Claims
- 1. A compound of Formula I
- 2. A compound of Formula I
- 3. A compound of Formula I
- 4. The compound of claim 2, wherein Z is C—R4, Y is S, X—W is C—C, and Q is absent.
- 5. The compound of claim 3, wherein Z is C—R4, Y is S, X—W is C—C, and Q is absent.
- 6. The compound of claim 4, wherein
R1 is:
1) Or(C1-C6)perfluoroalkyl, 2) OH, 3) CN, 4) halogen, 5) (C═O)rOs(C1-C6)alkyl, 6) (C═O)rOs(C2-C6)cycloalkyl, 7) (C═O)rOs(C2-C6)alkenyl, 8) (C═O)rOs(C2-C6)alkynyl, 9) (C═O)rOsaryl, 10) (C═O)rOsheterocyclyl, or 11) NRaRb, wherein r and s are independently 0 or 1, and said alkyl, cycloalkyl, alkenyl, alkynyl, aryl, and heterocyclyl is optionally substituted with one, two or three substituents selected from R7; R2 is R1 or H; R4 is H or (C1-C6)alkyl; R5 is:
1) H, 2) SO2Rc, 3) (C═O)rRc, wherein r is 0 or 1, or 4) CO2Rc; R6 is CN; R7 is:
1) Or(C═O)sNRaRb, 2) (C═O)rOsaryl, 3) (C═O)rOs-heterocyclyl, 4) halogen, 5) OH, 6) oxo, 7) O(C1-C3)perfluoroalkyl, 8) (C1-C3)perfluoroalkyl, 9) (C═O)rOs(C1-C6)alkyl, 10) CHO, 11) CO2H, 12) CN, or 13) (C3-C6)cycloalkyl,
wherein r and s are independently 0 or 1, and said aryl, heterocyclyl and cycloalkyl are optionally substituted with one, two or three substituents selected from Rd; Ra and Rb are independently:
1) H, 2) (C═O)r(C1-C6)alkyl, 3) (C═O)r(C3-C6)cycloalkyl, 4) S(O)2Rc, 5) (C═O)rheterocyclyl, 6) (C═O)raryl, or 7) CO2Rc,
wherein r is 0 or 1 and said alkyl, cycloalkyl, heterocyclyl, and aryl optionally substituted with one, two or three substituents selected from Rd, or Ra and Rb are taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one, two or three substituents selected from Rd; Rc is (C1-C6)alkyl, (C3-C6)cycloalkyl, or aryl; and Rd is selected from:
1) (C═O)rOs(C1-C6)alkyl, wherein r and s are independently 0 or 1, optionally substituted with up to three substituents selected from OH, (C1-C6)alkoxy, halogen, CN, oxo, N(Re)2 and S(O)2Rc, 2) Or(C1-C3)perfluoroalkyl, 3) (C0-C6)alkylene-S(O)mRc, wherein m is 0, 1, or 2, 4) oxo, 5) OH, 6) halo, 7) CN, 8) (C3-C6)cycloalkyl, optionally substituted with up to three substituents selected from OH, (C1-C6)alkoxy, halogen, CN, oxo, N(Re)2, and S(O)2Rc, 9) (C0-C6)alkylene-aryl, optionally substituted with up to three substituents selected from Re, 10) (C0-C6)alkylene-heterocyclyl, optionally substituted with up to three substituents selected from Re, 11) (C0-C6)alkylene-N(Re)2, 12) C(O)Rc, 13) CO2Rc, 14) C(O)H, and 15) CO2H; and Re is H, (C1-C6)alkyl, aryl, heterocyclyl, (C3-C6)cycloalkyl or S(O)2Rc.
