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　µM.　Compounds　5　g　and　5i　demonstrated　excellent　antiproliferative　activity　against　Huh-7　cells　(IC50　=　10.09　μM)　and　Hep3B　cells　(IC50　=　7.58　μM),　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.　©　2023　The　Authors