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

Initial evaluation of a series 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines revealed a C(10) 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(10) carboxamide. Herein, we describe several successful approaches toward generating both potent and acid-stable inhibitors of IGF-1R within the 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine template. (C) 2008 Elsevier Ltd. All rights reserved.