PYRIMIDINES AND PYRIDINES USEFUL AS INHIBITORS OF PROTEIN KINASES

• US 20110224197A1
• Filed: 09/09/2010
• Published: 09/15/2011
• Est. Priority Date: 03/10/2008
• Status: Abandoned Application

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Henkel, Gregory William, Neuberger, Timothy, Liu, Michael
• Application Number:
  US12/878,246
• Publication Number:
  US 20110224197A1
• Time in Patent Office: Days
• US Class Current: 514/228.2
• CPC Class Codes: A61K 31/4155 non condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4427 containing further heterocyclic ring systems
• CPC Class Codes: A61K 31/4436 containing a heterocyclic ring having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• 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 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 35/00 Antineoplastic agents
• 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

Abstract

The present invention relates to compounds useful as inhibitors of protein kinases, such as inhibitors of GSK-3. The invention provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders. The invention provides processes for preparing compounds of the invention. The invention provides methods of identifying compounds useful for treatment of diabetes, diabetic neuropathy, osteoporosis, Alzheimer'"'"'s disease, Huntington'"'"'s disease, Parkinson'"'"'s disease, AIDS-associated dementia, bipolar disorder, amyotrophic lateral sclerosis, multiple sclerosis, schizophrenia, leukocytopenia, cardiomyocyte hypertrophy, stroke, post-stroke, spinal cord injury, traumatic brain injury, Charcot-Marie-Tooth, peripheral nerve regeneration, and rheumatoid arthritis.

Claims

1. A method of treating a GSK-3 mediated condition, comprising administering to a patient a therapeutically effective amount of a compound of formula I

2. The method of claim 1, wherein Ht is

3. The method of claim 2, wherein Z¹ is N.

4. The method of claim 2, where in Z¹ is CH.

5. The method of claim 2, wherein R^a is halogen.

6. The method of claim 5, wherein R^a is F.

7. The method of claim 1, wherein Ht is

8. The method of claim 7, wherein R^b is H.

9. The method of claim 7, wherein R^b is CH₃.

10. The method of claim 1, wherein Ht is

11. The method of claim 10, wherein R^c is H.

12. The method of claim 10, wherein R^c is CH₃.

13. The method of claim 1, wherein ring D is phenyl optionally substituted with —

R⁵.

14. The method of claim 13, where in the phenyl is substituted with —

R⁵.

15. The method of claim 14, wherein the phenyl is substituted ortho relative to the attachment to the pyridine or pyrimidine ring.

16. The method of claim 15, wherein the phenyl is substituted with halogen.

17. The method of claim 16, wherein the phenyl is substituted with Cl.

18. The method of claim 14, wherein the phenyl is substituted with C_1-6 alkyl.

19. The method of claim 18, wherein the phenyl is substituted with CH₃.

20. The method of claim 14, wherein the phenyl is substituted with haloC_1-6 alkyl.

21. The method of claim 20, wherein the phenyl is substituted with CF₃.

22. The method of claim 1, wherein Ring D is a 3-8 membered monocyclic or 8-10 membered bicyclic cycloaliphatic, wherein cycloaliphatic is optionally substituted with —

R⁵.

23. The method of claim 22, wherein, Ring D is a 3-8 membered monocyclic cycloaliphatic.

24. The method of claim 22, wherein Ring D is a 8-10 membered bicyclic cycloaliphatic.

25. The method of claim 1, wherein Ring D is a 5-8 membered monocyclic heterocyclic.

26. The method of claim 25, wherein Ring D is tetrahydropyranyl.

27. The method of claim 1, wherein Ring D is adamantyl.

28. The method of claim 1, wherein R^Y is C_1-4 alkyl optionally substituted with NR₁R₂ or C_1-4 alkyl optionally substituted with a 4-8 membered monocyclic non-aromatic heterocyclyl optionally substituted with —

R¹⁰.

29. The method of claim 28, wherein R^Y is CH₃.

30. The method of claim 28, wherein R^Y is ethyl optionally substituted with NR₁R₂ or ethyl optionally substituted with a 4-8 membered monocyclic non-aromatic heterocyclyl optionally substituted with —

R¹⁰.

31. The method of claim 30, wherein R^Y is —

CH₂—

CH₂—

NR₁R₂.

32. The method of claim 30, wherein R^Y is —

CH₂—

CH₂-(4-8 membered monocyclic non-aromatic heterocyclyl) optionally substituted with —

R¹⁰.

33. The method of claim 1, wherein R^X is H or CH₃.

34. The method of claim 33, wherein R^X is CH₃.

35. The method of claim 1, wherein R^X and R^Y together with the atoms to which they are bound form phenyl.

36. The method of claim 1, wherein R^X and R^Y together with the atoms to which they are bound form a 6 to 8 membered cycloaliphatic.

37. The method of claim 1, wherein R^X and R^Y together with the atoms to which they are bound form a 5 to 8 membered heterocycle.

38. The method of claim 1, wherein the compound is selected from

39. The method of claim 1, wherein the GSK-3 mediated condition is treated by inhibiting the GSK-3 activity in an ex vivo or in vitro biological sample.

40. The method of claim 1, wherein the GSK-3 mediated condition is selected from diabetes, osteoporosis, Alzheimer'"'"'s disease, Huntington'"'"'s disease, Parkinson'"'"'s disease, AIDS-associated dementia, bipolar disorder, amyotrophic lateral sclerosis, multiple sclerosis, schizophrenia, leukocytopenia, stroke, neurological disorders, peripheral nerve regeneration, and rheumatoid arthritis.

41. The method of claim 40, wherein said disease is stroke.

42. The method of claim 40, wherein said disease is diabetes.

43. The method of claim 40, wherein said disease is schizophrenia.

44. The method of claim 40, wherein said disease is bipolar disorder.

45. The method of claim 40, wherein said disease is leukocytopenia.

46. The method of claim 40, wherein said disease is selected from stroke, spinal cord injury, traumatic brain injury, Charcot-Marie-Tooth, and diabetic neuropathy.

48. The method of claim 41, wherein the compound is administered after ischemia has occurred.

49. The method of claim 40, comprising the additional step of administering to said patient an additional therapeutic agent selected from an agent for treating diabetes, agent for treating osteoporosis, an agent for treating Alzheimer'"'"'s disease, an agent for treating Huntington'"'"'s disease, an agent for treating Parkinson'"'"'s disease, an agent for treating AIDS-associated dementia, an agent for treating bipolar disorder, an agent for treating amyotrophic lateral sclerosis, an agent for treating multiple sclerosis, an agent for treating schizophrenia, an agent for treating leukocytopenia, an agent for treating peripheral nerve regeneration, an agent for treating stroke, and an agent for treating rheumatoid arthritis, wherein:

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

b) 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.

50. The method of claim 49 comprising the additional step of administering to said patient an additional therapeutic agent selected from an agent for treating spinal cord injury, an agent for treating traumatic brain injury, an agent for treating Charcot-Marie-Tooth, or an agent for treating diabetic neuropathy.

47. (canceled)

51. A method for treating a GSK-3 mediated condition comprising administering an agent comprising a compound selected from

53. The method of claim 51, wherein the GSK-3 mediated condition is Post-Stroke, Spinal Cord Injury, Traumatic Brain Injury, Alzheimers, Parkinsons, Huntington, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, Diabetic Neuropathy, Charcot-Marie-Tooth, Leukocytopenia, Diabetes, Peripheral Nerve Regeneration, or Osteoporosis.

54. The method of claim 53, wherein the GSK-3 mediated condition is Post-Stroke.

52. (canceled)

55. (canceled)

56. (canceled)

57. (canceled)

58. (canceled)

59. (canceled)

60. (canceled)

61. (canceled)

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65. (canceled)

66. A method for identifying compounds useful for the treatment of GSK-3-mediated conditions comprising:

measuring the amount of auto-phosphorylation of the tyrosine of the GSK-3 enzyme relative to the serine/threonine kinase form for one or more test compounds.

67. A method for identifying compounds useful for the treatment of GSK-3-mediated conditions comprising:

measuring the amount of auto-phosphorylation of the tyrosine of the GSK-3 enzyme and

measuring the amount of phosphorylation of β

-catenin.

68. The method of claim 67, wherein the step of measuring comprises obtaining the β

-catenin IC50 value for the test compound, determining the GSK-3α

or GSK3β

p-TYR IC50 value, and dividing the β

-catenin IC50 value by the GSK-3α

or GSK3β

p-TYR IC50 value.

69. (canceled)

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79. A compound selected from