PPARγ modulators

1. A compound having the formula (I):

or a pharmaceutically acceptable salt thereof, wherein

Ar 1 is substituted or unsubstituted isoquinolinyl, pyrazolyl, imidazolyl, or pyridazinyl;

X is —S(O) k —, wherein the subscript k is an integer of from 0 to 2;

Y is a divalent linkage selected from the group consisting of —N(R 12 )—S(O) m —, —N(R 12 )C(O)— and —S(O) n —, wherein

R 12 is selected from the group consisting of hydrogen and alkyl; and the subscripts m and n are independently integers of from 0 to 2;

R 1 is selected from the group consisting of hydrogen, alkyl, arylalkyl, —CO 2 R 14 , —C(O)R 14 , —C(O)NR 15 R 16 ,

wherein

R 14 is selected from the group consisting of hydrogen, alkyl, or arylalkyl; and

R 15 and R 16 are independently selected from the group consisting of hydrogen and alkyl, or taken together with the nitrogen to which each is attached form a 5- or 6-membered ring; and

R 18 is selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, unsubstituted aryl, —OR 19 , —SR 19 and —NR 20 R 21 ; and

R 19 is H or (C 1 -C 8 )alkyl; and

R 20 and R 21 are independently selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl, or taken together with the nitrogen atom to which each is attached, form a 5-, 6- or 7-membered ring; and

R 2 is an aryl group.

2. The compound of claim 1 , wherein Ar 1 is isoquinolinyl, pyridazinyl, imidazolyl, or pyrazolyl.

3. The compound of claim 1 , wherein Ar 1 is selected from the group consisting of substituted or unsubstituted 4-isoquinolinyl, and 3-pyrazolyl.

4. The compound of claim 1 , wherein Ar 1 is substituted with 1 or 2 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O —(C 1 -C 6 )alkyl, —CF 3 , (C 1 -C 6 )alkyl and —NO 2 .

5. The compound of claim 4 , wherein Ar 1 is substituted with a substituent selected from the group consisting of halogen, —OCF 3 and —CF 3 .

6. The compound of claim 1 , wherein X is —S—.

7. The compound of claim 1 , wherein Y is —N(R 12 ) —S(O) 2 —.

8. The compound of claim 1 , wherein R 1 is selected from the group consisting of:

wherein

R 18 is selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, unsubstituted aryl, —OR 19 , —SR 19 and —NR 20 R 21 ;

R 19 is H or (C 1 -C 8 )alkyl; and

R 20 and R 21 are independently selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl, or taken together with the nitrogen atom to which each is attached, form a 5-, 6- or 7-membered ring.

9. The compound of claim 1 , wherein R 2 is a phenyl group substituted with from 1 to 3 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O(C 1 -C 8 )alkyl, —CF 3 , —CN, —C(O)—(C 1 -C 8 )alkyl, (C 1 -C 8 )alkyl and —NH 2 .

10. The compound of claim 9 , wherein Y is —N(R 12 )—S(O) 2 —.

11. The compound of claim 1 , wherein said compound is represented by a formula selected from the group consisting of:

12. The compound of claim 1 , having the formula:

13. The compound of claim 12 , wherein Ar 1 is isoquinolinyl, pyridazinyl, imidazolyl, or pyrazolyl.

14. The compound of claim 12 , wherein Ar 1 is selected from the group consisting of substituted or unsubstituted, 4-isoquinolinyl, and 3-pyrazolyl.

15. The compound of claim 12 , wherein Ar 1 is substituted with 1 or 2 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O—(C 1 -C 6 )alkyl, —CF 3 , (C 1 -C 6 )alkyl and —NO 2 .

16. The compound of claim 15 , wherein Ar 1 is substituted with a substituent selected from the group consisting of halogen, —OCF 3 and —CF 3 .

17. The compound of claim 12 , wherein X is —S—.

18. The compound of claim 12 , wherein Y is —N(R 12 )—S(O) 2 —.

19. The compound of claim 12 , wherein R 1 is selected from the group consisting of:

wherein

R 18 is selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, unsubstituted aryl, —OR 19 , —SR 19 and —NR 20 R 21 ;

R 19 is H or (C 1 -C 8 )alkyl; and

R 20 and R 21 are independently selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl, or taken together with the nitrogen atom to which each is attached, form a 5-, 6-or 7-membered ring.

20. The compound of claim 12 , wherein R 2 is a phenyl group substituted with from 1 to 3 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O(C 1 -C 8 )alkyl, —CF 3 , —CN, —C(O)—(C 1 -C 8 )alkyl, (C 1 -C 8 )alkyl and —NH 2 .

