CN107149602A

CN107149602A - The purposes of a class Benzazole compounds and its derivative in inverase is prepared in Radix Isatidis

Info

Publication number: CN107149602A
Application number: CN201610136144.9A
Authority: CN
Inventors: 石建功; 郭颖; 徐成博; 陈勍; 陈明华; 霸明宇; 朱承根; 唐克; 蒋建东; 郭庆兰; 林生; 杨永春
Original assignee: Institute of Materia Medica of CAMS
Current assignee: Institute of Materia Medica of CAMS
Priority date: 2016-03-10
Filing date: 2016-03-10
Publication date: 2017-09-12
Anticipated expiration: 2036-03-10
Also published as: CN107149602B

Abstract

The invention discloses a class as led to the Benzazole compounds and its derivative that are extracted in the Radix Isatidis shown in formula (I), and application of its pharmaceutically acceptable salt in inverase or health products is prepared；And disclose the preparation method of such compound and application of the pharmaceutical composition in inverase or health products is prepared containing such compound.

Description

A class Benzazole compounds and its derivative are in inverase is prepared in Radix Isatidis Purposes

Technical field

The present invention relates to a kind of indole derivatives and its pharmaceutically acceptable salt, their preparation method, contain this The pharmaceutical composition of class compound, and application of this kind of compound in terms of anti HIV-1 virus and resisiting influenza virus, belong to doctor Medicine technical field.

Background technology

Human immunodeficiency virus (Human Immunodeficiency Virus, HIV) is thin by infecting human immunity Born of the same parents, destroy human immune system, patient is ultimately succumbed to the complication such as severe infections or secondary tumors.Caused by the virus Disease be referred to as acquired immunodeficiency syndrome (Acquired Immunodeficiency Syndrome), i.e. AIDS Disease^[1]。

UNAIDS (UNAIDS) report display, by the end of the year 2012, global AIDS viral infection people Number is altogether 35,000,000 [32,200,000-3,880 ten thousand], including 3,300,000 children [3,000,000-370 ten thousand].Global AIDS is new within 2012 Send out the infected 2,300,000 [1,900,000-270 ten thousand], annual death toll 1,600,000 [1,400,000-190 ten thousand] [http:// www.actoronto.org/home.nsf/pages/hivaidsstatsworld HIV and AIDS Statistics– Worldwide].2012 years show that China is accumulative to report patients infected hiv and AIDS patients 43.4 ten thousand according to statistics, Dead 8.8 ten thousand people.By the end of the year 2011, estimation China survival AIDS patients 15.4 ten thousand people [http://www.avert.org/ hiv-aids-china.htm].Report also shows that China's HIV infection number rises year by year, and the epidemic situation was severe for some areas, because This preventing and controlling to AIDS still needs to deep expansion.

HIV belongs to Retroviridae lentivirus mankind's slow virus group, is divided into I type human immunodeficiency virus (HIV- 1) with II type human immunodeficiency virus (HIV-2), majority state AIDS patient is due to that the virus infection of HIV-1 types is caused, HIV-2 is mainly distributed on African western part^[2].AIDS can not be still cured, and without preventative vaccine.It is main using high at this stage Antiretroviral therapy (hi ghly active anti-retroviral therapy, HAART) is imitated, i.e., takes several simultaneously (being typically 3 kinds or 4 kinds) antiretroviral drugs are planted, wherein two efabirenzs and one kind are used in combination Non-nucleoside reverse transcriptase inhibitor or protease inhibitors are routine administration schemes^[3].By the end of the year 2013, existing 26 kinds of medicines Treatment of the thing approval listing for AIDS, these medicines are divided into 6 classes by mechanism of action：7 efabirenzs； 5 non-nucleoside reverse transcriptase inhibitors (Non-Nucleoside Reverse Transcriptase Inhibitors, NNRTIs)；10 protease inhibitors；2 integrase inhibitors；1 fusion inhibitor；1 CCR5 inhibitor.Pass through joint Medication can effectively reduce virus replication speed, recover patient immune function, reach the purpose of extension patient vitals.But it is due to nothing Method thoroughly removes virus, and patient needs lifelong medication, and drug-resistant virus necessarily lead to, under causing HAART therapeutic effects notable Drop.Therefore the new drug for researching and developing efficient overriding resistance HIV-1 viruses is treating AIDS field important topic.

