3,4-di-substituted pyridazinediones as CXC chemokine receptor antagonists

FIELD OF THE INVENTION

[0002] This invention relates to novel substituted pyridazinedione compounds, pharmaceutical compositions containing the compounds, and the use of the compounds in treating CXC chemokine-mediated diseases.

BACKGROUND OF THE INVENTION

[0003] Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T-cells, eosinophils, basophils, neutrophils and endothelial cells to sites of inflammation and tumor growth. There are two main classes of chemokines, the CXC-chemokines and the CC-chemokines. The class depends on whether the first two cysteines are separated by a single amino acid (CXC-chemokines) or are adjacent (CC-chemokines). The CXC-chemokines include interleukin-8 (IL-8), neutrophil-activating protein-1 (NAP-1), neutrophil-activating protein-2 (NAP-2), GROα, GROβ, GROγ, ENA-78, GCP-2, IP-10, MIG and PF4. CC chemokines include RANTES, MIP-1α, MIP-2β, monocyte chemotactic protein-1 (MCP-1), MCP-2, MCP-3 and eotaxin. Individual members of the chemokine families are known to be bound by at least one chemokine receptor, with CXC-chemokines generally bound by members of the CXCR class of receptors, and CC-chemokines by members of the CCR class of receptors. For example, IL-8 is bound by the CXCR-1 and CXCR-2 receptors.

[0004] Since CXC-chemokines promote the accumulation and activation of neutrophils, these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis. Baggiolini et al., FEBS Lett. 307, 97 (1992); Miller et al., Crit. Rev. Immunol. 12, 17 (1992); 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).

[0005] ELRCXC chemokines including IL-8, GROα, GROβ, GROγ, 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.

[0006] 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 GROα (Haghnegahdar et al. J. Leukoc Biology 2000 67 p. 53-62).

[0007] Many tumor cells 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.

[0008] Hence, the CXC-chemokine receptors represent promising targets for the development of novel anti-inflammatory and anti-tumor agents.

[0009] There remains a need for compounds that are capable of modulating activity at CXC-chemokine receptors. For example, conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophil and T-cell subsets into the inflammatory site and growth of tumors) would benefit by compounds that are inhibitors of IL-8 receptor binding.

SUMMARY OF THE INVENTION

[0010] The invention provides novel compounds represented by the formula (I):

[0011] pharmaceutically acceptable salts, solvates, isomers or prodrugs thereof, wherein:

[0012] R1 and R15 are the same or different and each is independently selected from the group consisting of:

[0013] a) H,

[0014] b) aryl,

[0015] c) heteroaryl,

[0016] d) alkyl,

[0017] e) arylalkyl,

[0018] f) heteroarylalkyl,

[0019] g) cycloalkyl,

[0020] h) heterocycloalkyl,

[0021] i) cycloalkylalkyl and

[0022] j) heterocycloalkylalkyl,

[0023] wherein said aryl, heteroaryl, alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, and heterocycloalkylalkyl groups are optionally substituted with one or more substituents selected from the group consisting of:

[0024] a) halogen,

[0025] b) CF3,

[0026] c) COR13,

[0027] d) OH,

[0028] e) NR13R14,

[0029] f) NO2,

[0030] g) cyano,

[0031] h) SO2OR13,

[0032] i) —Si(alkyl),

[0033] j) —Si(aryl)

[0034] k) CO2R13

[0035] l) CONR13R14,

[0036] m) SO2NR13R14,

[0037] n) SO2R13,

[0038] o) —OR13,

[0039] p) —O(C═O)R13,

[0040] q) —O(C═O)NR13R14,

[0041] r) —NR13COR14, and

[0042] s) —NR13CO2R14;

[0043] A is selected from the group consisting of:

[0044] B is selected from the group consisting of:

[0045] wherein:

[0046] R2 is selected from the group consisting of:

[0047] a) hydrogen,

[0048] b) OH,

[0049] c) C(O)OH,

[0050] d) SH,

[0051] e) SO2NR13R14,

[0052] f) NHC(O)R13,

[0053] g) NHSO2NR13R14,

[0054] h) NR13R14,

[0055] i) NHSO2R13,

[0056] j) C(O)NR13R14,

[0057] k) C(O)NHOR13,

[0058] l) C(O)NR13OH,

[0059] m) OC(O)R13 and

[0060] n) an optionally substituted heterocyclic acidic functional group, with the proviso that if R2 is SO2NR13R14, then at least one of R13 and R14 must be hydrogen;

[0061] R3 and R4 are the same or different and each is independently selected from the group consisting of:

[0062] a) hydrogen,

[0063] b) halogen,

[0064] c) alkyl,

[0065] d) alkoxy,

[0066] e) OH,

[0067] f) CF3,

[0068] g) OCF3,

[0069] h) NO2,

[0070] i) C(O)R13,

[0071] j) C(O)OR13,

[0072] k) C(O)NR13R14,

[0073] l) SO(t)NR13R14,

[0074] m) SO(t)R13,

[0075] n) C(O)NR13OR14,

[0076] p) cyano,

[0077] q) aryl and

[0078] r) heteroaryl,

[0079] wherein said aryl or heteroaryl group is optionally substituted with one or more R9 group;

[0080] R5 and R6 are the same or different and each is independently selected from the group consisting of

[0081] a) hydrogen,

[0082] b) halogen,

[0083] c) alkyl,

[0084] d) alkoxy,

[0085] e) CF3,

[0086] f) OCF3,

[0087] g) NO2,

[0088] h) C(O)R13,

[0089] i) C(O)OR13,

[0090] j) C(O)NR13R14,

[0091] k) SO(t)NR13R14,

[0092] l) C(O)NR13OR14,

[0093] m) cyano,

[0094] n) aryl and

[0095] o) heteroaryl,

[0096] wherein said aryl or heteroaryl group is optionally substituted with one or more R9 group;

[0097] R7 and R8 are the same or different and each is independently selected from the group consisting of

[0098] a) H,

[0099] b) alkyl,

[0100] c) aryl,

[0101] d) heteroaryl,

[0102] e) arylalkyl,

[0103] f) heteroarylalkyl,

[0104] g) cycloalkyl,

[0105] h) cycloalkylalkyl,

[0106] i) CO2R13,

[0107] j) CONR13R14,

[0108] k) fluoroalkyl,

[0109] l) alkynyl,

[0110] m) alkenyl,

[0111] n) alkynylalkyl,

[0112] o) alkenylalkyl and

[0113] p) cycloalkenyl,

[0114] wherein said alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, fluoroalkyl, alkynyl, alkenyl, alkynylalkyl, alkenylalkyl, and cycloalkenyl groups are optionally substituted with one or more substituents selected from the group consisting of:

[0115] a) halogen,

[0116] b) CF3,

[0117] c) COR13,

[0118] d) OH,

[0119] e) NR13R14,

[0120] f) NO2,

[0121] g) cyano,

[0122] h) SO2OR13,

[0123] i) —Si(alkyl),

[0124] j) —Si(aryl),

[0125] k) (R13)2R14Si,

[0126] l) CO2R13,

[0127] m) C(O)NR13R14,

[0128] n) SO2NR13R14,

[0129] o) SO2R13,

[0130] p) —OR13,

[0131] q) —O(C═O)R13,

[0132] r) —O(C═O)NR13R14,

[0133] s) —NR13C(O)R14 and

[0134] t) —NR13CO2R14;

[0135] R9 is selected from the group consisting of:

[0136] a) R13;

[0137] b) halogen;

[0138] c) —CF3;

[0139] d) —COR13;

[0140] e) —OR13;

[0141] f) —NR13R14;

[0142] g) —NO2;

[0143] h) cyano;

[0144] i) —SO2R13;

[0145] j) —SO2NR13R14;

[0146] k) —NR13COR14;

[0147] l) —CONR13R14;

[0148] m) —NR13CO2R14;

[0149] n) CO2R13, and

[0150] R10 and R11 are the same or different and each is independently selected from the group consisting of:

[0151] a) hydrogen,

[0152] b) halogen,

[0153] c) CF3,

[0154] d) OCF3,

[0155] e) NR13R14,

[0156] f) NR13C(O)NR13R14,

[0157] g) OH,

[0158] h) C(O)OR13,

[0159] i) SH,

[0160] j) SO(t)NR13R14,

[0161] k) SO2R13,

[0162] l) NHC(O)R13,

[0163] m) NHSO2NR13R14,

[0164] n) NHSO2R13,

[0165] o) C(O)NR13R14,

[0166] p) C(O)NR13OR14,

[0167] q) OC(O)R13 and

[0168] r) cyano;

[0169] R12 is selected from the group consisting of:

[0170] a) hydrogen,

[0171] b) OC(O)R13,

[0172] c) aryl,

[0173] d) heteroaryl,

[0174] e) arylalkyl,

[0175] f) cycloalkyl,

[0176] g) alkyl,

[0177] h) cycloalkylalkyl and

[0178] i) heteroarylalkyl,

[0179] wherein said aryl, heteroaryl, arylalkyl, cycloalkyl, alkyl, cycloalkylalkyl and heteroarylalkyl group are optionally substituted with one or more R9 group;

[0180] R13 and R14 are the same or different and each is independently selected from the group consisting of:

[0181] a) H,

[0182] b) alkyl,

[0183] c) aryl,

[0184] d) heteroaryl,

[0185] e) arylalkyl,

[0186] f) heteroarylalkyl,

[0187] g) cycloalkyl,

[0188] h) cycloalkylalkyl and

[0189] i) fluoroalkyl,

[0190] wherein said alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, and fluoroalkyl group are optionally substituted with one or more substituents selected from the group consisting of:

[0191] a) alkyl,

[0192] b) aryl,

[0193] c) arylalkyl,

[0194] d) fluoroalkyl,

[0195] e) cycloalkyl,

[0196] f) cycloalkylalkyl,

[0197] g) heteroaryl,

[0198] h) heteroarylalkyl,

[0199] i) amino,

[0200] j) carbonyl and

[0201] k) halogen; or

[0202] R13 and R14 when taken together with the atoms to which they are attached form a 3 to 7 membered heterocyclic ring, wherein when the ring formed is a 6 or 7 membered heterocyclic ring said ring optionally contains one to two additional heteroatoms independently selected from the group consisting of O, S and N, and wherein said heterocyclic ring is optionally substituted with one or more substituents selected from the group consisting of:

[0203] a) alkyl,

[0204] b) aryl,

[0205] c) arylalkyl,

[0206] d) fluoroalkyl,

[0207] e) cycloalkyl,

[0208] f) cycloalkylalkyl,

[0209] g) heteroaryl,

[0210] h) heteroarylalkyl,

[0211] i) amino,

[0212] j) carbonyl and

[0213] k) halogen;

[0214] n is 0-6;

[0215] m is 1-5;

[0216] p is 0-4 and

[0217] t is 1 or 2.

[0218] Another aspect of the invention is a pharmaceutical composition comprising the compound of formula (I) in combination or association with a pharmaceutically acceptable carrier or diluent.

[0219] Another aspect of the invention is a method of treating an α-chemokine mediated disease in a patient (e.g., a mammal such as a human being) in need of such treatment comprising administering to said patient a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0220] Another aspect of the invention is a method of treating a chemokine-mediated disease in a patient in need of such treatment, wherein the chemokine binds to a CXCR2 and/or CXCR1 receptor in said patient (e.g., a mammal, such as a human being), said method comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0221] Another aspect of the invention is a method of treating a chemokine-mediated disease in a patient in need of said treatment wherein the chemokine binds to a CXC receptor in said patient (e.g., a mammal, such as a human being), said method comprising administering to said patient a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0222] Examples of chemokine 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, glomerulonephritis or thrombosis, alzheimer's disease, graft vs. host reaction, allograft rejections and malaria. Angiogenic ocular disease (e.g., ocular inflammation (e.g., Uveitis), retinopathy of prematurity, diabetic retinopathy, macular degeneration with the wet type preferred and corneal neovascularization) is another example of a chemokine mediated diseases

[0223] Another aspect of the invention is a method of treating cancer in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0224] Another aspect of the invention is a method of treating cancer in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and administering a therapeutically effective amount of at least one known anti-cancer agent and/or radiation therapy.