21. The compound of claim 20 , wherein Y is —NH—S(O) 2 —.

22. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein

Ar 1 is substituted or unsubstituted isoquinolinyl, pyrazolyl, imidazolyl, or pyridazinyl;

X is —S(O) k —, wherein the subscript k is an integer of from 0 to 2;

Y is a divalent linkage selected from the group consisting of —N(R 12 )—S(O) m —, —N(R 12 )C(O)— and —S(O) n —, wherein

R 12 is selected from the group consisting of hydrogen and alkyl; and the subscripts m and n are independently integers of from 0 to 2;

R 1 is selected from the group consisting of hydrogen, alkyl, arylalkyl, —CO 2 R 14 , —C(O)R 14 , —C(O)NR 15 R 16 ,

wherein

R 14 is selected from the group consisting of hydrogen, alkyl, or arylalkyl; and

R 15 and R 16 are independently selected from the group consisting of hydrogen and alkyl, or taken together with the nitrogen to which each is attached form a 5- or 6-membered ring; and

R 18 is selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, unsubstituted aryl, —OR 19 , —SR 19 and —NR 20 R 21 ; and

R 19 is H or (C 1 -C 8 )alkyl; and

R 20 and R 21 are independently selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl, or taken together with the nitrogen atom to which each is attached, form a 5-, 6- or 7-membered ring; and

R 2 is an aryl group.

23. The pharmaceutical composition of claim 22 , wherein Ar 1 is isoquinolinyl, pyridazinyl, pyrazinyl, imidazolyl, or pyrazolyl.

24. The compound of claim 1 , wherein the compound of formula I is:

or a pharmaceutically acceptable salt thereof.

25. The pharmaceutical composition of claim 22 , comprising a pharmaceutically acceptable carrier or excipient and a compound having the formula:

or a pharmaceutically acceptable salt thereof.

26. The compound of claim 1 , wherein the compound or its pharmaceutically acceptable salt is an agonist of PPARγ.

27. A method for treating non-insulin-dependent diabetes mellitus (NIDDM) in a host, said method comprising administering to said host an efficacious amount of a compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein

Ar 1 is substituted or unsubstituted quinolinyl, isoquinolinyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, or pyridazinyl;

X is —S(O) k —, wherein the subscript k is an integer of from 0 to 2;

Y is a divalent linkage selected from the group consisting of —N(R 12 )—S(O) m , —N(R 12 )C(O)— and —S(O) m —, wherein

R 12 is selected from the group consisting of hydrogen and alkyl; and the subscripts m and n are independently integers of from 0 to 2;

R 1 is selected from the group consisting of hydrogen, alkyl, arylalkyl, —CO 2 R 14 , —C(O)R 14 , —C(O)NR 15 R 16 ,

wherein

R 14 is selected from the group consisting of hydrogen, alkyl, or arylalkyl; and

R 15 and R 16 are independently selected from the group consisting of hydrogen and alkyl, or taken together with the nitrogen to which each is attached form a 5- or 6-membered ring; and

R 18 is selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, unsubstituted aryl, —OR 19 , —SR 19 and —NR 20 R 21 ; and

R 19 is H or (C 1 -C 8 )alkyl; and

R 20 and R 21 are independently selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl, or taken together with the nitrogen atom to which each is attached, form a 5-, 6- or 7-membered ring; and

R 2 is an aryl group.

28. The method of claim 27 , wherein Ar 1 is selected from the group consisting of substituted or unsubstituted 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-quinolinyl, 4-isoquinolinyl, and 3-pyrazolyl.

29. The method of claim 27 , wherein the compound or its pharmaceutically acceptable salt is an agonist of PPARγ.

30. The method of claim 27 , wherein said host is a human.

31. The method of claim 27 , wherein said administering is oral.

32. The method of claim 27 , wherein said administering is topical.

33. The method of claim 27 , wherein said administering is parenteral.

34. The method of claim 27 , wherein Ar 1 is quinolinyl, isoquinolinyl, pyridyl, pyridazinyl, pyrimidyl, imidazolyl, or pyrazolyl.

