Example 157, Steps A-C, except using trifluoromethylsulfonylchloride in Step A above, the product can be prepared. Step A By using the nitro-amide from Preparative Example 13.3, Step A, the amidine structure can be prepared following a similar procedure to that in Tetrahedron Lett., 2000,41 (11), 1677-1680. StepB By using the product from Step A and the procedure set forth in Preparative Example 2, Step B, one could obtain the desired amine-amidine. By treating the nitro-amide from Preparative Example 13.3, Step B with POCI3 and subsequently MeNH2, according to procedures known in the art, one would obtain the desired compound. StepB By treating the product from Step A according to the procedure set forth in Preparative Example 13.3, Step E, one could obtain the desired compound. StepC By using the product from Step B and the procedure set forth in Preparative Example 2 Step B, one would obtain the desired compound. Step A By following a similar procedure as that described in Zh. Obshch. Khim., 27, 1957, 754, 757., but instead using 2,4-dichlorophenol and dimethylphosphinic chloride, one would obtain the desired compound. StepB By following a similar procedure as that described in J. Organomet. Chem.; 317,1986,11-22, one would obtain the desired compound. SteoC By following a similar procedure as that described in J. Amer. Chem. Soc, 77, 1955, 6221, one would obtain the desired compound. SteoD By following a similar procedure as that described in J. Med. Chem.. 27,1984, 654-659, one would obtain the desired compound. Step A By following a similar procedure as that described in Phosphorous, Sulfur Silicon Relat. Elem.; EN; 61,12,1991,119-129, but instead using 4-chlorophenol, one would obtain the desired compound. SteoB By using a similar procedure as that in Phosphorous, Sulfur Silicon Relat. Elem.; EN; 61,12,1991,119-129, but instead using MeMgBr, the desired compound could be prepared. SteoC By following a similar procedure as that described in J. Amer. Chem. Soc, 77, 1955, 6221, one would obtain the desired compound. SteoD By following a similar procedure as that described in J.Med. Chem., 27,1984, 654-659, one would obtain the desired compound. By following a similar procedure as that set forth in J. Org. Chem. 1998, 63, 2824-2828, but using CHaCCMgBr, one could obtain the desired compound. step A By following the procedure set forth in Preparative Example 13.1. Step B using 3-methoxythiophene, one can obtain the desired product. SteoB By using the product from step A and following the procedure set forth in Preparative Example 13.19, Step E, the desired compound can be obtained. StepC By using the product from Step B and following the procedure set forth In Preparative Example 13.20, Step A, one can obtain the desired compound. SteoD By using the product from Step C and following the procedure set forth in Preparative Example 13.3, Step B, the desired compound can be obtained. SteoE By treating the product from Step D with n-BuLi at -78°C in THF and quenching the resulting anion with CO2 according to standard literature procedure, one would obtain the desired compound following aqueous acid work up. StepF By using the product from Step E and the procedure set forth in Prepartive Example 13.19, Step C, one could obtain the desired compound. SteoG By using the product from step F and following the procedure set forth in Preparative Example 13.19, Step E, the desired compound can be obtained. SteoH " , - ■" By using the product from Step G and following the procedure set forth in Preparative Example 2, Step B, the desired compound can be obtained. Stepl By using the product from Step H and following the procedure set forth in Preparative Example 19, the desired compound can be prepared. To a solution of the HCI salt product (83 mg, 0.50 mmol) from Preparative Example 24, in EtOH (3 mL) at room temperature was added EtaN (55 ^L, 0.50 mmol) and the mixture was stin-ed for 10 