Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof

Patent metadata

Field	Value
Publication number	US-12018017-B2
Application number	US-202218073728-A
Country	US
Kind code	B2
Filing date	Dec 2, 2022
Priority date	May 12, 2017
Publication date	Jun 25, 2024
Grant date	Jun 25, 2024

Abstract

The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, ester, stereoisomer, tautomer, solvate, hydrate, or combination thereof:which inhibit the Apoptosis signal-regulating kinase 1 (ASK-1), which 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-alcohol steatohepatitis disease (NASH).

First claim

What is claimed:

1. A method of treating non-alcoholic fatty liver disease or non-alcoholic steatohepatitis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by Formula (I) or a pharmaceutically acceptable salt or ester thereof:

wherein;

is selected from

X 1 , X 2 and X 3 are each independently N or C(R 5 );
R 3 , R 4 and R 5 are each independently selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) —NO 2 ;
4) Cyano;
5) Optionally substituted —C 1 -C 8 alkyl;
6) Optionally substituted —C 3 -C 8 cycloalkyl;
7) Optionally substituted 3- to 8-membered heterocycloalkyl; and
8) Optionally substituted —C 1 -C 8 alkoxyl;
R is

R 1 is

R 2 is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) —NO 2 ;
4) Cyano;
5) Optionally substituted —C 1 -C 8 alkyl;
6) Optionally substituted —C 2 -C 8 alkenyl;
7) Optionally substituted —C 2 -C 8 alkynyl;
8) Optionally substituted —C 3 -C 8 cycloalkyl;
9) Optionally substituted aryl;
10) Optionally substituted arylalkyl;
11) Optionally substituted 3- to 8-membered heterocycloalkyl;
12) Optionally substituted heteroaryl;
13) Optionally substituted heteroarylalkyl;
14) —N(R 6 )(R 7 );
15) —S(O) 2 N(R 6 )(R 7 );
16) —N(R 6 )C(O)(R 7 ); and
17) —N(R 6 )S(O) 2 (R 7 ); and
R 6 and R 7 are independently selected from the group consisting of hydrogen, —C 1 -C 15 alkyl; cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1-3 substituents independently selected from halo, alkyl, alkylamino, dialkylamino, alkylC(O)NH—, arylC(O)NH—, heteroarylC(O)NH—, —CN, alkoxy, —CF 3 , aryl, and heteroaryl; alternatively, R 7 and R 6 are taken together with the nitrogen atom to which they are attached to form a heterocyclic.

2. The method of claim 1 , wherein R 1 is

3. The method of claim 1 , wherein R 2 is selected from the following:

4. The method of claim 1 , wherein R 3 is selected from the following:

wherein each group is optionally substituted.

5. The method of claim 1 , wherein the compound is represented by Formula (IVa-1), or a pharmaceutically acceptable salt or ester thereof:

wherein R 2 is selected from CH 3 , CF 3 , dimethylamino,

6. The method of claim 1 , wherein the compound is represented by Formula (IVb-1), or a pharmaceutically acceptable salt or ester thereof:

wherein R 2 is selected from CH 3 , CF 3 , dimethylamino,

7. The method of claim 1 , wherein the compound is represented by Formula (Va-1), or a pharmaceutically acceptable salt or ester thereof:

wherein R 2 is selected from CH 3 , CF 3 , dimethylamino,

8. The method of claim 1 , wherein the compound is represented by Formula (Vb-1), or a pharmaceutically acceptable salt or ester thereof:

wherein R 2 is selected from CH 3 , CF 3 , dimethylamino,

9. The method of claim 1 , wherein the compound is represented by Formula (VIa-1), or a pharmaceutically acceptable salt or ester thereof:

wherein R 2 is selected from CH 3 , CF 3 , dimethylamino,

10. The method of claim 1 , wherein the compound is represented by Formula (VIb-1), or a pharmaceutically acceptable salt or ester thereof:

wherein R 2 is selected from CH 3 , CF 3 , dimethylamino,

11. The method of claim 1 , wherein the compound is selected from the compounds set forth below or a pharmaceutically acceptable salt or ester thereof:

Compound
Structure

 5a

 6a

 7a

24a

25a

Assignees

• Enanta Pharm Inc

Inventors

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

Classifications

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title