IP Library › Patent Application 14432881

Patent Application

App. No. 14/432,881

ANTI-FIBROTIC PYRIDINONES

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Patent No.: US None
App. No.: 14/432,881

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Abstract

Disclosed are pyridinone compounds, method for preparing these compounds, and methods for treating fibrotic disorders.

Claims (557)

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 halogen, —CN, —C(O)R 8 , —SO 2 R 16 , C 1-6 alkyl optionally substituted with one or more R 4 , C 2-6 alkenyl optionally substituted with one or more R 4 , C 2-6 alkynyl optionally substituted with one or more R 4 , 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 selected from the group consisting of hydrogen, —(CH 2 ) n —(C 6-10 aryl), —(CH 2 ) n -(5-10 membered heteroaryl), —(CH 2 ) n —(C 3-10 carbocyclyl), and —(CH 2 ) n -(3-10 membered heterocyclyl), each 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 , —SO 2 R 16 , —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 )—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-fluro-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 selected from the group consisting of —(CH 2 ) n —(C 6-10 aryl), —(CH 2 ) n -(5-10 membered heteroaryl), —(CH 2 ) n —(C 3-10 carbocyclyl), and —(CH 2 ) n -(3-10 membered heterocyclyl), each 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 , —SO 2 R 16 , and —NO 2 ; and

3 . The compound of claim 1 or 2 , 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 or 2 , 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 any one of claims 1 to 6 , 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 fluoro.

9 . The compound of claim 7 , wherein R 4 is methyl.

10 . The compound of any one of claims 1 to 9 , wherein R 2 is halogen.

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

12 . The compound of any one of claims 1 to 9 , wherein R 2 is CN.

13 . The compound of any one of claims 1 to 9 , wherein R 2 is —OR 5 .

14 . The compound of claim 13 , 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 .

15 . The compound of claim 14 , wherein R 5 is hydrogen.

16 . The compound of claim 14 , wherein R 5 is optionally substituted C 1-6 alkyl.

17 . The compound of claim 16 , wherein R 5 is methyl or halogen substituted ethyl.

18 . The compound of claim 14 , wherein R 5 is C 6-10 aryl optionally substituted with one or more R 11 .

19 . The compound of claim 18 , wherein R 5 is phenyl optionally substituted with one or more R 11 .

20 . The compound of claim 14 , wherein R 5 is C 7-14 aralkyl optionally substituted with one or more R 11 .

21 . The compound of claim 20 , wherein R 5 is benzyl optionally substituted with one or more R 11 .

22 . The compound of claim 14 , wherein R 5 is optionally substituted C 2-8 alkoxyalkyl.

23 . The compound of claim 22 , wherein 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 .

24 . The compound of claim 14 , wherein R 5 is —(CH 2 ) n -(5 or 6 membered heterocyclyl) optionally substituted with one or more R 10 .

25 . The compound of claim 24 , wherein R 5 is

optionally substituted with one or more R 10 .

26 . The compound of claim 24 , wherein R 5 is selected from

each optionally substituted with one or more R 10 .

27 . The compound of any one of claims 1 to 9 , wherein R 2 is —NR 6 R 7 .

28 . The compound of claim 27 , 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 .

29 . The compound of claim 28 , wherein R 6 is hydrogen or C 1-6 alkyl.

30 . The compound of claim 28 or 29 , wherein R 7 is hydrogen.

31 . The compound of claim 28 or 29 , wherein R 7 is C 1-6 alkyl.

32 . The compound of claim 28 or 29 , wherein R 7 is C 6-10 aryl optionally substituted with one or more R 11 .

33 . The compound of claim 32 , wherein R 7 is phenyl optionally substituted with one or more R 11 .

34 . The compound of claim 32 , wherein R 7 is unsubstituted phenyl.

35 . The compound of claim 28 or 29 , wherein R 7 is C 7-14 aralkyl optionally substituted with one or more R 11 .

36 . The compound of claim 35 , wherein R 7 is benzyl or —(CH 2 ) 2 Ph, each optionally substituted with one or more R 11 .

37 . The compound of claim 35 , wherein R 7 is unsubstituted benzyl or unsubstituted —(CH 2 ) 2 Ph.

38 . The compound of claim 28 or 29 , wherein R 7 is (6 membered heteroaryl)alkyl optionally substituted with one or more R 11 .

39 . The compound of claim 38 , wherein R 7 is —CH 2 -pyridyl, —CH 2 -pyrazinyl, or —CH 2 -pyrimidinyl, each optionally substituted with one or more R 11 .

40 . The compound of claim 38 , wherein R 7 is —CH 2 -pyridyl, —CH 2 -pyrazinyl or —CH 2 -pyrimidinyl, each unsubstituted.

41 . The compound of claim 28 or 29 , wherein R 7 is —C(O)R 8 .

42 . The compound of claim 41 , wherein R 8 is selected from C 1-6 alkyl, C 6-10 aryl, or —NR 12 R 13 .

43 . The compound of claim 42 , wherein R 8 is selected from methyl, ethyl, propyl, isopropyl, butyl, pentyl or phenyl.

44 . The compound of claim 42 , wherein R 8 is —NR 12 R 13 .

45 . The compound of claim 44 , wherein each R 12 and R 13 is independently selected from hydrogen, C 1-6 alkyl, or benzyl.

46 . The compound of claim 28 or 29 , wherein R 7 is —C(O)OR 5 .

47 . The compound of claim 46 , 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 .