35. The method of claim 27 , wherein the compound of the formula is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

36. The method of claim 27 , wherein said compound is represented by a formula selected from the group consisting of:

37. The pharmaceutical composition of claim 22 , wherein said compound is represented by a formula selected from the group consisting of:

38. A compound having the formula (I):

or a pharmaceutically acceptable salt thereof, wherein

Ar 1 is substituted or unsubstituted quinolinyl;

X is —S(O) k —, wherein the subscript k is an integer of from 0 to 2;

Y is —N(R 12 )—S(O) m —, wherein

R 12 is selected from the group consisting of hydrogen and alkyl; and the subscripts m and n are independently integers of from 0 to 2;

R 1 is selected from the group consisting of alkyl, arylalkyl, —CO 2 R 14 , —C(O)R 14 , —C(O)NR 15 R 16 ,

wherein

R 14 is selected from the group consisting of hydrogen, alkyl, or arylalkyl; and

R 15 and R 16 are independently selected from the group consisting of hydrogen and alkyl, or taken together with the nitrogen to which each is attached form a 5- or 6-membered ring; and

R 18 is selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, unsubstituted aryl, —OR 19 , —SR 19 and —NR 20 R 21 ; and

R 19 is H or (C 1 -C 8 )alkyl; and

R 20 and R 21 are independently selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl, or taken together with the nitrogen atom to which each is attached, form a 5-, 6- or 7-membered ring; and

R 2 is an aryl group.

39. The compound of claim 38 , wherein Ar 1 is subsituted quinolinyl.

40. The compound of claim 38 , wherein Ar 1 is substituted or unsubstituted 3-quinolinyl.

41. The compound of claim 38 , wherein Ar 1 is substituted with 1 or 2 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O—(C 1 -C 6 )alkyl, —CF 3 , (C 1 -C 6 )alkyl and —NO 2 .

42. The compound of claim 41 , wherein Ar 1 is substituted with a substituent selected from the group consisting of halogen, —OCF 3 and —CF 3 .

43. The compound of claim 38 , wherein X is —S—.

44. The compound of claim 38 , wherein R 1 is selected from the group consisting of:

wherein

R 18 is selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, unsubstituted aryl, —OR 19 , —SR 19 and —NR 20 R 21 ;

R 19 is H or (C 1 -C 8 )alkyl; and

R 20 and R 21 are independently selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl, or taken together with the nitrogen atom to which each is attached, form a 5-, 6- or 7-membered ring.

45. The compound of claim 38 , wherein R 2 is a phenyl group substituted with from 1 to 3 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O(C 1 -C 8 )alkyl, —CF 3 , —CN, —C(O)—(C 1 -C 8 )alkyl, (C 1 -C 8 )alkyl and —NH 2 .

46. The compound of claim 38 , wherein said compound is represented by a formula selected from the group consisting of:

47. The compound of claim 38 , having the formula:

48. The compound of claim 38 , wherein the compound or its pharmaceutically acceptable salt is an agonist of PPARγ.

49. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 38 , or a pharmaceutically acceptable salt thereof.

50. A compound having the formula (I):

or a pharmaceutically acceptable salt thereof, wherein

Ar 1 is substituted or unsubstituted pyrimidyl,

X is —S(O) k —, wherein the subscript k is an integer of from 0 to 2;

Y is a divalent linkage selected from the group consisting of —N(R 12 )—S(O) m- and —N(R 12 )C(O)—, wherein

R 12 is selected from the group consisting of hydrogen and alkyl; and the subscripts m and n are independently integers of from 0 to 2;

R 1 is selected from the group consisting of hydrogen, alkyl, arylalkyl, —CO 2 R 14 , —C(O)R 14 , —C(O)NR 15 R 16 ,

wherein

R 14 is selected from the group consisting of hydrogen, alkyl, or arylalkyl; and

R 15 and R 16 are independently selected from the group consisting of hydrogen and alkyl, or taken together with the nitrogen to which each is attached form a 5- or 6-membered ring; and

R 18 is selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, unsubstituted aryl, —OR 19 , —SR 19 and —NR 20 R 21 ; and

R 19 is H or (C 1 -C 8 )alkyl; and

R 20 and R 21 are independently selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl, or taken together with the nitrogen atom to which each is attached, form a 5-, 6- or 7-membered ring; and

R 2 is an aryl group.

51. The compound of claim 50 , wherein Ar 1 is substituted pyrimidyl.

52. The compound of claim 50 , wherein Ar 1 is selected from the group consisting of substituted or unsubstituted 2-pyrimidyl, 4-pyrimidyl, and 5-pyrimidyl.

53. The compound of claim 50 , wherein Ar 1 is substituted with 1 or 2 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O—(C 1 -C 6 )alkyl, —CF 3 , (C 1 -C 6 )alkyl and —NO 2 .