- 7. The compound of claim 5, wherein
R1 is (C1-C10)alkylene-NRaRb, optionally substituted with one or two substituents selected from R7; R2 is selected from:
1) H, 2) Or(C1-C3)perfluoroalkyl, 3) OH, 4) CN, 5) halogen, 6) (C═O)rOs(C1-C6)alkyl, 7) (C═O)rOs(C2-C6)cycloalkyl, 8) (C═O)rOs(C2-C6)alkenyl, 9) (C═O)rOs(C2-C6)alkynyl, 10) (C═O)rOsaryl, and 11) NRaRb, wherein r and s are independently 0 or 1, and said alkyl, cycloalkyl, alkenyl, alkynyl, and aryl is optionally substituted with one or two substituents selected from R7; R4 is H or (C1-C6)alkyl; R5 is selected from:
1) H, 2) SO2Rc, 3) (C═O)rRc, wherein r is 0 or 1, and 4) CO2Rc; R6 is selected from:
1) aryl, wherein aryl is defined as phenyl or naphthyl, 2) (C3-C6)cycloalkyl 3) (C1-C6)alkyl, 4) (C2-C6)alkenyl, 5) (C2-C6)alkynyl, and 6) heterocyclyl,
wherein r and s are independently 0 or 1, and said aryl, cycloalkyl, alkyl, alkenyl, alkynyl and heterocyclyl optionally substituted with one or two substituents selected from R7; R7 is selected from:
1) Or(C═O)sNRaRb, 2) (C═O)rOsaryl, 3) (C═O)rOs-heterocyclyl, 4) halogen, 5) OH, 6) oxo, 7) O(C1-C3)perfluoroalkyl, 8) (C1-C3)perfluoroalkyl, and 9) (C═O)rOs(C1-C6)alkyl, 10) CHO, 11) CO2H, 12) CN, 13) (C3-C6)cycloalkyl,
wherein r and s are independently 0 or 1, and said aryl, heterocyclyl and cycloalkyl are optionally substituted with one, two or three substituents selected from Rd; Ra and Rb are independently selected from: 1) H, 2) (C═O)r(C1-C6)alkyl, 3) (C═O)r(C3-C6)cycloalkyl, 4) S(O)2Rc, 5) (C═O)rheterocyclyl, 6) (C═O)raryl, and 7) CO2Rc,
wherein r is 0 or 1 and said alkyl, cycloalkyl, heterocyclyl, and aryl optionally substituted with one to three substituents selected from Rd, or Ra and Rb are taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one to three substituents selected from Rd; Rc is (C1-C6)alkyl, (C3-C6)cycloalkyl, or aryl; and Rd is selected from:
1) (C═O)rOs(C1-C6)alkyl, wherein r and s are independently 0 or 1, optionally substituted with up to three substituents selected from OH, (C1-C6)alkoxy, halogen, CN, oxo, N(Re)2 and S(O)2Rc, 2) Or(C1-C3)perfluoroalkyl, 3) (C0-C6)alkylene-S(O)mRc, wherein m is 0, 1, or 2, 4) oxo, 5) OH, 6) halo, 7) CN, 8) (C3-C6)cycloalkyl, optionally substituted with up to three substituents selected from OH, (C1-C6)alkoxy, halogen, CN, oxo, N(Re)2, and S(O)2Rc, 9) (C0-C6)alkylene-aryl, optionally substituted with up to three substituents selected from Re, 10) (C0-C6)alkylene-heterocyclyl, optionally substituted with up to three substituents selected from Re, 11) (C0-C6)alkylene-N(Re)2, 12) C(O)Rc, 13) CO2Rc, 14) C(O)H, and 15) CO2H; and Re is H, (C1-C6)alkyl, aryl, heterocyclyl, (C3-C6)cycloalkyl or S(O)2Rc.
- 8. The compound of claim 4, wherein
R1 is (C1-C10)alkylene-NRaRb, optionally substituted with one or two substituents selected from R7; R2 is H, CN, halogen, (C1-C6)alkyl, or (C1-C6)alkyloxy; R4 is H or (C1-C6)alkyl; R5 is H, (C1-C6)alkyl, CO2(C1-C6)alkyl, or CO(C1-C6)alkyl; R6 is CN; R7 is selected from:
1) Or(C═O)sNRaRb, 2) (C═O)rOsaryl, 3) (C═O)rOs-heterocyclyl, 4) halogen, 5) OH, 6) oxo, 7) O(C1-C3)perfluoroalkyl, 8) (C1-C3)perfluoroalkyl, and 9) (C═O)rOs(C1-C6)alkyl, 10) CHO, 11) CO2H, 12) CN, 13) (C3-C6)cycloalkyl,
wherein r and s are independently 0 or 1, and said aryl, heterocyclyl and cycloalkyl are optionally substituted with one or two substituents selected from Rd; Ra and Rb are independently selected from:
1) H, 2) (C═O)r(C1-C6)alkyl, 3) (C═O)r(C3-C6)cycloalkyl, 4) S(O)2Rc, 5) (C═O)rheterocyclyl, 6) (C═O)raryl, and 7) CO2Rc,
wherein r is 0 or 1 and said alkyl, cycloalkyl, heterocyclyl, and aryl optionally substituted with one to three substituents selected from Rd, or Ra and Rb are taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one additional heteroatom selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one or two substituents selected from Rd; Rc is (C1-C6)alkyl, (C3-C6)cycloalkyl, or aryl; and Rd is selected from:
1) (C═O)rOs(C1-C6)alkyl, wherein r and s are independently 0 or 1, optionally substituted with up to three substituents selected from OH, (C1-C6)alkoxy, halogen, CN, oxo, N(Re)2 and S(O)2Rc, 2) Or(C1-C3)perfluoroalkyl, 3) (C0-C6)alkylene-S(O)mRc, wherein m is 0, 1, or 2, 4) oxo, 5) OH, 6) halo, 7) CN, 8) (C3-C6)cycloalkyl, optionally substituted with up to three substituents selected from OH, (C1-C6)alkoxy, halogen, CN, oxo, N(Re)2, and S(O)2Rc, 9) (C0-C6)alkylene-aryl, optionally substituted with one or two substituents selected from Re, 10) (C0-C6)alkylene-heterocyclyl, optionally substituted with one or two substituents selected from Re, 11) (C0-C6)alkylene-N(Re)2, 12) C(O)Rc, 13) CO2Rc, 14) C(O)H, and 15) CO2H; and Re is H, (C1-C6)alkyl, aryl, heterocyclyl, (C3-C6)cycloalkyl or S(O)2Rc.
- 9. The compound of claim 5, wherein
R1 is (C1-C10)alkylene-NRaRb optionally substituted with one or two substituents selected from R7; R2 is H, CN, halogen, (C1-C6)alkyl, or (C1-C6)alkyloxy; R4 is H or (C1-C6)alkyl; R5 is H, (C1C6)alkyl, CO2(C1-C6)alkyl, or CO(C1-C6)alkyl; R6 is phenyl, (C1-C6)alkyl, thienyl, naphthyl, pyrimidinyl, pyridazinyl, pyrazinyl, or pyridyl, optionally substituted with one or two substituents selected from CN, halogen, (C1-C6)alkyl, or (C1-C6)alkyloxy, CF3, OH, OCF3, and NRaRb; R7 is selected from:
1) Or(C═O)sNRaRb, 2) (C═O)rOsaryl, 3) (C═O)rOs-heterocyclyl, 4) halogen, 5) OH, 6) oxo, 7) O(C1-C3)perfluoroalkyl, 8) (C1-C3)perfluoroalkyl, and 9) (C═O)rOs(C1-C6)alkyl, 10) CHO, 11) CO2H, 12) CN, 13) (C3-C6)cycloalkyl,
wherein r and s are independently 0 or 1, and said aryl, heterocyclyl and cycloalkyl are optionally substituted with one or two substituents selected from Rd; Ra and Rb are independently selected from:
1) H, 2) (C═O)r(C1-C6)alkyl, 3) (C═O)r(C3-C6)cycloalkyl, 4) S(O)2Rc, 5) (C═O)rheterocyclyl, 6) (C═O)raryl, and 7) CO2Rc,
wherein r is 0 or 1 and said alkyl, cycloalkyl, heterocyclyl, and aryl optionally substituted with one to three substituents selected from Rd, or Ra and Rb are taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one additional heteroatom selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one or two substituents selected from Rd; Rc is (C1-C6)alkyl, (C3-C6)cycloalkyl, or aryl; and Rd is selected from:
1) (C═O)rOs(C1-C6)alkyl, wherein r and s are independently 0 or 1, optionally substituted with up to three substituents selected from OH, (C1-C6)alkoxy, halogen, CN, oxo, N(Re)2 and S(O)2Rc, 2) Or(C1-C3)perfluoroalkyl, 3) (C0-C6)alkylene-S(O)mRc, wherein m is 0, 1, or 2, 4) oxo, 5) OH, 6) halo, 7) CN, 8) (C3-C6)cycloalkyl, optionally substituted with up to three substituents selected from OH, (C1-C6)alkoxy, halogen, CN, oxo, N(Re)2, and S(O)2Rc, 9) (C0-C6)alkylene-aryl, optionally substituted with one or two substituents selected from Re, 10) (C0-C6)alkylene-heterocyclyl, optionally substituted with one or two substituents selected from Re, 11) (C0-C6)alkylene-N(Re)2, 12) C(O)Rc, 13) CO2Rc, 14) C(O)H, and 15) CO2H; and Re is H, (C1-C6)alkyl, aryl, heterocyclyl, (C3-C6)cycloalkyl or S(O)2Rc.