HIV1-RT (reverse transcriptase, RT) is that completion single stranded RNA reverse transcription is double-stranded DNA institute Necessary functional group, plays vital effect in HIV-1 life cycles, therefore RT turns into treatment AIDS-treating medicine Classical target spot^[4].The heterodimer that RT is made up of p66 subunits and p51 subunits, p66 is function subunit, is relied on RNA DNA polymerase activity, DNA rely on DNA polymerase activity and ribonuclease H (RNase H) activity.P66 subunits are divided into polymerization Enzymatic activity region and RNase H active regions, wherein polymerase activity regional sequence are highly conserved, are similar to the right hand of people, including " finger " (1-85 and 118-155 residues), " palm " (86-117 residues), " thumb " (238-318 residues) and bonding pad (319- 426 residues) area, polymerase active site be located at " palm " center, be one section of highly conserved region (including D110, D185 and D186).Non-nucleoside reverse transcriptase inhibitor is acted on away from the hydrophobicity " pocket " at the site 1nm of reverse transcriptase activity center (non-nucleoside inhibitor bindin g pocket, NNIBP), after such medicine is combined with reverse transcriptase, leads to The effective conformation for changing reverse transcriptase catalytic activity area is crossed, so that inhibitory enzyme and Binding Capacity^[5].The non-nucleosides listed at present Class RTI be respectively Delavirdine, NVP, efavirenz, according to Qu Weilin and rilpivirine.

Non-nucleoside reverse transcriptase inhibitor is important component in highly active antiretroviral therapy, generally and nucleosides Class RTI use in conjunction.With the long-term extensive uses of HAART, drug-resistant virus are produced therewith, and with multiple medicine The characteristics of resistance, so as to cause Endodontic failure.According to statistics, there are a kind of drug-resistant virus in clinical at least 50% patient's body.Nai Wei Even up and applied with efavirenz through clinical more than ten years, stable resistance strain occurred^[6].Clinical research find, etravirine and Rilpivirine was taken after 48 weeks, and the drug-resistant virus for both medicines can be produced in vivo.Therefore new non-nucleoside is researched and developed inverse Transcripting enzyme inhibitor is the emphasis in anti-AIDS field.

Table 1：Clinical common NNRTIs resistant mutational sites, incidence probability and resistance multiple

Viral disease is the Infectious Diseases of the mankind, and common disease has as caused by virus：(1) epidemic disease, such as Influenza, measles, parotitis etc.；(2) chronic infectious diseases, such as AIDS, hepatitis B；(3) latent infection disease, Such as herpetic keratitis；(4) some tumours, such as nasopharyngeal carcinoma, cervical carcinoma etc..The preventing and treating of viral disease is Medical and medicine The important subject in field, treat viral disease, especially simultaneously treat a variety of viral diseases drug research and Invention has important potential using value.

Influenza virus is the pathogen for causing influenza, is to cause one of Etiological of human death.Influenza disease Poison belongs to orthomyxoviridae family, is divided into first (A), second (B), third (C) three types according to the difference of internal protein antigenicity, with the mankind It is influenza A virus that relation is most close, and its genome is made up of 8 minus-strand RNAs, encodes at least ten kinds of albumen：Blood clotting Fibroin (Hemagglutinin, HA), neuraminidase (Neuraminidase, NA), polymerase (Polymerase basic protein1,PB1；Polymerase basic protein 2,PB2；Polymerase acidic protein 3, PA), nucleoprotein (Nucleoprotein, NP), stromatin (Matrix protein 1, M1；Matrix protein 2, M2), non-structural protein (Non-structural protein1, NS1；Non-structural protein 2,NS2).Influenza Virus strain is numerous, antigenic different by influenza A virus according to virus envelope protein hemagglutinin HA and neuraminidase NA Be divided into a variety of hypotypes, have now been found that 17 kinds of HA and 10 kinds of NA, HA and NA hypotypes can form various combination, such as H1N1, H2N2, H3N2, H5N1, H7N9 hypotype etc..

