Tetrazole containing apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
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 is 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 (NASH).
1. A compound represented by Formula I or a pharmaceutically acceptable salt or ester thereof:
wherein
is selected from the groups below
is
is
R 1 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 3- to 8-membered heterocycloalkyl;
9) Optionally substituted heteroaryl; and
10) Optionally substituted heteroarylalkyl;
R 2 is
X is N or C—R 3 ;
R 3 is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) Optionally substituted —C 1 -C 8 alkyl; and
4) Optionally substituted —C 1 -C 8 alkoxyl;
R 4 is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) Optionally substituted —C 1 -C 8 alkyl;
4) Optionally substituted —C 2 -C 8 alkenyl;
5) Optionally substituted —C 2 -C 8 alkynyl;
6) Optionally substituted —C 3 -C 8 cycloalkyl;
7) Optionally substituted aryl;
8) Optionally substituted arylalkyl;
9) Optionally substituted 3- to 8-membered heterocycloalkyl;
10) Optionally substituted heteroaryl;
11) Optionally substituted heteroarylalkyl; and
12) —N(R 5 )(R 6 );
wherein R 5 and R 6 are independently selected from the group consisting of hydrogen, —C 1 -C 8 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the —C 1 -C 8 alkyl, cycloalkyl, heterocycloalkyl, aryl, or 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 5 and R 6 are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic.
2. The compound of claim 1 , represented by one of Formulas (II-a), (II-c), (II-e), and (II-g), or a pharmaceutically acceptable salt thereof:
wherein
R 2 and R 4 are as defined in claim 1 .
3. The compound of claim 1 , represented by one of Formulas (III-a) ˜(III-n), or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 and R 4 are as defined in claim 1 .
4. The compound of claim 1 , represented by one of Formulas (IV-a) ˜(IV-n), or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 and R 4 are as defined in claim 1 .
5. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
6. The compound of claim 1 , selected from the compounds set forth below or a pharmaceutically acceptable salt thereof:
Com-
Com-
pound
Structure
pound
Structure
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16
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25
28
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35
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54
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