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.