min. The cyclobutenedione (100 mg, 0.33 mmol) from Preparative Example 19 in EtOH was then added in a single portion and the mixture was stirred for 12 h at room temperature. The mixture was concentrated under reduced pressure and was purified by preparative TLC (4 x 1000 ^M plates) eluting with CH2Cl2/MeOH (25:1) to afford 116 mg (91 % yield) of the desired product as a solid [MH+ 389.1, mp 241-243 °C]. EXAMPLES 201-209 Following the procedure set forth in Preparative Example 200 but using the appropriate amine hydrochlorides from Preparative Examples 25-33 as identified and the cyclobutenedione Intermediate from Preparative Example 19, the cyclobutenedione products in the Table below were obtained. The caide amine product from Preparative Example 33.2 and the cyclobutendione cx)mponent from Preparative Example 19.1 (36mg) were dissolved in MeOH/ DIEA (2.5ml/5/1) and irradiated via microwave (SOW, Ihr). The reaction was concentrated in vacuo and purified by Gilson semi-prep. HPLC to give the final product (68%, MH+=485.2). EXAMPLES 209.3-209.50 Following the procedure set forth in Example 209.2, but using the prepared amine from the Preparative Example indicated in the Table below, the following cyclobutenedione products were obtained. To a solution of amine (0.17 g, 1 mmol) from Preparative Example 34 in EtOH (3 mL) at room temperature was added the cydobutenedlone from Preparative Example 19 (100 mg, 0.33 mmol) in one portion. The resulting mixture was stirred for 5h (until TLC analysis revealed reaction complete) and was concentrated under reduced pressure. The crude residue was redlssolved in CH2CI2 (15 mL) and was washed sequentially with 10% KH2PO4 (2x15 mL) and brine (1x15 mL). The organic layer was dried (Na2S04) and concentrated under reduced pressure to afford the crude adduct. The crude product was purified by prep TLC (4 x 1000 uM plates) eluting with CH2Cl2/MeOH (20:1) to afford 83 mg (59% yield) of the desired product as a solid. EXAMPLES 211-260 Following the procedure set forth in Example 210 but using the commercially available amine or the prepared amine from the Preparative Example Indicated In the Table tjelow, the following cydobutenedlone products were obtained. To a solution of the amine (77 \iL, 0.66 mmol) in EtOH (3 mL) at room temperature was added the product from Preparative Example 19 (100 mg, 0.33 mmol) in one portion. The resulting mixture was stirred for 5h (until TLC analysis nevealed reaction complete) and was then concentrated under reduced pressure. The ::rude residue was redissolved In CH2CI2 (15 mL) and was washed sequentially with 10% KH2PO4 (2x15 mL) and brine (1x15 mL). The organic layer was dried [Na2S04) and concentrated under reduced pressure to afford the crude adduct. The :rude product was purified by prep TLC (4 x 1000 uM plates) eluting with DH2Cl2/MeOH (20:1) to afford 82 mg (72% yield) of the desired product as a solid, (mp 126.0-128.0 "C.I^H* 346) To a solution of the amine from Preparative Example 75.1 (11.3 g) in EtOH (100 mL) at room temperature was added the product from Preparative Example 19 (16.4 g) in one portion. The resulting mixture was stirred at reflux overnight and then concentrated under reduced pressure. The crude residue was redissolved in CH2CI2 (80 mL) and was washed with 10% KH2PO4 (120 mL). The solid precipitate that was generated was filtered, washed with water and dried under vacuo. The residue was recrystallized from methanol-methylene chloride to give a cream colored solid (16 g, 75% yield), (mp 105-108 "C, MH* 398.1). OtCfJ D If one were to use a similar procedure to that used in Preparative Example 13.19 Step B, except using the product from Step A above, one would obtain the desired compound. StepC If one were to use a similar procedure to that used in Synth. Commun. 