Discovery, process development, and scale-up of a benzoxazepine-containing mtor inhibitor

A family of novel, highly potent, and selective inhibitors of the mammalian target of rapamycin (mTOR) containing the benzoxazepine core were identified. The lead compound (XL388), which exhibited low-nanomolar activity and >1000-fold selectivity over related PI3K kinases, was chosen for further development as a potential oral treatment of several different tumor types. It inhibited cellular phosphorylation of substrates of mTOR complexes 1 and 2. It also showed good pharmacokinetics, moderate oral bioavailability, and dose-dependent antitumor activity in mice implanted with human breast and colon tumor xenografts. The synthesis of the clinical candidate was rapidly scaled up to enable first-in-human studies. A safe and scalable route and process were developed for the tetrahydrobenzo[f][1,4]oxazepine core fragment. The constituent fragments of XL388 were assembled using a telescoped sequence to manufacture 7.8 kg of active pharmaceutical ingredient under current Good Manufacturing Practice (cGMP), in 99.7 HPLC area % purity and a 21% overall yield over eight ynthetic steps. © 2018 American Chemical Society.