Bi-aryl meta-pyrimidine inhibitors of kinases
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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.
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Citations
103 Claims
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1. A compound having the structure (A):
- View Dependent Claims (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103)
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3. The compound of claim 1, wherein the compound is selected from the group consisting of compounds having formulas I-CLXII:
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4. The compound of claim 1, wherein the compound is
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5. The compound of claim 1, wherein the compound is
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6. The compound of claim 1, wherein the compound is
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7. The compound of claim 1, wherein the compound is selected from the group consisting of:
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8. The compound of claim 1, wherein the compound is selected from the group consisting of:
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9. The compound of claim 1, wherein the compound is selected from the group consisting of:
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10. The compound of claim 1, wherein the compound is selected from the group consisting of:
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11. The compound of claim 1, wherein the compound is selected from the group consisting of:
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12. The compound of claim 1, wherein the compound is selected from the group consisting of:
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13. The compound of claim 1, wherein the compound is selected from the group consisting of:
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14. The compound of claim 1, wherein the compound is
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15. The compound of claim 1, wherein the compound is selected from the group consisting of:
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16. The compound of claim 1, wherein the compound is selected from the group consisting of:
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17. The compound of claim 1, wherein the compound is
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18. The compound of claim 1, wherein the compound is
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19. The compound of claim 1, wherein the compound is
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20. The compound of claim 1, wherein the compound is
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21. The compound of claim 1, wherein the compound is selected from the group consisting of:
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22. The compound of claim 1, wherein the compound is
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23. The compound of claim 1, wherein the compound is selected from the group consisting of:
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24. The compound of claim 1, wherein the compound is selected from the group consisting of:
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25. The compound of claim 1, wherein the compound is selected from the group consisting of:
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26. The compound of claim 1, wherein the compound is
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27. The compound of claim 1, wherein the compound is selected from the group consisting of:
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28. The compound of claim 1, wherein the compound is
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29. The compound of claim 1, wherein the compound is selected from the group consisting of:
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30. The compound of claim 1, wherein the compound is selected from the group consisting of:
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31. The compound of claim 1, wherein the compound is selected from the group consisting of:
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32. The compound of claim 1, wherein the compound is
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33. The compound of claim 1, wherein the compound is
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34. The compound of claim 1, wherein the compound is selected from the group consisting of:
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35. The compound of claim 1, wherein the compound is
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36. The compound of claim 1, wherein the compound is selected from the group consisting of:
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37. The compound of claim 1, wherein the compound is selected from the group consisting of:
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38. The compound of claim 1, wherein the compound is selected from the group consisting of:
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39. The compound of claim 1, wherein the compound is
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40. The compound of claim 1, wherein the compound is selected from the group consisting of:
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41. The compound of claim 1, wherein the compound is selected from the group consisting of:
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42. The compound of claim 1, wherein the compound is selected from the group consisting of:
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43. The compound of claim 1, wherein the compound is
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44. The compound of claim 1, wherein the compound is
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45. The compound of claim 1, wherein the compound is
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46. The compound of claim 1, wherein the compound is selected from the group consisting of:
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47. The compound of claim 1, wherein the compound is
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48. The compound of claim 1, wherein the compound is
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49. The compound of claim 1, wherein the compound is selected from the group consisting of:
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50. The compound of claim 1, wherein the compound is
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51. The compound of claim 1, wherein the compound is selected from the group consisting of:
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52. The compound of claim 1, wherein the compound is
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53. The compound of claim 1, wherein the compound is
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54. The compound of claim 1, wherein the compound is selected from the group consisting of:
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55. The compound of claim 1, wherein the compound is selected from the group consisting of:
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56. The compound of claim 1, wherein the compound is
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57. The compound of claim 1, wherein the compound is
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58. The compound of claim 1, wherein the compound is
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59. The compound of claim 1, wherein the compound is
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60. The compound of claim 1, wherein the compound is
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61. The compound of claim 1, wherein the compound is selected from the group consisting of:
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62. The compound of claim 1, wherein the compound is
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63. The compound of claim 1, wherein the compound is selected from the group consisting of:
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64. The compound of claim 1, wherein the compound is
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65. The compound of claim 1, wherein the compound is
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66. The compound of claim 1, wherein the compound is
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67. The compound of claim 1, wherein the compound is selected from the group consisting of:
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68. The compound of claim 1, wherein the compound is
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69. The compound of claim 1, wherein the compound is
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70. The compound of claim 1, wherein the compound is
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71. The compound of claim 1, wherein the compound is
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72. The compound of claim 1, wherein the compound is
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73. The compound of claim 1, wherein the compound is
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74. The compound of claim 1, wherein the compound is
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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 claims 1-3, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxide(s), and individual diastereomers thereof, to a subject in need of such treatment.
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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.
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77. The method of claim 75, wherein the disorder is polycythemia vera.
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78. The method of claim 75, wherein the disorder is essential thrombocythemia.
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79. The method of claim 75, wherein the disorder is myeloid fibrosis with myeloid metaplasia.
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80. The method of claim 75, wherein the disorder is any myeloid-linked disorder.
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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.
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82. The method of claim 75, wherein the disorder is selected from a group consisting of ocular neovascularization, infantile haemangiomas;
- organ hypoxia, vascular hyperplasia, organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type 1 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, dermatitis, autoimmune thyroid disorders, ulcerative 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, glutamate neurotoxicity, hypoxia;
ischemic/reperfusion injury in stroke, myocardial ischemica, renal ischemia, heart attacks, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia, 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.
- organ hypoxia, vascular hyperplasia, organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type 1 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, dermatitis, autoimmune thyroid disorders, ulcerative 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, glutamate neurotoxicity, hypoxia;
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83. The method of claim 82, wherein the disorder is cardiovascular disease.
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84. The method of claim 82, wherein the disorder is a hematological disorder.
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85. The method of claim 75, wherein the disorder is chronic myelogenous leukemia (CML).
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86. The method of claim 85, wherein said chronic myelogenous leukemia is resistant to current treatments.
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87. The method of claim 75, wherein the disorder is a myeloproliferative disorder.
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88. The method of claim 87, wherein the myeloproliferative disorder arises due to mutations in a kinase.
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89. The method of claim 88, wherein the kinase is a JAK family kinase.
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90. The method of claim 87, wherein the myeloproliferative disorder arises due to gain-of-function of a JAK family kinase pathway.
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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.
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92. The method of claim 75, wherein the disorder is associated with a kinase.
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93. The method of claim 92, wherein the kinase is a JAK family kinase.
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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.
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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.
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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 claims 1-3, or N-oxides, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof.
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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.
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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.
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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.
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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 claims 1-3, or N-oxide(s), or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, to a subject in need of such treatment.
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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.
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102. The method of claim 100 or 101, wherein the disorder is an eye disease.
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103. The method of claim 102, wherein the topical administration comprises administering eye drops.
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3. The compound of claim 1, wherein the compound is selected from the group consisting of compounds having formulas I-CLXII:
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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:
Specification
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Current AssigneeImpact Biomedicines, Inc. (Bristol-Myers Squibb Company)
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Original AssigneeTargeGen, Inc. (Sanofi )
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InventorsHood, John, Renick, Joel, Cao, Jianguo, McPherson, Andrew, Zeng, Binqi, Noronha, Glenn, Soll, Richard, Pathak, Ved, Lohse, Daniel, Mak, Chi
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current514/275
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