The MAPK signaling pathway, comprising RAS, RAF, MEK, and ERK, plays a critical role in cellular proliferation and survival. Mutations in this pathway, particularly in BRAF, are implicated in various cancers, including melanoma (70–90%), thyroid cancer (30–50%), and others. Pyrimidine-sulfonamide derivatives have previously shown potent anticancer activity against mutant BRAF proteins. In this study, we synthesized urea-based pyrimidine cyclized sulfonamide derivatives and evaluated their computational, biological, and anticancer properties. The rational design of oxo-tetrahydro-pyrimidin-benzenesulfonamide hybrids (S01–S09) was based on the pharmacophoric features of earlier series, where solvent-accessible groups such as -NH2, -SH, and =S were replaced by the keto (-C=O) group during urea cyclization. The proposed compounds exhibited [αC-OUT/DFG-IN] conformations similar to FDA-approved second-generation drugs. All derivatives were spectrally characterized using GC-MS, IR, ¹H, and ¹³C NMR. The synthesized derivatives were tested for antiproliferative activity against two cancer cell lines and evaluated for BRAFV600E kinase inhibitory activity, with sorafenib as the standard. The results revealed that most compounds demonstrated promising anticancer activity, with compound S04 emerging as the most potent inhibitor of BRAFV600E. A structure-activity relationship (SAR) analysis indicated that electron-donating groups significantly enhance anticancer activity compared to electron-withdrawing groups.