Discovery of 2-ureidophenyltriazines bearing bridged morpholines as potent and selective ATP-competitive mTOR inhibitors

Incorporation of bridged morpholines in monocyclic triazine PI3K/mTOR inhibitors gave compounds with increased mTOR selectivity relative to the corresponding morpholine analogs. Compounds with ureidophenyl groups gave highly potent and selective mTOR inhibitors. Potency and selectivity was demonstrated both in vitro and in vivo through biomarker suppression studies. Select compounds exhibited potent inhibition of tumor growth in nude mouse xenograft assays upon PO and IV administration.

Graphical abstractIncorporation of bridged morpholines in monocyclic triazine PI3K/mTOR inhibitors gave compounds with increased mTOR selectivity relative to the corresponding morpholine analogs leading to compounds which suppressed mTOR biomarkers in vivo and possessed excellent efficacy in a murine xenograft model.Figure optionsDownload full-size imageDownload as PowerPoint slide