Conformationally-restricted cyclic sulfones as potent and selective mTOR kinase inhibitors

Novel conformationally-restricted mTOR kinase inhibitors with cyclic sulfone scaffold were designed. Synthesis and structure-activity relationship (SAR) studies are described with emphasis on optimization of the mTOR potency and selectivity against class I PI3K alpha kinase. PF-05139962 was identified with excellent mTOR biochemical inhibition, cellular potency, kinase selectivity and in vitro ADME properties. (C) 2012 Elsevier Ltd. All rights reserved.