Discovery of novel pyrrolopyrimidine/pyrazolopyrimidine derivatives bearing 1,2,3‐triazole moiety as c‐Met kinase inhibitors

Six series of pyrrolo[2,3‐ d ]pyrimidine and pyrazolo[3,4‐ d ]pyrimidine derivatives bearing 1,2,3‐triazole moiety were designed and synthesized, and some bio‐evaluation was also carried out. As a result, four points can be summarized: Firstly, some of compounds exhibited excellent cytotoxicity activity and selectivity with the IC 50 values in single‐digit μ m level. In particular, the most promising compound 16d showed equal activity to lead compound foretinib against A549, HepG2, and MCF ‐7 cell lines, with the IC 50 values of 4.79 ± 0.82, 2.03 ± 0.39, and 2.90 ± 0.43 μ m , respectively. Secondly, the SAR s and docking studies indicated that the in vitro antitumor activity of pyrrolo[2,3‐ d ]pyrimidine derivatives bearing 1,2,3‐triazole moiety was superior to the pyrazolo[3,4‐ d ]pyrimidine derivatives bearing 1,2,3‐triazole moiety. Thirdly, three selected compounds ( 16d , 18d , and 20d ) were further evaluated for inhibitory activity against the c‐Met kinase, and the 16d could inhibit the c‐Met kinase selectively by experiments of enzyme‐based selectivity. What is more, 16d could induce apoptosis of HepG2 cells and inhibitor the cell cycle of HepG2 on G2/M phase by acridine orange staining and cell cycle experiments, respectively.