The urate transporter 1 (URAT1) plays an important role in the reabsorption of uric acid, so URAT1 inhibitors are considered as the promising therapy for gout. To explore potent URAT1 inhibitors with new scaffold, we have designed a series of novel derivatives based on the scaffold hopping strategy by merging the structural feature of URAT1 inhibitor SHR4640 into probenecid. The subsequently structure-activity relationship study led to the discovery of a series of potent URAT1 inhibitors, including the typical acid derivative 8 (IC50 = 2.5 μM) and non-carboxylic acid derivative 10 (IC50 = 3.8 μM). Moreover, these compounds also exhibit excellent metabolic stability in human liver microsomes. In the docking study, compounds 8 and 10 fitted very well to the same binding pocket of Lesinurad. In hyperuricemic model mice, compounds 7, 8 and 10 exhibited significantly uric acid-lowering effect, and compound 8 revealed dose-dependent uric acid-lowering effect to the level of benzbromarone. Moreover, compound 8 has significant potential in alleviating chronic hyperuricemia, improving renal function, and reducing inflammation in chronic hyperuricemia mice. These results extend the chemical space in this field and might help to design more promising URAT1 inhibitors.