Novel 2-amino-4-(1H-imidazol)pyridine derivatives as potent brain-penetrant EGFR mutant inhibitors: Design, synthesis, biological evaluation, and molecular modeling study.

EGFR inhibitors, including Osimertinib, have achieved marked success in treating non-small-cell lung cancer (NSCLC). However, major challenges persist, including clinical resistance mutations in NSCLC and limited efficacy against EGFR-altered glioblastoma (GBM). This underscores the urgent need for brain-penetrant EGFR inhibitors capable of circumventing mutant resistance and targeting EGFR-driven GBM. To address this, we designed and synthesized a novel series of 2-amino-4-(1H-imidazol)pyridine derivatives as EGFR inhibitors and performed molecular modeling studies to elucidate their interactions with EGFR tyrosine kinase. The representative compound 8m displayed potent kinase inhibitory activity against EGFRL858R/T790M and EGFRL858R/T790M/C797S, and also suppressed the proliferation of NSCLC, GBM and Ba/F3-EGFRL858R/T790M/C797S cells. Further biological evaluation revealed that 8m has high kinase selectivity and favorable oral bioavailability (31.5% in SD rats). In vivo, compound 8m significantly suppressed tumor growth in a subcutaneous H1975 xenograft model (TGI: 94.18% and 96.10% at 5 and 10 mg/kg, respectively) and demonstrated anti-tumor efficacy in an intracranial H1975-Luc brain metastasis model. Collectively, the compounds reported herein serve as a promising scaffold for the development of EGFR inhibitors aimed at L858R/T790M, L858R/T790M/C797 and EGFRvIII mutants, and brain metastases.