Optimization of a series of 4,6-bis-anilino-1 H-pyrrolo[2,3- d]pyrimidine inhibitors of IGF-1R: Elimination of an acid-mediated decomposition pathway

Abstract

Initial evaluation of a series 4,6-bis-anilino-1 H-pyrrolo[2,3- d]pyrimidines revealed a C(1′) carboxamide was preferred for sub-micromolar in vitro potency against IGF-1R. Subsequent solution stability studies with 1 revealed a susceptibility toward acid-induced intramolecular cyclization with the C(1′) carboxamide. Herein, we describe several successful approaches toward generating both potent and acid-stable inhibitors of IGF-1R within the 4,6-bis-anilino-1 H-pyrrolo[2,3- d]pyrimidine template.