Anti-Fibrotic Pyridinones

• US 20180064692A1
• Filed: 04/20/2017
• Published: 03/08/2018
• Est. Priority Date: 10/02/2012
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Intermune Incorporated (Roche Holding AG)
• Inventors: Buckman, Brad O., Nicholas, John Beamond, Ramphal, Johnnie Y., Emayan, Kumaraswamy, Seiwert, Scott D.
• Granted Patent: US 10,376,497 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 9/007 Pulmonary tract; Aromatherapy
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 211/86 Oxygen atoms
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 217/24 Oxygen atoms
• CPC Class Codes: C07D 221/04 Ortho- or peri-condensed ring systems
• CPC Class Codes: C07D 223/10 attached in position 2
• CPC Class Codes: C07D 295/125 with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07D 498/04 : Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems

Abstract

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

Claims

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

2. The compound of claim 1, wherein

R² is selected from the group consisting of halogen, —

OR⁵, —

NR⁶R⁷, and —

C(O)R⁸;

R³ is selected from the group consisting of phenyl, —

(CH₂)_n-(5-10 membered heteroaryl), —

(CH₂)_n—

(C_3-10 carbocyclyl), and —

(CH₂)_n-(3-10 membered heterocyclyl), each optionally substituted with one or more R⁹;

each R⁹ 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, —

OR⁵, —

NR¹⁴R¹⁵, —

C(O)R⁸, —

SO₂R¹⁶, and —

NO₂; and

each R¹¹ 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 R¹ is a C_6-10 aryl optionally substituted with one or more R⁴.

4. The compound of claim 3, wherein R¹ is a phenyl optionally substituted with one or more R⁴.

5. The compound of claim 1, wherein R¹ is a 5-10 membered heteroaryl optionally substituted with one or more R⁴.

6. The compound of claim 5, wherein R¹ is a pyrazolyl or 1-methyl pyrazolyl optionally substituted with one or more R⁴.

7. The compound of claim 1, wherein each R⁴ is independently selected from halogen, or optionally substituted C_1-6 alkyl.

9. The compound of claim 7, wherein R⁴ is methyl.

12. The compound of claim 1, wherein R² is —

CN.

13. The compound of claim 1, wherein R² is —

OR⁵.

14. The compound of claim 13, wherein R⁵ 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 R¹¹, C_6-10 aryl optionally substituted with one or more R¹¹, and —

(CH₂)_n-(3-10 membered heterocyclyl) optionally substituted with one or more R¹⁰.

16. The compound of claim 14, wherein R⁵ is optionally substituted C_1-6 alkyl.

18. The compound of claim 14, wherein R⁵ is C_6-10 aryl optionally substituted with one or more R¹¹.

20. The compound of claim 14, wherein R⁵ is C_7-14 aralkyl optionally substituted with one or more R¹¹.

22. The compound of claim 14, wherein R⁵ is optionally substituted C_2-8 alkoxyalkyl.

23. The compound of claim 22, wherein R⁵ is selected from —

(CH₂)₂OCH₃, —

(CH₂)₂OC₃H₇ or —

(CH₂)₂O(CH₂)OCH₃.

24. The compound of claim 14, wherein R⁵ is —

(CH₂)_n-(5 or 6 membered heterocyclyl) optionally substituted with one or more R¹⁰.

26. The compound of claim 24, wherein R⁵ is selected from

27. The compound of claim 1, wherein R² is —

NR⁶R⁷.

28. The compound of claim 27, wherein each R⁶ and R⁷ is independently selected from hydrogen, C_1-6 alkyl, C_6-10 aryl optionally substituted with one or more R¹¹, C_7-14 aralkyl optionally substituted with one or more R¹¹, (5-10 membered heteroaryl)alkyl optionally substituted with one or more R¹¹, —

C(O)R⁸, or —

C(O)OR⁵.

29. The compound of claim 28, wherein R⁶ is hydrogen or C_1-6 alkyl.

31. The compound of claim 28, wherein R⁷ is C_1-6 alkyl.

32. The compound of claim 28, wherein R⁷ is C_6-10 aryl optionally substituted with one or more R¹¹.

35. The compound of claim 29, wherein R⁷ is C_7-14 aralkyl optionally substituted with one or more R¹¹.

36. The compound of claim 35, wherein R⁷ is benzyl or —

(CH₂)₂Ph, each optionally substituted with one or more R¹¹.

37. The compound of claim 35, wherein R⁷ is unsubstituted benzyl or unsubstituted —

(CH₂)₂Ph.

38. The compound of claim 29, wherein R⁷ is (6 membered heteroaryl)alkyl optionally substituted with one or more R¹¹.

50. The compound of claim 27, wherein R⁶ and R⁷ together with the nitrogen to which they are attached form a 6-10 membered heterocyclyl optionally substituted with one or more R¹⁰.

53. The compound of claim 1, wherein R¹⁰ is C_1-6 alkyl.

54. The compound of claim 1, wherein two geminal R¹⁰ together are oxo.

65. The compound of claim 1, wherein each R¹¹ is independently selected from —

CN, halogen, optionally substituted C_1-6 alkyl, optionally substituted C_1-6 alkoxy, —

O—

(CH₂)_n—

C_1-8 alkoxy, or —

C(O) NR¹²R¹³.

