Development of Bruton’s tyrosine kinase (BTK) inhibitors is of great value and significance in the treatment of B-cell malignancies and autoimmune diseases. Herein, a novel class of pyrazolopyrimidine-based BTK inhibitors were designed and evaluated in mantle cell lymphoma (MCL) cell lines. We demonstrated that target compounds had made great progress in improvement of antiproliferative activity compared to lead compound. Compounds 13c, 13g, 13h, 13l, 13n and 13o demonstrated effectively antiproliferative activity in MCL cells lines with single-digit micromolar potency. Furthermore, compound 13l specifically disturbed mitochondrial membrane potential and increased reactive oxygen species level in Z138 cells in a dose-dependent manner. 13l induced cell apoptosis through the caspase 3- mediated apoptotic pathway in Z138 cells. Overall, this study provides valuable lead compounds for developing antitumor agents.