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

Patent metadata

Field	Value
Publication number	US-11008304-B2
Application number	US-201916400529-A
Country	US
Kind code	B2
Filing date	May 1, 2019
Priority date	May 2, 2018
Publication date	May 18, 2021
Grant date	May 18, 2021

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

We claim:

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

wherein

is selected from the groups below

is

is

R 1 is selected from the group consisting of:
1) Hydrogen;
2) Optionally substituted —C 1 -C 8 alkyl;
3) Optionally substituted —C 2 -C 8 alkenyl;
4) Optionally substituted —C 2 -C 8 alkynyl;
5) Optionally substituted —C 3 -C 8 cycloalkyl;
6) Optionally substituted aryl;
7) Optionally substituted arylalkyl;
8) Optionally substituted 3- to 8-membered heterocycloalkyl;
9) Optionally substituted heteroaryl; and
10) Optionally substituted heteroarylalkyl;

R 2 is

X is N or C—R 3 ;
R 3 is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) Optionally substituted —C 1 -C 8 alkyl; and
4) Optionally substituted —C 1 -C 8 alkoxyl;

R 4 is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) Optionally substituted —C 1 -C 8 alkyl;
4) Optionally substituted —C 2 -C 8 alkenyl;
5) Optionally substituted —C 2 -C 8 alkynyl;
6) Optionally substituted —C 3 -C 8 cycloalkyl;
7) Optionally substituted aryl;
8) Optionally substituted arylalkyl;
9) Optionally substituted 3- to 8-membered heterocycloalkyl;
10) Optionally substituted heteroaryl;
11) Optionally substituted heteroarylalkyl; and
12) —N(R 5 )(R 6 );

wherein R 5 and R 6 are independently selected from the group consisting of hydrogen, —C 1 -C 8 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the —C 1 -C 8 alkyl, cycloalkyl, heterocycloalkyl, aryl, or 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 5 and R 6 are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic.

2. The compound of claim 1 , represented by one of Formulas (II-a), (II-c), (II-e), and (II-g), or a pharmaceutically acceptable salt thereof:

wherein

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

3. The compound of claim 1 , represented by one of Formulas (III-a) ˜(III-n), or a pharmaceutically acceptable salt thereof:

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

4. The compound of claim 1 , represented by one of Formulas (IV-a) ˜(IV-n), or a pharmaceutically acceptable salt thereof:

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

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

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

Com-

Com-

pound
Structure
pound
Structure

13

16

22

25

28

29

32

35

41

43

45

47

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

• C07D407/14

  containing three or more hetero rings · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P13/12

  of the kidneys · CPC title