Anti-fibrotic pyridinones

1. A compound having the structure of formula (I):

or a pharmaceutically acceptable salt thereof, wherein

R 1 is selected from the group consisting of C 6-10 aryl optionally substituted with one or more R 4 , 5-10 membered heteroaryl optionally substituted with one or more R 4 , C 3-10 carbocyclyl optionally substituted with one or more R 4 , and 3-10 membered heterocyclyl optionally substituted with one or more R 4 ;

R 2 is selected from the group consisting of halogen, —CN, —OR 5 , —SR 5 , —NR 6 R 7 , and —C(O)R 8 ;

R 3 is phenyl optionally substituted with one or more R 9 ;

each R 4 is independently selected from the group consisting of halogen, —CN, —OH, —C(O)R 8 , —SO 2 R 16 , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkoxy, optionally substituted C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , 5-10 membered heteroaryl optionally substituted with one or more R 11 , or independently two geminal R 4 together are oxo;

each R 5 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 2-8 alkoxyalkyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , and —(CH 2 ) n -(3-10 membered heterocyclyl) optionally substituted with one or more R 10 ;

R 6 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , (5-10 membered heteroaryl)alkyl optionally substituted with one or more R 11 , —C(O)R 8 , and —C(O)OR 5 ;

R 7 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , (5-10 membered heteroaryl)alkyl optionally substituted with one or more R 11 , —C(O)R 8 , and —C(O)OR 5 ;

or R 6 and R 7 together with the nitrogen to which they are attached form a 3-10 membered heterocyclyl optionally substituted with one or more R 10 ;

each R 8 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , and —OR 5 ;

each R 9 is independently selected from the group consisting of hydroxy, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkylthio, optionally substituted C 2-8 alkoxyalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 6-10 aryl, —OR 5 , —NR 14 R 15 , —C(O)R 8 , —CN, and —NO 2 ;

each R 10 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, and optionally substituted C 2-6 alkynyl, or independently two geminal R 10 together are oxo;

each R 11 is independently selected from the group consisting of halogen, —CN, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, —O—(CH 2 ) n -C 1-8 alkoxy, —C(O)R 8 , and optionally substituted C 1-6 alkoxy;

each R 12 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;

each R 13 is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , and C 7-14 aralkyl optionally substituted with one or more R 11 ;

R 14 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;

R 15 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-10 aryl, and —C(O)R 8 ;

each R 16 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , —NR 12 R 13 , and —OR 5 ;

Z is selected from oxygen and sulfur;

each n is independently an integer from 0 to 4; and

the bonds represented by a solid and dashed line are independently selected from the group consisting of a single bond and a double bond, provided that

when R 3 is H, then R 1 is selected from C 6-10 aryl optionally substituted with one or more R 4 , or 5-10 membered heteroaryl optionally substituted with one or more R 4 ;

when R 2 is —NH-(2-fluoro-4-bromo-phenyl), and R 1 is C(O)OH, then R 3 is not —CH 2 -phenyl;

when R 2 is methoxy, R 1 is 4-methoxyphenyl, and Z is O, then R 3 is not —(CH 2 )-2-fluoro-4-chloro-phenyl;

when R 3 is a phenyl; R 2 is OR 5 or NR 6 R 7 ; then R 1 is not triazolyl;

when R 3 is 4-methyl phenyl, R 2 is morpholinyl, and Z is O; then R 1 is not methyl; and

when R 3 is 4-methyl phenyl, R 2 is —N(CH 3 ) 2 , Z is O; then R 1 is not methyl.

2. The compound of claim 1 , wherein

R 2 is selected from the group consisting of halogen, —OR 5 , —NR 6 R 7 , and —C(O)R 8 ;

R 3 is phenyl optionally substituted with one or more R 9 ;

each R 9 is independently selected from the group consisting of halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1-6 alkylthio, optionally substituted C 2-8 alkoxyalkyl, optionally substituted C 3-10 carbocyclyl, optionally substituted C 6-10 aryl, —OR 5 , —NR 14 R 15 , —C(O)R 8 , and —NO 2 ; and

each R 11 is independently selected from the group consisting of halogen, —CN, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, and optionally substituted C 1-6 alkoxy.

