The BRD4 protein is associated with various diseases, which has been an attractive target for the treatment of cancer and inflammation. This paper is a follow-up to our previous studies, in which we report the structure-based design, synthesis, and evaluation of a new class of small-molecule BRD4 bromodomain inhibitors bearing a benzo[d]isoxazol scaffold. The SARs focused on exploration of the 2^¢ or 3^¢ position to afford novel inhibitors that may avoid potential metabolically unstable site. The most potent inhibitor 13f exhibited high binding affinity to BRD4(1) with a DT_m value of 7.8 °C as evaluated in thermal shift assay (TSA). The potent activity was also demonstrated by a peptide competition assay with an IC₅₀ value of 0.21 mM. The docking studies revealed the binding mode of the compounds with the active site of BRD4(1). In addition, in silico predictions indicated that these compounds possessed good drug-likeness and pharmacokinetic profile