CN105968095A - Indolylaryl-sulfone derivative, as well as preparation method and application thereof - Google Patents

Abstract

The invention discloses an indole aryl sulfone derivative as shown in general formula I and its pharmaceutically acceptable salt, ester or prodrug, its preparation method and a composition containing one or more of these compounds in The preparation is used in the prevention and treatment of human immunodeficiency virus (HIV) infection.

Description

Indole sulfone derivatives and their preparation methods and applications

technical field

The invention relates to a derivative and its preparation method and application, in particular to indole aryl sulfone derivatives and its preparation method and application, belonging to the technical field of medicine.

Background technique

In the HIV replication cycle, its own multifunctional protein reverse transcriptase (RT) plays a vital role, responsible for completing multiple key links such as RNA-directed DNA synthesis, RNA hydrolysis, and DNA-directed DNA synthesis. Therefore, using RT as the target of drug design to prevent and treat AIDS has the advantages of high inhibitory activity, good selectivity, and small side effects, and is an important strategy for the development of anti-HIV/AIDS drugs. According to different mechanisms of action and chemical structures, HIV-1 reverse transcriptase inhibitors can be mainly divided into nucleoside (t)ide reverse transcriptase inhibitors (N(t)RTIs) and non-nucleoside (Non-nucleoside reverse transcriptase inhibitors, NNRTIs) two types. Among them, the mechanism of action of NNRTIs is related to the distance from the catalytic active center of RT The allosteric pocket (NNIBP) specifically binds to the allosteric pocket (NNIBP), which leads to the loss of the important function of RT to inhibit the replication of the virus. Due to their binding specificity, NNRTIs usually have the advantages of high efficiency and low toxicity, and thus have become an important part of HAART. There are currently 5 such drugs approved by the FDA (nevirapine, delavirdine, efavirine, etravirine, rilpivirine). However, the amino acids in the binding pocket of NNRTIs are easily mutated, leading to the emergence and spread of drug-resistant virus strains, coupled with the low bioavailability of existing drugs and severe side effects caused by long-term medication, which greatly threatens the clinical application of such drugs. . Therefore, finding new anti-drug-resistant and low-toxicity NNRTIs is still an important topic in the research and development of anti-AIDS drugs.

Indolylaryl-sulfones (indolylaryl-sulfone, IAS) were first reported by Williams et al. from Merk Laboratory as a kind of HIV-1 NNRTIs structure skeleton with very good activity. The inhibitory effect of the lead compound L-737,126 on wild-type (WT) RT can reach 3nM, and the inhibitory effect on common clinical mutant virus strains K103N and Y181C can also reach submicromolar levels. In the subsequent structural modification, the anti-HIV-1 activity of multiple compounds was significantly improved, especially for the common drug-resistant virus strains in clinical practice. For example, the EC of compound EFF on wild-type HIV-1 The ₅₀ value is 2nM, and the inhibitory activity against a variety of common mutant virus strains Y181C, K103N, L100I and E138K remains at the nanomolar level. Therefore, using indole sulfone compounds as templates for extensive structural modification is of great significance for the discovery of new anti-HIV drugs with high efficiency, broad spectrum, good bioavailability and independent intellectual property rights.

Contents of the invention

Aiming at the deficiencies of the prior art, the present invention provides an indole aryl sulfone derivative, and the present invention also provides the preparation method, activity screening result and application of the above compound.

Technical scheme of the present invention is as follows:

1. Indole sulfone derivatives

The indole sulfone derivatives of the present invention or their pharmaceutically acceptable salts or prodrugs have the structure shown in the following general formula I:

in,

The substituent X at the 5-position of indole is halogen, CF ₃ or NO ₂ ;

n is equal to 0, 1, 2 or 3;

m and w are equal to 1 or 2 respectively;

R is (C _1-6 )alkyl-R ¹ , (C _3-7 )cycloalkyl-R ¹ , (C _2-6 )alkenyl-R ¹ , -C(O)R ¹ , -C (O)OR ¹ , -S(O)-R ¹ , -SO ₂ -R ¹ , NH-R ¹ , phenyl, 5- or 6-membered aromatic heterocycle, fused phenyl-unsaturated or Saturated 5- or 6-membered carbocycle, or fused phenyl-5- or 6-membered aromatic heterocycle;

Wherein R ¹ is selected from H, OH, SH, NH ₂ , O-(C _1-4 ) alkyl, S-(C _1-4 ) alkyl or NH-(C _1-4 ) alkyl; Phenyl, 5- or 6-membered heteroaromatic ring, fused phenyl-unsaturated or saturated 5- or 6-membered carbocycle, or fused phenyl-5- or 6-membered heteroaryl ring Each in turn is optionally substituted by 1 to 3 substituents independently selected from: (C _1-6 ) alkyl, halogen, CF ₃ , OCF ₃ , OH, NO ₂ , CN, SO ₂ NH ₂ , SO ₂ -(C _1-3 )alkyl, C(O)NH ₂ , C(O)(C _1-3 )alkyl, NH(C _1-3 )alkyl;

Preferably according to the invention,

The substituent X at the 5-position of indole is Cl or Br;

n is equal to 0 or 1;

m and w are equal to 2 at the same time;

_R is _CH2OH , _CH2COOCH2CH3 , substituted phenyl, pyridyl, _furyl , thienyl, or substituted triazolyl.

According to the present invention, it is further preferred that the compound of general formula I is one of the compounds of the following structures:

Two, the preparation method of indole sulfone derivatives

The preparation of indole sulfone derivatives of the present invention uses ethyl indole carboxylate (1) substituted at the 5-position as the starting material, and reacts with 3,5-dimethylthiophenol to obtain intermediate compound 2, the intermediate The body is oxidized by m-chloroperoxybenzoic acid to obtain intermediate compound 3, and the ethyl ester group of intermediate compound 3 is hydrolyzed to obtain intermediate compound 4, and intermediate compound 4 undergoes acylation reaction and removes the BOC protecting group to obtain the parent ring 6, Substituting different substituents on the mother ring 6 to obtain indole sulfone derivatives I;

The synthetic route is as follows:

Reagents and conditions: (i) 3,5-dimethylthiophenol, 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt , acetonitrile; (ii) m-chloroperoxybenzoic acid, dichloromethane, 0°C; (iii) lithium hydroxide, water, tetrahydrofuran, 50°C; (iv) Boc-protected nitrogen-containing cycloalkyl-amino, 2- (7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-ethyl-(3-dimethylaminopropyl)carbodiimide Hydrochloride, triethylamine, N,N-dimethylformamide; (v) trifluoroacetic acid, dichloromethane; (vi) potassium carbonate, N,N-dimethylformamide, benzyl halide, halogen substituted (vi) substituted formaldehyde, glacial acetic acid, sodium cyanoborohydride, tetrahydrofuran/acetonitrile.

Wherein, the definition of X, n, m, w, R is the same as that described in general formula I above.

Preferably according to the present invention, the preparation method of indole aryl sulfone derivatives comprises the following steps:

The preparation of indole aryl sulfone derivatives in the present invention uses 5-chloro/bromo-substituted ethyl indole carboxylate (1') as a starting material, and reacts with 3,5-dimethylthiophenol to prepare an intermediate compound 2', intermediate compound 2' is oxidized to intermediate compound 3' by m-chloroperoxybenzoic acid, lithium hydroxide hydrolyzes the ethyl ester group of intermediate compound 3' to obtain intermediate compound 4', intermediate compound 4' After acylation reaction with 1-Boc-4-aminopiperidine or 1-Boc-4-(aminomethyl)-piperidine, the intermediate compound 5' is obtained, and the Boc protecting group is removed under the action of trifluoroacetic acid to obtain the parent Ring 6', the parent ring 6' is substituted by different substituents to obtain indole sulfone derivatives I;

The synthetic route is as follows:

Reagents and conditions: (i) 3,5-dimethylthiophenol, 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt , acetonitrile; (ii) m-chloroperbenzoic acid, dichloromethane, 0°C; (iii) lithium hydroxide, water, tetrahydrofuran, 50°C; (iv) 1-BOC-4-aminopiperidine or 1-Boc -4-(aminomethyl)-piperidine, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride, triethylamine, N,N-dimethylformamide; (v) trifluoroacetic acid, dichloromethane; (vi) potassium carbonate, N , N-dimethylformamide, benzyl halide or halogen substituted alkyl; (vi) substituted formaldehyde, glacial acetic acid, sodium cyanoborohydride, tetrahydrofuran/acetonitrile;

Wherein, X is chlorine or bromine, n is equal to 0 or 1, and R is CH ₂ OH, CH ₂ COOCH ₂ CH ₃ , substituted phenyl, pyridyl, furyl, thienyl or substituted triazolyl.

For the specific preparation method, see Examples 1-24.

3. Application of indole sulfone derivatives

The indole aryl sulfone derivatives of the general formula I of the present invention exhibit remarkable antiviral activity, higher selectivity and resistance to drug resistance in the cell test (MT-4 cell) of inhibiting HIV replication. Therefore, the present invention also provides:

Application of the indole aryl sulfone derivatives of the general formula I in the preparation of anti-HIV drugs.

An anti-HIV pharmaceutical composition, comprising the compound of the present invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.

The compounds of the present invention may be used as such or in the form of pharmaceutically acceptable salts or solvates thereof. The pharmaceutically acceptable salts of the compounds of general formula I include conventional salts formed with pharmaceutically acceptable inorganic or organic acids, or inorganic or organic bases. Examples of suitable acid addition salts include those with hydrochloric, sulfuric, phosphoric, nitric, hydrobromic, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric acids , citric acid, pamoic acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzene Salts of sulfonic acid, hydroxybenzoic acid, hydroiodic acid, malic acid, tannic acid, etc. Examples of suitable base addition salts include those with sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethyl A salt formed of diamine, N-methylglucose, and procaine. When referring to the compounds of the present invention herein, the compounds of general formula I and pharmaceutically acceptable salts or solvates thereof are included.

According to the present invention, the compound of formula I of the present invention can form a pharmaceutical composition with conventional pharmaceutical carriers or excipients. The pharmaceutical composition can be administered orally or parenterally. The pharmaceutical composition of the present invention can be prepared into various dosage forms according to conventional methods in the art, including but not limited to tablets, capsules, solutions, suspensions, granules or injections, etc., for oral or parenteral administration.

The present invention designs a series of novel indole sulfone derivatives targeting the second channel on the basis of a comprehensive analysis of the binding mode and pharmacophore model of the indole aryl sulfone lead compound, as well as crystal research and molecular simulation research. The N-substituted piperidine group of DAPY-like NNRTIs is introduced into the indole sulfone molecule by using the drug design principle of skeleton transition, so that the extended group acts on the second channel, and it is hoped that the nitrogen atom on the piperidine can interact with the surrounding amino acid ( G138) form hydrogen bonds. At the same time, the substituents at the end adopt groups with various structures, but basically all include a hydrophilic group, such as a hydrophilic short chain and a benzyl group substituted by a hydrophilic substituent, etc. environment and thereby improve the water solubility of the compound. Activity results showed that all compounds had significant anti-wild-type HIV-1 effects, with EC ₅₀ values ranging from 0.62 μM to 0.006 μM. And most of the compounds also showed good inhibitory activity against multiple single mutant strains, such as mutant virus strains L100I, K103N, Y181C, E138K. I-2 and I-12 are two compounds with prominent inhibitory activity in this series, with EC ₅₀ values of 0.006 μM and 0.009 μM and SI of 1005 and 1476 for wild-type HIV-1, respectively. The structure-activity relationship analysis found that the smaller hydrophilic group on piperidine is more conducive to the improvement of activity. And enhancing the interaction with the conserved amino acid W229 and reducing the dependence on amino acids Y181 and Y188 is one of the strategies for improving the activity against mutant virus strains in the next step of modification. Therefore, indole sulfone derivatives have great development value. New structural modifications and in-depth research on the compounds of the present invention are helpful for the development of new anti-HIV drugs.

detailed description

The following examples help to understand the present invention, but the content of the present invention cannot be limited.

Example 1: N-(1-(3-methoxyphenyl)piperidin-4-yl)-5-bromo-3-(3,5-dimethylphenolsulfone)-1H-indole- Preparation of 2-formamide (I-1)

Ethyl 5-bromoindolecarboxylate (1') (0.10g, 0.373mmol) was placed in a round bottom flask, 10mL of acetonitrile was added, and 3,5-dimethylthiophenol (0.0516g, 0.373 mmol, 50 μL), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (0.10 g, 0.373 mmol). The reaction solution was continued to react for 6 hours. Acetonitrile was evaporated to dryness, 30 mL of water was added, extracted with dichloromethane (3×10 mL), the organic phases were combined, washed with saturated brine and dried over anhydrous magnesium sulfate. It was concentrated by filtration and purified by column chromatography (ethyl acetate:petroleum ether=1:8). The resulting white solid was recrystallized from ethyl acetate/petroleum ether to give 2'. Yield 50.5%.

Intermediate 2' (0.10g, 0.247mmol) was placed in a round-bottomed flask and dissolved in 10mL of dichloromethane, m-chloroperoxybenzoic acid (0.128g, 0.742mmol) was slowly added under stirring in an ice bath, and converted to React at room temperature for 3 hours until the reaction is complete. The reaction solution was diluted with dichloromethane, washed three times with sodium bisulfite and saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, concentrated by filtration, and recrystallized from ethyl acetate to obtain a white solid 3'. Yield: 68.8%.mp:205-207℃.ESI-MS:m/z 436.3(M+1).C ₁₉ H ₁₈ BrNO ₄ S[435.01].

The intermediate 3' (0.10g, 0.229mmol) obtained in the previous step was weighed in a round bottom flask, the mixed reagent THF/H ₂ O (6mL/6mL) was added, and lithium hydroxide (0.0165g, 0.687mmol) was added under stirring at room temperature , the reaction solution was changed to 50°C for 24 hours. The reaction solution was evaporated to THF, diluted with distilled water, adjusted to acidic (pH=2-3) with dilute hydrochloric acid, a large amount of white solid precipitated, filtered and dried to obtain intermediate 4'. Yield: 66.5%. mp: 215-217°C. ESI-MS: m/z 425.3 (M+ ₁₈ ). _C17H14BrNO4S [ _406.98 ].

Intermediate 4'(1.0g, 2.45mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.39g, 3.67mmol ), Boc-4-aminopiperidine (0.735g, 3.67mmol) were weighed together in a round bottom flask, N,N-dimethylformamide 10mL was added, and diisopropylethylamine (0.949g, 7.35mmol, 1.3mL), the reaction solution continued to react for 24 hours. Evaporate most of the solvent, redissolve in 100 mL of tetrahydrofuran, wash 3 times with saturated saline and aqueous sodium hydroxide solution, dry the tetrahydrofuran layer with anhydrous magnesium sulfate, filter and concentrate, and purify by column chromatography (ethyl acetate:petroleum ether=1:4) A white solid 5' was obtained, yield: 47.5%.

Intermediate 5' (0.5g, 0.848mmol) was placed in a round bottom flask, 2mL of dry dichloromethane was added, and 1mL of trifluoroacetic acid was added with stirring at room temperature. After 4 hours, a large amount of white precipitate appeared in the reaction solution, which was filtered and washed with dichloromethane to obtain intermediate IVa-6'. Yield: 75.4%. mp: 230-231 °C, ESI-MS: m/z 490.4 ( _M + ₁ ) _{C22H24BrN3O3S} [ _489.07 ].

Intermediate 6' (0.30g, 0.496mmol) and potassium carbonate (0.274g, 1.98mmol) were placed in a round bottom flask, and 10 mL of N,N-dimethylformamide was added. After stirring at room temperature for 10 minutes, 1-(bromomethyl)-3-methoxybenzene (0.274 g, 0.5992 mmol) was added, and stirring was continued at room temperature for 4 hours. Most of N,N-dimethylformamide was evaporated to dryness, 50 mL of water was added, extracted with ethyl acetate (3×10 mL), the organic phases were combined, washed with saturated brine and dried over anhydrous magnesium sulfate. It was concentrated by filtration and purified by column chromatography (ethyl acetate:petroleum ether=1:2). The obtained white solid was recrystallized from tetrahydrofuran/ethyl acetate to obtain I-1. Yield: 43.2%.mp: 175-177°C. ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ: 13.02(s, 1H, Indole-NH), 8.95(s, 1H, CONH), 8.09( s,1H,Indole-H),7.62(s,2H,Ph-H),7.50(q,2H,J=8.00Hz,Indole-H),7.26(t,2H,J=8.00Hz,Ph'- H), 6.88(s, 2H, Ph'-H), 6.83(d, 1H, J＝8.00Hz, Ph-H), 3.86(s, 1H, piperidine-H), 3.73(s, 3H, OCH ₃ ),3.46(s,2H,benzyl-CH ₂ ),2.79(s,2H,piperidine-H),2.31(s,6H,2×CH ₃ ),2.14(s,2H,piperidine-H),1.93( s, 2H, piperidine-H), 1.59 (s, 2H, piperidine-H). ¹³ C NMR (100MHz, DMSO-d ₆ , ppm) δ: 159.73 (C=O), 158.99, 143.05, 140.74, 139.43 ( 2×C),137.73,135.14,133.58,129.67,127.60,126.34,124.10(2×C),122.36,121.34,115.70(2×C),114.58,112.74,111.53,62.49(CH ₂ ),55.40(2 ×CH ₂ ), 52.07(O-CH ₃ ), 47.28, 31.65(2×CH ₂ ), 21.24(2×CH ₃ ).ESI-MS: m/z 610.3(M+1).C ₃₀ H ₃₂ BrN ₃ O ₄ S[609.13].

Example 2: 5-bromo-3-(3,5-dimethylphenylsulfone)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-1H-indole-2- Preparation of Acetamide (I-2)

The preparation method of I-2 is the same as that of I-1, except that bromoethanol (0.5992 mmol) is used instead of 1-(bromomethyl)-3-methoxybenzene. Yield: 40.1%.mp: 220-222°C. ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ: 13.20-12.59 (b, 1H, Indole-NH), 8.95 (d, 1H, J=8.00 Hz, CONH), 8.08(s, 1H, Indole-H), 7.63(s, 2H, Ph-H), 7.50(q, 2H, J=8.00Hz, Indole-H), 7.26(s, 1H, Ph -H),4.44(s,1H,OH),3.86(s,1H,piperidine-H),3.34(s,2H,CH ₂ ),2.91(s,2H,piperidine-H),2.45(s,2H , CH ₂ ), 2.31 (s, 6H, 2×CH ₃ ), 2.22 (s, 2H, piperidine-H), 1.91 (s, 2H, piperidine-H), 1.60 (s, 2H, piperidine-H). ¹³ C NMR (100MHz, DMSO-d ₆ , ppm) δ: 159.08 (C=O), 143.10, 139.41 (2×C), 137.89, 135.11, 133.66, 127.53, 126.34, 124.11 (2×C), 122.33, 115.73,115.65,111.49,60.59(CH ₂ ),58.98(CH ₂ ),52.54(2×CH ₂ ),47.13,31.47(2×CH ₂ ),21.25(2×CH ₃ ).ESI-MS: m/ z534.3(M+1).C ₂₄ H ₂₈ BrN ₃ O ₄ S[533.1].

Example 3: N-(1-(4-sulfonamidophenyl)piperidin-4-yl)-5-bromo-3-(3,5-dimethylphenolsulfone)-1H-indole-2 - Preparation of formamide (I-3)

The preparation method of I-3 is the same as that of I-1, except that 4-bromomethylbenzenesulfonamide (0.5992 mmol) is used instead of 1-(bromomethyl)-3-methoxybenzene. Yield: 42.1%.mp: 170-171°C. ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ: 13.01(s, 1H, Indole-NH), 8.97(s, 1H, CONH), 8.09( s,1H,Indole-H),7.80(d,2H,J＝8.00Hz,Ph'-H),7.62(s,2H,Ph-H),7.51-7.44(m,4H,Indole-H,Ph '-H),7.32(s,2H,SONH ₂ ),7.27(s,1H,Ph-H),3.87(s,1H,piperidine-H),3.56(s,2H,benzyl-CH ₂ ),2.81 (d, 2H, J=12.00Hz, piperidine-H), 2.31(s, 6H, 2×CH ₃ ), 2.20(t, 2H, J=12.00Hz, piperidine-H), 1.93(d, 2H, J =8.00Hz, piperidine-H), 1.63 (q, 2H, J=12.00Hz, piperidine-H). ¹³ C NMR (100MHz, DMSO-d ₆ , ppm) δ: 158.99 (C=O), 143.39, 143.20 ,143.03,139.44(2×C),137.70,135.16,133.54,129.41(2×C),127.63,126.30,126.11(2×C),124.10(2×C),122.36,115.71,115.69,111.55,61.88 (CH ₂ ), 52.10(2×CH ₂ ), 47.23(CH), 31.65(2×CH ₂ ), 21.25(2×CH ₃ ).ESI-MS: m/z 659.4(M+1).C ₂₉ H ₃₁ BrN ₄ O ₅ S ₂ [658.09].

Example 4: N-(1-(4-chlorophenyl)piperidin-4-yl)-5-bromo-3-(3,5-dimethylphenolsulfone)-1H-indole-2- Preparation of formamide (I-4)

The preparation method of I-4 is the same as that of I-1, except that 1-bromomethyl-4-chlorobenzene (0.5992 mmol) is used instead of 1-(bromomethyl)-3-methoxybenzene. Yield: 46.2%.mp: 229-230°C. ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ: 13.07-12.94 (br, 1H, Indole-NH), 8.97 (d, 1H, J=8.00 Hz,CONH),8.09(s,1H,Indole-H),7.62(s,2H,Ph-H),7.50(q,2H,J＝8.00Hz,Indole-H),7.30(d,2H,J =8.00Hz, Ph'-H),7.35(d,2H,J=8.00Hz,Ph'-H),7.26(s,1H,Ph-H),3.86(s,1H,piperidine-H),3.48 (s,2H,benzyl-CH ₂ ),2.80(d,2H,J=12.00Hz,piperidine-H),2.31(s,6H,2×CH ₃ ),2.17(t,2H,J=12.00Hz, piperidine-H), 1.93(d, 2H, J＝12.00Hz, piperidine-H), 1.61(q, 2H, J＝12.00Hz, piperidine-H). ¹³ C NMR(100MHz, DMSO-d ₆ , ppm) δ: 158.99(C=O), 143.02, 139.43(2×C), 138.12, 137.71, 135.15, 133.54, 131.84, 130.93(2×C), 128.62(2×C), 127.62, 126.29, 124.10(2× C),122.35,115.71,115.68,111.55,61.60(CH ₂ ),51.99(2×CH ₂ ),47.24(CH),31.64(2×CH ₂ ),21.24(2×CH ₃ ).ESI-MS: m/z 614.3(M+1).C ₂₉ H ₂₉ BrClN ₃ O ₃ S[613.08].

Example 5: N-(1-(3-cyanophenyl)piperidin-4-yl)-5-bromo-3-(3,5-dimethylphenolsulfone)-1H-indole-2- Preparation of formamide (I-5)

The preparation method of I-5 is the same as that of I-1, except that 1-bromomethyl-3-cyanobenzene (0.5992 mmol) is used instead of 1-(bromomethyl)-3-methoxybenzene. Yield: 42.3%.mp: 223-236°C. ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ: 13.03(s, 1H, Indole-NH), 8.97(d, 1H, J=8.00Hz, CONH), 8.09 (s, 1H, Indole-H), 7.76 (d, 2H, J = 12.00Hz, Ph'-H), 7.69 (d, 1H, J = 8.00Hz, Ph'-H), 7.63 ( s,2H,Ph-H),7.58(t,1H,J=8.00Hz,Ph'-H),7.50(q,2H,J=8.00Hz,Indole-H),7.26(s,1H,Ph- H), 3.87(s, 1H, piperidine-H), 3.56(s, 2H, benzyl-CH ₂ ), 2.81(d, 2H, J＝12.00Hz, piperidine-H), 2.31(s, 6H, 2× CH ₃ ), 2.21(t, 2H, J＝12.00Hz, piperidine-H), 1.94(d, 2H, J＝12.00Hz, piperidine-H), 1.63(q, 2H, J＝12.00Hz, piperidine-H ). ¹³ C NMR (100MHz, DMSO-d ₆ , ppm) δ: 158.98 (C=O), 143.01, 139.43 (2×C), 137.67, 135.16, 134.05, 133.58, 133.52, 132.48, 131.28, 129.95, 127.64 ,126.29,124.11(2×C),122.36,119.38,115.72,115.67,111.69,111.57,61.36(CH ₂ ),51.95(2×CH ₂ ),47.18(CH),31.61(2×CH ₂ ),21.24 (2×CH ₃ ).ESI-MS: m/z 605.4(M+1).C ₃₀ H ₂₉ BrN ₄ O ₃ S[604.11].

Example 6: 5-bromo-3-(3,5-dimethylphenylsulfone)-N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-1H-indole -Preparation of 2-formamide (I-6)

The preparation method of I-6 is the same as that of I-1, except that 3-(bromomethyl)pyridine hydrochloride (0.5992 mmol) is used instead of 1-(bromomethyl)-3-methoxybenzene. Yield: 47.8%.mp: 220-221°C. ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ: 13.02(s, 1H, Indole-NH), 8.97(d, 1H, J=8.00Hz, CONH), 8.51 (s, 1H, pyridine-H), 8.48 (d, 1H, J = 4.00Hz, pyridine-H), 8.09 (s, 1H, Indole-H), 8.48 (d, 1H, J = 8.00 Hz, pyridine-H), 7.63 (s, 2H, Ph-H), 7.50 (q, 2H, J = 8.00 Hz, Indole-H), 7.38 (dd, 1H, J ₁ = 8.00 Hz, J ₂ = 4.00 Hz,pyridine-H),7.26(s,1H,Ph-H),3.86(s,1H,piperidine-H),3.52(s,2H,benzyl-CH ₂ ),2.81(d,2H,J＝12.00 Hz, piperidine-H), 2.31(s, 6H, 2×CH ₃ ), 2.19(t, 2H, J＝12.00Hz, piperidine-H), 1.93(d, 2H, J＝12.00Hz, piperidine-H) ,1.61(q,2H,J=12.00Hz,piperidine-H). ¹³ C NMR(100MHz,DMSO-d ₆ ,ppm)δ:159.01(C=O),150.43,148.74,143.02,139.42(2×C ),137.73,136.90,135.14,134.38,133.54,127.61,126.28,124.11(2×C),123.90,122.35,115.70,115.68,111.55,59.67(CH ₂ ),51.97(2×CH _{2 2} (CH 2 ),47 ), 31.62(2×CH ₂ ), 21.24(2×CH ₃ ).ESI-MS: m/z 581.1(M+1).C ₂₈ H ₂₉ BrN ₄ O ₃ S[580.11].

Example 7: 5-bromo-3-(3,5-dimethylphenylsulfone)-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-1H-indole -Preparation of 2-formamide (I-7)

The preparation method of I-7 is the same as that of I-1, except that 4-(bromomethyl)pyridine hydrochloride (0.5992 mmol) is used instead of 1-(bromomethyl)-3-methoxybenzene. Yield: 46.6%.mp: 243-244°C. ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ: 13.03(s, 1H, Indole-NH), 8.98(d, 1H, J=8.00Hz, CONH), 8.53(d, 2H, J=4.00Hz, pyridine-H), 8.09(s, 1H, Indole-H), 7.63(s, 2H, Ph-H), 7.50(q, 2H, J=8.00 Hz, Indole-H), 7.35(d, 2H, J=8.00Hz, pyridine-H), 7.27(s, 1H, Ph-H), 3.88(s, 1H, piperidine-H), 3.53(s, 2H ,benzyl-CH ₂ ), 2.81(d,2H,J=12.00Hz,piperidine-H),2.31(s,6H,2×CH ₃ ),2.21(t,2H,J=8.00Hz,piperidine-H) , 1.94 (d, 2H, J = 8.00Hz, piperidine-H), 1.61 (q, 2H, J = 8.00Hz, piperidine-H). ¹³ C NMR (100MHz, DMSO-d ₆ , ppm) δ: 159.01 ( C＝O), 150.02(2×C), 148.27, 143.01, 139.43(2×C), 137.70, 135.16, 133.52, 127.64, 126.27, 124.11(4×C), 122.35, 115.72, 115.67, 111.57, 61.15( CH ₂ ), 52.13(2×CH ₂ ), 47.14(CH), 31.60(2×CH ₂ ), 21.14(2×CH ₃ ).ESI-MS: m/z 581.3(M+1).C ₂₈ H ₂₉ BrN ₄ O ₃ S[580.11].

Example 8: N-(1-(4-carbamoylphenyl)piperidin-4-yl)-5-bromo-3-(3,5-dimethylphenylsulfone)-1H-indole- Preparation of 2-formamide (I-8)

The preparation method of I-8 is the same as that of I-1, except that 4-(bromomethyl)benzamide (0.5992 mmol) is used instead of 1-(bromomethyl)-3-methoxybenzene. Yield: 48.1%.mp: 175-176°C. ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ: 13.02(s, 1H, Indole-NH), 8.97(d, 1H, J=8.00Hz, CONH), 8.09 (s, 1H, Indole-H), 7.94 (s, 1H, NH ₂ ), 7.86 (d, 2H, J=8.00Hz, Ph'-H), 7.63 (s, 2H, Ph-H ),7.50(q,2H,J=8.00Hz,Indole-H),7.40(d,2H,J=8.00Hz,Ph'-H),7.33(s,1H,NH ₂ ),7.27(s,1H ,Ph-H),3.86(s,1H,piperidine-H),3.54(s,2H,benzyl-CH ₂ ),2.81(d,2H,J＝12.00Hz,piperidine-H),2.31(s,6H , 2×CH ₃ ), 2.18(t, 2H, J=8.00Hz, piperidine-H), 1.93(d, 2H, J=8.00Hz, piperidine-H), 1.62(q, 2H, J=8.00Hz, piperidine-H). ¹³ C NMR (100MHz, DMSO-d ₆ , ppm) δ: 168.23 (C=O), 158.99 (C=O), 143.02, 142.50, 139.43 (2×C), 137.71, 135.15, 133.53 ,133.46,128.86(2×C),127.93(2×C),127.62,126.29,124.11(2×C),122.36,115.71,115.68,111.55,60.23(CH ₂ ),52.09(2×CH ₂ ), 47.25(CH), 31.65(2×CH ₂ ), 21.24(2×CH ₃ ).ESI-MS: m/z 623.1(M+1).C ₃₀ H ₃₁ BrN ₄ O ₄ S[622.12].

Example 9: N-(1-(4-sulfomethylphenyl)piperidin-4-yl)-5-chloro-3-(3,5-dimethylphenolsulfone)-1H-indole- Preparation of 2-formamide (I-9)

The preparation method of I-9 is the same as I-1, and the difference is that the starting material uses 5-chloro-indole carboxylate ethyl ester (0.373mmol) to replace 5-bromo-indole carboxylate ethyl ester, and the last step substituent uses 4- Bromomethylbenzenesulfonamide (0.5992 mmol) replaced 1-(bromomethyl)-3-methoxybenzene. Yield: 55.1%.mp: 179-180°C. ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ: 13.01(s, 1H, Indole-NH), 8.98(d, 1H, J=8.00Hz, CONH), 7.94(s, 1H, Indole-H), 7.91(d, 2H, J=8.00Hz, Ph'-H), 7.63(s, 2H, Ph-H), 7.61(d, 2H, J= 8.00Hz, Ph'-H), 7.55(d, 1H, J＝8.00Hz, Indole-H), 7.56(d, 1H, J＝8.00Hz, Indole-H), 7.26(s, 1H, Ph-H ), 3.87(s,1H,piperidine-H),3.61(s,2H,benzyl-CH ₂ ),3.21(s,2H,SO ₂ CH ₃ ),2.81(d,2H,J＝8.00Hz,piperidine- H), 2.31(s, 6H, 2×CH ₃ ), 2.22(t, 2H, J＝12.00Hz, piperidine-H), 1.94(d, 2H, J＝8.00Hz, piperidine-H), 1.61(q , 2H, J＝12.00Hz, piperidine-H). ¹³ C NMR (100MHz, DMSO-d ₆ , ppm) δ: 159.03 (C＝O), 145.49, 143.04, 139.86, 139.44 (2×C), 137.87, 135.15, 133.29, 129.76(2×C), 127.68, 127.43(2×C), 125.71, 125.10, 124.12(2×C), 119.34, 115.33, 111.72, 61.80(CH ₂ ), 52.11(2×CH ₂ ) ,47.19(CH),44.08(CH ₃ ),31.65(2×CH ₂ ),21.25(2×CH ₃ ).ESI-MS: m/z 614.3.4(M+1).C ₃₀ H ₃₂ ClN ₃ O ₅ S ₂ [613.15].

Example 10: 5-chloro-3-(3,5-dimethylphenylsulfone)-N-(1-(pyridin-3-ylmethyl)piperidine-4-yl)-1H-indole - Preparation of formamide (I-10)

The preparation method of I-10 is the same as that of I-9, except that 3-bromomethylpyridine hydrochloride (0.5992 mmol) is used instead of 4-bromomethylbenzenesulfonamide. Yield: 50.0%.mp: 224-225°C. ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ: 13.01(s, 1H, Indole-NH), 8.97(d, 1H, J=8.00Hz, CONH), 8.51 (s, 1H, pyridine-H), 8.48 (d, 1H, J = 4.00Hz, pyridine-H), 7.95 (s, 1H, Indole-H), 7.73 (d, 1H, J = 8.00 Hz,pyridine-H),7.63(s,2H,Ph-H),7.55(d,1H,J=8.00Hz,pyridine-H),7.38(q,2H,J=8.00Hz,Indole-H), 7.26(s,1H,Ph-H),3.86(s,1H,piperidine-H),3.53(s,2H,benzyl-CH ₂ ),2.81(d,2H,J＝8.00Hz,piperidine-H), 2.31(s,6H,2×CH ₃ ),2.19(t,2H,J=8.00Hz,piperidine-H),1.93(d,2H,J=8.00Hz,piperidine-H),1.62(q,2H, J＝12.00Hz, piperidine-H). ¹³ C NMR (100MHz, DMSO-d ₆ , ppm) δ: 159.02 (C＝O), 150.43, 148.74, 143.04, 139.42 (2×C), 137.87, 136.90, 135.14 ,134.39,133.29,127.68,125.71,125.09,124.12(2×C),123.89,119.35,115.33,111.73,59.67(CH ₂ ),51.97(2×CH ₂ ),47.22(CH),31.62(2×CH ₂ ),21.24(2×CH ₃ ).ESI-MS:m/z 537.4(M+1).C ₂₈ H ₂₉ ClN ₄ O ₃ S[536.16].

Example 11: 5-chloro-3-(3,5-dimethylphenylsulfone)-N-(1-(pyridin-3-ylmethyl)piperidine-4-yl)-1H-indole - Preparation of formamide (I-11) (see 0002466-43 for original record)

The preparation method of I-11 is the same as that of I-9, except that 4-bromomethylpyridine hydrochloride (0.5992 mmol) is used instead of 4-bromomethylbenzenesulfonamide. Yield: 50.5%.mp: 240-241°C. ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ: 13.02(s, 1H, Indole-NH), 8.98(d, 1H, J=8.00Hz, CONH), 8.52(d, 2H, J=4.00Hz, pyridine-H), 7.95(s, 1H, Indole-H), 7.63(s, 2H, Ph-H), 7.55(d, 1H, J=8.00Hz , Indole-H), 7.35 (d, 3H, J=8.00Hz, Indole-H, pyridine-H), 7.26 (s, 1H, Ph-H), 3.87 (s, 1H, piperidine-H), 3.53 ( s,2H,benzyl-CH ₂ ), 2.81(d,2H,J=12.00Hz,piperidine-H),2.31(s,6H,2×CH ₃ ),2.22(t,2H,J=12.00Hz,piperidine -H), 1.93(d, 2H, J＝12.00Hz, piperidine-H), 1.62(q, 2H, J＝12.00Hz, piperidine-H). ¹³ C NMR (100MHz, DMSO-d ₆ , ppm)δ :159.03(C＝O),150.02(2×C),148.26,143.03,139.43(2×C),137.85,135.15,133.28,127.69,125.71,125.11,124.12(2×C),124.09(2×C ),119.55,115.33,111.74,61.16(CH ₂ ),52.13(2×CH ₂ ),47.15(CH),31.62(2×CH ₂ ),21.24(2×CH ₃ ).ESI-MS: m/z 537.6(M+1).C ₂₈ H ₂₉ ClN ₄ O ₃ S[536.16].

Example 12: 5-chloro-3-(3,5-dimethylphenylsulfone)-N-(1-((4-methyl-5-oxo-4,5-dihydro-1H-1 , 2,4-triazol-3-yl)methyl)piperidin-4-yl)-1H-indole-carboxamide (I-12) preparation

The preparation method of I-12 is the same as that of I-9, the difference is to use 5-(bromomethyl)-4-methyl-2 hydrogen-1,2,4-triazolyl-3 (4 hydrogen) (0.5992mmol ) instead of 4-bromomethylbenzenesulfonamide. Yield: 53.1%.mp: 274-275°C. ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ: 13.02(s, 1H, Indole-NH), 11.52(s, 1H, triazole-NH), 8.95(d,1H,J=8.00Hz,CONH),7.94(s,1H,Indole-H),7.63(s,2H,Ph-H),7.55(d,1H,J=8.00Hz,Indole-H ),7.36(d,1H,J＝8.00Hz,Indole-H),7.26(s,1H,Ph-H),3.85(s,1H,piperidine-H),3.41(s,2H,benzyl-CH ₂ ), 3.17(s, 3H, CH ₃ ), 2.81(d, 2H, J＝12.00Hz, piperidine-H), 2.31(s, 6H, 2×CH ₃ ), 2.24(t, 2H, J＝12.00Hz , piperidine-H), 1.93 (d, 2H, J＝12.00Hz, piperidine-H), 1.62 (q, 2H, J＝12.00Hz, piperidine-H). ¹³ C NMR (100MHz, DMSO-d ₆ , ppm )δ: 159.04 (C=O), 155.89 (C=O), 145.35, 143.03, 139.43 (2×C), 137.84, 135.15, 133.28, 127.68, 125.70, 125.09, 124.12 (2×C), 119.35, 115.32 ,111.73,53.41(CH ₂ ),51.79(CH ₂ ),49.07(CH ₂ ),47.05(CH),31.52(2×CH ₂ ),27.28(CH ₃ ),21.23(2×CH ₃ ).ESI- MS: m/z 557.3(M+1).C ₂₆ H ₂₉ ClN ₆ O ₄ S[556.17].

Example 13: N-(1-(4-sulfonamidophenyl)piperidin-4-yl)-5-chloro-3-(3,5-dimethylphenolsulfone)-1H-indole-2 - Preparation of formamide (I-13)

The preparation method of I-13 is the same as that of I-9, except that 4-bromomethylbenzenesulfonamide (0.5992mmol) is used instead of 4-bromomethylbenzenesulfonamide. Yield: 52.1%.mp: 215-217°C. ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ: 13.01(s, 1H, Indole-NH), 8.97(d, 1H, J=8.00Hz, CONH),7.94(s,1H,Indole-H),7.81(d,2H,J＝8.00Hz,Ph'-H),7.63(s,2H,Ph-H),7.55-7.50(m,3H, Indole-H,SONH ₂ ),7.36-7.32(m,3H,Ph'-H,SONH ₂ ),7.26(s,1H,Ph-H),3.87(s,1H,piperidine-H),3.57(s ,2H,benzyl-CH ₂ ),2.81(d,2H,J＝12.00Hz,piperidine-H),2.31(s,6H,2×CH ₃ ),2.20(t,2H,J＝12.00Hz,piperidine- H), 1.94(d, 2H, J＝12.00Hz, piperidine-H), 1.63(q, 2H, J＝12.00Hz, piperidine-H). ¹³ C NMR (100MHz, DMSO-d ₆ , ppm)δ: 159.01(C=O), 143.20, 143.03, 139.44(2×C), 137.84, 135.15, 133.29, 129.41(2×C), 127.69, 126.11(2×C), 125.72, 125.10, 124.11(2×C) ,119.35,115.34,111.72,61.87(CH ₂ ),52.10(2×CH ₂ ),47.22(CH),31.65(2×CH ₂ ),21.24(2×CH ₃ ).ESI-MS: m/z 615.3 (M+1).C ₂₉ H ₃₁ ClN ₄ O ₅ S ₂ [614.14].

Example 14: N-(1-(4-carbamoylphenyl)piperidin-4-yl)-5-chloro-3-(3,5-dimethylphenylsulfone)-1H-indole- Preparation of 2-formamide (I-14)

The preparation method of I-14 is the same as that of I-9, except that 4-(bromomethyl)benzamide (0.5992 mmol) is used instead of 4-bromomethylbenzenesulfonamide. Yield: 56.6%.mp: 153-155°C. ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ: 13.01(s, 1H, Indole-NH), 8.97(d, 1H, J=8.00Hz, CONH),7.94(s,2H,Indole-H),7.86(d,2H,J＝8.00Hz,Ph'-H),7.63(s,2H,Ph-H),7.55-7.53(d,1H, Indole-H),7.40-7.32(m,4H,Ph'-H,CONH ₂ ),7.26(s,1H,Ph-H),3.87(s,1H,piperidine-H),3.54(s,2H, benzyl-CH ₂ ), 2.81(d, 2H, J=12.00Hz, piperidine-H), 2.31(s, 6H, 2×CH ₃ ), 2.18(t, 2H, J=12.00Hz, piperidine-H), 1.94 (d, 2H, J = 12.00Hz, piperidine-H), 1.63 (q, 2H, J = 12.00Hz, piperidine-H). ¹³ C NMR (100MHz, DMSO-d ₆ , ppm) δ: 168.25 (C =O), 159.01(C=O), 143.03, 139.43(2×C), 137.87, 135.15, 133.46, 133.28, 128.87, 127.93(4×C), 127.68, 125.70, 125.10, 124.12(2×C), 119.35,115.33,111.72,60.22(CH ₂ ),52.09(2×CH ₂ ),47.25(CH),31.64(2×CH ₂ ),21.24(2×CH ₃ ).ESI-MS: m/z 615.3( M+1).C ₃₀ H ₃₁ ClN ₄ O ₄ S[578.18].

Example 15: 5-Chloro-3-(3,5-dimethylphenylsulfone)-N-(1-(thiophene-3-methyl)piperidin-4-yl)-1H-indole- Preparation of 2-formamide (I-15)

Intermediate 6' is said to add 30mL of mixed solvent tetrahydrofuran/methanol (1/2) into a round bottom flask, heat it until the solution is clear, add acetic acid dropwise under stirring at 30-40°C until the pH is 4-5, add 3-thiophene-formaldehyde (0.060g, 0.535mmol) was reacted for 40 minutes, then sodium cyanoborohydride (0.056g, 0.89mmol) was added, and the reaction was continued for 10 hours. The reaction solution was directly concentrated and purified by column chromatography (ethyl acetate). Yield: 70.2%.mp: 230-231°C. ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ: 12.92(s, 1H, Indole-NH), 8.99(d, 1H, J=8.00Hz, CONH), 7.94(s, 1H, Indole-H), 7.63-7.54(m, 4H, thiophene-H, Ph-H), 7.44(d, 1H, J＝8.00Hz, Indole-H), 7.24(d ,1H,J＝8.00Hz,Indole-H),7.15-7.13(m,2H,thiophene-H,Ph-H),4.21(s,2H,thiophene-CH ₂ ),3.99(s,1H,piperidine- H),3.34(s,2H,piperidine-H),3.00(s,2H,piperidine-H),2.20(s,6H,2×CH ₃ ),2.04(s,2H,piperidine-H),1.64( s,2H,piperidine-H).ESI-MS:m/z 542.4(M+1).C ₂₇ H ₂₈ ClN ₃ O ₃ S ₂ [541.13].

Example 16: 5-Chloro-3-(3,5-dimethylphenylsulfone)-N-(1-(thiophene-2-methyl)piperidin-4-yl)-1H-indole- Preparation of 2-formamide (I-16)

The preparation method of I-16 is the same as that of I-15, except that 2-thiophene-formaldehyde (0.535 mmol) is used instead of 3-thiophene-formaldehyde. Yield: 69.6%.mp:225-256°C.ESI-MS:m/z 542.4(M+1).C ₂₇ H ₂₈ ClN ₃ O ₃ S ₂ [541.13].

Example 17: N-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)-5-chloro-3-(3,5-dimethylphenylsulfone)-1H- Preparation of indole-2-carboxamide (I-17)

The preparation method of I-17 is the same as that of I-15, except that 4-(trifluoromethyl)benzaldehyde (0.535 mmol) is used instead of 3-thiophene-formaldehyde. Yield: 69.8%.mp: 209-210°C. ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ: 13.00(s, 1H, Indole-NH), 8.97(d, 1H, J=8.00Hz, CONH),7.95(s,1H,Indole-H),7.70(d,2H,J＝8.00Hz,Ph'-H),7.63(s,2H,Ph-H),7.56-7.53(m,3H, J＝8.00Hz, Indole-H, Ph'-H), 7.35(d, 1H, J＝8.00Hz, Indole-H), 7.26(s, 1H, Ph-H), 3.88(s, 1H, piperidine- H), 3.59(s, 2H, benzyl-CH ₂ ), 2.81(d, 2H, J=12.00Hz, piperidine-H), 2.31(s, 6H, 2×CH ₃ ), 2.21(t, 2H, J =12.00Hz, piperidine-H), 1.94(d, 2H, J=12.00Hz, piperidine-H), 1.64(q, 2H, J=12.00Hz, piperidine-H). ¹³ C NMR (100MHz, DMSO-d ₆ , ppm) δ: 159.02 (C=O), 144.21, 143.05, 139.43 (2×C), 137.87, 135.14, 133.31, 129.71 (2×C), 128.18, 127.87, 127.68, 126.61, 125.73, 125.47, 125. ,124.11(2×C),119.35,115.34,111.72,61.83(CH ₂ ),52.08(2×CH ₂ ),47.21(CH),31.66(2×CH ₂ ),21.23(2×CH ₃ ).ESI -MS: m/z 604.4(M+1).C ₃₀ H ₂₉ ClF ₃ N ₃ O ₃ S[603.16].

Example 18: 5-chloro-3-(3,5-dimethylphenylsulfone)-N-(1-(furan-3-methyl)piperidin-4-yl)-1H-indole- Preparation of 2-formamide (I-18)

The preparation method of I-18 is the same as that of I-15, except that 3-furan-formaldehyde (0.535 mmol) is used instead of 3-thiophene-formaldehyde. Yield: 68.8%.mp: 223-224°C. ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ: 12.91(s, 1H, Indole-NH), 8.98(d, 1H, J=8.00Hz, CONH),7.79(s,1H,Indole-H),7.72(s,1H,furan-H),7.53(s,2H,Ph-H),7.44(d,1H,J＝8.00Hz,Indole-H ),7.24(d,1H,J＝8.00Hz,Indole-H),7.14(s,1H,Ph-H),6.57(s,1H,furan-H),6.46(s,1H,furan-H) ,4.24(s,2H,thiophene-CH ₂ ),3.98(s,1H,piperidine-H),3.31(s,2H,piperidine-H),2.98(s,2H,piperidine-H),2.20(s, 6H,2×CH ₃ ), 2.00(s,2H,piperidine-H),1.65(s,2H,piperidine-H).ESI-MS:m/z 526.2(M+1).C ₂₇ H ₂₈ ClN ₃ O ₄ S[525.15].

Example 19: N-(1-(4-nitrophenyl)piperidin-4-yl)-5-chloro-3-(3,5-dimethylphenylsulfone)-1H-indole-2 - Preparation of formamide (I-19)

The preparation method of I-19 is the same as that of I-15, except that 3-nitro-benzaldehyde (0.535 mmol) is used instead of 3-thiophene-formaldehyde. Yield: 65.6%.mp: 258-259°C, decomposed. ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ: 13.01(s, 1H, Indole-NH), 8.97(d, 1H, J=8.00Hz, CONH), 8.21(d, 2H, J=8.00Hz ,Ph'-H),7.94(s,1H,Indole-H),7.63-7.60(m,4H,Ph-H,Ph'-H),7.55(d,1H,J＝8.00Hz,Indole-H ), 7.35 (d, 1H, J=8.00Hz, Indole-H), 7.26 (s, 1H, Ph-H), 3.88 (s, 1H, piperidine-H), 3.63 (s, 2H, benzyl-CH ₂ ), 2.81(d, 2H, J=8.00Hz, piperidine-H), 2.31(s, 6H, 2×CH ₃ ), 2.23(t, 2H, J=8.00Hz, piperidine-H), 1.95(d, 2H, J＝12.00Hz, piperidine-H), 1.64 (q, 2H, J＝8.00Hz, piperidine-H). ¹³ C NMR (100MHz, DMSO-d ₆ , ppm) δ: 159.01 (C＝O), 147.59,147.01,143.03,139.43(2×C),137.84,135.15,133.29,130.02(2×C),127.68,125.71,125.10,124.11(2×C),123.85(2×C),119.35,115.53, 111.72,61.55(CH ₂ ),52.08(2×CH ₂ ),47.14(CH),31.65(2×CH ₂ ),21.24(2×CH ₃ ).ESI-MS: m/z 581.4(M+1) .C ₂₉ H ₂₉ ClN ₄ O ₅ S[580.15].

Example 20: 5-chloro-3-(3,5-dimethylphenylsulfone)-N-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-1H- Preparation of indole-2-carboxamide (I-20)

The preparation method of I-20 is the same as I-9, and the difference is that intermediate IVa-6 is made by 1-tert-butoxycarbonyl-4-aminomethylpiperidine (3.67mmol) instead of Boc-4-aminopiperidine, In the final step, bromoethanol (0.5992 mmol) was used as a substituent instead of 4-bromomethylbenzenesulfonamide. Yield: 50.0%.mp: 255-256°C. ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ: 13.02(s, 1H, Indole-NH), 9.08(d, 1H, J=4.00Hz, CONH),7.88(s,1H,Indole-H),7.65(s,2H,Ph-H),7.55(s,1H,J＝8.00Hz,Indole-H),7.35(s,1H,J＝8.00 Hz, Indole-H), 7.27(s, 1H, Ph-H), 5.28(s, 1H, OH), 3.37(s, 2H, CH ₂ ), 3.50(s, 2H, CH ₂ ), 3.40(s ,2H,CH ₂ ),3.11(s,2H,CH ₂ ),2.31(s,6H,2×CH ₃ ),2.29(s,2H,CH ₂ ),1.98(s,2H,CH ₂ ),1.86 (s,1H,CH),1.53(s,2H,CH ₂ ).ESI-MS:m/z 504.3(M+1).C ₂₅ H ₃₀ ClN ₃ O ₄ S[503.16].

Example 21: N-((1-(4-carbamoylphenyl)piperidin-4-yl)methyl)-5-chloro-3-(3,5-dimethylphenylsulfone)-1H - Preparation of indole-2-carboxamide (I-21)

The preparation method of I-21 is the same as that of I-20, except that 4-(bromomethyl)benzamido (0.5992 mmol) is used instead of bromoethanol. Yield: 52.3%.mp: 259-260°C. ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ: 12.93(s, 1H, Indole-NH), 8.98(d, 1H, J=8.00Hz, CONH), 7.92-7.90(m, 2H, Indole-H, NH ₂ ), 7.83(d, 2H, J=8.00Hz, Ph'-H), 7.61(s, 2H, Ph-H), 7.54(d ,1H,J=8.00Hz,Indole-H),7.37-7.52(m,5H,Indole-H,NH ₂ Ph-H,Ph'-H),3.50(s,2H,benzyl-CH ₂ ),3.32 -3.24(m,2H,CONH-CH ₂ ), 2.83(d,2H,J=12.00Hz,piperidine-H),2.30(s,6H,2×CH ₃ ),1.98(t,2H,J=8.00 Hz, piperidine-H), 1.76(d, 2H, J=8.00Hz, piperidine-H), 1.57(s, 1H, piperidine-H), 1.62(q, 2H, J=8.00Hz, piperidine-H). ESI-MS: m/z 593.5(M+1).C ₃₁ H ₃₃ ClN ₄ O ₄ S[592.19].

Example 22: N-((1-(2-fluorophenyl)piperidin-4-yl)methyl)-5-chloro-3-(3,5-dimethylphenylsulfone)-1H-ind Preparation of Indole-2-carboxamide (I-22)

The preparation method of I-22 is the same as that of I-20, except that 4-(bromomethyl)-2-fluorobenzene (0.5992mmol) is used instead of bromoethanol. Yield: 46.5%.mp: 193-194°C. ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ: 13.00(s, 1H, Indole-NH), 8.97(d, 1H, J=8.00Hz, CONH), 7.92 (d, 1H, J = 12.00Hz, Indole-H), 7.61 (s, 2H, Ph-H), 7.54 (d, 1H, J = 8.00Hz, Indole-H), 7.37-7.31 ( m,2H,Indole-H,Ph'-H),7.26(s,1H,Ph-H),7.14-7.04(m,3H,Ph'-H),3.47(s,2H,benzyl-CH ₂ ) ,3.27(t,2H,J=8.00Hz,CONH-CH ₂ ),2.82(d,2H,J=12.00Hz,piperidine-H),2.30(s,6H,2×CH ₃ ),1.97(t, 2H, J＝12.00Hz, piperidine-H), 1.94(d, 2H, J＝2.00Hz, piperidine-H), 1.57(s, 1H, piperidine-H), 1.30(q, 2H, J＝12.00Hz, piperidine-H).ESI-MS:m/z 568.5(M+1).C ₃₀ H ₃₁ ClFN ₃ O ₃ S[567.18].

Example 23: N-((1-(2-cyanophenyl)piperidin-4-yl)methyl)-5-chloro-3-(3,5-dimethylphenylsulfone)-1H- Preparation of indole-2-carboxamide (I-23)

The preparation method of I-23 is the same as that of I-20, except that 4-(bromomethyl)benzonitrile (0.5992 mmol) is used instead of bromoethanol. Yield: 52.6%.mp: 213-214°C. ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ: 13.00(s, 1H, Indole-NH), 8.96(d, 1H, J=8.00Hz, CONH),7.92(s,1H,Indole-H),7.80(d,1H,J=4.00Hz,Ph'-H),7.68(t,1H,J=8.00Hz,Ph'-H),7.61( s,2H,Ph-H),7.57-7.30(m,4H,Indole-H,Ph'-H),7.24(s,1H,Ph-H),3.63(s,2H,benzyl-CH ₂ ), 3.26(t, 2H, J＝8.00Hz, CONH-CH ₂ ), 2.82(d, 2H, J＝12.00Hz, piperidine-H), 2.30(s, 6H, 2×CH ₃ ), 2.06(t, 2H ,J=12.00Hz,piperidine-H),1.76(d,2H,J=12.00Hz,piperidine-H),1.59(s,1H,piperidine-H),1.29(q,2H,J=12.00Hz,piperidine -H).ESI-MS: m/z 575.5(M+1).C ₃₁ H ₃₁ ClN ₄ O ₃ S[574.18].

Example 24: Ethyl 3-(4-((5-chloro-3-(3,5-dimethylphenylsulfonyl)1H-indole-2-carboxamide)methyl)piperidin-1-yl ) preparation of propionic acid (I-24)

The preparation method of I-24 is the same as that of I-20, except that ethyl 3-bromoacetic acid (0.5992 mmol) is used instead of bromoethanol. Yield: 45.6%.mp: 194-195°C. ¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ: 13.01(s, 1H, Indole-NH), 8.96(s, 1H, CONH), 7.92( s,1H,Indole-H),7.61(s,2H,Ph-H),7.80(d,1H,J＝8.00Hz,Indole-H),7.34(d,1H,J＝8.00Hz,Indole-H ), 7.26(s, 1H, Ph-H), 4.07(q, 2H, J=4.00Hz, O-CH ₂ ), 3.25(t, 2H, J=4.00Hz, CO-CH ₂ ), 2.82(d ,2H,J=12.00Hz,piperidine-H),2.57(d,2H,J=8.00Hz,CH ₂ ),2.46(d,2H,J=8.00Hz,CH ₂ ),2.31(s,6H,2 ×CH ₃ ), 1.98(t, 2H, J=12.00Hz, piperidine-H), 1.75(d, 2H, J=12.00Hz, piperidine-H), 1.56(s, 1H, piperidine-H), 1.25- 1.15(m,5H,piperidine-H,CH ₃ ).ESI-MS:m/z 560.4(M+1).C ₂₈ H ₃₄ ClN ₃ O ₅ S[559.19].

Embodiment 25: Anti-HIV activity experiment (MT-4 cell model)

Explanation of terms:

MT-4 cells: human acute lymphoblastic leukemia cells.

MTT analysis method: MTT is 3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide, trade name: thiazole blue.

Nevirapine: The anti-AIDS drug nevirapine.

Efavirenz: Efavirenz, a listed anti-AIDS drug.

Delavirdine: The anti-AIDS drug Delavirdine.

Etravirine: Etravirine, a listed anti-AIDS drug.

DMSO: dimethylsulfoxide.

Test Principle

Because the MT-4 cell that HIV infects can take place lesion within a certain period of time (5-7 days), therefore add the compound solution to be detected of appropriate concentration in the MT-4 cell suspension liquid that HIV infects, after a period of time (5-7 days) After 7 days) of culture, the viability of MT-4 cells was measured by MTT assay, and the drug concentration (EC ₅₀ ) that protected 50% of the cells from cytopathic changes was 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 HIV-uninfected cells to develop pathological changes was obtained, and the selectivity index (SI=CC ₅₀ /EC ₅₀ ) was calculated.

Principle of MTT assay: MTT is bromide-3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium nitrogen, which can be compared with living intracellular succinate dehydrogenase Binds without reacting with dead cells. At present, the MTT method is a rapid and concise enzymatic analysis method that reflects cell viability.

Test Materials and Methods

(1) HIV-1 (IIIB), HIV-2 (ROD) strains, HIV-1 double mutation (K103N/Y181C) drug-resistant strain RES056: provided by the Institute of Microbiology and Immunology, Rega Institute, University of Leuven, Belgium.

(2) MT-4 cells: provided by the Institute of Microbiology and Immunology, Rega Institute, University of Leuven, Belgium.

(3) MTT: purchased from Sigma, USA.

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

(5) Positive control drugs: Nevirapine (NVP), Efavirenz (EFV), Delavirdine (DLV), Etravirine (ETV).

(6) Test method: the sample is diluted and added to the suspension of HIV-infected MT-4 cells. After a period of time, the cell viability is measured by MTT colorimetry, and the absorbance (A) value is recorded at 590nm in a microplate reader , Calculate EC ₅₀ , CC ₅₀ and SI.

(7) MTT staining method: After adding samples and incubating for a period of time, add 20 μL of MTT solution (5 mg/mL) to each well, continue to cultivate for several hours, discard the staining solution, and add 150 μL DMSO to each well, mix well, and dissolve in enzyme Absorbance was recorded at 590nm in a standard reader.

The specific operation is as follows: the compound was dissolved in DMSO or water and then diluted with phosphate buffer, and 3×10 ⁵ MT-4 cells were pre-incubated with 100 μL of compound solutions of different concentrations at 37° C. for 1 h. Then 100 μL of appropriate concentration of virus dilution was added to the mixture, and the cells were incubated at 37° C. for 1 h. After three washes, cells were resuspended in culture medium with or without compound, respectively. The cells were then incubated for another 7 days at 37°C in a 5% CO ₂ environment, and the original culture medium was supplemented with the culture medium with or without the compound on the third day after infection. Each culture condition was repeated twice. The cytopathic effect on the virus was monitored daily using inverted light microscopy. In general, the virus dilutions used in this experiment are often cytopathic by the fifth day after virus infection. The inhibitory concentration of the drug is expressed by the concentration (EC ₅₀ ) at which the drug produces 50% inhibitory effect on the cytopathic effect of the virus and has no direct toxicity to the cells. It is worth emphasizing that when the compound is poorly soluble in water and needs to be dissolved with DMSO, the volume ratio concentration of DMSO relative to water is generally lower than 10% (the final concentration of DMSO in MT-4 cell culture medium is less than 2% ). Because DMSO can affect the antiviral activity of the test compound, the antiviral activity comparison blank experiment containing the same concentration of DMSO solution should also be performed in parallel. In addition, the final concentration of DMSO (1/1000) was much lower than the concentration required to affect HIV-1 replication in MT-4 cells.

The in vitro anti-HIV-1(IIIB) and HIV-1 double mutant RES056 drug-resistant strain screening data of the target compound were provided by the Institute of Microbiology and Immunology, Rega Institute, University of Leuven, Belgium. Measured in parallel experiments, the results are shown in Tables 1, 2, and 3.

Table 1 Cellular activity and toxicity of compounds against wild-type HIV-1 (IIIB) and double mutant strain (F227L/V106A, RES056)

^a : half effective concentration; ^b : wild type HIV-1 strain; ^c : double mutant HIV-1 strain; ^d : half lethal concentration.

Table 2 Cell activity of compounds against HIV-1 single mutants (L100I, K103N, Y181C, Y188L, E138K)

^a : same as Table 1; ^e : single mutant HIV-1 strain.

Table 3 The selection index (SI) of compounds against wild-type HIV-1(IIIB) and various single (L100I, K103N, Y181C, Y188L, E138K) or double (F227L/V106A, RES056) mutants

^{b, c, e} : same table 1; ^f : therapeutic index.

Embodiment 26: Anti-reverse transcriptase activity test experiment

In this experiment, the colorimetric reverse transcriptase activity assay was used. The kit used, Reverse Transcriptase Assay, colorimetric Version 13.0 was purchased from Roche, and the positive control drugs were nevirapine and etravirine. (See ① Hofman, A.D. & Banapour, B. & Levy, J.A. (1985) Virology 147, 326-335. ② Ukkonen, P. et al. (1988) Eur. J. Clin. Microbiol. & Infect. Dis. 7, 518-523.)

Test Principle

The colorimetric reverse transcriptase activity assay uses the template/primer polymer poly(A)×oligo(dT) as the starting material and uses digoxigenin and biotin-labeled nucleotides instead of radioisotopes [ ³ H]- or [ ³² P]-labeled nucleotides, these are the advantages of this method. The synthesized DNA is an important parameter for determining the activity of reverse transcriptase. The following sandwich ELISA assay method was used for detection and quantification of DNA: biotin-labeled DNA can be combined with a microplate module coated with streptavidin ( MP) surface for binding. In the next step, the digoxigenin antibody polymerized with peroxidase needs to bind to the digoxigenin-labeled DNA. Finally, the substrate of peroxidase 2,2-azino-bis(3-ethyl-benzothiazole-6-sulfonic acid) diammonium salt (ABTS) is added to decompose them under the catalysis of the enzyme, A product with a distinct color was produced. The absorbance of the microplate loaded with samples is measured by a microplate reader, and the absorbance value is directly related to the activity of reverse transcriptase, and the inhibitory concentration of the compound on reverse transcriptase can be obtained by calculating the formula.

testing method

(1) First prepare various working solutions, dissolve the sample with an appropriate amount of dimethyl sulfoxide (DMSO), and dilute it into 5 concentration gradients with lysis buffer. In separate reaction tubes, 4–6 ng of recombinant HIV-1-RT was diluted with lysis buffer (20 μL/well). At the same time, prepare a negative control group with only lysis buffer without RT. Then, 20 μL of buffer solutions containing different concentrations of the tested samples and 20 μL of reactant mixture were added to each reaction tank, and incubated at 37 degrees Celsius for one hour.

(2) Prepare enough micro-version modules and install them firmly in the frame according to the direction. Transfer the incubated sample (60 μL) to the well of the microplate, cover it with a film and incubate for the second time at 37°C for one hour.

The solution was removed, and each well was rinsed carefully 5 times with washing solution, each time with 250 μL, and left for 30 seconds. Add 200 μL of anti-digoxigenin-peroxidase polymer to each well, cover the microplate with film and incubate for the third time at 37°C for one hour.

(3) The solution was removed, and each well was carefully washed 5 times with washing solution, each time with 250 μL, and kept for 30 seconds. Add 200 μL of ABTS solution to each well and incubate at 15-25°C until a green color appears and is sufficient for photometric detection (generally 10-30 minutes).

(4) Use a microplate reader to measure the absorbance value of the loaded sample at a wavelength of 405 nm, and calculate the inhibitory concentration of the compound to reverse transcriptase by the following formula.

Inhibition rate % = (positive control fluorescence intensity - sample fluorescence intensity) / (positive control fluorescence intensity - background fluorescence intensity) × 100% to perform linear regression, bring the inhibition rate into the linear equation, and the obtained concentration C is IC ₅₀ , the unit Yes (μg/mL), and then converted to μM according to the molecular weight of the compound. This experiment selected a representative compound with the best cell activity, as well as positive control drugs nevirapine (NVP) and etravirine (ETV). The experimental results are shown in the table 4.

Table 4 represents compound to HIV-1 reverse transcriptase inhibitory activity

The above-mentioned experimental results show: the compound with general formula I of the present invention is a class of HIV-1 inhibitors with novel structural skeleton, as shown in the above table I, all the compounds of series IVa have significant anti-wild type HIV-1 effect , with _EC50 values ranging from 0.62 μM to 0.006 μM. And most of the compounds also showed good inhibitory activity against multiple single mutant strains, such as mutant virus strains L100I, K103N, Y181C, E138K. Compounds I-2 and I-12 have outstanding inhibitory activity, with EC ₅₀ values of 0.006 μM and 0.009 μM for wild-type HIV-1, and SI of 1005 and 1476, which are better than the marketed drugs NVP and DLV, and compared with the marketed drugs EFV, ETV and lead compound EFF belong to the same order of magnitude. Both I-2 and I-12 maintain submicromolar activity against single or double mutant strains such as L100I, K103N, Y181C, E138K, and F227L/V106A, which are generally superior to marketed drugs NVP and DLV. For some single mutant virus strains such as L100I and K103N, the inhibitory effect of I-2 is slightly stronger than that of the marketed drug EFV, and is at the same level as the lead compound EFF. It is particularly emphasized that the Y188L mutant virus strain, which is very sensitive to indole sulfone compounds, has an EC ₅₀ value of I-12 of 0.84 μM, which is better than the lead compound EFF (EC ₅₀ = 1.3 μM), and has achieved unexpected effects . In addition, the inhibitory activity of I-14 to Y181C/K103N, the most clinically severe double mutant virus strain, was superior to that of the marketed drug DLV, and was at the same level as the lead EFF and the marketed drug NVP. In view of the novelty of the structure of the indole aryl sulfone derivatives involved in the present invention, the significant inhibitory activity against wild-type and various mutant HIV-1, and the progress relative to some existing compounds, it has greater development value. New structural modifications and in-depth research on this basis will help to obtain more excellent effects, and have the potential to develop into a new class of anti-HIV drugs with a new structure.

Claims (7)

1. Indole sulfone derivatives or pharmaceutically acceptable salts or prodrugs thereof, characterized in that they have the structure shown in the following general formula I: in, The substituent X at the 5-position of indole is halogen, CF ₃ or NO ₂ ; n is equal to 0, 1, 2 or 3; m, w each independently equal to 1 or 2; R is (C _1-6 )alkyl-R ¹ , (C _3-7 )cycloalkyl-R ¹ , (C _2-6 )alkenyl-R ¹ , -C(O)R ¹ , -C (O)OR ¹ , -S(O)-R ¹ , -SO ₂ -R ¹ , NH-R ¹ , phenyl, 5- or 6-membered aromatic heterocycle, fused phenyl-unsaturated or Saturated 5- or 6-membered carbocycle, or fused phenyl-5- or 6-membered aromatic heterocycle; Wherein R ¹ is selected from H, OH, SH, NH ₂ , O-(C _1-4 ) alkyl, S-(C _1-4 ) alkyl or NH-(C _1-4 ) alkyl; Phenyl, 5- or 6-membered heteroaromatic ring, fused phenyl-unsaturated or saturated 5- or 6-membered carbocycle, or fused phenyl-5- or 6-membered heteroaryl ring Each in turn is optionally substituted by 1 to 3 substituents independently selected from: (C _1-6 ) alkyl, halogen, CF ₃ , OCF ₃ , OH, NO ₂ , CN, SO ₂ NH ₂ , SO ₂ -(C _1-3 )alkyl, C(O)NH ₂ , C(O)(C _1-3 )alkyl, NH(C _1-3 )alkyl. 2. the compound as claimed in claim 1 is characterized in that, in general formula I, The substituent X at the 5-position of indole is Cl or Br; n is equal to 0 or 1; m and w are equal to 2 at the same time; _R is _CH2OH , _CH2COOCH2CH3 , substituted phenyl, pyridyl, _furyl , thienyl, or substituted triazolyl. 3. The compound as claimed in claim 1 or 2, characterized in that it is one of the compounds of the following structures: 4. the preparation method of indole aryl sulfone derivatives as claimed in claim 1 or 2, comprises the steps: be starting raw material with the ethyl indole carboxylate (1) of 5-position substitution, with 3,5- The intermediate compound 2 is obtained by the reaction of dimethylthiophenol, the intermediate compound is oxidized by m-chloroperbenzoic acid to obtain the intermediate compound 3, and the ethyl ester group of the intermediate compound 3 is hydrolyzed to obtain the intermediate compound 4, the intermediate compound 4 After the acylation reaction and removal of the BOC protecting group, the parent ring 6 is obtained, and different substituents are substituted for the parent ring 6 to obtain the indole sulfone derivative I; The synthetic route is as follows: Reagents and conditions: (i) 3,5-dimethylthiophenol, 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt , acetonitrile; (ii) m-chloroperoxybenzoic acid, dichloromethane, 0°C; (iii) lithium hydroxide, water, tetrahydrofuran, 50°C; (iv) Boc-protected nitrogen-containing cycloalkyl-amino, 2- (7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-ethyl-(3-dimethylaminopropyl)carbodiimide Hydrochloride, triethylamine, N,N-dimethylformamide; (v) trifluoroacetic acid, dichloromethane; (vi) potassium carbonate, N,N-dimethylformamide, benzyl halide, halogen substituted (vi) substituted formaldehyde, glacial acetic acid, sodium cyanoborohydride, tetrahydrofuran/acetonitrile. Wherein, the definition of X, n, m, w, R is the same as that described in general formula I in claim 1 or 2. 5. the preparation method of indole aryl sulfone derivatives as claimed in claim 3, comprises the steps: be starting raw material with 5-chloro/bromo-substituted ethyl indole carboxylate (1 '), with 3,5 -Dimethylthiophenol reacts to produce intermediate compound 2', intermediate compound 2' is oxidized to intermediate compound 3' through m-chloroperoxybenzoic acid, and lithium hydroxide converts the ethyl ester group of intermediate compound 3' Hydrolysis to obtain intermediate compound 4', intermediate compound 4' and 1-Boc-4-aminopiperidine or 1-Boc-4-(aminomethyl)-piperidine undergoes acylation reaction to obtain intermediate compound 5', and Remove the Boc protecting group under the action of trifluoroacetic acid to obtain the parent ring 6', and substitute different substituents on the parent ring 6' to obtain the indole sulfone derivative I; The synthetic route is as follows: Reagents and conditions: (i) 3,5-dimethylthiophenol, 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt , acetonitrile; (ii) m-chloroperbenzoic acid, dichloromethane, 0°C; (iii) lithium hydroxide, water, tetrahydrofuran, 50°C; (iv) 1-BOC-4-aminopiperidine or 1-Boc -4-(aminomethyl)-piperidine, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-ethyl- (3-Dimethylaminopropyl) carbodiimide hydrochloride, triethylamine, N,N-dimethylformamide; (v) trifluoroacetic acid, dichloromethane; (vi) potassium carbonate, N , N-dimethylformamide, benzyl halide or halogen substituted alkyl; (vi) substituted formaldehyde, glacial acetic acid, sodium cyanoborohydride, tetrahydrofuran/acetonitrile; Wherein, X is chlorine or bromine, n is equal to 0 or 1, and R is CH ₂ OH, CH ₂ COOCH ₂ CH ₃ , substituted phenyl, pyridyl, furyl, thienyl or substituted triazolyl. 6. Use of the compound according to any one of claims 1-3 in the preparation of anti-HIV drugs. 7. An anti-HIV pharmaceutical composition, comprising the compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.