1980, 10, p. 107, except using the product from Step B above and t-butanol, one would obtain the desired compound. StepD If one were to use a similar procedure to that used in Synthesis, 1986,1031, except using the product from Step C above, one would obtain the desired sulfonamide compound. StepE If one were to use a similar procedure to that used in Preparative Example 13.19 Step E, except using the product from Step D above, one would obtain the desired compound. SteoF If one were to use a similar procedure to that used in Preparative Example 19, except using the product from Step E above and adding potassium carbonate as base, one would obtain the desired compound. SteoG If one were to follow the procedure set forth in Example 210, except using the product from Step F above and the amine from Preparative Example 75.9, then one would obtain the title compound. step A If one were to treat the product from Step C of Example 1125 with BuLI (2.2 eq.) in THF followed by quenching of the reaction mixture with N,N,-dimethylsulfamoyl chloride (1.1 eq.) then one would obtain SteoB If one were to use the product of Step A above and one were to follow Steps E, F and G of Example 1125, except using the amine from Preparative Example 75.49 in Step G, then one would obtain the title compound. A To a solution of 3-methoxythiophene (3 g) jn dlchloromethane (175 mL) at -) was added chlorosulfonlc acid (8.5 mL) dropwise. The mixture was stirred for 15 at -78°C and 1.5 h at room temp. Afterwards, the mixture was poured carefully crushed Ice. and extracted with dichloromethane Thp eytrarts wprA \Ai» brine, dried over magnesium sulfate, filtered through a 1-in silica gel pad. The filtrate was concentrated In vacuo to give the desired compound (4.2 g). StepB The product from Step A above (4.5 g) was dissolved in dichloromethane (140 mL) and added with triethylamine (8.8 mL) followed by diethyl amine in THF {2M, 21 mL). The resulting mixture was stirred at room temperature overnight. The mixture was washed with brine and saturated bicarbonate (aq) and brine again, dried over sodium sulfate, filtered through a 1-ln silica gel pad. The filtrate was concentrated in vacuo to give the desired compound (4.4 g). StepC The product from Step B above (4.3 g) was dissolved In dichloromethane (125 mL) and cooled in a -78°C bath. A solution of boron tribromide (1.0 M in dichloromethane, 24.3 mL) was added. The mixture was stirred for 4 h while the temperature was increased slowly from -78°C to 10°C. H2O was added, the two layers were separated, and the aqueous layer was extracted with dichloro- methane. The combined organic layer and extracts were wahed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 3.96 g of the desired hydroxy-compound. StepD The product from step C above (3.96 g) was dissolved In 125 mL of dichloromethane, and added with potassium cartDonate (6.6 g) followed by bromine (2 mL). The mixture was stirred for 5 h at room temperature, quenched with 100 mL of H2O. The aqueous mixture was addjusted to pH ~ 5 using a 0.5N hydrogen chloride aqueous solution, and extracted with dichloromethane. The extracts were washed with brine, dried over sodium sulfate, and filtered through a cellte pad. The filtrate was concentrated in vacuo to afford 4.2 g of the desired bromo-compound. StepE The product finom Step D (4.2 g) was dissolved in 100 mL of acetone and added with potassium caribonate (10 g) followed by iodomethane (9 mL), The mixture was heated to reflux and continued for 3.5 h. After cooled to room temperature, the mixture was filtered through a Celite pad. The filtrate was concentrated in vacuo to a dark brown residue, which was purified by flash column chromatography eluting with dichloromethane-hexanes (1:1, v/v) to give 2.7 g of the desired product. StepF The product from step E (2.7 g) was converted to the desired imine compound (3 g), following the similar procedure to that of Preparative Example 13.19 step D. StepG The imine product from step F (3 g) was dissolved in 80 mL of dichloromethane and cooled in a -78°C