Abstract: Based on the reported inhibitors TH287, 17 five-membered heterocyclopyrimidine derivatives were designed and synthesized by cyclization, scaffold hopping, bioisosterism and molecular docking technology. The bioassays determined by malachite green method demonstrated that the target compounds displayed good inhibitory activity against MTH1. Among them, the IC₅₀ value of 7 compounds was less than 1 μmol/L, suggesting that these compounds may be candidates for further investigation.