Bi-aryl meta-pyrimidine inhibitors of kinases

• US 20070259904A1
• Filed: 04/26/2007
• Published: 11/08/2007
• Est. Priority Date: 11/01/2005
• Status: Active Grant

• Current Assignee: Impact Biomedicines, Inc. (Bristol-Myers Squibb Company)
• Original Assignee: TargeGen, Inc. (Sanofi )
• Inventors: Hood, John, Renick, Joel, Cao, Jianguo, McPherson, Andrew, Zeng, Binqi, Noronha, Glenn, Soll, Richard, Pathak, Ved, Lohse, Daniel, Mak, Chi
• Granted Patent: US 7,825,246 B2
• Time in Patent Office: Days
• US Class Current: 514/275
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/12 Keratolytics, e.g. wart or anti-corn preparations
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/20 : for DNA viruses
• CPC Class Codes: A61P 31/22 : for herpes viruses
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 39/02 : Antidotes
• CPC Class Codes: A61P 41/00 : Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 239/42 : One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 239/48 : Two nitrogen atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links

Abstract

The invention provides biaryl meta-pyrimidine compounds having the general structure (A). The pyrimidine compounds of the invention are capable of inhibiting kinases, such as members of the Jak kinase family, and various other specific receptor and non-receptor kinases.

Claims

1. A compound having the structure (A):

3. The compound of claim 1, wherein the compound is selected from the group consisting of compounds having formulas I-CLXII:

