Pyrrolo[2,3-b]pyridine derivatives as potent Bruton's tyrosine kinase inhibitors

A series of pyrrolo[2,3-b]pyridine-based derivatives were designed as potent Bruton's tyrosine kinase (BTK) inhibitors by using a scaffold-hopping strategy. Structure-activity relationship studies identified five compounds (3n, 3p, 3q, 3r, and 3s) with IC50 of less than 10 nM in BTK enzyme assay and five compounds (3m, 3n, 3o, 3p, and 3t) with IC50 of less than 20 nM in Ramos cell assay. As one of the most potent inhibitors, compound 3p exhibited superior activity to that of compound 1 (RN486) and pyrrolo[ 2,3-d]pyrimidine derivative 2 in both BTK enzymatic (IC50 = 6.0 nM) and cellular inhibition (IC50 = 14 nM) assays. In addition, 3p displayed favorable overall pharmacokinetic profiles compared with 1 and 2. (C) 2015 Elsevier Ltd. All rights reserved.