Design, synthesis and evaluation of the Brigatinib analogues as potent inhibitors against tertiary EGFR mutants (EGFR and EGFR).

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated encouraging clinical outcomes for patients with EGFR-mutated non-small cell lung cancer, a considerable number of patients will develop drug resistance and eventually undergo disease progression after taking EGFR-TKIs for a period of time. EGFR and EGFR are two most prevalent tertiary EGFR mutants identified in Osimertinib-resistant tumors and currently there is no therapy approved clinically targeting these mutants. In this study, we designed and synthesized a series of novel 4th generation EGFR inhibitors based on scaffold of Brigatinib. After extensive SAR studies, compound 23, the most promising candidate, exhibited strong biochemical potencies against EGFR, EGFR and other clinically relevant EGFR mutants while sparing wild type EGFR. In cellular assays, compound 23 potently inhibited proliferation of BaF3 and PC-9. Moreover, compound 23 demonstrated good DMPK profile in mouse PK study.