Compositions useful as inhibitors of protein kinases

• US 20050137201A1
• Filed: 09/07/2004
• Published: 06/23/2005
• Est. Priority Date: 09/04/2003
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Li, Pan, Lauffer, David J., Aronov, Alex, Tomlinson, Ronald C.
• Granted Patent: US 7,446,199 B2
• Time in Patent Office: Days
• US Class Current: 514/249
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• 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 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 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• 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 35/04 : specific for metastasis
• 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 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• 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 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The present invention relates to compounds useful of inhibitors of protein kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.

Claims

1. A compound of formula I:

2. A compound of formula I:

6. The compound according to claim 2, wherein Ring B is an optionally substituted 5-membered heteroaryl ring having one nitrogen and 0-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur.

7. The compound according to claim 2, wherein Ring B is an optionally substituted 6-membered heteroaryl ring having 1-3 nitrogens.

8. The compound according to claim 7, wherein Ring B is an optionally substituted pyrido ring.

9. The compound according to claim 7, wherein Ring B is an optionally substituted pyrimido ring.

10. The compound according to claim 7, wherein Ring B is an optionally substituted pyrazino ring.

11. The compound according to claim 7, wherein Ring B is an optionally substituted pyridazo ring.

12. The compound according to claim 2, wherein Ring B is an optionally substituted phenyl ring.

13. The compound according to claim 2, wherein R¹ is an optionally substituted phenyl ring.

14. The compound according to claim 2, wherein R¹ is an optionally substituted pyridyl or pyrimidinyl ring.

15. The compound according to claim 2, wherein Ring A is an optionally substituted ring selected from isoxazolyl, imidazolyl, triazolyl, or tetrazolyl.

16. The compound according to claim 15, wherein Ring A is selected from the following rings:

17. The compound according to claim 16, wherein Ring A is selected from:

18. The compound according to claim 15, wherein Ring A is:

19. The compound according to claim 2, wherein W is CH.

22. A composition comprising an effective amount of a compound according to claim 2, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

23. The composition according to claim 22, wherein said compound is in an amount sufficient to detectably inhibit c-Met, GSK3, JAK, SYK, or KDR protein kinase activity.

24. The composition according to claim 22, additionally comprising a therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.

25. A method of inhibiting c-Met, GSK3, JAK, SYK, KDR, FLT-3, c-Kit, Aurora, or TAK-1 kinase activity in:

(a) a patient;

or

(b) a biological sample;

which method comprises administering to said patient, or contacting said biological sample with;

a) a composition according to claim 22;

or

b) a compound according to claim 2.

26. A method of treating or lessening the severity of a cancer or a proliferative disorder in a patient in need thereof, comprising the step of administering to said patient:

a) a composition according to claim 22;

or

b) a compound according to claim 2.

27. The method according to claim 26, comprising the additional step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, wherein said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.

28. A method of treating or lessening the severity of renal cancer in a patient in need thereof, comprising administering to said patient a composition according to claim 22.

29. A method of treating or lessening the severity of a disease or condition selected from glioblastoma, a gastric carcinoma, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, or lung cancer in a patient in need thereof, comprising administering to said patient a composition according to claim 22.

30. The method according to claim 29, wherein said disease or condition is glioblastoma, breast cancer, colon cancer, or liver cancer.

31. A method of inhibiting tumor metastasis in a patient, comprising administering to said patient a composition according to claim 22.

32. A method of treating asthma in a patient in need thereof, comprising administering to said patient a composition according to claim 22.

33. A method of treating or lessening the severity of a disease or condition selected from allergic disorders, proliferative disorders, autoimmune disorders, conditions associated with organ transplant, inflammatory disorders, immunologic ally mediated disorders, viral diseases, or destructive bone disorders, comprising the step of administering to said patient:

a composition according to claim 22;

or a compound according to claim 2.

34. The method of claim 33, further comprising the step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, a treatment for Alzheimer'"'"'s Disease, a treatment for Parkinson'"'"'s Disease, an agent for treating Multiple Sclerosis (MS), a treatment for asthma, an agent for treating schizophrenia, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an agent for treating a blood disorder, and an agent for treating an immunodeficiency disorder, wherein:

said additional therapeutic agent is appropriate for the disease being treated; and

said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.

35. The method of claim 33, wherein the disease or condition is a cancer.

36. The method of claim 35, wherein the cancer is selected from the group consisting of breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin'"'"'s, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, and leukemia.

37. The method of claim 33, wherein the disease or condition is selected from autoimmune diseases, inflammatory diseases, metabolic, neurological and neurodegenerative diseases, cardiovascular diseases, allergy, asthma, diabetes, Alzheimer'"'"'s disease, Huntington'"'"'s disease, Parkinson'"'"'s disease, AIDS-associated dementia, amyotrophic lateral sclerosis (AML, Lou Gehrig'"'"'s disease), multiple sclerosis (MS), schizophrenia, cardiomyocyte hypertrophy, reperfusion/ischemia, and baldness.

38. The method of claim 33, wherein the disease or condition is selected from cancer, Alzheimer'"'"'s disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune disease.

39. The method of claim 33, wherein the disease or condition is selected from hypercalcemia, osteoporosis, osteoarthritis, cancer, bone metastasis, and Paget'"'"'s disease.

40. The method of claim 33, wherein the disease or condition is selected from immune responses, allergic or type I hypersensitivity reactions, and asthma, autoimmune diseases, transplant rejection, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, multiple sclerosis, neurodegenerative disorders, Familial amyotrophic lateral sclerosis (FALS), solid and hematologic malignancies, leukemias and lymphomas.

41. The method of claim 33, wherein the disease or condition is selected from hematopoietic disorders, acute-myelogenous leukemia (AML), acute-promyelocytic leukemia (APL), and acute lymphocytic leukemia (ALL).

42. The method of claim 33, wherein the disease or condition is an allergic disorder.

43. The method of claim 42, wherein the disease or condition is asthma.

3. A compound of formula I:

4. A compound of formula I:

5. A compound of formula I:

20. A compound selected from the group consisting of:

21. A compound selected from the group consisting of nos. 33-155.