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

A compound represented by Formula I or a pharmaceutically acceptable salt or ester thereof:

• wherein
• is optionally substituted aryl or optionally substituted heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S;
• provided that
• is not
• is
• is
• R1 and R2 are each independently selected from the group consisting of:
• 1) Hydrogen;
• 2) Optionally substituted —C1-C8 alkyl;
• 3) Optionally substituted —C2-C8 alkenyl;
• 4) Optionally substituted —C2-C8 alkynyl;
• 5) Optionally substituted —C3-C8 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;
• X is N or C—R3;
• R3 is selected from the group consisting of:
• 1) Hydrogen;
• 2) Halogen;
• 3) Optionally substituted —C1-C8 alkyl;
• and
• 4) Optionally substituted —C1-C8 alkoxyl;
• R4 is selected from the group consisting of:
• 1) Hydrogen;
• 2) Halogen;
• 3) Optionally substituted —C1-C8 alkyl;
• 4) Optionally substituted —C2-C8 alkenyl;
• 5) Optionally substituted —C2-C8 alkynyl;
• 6) Optionally substituted —C3-C8 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(R5)(R6);
• wherein R5 and R6 are independently selected from the group consisting of hydrogen, —C1-C8 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein the —C1-C8 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, —CF3, aryl, and heteroaryl;
• alternatively, R5 and R6 are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic.