The Discovery of Bridged Benzoazepine Amides as Selective Allosteric Modulators of RIPK1

Receptor-interacting protein kinase 1 (RIPK1) plays an essential role in necroptosis, a form of inflammatory, caspase-independent, programmed cell death. Allosteric inhibitors of RIPK1 have been shown to block necroptotic cell death and thus may offer potential therapeutic opportunities across a range of infectious, autoimmune, and neurodegenerative diseases. We report the structure-informed discovery of a novel series of bridged benzoazepine amides as part of our efforts to develop a CNS-penetrant small-molecule inhibitor of RIPK1 with a low projected oral human dose.