Through a 3D conformer based scaffold hopping protocol based on previously reported mutant-selective EGFR inhibitors, we designed and synthesized a series of pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione derivatives as novel potent and selective EGFR^L858R/T790M inhibitors. For three compounds (20b, 20c and 20g) in this series, our design strategy to occupy S2 pocket boosts the inhibitions against double-mutant EGFR and brings the IC₅₀ to a subnanomolar level. After three round SAR explorations, one of the most promising compounds 20g shows a favorable selectivity at both in vitro and in vivo levels, indicating that compound 20g might be used as a promising drug candidate to overcome EGFR^L858R/T790M drug-resistance mutation. Further evaluation for the candidate compound is still ongoing, and will be reported in due course.