HETEROCYCLIC RECEPTOR AGONISTS FOR THE TREATMENT OF DIABETES AND METABOLIC DISORDERS

• US 20090054475A1
• Filed: 12/26/2007
• Published: 02/26/2009
• Est. Priority Date: 12/28/2006
• Status: Active Grant

• Current Assignee: CymaBay Therapeutics Inc.
• Original Assignee: Metabolix Incorporated
• Inventors: Johnson, Jeffrey D., Chen, Xin, Zhu, Yan, Song, Jiangao, Cheng, Peng, Zhao, Zuchun, Ma, Jingyuan, Rabbat, Christopher J., Nashashibi, Imad, Murphy, Alison, Clemens, L. Edward, Wilson, Maria E.
• Granted Patent: US 7,638,541 B2
• Time in Patent Office: Days
• US Class Current: 514/275
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 277/42 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• 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 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

Compounds and methods are provided for the treatment of, inter alia, Type II diabetes and other diseases associated with poor glycemic control. The compounds of the invention are orally active.

Claims

1. A compound having the Formula I:

2. A compound of claim 1, wherein two of X, Y and Z are independently selected from the group consisting of O, N, N(R³) and S.

3. A compound of claim 1, wherein each of X, Y and Z are independently selected from the group consisting of O, N, N(R³) and S.

4. A compound of claim 1, wherein the ring having X, Y and Z is selected from the group consisting of:

5. A compound of claim 1, wherein A is CR⁴.

6. A compound of claim 1, wherein r is 1, s is 0 or 1, q is 0 and Ar is phenyl or naphthyl, optionally substituted with from 1 to 5 R⁶ substituents.

7. A compound of claim 1, wherein r is 1, s is 0 or 1, q is 0 and Ar is a 5-membered heteroaryl ring, optionally substituted with from 1 to 3 R⁶ substituents.

8. A compound of claim 1, wherein r is 1, s is 0 or 1, q is 0 and Ar is a 5-membered heteroaryl ring selected from the group consisting of oxazolyl, thiazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, furanyl, thienyl, triazolyl, pyrrolyl, isoxazolyl, isothiazolyl, and pyrazolyl, each of which is optionally substituted with from 1 to 3 R⁶ substituents.

9. A compound of claim 1, wherein r is 1, s is 0 or 1, q is 0 and Ar is a 6-membered heteroaryl ring, optionally substituted with from 1 to 3 R⁶ substituents.

10. A compound of claim 1, wherein r is 1, s is 0 or 1, q is 0 and Ar is selected from the group consisting of pyridyl, pyrimidinyl and pyrazinyl, each of which is optionally substituted with from 1 to 3 R⁶ substituents.

11. A compound of claim 1, wherein r is 1, s is 0 or 1, q is 0, and n is 2.

12. A compound of claim 1, wherein r is 1, s is 0 or 1, q is 0, n is 2 and one CH₂ of L is replaced by O, S or N(R⁵).

13. A compound of claim 1, wherein r is 1;

s is 0 or 1;

q is 0;

n is 2 and one CH₂ of L is replaced by O;

A is selected from the group consisting of CH, C(CH₃), CF and C(OH);

the ring having X, Y and Z as ring members is selected from the group consisting of thiazole, oxazole, thiadiazole and oxadiazole.

14. A compound of claim 13, wherein Ar is phenyl, optionally substituted with from 1 to 3 R⁶ substituents.

15. A compound of claim 14, wherein R¹ is a 5- to 10-membered heteroaryl group, and is optionally substituted with from one to two substituents independently selected from halo, C_1-10 alkyl, C_1-10 haloalkyl, C_3-7 cycloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, aryl, heteroaryl, CN, NO₂, —

OR^a, —

NR^aR^b, —

CO₂R^a, —

CONR^aR^b, —

NR^aCOR^b, —

NR^aCO₂R^b, —

S(O)_mR^a, —

NR^aS(O)₂R^b, and —

SO₂NR^aR^b.

