Claims
- 1. A compound of formula (I):
- 2. The compound of claim 1, wherein R1 is selected from the group consisting of H; unsubstituted (C1-C8)alkyl; (C1-C8)alkyl substituted with OR′, OC(O)R′, CO2R′, CONR′R″, OC(O)NR′R″, NR″C(O)R′, NR″CO2R′, hydroxy(C1-C8)alkyl or amino(C1-C8)alkyl; hetero(C1-C8)alkyl; fluoro(C1-C4)alkyl; cycloalkyl(C1-C8)alkyl; heterocyclo(C1-C8)alkyl; aryl; aryl(C1-C8)alkyl; arylhetero(C1-C8)alkyl and heteroaryl.
- 3. The compound of claim 1, wherein R1 is selected from the group consisting of H, (C1-C8)alkyl, hetero(C1-C8)alkyl and aryl.
- 4. The compound of claim 3, wherein R1 is (C1-C8)alkyl substituted with OR′, NR′R″, OC(O)R′, CO2R′, CONR′R″, OC(O)NR′R″, NR″C(O)R′, NR″CO2R′, hydroxy(C1-C8)alkyl or amino(C1-C8)alkyl.
- 5. The compound of claim 3, wherein R1 is cyclo(C1-C8)alkyl.
- 6. The compound of claim 5, wherein R1 is cyclohexyl.
- 7. The compound of claim 3, wherein R1 is heterocyclo(C1-C8)alkyl.
- 8. The compound of claim 7, wherein R1 is tetrahydropyranyl.
- 9. The compound of claim 3, wherein R1 is phenyl.
- 10. The compound of claim 9, wherein R1 is phenyl substituted with OR′, NR′R″, OC(O)R′, CO2R′, CONR′R″, OC(O)NR′R″, NR″C(O)R′, NR″CO2R′, hydroxy(C1-C8)alkyl or amino(C1-C8)alkyl.
- 11. The compound of claim 10, wherein R1 is phenyl substituted with hydroxy(C1-C4)alkyl.
- 12. The compound of claim 4, wherein R1 is selected from the group consisting of:
- 13. The compound of claim 1, wherein Z1 and Z2 are combined to form an additional fused 6-membered cycloalkane, heteroaromatic or heterocycloalkane ring.
- 14. The compound of claim 13, wherein Z1 and Z2 are combined to form an additional fused benzene ring.
- 15. The compound of claim 13, wherein Z1 and Z2 are combined to form an additional fused cyclohexane ring.
- 16. The compound of claim 13, wherein Z1 and Z2 are combined to form an additional fused pyridine ring.
- 17. The compound of claim 13, wherein Z1 and Z2 are combined to form an additional fused tetrahydropyran ring.
- 18. The compound of claim 1, having the formula (II):
- 19. The compound of claim 18, having the formula (IIa):
- 20. The compound of claim 19, wherein R6 and R7 are independently selected from the group consisting of H, halogen, (C1-C4)alkyl, CO2R′, NR′R″, OR′, OC(O)R′, N(R″)C(O)R′ and N(R″)C(O)NR′R″.
- 21. The compound of claim 19, wherein R6 is selected from the group consisting of
- 22. The compound of claim 19, wherein R7 is selected from the group consisting of
- 23. The compound of claim 19, wherein R8 is H or OH.
- 24. The compound of claim 18, having the formula (IIb):
- 25. The compound of claim 18, having the formula (IIc):
- 26. The compound of claim 1, having the formula (III):
- 27. The compound of claim 1, wherein Y is selected from the group consisting of C(O), C(O)NR′, S(O)m and CR3R4.
- 28. The compound of claim 27, wherein Y is C(O).
- 29. The compound of claim 27, wherein Y is C(O)NH.
- 30. The compound of claim 27, wherein Y is SO2.
- 31. The compound of claim 27, wherein Y is CH2.
- 32. The compound of claim 1, wherein R2 is aryl or heteroaryl.
- 33. The compound of claim 32, wherein R2 is phenyl.
- 34. The compound of claim 33, wherein R2 is phenyl substituted with at least one substituent selected from the group consisting of halogen, (C1-C4)alkyl, perfluoro(C1-C4)alkyl, hetero(C1-C4)alkyl, aryl, aryl(C1-C4)alkyl, heteroaryl, CN, CO2R′, CONR′R″, NR′R″, NO2, OR′, SR′, C(O)R′, N(R″)C(O)R′, N(R″)CO2R′, N(R″)C(O)NR′R″, S(O),NR′R″, S(O)mR′ and N(R″)S(O)mR′, wherein the subscript m is an integer from 1 to 2.
- 35. The compound of claim 34, wherein R2 is phenyl substituted with at least one substituent selected from the group consisting of perfluoro(C1-C4)alkyl, aryl, heteroaryl, CONR′R″, NO2, S(O)mNR′R″ and S(O)mR′.
- 36. The compound of claim 35, wherein R2 is phenyl substituted with at least one substituent selected from the group consisting of CF3, CF2R′, phenyl, tetrazolyl, triazolyl, CONHR′, NO2, SO2NHR′ and SO2R′.
- 37. The compound of claim 32, wherein R2 is thiophenyl or furyl.
- 38. The compound of claim 1, wherein Z1 and Z2 are combined to form an additional fused aromatic or heteroaromatic ring and Y is selected from the group consisting of C(O), C(O)NR′, S(O)m and CR3R4.
- 39. The compound of claim 38, wherein Z1 and Z2 are combined to form an additional fused benzene ring.
- 40. The compound of claim 39, having the formula (IV):
- 41. The compound of claim 39, having the formula (V):
- 42. The compound of claim 39, having the formula (VI):
- 43. The compound of claim 38, wherein Z1 and Z2 are combined to form an additional fused pyridine ring and Y is C(O).
