CN115260081B - A kind of sulfonamide indole aryl sulfone derivative and its preparation method and application - Google Patents

Abstract

The invention discloses a sulfonamide indole aryl sulfone derivative and its preparation method and application. The sulfonamide indole aryl sulfone derivative or its pharmaceutically acceptable salt has the structure shown in the following general formula I. The present invention also includes a preparation method of the sulfonamide indole aryl sulfone derivative and the Application in the preparation of drugs for the treatment and prevention of human immunodeficiency virus (HIV).

Description

A sulfonamide indole aryl sulfone derivative and its preparation method and application

Technical Field

The invention belongs to the technical field of organic compound synthesis and pharmaceutical application, and specifically relates to a sulfonamide indole aryl sulfone derivative HIV-1 reverse transcriptase inhibitor and a preparation method and application thereof.

Background Art

Acquired immunodeficiency syndrome (AIDS) is an infectious disease that seriously threatens human life and health and global economic development. Its main pathogen is HIV type 1 (HIV-1). Reverse transcriptase (RT) plays a key role in the life cycle of HIV, and non-nucleoside reverse transcriptase inhibitors (NNRTIs) targeting this target have become an important part of highly effective antiretroviral therapy (HAART). However, with the widespread clinical application of NNRTIs, serious toxic side effects, drug-resistant strains, and poor pharmacokinetic properties have reduced their efficacy. As a chronic infectious disease, AIDS requires long-term or even lifelong medication. In addition, the virus itself mutates rapidly. Therefore, the development of new, highly effective, low-toxic and anti-resistance HIV-1 NNRTIs is a major and urgent clinical need.

Indolylarylsulfone (IAS) compounds are a class of HIV-1 NNRTIs with unique structures. The lead compound II-3 has a nanomolar effective concentration against wild-type HIV-1. However, its high cytotoxicity is an important factor restricting its clinical application. Structural biology and preliminary structure-activity relationship studies have shown that the 2-amide of indole is a favorable site for structural modification.

In order to further enhance the activity, resistance to drug resistance and improve the drugability of indole aryl sulfone compounds, especially to focus on reducing their cytotoxicity, the present invention discloses a class of sulfonamide indole aryl sulfone HIV-1 non-nucleoside reverse transcriptase inhibitors with a new structure, which has not been reported in the prior art.

Summary of the invention

In view of the deficiencies of the prior art, the present invention provides a sulfonamide indole aryl sulfone derivative HIV-1 reverse transcriptase inhibitor and a preparation method thereof. The present invention also provides the activity screening results of the above-mentioned compound as an HIV-1 reverse transcriptase inhibitor and its application.

The technical solution of the present invention is as follows:

1. Sulfonamide indole aryl sulfone derivatives

A sulfonamide indole aryl sulfone derivative, or a pharmaceutically acceptable salt thereof, has a structure shown in general formula I:

in,

n=0,1,2,3,4,5;

R is: cycloalkyl, benzene ring, substituted benzene ring, substituted naphthalene ring, various substituted six-membered heterocycles, various substituted five-membered heterocycles, various substituted benzo six-membered heterocycles and hydrocarbon chain structures of various lengths; the substituents are selected from methyl, halogen, nitro, cyano, phenyl and acetylamino.

According to the preferred embodiment of the present invention,

n=1,2,3,4;

R is: cycloalkyl, benzene ring, monosubstituted benzene ring, naphthalene ring, substituted pyridine ring, furan ring, thiophene ring; the substituent is selected from methyl, fluorine, chlorine, nitro, cyano, phenyl, acetylamino.

According to the present invention, the sulfonamide indole aryl sulfone derivative represented by the general formula I is one of the following compounds:

The "pharmaceutically acceptable salt" described in the present invention refers to a salt of a compound that is suitable for contact with human or lower animal tissues without undue toxicity, irritation, and allergic reaction within a reliable pharmaceutical evaluation range, has a fairly reasonable benefit-risk ratio, is usually water- or oil-soluble or dispersible, and can be effectively used for its intended purpose. It includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts, which can be used for the intended purpose and are compatible with the chemical properties of the compound of formula I. For a list of suitable salts, see Birge, S.M. et al., J.Pharm.Sci., 1977, 66, 1-19.

2. Preparation method of sulfonamide indole aryl sulfone derivatives

A preparation method of sulfonamide indole aryl sulfone derivatives, comprising: using 5-chloro-1H-indole-2-carboxylic acid ethyl ester as a raw material, reacting with 3,5-dimethylbenzenethiol in the presence of 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane ditetrafluoroborate to obtain intermediate 1 through aromatic nucleophilic substitution reaction, then reacting with m-chloroperbenzoic acid in dichloromethane to obtain intermediate 2, and then hydrolyzing with lithium hydroxide in a mixed solvent of tetrahydrofuran: water = 1:1 to obtain intermediate 3; on the other hand, using triethylamine as an acidifying agent, reacting sulfonyl chlorides (R) with different substitutions and amino groups (L) with different carbon chain lengths protected by Boc in dichloromethane to obtain intermediates 4R _n L _n with different structures, then deprotecting with trifluoroacetic acid in dichloromethane to obtain intermediates 5R _n L _n with different substitutions, and finally subjecting intermediates 5 with different structures to amide condensation with intermediate 3 to obtain different target products;

The synthetic route is as follows:

Reagents and conditions: (i) 3,5-dimethylthiophenol, 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane ditetrafluoroborate, acetonitrile, room temperature; (ii) m-chloroperbenzoic acid, dichloromethane, 0°C to room temperature; (iii) lithium hydroxide, tetrahydrofuran: water = 1:1, room temperature; (iv) Et ₃ N, DCM, 0°C to room temperature; (v) trifluoroacetic acid, dichloromethane, room temperature; (vi) HATU, DIEA, DCM, 0°C to room temperature.

R is as described in the above general formula I.

The room temperature described in the present invention is 20-30°C.

The preparation method of the sulfonamide indole aryl sulfone derivative of the present invention comprises the following specific steps:

(1) 5-chloro-1H-indole-2-carboxylic acid ethyl ester, 3,5-dimethylbenzenethiol, 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt and solvent acetonitrile are added to a round-bottom flask and stirred at room temperature for 6 hours. After the reaction is completed, the solvent of the reaction solution is evaporated to dryness, and dichloromethane and saturated sodium chloride solution are added for extraction. The organic phase is separated, anhydrous magnesium sulfate is added for drying, and the filtrate is filtered and concentrated under reduced pressure. The obtained crude product is separated and purified by silica gel column chromatography to obtain intermediate 1.

(2) Dissolve the intermediate 1 in dichloromethane, add m-chloroperbenzoic acid under ice bath conditions, and transfer to room temperature after 30 minutes. Continue to react for 4 hours. After the reaction is completed, transfer the reaction solution into a separatory funnel, add dichloromethane to dilute, wash with saturated sodium bisulfite solution three times, then add saturated sodium chloride solution to wash once, and finally dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. The resulting crude product is separated and purified by silica gel column chromatography to obtain intermediate 2.

(3) The intermediate 2 was dissolved in a mixed solvent of tetrahydrofuran/water in a volume ratio of 1:1, lithium hydroxide was added, and the mixture was stirred at room temperature for 8 hours. After the reaction was completed, most of the solvent was evaporated under reduced pressure, and a 1N dilute HCl solution was added dropwise to adjust the pH to 3-4. During this process, a white solid was generated, which was filtered and the filter cake was dried to obtain the intermediate 3.

(4) Under ice bath conditions, Boc-protected primary amines of different carbon chain lengths were dissolved in dichloromethane, stirred for 5 minutes, and then triethylamine was added, and then sulfonyl chlorides of different substitutions were slowly added. After 5 minutes, the mixture was transferred to room temperature for reaction. After the reaction was completed, appropriate amounts of water and dichloromethane were added to the reaction solution for extraction. The organic phases were combined, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, filtered, concentrated, and finally subjected to column chromatography to obtain the corresponding target intermediate 4.

(5) The corresponding intermediate 4 was dissolved in dichloromethane, and trifluoroacetic acid was added dropwise under stirring at room temperature for 1 h. After the reaction was completed, most of the reaction solution was evaporated under reduced pressure, and a saturated sodium bicarbonate solution was added to adjust the pH to neutral. Solids precipitated during the process, and the corresponding intermediate 5 was obtained by recrystallization from ethyl acetate.

(6) Under ice bath conditions, the intermediate 3 was dissolved in DCM, and N,N-diisopropylethylamine and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) were added. After stirring for 30 minutes, the corresponding intermediate 5 was added and the mixture was transferred to room temperature for reaction. After the reaction was completed, appropriate amount of water and dichloromethane were added to the reaction solution for extraction. The organic phases were combined, washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate, filtered, concentrated, and finally subjected to column chromatography to obtain the corresponding target compound.

3. Application of sulfonamide indole aryl sulfone derivatives

The present invention discloses the screening results of the anti-HIV-1 activity of sulfonamide indole aryl sulfone derivatives and their first application as HIV-1 inhibitors. Experiments prove that the sulfonamide indole aryl sulfone derivatives of the present invention can be used as HIV-1 inhibitors for preparing anti-AIDS drugs. The present invention also provides the application of the above compounds in preparing anti-HIV-1 drugs.

Anti-HIV-1 activity and toxicity experiments of target compounds

A class of sulfonamide indole aryl sulfone derivatives synthesized according to the above method were screened for activity against HIV-1 (IIIB) at the cellular level, single-resistant mutants L100I, K103N, Y181C, Y188L, and double mutants RES056 (K103N/Y181C), F227L/V106A. As shown in Table 1, the substituted sulfonamide indole aryl sulfone derivatives have significant anti-HIV-1 activity, and the _EC50 values of all compounds are at the nanomolar or subnanomolar level. Among them, 8 compounds ( _R7L4 , _{R9L4 , R10L2 , R10L3 , R10L4} , _R10L5 , _R11L4 , _{R13L2 )} have single _- nanomolar activity against wild-type strains, especially _R10L4 ( _EC50 = 0.0066±0.0021μM) and _{R13L2 ( EC50} = _0.0041 ±0.0008μM), which are more active than the marketed drugs _{nevirapine ( EC50} = 0.13±0.041μM) and zidovudine ( _{EC50 =} =0.024±0.0071μM), etravirine (EC ₅₀ ＝0.011±0.0092μM), which is comparable to the lead compound II-3 (EC ₅₀ ＝0.0041±0.0014μM) and efavirenz (EC ₅₀ ＝0.0038±0.00063μM); and compound R ₁₀ L ₄ has an inhibitory effect on L100I (EC ₅₀ ＝0.017±0.0017μM), Y181C (EC ₅₀ ＝0.045±0.010μM), E138K (EC ₅₀ ＝0.017±0.0070μM), F227L+V106A (EC ₅₀ =0.087±0.035 μM) and other mutants had significant inhibitory effects, which were better than the marketed drugs nevirapine and etravirine (Table 2).

The most noteworthy thing is that the cytotoxicity of compounds R ₁₀ L ₄ (CC ₅₀ =216.51±0.52μM, SI=32804) and R ₁₃ L ₂ (CC ₅₀ =172.00±6.91μM, SI=42369) is significantly lower than that of lead compound II-3 (CC ₅₀ =5.52±0.77μM, SI=2159), and the cytotoxicity of compounds R ₁₀ L ₄ and R ₁₃ L ₂ is 0.025 times and 0.032 times that of II-3, respectively, which greatly improves the drug safety index. The structural modification of the amide at the 2-position of the lead compound in the present invention has produced an unexpected creative discovery. In addition, the safety of this type of compound is not inferior to that of the marketed drugs nevirapine (CC ₅₀ >15.02μM, SI>114), zidovudine (CC ₅₀ >7.48μM, SI>312), efavirenz (CC ₅₀ >6.34μM, SI>1622), and etravirine (CC ₅₀ >4.59μM, SI>412). In addition, the inhibitory activity test showed that the target of this series of compounds was reverse transcriptase, among which the representative compounds with the best inhibitory activity were R ₉ L ₂ (IC ₅₀ =0.055±0.0055μM), R ₁₀ L ₄ (IC ₅₀ =0.077±0.0087μM) and R ₁₃ L ₂ (IC ₅₀ =0.057±0.012μM) (Table 3); therefore, substituted sulfonamide indole aryl sulfone derivatives are worthy of further research and development as reverse transcriptase inhibitors and can be further studied and developed as lead compounds against HIV-1.