bath. A solution of boron tribromide (1.0 M in dichloromethane, 9.2 mL) was added dropwise. The mixture was stlred for 4.25 h from -78°C to 5°C. H2O (50 mL) was added, and the layers were separated. The aqueous layer was extracted with dichloromethane. The organic layer and extracts were combined, washed with brine, and concentrated to an oily residue. The residue was dissolved in 80 mL of methanol, stin-ed with sodium acetate (1.5 g) and hydroxyamine hydrochloride (0.95 g) at room temperature for 2 h. The mixture was poured into an aqueous mixture of sodium hydroxide (1.0 M aq, 50 mL) and ether (100 mL). The two layers were separated. The aqueous layer was washed with ether three times. The combined ether washings were re-extracted with H2O once. The aqueous layers were combined, washed once with dichloromethane, adjusted to pH ~ 6 using 3.0 M and 0.5 M hydrogen chloride aqueous solutions, and extracted with dichloromethane. The organic extracts were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 1.2 g of desired amine compound. StepH The product from step F (122 mg) was stirred with diethyoxysquarate (0.25 mL) and potassium carbonate (75 mg) in 5 mL of ethanol at room temperature for 5 h. The mixture was diluted with dichloromethane, filtered through a Celite pad, and concentrated to an oily residue, which was separated by preparative TLC (CH2CI2-MeOH= 15:1, vA/) to give 91 mg of the desired product step I Following the procedure set forth in Example 210, and using the amine from Preparative Example 75.9, the product (43 mg) from Step H was converted to the desired compound (20 mg). This invention provides novel compounds of the formula (I): a prodrug thereof, or a pharmaceutically acceptable salt or solvate of the compound or of said prodrug; wherein A is selected from: herein, R7 and R8 are the same or different and are independently selected from the roup consisting of H; optionally substituted or unsubstituted alkyl, aryl, heteroaryl, rylalkyl, heteroarylalkyi, cycloalkyi, cycloalkylalkyl. C02R^^. C0NR"R^\ fluoroalkyi, Ikynyl, alkenyl, alkynylalkyl, alkenylalkyl, and cycloalkenyl, wherein said substituents on said substituted groups are selected from the roup consisting of: a) cyano; b) COZR^; c) CONR^R^ d) SOzNR^R®, e) SOzR^; f) NO2; g) CF3; h)-OR^; i) -NR^R^ j) -0(C=0)R"; k) -0(C=0)NR^R°. and I) halogen; R® is selected from one or more of the groups consisting of: a) R^-b)R^ c) halogen; d) -CF3; e) -COR^; f) -OR^; g)-NR^R^ h) -NO2; i) -CN; J) -SO2R": k) -SOzNR^R^; I) -NR^COR®; m) -CONR^R®; R2 is hydrogen. OH. C(0)OH. SH. SOSNR"^R"". NHC(0)R". NHS02NR^3R^\ NHSOzR^^ C(0)NR"R^*. C(0)NHOR^^ C(0)NR^^OH, OC(0)R^^ or an optionally substituted cyclic or iieterocyciic acidic functional group, with the proviso that if R^ is S02NR"R^"*. at least one of R^^and R^"* must be hydrogen; R^ and R^ are independently hydrogen, halogen, alkyl, alkoxy. OH. CF3, OCF3. NO2. C(0)R^^ C(0)OR^^ C(0)NR"^R"*. S0(t)NR"^R^^S0(t)R^^ C(0)NR"OR^^ wherein tiie substituents on the optionally substituted groups may be selected from one or more R^ groups. R^ and R^ independently represent hydrogen, halogen, alkyl, alkoxy, CF3, OCF3, NO2, C(0)R", C(0)OR", C(0)NR"R^^ SO(l)NR"R^^ C(0)NR^^OR^^, cyano, or an optionally substituted aryl or heteroaryl group, wherein the substituents on the optionally substituted groups may be selected from one or more R^ groups. R^° and R**^ independently represent hydrogen, halogen, CF3, OCF3, NR^^R^*, NR"C(0)NR"R"^ OH. C(0)0R". SH. SO(t)NR^^R^^S02R". NHC(0)R". NHS02NR^^R^*, NHS02R^^ C(0)NR"R"^ C(0)NR^^0R"*, 0C(0)R" or cyano. R^^ is hydrogen, OC(0)R^^, or an optionally substituted aryl, heteroaryl, arylalkyi, cycloalkyi, alkyl, cycloalkylalkyi or heteroarylalkyi group; R^^ and R^"* are the same or different and are independently selected from the group consisting of H; optionally substituted or unsubstituted alkyl. aryl. heteroaryl, arylalkyi, heteroarylalkyi, cycloalkyi, cycloalkylalkyi, and