- 44. The compound of claim 1, wherein Z1 and Z2 are combined to form an additional fused aromatic or heteroaromatic ring and R1 is selected from the group consisting of H, (C1-C8)alkyl, hetero(C1-C8)alkyl and aryl.
- 45. The compound of claim 1, wherein Z1 and Z2 are combined to form an additional fused aromatic or heteroaromatic ring and R2 is aryl.
- 46. The compound of claim 1, wherein R1 is selected from the group consisting of H, (C1-C8)alkyl, hetero(C1-C8)alkyl and aryl and Y is C(O) or C(O)NH.
- 47. The compound of claim 1, wherein R1 is selected from the group consisting of H, (C1-C8)alkyl, hetero(C1-C8)alkyl and aryl and R2 is aryl.
- 48. The compound of claim 1, wherein Y is C(O) or C(O)NH and R2 is aryl.
- 49. The compound of claim 1, wherein Z1 and Z2 are combined to form an additional fused aromatic or heteroaromatic ring, Y is C(O) or C(O)NR′ and R2 is aryl.
- 50. A compound of claim 40, having the formula (VII):
- 51. The compound of claim 50, wherein at least one of R9, R10, R11, R12 and R13 is selected from halogen, (C1-C4)alkyl, perfluoro(C1-C4)alkyl, (C1-C4)heteroalkyl, aryl, aryl(C1-C4)alkyl, heteroaryl, CN, CO2R′, CONR′R″, NR′R″, NO2, OR′, SR′, C(O)R′, N(R″)C(O)R′, N(R″)CO2R′, N(R″)C(O)NR′R″, S(O)mNR′R″, S(O)mR′ and N(R″)S(O)mR′.
- 52. The compound of claim 51, wherein at least one of R9, R10, R11, R12 and R13 is selected from perfluoro(C1-C4)alkyl, aryl, heteroaryl, CONR′R″, NO2, S(O)mNR′R″ and S(O)mR′.
- 53. The compound of claim 50, wherein R10 is NO2.
- 54. The compound of claim 53, having the formula (VIIc):
- 55. The compound of claim 50, wherein R10 is CF3.
- 56. The compound of claim 55, having the formula (VIId):
- 57. The compound of claim 50, wherein R10 is S(O)mNR′R″ or S(O)mR′.
- 58. The compound of claim 57, wherein R10 is selected from the group consisting of:
- 59. The compound of claim 1, wherein Z1 and Z2 are combined to form an additional fused aromatic or heteroaromatic ring, Y is C(O) or C(O)NR′ and R1 is selected from the group consisting of H, (C1-C8)alkyl, hetero(C1-C8)alkyl and aryl.
- 60. The compound of claim 1, wherein Z1 and Z2 are combined to form an additional fused aromatic or heteroaromatic ring, R1 is selected from the group consisting of H, (C1-C8)alkyl, hetero(C1-C8)alkyl and aryl and R2 is aryl.
- 61. The compound of claim 1, wherein Y is C(O) or C(O)NR′; R1 is selected from the group consisting of H, (C1-C8)alkyl, hetero(C1-C8)alkyl and aryl; and R2 is aryl.
- 62. The compound of claim 60, having a formula selected from the group consisting of
- 63. The compound of claim 50, having the formula (VIIa):
- 64. The compound of claim 50, having the formula (VIIb):
- 65. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of any one of claims 1-64
- 66. A method of treating an inflammatory condition, a cell proliferative disorder or an immune disorder, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of any one of claims 1-64.
- 67. A method of treating rheumatoid arthritis, inflammatory bowel disease, allergic disease, cancer, psoriasis, asthma, multiple sclerosis, graft rejection or sepsis, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of any one of claims 1-64.
- 68. A method of treating an IRAK-responsive condition or disorder, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1.
- 69. A method of treating a condition or disorder mediated by IRAK, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1.
- 70. A method for treating a condition or disorder mediated by NF-κB, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1.
- 71. The method of any one of claims 68, 69 and 70, wherein said condition or disorder is selected from the group consisting of rheumatoid arthritis, inflammatory bowel disease, allergic disease, cancer, psoriasis, asthma, multiple sclerosis, graft rejection and sepsis.
- 72. The method of any one of claims 68, 69 and 70, wherein said compound is administered orally, parenterally or topically.
- 73. The method of any one of claims 68, 69 and 70, wherein said compound is administered in combination with a second therapeutic agent selected from the group consisting of methotrexate, sulfasalazine, a COX-2 inhibitor, hydroxychloroquine, cyclosporine A, D-penicillamine, infliximab, etanercept, auranofin, aurothioglucose, sulfasalazine, sulfasalazine analogs, mesalamine, corticosteroids, corticosteroid analogs, 6-mercaptopurine, cyclosporine A, methotrextate and infliximab, interferon β-1β, interferon β-1α, azathioprine, glatiramer acetate, a glucocorticoid and cyclophosphamide.
- 74. A method for modulating IRAK, comprising contacting a cell with a compound of claim 1.
- 75. A method for decreasing NF-κB activation, comprising contacting a cell with a compound of claim 1.
- 76. A method for modulating IRAK, comprising contacting an IRAK protein with a compound of claim 1.
- 77. The method of claim 76, wherein said compound inhibits IRAK.
- 78. The method of claim 76, wherein said compound activates IRAK.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is related to and claims the benefit of U.S. application Serial No. 60/327,818, filed Oct. 9, 2001, the disclosure of which is incorporated by reference herein.
Provisional Applications (1)
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Number |
Date |
Country |
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60327818 |
Oct 2001 |
US |