The sulfonamide indole aryl sulfone derivatives of the present invention can be used as HIV-1 inhibitors, and specifically used as HIV-1 inhibitors for preparing anti-AIDS drugs.

An anti-HIV-1 pharmaceutical composition comprises the sulfonamide indole aryl sulfone derivative of the present invention and one or more pharmaceutically acceptable carriers or excipients.

The present invention provides sulfonamide indole aryl sulfone derivatives and preparation methods thereof, and also provides anti-HIV-1 activity screening results of some compounds and their first application in the antiviral field. Experiments have shown that the sulfonamide indole aryl sulfone derivatives of the present invention can be used as HIV-1 inhibitors and have high application value. Specifically, they are used as HIV-1 inhibitors for the preparation of anti-AIDS drugs.

DETAILED DESCRIPTION

The following examples are helpful for understanding the present invention, but they cannot limit the content of the present invention. The percentages are all mass percentages.

Example 1: Preparation of intermediate 5-chloro-3-((3,5-dimethylphenyl)thio)-1H-indole-2-carboxylic acid ethyl ester (1)

Ethyl 5-chloro-1H-indole-2-carboxylate (1, 0.5 g, 2.13 mmol, 1 eq.), 3,5-dimethylbenzenethiol (308 μL, 2.34 mmol, 1.1 eq.), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (0.83 g, 2.55 mmol, 1.1 eq.), and acetonitrile (25 mL) were added to a round-bottom flask and stirred at room temperature for 6 hours; After the reaction was completed, the acetonitrile solvent was evaporated to dryness, dichloromethane (15 mL) was added to dissolve, and then a saturated sodium chloride solution (50 mL) was added to extract the dissolved phase. The aqueous phase was then extracted with dichloromethane (15 mL×2). The dichloromethane solutions were combined, anhydrous magnesium sulfate was added to dry the mixture, the mixture was filtered, the filtrate was concentrated, the sample was mixed with silica gel, and the intermediate 1 was separated and purified by silica gel column chromatography (eluent ethyl acetate: petroleum ether=1:12) to obtain the intermediate 1 with a yield of 57% as a white solid with a melting point of 135-136°C.

Spectral data:

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.55 (s, 1H, Indole-NH), 7.56 (d, J = 8.8Hz, 1H, Indole-H), 7.39 (d, J = 2.0Hz, 1H ,Indole-H),7.34(dd,J＝8.7,2.1Hz,1H,Indole-H),6.77(s,1H,Ar-H),6.72(s,2H,Ar-H),4.33(q, J＝7.1Hz, 2H, OCH ₂ ), 2.14 (s, 6H, 2×CH ₃ ), 1.26 (t, J＝7.1Hz, 3H, CH ₃ ).ESI-MS: m/z 358.39 (M-1 ) ^- .C ₁₉ H ₁₈ ClNO ₂ S[359.07].

Example 2: Preparation of intermediate 5-chloro-3-((3,5-dimethylphenyl)sulfonyl)-1H-indole-2-carboxylic acid ethyl ester (2)

Intermediate 1 (0.1 g, 0.277 mmol, 1 eq.) was dissolved in 10 mL of dichloromethane and stirred in an ice bath. Meta-chloroperbenzoic acid (0.143 g, 0.831 mmol, 3 eq.) was slowly added to the reaction flask. After 30 minutes, the ice bath was removed and the reaction was transferred to room temperature for stirring. After 4 hours, the reaction was completed, 20 mL of dichloromethane was added for dilution, and saturated sodium bisulfite solution (10 mL × 3) and saturated sodium bicarbonate solution (10 mL × 3) were added in sequence for washing. The organic phases were combined, filtered, and the light yellow solid in the organic phase was collected. The intermediate 2 was recrystallized from ethyl acetate at 80 ° C, with a yield of 72%, as a white solid with a melting point of 210-211 ° C.

Spectral data:

¹ H NMR (400MHz, DMSO-d ₆ ) δ13.29(s,1H,NH),8.24(s,1H,Ar-H),7.68–7.59(m,3H,Ar-H),7.44(d, J＝8.8Hz,1H,Ar-H),7.28(s,1H,Ar-H),4.37(q,J＝6.9Hz,2H,CH ₂ ),2.33(s,6H,CH ₃ ×2), 1.30 (t, J=6.9Hz, 3H, CH ₃ ).ESI-MS: m/z 390.40 (M-1) ^- .C ₁₉ H ₁₈ ClNO ₄ S[391.06].

Example 3: Preparation of intermediate 5-chloro-3-((3,5-dimethylphenyl)sulfonyl)-1H-indole-2-carboxylic acid (3)

The intermediate 2 (0.1 g, 0.255 mmol, 1 eq.) was dissolved in a mixed solvent of tetrahydrofuran/water (10 mL) in a volume ratio of 1:1, and lithium hydroxide (32 mg, 0.765 mmol, 3 eq.) was added under stirring at room temperature, and stirred at room temperature for 8 hours. After the reaction was completed, most of the solvent was evaporated under reduced pressure, and then a 1N dilute HCl solution was added dropwise to adjust the pH to 3-4. During this process, a white solid was generated, which was filtered and dried to obtain the intermediate 3 with a yield of 66%. It was a white solid with a melting point of 270°C.

Spectral data:

¹ H NMR (400MHz, DMSO-d ₆ ) δ14.22(s,1H,COOH),13.10(s,1H,NH),8.21(s,1H,Ar-H),7.63(s,2H,Ar- H),7.56(d,J＝8.7Hz,1H,Ar-H),7.40(d,J＝8.8Hz,1H,Ar-H),7.26(s,1H,Ar-H),2.31(s, 6H,2×CH ₃ ).ESI-MS: m/z 362.02(M-1) ^- .C ₁₇ H ₁₄ ClNO ₄ S[363.03].

Example 4: Preparation of Intermediate 4

Under ice bath conditions, Boc-protected primary amines of different carbon chain lengths (0.1 g, 1 eq) were dissolved in dichloromethane, and triethylamine (3.0 eq.) was added after stirring for 5 minutes, and sulfonyl chlorides of different substitutions (1.2 eq.) were slowly added. After 5 minutes, the mixture was transferred to room temperature for reaction. After the reaction was completed, appropriate amount of water and dichloromethane were added to the reaction solution for extraction, the organic phases were combined, washed with saturated sodium chloride solution, then dried with anhydrous sodium sulfate, filtered, concentrated, and finally subjected to column chromatography to obtain the corresponding target intermediate 4.

Example 5: Preparation of Intermediate 5

The corresponding differently substituted intermediate 4 (0.1 g, 1 eq) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 eq) was added dropwise under stirring at room temperature, and the reaction was carried out for 1 h. After the reaction was completed, most of the reaction solution was evaporated under reduced pressure, and a saturated sodium bicarbonate solution was added to adjust the pH to neutral. Solids precipitated during the process, and the corresponding target intermediate 5 was obtained by recrystallization from ethyl acetate.

Example 6: General method for preparing target compounds (R ₁ L ₂ ～R ₁₆ L ₂ )

Under ice bath conditions, the intermediate 3 was dissolved in DCM, and N,N-diisopropylethylamine and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) were added. After stirring for 30 minutes, the corresponding substituted intermediate 5 was added, and the reaction was transferred to room temperature. After the reaction was completed, an appropriate amount of water and dichloromethane were added to the reaction solution for extraction, the organic phases were combined, washed with saturated sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, concentrated, and finally the target compounds (R ₁ L ₂ ～R ₁₆ L ₂ ) were obtained by column chromatography.

Representative compound spectral data:

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(2-((4-methylphenyl)sulfonamido)ethyl)-1H-indole-2-carboxamide (R ₁ L ₂ )

The sulfonyl chloride raw material used is p-toluenesulfonyl chloride, a white solid with a yield of 57% and a melting point of 208-210°C. ^1. 42–7.31(m,3H),7.25(s,1H),3.40( _q ,J＝6.6Hz,2H),2.97(p,J＝6.7,5.3Hz,2H),2.34(s,3H),2.29(s,6H). ¹³ C NMR (150MHz, DMSO-d ₆ )δ159.90,143.21,142.94,139.43,137.89,137.26,135.15,133.26,130.12,127.76,127.01,125.66,125.22,124.16,119.42,115.33,112.11,4 1.96,39.71,21.37,21.18.ESI-MS:m/z560.11(M+1) ⁺ .C ₂₆ H ₂₆ ClN ₃ O ₅ S ₂ [559.10].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(3-((4-methylphenyl)sulfonamido)propyl)-1H-indole-2-carboxamide (R ₁ L ₃ )

The sulfonyl chloride raw material used is the same as above, white solid, yield 62%, melting point: 194-196°C. ¹ H NMR (400MHz, DMSO-d ₆ ) δ13.00 (s, 3H), 8.94 (t, J = 5.6Hz, 3H), 7.92 (d, J = 2.1Hz, 3H), 7.77–7.58 (m, 15H), 7.53 (d, J = 8.8Hz, 3H), 7.45–7.30 (m, 9H), 7.26 (s, 3H), 3.34 (d, J = 5.0Hz, 15H), 2.87 (q, J = 7.0Hz, 9H), 2.69 (s, 2H), 2.33 (d, J = 17.2Hz, 27H), 1.72 (p, J = 7.1Hz, 6H). ¹³ C NMR (150MHz, DMSO-d ₆ )δ159.79,143.04,142.95,139.40,138.16,137.75,135.09,133.28,130.03,127.68,126.97,125.67,125.09,124.15,119.36,115.28,111.89,4 0.91,37.57,29.52,21.38,21.21.ESI-MS:m/z 574.12(M+1) ⁺ .C ₂₇ H ₂₈ ClN ₃ O ₅ S ₂ [573.12].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(4-((4-methylphenyl)sulfonamido)butyl)-1H-indole-2-carboxamide (R ₁ L ₄ )

The sulfonyl chloride raw material used is the same as above, white solid, yield 45%, melting point: 194-196°C. ¹ H NMR (400MHz, DMSO-d ₆ ) δ13.01(s,1H),8.95(t,J＝5.6Hz,1H),7.95(d,J＝2.0Hz,1H),7.72–7.60(m,4H),7.54(dd,J＝7.3,4.9Hz,2H),7.42–7.31(m,3H), 7.25(s,1H),3.33–3.27(m,2H),2.77(p,J＝6.5Hz,2H),2.36(s,3H),2.30(s,6H),1.55(ddt,J＝21.0,14.5,7.5Hz,4H). ¹³ C NMR (150MHz, DMSO-d ₆ )δ159.59,143.05,142.91,139.42,138.20,137.71,135.12,133.26,130.02,127.70,126.96,125.77,125.11,124.11,119.40,115.29,111.82,4 2.68,39.38,26.90,26.44,21.38,21.21.ESI-MS:m/z 588.14(M+1) ⁺ .C ₂₈ H ₃₀ ClN ₃ O ₅ S ₂ [587.13].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(5-((4-methylphenyl)sulfonamido)pentyl)-1H-indole-2-carboxamide (R ₁ L ₅ )

The sulfonyl chloride raw material used is the same as above, white solid, yield 58%, melting point: 144-146°C. ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.98(s,1H),8.91(t,J＝5.6Hz,1H),7.94(d,J＝2.1Hz,1H),7.67(d,J＝8.2Hz,2H),7.62(d,J＝1.5Hz,2H),7.56–7.46(m,2H),7.4 1–7.31(m,3H),7.26(s,1H),3.29(d,J＝6.3Hz,2H),2.73(q,J＝6.6Hz,2H),2.37(s,3H),2.31(s,6H),1.58–1.29(m,6H). ¹³ C NMR (150MHz, DMSO-d ₆ )δ159.57,143.08,142.90,139.40,138.26,137.81,135.10,133.26,130.02,127.69,126.95,125.77,125.09,124.09,119.40,115.28,111.75,4 2.93,39.72,29.16,28.77,23.95,21.38,21.21.ESI-MS:m/z 602.15(M+1) ⁺ .C ₂₉ H ₃₂ ClN ₃ O ₅ S ₂ [601.15].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(2-((4-methoxyphenyl)sulfonamido)ethyl)-1H-indole-2-carboxamide (R ₂ L ₂ )

