Anti-fibrotic pyridinones

• US 10,376,497 B2
• Filed: 04/20/2017
• Issued: 08/13/2019
• 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.
• Primary Examiner(s): Rahmani, Niloofar
• Application Number:
  US15/492,828
• Publication Number:
  US 20180064692A1
• Time in Patent Office: 845 Days
• Field of Search: 546255
• 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 pyrazolyl or 1-methyl pyrazolyl optionally substituted with one or more R⁴.

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

5. The compound of claim 4, wherein R⁴ is methyl.

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

CN.

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

OR⁵.

8. The compound of claim 7, 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.

9. The compound of claim 8, wherein R⁵ is optionally substituted C_1-6 alkyl.

10. The compound of claim 8, wherein R⁵ is C_6-10 aryl optionally substituted with one or more R¹¹.

11. The compound of claim 8, wherein R⁵ is C_7-14 aralkyl optionally substituted with one or more R¹¹.

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

13. The compound of claim 12, wherein R⁵ is selected from —

(CH₂)₂OCH₃, —

(CH₂)₂OC₃H₇ or —

(CH₂)₂O(CH₂)OCH₃.

14. The compound of claim 8, wherein R⁵ is —

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

15. The compound of claim 14, wherein R⁵ is selected from

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

NR⁶R⁷.

17. The compound of claim 16, 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.

18. The compound of claim 17, wherein R⁶ is hydrogen or C_1-6 alkyl.

19. The compound of claim 17, wherein R⁷ is C_1-6 alkyl.

20. The compound of claim 17, wherein R⁷ is C_6-10 aryl optionally substituted with one or more R¹¹.

21. The compound of claim 18, wherein R⁷ is C_7-14 aralkyl optionally substituted with one or more R¹¹.

22. The compound of claim 21, wherein R⁷ is benzyl or —

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

23. The compound of claim 21, wherein R⁷ is unsubstituted benzyl or unsubstituted —

(CH₂)₂Ph.

24. The compound of claim 18, wherein R⁷ is (6 membered heteroaryl)alkyl optionally substituted with one or more R¹¹.

25. The compound of claim 16, 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.

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

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

28. 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.

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

30. The compound of claim 29, wherein R⁹ is selected from hydroxy, halogen, optionally substituted C_1-6 alkyl, —

OR⁵, or —

NR¹⁴R¹⁵.

31. The compound of claim 30, wherein R⁵ is selected from hydrogen, C_1-6 alkyl, halo substituted C_1-6 alkyl, or C_2-8 alkoxyalkyl.

32. The compound of claim 29, wherein R³ is unsubstituted.

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

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

35. The compound of claim 1, wherein the compound is selected from the group consisting of Compounds 120-162, 402-414, 523-535, 537-540, 542-545, 550, 664 and 696-707:

37. 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.

36. 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: