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

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 EGFR^T790M 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 EGFR^WT 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.