High Resolution Image Download MS PowerPoint Slide In this study, 20 new compounds with thiadiazole structures were synthesized based on Alpelisib. The benzene ring, a bioisostere of the pyridine ring in the lead compound, was used in the synthesized compounds, and derivatives containing different substituents were used to observe modifications that could affect activity. Furthermore, because combined therapies are known to be more effective in cancer therapy, attempts were made to design compounds capable of dual inhibition of EGFR-COX-2 by adding sulfonamide substitutions to some compounds. The structures of the compounds were confirmed by IR, 1 H NMR, 13 C NMR, and HRMS spectral analyses. A549 and MCF-7 cell lines were used to measure anticancer activity, and in vitro assays were conducted. For compounds 3j and 3o, further activity studies, molecular docking, and molecular dynamics studies were performed. The compounds’ EGFR and COX-2 inhibitory potential was investigated.