The Tamiflu of current clinical practice, two classes are broadly divided into by the mechanism of action：One class is to suppress M2 ion channels The amantadine and Rimantadine of albumen；Another kind of is to suppress the neuraminidase inhibitor that influenza virus is disengaged, Oseltamivir, Zha Na meter Wei and Peramivir.Statistics shows that current all Tamiflu listed occur in that multidrug resistant disease strain, Because drug resistance is excessively serious, American Centers for Disease Control and Prevention have been proposed that amantadine, Rimantadine class medicine not as Clinical treatment is used.Except above-mentioned antiviral drug beyond the region of objective existence, such as a variety of singles and Chinese traditional compound medicine, banlangen granules, banlangen keli, swap buffers Oral liquid etc., is also effective medicine of resisiting influenza virus.

Radix Isatidis is cruciferae isatis (Isatis tinctoria L.) and careless smalt (I.indi gotica Fort. there is cultivation root), all parts of the country, and aboundresources is also the traditional conventional Chinese medicine of China, sharp with clearing heat and detoxicating, cool blood The effect of pharynx, clinically it is used for treatment influenza, mumps, popular hepatitis B, monovesicle viral angle The viral infectious diseases such as film inflammation, pharyngitis, flat wart, blood-shoot-eye illness, dacryocystitis, varicella, measles^[7,8].Version in 2010《Middle traditional Chinese medicines Allusion quotation》Specifying Radix Isatidis has clearing heat and detoxicating, cool blood relieving sore-throat effect, malicious during for warm epidemic disease, and pharyngalgia of generating heat, febrile virulent maculae, mumps is rotten Larynx scarlet fever, major part pestilence, erysipelas and carbuncle swells.Especially Radix Isatidis and its preparation is used as China in SARS and avian influenza prevention One of emergent herbal species are recommended to play important function.

The pharmaceutical research of conventional Radix Isatidis is concentrated mainly on its water or alcohol extracting thing and its parenteral solution being made and separation In terms of the activity rating for obtaining position, correlative study result shows isatis-root injection to influenza A virus, encephalitis B disease Poison and mumps virus etc. have suppression infection and Inhibit proliferaton effect, have to hemorrhagic fever viruse, herpes simplex virus and significantly kill the virus Effect^[7], to hepatitis B surface antibody (HBsA g), hepatitis B virus antigen (HBeA g), hepatitis B virus Former (HBcA g) and HBV-DNA significantly inhibit effect^[9]；Isatis root extract or isolated position, which have, suppresses people's list The pure type of property herpesviral HSV-I and HSV- II virus, suppression TK genetic transcriptions^[10,11], suppress HSV-I to Hep-2 cell infections, HSV-I is inactivated^[12], suppress MDCK (MDCK) inoculation PR8 plant of people's Influenza A1 virus (A/PR/8/34, H1N1) answer System^[13,14], suppress human cytomegalovirus HCMV^[15], suppress Hela cell line transfection mumps virus^[16]With suppression pig The malicious before and after cytopathy of kidney cell infection pseudorabies^[17]Deng effect.And show that Radix Isatidis is carried in some evaluations Take activity and the work of positive control ACV (Aciclovir), Zidovudine (Zidovudine, AZT) or poly IC of thing Property is suitable or stronger.In addition, Radix Isatidis ethanol extract and its separated part have to staphylococcus aureus, pseudomonas aeruginosa Inhibitory action, foot swelling caused by paraxylene cause mice auricle swelling and carrageenan significantly inhibits effect, effect and sun Property comparison medicine Indomethacin is suitable^[18,19].As can be seen here, the antivirus action of isatis root extract is definitely affirmed.