16. A compound of claim 15, wherein R¹ is a pyridine or pyrimidine, and is optionally substituted with from one to two substituents independently selected from halo, C_1-10 alkyl, C_1-10 haloalkyl, C_3-7 cycloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, aryl, heteroaryl, CN, NO₂, —

OR^a, —

NR^aR^b, —

CO₂R^a, —

CONR^aR^b, —

NR^aCOR^b, —

NR^aCO₂R^b, —

S(O)_mR^a, —

NR^aS(O)₂R^b, and —

SO₂NR^aR^b.

17. A compound of claim 14, wherein R¹ is selected from the group consisting of —

X¹—

COR^a, —

X¹—

CO₂R^a, —

X¹—

CONR^aR^b and —

SO₂R^a.

18. A compound of claim 17, wherein Ar is substituted with from 1 to 2 R⁶ substituents independently selected from the group consisting of halo, C_1-10 alkyl, C_1-10 haloalkyl, CN, NO₂, —

OR^a, —

NR^aR^b, —

COR^a, —

CO₂R^a, —

CONR^aR^b, —

NR^aCOR^b, —

NR^aCO₂R^b, —

S(O)_mR^a, —

NR^aS(O)_mR^b, —

SO₂NR^aR^b, a 4- to 5-membered heterocyclo group, and a 5- to 6-membered heteroaryl group.

19. A compound of claim 18, wherein each R⁶ is independently selected from the group consisting of halo, —

OR^a, —

NR^aR^b, —

NR^aCOR^b, —

NR^aCO₂R^b, —

S(O)_mR^a, —

NR^aS(O)_mR^b, —

SO₂NR^aR^b, a 4- to 5-membered heterocyclo group, and a 5- to 6-membered heteroaryl group.

20. A compound of Formula II:

21. A compound of claim 20, wherein R¹ is selected from the group consisting of —

X¹—

COR^a, —

X¹—

CO₂R^a, —

X¹—

CONR^aR^b, SO₂R^a, aryl, heteroaryl, substituted aryl and substituted heteroaryl.

22. A compound of claim 21, wherein R¹ is selected from the group consisting of pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl, phenyl, substituted phenyl, imidazolyl, substituted imidazolyl, triazolyl, substituted triazolyl, oxazolyl, substituted oxazolyl, thiazolyl, substituted thiazolyl, oxadiazolyl, substituted oxadiazolyl, tetrazolyl, and substituted tetrazolyl.

23. A compound of claim 22, wherein said pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, and tetrazolyl is further substituted with from one to three substituents selected from the group consisting of halo, C_1-10alkyl, C_1-10haloalkyl, C_3-7cycloalkyl, aryl, heteroaryl, NO₂, —

OR^a, —

NR^aR^b, CO₂R^a, —

CONR^aR^b, —

S(O)_mR^a, —

NR^aS(O)₂R^b, and —

SO₂NR^aR^b.

24. A compound of claim 20, wherein D is O.

25. A compound of claim 24, wherein R¹ is —

X¹—

COR^a, —

X¹—

CO₂R^a, —

X¹—

CONR^aR^b, SO₂R^a, aryl, heteroaryl, substituted aryl or substituted heteroaryl.

26. A compound of claim 25, wherein R¹ is selected from the group consisting of pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl, phenyl, substituted phenyl, imidazolyl, substituted imidazolyl, triazolyl, substituted triazolyl, oxazolyl, substituted oxazolyl, thiazolyl, substituted thiazolyl, oxadiazolyl, substituted oxadiazolyl, tetrazolyl, and substituted tetrazolyl.

27. A compound of claim 26, wherein said pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, and tetrazolyl is further substituted with from one to three substituents selected from the group consisting of halo, C_1-10alkyl, C_1-10haloalkyl, C_3-7 cycloalkyl, aryl, heteroaryl, NO₂, —

OR^a, —

NR^aR^b, CO₂R^a, —

CONR^aR^b, —

S(O_mR^a, —

NR^aS(O)₂R^b, and —

SO₂NR^aR^b.

28. A compound of claim 20, wherein J, K, T, and U are all C.

29. A compound of claim 28, wherein R¹ is selected from the group consisting of —

X¹—

COR^a, —

X¹CO₂R^a, —

X¹—

CONR^aR^b, SO₂R^a, aryl, heteroaryl, substituted aryl and substituted heteroaryl.

