Selective estrogen receptor modulators (SERMs) are a class of drugs that act on the estrogen receptor (ER). SERMs are used for treatment and reduction of risk of breast cancer. Herewith we had designed, synthesized and evaluated chalcone-phenylpyran-2-one derivatives bearing N,N-dimethyl ethalamine side chain for their anti-breast cancer activity using MCF-7 and Zr-75-1 cell lines in-vitro. The pharmacological data indicated that most of tested compounds showed moderate to significant cytotoxicity and high selectivity toward estrogen receptor. The SAR analyses indicated that compounds 5f with 2,6 dichloro substitution was more effective. Docking study was performed to predict binding orientation towards the estrogen receptor-α.