[0225] Another aspect of the invention is a method of treating cancer in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and administering a therapeutically effective amount of at least one known anti-cancer agent and/or radiation therapy, wherein said anti-cancer agent is selected from the group consisting of alkylating agents, antimetabolites, natural products and their derivatives, hormones, anti-hormones, anti-angiogenic agents and steroids (including synthetic analogs), and synthetics.

[0226] Another aspect of the invention is a method of inhibiting angiogenesis in a patient in need of such inhibition comprising administering to said patient an angiogenesis-inhibiting amount of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0227] Another aspect of the invention is a method of inhibiting angiogenesis in a patient in need of such inhibition comprising administering to said patient an angiogenesis-inhibiting amount of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and administering at least one known anti-angiogenesis compound.

[0228] Another aspect of the invention is a method of inhibiting angiogenesis in a patient in need of such inhibition comprising administering to said patient an angiogenesis-inhibiting amount of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and administering at least one known anti-angiogenesis compound, wherein said anti-angiogenesis compound is selected from the group consisting of Marimastat, AG3340, Col-3, Neovastat, BMS-275291, Thalidomide, Squalamine, Endostatin, SU-5416, SU-6668, Interferon-alpha, Anti-VEGF antibody, EMD121974, CAI, Interleukin-12, IM862, Platelet Factor-4, Vitaxin, Angiostatin, Suramin, TNP-470, PTK-787, ZD-6474, ZD-101, Bay 129566, CGS27023A, VEGF receptor kinase inhibitors, docetaxel (e.g., Taxotere), and paclitaxel (e.g., Taxol).

[0229] Another aspect of the invention is a method of treating a disease in a patient in need of such treatment, said disease selected from the group consisting of gingivitis, respiratory viruses, herpes viruses, hepatitis viruses, HIV, Kaposi's sarcoma associated virus and atherosclerosis comprising administering to said patient a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0230] Another aspect of the invention is a method of treating an angiogenic ocular disease in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0231] Another aspect of the invention is a method of treating an angiogenic ocular disease in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein said angiogenic ocular disease is selected from the group consisting of ocular inflammation (e.g., Uveitis), retinopathy of prematurity, diabetic retinopathy, macular degeneration with the wet type preferred and corneal neovascularization.

[0232] Another aspect of the invention is a method of treating cancer in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and wherein said cancer being treated is selected from the group consisting of melanoma, gastric carcinoma or non-small cell lung carcinoma.

[0233] Another aspect of the invention is a method of treating cancer in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and administering at least one known anti-cancer agent and/or radiation therapy, and wherein said cancer being treated is selected from the group consisting of melanoma, gastric carcinoma or non-small cell lung carcinoma.

[0234] Another aspect of the invention is a method of treating cancer in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and administering at least one known anti-cancer agent and/or radiation therapy, wherein said cancer being treated is selected from the group consisting of melanoma, gastric carcinoma or non-small cell lung carcinoma, and wherein said anti-cancer agent is selected from the group consisting of alkylating agents, antimetabolites, natural products and their derivatives, hormones, anti-hormones, anti-angiogenic agents and steroids (including synthetic analogs), and synthetics.

[0235] Another aspect of the invention is a method of treating cancer in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and administering at least one known anti-cancer agent and/or radiationtherapy, wherein said cancer being treated is selected from the group consisting of melanoma, gastric carcinoma or non-small cell lung carcinoma, wherein said anti-cancer agent is selected from the group consisting of alkylating agents, antimetabolites, natural products and their derivatives, hormones, anti-hormones, anti-angiogenic agents and steroids (including synthetic analogs), and synthetics, and wherein said anti-angiogenic agent is selected form the group consisting of Marimastat, AG3340, Col-3, Neovastat, BMS-275291, Thalidomide, Squalamine, Endostatin, SU-5416, SU-6668, Interferon-alpha, Anti-VEGF antibody, EMD121974, CAI, lnterleukin-12, IM862, Platelet Factor-4, Vitaxin, Angiostatin, Suramin, TNP-470, PTK-787, ZD-6474, ZD-101, Bay 129566, CGS27023A, VEGF receptor kinase inhibitors, docetaxel (e.g., Taxotere), and paclitaxel (e.g., Taxol).

[0236] Another aspect of the invention is a method of treating cancer in a patient in need of such treatment comprising administering to said patient 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.

[0237] Another aspect of the invention is a method of treating cancer in a patient in need of such treatment comprising administering to said patient, concurrently or sequentially, an effective amount of (a) a compound of formula (I) and (b) a microtubule affecting agent (e.g., paclitaxel).

DETAILED DESCRIPTION

[0238] 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.

[0239] 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.

[0240] 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.

[0241] The term halogen or halo is intended to include fluorine, chlorine, bromine or iodine.

[0242] The term fluoroalkyl 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.

[0243] Aryl represents a carbocyclic group having from 6 to 14 carbon atoms and having at least one benzenoid ring, with all available substitutable aromatic carbon atoms of the carbocyclic group being intended as possible points of attachment. Examples include, but are not limited to, phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, anthracenyl, fluorenyl and the like. The aryl group can be substituted with one, two, or three substituents independently selected from lower alkyl, halo, cyano, nitro, haloalkyl, hydroxy, alkoxy, carboxy, carboxyalkyl, carboxamide, mercapto, sulfhydryl, amino, alkylamino, dialkylamino, sulfonyl, sulfonamido, aryl and heteroaryl.

[0244] aralkyl—represents a moiety containing an aryl group linked vial a lower alkyl;

[0245] alkylaryl—represents a moiety containing a lower alkyl linked via an aryl group;

[0246] cycloalkyl—represents a saturated carbocyclic ring having from 3 to 8 carbon atoms, preferably 5 or 6, which can be substituted.

[0247] 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, tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, piperazine, tetrahydropyridine, tetrahydropyrimidine, tetrahydrothiophene, tetrahydrothiopyran, morpholine, hydantoin, valerolactam, pyrrolidinone, and the like.

[0248] The term heterocyclic acidic functional group is intended to include groups such as, pyrrole, imidazole, triazole, tetrazole, and the like. Such groups can be unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of lower alkyl, halo, cyano, nitro, haloalkyl, hydroxy, alkoxy, carboxy, carboxyalkyl, carboxamide, sulfhydryl, amino, alkylamino, dialkylamino, sulfonyl, sulfonamido, aryl and heteroaryl.

[0249] 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 —O—, —S, and —N═, provided that the rings do not possess adjacent oxygen and/or sulfur atoms. The heteroaryl group can be substituted with one, two, or three substituents independently selected from lower alkyl, halo, cyano, nitro, haloalkyl, hydroxy, alkoxy, carboxy, carboxyalkyl, carboxamide, sulfhydryl, amino, alkylamino and dialkylamino.

[0250] 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).

[0251] Also included in the invention are tautomers, enantiomers and other optical isomers of compounds of Formula I, as well as pharmaceutically acceptable salts and solvates thereof.

[0252] 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-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

[0253] 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.

[0254] Examples of “one or more”, as used herein, include (a) 1, 2 or 3, (b) 1 or 2, and (c) 1.

[0255] Examples of “at least one”, as used herein, include (a) 1, 2 or 3, (b) 1 or 2, and (c) 1.

[0256] The following terms may be referred to herein by the abbreviations indicated: tetrahydrofuran (THF), ethanol (EtOH), methanol (MeOH), acetic acid (HOAc or AcOH), ethyl acetate (EtOAc), N,N-dimethylformamide (DMF), trifluoroacetic acid (TFA), trifluoroacetic anhydride (TFM), 1-hydroxybenzotriazole (HOBT), m-chloroperbenzoic acid (MCPBA), triethylamine (Et3N), diethyl ether (Et2O), ethyl chloroformate (ClCO2Et), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (DEC), N,N′-dicyclohexylcarbodiimide (DCC), sodium hydroxide (NaOH), magnesium sulfate (MgSO4), dichloromethane (CH2Cl2), ammonium hydroxide (NH4OH), sodium sulfate (Na2SO4), thin layer chromatography (TLC).

[0257] In a preferred group of compounds of formula (I), A is selected from the group consisting of

[0258] wherein,

[0259] R7 and R8 are the same or different and each is independently selected from the group consisting of

[0260] a) H,

[0261] b) alkyl,

[0262] c) aryl,

[0263] d) heteroaryl,

[0264] e) arylalkyl,

[0265] f) heteroarylalkyl,

[0266] g) cycloalkyl,

[0267] h) cycloalkylalkyl,

[0268] i) CO2R13,

[0269] j) CONR13R14,

[0270] k) fluoroalkyl,

[0271] l) alkynyl,

[0272] m) alkenyl,

[0273] n) alkynylalkyl,

[0274] o) alkenylalkyl and

[0275] p) cycloalkenyl,

[0276] wherein said alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, fluoroalkyl, alkynyl, alkenyl, alkynylalkyl, alkenylalkyl, and cycloalkenyl groups are optionally substituted with one or more substituents selected from the group consisting of:

[0277] a) cyano;

[0278] b) CO2R13;

[0279] c) C(O)NR13R14;

[0280] d) SO2NR13R14,

[0281] e) NO2;

[0282] f) CF3;

[0283] g) —OR13;

[0284] h) —NR13R14;

[0285] i) —O(C═O)R13;

[0286] j) —O(C═O)NR13R14, and

[0287] k) halogen;

[0288] R9 is selected from the group consisting of:

[0289] a) R13,

[0290] b) halogen,

[0291] c) —CF3,

[0292] d) —COR13,

[0293] e) —OR13,

[0294] f) —NR13R14,

[0295] g) —NO2,

[0296] h) cyano,

[0297] i) —SO2R13,

[0298] j) —SO2NR13R14,

[0299] k) —NR13COR14,

[0300] l) —CONR13R14,

[0301] m) —NR13CO2R14,

[0302] n) CO2R13 and

[0303] B is selected from the group consisting of:

[0304] wherein,

[0305] R2 is selected from the group consisting of:

[0306] a) hydrogen,

[0307] b) OH,

[0308] c) C(O)OH,

[0309] d) SH,

[0310] e) SO2NR13R14,

[0311] f) NHC(O)R13,

[0312] g) NHSO2NR13R14,

[0313] h) NR13R14,

[0314] i) NHSO2R13,

[0315] j) C(O)NR13R14,

[0316] k) C(O)NHOR13,

[0317] l) C(O)NR13OH,

[0318] m) OC(O)R13 and

[0319] n) an optionally substituted heterocyclic acidic functional group, with the proviso that if R2 is SO2NR13R14, at least one of R13 and R14 must be hydrogen;

[0320] R3 and R4 are the same or different and each is independently selected from the group consisting of:

[0321] a) hydrogen,

[0322] b) halogen,

[0323] c) alkyl,

[0324] d) alkoxy,

[0325] e) OH,

[0326] f) CF3,

[0327] g) OCF3,

[0328] h) NO2,

[0329] i) C(O)R13,

[0330] j) C(O)OR13,

[0331] k) C(O)NR13R14,

[0332] l) SO(t)NR13R14,

[0333] m) SO(t)R13,

[0334] n) C(O)NR13OR14,

[0335] p) cyano,

[0336] q) aryl and

[0337] r) heteroaryl,

[0338] wherein said aryl or heteroaryl group is optionally substituted with one or more R9 group;

[0339] R5 and R6 are the same or different and each is independently selected from the group consisting of:

[0340] a) hydrogen,

[0341] b) halogen,

[0342] c) alkyl,

[0343] d) alkoxy,

[0344] e) CF3,

[0345] f) OCF3,

[0346] g) NO2,

[0347] h) C(O)R13,

[0348] i) C(O)OR13,

[0349] j) C(O)NR13R14,

[0350] k) SO(t)NR13R14,

[0351] l) C(O)NR13OR14,

[0352] m) cyano,

[0353] n) aryl and

[0354] o) heteroaryl,

[0355] wherein said aryl or heteroaryl group is optionally substituted with one or more R9 group;

