Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
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).
1. A method of treating non-alcoholic fatty liver disease or non-alcoholic steatohepatitis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 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 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
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 ); and
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 method of claim 1 , wherein R 1 is
3. The method of claim 1 , wherein R 2 is selected from the following:
4. The method of claim 1 , wherein R 3 is selected from the following:
wherein each group is optionally substituted.
5. The method of claim 1 , wherein the compound is represented by Formula (IVa-1), or a pharmaceutically acceptable salt or ester thereof:
wherein R 2 is selected from CH 3 , CF 3 , dimethylamino,
6. The method of claim 1 , wherein the compound is represented by Formula (IVb-1), or a pharmaceutically acceptable salt or ester thereof:
wherein R 2 is selected from CH 3 , CF 3 , dimethylamino,
7. The method of claim 1 , wherein the compound is represented by Formula (Va-1), or a pharmaceutically acceptable salt or ester thereof:
wherein R 2 is selected from CH 3 , CF 3 , dimethylamino,
8. The method of claim 1 , wherein the compound is represented by Formula (Vb-1), or a pharmaceutically acceptable salt or ester thereof:
wherein R 2 is selected from CH 3 , CF 3 , dimethylamino,
9. The method of claim 1 , wherein the compound is represented by Formula (VIa-1), or a pharmaceutically acceptable salt or ester thereof:
wherein R 2 is selected from CH 3 , CF 3 , dimethylamino,
10. The method of claim 1 , wherein the compound is represented by Formula (VIb-1), or a pharmaceutically acceptable salt or ester thereof:
wherein R 2 is selected from CH 3 , CF 3 , dimethylamino,
11. The method of claim 1 , wherein the compound is selected from the compounds set forth below or a pharmaceutically acceptable salt or ester thereof:
Compound
Structure
5a
6a
7a
24a
25a
28a
30a
32a
33a
49a
51a
53a
55a
58a
61a
12. The method of claim 1 , wherein the compound has the structure
or a pharmaceutically acceptable salt thereof.
13. The method of claim 1 , wherein the compound has the structure
or a pharmaceutically acceptable salt thereof.
14. The method of claim 1 , wherein the compound has the structure
or a pharmaceutically acceptable salt thereof.