Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors and the Discovery of CC-115

We report here the
synthesis and structure–activity relationship
(SAR) of a novel series of triazole containing mammalian target of
rapamycin (mTOR) kinase inhibitors. SAR studies examining the potency,
selectivity, and PK parameters for a series of triazole containing
4,6- or 1,7-disubstituted-3,4-dihydropyrazino­[2,3-b]­pyrazine-2­(1H)-ones resulted in the identification of triazole containing
mTOR kinase inhibitors with improved PK properties. Potent compounds
from this series were found to block both mTORC1­(pS6) and mTORC2­(pAktS473)
signaling in PC-3 cancer cells, in vitro and in vivo. When assessed
in efficacy models, analogs exhibited dose-dependent efficacy in tumor
xenograft models. This work resulted in the selection of CC-115 for
clinical development.