[0356] R10 and R11 are the same or different and each is independently selected from the group consisting of:

[0357] a) hydrogen,

[0358] b) halogen,

[0359] c) CF3,

[0360] d) OCF3,

[0361] e) NR13R14,

[0362] f) NR13C(O)NR13R14,

[0363] g) OH,

[0364] h) C(O)OR13,

[0365] i) SH,

[0366] j) SO(t)NR13R14,

[0367] k) SO2R13,

[0368] l) NHC(O)R13,

[0369] m) NHSO2NR13R14,

[0370] n) NHSO2R13,

[0371] o) C(O)NR13R14,

[0372] p) C(O)NR13OR 14,

[0373] q) OC(O)R13 and

[0374] r) cyano;

[0375] R12 is selected from the group consisting of:

[0376] a) hydrogen,

[0377] b) OC(O)R13,

[0378] c) aryl,

[0379] d) heteroaryl,

[0380] e) arylalkyl,

[0381] f) cycloalkyl,

[0382] g) alkyl,

[0383] h) cycloalkylalkyl and

[0384] i) heteroarylalkyl

[0385] wherein said aryl, heteroaryl, arylalkyl, cycloalkyl, alkyl, cycloalkylalkyl or heteroarylalkyl group is optionally substituted with one or more R9 group;

[0386] R13 and R14 are the same or different and each is independently selected from the group consisting of:

[0387] a) H;

[0388] b) alkyl,

[0389] c) aryl,

[0390] d) heteroaryl,

[0391] e) arylalkyl,

[0392] f) heteroarylalkyl,

[0393] g) cycloalkyl,

[0394] h) cycloalkylalkyl and

[0395] i) fluoroalkyl,

[0396] wherein said alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, and fluoroalkyl groups are optionally substituted with one or more substituents selected from the group consisting of:

[0397] a) alkyl,

[0398] b) aryl,

[0399] c) arylalkyl,

[0400] d) fluoroalkyl,

[0401] e) cycloalkyl,

[0402] f) cycloalkylalkyl,

[0403] g) heteroaryl,

[0404] h) heteroarylalkyl,

[0405] i) amino,

[0406] j) carbonyl and

[0407] k) halogen or

[0408] R13 and R14 when taken together with the atoms to which they are attached can form a 3 to 7 membered heterocyclic ring wherein when the ring formed is a 6 or 7 membered heterocyclic ring, said ring optionally contains one to two additional heteroatoms independently selected from the group consisting of O, S and N and wherein said heterocyclic ring can be substituted with one or more substituents selected from the group consisting of:

[0409] a) alkyl,

[0410] b) aryl,

[0411] c) arylalkyl,

[0412] d) fluoroalkyl,

[0413] e) cycloalkyl,

[0414] f) cycloalkylalkyl,

[0415] g) heteroaryl,

[0416] h) heteroarylalkyl,

[0417] i) amino,

[0418] j) carbonyl and

[0419] k) halogen;

[0420] n is 0-6;

[0421] m is 1-5;

[0422] p is 0-4 and

[0423] t is 1 or 2.

[0424] Preferably, R1 and R15 are the same or different and are individually selected from the group consisting of H, methyl, aryl and cyclohexyl.

[0425] More preferably, A is selected from the group consisting of:

[0426] wherein,

[0427] R7 and R8 are the same or different and each is independently selected from the group consisting of H, alkyl, fluoroalkyl such as, CF3 and CF2CH3, cycloalkyl and cycloalkylalkyl, such as, for example, methyl, ethyl, t-butyl, isopropyl, cyclopropyl, cyclopropylmethyl and cyclohexyl and

[0428] R9 is selected from the group consisting of H, halogen (e.g. bromine, fluorine or chlorine), CH3, CF3, fluoroalkyl, cyano, —OCH3, and NO2.

[0429] More preferably, B is selected from the group consisting of:

[0430] wherein

[0431] R2 is selected from the group consisting of H, OH, NHC(O)R13 and NHSO2R13;

[0432] R3 is selected from the group consisting of SO2NR13R14, NO2, cyano, C(O)NR13R14, SO2R13; and C(O)OR13;

[0433] R4 is selected from the group consisting of H, NO2, halo, cyano, CH3 and CF3;

[0434] R5 is selected from the group consisting of H, CF3, NO2, halo and cyano;

[0435] R6 is selected from the group consisting of H, alkyl and CF3;

[0436] R10 and R11 are the same or different and each is independently selected from the group consisting of:

[0437] a) hydrogen,

[0438] b) halo,

[0439] c) CF3,

[0440] d) OCF3,

[0441] e) NR13R14,

[0442] f) NR13C(O)NR13R14,

[0443] g) OH,

[0444] h) C(O)OR13,

[0445] i) SH,

[0446] j) SO(t)NR13R14,

[0447] k) SO2R13,

[0448] l) NHC(O)R13,

[0449] m) NHSO2NR13R14,

[0450] n) NHSO2R13,

[0451] o) C(O)NR13R14,

[0452] p) C(O)NR13OR14,

[0453] q) OC(O)R13,

[0454] r) COR13,

[0455] s) OR13 and

[0456] t) cyano;

[0457] R12 is selected from the group consisting of hydrogen and C(O)OR13;

[0458] R13 and R14 are the same or different and each is independently selected from the group consisting of methyl, ethyl and isopropyl; or

[0459] R13 and R14 when taken together with the atoms to which they are attached can form a 3 to 7 membered heterocyclic ring wherein when the ring formed is a 6 or 7 membered heterocyclic ring, said ring optionally contains one to two additional heteroatoms independently selected from the group consisting of O, S and N and wherein said heterocyclic ring can be substituted with one or more substituents selected from the group consisting of:

[0460] a) alkyl,

[0461] b) aryl,

[0462] c) arylalkyl,

[0463] d) fluoroalkyl,

[0464] e) cycloalkyl,

[0465] f) cycloalkylalkyl,

[0466] g) heteroaryl,

[0467] h) heteroarylalkyl,

[0468] i) amino,

[0469] j) carbonyl and

[0470] k) halogen.

[0471] Even more preferably, A is selected from:

[0472] wherein,

[0473] R7 is selected from the group consisting of H, CF3, fluoroalkyl, alkyl and cycloalkyl;

[0474] R8 is selected from the group consisting of H, alkyl and fluoroalkyl;,

[0475] R9 is selected from the group consisting of H, F, Cl, Br, CF3, alkyl and fluroalkyl.

[0476] Still even more preferably, A is selected from the group consisting of:

[0477] wherein,

[0478] R7 is selected from the group consisting of H, CF3, CF2CH3, methyl, ethyl, isopropyl, cyclopropyl and t-butyl;

[0479] R8 is H;

[0480] R9 is selected from the group consisting of H, F, Cl, Br, CF3, alkyl and fluroalkyl; and

[0481] B is:

[0482] wherein:

[0483] R2 is selected from the group consisting of H, OH, NHC(O)R13 and NHSO2R13;

[0484] R3 is selected from the group consisting of SO2NR13R14, NO2, cyano, C(O)NR13R14, SO2R13; and C(O)OR13;

[0485] R4 is selected from the group consisting of H, NO2, halo, cyano, CH3 and CF3;

[0486] R5 is selected from the group consisting of H, CF3, NO2, halo and cyano;

[0487] R6 is selected from the group consisting of H, alkyl and CF3; and

[0488] R13 and R14 are the same or different and each is independently selected from the group consisting of methyl, ethyl and isopropyl; or

[0489] R13 and R14 when taken together with the atoms to which they are attached can form a 3 to 7 membered heterocyclic ring wherein when the ring formed is a 6 or 7 membered heterocyclic ring, said ring optionally contains one to two additional heteroatoms independently selected from the group consisting of O, S and N and wherein said heterocyclic ring can be substituted with one or more substituents selected from the group consisting of:

[0490] a) alkyl,

[0491] b) aryl,

[0492] c) arylalkyl,

[0493] d) fluoroalkyl,

[0494] e) cycloalkyl,

[0495] f) cycloalkylalkyl,

[0496] g) heteroaryl,

[0497] h) heteroarylalkyl,

[0498] i) amino,

[0499] j) carbonyl and

[0500] k) halogen.

[0501] Yet even still more preferred,

[0502] A is selected from the group consisting of:

[0503] and B is:

[0504] wherein:

[0505] R2 is selected from the group consisting of H, OH, NHC(O)R13 and NHSO2R13;

[0506] R3 is selected from the group consisting of SO2NR13R14, C(O)NR13R14, SO2R13, NO2 or cyano;

[0507] R4 is selected from the group consisting of H, NO2, CF3, CH3, halo and cyano,

[0508] R5 is selected from the group consisting of H, halo, NO2, cyano and CF3;

[0509] R6 is selected from the group consisting of H, CF3 and alkyl;

[0510] R7 is selected from the group consisting of H, CF3, CF2CH3, methyl, ethyl, isopropyl, cyclopropyl and t-butyl;

[0511] R8 is H;

[0512] R9 is selected from the group consisting of H, F, Cl, Br, CF3, alkyl, and fluroalkyl; and

[0513] R13 and R14 are each independently selected from the group consisting of methyl and ethyl.

[0514] Most preferably,

[0515] A is selected from the group consisting of:

[0516] and B is

[0517] wherein,

[0518] R2 is —OH;

[0519] R3 is CONR13R14;

[0520] R4 is selected from the group consisting of H, CH3, halo and CF3;

[0521] R5 is selected from the group consisting of H and cyano;

[0522] R6 is selected from the group consisting of H, CH3 and CF3; and

[0523] R13 and R14 are each methyl.

[0524] Representative compounds of the invention are listed below:

[0525] Preferred compounds of the invention are listed below.

[0526] More preferred compounds of the invention are listed below:

[0527] For compounds of the invention having at least one asymmetrical carbon atom, all isomers, including diastereomers, enantiomers and rotational isomers are contemplated as being part of this invention. The invention includes d and l isomers in both pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, or by separating isomers of a compound of formula (I).

[0528] Compounds of formula (I) 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 purposes of this invention.

[0529] A compound of formula (I) may form pharmaceutically acceptable salts with organic and inorganic acids or bases. Examples of suitable bases for salt formation include but are not limited to sodium hydroxide, lithium hydroxide, potassium hydroxide, and calcium hydroxide. Salts of phenols can be made by heating acidic compounds with any of the above mentioned bases according to procedures well known to those skilled in the art. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, 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 forms 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 sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, ammonia or sodium bicarbonate. The neutral forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective neutral forms for purposes of the invention.

[0530] For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers 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 in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.

[0531] 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.

[0532] Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g., nitrogen.

[0533] Also included are solid form preparations that 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.

[0534] 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.

[0535] The compounds of the invention may also be delivered by direct application to the tumor site following surgery, e.g., in a sponge preparation.

[0536] Preferably the compound is administered orally.

[0537] Preferably, the pharmaceutical preparation is in a unit dosage form. 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.

[0538] 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 application.

[0539] 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.

[0540] 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.

[0541] Another aspect of the invention is a method for 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 chemotherapeutic agent (i.e. an antineoplastic agent, microtubule affecting agent or anti-angiogenesis agent).

[0542] In a preferred embodiment, a compound of formula (I) is combined with one of the following antineoplastic agents: gemcitabine, paclitaxel (Taxol®), 5-Fluorouracil (5-FU), cyclophosphamide (Cytoxan®), temozolomide, taxotere or Vincristine.

[0543] Classes of compounds that can be used as the chemotherapeutic agent (antineoplastic agent) include: alkylating agents, antimetabolites, natural products and their derivatives, hormones, anti-hormones, anti-angiogenic agents and steroids (including synthetic analogs), and synthetics. Examples of compounds within these classes are given below.

[0544] Alkylating agents (including nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes): Uracil mustard, Chlormethine, Cyclophosphamide (Cytoxan®), Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylene-melamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, and Temozolomide.

[0545] Antimetabolites (including folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors): Methotrexate, 5-Fluorouracil, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, Pentostatine, and Gemcitabine.

