Inhibitors of diacylglycerol acyltransferase

1. A compound of formula (I):

wherein:

X is oxygen, sulfur or nitrogen;

Y is carbon or nitrogen;

Z is carbon or nitrogen;

R1 is lower alkyl, halo lower alkyl, alkoxy, lower alkyl alkoxy or absent;

R2, R2′, independently of each other, is halogen, alkoxy, lower alkyl, haloloweralkyl, haloalkoxy, benzyloxy or absent;

R3 is hydrogen or lower alkyl, wherein if X is oxygen or sulfur, then R3 is absent; and

Q is piperazine-1-carboxylic acid lower alkyl ester, piperidine-1-carboxylic acid lower alkyl ester, piperazin-1-yl-2,2-dimethyl-4-oxo-lower akanoic acid, piperidin-1-yl-2,2-dimethyl-4-oxo-lower alkanoic acid, piperazine-1-carbonyl-4-cyclohexanecarboxylic acid benzyl ester, piperazine-1-carbonyl-4-cyclohexanecarboxylic acid, piperidine-1-carbonyl-4-cyclohexanecarboxylic acid, piperazine-1-carbonyl-2-cyclopentanecarboxylic acid, N-lower alkoxy lower alkyl-N-lower alkyl-amino, N-cycloloweralkyl-N-lower alkyl-amino, N-pyrrolidine-1-carboxylic acid lower alkyl ester, O-pyrrolidine-1-carboxylic acid lower alkanoic ester, O-pyrrolidine-1-carboxylic acid lower alkyl ester, pyrrolidine-3-ylamino-1-carboxylic acid lower alkyl ester, pyrrolidin-3-ylamino-1-carboxylic acid lower alkyl amide, piperidin-1-yl-4-oxo-2-phenyl-lower alkanoic acid, piperidine-1-carbonyl-2-cyclopentanecarboxylic acid, piperidin-1-yl-2-oxo-lower alkyl-cyclopentanecarboxylic acid, piperazin-1-yl-4-oxo-lower alkyl acid, piperidin-1-yl-4-oxo-lower alkanoic acid, piperazin-1-yl-2-oxo-ethyl-3-methyl-lower alkanoic acid, piperazin-1-yl-4-oxo-2-cyclohexyl-butyric acid, pyrrolidine-3-oxy-1-carboxylic acid lower alkyl ester, pyrrolidine-3-oxy-1-carboxylic acid lower alkyl ester, pyrrolidin-3-oxy-1-yl-2,2-dimethyl-4-oxo-lower alkanoic acid, pyrrolidin-3-oxy-1-yl-4-benzoic acid, 2,4-dioxo-thiazolidin-5-yl-acetyl-piperazin-1-yl or piperazin-1-yl-4-benzoic acid,

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein X is sulfur.

3. The compound according to claim 1 , wherein X is nitrogen.

4. The compound according to claim 1 , wherein Y is carbon.

5. The compound according to claim, 1 , wherein Z is nitrogen.

6. The compound according to claim 1 , wherein Z is carbon.

7. The compound according to claim 1 , wherein R1 is hydrogen or lower alkyl.

8. The compound according to claim 1 , wherein R2 or R2′, independently of each other, is alkoxy, lower alkyl or absent.

9. The compound according to claim 1 , wherein R3 is lower alkyl or hydrogen.

10. The compound according to claim 1 , wherein Q is piperazine-1-carboxylic acid tert-butyl ester, piperazine-1-carboxylic acid ethyl ester, piperazin-1-yl-2,2-dimethyl-4-oxo-butyric acid, piperidin-1-yl-2,2-dimethyl-4-oxo-butyric acid, piperazine-1-carbonyl-trans-4-cyclohexanecarboxylic acid, piperidine-1-carbonyl-trans-4-cyclohexanecarboxylic acid, (1R, 2R)-piperazine-1-carbonyl-2-cyclopentanecarboxylic acid, N-2-methoxyethyl-N-methyl-amino, N-cyclopropyl-N-methyl-amino or (S)-pyrrolidin-3-ylamino-1-carboxylic acid ethyl ester.

11. The compound according to claim 1 , wherein Q is piperidin-1-yl-4-oxo-2-phenyl-butyric acid, piperidin-1-yl-2-oxo-ethyl-cyclopentanecarboxylic acid, piperazin-1-yl-4-oxo-butyric acid, piperazin-1-yl-2-oxo-ethyl-3-methyl-butyric acid, (S)-pyrrolidin-3-ylamino-1-carboxylic acid tert-butyl amide, (S)-pyrrolidin-3-yloxy-1-yl-2,2-dimethyl-4-oxo-butyric acid, (S)-pyrrolidin-3-yloxy-1-yl-4-benzoic acid, (S)-pyrrolidin-3-yloxy-1-carboxylic acid ethyl ester, or 2,4-dioxo-thiazolidin-5-yl-acetyl-piperazin-1yl.