48 . The compound of claim 47 , wherein R 5 is selected from methyl, ethyl, isopropyl, butyl.

49 . The compound of claim 47 , wherein R 5 is selected from phenyl or benzyl, each optionally substituted with one or more R 11 .

50 . The compound of claim 27 , 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 .

51 . The compound of claim 50 , 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 .

52 . The compound of claim 50 or 51 , wherein the heterocyclyl formed by R 6 and R 7 together with the nitrogen to which they are attached is unsubstituted.

53 . The compound of any one of claims 1 to 52 , wherein R 10 is C 1-6 alkyl.

54 . The compound of any one of claims 1 to 52 , wherein two geminal R 10 together are oxo.

55 . The compound of any one of claims 1 to 9 , wherein R 2 is —SR 5 .

56 . The compound of claim 55 , wherein R 5 is C 6-10 aryl optionally substituted with one or more R 11 .

57 . The compound of claim 55 or 56 , wherein R 5 is optionally substituted phenyl.

58 . The compound of any one of claims 1 to 9 , wherein R 2 is —C(O)R 8 .

59 . The compound of claim 58 , wherein R 8 is selected from —NR 12 R 13 .

60 . The compound of claim 59 , 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 .

61 . The compound of claim 60 , 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 .

62 . The compound of claim 61 , wherein the phenyl or benzyl is unsubstituted.

63 . The compound of any one of claims 1 to 9 , wherein R 2 is —C(O)OR 5 .

64 . The compound of claim 63 , wherein R 5 is hydrogen or C 1-6 alkyl.

65 . The compound of any one of claims 1 to 64 , 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 .

66 . The compound of claim 65 , wherein R 11 is selected from —CN, —Cl, —F, —CH 3 , —OCH 3 , —OC 2 H 5 , —CF 3 , —OCF 3 , —O—(CH 2 ) 2 —OCH 3 , or —C(O)NH 2 .

67 . The compound of any one of claims 1 to 66 , wherein R 3 is —(CH 2 ) n —(C 6-10 aryl) optionally substituted with one or more R 9 .

68 . The compound of claim 67 , wherein R 3 is —(CH 2 ) n -phenyl, optionally substituted with one or more R 9 .

69 . The compound of claim 68 , wherein n is 0.

70 . The compound of any one of claims 67 to 69 , wherein R 9 is selected from hydroxy, halogen, optionally substituted C 1-6 alkyl, —OR 5 , or —NR 14 R 15 .

71 . The compound of claim 70 , wherein R 9 is selected from hydroxy, fluoro, chloro, methyl, ethyl, or trifluoromethyl.

72 . The compound of claim 70 , wherein R 9 is —OR 5 .

73 . The compound of claim 72 , wherein R 5 is selected from hydrogen, C 1-6 alkyl, halo substituted C 1-6 alkyl, or C 2-8 alkoxyalkyl.

74 . The compound of claim 73 , wherein R 5 is selected from trifluoromethyl, ethyl or —(CH 2 ) 2 OCH 3 .

75 . The compound of claim 70 , wherein R 9 is —NH—C(O)R 8 .

76 . The compound of claim 75 , wherein R 9 is selected from —NH—C(O)—C 1-6 alkyl, or —NH—C(O)—NH 2 .

77 . The compound of claims 67 to 69 , wherein R 3 is unsubstituted.

78 . The compound of any one of claims 1 and 3 to 66 , wherein R 3 is hydrogen.

79 . The compound of any one of claims 1 to 77 , wherein Z is oxygen.

80 . The compound of any one of claims 1 to 79 , wherein the bonds represented by a solid and dashed line are double bonds.

81 . 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, 545-551,664 and 696-707 of Table 1.

82 . A compound having the structure of formula (II):

or a pharmaceutically acceptable salt thereof, wherein

R 2 is 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;

Y is selected from N and CR 4 ;

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, 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 adjacent R 4 together with the carbon atoms to which they are attached form a fused ring selected from the group consisting of optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, optionally substituted C 3-7 carbocyclyl, and optionally substituted 3-7 membered heterocyclyl;

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 ;

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.

83 . The compound of claim 82 , wherein if R 3 is hydrogen, then

and the two adjacent R 4 together with the carbon atoms to which they are attached form a fused ring selected from optionally substituted 5 or 6 membered heteroaryl or optionally substituted 5 or 6 membered heterocyclyl.

84 . The compound of claim 82 , wherein formula (II) is also represented by formula (IIa):

85 . The compound of any one of claims 82 to 84 , wherein R 2 is selected from optionally substituted C 1-6 alkyl.

86 . The compound of claim 85 , wherein R 2 is selected from methyl, ethyl, isopropyl, or trifluoromethyl.

87 . The compound of claim 86 , wherein R 2 is methyl.

88 . The compound of any one of claims 82 , 83 , and 85 to 87 , wherein R 3 is hydrogen.

89 . The compound of any one of claims 82 to 87 , wherein R 3 is selected from —(CH 2 ) n —(C 6-10 aryl), optionally substituted with one or more R 9 .

90 . The compound of claim 89 , wherein R 3 is —(CH 2 ) n -phenyl optionally substituted with one or more R 9 .

91 . The compound of any one of claims 82 and 84 to 87 , wherein R 3 is selected from —(CH 2 ) n -(9 membered heterocyclyl), optionally substituted with one or more R 9 .

92 . The compound of claim 91 , wherein R 3 is selected from

each optionally substituted with one or more R 9 .

