Process Development of a Tricyclic Diazepine-Based IDH1 Mutant Inhibitor

Process development to improve synthetic access to a potent, selective, and brain-penetrant tricyclic diazepine clinical candidate that inhibits mutant IDH1 is described. A variety of disconnections were evaluated to determine the preferred sequence of fragment coupling. The optimized route involves a metal-catalyzed C–N coupling/reductive cascade to form the central diazepine core, improved entries to both the zigzag morpholine and cyclohexyl acid peripheral pieces, and an efficient end-game sequence of acylation, C–N coupling, and deprotection. In addition, a dynamic acylation process that enables selective acylation at N6 of an unprotected diazepine core is described.