The sulfonyl chloride raw material used is p-methoxybenzenesulfonyl chloride, a white solid with a yield of 70% and a melting point of 218-220°C. ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.96 (s, 1H), 9.01 (t, J = 5.8Hz, 1H), 7.94 (d, J = 2.1Hz, 1H), 7.85–7.70 (m, 2H), 7.61 (d, J = 2.6Hz, 3H), 7.54 (d, J = 8.7Hz, 1H), 7. 35(dd,J＝8.8,2.1Hz,1H),7.26(s,1H),7.15–7.04(m,2H),3.81(s,3H),3.40(q,J＝6.6Hz,2H),2.95(q,J＝6.6Hz,2H),2.30(s,6H). ¹³ C NMR (150MHz, DMSO-d ₆ )δ162.67,159.89,142.94,139.43,137.27,135.15,133.26,132.39,129.15,127.75,125.65,125.21,124.16,119.42,115.33,114.85,112.11,5 6.06,41.96,39.70,21.19.ESI-MS: m/z 576.10(M+1) ⁺ .C ₂₆ H ₂₆ ClN ₃ O ₆ S ₂ [575.10].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(3-((4-methoxyphenyl)sulfonamido)propyl)-1H-indole-2-carboxamide (R ₂ L ₃ )

The sulfonyl chloride raw material used is the same as above, white solid, yield 60%, melting point: 186-188°C. ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.98 (s, 1H), 8.92 (t, J = 5.6Hz, 1H), 7.92 (d, J = 2.0Hz, 1H), 7.78–7.70 (m, 2H), 7.61 (s, 2H), 7.52 (dd, J = 7.3, 3.4Hz, 2H), 7.34 (dd, ¹³ C NMR (150MHz,DMSO-d ₆ )δ162.53,159.78,143.03,139.40,137.75,135.10,133.27,132.69,129.08,127.68,125.66,125.09,124.15,119.36,115.28,114.76,111.90,5 6.03,40.89,37.59,29.48,21.22.ESI-MS:m/z 590.12(M+1) ⁺ .C ₂₇ H ₂₈ ClN ₃ O ₆ S ₂ [589.11].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(4-((4-methoxyphenyl)sulfonamido)butyl)-1H-indole-2-carboxamide (R ₂ L ₄ )

The sulfonyl chloride raw material used is the same as above, white solid, yield 55%, melting point: 182-184°C. ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.97 (s, 1H), 8.91 (t, J = 5.6Hz, 1H), 7.93 (d, J = 2.0Hz, 1H), 7.76–7.68 (m, 2H), 7.61 (s, 2H), 7.53 (d, J = 8.7Hz, 1H), 7.43 (t, J = 5. 9Hz,1H),7.34(dd,J＝8.7,2.1Hz,1H),7.26(s,1H),7.15–7.03(m,2H),3.81(s,3H),2.76(q,J＝6.5Hz,2H),2.30(s,6H),1.66–1.44(m,4H). ¹³ C NMR(150 MHz,DMSO-d ₆ )δ162.51,159.60,143.06,139.42,137.72,135.12,133.26,132.75,129.07,127.70,125.76,125.11,124.10,119.40,115.29,114.75,111.81,5 6.05,42.67,39.40,26.87,26.47,21.21.ESI-MS:m/z 604.13(M+1) ⁺ .C ₂₈ H ₃₀ ClN ₃ O ₆ S ₂ [603.13].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(5-((4-methoxyphenyl)sulfonamido)pentyl)-1H-indole-2-carboxamide (R ₂ L ₅ )

The sulfonyl chloride raw material used is the same as above, white solid, yield 65%, melting point: 162-164°C. ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.95(s,1H),8.89(t,J＝5.6Hz,1H),7.93(d,J＝2.0Hz,1H),7.75–7.67(m,2H),7.60(s,2H),7.53(d,J＝8.8Hz,1H),7.39(t,J＝ 5.8Hz,1H),7.34(dd,J＝8.8,2.1Hz,1H),7.26(s,1H),7.13–7.04(m,2H),3.82(s,3H),2.71(q,J＝6.6Hz,2H),1.57–1.25(m,6H). ¹³ CNMR(150MHz,DMSO-d ₆ )δ162.50,159.58,143.08,139.40,137.83,135.10,133.26,132.80,129.06,127.69,125.76,125.08,124.09,119.39,115.28,114.75,111.75,5 6.06,42.92,39.72,29.14,28.78,23.98,21.21.ESI-MS:m/z 618.15(M+1) ⁺ .C ₂₉ H ₃₂ ClN ₃ O ₆ S ₂ [617.14].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(2-((4-nitrophenyl)sulfonamido)ethyl)-1H-indole-2-carboxamide (R ₃ L ₂ )

The sulfonyl chloride raw material used is p-nitrobenzenesulfonyl chloride, a white solid, with a yield of 65% and a melting point of 236-238°C. ¹ HNMR (600MHz, DMSO-d ₆ ) δ12.95(s,1H),9.03(t,J＝5.8Hz,1H),8.46–8.34(m,2H),8.19(t,J＝5.8Hz,1H),8.11–8.03(m,2H),7.93(d,J＝2.1Hz,1H),7.60( s,2H),7.54(d,J＝8.8Hz,1H),7.35(dd,J＝8.7,2.1Hz,1H),7.25(s,1H),3.43(q,J＝6.5Hz,2H),3.08(q,J＝6.5Hz,2H),2.29(s,6H). ¹³ C NMR (150MHz, DMSO-d ₆ )δ159.88,150.03,146.42,142.89,139.45,136.97,135.18,133.25,128.54,127.81,125.67,125.30,125.05,124.12,119.44,115.36,112.13,9 2.55,84.00,42.03,39.70,21.18.ESI-MS:m/z 591.08(M+1) ⁺ .C ₂₅ H ₂₃ ClN ₄ O ₇ S ₂ [590.07].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(3-((4-nitrophenyl)sulfonamido)propyl)-1H-indole-2-carboxamide (R ₃ L ₃ )

The sulfonyl chloride raw material used is the same as above, white solid, yield 80%, melting point: 174-176°C. ¹ H NMR (600MHz, DMSO-d ₆ ) δ12.90 (s, 1H), 8.86 (t, J = 5.6Hz, 1H), 8.34–8.25 (m, 2H), 8.04–7.94 (m, 3H), 7.83 (d, J = 2.1Hz, 1H), 7.52 (d, J = 1.5Hz, 2H), 7.45 (d ,J＝8.7Hz,1H),7.26(dd,J＝8.7,2.1Hz,1H),7.17(s,1H),3.28(q,J＝6.6Hz,2H),2.92(q,J＝6.9Hz,2H),2.23(s,6H),1.67(p,J＝7.1Hz,2H). ¹³ C NMR (150MHz, DMSO-d ₆ )δ159.89,149.95,146.64,142.99,139.38,137.83,135.07,133.29,128.51,127.67,125.59,125.07,124.97,124.14,119.32,115.25,111.86,4 1.00,37.46,29.52,21.21.ESI-MS: m/z 605.09(M+1) ⁺ .C ₂₆ H ₂₅ ClN ₄ O ₇ S ₂ [604.09].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(4-((4-nitrophenyl)sulfonamido)butyl)-1H-indole-2-carboxamide (R ₃ L ₄ )

The sulfonyl chloride raw material used is the same as above, white solid, yield 60%, melting point: 186-188°C. ¹ H NMR (600MHz, DMSO-d ₆ ) δ12.98 (s, 1H), 8.93 (t, J = 5.6Hz, 1H), 8.44–8.35 (m, 2H), 8.09–8.03 (m, 2H), 8.02 (t, J = 5.8Hz, 1H), 7.94 (d, J = 2.1Hz, 1H), 7.61 (d ,J＝1.5Hz,2H),7.53(d,J＝8.7Hz,1H),7.34(dd,J＝8.7,2.1Hz,1H),7.25(s,1H ),3.31(d,J＝5.6Hz,4H),2.88(q,J＝6.5Hz,2H),2.30(s,6H),1.64–1.50(m,4H ). ^13C NMR (150MHz, DMSO-d ₆ ) δ159.64,149.98,146.73,143.04,139.41,137.72,135.11,133.27,128.48,127.70,125.74,125.11,125.01,124.10,119.39, 115.29,111.81,42.76,39.33,26.97,26.38,21.21.ESI-MS: m/z 619.11(M+1) ⁺ .C ₂₇ H ₂₇ ClN ₄ O ₇ S ₂ [618.10].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(5-((4-nitrophenyl)sulfonamido)pentyl)-1H-indole-2-carboxamide (R ₃ L ₅ )

The sulfonyl chloride raw material used is the same as above, white solid, yield 67%, melting point: 156-158°C. ¹ H NMR (600MHz, DMSO-d ₆ ) δ12.89 (s, 1H), 8.84 (t, J = 5.6Hz, 1H), 8.37–8.28 (m, 2H), 8.01–7.94 (m, 2H), 7.91 (t, J = 5.7Hz, 1H), 7.86 (d, J = 2.1Hz, 1H), 7.54 (d . ^13C NMR(150MHz,DMSO-d6)δ159.60,149.98,146.76,143.07,139.40,137.82,135.09,133.26,128.48,127.69,125.75,125.08,125.01,124.08,119.38,11 5.28,111.74,42.99,29.22,28.71,23.86,21.21.ESI-MS:m/z 633.12(M+1) ⁺ .C ₂₈ H ₂₉ ClN ₄ O ₇ S ₂ [632.12].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(2-((4-fluorophenyl)sulfonamido)ethyl)-1H-indole-2-carboxamide (R ₄ L ₂ )

The sulfonyl chloride raw material used is p-fluorobenzenesulfonyl chloride, a white solid with a yield of 65% and a melting point of 201-203°C. ¹ HNMR(600MHz, DMSO-d ₆ )δ12.96(s,1H),9.02(t,J＝5.8Hz,1H),7.94(d,J＝2.1Hz,1H),7.92–7.87(m,2H),7.83(t,J＝6.0Hz,1H),7.61(d,J＝1.6Hz,2H),7.5 4(d,J＝8.8Hz,1H),7.47–7.40(m,2H),7.35(dd,J＝8.8,2.1Hz,1H),7.25(s,1H),3.48–3.36(m,2H),3.05–2.95(m,2H),2.30(s,6H). ¹³ C NMR (150MHz, DMSO-d ₆ )δ165.46,163.79,159.92,142.94,139.43,137.21,137.17,137.15,135.16,133.26,130.02,129.96,127.77,125.66,125.24,124.15,119.43,1 16.94,116.79,115.34,112.13,41.97,21.18.ESI-MS:m/z 564.08(M+1) ⁺ .C ₂₅ H ₂₃ ClFN ₃ O ₅ S ₂ [563.08].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(3-((4-fluorophenyl)sulfonamido)propyl)-1H-indole-2-carboxamide (R ₄ L ₃ )

The sulfonyl chloride raw material used is the same as above, white solid, yield 68%, melting point: 160-162°C. ¹ H NMR (600MHz, DMSO-d ₆ ) δ12.98 (s, 1H), 8.94 (t, J = 5.6Hz, 1H), 7.92 (d, J = 2.1Hz, 1H), 7.89–7.84 (m, 2H), 7.73 (t, J = 5.9Hz, 1H), 7.62 (d, J = 1.5Hz, 2H), 7.53 (d,J＝8.7Hz,1H),7.45–7.37(m,2H),7.34(dd,J＝8.7,2.1Hz,1H),7.25(s,1H),3.45–3.19(m,4H),2.91(q,J＝6.7Hz,2H),2.31(s,6H),1.73(p,J＝7.1Hz,2 H) ^.13C NMR (150MHz, DMSO-d ₆ ) δ165.35,163.69,159.83,143.04,139.39,137.80,137.43,135.09,133.28,129.94,129.88,127.67,125.64,125.08,124.15, 119.35,116.82,116.67,115.27,111.88,40.93,37.54,29.50,21.21.ESI-MS: m/z578.10(M+1) ⁺ .C ₂₆ H ₂₅ ClFN ₃ O ₅ S ₂ [577.09].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(4-((4-fluorophenyl)sulfonamido)butyl)-1H-indole-2-carboxamide (R ₄ L ₄ )

The sulfonyl chloride raw material used is the same as above, white solid, yield 45%, melting point: 178-180°C. ¹ H NMR (600MHz, DMSO-d ₆ ) δ12.92 (s, 1H), 8.86 (t, J = 5.6Hz, 1H), 7.87 (d, J = 2.1Hz, 1H), 7.83–7.72 (m, 2H), 7.59 (t, J = 5.9Hz, 1H), 7.55 (d, J = 1.6Hz, 2H), 7.46 (d,J＝8.7Hz,1H),7.38–7.32(m,2H),7.27(dd,J＝8.7,2.1Hz,1H),7.18(s,1H),3.23(t,J＝6.4Hz,2H),2.73(q,J＝6.5Hz,2H),2.23(s,6H),1.58–1.34(m,4 H) ^.13C NMR (150MHz, DMSO-d ₆ ) δ165.33,163.66,159.62,143.06,139.41,137.73,137.48,137.46,135.12,133.27,129.93,129.87,127.70,125.76,125.10, 124.11,119.40,116.81,116.66,115.29,111.81,42.69,39.36,26.90,26.42,21.21.ESI-MS: m/z 592.11(M+1) ⁺ .C ₂₇ H ₂₇ ClFN ₃ O ₅ S ₂ [591.11].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(5-((4-fluorophenyl)sulfonamido)pentyl)-1H-indole-2-carboxamide (R ₄ L ₅ )

The sulfonyl chloride raw material used is the same as above, white solid, yield 56%, melting point: 158-160°C. ¹ H NMR(600MHz,DMSO-d ₆ )δ12.98(s,1H),8.92(t,J＝5.6Hz,1H),7.94(d,J＝2.1Hz,1H),7.89–7.80(m,2H),7.68–7.58(m,3H),7.53(d,J＝8.8Hz,1H),7.47–7.38(m,2H),7.34(dd,J＝8.8,2.1Hz,1H),7.25(s,1H),3.30(q,J＝6.7Hz,2H),2.82–2.70(m,2H),2.30(s,6H),1.56–1.30(m,6H). ¹³ CNMR(150MHz,DMSO-d ₆ )δ165.32,163.65,159.59,143.08,139.40,137.84,137.54,137.52,135.10,133.26,129.92,129.86,127.68,125.75,125.08,124.09,119.38,1 16.81,116.66,115.28,111.74,42.93,29.15,28.76,23.92,21.21.ESI-MS:m/z 606.13(M+1) ⁺ .C ₂₈ H ₂₉ ClFN ₃ O ₅ S ₂ [605.12].

5-Chloro-N-(2-((4-cyanophenyl)sulfonamido)ethyl)-3-((3,5-dimethylphenyl)sulfonyl)-1H-indole-2-carboxamide (R ₅ L ₂ )

The sulfonyl chloride raw material used is p-cyanobenzenesulfonyl chloride, a white solid with a yield of 69% and a melting point of 198-200°C. ¹ HNMR (600MHz, DMSO-d ₆ ) δ12.88 (s, 1H), 8.96 (t, J = 5.8Hz, 1H), 8.04 (t, J = 5.9Hz, 1H), 8.01–7.96 (m, 2H), 7.94–7.89 (m, 2H), 7.87 (d, J = 2.1Hz, 1H), 7.53 (d ,J＝1.6Hz,2H),7.47(d,J＝8.8Hz,1H),7.28(dd,J＝8.8,2.1Hz,1H),7.18(s,1H),3.39–3.30(m,2H),2.97(q,J＝6.5Hz,2H),2.22(s,6H). ¹³ C NMR (150MHz, DMSO -d ₆ )δ159.90,144.93,142.90,139.45,137.06,135.19,133.92,133.25,127.81,127.73,125.67,125.29,124.14,119.44,118.08,115.46,115.36,1 12.13,41.98,39.69,21.19.ESI-MS:m/z 571.09(M+1) ⁺ .C ₂₆ H ₂₃ ClN ₄ O ₅ S ₂ [570.08].

5-Chloro-N-(3-((4-cyanophenyl)sulfonamido)propyl)-3-((3,5-dimethylphenyl)sulfonyl)-1H-indole-2-carboxamide (R ₅ L ₃ )

The sulfonyl chloride raw material used is the same as above, white solid, yield 65%, melting point: 208-210°C. ¹ H NMR (600MHz, DMSO-d ₆ ) δ12.99(s,1H),8.94(t,J＝5.6Hz,1H),8.06–7.99(m,3H),7.99–7.95(m,2H),7.91(d,J＝2.1Hz,1H),7.61(d,J＝1.6Hz,2H),7.53(d ,J＝8.8Hz,1H),7.34(dd,J＝8.7,2.1Hz,1H),7.26(s,1H),3.35(q,J＝6.7Hz,2H),2.96(q,J＝6.9Hz,2H),2.31(s,6H),1.73(p,J＝7.1Hz,2H). ¹³ C NMR (150MHz, DMSO-d ₆ )δ159.88,145.18,143.02,139.38,137.86,135.09,133.83,133.29,127.69,127.66,125.60,125.07,124.16,119.32,118.16,115.29,115.27,1 11.87,40.97,37.47,29.55,21.23.ESI-MS:m/z 585.10(M+1) ⁺ .C ₂₇ H ₂₅ ClN ₄ O ₅ S ₂ [584.10].

5-Chloro-N-(4-((4-cyanophenyl)sulfonamido)butyl)-3-((3,5-dimethylphenyl)sulfonyl)-1H-indole-2-carboxamide (R ₅ L ₄ )

The sulfonyl chloride raw material used is the same as above, white solid, yield 51%, melting point: 176-178°C. ¹ H NMR (600MHz, DMSO-d ₆ ) δ12.99 (s, 2H), 8.94 (t, J = 5.6Hz, 2H), 8.07 (d, J = 8.4Hz, 4H), 7.99–7.91 (m, 8H), 7.62 (s, 4H), 7.54 (d, J = 8.7Hz, 2H), 7.34 (dd, J = 8. ¹³ C NMR 0MHz, DMSO-d ₆ )δ159.64,145.25,143.04,139.41,137.74,135.12,133.85,133.26,127.70,127.68,125.73,125.11,124.11,119.39,118.18,115.29,115.27,1 11.81,55.34,42.72,39.33,26.97,26.38,21.22.ESI-MS:m/z 599.12(M+1) ⁺ .C ₂₈ H ₂₇ ClN ₄ O ₅ S ₂ [598.11].

5-Chloro-N-(5-((4-cyanophenyl)sulfonamido)pentyl)-3-((3,5-dimethylphenyl)sulfonyl)-1H-indole-2-carboxamide (R ₅ L ₅ )

The sulfonyl chloride raw material used is the same as above, white solid, yield 61%, melting point: 168-170°C. ¹ H NMR (600MHz, DMSO-d ₆ ) δ12.91 (s, 1H), 8.85 (t, J = 5.6Hz, 1H), 8.00 (d, J = 8.5Hz, 2H), 7.91–7.79 (m, 4H), 7.54 (s, 2H), 7.46 (d, J = 8.7Hz, 1H), 7.26 (dd, J = 8.8,2.1Hz,1H),7.18(s,1H),3.25–3.19(m,2H),2.73(q,J＝6.8,6.3Hz,2H),2.45–2.42(m,2H),2.23(s,6H),1.49–1.24(m,6H). ¹³ CNMR(150MHz,DMSO-d ₆ )δ159.61,145.30,143.07,139.40,137.84,135.10,133.85,133.26,127.67,125.74,125.08,124.10,119.38,118.19,115.28,115.26,111.74,4 2.96,29.22,28.72,23.85,21.22.ESI-MS:m/z 613.13(M+1) ⁺ .C ₂₉ H ₂₉ ClN ₄ O ₅ S ₂ [612.13].

N-(2-((4-bromophenyl)sulfonamido)ethyl)-5-chloro-3-((3,5-dimethylphenyl)sulfonyl)-1H-indole-2-carboxamide (R ₆ L ₂ )

The sulfonyl chloride raw material used is p-bromobenzenesulfonyl chloride, white solid, yield 64%, melting point: 220-222°C. ¹ HNMR (600MHz, DMSO-d ₆ )δ12.95(s,1H),9.02(tt,J＝5.5,2.4Hz,1H),7.95(q,J＝2.2Hz,1H),7.89(td,J＝6.0,2.0Hz,1H),7.81(d,J＝8.5Hz,2H),7.76(dt,J＝8.5,1.7Hz,2H),7.6 1(s,2H),7.55(dd,J＝8.8,1.5Hz,1H),7.35(dd,J＝8.8,2.1Hz,1H),7.24(d,J＝3.6Hz,1H),3.46–3.39(m,2H),3.01(qd,J＝5.9,3.0Hz,2H),2.29(s,6H) ^{1. 3} C NMR (150MHz, DMSO-d ₆ )δ159.92,142.96,140.10,139.44,137.17,135.17,133.29,132.82,129.04,127.80,126.77,125.71,125.26,124.15,119.47,115.36,112.1 6,41.99,21.19.ESI-MS:m/z 624.00(M+1) ⁺ .C ₂₅ H ₂₃ BrClN ₃ O ₅ S ₂ [623.00].

N-(3-((4-bromophenyl)sulfonamido)propyl)-5-chloro-3-((3,5-dimethylphenyl)sulfonyl)-1H-indole-2-carboxamide (R ₆ L ₃ )

The sulfonyl chloride raw material used is the same as above, white solid, yield 80%, melting point: 162-164°C. ¹ H NMR (600MHz, DMSO-d ₆ ) δ12.98 (s, 1H), 8.94 (t, J = 5.6Hz, 1H), 7.93 (d, J = 2.1Hz, 1H), 7.82–7.76 (m, 3H), 7.76–7.71 (m, 2H), 7.62 (d, J = 1.6Hz, 2H), 7.53 (d ,J＝8.7Hz,1H),7.34(dd,J＝8.7,2.1Hz,1H),7.25(s,1H),3.36(q,J＝6.7Hz,2H),2.93(q,J＝6.7Hz,2H),2.31(s,6H),1.74(p,J＝7.1Hz,2H). ¹³ C NMR (150MHz, DMSO-d ₆ )δ159.85,143.05,140.36,139.40,137.79,135.10,133.30,132.72,128.99,127.70,126.56,125.67,125.10,124.16,119.37,115.28,111.91,4 0.95,37.53,29.53,21.22.ESI-MS:m/z 638.02(M+1) ⁺ .C ₂₆ H ₂₅ BrClN ₃ O ₅ S ₂ [637.01].

N-(4-((4-bromophenyl)sulfonamido)butyl)-5-chloro-3-((3,5-dimethylphenyl)sulfonyl)-1H-indole-2-carboxamide (R ₆ L ₄ )

The sulfonyl chloride raw material used is the same as above, white solid, yield 82%, melting point: 188-190°C. ¹ H NMR (600MHz, DMSO-d ₆ ) δ12.98 (s, 1H), 8.93 (t, J = 5.7Hz, 1H), 7.95 (d, J = 2.1Hz, 1H), 7.83–7.78 (m, 2H), 7.74 (d, J = 8.6Hz, 3H), 7.62 (d, J = 1.6Hz, 2H), 7.5 4(d,J＝8.7Hz,1H),7.34(dd,J＝8.7,2.1Hz,1H),7.26(s,1H),2.82(q,J＝6.4Hz,2H),2.31(s,6H),1.63–1.49(m,4H). ¹³ C NMR (150MHz, DMSO-d ₆ )δ159.63,143.07,140.41,139.43,137.72,135.13,133.28,132.72,128.99,127.72,126.51,125.78,125.12,124.11,119.42,115.30,111.83,4 2.70,39.36,26.93,26.41,21.22.ESI-MS: m/z 652.03(M+1) ⁺ .C ₂₇ H ₂₇ BrClN ₃ O ₅ S ₂ [651.03].