93 . The compound of any one of claims 82 and 84 to 87 , wherein R 3 is selected from —(CH 2 ) n -(10 membered heterocyclyl), optionally substituted with one or more R 9 .

94 . The compound of claim 93 , wherein R 3 is selected from

each optionally substituted with one or more R 9 .

95 . The compound of any one of claims 89 to 94 , wherein n is 0.

96 . The compound of any one of claims 82 to 95 , wherein each R 9 is independently selected from cyano, halogen, optionally substituted C 1-6 alkyl, —OR 5 , —NR 14 R 15 or —C(O)R 8 .

97 . The compound of claim 96 , wherein R 9 is selected from methyl, ethyl, propyl isopropyl, or trifluoromethyl.

98 . The compound of claim 96 , wherein R 9 is selected from fluoro or chloro.

99 . The compound of claim 96 , wherein R 9 is —OR 5 , and wherein R 5 is selected from optionally substituted C 1-6 alkyl.

100 . The compound of claim 96 or 99 , wherein R 5 is selected from methyl, ethyl, propyl, isopropyl or trifluoromethyl.

101 . The compound of claim 96 , wherein R 9 is —NR 14 R 15 , and wherein each R 14 and R 15 is independently selected from hydrogen, C 1-6 alkyl or —C(O)R 8 .

102 . The compound of claim 101 , wherein R 8 is selected from optionally substituted C 1-6 alkyl, —OR 5 or —NR 12 R 13 .

103 . The compound of claim 102 , wherein each R 12 and R 13 is independently selected from hydrogen or C 1-6 alkyl.

104 . The compound of claim 102 , wherein R 5 is selected from hydrogen or C 1-6 alkyl.

105 . The compound of any one of claims 96 and 101 to 103 , wherein each R 14 and R 15 is independently selected from hydrogen, methyl, ethyl, —C(O)NH 2 , —C(O)NHCH 3 , —C(O)N(CH 3 ) 2 , —C(O)OH or —C(O)OEt.

106 . The compound of claim 96 , wherein R 9 is —C(O)R 8 .

107 . The compound of claim 96 or 106 , wherein R 8 is selected from optionally substituted C 1-6 alkyl or —NR 12 R 13 .

108 . The compound of claim 107 , wherein each of R 12 or R 13 is independently selected from hydrogen or C 1-6 alkyl.

109 . The compound of any one of claims 89 to 95 , wherein R 3 is unsubstituted.

110 . The compound of any one of claims 82 to 109 , wherein all Y is CR 4 .

111 . The compound of any one of claims 82 to 109 , wherein at least one Y in

is N.

112 . The compound of claim 111 , wherein

is selected from

each optionally substituted with one to four R 4 .

113 . The compound of claim 111 , wherein two of Y in

are N.

114 . The compound of claim 113 , wherein

is selected from

each optionally substituted with one to three R 4 .

115 . The compound of any one of claims 82 to 114 , wherein R 4 is selected from hydrogen, halogen, —CN, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy or 5 membered heteroaryl optionally substituted with one or more R 11 .

116 . The compound of claim 115 , wherein R 4 is selected from hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or thiazolyl.

117 . The compound of any one of claims 82 to 114 , wherein two adjacent R 4 together with the carbon atoms to which they are attached form a fused ring selected from optionally substituted 5 or 6 membered heteroaryl or optionally substituted 5 or 6 membered heterocyclyl.

118 . The compound of claim 117 , wherein the optionally substituted 5 or 6 membered heterocyclyl formed by two adjacent R 4 together with the carbon atoms to which they are attached is selected from

wherein each R 17 is independently selected from hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , or optionally substituted C 2-8 alkoxyalkyl.

119 . The compound of claim 118 , wherein R 17 is selected from hydrogen, methyl, ethyl, —(CH 2 ) 2 OH or —(CH 2 ) 2 OCH 3 .

120 . The compound of claim 117 , wherein the optionally substituted 5 or 6 membered heteroaryl formed by two adjacent R 4 together with the carbon atoms to which they are attached is selected from

wherein each R 18 is independently selected from hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, C 6-10 aryl optionally substituted with one or more R 11 , C 7-14 aralkyl optionally substituted with one or more R 11 , or optionally substituted C 2-8 alkoxyalkyl.

121 . The compound of claim 120 , wherein R 18 is selected from hydrogen or methyl.

122 . The compound of any one of claims 117 to 121 , wherein the substituent on the 5 or 6 membered heteroaryl or 5 or 6 membered heterocyclyl formed by two adjacent R 4 together with the carbon atoms to which they are attached is selected from C 1-6 alkyl, C 1-6 alkoxy, oxo or halogen.

123 . The compound of claim 122 , wherein the substituent on the 5 or 6 membered heteroaryl or 5 or 6 membered heterocyclyl formed by two adjacent R 4 together with the carbon atoms to which they are attached is selected from methyl, fluoro, or oxo.

124 . The compound of any one of claims 82 to 123 , wherein Z is oxygen.

125 . The compound of any one of claims 82 , 83 and 85 to 124 , wherein the bonds represented by a solid and dashed line are double bonds, provided that when the optionally substituted 5 or 6 membered heteroaryl formed by two adjacent R 4 together with the carbon atoms to which they are attached is selected from

one of the bonds represented by a solid and dashed line in

is a single bond.

126 . The compound of claim 82 , wherein the compound is selected from the group consisting of Compounds 163-216, 241-243, 245, 246, 248-252, 254, 255, 258-261, 263, 415-430, 552-561, 566 and 629 of Table 1.

