Selective inhibitors of mTOR kinase based upon saturated heterocycles fused to a pyrimidine core were designed and synthesized. Each series produced compounds with Ki < 10nM for the mTOR kinase and > 500-fold selectivity over closely related PI3 kinases. This potency translated into strong pathway inhibition as measured by phosphorylation of mTOR substrate proteins and antiproliferative activity in cell lines with a constitutively active PI3K pathway. Two compounds exhibiting suitable mouse PK were profiled in in vivo tumor models and were shown to suppress mTORC1 and mTORC2 signaling for over 12 hours when dosed orally. Both compounds were additionally shown to suppress tumor growth in vivo in a PC3 prostate cancer model over a 14 day study.