Covalent Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib are approved for treating patients with B-cell malignancies, but their long-term efficacy is limited due to their toxicity (i.e., on-target and off-target inhibition of kinases) and acquired resistance (i.e., BTK C481 mutation). AS-1763 is a potent, highly selective, orally active, non-covalent inhibitor of both wild-type and C481S-mutant BTK. AS-1763 strongly inhibits the proliferation of B cell lymphoma cell line OCI-LY10 carrying wild-type and C481S-mutatant BTK in vitro and in vivo.