Since the eighties in last century, domestic and foreign scholars are also persistently ground to the chemical composition of Radix Isatidis and its leaf Study carefully, it is separated to identify including alkaloid, lignanoid, ceramide and flavones, and epigoitrin and 2- hydroxyl -3- cyclobutenyls Nearly more than 80 compounds of the various structures such as thiocyanic acid.Although under study for action it has also been found that indole alkaloid constituents such as indigo red The compositions such as derivative, tryptamines ketone, 2,4 (1H, 3H)-quinoline azoles diketone, adenosine have certain antitumor, antibacterial and disease-resistant respectively The pharmacological activity such as poison^[20~22]；The compositions such as syringic acid, salicylic acid, ortho-aminobenzoic acid, benzoic acid and 4 (3H)-quinazolones have aobvious The effects such as antiendotoxin, suppression TNF α and the NO releases of work^[23-30], and suppress the activity or reduction cell point of 5-LO Secrete the effect of leukotriene B (4) level^[31~33].Yet with the limitation of sample size and Pharmacological Evaluation model, most compounds Not carry out determination of activity evaluation, particularly reported content and activity intensity of compound etc. be difficult to isatis root extract and It is anti-a variety of viral strongly active corresponding that separated part is shown.As can be seen here the antiviral activity in isatis root extract into It is not fully understood before subhead.

Based on background above, with reference in conventional Radix Isatidis chemical constitution study, majority is extracted with ethanol or methanol, and The tradition application of Radix Isatidis and Pharmacological Evaluation it is many with decocting boil based on situation, we have carried out Radix Isatidis water boiling and extraction thing Research, from the separation of chemically composition, antiviral activity evaluation, thaumatropy association and derivatization and structure-activity relationship etc. just Face, carries out system in-depth study^[34~36].Being found that one under study for action has the N- alkane for significantly inhibiting HIV-1 replication activities Epoxide indole derivatives, methyl -2- [2- (1- methoxyl group -1H- indol-3-yls) acetamide] benzoic ether { Methyl 2- [2- (1-methoxy-1H-indol-3-yl) acetamido] benzoate, 1 }.Therefore, using the compound as guide structure, Optimized by structural modification, obtain the creative result of the present invention.

Indole derivatives are not only widely present in plant, and many medicines clinically used contain indoles result Unit, they have a variety of various bioactivity, such as anti-inflammatory, antitumor, antiviral, antibacterial.Meanwhile, also there is document Report that some indole derivatives have good Anti-HIV-1 Active^[37,38].However, compound shown in these documents is not only equal Belong to derivative unsubstituted on indoles N, and exist between overall structure and the structure of the compounds of this invention dramatically different.

In addition, also there is document report indole nitrogen atom to be lived for the labyrinth derivative and its cell toxicant of alkoxy substitution Property^[39], but do not find that they have AntiHIV1 RT activity and anti-influenza virus activity.

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The content of the invention

Present invention solves the technical problem that being to provide a class Benzazole compounds and its pharmaceutically acceptable salt, Yi Jiqi Preparation method, pharmaceutical composition and application of such compound in AntiHIV1 RT activity or anti-influenza virus medicament or health products are prepared.

Technical scheme first aspect there is provided a class Benzazole compounds and its pharmaceutically acceptable salt, Its structural formula is as shown in logical formula (I)：

Wherein,

N is selected from 1,2,3,4 integer；

R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C_1-6Alkyl or C_1-6Alkoxy；

X is selected from hydrogen, substituted or unsubstituted C_1-16Alkyl, C_3-6Cycloalkyl, C_1-6Alkanoyl, substituted or unsubstituted benzyl Base, substituted or unsubstituted benzoyl；Wherein described substituent is optionally by following substituent group：OH、C_1-6Alkyl, C_1-6Alkane Epoxide, halogen, NH₂、NO₂, cyano group, carboxyl, phenyl, C_1-6Unsaturated alkyl, C_3-6Cycloalkyl, C_1-6Alkoxy acyl；

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

Z is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridine radicals；Wherein described substituent optionally by with Lower substituent group：Halogen, C_1-6Alkyl, C_1-6Alkoxy, cyano group, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C_1-6Alcoxyl acyl Base.

