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

Indolylaryl-sulfone derivative, as well as preparation method and application thereof Download PDF

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CN105968095A
CN105968095A CN201610305158.9A CN201610305158A CN105968095A CN 105968095 A CN105968095 A CN 105968095A CN 201610305158 A CN201610305158 A CN 201610305158A CN 105968095 A CN105968095 A CN 105968095A
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indole
acid
piperidine
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preparation
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CN105968095B (en
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刘新泳
李潇
展鹏
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Shandong University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P20/00—Technologies relating to chemical industry
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses an indolylaryl-sulfone derivative shown in general formula I, a pharmaceutically acceptable salt, ester or prodrug and preparation method thereof and application of a composition containing one or more such compounds to preparation of a medicament for preventing and treating HIV (human immunodeficiency virus) infection. The formula is shown in the description.

Description

Indole virtue sulfone derivatives and preparation method and application
Technical field
The present invention relates to a kind of derivant and preparation method and application, particularly to indole virtue sulfone derivatives and system thereof Preparation Method and application, belong to pharmaceutical technology field.
Background technology
In HIV replicative cycle, himself multi-functional albumen reverse transcriptase (RT) plays vital effect, negative Blamed DNA synthesis that RNA instructs, multiple key links such as DNA synthesis that the hydrolysis of RNA and DNA instruct.Therefore, with RT Prevent and treat acquired immune deficiency syndrome (AIDS) as the target spot of drug design and there is the advantages such as inhibitory activity is high, selectivity is good, toxic and side effects is little, be current The Critical policies of research and development AntiHIV1 RT activity/AIDS medicine.According to mechanism of action and the difference of chemical constitution, HIV1-RT inhibitor Can be divided mainly into nucleoside (sour) (nucleos (t) ide reverse transcriptase inhibitors, N (t) RTIs) and Non-nucleoside (Non-nucleoside reverse transcriptase inhibitors, NNRTIs) two classes.Wherein, The mechanism of action of NNRTIs is and distance RT catalytic active centerAllostery pocket (NNIBP) specific binding, and then The forfeiture causing RT critical function suppresses the duplication of virus.The specificity combined due to it, NNRTIs is generally of efficient, low The advantage of poison, because becoming the important component part of HAART.Such medicine of the listing of FDA approval at present has 5 (nevirapine,delavirdine,efavirine,etravirine,rilpivirine).But owing to NNRTIs combines The aminoacid of pocket is easily undergone mutation and is caused the generation of multidrug resistant disease strain and spread, and the most existing drug bioavailability is low And the serious toxic and side effects that long-term prescription brings makes the clinical practice of such medicine by great threat.Therefore, find newly The NNRTIs of type overriding resistance low toxicity is still the important topic of current anti-AIDS drug research and development.
Indole virtue sulfone compound (indolylaryl-sulfone, IAS) is by the Williams of Merk laboratory the earliest Et al. a class of report there is the HIV-1NNRTIs structural framework of very well activity.Lead compound L-737,126 is to wild type (WT) RT inhibitory action can reach 3nM, also can reach the inhibitory action of clinical common variant viral strain K103N, Y181C simultaneously Sub-micromolar level.In structure of modification subsequently, the activity of the anti-HIV-1 of multiple compounds all significantly improves, particularly pin Clinical common multidrug resistant disease strain is respectively provided with the strongest inhibitory action, such as the compound EFF EC to wild type HIV-150Value is 2nM, keeps nanomolar range to the inhibitory activity of multiple common mutations Strain Y181C, K103N, L100I and E138K.Cause This, with indole virtue sulfone compound as template, carry out structural modification widely, to find high-efficiency broad spectrum, bioavailability good and The novel inverase with independent intellectual property right is significant.
Summary of the invention
For the deficiencies in the prior art, the invention provides a kind of indole virtue sulfone derivatives, the present invention also provides for above-mentioned The preparation method of compound and screening active ingredients result and application.
Technical scheme is as follows:
One, indole virtue sulfone derivatives
The indole virtue sulfone derivatives of the present invention or its pharmaceutically acceptable salt or prodrug, have shown in below formula I Structure:
Wherein,
The substituent X of indole 5-position is halogen, CF3Or NO2；
N is equal to 0,1,2 or 3；
M, w are the most individually equal to 1 or 2；
R is (C1-6) alkyl-R1、(C3-7) cycloalkyl-R1、(C2-6) alkenyl-R1、-C(O)R1、-C(O)OR1、-S(O)- R1、-SO2-R1、NH-R1, phenyl, 5-or 6-unit heteroaromatic, condense phenyl-undersaturated or saturated 5-or 6-unit carbocyclic ring, Or the phenyl-5-that condenses or 6-unit heteroaromatic；
Wherein R1Selected from H, OH, SH, NH2、O-(C1-4) alkyl, S-(C1-4) alkyl or NH-(C1-4) alkyl；Described benzene Base, 5-or 6-unit heteroaromatic, phenyl-undersaturated or saturated 5-or the 6-unit carbocyclic ring condensed or the phenyl-5-condensed or 6- Unit's heteroaromatic is the most optionally independently selected from following substituent group by 1 to 3 and replaces: (C1-6) alkyl, halogen, CF3、 OCF3、OH、NO2、CN、SO2NH2、SO2-(C1-3) alkyl, C (O) NH2、C(O)(C1-3) alkyl, NH (C1-3) alkyl；
According to currently preferred,
The substituent X of indole 5-position is Cl or Br；
N is equal to 0 or 1；
M and w is simultaneously equal to 2；
R is CH2OH、CH2COOCH2CH3, substituted phenyl, pyridine radicals, furyl, thienyl or substituted triazolyl.
According to the present invention, it is further preferred that one of compound that compound of Formula I is having structure:
Two, the preparation method of indole virtue sulfone derivatives
The preparation of indole virtue sulfone derivatives of the present invention with 5-position substituted indolecarboxylic acid ethyl ester (1) as initiation material, with 3,5-thiophenol dimethyl benzene reactions prepare midbody compound 2, and intermediate obtains intermediate through metachloroperbenzoic acid oxidation Compound 3, hydrolyzes the ethoxycarbonyl of midbody compound 3 and obtains midbody compound 4, and midbody compound 4 is through acylation reaction And slough BOC protection group and obtain female ring 6, different substituent groups replaces prepared indole virtue sulfone derivatives I to female ring 6；
Synthetic route is as follows:
Reagent and condition: (i) 3,5-thiophenol dimethyl benzene, 1-chloromethyl-4-fluoro-1,4-diazabicyclo [2.2.2] is pungent Alkane two (Tetrafluoroboric acid) salt, acetonitrile；(ii) metachloroperbenzoic acid, dichloromethane, 0 DEG C；(iii) Lithium hydrate, water, tetrahydrochysene furan Mutter, 50 DEG C；(iv) the nitrogenous cycloalkyl-amino of Boc protection, 2-(7-azo BTA)-N, N, N', N'-tetramethylurea Hexafluorophosphoric acid ester, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, triethylamine, N,N-dimethylformamide； (v) trifluoroacetic acid, dichloromethane；(vi) potassium carbonate, DMF, halogen benzyl, the alkyl of halogen substiuted；(vi) replace Formaldehyde, glacial acetic acid, sodium cyanoborohydride, oxolane/acetonitrile.
Wherein, X, n, m, w, R are defined as above described in formula I.
According to currently preferred, the preparation method of indole virtue sulfone derivatives, comprise the steps:
The preparation of indole virtue sulfone derivatives of the present invention is with 5-chlorine bromine substituted indolecarboxylic acid ethyl ester (1 ') for initial former Material, with 3, the reaction of 5-thiophenol dimethyl benzene prepares midbody compound 2 ', and midbody compound 2 ' is through metachloroperbenzoic acid oxygen Change to midbody compound 3 ', the ethoxycarbonyl of midbody compound 3 ' is hydrolyzed and obtains midbody compound 4 ' by Lithium hydrate, Midbody compound 4 ' obtains intermediate with 1-Boc-4-amino piperidine or 1-Boc-4-(aminomethyl)-piperidines through acylation reaction Compound 5 ', and under trifluoroacetic acid effect, slough Boc protection group obtain female ring 6 ', female ring 6 ' is taken by different substituent groups In generation, prepares indole virtue sulfone derivatives I；
Synthetic route is as follows:
Reagent and condition: (i) 3,5-thiophenol dimethyl benzene, 1-chloromethyl-4-fluoro-1,4-diazabicyclo [2.2.2] is pungent Alkane two (Tetrafluoroboric acid) salt, acetonitrile；(ii) metachloroperbenzoic acid, dichloromethane, 0 DEG C；(iii) Lithium hydrate, water, tetrahydrochysene furan Mutter, 50 DEG C；(iv) 1-BOC-4-amino piperidine or 1-Boc-4-(aminomethyl)-piperidines, 2-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, triethylamine, N, N- Dimethylformamide；(v) trifluoroacetic acid, dichloromethane；(vi) potassium carbonate, N,N-dimethylformamide, halogen benzyl or halogen substiuted Alkyl；(vi) substituted formaldehyde, glacial acetic acid, sodium cyanoborohydride, oxolane/acetonitrile；
Wherein, X is chlorine or bromine, and n is equal to 0 or 1, and R is CH2OH、CH2COOCH2CH3, substituted phenyl, pyridine radicals, furan Base, thienyl or substituted triazolyl.
Concrete preparation method detailed in Example 1-24.
Three, the application of indole virtue sulfone derivatives
The performance in the test cell line (MT-4 cell) that suppression HIV replicates of the indole virtue sulfone derivatives of formula I of the present invention Go out significant antiviral activity, higher selectivity and anti-drug resistance.Therefore, present invention also provide that
The application in the medicine preparing AntiHIV1 RT activity of the indole virtue sulfone derivatives of formula I.
A kind of inverase compositions, comprises compound of the present invention or its pharmaceutically acceptable salt and one Or multiple pharmaceutically acceptable carrier or excipient.
The compounds of this invention both can also the form of its pharmaceutically acceptable salt or solvate can use with itself. The pharmaceutically acceptable salt of compound of Formula I include with pharmaceutically acceptable mineral acid or organic acid or inorganic base or The conventional salt that organic base is formed.The suitably example of acid-addition salts includes and hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, hydrobromic acid, high chlorine Acid, fumaric acid, acetic acid, propanoic acid, succinic acid, hydroxyacetic acid, formic acid, lactic acid, maleic acid, tartaric acid, citric acid, flutter acid, the third two Acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzene The salt that sulfonic acid, hydroxy benzoic acid, hydroiodic acid, malic acid, tannic acid etc. are formed.Suitably the example of base addition salts include with sodium, lithium, Potassium, magnesium, aluminum, calcium, zinc, N, N '-dibenzyl-ethylenediamin, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl By the salt formed with procaine etc..Referred to herein to the compounds of this invention time, including compound of Formula I and pharmaceutically may be used The salt accepted or solvate.
According to the present invention, formula I can form pharmaceutical composition with Conventional pharmaceutical carriers or excipient.This medicine Compositions can pass through oral or parenteral administration.The pharmaceutical composition of the present invention can be prepared as by this area conventional method Various dosage forms, include but not limited to tablet, capsule, solution, suspension, granule or injection etc., oral administration or non-bowel way Footpath is administered.
The present invention to the combination of indole virtue sulfone class lead compound and Pharmacophore Model and Crystal study and point On the basis of sub-simulation study is analyzed comprehensively, devise a series of new indole virtue sulfone derivative for second channel.Use The N-substituted piperidine group of DAPY class NNRTIs is incorporated in indole virtue sulfone molecule by the drug design principle of skeleton transition, makes to prolong The group stretched acts on second channel, it is desirable on piperidines, nitrogen-atoms can form hydrogen bond action with aminoacid around (G138).With Time end substituent group use the group of various structures, but the most all include a hydrophilic radical, such as hydrophilic short chain and parent The aqueous substituted benzyls of substituent group etc., to adapt to the microenvironment of albumen/solvent open region and to improve the water solublity of compound whereby. Activity Results shows that all compounds all have significant anti-wild type HIV-1 effect, EC50Value scope is 0.62 μM and arrives 0.006μM.And majority of compounds also show good inhibitory activity to multiple single mutation strain, such as variant viral strain L100I、K103N、Y181C、E138K.I-2 and I-12 is two compounds that in this series, inhibitory activity is more prominent, 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 finds on piperidines The group of hydrophilic small volume is more beneficial for activity raising.And strengthen the interaction with conservative amino acid W229, fall The low dependency for aminoacid Y181, Y188, is to improve one of strategy active to mutated viruses strain during next step is modified.Cause This, indole virtue sulfone derivatives has bigger Development volue.The compound of the present invention carries out new structural modification and deep Enter research to contribute to developing the inverase made new advances.
Detailed description of the invention
Contribute to understanding the present invention by following embodiment, but present disclosure can not be limited.
Embodiment 1:N-(1-(3-methoxyphenyl) piperidin-4-yl) the bromo-3-of-5-(3,5-xylenol sulfuryl)-1H- The preparation of indole 2-carboxamides (I-1)
5-bromo indole Ethyl formate (1 ') (0.10g, 0.373mmol) is placed in round-bottomed flask, adds acetonitrile 10mL, room temperature 3 it are sequentially added under stirring, 5-thiophenol dimethyl benzene (0.0516g, 0.373mmol, 50 μ L), the fluoro-Isosorbide-5-Nitrae-phenodiazine of 1-chloromethyl-4- Miscellaneous dicyclo [2.2.2] octane two (Tetrafluoroboric acid) salt (0.10g, 0.373mmol).Reactant liquor continues reaction 6 hours.It is evaporated second Nitrile, adds water 30mL, dichloromethane extraction (3 × 10mL), and organic facies merges, and after saturated aqueous common salt washing, anhydrous magnesium sulfate is done Dry.Filtering and concentrating, column chromatography purification (ethyl acetate: petroleum ether=1:8).Gained white solid ethyl acetate/petroleum ether is heavily tied Brilliant 2 '.Productivity 50.5%.
Intermediate 2 ' (0.10g, 0.247mmol) is placed in round-bottomed flask and dissolves with 10mL dichloromethane, under ice bath stirring It is slowly added into metachloroperbenzoic acid (0.128g, 0.742mmol), transfers room temperature reaction extremely reaction in 3 hours after 30 minutes to complete. After reactant liquor adds dchloromethane, wash 3 times with the saturated aqueous solution of sodium sulfite and sodium bicarbonate successively, anhydrous Magnesium sulfate is dried, filtering and concentrating, and re-crystallizing in ethyl acetate obtains white solid 3 '.Productivity: 68.8%.mp:205-207 DEG C of .ESI- MS:m/z 436.3(M+1).C19H18BrNO4S[435.01].
Upper step prepares intermediate 3 ' (0.10g, 0.229mmol) and claims in round-bottomed flask, adds mix reagent THF/H2O (6mL/6mL), lower addition Lithium hydrate (0.0165g, 0.687mmol) being stirred at room temperature, reactant liquor transfers 50 DEG C to and reacts 24 hours. Reactant liquor is evaporated THF, adds distilled water diluting, and dilute hydrochloric acid adjusts pH to acid (pH=2-3), separates out a large amount of white solid, filters And be dried, obtain intermediate 4 '.Productivity: 66.5%.mp:215-217 DEG C of .ESI-MS:m/z 425.3 (M+18) .C17H14BrNO4S [406.98]。
Intermediate 4 ' (1.0g, 2.45mmol), 2-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluoro phosphorus Acid esters (1.39g, 3.67mmol), Boc-4-amino piperidine (0.735g, 3.67mmol) nominal, in round-bottomed flask, adds N, N- Dimethylformamide 10mL, is stirred at room temperature lower addition diisopropylethylamine (0.949g, 7.35mmol, 1.3mL), and reactant liquor continues React 24 hours.Being evaporated major part solvent, oxolane 100mL redissolves, the sodium hydrate aqueous solution washing 3 of saturated saline solution Secondary, oxolane layer anhydrous magnesium sulfate is dried, and filtering and concentrating column chromatography purification (ethyl acetate: petroleum ether=1:4) obtains white solid Body 5 ', productivity: 47.5%.
Intermediate 5 ' (0.5g, 0.848mmol) is placed in round-bottomed flask, adds the dichloromethane 2mL being dried, is stirred at room temperature Lower addition trifluoroacetic acid 1mL.After 4 hours, there are a large amount of white precipitates in reactant liquor, filters and dichloromethane washing, obtains middle Body IVa-6 '.Productivity: 75.4%.mp:230-231 DEG 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) are co-located in round-bottomed flask, add Enter N,N-dimethylformamide 10mL.After being stirred at room temperature lower 10 minutes add 1-(bromomethyl)-3-methoxybenzene (0.274g, 0.5992mmol), continue to be stirred at room temperature 4 hours.Being evaporated major part DMF, add water 50mL, and ethyl acetate extracts Taking (3 × 10mL), organic facies merges, and after saturated aqueous common salt washing, anhydrous magnesium sulfate is dried.Filtering and concentrating, column chromatography purification (second Acetoacetic ester: petroleum ether=1:2).Gained white solid oxolane/re-crystallizing in ethyl acetate obtains I-1.Productivity: 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) and 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].
The bromo-3-of embodiment 2:5-(3,5-dimethyl benzene sulfuryl)-N-(1-(2-ethoxy) piperidin-4-yl)-1H-indole- The preparation of 2-acetamide (I-2)
The same I-1 of preparation method of I-2, except that use bromoethanol (0.5992mmol) to replace 1-(bromomethyl)-3- Methoxybenzene.Productivity: 40.1%.mp:220-222 DEG C.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) and 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-xylenol sulfuryl)-1H- The preparation of indole 2-carboxamides (I-3)
The same I-1 of preparation method of I-3, except that use 4-bromomethyl benzsulfamide (0.5992mmol) to replace 1- (bromomethyl)-3-methoxybenzene.Productivity: 42.1%.mp:170-171 DEG C.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) and 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-chlorphenyl) piperidin-4-yl) the bromo-3-of-5-(3,5-xylenol sulfuryl)-1H-Yin The preparation of diindyl-2-Methanamide (I-4)
The same I-1 of preparation method of I-4, except that use 1-bromomethyl-4-chlorobenzene (0.5992mmol) to replace 1-(bromine Methyl)-3-methoxybenzene.Productivity: 46.2%.mp:229-230 DEG C.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) and 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-benzonitrile base) piperidin-4-yl) the bromo-3-of-5-(3,5-xylenol sulfuryl)-1H-Yin The preparation of diindyl-2-Methanamide (I-5)
The same I-1 of preparation method of I-5, except that use 1-bromomethyl-3-cyano group benzene (0.5992mmol) to replace 1- (bromomethyl)-3-methoxybenzene.Productivity: 42.3%.mp:223-236 DEG C.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].
The bromo-3-of embodiment 6:5-(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 use 3-(bromomethyl) pyridine hydrochloride (0.5992mmol) to replace 1-(bromomethyl)-3-methoxybenzene.Productivity: 47.8%.mp:220-221 DEG C.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) and 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].
The bromo-3-of embodiment 7:5-(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 use 4-(bromomethyl) pyridine hydrochloride (0.5992mmol) to replace 1-(bromomethyl)-3-methoxybenzene.Productivity: 46.6%.mp:243-244 DEG C.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) and 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-Carbamoylphenyl) piperidin-4-yl) the bromo-3-of-5-(3,5-dimethyl benzene sulfuryl)- The preparation of 1H-indole 2-carboxamides (I-8)
The same I-1 of preparation method of I-8, except that use 4-(bromomethyl) benzamide (0.5992mmol) to replace 1- (bromomethyl)-3-methoxybenzene.Productivity: 48.1%.mp:175-176 DEG C.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-sulphur aminomethyl phenyl) piperidin-4-yl) the chloro-3-of-5-(3,5-xylenol sulfuryl)-1H- The preparation of indole 2-carboxamides (I-9)
The same I-1 of preparation method of I-9, except that initiation material uses 5-chloro-indolecarboxylic acid ethyl ester (0.373mmol) Replacing 5-bromo-indolecarboxylic acid ethyl ester, final step substituent group uses 4-bromomethyl benzsulfamide (0.5992mmol) to replace 1-(bromine Methyl)-3-methoxybenzene.Productivity: 55.1%.mp:179-180 DEG C.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].
The chloro-3-of embodiment 10:5-(3,5-3,5-dimethylphenyl sulfuryl)-N-(1-(pyridin-3-yl methyl) piperidines-4-yl)- The preparation of 1H-indole-Methanamide (I-10)
The same I-9 of preparation method of I-10, except that use 3-bromo methyl cycloheptapyridine hydrochlorate (0.5992mmol) to replace 4-bromomethyl benzsulfamide.Productivity: 50.0%.mp:224-225 DEG C.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) and 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].
The chloro-3-of embodiment 11:5-(3,5-3,5-dimethylphenyl sulfuryl)-N-(1-(pyridin-3-yl methyl) piperidines-4-yl)- The preparation (0002466-43 is shown in protocol) of 1H-indole-Methanamide (I-11)
The same I-9 of preparation method of I-11, except that use 4-bromo methyl cycloheptapyridine hydrochlorate (0.5992mmol) to replace 4-bromomethyl benzsulfamide.Productivity: 50.5%.mp:240-241 DEG C.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) and 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].
The chloro-3-of embodiment 12:5-(3,5-3,5-dimethylphenyl sulfuryl)-N-(1-((4-methyl-5-oxygen-4,5-dihydro-1H- 1,2,4-triazole-3-base) methyl) piperidin-4-yl) preparation of-1H-indole-Methanamide (I-12)
The same I-9 of preparation method of I-12, except that use 5-(bromomethyl)-4-methyl-2 hydrogen-1,2,4-triazolyl- 3 (4 hydrogen) (0.5992mmol) replaces 4-bromomethyl benzsulfamide.Productivity: 53.1%.mp:274-275 DEG C.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) the chloro-3-of-5-(3,5-xylenol sulfuryl)- The preparation of 1H-indole 2-carboxamides (I-13)
The same I-9 of preparation method of I-13, except that use 4-bromomethyl benzsulfamide (0.5992mmol) to replace 4- Bromomethyl benzsulfamide.Productivity: 52.1%.mp:215-217 DEG C.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) and 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-Carbamoylphenyl) piperidin-4-yl) the chloro-3-of-5-(3,5-dimethyl benzene sulfuryl)- The preparation of 1H-indole 2-carboxamides (I-14)
The same I-9 of preparation method of I-14, except that use 4-(bromomethyl) benzamide (0.5992mmol) to replace 4- Bromomethyl benzsulfamide.Productivity: 56.6%.mp:153-155 DEG C.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) and 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].
The chloro-3-of embodiment 15:5-(3,5-3,5-dimethylphenyl sulfuryl)-N-(1-(thiophene-3-methyl) piperidin-4-yl)-1H- The preparation of indole 2-carboxamides (I-15)
Intermediate 6 ' claims to add mixed solvent oxolane/methanol (1/2) 30mL post-heating in round-bottomed flask to solution Clarification, the 30-40 DEG C of lower acetic acid that instills of stirring is 4-5 to pH, and addition 3-thiophene-formaldehyde (0.060g, 0.535mmol) reacts 40 points Clock, is subsequently added sodium cyanoborohydride (0.056g, 0.89mmol), continues reaction 10 hours.The direct evaporating column of reactant liquor chromatographs Purification (ethyl acetate).Productivity: 70.2%.mp:230-231 DEG C.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].
The chloro-3-of embodiment 16:5-(3,5-3,5-dimethylphenyl 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 use 2-thiophene-formaldehyde (0.535mmol) replacement 3-thiophene- Formaldehyde.Productivity: 69.6%.mp:225-256 DEG C of .ESI-MS:m/z 542.4 (M+1) .C27H28ClN3O3S2[541.13].
Embodiment 17:N-(1-(4-(trifluoromethyl) phenyl) piperidin-4-yl) the chloro-3-of-5-(3,5-dimethyl benzene sulfuryl)- The preparation of 1H-indole 2-carboxamides (I-17)
The same I-15 of preparation method of I-17, except that use 4-(trifluoromethyl) benzaldehyde (0.535mmol) to replace 3-thiophene-formaldehyde.Productivity: 69.8%.mp:209-210 DEG C.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), and 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) and 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].
The chloro-3-of embodiment 18:5-(3,5-3,5-dimethylphenyl sulfuryl)-N-(1-(furan-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 use 3-furan-formaldehyde (0.535mmol) replacement 3-thiophene- Formaldehyde.Productivity: 68.8%.mp:223-224 DEG C.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-nitrobenzophenone) piperidin-4-yl) the chloro-3-of-5-(3,5-dimethyl benzene sulfuryl)-1H-Yin The preparation of diindyl-2-Methanamide (I-19)
The same I-15 of preparation method of I-19, except that use 3-nitro-benzaIdehyde (0.535mmol) to replace 3-thiophene Fen-formaldehyde.Productivity: 65.6%.mp: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) and 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].
The chloro-3-of embodiment 20:5-(3,5-3,5-dimethylphenyl sulfuryl)-N-((1-(2-ethoxy) 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 compound IV a-6 is by 1-tertbutyloxycarbonyl-4-aminomethylpiperidine (3.67mmol) replacing Boc-4-amino piperidine to prepare, final step substituent group uses bromoethanol (0.5992mmol) to replace 4-bromine Methyl benzenesulfonamide.Productivity: 50.0%.mp:255-256 DEG C.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-carbamyl phenyl) piperidin-4-yl) methyl) the chloro-3-of-5-(3,5-dimethyl benzene sulfone Base) preparation of-1H-indole 2-carboxamides (I-21)
The same I-20 of preparation method of I-21, except that use 4-(bromomethyl) benzamido (0.5992mmol) generation For bromoethanol.Productivity: 52.3%.mp:259-260 DEG C.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-fluorophenyl) piperidin-4-yl) methyl) the chloro-3-of-5-(3,5-dimethyl benzene sulfuryl)- The preparation of 1H-indole 2-carboxamides (I-22)
The same I-20 of preparation method of I-22, except that use 4-(bromomethyl)-2-fluorobenzene (0.5992mmol) to replace Bromoethanol.Productivity: 46.5%.mp:193-194 DEG C.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-phenyl) piperidin-4-yl) methyl) the chloro-3-of-5-(3,5-dimethyl benzene sulfuryl)- The preparation of 1H-indole 2-carboxamides (I-23)
The same I-20 of preparation method of I-23, except that use 4-(bromomethyl) benzonitrile (0.5992mmol) to replace bromine Ethanol.Productivity: 52.6%.mp:213-214 DEG C.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 benzene sulfuryl) 1H-indole 2-carboxamides) methyl) piperazine Pyridine-1-base) preparation of propanoic acid (I-24)
The same I-20 of preparation method of I-24, except that use ethyl 3-bromoacetic acid (0.5992mmol) to replace bromine second Alcohol.Productivity: 45.6%.mp:194-195 DEG C.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 (human immunodeficiency virus)-resistant activity experiment (MT-4 cell model)
Term is explained:
MT-4 cell: people's acute lymphoblastic leukemia cell.
MTT analytic process: MTT is 3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide bromide, 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.
Test philosophy
Owing to the MT-4 cell (5-7 days) within a certain period of time of HIV can occur pathological changes, therefore to the MT-of HIV 4 cell suspension add the compound solution to be detected of debita spissitudo, through after a while after the cultivation of (5-7 days), uses MTT Assay MT-4 cell viability, obtains protecting 50% cell to avoid cytopathic drug level (EC50) mesh can be drawn The activity of the AntiHIV1 RT activity of mark compound.Obtain target compound simultaneously and make the concentration of the 50% cell generation pathological changes being uninfected by HIV (CC50), calculate selection coefficient (selectivity index, SI=CC50/EC50)。
MTT analytic process principle: MTT i.e. bromination-3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazoliumbromide nitrogen, can be with The intracellular succinate dehydrogenase lived combines, and does not reacts with dead cell.Mtt assay is a kind of quick, succinct at present The method of analyzing enzyme of reflection cell viability.
Test material and method
(1) HIV-1 (IIIB), HIV-2 (ROD) strain, HIV-1 double sudden change (K103N/Y181C) persister RES056: by Belgium's Leuven university Rega academy microbiological inhibitory institute provides.
(2) MT-4 cell: provided by Belgium's Leuven university Rega academy microbiological inhibitory institute.
(3) MTT: purchased from Sigma Co., USA.
(4) sample treatment: sample is dissolved in DMSO before use and is made into debita spissitudo, and make 5 times of dilutions with distilled water, each 5 Dilution factor.
(5) positive control drug: Nevirapine (NVP), Efavirenz (EFV), Delavirdine (DLV), Etravirine(ETV)。
(6) method of testing: join after diluted sample in HIV MT-4 cell suspension, use through after a period of time MTT colorimetric method for determining cell viability, in microplate reader, records absorbance (A) value at 590 nm, calculates EC50、CC50And SI。
(7) MTT staining: after adding sample culturing a period of time, then MTT solution (5mg/mL) 20 μ L is added to every hole, Continue to cultivate some hours, abandon dyeing liquor, and add 150 μ L DMSO to every hole, be sufficiently mixed, in microplate reader, at 590nm Lower record absorbance.
Concrete operations are as follows: will dilute, by 3 × 10 with phosphate buffer after compound DMSO or water dissolution5MT-4 The compound solution of cell and 100 μ L variable concentrations is at 37 DEG C of common preincubate 1h.Then in this mixture, add 100 μ L fit When the viral dilution liquid of concentration, cell is hatched 1h in 37 DEG C.After washing three times, cell is suspended in the most respectively containing or not In culture matrix containing compound.Then by cell at 5%CO2In environment, hatch again at 37 DEG C 7 days, and in metainfective Within 3rd day, supplement original fluid with the culture matrix with or without compound.The all repetitive operations twice of every kind of condition of culture.Right The cytopathic effect of virus all uses reverse optical microscope to monitor every day.In general, viral dilution used in this experiment Liquid usually can occur cytopathy in the 5th day after virus infects.Drug inhibition concentration is with drug on viral cytopathic effect Produce 50% inhibitory action and simultaneously to cell without the concentration (EC of direct toxicity50) represent.It is emphasized that when compound water Dissolubility is poor, when needing could dissolve with DMSO, from the point of view of DMSO volume by volume concentration is relative to water, typically can be less than 10% (DMSO In MT-4 cell culture medium, ultimate density is less than 2%).Because DMSO can affect test compound antiviral activity, to containing The antiviral activity contrast blank experiment having same concentrations DMSO solution also should be carried out by operation repetitive.It addition, DMSO is the denseest Degree (1/1000) replicates desired concn well below affecting HIV-1 in MT-4 cell.
The In Vitro Anti HIV-1 (IIIB) of target compound and HIV-1 double sudden change RES056 persister screening active ingredients data by Belgium's Leuven university Rega academy microbiological inhibitory institute provides, and all of activity data is all through at least two Secondary independent, parallel experiment records, and the results are shown in Table 1,2,3.
Table 1 compound anti-wild type HIV-1 (IIIB) and the cytoactive of double-mutant strain (F227L/V106A, RES056) And toxicity
a: medium effective concentration；b: wild type HIV-1 strain；c: double sudden change HIV-1 strains；d: median lethal concentration.
The cytoactive of table 2 compound anti-HIV-1 single mutation strain (L100I, K103N, Y181C, Y188L, E138K)
a: with table 1；e: single mutation type HIV-1 strain.
Table 3 compound anti-wild type HIV-1 (IIIB) and multiple list (L100I, K103N, Y181C, Y188L, E138K) Or the selection index (SI) of double (F227L/V106A, RES056) mutant
B, c, e: with table 1；f: therapeutic index.
Embodiment 26: anti-reverse transcription enzymatic activity test experiments
This experiment uses chromatmetry reverse transcriptase activity determination experiment, used test kit Reverse Transcriptase Assay, colorimetric Version 13.0 is purchased from Roche Holding Ag, and how positive control medicine is selected Wei Laping and according to Qu Weilin.(see 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 measures and uses template/primer-oligomerization thing poly (A) × oligo (dT) as initial former Material, and with digoxin and biotin labeled nucleotide replacement radiosiotope [3H]-or [32P] nucleotide of-labelling, In place of these are the advantage of the method.Synthesized by the DNA that goes out be the important parameter measuring reverse transcriptase activity, detection and quantitatively DNA employs the ELISA assay method of following sandwich style: biotin labeled DNA can be coated antibiotin strepto- The surface of micro-edition module (MP) of rhzomorph is combined.In an ensuing step, the digoxin being polymerized peroxidase resists Body needs to be attached on the DNA of digoxigenin labeled.Finally, the substrate 2 of peroxidase, 2-azino-two (3-ethyl-benzene are added And thiazole-6-sulfonic acid) di-ammonium salts (ABTS), make them decompose under the catalytic action of enzyme, produce the product with obvious color. Being measured by microplate reader and be loaded with the microplate absorbance of sample, this absorbance presents with the activity of reverse transcriptase and directly associates, The compound inhibition concentration to reverse transcriptase is can be calculated by formula.
Method of testing
(1) first configure various working solution, and sample appropriate dimethyl sulfoxide (DMSO) is dissolved, and slow with cracking Rush liquid and be diluted to 5 Concentraton gradient.In the reaction tube that each are different, by 4 6ng Recombinant HIV-1-RT lysis buffers (20 μ L/well) dilution.Meanwhile, preparation only has lysis buffer not have the negative control group of RT.The most each retort adds 20 μ L contains buffer solution and the 20 μ L reactant mixed liquors of variable concentrations institute test sample, hatch under 37 degrees Celsius one little Time.
(2) prepare micro-edition enough module, be fixedly mounted in framework according to direction.The sample (60 μ L) that will hatch Transferring in the hole of microplate, after covering with thin film, second time 37 degrees Celsius hatches one hour.
Being removed by solution, every hole washing liquid is carefully rinsed 5 times, every all over 250 μ L, retains 30 seconds.Every hole adds 200 μ L Anti-digoxin-peroxidase polymer, after being covered by microplate thin film, third time is hatched one hour under 37 degrees Celsius.
(3) being removed by solution, every hole washing liquid is carefully rinsed 5 times, every all over 250 μ L, retains 30 seconds.Every hole adds 200 μ L ABTS solution, hatch under 15-25 degree Celsius, until green color occurs and enough passes through photometric detection (generally 10- 30 minutes).
(4) it is loaded with sample absorbance at wavelength 405nm, by can be calculated of below equation by microplate reader mensuration The compound inhibition concentration to reverse transcriptase.
Suppression ratio %=(positive control fluorescence intensity-fluorescent intensity)/(positive control fluorescence intensity-background fluorescence Intensity) × 100% carry out linear regression, bring suppression ratio into linear equation, the concentration C tried to achieve is IC50, unit is (μ g/ ML), being converted into μM further according to compound molecular weight, this experiment have chosen a best representative compound of cytoactive, with And positive control drug nevirapine (NVP) and etravirine (ETV), experimental result is shown in Table 4.
Table 4 representation compound is to HIV1-RT inhibitory activity
Above-mentioned test result indicate that: having compounds of formula I of the present invention is the HIV-1 that a class has new structure skeleton Inhibitor, as above shown in Table I, the compound of all series IVa all has significant anti-wild type HIV-1 effect, EC50Value model Enclose is 0.62 μM to 0.006 μM.And majority of compounds also show good inhibitory activity to multiple single mutation strain, as Variant viral strain L100I, K103N, Y181C, E138K.Compound I-2 and I-12 inhibitory activity are more prominent, to wild type HIV-1 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 such as F227L/V106A all keeps the activity of more than sub-micromolar, is generally better than marketed drug NVP and DLV.And For some single mutation Strain such as L100I and K103N, the inhibitory action of I-2 is slightly better than marketed drug EFV, and with guideization Compound EFF is in same level.Especially it is emphasized that to the highstrung Y188L mutated viruses strain of indole virtue sulfone compound, The EC of I-1250Value is 0.84 μM, is better than lead compound EFF (EC50=1.3 μMs), achieve beyond thought effect.Additionally, The inhibitory activity of double mutated viruses strain Y181C/K103N that I-14 is the most serious to clinic is better than marketed drug DLV, with guide EFF It is in same level with marketed drug NVP.In view of the novelty of indole virtue sulfone derivatives structure involved in the present invention, to open country The progressive of raw type and the significant inhibitory activity of various mutations type HIV-1 and relatively some existing compound, thus tool There is bigger Development volue.Carry out new structural modification on this basis and further investigation contributes to obtaining more excellent effect Really, and there are the potentiality developing into a class brand new anti-HIV new medicament.

Claims (7)

1. indole virtue sulfone derivatives or its pharmaceutically acceptable salt or prodrug, it is characterised in that have shown in below formula I Structure:
Wherein,
The substituent X of indole 5-position is halogen, CF3Or NO2；
N is equal to 0,1,2 or 3；
M, w are the most individually equal to 1 or 2；
R is (C1-6) alkyl-R1、(C3-7) cycloalkyl-R1、(C2-6) alkenyl-R1、-C(O)R1、-C(O)OR1、-S(O)-R1、- SO2-R1、NH-R1, phenyl, 5-or 6-unit heteroaromatic, 5-or the 6-unit carbocyclic ring or thick of phenyl-undersaturated or saturated that condenses Phenyl-the 5-closed or 6-unit heteroaromatic；
Wherein R1Selected from H, OH, SH, NH2、O-(C1-4) alkyl, S-(C1-4) alkyl or NH-(C1-4) alkyl；Described phenyl, 5- 6-unit heteroaromatic, phenyl-undersaturated or saturated 5-or the 6-unit carbocyclic ring condensed or the phenyl-5-condensed or 6-unit virtue Heterocycle is the most optionally independently selected from following substituent group by 1 to 3 and replaces: (C1-6) alkyl, halogen, CF3、OCF3、OH、 NO2、CN、SO2NH2、SO2-(C1-3) alkyl, C (O) NH2、C(O)(C1-3) alkyl, NH (C1-3) alkyl.
2. compound as claimed in claim 1, it is characterised in that in formula I,
The substituent X of indole 5-position is Cl or Br；
N is equal to 0 or 1；
M and w is simultaneously equal to 2；
R is CH2OH、CH2COOCH2CH3, substituted phenyl, pyridine radicals, furyl, thienyl or substituted triazolyl.
3. compound as claimed in claim 1 or 2, it is characterised in that for one of the compound of having structure:
4. the preparation method of indole virtue sulfone derivatives as claimed in claim 1 or 2, comprises the steps: to replace with 5-position Indolecarboxylic acid ethyl ester (1) be initiation material, with 3,5-thiophenol dimethyl benzene reaction prepare midbody compound 2, intermediate warp Metachloroperbenzoic acid oxidation obtains midbody compound 3, is hydrolyzed by the ethoxycarbonyl of midbody compound 3 and obtains intermediate compound Thing 4, midbody compound 4 is through acylation reaction and sloughs BOC protection group and obtains female ring 6, and female ring 6 is carried out by different substituent groups Replace and prepare indole virtue sulfone derivatives I；
Synthetic route is as follows:
Reagent and condition: (i) 3,5-thiophenol dimethyl benzene, 1-chloromethyl-4-fluoro-1,4-diazabicyclo [2.2.2] octane two (Tetrafluoroboric acid) salt, acetonitrile；(ii) metachloroperbenzoic acid, dichloromethane, 0 DEG C；(iii) Lithium hydrate, water, oxolane, 50℃；(iv) the nitrogenous cycloalkyl-amino of Boc protection, 2-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluoro Phosphate ester, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, triethylamine, N,N-dimethylformamide；(v) three Fluoroethanoic acid, dichloromethane；(vi) potassium carbonate, DMF, halogen benzyl, the alkyl of halogen substiuted；(vi) substituted first Aldehyde, glacial acetic acid, sodium cyanoborohydride, oxolane/acetonitrile.
Wherein, the definition of X, n, m, w, R is with described in the formula I in claim 1 or 2.
5. the preparation method of indole virtue sulfone derivatives as claimed in claim 3, comprises the steps: to replace with 5-chlorine bromine Indolecarboxylic acid ethyl ester (1 ') be initiation material, with 3,5-thiophenol dimethyl benzene reaction prepare midbody compound 2 ', intermediate Compound 2 ' through metachloroperbenzoic acid aoxidize to midbody compound 3 ', Lithium hydrate is by the ethyl ester of midbody compound 3 ' Base hydrolysis obtains midbody compound 4 ', and midbody compound 4 ' and 1-Boc-4-amino piperidine or 1-Boc-4-(aminomethyl)- Piperidines obtains midbody compound 5 ' through acylation reaction, and sloughs Boc protection group under trifluoroacetic acid effect and obtain female ring 6 ', Different substituent groups replaces prepared indole virtue sulfone derivatives I to female ring 6 '；
Synthetic route is as follows:
Reagent and condition: (i) 3,5-thiophenol dimethyl benzene, 1-chloromethyl-4-fluoro-1,4-diazabicyclo [2.2.2] octane two (Tetrafluoroboric acid) salt, acetonitrile；(ii) metachloroperbenzoic acid, dichloromethane, 0 DEG C；(iii) Lithium hydrate, water, oxolane, 50℃；(iv) 1-BOC-4-amino piperidine or 1-Boc-4-(aminomethyl)-piperidines, 2-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, triethylamine, N, N-diformazan Base Methanamide；(v) trifluoroacetic acid, dichloromethane；(vi) potassium carbonate, N,N-dimethylformamide, halogen benzyl or the alkane of halogen substiuted Base；(vi) substituted formaldehyde, glacial acetic acid, sodium cyanoborohydride, oxolane/acetonitrile；
Wherein, X is chlorine or bromine, and n is equal to 0 or 1, and R is CH2OH、CH2COOCH2CH3, substituted phenyl, pyridine radicals, furyl, thiophene Fen base or substituted triazolyl.
6. compound application in preparing inverase as described in any one of claim 1-3.
7. an inverase compositions, comprises compound described in any one of claim 1-3 or its pharmaceutically acceptable salt And one or more pharmaceutically acceptable carriers or excipient.
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CN106748921A (en) * 2016-12-16 2017-05-31 上海应用技术大学 A kind of fragrant sulfuryl difluoroacetic acid salt compounds, preparation method and applications
CN112898193A (en) * 2021-01-23 2021-06-04 山东大学 Indole aryl sulfone derivative and preparation method and application thereof
CN112920208A (en) * 2021-01-28 2021-06-08 山东大学 Boric acid-containing indole aryl sulfone derivative and preparation method and application thereof

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Publication number Priority date Publication date Assignee Title
CN106748921A (en) * 2016-12-16 2017-05-31 上海应用技术大学 A kind of fragrant sulfuryl difluoroacetic acid salt compounds, preparation method and applications
CN106748921B (en) * 2016-12-16 2018-06-22 上海应用技术大学 A kind of virtue sulfuryl difluoroacetic acid salt compounds, preparation method and applications
CN112898193A (en) * 2021-01-23 2021-06-04 山东大学 Indole aryl sulfone derivative and preparation method and application thereof
CN112898193B (en) * 2021-01-23 2022-08-05 山东大学 Indole aryl sulfone derivative and preparation method and application thereof
CN112920208A (en) * 2021-01-28 2021-06-08 山东大学 Boric acid-containing indole aryl sulfone derivative and preparation method and application thereof

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