Insulin-like growth factor-1 receptor (IGF-1R) kinase inhibitors: SAR of a series of 3-[6-(4-substituted-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridine-2-one

Abstract A series of 3-[6-(4-substitued-piperazin-1-yl)-4-methyl-1 H -benzimidazol-2-yl]-1 H -pyridine-2-one were synthesized to modulate CYP3A4 inhibition and improve aqueous solubility of our prototypical compound BMS-536924 ( 1 ), while maintaining potent IGF-1R inhibitory activity. Structure–activity and structure–solubility studies led to the identification of BMS-577098 ( 27 ), which demonstrates oral in vivo efficacy in animal models. The improvement was achieved by replacing morpholine with more polar bio-isoster piperazine and modulating the basicity of distal nitrogen with appropriate substitutions.