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Bromodomain‐containing protein 4 (BRD4) plays an extremely important physiological role in cancer, and the BRD4 inhibitors can effectively inhibit the proliferation of tumor cells. By taking BI‐2536 (PLK1 and BRD4 inhibitor) as the lead compound, sixteen novel BRD4 inhibitors with the 4,4‐difluoro‐1‐methyl‐N,6‐diphenyl‐5,6‐dihydro‐4H‐pyrimido[4,5‐b] [1,2,4] triazolo[4,3‐d] [1,4] diazepine‐8‐amine structure were designed and synthetized. Among the target compounds, compound 15h exhibited outstanding inhibition for BRD4‐BD1 (IC50 value of 0.42 μM) in the BRD4‐BD1 inhibitory activity assay. Additionally, cell growth inhibition assay demonstrated that compound 15h potently suppressed the proliferation of MV4‐11 cells (IC50 value of 0.51 μM). Besides, compound 15h induced apoptosis and G0/G1 cycle arrest in MV4‐11 leukemia cells effectively, and downregulated the expression of c‐Myc in a dose‐dependent manner. In summary, the optimal compound 15h is expected to become the clinical therapeutic drug for further research.