Novel anilinopyrimidine derivatives as potential EGFR^T790M/C797S Inhibitors: Design, Synthesis, biological activity...

EGFR^T790M/C797S is an important target for the development of new generation of EGFR kinase inhibitors without drug resistance. In this work, a series of anilinopyrimidine derivatives that targeting EGFR^T790M/C797S were designed, synthesized, and evaluated in vitro for the inhibitory effect on triple mutations kinases and cell lines. Based on the pharmacology data, the anilinopyrimidine derivatives showed high inhibitory activity on triple mutations kinases (EGFR^{del 18/T790M/C797S} and EGFR^{L858R/T790M/C797S}) as well as the cell line Ba/F3 with highly expression of EGFR^{del 18/T790M/C797S}. In addition, the anilinopyrimidine derivatives had a more than 50-fold selectivity towards EGFR^{del 18/T790M/C797S} as compared with EGFR^WT. In vivo antitumor activity test also indicated that 8j had good pharmacokinetic parameters, low toxicity and better inhibitory activity. Overall, the anilinopyrimidine derivatives could be regarded as promising candidates for the further development of novel EGFR^T790M/C797S inhibitors for clinical application.