Apoptosis signal-regulating kinase 1 inhibitors

摘要

The present invention relates to apoptosis signal-regulating kinase 1 (“ASK1”) inhibiting compounds of the formula;
wherein the variables are as defined herein. The invention also relates to pharmaceutical compositions, kits and articles of manufacture comprising such compounds; methods and intermediates useful for making the compounds; and methods of using said compounds.

主权项

1. A compound of the formula:a stereoisomer thereof or a pharmaceutically acceptable salt of the compound or stereoisomer, wherein
m is 0, 1, or 2; R0 is selected from the group consisting ofin which * represents a point of attachment;
each R is independently selected from the group consisting of hydroxy, nitro, halo, cyano, hetero(C1-5)aryloxy, (C1-6)alkyl, amino(C1-6)alkyl, and halo(C1-6)alkyl, each unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halo, (C1-6)alkoxy, halo(C1-6)alkoxy, amino, (C1-6)alkyl, hydroxy(C1-6)alkyl, halo(C1-6)alkyl, perhalo(C1-6)alkyl, amino(C1-6)alkyl, hydroxy(C1-6)alkoxy, halo(C1-6)alkoxy, perhalo(C1-6)alkoxy, R9-carbonyl(C1-6)alkyl, R9-sulfonyl(C1-6)alkyl, R9-carbonyl, and R9-sulfonyl; R1 is selected from the group consisting of cyano, (C1-6)alkyl, (C2-6)alkenyl, (C3-6)cycloalkyl, and sulfonyl, each unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of hydroxy, halo, cyano, amino, carbonylamino, sulfonylamino, (C3-6)cycloalkyl, oxycarbonyl, hydroxycarbonyl, aminocarbonyl, sulfonyl, aminosulfonyl, wherein the amino, carbonylamino, sulfonylamino, oxycarbonyl, aminocarbonyl, sulfonyl, and aminosulfonyl are each unsubstituted or further substituted with 1-2 substituents independently selected from the group consisting of (C1-6)alkyl, halo(C1-6)alkyl, perhalo(C1-6)alkyl, and (C3-6)cycloalkyl; R2 is selected from the group consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C1-6)alkoxy, carbonyl, oxycarbonyl, aminocarbonyl, sulfonyl, sulfinyl, (C1-6)alkyl, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, carbonyl(C1-6)alkyl, thiocarbonyl(C1-6)alkyl, sulfonyl(C1-6)alkyl, and sulfinyl(C1-6)alkyl, each unsubstituted or substituted with 1-3 substituents each of which is independently selected from the group consisting of hydroxy, unsubstituted amino, mono-substituted amino, di-substituted amino, (C1-6)alkyl, and halo(C1-6)alkyl; R3 is selected from the group consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C1-6)alkoxy, carbonyl, oxycarbonyl, aminocarbonyl, sulfonyl, sulfinyl, (C1-6)alkyl, halo(C1-6)alkyl, hydroxy(C1-6)alkyl, carbonyl(C1-6)alkyl, thiocarbonyl(C1-6)alkyl, sulfonyl(C1-6)alkyl, and sulfinyl(C1-6)alkyl, each unsubstituted or substituted with 1-3 substituents each of which is independently selected from the group consisting of hydroxy, halo, (C1-6)alkyl, halo(C1-6)alkyl, and perhalo(C1-6)alkyl; R4 is selected from the group consisting of hydroxy, unsubstituted amino, (C1-6)alkylamino, (di-(C1-6)alkyl)amino, (C1-6)alkoxy, and (C1-6)alkyl; R8 is —(CR23R23′)pOH; R9 is selected from the group consisting of hydroxy, unsubstituted amino, (C1-6)alkylamino, (di-(C1-6)alkyl)amino, (C1-6)alkoxy, and (C1-6)alkyl; R10 is selected from the group consisting of hydroxy, unsubstituted amino, (C1-6)alkylamino, (di-(C1-6)alkyl)amino, (C1-6)alkoxy, and (C1-6)alkyl; R21 is selected from the group consisting of —C(R23)3, —(CR23R23′)p—C(R23)3, —(CR23R23′)pOH, —(CR23R23′)pC(O)R10, —(CR23R23′)pS(O)2R10, and —O(CR23R23)pOH, R22 is selected from the group consisting of hydrogen, (C1-6)alkyl, hydroxy(C1-6)alkyl and halo(C1-6)alkyl; R23 and R23′ are each independently selected from the group consisting of hydrogen, halo, hydroxy, and (C1-6)alkyl; k is 1, 2, 3, or 4; p is 1, 2, 3, or 4; and q is 1, 2, 3 or 4.