The synthesis of 4-arylamido-2-arylaminoprimidines as potent EGFR T790M/L858R inhibitors for NSCLC

A series of 4-arylamido-2-arylaminoprimidines bearing acrylamide pharmacophore were synthesized as potent EGFR(T790M/L858R) inhibitors among which 9c (IC50=0.5872 nM), 9d (IC50=2.213 nM), or 9h (IC50=12.57 nM) showed more potent anti-EGFR(T790M/L858R) activity compared with AZD-9291 (IC50=20.80 nM) and possessed high SI displaying 307.6, 56.5, or 12.5 for EGFR(T790M/L858R) over the wild-type respectively. 9h also showed pretty good activity against H 1975 cells with an IC50 of 1.664 mu M and exhibited low toxicity against the normal HBE cells (IC50 > 20 mu M). 9h had moderate selectivity for H 1975 over A 431 (SI=7.0) and the other selected cell lines. Morphological staining results further indicated that 9h could promote apoptosis. Hence, 9h was a promising compound for further investigation as a potential EGFR(T790M/L858R) inhibitor for the treatment of NSCLC.