Apoptosis signal-regulating kinase inhibitors

A method of inhibiting ASK1 activity comprising administering a compound of formula (I):

• wherein:
• R1 is alkyl of 1-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-10 carbon atoms, alkynyl of 2-10 carbon atoms, aryl, heteroaryl or heterocycyl, all of which are optionally substituted with 1, 2, or 3 substituents selected from halo, oxo, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, heterocyclyl, phenyl, phenoxy, halo, —CN, —O—R6, —C(O)—R6, —OC(O)—R6—C(O)—O—R6, —N(R6)—C(O)—O—R7, —N(R6)—C(O)—R7, —N(R6)—C(O)—N(R6)(R7), and —C(O)—N(R6)(R7), wherein alkyl, cycloalkyl, heterocyclyl, phenyl, and phenoxy are optionally substituted by 1, 2, or 3 substituents selected from alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxyl, and halo;
• provided that R1 is not methyl when R3 is morpholinyl or furyl;
• wherein R6 and R7 are independently selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, or cycloalkyl of 3-8 carbon atoms;
• or
• R6 and R7 when taken together with the nitrogen to which they are attached form a heterocycle;
• R2 is hydrogen, halo, cyano, alkoxy, or alkyl optionally substituted by halo;
• R3 is aryl, heteroaryl, or heterocyclyl, all of which are optionally substituted with 1, 2 or 3 substituents selected from alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halo, haloalkoxy, oxo, —CN, —O—R6, —O—C(O)—R6, —O—C(O)—N(R6)(R7), —S—R6, —N(R6)(R7), —S(═O)—R6, —S(═O)2R6, —S(═O)2—N(R6)(R7), —S(═O)2—O—R6, —N(R6)—C(O)—R7, —N(R6)—C(O)—O—R7, —N(R6)—C(O)—N(R6)(R7), —C(O)—R6, —C(O)—O—R6, —C(O)—N(R6)(R7), and —N(R6)—S(═O)2—R7, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl or heterocyclyl is further optionally substituted with one or more substituents selected from halo, hydroxyl, oxo, —CN, and —O—R6;
• with the proviso that the heteroaryl or heterocyclyl moiety includes at least one ring nitrogen atom;
• X1, X2, X3, X4, X5, X6, X7 and X8 are independently C(R4) or N, in which each R4 is independently hydrogen, hydroxyl, halo, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, or cycloalkyl of 3-8 carbon atoms, wherein the alkyl or cycloalkyl is further optionally substituted with one or more substituents selected from halo, hydroxyl, oxo, —CF3, —O—CF3, —N(R6)(R7), —C(O)—R6, —C(O)—O—R7, —C(O)—N(R6)(R7), —CN, —O—R6;
• or
• X5 and X6 or X6 and X7 are joined to provide fused cycloalkyl, fused aryl, or fused heteroaryl, all of which are optionally substituted with alkyl of 1-6 carbon atoms, hydroxyl, or halo;
• and
• with the proviso that at least one of X2, X3, and X4 is C(R4);
• at least two of X5, X6, X7, and X8 are C(R4);
• and
• at least one of X2, X3, X4, Xe, X6, X7 and X8 is N;
• or a pharmaceutically acceptable salt thereof.