2,6-Disubstituted quinazolines, quinoxalines, quinolines and isoquinolines and methods of their use as inhibitors of RAF kinase

• US 20050085482A1
• Filed: 10/15/2004
• Published: 04/21/2005
• Est. Priority Date: 10/16/2003
• Status: Active Grant

• Current Assignee: Novartis Vaccines And Diagnostics Incorporated (Novartis Ag)
• Original Assignee: Chiron Corporation (Bayer AG)
• Inventors: Renhowe, Paul A., Subramanian, Sharadha, Ramurthy, Savithri
• Granted Patent: US 7,691,866 B2
• Time in Patent Office: Days
• US Class Current: 514/248
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C04B 35/632 Organic additives
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings

Abstract

New substituted quinazoline, quinoxaline, quinoline and isoquinoline compounds, compositions and methods of inhibition of Raf kinase activity in a human or animal subject are provided. The new compounds compositions may be used either alone or in combination with at least one additional agent for the treatment of a Raf kinase mediated disorder, such as cancer.

Claims

1. A compound of the formula (I):

2. A compound of claim 1 wherein X₁ is N.

3. A compound of claim 1 wherein X₂ is N.

4. A compound of claim 1 wherein both X₁ and X₂ are N.

5. A compound of claim 1 wherein Y is O.

6. A compound of claim 1 wherein A₁ is selected from the group consisting of substituted or unsubstituted phenyl, phenylalkyl, pyridyl, pyrimidinyl, pyridylalkyl, pyrimidinylalkyl, alkylbenzoate, thiophene, thiophene-2-carboxylate, indenyl, 2,3-dihydroindenyl, tetralinyl, triflourophenyl, (triflouromethyl)thiophenyl, morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-dihydroindolyl, 1-aceyt1-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl, imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, napththalenyl, benzophenone, anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl, phenylalkylsulfonyl, 9H-flouren-1-yl, piperidin-1-yl, piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl, furanyl, N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl, hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl, and 1,4′

-bipiperidin-1′

-yl.

7. A compound of claim 1 wherein A₁ is substituted or unsubstituted phenyl.

8. A compound of claim 7 wherein A₁ is substituted phenyl selected from the group consisting of substituted or unsubstituted hydroxyphenyl, hydroxyalkylphenyl, alkylphenyl, dialkylphenyl, trialkylphenyl, alkoxyphenyl, dialkoxyphenyl, alkoxyalkylphenyl, halophenyl, dihalophenyl, haloalkylphenyl, haloalkoxyphenyl, alkylhalophenyl, alkoxyhalophenyl, alkylthiophenyl, aminophenyl, nitrophenyl, acetylphenyl, sulfamoylphenyl, biphenyl, alkoxybiphenyl, cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl, morpholinylphenyl, heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkylphenyl, furanylphenyl, (1,4′

-bipiperidin-1′

-ylcarbonyl)phenyl, pyrimidin-5-ylphenyl, and quinolidinylphenyl.

9. A compound of claim 8 wherein A₁ is substituted phenyl selected from the group consisting of chlorophenyl, flourophenyl, bromophenyl, iodophenyl, dichlorophenyl, difluorophenyl, dibromophenyl, flurorchlorophenyl, bromochlorophenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, alkylbromophenyl, trifluoromethylbromophenyl, alkylchlorophenyl, triflouromethylchlorophenyl, alkylflourophenyl, and triflouromethylfluorophenyl.

10. A compound of claim 1 wherein A₂ is substituted or unsubstituted pyridyl.

11. A compound of claim 1 wherein Z is

12. A compound of claim 1 wherein Z is

13. A compound of claim 1 wherein Z is

14. A compound of claim 1 wherein R₃ is loweralkoxy.

16. A compound of claim 1 wherein R₄ is hydrogen.

17. A compound of claim 1 wherein R₄ is loweralkyl.

18. A compound of claim 17 wherein R₄ is methyl.

19. A compound of claim 1 having the formula (V):

20. A compound of claim 1 wherein Z is

78. A composition comprising an amount of a compound of claims 1, 21, 30, or 59 effective to inhibit Raf activity in a human or animal subject when administered thereto, together with a pharmaceutically acceptable carrier.

