Investigation on the chemical space of the substituted triazole thio-benzoxazepinone RIPK1 inhibitors

As a key upstream kinase involved in the activation of Necroptosis, receptor-interacting protein kinase 1 (RIPK1) plays a vital role in the treatment of relevant inflammatory diseases. Recently, we described the thio-benzoxazepinones as RIPK1 Necroptosis inhibitors. On this basis, we further explored the chemical space of the thio-benzoxazepinones by introducing substitutions on the triazole group and evaluated their anti-necroptotic activity. The structure-activity relationship (SAR) was extended for this series of new derivatives. The best compound 2 with methyl and compound 10 with fluoroethyl were obtained and both specifically inhibited Necroptosis rather than Apoptosis with EC₅₀ values of 2.5 and 8.9 nM, respectively. They blocked the downstream necroptotic pathway to prevent Cell Lysis and prevent in vivo inflammation in a dose-dependent manner. This work provides that substituted thio-benzoxazepines can better occupy the hydrophobic cavity and enhance the hydrophobic interaction as promising lead compounds to enhance the in vivo activity of this class of compounds.