A series of amide-functionalized pyrimidine derivatives (6a–6r) were synthesized via a three-steproute involving (1) multicomponent assembly of 2-(4-methylpyrimidin-5-yl) acetonitrile (4), (2)LiAlH₄ reduction to the primary amine (5), and (3) DCC/DMAP-mediated coupling with diversecarboxylic acids. The compounds were obtained in good yields (65–92%) and high purity (>95%,NMR/HRMS). Molecular docking studies against EGFR (PDB: 6LUD) and CDK-4 (PDB: 7SJ3) revealedstrong binding affinities for hydroxy-substituted derivatives, particularly 6k (EGFR: −7.245kcal/mol), 6j (CDK-4: −8.72 kcal/mol), and 6l (CDK-4: −9.23 kcal/mol), highlighting the role ofhydrogen-bonding interactions. Cytotoxicity screening (MTT assay) against A-549 (lung), HCT-116(colorectal), PANC-1 (pancreatic), and HaLa (cervical) cancer cells identified 6l (2-hydroxy-4-methoxyphenyl) as the most potent inhibitor (IC₅₀ = 5.87–7.86 μM), with 3–7-fold selectivity overnormal HEK-293 cells. Structure-activity relationships demonstrated that electron-donatinghydroxy/methoxy groups enhanced activity, while nitro or bulky substituents reduced potency.Notably, 6j (3,4-dihydroxyphenyl) exhibited exceptional activity against HCT-116 (IC₅₀ = 5.67 μM),correlating with its high CDK-4 binding affinity. The combined in silico and in vitro results suggestthat these pyrimidine hybrids act via dual EGFR/CDK-4 inhibition, with 6b, 6j, and 6l emerging aspromising anticancer leads due to their potent cytotoxicity, kinase selectivity, and favorable safetyprofiles. This study provides a robust framework for further optimization of pyrimidine-basedtherapeutics.KeywordsPyrimidine derivatives, Multicomponent synthesis, EGFR, CDK-4, Molecular docking, Anticanceractivity.