Indole derivatives as 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 alleviating, abating or ameliorating T-cell lymphoma or leukemia in a subject in need thereof, comprising administering to the subject a pharmaceutical composition containing a therapeutically effective amount of a 1,3-disubstituted-1H-indole-6-carboxylic acid hydroxyamide compound,
wherein the substituent at the 1-position is —X2—R2 and the substituent at the 3-position is R3, wherein:
X2 is a substituted or unsubstituted group selected from among C2-C6alkylene, C1-C6heteroalkylene; —C(═O)—, and —C(═O)—C1-C6alkylene;R2 is a substituted or unsubstituted group selected from among aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;
where if R2 is substituted, then each substituent on R2 is selected from among hydrogen, halogen, —CN, —NO2, —S(═O)2NH2, —CO2H, —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, OC(═O)N(R10)2, NR10C(═O)O—R11, —OC(═O)O—R11, —NHC(═O)NH—R11, —OC(═O)—R11, —N(R10)2, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6alkoxy, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R10 is hydrogen, or a substituted or unsubstituted group selected from among C1-C6alkyl, C1-C6heteroalkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl;R11 is a substituted or unsubstituted group selected from among C1-C6alkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, aryl, or heteroaryl;R3 is hydrogen, halogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6alkoxy, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted phenyl, or —X6—R6;
X6 is a C1-C6alkylene, C1-C6fluoroalkylene, C2-C6alkenylene, C2-C6heteroalkylene;R6 is hydrogen, halogen, —CN, hydroxy, amino, C1-C6alkylamino, di(C1-C6alkyl)amino, C1-C6alkoxy, C3-C8cycloalkyl, C2-C8heterocycloalkyl, phenyl, heteroaryl, or —X7—R7 X7 is a bond, —O—, —S—, —S(═O)—, —S(═O)2—, —NRa—, —C(═O)—, —C(═O)O—, —OC(═O)—, —NHC(═O)—, —C(═O)NRa—, —S(═O)2NRa—, —NHS(═O)2—, —OC(═O)NRa—, —NHC(═O)O—, —OC(═O)O—, or —NHC(═O)NRa—;R7 is hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6heteroalkyl, C1-C6haloalkyl, C3-C8cycloalkyl, cycloalkylalkyl, C2-C8heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
Ra is selected from among hydrogen, C1-C6alkyl, C2-C6alkenyl, hydroxy, C1-C6alkoxy, C1-C6fluoroalkoxy, C1-C6heteroalkyl; orRa and R7 together with the N atom to which they are attached form a 5-, 6-, or 7-membered heterocycloalkyl;or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, or pharmaceutically acceptable prodrug thereof.