Design, Synthesis, and Evaluation of Novel 2,4-disubstituted Pyrimidine Derivatives as Double Mutant Epidermal Growth Factor Receptor-L858R/T790M Tyrosine Kinase Inhibitors

A series of 2,4-disubstituted pyrimidine derivatives bearing 5-substituted-1,3,4 thidiazole were devised and synthesized based on the binding mode of the approved drug Osimertinib with the ATP competitive site of EGFR-L858R/T790M in order to increase selectivity towards double mutant EGFR and potent antitumor activity. Their cellular bioactivity and corresponding enzyme inhibition were studied, and it was revealed that several compounds had significant biological activity and selectivity when compared to the control compounds. One of the most promising compound 8, substantially suppressed the proliferation of H1975 cells and showed significant inhibition of double mutant EGFR-L858R/T790M TK with IC50 values of 0.170 and 0.0064 mu M, respectively. Molecular mechanic simulation provides structural evidence of selective kinase inhibitory activity. Density functional theory (DFT/B3LYP) methods with the 6-311G**++ basic basis set were used to compute the theoretical vibrational frequencies and optimal geometric parameters. In addition, MESPs analysis, HUMO and LUMO quantum parameters of the most active compound 8 were calculated, and the results were viewed.