67. The compound of claim 1, wherein R³ is phenyl optionally substituted with one or more R⁹, and wherein n is 0.

70. The compound of claim 67, wherein R⁹ is selected from hydroxy, halogen, optionally substituted C_1-6 alkyl, —

OR⁵, or —

NR¹⁴R¹⁵.

73. The compound of claim 70, wherein R⁵ is selected from hydrogen, C_1-6 alkyl, halo substituted C_1-6 alkyl, or C_2-8 alkoxyalkyl.

77. The compound of claim 67, wherein R³ is unsubstituted.

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

80. The compound of claim 1, 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, 523-545, 550, 551, 664 and 696-707 of Table 1 or pharmaceutically acceptable salts thereof.

296. 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.

297. A method of treating a fibrotic condition, comprising administering a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

8. (canceled)

10-11. -11. (canceled)

15. (canceled)

17. (canceled)

19. (canceled)

21. (canceled)

25. (canceled)

30. (canceled)

33-34. -34. (canceled)

39-49. -49. (canceled)

51-52. -52. (canceled)

55-64. -64. (canceled)

66. (canceled)

68-69. -69. (canceled)

71-72. -72. (canceled)

74-76. -76. (canceled)

78. (canceled)

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

83. The compound of claim 82, wherein if R³ is hydrogen, then

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

85. The compound of claim 82, wherein R² is selected from optionally substituted C_1-6 alkyl.

87. The compound of claim 85, wherein R² is methyl.

88. The compound of claim 82, wherein R³ is hydrogen.

89. The compound of claim 82, wherein R³ is selected from —

(CH₂)_n—

(C_6-10 aryl), optionally substituted with one or more R⁹.

90. The compound of claim 89, wherein R³ is —

(CH₂)_n-phenyl optionally substituted with one or more R⁹, and wherein n is 0.

96. The compound of claim 82, wherein each R⁹ is independently selected from cyano, halogen, optionally substituted C_1-6 alkyl, —

OR⁵, —

NR¹⁴R¹⁵ or —

C(O)R⁸.

97. The compound of claim 96, wherein R⁹ is selected from methyl, ethyl, propyl isopropyl, trifluoromethyl, fluoro, or chloro.

99. The compound of claim 96, wherein R⁹ is —

OR⁵, and wherein R⁵ is selected from optionally substituted C_1-6 alkyl.

100. The compound of claim 96, wherein R⁵ is selected from methyl, ethyl, propyl, isopropyl or trifluoromethyl.

101. The compound of claim 96, wherein R⁹ is —

NR¹⁴R¹⁵, and wherein each R¹⁴ and R¹⁵ is independently selected from hydrogen, C_1-6 alkyl or —

C(O)R⁸.

105. The compound of claim 96, wherein each R¹⁴ and R¹⁵ is independently selected from hydrogen, methyl, ethyl, —

C(O)NH₂, —

C(O)NHCH₃, —

C(O)N(CH₃)₂, —

C(O)OH or —

C(O)OEt.

109. The compound of claim 89, wherein R³ is unsubstituted.

110. The compound of claim 82, wherein all Y are CR⁴.

111. The compound of claim 82, wherein at least one Y in

112. The compound of claim 111, wherein

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

114. The compound of claim 113, wherein

115. The compound of claim 82, wherein R⁴ 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 R¹¹.

116. The compound of claim 115, wherein R⁴ is selected from hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or thiazolyl.

117. The compound of claim 82, wherein two adjacent R⁴ 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 R⁴ together with the carbon atoms to which they are attached is selected from

119. The compound of claim 118, wherein R¹⁷ is selected from hydrogen, methyl, ethyl, —

(CH₂)₂OH or —

(CH₂)₂OCH₃.

120. The compound of claim 117, wherein the optionally substituted 5 or 6 membered heteroaryl formed by two adjacent R⁴ together with the carbon atoms to which they are attached is selected from

122. The compound of claim 117, wherein the substituent on the 5 or 6 membered heteroaryl or 5 or 6 membered heterocyclyl formed by two adjacent R⁴ 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 R⁴ together with the carbon atoms to which they are attached is selected from methyl, fluoro, or oxo.

124. The compound of claim 82, wherein Z is oxygen.

125. The compound of claim 82, 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 R⁴ together with the carbon atoms to which they are attached is selected from

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, 552-557, 559-561, 566 and 629 of Table 1 or pharmaceutically acceptable salts thereof.

86. (canceled)

91-95. -95. (canceled)

98. (canceled)

102-104. -104. (canceled)

106-108. -108. (canceled)

121. (canceled)

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

128-294. -294. (canceled)

295. A compound selected from the group consisting of Compounds 1-28, 64-84, 217-240, 244, 247, 253, 256, 257, 262, 264-283, 285, 287-339, 341-391, 431, 433, 434, 438-440, 442, 446-512, 513-522, 546-549, 558, 570 575, 585, 609, 610, 627, 628, 630, 632, 633, 639, 641, 656, 666-668, 708 and 709 of Table 1.

298-301. -301. (canceled)