6-Substituted-4-(3-bromophenylamino)quinazolines as putative irreversible inhibitors of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER-2) tyrosine kinases with enhanced antitumor activity

A series of new 6-substituted-4-(3-bromophenylamino)quinazoline derivatives that may function as irreversible inhibitors of epidermal growth factor re ceptor (EGFR) and human epidermal growth factor receptor (HER-2) tyrosine k inases have been prepared. These inhibitors have, at the C-6 position, buty namide, crotonamide, and methacrylamide Michael acceptors bearing water-sol ublilizing substituents. These compounds were prepared by acylation of 6-am ino-4(3-bromophenylamino)quinazoline with unsaturated acid chlorides or mix ed anhydrides. We show that attaching a basic functional group onto the Mic hael acceptor results in greater reactivity, due to intramolecular catalysi s of the Michael addition and/or an inductive effect of the protonated basi c group. This, along with improved water solubility, results in compounds w ith enhanced biological properties. We present molecular modeling and exper imental evidence that these inhibitors interact covalently with the target enzymes. One compound, 16a, was shown to have excellent oral activity in a human epidermoid carcinoma (A431) xenograft model in nude mice.