127 . A compound having the structure of formula (III):

or a pharmaceutically acceptable salt thereof, wherein

ring A is selected from the group consisting of phenyl, 5-6 membered heteroaryl, C 3-7 carbocyclyl, and 3-7 membered heterocyclyl, each optionally substituted with one or more R 4 ;

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 ;

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 3 is phenyl optionally substituted with one or more R 9 , and Z is O; then ring A cannot be optionally substituted phenyl;

when ring A is selected from cyclopentenyl, optionally substituted pyrrolyl or optionally substituted dihydropyrrolidinyl, R 3 is phenyl optionally substituted with one or more R 9 , and Z is O; then R 1 is not halogen, 3-methoxy phenyl or 3,5-dimethoxy phenyl;

when ring A is pyridyl, R 1 is optionally substituted phenyl, and Z is O; then n in R 3 is zero and R 3 is not halogen substituted phenyl;

when ring A is optionally substituted pyrimidyl, R 3 is phenyl or benzyl, and Z is O; then R 1 is not methyl or benzyl;

when ring A is optionally substituted furanyl, R 3 is phenyl optionally substituted with one or more R 9 , and Z is O; then R 1 is not fluoro;

when ring A is optionally substituted pyrrolyl, R 3 is phenyl optionally substituted with one or more R 9 , and Z is O; then R 1 is not methyl;

when ring A is tetrahydrofuranyl, R 3 is phenyl, and Z is O; then R 1 is not methyl or phenyl; and

when ring A is pyradizinyl, R 3 is 4-NO 2 -phenyl, and Z is O; then R 1 is not methyl.

128 . The compound of claim 127 , wherein

129 . The compound of claim 127 , wherein R 1 is selected from halogen, C 1-6 alkyl optionally substituted with one or more R 4 , C 6-10 aryl optionally substituted with one or more R 4 , or 5 to 6 membered heteroaryl optionally substituted with one or more R 4 .

130 . The compound of claim 129 , wherein R 1 is bromo or fluoro.

131 . The compound of claim 129 , wherein R 1 is methyl optionally substituted with one or more R 4 .

132 . The compound of claim 129 , wherein R 1 is phenyl optionally substituted with one or more R 4 .

133 . The compound of claim 129 , wherein R 1 is pyridazinyl optionally substituted with one or more R 4 .

134 . The compound of claim 129 , wherein R 1 is pyrazolyl or 1-methyl pyrazolyl optionally substituted with one or more R 4 .

135 . The compound of any one of claims 127 to 134 , wherein R 3 is hydrogen.

136 . The compound of any one of claims 127 to 134 , wherein R 3 is selected from —(CH 2 ) n —(C 6-10 aryl) optionally substituted with one or more R 9 .

137 . The compound of claim 136 , wherein R 3 is phenyl, optionally substituted with one or more R 9 .

138 . The compound of claim 136 or 137 , wherein R 3 is unsubstituted.

139 . The compound of claim 136 or 137 , wherein R 9 is selected from cyano, halogen, optionally substituted C 1-6 alkyl, or optionally substituted C 1-6 alkoxy.

140 . The compound of claim 139 , wherein R 9 is selected from cyano, fluoro, chloro, methyl, ethyl, ethoxy, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy.

141 . The compound of any one of claims 127 to 140 , wherein ring A is selected from 6-membered heteroaryl, 5-membered heterocyclyl or 6-membered heterocyclyl, each optionally substituted with one or more R 4 .

142 . The compound of claim 141 , wherein ring A is selected from

each optionally substituted with one or more R 4 ; and

wherein each R 17 is independently selected from hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-8 alkoxyalkyl, optionally substituted C-carboxy, acyl, 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 .

143 . The compound of claim 142 , ring A is selected from

each optionally substituted with one or more R 4 .

144 . The compound of claim 142 or 143 , wherein ring A is selected from

each optionally substituted with one or more R 4 .

145 . The compound of any one of claims 142 to 144 , wherein R 17 is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, —(CH 2 ) 2 F, —(CH 2 ) 2 OH, —(CH 2 ) 2 OCH 3 , —(CH 2 ) 2 OC 2 H 5 , —(CH 2 ) 2 OC 3 H 7 , —C(O)O-t-Bu, —C(O)CH 3 or benzyl.

146 . The compound of any one of claims 127 to 145 , wherein R 4 is selected from halogen, optionally substituted C 1-6 alkyl, or C 7-14 aralkyl optionally substituted with one or more R 11 , or two geminal R 4 together are oxo.

147 . The compound of claim 146 , wherein R 4 is selected from fluoro, methyl, trifluoromethyl, —(CH 2 ) 2 OH, benzyl, or two geminal R 4 together are oxo.

148 . The compound of any one of claims 141 to 145 , wherein ring A is unsubstituted.

149 . The compound of any one of claims 127 to 148 , wherein Z is oxygen.

150 . The compound of any one of claims 127 to 149 , wherein the bonds represented by a solid and dashed line are double bonds, provided that when ring A is

one of the bonds represented by a solid and dashed line is a single bond.

151 . The compound of any one of claims 127 to 150 , wherein the compound is selected from the group consisting of Compounds 29-63, 392-400, 568-575, 577, 579-589, 591-594, 596-610, 614, 615, 617, 619, 620, 624-626, 630-636, 639-661, 665, and 669-695 of Table 1.

