In order to improve the antiproliferative activity of androgen receptor (AR) antagonists, which used clinically for the treatment of prostate cancer that is a major cause of male death in worldwide, we report the design and synthesis of a series of tetrahydrofuran cyclic urea-based non-steroidal small molecule ARantagonists and exhibit potent AR antagonistic activity. These molecules with higher stereochemical aspects have been achieved by changing the hydantoin analogue antiandrogens to 4-(2-oxohexahydro-1H-furo[3,4-d] imidazol-1-yl)-2-(trifluoromethyl)benzonitrile analogues. Here, the thio-hydantoin pharmacophore of the recently reported antagonists is replaced by tetrahydrofuran cyclic urea. The antiproliferative properties ofthese molecules have been evaluated against androgen-dependent (LNCaP) cell line. Among the reported molecules, 4-(2-oxohexahydro-1H-furo[3,4-d]imidazol-1-yl)-2-(trifluoromethyl)benzonitrile (AR04) showed significantly improved in vitro activity, IC₅₀ = 3.926 lM. Molecular structure-activity relationship studiesconfirm that the oxetane analogue AR04 is distinct from other synthesized AR antagonists. These results have suggested that AR04 exhibiting their potential as a lead compound for the alternative treatment of prostate cancer.