3. The compound of claim 1 , wherein R 1 is a C 6-10 aryl optionally substituted with one or more R 4 .

4. The compound of claim 3 , wherein R 1 is a phenyl optionally substituted with one or more R 4 .

5. The compound of claim 1 , wherein R 1 is a 5-10 membered heteroaryl optionally substituted with one or more R 4 .

6. The compound of claim 5 , wherein R 1 is a pyrazolyl or 1-methyl pyrazolyl optionally substituted with one or more R 4 .

7. The compound of claim 1 , wherein each R 4 is independently selected from halogen, or optionally substituted C 1-6 alkyl.

8. The compound of claim 7 , wherein R 4 is (i) fluoro, or (ii) methyl.

9. The compound of claim 1 , wherein R 2 is (i) halogen, (ii) —CN, or (iii) —OR 5 .

10. The compound of claim 9 , wherein R 2 is selected from bromo or chloro.

11. The compound of claim 9 , wherein R 5 is selected from hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-8 alkoxyalkyl, C 7-14 aralkyl optionally substituted with one or more R 11 , C 6-10 aryl optionally substituted with one or more R 11 , and —(CH 2 ) n -(3-10 membered heterocyclyl) optionally substituted with one or more R 10 .

12. The compound of claim 11 , wherein R 5 is (i) hydrogen, or (ii) optionally substituted C 1-6 alkyl.

13. The compound of claim 12 , wherein R 5 is methyl or halogen substituted ethyl.

14. The compound of claim 11 , wherein R 5 is (i) C 6-10 aryl optionally substituted with one or more R 11 , (ii) C 7-14 aralkyl optionally substituted with one or more R 11 , (iii) optionally substituted C 2-8 alkoxyalkyl, or (iv) —(CH 2 ) n -(5 or 6 membered heterocyclyl) optionally substituted with one or more R 10 .

15. The compound of claim 14 , wherein R 5 is (i) phenyl optionally substituted with one or more R 11 , (ii) benzyl optionally substituted with one or more R 11 , or (iii) R 5 is selected from —(CH 2 ) 2 OCH 3 , —(CH 2 ) 2 OC 3 H 7 or —(CH 2 ) 2 O(CH 2 )OCH 3 .

16. The compound of claim 11 , wherein (i) R 5 is

optionally substituted with one or more R 10 , or (ii) R 5 is selected from

each optionally substituted with one or more R 10 .

17. The compound of claim 1 , wherein R 2 is —NR 6 R 7 .

18. The compound of claim 17 , wherein each R 6 and R 7 is independently selected from hydrogen, C 1-6 alkyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , (5-10 membered heteroaryl)alkyl optionally substituted with one or more R 11 , —C(O)R 8 , or —C(O)OR 5 .

19. The compound of claim 18 , wherein R 6 is hydrogen or C 1-6 alkyl.

20. The compound of claim 18 , wherein R 7 is hydrogen.

21. The compound of claim 18 , wherein R 7 is C 1-6 alkyl.

22. The compound of claim 18 , wherein R 7 is C 6-10 aryl optionally substituted with one or more R 11 .

23. The compound of claim 22 , wherein R 7 is (i) phenyl optionally substituted with one or more R 11 , or (ii) unsubstituted phenyl.

24. The compound of claim 18 , wherein R 7 is C 7-14 aralkyl optionally substituted with one or more R 11 .

25. The compound of claim 24 , wherein R 7 is (i) benzyl or —(CH 2 ) 2 Ph, each optionally substituted with one or more R 11 , or (ii) unsubstituted benzyl or unsubstituted —(CH 2 ) 2 Ph.

26. The compound of claim 18 , wherein R 7 is (6 membered heteroaryl)alkyl optionally substituted with one or more R 11 .

27. The compound of claim 26 , wherein R 7 is (i) —CH 2 -pyridyl, —CH 2 -pyrazinyl, or —CH 2 -pyrimidinyl, each optionally substituted with one or more R 11 , or (ii) —CH 2 -pyridyl, —CH 2 -pyrazinyl or —CH 2 -pyrimidinyl, each unsubstituted.

28. The compound of claim 18 , wherein R 7 is —C(O)R 8 .

29. The compound of claim 28 , wherein R 8 is selected from C 1-6 alkyl, C 6-10 aryl, or —NR 12 R 13 .

30. The compound of claim 29 , wherein R 8 is selected from methyl, ethyl, propyl, isopropyl, butyl, pentyl or phenyl.

31. The compound of claim 29 , wherein R 8 is —NR 12 R 13 .

32. The compound of claim 31 , wherein each R 12 and R 13 is independently selected from hydrogen, C 1-6 alkyl, or benzyl.

