CN105968095B

CN105968095B - Indoles virtue sulfone derivatives and the preparation method and application thereof

Info

Publication number: CN105968095B
Application number: CN201610305158.9A
Authority: CN
Inventors: 刘新泳; 李潇; 展鹏
Original assignee: Shandong University
Current assignee: Shandong University
Priority date: 2016-05-10
Filing date: 2016-05-10
Publication date: 2018-10-30
Anticipated expiration: 2036-05-10
Also published as: CN105968095A

Abstract

Application of the composition the invention discloses a kind of indoles virtue sulfone derivatives and its pharmaceutically acceptable salt, ester or prodrug as shown in general formula I, preparation method and containing one or more such compounds in preparing prevention and treatment human immunodeficiency virus (HIV) and infecting.

Description

Indoles virtue sulfone derivatives and the preparation method and application thereof

Technical field

The present invention relates to a kind of derivatives and the preparation method and application thereof, more particularly to indoles virtue sulfone derivatives and its system Preparation Method and application, belong to pharmaceutical technology field.

Background technology

In HIV replicative cycles, its own multi-functional albumen reverse transcriptase (RT) plays vital effect, bears Duty completes multiple key links such as the DNA synthesis of DNA synthesis, the hydrolysis of RNA and DNA guidances of RNA guidances.Therefore, with RT There are the advantages such as inhibitory activity is high, selectivity is good, toxic side effect is small to prevent AIDS as the target spot of drug design, be current Research and develop the Critical policies of AntiHIV1 RT activity/AIDS drugs.According to mechanism of action and the difference of chemical constitution, HIV-1 reverse transcriptase inhibitor Can be divided mainly into nucleosides (acid) (nucleos (t) ide reverse transcriptase inhibitors, N (t) RTIs) and Two classes of non-nucleosides (Non-nucleoside reverse transcriptase inhibitors, NNRTIs).Wherein, The mechanism of action of NNRTIs is and distance RT catalytic active centersAllostery pocket (NNIBP) specific binding, in turn The forfeiture of RT critical functions is caused to inhibit the duplication of virus.Due to the specificity of its combination, NNRTIs usually has efficient, low The advantage of poison, thus have become the important component of HAART.Such drug of the listing of FDA approvals at present has 5 (nevirapine,delavirdine,efavirine,etravirine,rilpivirine).But since NNRTIs is combined The amino acid of pocket easily mutates and causes the generation and sprawling of multidrug resistant disease strain, and existing drug bioavailability is low in addition And the serious toxic side effect that long-term administration is brought makes the clinical application of such drug by great threat.Therefore, it finds new The NNRTIs of type overriding resistance low toxicity is still the important topic of current anti-AIDS drug research and development.

Indoles virtue sulfone compound (indolylaryl-sulfone, IAS) is by the Williams in the laboratories Merk earliest Et al. one kind of report there is fine active HIV-1NNRTIs structural frameworks.Lead compound L-737,126 is to wild type (WT) RT inhibiting effect can reach 3nM, while also can reach to the inhibiting effect of clinical common variant viral strain K103N, Y181C Sub-micromolar is horizontal.In subsequent structure of modification, the activity of the anti-HIV-1 of multiple compounds all significantly improves, especially needle Very strong inhibiting effect is all had to clinical common multidrug resistant disease strain, if compound EFF is to the EC of wild type HIV-1₅₀Value is 2nM keeps nanomolar range to the inhibitory activity of a variety of common mutations Strain Y181C, K103N, L100I and E138K.Cause This carries out extensive structural modification using indoles virtue sulfone compound as template, to find high-efficiency broad spectrum, bioavilability it is good and Novel inverase with independent intellectual property right is of great significance.

Invention content

In view of the deficiencies of the prior art, the present invention provides a kind of indoles virtue sulfone derivatives, the present invention also provides above-mentioned The preparation method and active ingredients result of compound and application.

Technical scheme is as follows：

One, indoles virtue sulfone derivatives

The indoles virtue sulfone derivatives or its pharmaceutically acceptable salt or prodrug of the present invention, have shown in following general formula I Structure：

Wherein,

The substituent X that indoles is 5- is halogen, CF₃Or NO₂；

N is equal to 0,1,2 or 3；

M, w are respectively individually equal to 1 or 2；

R is (C_1-6) alkyl-R¹、(C_3-7) naphthenic base-R¹、(C_2-6) alkenyl-R¹、-C(O)R¹、-C(O)OR¹、-S(O)- R¹、-SO₂-R¹、NH-R¹, phenyl, 5- or 6- members heteroaromatic, condensed phenyl-be undersaturated or 5- the or 6- members carbocyclic ring of saturation, Or condensed phenyl -5- or 6- member heteroaromatics；

Wherein R¹Selected from H, OH, SH, NH₂、O-(C_1-4) alkyl, S- (C_1-4) alkyl or NH- (C_1-4) alkyl；The benzene Base, 5- or 6- members heteroaromatic, condensed phenyl-be undersaturated or 5- or 6- members carbocyclic ring or the condensed phenyl -5- or 6- of saturation First heteroaromatic is respectively optionally independently selected from following substituent group by 1 to 3 successively and replaces：(C_1-6) alkyl, halogen, CF₃、 OCF₃、OH、NO₂、CN、SO₂NH₂、SO₂-(C_1-3) alkyl, C (O) NH₂、C(O)(C_1-3) alkyl, NH (C_1-3) alkyl；

According to currently preferred,

The substituent X that indoles is 5- is Cl or Br；

N is equal to 0 or 1；

M and w is equal to 2 simultaneously；

R is CH₂OH、CH₂COOCH₂CH₃, substitution phenyl, pyridyl group, furyl, thienyl or substituted triazolyl.

According to the present invention, it is further preferred that compound of Formula I is one of the compound of having structure：

Two, the preparation method of indoles virtue sulfone derivatives

The indolecarboxylic acid ethyl ester (1) that the preparation of indoles virtue sulfone derivatives of the present invention is replaced with 5- is starting material, with Midbody compound 2 is made in the reaction of 3,5- thiophenol dimethyl benzenes, and intermediate 2 aoxidizes to obtain intermediate through metachloroperbenzoic acid Object 3 is closed, the ethoxycarbonyl of midbody compound 3 is hydrolyzed to obtain midbody compound 4, midbody compound 4 passes through acylation reaction And slough Boc protecting groups and obtain female ring 6, different substituent groups carries out female ring 6 to replace obtained indoles virtue sulfone derivatives I；

Synthetic route is as follows：

Reagent and condition:(i) 3,5- thiophenol dimethyl benzenes, the fluoro- 1,4- diazabicyclos [2.2.2] of 1- chloromethyls -4- are pungent Alkane two (tetrafluoro boric acid) salt, acetonitrile；(ii) metachloroperbenzoic acid, dichloromethane, 0 DEG C；(iii) lithium hydroxide, water, tetrahydrochysene furan It mutters, 50 DEG C；(iv) boc-protected nitrogenous naphthenic base-amino, 2- (7- azos benzotriazole)-N, N, N', N'- tetramethylureas Hexafluorophosphoric acid ester, 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride, triethylamine, N,N-dimethylformamide； (v) trifluoroacetic acid, dichloromethane；(vi) potassium carbonate, n,N-Dimethylformamide, halogen benzyl, the alkyl of halogen substitution；(vii) it takes The formaldehyde in generation, glacial acetic acid, sodium cyanoborohydride, tetrahydrofuran/acetonitrile

Wherein, X, n, m, w, R are defined as above described in general formula I.

According to currently preferred, the preparation method of indoles virtue sulfone derivatives includes the following steps：

The preparation of indoles virtue sulfone derivatives of the present invention is that starting is former with the indolecarboxylic acid ethyl ester (1 ') that 5- chlorine bromines replace Material reacts with 3,5- thiophenol dimethyl benzenes and midbody compound 2 ' is made, and midbody compound 2 ' is through metachloroperbenzoic acid oxygen Change obtains midbody compound 3 ', and lithium hydroxide hydrolyzes the ethoxycarbonyl of midbody compound 3 ' to obtain midbody compound 4 ', Midbody compound 4 ' obtains intermediate with 1-Boc-4- amino piperidines or 1-Boc-4- (aminomethyl)-piperidines by acylation reaction Compound 5 ', and slough Boc protecting groups under trifluoroacetic acid effect and obtain female ring 6 ', different substituent groups takes female ring 6 ' Indoles virtue sulfone derivatives I is made in generation；

Synthetic route is as follows：

Reagent and condition:(i) 3,5- thiophenol dimethyl benzenes, the fluoro- 1,4- diazabicyclos [2.2.2] of 1- chloromethyls -4- are pungent Alkane two (tetrafluoro boric acid) salt, acetonitrile；(ii) metachloroperbenzoic acid, dichloromethane, 0 DEG C；(iii) lithium hydroxide, water, tetrahydrochysene furan It mutters, 50 DEG C；(iv) 1-BOC-4- amino piperidines or 1-Boc-4- (aminomethyl)-piperidines, 2- (7- azos benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester, 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride, triethylamine, N, N- Dimethylformamide；(v) trifluoroacetic acid, dichloromethane；(vi) potassium carbonate, N,N-dimethylformamide, halogen benzyl or halogen substitution Alkyl；(vii) formaldehyde replaced, glacial acetic acid, sodium cyanoborohydride, tetrahydrofuran/acetonitrile；

Wherein, X is chlorine or bromine, and n is equal to 0 or 1, R CH₂OH、CH₂COOCH₂CH₃, substitution phenyl, pyridyl group, furans Base, thienyl or substituted triazolyl.

Specific preparation method detailed in Example 1-24.

Three, the application of indoles virtue sulfone derivatives

The performance in the test cell line (MT-4 cells) for inhibiting HIV to replicate of the indoles virtue sulfone derivatives of general formula I of the present invention Go out significant antiviral activity, higher selectivity and anti-drug resistance.Therefore, the present invention also provides：

Application of the indoles virtue sulfone derivatives of general formula I in the drug for preparing AntiHIV1 RT activity.

A kind of inverase composition, including compound of the present invention or its pharmaceutically acceptable salt and one kind Or a variety of pharmaceutically acceptable carriers or excipient.

The compounds of this invention can also both be used by itself in the form of its pharmaceutically acceptable salt or solvate. The pharmaceutically acceptable salt of compound of Formula I include with pharmaceutically acceptable inorganic acid or organic acid or inorganic base or The conventional salt that organic base is formed.The example of suitable acid-addition salts includes and hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, high chlorine Acid, acetic acid, propionic acid, succinic acid, hydroxyacetic acid, formic acid, lactic acid, maleic acid, tartaric acid, citric acid, flutters acid, the third two at fumaric acid Acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzene The salt of the formation such as sulfonic acid, hydroxybenzoic acid, hydroiodic acid, malic acid, tannic acid.The example of suitable base addition salts include with sodium, lithium, Potassium, magnesium, aluminium, calcium, zinc, N, N '-dibenzyl-ethylenediamins, chloroprocaine, choline, diethanol amine, ethylenediamine, N- methyls By the salt with the formation such as procaine.When the compounds of this invention is referred to herein, including compound of Formula I and its pharmaceutically may be used The salt or solvate of receiving.

According to the present invention, formula Compound I can form pharmaceutical composition with Conventional pharmaceutical carriers or excipient.The medicine Compositions can be administered by oral or parenteral approach.The pharmaceutical composition of the present invention can be prepared by this field conventional method Various dosage forms, including but not limited to tablet, capsule, solution, suspension, granule or injection etc., by oral administration or non-bowel way Diameter is administered.

The present invention to the combination and Pharmacophore Model and Crystal study of indoles virtue sulfone class lead compound and point Sub- analog study on the basis of analysis, devises a series of new indole virtue sulfone derivatives for second channel comprehensively.With The N- substituted piperidine groups of DAPY classes NNRTIs are introduced into indoles virtue sulfone molecule by the drug design principle of skeleton transition, make to prolong The group stretched acts on second channel, it is desirable to which nitrogen-atoms can form hydrogen bond action with amino acid around (G138) on piperidines.Together When end substituent group use various structures group, but substantially all include a hydrophilic radical, such as hydrophily short chain and parent The benzyl etc. of aqueous substituent group substitution, to adapt to the microenvironment of albumen/solvent open region and improve the water solubility of compound whereby. Activity Results show that all compounds all have significant anti-wild type HIV-1 effects, EC₅₀Ranging from 0.62 μM of value arrives 0.006μM.And majority of compounds also shows good inhibitory activity to a variety of single mutation strains, such as variant viral strain L100I,K103N,Y181C,E138K.I-2 and I-12 is inhibitory activity two compounds more outstanding in the series, to open country The EC of raw type HIV-1₅₀Value is respectively 0.006 μM and 0.009 μM, and SI is 1005 and 1476.Structure-activity analysis is found on piperidines The group of hydrophilic small volume is more advantageous to active raising.And enhance the interaction with conservative amino acid W229, drop The low dependence for amino acid Y181, Y188 is improved to one of active strategy of mutant strain in modifying in next step.Cause This, indoles virtue sulfone derivatives have larger Development volue.New structural modification and depth are carried out in the compound of the present invention Entering research helps to develop new inverase.

Specific implementation mode

Contribute to understand the present invention by following embodiments, but present disclosure cannot be limited.

Embodiment 1：N- (1- (3- methoxyphenyls) piperidin-4-yl) the bromo- 3- of -5- (3,5- xylenols sulfuryl) -1H- The preparation of indole 2-carboxamides (I-1)

5- bromo indole Ethyl formates (1 ') (0.10g, 0.373mmol) are placed in round-bottomed flask, and acetonitrile 10mL, room temperature is added 3,5- thiophenol dimethyl benzenes (0.0516g, 0.373mmol, 50 μ L), the fluoro- Isosorbide-5-Nitrae-phenodiazines of 1- chloromethyls -4- are sequentially added under stirring Miscellaneous two (tetrafluoro boric acid) salt (0.10g, 0.373mmol) of bicyclic [2.2.2] octane.The reaction was continued 6 hours for reaction solution.It is evaporated second Water 30mL is added in nitrile, and dichloromethane extracts (3 × 10mL), and organic phase merges, and anhydrous magnesium sulfate is dry after saturated common salt water washing It is dry.Filtering and concentrating, column chromatography purify (ethyl acetate：Petroleum ether=1:8).Gained white solid ethyl acetate/petroleum ether is tied again It is brilliant to obtain 2 '.Yield 50.5%.

Intermediate 2 ' (0.10g, 0.247mmol) is placed in round-bottomed flask to be dissolved with 10mL dichloromethane, under ice bath stirring It is slowly added into metachloroperbenzoic acid (0.128g, 0.742mmol), room temperature reaction is switched to after 30 minutes 3 hours to the reaction was complete. After dichloromethane dilution is added in reaction solution, washed 3 times with the saturated aqueous solution of sodium hydrogensulfite and sodium bicarbonate successively, it is anhydrous Magnesium sulfate is dried, and filtering and concentrating, re-crystallizing in ethyl acetate obtains white solid 3 '.Yield：68.8%.mp:205-207℃.ESI- MS:m/z 436.3(M+1).C₁₉H₁₈BrNO₄S[435.01].

Upper step is made intermediate 3 ' (0.10g, 0.229mmol) and claims in round-bottomed flask, and mix reagent THF/H is added₂O (6mL/6mL), is stirred at room temperature lower addition lithium hydroxide (0.0165g, 0.687mmol), and reaction solution switchs to 50 DEG C and reacts 24 hours. Reaction solution is evaporated THF, and distilled water dilution is added, and a large amount of white solids are precipitated to acid (pH=2-3) in dilute hydrochloric acid tune pH, filter And it is dry, obtain intermediate 4 '.Yield：66.5%.mp:215-217℃.ESI-MS:m/z 425.3(M+18).C₁₇H₁₄BrNO₄S [406.98]。

Intermediate 4 ' (1.0g, 2.45mmol), 2- (7- azos benzotriazole)-N, N, N', N'- tetramethylurea hexafluoro phosphorus N, N- is added in round-bottomed flask in acid esters (1.39g, 3.67mmol), Boc-4- amino piperidines (0.735g, 3.67mmol) nominal Dimethylformamide 10mL, is stirred at room temperature lower addition diisopropylethylamine (0.949g, 7.35mmol, 1.3mL), and reaction solution continues Reaction 24 hours.It is evaporated most of solvent, tetrahydrofuran 100mL redissolves, the sodium hydrate aqueous solution washing 3 of the saline solution of saturation Secondary, tetrahydrofuran layer anhydrous magnesium sulfate drying, filtering and concentrating column chromatography purifies (ethyl acetate：Petroleum ether=1:4) it obtains white solid Body 5 ', yield：47.5%.

Intermediate 5 ' (0.5g, 0.848mmol) is placed in round-bottomed flask, and dry dichloromethane 2mL is added, is stirred at room temperature Lower addition trifluoroacetic acid 1mL.There are a large amount of white precipitates in reaction solution after 4 hours, filters and dichloromethane washs, obtain intermediate Body 6 '.Yield：75.4%.mp:230-231℃,ESI-MS:m/z 490.4(M+1)C₂₂H₂₄BrN₃O₃S[489.07]。

Intermediate 6 ' (0.30g, 0.496mmol) and potassium carbonate (0.274g, 1.98mmol) are co-located in round-bottomed flask, are added Enter N,N-dimethylformamide 10mL.Be stirred at room temperature down be added after ten minutes 1- (bromomethyl) -3- methoxybenzenes (0.274g, 0.5992mmol), continue to be stirred at room temperature 4 hours.It is evaporated most of n,N-Dimethylformamide, adds water 50mL, ethyl acetate extraction It takes (3 × 10mL), organic phase merges, and anhydrous magnesium sulfate is dried after saturated common salt water washing.Filtering and concentrating, column chromatography purify (second Acetoacetic ester：Petroleum ether=1:2).Gained white solid tetrahydrofuran/re-crystallizing in ethyl acetate obtains I-1.Yield：43.2%.mp: 175-177℃.¹H NMR(400MHz,DMSO-d₆,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,OCH₃),3.46(s,2H,benzyl-CH₂),2.79(s,2H,piperidine-H), 2.31(s,6H,2×CH₃),2.14(s,2H,piperidine-H),1.93(s,2H,piperidine-H),1.59(s,2H, piperidine-H).¹³C NMR(100MHz,DMSO-d₆,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(CH₂),55.40(2×CH₂),52.07(O- CH₃),47.28,31.65(2×CH₂),21.24(2×CH₃).ESI-MS:m/z 610.3(M+1).C₃₀H₃₂BrN₃O₄S [609.13].

Embodiment 2：The bromo- 3- of 5- (3,5- dimethyl benzenes sulfuryl)-N- (1- (2- ethoxys) piperidin-4-yl) -1H- indoles - The preparation of 2- acetamides (I-2)

The same I-1 of preparation method of I-2, except that replacing 1- (bromomethyl) -3- using bromoethanol (0.5992mmol) Methoxybenzene.Yield：40.1%.mp:220-222℃.¹H NMR(400MHz,DMSO-d₆,ppm)δ:13.20-12.59(b, 1H, Indole-NH), 8.95 (d, 1H, J=8.00Hz, 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,CH₂),2.91(s,2H,piperidine-H),2.45(s,2H,CH₂),2.31(s,6H, 2×CH₃),2.22(s,2H,piperidine-H),1.91(s,2H,piperidine-H),1.60(s,2H,piperidine- H).¹³C NMR(100MHz,DMSO-d₆,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 (CH₂),58.98(CH₂),52.54(2×CH₂),47.13,31.47(2×CH₂),21.25(2×CH₃).ESI-MS:m/z 534.3(M+1).C₂₄H₂₈BrN₃O₄S[533.1].

Embodiment 3：N- (1- (4- sulfonamide phenyl) piperidin-4-yl) the bromo- 3- of -5- (3,5- xylenols sulfuryl) -1H- The preparation of indole 2-carboxamides (I-3)

The same I-1 of preparation method of I-3, except that replacing 1- using 4- bromomethyls benzsulfamide (0.5992mmol) (bromomethyl) -3- methoxybenzenes.Yield：42.1%.mp:170-171℃.¹H NMR(400MHz,DMSO-d₆,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,SONH₂),7.27(s,1H, Ph-H),3.87(s,1H,piperidine-H),3.56(s,2H,benzyl-CH₂), 2.81 (d, 2H, J=12.00Hz, piperidine-H),2.31(s,6H,2×CH₃), 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)¹³C NMR(100MHz, DMSO-d₆,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(CH₂),52.10(2×CH₂),47.23(CH),31.65(2×CH₂),21.25(2×CH₃) .ESI-MS:m/z 659.4(M+1).C₂₉H₃₁BrN₄O₅S₂[658.09].

Embodiment 4：N- (1- (4- chlorphenyls) piperidin-4-yl) the bromo- 3- of -5- (3,5- xylenols sulfuryl) -1H- Yin The preparation of diindyl -2- formamides (I-4)

The same I-1 of preparation method of I-4, except that replacing 1- (bromines using 1- bromomethyl -4- chlorobenzenes (0.5992mmol) Methyl) -3- methoxybenzenes.Yield：46.2%.mp:229-230℃.¹H NMR(400MHz,DMSO-d₆,ppm)δ:13.07- 12.94 (br, 1H, Indole-NH), 8.97 (d, 1H, J=8.00Hz, 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- CH₂), 2.80 (d, 2H, J=12.00Hz, piperidine-H), 2.31 (s, 6H, 2 × CH₃), 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).¹³C NMR(100MHz,DMSO-d₆,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(CH₂),51.99(2×CH₂),47.24 (CH),31.64(2×CH₂),21.24(2×CH₃).ESI-MS:m/z 614.3(M+1).C₂₉H₂₉BrClN₃O₃S[613.08].

Embodiment 5：N- (1- (3- benzonitriles base) piperidin-4-yl) the bromo- 3- of -5- (3,5- xylenols sulfuryl) -1H- Yin The preparation of diindyl -2- formamides (I-5)

The same I-1 of preparation method of I-5, except that replacing 1- using 1- bromomethyl -3- cyano benzene (0.5992mmol) (bromomethyl) -3- methoxybenzenes.Yield：42.3%.mp:223-236℃.¹H NMR(400MHz,DMSO-d₆,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-CH₂), 2.81 (d, 2H, J=12.00Hz, piperidine-H), 2.31 (s,6H,2×CH₃), 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)¹³C NMR(100MHz,DMSO-d₆,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(CH₂),51.95(2×CH₂),47.18(CH),31.61(2×CH₂),21.24(2×CH₃).ESI-MS: m/z 605.4(M+1).C₃₀H₂₉BrN₄O₃S[604.11].

Embodiment 6：The bromo- 3- of 5- (3,5- dimethyl benzene benzene sulfuryl)-N- (1- (pyridin-3-yl methyl) piperidin-4-yl)- The preparation of 1H- indole 2-carboxamides (I-6)

The same I-1 of preparation method of I-6, except that being replaced using 3- (bromomethyl) pyridine hydrochloride (0.5992mmol) 1- (bromomethyl) -3- methoxybenzenes.Yield：47.8%.mp:220-221℃.¹H NMR(400MHz,DMSO-d₆,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=8.00Hz, pyridine-H), 7.63 (s, 2H, Ph-H), 7.50 (q, 2H, J=8.00Hz, Indole-H), 7.38 (dd, 1H, J₁=8.00Hz, J₂= 4.00Hz,pyridine-H),7.26(s,1H,Ph-H),3.86(s,1H,piperidine-H),3.52(s,2H,benzyl- CH₂), 2.81 (d, 2H, J=12.00Hz, piperidine-H), 2.31 (s, 6H, 2 × CH₃), 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).¹³C NMR(100MHz,DMSO-d₆,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(CH₂),51.97(2×CH₂),47.22(CH), 31.62(2×CH₂),21.24(2×CH₃).ESI-MS:m/z 581.1(M+1).C₂₈H₂₉BrN₄O₃S[580.11].

Embodiment 7：The bromo- 3- of 5- (3,5- dimethyl benzene benzene sulfuryl)-N- (1- (pyridin-4-yl methyl) piperidin-4-yl)- The preparation of 1H- indole 2-carboxamides (I-7)

The same I-1 of preparation method of I-7, except that being replaced using 4- (bromomethyl) pyridine hydrochloride (0.5992mmol) 1- (bromomethyl) -3- methoxybenzenes.Yield：46.6%.mp:243-244℃.¹H NMR(400MHz,DMSO-d₆,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=8.00Hz, 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-CH₂), 2.81 (d, 2H, J=12.00Hz, piperidine-H), 2.31 (s, 6H, 2 × CH₃), 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).¹³C NMR(100MHz,DMSO-d₆,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(CH₂),52.13(2×CH₂),47.14(CH),31.60(2×CH₂),21.14(2 ×CH₃).ESI-MS:m/z 581.3(M+1).C₂₈H₂₉BrN₄O₃S[580.11].

Embodiment 8：N- (1- (4- Carbamoylphenyls) piperidin-4-yl) bromo- 3- of -5- (3,5- dimethyl benzenes sulfuryl) - The preparation of 1H- indole 2-carboxamides (I-8)

The same I-1 of preparation method of I-8, except that replacing 1- using 4- (bromomethyl) benzamide (0.5992mmol) (bromomethyl) -3- methoxybenzenes.Yield：48.1%.mp:175-176℃.¹H NMR(400MHz,DMSO-d₆,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, NH₂), 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, NH₂),7.27(s,1H,Ph-H),3.86(s,1H, piperidine-H),3.54(s,2H,benzyl-CH₂), 2.81 (d, 2H, J=12.00Hz, piperidine-H), 2.31 (s,6H,2×CH₃), 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)¹³C NMR(100MHz,DMSO-d₆,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(CH₂),52.09(2×CH₂),47.25(CH),31.65(2×CH₂),21.24(2×CH₃) .ESI-MS:m/z 623.1(M+1).C₃₀H₃₁BrN₄O₄S[622.12].

Embodiment 9：N- (1- (4- sulphurs aminomethyl phenyl) piperidin-4-yl) the chloro- 3- of -5- (3,5- xylenols sulfuryl) -1H- The preparation of indole 2-carboxamides (I-9)

The same I-1 of preparation method of I-9, except that starting material uses the chloro- indolecarboxylic acid ethyl esters (0.373mmol) of 5- Instead of the bromo- indolecarboxylic acid ethyl esters of 5-, final step substituent group replaces 1- (bromines using 4- bromomethyls benzsulfamide (0.5992mmol) Methyl) -3- methoxybenzenes.Yield：55.1%.mp:179-180℃.¹H NMR(400MHz,DMSO-d₆,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-CH₂),3.21(s,2H,SO₂CH₃), 2.81 (d, 2H, J=8.00Hz, piperidine-H), 2.31(s,6H,2×CH₃), 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)¹³C NMR(100MHz,DMSO-d₆,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(CH₂),52.11(2×CH₂),47.19(CH),44.08(CH₃),31.65(2×CH₂),21.25(2×CH₃).ESI- MS:m/z 614.3.4(M+1).C₃₀H₃₂ClN₃O₅S₂[613.15].

Embodiment 10：The chloro- 3- of 5- (3,5- 3,5-dimethylphenyls sulfuryl)-N- (1- (pyridin-3-yl methyl) piperidines -4-yl) - The preparation of 1H- indoles-formamide (I-10)

The same I-9 of preparation method of I-10, except that being replaced using 3- bromo methyl cycloheptapyridines hydrochloride (0.5992mmol) 4- bromomethyl benzsulfamides.Yield：50.0%.mp:224-225℃.¹H NMR(400MHz,DMSO-d₆,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=8.00Hz, 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-CH₂), 2.81 (d, 2H, J= 8.00Hz,piperidine-H),2.31(s,6H,2×CH₃), 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)¹³C NMR (100MHz,DMSO-d₆,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(CH₂),51.97(2×CH₂),47.22(CH),31.62(2×CH₂),21.24(2×CH₃) .ESI-MS:m/z 537.4(M+1).C₂₈H₂₉ClN₄O₃S[536.16].

Embodiment 11：The chloro- 3- of 5- (3,5- 3,5-dimethylphenyls sulfuryl)-N- (1- (pyridin-3-yl methyl) piperidines -4-yl) - The preparation of 1H- indoles-formamide (I-11) (original record is shown in 0002466-43)

The same I-9 of preparation method of I-11, except that being replaced using 4- bromo methyl cycloheptapyridines hydrochloride (0.5992mmol) 4- bromomethyl benzsulfamides.Yield：50.5%.mp:240-241℃.¹H NMR(400MHz,DMSO-d₆,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-CH₂), 2.81 (d, 2H, J=12.00Hz, piperidine-H), 2.31 (s, 6H, 2 × CH₃),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).¹³C NMR(100MHz,DMSO-d₆,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(CH₂),52.13(2×CH₂),47.15(CH), 31.62(2×CH₂),21.24(2×CH₃).ESI-MS:m/z 537.6(M+1).C₂₈H₂₉ClN₄O₃S[536.16].

Embodiment 12：The chloro- 3- of 5- (3,5- 3,5-dimethylphenyls sulfuryl)-N- (1- ((4- methyl -5- oxygen -4,5- dihydros -1H- 1,2,4- triazole -3- bases) methyl) piperidin-4-yl) and -1H- indoles-formamide (I-12) preparation

The same I-9 of preparation method of I-12, except that using -2 hydrogen -1,2,4- triazolyls of 5- (bromomethyl) -4- methyl - 3 (4 hydrogen) (0.5992mmol) replace 4- bromomethyl benzsulfamides.Yield：53.1%.mp:274-275℃.¹H NMR (400MHz,DMSO-d₆,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-CH₂),3.17(s,3H,CH₃), 2.81 (d, 2H, J=12.00Hz, piperidine-H), 2.31(s,6H,2×CH₃), 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)¹³C NMR(100MHz,DMSO-d₆,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(CH₂),51.79(CH₂), 49.07(CH₂),47.05(CH),31.52(2×CH₂),27.28(CH₃),21.23(2×CH₃).ESI-MS:m/z 557.3(M +1).C₂₆H₂₉ClN₆O₄S[556.17].

Embodiment 13：N- (1- (4- sulfonamide phenyl) piperidin-4-yl) chloro- 3- of -5- (3,5- xylenols sulfuryl) - The preparation of 1H- indole 2-carboxamides (I-13)

The same I-9 of preparation method of I-13, except that replacing 4- using 4- bromomethyls benzsulfamide (0.5992mmol) Bromomethyl benzsulfamide.Yield：52.1%.mp:215-217℃.¹H NMR(400MHz,DMSO-d₆,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,SONH₂),7.36-7.32(m,3H, Ph’-H,SONH₂),7.26(s,1H,Ph-H),3.87(s,1H,piperidine-H),3.57(s,2H,benzyl-CH₂), 2.81 (d, 2H, J=12.00Hz, piperidine-H), 2.31 (s, 6H, 2 × CH₃), 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).¹³C NMR(100MHz,DMSO-d₆,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(CH₂),52.10(2×CH₂),47.22(CH),31.65(2× CH₂),21.24(2×CH₃).ESI-MS:m/z 615.3(M+1).C₂₉H₃₁ClN₄O₅S₂[614.14].

Embodiment 14：N- (1- (4- Carbamoylphenyls) piperidin-4-yl) chloro- 3- of -5- (3,5- dimethyl benzenes sulfuryl) - The preparation of 1H- indole 2-carboxamides (I-14)

The same I-9 of preparation method of I-14, except that replacing 4- using 4- (bromomethyl) benzamide (0.5992mmol) Bromomethyl benzsulfamide.Yield：56.6%.mp:153-155℃.¹H NMR(400MHz,DMSO-d₆,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, CONH₂),7.26(s,1H,Ph-H),3.87(s,1H,piperidine-H),3.54(s,2H,benzyl-CH₂),2.81(d, 2H, J=12.00Hz, piperidine-H), 2.31 (s, 6H, 2 × CH₃), 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).¹³C NMR(100MHz,DMSO-d₆,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(CH₂),52.09(2×CH₂),47.25(CH), 31.64(2×CH₂),21.24(2×CH₃).ESI-MS:m/z 615.3(M+1).C₃₀H₃₁ClN₄O₄S[578.18].

Embodiment 15：The chloro- 3- of 5- (3,5- 3,5-dimethylphenyls sulfuryl)-N- (1- (thiophene -3- methyl) piperidin-4-yl) -1H- The preparation of indole 2-carboxamides (I-15)

Intermediate 6 ' claims to be heated to solution after mixed solvent tetrahydrofuran/methanol (1/2) 30mL is added in round-bottomed flask Clarification, the lower instillation acetic acid of 30-40 DEG C of stirring to pH is 4-5, and 3- thiophene-formaldehyde (0.060g, 0.535mmol) is added and reacts 40 points Sodium cyanoborohydride (0.056g, 0.89mmol) is then added in clock, and the reaction was continued 10 hours.Reaction solution directly concentrates column chromatography It purifies (ethyl acetate).Yield：70.2%.mp:230-231℃.¹H NMR(400MHz,DMSO-d₆,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-CH₂),3.99(s,1H, piperidine-H),3.34(s,2H,piperidine-H),3.00(s,2H,piperidine-H),2.20(s,6H,2× CH₃),2.04(s,2H,piperidine-H),1.64(s,2H,piperidine-H).ESI-MS:m/z 542.4(M+1) .C₂₇H₂₈ClN₃O₃S₂[541.13].

Embodiment 16：The chloro- 3- of 5- (3,5- 3,5-dimethylphenyls sulfuryl)-N- (1- (thiophene -2- methyl) piperidin-4-yl) -1H- The preparation of indole 2-carboxamides (I-16)

The same I-15 of preparation method of I-16, except that replacing 3- thiophene-using 2- thiophene-formaldehyde (0.535mmol) Formaldehyde.Yield：69.6%.mp:225-256℃.ESI-MS:m/z 542.4(M+1).C₂₇H₂₈ClN₃O₃S₂[541.13].

Embodiment 17：N- (1- (4- (trifluoromethyl) phenyl) piperidin-4-yl) chloro- 3- of -5- (3,5- dimethyl benzenes sulfuryl) - The preparation of 1H- indole 2-carboxamides (I-17)

The same I-15 of preparation method of I-17, except that being replaced using 4- (trifluoromethyl) benzaldehyde (0.535mmol) 3- thiophene-formaldehyde.Yield：69.8%.mp:209-210℃.¹H NMR(400MHz,DMSO-d₆,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- CH₂), 2.81 (d, 2H, J=12.00Hz, piperidine-H), 2.31 (s, 6H, 2 × CH₃), 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).¹³C NMR(100MHz,DMSO-d₆,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, 125.73,125.47,125.08,124.11(2×C),119.35,115.34,111.72,61.83(CH₂),52.08(2× CH₂),47.21(CH),31.66(2×CH₂),21.23(2×CH₃).ESI-MS:m/z 604.4(M+1).C₃₀H₂₉ClF₃N₃O₃S [603.16].

Embodiment 18：The chloro- 3- of 5- (3,5- 3,5-dimethylphenyls sulfuryl)-N- (1- (furans -3- methyl) piperidin-4-yl) -1H- The preparation of indole 2-carboxamides (I-18)

The same I-15 of preparation method of I-18, except that replacing 3- thiophene-using 3- furans-formaldehyde (0.535mmol) Formaldehyde.Yield：68.8%.mp:223-224℃.¹H NMR(400MHz,DMSO-d₆,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-CH₂),3.98 (s,1H,piperidine-H),3.31(s,2H,piperidine-H),2.98(s,2H,piperidine-H),2.20(s, 6H,2×CH₃),2.00(s,2H,piperidine-H),1.65(s,2H,piperidine-H).ESI-MS:m/z 526.2(M +1).C₂₇H₂₈ClN₃O₄S[525.15].

Embodiment 19：N- (1- (4- nitrobenzophenones) piperidin-4-yl) the chloro- 3- of -5- (3,5- dimethyl benzenes sulfuryl) -1H- Yin The preparation of diindyl -2- formamides (I-19)

The same I-15 of preparation method of I-19, except that replacing 3- thiophenes using 3- nitro-benzaIdehydes (0.535mmol) Pheno-formaldehyde.Yield：65.6%.mp:It 258-259 DEG C, decomposes.¹H NMR(400MHz,DMSO-d₆,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- CH₂), 2.81 (d, 2H, J=8.00Hz, piperidine-H), 2.31 (s, 6H, 2 × CH₃), 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).¹³C NMR(100MHz,DMSO-d₆,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(CH₂),52.08(2×CH₂),47.14(CH), 31.65(2×CH₂),21.24(2×CH₃).ESI-MS:m/z 581.4(M+1).C₂₉H₂₉ClN₄O₅S[580.15].

Embodiment 20：The chloro- 3- of 5- (3,5- 3,5-dimethylphenyls sulfuryl)-N- ((1- (2- ethoxys) piperidin-4-yl) methyl)- The preparation of 1H- indole 2-carboxamides (I-20)

The same I-9 of preparation method of I-20, except that intermediate 6 ' is by 1- tertbutyloxycarbonyl -4- aminomethylpiperidines (3.67mmol) is made instead of Boc-4- amino piperidines, and final step substituent group replaces 4- bromines using bromoethanol (0.5992mmol) Methyl benzenesulfonamide.Yield：50.0%.mp:255-256℃.¹H NMR(400MHz,DMSO-d₆,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=8.00Hz, Indole-H), 7.27 (s, 1H, Ph-H), 5.28 (s,1H,OH),3.37(s,2H,CH₂),3.50(s,2H,CH₂),3.40(s,2H,CH₂),3.11(s,2H,CH₂),2.31(s, 6H,2×CH₃),2.29(s,2H,CH₂),1.98(s,2H,CH₂),1.86(s,1H,CH),1.53(s,2H,CH₂).ESI-MS: m/z 504.3(M+1).C₂₅H₃₀ClN₃O₄S[503.16].

Embodiment 21：N- ((1- (4- carbamyls phenyl) piperidin-4-yl) methyl) the chloro- 3- of -5- (3,5- dimethyl benzene sulfones Base) -1H- indole 2-carboxamides (I-21) preparation

The same I-20 of preparation method of I-21, except that using 4- (bromomethyl) benzamido (0.5992mmol) generation For bromoethanol.Yield：52.3%.mp:259-260℃.¹H NMR(400MHz,DMSO-d₆,ppm)δ:12.93(s,1H, ), Indole-NH 8.98 (d, 1H, J=8.00Hz, CONH), 7.92-7.90 (m, 2H, Indole-H, NH₂),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,NH₂Ph-H,Ph’-H),3.50(s,2H,benzyl-CH₂),3.32-3.24(m,2H,CONH-CH₂),2.83(d, 2H, J=12.00Hz, piperidine-H), 2.30 (s, 6H, 2 × CH₃), 1.98 (t, 2H, J=8.00Hz, 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).C₃₁H₃₃ClN₄O₄S[592.19].

Embodiment 22：N- ((1- (2- fluorophenyls) piperidin-4-yl) methyl) chloro- 3- of -5- (3,5- dimethyl benzenes sulfuryl) - The preparation of 1H- indole 2-carboxamides (I-22)

The same I-20 of preparation method of I-22, except that being replaced using 4- (bromomethyl) -2- fluorobenzene (0.5992mmol) Bromoethanol.Yield：46.5%.mp:193-194℃.¹H NMR(400MHz,DMSO-d₆,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-CH₂), 3.27 (t, 2H, J=8.00Hz, CONH-CH₂),2.82 (d, 2H, J=12.00Hz, piperidine-H), 2.30 (s, 6H, 2 × CH₃), 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).C₃₀H₃₁ClFN₃O₃S[567.18].

Embodiment 23：N- ((1- (2- cyano-phenyls) piperidin-4-yl) methyl) chloro- 3- of -5- (3,5- dimethyl benzenes sulfuryl) - The preparation of 1H- indole 2-carboxamides (I-23)

The same I-20 of preparation method of I-23, except that replacing bromine using 4- (bromomethyl) benzonitrile (0.5992mmol) Ethyl alcohol.Yield：52.6%.mp:213-214℃.¹H NMR(400MHz,DMSO-d₆,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-CH₂), 3.26 (t, 2H, J=8.00Hz, CONH-CH₂),2.82(d,2H, J=12.00Hz, piperidine-H), 2.30 (s, 6H, 2 × CH₃), 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).C₃₁H₃₁ClN₄O₃S[574.18].

Embodiment 24：Ethyl 3- (4- ((the chloro- 3- of 5- (3,5- dimethyl benzenes sulfuryl) 1H- indole 2-carboxamides) methyl) piperazines Pyridine -1- bases) propionic acid (I-24) preparation

The same I-20 of preparation method of I-24, except that replacing bromine second using ethyl 3- bromoacetic acids (0.5992mmol) Alcohol.Yield：45.6%.mp:194-195℃.¹H NMR(400MHz,DMSO-d₆,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-CH₂), 3.25 (t, 2H, J=4.00Hz, CO-CH₂), 2.82 (d, 2H, J=12.00Hz, piperidine-H), 2.57 (d, 2H, J=8.00Hz, CH₂), 2.46 (d, 2H, J=8.00Hz, CH₂),2.31(s,6H,2×CH₃), 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,CH₃).ESI-MS:m/z 560.4(M+1) .C₂₈H₃₄ClN₃O₅S[559.19].

Embodiment 25：HIV-resistant activity tests (MT-4 cell models)

Term is explained：

MT-4 cells：People's acute lymphoblastic leukemia cell.

MTT analytic approach：MTT is 3- (4,5- dimethylthiazoles -2) -2,5- diphenyltetrazolium bromide bromides, trade name:Thiophene Azoles is blue.

Nevirapine：Anti-AIDS marketed drug nevirapine.

Efavirenz：Anti-AIDS marketed drug efavirenz.

Delavirdine：Anti-AIDS marketed drug Delavirdine.

Etravirine：Anti-AIDS marketed drug etravirine.

DMSO：Dimethyl sulfoxide (DMSO).

Test philosophy

Since lesion can occur for (5-7 days) within a certain period of time for the MT-4 cells of HIV infection, to the MT- of HIV infection The compound solution to be detected that debita spissitudo is added in 4 cell suspensions uses MTT through after a period of time after the culture of (5-7 days) Assay MT-4 cell viabilities obtain drug concentration (EC of 50% cell of protection from cytopathy₅₀) it can obtain mesh Mark the activity of the AntiHIV1 RT activity of compound.The concentration that target compound makes 50% cell for being uninfected by HIV that lesion occur is obtained simultaneously (CC₅₀), calculate selection coefficient (selectivity index, SI=CC₅₀/EC₅₀)。

MTT analytic approach principles：MTT, that is, bromination -3- (4,5- dimethyl -2- thiazolyls) -2,5- diphenyltetrazoliumbromide nitrogen, can be with Intracellular succinate dehydrogenase living is combined, without reacting with dead cell.Mtt assay is a kind of quick, succinct at present Reflect the method for analyzing enzyme of cell viability.

Test material and method

(1) bis- mutation (K103N/Y181C) the persister RES056 of HIV-1 (IIIB), HIV-2 (ROD) strain, HIV-1：By Microbiological inhibitory research institute of Belgian Rega research institutes of Leuven universities provides.

(2) MT-4 cells：It is provided by microbiological inhibitory research institute of Belgian Rega research institutes of Leuven universities.

(3)MTT：Purchased from Sigma Co., USA.

(4) sample treatment：Sample is dissolved in DMSO and is made into debita spissitudo before use, is used in combination distilled water to make 5 times and dilutes, each 5 Dilution.

(5) positive control drug：Nevirapine(NVP),Efavirenz(EFV),Delavirdine(DLV), Etravirine(ETV)。

(6) test method：It is added in HIV infection MT-4 cell suspensions after sample dilution, uses after a period of time MTT colorimetric method for determining cell viabilities record absorbance (A) value, calculate EC at 590 nm in microplate reader₅₀、CC₅₀And SI。

(7) MTT decoration methods：Be added sample culturing for a period of time after, then to every hole be added MTT solution (5mg/mL) 20 μ L, Continue to cultivate several hours, abandons dyeing liquor, and 150 μ L DMSO are added to every hole, be sufficiently mixed, in microplate reader, in 590nm Lower record absorbance.

Concrete operations are as follows：Compound is diluted with after DMSO or water dissolution with phosphate buffer, by 3 × 10⁵MT-4 The compound solution of cell and 100 μ L various concentrations is in 37 DEG C of common preincubate 1h.Then it is suitable that 100 μ L are added into the mixture When the viral dilution of concentration, cell is incubated 1h in 37 DEG C.Washing three times after, cell is suspended in respectively again containing or not In culture substrate containing compound.Then by cell in 5%CO₂In environment, it is incubated again at 37 DEG C 7 days, and in metainfective Third day supplements original fluid with the culture substrate with or without compound.The all repetitive operations of each condition of culture are twice.It is right The cytopathic effect of virus all uses reverse optical microscope to monitor daily.In general, viral dilution used in this experiment Usually cytopathy can occur in the 5th day after virus infects for liquid.Drug inhibition concentration acts on pathological changes caused by virus with drug Generate 50% inhibiting effect and simultaneously to concentration (EC of the cell without direct toxicity₅₀) indicate.It is emphasized that working as compound water Dissolubility is poor, and when needing to be dissolved with DMSO, DMSO volume by volume concentrations can generally be less than 10% (DMSO for water In MT-4 cell culture mediums 2%) ultimate density is less than.Because DMSO can influence to test compound antiviral activity, to containing There is the antiviral activity comparison blank assay of same concentrations DMSO solution also should operation repetitive progress.In addition, DMSO is finally dense Degree (1/1000) replicates required concentration well below HIV-1 is influenced in MT-4 cells.

The bis- mutation RES056 persisters screening active ingredients data of external anti-HIV-1 (IIIB) and HIV-1 of target compound by Microbiological inhibitory research institute of Belgian Rega research institutes of Leuven universities provides, and all activity datas all pass through at least two Secondary independent, parallel experiment measures, and the results are shown in Table 1,2,3.

The cell activity of the anti-wild type HIV-1 (IIIB) of 1 compound of table and double-mutant strain (F227L/V106A, RES056) And toxicity

^a:Medium effective concentration；^b:Wild type HIV-1 strains；^c:Double mutation HIV-1 strains；^d:Half lethal concentration

The cell activity of 2 compound anti-HIV-1 single mutation strain (L100I, K103N, Y181C, Y188L, E138K) of table

^a:With table 1；^e:Single mutation type HIV-1 strains

The anti-wild type HIV-1 (IIIB) of 3 compound of table and a variety of lists (L100I, K103N, Y181C, Y188L, E138K) or The selection index (SI) of bis- (F227L/V106A, RES056) mutant strains

^b’c’With table 1；^e:With table 2；^f:Therapeutic index.

Embodiment 26：Anti-reverse transcription enzymatic activity test experiments

This experiment uses chromatmetry reverse transcriptase activity determination experiment, used kit Reverse Transcriptase Assay, colorimetric Version 13.0 is purchased from Roche Holding Ag, and how is positive control medicine selection Wei Laping and according to Qu Weilin.(referring to 1. Hofman, A.D.&Banapour, B.&Levy, J.A. (1985) Virology 147, 326–335.②Ukkonen,P.et al.(1988)Eur.J.Clin.Microbiol.&Infect.Dis.7,518–523.)

Test philosophy

Chromatmetry reverse transcriptase activity measurement uses template/primer-oligomerization object poly (A) × oligo (dT) former as starting Material, be used in combination the nucleotide of digoxin and biotin labeling replace use radioactive isotope [³H]-or [³²P]-label nucleotide, These are the advantage places of the method.It is synthesized go out DNA be the important parameter for measuring reverse transcriptase activity, detection and quantitative DNA has used the ELISA assay methods of following sandwich style：The DNA of biotin labeling can be coated with antibiotin strepto- The surface of micro- edition module (MP) of rhzomorph is combined.In a next step, the digoxin for having polymerize peroxidase is anti- Body needs to be attached on the DNA of digoxigenin labeled.Finally, the substrate 2 of peroxidase is added, 2- joins (the 3- ethyls-benzene of nitrogen-two And thiazole -6- sulfonic acid) di-ammonium salts (ABTS), so that them is decomposed under the catalytic action of enzyme, generates the product with apparent color. The microplate absorbance for being loaded with sample is measured by microplate reader, this absorbance value is presented with the activity of reverse transcriptase and is directly associated with, Inhibition concentration of the compound to reverse transcriptase is can be calculated by formula.

Test method

(1) various working solutions are configured first, and sample is dissolved with appropriate dimethyl sulfoxide (DMSO) (DMSO), are used in combination cracking slow Fliud flushing is diluted to 5 concentration gradients.In each different reaction tube, by 4-6ng Recombinant HIV-1-RT lysis buffers (20 μ L/well) dilution.Meanwhile preparing only have lysis buffer without the negative control group of RT.Then each retort is added 20 μ L contain the buffer solution and 20 μ L reactant mixed liquors of various concentration institute test sample, are incubated under 37 degrees Celsius one small When.

(2) prepare micro- edition enough module, be fixedly mounted in frame according to direction.By the sample being incubated (60 μ L) It is transferred in the hole of microplate, second of 37 degrees Celsius of incubation one hour after being covered with film.

Solution is removed, is carefully rinsed with washing lotion 5 times per hole, it is every all over using 250 μ L, reservation 30 seconds.200 μ L are added per hole Anti- digoxin-peroxidase polymer, third time is incubated one hour under 37 degrees Celsius after microplate is covered with film.

(3) solution is removed, is carefully rinsed with washing lotion 5 times per hole, it is every all over using 250 μ L, reservation 30 seconds.It is added per hole 200 μ L ABTS solution, are incubated under 15-25 degrees Celsius, until green color occurs and enough by photometric detection (generally 10- 30 minutes).

(4) it is loaded with absorbance value of the sample at wavelength 405nm with microplate reader measurement, being calculated by the following formula can must change Close inhibition concentration of the object to reverse transcriptase.

Inhibiting rate %=(positive control fluorescence intensity-fluorescent intensity)/(positive control fluorescence intensity-background fluorescence Intensity) × 100% carry out linear regression, bring inhibiting rate into linear equation, the concentration C acquired is both IC₅₀, unit is (μ g/ ML), it is converted into μM further according to compound molecular weight, this experiment has chosen a best representative compound of cell activity, with And positive control drug nevirapine (NVP) and etravirine (ETV), experimental result is shown in Table 4.

4 representation compound of table is to HIV-1 reverse transcriptase inhibitory activity

It is above-mentioned the experimental results showed that：It is HIV-1 of the one kind with new structure skeleton with compounds of formula I of the present invention Inhibitor, as shown in Table 1, wherein all compounds all have significant anti-wild type HIV-1 effects, EC₅₀Value is ranging from 0.62 μM to 0.006 μM.And majority of compounds also shows good inhibitory activity to a variety of single mutation strains, such as makes a variation Strain L100I, K103N, Y181C, E138K.Compound I-2 and I-12 inhibitory activity is more prominent, to wild type HIV-1's EC₅₀Value is respectively 0.006 μM and 0.009 μM, and SI is 1005 and 1476, is better than marketed drug NVP and DLV, with marketed drug EFV, ETV and lead compound EFF belong to the same order of magnitude.I-2 and I-12 to L100I, K103N, Y181C, E138K and The single or double mutant strain such as F227L/V106A all keeps the activity of sub-micromolar or more, is generally better than marketed drug NVP and DLV.And For certain single mutation Strain such as L100I and K103N, the inhibiting effect of I-2 is slightly better than marketed drug EFV, and with guideization It closes object EFF and is in same level.Special emphasis is the Y188L mutant strain very sensitive to indoles virtue sulfone compound, The EC of I-12₅₀Value is 0.84 μM, is better than lead compound EFF (EC₅₀=1.3 μM), achieve unexpected effect.In addition, I-14 is better than marketed drug DLV to the inhibitory activity of double mutant strain Y181C/K103N of clinical most serious, with guide EFF It is in same level with marketed drug NVP.In view of the novelty of indoles virtue sulfone derivatives structure according to the present invention, to open country Raw type and the significant inhibitory activity of various mutations type HIV-1 and the progressive of relatively certain existing compounds, thus have There is larger Development volue.Carrying out new structural modification and further investigation on this basis helps to obtain more excellent effect Fruit, and with the potentiality for developing into a kind of brand new anti-HIV new medicament.

Claims

1. indoles virtue sulfone derivatives or its pharmaceutically acceptable salt, which is characterized in that have and tied shown in following general formula I Structure：

Wherein,

The substituent X that indoles is 5- is Cl or Br；

N is equal to 0 or 1；

M and w is equal to 2 simultaneously；

R is CH₂OH、CH₂COOCH₂CH₃, by 1 to 3 C_1-6Alkyl, halogen, CF₃、OCF₃、OH、NO₂、CN、SO₂NH₂、SO₂-C_1-3 Alkyl, C (O) NH₂、C(O)C_1-3Alkyl, NHC_1-3Alkyl-substituted phenyl, pyridyl group, furyl, thienyl or by 1 to 3 C_1-6Alkyl, halogen, CF₃、OCF₃、OH、NO₂、CN、SO₂NH₂、SO₂-C_1-3Alkyl, C (O) NH₂、C(O)C_1-3Alkyl, NHC_1-3Alkane The triazolyl of base substitution.

2. indoles virtue sulfone derivatives, it is characterised in that be one of the compound of having structure：

3. the preparation method of indoles virtue sulfone derivatives as described in claim 1, includes the following steps：The Yin replaced with 5- Diindyl Ethyl formate 1 is starting material, is reacted with 3,5- thiophenol dimethyl benzenes and midbody compound 2 is made, intermediate 2 is through m-chloro mistake Oxybenzoic acid aoxidizes to obtain midbody compound 3, and the ethoxycarbonyl of midbody compound 3 is hydrolyzed to obtain midbody compound 4, in Intermediate compounds therefor 4, which passes through acylation reaction and sloughs Boc protecting groups, obtains female ring 6, and different substituent groups carries out substitution system to female ring 6 Obtain indoles virtue sulfone derivatives I；

Synthetic route is as follows：

Reagent and condition:(i) 3,5- thiophenol dimethyl benzenes, fluoro- 1,4- diazabicyclos [2.2.2] octanes of 1- chloromethyls -4- two (tetrafluoro boric acid) salt, acetonitrile；(ii) metachloroperbenzoic acid, dichloromethane, 0 DEG C；(iii) lithium hydroxide, water, tetrahydrofuran, 50℃；(iv) boc-protected nitrogenous naphthenic base-amino, 2- (7- azos benzotriazole)-N, N, N', N'- tetramethylurea hexafluoros Phosphate, 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride, triethylamine, N,N-dimethylformamide；(v) three Fluoroacetic acid, dichloromethane；(vi) potassium carbonate, N,N-dimethylformamide, R-CH₂- X '；(vii) formaldehyde replaced, glacial acetic acid, Sodium cyanoborohydride, tetrahydrofuran/acetonitrile；

Wherein, the definition of X, m, w, R are the same as described in the general formula I in claim 1；N=0；X ' are halogen.

4. the preparation method of indoles virtue sulfone derivatives as described in claim 1, includes the following steps：Replaced with 5- chlorine bromines Indolecarboxylic acid ethyl ester 1 ' be starting material, with 3,5- thiophenol dimethyl benzenes react be made midbody compound 2 ', intermediate It closes object 2 ' and aoxidizes to obtain midbody compound 3 ' through metachloroperbenzoic acid, lithium hydroxide is by the ethoxycarbonyl of midbody compound 3 ' Hydrolysis obtains midbody compound 4 ', midbody compound 4 ' and 1-Boc-4- amino piperidines or 1-Boc-4- (aminomethyl)-piperazine Pyridine obtains midbody compound 5 ' by acylation reaction, and sloughs Boc protecting groups under trifluoroacetic acid effect and obtain female ring 6 ', no Same substituent group carries out female ring 6 ' to replace obtained indoles virtue sulfone derivatives I；

Synthetic route is as follows：

Reagent and condition:(i) 3,5- thiophenol dimethyl benzenes, fluoro- 1,4- diazabicyclos [2.2.2] octanes of 1- chloromethyls -4- two (tetrafluoro boric acid) salt, acetonitrile；(ii) metachloroperbenzoic acid, dichloromethane, 0 DEG C；(iii) lithium hydroxide, water, tetrahydrofuran, 50℃；(iv) 1-Boc-4- amino piperidines or 1-Boc-4- (aminomethyl)-piperidines, 2- (7- azos benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters, 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride, triethylamine, N, N- diformazans Base formamide；(v) trifluoroacetic acid, dichloromethane；(vi) potassium carbonate, N,N-dimethylformamide, R-CH₂- X ＂；(vii) replace Formaldehyde, glacial acetic acid, sodium cyanoborohydride, tetrahydrofuran/acetonitrile；

Wherein, X is chlorine or bromine, and n is equal to 0 or 1, and X ＂ are halogen；R is CH₂OH、CH₂COOCH₂CH₃, by 1 to 3 C_1-6Alkyl, halogen Element, CF₃、OCF₃、OH、NO₂、CN、SO₂NH₂、SO₂-C_1-3Alkyl, C (O) NH₂、C(O)C_1-3Alkyl, NHC_1-3Alkyl-substituted benzene Base, pyridyl group, furyl, thienyl or by 1 to 3 C_1-6Alkyl, halogen, CF₃、OCF₃、OH、NO₂、CN、SO₂NH₂、SO₂-C_1-3 Alkyl, C (O) NH₂、C(O)C_1-3Alkyl, NHC_1-3Alkyl-substituted triazolyl.

5. application of the compound as claimed in claim 1 or 2 in preparing inverase.

6. a kind of inverase composition, including compound described in claims 1 or 2 or its pharmaceutically acceptable salt and One or more pharmaceutically acceptable carriers or excipient.