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The retinoic acid receptor-related orphan receptor γt (RORγt) is an important nuclear receptor that regulates the differentiation of Th17 cells and production of interleukin 17(IL-17). RORγt agonists increase basal activity of RORγt and could provide a potential approach to cancer immunotherapy. Herein, hit compound 1 was identified as a weak RORγt agonist during in-house library screening. Changes in LHS core of 1 led to the identification of tetrahydroquinoline compound 6 as a partial RORγt agonist (max. act. = 39.3%). Detailed structure-activity relationship on substituent of the LHS core, amide linker and RHS arylsulfonyl moiety was explored and a novel series of tetrahydroquinolines and benzomorpholines was discovered as potent RORγt agonists. Tetrahydroquinoline compound 8g (EC 50 = 8.9 ± 0.4 nM, max. act. = 104.5%) and benzomorpholine compound 9g (EC 50 = 7.5 ± 0.6 nM, max. act. = 105.8%) were representative compounds with high RORγt agonistic activity in dual FRET assay, and they showed good activity in cell-based Gal4 reporter gene assay and Th17 cell differentiation assay (104.5% activation at 300 nM of 8g ; 59.4% activation at 300 nM of 9g). The binding modes of 8g and 9g as well as the two RORγt inverse agonists accidentally discovered were also discussed. Image 1 • A series of tetrahydroquinolines and benzomorpholines was discovered as novel RORγt agonists. • The structure-activity relationships of the left-hand-side moiety, linker and right-hand-side moiety were explored. • The representative lead compounds 8g and 9g showed greatly increased RORγt agonistic activity in dual FRET assay. • 8g and 9g also performed good RORγt agonistic effect in Gal4 reporter gene assay and Th17 cell differentiation assay. • The binding modes of 8g and 9g in RORγt ligand binding domain were discussed by docking studies. [ABSTRACT FROM AUTHOR]