33. The compound of claim 18 , wherein R 7 is —C(O)OR 5 .

34. The compound of claim 33 , wherein R 5 is selected from hydrogen, C 1-6 alkyl, C 6-10 aryl optionally substituted with one or more R 11 , or C 7-14 aralkyl optionally substituted with one or more R 11 .

35. The compound of claim 34 , wherein R 5 is (i) selected from methyl, ethyl, isopropyl, and butyl, or (ii) selected from phenyl or benzyl, each optionally substituted with one or more R 11 .

36. The compound of claim 17 , wherein R 6 and R 7 together with the nitrogen to which they are attached form a 6-10 membered heterocyclyl optionally substituted with one or more R 10 .

37. The compound of claim 36 , wherein the heterocyclyl formed by R 6 and R 7 together with the nitrogen to which they are attached is selected from

each optionally substituted with one or more R 10 .

38. The compound of claim 36 , wherein the heterocyclyl formed by R 6 and R 7 together with the nitrogen to which they are attached is unsubstituted.

39. The compound of claim 1 , wherein R 10 is C 1-6 alkyl.

40. The compound of claim 1 , wherein two geminal R 10 together are oxo.

41. The compound of claim 1 , wherein R 2 is —SR 5 .

42. The compound of claim 41 , wherein R 5 is C 6-10 aryl optionally substituted with one or more R 11 .

43. The compound of claim 41 , wherein R 5 is optionally substituted phenyl.

44. The compound of claim 1 , wherein R 2 is —C(O)R 8 .

45. The compound of claim 44 , wherein R 8 is selected from —NR 12 R 13 .

46. The compound of claim 45 , wherein each R 12 and R 13 is independently selected from hydrogen, optionally substituted C 1-6 alkyl, C 6-10 aryl optionally substituted with one or more R 11 , or C 7-14 aralkyl optionally substituted with one or more R 11 .

47. The compound of claim 46 , wherein each R 12 and R 13 is independently selected from hydrogen, C 1-6 alkyl, phenyl optionally substituted with one or more R 11 , or benzyl optionally substituted with one or more R 11 .

48. The compound of claim 47 , wherein the phenyl or benzyl is unsubstituted.

49. The compound of claim 1 , wherein R 2 is —C(O)OR 5 .

50. The compound of claim 49 , wherein R 5 is hydrogen or C 1-6 alkyl.

51. The compound of claim 1 , wherein each R 11 is independently selected from —CN, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, —O—(CH 2 ) n —C 1-8 alkoxy, or —C(O) NR 12 R 13 .

52. The compound of claim 51 , wherein R 11 is selected from —CN, —C, —F, —CH 3 , —OCH 3 , —OC 2 H 5 , —CF 3 , —OCF 3 , —O—(CH 2 ) 2 —OCH 3 , or —C(O)NH 2 .

53. The compound of claim 1 , wherein R 9 is selected from hydroxy, halogen, optionally substituted C 1-6 alkyl, —OR 5 , or —NR 14 R 15 .

54. The compound of claim 53 , wherein R 9 is (i) selected from hydroxy, fluoro, chloro, methyl, ethyl, or trifluoromethyl, (ii) —OR 5 , or (iii) —NH—C(O)R 8 .

55. The compound of claim 1 , wherein R 5 is selected from hydrogen, C 1-6 alkyl, halo substituted C 1-6 alkyl, or C 2-8 alkoxyalkyl.

56. The compound of claim 55 , wherein R 5 is selected from trifluoromethyl, ethyl or —(CH 2 ) 2 OCH 3 .

57. The compound of claim 54 , wherein R 9 is selected from —NH—C(O)—C 1-6 alkyl, or —NH—C(O)—NH 2 .

58. The compound of claim 1 , wherein R 3 is unsubstituted.

59. The compound of claim 1 , wherein R 3 is hydrogen.

60. The compound of claim 1 , wherein Z is oxygen.

61. The compound of claim 1 , wherein the bonds represented by a solid and dashed line are double bonds.

62. The compound of claim 1 , wherein the compound is selected from the group consisting of Compounds 85-162, 401-414, 523-538, 540, 541, 543, 545, 550, 551,664 and 696-707:

63. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.