N-(5-((4-bromophenyl)sulfonamido)pentyl)-5-chloro-3-((3,5-dimethylphenyl)sulfonyl)-1H-indole-2-carboxamide (R ₆ L ₅ )

The sulfonyl chloride raw material used was the same as above, white solid, yield 78%, melting point: 146-148°C. ¹ H NMR (600MHz, DMSO-d ₆ )δ12.97(s,1H),8.92(t,J＝5.6Hz,1H),7.94(d,J＝2.1Hz,1H),7.82–7.78(m,2H),7.73(d,J＝2.0Hz,1H),7.72–7.67(m,2H),7.62(d,J＝1.5Hz,2H),7.54(d,J＝8.7Hz,1H),7.34( dd,J＝8.8,2.1Hz,1H),7.25(s,1H),3.30(t,J＝6.6Hz,5H),2.80–2.74(m,2H),2.30(s,6H),1.53(p,J＝7.3Hz,2H),1.44(h,J＝8.5,7.8Hz,2H),1.36(qd,J =8.5,7.2,2.2Hz,2H). ¹³ C NMR (150MHz, DMSO-d ₆ ) δ162.76,159.60,143.10,140.46,139.41,137.81,135.11,133.28,132.72,128.98,127.71,126.50,125.79,125.10,124 .10,119.41,115.29,111.76,42.94,39.70,36.23,31.26,29.19,28.75,23.91,21.22.ESI-MS:m/z 666.05(M+1) ⁺ .C ₂₈ H ₂₉ BrClN ₃ O ₅ S ₂ [665.04] .

5-Chloro-N-(2-((4-chlorophenyl)sulfonamido)ethyl)-3-((3,5-dimethylphenyl)sulfonyl)-1H-indole-2-carboxamide (R ₇ L ₂ )

The sulfonyl chloride raw material used is p-chlorobenzenesulfonyl chloride, a white solid with a yield of 77% and a melting point of 218-220°C. ¹ HNMR (600MHz, DMSO-d ₆ ) δ12.89 (s, 2H), 8.96 (t, J = 5.8Hz, 2H), 7.87 (d, J = 2.1Hz, 2H), 7.83 (t, J = 5.9Hz, 2H), 7.76 (d, J = 8.4Hz, 4H), 7.59 (d, J = 8.6Hz, 3H), 7. ¹³ C NMR -d ₆ )δ159.93,142.94,139.65,139.45,137.88,137.18,135.17,133.28,129.88,128.94,127.79,125.68,125.26,124.78,124.16,119.45,115.36,1 12.14,41.97,21.18.ESI-MS:m/z 580.05(M+1) ⁺ .C ₂₅ H ₂₃ Cl ₂ N ₃ O ₅ S ₂ [579.05].

5-Chloro-N-(3-((4-chlorophenyl)sulfonamido)propyl)-3-((3,5-dimethylphenyl)sulfonyl)-1H-indole-2-carboxamide (R ₇ L ₃ )

The sulfonyl chloride raw material used is the same as above, white solid, yield 79%, melting point: 184-186°C. ¹ H NMR (600MHz, DMSO-d ₆ ) δ12.91 (s, 1H), 8.87 (t, J = 5.7Hz, 1H), 7.85 (d, J = 2.1Hz, 1H), 7.74 (dd, J = 8.6, 6.6Hz, 3H), 7.60–7.53 (m, 4H), 7.46 (d, J = 8.7Hz, _1H ) ¹³ C NMR )δ159.86,143.04,139.92,139.40,137.81,137.67,135.10,133.30,129.78,128.89,127.69,125.65,125.09,124.17,119.36,115.28,111.90,4 0.94,37.53,29.52,21.22.ESI-MS:m/z 594.07(M+1) ⁺ .C ₂₆ H ₂₅ Cl ₂ N ₃ O ₅ S ₂ [593.06].

5-Chloro-N-(4-((4-chlorophenyl)sulfonamido)butyl)-3-((3,5-dimethylphenyl)sulfonyl)-1H-indole-2-carboxamide (R ₇ L ₄ )

The sulfonyl chloride raw material used is the same as above, white solid, yield 75%, melting point: 196-198°C. ¹ H NMR (600MHz, DMSO-d ₆ ) δ12.99 (s, 1H), 8.94 (t, J = 5.7Hz, 1H), 7.95 (t, J = 1.8Hz, 1H), 7.84–7.79 (m, 2H), 7.74 (t, J = 5.8Hz, 1H), 7.69–7.64 (m, 2H), 7.64–7 .61(m,2H),7.54(d,J＝8.7Hz,1H),7.34(dd,J＝8.8,2.1Hz,1H),7.25(s,1H),3.31(t,J＝6.3Hz,2H),2.30(s,6H),1.63–1.49(m,4H). ¹³ C NMR (150MHz, DMSO-d ₆ )δ159.64,143.07,139.98,139.43,137.73,137.63,135.13,133.28,129.78,128.88,127.72,125.77,125.12,124.12,119.41,115.30,111.83,4 2.70,39.36,26.92,26.41,21.21.ESI-MS:m/z 608.08(M+1) ⁺ .C ₂₇ H ₂₇ Cl ₂ N ₃ O ₅ S ₂ [607.08].

5-Chloro-N-(5-((4-chlorophenyl)sulfonamido)pentyl)-3-((3,5-dimethylphenyl)sulfonyl)-1H-indole-2-carboxamide (R ₇ L ₅ )

The sulfonyl chloride raw material used is the same as above, white solid, yield 82%, melting point: 144-146°C. ¹ H NMR (600MHz, DMSO-d ₆ ) δ12.98 (s, 1H), 8.92 (t, J = 5.6Hz, 1H), 7.95 (d, J = 2.1Hz, 1H), 7.83–7.78 (m, 2H), 7.73–7.60 (m, 5H), 7.54 (d, J = 8.7Hz, 1H), 7.34 (dd . (m,1H). ¹³ C NMR(150MHz,DMSO-d ₆ )δ159.61,143.08,140.03,139.41,137.83,137.61,135.11,133.27,129.78,128.88,128.15,127.70,125.77,125.10,124.10,119.40,115.29,111.75,42.94,42.85,39.75,39.69,39.49,29.17,29.02,28.75,28.18,23.90,23.69,21.21.ESI-MS:m/z 622.10(M+1) ⁺ .C ₂₈ H ₂₉ Cl ₂ N ₃ O ₅ S ₂ [621.09].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(2-(thiophene-2-sulfonylamino)ethyl)-1H-indole-2-carboxamide (R ₈ L ₂ )

The sulfonyl chloride raw material used is 2-thiophenesulfonyl chloride, a white solid with a yield of 80% and a melting point of 216-218°C. ¹ HNMR (600MHz, DMSO-d ₆ ) δ12.90(s,1H),8.98(t,J＝5.8Hz,1H),7.91(t,J＝5.9Hz,1H),7.87(dd,J＝5.2,1.5Hz,2H),7.58–7.54(m,3H),7.47(d,J＝8.7Hz,1H) ,7.27(dd,J＝8.7,2.1Hz,1H),7.17(s,1H),7.13(dd,J＝5.0,3.7Hz,1H),3.37(q,J＝6.6Hz,2H),3.00(q,J＝6.6Hz,2H),2.23(s,6H). ¹³ C NMR (150MHz, DMSO-d ₆ )δ159.99,142.96,141.60,139.44,137.34,135.16,133.28,133.08,132.10,128.21,127.77,125.65,125.23,124.19,119.43,115.34,112.16,4 2.19,39.61,21.21.ESI-MS: m/z 552.05(M+1) ⁺ .C ₂₃ H ₂₂ ClN ₃ O ₅ S ₃ [551.04].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(3-(thiophene-2-sulfonylamino)propyl)-1H-indole-2-carboxamide (R ₈ L ₃ )

The sulfonyl chloride raw material used is the same as above, white solid, yield 70%, melting point: 136-138°C. ¹ H NMR (600MHz, DMSO-d ₆ ) δ12.93 (s, 1H), 8.89 (t, J = 5.7Hz, 1H), 7.90-7.79 (m, 3H), 7.56 (d, J = 1.6Hz, 2H), 7.53 (dd, J = 3.7, 1.4Hz, 1H), 7.46 (d, J = 8.7Hz, 1H), 7.27(dd,J＝8.7,2.1Hz,1H),7.18(s,1H),7.10(dd,J＝5.0,3.7Hz,1H),3.33–3.26(m,2H),2.92(q,J＝6.7Hz,2H),2.82(s,1H),2.23(s,6H),1.69(p,J＝7.1 Hz,2H). ¹³ C NMR (150MHz, DMSO-d ₆ ) δ162.76,159.85,143.05,141.97,139.41,137.82,135.11,133.29,132.74,131.86,128.10,127.69,125.66,125.10,124.18, 119.36,115.29,111.90,41.17,37.58,36.23,31.25,29.42,21.22.ESI-MS: m/z566.06(M+1) ⁺ .C ₂₄ H ₂₄ ClN ₃ O ₅ S ₃ [565.06].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(4-(thiophene-2-sulfonylamino)butyl)-1H-indole-2-carboxamide (R ₈ L ₄ )

The sulfonyl chloride raw material used was the same as above, white solid, yield 76%, melting point: 188-190°C. ¹ H NMR (600MHz, DMSO-d ₆ )δ12.93(s,1H),8.88(t,J＝5.6Hz,1H),7.87(d,J＝2.1Hz,1H),7.84(dd,J＝5.0,1.4Hz,1H),7.75(t,J＝5.8Hz,1H),7.55(d,J＝1.6Hz,2H),7.52(dd,J＝3.7,1.4Hz,1H),7. 46(d,J＝8.7Hz,1H),7.27(dd,J＝8.7,2.1Hz,1H),7.18(s,1H),7.10(dd,J＝5.0,3.7Hz,1H),3.25(t,J＝6.4Hz,2H),2.82(q,J＝6.4Hz,2H),2.23(s,6H),1.5 7–1.44(m,4H). ¹³ C NMR (150MHz, DMSO-d ₆ ) δ159.65,143.06,142.02,139.43,137.77,135.13,133.27,132.70,132.66,131.80,128.09,127.71,125.76,125.12,124 .13,119.41,115.30,111.82,42.92,39.38,26.78,26.45,21.22.ESI-MS:m/z 580.08(M+1) ⁺ .C ₂₅ H ₂₆ ClN ₃ O ₅ S ₃ [579.07].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(5-(thiophene-2-sulfonylamino)pentyl)-1H-indole-2-carboxamide (R ₈ L ₅ )

The sulfonyl chloride raw material used was the same as above, white solid, yield 77%, melting point: 168-170°C. ¹ H NMR (600MHz, DMSO-d ₆ )δ13.00(s,1H),8.94(t,J＝5.7Hz,1H),7.97–7.89(m,2H),7.79(t,J＝5.8Hz,1H),7.63(d,J＝1.6Hz,2H),7.58(dd,J＝3.7,1.4Hz,1H),7.54(d,J＝8.7Hz,1H),7.34(dd,J＝8. 7,2.1Hz,1H),7.25(s,1H),7.18(dd,J＝5.0,3.7Hz,1H),3.32(d,J＝6.4Hz,2H),2.91–2.82(m,2H),2.31(s,6H),1.51(dp,J＝40.7,7.2Hz,4H),1.38(td, J＝8.4,3.9Hz,2H). ¹³ CNMR (150MHz, DMSO-d ₆ ) δ159.62,143.09,142.10,139.41,138.77,137.86,135.11,134.72,133.27,132.65,131.77,128.08,127.70,125.76,125 .09,124.80,124.11,120.34,119.40,115.29,111.76,43.17,39.72,29.04,28.78,23.96,21.22.ESI-MS:m/z 594.10(M+1) ⁺ .C ₂₆ H ₂₈ ClN ₃ O ₅ S ₃ [593.09].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(2-(phenylsulfonamido)ethyl)-1H-indole-2-carboxamide (R ₉ L ₂ )