152 . A compound having the structure of formula (IV):

or a pharmaceutically acceptable salt thereof, wherein

R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl optionally substituted with one or more R 4 , C 2-6 alkenyl optionally substituted with one or more R 4 , C 2-6 alkynyl optionally substituted with one or more R 4 , 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 ;

each R 2 is independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, —CN, —OR 5 , —NR 6 R 7 , and —C(O)R 8 ,

or both R 2 together with the carbon atoms to which they are attached form a fused ring selected from the group consisting of phenyl, 5-6 membered heteroaryl, C 3-7 carbocyclyl, and 3-7 membered heterocyclyl, each optionally substituted with one or more R 4 ;

each R 4 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;

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 , —(CH 2 ) n -(3-10 membered heterocyclyl) optionally substituted with one or more R 10 , and —(CH 2 ) n —(C 6-10 aryl) optionally substituted with one or more R 11 ;

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

each R 8 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, —NR 12 R 13 , and —OR 5 ;

each Y is independently N or CR 9 ;

or independently two adjacent R 9 together with the ring atoms to which they are attached form a fused optionally substituted 3-10 membered heterocyclyl or a fused optionally substituted 5-10 membered heteroaryl;

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

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 ;

Z is selected from oxygen and sulfur;

n is an integer from 0 to 4;

m is an integer from 1 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.

153 . The compound of claim 152 , wherein R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl optionally substituted with one or more R 4 , or 5-membered heteroaryl optionally substituted with one or more R 4 .

154 . The compound of claim 153 , wherein R 1 is selected from methyl, phenyl, pyrazolyl, or 1-methyl pyrazolyl, each optionally substituted with one or more R 4 .

155 . The compound of claim 154 , wherein R 1 is unsubstituted.

156 . The compound of any one of claims 152 to 154 , wherein R 2 is selected from hydrogen or optionally substituted C 1-6 alkyl.

157 . The compound of any one of claims 152 to 156 , wherein all Y are CR 4 .

158 . The compound of any one of claims 152 to 156 , wherein at least one Y is N.

159 . The compound of any one of claims 152 to 158 , wherein R 4 is selected from halogen, C 1-6 alkyl or C 1-6 alkoxy.

160 . The compound of claim 159 , wherein R 4 is selected from fluoro or methyl.

161 . The compound of any one of claims 152 to 160 , wherein m is 1.

162 . The compound of any one of claims 152 to 160 , wherein m is 2.

163 . The compound of any one of claims 152 to 160 , wherein m is 3.

164 . The compound of any one of claims 152 to 163 , wherein Z is oxygen.

165 . The compound of any one of claims 152 to 164 , wherein the bonds represented by a solid and dashed line are double bonds.

166 . The compound of claim 152 , wherein the compound is selected from the group consisting of Compounds 21-26 of Table 1.

167 . A compound having the structure of formula (V):

or a pharmaceutically acceptable salt thereof, wherein

A is a C 5-7 carbocyclyl optionally substituted with one or more R 4 ;

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

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 ;

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.

168 . The compound of claim 167 , wherein each R 2 is independently selected from hydrogen, C 1-6 alkyl or —OR 5 .

169 . The compound of claim 168 , wherein R 2 is hydrogen.

170 . The compound of any one of claims 167 to 169 , wherein R 3 is —(CH 2 ) n —(C 6-10 aryl), optionally substituted with one or more R 9 .

171 . The compound of claim 170 , wherein R 3 is phenyl, optionally substituted with one or more R 9 .

172 . The compound of claim 171 , wherein R 9 is selected from halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-8 alkoxyalkyl, —OR 5 , or —NR 14 R 15 .

173 . The compound of claim 172 , wherein R 9 is selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, —NHCH 3 , —NH 2 , or —NHC(O)CH 3 .

174 . The compound of claim 173 , wherein R 9 is trifluoromethoxy.

175 . The compound of any one of claims 167 to 174 , wherein ring A is a C 5 carbocyclyl optionally substituted with one or more R 4 .

176 . The compound of any one of claims 167 to 174 , wherein ring A is a C 6 carbocyclyl optionally substituted with one or more R 4 .

177 . The compound of any one of claims 167 to 176 , wherein R 4 is selected from halogen, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, or independently two geminal R 4 together are oxo.

178 . The compound of any one of claims 167 , 175 and 176 , wherein ring A is unsubstituted.

179 . The compound of any one of claims 167 to 178 , wherein Z is oxygen.

180 . The compound of any one of claims 167 to 179 , wherein the bonds represented by a solid and dashed line are double bonds.

181 . The compound of claim 167 , wherein the compound is selected from the group consisting of Compounds 27 and 28 of Table 1.

182 . A compound having the structure of formula (VIa):

or a pharmaceutically acceptable salt thereof, wherein

R 1 is a C 4-7 carbocyclyl optionally substituted with one or more R 4 ;

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

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 ;

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.

183 . The compound of claim 182 , wherein R 1 is a C 4 carbocyclyl optionally substituted with one or more R 4 .

184 . The compound of claim 182 , wherein R 1 is a C 5 carbocyclyl optionally substituted with one or more R 4 .

185 . The compound of claim 182 , wherein R 1 is a C 6 carbocyclyl optionally substituted with one or more R 4 .

186 . The compound of any one of claims 182 to 185 , wherein R 4 is selected from halogen, optionally substituted C 1-6 alkyl, or optionally substituted C 1-6 alkoxy.

187 . The compound of claim 186 , wherein R 4 is selected from fluoro, chloro, methyl, methoxy, ethoxy, trifluoromethyl, or trifluoromethoxy.

188 . The compound of claim 182 , wherein R 1 is unsubstituted.

