A novel class of aminopyrimidine-based Bruton’s tyrosine kinase (BTK) and FMS-like tyrosine kinase 3 (FLT3) dual-target inhibitors based on the BTK inhibitor spebrutinib was designed for the treatment of acute myeloid leukemia. Representative compounds 14d, 14g, 14j and 14m effectively inhibited BTK, FLT3, and FLT3(D835Y) mutant activities with low nanomolar IC₅₀’s. These compounds displayed potent antiproliferative activities against leukemia cells with IC₅₀’s of 0.29-950 nM. In particular, 14m had IC₅₀ values 101-1045 times lower than those of spebrutinib against all cancer cell lines tested. Compound 14m effectively induced autophagy and apoptosis in MV-4-11 cells through regulating related proteins in a dose-dependent manner. Finally, intraperitoneal administration of 14m at 20 mg/kg significantly repressed the growth of MV-4-11 cells with a TGI value of 95.68% with no apparent toxicity. These BTK/FLT3 dual-target inhibitors represent promising leads for further structural optimization and antitumor mechanism studies.