Discovery of Mammalian Target of Rapamycin (mTOR) Kinase Inhibitor CC-223

We report here the synthesis and
structure–activity relationship
(SAR) of a novel series of mammalian target of rapamycin (mTOR) kinase
inhibitors. A series of 4,6- or 1,7-disubstituted-3,4-dihydropyrazino­[2,3-b]­pyrazine-2­(1H)-ones were optimized for
in vivo efficacy. These efforts resulted in the identification of
compounds with excellent mTOR kinase inhibitory potency, with exquisite
kinase selectivity over the related lipid kinase PI3K. The improved
PK properties of this series allowed for exploration of in vivo efficacy
and ultimately the selection of CC-223 for clinical development.