CINNAMIC ACID HYDROXYAMIDES AS INHIBITORS OF HISTONE DEACETYLASE 8

摘要

Described herein are compounds and pharmaceutical compositions containing such compounds, which inhibit the activity of histone deacetylase 8 (HDAC8). Also described herein are methods of using such HDAC8 inhibitors, alone and in combination with other compounds, for treating diseases or conditions that would benefit from inhibition of HDAC8 activity.

主权项

1. A compound having a structure of Formula I: wherein:
R1 and R2 are each independently H, OH, halogen, or C1-C6alkyl;L and La are each independently a bond, O, S, NR3, —NR10C(═O)—R11, S(═O), S(═O)2, NHS(═O)2, —C1-C6alkylene-, —C2-C6alkenylene-, —C2-C6alkynylene-, —C1-C6heteroalkylene-, —C1-C6alkylene-O—, —C1-C3alkylene-O—C1-C3alkylene-, —C1-C6alkylene-NR3—, —C1-C3alkylene-NR3—C1-C3alkylene-, —C1-C6alkylene-C(═O)NR3—, —C1-C3alkylene-C(═O)NR3—C1-C3alkylene-, —C1-C6alkylene-NR3C(═O)—, —C1-C3 alkylene-NR3C(═O)—C1-C3alkylene-, —C1-C6alkylene-S—, —C1-C3alkylene-S—C1-C3 alkylene-, —C1-C6alkylene-S(═O)—, —C1-C3alkylene-S(═O)—C1-C3alkylene, —C1-C6alkylene-S(═O)2—, —C1-C3alkylene-S(═O)2—C1-C3alkylene, C(═O)—, or C(═O)—C1-C6alkylene; X is a substituted or unsubstituted group selected from among aryl, heteroaryl, C3-C10cycloalkyl, and C2-C10heterocycloalkyl; where if X is substituted, then X is substituted with 1, 2, 3, 4, or 5 groups selected from among halogen, C1-C6alkoxy, C1-C6fluoroalkoxy, aminoC1-C6alkoxy, C1-C3alkylaminoC1-C3alkoxy, hydroxyC1-C3alkylaminoC1-C3alkoxy, C2-C8heterocycloalkylC1-C3alkoxy, C2-C8heterocycloalkylC1-C2alkyl, —CN, —NO2, —CO2R10, —C(═O)R11, —S—R11, —S(═O)—R11, —S(═O)2—R11, —NR10C(═O)—R11, —C(═O)N(R10)2, —S(═O)2N(R10)2, —NR10S(═O)2—R11, —OC(═O)N(R10)2, —NR10C(═O)O—R11, —OC(═O)O—R11, —NHC(═O)NH—R11, —OC(═O)—R11, —N(R10)2, —C1-C2alkylN(R10)2, C1-C6alkyl, C1-C6fluoroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C3-C8cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; Y is H or a substituted or unsubstituted group selected from among C1-C6alkyl, —CO2R10, —C(═O)R11, —NR10C(═O)—R11, —C(═O)N(R10)2, aryl, heteroaryl, C3-C10cycloalkyl, and C2-C10heterocycloalkyl; where if Y is substituted, then Y is substituted with 1, 2, 3, 4, or 5 groups selected from among halogen, C1-C6alkoxy, C1-C6fluoroalkoxy, aminoC1-C6alkoxy, C1-C3alkylaminoC1-C3alkoxy, hydroxyC1-C3alkylaminoC1-C3alkoxy, C2-C8heterocycloalkylC1-C3alkoxy, C2-C8heterocycloalkylC1-C2alkyl, —CN, —NO2, —CO2R10, —C(═O)R11, —S—R11, —S(═O)—R11, —S(═O)2—R11, —NR10C(═O)—R11, —C(═O)N(R10)2, —S(═O)2N(R10)2, —NR10S(═O)2—R11, —OC(═O)N(R10)2, —NR10C(═O)O—R11, —OC(═O)O—R11, —NHC(═O)NH—R11, —OC(═O)—R11, —N(R10)2, —C1-C2alkylN(R10)2, C1-C6alkyl, C1-C6fluoroalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6heteroalkyl, C3-C8cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
R10 is hydrogen, or a substituted or unsubstituted group selected from among C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, aryl, and heteroaryl;R11 is a substituted or unsubstituted group selected from among C1-C6alkyl, C1-C6fluoroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, aryl, and heteroaryl; R3 is H, C1-C6alkyl, phenyl or benzyl; or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, or pharmaceutically acceptable prodrug thereof.