Imidazo[1,5-a]pyrazines: Orally efficacious inhibitors of mTORC1 and mTORC2

The discovery and optimization of a series of imidazo[1,5-a]pyrazine inhibitors of mTOR is described. HTS hits were optimized for potency, selectivity and metabolic stability to provide the orally bioavailable proof of concept compound 4c that demonstrated target inhibition in vivo and concomitant inhibition of tumor growth in an MDA-MB-231 xenograft model.

Graphical abstractThe discovery of a selective and orally efficacious imidazo[1,5-a]pyrazine mTOR inhibitor (4c) via optimization of an HTS hit is described.Figure optionsDownload full-size imageDownload as PowerPoint slide