54. The compound of claim 53 , wherein Ar 1 is substituted with a substituent selected from the group consisting of halogen, —OCF 3 and —CF 3 .

55. The compound of claim 50 , wherein X is —S—.

56. The compound of claim 50 , wherein Y is —N(R 12 )—S(O) 2 —.

57. The compound of claim 50 , wherein R 1 is selected from the group consisting of:

wherein

R 18 is selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, unsubstituted aryl, —OR 19 , —SR 19 and —NR 20 R 21 ;

R 19 is H or (C 1 -C 8 )alkyl; and

R 20 and R 21 are independently selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl, or taken together with the nitrogen atom to which each is attached, form a 5-, 6- or 7-membered ring.

58. The compound of claim 50 , wherein R 2 is a phenyl group substituted with from 1 to 3 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O(C 1 -C 8 )alkyl, —CF 3 , —CN, —C(O)—(C 1 -C 8 )alkyl, (C 1 -C 8 )alkyl and —NH 2 .

59. The compound of claim 58 , wherein Y is —N(R 12 )—S(O) 2 —.

60. The compound of claim 50 , wherein said compound is represented by a formula selected from the group consisting of:

61. The compound of claim 50 , having the formula:

62. The compound of claim 50 , wherein the compound or its pharmaceutically acceptable salt is an agonist of PPARγ.

63. The compound of claim 50 , wherein the compound of formula I is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

64. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and the compound of claim 50 , or a pharmaceutically acceptable salt thereof.

65. The pharmaceuticla composition of claim 64 , comprising a pharmaceutically acceptable carrier or excipient and a compound selected from the group conisting of:

or a pharmaceutically acceptable salt thereof.

66. A compound having the formula (I):

or a pharmaceutically acceptable salt thereof, wherein

Ar 1 is substituted or unsubstituted pyridyl;

X is —S(O) k —, wherein the subscript k is an integer of from 0 to 2;

Y is a divalent linkage selected from the group consisting of —N(R 12 )—S(O) m- , —N(R 12 )C(O)— and —S(O) n —, wherein

R 12 is selected from the group consisting of hydrogen and alkyl; and the subscripts m and n are independently integers of from 0 to 2;

R 1 is selected from the group consisting of

 wherein

R 18 is selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, unsubstituted aryl, —OR 19 , —SR 19 and —NR 20 R 21 ; and

R 19 is H or (C 1 -C 8 )alkyl; and

R 20 and R 21 are independently selected from the group consisting of hydrogen and (C 1 -C 8 )alkyl, or taken together with the nitrogen atom to which each is attached, form a 5-, 6- or 7-membered ring; and

R 2 is an aryl group.

67. The compound of claim 66 , wherein Ar 1 is substituted pyridyl.

68. The compound of claim 66 , wherein Ar 1 is selected from the group consisting of substituted or unsubstituted 2-pyridyl, 3-pyridyl, and 4-pyridyl.

69. The compound of claim 66 , wherein Ar 1 is substituted with 1 or 2 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O—(C 1 -C 6 )alkyl, —CF 3 , (C 1 -C 6 )alkyl and —NO 2 .

70. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and the compound of claim 66 , or a pharmaceutically acceptable salt thereof.

71. The compound of claim 66 , wherein X is —S—.

72. The compound of claim 66 , wherein Y is —N(R 12 )—S(O) 2 —.

73. The compound of claim 66 , wherein R 2 is a phenyl group substituted with from 1 to 3 substituents selected from the group consisting of halogen, —OCF 3 , —OH, —O(C 1 -C 8 )alkyl, —CF 3 , —CN, —C(O)—(C 1 -C 8 )alkyl, (C 1 -C 8 )alkyl and —NH 2 .

74. The compound of claim 73 , wherein Y is —N(R 12 )—S(O) 2 —.

75. The compound of claim 66 , wherein said compound is represented by a formula selected from the group consisting of:

76. The compound of claim 66 , having the formula:

77. The compound of claim 66 , wherein the compound of formula I is

or a pharmaceutically acceptable salt thereof.

78. The compound of claim 66 , wherein the compound or its pharmaceutically acceptable salt is an agonist of PPARγ.

79. The compound of claim 70 , wherein Ar 1 is substituted with a substituent selected from the group consisting of halogen, —OCF 3 and —CF 3 .

80. The pharmaceutical composition of claim 70 , comprising a pharmaceutically acceptable carrier or excipient and a compound having the formula

or a pharmaceutically acceptable salt thereof.