Selective inhibitors of histone deacetylase

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 method of treating T-cell lymphoma or leukemia in a mammal in need thereof, comprising administering to the mammal a pharmaceutical composition comprising:
(a) a therapeutically effective amount of a compound of Formula B: wherein: R1 is —C(═O)NHOH; X2 is a bond, —C1-C6alkylene-, —C2-C6alkenylene-, —C2-C6alkynylene-, —C1-C6heteroalkylene-, C1-C6fluoroalkylene, C2-C6fluoroalkenylene, C1-C6haloalkylene, C2-C6haloalkenylene, —C1-C6alkylene-O—, —C1-C3alkylene-O—C1-C3alkylene-, —C1-C6alkylene-NH—, —C1-C3alkylene-NH—C1-C3 alkylene-, —C1-C6alkylene-C(═O)NH—, —C1-C3alkylene-C(═O)NH—C1-C3alkylene-, —C1-C6alkylene-NHC(═O)—, —C1-C3alkylene-NHC(═O)—C1-C3alkylene-, —C1-C6alkylene-S—, —C1-C3 alkylene-S—C1-C3alkylene-, —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; R2 is a substituted or unsubstituted group selected from aryl, heteroaryl, C3-C10cycloalkyl, and C2-C10heterocycloalkyl; where if R2 is substituted, then R2 is substituted with 1, 2, or 3 groups selected from among halogen, C1-C6alkoxy, C1-C6fluoroalkoxy, aminoC1-C6alkoxy, C1-C3 alkylaminoC1-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, 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; each R3 is independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6alkoxy, substituted or unsubstituted C1-C6fluoroalkoxy, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted phenyl, or C1-C6aminoalkyl; or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, or pharmaceutically acceptable solvate thereof; and (b) a pharmaceutically acceptable diluent, excipient, or carrier.