[0546] Natural products and their derivatives (including vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins): Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, paclitaxel (paclitaxel 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-α), Etoposide, and Teniposide.

[0547] Hormones and steroids (including synthetic analogs): 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Tamoxifen, Methylprednisolone, Methyl-testosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, Zoladex.

[0548] Synthetics (including inorganic complexes such as platinum coordination complexes): Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, and Hexamethylmelamine.

[0549] Anti-angiogenic agents include Marimastat, AG3340, Col-3, Neovastat, BMS-275291, Thalidomide, Squalamine, Endostatin, SU-5416, SU-6668, Interferon-alpha, Anti-VECF antibody, EMD121974, CAI, Interleukin-12, IM862, Platelet Factor-4, Vitaxin, Angiostatin, Suramin, TNP-470, PTK-787, ZD-6474, ZD-101, Bay 129566, CGS27023A, taxotere and Taxol.

[0550] 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., 1996 edition (Medical Economics Company, Montvale, N.J. 07645-1742, USA); the disclosure of which is incorporated herein by reference thereto.

[0551] 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, microtubule stabilizing agents or agents which disrupt microtubule formation.

[0552] 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), Halichondrin 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), thiocolchicine (NSC 361792), trityl cysteine (NSC 83265), vinblastine sulfate (NSC 49842), vincristine sulfate (NSC 67574), epothilone A, epothilone, and discodermolide (see Service, (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.

[0553] Particularly preferred agents are compounds with paclitaxel-like activity. These include, but are not limited to paclitaxel and paclitaxel derivatives (paclitaxel-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. Pat. 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).

[0554] 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, Horwitz (1992) Trends Pharmacol. Sci. 13: 134-146, Rowinsky (1990) J. Natl. Canc. Inst. 82: 1247-1259).

[0555] 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).

[0556] 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.).

[0557] 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. Sci., 45(2):145-150.

[0558] 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. Pat. No. 5,569,720 also provides in vitro and in vivo assays for compounds with paclitaxel-like activity.

[0559] 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, N.J. 07645-1742, USA); the disclosure of which is incorporated herein by reference thereto.

[0560] The amount and frequency of administration of the compounds of formula (I) 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) 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. Intermittent therapy (e.g., one week out of three weeks or three out of four weeks) may also be used.

[0561] 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.

[0562] In the methods of this invention, a compound of formula (I) 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 the radiation and the compound of formula (I), should be administered simultaneously or essentially simultaneously. The advantage of a simultaneous or essentially simultaneous administration is well within the determination of the skilled clinician.

[0563] Also, in general, the compound of formula (I) 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) 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.

[0564] The particular choice of a compound of formula (I), and chemotherapeutic 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.

[0565] The compound of formula (I), 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).

[0566] If the compound of formula (I) 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 the chemotherapeutic agent and/or radiation, may not be important. Thus, the compound of formula (I) may be administered first followed by the administration of the chemotherapeutic agent and/or radiation; or the chemotherapeutic agent and/or radiation may be administered first followed by the administration of the compound of formula (I). This alternate 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 a compound of formula (I) followed, where determined advantageous, by the administration of the chemotherapeutic agent and/or radiation, and so on until the treatment protocol is complete.

[0567] Thus, in accordance with experience and knowledge, the practicing physician can modify each protocol for the administration of a component (therapeutic agent—i.e., the compound of formula (I), chemotherapeutic agent or radiation) of the treatment according to the individual patient's needs, as the treatment proceeds.

[0568] 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

[0569] 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-α chemokine which may be demonstrated by the following in vitro assays.

[0570] Receptor Binding Assays:

[0571] CXCR1 SPA Assay

[0572] For each well of a 96 well plate, a reaction mixture of 10 μg hCXCR1-CHO overexpressing membranes (Biosignal) and 200 μg/well WGA-SPA beads (Amersham) in 100 μl is prepared in CXCR1 assay buffer (25 mM HEPES, pH 7.8, 2 mM CaCl2, 1 mM MgCl2, 125 mM NaCl, 0.1% BSA) (Sigma). A 0.4 nM stock of ligand, [125I]-IL-8 (NEN) is prepared in the CXCR1 assay buffer. 20× stock solutions of test compounds are prepared in DMSO (Sigma). A 6× stock solution of IL-8 (R&D) is prepared in CXCR2 assay buffer. The above solutions are added to a 96-well assay plate (PerkinElmer) as follows: 10 μl test compound or DMSO, 40 μl CXCR1 assay buffer or IL-8 stock, 100 μl of reaction mixture, 50 μl of ligand stock (Final [Ligand]=0.1 nM). The assay plates are shaken for 5 minutes on plate shaker, then incubated for 8 hours before cpm/well are determined in Microbeta Trilux counter (PerkinElmer). % Inhibition of Total binding-NSB (250 nM IL-8) is determined for IC50 values.

[0573] CXCR2 SPA Assay

[0574] For each well of a 96 well plate, a reaction mixture of 4 μg hCXCR2-CHO overexpressing membranes (Biosignal) and 200 μg/well WGA-SPA beads (Amersham) in 100 μl is prepared in CXCR2 assay buffer (25 mM HEPES, pH 7.4, 2 mM CaCl2, 1 mM MgCl2). A 0.4 nM stock of ligand, [125I]-IL-8 (NEN), is prepared in the CXCR2 assay buffer. 20× stock solutions of test compounds are prepared in DMSO (Sigma). A 6× stock solution of GRO-α (R&D) is prepared in CXCR2 assay buffer. The above solutions are added to a 96-well assay plate (PerkinElmer or Corning) as follows: 10 μl test compound or DMSO, 40 μl CXCR2 assay buffer or GRO-α stock, 100 μl of reaction mixture, 50 μl of ligand stock (Final [Ligand]=0.1 nM). When 40× stock solutions of test compounds in DMSO are prepared, then the above protocol is used except instead 5 μl test compound or DMSO and 45 μl CXCR2 assay buffer are used. The assay plates are shaken for 5 minutes on a plate shaker, then incubated for 2-8 hours before cpm/well are determined in Microbeta Trilux counter (PerkinElmer). % Inhibition of total binding minus non-specific binding (250 nM Gro-α or 50 μM antagonist) is determined and IC50 values calculated.

[0575] Calcium Fluorescence Assay (FLIPR)

[0576] HEK 293 cells stably transfected with hCXCR2 and Gαι/q are 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 are then incubated with 4 mM fluo-4, AM (Molecular Probes) in Dye Loading Buffer (1% FBS, HBSS w. Ca & Mg, 20 mM HEPES (Cellgro), Probenicid (Sigma)) for 1 hour. The cultures are washed with wash buffer (HBSS w Ca, & Mg, 20 mM HEPES, Probenicid (2.5 mM)) three times, then 100 μl/well wash buffer is added.

[0577] During incubation, compounds are prepared as 4× stocks in 0.4% DMSO (Sigma) and wash buffer and added to their respective wells in the first addition plate. IL-8 or GRO-α (R&D Systems) concentrations are prepared 4× in wash buffer +0.1% BSA and added to their respective wells in second addition plate.

[0578] Culture plate and both addition plates are then placed in the FLIPR imaging system to determine change in calcium fluorescence upon addition of compound and then ligand. Briefly, 50 μl of compound solutions or DMSO solution is 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 μl of ligand is then added and the change in calcium fluorescence measured by the FLIPR instrument for 1 minute. The area under each stimulation curve is determined and the values are used to determine % Stimulation by compound (agonist) and % Inhibition of Total Calcium response to ligand (0.3 nM IL-8 or GRO-α) for IC50 values of the test compounds.

[0579] Chemotaxis Assays for 293-CXCR2

[0580] 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:

[0581] 1. Inserts are coated with collagenIV (2 μg/ml) for 2 hrs at 37° C.

[0582] 2. The collagen is removed and inserts are allowed to air dry overnight.

[0583] 3. Cells are labeled with 10 μM calcein AM (Molecular Probes) for 2 hrs. Labeling is done in complete media with 2% FBS.

[0584] 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 0.25 nM 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.

[0585] 5. Plate is incubated for 2 hrs and inserts are removed and placed in a new 24 well. Fluorescence is detected at excitation=485 nM and emission=530 nM.

[0586] Cytotoxicity Assays

[0587] 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:

[0588] 1. 293-CXCR2 cells are plated overnight at a concentration of 5000 cells per well in complete media.

[0589] 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 48 hrs. Cells are labeled with 1 μM calcein AM for 15 minutes to determine cell viability. Detection method is the same as above.

[0590] Soft Agar Assay

[0591] 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 (1 mg/ml in PBS). Plates are then scanned to determine colony number and size. IC50 is determined by comparing total area vs. compound concentration.

[0592] Compounds of this invention may exhibit a range of CXCR2 receptor binding activities from about 1 nM to about 10,000 nM.

[0593] Compounds of formula (I) may be produced by processes known to those skilled in the art in the following reaction schemes and in the preparations and examples below.

[0594] Condensation of dibromomaleic anhydride with a substituted or unsubstituted hydrazine would give the cyclic hydrazide derivative B. Condensation of B with one equivalent of an amine (ANH2) would give C, while the addition of a second amine (BNH2) would give D.

[0595] Alternatively, a cyclic hydrazide with an available acidic N-H could be deprotonated with a base and alkylated by a suitable electrophile to give the corresponding N-substituted cyclic hydrazide. This intermediate could be carried further to the desired target as described in Scheme I.

[0596] The following examples illustrate the preparation of some of the compounds of the invention and are not to be construed as limiting the invention disclosed herein. Alternate mechanistic pathways and analogous structures will be apparent to those skilled in the art.

Preparative Example 1

[0597]

[0598] 3-Nitrosalicylic acid (500 mg, 2.7 mmol), DCC (563 mg) and ethyl acetate (10 mL) were combined and stirred for 10 min. (R)-(−)-2-pyrrolidinemethanol (0.27 mL) was added and the resulting suspension was stirred at room temperature overnight. The solid was filtered and the filtrate washed with 1N NaOH. The aqueous phase was acidified and extracted with EtOAc. The resulting organic phase was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the residue by preparative plate chromatography (silica gel, 5% MeOH/CH2Cl2 saturated with AcOH) gave the product (338 mg, 46%, MH+=267).

Preparative Example 2

[0599]

[0600] 3-Nitrosalicylic acid (9.2 g), bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP, 23 g) and N,N-diisopropylethylamine (DIEA, 26 mL) in anhydrous CH2Cl2 (125 mL) were combined and stirred at 25° C. for 30 min. (R)-(+)-3-pyrrolidinol (8.7 g) in CH2Cl2 (25 mL) was added over 25 min and the resulting suspension was stirred at room temperature overnight. The mixture was extracted with 1M NaOH (aq) and the organic phase was discarded. The aqueous phase was acidified with 1M HCl (aq), extracted with EtOAc, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the crude product (7 g) which was used without further purification.

[0601] Step B

[0602] 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/CH2Cl2 saturated with NH4OH) to give the product (2.5 g, 41%, MH+=223).

Preparative Example 3-9

[0603] Following the procedures set forth in Preparative Example 2 but using the carboxylic acid, amine, and appropriate coupling agent (PyBrop) listed in the Table below, the amide product was obtained and used without further purification.

11. Coupling AgentPrep.2. % YieldEx.Carboxylic acidAmineAmide Product3. MH+3

1. PyBrop 2. 87%, 86% 3. 1814

1. PyBroP 2. 49% 3. 2095

NH3

1. PyBroP 2. 95% 3. 1536

1. PyBroP 2. 83% 3. 1677

1. PyBroP 2. 76% 3. 2238

1. PyBroP 2. 59, 69 3. 2079

1. PyBroP 2. 49, 86 3. 237

Preparative Example 10

[0604]

[0605] Step A

[0606] Following a similar procedure as in Preparative Example 1 except substituting dimethylamine (2M in THF, 33 mL) for (R)-(−)-2-pyrrolidinemethanol and 5-methylsalicylic acid (5 g) for 3-nitrosalicylic acid, the product was prepared (6.5 g).

[0607] Step B

[0608] 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 CH2Cl2, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the product as a solid (2.1 g, 44%, MH+=225).

[0609] Step C

[0610] The product was prepared following a similar procedure as described in Preparative Example 2, Step B (0.7 g, 99%, MH+=195).

Preparative Example 11

[0611]

[0612] Step A

[0613] Following a similar procedure as in Preparative Example 2 Step A, except substituting dimethylamine for (R)-(−)-2-pyrrolidinemethanol, the product was prepared.

[0614] Step B

[0615] The product from step A above (8 g) was combined with iodine (9.7 g), silver sulfate (11.9 g), EtOH (200 mL) and water (20 mL) and stirred overnight. Filtration, concentration of the filtrate, re-dissolution in CH2Cl2 and washing with 1M HCl (aq) gave an organic solution which was dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford the product (7.3 g, 57%, MH+=337).

[0616] Step C

[0617] The product from Step B above (3.1 g) was combined with DMF(50 mL) and Mel (0.6 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 CH2Cl2, washed with 1M NaOH (aq), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification through a silica gel column (EtOAc/Hex, 1:1) gave the product (1.3 g, 41%, MH+=351).

[0618] Step D

[0619] The product from Step D above (200 m g), 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 MgSO4, filtered, concentrated in vacuo and purified by preparative plate chromatography (Silica, EtOAc/Hex, 1:1) to give the product (62 mg, 44%, MH+=250).

[0620] Step E

[0621] BBr3 (1.3 mL, 1M in CH2Cl2) was added to a CH2Cl2 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 CH2Cl2, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give the product (158 mg, MH+=236).

[0622] Step F

[0623] A mixture of the product from step E above (160 mg), platinum oxide (83%, 19 mg), and EtOH (20 mL) was stirred under hydrogen (25-40 psi) for 1.5 hr. Filtration through celite and concentration in vacuo afforded the product (165 mg, MH+=206).

Preparative Example 12

[0624]

[0625] Step A

[0626] Following a similar procedure as in Preparative Example 1 except substituting dimethylamine (2M in THF, 50 mL) for (R)-(−)-2-pyrrolidinemethanol and 4-methylsalicylic acid (15 g) for 3-nitrosalicylic acid, the product was prepared (6.3 g, 35%).

[0627] Step B

[0628] The product from step A above (1.5 g) was combined with iodine (2.1 g), NaHCO3 (1.1 g), EtOH (40 mL) and water (10 mL) and stirred overnight. Filtration, concentration of the filtrate, re-dissolution in CH2Cl2 and washing with 1M HCl (aq) gave an organic solution which was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 0.5-0.7% MeOH/CH2Cl2) gave the product (0.3 g, 57%, MH+=306).

[0629] Step C

[0630] 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 CH2Cl2, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give the product as a solid (0.8 g, 92%, MH+=351).

[0631] Step D

[0632] 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 parr shaker under hydrogen (45 psi) for 1.5 hr. Filtration through celite 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).

Preparative Example 13

[0633]

[0634] Step A

[0635] 3-Nitro-1,2-phenylenediamine(10 g), sodium nitrite (5.4 g) and acetic acid (20 mL) were heated at 60° 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.

[0636] Step B

[0637] The product from Step A above (2.8 g) was stirred 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 (2.2 g, MH+=135).

Preparative Example 14

[0638]

[0639] Step A

[0640] 4-Bromopyrazole-3-carboxylic acid was prepared according to known methods, see: Yu. A. M.; Andreeva, M. A.; Perevalov, V. P.; Stepanov, V. I.; Dubrovskaya, V. A.; and Seraya, V. I. in Zh. Obs. Khim. (Journal of General Chemistry of the USSR) 1982, 52, 2592, and refs cited therein.

[0641] Step B

[0642] To a solution of 4-bromopyrazole-3-carboxylic acid (2.0 g), available from step A, in 65 mL of anhydrous DMF was added bromotripyrrolidinophosphonium hexafluorophosphate (PyBrop, 4.60 g), dimethyl amine (10 mL, 2.0 M in THF) and diisopropylethyl amine (5.2 mL) at 25° C. The mixture was stirred for 26 h, and concentrated under reduced pressure to an oily residue. This residue was treated with a 1.0 M NaOH aqueous solution, and extracted with ethyl acetate (4×50 mL). The organic extracts were combined, washed with brine, and dried with anhydrous Na2SO4. Removal of solvents yielded an oil, which was purified by preparative thin layer chromatography, eluting with CH2Cl2—MeOH (20:1), to give 1.09 g of the amide product (48%, MH+=232.0).

[0643] Step C

[0644] To a solution of the amide (0.67 g), obtained from step B, in 8 mL of concentrated sulfuric acid at 0° C. was added potassium nitrate (1.16 g) in small portions. The cooling bath was removed and the mixture was heated at 110° C. for 6 h. After cooled to 25° C., the mixture was poured into 80 mL of H2O, and an additional 20 mL of H2O was used as rinsing. The aqueous mixture was extracted with CH2Cl2 (100 mL×4). The combined extracts were washed with brine (50 mL), sat. NaHCO3 aqueous solution (50 mL), brine (50 mL), and dried over Na2SO4. Evaporation of solvent gave a light yellow 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)

[0645] Step D

[0646] 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 yellowish mixture was poured into 30 mL of H2O, and the aqueous mixture was extracted with ethyl acetate (30 mL×4). The extracts were combined, washed with brine (10 mL), 5% NaHCO3 aqueous solution (10 mL) and brine (10 mL). The organic layer was dried with Na2SO4 and concentrated under reduced pressure to a residue, which was purified by preparative thin layer chromatography eluting with CH2Cl2—MeOH (20:1 ) to give the hydroxylated product (5 mg, 10%, MH+=215.3).

[0647] Step E

[0648] If one were to treat the hydroxylated product of Step D with H2 under the conditions of 10% palladium on carbon in ethanol, one would obtain the hydroxylamino compound.

Preparative Example 15

[0649]

[0650] Step A

[0651] Following a similar procedure used in Preparative Example 12 Step C except starting with the known compound, 4-methyl-pyrimidin-5-ol, the product of Step A could be prepared.

[0652] Step B

[0653] Following a similar oxidation procedure used in Preparative Example 14 Step A starting with the product from Step A above, the product of Step B could be prepared.

[0654] Step C

[0655] Following a similar procedure used in Preparative Example 10 Step A starting with the product from Step B above, the product of Step C could be prepared.

[0656] Step D

[0657] Following a similar procedure used in Preparative Example 11 Step F starting with the product of Step C above, the product of Step D could be prepared.

Preparative Example 16

[0658]

[0659] Step A

[0660] Following a similar procedure used in Preparative Example 10 Step A starting with the known 4-hydroxynicotinic acid, the product could be prepared.

[0661] Step B

[0662] Following a similar procedure used in Preparative Example 12 Step C starting with the product from Step A above, the product of Step B could be prepared.

[0663] Step C

[0664] Following a similar procedure used in Preparative Example 11 Step F starting with product from Step C above, the amine product could be prepared.

Preparative Example 17

[0665]

[0666] Step A

[0667] Following a similar procedure used in Preparative Example 12 Step C but starting with the compound in Step A above, the nitro product could be prepared.

[0668] Step B

[0669] Stirring the nitro product from Step A above, with a suitable Pt or Pd catalyst and EtOH under a hydrogen atmosphere (1-4 atm), the amine product could be obtained.

Preparative Example 18

[0670]

[0671] Step A

[0672] To a solution of 5-nitro-3-pyrazolecarboxylic acid (5.0 g, 31.83 mmol) in 160 mL of acetonitrile at room temperature was added bromotripyrrolidinophosphonium hexa-fluorophosphate (PyBrop, 14.9 g, 31.98 mmol) in small portions. A 2.0 M solution of dimethylamine in THF (40.0 mL, 80.0 mmol) was added to the mixture followed by a solution of diisopropylethylamine (14.0 mL, 80.2 mmol). After stirred for 36 h, the mixture was concentrated under reduced pressure to a residue, a mixture of solid and oil. Small volume of CH2Cl2 was added until all oily material was dissolved and fine colorless solid precipitated out. The solid was collected by filtration as the first crop of the product. The filtrate was concentrated to an oily residue which was treated with a mixture of CH2Cl2— hexanes (˜1:1, v/v), and the colorless precipitation was filtered out as the second crop of the product. The combined solid product was further dried on high vacuum for several hours to afford 5.86 g (100%) of N,N′-dimethyl 5-nitro-3-pyrazolecarboxamide as a solid (MH+=185.0).

[0673] Step B

[0674] To a solution of N,N′-dimethyl 5-nitro-3-pyrazole amide (5.86 g, 31.83 mmol, available from step A) in 215 mL of anhydrous THF at room temperature was added solid lithium methoxide in small portions. After 45 min, iodomethane was added dropwise. Stirring was continued for 2.5 days. The mixture was filtered through a 1.5-in silica gel pad, rinsing with large excess volume of ethyl acetate. The combined filtrate and rinsing were concentrated to a dark yellow oil, which was purified by flash column chromatography, eluting with hexanes, CH2Cl2, and CH2Cl2—MeOH (50:1). Removal of solvents afforded 5.10 g (81%) of N,N′-dimethyl 1-methyl-5-nitro-3-pyrazole amide as a solid (MH+=199.0), contaminated by ˜13% of 2-methylated isomer.

[0675] Step C

[0676] A solution of N,N′-dimethyl 1-methyl-5-nitro-3-pyrazolecarboxamide (5.10 g, 25.29 mmol), obtained from step B, in 250 mL of ethanol was degassed via house vacuum, and then refilled with nitrogen. Solid palladium (10% on activated carbon, wet with <50% water, 2.5 g) was added, the black suspension was degassed via house vacuum and then refilled with hydrogen gas supplied by a gas balloon. The mixture was stirred at room temperature under a hydrogen atmosphere for 4 h, and filtered through a Celite pad, which was rinsed with ethanol. The filtrate and rinsing were combined, concentrated under reduced pressure to give 4.17 g (98%) of the amino-pyrazole product as a solid (MH+=169.0).

[0677] Step D

[0678] To a stirred solution of amino-pyrazole (1.0 g, 5.95 mmol), prepared in step C, in 40 mL of CH2Cl2 at room temperature was added benzyl chloroformate (2.7 mL, 17.97 mmol). Solid potassium carbonate (4.1 g, 29.71 mmol) was added in one portion. After 24 h, methanol (5 mL) was added to the mixture, and stirring was continued for additional 2 h. Insoluble material was removed by filtration, and washed with methanol. The combined filtrate and rinsing were concentrated under reduced pressure to a thick syrup, which was separated by preparative TLC (CH2Cl2—MeOH=30:1). The silica was extracted with MeOH and CH2Cl2, the extracts were filtered and concentrated under reduced pressure to yield 1.16 g (64%) of the pyrazole benzyl carbamate as a solid (MH+=303.1).

[0679] Step E

[0680] To a stirred solution of pyrazole benzyl carbamate (1.0 g, 3.31 mmol), obtained from step D, in 100 mL of toluene at room temperature was added “Clayfen” (see note below) (3.5 g ) in one portion. The dark purplish suspension was heated to 70° C. and continued at 70-80° C. for 2.5 d. After cooled to room temperature, the mixture was filtered through a thin Celite pad. The solid residue and the filtration pad were rinsed with CH2Cl2, and filtered. The combined filtrates were concentrated to a yellowish oil, which was purified by preparative TLC (CH2Cl2—MeOH=20:1). The silica was extracted with CH2Cl2 and methanol, the extracts were filtered and concentrated under reduced pressure to give 0.822 g (72%) of the nitro-pyrazole benzyl carbamate as an oil (MH+=348.1). Note: “Clayfen”, clay-supported Iron (III) nitrate, was prepared according to literature procedures, see: Cornelis, A.; Laszlo, P. Synthesis, 1980, 849. To a stirred acetone solution (30 mL) at room temperature was added solid Fe(NO3)3.9H2O (1.8 g) in small portions. After 5 min, K-10 bentonite clay (2.4 g) was added. Stirring was continued for 30 min, and the resulting suspension was concentrated under reduced pressure (water bath temperature<=30° C.). The freshly prepared material was used right away in the reaction above.

[0681] Step F

[0682] A solution of nitro-pyrazole benzyl carbamate (410.0 g, 1.18 mmol), available from step E, in 20 mL of ethanol was degassed via house vacuum, and refilled with nitrogen. Solid palladium (10% on activated carbon, wet with <50% H2O, 280.0 mg) was added. The black suspension was degassed via house vacuum, and refilled with hydrogen gas supplied by a gas balloon. The mixture was stirred for 20 h under a hydrogen atmosphere, and filtered through a 1-in Celite pad, rinsing with excess volume of methanol. The filtrate and rinsing were concentrated to a reddish oil, which was purified by preparative TLC (CH2Cl2—MeOH=15:1). The silica was extracted with methanol, the extracts were filtered, and the filtrate was concentrated under reduced pressure to an oil, which solidified while being dried on high vacuum, yielding 120.0 mg (56%) of diamino-pyrazole product (MH+=184.0).

Preparative Example 19

[0683]

[0684] Step A

[0685] Nitro-pyrazole benzyl carbamate was prepared from 5-nitro-3 pyrazolecarboxylic acid according to the procedure described in Preparative Example 18.

[0686] Step B

[0687] To a solution of nitro-pyrazole benzyl carbamate (410.0 mg, 1.18 mmol), obtained from step A, in 17 mL of ethyl acetate at room temperature was added Tin (II) chloride dihydrate (1.33 g, 5.90 mmol) in one portion. The mixture was heated to 80° C. and continued for 2 h. after cooled to room temperature, a saturated NaHCO3 aqueous solution was added dropwise to the mixture until pH approximately 7. An additional volume of ethyl acetate (20 mL) was added, the mixture was stirred overnight, and filtered through a 1-in Celite pad. The two layers of the filtrate were separated. The organic layer was washed with brine once. The aqueous washing was combined with the aqueous layer, and extracted with ethyl acetate once. The combined organic layers were dried with Na2SO4, filtered and concentrated, further dried on high vacuum, to afford 361.5 mg (97%) of amino-pyrazole benzyl carbamate as a solid (MH+=318.1).

[0688] Step C

[0689] To a stirred solution of amino-pyrazole benzyl carbamate (180.0 mg, 0.57 mmol), prepared in step B, in 11 mL of CH2Cl2 at −78° C. was added triethylamine (0.32 mL, 2.30 mmol). A 1.0 M solution of methanesulfonyl chloride in CH2Cl2 (1.7 mL, 1.7 mmol) was added dropwise along the inside wall of the flask. The mixture was stirred for 2.5 h while the temperature of the cooling bath was increased slowly from −78° C. to −25° C. A saturated NaHCO3 aqueous solution (5 mL) was added to the mixture, and it was further diluted with 25 mL of CH2Cl2. The cooling bath was removed, stirring was continued for an additional 1.5 h, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (30 mL), and the combined organic layers were washed with a saturated NaHCO3 aqueous solution (30 mL) and brine (30 mL). The organic layer was dried by Na2SO4, and concentrated to an oil, which was purified by preparative TLC (CH2Cl2—MeOH=20:1). The silica was extracted with CH2Cl2 and methanol, the extracts were filtered and concentrated to a colorless oil, solidified while being dried on high vacuum, yielding 185.7 mg (83%) of the pyrazole methylsulfonamide as a solid (MH+=396.1).

[0690] Step D

[0691] To a nitrogen flushed solution of pyrazole methylsulfonamide (275.0 mg, 0.70 mmol), from step C, in 10 mL of ethanol was added solid palladium (10% on activated carbon, wet with <50% water, 550.0 mg). The suspension was degassed via house vacuum, then filled with hydrogen gas supplied by a gas balloon. The mixture was stirred for 3.5 h under a hydrogen atmosphere, and filtered through a layer of Celite. The solid residue and the filtration pad were rinsed with ethanol and ethyl acetate, the combined filtrate and rinsing were concentrated under reduced pressure to give 173.0 mg (95%) of amino-pyrazole methylsulfonamide as a solid (MH+=262.0).

Preparative Example 20

[0692]

[0693] Step A

[0694] Pyrazole benzyl carbamate was prepared from 5-nitro-3-pyrazolecarboxylic acid in 4 steps according to the procedure described in Preparative Example 18.

[0695] Step B

[0696] To a solution of pyrazole benzyl carbamate (115.0 mg, 0.38 mmol), prepared in step A, in 6 mL of CH2Cl2 at room temperature was added solid potassium carbonate in one portion. A solution of bromine was added dropwise to the stirred mixture. After 6 h, 30 mL of H2O was added, and the mixture was extracted with CH2Cl2 (30 mL×3). The combined organic extracts were washed with a 10% Na2S2O3 aqueous solution (20 mL), a saturated NaHCO3 aqueous solution (20 mL) and brine (20 mL), and dried with Na2SO4. Evaporation of solvent gave a slightly yellow oil, which was purified by preparative TLC (CH2Cl2—MeOH=20:1). The silica was extracted with CH2Cl2 and methanol, the extracts were filtered and concentrated under reduced pressure to afford an oil, which was further dried on high vacuum, yielding 134.2 mg (93%) of the bromo-pyrazole benzyl carbamate (MH+=381).

[0697] Step C

[0698] Treatment of the bromo-pyrazole benzyl carbamate compound from step B with n-butyllithium followed by the addition of methyl borate would convert the bromo-pyrazole benzyl carbamate to the corresponding boronic ester. Subsequent one-pot oxidation of the boronic ester with H2O2 aqueous solution would afford the hydroxy-pyrazole benzyl carbamate.

[0699] Step D

[0700] Treatment of the hydroxy-pyrazole benzyl carbamate from step C with hydrogen under the conditions of palladium (10% on activated carbon) in ethanol would afford the desired amino-hydroxy pyrazole.

Preparative Example 21

[0701]

[0702] Step A

[0703] To a solution of methyl 3-methoxythiophene carboxylate (2.0 g, 11.6 mmol) in 20 mL of THF at room temperature was added dropwise a 1.0 M sodium hydroxide aqueous solution (17.0 mL, 17.0 mmol). After addition, the mixture was heated to 75° C. (oil bath temperature) and continued for 18 h. The mixture was cooled to room temperature, treated with a 1.0 M hydrochloride aqueous solution until pH approximately being 2. The acidified mixture was extracted with 100 mL of CH2Cl2—CH3CN (1:1, v/v), 50 mL of CH2Cl2, and 50 mL of CH3CN. The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure to a solid, which was further dried on high vacuum, yielding 1.84 g (100%) of 3-methoxythiophene carboxylic acid (MH+=159.0).

[0704] Step B

[0705] To a suspension of 3-methoxythiophene carboxylic acid (1.84 g, 11.61 mmol), from step A, in 60 mL of acetonitrile at room temperature was added bromotripyrroli-dinophosphonium hexafluorophosphate (PyBrop, 5.40 g, 11.60 mmol), dimethyl amine (2.0 M in THF, 14.5 ml, 29.0 mmol) and diisopropylethyl amine (5.0 mL, 28.63 mmol) successively. After stirred for 1.5 day, the mixture was concentrated under reduced pressure to a yellow oil, which was purified by preparative TLC (CH2Cl2—MeOH=40:1). The silica was extracted with CH2Cl2 and methanol, the extracts were filtered and concentrated to an oil, which was further dried on high vacuum, yielding 4.16 g of N,N-dimethyl 3-methoxythiophene amide (contaminated by PyBrop impurity) (MH+=186.0).

[0706] Step C

[0707] To a vigorously stirred solution of thiophene amide (4.16 g, prepared in step B) in 6 mL of concentrated sulfuric acid at −10° C. was added dropwise fuming nitric acid (0.6 mL, 14.28 mmol). After 1.5 h, the mixture was poured into 80 mL of a mixture of 1.0 M NaOH aqueous solution and ice (1:1, v/v). An additional 40 mL of H2O was used to facilitate the transfer. The yellow precipitates were collected by filtration, washed with H2O twice, and dried on high vacuum, to give 1.67 g of the nitro-thiophene product. The aqueous filtrates were extracted with CH2Cl2 (50 mL×3). The extracts were washed with a sat. NaHCO3 aqueous solution (30 mL) and brine (30 mL), and dried with Na2SO4. Evaporation of solvent afforded a yellow oil, which was purified by preparative TLC (CH2Cl2—MeOH=50:1) to give an additional 0.144 g of the nitro-thiophene as a solid (1.81 g total, 68% over two steps, MH+=231.0).

[0708] Step D

[0709] To a vigorously stirred solution of methoxy-nitro-thiophene (900.0 mg, 3.91 mmol), obtained from step C, in 55 mL of anhydrous CH2Cl2 at −78° C. was added dropwise along the inside wall of the flask a 1.0 M solution of boron tribromide in CH2Cl2 during a 15 min period. The mixture was stirred for 4 h while the temperature of the cooling bath was increased slowly from −78° C. to −10° C., and poured into 100 mL of a mixture of ice and H2O (1:1, v/v). Additional 30 mL of H2O and 30 mL of CH2Cl2 were used to rinse the flask. The combined mixture was stirred at room temperature over night, the two layers were separated, and the aqueous layer was extracted with CH2Cl2 (50 mL×3). The organic layers were combined, washed with a sat. NaHCO3 aqueous solution (50 mL×2) and brine (50 mL×2), dried with Na2SO4, and concentrated to a yellow solid. The crude product was purified by flash column chromatography, eluting with hexanes, CH2Cl2— hexanes (1:1 and 2:1). Removal of solvents afforded a solid, which was further dried on high vacuum, giving 615.2 mg (73%) of the hydroxy-nitro-thiophene amide (MH+=217.0).

[0710] Step E

[0711] To a nitrogen flushed solution of hydroxy-nitro-thiphene amide (610.0 mg, 2.82 mmol), prepared in step D, in 60 mL of ethanol was added palladium hydroxide (20 wt % on activated carbon, wet with <=50% water, 610.0 mg). The suspension was degassed via house vacuum and refilled with hydrogen gas from a gas balloon. The mixture was first stirred at room temperature under a hydrogen atmosphere for 2 h, then heated to 70-80° C. and continued for 20 h. Solid material was removed by filtration through a 1-in Celite pad, the filtration pad was washed with 100 mL of ethanol, and the combined filtrates were concentrated to a light yellow solid. The crude product was treated with a mixture of CH2Cl2—MeOH (˜1:1, v/v), off-white solids precipitated out and collected by filtration as the first crop of the product (75.4 mg). The filtrate was concentrated to a solid residue, which was purified by flash column chromatography, eluting with CH2Cl2-EtOH (10:1 and 2:1). Removal of solvents afforded 226.8 mg of the amino-hydroxy-thiophene amide as a solid (302.2 mg total, 58%, MH+=187.0).

Preparative Example 22

[0712]

[0713] Step A

[0714] 2-Thiophenecarbonyl chloride (2.0 mL, 18.7 mmol) was dissolved in 100 mL dichloromethane. After addition of diisopropylethylamine (4.1 mL, 23.4 mmol) and Boc-piperazine (3.66 g, 19.7 mmol), the mixture was stirred for 4 h at room temperature. The resulting cloudy mixture was put into water (500 mL) and acidified with 3N HCl to pH˜1. Extraction with dichloromethane (2×100 mL) and drying over sodium sulfate resulted in sufficiently pure product that was used in the next step without any further purification.

[0715]

1
H NMR (300 MHz, d6-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).

[0716] Step B

[0717] The crude material from Step A was dissolved in trifluoroacetic acid/dichloromethane (75 mL, 4/1). After stirring for 2 h, the reaction mixture was put into 1N sodium hydroxide (400 mL). Extraction with dichloromethane (2×100 mL) and drying over sodium sulfate resulted in sufficiently pure product that was used in Step C without any further purification.

