For more in-depth exploration of the chemical space around the entrance channel of HIV-1 reverse transcriptase (RT), a series of novel indolylarylsulfones (IASs) bearing different chiral N-substituted pyrrolidine, azetidine or substituted sulfonamide groups at indole-2-carboxamide were designed and synthesized as potent HIV NNRTIs by structure-guided scaffold morphing approach. All the IASs exhibited moderate to excellent potency against wild-type HIV-1 with EC<sub>50</sub> values ranging from 0.0043 μM to 4.42 μM. Notably, compound 27 (EC<sub>50</sub> = 4.7 nM, SI = 5183) and 33 (EC<sub>50</sub> = 4.3 nM, SI = 7083) were identified as the most potent compounds, which were more active than nevirapine, lamivudine and efavirenz, and also reached the same order of etravirine. Furthermore, some compounds maintained excellent activity against various single HIV-1 mutants (L100I, K103 N, E138K, Y181C) as well as one double mutant (F227L/V106A) with EC<sub>50</sub> values in low-micromolar concentration ranges. Notably, 34 displayed outstanding potency against F227L/V106A (EC<sub>50</sub> = 0.094 μM), and also showed exceptional activity against E138K (EC<sub>50</sub> = 0.014 μM), L100I (EC<sub>50</sub> = 0.011 μM) and K103 N (EC<sub>50</sub> = 0.025 μM). Additionally, most compounds showed markedly reduced cytotoxicity (CC<sub>50</sub>) compared to lead compounds, especially 36 (CC<sub>50</sub> > 234.91 μM, SI > 18727) and 37 (CC<sub>50</sub> > 252.49 μM, SI > 15152). Preliminary SARs and molecular modeling studies were also discussed in detail, which may provide valuable insights for further optimization.