30. A compound of claim 29, wherein R¹ is selected from the group consisting of pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl, phenyl, substituted phenyl, imidazolyl, substituted imidazolyl, triazolyl, substituted triazolyl, oxazolyl, substituted oxazolyl, thiazolyl, substituted thiazolyl, oxadiazolyl, substituted oxadiazolyl, tetrazolyl, and substituted tetrazolyl.

31. A compound of claim 30, wherein said pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, and tetrazolyl is further substituted with from one to three substituents selected from the group consisting of halo, C_1-10alkyl, C_1-10haloalkyl, C_3-7 cycloalkyl, aryl, heteroaryl, NO₂, —

OR^a, —

NR^aR^b, CO₂R^a, —

CONR^aR^b, —

S(O)_mR^a, —

NR^aS(O)₂R^b, and —

SO₂NR^aR^b.

32. A compound of claim 31, wherein the subscript p is an integer of from 1 to 3 and each R⁷ is independently selected from the group consisting of halo, C_1-10alkyl, C_1-10haloalkyl, CN, NO₂, —

OR^a, —

NR^aR^b, —

COR^a, —

CO₂R^a, —

CONR^aR^b, —

NR^aCOR^b, —

NR^aCO₂R^b, —

S(O)_mR^a, —

NR^aS(O)_mR^b, —

SO₂NR^aR^b, a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said heterocyclo groups, said aryl and heteroaryl groups are optionally substituted with from one to four substituents independently selected from halo, oxo, C_1-4 alkyl, C_1-4haloalkyl, C_3-7 cycloalkyl, CN, NO₂, —

OR^a—

NR^aR^b, —

CO₂R^a, —

CONR^aR^b, NR^aCOR^b, —

NR^aCOR^b, —

S(O)_mR^a, —

NR^aS O₂R^b, and —

SO₂NR^aR^b and wherein the subscript m is an integer of from 0 to 2.

33. A compound of claim 20, wherein at least one of J, K, T, and U is N.

34. A compound of claim 33, wherein D is O.

35. A compound of claim 34, wherein R¹ is selected from the group consisting of —

X¹—

COR^a, —

X¹CO₂R^a, —

X¹—

CONR^aR^b, SO₂R^a, aryl, heteroaryl, substituted aryl and substituted heteroaryl.

36. A compound of claim 35, wherein R¹ is selected from the group consisting of pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl, phenyl, substituted phenyl, imidazolyl, triazolyl, substituted triazolyl, substituted imidazolyl, thiazolyl, substituted thiazolyl, oxazolyl, substituted oxazolyl, oxadiazolyl, substituted oxadiazolyl, tetrazolyl, and substituted tetrazolyl.

37. A compound of claim 36, wherein said pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, and tetrazolyl is further substituted with from one to three substituents selected from the group consisting of halo, C_1-10alkyl, C_1-10haloalkyl, C_3-7 cycloalkyl, aryl, heteroaryl, NO₂, —

OR^a, —

NR^aR^b, CO₂R^a, —

CONR^aR^b, S(O)_mR^a, —

NR^aS(O)₂R^b, and —

SO₂NR^aR^b.

38. A compound of claim 37, wherein the subscript p is an integer of from 1 to 3 and each R⁷ is independently selected from the group consisting of halo, C_1-10alkyl, C_1-10haloalkyl, CN, NO₂, —

OR^a, —

NR^aR^b, —

COR^a, —

CO₂R^a, —

CONR^aR^b, —

NR^aCOR^b, —

NR^aCO₂R^b, —

S(O)_mR^a, —

NR^aS(O)_mR^b, —

SO₂NR^aR^b, a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said heterocyclo groups, said aryl and heteroaryl groups are optionally substituted with from one to four substituents independently selected from halo, oxo, C_1-4 alkyl, C_1-4haloalkyl, C_3-7 cycloalkyl, CN, NO₂, —

OR^a, —

NR^aR^b, —

CO₂R^a, —

CONR^aR^b, —

NR^aCOR^b, —

NRCO₂R^b, —

S(O)_mR^a, —

NR^aSO₂R^b, and —

SO₂NR^aR^b and wherein the subscript m is an integer of from 0 to 2.

39. A compound of claim 20, wherein J, T, and U are all C;

and D is O.

40. A compound of claim 39, wherein each R⁷ is a member independently selected from the group consisting of halo, C_1-10 alkyl, C_1-10 haloalkyl, CN, NO₂, —

OR^a, —

NR^aR^b, COR^a, —

CO₂R^a, —

CONR^aR^b, —

NR^aCOR^b, —

NR^aCOR^b, —

S(O)_mR^a, NR^aS(O)_mR^b, —

SO₂NR^aR^b, a 4- to 5-membered heterocyclo group, and a 5- to 6-membered heteroaryl group and wherein the subscript m is an integer of from 0 to 2;

each R² is a member independently selected from the group consisting of halo, C_1-5alkyl, C_1-5haloalkyl; and

the subscript q is an integer of from 0 to 2.

41. A compound of claim 40, wherein each R⁷ is independently selected from the group consisting of halo, C_1-5alkyl, C_1-5haloalkyl, —

SOR^a, —

SO₂R^a, and 5-membered heteroaryl group.

42. A compound of claim 41, wherein each R⁷ is independently selected from the group consisting of fluoro, chloro, methyl, ethyl, —

CF₃, —

SO₂C_1-3alkyl, imidazolyl, triazolyl, and tetrazolyl and wherein the subscript p is integer of from 1 to 2.

43. A compound of claim 42, wherein R¹ is selected from the group consisting of —

X¹—

COR^a, —

X¹—

CO₂R^a, —

X¹—

CONR^aR^b, SO₂R^a, aryl, heteroaryl, substituted aryl and substituted heteroaryl.

44. A compound of claim 43, wherein R¹ is selected from the group consisting of is aryl, heteroaryl, substituted aryl and substituted heteroaryl.

45. A compound of claim 44, wherein R¹ is selected from the group consisting of pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl, phenyl, substituted phenyl, imidazolyl, triazolyl, substituted triazolyl, substituted imidazolyl, oxazolyl, substituted oxazolyl, thiazolyl, substituted thiazolyl, oxadiazolyl, substituted oxadiazolyl, tetrazolyl, and substituted tetrazolyl.

46. A compound of claim 43, wherein R¹ is selected from the group consisting of pyrimidinyl, substituted pyrimidinyl, oxadiazolyl, substituted oxadiazolyl, and —

X¹—

CO₂R^a and wherein X¹ is a bond.

47. A compound of claim 39, wherein X is S, Y is C, Z is N;

R¹ is selected from the group consisting of pyrimidinyl, substituted pyrimidinyl, pyridyl, and substituted pyridyl, each R⁷ is independently selected from the group consisting of fluoro and tetrazolyl.

49. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 20.

50. A method of treating a disease or condition selected from the group consisting of Type I diabetes, Type II diabetes and metabolic syndrome, said method comprising administering to a subject in need of such treatment an effective amount of a compound of claim 20.

51. The method of claim 50, wherein said disease is Type II diabetes.

52. A method of stimulating insulin production, said method comprising administering an effective amount of a compound of claim 20 to a mammal.

53. The method of claim 52, wherein said mammal is a human.

54. The method of claim 53, wherein insulin is produced by a beta cell of said mammal.

55. A method of stimulating glucose-dependent insulin secretion, said method comprising administering an effective amount of a compound of claim 20 to a mammal.

56. The method of claim 55, wherein said mammal is a human.

57. The method of claim 56, wherein insulin is produced by a beta cell of said mammal.

58. A method of lowering blood glucose in a mammal, said method comprising administering an effective amount of a compound of claim 20 to a mammal.

59. The method of claim 58 wherein said mammal is a human.

60. A method of lowering blood triglyceride levels in a mammal, said method comprising administering an effective amount of a compound of claim 20 to a mammal.

61. The method of claim 60 wherein said mammal is a human.

48. A compound as disclosed in Examples 1 to 210.