12. A compound, selected from the group consisting of:

4-(4-{5-[(4-chloro-benzo[b]thiophene-2-carbonyl)-amino]-pyridin-2-yl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyrie acid,

4-(4-{5-[(5-bromo-benzo[b]thiophene-2-carbonyl)-amino]-pyridin-2-yl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyric acid,

4-(4-{5-[(4,5-dichloro-1-ethyl-1H-indole-2-carbonyl)-amino]-pyridin-2-yl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyric acid,

trans-4-(4-{5-[(1-ethyl-4-methoxy-1H-indole-2-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carbonyl)-cyclohexane carboxylic acid,

(1R,2R)-2-(4-4-[(4-ethoxy-1-ethyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid,

(S)-3-{5-[(4-chloro-benzo[b]thiophene-2-carbonyl)-amino]-pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid ethyl ester,

1-ethyl-4-methyl-1H-indole-2-carboxylic acid [6-((S)-1-tert-butylcarbarnoyl-pyrrolidin-3-ylamino)-pyridin-3-yl]-amide,

4-(4-{4-[(4,5-dichloro-1-ethyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyric acid,

4-((S)-3-{4-[(4-ethoxy-1-ethyl-1H-indole-2-carbonyl)-amino]-phenoxy}-pyrrolidin-1-yl)-2,2-dimethyl-4-oxo butyric acid,

4-((S)-3-{4-[(4-ethoxy-1-ethyl-1H-indole-2-carbonyl)-amino]-phenoxy}-pyrrolidin-1-yl)-benzoic acid,

4-ethoxy-1-ethyl-1H-indole-2-carboxylic acid (4-{4-[2-(2,4-dioxo-thiazolidin-5-yl)-acetyl]-piperazin-1-yl}-phenyl)-amide,

3-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenoxyl}-pyrrolidine-1-carboxylic acid ethyl Ester,

4-(4-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyric acid,

trans-4-(4-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid and

trans-4-(4-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-cyclohexanecarboxylic acid or a pharmaceutical acceptable salt thereof.

13. The compound of claim 1 wherein said compound has the formula:

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 13 wherein Q is piperazine-1-carboxylic acid lower alkyl ester, piperazin-1-yl-2,2-dimethyl-4-oxo-lower alkanoic acid, piperazine-1-carbonyl-4-cyclohexanecarboxylic acid benzyl ester, piperazine-1-carbonyl-4-cyclohexanecarboxylic acid, piperazine-1-carbonyl-2-cyclopentanecarboxylic acid, piperazin-1-yl-4-oxo-lower alkanoic acid, piperidin-1-yl-4-oxo-lower alkanoic acid, piperazin-1-yl-2-oxo-ethyl-3-methyl-lower alkanoic acid, piperazin-1-yl-4-oxo-2-cyclohexyl-lower alkanoic acid, 2,4-dioxo-thiazolidin-5-yl-acetyl-piperazin-1-yl or piperazin-1-yl-4-lower alkanoic acid.

15. The compound of claim 14 wherein said compound is 4-(4-{5-[(4-ethoxy-1-ethyl-1H-indole-2-carbonyl)-amino]-pyridin-2-yl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyric acid or a pharmaceutically acceptable salt thereof.

16. The compound of claim 14 wherein said compound is 4-{5-[(1-ethyl-4,6-dimethoxy-1H-indole-2-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester or a pharmaceutically acceptable salt thereof.

17. The compound of claim 14 wherein said compound is 4-(4-{5-[(4,5-dichloro-1-ethyl-1H-indole-2-carbonyl)-amino]-pyridin-2-yl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyric acid or a pharmaceutically acceptable salt thereof.

18. The compound of claim 14 wherein said compound is 4-(4-{5-[(1-ethyl-4-methoxy-1H-indole-2-carbonyl)-amino]-pyridin-2-yl)-piperazine-1-carbonyl)-cyclohexanecarboxylic acid or a pharmaceutically acceptable salt thereof.

19. The compound of claim 14 wherein said compound is 4-(4-{5-[(1-ethyl-4-methoxy-1H-indole-2-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid benzyl ester or a pharmaceutically acceptable salt thereof.

20. The compound of claim 14 wherein said compound is 4-{5-[(4-chloro-benzo[b]thiophene-2-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester or a pharmaceutically acceptable salt thereof.

21. The compound of claim 14 wherein said compound is 4-{5-[(4-ethoxy-1-ethyl-1H-indole-2-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester or a pharmaceutically acceptable salt thereof.

22. The compound of claim 13 wherein Q is N-lower alkoxy lower alkyl-N-lower alkyl-amino or N-cycloloweralkyl-N-lower alkyl-amino.