79. A composition of claim 78 which further comprises at least one additional agent for the treatment of cancer.

80. A composition of claim 79 in which the at least one additional agent for the treatment of cancer is selected from irinotecan, topotecan, gemcitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab, trastuzumab, dacarbazine, aldesleukin, capecitabine, and Iressa (gefitinib).

81. A method of inhibiting Raf kinase activity in a human or animal subject, comprising administering to the human or animal subject a composition comprising an amount of a compound of claims 1, 21, 40, or 59 effective to inhibit Raf kinase activity in the human or animal subject.

82. A method for treating a cancer disorder in a human or animal subject, comprising administering to the human or animal subject a composition comprising an amount of a compound of claims 1, 21, 40, or 59 effective to inhibit Raf kinase activity in the human or animal subject.

83. A method of claim 82 which further comprises administering to the human or animal subject at least one additional agent for the treatment of cancer.

84. A method of claim 82 in which the at least one additional agent for the treatment of cancer is selected from irinotecan, topotecan, gemcitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab, trastuzumab, dacarbazine, aldesleukin, capecitabine, and Iressa (gefitinib).

85. A method for treating a hormone dependent cancer disorder in a human or animal subject, comprising administering to the human or animal subject a composition comprising an amount of a compound of claims 1, 21, 40, or 59 effective to inhibit Raf kinase activity in the human or animal subject.

86. A method of claim 85 wherein the hormone dependent cancer is breast cancer or prostate cancer.

87. A method of claim 85 which further comprises administering to the human or animal subject at least one additional agent for the treatment of cancer.

88. A method of claim 87 in which the at least one additional agent for the treatment of cancer is selected from irinotecan, topotecan, gemcitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab, trastuzumab, dacarbazine, aldesleukin, capecitabine, and Iressa (gefitinib).

89. A method for treating a hematological cancer disorder in a human or animal subject, comprising administering to the human or animal subject a composition comprising an amount of a compound of claims 1, 21, 40, or 59 effective to inhibit Raf kinase activity in the human or animal subject.

90. A method of claim 89 which further comprises administering to the human or animal subject at least one additional agent for the treatment of cancer.

91. A method of claim 90 in which the at least one additional agent for the treatment of cancer is selected from irinotecan, topotecan, gemcitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab, trastuzumab, dacarbazine, aldesleukin, capecitabine, and Iressa (gefitinib).

92. A compound of claims 1, 21, 40, or 59 for use in the treatment of cancer.

93. Use of a compound of claims 1, 21, 40, or 59 in the manufacture of a medicament for the treatment of cancer.

15. A compound of claim 15 wherein R₃ is methoxy.

21. A compound of the formula (II):

22. A compound of claim 21 wherein X₁ is CH.

23. A compound of claim 21 wherein R₄ is hydrogen.

24. A compound of claim 21 wherein R₄ is methyl.

25. A compound of claim 21 wherein A₁ is selected from the group consisting of substituted or unsubstituted phenyl, phenylalkyl, pyridyl, pyrimidinyl, pyridylalkyl, pyrimidinylalkyl, alkylbenzoate, thiophene, thiophene-2-carboxylate, indenyl, 2,3-dihydroindenyl, tetralinyl, triflourophenyl, (triflouromethyl)thiophenyl, morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-dihydroindolyl, 1-aceytl-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl, imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, napththalenyl, benzophenone, anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl, phenylalkylsulfonyl, 9H-flouren-1-yl, piperidin-1-yl, piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl, furanyl, N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl, hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl, and 1,4′

-bipiperidin-1′

-yl.