The sulfonyl chloride raw material used is benzenesulfonyl chloride, a white solid with a yield of 76% and a melting point of 228-230°C. ¹ H NMR (600MHz, DMSO-d ₆ ) δ12.89 (s, 1H), 8.95 (t, J = 5.8Hz, 1H), 7.86 (d, J = 2.1Hz, 1H), 7.79–7.75 (m, 2H), 7.72 (t, J = 6.0Hz, 1H), 7.60–7.50 (m, 5H), 7.47 (d,J＝8.7Hz,1H),7.27(dd,J＝8.7,2.1Hz,1H),7.17(s,1H),3.34(q,J＝6.6Hz,2H),2.91(q,J＝6.7Hz,2H),2.22(s,6H). ¹³ C NMR (150MHz, DMSO-d ₆ )δ159.95,142.95,140.75,139.44,138.80,137.31,135.16,133.26,132.96,129.75,127.76,126.95,125.64,125.23,124.79,124.18,119.42,1 15.34,112.13,41.96,39.72,21.20.ESI-MS:m/z 546.09(M+1) ⁺ .C ₂₅ H ₂₄ ClN ₃ O ₅ S ₂ [545.09].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(3-(phenylsulfonamido)propyl)-1H-indole-2-carboxamide (R ₉ L ₃ )

The sulfonyl chloride raw material used is the same as above, yellow solid, yield 79%, melting point: 200-202°C. ¹ H NMR (600MHz, DMSO-d ₆ ) δ12.92 (s, 1H), 8.87 (t, J = 5.6Hz, 1H), 7.86 (d, J = 2.0Hz, 1H), 7.77–7.72 (m, 2H), 7.62 (t, J = 5.9Hz, 1H), 7.57–7.53 (m, 3H), 7.50 (dd . 1Hz,2H). ¹³ C NMR (150MHz, DMSO-d ₆ ) δ159.83,143.05,141.05,139.40,137.79,135.10,133.29,132.76,129.64,127.70,126.90,125.67,125.10,124.17,119.37, 115.29,111.90,40.94,37.57,29.57,21.21.ESI-MS:m/z 560.11(M+1) ⁺ .C ₂₆ H ₂₆ ClN ₃ O ₅ S ₂ [559.10].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(4-(phenylsulfonamido)butyl)-1H-indole-2-carboxamide (R ₉ L ₄ )

The sulfonyl chloride raw material used was the same as above, yellow solid, yield 83%, melting point: 186-188°C. ¹ H NMR (600MHz, DMSO-d ₆ )δ12.92(s,1H),8.86(t,J＝5.6Hz,1H),7.87(d,J＝2.1Hz,1H),7.77–7.71(m,2H),7.58–7.49(m,6H),7.46(d,J＝8.7Hz,1H),7.27(dd,J＝8.8,2.1Hz,1H),3.23(d,J＝6.3Hz,2H),2.73(q,J＝6.5Hz,2H),2.23(s,6H),1.54–1.41(m,4H). ¹³ C NMR (150MHz, DMSO-d ₆ )δ159.63,143.06,141.06,139.43,137.75,135.13,133.27,132.73,129.63,127.71,126.90,125.76,125.12,124.12,119.40,115.30,111.81,4 2.69,39.37,26.92,26.42,21.22.ESI-MS:m/z 574.12(M+1) ⁺ .C ₂₇ H ₂₈ ClN ₃ O ₅ S ₂ [573.12].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(5-(phenylsulfonamido)pentyl)-1H-indole-2-carboxamide (R ₉ L ₅ )

The sulfonyl chloride raw material used was the same as above, yellow solid, yield 77%, melting point: 198-200°C. ¹ H NMR (600MHz, DMSO-d ₆ )δ12.91(s,1H),8.84(t,J＝5.7Hz,1H),7.86(d,J＝2.1Hz,1H),7.72(dt,J＝7.0,1.4Hz,2H),7.59–7.48(m,6H),7.46(d,J＝8.7Hz,1H),7.27(dd,J＝8.7,2. 1Hz,1H),7.18(s,1H),3.25–3.19(m,2H),2.71–2.65(m,2H),2.23(s,6H),1.43(q,J＝7.4Hz,2H),1.35(h,J＝7.3Hz,2H),1.27(qd,J＝8.5,7.2,2.0Hz,2 H) ^.13C NMR (150MHz, DMSO-d ₆ ) δ159.60,143.09,141.14,139.41,137.85,135.11,133.27,132.72,129.62,127.69,126.89,125.76,125.09,124.10,119.39, 115.29,111.75,42.94,39.70,29.19,28.76,23.92,21.22.ESI-MS:m/z 588.14(M+1) ⁺ .C ₂₈ H ₃₀ ClN ₃ O ₅ S ₂ [587.13].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(2-(pyridine-3-sulfonylamino)ethyl)-1H-indole-2-carboxamide (R ₁₀ L ₂ )

The sulfonyl chloride raw material used was 3-pyridinesulfonyl chloride, a white solid, with a yield of 76%, and a melting point of 216-218°C. ¹ HNMR (600 MHz, DMSO-d ₆ )δ12.97(s,1H),9.06(t,J＝5.8Hz,1H),9.02–8.98(m,1H),8.82(dd,J＝4.8,1.6Hz,1H),8.22(dt,J＝8.0,2.0Hz,1H),8.06(t,J＝5.9Hz,1H),7.94(d,J＝2. 1Hz,1H),7.66(ddd,J＝8.1,4.8,0.9Hz,1H),7.62(d,J＝1.5Hz,2H),7.55(d,J＝8.8Hz,1H),7.35(dd,J＝8.8,2.1Hz,1H),7.25(s,1H),3.47–3.40(m,2H),3. 05(q,J＝6.6Hz,2H). ¹³ CNMR (150MHz, DMSO-d ₆ ) δ159.97,153.61,147.54,142.93,139.45,137.21,137.14,135.17,135.02,133.27,127.78,125.66,125.25,124.81,124 .18,119.43,115.36,112.15,41.95,39.70,21.19.ESI-MS:m/z547.09(M+1) ⁺ .C ₂₄ H ₂₃ ClN ₄ O ₅ S ₂ [546.08].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(3-(pyridine-3-sulfonylamino)propyl)-1H-indole-2-carboxamide (R ₁₀ L ₃ )

The sulfonyl chloride raw material used is the same as above, white solid, yield 82%, melting point: 178-180°C. ¹ H NMR (600MHz, DMSO-d ₆ ) δ12.92(s,1H),8.92–8.85(m,2H),8.73(dd,J＝4.8,1.6Hz,1H),8.12(dt,J＝8.1,2.0Hz,1H),7.89(t,J＝5.8Hz,1H),7.85(d,J＝2.1Hz ,1H),7.58–7.52(m,3H),7.45(d,J＝8.7Hz,1H),7.26(dd,J＝8.8,2.1Hz,1H),7.17(s,1H),3.29(q,J＝6.6Hz,2H),2.90(q,J＝6.7Hz,2H),2.23(s,6H) ^13. C NMR(150MHz,DMSO-d ₆ )δ159.88,153.42,147.49,143.05,139.39,137.87,137.41,135.09,134.93,133.29,127.68,125.63,125.08,124.72,124.18,119.35,115.2 7,111.90,40.93,37.50,31.39,29.59,21.21,14.54,14.38.ESI-MS: m/z561.10(M+1) ⁺ .C ₂₅ H ₂₅ ClN ₄ O ₅ S ₂ [560.10].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(4-(pyridine-3-sulfonamido)butyl)-1H-indole-2-carboxamide (R ₁₀ L ₄ )

The sulfonyl chloride raw material used is the same as above, white solid, yield 71%, melting point: 198-200°C. ¹ H NMR (600MHz, DMSO-d ₆ ) δ12.92 (s, 1H), 8.91–8.85 (m, 2H), 8.74 (dd, J = 4.8, 1.6Hz, 1H), 8.11 (dt, J = 8.1, 2.0Hz, 1H), 7.87 (d, J = 2.1Hz, 1H), 7.81 (t, J = 5.8Hz ,1H),7.59–7.54(m,3H),7.46(d,J＝8.7Hz,1H),7.27(dd,J＝8.7,2.1Hz,1H) ,7.17(s,1H),3.26–3.22(m,2H),2.79(q,J＝6.4Hz,2H),2.23(s,6H),1.56–1 .42(m,4H). ¹³ C NMR (150MHz, DMSO-d ₆ ) δ159.66,153.40,147.49,143.06,139.43,138.81,137.76,137.43,135.13,134.93,133.27,127.71,125.75,125.11,124.72 ,124.13,119.40,115.30,111.82,42.69,39.35,26.96,26.39,21.22.ESI-MS:m/z 575.12(M+1) ⁺ .C ₂₆ H ₂₇ ClN ₄ O ₅ S ₂ [574.11].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(5-(pyridine-3-sulfonylamino)pentyl)-1H-indole-2-carboxamide (R ₁₀ L ₅ )

The sulfonyl chloride raw material used was the same as above, white solid, yield 74%, melting point: 178-180°C. ¹ H NMR (600MHz, DMSO-d ₆ )δ12.92(s,1H),8.90–8.83(m,2H),8.74(dd,J＝4.8,1.6Hz,1H),8.10(dt,J＝8.0,2.0Hz,1H),7.86(d,J＝2.1Hz,1H),7.79(t,J＝5.8Hz,1H),7.57(ddd,J＝8.1,4.8,0.8Hz,2H),7.55(d,J＝1.6Hz,2H),7.46( d,J＝8.7Hz,1H),7.27(dd,J＝8.8,2.1Hz,1H),7.19–7.16(m,1H),3.23(q,J＝6.6Hz,2H),2.74(q,J＝7.0Hz,2H),2.23(s,6H),1.45(p,J＝7.3Hz,2H),1.37( p, J＝7.2Hz, 2H), 1.28 (qd, J＝8.6, 7.3, 2.2Hz, 2H). ¹³ C NMR (150MHz, DMSO-d ₆ ) δ159.61,153.39,147.48,143.08,139.41,137.85,137.50,135.11,134.92,133.27,127.69,125.75,125.09,124.72,124 .11,119.39,115.29,111.75,42.92,39.68,29.21,28.74,23.87,21.21.ESI-MS:m/z589.13(M+1) ⁺ .C ₂₇ H ₂₉ ClN ₄ O ₅ S ₂ [588.13].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(2-((2-fluorophenyl)sulfonamido)ethyl)-1H-indole-2-carboxamide (R ₁₁ L ₂ )

The sulfonyl chloride raw material used is o-fluorobenzenesulfonyl chloride, white solid, yield 82%, melting point: 210-212°C. ¹ HNMR (600MHz, DMSO-d ₆ )δ12.89(s,1H),8.96(t,J＝5.8Hz,1H),8.01(t,J＝5.9Hz,1H),7.86(d,J＝2.1Hz,1H),7.76(td,J＝7.6,1.8Hz,1H),7.65-7.58(m,1H),7.54(d,J＝1.6Hz,2H),7.47(d,J＝8.8Hz,2H) z,1H),7.37(ddd,J＝10.6,8.3,1.1Hz,1H),7.32(td,J＝7.6,1.1Hz,1H),7.27(dd,J＝8.8,2.1Hz,1H),7.16(s,1H),3.36(q,J＝6.7Hz,2H),3.04(q,J＝6.7Hz, 2H),2.22(s,6H). ¹³ C NMR (150MHz, DMSO-d ₆ ) δ159.96,159.51,157.83,142.96,139.43,138.83,137.30,135.77,135.71,135.15,134.79,133.26,130.10,128.79,128.6 9,127.77,125.65,125.39,125.37,125.23,124.18,119.43,117.84,117.70,115.33,112.15,41.81,39.86,21.18.ESI-MS:m/z 564.08(M+1) ⁺ .C ₂₅ H ₂₃ ClFN ₃ O ₅ S ₂ [563.08].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(3-((2-fluorophenyl)sulfonamido)propyl)-1H-indole-2-carboxamide (R ₁₁ L ₃ )

The sulfonyl chloride raw material used was the same as above, white solid, yield 70%, melting point: 218-220°C. ¹ H NMR (600MHz, DMSO-d ₆ )δ12.92(s,1H),8.87(t,J＝5.6Hz,1H),7.92(t,J＝5.8Hz,1H),7.86(t,J＝1.6Hz,1H),7.74(td,J＝7.6,1.8Hz,1H),7.60(dddt,J＝11.2,9.2,6.1,3.0Hz,1H),7.55(d,J＝1.6Hz,2 H),7.46(d,J＝8.8Hz,1H),7.35(ddd,J＝10.6,8.3,1.1Hz,1H),7.32–7.23(m,2H),7.16(s,1H),3.29(t,J＝6.6Hz,2H),2.95(q,J＝6.6Hz,2H),2.22(s,6H) ,1.68(p,J＝7.1Hz,2H). ¹³ C NMR(150MHz,DMSO-d ₆ )δ159.84,159.51,157.83,143.04,139.40,137.76,135.58,135.52,135.10,133.29,130.11,129.05,128.95,127.70,125.67,125.29,125.27,1 25.10,124.16,119.37,117.75,117.62,115.28,111.91,55.34,40.81,37.51,36.23,31.25,29.69,21.20.ESI-MS:m/z578.10(M+1) ⁺ .C ₂₆ H ₂₅ ClFN ₃ O ₅ S ₂ [577.09].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(4-((2-fluorophenyl)sulfonamido)butyl)-1H-indole-2-carboxamide (R ₁₁ L ₄ )

