Design, synthesis and biological evaluation of novel diaminopyrimidine derivatives as covalent fibroblast growth factor receptor 4 inhibitors

Covalent kinase inhibitors are receiving increasing attention as therapeutics with clinical benefits. A series of diaminopyrimidine derivatives incorporating reactive acrylamide warhead to covalently bind to cysteine 552 in FGFR4 were designed and synthesized. Among them, compound 5 h showed potent inhibitory activity against FGFR4 with an IC50 value of 0.1657 mu M. Compounds 5 g and 5i demonstrated excellent antiproliferative activity against Huh-7 cells (IC50 = 10.09 mu M) and Hep3B cells (IC50 = 7.58 mu M), respectively. Molecular docking and MD simulations revealed the binding modes of compound 5 h within the ATP pocket and paved the way for further structural optimization as covalent FGFR4 inhibitors.