Discovery and Preclinical Evaluation of [4-[[1-(3-fluorophenyl)methyl]-1<i>H</i>-indazol-5-ylamino]-5-methylpyrrolo[2,1-<i>f</i>][1,2,4]triazin-6-yl]carbamic Acid, (3<i>S</i>)-3-Morpholinylmethyl Ester (BMS-599626), a Selective and Orally Efficacious Inhibitor of Human Epidermal Growth Factor Receptor 1 and 2 Kinases

Abstract

Structure-activity relationships in a series of 4-[1H-indazol-5-ylamino]pyrrolo[2,1-f][1,2,4]triazine-6-carbamates identified dual human epidermal growth factor receptor (HER)1/HER2 kinase inhibitors with excellent biochemical potency and kinase selectivity. On the basis of its favorable pharmacokinetic profile and robust in vivo activity in HER1 and HER2 driven tumor models, 13 (BMS-599626) was selected as a clinical candidate for treatment of solid tumors.