Design,Synthesis, and Biological Evaluation of 1‐Benzyl‐1H‐pyrazole Derivatives as Receptor Interacting Protein 1 Kinase Inhibitors

Receptor interacting protein 1 (RIP1) kinase plays an important role in necroptosis, and inhibitors of the RIP1 kinase are thought to have a potential therapeutic value in the treatment of diseases related to necrosis. Herein, we report the structural optimization of a RIP1 kinase inhibitor, 1‐(2,4‐dichlorobenzyl)‐3‐nitro‐1H‐pyrazole ( 1a ). A number of 1‐benzyl‐1H‐pyrazole derivatives were synthesized and structure‐activity relationship (SAR) analysis led to the discovery of a potent compound, 4b , which showed a K_d value of 0.078 μm against the RIP1 kinase and an EC₅₀ value of 0.160 μm in a cell necroptosis inhibitory assay. Compound 4b also displayed considerable ability to protect the pancreas in an l ‐arginine‐induced pancreatitis mouse model.