- 10. A compound selected from:
2-[4-(4-methyl-5-oxo-[1,4]diazepan-1-ylmethyl)-pyridin-2-ylamino]-thiazole-5-carbonitrile; 2-[4-(4-acetyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-thiazole-5-carbonitrile; 2-[4-(4-methanesulfonyl-piperazin-1-ylmethyl)-pyridin-2-ylamino]-thiazole-5-carbonitrile; 2-[4-(1,1-dioxo-thiomorpholin-4-ylmethyl)-pyridin-2-ylamino]-thiazole-5-carbonitrile; 2-{4-[4-(2-hydroxy-ethanoyl)-piperazin-1-ylmethyl]-pyridin-2-ylamino}-thiazole-5-carbonitrile; N-{1-[2-(5-cyano-thiazol-2-ylamino)-pyridin-4-ylmethyl]-pyrrolidin-3-yl}-methanesulfonamide; 4-({2-[(5-cyano-1,3-thiazol-2-yl)amino]-4-pyridinyl}methyl)-N,N-dimethyl-1-piperazinecarboxamide; 2-[(4-{[(5-oxo-3-pyrrolidinyl)amino]methyl}-2-pyridinyl)amino]-1,3-thiazol-5-carbonitrile; 4-({2-[(5-cyano-1,3-thiazol-2-yl)amino]-4-pyridinyl}methyl)-1-piperazinecarboxamide; -167 - 2-[(4-{[3-(methylsulfonyl)-1-pyrrolidinyl]methyl}-2-pyridinyl)amino]-1,3-thiazole-5-carbonitrile; 2-[4-(4-methyl-3-oxo-piperazin-1-ylmethyl)-pyridin-2-ylamino]-thiazole-5-carbonitrile; 2-(4-morpholin-4-ylmethyl-pyridin-2-ylamino)-thiazole-5-carbonitrile; 2-(4-{[(piperidin-4-ylmethyl)-amino]-methyl}-pyridin-2-ylamino)-thiazole-5-carbonitrile; and 2-(4-piperazin-1-ylmethyl-pyridin-2-ylamino)-thiazole-5-carbonitrile, or a pharmaceutically acceptable salt or N-oxide thereof.
- 11. A compound selected from:
[4-(4-methanesulfonyl-piperazin-1-ylmethyl)-pyridin-2-yl]-(5-phenyl-thiazol-2-yl)-amine; 1-methyl-4-[2-(5-phenyl-thiazol-2-ylamino)-pyridin-4-ylmethyl]-piperazin-2-one; 1-{4-[2-(5-phenyl-thiazol-2-ylamino)-pyridin-4-ylmethyl]-piperazin-1-yl}-ethanone; 1-ethyl-4-[2-(5-phenyl-thiazol-2-ylamino)-pyridin-4-ylmethyl]-piperazine-2,3-dione; (5-phenyl-thiazol-2-yl)-(4-pyrrolidin-1-ylmethyl-pyridin-2-yl)-amine; (5-phenyl-thiazol-2-yl)-[5-(3-piperidin-1-yl-propyl)-pyridin-2-yl]-amine; 1-[2-(5-phenyl-thiazol-2-ylamino)-pyridin-4-ylmethyl]-piperidine-4-carboxylic acid; 1-[2-(5-phenyl-thiazol-2-ylamino)-pyridin-4-ylmethyl]-piperidine-3-carboxylic acid; and 1-[2-(5-phenyl-thiazol-2-ylamino)-pyridin-4-ylmethyl]-piperidine-2-carboxylic acid, or a pharmaceutically acceptable salt or N-oxide thereof.
- 12. A pharmaceutical composition which is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.
- 13. A method of treating or preventing cancer in a mammal in need of such treatment which is comprised of administering to said mammal a therapeutically effective amount of a compound of claim 1.
- 14. A method of treating cancer or preventing cancer in accordance with claim 13 wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung.
- 15. A method of treating or preventing cancer in accordance with claim 13 wherein the cancer is selected from histiocytic lymphoma, lung adenocarcinoma, small cell lung cancers, pancreatic cancer, gioblastomas and breast carcinoma.