[0718]

1
H NMR (300 MHz, d6-DMSO) 2.81 (dd, 4H), 3.63 (dd, 4H), 7.21 (dd, 1H), 7.46 (d, 1H), 7.82 (d, 1H).

[0719] Step C

[0720] The crude material (3.50 g, 17.8 mmol) from Step B was dissolved in dichloromethane (100 mL). After addition of diisopropylethylamine (18.7 mL, 107 mmol), 3-nitrosalicylic acid (3.3 g, 18.0 mmol), and PyBrOP (10.4 g, 22.3 mmol), the resulting yellow mixture was stirred over night at room temperature before being put into 1N sodium hydroxide (200 mL). Extraction with dichloromethane (2×200 mL) removed all PyBrOP by-products. The aqueous phase was acidified with 3N HCl and subsequently extracted with dichloromethane (3×100 mL). 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 (2.31 g, 34% over 3 steps).

[0721]

1
H NMR (300 MHz, d6-DMSO) 3.30-3.90 (m, 8H), 7.10-8.20 (m, double signals due to E/Z-isomers, 6H), 10.82 (s, 1H).

[0722] Step D

[0723] The nitro-compound (2.3 g, 6.4 mmol) from Step C was dissolved in methanol (50 mL) 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 (1.78 g, 84%).

[0724]

1
H NMR (300 MHz, d6-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).

Preparative Example 23

[0725]

[0726] Step A

[0727] Picolinic acid (3.0 g, 24.3 mmol) was suspended in SOCl2 (15 mL). After addition of dimethylformamide (5 drops), the reaction mixture was stirred for 4 hours. During this period the color changed from white to green to brown to finally dark wine-red and all solid went into solution. Evaporation of the solvent yielded the corresponding acid chloride as HCl-salt. Without any further purification, the solid was suspended in 120 mL dichloromethane. After addition of diisopropylethylamine (12.7 mL, 73 mmol) and Boc-piparazine (4.8 g, 25.5 mmol), the reaction was stirred over night at room temperature. The resulting cloudy mixture was put into water (500 mL) and extracted with dichloromethane (2×100 mL). Drying over sodium sulfate resulted in sufficiently pure product that was used in Step B without any further purification.

[0728]

1
H NMR (300 MHz, d6-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).

[0729] Step B

[0730] The crude material from Step A was dissolved in trifluoroacetic acid/dichloromethane (75 mL, 4/1). After stirring for 2days, the reaction mixture was put into 1N sodium hydroxide (400 mL). Extraction with dichloromethane (2×100 mL) and drying over sodium sulfate resulted in sufficiently pure product that was used in Step C without any further purification.

[0731]

1
H NMR (300 MHz, d6-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, 1H).

[0732] Step C

[0733] The crude material (1.35 g, 7.06 mmol) from Step B was dissolved in dichloromethane (50 mL). After addition of diisopropylethylamine (3.7 mL, 21.2 mmol), 3-nitrosalicylic acid (1.36 g, 7.41 mmol), and PyBrOP (3.62 g, 7.77 mmol), the resulting yellow mixture was stirred over night at room temperature before being put into 1N sodium hydroxide (300 mL). Extraction with dichloromethane (2×100 mL) removed any PyBrOP products. The aqueous phase was acidified with 3N HCl. Careful 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 (3×100 mL). 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 (1.35 g, 16% over 3 steps).

[0734]

1
H NMR (300 MHz, d6-DMSO) 3.30-3.95 (m, 8H), 7.22 (m, 1H), 7.61 (m, 1H), 7.73 (d, 2H), 8.03 (m, 1H), 8.17 (m, 1H), 8.69 (m, 1H), 10.82 (s, 1H).

[0735] Step D

[0736] The nitro-compound (1.35 g, 3.79 mmol) from Step C was dissolved in methanol (60 mL) 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=20/1) to yield the desired product (1.10 g, 89%).

[0737]

1
H NMR (300 MHz, d6-DMSO) 3.50-3.85 (m, 8H), 6.47 (dd 1H), 6.74 (m, 2H), 7.59 (dd, 1H), 7.71 (d, 1H), 8.04 (dd, 1H), 8.68 (d, 1H).

Preparative Example 24

[0738]

[0739] Step 1

[0740]

3
-Nitrosalicylic acid (3.61 g, 0.0197 g), DCC (2.03 g, 0.0099 mol) and ethyl acetate (130 mL) were combined in a round bottom flask and stirred for 15 min. 4-Dimethylcarbamoyl-piperazine-2-carboxylic acid ethyl ester (4.51 g, 0.0197 g) was added, and the reaction was stirred for 72 hours. The reaction mixture was concentrated then dissolved in dichloromethane. The organic phase was washed once with 0.1N sodium hydroxide. The aqueous phase was back extracted once with dichloromethane. The aqueous phase was acidified and wash three times with ethyl acetate. The aqueous phase was concentrated and purified by column chromatography (5% methanol/DCM).

[0741] MS: calculated: 394.15. found: 395.0.

[0742]

1
H NMR (300 MHz, CDCl3) 1.32 (t, 3H), 2.86 (m, 7H), 3.15 (m, 1H), 3.51 (m, 4H), 4.24 (m, 3H), 7.15 (m, 1H), 7.66 (m, 1H), 8.20 (m, 1H), 10.86 (bs, 1H).

[0743] Step 2

[0744]

4
-Dimethylcarbamoyl-1-(2-hydroxy-3-nitro-benzoyl)-piperazine-2-carboxylic acid ethyl ester (0.80 g, 0.002 mol) and methanol (50 mL) were combined in a round bottom flask. The system was purged with argon. To the solution was added 5% palladium on carbon (˜100 mg). 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 (0.74 g, 0.002 mol, 100%).

[0745] MS: calculated: 364.17. found: 365.1.

[0746]

1
H NMR (300 MHz, CDCl3) 1.27 (t, 3H), 2.85 (m, 8H), 3.18 (1H), 3.45 (m, 3H), 4.19 (m, 3H), 3.90 (m, 3H)

[0747] Step 3

[0748] 1-(3-Amino-2-hydroxy-benzoyl)-4-dimethylcarbamoyl-piperazine-2-carboxylic acid ethyl ester (0.74 g, 0.002 mol) was suspended in a solution of dioxane (10 mL) and water (10 mL). Lithium hydroxide (0.26 g, 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.

[0749] MS: calculated: 336.14. found: 337.1.

[0750]

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 25

[0751]

[0752] The product from Preparative Example 1 was stirred with 10% Pd/C 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, 4% MeOH/CH2Cl2 saturated with NH4OH) to give the product (129 mg, 43%, MH+=237).

Preparative Example 26

[0753]

[0754] In essentially the same manner as described in Preparative Example 25, the amine product above was obtained; (50% yield, MH+=300.1).

Preparative Example 27

[0755]

[0756] The product is prepared according to the literature procedure (Zh.Obshch.Khim.; 24; 1954; 1216, 1220; engl. Ausg. S. 1205, 1207).

Preparative Example 28-31

[0757] Following the procedure in Preparative Example 27, using the indicated commercially available hydrazines shown in the table below, the following cyclic dibromo hydrazide products could be prepared.

2PrepEx.HydrazineProduct28

Preparative Example 32

[0758]

[0759] The product is prepared according to the literature procedure (Farmaco Ed. Sci. IT; 32; 1977; 173-179).

Preparative Example 33

[0760]

[0761] Following the procedure described in the literature (J.Heterocycl.Chem.; EN; 34; 4; 1997; 1307-1314) using benzyl bromide instead of 1-chloro-propan-2-one, the product could be obtained.

Preparative Example 34

[0762]

[0763] Following a similar procedure as that outlined in the literature (Farmaco Ed. Sci. IT; 32; 1977; 173-179) using the product from Preparative Example 3 instead of 2-methylamino-benzenethiol, the product would be obtained.

Preparative Example 35-133

[0764] Following the procedure set forth in Preparative Example 34 using the amine and dibromo intermediates from the Preparative Examples indicated, the products in the table below would be obtained.

3(Prep Ex)(Prep Ex)Ex.AmineDibromoProduct35 527

36 727

37 627

382327

392427

401527

411127

100

101

422127

102

103

431427

104

105

441227

106

107

451927

108

462027

109

471827

110

481627

111

112

49 328

113

114

50 528

115

116

51 428

117

118

52 828

119

120

53 728

121

122

54 928

123

124

55 628

125

126

562628

127

128

572328

129

130

582228

131

132

592428

133

134

601528

135

136

611628

137

138

621728

139

140

631128

141

142

641328

143

652128

144

145

661428

146

147

671228

148

149

681928

150

691428

151

152

701828

153

154

155

156

72 328

157

158

73 528

159

160

74 428

161

162

75 828

163

164

76 728

165

166

77 928

167

168

78 628

169

170

792628

171

172

802328

173

174

812228

175

176

822428

177

178

831528

179

180

841628

181

182

851728

183

184

861128

185

186

871328

187

882128

188

189

891428

190

191

901228

192

193

911928

194

921428

195

196

931828

197

94 329

198

199

95 529

200

201

96 429

202

203

97 829

204

205

98 729

206

207

99 929

208

209

100 629

210

211

1012629

212

213

1022329

214

215

1032229

216

217

1042429

218

219

1051529

220

221

1061629

222

223

1071729

224

225

1081129

226

227

1091329

228

1102129

229

230

1111429

231

232

1121229

233

234

1131929

235

1141429

236

237

1151829

238

116 330

239

240

117 730

241

242

118 630

243

244

1191130

245

246

1201630

247

248

121 331

249

250

122 731

251

252

123 631

253

254

1241131

255

256

1251631

257

258

126 332

259

260

127 732

261

262

128 632

263

264

1291132

265

266

1301632

267

268

131 333

269

270

132 733

271

272

133 633

273

274

133.11133

275

276

133.21633

277

278

Preparative Example 134

[0765]

279

[0766] Step A

[0767] To a solution of N-protected amino acid (1.5 g, 6.9 mmol) in CH2Cl2 (25 mL) at room temperature was added DIPEA (3.6 mL, 20.7 mmol), and (PyBrop) (3.4 g, 6.9 mmol) followed by MeNH2 (6.9 mL, 13.8 mmol, 2.0 M in CH2Cl2). The resulting solution was stirred for 18 h at room temperature (until TLC analysis deemed the reaction to be complete). The resulting mixture was washed sequentially with 10% citric acid (3×20 mL), sat. aq. NaHCO3 (3×20 mL), and brine (3×20 mL). The organic layer was dried (Na2SO4), 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.

[0768] Step B

[0769] To a round bottom flask charged with the N-protected amide (1.0 g, 4.35 mmol) from Step A above, was added 4N HCl/dioxane (10 mL). The mixture was stirred at room temperature for 2 h. The mixture was diluted with Et2O (20 mL) and concentrated under reduced pressure. The crude product was treated with Et2O (2×20 mL) and concentrated under reduced pressure to afford 0.72 g (˜100% yield) of crude product as the HCl salt. This material was used without further purification or characterization.

Preparative Examples 135-137

[0770] Following the procedure set forth in Preparative Example 134 but using the commercially available N-protected amino acids and amines indicated, the amine hydrochloride products in the Table below were obtained.

4PrepEx.Amino acidAmineProductYield (%)135

280

281

282

68%136

283

284

285

68%137

286

287

288

97%

Preparative Example 138

[0771]

289

[0772] To a solution of 3-chlorobenzaldehyde (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 stirred for 20 min. EtMgBr (6.0 mL, 3.0 M in Et2O) was added dropwise and the mixture was refluxed for 24 h. The mixture was cooled to room temperature, poured into sat. aq. NH4Cl (50 mL), and then extracted with CH2Cl2 (3×50 volumes). The organic layers were combined and concentrated under reduced pressure. The crude residue was stirred with 3 M HCl (25 mL) for 30 min, the aqueous layer was then extracted with CH2Cl2 (3×15 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 obtained. The aqueous layer was extracted with CH2Cl2 (3×15 mL) and the organic layers were combined. The organic layer was washed with brine (1×25 mL), dried (Na2SO4), 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.

