In nonsmall cell lung cancer (NSCLC), the threonine(790)-methionine(790) (T790M) 
point mutation of EGFR kinase is one of the leading causes of acquired 
resistance to the first generation tyrosine kinase inhibitors (TKIs), such as 
gefitinib and erlotinib. Herein, we describe the optimization of a series of 
7-oxopyrido[2,3-d]pyrimidinyl-derived irreversible inhibitors of EGFR kinase. 
This led to the discovery of compound 24 which potently inhibits 
gefitinib-resistant EGFR(L858R,T790M) with 100-fold selectivity over wild-type 
EGFR. Compound 24 displays strong antiproliferative activity against the H1975 
nonsmall cell lung cancer cell line, the first line mutant HCC827 cell line, and 
promising antitumor activity in an EGFR(L858R,T790M) driven H1975 xenograft 
model sparing the side effects associated with the inhibition of wild-type EGFR.