Due to the increasing evidence linking the PI3Kγ pathway to various disease states, PI3Kγ is becoming an important target for cancer treatment. Herein we designed and synthesized a novel series of N,4-diphenylpyrimidin-2-amine derivatives with low CDOCKER_INTERACTION_ENERGY and then evaluated their PI3Kγ in vitro inhibitory activities and in vitro antiproliferation assays against four human cancer cells. Among the compounds we synthesized, compound C8 (IC₅₀ = 65 nM) demonstrated the most potent inhibitory activity against PI3Kγ kinase as well as at the cellular level, compared to the control drug TG100713 (IC₅₀ = 127 nM). Moreover, molecular docking analysis was also performed to determine possible binding modes between PI3Kγ and the target compounds.