23. The compound of claim 22 wherein said compound is 1-ethyl-5-trifluoromethoxy-1H-indole-2-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide or a pharmaceutically acceptable salt thereof.

24. The compound of claim 22 wherein said compound is 2-(4-{4-[(4-ethoxy-1-ethyl-1H-indole-2-carbonyl)-amino]phenyl}-piperidine-1-carbonyl)-cyclopentanecarboxylic acid or a pharmaceutically acceptable salt thereof.

25. The compound of claim 22 wherein said compound is 1-ethyl-5-methoxy-1H-indole-2-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide or a pharmaceutically acceptable salt thereof.

26. The compound of claim 22 wherein said compound is 5-chloro-1-ethyl-1H-indole-2-carboxylic acid [6-(cyclopropyl-methyl-amino)-pyridin-3-yl]amide or a pharmaceutically acceptable salt thereof.

27. The compound of claim 13 wherein Q is N-pyrrolidine-1-carboxylic acid lower alkyl ester, O-pyrrolidine-1-carboxylic acid lower alkanoic ester, O-pyrrolidine-1-carboxylic acid lower alkyl ester, pyrrolidine-3-ylamino-1-carboxylic acid lower alkyl ester, pyrrolidin-3-ylamino-1-carboxylic acid tert-butyl amide, pyrrolidine-3-oxy-1-carboxylic acid lower alkyl ester, pyrrolidine-3-oxy-1-carboxylic acid lower alkyl ester, pyrrolidin-3-oxy-1-yl-2,2-dimethyl-4-oxo-lower alkanoic acid, or pyrrolidin-3-oxy-1-yl-4-benzoic acid.

28. The compound of claim 27 wherein said compound is 3-{5-[(5-bromo-1-ethyl-1H-indole-2-carbonyl)-amino]-pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof.

29. The compound of claim 27 wherein said compound is 3-{5-[(1-ethyl-5-methoxy-1H-indole-2-carbonyl)-amino]-pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof.

30. The compound of claim 27 wherein said compound is 1-ethyl-4-methyl-1H-indole-2-carboxylic acid [6-1-tert-butylcarbamoyl-pyrrolidin-3-ylamino)-pyridin-3-yl]-amide or a pharmaceutically acceptable salt thereof.

31. The compound of claim 27 wherein said compound is (3-{5-[(1-ethyl-4,6-dimethoxy-1H-indole-2-carbonyl)-amino]-pyridin-2-ylamino}pyrrolidine-1-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof.

32. The compound of claim 27 wherein said compound is (S)-3-{5-[(1-ethyl-4-methyl-1H-indole-2-carbonyl)-amino]-pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof.

33. The compound of claim 27 wherein said compound is 3-{5-[(4-ethoxy-1-ethyl-1H-indole-2-carbonyl)-amino]-pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof.

34. The compound of claim 1 wherein said compound is

or a pharmaceutically acceptable salt thereof.

35. The compound of claim 34 wherein Q is piperazine-1-carboxylic acid lower alkyl ester, piperazin-1-yl-2,2-dimethyl-4-oxo-lower alkanoic acid, piperazine-1-carbonyl-4-cyclohexanecarboxylic acid benzyl ester, piperazine-1-carbonyl-4-cyclohexanecarboxylic acid, piperazine-1-carbonyl-2-cyclopentanecarboxylic acid, piperazin-1-yl-4-oxo-lower alkanoic acid, piperidin-1-yl-4-oxo-lower alkanoic acid, piperazin-1-yl-2-oxo-ethyl-3-methyl-lower alkanoic acid, piperazin-1-yl-4-oxo-2-cyclohexyl-lower alkanoic acid, 2,4-dioxo-thiazolidin-5-yl-acetyl-piperazin-1-yl or piperazin-1-yl-4-lower alkanoic acid.

36. The compound of claim 35 wherein said compound is (2-(4-{4-[(4-ethoxy-1-ethyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid or a pharmaceutically acceptable salt thereof.

37. The compound of claim 35 wherein said compound is 4-(4-{4-[(4,5-diehloro-1-ethyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyric acid or a pharmaceutically acceptable salt thereof.

38. The compound of claim 35 wherein said compound is 4-ethoxy-1-ethyl-1H-indole-2-carboxylic acid (4-{4-[2-(2,4-dioxo-thiazolidin-5-yl)-acetyl]-piperazin-1-yl}-phenyl)-amide or a pharmaceutically acceptable salt thereof.

39. The compound of claim 35 wherein said compound is 4-(4-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyric acid or a pharmaceutically acceptable salt thereof.

40. The compound of claim 35 wherein said compound is 4-(4-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclohexanecarboxylic acid or or a pharmaceutically acceptable salt thereof.

