In this study, a simple and readily available bifunctional compound, terephthalaldehyde, was employed to synthesize the bis-pyrimidinthione derivative 4. The thiocarbonyl group and adjacent NH functionalities underwent Michael-type additions with activated unsaturated compounds—namely arylidenemalonitrile and DMAD—yielding bis-thiazine derivatives 6a–f and bis-thiazole 8, respectively. Additionally, reaction of derivative 4 with various aromatic amines and formaldehyde under Mannich conditions afforded bis-thiadiazines 10. All synthesized compounds were characterized using NMR and MS techniques. Molecular docking studies targeting the VEGFR2/KDR receptor (PDB ID: 3CPC) revealed high binding affinity, particularly for compound 10i. ADMET analysis further indicated favorable drug-like properties for selected compounds. In vitro cytotoxicity against the MCF-7 human breast cancer cell line showed that compound 10i had the strongest activity (IC₅₀ = 2.60 ± 1.41 µM), followed by 10 g (3.75 ± 2.52 µM) and 6f (3.97 ± 1.85 µM), all comparable to or exceeding the activity of sorafenib (3.51 ± 1.43 µM). VEGFR-2 enzyme inhibition assays for compounds 10g and 10i yielded IC₅₀ values of 8.06 ± 3.32 µM and 5.15 ± 2.89 µM, respectively, relative to sorafenib (3.12 ± 1.79 µM). These findings position compound 10i as a promising candidate for VEGFR-2-targeted anticancer therapy.