26. A compound of claim 25 wherein A₁ is substituted or unsubstituted phenyl.

27. A compound of claim 25 wherein A₁ is substituted phenyl selected from the group consisting of substituted or unsubstituted hydroxyphenyl, hydroxyalkylphenyl, alkylphenyl, dialkylphenyl, trialkylphenyl, alkoxyphenyl, dialkoxyphenyl, alkoxyalkylphenyl, halophenyl, dihalophenyl, haloalkylphenyl, haloalkoxyphenyl, alkylhalophenyl, alkoxyhalophenyl, alkylthiophenyl, aminophenyl, nitrophenyl, acetylphenyl, sulfamoylphenyl, biphenyl, alkoxybiphenyl, cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl, morpholinylphenyl, heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkylphenyl, furanylphenyl, (1,4′

-bipiperidin-1′

-ylcarbonyl)phenyl, pyrimidin-5-ylphenyl, and quinolidinylphenyl.

28. A compound of claim 25 wherein A₁ is substituted phenyl selected from the group consisting of chlorophenyl, flourophenyl, bromophenyl, iodophenyl, dichlorophenyl, difluorophenyl, dibromophenyl, flurorchlorophenyl, bromochlorophenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, alkylbromophenyl, trifluoromethyl-bromophenyl, alkylchlorophenyl, triflouromethylchlorophenyl, alkylflourophenyl, and triflouromethylfluorophenyl.

29. A compound of claim 21 wherein A₂ is substituted or unsubstituted pyridyl.

30. A compound of claim 21 wherein Z is

31. A compound of claim 21 wherein Z is

32. A compound of claim 21 wherein Z is

33. A compound of claim 21 wherein R₃ is loweralkoxy.

34. A compound of claim 33 wherein R₃ is methoxy.

35. A compound of claim 21 wherein R₄ is hydrogen.

36. A compound of claim 21 wherein R₄ is loweralkyl.

37. A compound of claim 36 wherein R₄ is methyl.

38. A compound of claim 21 wherein Z is

39. A compound of claim 21 having the formula (VI):

40. A compound of the formula (III):

41. A compound of claim 40 wherein X₂ is CH.

42. A compound of claim 40 wherein R₄ is hydrogen.

43. A compound of claim 40 wherein R₄ is methyl.

44. A compound of claim 40 wherein A₁ is selected from the group consisting of substituted or unsubstituted phenyl, phenylalkyl, pyridyl, pyrimidinyl, pyridylalkyl, pyrimidinylalkyl, alkylbenzoate, thiophene, thiophene-2-carboxylate, indenyl, 2,3-dihydroindenyl, tetralinyl, triflourophenyl, (triflouromethyl)thiophenyl, morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-dihydroindolyl, 1-aceytl-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl, imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, napththalenyl, benzophenone, anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl, phenylalkylsulfonyl, 9H-flouren-1-yl, piperidin-1-yl, piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl, furanyl, N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl, hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl, and 1,4′

-bipiperidin-1′

-yl.

45. A compound of claim 44 wherein A₁ is substituted or unsubstituted phenyl.

46. A compound of claim 44 wherein A₁ is substituted phenyl selected from the group consisting of substituted or unsubstituted hydroxyphenyl, hydroxyalkylphenyl, alkylphenyl, dialkylphenyl, trialkylphenyl, alkoxyphenyl, dialkoxyphenyl, alkoxyalkylphenyl, halophenyl, dihalophenyl, haloalkylphenyl, haloalkoxyphenyl, alkylhalophenyl, alkoxyhalophenyl, alkylthiophenyl, aminophenyl, nitrophenyl, acetylphenyl, sulfamoylphenyl, biphenyl, alkoxybiphenyl, cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl, morpholinylphenyl, heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkylphenyl, furanylphenyl, (1,4′

-bipiperidin-1′

-ylcarbonyl)phenyl, pyrimidin-5-ylphenyl, and quinolidinylphenyl.

47. A compound of claim 44 wherein A₁ is substituted phenyl selected from the group consisting of chlorophenyl, flourophenyl, bromophenyl, iodophenyl, dichlorophenyl, difluorophenyl, dibromophenyl, flurorchlorophenyl, bromochlorophenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, alkylbromophenyl, trifluoromethyl-bromophenyl, alkylchlorophenyl, triflouromethylchlorophenyl, alkylflourophenyl, and triflouromethylfluorophenyl.

