Strategies to Mitigate the Bioactivation of 2-Anilino-7-Aryl-Pyrrolo[2,1-<i>f</i>][1,2,4]triazines: Identification of Orally Bioavailable, Efficacious ALK Inhibitors

Abstract

Chemical strategies to mitigate cytochrome P450-mediated bioactivation of novel 2,7-disubstituted pyrrolo­[2,1-<i>f</i>]­[1,2,4]­triazine ALK inhibitors are described along with synthesis and biological activity. Piperidine-derived analogues showing minimal microsomal reactive metabolite formation were discovered. Potent, selective, and metabolically stable ALK inhibitors from this class were identified, and an orally bioavailable compound (<b>32</b>) with antitumor efficacy in ALK-driven xenografts in mouse models was extensively characterized