As a continuation to our previous research, twenty-eight aromatic-heterocyclic biphenyls were designed and synthesized as novel Bcr-Abl inhibitors. The title compounds were investigated for their antiproliferative activities against wild K562 cells and Imatinib-resistant K562 cells (K562R). The results indicated that most of them exhibited potent Bcr-Abl inhibition and moderate antiproliferative potency against K562 cells. Furthermore, three compounds 3, 7 and 21 displayed moderate antiproliferative activities against K562R cells. Molecular docking indicated that 3 bound more tightly with Bcr-Abl(T315I) compared to Bcr-Abl(WT). The higher affinity was consistent with its relatively promising K562R cell growth inhibition. These aromatic-heterocyclic biphenyls could be considered as novel lead compound for optimized as Bcr-Abl(T315I) inhibitors. They provide a good starting point for the further development of novel anti-leukemia agents capable of dealing with clinical acquired resistance against Imatinib.