DIACYLGLYCEROL ACYLTRANSFERASE INHIBITORS

• US 20090076275A1
• Filed: 09/10/2008
• Published: 03/19/2009
• Est. Priority Date: 09/19/2007
• Status: Abandoned Application

• Current Assignee: VIA Pharmaceuticals, Inc.
• Original Assignee: VIA Pharmaceuticals, Inc.
• Inventors: Li, Shiming, McDermott, Lee Apostle, Yun, Weiya, Hamilton, Matthew Michael, Bolin, David Robert, Cai, Jianping, Cheung, Adrian Wai-Hing, Goodnow, Robert Alan JR.
• Application Number:
  US12/207,674
• Publication Number:
  US 20090076275A1
• Time in Patent Office: Days
• US Class Current: 546/119
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Provided herein are compounds of the formula (I):

as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as, for example, obesity, type II diabetes mellitus and metabolic syndrome.

Claims

1. A compound of formula (I):

wherein;

R¹ is H, lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

R² is H, lower alkyl, haloloweralkyl or lower alkyl-alkoxy;

R³ is H, amino or ═

O;

R⁴ is H or ═

O or absent

R⁵ is lower alkyl, lower alkyl-alkoxy, alkoxyalkoxyalkyl, CH₂C(O)OCH₃, cycloalkyl,heterocycloalkyl, lower alkyl-hydroxy, aryl, heteroaryl, lower alkyl-aryl or lower alkyl-heteroaryl;

R⁶ is H, lower alkyl or alkoxy;

R⁷ is H, lower alkyl or alkoxy;

R⁸ is H, lower alkyl, haloalkyl or absent;

X is S, C, O or N;

Y is C or N;

Z is C, N, O or S; and

A, D, E, G, independently of each other, is C or N,

and pharmaceutically acceptable salts thereof.

2. The compound according to claim 1, wherein:

R¹ is lower alkyl, cycloalkyl or heterocycloalkyl; and

R⁵ is aryl, heteroaryl, lower alkyl-aryl or lower alkyl-heteroaryl.

3. The compound according to claim 1, wherein:

R¹ is lower alkyl, cycloalkyl or heterocycloalkyl; and

R⁵ is lower alkyl, lower alkyl-alkoxy, alkoxyalkoxyalkyl, CH₂C(O)OCH₃, cycloalkyl, heterocycloalkyl, lower alkyl-hydroxy.

4. The compound according to claim 1, wherein:

R¹ is aryl or heteroaryl; and

R⁵ is lower alkyl, lower alkyl-alkoxy, alkoxyalkoxyalkyl, CH₂C(O)OCH₃, cycloalkyl, heterocycloalkyl or lower alkyl-hydroxy.

5. The compound according to claim 1, wherein:

R¹ is aryl or heteroaryl; and

R⁵ is aryl, heteroaryl, lower alkyl-aryl or lower alkyl-heteroaryl.

6. The compound according to claim 1, wherein X is O and Z is N.

7. The compound according to claim 1, wherein D is N and E is N.

8. The compound according to claim 1, wherein X, Y and Z are N.

9. The compound according to claim 1, wherein X is N and Z is S.

10. The compound according to claim 1, wherein D is C and E is N

11. The compound according to claim 1, wherein R¹ is t-butyl, cyclohexyl, pyridyl or phenyl, unsubstituted or substituted with halogen, or haloloweralkoxy

12. The compound according to claim 1, wherein R² is a methyl, ethyl, isopropyl, trifluoromethyl or methoxymethyl group.

13. The compound according to claim 1, wherein R³ is amino.

14. The compound according to claim 1, wherein R⁴ is ═

O.

15. The compound according to claim 1, wherein R⁵ is methyl, ethyl, propyl, isopropyl, methoxy-ethyl, hydroxy-ethyl, methoxy-ethoxy ethyl, acetic acid methyl ester, cyclohexyl, phenyl, unsubstituted or substituted with lower alkyl, CH₂-phenyl, unsubstituted or substituted with alkoxy, or piperidine, unsubstituted or substituted with C(O)OCH₂CH₃.

16. The compound according to claim 1, wherein R⁶ is a methoxy group.

17. The compound according to claim 1, wherein R⁷ is a methoxy group.

18. The compound according to claim 1, wherein R⁸ is a trifluoromethyl group.

18-1. The compound according to claim 1, wherein X is O.

19. The compound according to claim 1, wherein Y is C.

20. The compound according to claim 1, wherein Z is N.

21. The compound according to claim 1, wherein D is N.

22. The compound according to claim 1, wherein E is N.

23. The compound according to claim 1, wherein G is C.

25. The compound according to claim 1, wherein said compound is:

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(1-ethyl-3-oxo-2,3-dihydro-1H-indazol-5-yl)-amide,

5-Methyl-2-phenyl-2H-[1,2,3]triazole-4-carboxylic acid(3-oxo-1-propyl-2,3-dihydro-H-indazol-5-yl)-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(1-isopropyl-3-oxo-2,3-dihydro-1H-indazol-5-yl)-amide,

1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid(1-ethyl-3-oxo-2,3-dihydro-1H-indazol-5-yl)-amide,

4-Methyl-2-phenyl-thiazole-5-carboxylic acid(3-oxo-1-propyl-2,3-dihydro-1H-indazol-5-yl)-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(3-oxo-1-propyl-2,3-dihydro-1H-indazol-5-yl)-amide,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid(3-amino-1-isopropyl-1H-indazol-5-yl)-amide,

{3-Oxo-5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-2,3-dihydro-indazol-1-yl}-acetic acid methyl ester,

2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [1-(2-methoxy-ethyl)-3-oxo-2,3-dihydro-1H-indazol-5-yl]-amide or

2- (2-Trifluoromethoxy-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid(1-ethyl-3-oxo-2,3-dihydro-1H-indazol-5-yl)-amide.