4. The compound of claim 1, wherein the compound is

5. The compound of claim 1, wherein the compound is

6. The compound of claim 1, wherein the compound is

7. The compound of claim 1, wherein the compound is selected from the group consisting of:

8. The compound of claim 1, wherein the compound is selected from the group consisting of:

9. The compound of claim 1, wherein the compound is selected from the group consisting of:

10. The compound of claim 1, wherein the compound is selected from the group consisting of:

11. The compound of claim 1, wherein the compound is selected from the group consisting of:

12. The compound of claim 1, wherein the compound is selected from the group consisting of:

13. The compound of claim 1, wherein the compound is selected from the group consisting of:

14. The compound of claim 1, wherein the compound is

15. The compound of claim 1, wherein the compound is selected from the group consisting of:

16. The compound of claim 1, wherein the compound is selected from the group consisting of:

17. The compound of claim 1, wherein the compound is

18. The compound of claim 1, wherein the compound is

19. The compound of claim 1, wherein the compound is

20. The compound of claim 1, wherein the compound is

21. The compound of claim 1, wherein the compound is selected from the group consisting of:

22. The compound of claim 1, wherein the compound is

23. The compound of claim 1, wherein the compound is selected from the group consisting of:

24. The compound of claim 1, wherein the compound is selected from the group consisting of:

25. The compound of claim 1, wherein the compound is selected from the group consisting of:

26. The compound of claim 1, wherein the compound is

27. The compound of claim 1, wherein the compound is selected from the group consisting of:

28. The compound of claim 1, wherein the compound is

29. The compound of claim 1, wherein the compound is selected from the group consisting of:

30. The compound of claim 1, wherein the compound is selected from the group consisting of:

31. The compound of claim 1, wherein the compound is selected from the group consisting of:

32. The compound of claim 1, wherein the compound is

33. The compound of claim 1, wherein the compound is

34. The compound of claim 1, wherein the compound is selected from the group consisting of:

35. The compound of claim 1, wherein the compound is

36. The compound of claim 1, wherein the compound is selected from the group consisting of:

37. The compound of claim 1, wherein the compound is selected from the group consisting of:

38. The compound of claim 1, wherein the compound is selected from the group consisting of:

39. The compound of claim 1, wherein the compound is

40. The compound of claim 1, wherein the compound is selected from the group consisting of:

41. The compound of claim 1, wherein the compound is selected from the group consisting of:

42. The compound of claim 1, wherein the compound is selected from the group consisting of:

43. The compound of claim 1, wherein the compound is

44. The compound of claim 1, wherein the compound is

45. The compound of claim 1, wherein the compound is

46. The compound of claim 1, wherein the compound is selected from the group consisting of:

47. The compound of claim 1, wherein the compound is

48. The compound of claim 1, wherein the compound is

49. The compound of claim 1, wherein the compound is selected from the group consisting of:

50. The compound of claim 1, wherein the compound is

51. The compound of claim 1, wherein the compound is selected from the group consisting of:

52. The compound of claim 1, wherein the compound is

53. The compound of claim 1, wherein the compound is

54. The compound of claim 1, wherein the compound is selected from the group consisting of:

55. The compound of claim 1, wherein the compound is selected from the group consisting of:

56. The compound of claim 1, wherein the compound is

57. The compound of claim 1, wherein the compound is

58. The compound of claim 1, wherein the compound is

59. The compound of claim 1, wherein the compound is

60. The compound of claim 1, wherein the compound is

61. The compound of claim 1, wherein the compound is selected from the group consisting of:

62. The compound of claim 1, wherein the compound is

63. The compound of claim 1, wherein the compound is selected from the group consisting of:

64. The compound of claim 1, wherein the compound is

65. The compound of claim 1, wherein the compound is

66. The compound of claim 1, wherein the compound is

67. The compound of claim 1, wherein the compound is selected from the group consisting of:

68. The compound of claim 1, wherein the compound is

69. The compound of claim 1, wherein the compound is

70. The compound of claim 1, wherein the compound is

71. The compound of claim 1, wherein the compound is

72. The compound of claim 1, wherein the compound is

73. The compound of claim 1, wherein the compound is

74. The compound of claim 1, wherein the compound is

75. A method for treating an angiogenic-associated disorder, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of any one of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxide(s), and individual diastereomers thereof, to a subject in need of such treatment.

76. The method of claim 75, wherein the disorder is a myeloproliferative disorder, polycythemia vera, essential thrombocythemia, myeloid fibrosis with myeloid metaplasia, any other myeloid-linked disorder, proliferative diabetic retinopathy, a cancer, eye disease, inflammation, psoriasis, any disease related to angiogenesis, or a viral infection.

77. The method of claim 75, wherein the disorder is polycythemia vera.

78. The method of claim 75, wherein the disorder is essential thrombocythemia.

79. The method of claim 75, wherein the disorder is myeloid fibrosis with myeloid metaplasia.

80. The method of claim 75, wherein the disorder is any myeloid-linked disorder.

81. The method of claim 76, wherein the cancer is selected from a group consisting of an alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer and brain cancer.

82. The method of claim 75, wherein the disorder is selected from a group consisting of ocular neovasculariaztion, infantile haemangiomas;

organ hypoxia, vascular hyperplasia, organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes, or Type II diabetes, and complications from diabetes, inflammatory disease, acute pancreatitis, chronic pancreatitis, asthma, allergies, adult respiratory distress syndrome, cardiovascular disease, liver disease, other blood disorders, asthma, rhinitis, atopic, dermatitits, autoimmune thryroid disorders, ulerative colitis, Crohn'"'"'s disease, metastatic melanoma, Kaposi'"'"'s sarcoma, multiple myeloma, conditions associated with cytokines, and other autoimmune diseases including glomerulonephritis, scleroderma, chronic thyroiditis, Graves'"'"' disease, autoimmune gastritis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, allergic asthma, atopic dermatitis, allergic rhinitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, graft vs host disease, motor neuron disease, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, amyotrophic lateral sclerosis, Huntington'"'"'s disease, cerebral ischemia, or neurodegenerative disease caused by traumatic injury, strike, gluatamate neurtoxicity, hypoxia;

ischemic/reperfusion injury in stroke, myocardial ischemica, renal ischemia, heart attacks, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hyoxia, platelet aggregation, allergic contact dermatitis, hypersensitivity pneumonitis, systemic lupus erythematosus, juvenile arthritis, Sjogren'"'"'s Syndrome, scleroderma, polymyositis, ankylosing spondylitis, psoriatic arthritis, Epstein Barr Virus, Hepatitis B, Hepatitis C, HIV, HTLV1, Vaicella-Zoster Virus, Human Papilloma Virus, food allergy, cutaneous inflammation, and immune suppression induced by solid tumors.

