Anti-fibrotic pyridinones

• US 10,233,195 B2
• Filed: 03/31/2015
• Issued: 03/19/2019
• Est. Priority Date: 04/02/2014
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Intermune Incorporated (Roche Holding AG)
• Inventors: Ramphal, Johnnie Y., Buckman, Brad Owen, Emayan, Kumaraswamy, Nicholas, John Beamond, Seiwert, Scott D.
• Primary Examiner(s): Rahmani, Niloofar
• Application Number:
  US15/128,061
• Publication Number:
  US 20170121345A1
• Time in Patent Office: 1,449 Days
• Field of Search: 514300
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 225/20 having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 25/18 Polycyclic aromatic halogenated hydrocarbons
• CPC Class Codes: C07D 209/34 in position 2
• CPC Class Codes: C07D 211/76 attached in position 2 or 6
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 213/69 Two or more oxygen atoms
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 221/04 Ortho- or peri-condensed ring systems
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/02 containing two 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 413/02 : containing two hetero rings
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : 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 (III):

2. The compound of claim 1, wherein

R³ is selected from the group consisting of C_6-10 aryl, 5-10 membered heteroaryl, C_3-10 carbocyclyl, and 3-10 membered heterocyclyl, each optionally substituted with one or more R⁹.

3. The compound of claim 1, wherein R¹ is selected from C_6-10 aryl optionally substituted with one or more R⁴, or 5 to 9 membered heteroaryl optionally substituted with one or more R⁴.

4. The compound of claim 2, wherein at least one of the hydrogen atoms of R¹ is deuterium.

5. The compound of claim 2, wherein R¹ is 5 to 6 membered heteroaryl optionally substituted with one or more R⁴.

6. The compound of claim 5, wherein R¹ is pyridazinyl optionally substituted with one or more R⁴.

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

8. The compound of claim 7, wherein R¹ is 1-CD₃ pyrazolyl.

9. The compound of claim 1, wherein R³ is hydrogen.

10. The compound of claim 1, wherein R³ is selected from C_6-10 aryl optionally substituted with one or more R⁹.

11. The compound of claim 10, wherein R³ is phenyl, optionally substituted with one or more R⁹.

12. The compound of claim 10, wherein R³ is unsubstituted.

13. The compound of claim 10, wherein R⁹ is selected from cyano, halogen, optionally substituted C_1-6 alkyl, or optionally substituted C_1-6 alkoxy.

14. The compound of claim 13, wherein R⁹ is selected from cyano, fluoro, chloro, methyl, ethyl, ethoxy, methoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy.

15. The compound of claim 10, wherein two adjacent R⁹ together with the carbon atoms to which they are attached to form an optionally substituted fused 5 to 6 membered heteroaryl.

16. The compound of claim 15, wherein the 5 to 6 membered heteroaryl is selected from imidazolyl or oxazolyl.

17. The compound of claim 1, wherein ring A is selected from 5-membered heteroaryl or 6-membered heteroaryl, each optionally substituted with one or more R⁴.

18. The compound of claim 1, wherein at least one hydrogen atom of ring A is deuterium.

19. The compound of claim 17, wherein ring A is selected from

20. The compound of claim 19, wherein ring A is selected from

21. The compound of claim 18, wherein ring A is selected from

22. The compound of claim 19, wherein R¹⁷ is selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, —

(CH₂)₂F, —

(CH₂)₂OH, —

(CH₂)₂OCH₃, —

(CH₂)₂OC₂H₅, —

(CH₂)₂OC₃H₇, —

C(O)O-t-Bu, —

C(O)CH₃ or benzyl, and wherein one of the hydrogen is deuterium.

23. The compound of claim 18, wherein ring A is selected from

24. The compound of claim 1, wherein R⁴ is selected from halogen, optionally substituted C_1-6 alkyl, or C_7-14 aralkyl optionally substituted with one or more R¹¹, or two geminal R⁴ together are oxo.

25. The compound of claim 24, wherein R⁴ is selected from fluoro, methyl, trifluoromethyl, —

(CH₂)₂OH, benzyl, or two geminal R⁴ together are oxo.

26. The compound of claim 17, wherein ring A is unsubstituted.

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

28. The compound of claim 1, wherein the bonds represented by a solid and dashed line are double bonds, provided that when ring A is

29. The compound of claim 1, wherein the compound is selected from Compound 724 of Table 1, or a pharmaceutically acceptable salt thereof.

30. 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.

31. 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.