Discovery of Novel Bruton's Tyrosine Kinase (BTK) Inhibitors Bearing a N,9-Diphenyl-9H-purin-2-amine Scaffold

摘要

Based on the pyrimidine skeleton of EGFR(T790M) inhibitors, a series of N,9-diphenyl-9H-purin-2-amine derivatives were identified as effective BTK inhibitors. Among these compounds, inhibitors 10d, 10i, and 10j, possessing IC50 values of 0.5, 0.5, and 0.4 nM, displayed anti-BTK kinase activity that was as potent as the reference compounds. In particular, compound 10j suppressed the proliferation of two typical B-cell leukemia cell lines expressing high levels of BTK with concentrations of 7.75 and 12.6 mu M. The activity of the subject compound as determined by the CCK-8 method and apoptosis analysis validated that inhibitor 10j is slightly more potent than AVL-292 and ibrutinib. The experimental explorations suggested that I0j could serve as a valuable molecule for control of leukemia developments