83. The method of claim 82, wherein the disorder is cardiovascular disease.

84. The method of claim 82, wherein the disorder is a hematological disorder.

85. The method of claim 75, wherein the disorder is chronic myelogenous leukemia (CML).

86. The method of claim 85, wherein said chronic myelogenous leukemia is resistant to current treatments.

87. The method of claim 75, wherein the disorder is a myeloproliferative disorder.

88. The method of claim 87, wherein the myeloproliferative disorder arises due to mutations in a kinase.

89. The method of claim 88, wherein the kinase is a JAK family kinase.

90. The method of claim 87, wherein the myeloproliferative disorder arises due to gain-of-function of a JAK family kinase pathway.

91. The method of claim 87, wherein the myeloproliferative disorder arises as a result of gene or protein fusions due to gain-of-function of a JAK family kinase pathway.

92. The method of claim 75, wherein the disorder is associated with a kinase.

93. The method of claim 92, wherein the kinase is a JAK family kinase.

94. A pharmaceutical composition comprising at least one compound of any one of claims 1-3, or its N-oxides, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, and a pharmaceutically acceptable carrier therefore.

95. An article of manufacture comprising packaging material and a pharmaceutical composition contained within the packaging material, wherein the packaging material comprises a label which indicates that the pharmaceutical composition can be used for treatment of angiogenic-associated disorders, and wherein the pharmaceutical composition comprises at least one compound of any one of claims 1-3, or N-oxide(s), or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof.

96. An article of manufacture comprising packaging material and a pharmaceutical composition contained within the packaging material, wherein the packaging material comprises a label which indicates that the pharmaceutical composition can be used for treatment of myeloproliferative disorder, proliferative diabetic retinopathy, a cancer, eye disease, inflammation, psoriasis, or a viral infection, and wherein the pharmaceutical composition comprises at least one compound of any one of claim 1, or N-oxides, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof.

97. The article of manufacture of claim 96, wherein the disorder is selected from a group consisting of an alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer and brain cancer.

98. A method of treating angiogenic-associated disorder, comprising the administration of a therapeutically effective amount of at least one compound of any one of claims 1-3, or N-oxide(s), or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, in combination with an anti-inflammatory agent, chemotherapeutic agent, immunomodulatory agent, therapeutic antibody, or a protein kinase inhibitor, to a subject in need of such treatment.

99. A process for making a pharmaceutical composition comprising combining a combination of at least one compound of any one of claims 1-3, or its N-oxide(s), or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms salts and individual diastereomers thereof, and a pharmaceutically acceptable carrier.

100. A method of treating angiogenic-associated disorder, comprising the topical administration of a therapeutically effective amount of at least one compound of any one of claim 1, or N-oxide(s), or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, to a subject in need of such treatment.

101. The method of claim 100, wherein the administration is carried out in combination with administering an anti-inflammatory agent, chemotherapeutic agent, immunomodulatory agent, therapeutic antibody, or a protein kinase inhibitor.

102. The method of claim 100 or 101, wherein the disorder is an eye disease.

103. The method of claim 102, wherein the topical administration comprises administering eye drops.

2. A compound comprising a first moiety chemically connected to a second moiety, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual diastereomers thereof, wherein the first moiety is selected from the group consisting of:

104. A compound having the structure (B):

105. The compound of claim 104, having the structure (C):

106. The compound of claim 104, having the structure (D):

107. The compound of claim 104, having the structure (E):

108. The compound of claim 104, having the structure (F):

109. The compound of claim 104, having the structure (G):

110. The compound of claim 104, having the structure (H):

111. The compound of claim 104, having the structure (I):

112. The compound of claim 104, having the structure (J):