Optimization of 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor receptor-2 kinase activity

摘要: A series of new 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitrile derivatives that function as irreversible inhibitors human epidermal growth factor receptor-2 (HER-2) and receptor (EGFR) kinases have been prepared. These compounds demonstrated enhanced activities for inhibiting HER-2 kinase the positive cells compared to our EGFR inhibitor 86 (EKB-569). Three synthetic routes were used prepare these compounds. They prepared mostly by acylation 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or amination 4-chloro-6-(crotonamido)quinoline-3-carbonitriles monocyclic bicyclic anilines. The third route was developed a key intermediate, 6-acetamido-4-chloroquinoline-3-carbonitrile, involved safer cyclization step. We show attaching large lipophilic group at para position 4-(arylamino) ring results in improved potency kinase. also importance basic dialkylamino end Michael acceptor activity, due intramolecular catalysis addition. This, along water solubility, resulted biological properties. present molecular modeling consistent proposed mechanism inhibition. Binding studies one compound, 25o (C-14 radiolabeled), showed it binds irreversibly protein BT474 cells. Furthermore, excellent oral especially overexpressing xenografts. Compound (HKI-272) selected further is currently phase I clinical trials treatment cancer.