To thoroughly investigate the uncharted chemical space around the entrance channel of HIV-1 reverse transcriptase (RT) and to improve the physicochemical properties, we introduced different spiro ring structures with high Fsp<sup>3</sup> values as linkers at indole-2-carboxamide, attaching to various terminal substituents to enhance the interactions with the entrance channel. All the newly designed and synthesized indolylarylsulfone (IAS) derivatives exhibited moderate to excellent potency against wild-type HIV-1 with EC<sub>50</sub> values ranging from 0.0053 to 0.19 μM. Among them, compounds SO-7g (EC<sub>50</sub> = 0.0053 μM) and SO-7h (EC<sub>50</sub> = 0.009 μM, SI > 21552) were identified as the most two potent compounds, which displayed 30- and 16-fold improvement than nevirapine and zidovudine and comparable potency to efavirenz and etravirine. Moreover, SO-7g maintained the promising activity against a variety of mutant strains, especially for L100I (EC<sub>50</sub> = 0.047 μM), K103 N (EC<sub>50</sub> = 0.056 μM), and E138K (EC<sub>50</sub> = 0.040 μM). Notably, the introduction of spiro rings could effectively reduce the cytotoxicity (CC<sub>50</sub>) and greatly improve the selectivity index compared to lead compound, exemplified by SO-7h (CC<sub>50</sub> > 214.4 μM, SI > 21552) and SO-7a (CC<sub>50</sub> > 233.2 μM, SI > 20933). Additionally, the preliminary SARs based on antiviral activity and molecular simulation perspective were analyzed with a detailed description, which could point out the direction for further structural optimization.