With the aim of further boosting the potency, we retained the optimal bicyclic R 2 substituent and turned our focus back to R 1 , and this time, we would give priority to aryl substituents in view of their high feasibility for structural derivatization. As the starting point of derivatization, 9a bearing a phenyl group as R 1 was synthesized (Table ), and similar to its pyridyl counterpart 7c and 7d, 9a presented a single-digit IC50. In the subsequent docking study on 9a (Fig. ), in addition to the anticipated identical binding pose to compound 6, we also found that Asp101 near the phenyl ring might be utilized to produce an additional interaction, thereby contributing to the activity. To build polar contact with the acidic residue, we regarded aliphatic amine as an excellent choice because the its basic N atom could be easily protonated and interact with the carboxy anion via salt bridge interaction-a noncovalent interaction that stronger than hydrogen bond . Based on this hypothesis, we designed and synthesized compounds 9b-9l as can be seen in Table . According to the distances that measured in the docking model (Fig. ), we attached several aliphatic-amine-containing side chains to the 3-or 4-position of the phenyl ring, the resulting 9b-9e were slightly more potent than phenyl compound 9a. To fix these N atoms to the optimal position, we locked them into six-membered rings and obtained tetrahydroisoquinoline compound 9f and 9g, among which 9f