Small molecule inhibitors of biphenyl structure as core backbone have shown a significant effect on PD-1/PD-L1 axis, and 2-amino-pyrimidine structure is a promising privileged scaffold in medicinal chemistry and drug discovery. We designed by combination principles and synthesized 27 novel compounds with N-((2-methyl-[1,1'-biphenyl]-3-yl)methyl)pyrimidin-2-amine as a basic skeletal structure, and their anti-cancer activity was evaluated. Among compounds, 15a-d and 16b displayed strong anti-cancer effects on 9 tested cancer cell lines, in particular, the 16b did the highest inhibitive activity, but against HepG2 cells, and possessed the lowest IC<sub>50</sub> value of 2.08 μΜ towards HT-29 cells.