A series
of brigatinib derivatives were designed and synthesized
as new potent and selective EGFRT790M/C797S inhibitors.
One of the most potent and selective compounds 18k strongly
suppressed the EGFRL858R/T790M/C797S and EGFR19Del/T790M/C797S kinases with IC50 values of 0.7 and 3.6 nM, respectively,
which were over 54-fold more potent than the lead compound. 18k also demonstrated promising EGFRT790M/C797S mutant selectivity, and was 94-fold less potent against the wild
type EGFR. A cocrystal structure of EGFRT790M/C797S with
a close derivative 18f was solved to provide insight
on the inhibitor’s binding mode. Moreover, compound 18k was orally bioavailable and demonstrated highly desirable PK properties,
making it a promising lead compound for further structural optimization.