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

Patent metadata

Field	Value
Publication number	US-10246439-B2
Application number	US-201815988783-A
Country	US
Kind code	B2
Filing date	May 24, 2018
Priority date	May 25, 2017
Publication date	Apr 2, 2019
Grant date	Apr 2, 2019

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-alcohol steatohepatitis disease (NASH).

First claim

What is claimed is:

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

wherein;
X 1 and X 2 are independently C(R 8 ) or N;
X 3 is C(R 9 ) or N, in which R 9 is selected from the group consisting of hydrogen, optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 1 -C 8 alkoxy or halo;
X 4 is S, O, or N(R 10 );
R 1 is selected from

wherein 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 3 , 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 3- to 8-membered heterocycloalkyl-alkyl;
13) Substituted or unsubstituted heteroaryl;
14) Substituted or unsubstituted heteroarylalkyl;
15) —N(R 6 )(R 7 );
16) —S(O) 2 N(R 6 )(R 7 );
17) —N(R 6 ) C(O)R 7 ;
18) —N(R 6 ) S(O) 2 R 6 ; and
9) —OR 6 ;
R 6 and R 7 are independently selected from the group consisting of hydrogen, —C 1 -C 8 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each —C 1 -C 8 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with 1-3 substituents independently selected from halo, alkyl, cycloalkyl, 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 heterocycloalkyl group; and
R 10 is selected from the group consisting of hydrogen, —C 1 -C 8 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each —C 1 -C 8 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with 1-3 substituents independently selected from halo, alkyl, cycloalkyl, alkylamino, dialkylamino, alkylC(O)NH—, arylC(O)NH—, heteroarylC(O)NH—, —CN, alkoxy, —CF 3 , aryl, and heteroaryl.

2. The compound of claim 1 , represented by one of Formula IIa˜Formula IIh or a pharmaceutically acceptable salt thereof:

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

3. The compound of claim 1 , represented by one of Formula IIIa˜Formula IIId or a pharmaceutically acceptable salt thereof:

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

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

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

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

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

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

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

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

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

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

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

TABLE 1

Compound
R 3
X 3

 1
H
C—H

 2
Methyl
C—H

 3
—CF 3
C—H

 4
Ethyl
C—H

 5
Propyl
C—H

 6
Allyl
C—H

 7
i-Propyl
C—H

 8
Butyl
C—H

 9
t-Butyl
C—H

 10
Benzyl
C—H

 11

C—H

 12

C—H

 13

C—H

 14

C—H

 15

Assignees

• Enanta Pharm Inc

Inventors

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

Classifications

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• C07D451/02

  containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D491/08

  Bridged systems · CPC title