Recent advances in synthetic strategies of fourth-generation EGFR tyrosine kinase inhibitors under clinical trials for the treatment of resistant non-small cell lung cancer (NSCLC).

Abstract

The present review summarizes recent advances in the synthetic strategies and biological profiles of fourth-generation EGFR-TK inhibitors currently undergoing clinical investigation for resistant Non-Small Cell Lung Cancer (NSCLC) to overcome the C797S mutation associated with Osimertinib. Representative clinical candidates, including TQB-3804, BPI-361175, BLU-945, BBT-176, BDTX-1535, QLH11811, HS-10375, and H002, are discussed with particular emphasis on synthetic route design, key intermediates, medicinal chemistry optimization, and pharmacological activity. The reported synthetic methodologies prominently involve transition-metal-catalyzed cross-coupling reactions, nucleophilic aromatic substitution, reductive amination, heterocycle construction, and late-stage functionalization strategies for the efficient assembly of structurally complex EGFR inhibitors. Several of these compounds demonstrated remarkable potency against resistant EGFR mutant variants together with improved mutant selectivity and reduced off-target toxicity. In addition, advances in scaffold design, phosphine oxide incorporation, and conformationally optimized heterocyclic frameworks have contributed significantly to the development of next-generation mutant-selective inhibitors. Overall, this review provides a contemporary overview of synthetic innovations in fourth-generation EGFR inhibitor development and highlights emerging strategies for overcoming resistance-associated EGFR mutations in advanced NSCLC.