Thalidomide, a once notorious sedative, is now clinically used as an antitumor agent. We aimed to use it as a lead compound for designing pyrimidine–phthalimide hybrids. Nucleophilic substitution reaction of thalidomide analog 4 with primary and/or secondary aliphatic amines afforded pyrimidine–phthalimide hybrids 5a–g, 6 and 7a–d. Compound 7c showed high antiproliferative activity against four cell lines: HepG-2 (IC₅₀: 7.86 ± 0.5 μM), MCF-7 (IC₅₀: 2.77 ± 0.1 μM), HCT-116 (IC₅₀: 5.73 ± 0.4 μM) and PC-3 (IC₅₀: 8.32 ± 0.5 μM), with selective cytotoxicity for WI-38 (IC₅₀: 43.2 ± 2.56 μM). 7c arrested MCF-7 cells at S phase of the cell cycle and increased the total apoptotic cells by 50-fold. 7c inhibited VEGFR2 in vitro (IC₅₀: 0.130 ± 0.02 μM). 7c was capable of binding at the VEGFR2 binding site, forming hydrogen bond interactions with Asp1046 and Glu885 in a similar way to sorafenib.