Rearranged during transfection (RET) is a promising target for antitumor drug development. Multikinase inhibitors (MKI) have been developed for RET-driven cancers but displayed limited efficacy in disease control. Two selective RET inhibitors were approved by FDA in 2020 and proved potent clinical efficacy. However, the discovery of novel RET inhibitors with high target selectivity and improved safety is still highly desirable. Herein, we reported a class of 3,5-diaryl-1H-pyrazol-based ureas as new RET inhibitors. The representative compounds 17a/b displayed high selectivity to other kinases, and potently inhibited isogenic BaF3-CCDC6-RET cells harboring wild-type, or gatekeeper mutation (V804M). They also displayed moderate potency against BaF3-CCDC6-RET-G810C with solvent-front mutation. Compound 17b showed better pharmacokinetics properties and demonstrated promising oral in vivo antitumor efficacy in a BaF3-CCDC6-RET-V804M xenograft model. It may be utilized as a new lead compound for further development.