Synthesis and biological evaluation of novel tricyclic oxazine and oxazepine fused quinazolines. Part 1: erlotinib analogs.

Two series of novel tricyclic oxazine and oxazepine fused quinazolines have been designed and synthesized. The in vitro antitumor effect of the title compounds was screened on N87, A431, H1975, BT474 and Calu-3 cell lines. Compared to erlotinib and gefitinib, compounds 1a-1h were found to demonstrate more potent antitumor activities. Several derivatives could counteract EGF-induced phosphorylation of EGFR in cells, and their potency was comparable to the reference compounds. Compounds 1a-1h were chosen for further evaluation of EGFR and HER2 in vitro kinase inhibitory activity. Compounds 1b-1f, 1h effectively inhibited the in vitro kinase activity of EGFR and HER2 with similar efficacy as erlotinib and gefitinib.