N-LINKED HETEROCYCLIC RECEPTOR AGONISTS FOR THE TREATMENT OF DIABETES AND METABOLIC DISORDERS

• US 20090137590A1
• Filed: 07/10/2008
• Published: 05/28/2009
• Est. Priority Date: 07/19/2007
• Status: Active Grant

• Current Assignee: CymaBay Therapeutics Inc.
• Original Assignee: Metabolix Incorporated
• Inventors: Cheng, Peng, Chen, Xin, Zhu, Yan, Song, Jiangao, Zhao, Zuchun, Ma, Jingyuan, Rabbat, Christopher J., Nashashibi, Imad, Murphy, Alison, Shi, Dong Fang, Novack, Aaron
• Granted Patent: US 8,183,381 B2
• Time in Patent Office: Days
• US Class Current: 514/236.200
• 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 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• 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 413/14 containing three or more hetero rings
• 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.

Claims

1. A compound of Formula (I):

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

3. A compound of claim 2, wherein the ring having X, Y and Z is selected from the group consisting of

4. A compound of claim 1, wherein each R⁶ is independently selected from the group consisting of H, halo, —

NR^aR^b, —

NR^aC(O)R^b, —

S(O)R^a, —

S(O)₂R^a, C_1-3alkyl, C_1-3haloalkyl, substituted heteroaryl and unsubstituted heteroaryl.

5. A compound of claim 4 wherein each R⁶ is independently selected from the group consisting of H, fluoro, chloro, methyl, ethyl, —

CF₃, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, —

S(O)R^a, and —

S(O)₂R^a.

6. A compound of claim 1, wherein Ar is a six-membered aryl optionally substituted with from 1 to 3 R⁶ substituents or a heteroaryl, optionally substituted with from 1 to 3 R⁶ substituents.

7. A compound of claim 6, wherein Ar is selected from the group consisting of optionally substituted six-membered aryl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, and optionally substituted pyridazinyl.

8. A compound of claim 1, wherein the subscript n is 2.

9. A compound of claim 1, wherein R¹ is selected from the group consisting of —

X¹—

C(O)R^a, —

X¹—

C(O)OR^a, optionally substituted aryl group and optionally substituted heteroaryl group.

10. A compound of claim 9, wherein R¹ is —

C(O)OR^a, pyrimidine optionally substituted with from one to two substituents independently selected from the group consisting of halo, C_3-6cycloalkyl, C_1-10alkyl, and C_1-10substituted alkyl, or oxadiazole optionally substituted with from one to two substituents independently selected from the group consisting of halo, C_3-6cycloalkyl, C_1-10alkyl, and C_1-10substituted alkyl.

11. A compound of Formula II:

12. A compound of claim 11, wherein q is 0 or 1 and, both R⁷ and R⁸ are H.

13. A compound of claim 11, wherein the ring having X, Y, and Z is selected from the group consisting of

14. A compound of claim 13, wherein R³ is H.

15. A compound of claim 11, wherein R¹ is selected from the group consisting of —

X¹—

C(O)R^a, —

X¹—

C(O)OR^a, optionally substituted aryl and optionally substituted heteroaryl group.

16. A compound of claim 15, wherein R¹ is —

C(O)OR^a, pyrimidine optionally substituted with from one to two substituents independently selected from the group consisting of halo, C_3-6cycloalkyl, C_3-6substituted cycloalkyl, C_1-10alkyl, and C_1-10substituted alkyl, or oxadiazole optionally substituted with from one to two substituents independently selected from the group consisting of halo, C_3-6cycloalkyl, C_1-10alkyl, and C_1-10substituted alkyl.

17. A compound of claim 11, wherein the subscript k is 1 or 2;

18. A compound of claim 17, wherein each R⁶ is independently selected from the group consisting of halo, —

NR^aR^b, —

NR^aC(O)R^b, —

S(O)R^a, —

S(O)₂R^a, C_1-3alkyl, C_1-3haloalkyl substituted heteroaryl and unsubstituted heteroaryl.

19. A compound of claim 18 wherein k is 2, and each R⁶ is independently selected from the group consisting of H, fluoro, chloro, methyl, ethyl, —

CF₃, imidazolyl, triazolyl, tetrazolyl, —

S(O)R^a, and —

S(O)₂R^a.

20. A compound of claim 17 wherein R¹ is a heteroaryl group optionally substituted with from one to two substituents selected from the group consisting of halo, C_1-6alkyl, and C_1-6haloalkyl, and each R⁶ is independently selected from the group consisting of halo, —

NR^aR^b, —

NR^aC(O)R^b, —

S(O)R^a, —

S(O)₂R^a, C_1-3alkyl, C_1-3haloalkyl substituted heteroaryl and unsubstituted heteroaryl.

21. A compound of claim 20, wherein R¹ is a substituted pyrimidinyl or substituted oxadiazolyl group, and each R⁶ is independently selected from the group consisting of fluoro, chloro, methyl, ethyl, —

CF₃, imidazolyl, triazolyl, tetrazolyl, —

S(O)R^a, and —

S(O)₂R^a.

22. A compound of claim 17, wherein k is 2, R¹ is a pyrimidinyl group optionally substituted with from one to two substituents selected from the group consisting of halo, C_1-6alkyl, and C_1-6haloalkyl, and each R⁶ is independently selected from the group consisting of H, fluoro, chloro, methyl, ethyl, —

CF₃, imidazolyl, triazolyl, tetrazolyl, —

S(O)R^a, and —

S(O)₂R^a.

24. A method of raising intracellular levels of cyclic AMP (cAMP), said method comprising exposing a cell that expresses GPR119 to a compound of claim 11.

25. The method of claim 24, wherein said cell is a cell selected from the group consisting of a pancreatic cell, an islet cell, a beta cell, an intestinal endocrine cell, an L cell and a K cell.

26. A method of stimulating insulin production in a mammal, said method comprising administering an effective amount of a compound of claim 11 to said mammal.

27. A method of lowering blood glucose in a mammal, said method comprising administering an effective amount of a compound of claim 11 to said mammal.

28. A method of stimulating production of glucagon-like peptide 1 (GLP-1) or glucose dependent insulinotropic polypeptide (GIP) in a mammal, said method comprising administering an effective amount of a compound of claim 11 to said mammal.

29. A method of treating diabetes in a mammal, said method comprising administering an effective amount of a compound of claim 11 to said mammal.

30. A method of treating type 2 diabetes in a mammal, said method comprising administering an effective amount of a compound of claim 11 to said mammal.

23. A compound or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or ester thereof as disclosed in examples 1-113.