Discovery of a novel class anti-proliferative agents and potential inhibitors of EGFR tyrosine kinases based on 4-anilinotetrahydropyrido[4,3-d]pyrimidine scaffold: Design, synthesis and biological evaluations

Abstract A novel series of 4-arylamino-6/7-substituted-5,6,7,8-tetrahydropyrido[4,3- d ]pyrimidines were designed, synthesized and their biological activities as the potential anti-proliferative agents and EGFR kinase inhibitors were evaluated. Both of N -acrylamide fragment in THPPs and 4-aniline groups with substituents played key roles for their significant anti-proliferative activities against four cancer cell lines (HT29, A549, H460 and H1975). Especially inhibitory activity of Gefitinib-resistant H1975 were showed more favorable, which could be observed from compounds 13b , 13c , 13n , 13o , 13p , 13r , 13s , 13u and 24c obviously. By evaluation of inhibiting EGFR and HER2 kinases, seven compounds ( 13b , 13g , 13n , 13o , 13p , 13r and 13s ) showed stronger EGFR potency with IC 50  ⩽ 18 nM, which could also be understood by preliminary docking study of 13b with EGFR kinase. In view of the primary SAR, bisarylaniline derivatives ( 13o , 13p , 13r and 13s ) showed obvious improvements on HER2 inhibition, which indicated their being potential EGFR/HER2 dual kinase inhibitors.