Anti-fibrotic pyridinones

• US 10,544,161 B2
• Filed: 01/16/2019
• Issued: 01/28/2020
• 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:
  US16/249,024
• Publication Number:
  US 20190144467A1
• Time in Patent Office: 377 Days
• Field of Search: 514300, 546119
• 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 or 5-10 membered heteroaryl.

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 3, wherein R¹ is phenyl optionally substituted with one or more R⁴.

5. The compound of claim 3, wherein R¹ is 9 membered heteroaryl optionally substituted with one or more R⁴.

6. The compound of claim 5, wherein R¹ is imidazo[1,2-a]pyridin-yl.

7. The compound of claim 3, wherein R¹ is selected from pyridyl or pyridazinyl optionally substituted with one or more R⁴.

8. The compound of claim 3, wherein R¹ is pyrazolyl or 1-methyl pyrazolyl optionally substituted with one or more R⁴.

9. The compound of claim 4, wherein R³ is phenyl 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.

10. The compound of claim 9, wherein the 5 to 6 membered heteroaryl is selected from imidazolyl or oxazolyl.

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

12. The compound of claim 11, wherein ring A is selected from:

13. The compound of claim 12, wherein ring A is selected from:

14. The compound of claim 12, 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.

15. 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.

16. The compound of claim 15, wherein R⁴ is selected from fluoro, methyl, trifluoromethyl, —

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

17. The compound of claim 12, wherein ring A is unsubstituted.

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

19. The compound of claim 1, wherein the compound is selected from the group consisting of Compounds 727, 728, 733, 734, 737 and 738 of Table 1.

20. 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.