Pyridine-containing macroheterococylic compounds as kinase inhibitors

Abstract

This invention is directed to pyridine-containing macroheterocyclic compounds useful as kinase inhibitors, methods for producing such compounds and methods for treating or preventing a kinase mediated disorder.

Description

Claims

1. A compound of Formula (I)

2. The compound of claim 1, wherein A is CH such that the A-containing ring system of Formula (I) is 1H-indole.

3. The compound of claim 1, wherein R1 and R3 are each selected from the group consisting of hydrogen, methyl, methoxy, halogen, and hydroxy.

4. The compound of claim 3, wherein R1 and R3 are each hydrogen.

5. The compound of claim 1, wherein R4 and R5 are each C3-4alkylene.

6. The compound of claim 5, wherein R4 and R5 are each n-propylene or n-butylene.

7. The compound of claim 1, wherein R2 is C6-10aryl or NRaRb; wherein C6-10aryl is optionally substituted with one or two substituents independently selected from the group consisting of C1-4alkyl and halogen.

8. The compound of claim 7, wherein R2 is phenyl optionally substituted with one to two methyl substituents.

9. The compound of claim 8, wherein R2 is phenyl optionally substituted with one methyl substituent.

10. The compound of claim 9, wherein R2 is 4-methyl-phenyl.

11. The compound of claim 1, wherein Ra and Rb are each C1-4alkyl; or Ra and Rb are taken together with the atoms to which they are attached to form a 5 to 6 membered monocyclic ring.

12. The compound of claim 11, wherein Ra and Rb are each C1-2alkyl; or Ra and Rb are taken together with the atoms to which they are attached to form a 5-membered monocyclic ring.

13. A compound of Formula (Ia)

14. The compound of claim 13, wherein R1 and R3 are each hydrogen.

15. The compound of claim 13, wherein: R4 and R5 are each n-propylene or n-butylene;R2 is phenyl or NRaRb; wherein phenyl is optionally substituted with one to two methyl substituents; andRa and Rb are each C1-2alkyl; or Ra and Rb are taken together with the atoms to which they are attached to form a 5-membered monocyclic ring.

16. The compound of claim 13, wherein R2 is 4-methyl-phenyl or NRaRb.

17. A compound selected from the group consisting of:

18. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

19. A pharmaceutical composition comprising the compound of claim 13 and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition made by mixing a compound of claim 1 and a pharmaceutically acceptable carrier.

21. A pharmaceutical composition made by mixing a compound of claim 13 and a pharmaceutically acceptable carrier.

22. Use of the compound of claim 1 for the preparation of a medicament for treating or ameliorating a glycogen synthase kinase-3β mediated disorder in a subject in need thereof.

23. The use of claim 22, wherein the disorder is selected from the group consisting of diabetes, inflammatory diseases, dermatological disorders, schizophrenia, manic depression and Alzheimer's disease.

24. A method for treating or preventing a kinase-mediated disorder in a subject in need thereof comprising the step of administering to the subject a therapeutically effective amount of the compound of claim 1.

25. The method of claim 24, wherein the kinase is glycogen synthase kinase-3.

26. The method of claim 25, wherein the kinase is glycogen synthase kinase-3β.

27. The method of claim 24, wherein said therapeutically effective amount comprises a dose range of from about 0.001 mg/kg/day to about 300 mg/kg/day.

28. The method of claim 24, wherein the disorder is selected from the group consisting of diabetes, inflammatory diseases, dermatological disorders and CNS disorders.

29. The method of claim 28, wherein the CNS disorder is selected from the group consisting of schizophrenia, bipolar disorder, and Alzheimer's disease.

30. A method for treating or preventing a kinase-mediated disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of claim 13.

31. The method of claim 30, wherein the kinase is glycogen synthase kinase-3β.

32. The method of claim 30, wherein said therapeutically effective amount comprises a dose range of from about 0.001 mg/kg/day to about 300 mg/kg/day.

33. The method of claim 30, wherein the kinase-mediated disorder is selected from the group consisting of diabetes, inflammatory diseases, dermatological disorders, schizophrenia, bipolar disorder, and Alzheimer's disease.

34. A process for synthesizing a compound of Formula (I):

35. The process of claim 34, wherein the compound of Formula A6 is present in a range of from about 1 molar equivalents to about 10 molar equivalents.

36. The process of claim 35, wherein the compound of Formula A6 is present in a range of from about 4 molar equivalents to about 8 molar equivalents.

37. The process of claim 34, wherein the cobalt catalyst is CpCo(CO)2.

38. The process of claim 34, wherein the cobalt catalyst is present in a range of from about 0.1 molar equivalents to about 1 molar equivalent.

39. The process of claim 38, wherein the cobalt catalyst is present in a range of from about 0.2 molar equivalents to about 0.5 molar equivalents.

40. The process of claim 34, wherein the cobalt catalyst is present in an aprotic organic solvent.

41. The process of claim 40, wherein the aprotic organic solvent is selected from toluene, 1,4-dioxane, or dimethoxyethane.

42. The process of claim 41, wherein the aprotic organic solvent is selected from 1,4-dioxane or dimethoxyethane.

43. The process of claim 34, wherein the reaction of the compound of Formula A6 with the compound of Formula A7 is optionally conducted in the presence of triphenylphosphine, is optionally at an elevated temperature and is optionally under an inert atmosphere.

44. The process of claim 43, wherein the temperature is from about 60° C. to about 140° C.

45. The process of claim 44, wherein the temperature is from about 80° C. to about 110° C.

46. The process of claim 43, wherein the inert atmosphere is Argon.

47. The process of claim 43, wherein triphenylphosphine is present in a range of from about 0.1 molar equivalents to about 1 molar equivalent.

48. The process of claim 47, wherein triphenylphosphine is present in a range of from about 0.2 molar equivalents to about 0.5 molar equivalents.

49. The process of claim 34, wherein the compound of Formula (I) is selected from a compound wherein: A is CH such that the A-containing ring system of Formula (I) is 1H-indole;R1 and R3 are each selected from the group consisting of hydrogen, methyl, methoxy, halogen, and hydroxy;R4 and R5 are each C3-4alkylene;R2 is C6-10aryl or NRaRb; wherein C6-10aryl is optionally substituted with one or two substituents independently selected from the group consisting of C1-4alkyl and halogen; andRa and Rb are each C1-4alkyl; or Ra and Rb are taken together with the atoms to which they are attached to form a 5 to 6 membered monocyclic ring.