fluoroalkyl, or R^^ and R^* when taken together form an optionally substituted 3 to 7 membered heterocyclic ring containing one to two heteroatoms selected from O, S and N, and wherein the substituents on the optionally substituted groups may be selected from one or more R^ groups; and tisi or 2. The definitions below refer to the formula I that directly precedes these definitions. These definitions apply regardless of whether a term Is used by itself or in combination with other terms. Hence the definition of "alkyl" applies to "alky!" as well as to the "alky!" portions of "alkoxy", etc. When any variable (e.g., aryl, R^) occurs more than one time in any constituent, its definition on each occurrence is independent of its definition at every other occun-ence. Also, combinations of substituents and/or variables are permissible only If such combinations result in stable compounds. Alkyl represents a straight or branched saturated hydrocarbon chain having the designated number of carbon atoms. Where the number of carbon atoms is not specified, 1 to 20 carbons are intended. The term halogen or Halo is intended to include fluorine, chlorine, bromine or iodine. The term fluoroalkyi represents a straight or branched saturated hydrocarbon chain having the designated number of carbon atoms, substituted with one or more fluorine atoms. Where the number of carbon atoms is not specified, 1 to 20 carbons are intended Aryl refers to a mono- or bicyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl, fluorenyl and the like. The aryl group can be unsubstituted or substituted with one, two, or three substituents independently selected from lower alkyl, halo, cyano, nitro, haloalkyl, hydroxy, alkoxy, carboxy, carboxyalkyi, carboxamide, mercapto, sulfhydryl, amino, alkylamino, dialkylamino, sulfonyl, sulfonamide, aryl and heteroaryl. The term heterocycle or heterocyclic ring is defined by all non-aromatic, heterocyclic rings of 3-7 atoms containing 1-3 heteroatoms selected from N, O and S, such as oxirane, oxetane, tetrahydroft;ran, tetrahydropyran, pyrrolidine, piperidine, piperazine, tetrahydropyridine, tetrahydropyrimldine, tetrahydrothiophene, tetrahydrothlopyran, morphollne, hydantoin, valerolactam, pyrrolidinone, and the like. The term heterocyclic acidic functional group Is intended to include groups such as, pyrrole. Imidazole, triazole, tetrazole, and the like. Heteroaryl refers to 5- or 10-membered single or benzofused aromatic rings consisting of 1 to 3 heteroatoms independently selected from the group consisting of -0-, -S, and -N=, provided that the rings do not possess adjacent oxygen and/or sulfur atoms. The heteroaryl group can be unsubstituted or substituted with one, two, or three substituents independently selected from lower alkyl, halo, cyano, nitro, haloalkyi, hydroxy, alkoxy, carboxy, carboxyalkyi, carboxamide, sulfhydryl, amino, alkylamino and dialkylamino. N-oxides can form on a tertiary nitrogen present in an R substituent, or on =N-in a heteroaryl ring substituent and are included in the compounds of formula I. The preferred groups described below refer to the formula I that directly precedes these preferred groups. In a preferred group of compounds of formula I, A is selected from the group consisting of: wherein, R^ and R® are the same or different and are independently selected from alkyl and cycloalkyi such as, for example, methyl, ethyl, t-butyl, isopropyl and cyclohexyl with methyl, ethyl, t-butyl and Isopropyl being most preferred and, R^ is selected from one or more moieties selected from the group halogen (e.g. Bromine, Fluorine or Chlorine), CH3. CF3. cyano, -OCH3, and NO2, and n = 0-6. Preferrably, B is wherein R2 is selected from the group consisting of OH. NHC(0)R^^ and NHSO2R": R^ is selected from the group consisting of SOaNR^^R^*. NO2, cyano, C(0) NR"R^*, SO2R"; and e(0)OR"; R* is selected from the group consisting of H, NO2, cyano