Structure-activity study of quinazoline derivatives leading to the discovery of potent EGFR-T790M inhibitors

• Structure-activity relationship of quinazoline derivatives was described.
• New compounds showed massive improvements over afatinib against H1975.
• Two safe and effective irreversible inhibitors (7q & 8f) were discovered.
• 7q and 8f showed higher in vivo efficacy and safety than afatinib against H1975.
• 7q and 8f demonstrated good pharmacokinetic profiles and oral bioavailability.

We have developed a series of 6, 7-disubstituted-4-(arylamino) quinazoline derivatives that functioned as irreversible EGFR inhibitors, and these compounds exhibited excellent enzyme inhibition potency. As compared with afatinib, some of them showed significantly enhanced activities towards H1975 cells (EGFR-T790M). Furthermore, the optimized compounds 7q and 8f also demonstrated good pharmacokinetic profiles, oral bioavailability as well as excellent in vivo efficacy in H1975 and HCC827 xenografts at a non-toxic dose. Based on the improved safety and efficacy against EGFR-T790M resistance, 7q and 8f are promising candidates for further studies.

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