Preparative Examples 139-142

[0773] Following the procedure set forth in Preparative Example 138 but using the commercially available aldehydes and Grignard reagents indicated, the amine products listed in the Table below were obtained.

5PrepGrignard1 .Yield (%)Ex.AldehydeReagentAmine Product2. MH+139

290

EtMgBr

291

1. 73% 2. 154140

292

EtMgBr

293

1. 55% 2. 180141

294

EtMgBr

295

1. 80% 2. 166142

296

i-PrMgBr

297

1. 20% 2. 150

Preparative Example 143

[0774]

298

[0775] Step A

[0776] 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 Na2SO4 (anhydrous). Filtration and concentration afforded the desired oxime (2.9 g, 96%) which was used directly in Step B without further purification.

[0777] Step B

[0778] 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. The mixture was stirred at room temperature overnight. The solid was filtered and the mixture reduced under vacuo. Aqueous NaOH (2 M) was added and the mixture was extracted several times with CH2Cl2. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to afford the product (1.4 g, 50%).

Preparative Example 144-148

[0779] Following the procedure set forth in Preparative Example 143 but using the commercially available ketones indicated, the amine products listed in the table below were obtained.

6PrepEx-am-1. Yield (%)pleKetoneAmine Product2. MH+144

299

300

1. 47% 2. 174145

301

302

1. 71% 2. 190146

303

304

1. 78% 2. 191147

305

306

1. 80% 2. 190148

307

308

1. 9% 2. 156

Preparative Example 149

[0780]

309

[0781] Step A

[0782] To a solution of (D)-valinol (4.16 g, 40.3 mmol) in CH2Cl2 (60 mL) at 0° C. was added MgSO4 (20 g) followed by dropwise addition of 3-fluorobenzaldehyde (5.0 g, 40.3 mmol). The heterogenous solution was stirred at 0° C. for 2 h, was allowed to warm to room temperature and was stirred overnight (14 h). The mixture was filtered and the drying agent was washed with CH2Cl2 (2×10 mL). The filtrate was concentrated under reduced pressure to afford 8.4 g (100%) of a colorless oil which was taken onto the next step without further purification.

[0783] Step B

[0784] To a solution of the imine (8.4 g, 40.2 mmol) from Step A in CH2Cl2 (60 mL) at room temperature was added Et3N (6.2 mL, 44.5 mmol) followed by dropwise addition of TMSCl (5.7 mL, 44.5 mmol). The mixture was stirred for 6 h at room temperature whereupon the precipitate that had formed was filtered off and washed with CH2Cl2 (2×10 mL). The combined filtrate was concentrated under reduced pressure and was taken up in Et2O/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 a red oil. This material was taken onto the next step without further purification.

[0785] Step C

[0786] To a solution of Etl (4.0 g, 25.6 mmol) in Et2O (40 mL) at −78° C. was added t-BuLi (30.1 mL, 51.2 mmol, 1.7 M in pentane) and the mixture was stirred 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 Et2O (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. whereupon 3M HCl (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 Et2O (2×30 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 obtained. The aqueous layer was extracted with Et2O (3×30 mL) and the combined layers were washed with brine (1×30 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to afford 4.8 g (94% yield) of the amine as a red oil. This material was taken on crude to the next step without further purification.

[0787] Step D

[0788] To a solution of amine (4.5 g, 18.8 mmol) from Step C in MeOH (80 mL) at room temperature was added MeNH2 (25 mL, 40% in water) followed by the addition of a solution of H5IO6 (14.0 g, 61.4 mmol) in H2O (25 mL). The heterogenous mixture was stirred 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 Et2O (4×60 mL). The combined organic layers were concentrated to a volume of 30 mL whereupon 3M HCl (75 mL) was added. The mixture was stirred overnight (12 h at room temperature) whereupon the mixture was concentrated to remove the volatiles. The aqueous layer was extracted with Et2O (3×40 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 Et2O (3×60 mL) and the combined organic layers were dried (MgSO4). The organic layer was concentrated under reduced pressure to afford 2.8 g (97% yield) of the desired amine as a yellow oil [MH+ 154]. This compound was proven to be >85% pure by 1NMR and was used without further purification.

Preparative Example 150-156

[0789] Following the procedure set forth in Preparative Example 149 but using the commercially available aldehydes, amino alcohols, and organolithium reagents indicated, the optically pure amine products in the Table below were obtained.

7PrepAminoOrgano1. Yield (%)Ex.AldehydeAlcohollithiumProduct2. MH+150

310

311

312

313

1. 54% 2. 166151

314

315

EtLi

316

1. 42% 2. 142152

317

318

319

320

1. 62% 2. 148153

321

322

t-BuLi

323

1. 27% 2. 256154

324

325

t-BuLi

326

1. 15% 2. 164155

327

328

EtLi

329

1. 29% 2. 126156

330

331

EtLi

332

1. 35% 2. 126

Preparative Example 157

[0790]

333

[0791] The product was prepared according to methods previously described: J. Med. Chem, 1996, 39, 3319-3323.

Preparative Example 158

[0792]

334

[0793] The product was prepared according to methods previously described: J. Med. Chem. 1996, 39, 3319-3323.

Preparative Example 159

[0794]

335

[0795] The product was prepared according to methods previously described: Chem. Pharm. Bull. 1991, 39, 181-183.

Preparative Example 160

[0796]

336

[0797] The product was prepared according to methods previously described: Chem. Pharm. Bull. 1991, 39, 181-183.

Preparative Example 161

[0798]

337

[0799] The product was prepared according to methods previously described: J. Med. Chem. 1988, 31, 2176-2186.

Preparative Example 162

[0800]

338

[0801] The product was prepared according to methods previously described: J. Org. Chem. 1978, 43, 892-898.

Preparative Example 163

[0802]

339

[0803] The product was prepared according to methods previously described: J. Org. Chem. 1987, 52, 4437-4444.

Preparative Example 164

[0804]

340

[0805] The product was prepared according to methods previously described: Bull. Chem. Soc. Jpn. 1962, 35, 11-16.

Example 500

[0806]

341

[0807] Following essentially the same procedure set forth in Preparative Example 34 (outlined in the literature Farmaco Ed. Sci.; IT; 32;1977; 173-179) using the product from Preparative Example 34 and benzyl amine, one could obtain the product.

Examples 501-828

[0808] Following essentially the same procedure set forth in Example 500 using the products from the Preparative Examples and the prepared or commercially available amines indicated, the products in the table below could be obtained.

8ProductAmineofEx.(Prep Ex)Prep. ExProduct501

342

343

502

344

345

503

346

347

504

348

349

505

350

351

506

352

353

507

354

355

508

356

357

509

358

359

510

360

361

511

362

363

512

364

365

513

366

367

514

368

369

515

370

371

516

372

373

517

374

375

518

376

377

519

378

379

520

380

381

521

382

383

522

384

385

523

386

387

524

388

389

525

390

391

526

392

393

527

394

395

528

396

397

529

398

399

530

400

401

531

402

403

532

404

405

533

406

407

534

408

409

535

410

411

536

412

413

537

414

415

538

416

417

540

418

419

541

420

421

542

422

423

543

424

425

544

426

427

545

428

429

546

430

431

547

432

433

548

434

435

549

436

437

550

438

439

551

440

441

552

442

443

553

444

445

554

446

447

555

448

449

556

450

451

557

452

453

558

454

455

559

456

457

560

458

459

561

460

461

562

462

463

563

464

465

564

466

467

565

468

469

566

470

471

567

472

473

568

474

475

569

476

477

570

478

479

571

480

481

572

482

483

573

484

485

574

486

487

575

488

489

576

490

491

577

492

493

578

494

495

579

496

497

580

498

499

581

500

501

582

502

503

583

504

505

584

506

507

585

508

509

586

510

511

587

512

513

588

514

515

589

516

517

590

518

519

591

520

521

592

522

523

593

524

525

594

526

527

595

528

529

596

530

531

597

532

533

598

534

535

599

536

537

600

538

539

601

540

541

602

542

543

603

544

545

605

546

547

607

548

549

608

550

551

609

552

553

610

554

555

611

556

557

612

558

559

613

560

561

614

562

563

615

564

565

616

566

567

617

568

569

618

570

571

619

572

573

620

574

575

621

576

577

622

578

579

623

580

581

624

582

583

625

584

585

626

586

587

627

588

589

628

590

591

629

592

593

630

594

595

631

596

597

632

598

599

633

600

601

634

602

603

635

604

605

636

606

607

637

608

609

638

610

611

639

612

613

640

614

615

641

616

617

642

618

619

643

620

621

644

622

623

645

624

625

646

626

627

647

628

629

648

630

631

649

632

633

650

634

635

651

636

637

652

638

639

653

640

641

654

642

643

655

644

645

656

646

647

657

648

649

658

650

651

659

652

653

660

654

655

661

656

657

662

658

659

663

660

661

664

662

663

665

664

665

666

667

668

669

668

670

671

669

672

673

670

674

109

675

671

676

677

672

678

679

673

680

681

674

682

683

675

684

685

676

686

687

678

688

101

689

679

690

691

680

692

693

681

694

695

682

696

697

683

698

102

699

684

700

103

701

685

702

104

703

686

704

705

687

706

707

688

708

709

689

710

711

690

712

713

691

714

715

692

716

717

693

718

719

694

720

721

695

722

111

723

696

724

111

725

697

726

727

698

728

729

699

730

731

700

732

733

701

734

735

702

736

737

703

738

739

704

740

741

705

742

743

706

744

108

745

707

746

108

747

708

748

749

709

750

751

710

752

753

711

754

755

712

756

107

757

713

758

106

759

714

760

761

715

762

763

716

764

765

717

766

100

767

718

768

769

719

770

771

720

772

773

721

774

112

775

722

776

777

723

778

779

724

780

781

725

782

783

726

784

110

785

727

786

105

787

728

788

789

729

790

791

730

792

793

731

794

116

795

732

796

116

797

733

798

116

799

734

800

116

801

735

802

116

803

736

804

116

805

737

806

119

807

738

808

116

809

739

810

116

811

740

812

120

813

741

814

118

815

742

816

116

817

743

818

116

819

744

820

116

821

745

822

117

823

746

824

116

825

747

826

116

827

748

828

116

829

749

830

116

831

750

832

116

833

751

834

126

835

752

836

126

837

753

838

126

839

734

840

126

841

755

842

126

843

756

844

126

845

757

846

129

847

758

848

126

849

759

850

126

851

760

852

130

853

761

854

128

855

762

856

126

857

763

858

126

859

764

860

126

861

765

862

127

863

766

864

126

865

767

866

126

867

768

868

126

869

769

870

126

871

770

872

126

873

771

874

131

875

772

876

131

877

773

878

131

879

774

880

131

881

775

882

131

883

776

884

131

885

777

886

133.1

887

778

888

131

889

779

890

131

891

780

892

133.2

893

781

894

133

895

782

896

131

897

783

898

131

899

784

900

131

901

785

902

132

903

786

904

131

905

787

906

131

907

788

908

131

909

789

910

131

911

790

912

131

913

791

914

121

915

792

916

121

917

793

918

121

919

794

920

121

921

795

922

121

923

796

924

121

925

797

926

124

927

798

928

121

929

799

930

121

931

800

932

125

933

801

934

123

935

802

936

121

937

803

938

121

939

804

940

121

941

805

942

122

943

806

944

121

945

807

946

121

947

808

948

121

949

809

950

121

951

810

952

121

953

811

954

955

812

956

957

813

958

959

814

960

961

815

962

963

816

964

965

817

966

967

818

968

969

819

970

971

820

972

113

973

821

974

114

975

822

976

115

977

823

978

979

824

980

981

825

982

983

826

984

985

827

986

987

828

988

989

[0809] While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

3,4-di-substituted pyridazinediones as CXC chemokine receptor antagonists

Information

Publication Number

Date Filed

Date Published

Inventors

Original Assignees

CPC

US Classifications

International Classifications

Abstract

Description

Claims

REFERENCE TO RELATED APPLICATION

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