The discovery and optimisation of pyrido[2,3- d]pyrimidine-2,4-diamines as potent and selective inhibitors of mTOR kinase

We describe a novel series of potent inhibitors of the kinase activity of mTOR. The compounds display good selectivity relative to other PI3K-related kinase family members and, in cellular assays, inhibit both mTORC1 and mTORC2 complexes and exhibit good antiproliferative activity. The discovery and optimization of a novel series of inhibitors of mTOR kinase are described. Compound 31, KU-63794, has low nanomolar potency against mTOR kinase and is highly selective relative to other PI3K-related kinases.