Preparation of benzimidazole, indole, azaindole, and pyrrole hydroxyamides as selective inhibitors of histone deacetylase 8 for treating cancer, arthritis, and other diseases.

Abstract

Described herein are 1,2-disubstituted-1H-benzimidazole-6-carboxylic acid hydroxyamide compds., 1,3-disubstituted-indole-6-carboxylic acid hydroxyamide compds., 1,3-disubstituted-azaindole-6-carboxylic acid hydroxyamide compds., substituted-1H-pyrrol-2-yl-N-hydroxyacrylamide compds., and other selective HDAC8 inhibitors, pharmaceutically acceptable salts, N-oxides, active metabolites, prodrugs, and solvates thereof. Methods of prepg. such compds., pharmaceutical compns. contg. them, and methods of using them, alone and in combination with other compds., for treating diseases or conditions that would benefit from inhibition of HDAC8 activity are also disclosed. Example compd. I was prepd. in a 5-step reaction that involved reaction of Et 4-amino-3-(benzylamino)benzoate with tri-Et orthoformate to form a benzimidazole intermediate that was subsequently converted to carboxamide I. In an HDAC activity assay where enzyme activity was measured using a continuous trypsin-coupled assay, I behaved as a selective HDAC8 inhibitor with an IC50 of < 1 μM. [on SciFinder(R)]