and CF3; R^ is selected from the group consisting of H, CF3, NO2, halogen and cyano; and R^ is selected from the group consisting of H, alkyl and CF3. R^^ and R^* are independently selected from methyl, ethyl and isopropyl or when taken together R^^ and R^^ form a 3 to 7 membered heterocyclic ring containing one to two heteroatoms selected from O, S and N, optionally substituted with one or more R® groups. Most preferably, A is selected from: Most Preferably, for compounds of the present Invention, R^is-OH; R^ is CONR^^R^""; R* is H; R^ is H or cyano; R^ is H or aikyl; R^, R® are independently selected from H, methyl, ethyl, isopropyl and t-butyl: R^^ and R^^ are independently selected from methyl and ethyl. In one ennbodiment of the methods of treatment of this invention using compounds of formula lA, or in the use for manufacture of a medicament using compounds of formula lA, B is selected from the group consisting of. Additional representative embodiments of the novel compounds of this invention are described below. The embodiments have been numbered for purposes of reference thereto. Embodiment No. 47 is directed to compounds of fonnula lA wherein B is selected from the group consisting of. /herein ail substituents are as defined for formula lA. Embodiment No. 53 is directed to compounds of formula lA wherein B is lelected from the group consisting of: vherein all substituents are as defined for formula lA. Embodiment No. 54 is directed to any one of the Embodiment Nos. 48 to 53 vherein the compound of formula lA is a pharmaceutically acceptable salt. Embodiment No. 55 is directed to any one of the Embodiment Nos. 48 to 53 vherein the compound of fonnula lA is a sodium salt. Embodiment No. 56 is directed to any one of the Embodiment Nos. 48 to 53 vherein the compound of formula lA is a calcium salt. Embodiment No. 57 Is directed to a pharmaceutical composition comprising at east one (e.g., 1 to 3, usually 1) compound of formula lA as described in any one of he Embodiment Nos. 48 to 53 in combination with a pharmaceutically acceptable :arrier. Embodiment No. 58 is directed to a method of treating any one of the diseases Jescribed above comprising administering to a patient in need of such treatment an effective amount (e.g., a therapeutically effective amount) of a compound of formula A as described In any one of the Embodiment Nos. 48 to 53. The diseases referred o in this emlxMJiment are those described in the methods of treatment using x)mpounds of formula I. Embodiment No. 59 is directed to the use of a compound of formula lA as described in any one of the Embodiment Nos. 48 to 53 for the manufacture of a medicament for the treatment any one of the diseases described above. The diseases referred in this embodiment are those described in the methods of treatment using compounds of formula I. WE CLAIM: 1. A compound of the formula R4 is selected from the group consisting of hydrogen, cyano. halogen, alkyl, aikoxy. -OH, wherein the substituents on the substituted R* groups are the same or different and independently sheeted from 1-6 R® groups: R* and R° are the same or different and are independently selected from the group consisting of hydrogen, halogen, alkyi, aikoxy, -CF3, -OCF3, -NO2. -C(0)R". -C{0)OR^", .C(0)NR"R^*, -S0„)NR^^R^*, -C(0)NR"0R". cyano, an unsubstituted or substituted aryl and unsubstituted or substituted heteroaryl group. wherein ttie substituents on the substituted R^ and R^ groups are the same or different and independently selected from 1-6 R^ groups; R^ and R* are the sanrte or different and are independ^itty selected from the group consisting of H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted ar/lalkyi, unsubstituted or substituted heteroarylalkyi, unsubstituted or substituted cydoalkyl. unsubstituted or substituted cycloalkylalkyi, -CO2R"", -CONR^R^*, fluoroalkyl. alkynyl. alkenyl and cycloalkenyl. wherein the substituents on the substituted R^ and R" groups are selected from the group consisting of a)H. R^" and R" are the same or different and are independently selected from the group consisting of hydrogen, liaJogen, -CF3. -OCF3. -NR"^R". -NR"C(0)NR"R", -OH, -C(0)0R", -SH, -S0(„NR"R"*. -SO2R". -NHC{0)R",-NHS02NR"R"^. -NHSO2R". -C(0)NR"R^*. -C(0)NR"0R"*, -0C(0)R" and cyano; R" is hydrogen, -OC(0)R". or an unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalicyl, unsubstituted or substituted cycfoaikyl. unsubstituted or substituted all^, unsubstituted or substituted cycloaikyiallcyl or unsubstituted or substituted heteroarylaikyl group, wherein the substituents on the substituted R**^ groups are the same or diiferent and independently selected from 1-6 R* groups; R" and R^*are the same or different and are independently selected from the group consisting of H. unsubstituted or substituted alltyt, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl. unsubstituted or substituted arylalkyl. unsubstituted or substituted heteroarylaikyl, unsubstituted or substituted cycioaikyi, unsubstituted or substituted cycloalkyfalkyi, and unsubstituted or substituted fiuoroalkyl. or R" and R^* can be taken together when both are attached to a nltn^gen atom to form an unsubstituted or substituted 3 to 7 membered heterocylic ring containing one to two heteroatoms selected from oxygen, sulfur and nitrogen. wherein the substitutents on the substituted R"^ arui R^* groups are the same or different and independently selected from 1-6 of H, alkyl, aryl, arylalkyl, fluroalkyl, cydoalkyl, cydoalkylaikyl. heteroaryl, heteroarylaikyl, amino, -C(0)OR", -C(0)NR^*R^^. -S(0),NR^*R^«. -C(0)R^^ -SOzR"^ -NHC(0)NR"R"* and halogen; R" and R"® are the same or different and are independently selected from the group consisting of H, aJkyI, aryl. aryialkyt, cycloalkyi and heteroaryl; R^^ is -S02alkyi, -SO2 aryl, -SO2 cycloalkyi or-SOaheteroaryl; R^ is alkyl. cydoalkyl. -CN. -NO2. or -SO2R"*; R^* are the same or different and are independently selected from the group consisting of unsubstituted or substituted alky), unsubstituted or substituted aryl, unsubstituted or sut)stituted heteroar>i and unsubstituted or sutistituted cycloalkyi; wherein the substttuents on the substituted R^^ groups are the same or different and independently selected from 1 -6 R^ groups; and t is 0.1 or 2. 3. The compound as claimed in claim 1, wherein A is selected from the group comsisting of: wherein. R^ is H. -CF3, -CF2CH3, methyl, ethyl, isopropyl. cyclopropyl ort-butyl; R" is H; R® is H. F, CI. Br, alkyl or -CF3. and B is: wherein: R2 is OH; R^ is -C(0) NRVR"* ; R* is H, -NO2, cyano, -CH3 or -CF3: R* is H, -CF3, -NO2. halogen or cyano; and R^isH. alkylor-CFa; R^^ is H. halogen oralkyJ; and R^" and R"* are the same or different and are independently methyl, ethyl or isppropyf; or R"^ and R^* when taken together with the nitrogen they are attached to in the groups -NR"R^^ -C(0)NR^^^^, -S02NR"R^*, -0C(0)NR"^R^"*. -CONR^R"*. -NR"C(0)NR"R^*. -S0,NR"*R^\ -NHS02NR"R" preferably fonn an unsubstituted or substituted 3 to 7 membered, saturated heterocyclic ring optionally containing one additional heteroatom selected from O, S or NR^* wherein R" is selected from H, alkyl. aryl. heteroaryl. -C(0)R"^ -SO2R"" and -C(0)NR"^R^. wherein R" and R^ are the same or different and each is independently selected from alkyl, aryl and heteroaryl, wherein the substituents on the substituted cyclized R^^ and R^* groups are the same or different and independently selected from 1 to 3 of alkyl. aryl, hydroxy, hydroxyalkyi, alkoxy, alkoxyalkyl, arylalkyl. fluoroaikyi, cydoalkyi, cycloalkylalkyl. hrteroaryl, heteroarylalkyl. amino, -C(0)OR^*. -C{0)NR"*R"^, -S0,NR"R"», -C(0)R". -SO2R"*. -NHC(0)NR""R^^ and halogen, and wherein R"^ and R^^ are the same or different and are independently selected from the group consisting of H, alkyl, aryl, arylalkyl, cydoalkyi and heteroaryl; wherein: R^ is OH; R"is -C(0)NR^^R^"*; R* is H. -NO2, -CF3.