In this article, two series of pyrimidine hybrids, 2-((4-amino-6-(1,3-dioxoisoindolin-2-yl)pyrimidin-2-yl)thio)-N′-(alkylbenzylidene)acetohydrazides (6a–g) (Series I) and 6-amino-5-((alkylamino)(phenyl)methyl)pyrimidine-2,4(1H,3H)-diones (10a–d) (Series II), were synthesized using catalyst-free condensation of acid hydrazide 4 with different aromatic aldehydes and nucleophilic substitution reactions of chloromethylpyrimidine with different aliphatic amines , respectively. Compared to gefitinib (IC50 = 4.1 ± 0.01 μM) and thalidomide (IC50 = 13.4 ± 0.5 μM), compounds 6c and 10b exhibited moderate anti-proliferative activity against the MCF-7 breast cancer cell line, with IC50 values of 37.7 ± 3.6 and 31.8 ± 2.0 μM, respectively. They demonstrated selective cytotoxicity toward MCF-7 cells over normal WI38 fibroblasts, with IC50 values of 87.3 ± 2.6 μM (6c) and >100 μM (10b). Both compounds showed potent in vitro EGFR-TK enzyme inhibition, with IC50 values of 0.9 ± 0.03 μM (6c) and 0.7 ± 0.02 μM (10b). Molecular docking simulations revealed that 6c and 10b effectively bind to the EGFR ATP-binding site, forming hydrogen bonds with the key hinge region amino acid Met793, similar to gefitinib. In silico studies confirmed that both compounds fit the criteria for orally bioavailable drug candidates, showing high gastrointestinal absorption and no predicted adverse effects on the central nervous system or liver. Additionally, both compounds were predicted to be non-carcinogenic and non-mutagenic.