48. A compound of claim 40 wherein A₂ is substituted or unsubstituted pyridyl.

49. A compound of claim 40 wherein Z is

50. A compound of claim 40 wherein Z is

51. A compound of claim 40 wherein Z is

52. A compound of claim 40 wherein R₃ is loweralkoxy.

53. A compound of claim 52 wherein R₃ is methoxy.

54. A compound of claim 40 wherein R₄ is hydrogen.

55. A compound of claim 40 wherein R₄ is loweralkyl.

56. A compound of claim 55 wherein R₄ is methyl.

57. A compound of claim 40 wherein Z is

58. A compound of claim 40 having the formula (VII):

59. A compound of the formula (IV):

60. A compound of claim 59 wherein R₄ is hydrogen.

61. A compound of claim 59 wherein R₄ is methyl.

62. A compound of claim 59 wherein Y is O.

63. A compound of claim 59 wherein A₁ is selected from the group consisting of substituted or unsubstituted phenyl, phenylalkyl, pyridyl, pyrimidinyl, pyridylalkyl, pyrimidinylalkyl, alkylbenzoate, thiophene, thiophene-2-carboxylate, indenyl, 2,3-dihydroindenyl, tetralinyl, triflourophenyl, (triflouromethyl)thiophenyl, morpholinyl, N-piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-dihydroindolyl, 1-aceyt1-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-1-ylalkyl, 4-amino(imino)methylphenyl, isoxazolyl, indazolyl, adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl, benzimidazolyl, imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, napththalenyl, benzophenone, anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl, phenylalkylsulfonyl, 9H-flouren-1-yl, piperidin-1-yl, piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl, furanyl, N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-1-yl, hydroxypyrrolidn-1-yl, dialkylaminopyrrolidin-1-yl, and 1,4′

-bipiperidin-1′

-yl.

64. A compound of claim 63 wherein A₁ is substituted or unsubstituted phenyl.

65. A compound of claim 63 wherein A₁ is substituted phenyl selected from the group consisting of substituted or unsubstituted hydroxyphenyl, hydroxyalkylphenyl, alkylphenyl, dialkylphenyl, trialkylphenyl, alkoxyphenyl, dialkoxyphenyl, alkoxyalkylphenyl, halophenyl, dihalophenyl, haloalkylphenyl, haloalkoxyphenyl, alkylhalophenyl, alkoxyhalophenyl, alkylthiophenyl, aminophenyl, nitrophenyl, acetylphenyl, sulfamoylphenyl, biphenyl, alkoxybiphenyl, cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl, morpholinylphenyl, heterocyclylcarbonylphenyl, heterocyclylphenyl, heterocyclylalkylphenyl, furanylphenyl, (1,4′

-bipiperidin-1′

-ylcarbonyl)phenyl, pyrimidin-5-ylphenyl, and quinolidinylphenyl.

66. A compound of claim 63 wherein A₁ is substituted phenyl selected from the group consisting of chlorophenyl, flourophenyl, bromophenyl, iodophenyl, dichlorophenyl, difluorophenyl, dibromophenyl, flurorchlorophenyl, bromochlorophenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, alkylbromophenyl, trifluoromethyl-bromophenyl, alkylchlorophenyl, triflouromethylchlorophenyl, alkylflourophenyl, and triflouromethylfluorophenyl.

67. A compound of claim 59 wherein A₂ is substituted or unsubstituted pyridyl.

68. A compound of claim 59 wherein Z is

69. A compound of claim 59 wherein Z is

70. A compound of claim 59 wherein Z is

71. A compound of claim 59 wherein Z is

72. A compound of claim 59 wherein R₃ is loweralkoxy.

73. A compound of claim 72 wherein R₃ is methoxy.

74. A compound of claim 59 wherein R₄ is hydrogen.

75. A compound of claim 59 wherein R₄ is loweralkyl.

76. A compound of claim 75 wherein R₄ is methyl.

77. A compound of claim 59 having the formula (VIII):