Structure-activity relationship investigation for imidazopyrazole-3-carboxamide derivatives as novel selective inhibitors of Bruton's tyrosine kinase

BTK (Bruton's tyrosine kinase) inhibitors are the most promising drugs for the treatment of hematological tumors. A high selectivity of BTK inhibitors ensures reduced side effects from off-targeting. Accordingly, here, based on Zanubrutinib, we designed and synthesized a new range of imidazopyrazole-3-carboxamide derivatives as novel BTK inhibitors that retained the amide group for improved selectivity. These compounds revealed potent inhibitory activity against BTK in vitro. Remarkably, compounds 12a (IC50 5.2 nM) and 18a (IC50 4.9 nM) possessed the highest kinase selectivity. Both of these effectively inhibited the auto-phosphorylation of BTK, blocked the cell cycle in G0/G1 phase, and induced apoptosis in the TMD8 cells. In a TMD8 cells xenograft model, a twice-daily dose of compound 12a at 25 mg/kg and a thrice-daily dose of compound 18a at 15 mg/kg significantly suppressed the tumor growth without obvious toxicity. Collectively, 12a and 18a are the potential selective BTK inhibitors that can be developed further.