The sulfonyl chloride raw material used was the same as above, yellow solid, yield 77%, melting point: 210-212°C. ¹ H NMR (600MHz, DMSO-d ₆ )δ12.92(s,1H),8.86(t,J＝5.6Hz,1H),7.89–7.83(m,2H),7.73(td,J＝7.6,1.8Hz,1H),7.60(dddd,J＝8.2,7.0,5.0,1.8Hz,1H),7.55(d,J＝1.7Hz,2H),7. 46(d,J＝8.7Hz,1H),7.36(ddd,J＝10.5,8.3,1.1Hz,1H),7.32–7.24(m,2H),7.17(s,1H),3.24(t,J＝6.4Hz,2H),2.85(q,J＝6.4Hz,2H),2.23(s,6H),1.55– 1.42(m,4H). ¹³ C NMR (150MHz, DMSO-d ₆ ) δ159.62,159.51,157.83,143.06,139.43,137.72,135.53,135.48,135.13,133.27,130.11,129.09,129.00,127.72,125.77 ,125.30,125.28,125.12,124.12,119.41,117.74,117.60,115.30,111.82,42.55,39.34,27.01,26.33,21.21.ESI-MS:m/z 592.11(M+1) ⁺ .C ₂₇ H ₂₇ ClFN ₃ O ₅ S ₂ [591.11].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(2-((3-fluorophenyl)sulfonamido)ethyl)-1H-indole-2-carboxamide (R ₁₂ L ₂ )

The sulfonyl chloride raw material used is m-fluorobenzenesulfonyl chloride, white solid, yield 82%, melting point: 206-208°C. ¹ HNMR (600MHz, DMSO-d ₆ )δ12.89(s,1H),8.96(t,J＝5.8Hz,1H),7.86(t,J＝4.5Hz,2H),7.61(td,J＝5.2,4.4,2.1Hz,1H),7.59(dd,J＝7.8,5.1Hz,1H),7.56–7.52(m,3H),7.47(d, J＝8.8Hz,1H),7.44(ddt,J＝9.2,6.3,1.7Hz,1H),7.28(dd,J＝8.7,2.1Hz,1H),7.17(s,1H),3.38–3.32(m,2H),2.95(dt,J＝7.6,6.1Hz,2H),2.22(s,6H) 1. ³ C NMR(150MHz,DMSO-d ₆ )δ163.11,161.46,159.95,142.94,142.91,142.87,139.44,137.20,135.17,133.27,132.21,132.16,127.78,125.67,125.25,124.17,123.24,123.22,120.22,120.08,119.43,115.35,114.10,113.94,112.15,41.99,21.18.ESI-MS:m/z 564.08(M+1) ⁺ .C ₂₅ H ₂₃ ClFN ₃ O ₅ S ₂ [563.08].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(3-((3-fluorophenyl)sulfonamido)propyl)-1H-indole-2-carboxamide (R ₁₂ L ₃ )

The sulfonyl chloride raw material used was the same as above, white solid, yield 65%, melting point: 186-188°C. ¹ H NMR (600MHz, DMSO-d ₆ )δ12.91(s,1H),8.86(t,J＝5.7Hz,1H),7.85(d,J＝2.1Hz,1H),7.76(t,J＝5.9Hz,1H),7.60(dt,J＝7.8,1.5Hz,1H),7.58-7.54(m,2H),7.54-7.51(m,2H),7.45(d,J＝8.8Hz ,1H),7.42(dddd,J＝9.0,8.0,2.7,1.4Hz,1H),7.26(dd,J＝8.7,2.1Hz,1H),7.17(s,1H),3.28(q,J＝6.7Hz,2H),2.87(q,J＝6.7Hz,2H),2.23(s,6H),1.67(p ,J＝7.1Hz,2H). ¹³ C NMR(150MHz,DMSO-d ₆ )δ163.08,161.44,159.85,143.24,143.20,143.06,139.39,137.81,135.09,133.29,132.08,132.03,127.68,125.66,125.09,124.16,123.17,123.15,120.01,119.87,119.36,115.28,114.02,113.86,111.91,40.97,37.52,29.57,21.21.ESI-MS:m/z578.10(M+1) ⁺ .C ₂₆ H ₂₅ ClFN ₃ O ₅ S ₂ [577.09].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(4-((3-fluorophenyl)sulfonamido)butyl)-1H-indole-2-carboxamide (R ₁₂ L ₄ )

The sulfonyl chloride raw material used is the same as above, yellow solid, yield 72%, melting point: 196-198°C. ¹ H NMR (600MHz, DMSO-d ₆ ) δ12.93(s,1H),8.88(t,J＝5.7Hz,1H),7.87(d,J＝2.1Hz,1H),7.71(t,J＝5.9Hz,1H),7.61–7.52(m,5H),7.52–7.48(m,1H),7.48–7 .39(m,3H),7.27(dd,J＝8.7,2.1Hz,1H),7.20–7.16(m,1H),3.24(q,J＝6.5Hz,2H),2.76(q,J＝6.4Hz,2H),2.23(s,6H),1.55–1.41(m,4H). ¹³ C NMR(150MHz, DMSO-d ₆ )δ163.08,161.44,159.65,143.23,143.19,143.05,139.43,137.76,135.13,133.27,132.09,132.04,127.70,125.74,125.11,124.13,123.18,1 23. 16,123.13,119.99,119.85,119.39,115.30,114.00,113.96,113.84,113.80,111.81,42.72,42.53,39.34,26.93,26.64,26.39,21.21.ESI-MS:m /z 592.11(M+1) ⁺ .C ₂₇ H ₂₇ ClFN ₃ O ₅ S ₂ [591.11].

5-Chloro-N-(2-(cyclopropanesulfonamido)ethyl)-3-((3,5-dimethylphenyl)sulfonyl)-1H-indole-2-carboxamide (R ₁₃ L ₂ )

The sulfonyl chloride raw material used was cyclopropanesulfonyl chloride, white solid, yield 66%, melting point: 210-212°C. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 9.02 (t, J = 5.8 Hz, 1H), 7.87 (d, J = 2.1 Hz, 1H), 7.58 (d, J = 1.6 Hz, 2H), 7.48 (d, J = 8.8 Hz, 1H), 7.28 (dd, J = 8.8, 2.1 Hz, 1H), 7.18 (s, 1H), 7.12 (t, J = 6.1 Hz, 1H), 3.46-3.40 (m, 2H), 3.20-3.13 (m, 2H), 2.43 (p, J = 1.9 Hz, 1H), 2.24 (s, 6H). ¹³ C NMR (150 MHz, DMSO-d ₆ )δ160.07,142.99,139.44,137.53,135.16,133.30,127.76,125.64,125.21,124.23,119.40,115.35,112.12,42.01,40.59,40.27,29.85,21.21 ,5.20.ESI-MS:m/z510.09(M+1) ⁺ .C ₂₂ H ₂₄ ClN ₃ O ₅ S ₂ [509.09].

N-(2-([1,1'-biphenyl]-4-sulfonamido)ethyl)-5-chloro-3-((3,5-dimethylphenyl)sulfonyl)-1H-indole-2-carboxamide (R ₁₄ L ₂ )

The sulfonyl chloride raw material used was biphenylsulfonyl chloride, a white solid, with a yield of 74%, and a melting point of 252-254°C. ¹ H NMR (600 MHz, DMSO-d ₆ )δ12.89(s,1H),8.97(t,J＝5.8Hz,1H),7.87(d,J＝2.1Hz,1H),7.86–7.82(m,2H),7.82–7.75(m,3H),7.64–7.59(m,2H),7.54(d,J＝1.7Hz,2H),7.45(d ,J＝8.8Hz,1H),7.44–7.39(m,2H),7.38–7.33(m,1H),7.26(dd,J＝8.7,2.1Hz,1H),7.14(s,1H),3.42–3.35(m,2H),2.98(q,J＝6.6Hz,2H),2.19(s,6H). ¹³ C NMR (150MHz, DMSO-d ₆ )δ159.93,144.51,142.94,139.52,139.44,138.94,137.19,135.16,133.26,129.54,128.92,127.90,127.80,127.68,127.48,125.69,125.2 5,124.16,119.45,115.34,112.14,42.05,21.17.ESI-MS:m/z 622.12(M+1) ⁺ .C ₃₁ H ₂₈ ClN ₃ O ₅ S ₂ [621.12].

5-Chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(2-(naphthalene-2-sulfonylamino)ethyl)-1H-indole-2-carboxamide (R ₁₅ L ₂ )

The sulfonyl chloride raw material used was 2-naphthalenesulfonyl chloride, a white solid, with a yield of 79%, and a melting point of 252-254°C. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ12.84 (s, 1H), 8.94 (t, J=5.8 Hz, 1H), 8.40 (d, J=1.9 Hz, 1H), 8.06 (t, J=8.5 Hz, 2H), 7.96–7.91 (m, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.84–7.77 (m, 2H), 7.59 (dddd, J=21.6 Hz, 2H). ,8.2,6.9,1.4Hz,2H),7.51(d,J＝1.7Hz,2H),7.44(d,J＝8.8Hz,1H),7.26(dd,J＝8.7,2.1Hz,1H),7.13(s,1H),3.37–3.32(m,2H),2.96(q,J＝6.6Hz,2H), 2.17(s,6H). ¹³ CNMR (150MHz, DMSO-d ₆ ) δ159.91,142.93,139.41,137.76,137.20,135.13,134.65,133.25,132.21,129.93,129.60,129.15,128.26,128.02,127 .89,127.76,125.66,125.22,124.14,122.67,119.43,115.34,112.11,42.04,39.74,21.14.ESI-MS:m/z 596.11(M+1) ⁺ .C ₂₉ H ₂₆ ClN ₃ O ₅ S ₂ [595.10].

N-(2-((4-acetylaminophenyl)sulfonamido)ethyl)-5-chloro-3-((3,5-dimethylphenyl)sulfonyl)-1H-indole-2-carboxamide (R ₁₆ L ₂ )

The sulfonyl chloride raw material used is acetamidobenzenesulfonyl chloride, a white solid, with a yield of 61% and a melting point of 254-256°C. ¹ H NMR (600MHz, DMSO-d ₆ ) δ12.88(s,2H),10.22(s,2H),8.93(t,J＝5.8Hz,2H),7.86(d,J＝2.1Hz,2H),7.72–7.65(m,8H),7.59–7.51(m,7H),7.46(d,J＝8 .7Hz, 2H), 7.27 (dd, J＝8.7, 2.1Hz, 2H), 7.17 (s, 2H), 3.35–3.29 (m, 5H), 2.89 (q, J＝6.6Hz, 4H), 2.22 (s, 13H), 2.00 (s, 6H). ¹³ C NMR (150MHz, DMSO-d ₆ )δ169.40,159.93,143.35,142.96,139.44,137.31,135.15,134.33,133.27,128.15,127.76,125.66,125.21,124.79,124.17,119.43,119.17,1 15.34,112.13,41.96,39.69,24.56,21.22,21.19.ESI-MS: m/z 603.11(M+1) ⁺ .C ₂₇ H ₂₇ ClN ₄ O ₆ S ₂ [602.10].

Example 9: In vitro anti-HIV-1 activity test of target compounds

Test principle: The MTT method is used to screen the anti-HIV activity of compounds in vitro. The detection principle is: MTT can combine with succinate dehydrogenase in living cells to reduce to water-insoluble blue-purple crystalline formazan and deposit in cells, while dead cells do not have this function. Dimethyl sulfoxide can dissolve the formazan in cells, and the absorbance (A) value at 590nm detected by a microplate reader can indirectly reflect the number of living cells. Within a certain range of cell numbers, the amount of MTT crystals formed is proportional to the number of cells.

