Tetrazole containing apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof

Patent metadata

Field	Value
Publication number	US-12459923-B2
Application number	US-202318383949-A
Country	US
Kind code	B2
Filing date	Oct 26, 2023
Priority date	May 2, 2018
Publication date	Nov 4, 2025
Grant date	Nov 4, 2025

Abstract

The present invention discloses compounds of Formula (I), and pharmaceutically acceptable salts and esters thereof:

which inhibit the Apoptosis signal-regulating kinase 1 (ASK-1), which is associated with autoimmune disorders, neurodegenerative disorders, inflammatory diseases, chronic kidney disease, cardiovascular disease. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from ASK-1 related disease. The invention also relates to methods of treating an ASK-1 related disease in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The present invention specifically relates to methods of treating ASK-1 associated with hepatic steatosis, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

First claim

The invention claimed is:

1 . A compound represented by Formula I or a pharmaceutically acceptable salt or ester thereof:

wherein

R 1 is trifluoromethyl, isopropyl, cyclopropyl or t-butyl;

R 2 is
X is N or C-R 3 ;
R 3 is fluorine or methoxy; and
R 4 is methyl, difluoromethyl or trifluoromethyl.

2 . The compound of claim 1 , represented by Formula (II-a) or Formula (II-e), or a pharmaceutically acceptable salt thereof:

wherein

R 2 and R 4 are as defined in claim 1 .

3 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

4 . A method for the treatment of an ASK-1 mediated disease or condition selected from the group consisting of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, diabetic nephropathy, myocardial ischemia, and glomerulonephritis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds of claim 1 .

5 . The compound of claim 1 , selected from the compounds set forth below or a pharmaceutically acceptable salt thereof:

Compound
Structure

13

16

22

28

29

32

48

50

52

54

57

77

6 . The compound of claim 5 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

7 . The compound of claim 5 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

8 . The method of claim 4 , wherein the ASK-1 mediated disease or condition is nonalcoholic fatty liver disease.

9 . The method of claim 4 , wherein the ASK-1 mediated disease or condition is nonalcoholic steatohepatitis.

10 . The method of claim 4 , wherein the ASK-1 mediated disease or condition is diabetic nephropathy.

11 . The method of claim 4 , wherein the ASK-1 mediated disease or condition is myocardial ischemia.

12 . The method of claim 4 , wherein the ASK-1 mediated disease or condition is glomerulonephritis.

Assignees

• Enanta Pharm Inc

Inventors

• Wang Guoqiang
• Shen Ruichao
• Granger Brett
• He Jing
• Xing Xuechao
• He Yong
• Long Jiang
• Ma Jun
• Wang Bin
• Or Yat Sun

Classifications

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• A61P13/12

  of the kidneys · CPC title