41. The compound of claim 34 wherein Q is piperidin-1-yl-2,2-dimethyl-4-oxo-lower alkanoic acid, piperidine-1-carbonyl-trans-4-cyclohexanecarboxylic acid, piperidin-1-yl-4-oxo-2-phenyl-lower alkanoic acid, piperidine-1-carbonyl-2-cyclopentanecarboxylic acid, piperidin-1-yl-2-oxo-ethyl-cyclopentanecarboxylic acid, or piperidin-1-yl-4-oxo-lower alkanoic acid.

42. The compound of claim 41 wherein said compound is 4-(4-{4-[(7-methoxy-3-methyl-1h-indole-2-carbonyl)-amino]-phenyl}-piperidine-1-carbonyl)-cyclohexanecarboxylic acid or pharmaceutically acceptable salts thereof.

43. The compound of claim 34 wherein Q is N-pyrrolidine-1-carboxylic acid lower alkyl ester, O-pyrrolidine-1-carboxylic acid lower alkanoic ester, O-pyrrolidine-1-carboxylic acid lower alkyl ester, pyrrolidine-3-ylamino-1-carboxylic acid lower alkyl ester, pyrrolidin-3-ylamino-1-carboxylic acid tert-butyl amide, pyrrolidine-3-oxy-1-carboxylic acid lower alkyl ester, pyrrolidine-3-oxy-1-carboxylic acid lower alkyl ester, pyrrolidin-3-oxy-1-yl-2,2-dimethyl-4-oxo-lower alkanoic acid, or pyrrolidin-3-oxy-1-yl-4-benzoic acid.

44. The compound of claim 43 wherein said compound is 4-3-{4-[(4-ethoxy-1-ethyl-1H-indole-2-carbonyl)-amino]-phenoxy}-pyrrolidin-1-yl)-2,2-dimethyl-4-oxo-butyric acid or a pharmaceutically acceptable salt thereof.

45. The compound of claim 43 wherein said compound is 4-((S)-3-{4-[(4-ethoxy-1-ethyl-1H-indole-2-carbonyl)-amino]-phenoxy}-pyrrolidin-1-yl)-benzoic acid or a pharmaceutically acceptable salt thereof.

46. The compound of claim 43 wherein said compound is 3-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenoxyl-pyrrolidine-1-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof.

47. The compound of claim 1 wherein said compound has the formula:

or a pharmaceutically acceptable salt thereof.

48. The compound of claim 47 wherein Q is piperazine-1-carboxylic acid lower alkyl ester, piperazin-1-yl-2,2-dimethyl-4-oxo-lower alkanoic acid, piperazine-1-carbonyl-4-cyclohexanecarboxylic acid benzyl ester, piperazine-1-carbonyl-4-cyclohexanecarboxylic acid, piperazine-1-carbonyl-2-cyclopentanecarboxylic acid, piperazin-1-yl-4-oxo-lower alkanoic acid, piperidin-1-yl-4-oxo-lower alkanoic acid, piperazin-1-yl-2-oxo-ethyl-3-methyl-lower alkanoic acid, piperazin-1-yl-4-oxo-2-cyclohexyl-lower alkanoic acid, 2,4-dioxo-thiazolidin-5-yl-acetyl-piperazin-1-yl or piperazin-1-yl-4-lower alkanoic acid.

49. The compound of claim 48 wherein said compound is 4-(4-{5-[(4-chloro-benzo[b]thiophene-2-carbonyl)-amino]-pyridin-2-yl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyric acid.

50. The compound of claim 48 wherein said compound is 4-(4-{5-[(5-bromo-benzo[b]thiophene-2-carbonyl)-amino]-pyridin-2-yl}-piperazin-1-yl)-2,2-dimethyl-4-oxo-butyric acid.

51. The compound of claim 47 wherein Q is N-pyrrolidine-1-carboxylic acid lower alkyl ester, O-pyrrolidine-1-carboxylic acid lower alkanoic ester, O-pyrrolidine-1-carboxylic acid lower alkyl ester, pyrrolidine-3-ylamino-1-carboxylic acid lower alkyl ester, pyrrolidin-3-ylamino-1-carboxylic acid tert-butyl amide, pyrrolidine-3-oxy-1-carboxylic acid lower alkyl ester, pyrrolidine-3-oxy-1-carboxylic acid lower alkyl ester, pyrrolidin-3-oxy-1-yl-2,2-dimethyl-4-oxo-lower alkanoic acid, or pyrrolidin-3-oxy-1-yl-4-benzoic acid.

52. The compound of claim 51 wherein said compound is 3-{5-[(4-chloro-benzo[b]thiophene-2-carbonyl)-amino]-pyridin-2-ylamino}-pyrrolidine-1-carboxylic acid ethyl ester hydrochloride or pharmaceutically acceptable salts thereof.