Since HIV-infected MT-4 cells will develop pathological changes within a certain period of time (5-7 days), a solution of the compound to be tested is added to the suspension of HIV-infected MT-4 cells. After a period of culture (5-7 days), the viability of MT-4 cells is determined by MTT analysis. The drug concentration (EC ₅₀ ) that protects 50% of cells from cytopathic changes is obtained to obtain the anti-HIV activity of the target compound. At the same time, the concentration (CC ₅₀ ) at which the target compound causes 50% of cells not infected with HIV to develop pathological changes is obtained, and the selectivity index (SI=CC ₅₀ /EC ₅₀ ) is calculated.

Test Materials and Methods:

(1) HIV-1(III _B ): provided by Rega Institute, Faculty of Medicine, University of Leuven, Belgium.

(2) MT-4 cells: provided by Rega Institute, Faculty of Medicine, University of Leuven, Belgium.

(3) MTT: purchased from Sigma, USA.

(4) Sample treatment: Before use, the sample was dissolved in DMSO to an appropriate concentration and diluted 5 times with double distilled water, with 5 dilutions each.

(5) Positive control drugs: nevirapine (NVP), efavirenz (EFV), etravirine (ETR), zidovudine (AZT), and lead compound (II-3).

(6) Test method: The sample was diluted and added to the suspension of HIV-infected MT-4 cells. After a period of time, the cell viability was determined by MTT colorimetry. The absorbance (A) value at 590 nm was recorded using an ELISA reader, and the EC ₅₀ , CC ₅₀ and SI were calculated.

(7) MTT colorimetric method: After adding the sample solution and incubating for a period of time, add 20 μL of MTT solution (5 mg/mL) to each well. After continuing to incubate for several hours, discard the staining solution and add 150 μL of DMSO to each well. Mix thoroughly and measure the absorbance (A) value at 590 nm using an ELISA reader.

Experimental methods:

In a 96-well cell culture plate, add 50 μL of 1×10 ⁴ MT-4 cell culture medium, then add 20 μL of MT-4 cell suspension infected with HIV-1 (III _B ) or HIV-2 (ROD) (100 times CCID ₅₀ per ml) or blank culture medium (toxicity assay), then add different concentrations of the test compound solution or positive control drug, and design 3 replicates for each concentration. Then, the cells are cultured at 37°C in a 5% CO ₂ atmosphere for 5 days, and 20 μL (5 mg/mL) of MTT solution is added to each well, and the culture is continued for 2 hours, and then DMSO is added. The absorbance of the reaction solution at 540 nm is measured using an ELISA instrument, and the cell proliferation rate P% at different concentrations of the compound is calculated. At the same time, blank and drug control groups and positive drug control groups are set up, and the concentration required for the compound to protect 50% of the cells from HIV-induced cytopathic effects (EC ₅₀ ) is calculated. Calculation of the selection index: SI = CC ₅₀ /EC ₅₀ .

Experimental results:

According to the above experimental method, the synthesized sulfonamide indole aryl sulfone derivatives were screened for anti-HIV-1 (III _B ) activity at the cellular level, single mutant strains L100I, K103N, Y181C, Y188L, E138K and double mutant strains F227L+V106A and RES056 (K103N/Y181C). The activity results are shown in Tables 1 and 2.

Table 1 Anti-HIV-1(III _B ) Cellular Activity and Cytotoxicity (MT-4 Cells) of Sulfonamide Indole Aryl Sulfone Derivatives

Note: ^a _EC50 : the concentration of the compound that protects 50% of MT-4 cells infected with HIV-1 from cytopathic effects; ^b _CC50 : the concentration of the compound that causes 50% of cells not infected with HIV-1 to develop cytopathic effects; ^c Selectivity coefficient: the ratio of _CC50 / _EC50 ; NVP, AZT, EFV, and ETR represent the marketed drugs nevirapine, zidovudine, efavirenz, and etravirine, respectively.

Table 2 Inhibitory activity of sulfonamide indole aryl sulfone derivatives against HIV resistant strains (MT-4 cells)

Note: ^a EC ₅₀ : the concentration of the compound that protects 50% of MT-4 cells infected with HIV-1 from cytopathic effects; NVP, AZT, EFV, and ETR represent the marketed drugs nevirapine, zidovudine, efavirenz, and etravirine, respectively.

Example 10: Inhibitory activity of target compounds against wild-type HIV-1 RT

In order to confirm the targets of the newly designed compounds, we performed HIV-1RT inhibition assay on this series of compounds.

Test principle: RT uses Poly(A) as template, oligo(dT) ₁₅ as primer, biotin and digoxigenin (DIG) double-labeled dNTPs as substrate to perform reverse transcription, and then produce DNA/RNA hybrid double-stranded molecules. After reverse transcription is completed, the double-labeled hybrid double-stranded molecules are bound to the inner coated streptavidin. Then, peroxidase-coupled digoxigenin antibody is added to bind to the DNA chain. Finally, the substrate ABTS is added, and its reaction with peroxidase will cause a color change. The absorbance value of the reaction solution is detected by an enzyme reader to indirectly obtain the enzyme inhibitory activity of the compound.

Experimental method: Place the reaction mixture containing the template/primer complex, nucleotides (dNTPs) and RT in an incubation buffer containing the test compound and incubate at 37°C for 1 hour. Then transfer the reaction mixture to a streptavidin-coated microplate and incubate at 37°C for 1 hour. Wash the wells 5 times with the wash buffer, remove all the buffer, add the digoxigenin antibody-peroxidase solution, and incubate for another 1 hour. Repeat the above washing operation, remove all the buffer, add the ABTS substrate solution, and immediately measure the absorbance value of each sample well with an ELISA reader. At the same time, set up a negative control group (with RT and no inhibitor) and a blank group (without inhibitor, no RT).

Inhibition rate calculation:

After obtaining the inhibition rate of the test compound, the concentration logarithm and inhibition rate linear regression equation were substituted to obtain the _IC50 value (the concentration of the test sample corresponding to when the inhibition rate of the compound on RT is 50%).

Experimental results:

According to the above experimental method, the synthesized indole aryl sulfone derivatives were subjected to an anti-HIV reverse transcriptase inhibition experiment, and the activity results are shown in Table 3.

Table 3. Inhibitory activity of sulfonamide indole aryl sulfone derivatives against HIV-1 wild-type RT

^a IC ₅₀ : The concentration of the compound that has a 50% inhibitory effect on reverse transcriptase.

Claims (6)

1. A sulfonamide indolyl aryl sulfone derivative, or a pharmaceutically acceptable salt thereof, having a structure represented by the following formula I:

wherein,

n＝1,2,3,4；

r is: benzene ring, mono-substituted benzene ring, naphthalene ring, substituted pyridine ring, thiophene ring; the substituent is selected from methyl, fluorine, chlorine, nitro, cyano, phenyl and acetamido.

2. A sulfonamide indolyl aryl sulfone derivative, characterized in that the compound is one of the following:

3. the process for producing a sulfonamide indolyl aryl sulfone derivative according to claim 1, which comprises reacting 5-chloro-1H-indole-2-carboxylic acid ethyl ester with 3, 5-dimethylbenzene thiol in 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [ 2.2.2.2:]under the action of octane ditetrafluoroborate, an aromatic nucleophilic substitution reaction is carried out to obtain an intermediate 1, then the intermediate 1 and m-chloroperoxybenzoic acid are subjected to oxidation reaction in methylene dichloride to obtain an intermediate 2, and then tetrahydrofuran is used for the reaction: water = 1:1 is hydrolyzed by lithium hydroxide in the mixed solvent to obtain the intermediateAn intermediate 3; on the other hand, triethylamine is used as an acid binding agent, and differently substituted sulfonyl chloride (R) and amino (L) with different carbon chain lengths protected by Boc are reacted in dichloromethane to generate intermediate 4R with different structures _n L _n Subsequent deprotection of the resulting mixture with trifluoroacetic acid in dichloromethane affords the differently substituted intermediate 5R _n L _n Finally, condensing the intermediate 5 with different structures with the intermediate 3 amide to obtain different target products;

the synthetic route is as follows:

reagents and conditions: (i) 3, 5-Dimethylsulfanyl, 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2]Octane ditetrafluoroborate, acetonitrile, room temperature; (ii) M-chloroperoxybenzoic acid, dichloromethane, 0 ℃ to room temperature; (iii) lithium hydroxide, tetrahydrofuran: water = 1:1, room temperature; (iv) Et (Et) ₃ N, DCM,0 ℃ to room temperature; (v) trifluoroacetic acid, dichloromethane, room temperature; (vi) HATU, DIEA, DCM, from 0 ℃ to room temperature;

r is as described in formula I of claim 1.

4. A process for the preparation of the sulfonamide indolyl aryl sulfone derivative of claim 3 comprising the specific steps of:

(1) Adding 5-chloro-1H-indole-2-carboxylic acid ethyl ester, 3, 5-dimethylbenzene thiol, 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroboric acid) salt and solvent acetonitrile into a round bottom flask, and stirring for 6 hours at room temperature; after the reaction is finished, evaporating the reaction solution to dryness, adding dichloromethane and saturated sodium chloride solution for extraction, separating out an organic phase, adding anhydrous magnesium sulfate for drying, filtering, concentrating the filtrate under reduced pressure, and separating and purifying the obtained crude product by silica gel column chromatography to obtain an intermediate 1;

(2) Dissolving the intermediate 1 in dichloromethane, adding m-chloroperoxybenzoic acid under ice bath condition, converting to room temperature after 30 minutes, and continuing to react for 4 hours; after the reaction is finished, transferring the reaction solution into a separating funnel, adding dichloromethane for dilution, washing for 3 times by using a saturated sodium bisulphite solution, then adding a saturated sodium chloride solution for washing for 1 time, finally drying by using anhydrous magnesium sulfate in sequence, filtering, concentrating under reduced pressure, and separating and purifying the obtained crude product by using a silica gel column chromatography to obtain an intermediate 2;

(3) Dissolving the intermediate 2 in a tetrahydrofuran/water mixed solvent with the volume ratio of 1:1, adding lithium hydroxide, and stirring at room temperature for 8 hours; after the reaction is finished, evaporating most of the solvent under reduced pressure, then dropwise adding 1N dilute HCl solution, adjusting the pH to 3-4, generating white solid in the process, carrying out suction filtration, and drying a filter cake to obtain an intermediate 3;

(4) Under ice bath condition, primary amine with different carbon chain lengths protected by Boc is dissolved in dichloromethane, triethylamine is added after stirring for 5 minutes, different substituted sulfonyl chlorides are slowly added, after 5 minutes, the mixture is transferred to room temperature for reaction; after the reaction is finished, adding a proper amount of water and dichloromethane into the reaction solution for extraction, merging organic phases, adding a saturated sodium chloride solution for washing, then drying by using anhydrous sodium sulfate, filtering, concentrating, and finally obtaining a corresponding target intermediate 4 through column chromatography;

(5) Dissolving the corresponding intermediate 4 in dichloromethane, dropwise adding trifluoroacetic acid under stirring at room temperature, and reacting for 1h; after the reaction is finished, decompressing and steaming most of the reaction liquid, adding saturated sodium bicarbonate solution to adjust the pH to be neutral, separating out solids in the process, and recrystallizing ethyl acetate to obtain a corresponding intermediate 5;

(6) Under ice bath condition, intermediate 3 is dissolved in DCM, N, N-diisopropylethylamine and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate are added, after stirring for 30 minutes, the corresponding intermediate 5 is added, and the mixture is transferred to room temperature for reaction; after the reaction is finished, adding a proper amount of water and dichloromethane into the reaction solution, extracting, merging organic phases, adding a saturated sodium chloride solution for washing, then drying by using anhydrous sodium sulfate, filtering, concentrating, and finally obtaining the corresponding target compound through column chromatography.

5. Use of sulfonamide indolyl aryl sulfone derivatives according to claim 1 or 2 for the preparation of a medicament for the treatment and prophylaxis of aids.

6. An anti-HIV pharmaceutical composition comprising a sulfonamide indolyl aryl sulfone derivative according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.