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

Patent metadata

Field	Value
Publication number	US-10968199-B2
Application number	US-201916546736-A
Country	US
Kind code	B2
Filing date	Aug 21, 2019
Priority date	Aug 22, 2018
Publication date	Apr 6, 2021
Grant date	Apr 6, 2021

Abstract

The present invention discloses compounds of Formula (I),

and pharmaceutically acceptable salts 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 compound represented by Formula I or a pharmaceutically acceptable salt thereof:

wherein
R 1 is selected from the following:

wherein R 4 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 heterocycloalkyl;
9) Optionally substituted heteroaryl; and
10) Optionally substituted heteroarylalkyl;

is selected from

wherein
X 2 and X 3 are each independently selected from N or C(R 5 ); R 5 and R 6 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; and 7) Optionally substituted 3- to 8-membered heterocycloalkyl;
X 1 is N or C(R 11 ), R 11 is hydrogen, halogen or optionally substituted alkoxy;

is selected from —C 3 -C 8 cycloalkyl and —C 4 -C 8 cycloalkenyl, each of which, is optionally substituted with one or more substituents, which are not R 3 ;
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 7 )(R 8 );
15) —S(O) 2 N(R 7 )(R 8 );
16) —N(R 7 )C(O)(R 8 ); and
17) —N(R 7 )S(O)2(R 8 );

R 3 is selected from the group consisting of:
1) —NO 2 ;
2) Cyano;
3) —N(R 7 )(R 8 );
4) —N(R 9 )C(O)N(R 7 )(R 8 );
5) —N(R 7 )C(O)(R 8 );
6) —N(R 7 )C(O) 2 (R 8 );
7) —N(R 9 )S(O) 2 N(R 7 )(R 8 );
8) —N(R 7 )S(O) 2 (R 8 );
9) —C(O) 2 (R 7 );
10) —C(O)N(R 7 )(R 8 );
11) —C(O)N(R 7 )S(O) 2 (R 8 );
12) —CH 2 (O)C(O) 2 (R 7 );
13) —CH 2 (O)C(O)N(R 7 )(R 8 );
14) Optionally substituted —C 1 -C 8 alkyl;
15) Optionally substituted —C 2 -C 8 alkenyl;
16) Optionally substituted —C 2 -C 8 alkynyl;
17) Optionally substituted —C 3 -C 8 cycloalkyl;
18) Optionally substituted aryl;
19) Optionally substituted arylalkyl;
20) Optionally substituted 3- to 8-membered heterocycloalkyl;
21) Optionally substituted heteroaryl; and
22) Optionally substituted heteroarylalkyl;
wherein R 7 , R 8 , and R 9 are independently selected from the group consisting of hydrogen, —C 1 -C 8 alkyl, —C 3 -C 8 cycloalkyl, 3- to 8-membered heterocycloalkyl, aryl, and heteroaryl, all of which are optionally substituted with 1-3 substituents selected from halo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide, —CN, alkoxy, —CF 3 , aryl, and heteroaryl;

alternatively, R 7 and R 8 are taken together with the nitrogen atom to which they are attached to form a heterocyclic.

2. The compound of claim 1 , wherein

s selected from the following:

wherein each of the above shown groups is optionally substituted.

3. The compound of claim 1 , which is represented by Formula (VIIa), (VIIb), or (VIIc), or a pharmaceutically acceptable salt thereof:

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

4. The compound of claim 1 , which is represented by Formula (IIa) or (IIb), or a pharmaceutically acceptable salt thereof:

wherein R 3 , R 4 ,

and X 1 are as defined in claim 1 .

5. The compound of claim 1 , which is represented by Formula (VIIIa) or (VIIIb), or a pharmaceutically acceptable salt thereof:

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

6. The compound of claim 1 , which represented by Formula (IIIa), (IIIb), (IVa), (IVb), (Va), or (Vb) or a pharmaceutically acceptable salt thereof:

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

7. The compound of claim 1 , which is selected from compounds of Formula (IIIa) or a pharmaceutically acceptable salt thereof:

wherein R 3 and R 4 are delineated for each compound in Table 1,

TABLE 1

com-

pound
R 3
R 4

1

2

3

Assignees

• Enanta Pharm Inc

Inventors

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

Classifications

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title