- 16. A method of treating or preventing a disease in which angiogenesis is implicated, which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1.
- 17. A method in accordance with claim 19 wherein the disease is an ocular disease.
- 18. A method of treating or preventing retinal vascularization which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of compound of claim 1.
- 19. A method of treating or preventing diabetic retinopathy which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of compound of claim 1.
- 20. A method of treating or preventing age-related macular degeneration which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1.
- 21. A method of treating or preventing inflammatory diseases which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1.
- 22. A method according to claim 21 wherein the inflammatory disease is selected from rheumatoid arthritis, psoriasis, contact dermatitis and delayed hypersensitivity reactions.
- 23. A method of treating or preventing a tyrosine kinase-dependent disease or condition which comprises administering a therapeutically effective amount of a compound of claim 1.
- 24. A pharmaceutical composition made by combining the compound of claim 1 and a pharmaceutically acceptable carrier.
- 25. A process for making a pharmaceutical composition which comprises combining a compound of claim 1 with a pharmaceutically acceptable carrier.
- 26. A method of treating or preventing bone associated pathologies selected from osteosarcoma, osteoarthritis, and rickets which comprises administering a therapeutically effective amount of a compound of claim 1.
- 27. The composition of claim 12 further comprising a second compound selected from:
1) an estrogen receptor modulator, 2) an androgen receptor modulator, 3) retinoid receptor modulator, 4) a cytotoxic agent, 5) an antiproliferative agent, 6) a prenyl-protein transferase inhibitor, 7) an HMG-CoA reductase inhibitor, 8) an HIV protease inhibitor, 9) a reverse transcriptase inhibitor, and 10) another angiogenesis inhibitor.
- 28. The composition of claim 27, wherein the second compound is another angiogenesis inhibitor selected from the group consisting of a tyrosine kinase inhibitor, an inhibitor of epidermal-derived growth factor, an inhibitor of fibroblast-derived growth factor, an inhibitor of platelet derived growth factor, an MMP inhibitor, an integrin blocker, interferon-α, interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, and an antibody to VEGF.
- 29. The composition of claim 27, wherein the second compound is an estrogen receptor modulator selected from tamoxifen and raloxifene.
- 30. A method of treating cancer which comprises administering a therapeutically effective amount of a compound of claim 1 in combination with radiation therapy.
- 31. A method of treating or preventing cancer which comprises administering a therapeutically effective amount of a compound of claim 1 in combination with a compound selected from:
1) an estrogen receptor modulator, 2) an androgen receptor modulator, 3) retinoid receptor modulator, 4) a cytotoxic agent, 5) an antiproliferative agent, 6) a prenyl-protein transferase inhibitor, 7) an HMG-CoA reductase inhibitor, 8) an HIV protease inhibitor, 9) a reverse transcriptase inhibitor, and 10) another angiogenesis inhibitor.
- 32. A method of treating cancer which comprises administering a therapeutically effective amount of a compound of claim 1 in combination with radiation therapy and a compound selected from:
1) an estrogen receptor modulator, 2) an androgen receptor modulator, 3) retinoid receptor modulator, 4) a cytotoxic agent, 5) an antiproliferative agent, 6) a prenyl-protein transferase inhibitor, 7) an HMG-CoA reductase inhibitor, 8) an HIV protease inhibitor, 9) a reverse transcriptase inhibitor, and 10) another angiogenesis inhibitor.
- 33. A method of treating or preventing cancer which comprises administering a therapeutically effective amount of a compound of claim 1 and paclitaxel or trastuzumab.
- 34. A method of treating or preventing cancer which comprises administering a therapeutically effective amount of a compound of claim 1 and a GPIIb/IIIa antagonist.
- 35. The method of claim 34 wherein the GPIIb/IIIa antagonist is tirofiban.
- 36. A method of reducing or preventing tissue damage following a cerebral ischemic event which comprises administering a therapeutically effective amount of a compound of Claim I.
RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. § 119(e) from U.S. Provisional Application 60/153,348, filed Sep. 10th, 1999.
Provisional Applications (1)
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Number |
Date |
Country |
|
60153348 |
Sep 1999 |
US |
Continuations (1)
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Number |
Date |
Country |
Parent |
09658680 |
Sep 2000 |
US |
Child |
10062351 |
Feb 2002 |
US |