Design, synthesis and SAR study of 2-aminopyrimidines with diverse Michael addition acceptors for chemically tuning the potency against EGFRL858R/T790M

Abstract The covalent binding nature of irreversible kinase inhibitors potentially increases the severity of “off-target” toxicity. Based on our continual strategy of chemically tuning the Michael addition acceptors, herein, we further explore the relationship among the electronic nature of Michael addition acceptors and EGFRT790M mutation selectivity as well as “off-target” toxicity balance. By perturbing the electronic nature of acrylamide moiety, compound 8a with a chloro-group at the α-position of the Michael addition acceptor was identified. It was found that 8a retained the excellent EGFR L858R/T790M potency (IC50 = 3.9 nM) and exhibited good anti-proliferative activities against the gefitinib-resistant NCI-H1975 cells (IC50 = 0.75 μM). Moreover, 8a displayed a significant EGFRWT selectivity and much weaker inhibitory activity against non-EGFR dependent SW620 cell and COS7. Preliminary study showed that 8a could arrest NCI-H1975 cells in G0/G1 phase. This work provides a promising chemical tuned strategy for balancing the mutant-EGFR potency and selectivity as well as “off-target” toxicity.