189 . The compound of any one of claims 182 to 188 , wherein each R 2 is independently selected from hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR 5 or —NR 6 R 7 .

190 . The compound of claim 189 , wherein R 2 is hydrogen.

191 . The compound of claim 189 , wherein R 2 is halogen.

192 . The compound of claim 189 , wherein R 2 is optionally substituted C 1-6 alkyl.

193 . The compound of claim 192 , wherein R 2 is selected from methyl or trifluoromethyl.

194 . The compound of any one of claims 182 to 193 , wherein R 3 is selected from —(CH 2 ) n —(C 6-10 aryl), optionally substituted with one or more R 9 .

195 . The compound of claim 194 , wherein R 3 is phenyl, optionally substituted with one or more R 9 .

196 . The compound of claim 195 , wherein R 9 is selected from halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-8 alkoxyalkyl, —OR 5 , or —NR 14 R 15 .

197 . The compound of claim 196 , wherein R 9 is selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, —NHCH 3 , —NH 2 , or —NHC(O)CH 3 .

198 . The compound of claim 195 , wherein R 3 is unsubstituted phenyl.

199 . The compound of any one of claims 182 to 198 , wherein Z is oxygen.

200 . The compound of any one of claims 182 to 199 , wherein the bonds represented by a solid and dashed line are double bonds.

201 . The compound of claim 182 , wherein the compound is selected from the group consisting of Compounds 64-66 of Table 1.

202 . A compound having the structure of formula (VII):

or a pharmaceutically acceptable salt thereof, wherein

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

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 ;

Q is selected from C(O) and S(O) t ;

Z is selected from oxygen and sulfur;

each n is independently an integer from 0 to 4;

t is 1 or 2; 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.

203 . The compound of claim 202 , wherein each R 2 is independently selected from hydrogen, halogen, optionally substituted C 1-6 alkyl, —OR 5 or —NR 6 R 7 .

204 . The compound of claim 203 , wherein R 2 is hydrogen.

205 . The compound of claim 203 , wherein R 2 is halogen.

206 . The compound of claim 203 , wherein R 2 is optionally substituted C 1-6 alkyl.

207 . The compound of claim 206 , wherein R 2 is methyl or trifluoromethyl.

208 . The compound of any one of claims 202 to 207 , wherein R 3 is selected from —(CH 2 ) n —(C 6-10 aryl), optionally substituted with one or more R 9 .

209 . The compound of claim 208 , wherein R 3 is phenyl optionally substituted with one or more R 9 .

210 . The compound of claim 209 , wherein R 9 is selected from halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-8 alkoxyalkyl, —OR 5 , or —NR 14 R 15 .

211 . The compound of claim 210 , wherein R 9 is selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, —NHCH 3 , —NH 2 , or —NHC(O)CH 3 .

212 . The compound of claim 209 , wherein R 3 is unsubstituted phenyl.

213 . The compound of any one of claims 202 to 212 , wherein Q is C(O).

214 . The compound of any one of claims 202 to 212 , wherein Q is S(O) t .

215 . The compound of claim 214 , wherein t is 2.

216 . The compound of any one of claims 202 to 215 , wherein R 16 is selected from optionally substituted 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 , —NR 12 R 13 , or —OR 5 .

217 . The compound of claim 216 , wherein R 16 is optionally substituted C 1-6 alkyl.

218 . The compound of claim 217 , wherein R 16 is selected from methyl, ethyl, propyl, isopropyl, or butyl.

219 . The compound of claim 216 , wherein R 16 is phenyl optionally substituted with one or more R 11 .

220 . The compound of claim 219 , wherein R 16 is unsubstituted phenyl.

221 . The compound of claim 216 , wherein R 16 is benzyl optionally substituted with one or more R 11 .

222 . The compound of claim 221 , wherein R 16 is unsubstituted benzyl.

223 . The compound of claim 216 , wherein R 16 is —NR 12 R 13 .

224 . The compound of claim 223 , wherein each R 12 and R 13 is independently selected from hydrogen or optionally substituted C 1-6 alkyl.

225 . The compound of claim 216 , wherein R 16 is —OR 5 .

226 . The compound of claim 225 , wherein R 5 is selected from hydrogen or optionally substituted C 1-6 alkyl.

227 . The compound of claim 226 , wherein R 5 is selected from methyl, ethyl, propyl, isopropyl, or butyl.

228 . The compound of any one of claims 202 to 227 , wherein Z is oxygen.

229 . The compound of any one of claims 202 to 228 , wherein the bonds represented by a solid and dashed line are double bonds.

230 . The compound of claim 202 , wherein the compound is selected from the group consisting of Compounds 67-76 of Table 1.

231 . A compound having the structure of formula (VIb):

R 3 is selected from the group consisting of —(CH 2 ) 1-4 —(C 6-10 aryl), —(CH 2 ) 1-4 -(5-10 membered heteroaryl), —(CH 2 ) 1-4 —(C 3-10 carbocyclyl), and —(CH 2 ) 1-4 43-10 membered heterocyclyl), each optionally substituted with one or more R 9 ;

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

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 ;

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 1 is selected from the group consisting of optionally substituted C 6-10 aryl, optionally substituted 5 to 10 membered heteroaryl, optionally substituted 6 to 10 membered heterocyclyl, optionally substituted hexyl, optionally substituted alkyl, optionally substituted alkenyl; each of R 2 is hydrogen or one of R 2 is hydrogen and the other R 2 is methyl; and Z is O; then R 3 is not —CH 2 -phenyl substituted with one or more halogen atoms; and provided that

R 1 is not 4-methoxy phenyl.

