Three series of substituted pyrimidines were designed and synthesized. All target compounds were screened for kinase inhibitory activities against PI3Kα, and most IC₅₀ values were found within the nanomolar range. Compounds 5d and 5p displayed comparable activities relative to the positive control 5a. 5p also showed a significant isozyme selectivity (PI3Kβ/α). Furthermore, the cytotoxicities of these pyrimidines against human cancer cell lines were evaluated and the in vivo anticancer effect of 5d was also tested.