-CH3orcyano. R* is H. halogen, -NOz, cyano or -CF3; R^ is H, -CFa or alkyl. R^ is H. -CF3. -CF2CH3, methyl, ethyl, isopropyl, cyclopropyi ort-butyl; R° is H; R^ is H. F, CI. Br, alkyl. cycloalkyi or -CF3: R" is H, halogen or alkyl; and R" and R^* are independently methyl or ethy). 5. The compound as claimed in claim 1, wherein A is selected from the group comsisting of: wheneln. R^ is -OH; R^is -CONR"^^*; R^ is H. -CH3 or -CF3,- R* is H or cyano; R^ is H. -CH3 or -CF3: R^^ is H, and R" and R^* am methyl. wherein, R^ and R® are the same or different and are independently selected from the group consisting of H; optionally substituted or unsubstituted alkyl, aryl, heteroaryl, arylalkyl. heteroar)rtalkyI. cydoalkyl. cycloalkylalkyl. COzR"^, CONR^^R^"*. fluoroalkyl. alkynyi. aikenyl. alkynyfalkyi, alkenyialkyi, and cycloalkenyi, wherein said substifaients on said substituted groups are selected from the wherein. R^ is OH; R^ C(0)NR"R" [:(0)NR"0R""": R* hydrogen, halogen, alkyi, alkoxy. OH, CF3. OCF3. NO2. C(0)R". C(0)0R", C(0)NR"R". S0(„NR"R". S0(„R". C(0)NR"0R^*. , cyano. optionally substituted aryi or heteroaryl, wherein the substituents on the optionally substituted groups may be selected from one or more R* groups; R" and R* independently represent hydrogen, halogen, alkyl. alkoxy, CF3. OCF3. NO2, C(0)R". C(0)0R". C(0>NR"R^\ SO(t)NR"R", C(0)NR"0R^"*. cyano. or an optionally substituted aryl or heteroary) group. wherein the substituents on the optionally substituted groups may be selected from one or more R* groups; R^^and R" independently represent hydrogen, halogen, CF3. OCF3. NR^R^". NR"C(0)NR"R^^. OH. C(0)0R", SH. SO(t)NR"R^*.S02R". NHC(0)R", NHS02NR"R". NHSO2R". C(0)NR"R". C(0)NR^\)R?*. 0C(0)R" or cyano. R" IS hydrogen, OC(0)R^", or an optionally substituted aryl. heteroaryl. arylalkyl. cydoalkyt. alkyi. cydoalkylalkyt or heteroarylalkyi group; R^" and R^^are the same or different and are independently selected from the group consisting of H; optionally substituted or unsubstituted alkyl. aryl, heteroaryl, arylalkyl, heteroarylalkyi. cycloalkyl. cyctoalkylatkyl. and fluoroalkyi. or R^" arwJ R^* when taken together form an optionally substituted 3 to 7 membered heterocyclic ring containing one to two heteroatoms selected from O. S and N, and wherein the substituents on the optionally substituted groups may be selected from one or more R* groups, and tis 1 or 2. 7. The compound of claim 1, wherein B is: R" is -C(0)NR"R"*. 8. The compound of claim 7, wherein R^" and R"** are each the same or different alkyl group. 9. The compound of claim 1, wherein B is: 10. The compound of claim 9, wherein R" and R^* are each the same or different alkyl group, 11. The compound of claiml, wherein B is: 12. The compound of claim 11, wherein 13. The compound of claim 11 or 12, wherein R^is-C(0)NR"R^*. 14. The compound of any one of claims llto 13, wherein R" and R^^ are independently selected from the group consisting c alkyi, unsubstituted heteroaryl and substituted heteroaryi. 15. The compound of claim 14, wherein one of R" or R^* is alkyl 16. The compound of claim 15, wherein said alkyl is methyl. 17. The compound of claim 1, wherein B is: 18. The compound of any one of claims 7 to 17, wherein A is: wherein the furan ring is unsubstituted or substitued. 19. The compound of claim 18 wherein the furan ring is substituted. 20. The compound of claim 19, wherein the furan ring is substituted with at least one alkyl group. 21. The compound of any one of claims 18 to 20, wherein R" and R° are the same or different and each is selected from the group consisting of: H and alkyl. 22. The compound of claim 21, wherein R^ is H, and R^ is alkyl 41. A pharmaceutical composition comprising an effective amount of a compound of any-of claims 1 to 40 in combunation with a pharmaceutically acceptable carrier.

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