Different pharmacophore structures were introduced to the 3-hydroxy-indolin-2-one core scaffold by Aldol condensation reaction, and several new fluorine-containing 3-hydroxy-indolin-2-one derivatives were designed and prepared. Their structures were identified by 1HNMR, 13CNMR and HRMS. And the antiproliferative activities of target molecules against non-small cell lung cancer A549 cells were evaluated by CCK-8 assay.The results showed that compounds IIIe and IIIf displayed stronger antiproliferative activities, with IC50 values of 19.494 and 24.804 μmol/L, respectively. Flow cytometry and Hoechst 33342 staining demonstrated that compound IIIe could trigger cell cycle arrest at G2 phase and induce apoptosis of A549 cells. Moreover, western blot indicated that compound IIIe could upregulate the levels of P53 and Cleaved Caspase-3, and downregulate the level of Survivin.Molecular docking simulation showed that compound IIIe could bind to the ATP pocket of PI3K-δ.Together, these data revealed that compound IIIe maybe a potential candidate for the treatment of non-small cell lung cancer.