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Bruton’s tyrosine kinase (BTK) is a key component of the B cell receptor (BCR) signaling pathway and plays a crucial role in B cell malignancies and autoimmune disorders;thus,it is an attractive target for the treatment of B cell related diseases.Here,we evaluated the BTK inhibitory activity of a series of pyrimido[4,5-d][1,3]oxazin-2-one derivatives.Combining this evaluation with structure-activity relationship (SAR) analysis,we found that compound 2 exhibited potent BTK kinase inhibitory activity,with an ICso of 7 nM.This derivative markedly inhibited BTK activation in TMD8 B cell lymphoma cells and thus inhibited the in vitro growth of the cells.Further studies revealed that compound 2 dose dependently arrested TMD8 cells at G1 phase,accompanied by decreased levels of Rb,phosphorylated Rb,and cyclin D1.Moreover,following treatment with compound 2,TMD8 cells underwent apoptosis associated with PARP and caspase 3 cleavage.Interestingly,the results of the kinase activity assay on a small panel of 35 kinases showed that the kinase selectivity of compound 2 was superior to that of the first-generation inhibitor ibrutinib,suggesting that compound 2 could be a second-generation inhibitor of BTK.In conclusion,we identified a potent and highly selective BTK inhibitor worthy of further development.