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

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

• wherein;
• X1 and X2 are independently C(R8) or N;
• X3 is C(R9) or N, in which R9 is selected from the group consisting of hydrogen, optionally substituted —C1-C8 alkyl, optionally substituted —C1-C8 alkoxy or halo;
• X4 is S, O, or N(R10);
• R1 is selected from
• wherein R4 is selected from the group consisting of:
• 1) Hydrogen;
• 2) Substituted or unsubstituted —C1-C8 alkyl;
• 3) Substituted or unsubstituted —C2-C8 alkenyl;
• 4) Substituted or unsubstituted —C2-C8 alkynyl;
• 5) Substituted or unsubstituted —C3-C8 cycloalkyl;
• 6) Substituted or unsubstituted aryl;
• 7) Substituted or unsubstituted arylalkyl;
• 8) Substituted or unsubstituted 3- to 8-membered heterocycloalkyl;
• 9) Substituted or unsubstituted heteroaryl;
• and
• 10) Substituted or unsubstituted heteroarylalkyl;
• R2, R3, R5 and R8 are each independently selected from the group consisting of:
• 1) Hydrogen;
• 2) Halogen;
• 3) —NO2;
• 4) Cyano;
• 5) Substituted or unsubstituted —C1-C8 alkyl;
• 6) Substituted or unsubstituted —C2-C8 alkenyl;
• 7) Substituted or unsubstituted —C2-C8 alkynyl;
• 8) Substituted or unsubstituted —C3-C8 cycloalkyl;
• 9) Substituted or unsubstituted aryl;
• 10) Substituted or unsubstituted arylalkyl;
• 11) Substituted or unsubstituted 3- to 8-membered heterocycloalkyl;
• 12) Substituted or unsubstituted 3- to 8-membered heterocycloalkyl-alkyl;
• 13) Substituted or unsubstituted heteroaryl;
• 14) Substituted or unsubstituted heteroarylalkyl;
• 15) —N(R6)(R7);
• 16) —S(O)2N(R6)(R7);
• 17) —N(R6) C(O)R7;
• 18) —N(R6) S(O)2R6;
• and
• 9) —OR6;
• R6 and R7 are independently selected from the group consisting of hydrogen, —C1-C8 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each —C1-C8 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with 1-3 substituents independently selected from halo, alkyl, cycloalkyl, alkylamino, dialkylamino, alkylC(O)NH—, arylC(O)NH—, heteroarylC(O)NH—, —CN, alkoxy, —CF3, aryl, and heteroaryl;
• alternatively, R6 and R7 are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocycloalkyl group;
• and
• R10 is selected from the group consisting of hydrogen, —C1-C8 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each —C1-C8 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with 1-3 substituents independently selected from halo, alkyl, cycloalkyl, alkylamino, dialkylamino, alkylC(O)NH—, arylC(O)NH—, heteroarylC(O)NH—, —CN, alkoxy, —CF3, aryl, and heteroaryl.