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

Patent metadata

Field	Value
Publication number	US-10988458-B2
Application number	US-202016866778-A
Country	US
Kind code	B2
Filing date	May 5, 2020
Priority date	May 12, 2017
Publication date	Apr 27, 2021
Grant date	Apr 27, 2021

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 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 selected from 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 selected from the group consisting of

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 );
wherein 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 compound of claim 1 , wherein R 1 is

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

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

wherein each group is optionally substituted.

5. The compound of claim 1 , which is represented by Formula (Ia), (Ib), (Ic), or (Id), or a pharmaceutically acceptable salt or ester thereof:

wherein

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

6. The compound of claim 1 , which is represented by one of Formulae (IIa-1) to (IIa-4) or (IIb-1) to (IIb-4), or a pharmaceutically acceptable salt or ester thereof:

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

7. The compound of claim 1 , which is selected from compounds of Formula (IVa-1), (IVa-2), (IVa-3), or (IVa-4), or a pharmaceutically acceptable salt or ester thereof:

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

8. The compound of claim 1 , which is selected from compounds of Formula (IVb-1), (IVb-2), (IVb-3), or (IVb-4), or a pharmaceutically acceptable salt or ester thereof:

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

9. The compound of claim 1 , which is selected from compounds of Formula (Va-1), (Va-2), (Va-3), or (Va-4), or a pharmaceutically acceptable salt or ester thereof:

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

10. The compound of claim 1 , which is selected from compounds of Formula (Vb-1), (Vb-2), (Vb-3), or (Vb-4), or a pharmaceutically acceptable salt or ester thereof:

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

11. The compound of claim 1 , which is selected from compounds of Formula (VIa-1), (VIa-2), (VIa-3), or (VIa-4), or a pharmaceutically acceptable salt thereof:

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

12. The compound of claim 1 , which is selected from compounds of Formula (VIb-1), (VIb-2), (VIb-3), or (VIb-4), or a pharmaceutically acceptable salt or ester thereof:

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

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

14. A method for treating an ASK-1 mediated disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of one or more compounds of Formula (I) according to claim 1 .

15. The method according to claim 14 , wherein the ASK-1 mediated disease or condition is selected from the group consisting of an autoimmune disorder, a neurodegenerative disorder, an inflammatory disease, chronic kidney disease, renal disease, cardiovascular disease, a metabolic disease, or an acute or chronic liver disease.

16. The method according to claim 15 , wherein the ASK-1 mediated disease or condition is a chronic liver disease selected from the group consisting of primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primar

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

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title