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

Patent metadata

Field	Value
Publication number	US-10683289-B2
Application number	US-201916400498-A
Country	US
Kind code	B2
Filing date	May 1, 2019
Priority date	May 2, 2018
Publication date	Jun 16, 2020
Grant date	Jun 16, 2020

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 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 disease (NASH).

First claim

What is claimed is:

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

wherein R 1 is selected from

X 1 and X 2 are each independently C(R 8 ) or N;
X 3 is C(R 9 ) or N;
R 9 is selected from the group consisting of hydrogen, optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 1 -C 8 alkoxy and halogen;
X 4 is S, S(O), or SO 2 ;
R 4 is selected from the group consisting of:
1) Hydrogen;
2) Substituted or unsubstituted —C 1 -C 8 alkyl;
3) Substituted or unsubstituted —C 2 -C 8 alkenyl;
4) Substituted or unsubstituted —C 2 -C 8 alkynyl;
5) Substituted or unsubstituted —C 3 -C 8 cycloalkyl;
6) Substituted or unsubstituted aryl;
7) Substituted or unsubstituted arylalkyl;
8) Substituted or unsubstituted 3- to 8-membered heterocycloalkyl;
9) Substituted or unsubstituted heteroaryl; and
10) Substituted or unsubstituted heteroarylalkyl;

R 2 , R 5 and R 8 are each independently selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) —NO 2 ;
4) Cyano;
5) Substituted or unsubstituted —C 1 -C 8 alkyl;
6) Substituted or unsubstituted —C 2 -C 8 alkenyl;
7) Substituted or unsubstituted —C 2 -C 8 alkynyl;
8) Substituted or unsubstituted —C 3 -C 8 cycloalkyl;
9) Substituted or unsubstituted aryl;
10) Substituted or unsubstituted arylalkyl;
11) Substituted or unsubstituted 3- to 8-membered heterocycloalkyl;
12) Substituted or unsubstituted heteroaryl;
13) Substituted or unsubstituted 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 6 ;
wherein R 6 and R 7 are independently selected from the group consisting of hydrogen, —C 1 -C 8 alkyl, —C 1 -C 8 alkenyl, —C 1 -C 8 alkynyl, —C 3 -C 8 cycloalkyl, aryl, heterocycloalkyl, heteroaryl, and heteroarylalkyl, all of which are optionally substituted with 1-3 substituents selected from halo, alkyl, alkylamino, dialkylamino, alkylC(O)NH—, arylC(O)NH—, heteroarylC(O)NH—, —CN, alkoxy, —CF 3 , aryl, and heteroaryl;

alternatively, R 6 and R 7 are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic;
R 3 is selected from the group consisting of:
1) Substituted or unsubstituted —C 1 -C 8 alkyl;
2) Substituted or unsubstituted —C 2 -C 8 alkenyl;
3) Substituted or unsubstituted —C 2 -C 8 alkynyl;
4) Substituted or unsubstituted —C 3 -C 8 cycloalkyl;
5) Substituted or unsubstituted aryl;
6) Substituted or unsubstituted arylalkyl;
7) Substituted or unsubstituted 3- to 8-membered heterocycloalkyl;
8) Substituted or unsubstituted heteroaryl;
9) Substituted or unsubstituted heteroarylalkyl;
10) —C(O)R 6 ;
11) —C(O)OR 6 ;
12) —C(O)N(R 6 )(R′);
13) —SO 2 R 6 ; and
14) hydrogen
R 10 and R 11 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted —C 1 -C 8 alkyl; alternatively, R 10 and R 11 are taken together with the carbon to which they are attached to form an optionally substituted cycloalkyl, cycloalkenyl or heterocyclic; and n is 0, 1 or 2.

2. The compound of claim 1 , wherein R 3 is one of the following groups,

wherein each group is optionally substituted.

3. The compound of claim 1 , wherein R 4 is one of the following groups,

wherein each group is optionally substituted.

4. The compound of claim 1 , represented by Formula Ib or a pharmaceutically acceptable salt thereof:

wherein R 1 , R 2 , R 3 , R 10 , R 11 , X 1 , X 2 , X 3 and n are as defined in claim 1 .

5. The compound of claim 1 , represented by Formula II or a pharmaceutically acceptable salt thereof:

wherein R 1 , R 2 , R 3 , R 10 , R 11 , X 2 , X 3 , X 4 and n are as defined in claim 1 .

6. The compound of claim 1 represented by Formula III or a pharmaceutically acceptable salt thereof:

wherein R 1 , R 2 , R 3 , R 10 , R, X 3 , X 4 and n are as defined in claim 1 .

7. The compound of claim 1 represented by Formula IV or a pharmaceutically acceptable salt thereof:

wherein R 1 , R 3 , R 10 , R 11 , X 3 , X 4 and n are as defined in claim 1 .

8. The compound of claim 1 represented by Formula V or Formula XIII, or a pharmaceutically acceptable salt thereof:

wherein R 3 , R 4 , R 5 , R 10 , R 11 , X 3 , X 4 and n are as defined in claim 1 .

9. The compound of claim 1 represented by Formula VII, Formula X, Formula XIV, or Formula XVII, or a pharmaceutically acceptable salt thereof:

wherein R 3 , R 10 , R 11 , X 3 , X 4 and n are as defined in claim 1 .

10. The compound of claim 1 represented by Formula VIII, or Formula XI, Formula XV, or Formula XVIII, or a pharmaceutically acceptable salt thereof:

wherein R 3 , X 3 , X 4 and n are as defined in claim 1 .

11. The compound of claim 1 , which is selected from compounds of Formula IX, or a pharmaceutically acceptable salt thereof:

wherein R 3 , X 3 , and n are delineated for each compound in Table 1:

TABLE 1

compound
R 3
X 3
n

1
H
C—H
0

2
Methyl
C—H
0

3
Ethyl
C—H
0

4
Propyl
C—H
0

5
Allyl
C—H
0

6
i-Propyl
C—H
0

7

Assignees

• Enanta Pharm Inc

Inventors

• Granger Brett
• Wang Guoqiang
• Shen Ruichao
• He Jing
• Or Yat Sun

Classifications

• C07D417/14 Primary

  containing three or more hetero rings · CPC title