232 . The compound of claim 231 , wherein R 1 is selected from C 1-6 alkyl optionally substituted with one or more R 4 , 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 .

233 . The compound of claim 232 , wherein R 1 is selected from C 1-6 alkyl optionally substituted with one or more R 4 .

234 . The compound of claim 233 , wherein R 1 is selected from methyl, ethyl, propyl, or isopropyl.

235 . The compound of claim 232 , wherein R 1 is phenyl optionally substituted with one or more R 4 .

236 . The compound of claim 232 , wherein R 1 is selected from 5 or 6 membered heteroaryl, each optionally substituted with one or more R 4 .

237 . The compound of claim 236 , wherein R 1 is selected from pyrazolyl or 1-methyl pyrazolyl, each optionally substituted with one or more R 4 .

238 . The compound of any one of claims 231 to 237 , wherein R 4 is selected from halogen or optionally substituted C 1-6 alkyl.

239 . The compound of claim 238 , wherein R 4 is fluoro.

240 . The compound of any one of claims 231 to 237 , wherein R 1 is unsubstituted.

241 . The compound of any one of claims 231 to 240 , wherein each R 2 is independently selected from hydrogen, halogen, or optionally substituted C 1-6 alkyl.

242 . The compound of claim 241 , wherein R 2 is hydrogen.

243 . The compound of any one of claims 231 to 242 , wherein R 3 is —(CH 2 ) 1-4 —(C 6-10 aryl), optionally substituted with one or more R 9 .

244 . The compound of claim 243 , wherein R 3 is —(CH 2 ) 1-4 -phenyl, optionally substituted with one or more R 9 .

245 . The compound of claim 244 , wherein R 3 is —(CH 2 )-phenyl, optionally substituted with one or more R 9 .

246 . The compound of claim 244 , wherein R 3 is —(CH 2 ) 2 -phenyl, optionally substituted with one or more R 9 .

247 . The compound of any one of claims 231 to 246 , wherein R 9 is selected from halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-8 alkoxyalkyl, —OR 5 , —C(O)R 8 or —NR 14 R 15 .

248 . The compound of claim 247 , wherein R 9 is selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, —C(O)CH 3 , —NHCH 3 , —NH 2 , or —NHC(O)CH 3 .

249 . The compound of any one of claims 243 to 246 , wherein R 3 is unsubstituted.

250 . The compound of any one of claims 231 to 249 , wherein Z is oxygen.

251 . The compound of any one of claims 231 to 250 , wherein the bonds represented by a solid and dashed line are double bonds.

252 . The compound of claim 231 , wherein the compound is selected from the group consisting of Compounds 77-80 of Table 1.

253 . A compound having the structure of formula (VIII):

R 3 is selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, —(CH 2 ) n —(C 6-10 aryl) optionally substituted with one or more R 9 , —(CH 2 ) n -(5-10 membered heteroaryl) optionally substituted with one or more R 9 , —(CH 2 ) n —(C 3-10 carbocyclyl) optionally substituted with one or more R 9 , and —(CH 2 ) n -(3-10 membered heterocyclyl) optionally substituted with one or more R 9 ;

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 17 is independently selected from the group consisting of hydrogen, oxo, halogen, —CN, —C(O)R 8 , —SO 2 R 16 , C 1-6 alkyl optionally substituted with one or more R 4 , C 2-6 alkenyl optionally substituted with one or more R 4 , C 2-6 alkynyl optionally substituted with one or more R 4 , 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 ,

or independently two adjacent R 17 together with the carbon atoms to which they are attached form a fused phenyl or 5-6 membered heteroaryl, each optionally substituted with one or more R 4 ;

Z is selected from oxygen and sulfur;

each n is independently an integer from 0 to 4;

s is 0, 1, or 3; 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.

254 . The compound of claim 253 , wherein R 3 is selected from optionally substituted C 1-6 alkyl or —(CH 2 ) n —(C 6-10 aryl) optionally substituted with one or more R 9 .

255 . The compound of claim 254 , wherein R 3 is —(CH 2 ) n —(C 6-10 aryl) optionally substituted with one or more R 9 .

256 . The compound of claim 255 , wherein R 3 is phenyl optionally substituted with one or more R 9 .

257 . The compound of any one of claims 253 to 256 , wherein R 9 is selected from halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-8 alkoxyalkyl, —OR 5 , —C(O)R 8 or —NR 14 R 15 .

258 . The compound of claim 257 , wherein R 9 is selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, —C(O)CH 3 , —NHCH 3 , —NH 2 , or —NHC(O)CH 3 .

259 . The compound of claim 256 , wherein R 3 is unsubstituted phenyl.

260 . The compound of claim 254 , wherein R 3 is optionally substituted C 1-6 alkyl.

261 . The compound of any one of claims 253 to 260 , wherein each R 17 is independently selected from hydrogen, halogen, optionally substituted C 1-6 alkyl or oxo.

262 . The compound of claim 261 , wherein each R 17 is hydrogen.

263 . The compound of any one of claims 253 to 260 , wherein two adjacent R 17 together with the carbon atoms to which they are attached form a fused phenyl optionally substituted with one or more R 4 .

264 . The compound of claim 263 , wherein at least one R 17 is oxo.

265 . The compound of claim 263 , wherein at least one R 17 is optionally substituted C 1-6 alkyl.

266 . The compound of any one of claims 263 to 265 , wherein the fused phenyl is unsubstituted.

267 . The compound of any one of claims 253 to 260 , wherein two adjacent R 17 together with the carbon atoms to which they are attached form a fused 5-6 membered heteroaryl, optionally substituted with one or more R 4 .

268 . The compound of claim 267 , wherein at least one R 17 is oxo.

269 . The compound of claim 267 , wherein at least one R 17 is optionally substituted C 1-6 alkyl.

270 . The compound of any one of claims 267 to 269 , wherein the fused 5-6 membered heteroaryl is unsubstituted.

271 . The compound of any one of claims 263 to 265 and 267 to 269 , wherein R 4 is selected from halogen or optionally substituted C 1-6 alkyl.

272 . The compound of any one of claims 253 to 271 , wherein n is 0.

273 . The compound of any one of claims 253 to 271 , wherein n is 1.

274 . The compound of any one of claims 253 to 271 , wherein n is 3.

275 . The compound of any one of claims 253 to 274 , wherein Z is oxygen.

276 . The compound of claim 253 , wherein the compound is selected from the group consisting of Compounds 81, 82, and 513-519 of Table 1.

277 . A compound having the structure of formula (IX):

R 1 is selected from the group consisting of hydrogen, halogen, —CN, —C(O)R 8 , —SO 2 R 16 , C 1-6 alkyl optionally substituted with one or more R 4 , C 2-6 alkenyl optionally substituted with one or more R 4 , C 2-6 alkynyl optionally substituted with one or more R 4 , 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 ;

or both R 2 together with the carbon atoms to which they are attached form a fused ring selected from the group consisting of C 3-7 carbocyclyl and 3-7 membered heterocyclyl, each optionally substituted with one or more R 4 ;

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

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 ;

Z is selected from oxygen and sulfur; and

each n is independently an integer from 0 to 4.

278 . The compound of claim 277 , wherein R 1 is selected from C 1-6 alkyl optionally substituted with one or more R 4 , 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 .

279 . The compound of claim 278 , wherein R 1 is C 1-6 alkyl optionally substituted with one or more R 4 .

280 . The compound of claim 278 , wherein R 1 is C 6-10 aryl optionally substituted with one or more R 4 .

281 . The compound of claim 280 , wherein R 1 is phenyl optionally substituted with one or more R 4 .

282 . The compound of claim 278 , wherein R 1 is 5 or 6 membered heteroaryl optionally substituted with one or more R 4 .

283 . The compound of claim 282 , wherein R 1 is pyrazolyl or 1-methyl pyrazolyl optionally substituted with one or more R 4 .

284 . The compound of any one of claims 278 to 283 , wherein R 4 is selected from halogen, optionally substituted C 1-6 alkyl or optionally substituted C 1-6 alkoxy.

285 . The compound of any one of claims 278 to 283 , wherein R 1 is unsubstituted.

286 . The compound of any one of claims 277 to 285 , wherein each R 2 is independently selected from hydrogen, halogen or optionally substituted C 1-6 alkyl.

287 . The compound of claim 286 , wherein R 2 is hydrogen.

288 . The compound of any one of claims 277 to 287 , wherein R 3 is —(CH 2 ) n —(C 6-10 aryl), optionally substituted with one or more R 9 .

289 . The compound of claim 288 , wherein R 3 is phenyl optionally substituted with one or more R 9 .

290 . The compound of claim 288 or 289 , wherein R 9 is selected from halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-8 alkoxyalkyl, —OR 5 , —C(O)R 8 or —NR 14 R 15 .

291 . The compound of claim 290 , wherein R 9 is selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, —C(O)CH 3 , —NHCH 3 , —NH 2 , or —NHC(O)CH 3 .

292 . The compound of claim 288 or 289 , wherein R 3 is unsubstituted.

293 . The compound of any one of claims 277 to 292 , wherein Z is oxygen.

294 . The compound of claim 277 , wherein the compound is selected from the group consisting of Compounds 83, 84, 520-522 of Table 1.

295 . A compound selected from the group consisting of Compounds 1-20, 217-240, 244, 247, 253, 256, 257, 262, 264-283, 285, 287-339, 341-391, 431, 433, 434, 438-440, 442, 446-512, 546-549, 575, 585, 609, 610, 627, 628, 630, 632, 633, 639, 641, 656, 666-668, 708 and 709 of Table 1.

296 . A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 to 295 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

297 . A method of treating a fibrotic condition, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 295 , a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 296 to a subject in need thereof.

298 . The method of claim 297 , comprising identifying the subject as having or at risk of having said fibrotic condition.

299 . The method of claim 297 or 298 , wherein the fibrotic condition is selected from pulmonary fibrosis, dermal fibrosis, pancreatic fibrosis, liver fibrosis, and renal fibrosis.

300 . The method of claim 299 , wherein the fibrotic condition is idiopathic pulmonary fibrosis.

301 . The method of any one of claims 297 to 300 , wherein the subject is a human.

302 . Use of a therapeutically effective amount of a compound of any one of claims 1 to 295 , a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 296 in the preparation of a medicament for treating a fibrotic condition.

303 . A therapeutically effective amount of a compound of any one of claims 1 to 295 , a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 296 for use in the treatment of a fibrotic condition.

Assignments (1)

CERTIFICATE OF CHANGE OF COMPANY'S ADDRESS Recorded Jul 27, 2018

From: INTERMUNE, INC.

To: INTERMUNE, INC.

Reel/Frame 046638/0466 →