Oxopyrido[2,3-d]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors

In nonsmall cell lung cancer (NSCLC), the threonine790–methionine790 ( T790M) point mutationof EGFR kinase is one of the leading causes of acquired resistance to the first generation tyrosine kinase inhibitors(TKIs), such as gefitiniband 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 EGFRL858R, T790Mwith 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 EGFRL858R, T790Mdriven H1975 xenograft model sparing the side effects associated with the inhibition of wild-type EGFR.