It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to compound shown in formula (IA) And its pharmaceutically acceptable salt

Wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C_1-6Alkyl or C_1-6Alkoxy；

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IA1) Thing and its pharmaceutically acceptable salt

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

R₁To be monosubstituted or polysubstituted, selected from hydrogen, halogen, C_1-6Alkyl, C_1-6Alkoxy, cyano group, trifluoromethyl, nitro, Hydroxyl, amino, carboxyl, C_1-6Alkoxy acyl；Wherein described is monosubstituted monosubstituted selected from ortho position, meta, contraposition；Described is more Substitution is selected from two substitutions, three substitutions, four substitutions, five substitutions.

It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IA1a) Thing and its pharmaceutically acceptable salt

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IA1b) Thing and its pharmaceutically acceptable salt

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IA1c) Thing and its pharmaceutically acceptable salt

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IA1d) Thing and its pharmaceutically acceptable salt

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IA1e) Thing and its pharmaceutically acceptable salt

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IA1f) Thing and its pharmaceutically acceptable salt

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IA1g) Thing and its pharmaceutically acceptable salt

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IA1h) Thing and its pharmaceutically acceptable salt

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IA1i) Thing and its pharmaceutically acceptable salt

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

R₁To be monosubstituted or polysubstituted, selected from hydrogen, halogen, C_1-6Alkyl, C_1-6Alkoxy, cyano group, trifluoromethyl, nitro, Hydroxyl, amino, carboxyl, C_1-6Alkoxy acyl；Wherein described is monosubstituted monosubstituted selected from ortho position, meta, contraposition；Described is more Substitution is selected from two substitutions, three substitutions, four substitutions, five substitutions；

R₁' it is selected from hydrogen, halogen, C_1-6Alkyl, C_1-6Alkoxy.

It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IA1j) Thing and its pharmaceutically acceptable salt

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

R₁" it is selected from C_1-6Alkyl, phenyl.

It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IA2) Thing and its pharmaceutically acceptable salt

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

R₂To be monosubstituted or polysubstituted, selected from hydrogen, halogen, C_1-6Alkyl, C_1-6Alkoxy, cyano group, trifluoromethyl, nitro, Hydroxyl, amino, carboxyl, C_1-6Alkoxy acyl；The wherein described monosubstituted ortho position selected from amide groups, meta are monosubstituted；Described It is polysubstituted to be selected from two substitutions, three substitutions, four substitutions.

It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IA2 ') Thing and its pharmaceutically acceptable salt

X is selected from substituted or unsubstituted C_1-6Alkyl；Wherein described substituent is optionally by following substituent group：OH、C_1-6 Alkyl, C_1-6Alkoxy, halogen, NH₂、NO₂, cyano group, carboxyl, phenyl, C_1-6Unsaturated alkyl, C_3-6Cycloalkyl, C_1-6Alcoxyl acyl Base；

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IA2a) Thing and its pharmaceutically acceptable salt

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IA2b) Thing and its pharmaceutically acceptable salt

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IA2c) Thing and its pharmaceutically acceptable salt

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

R₂To be monosubstituted or polysubstituted, selected from hydrogen, halogen, C_1-6Alkyl, C_1-6Alkoxy, cyano group, trifluoromethyl, nitro, Hydroxyl, amino, carboxyl, C_1-6Alkoxy acyl；The wherein described monosubstituted ortho position selected from amide groups, meta are monosubstituted；It is described It is polysubstituted be selected from two substitutions, three substitution, four substitutions.

It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IA2d) Thing and its pharmaceutically acceptable salt

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IA2e) Thing and its pharmaceutically acceptable salt

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IA3) Thing and its pharmaceutically acceptable salt

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

R₂To be monosubstituted or polysubstituted, selected from hydrogen, halogen, C_1-6Alkyl, C_1-6Alkoxy, cyano group, trifluoromethyl, nitro, Hydroxyl, amino, carboxyl, C_1-6Alkoxy acyl；The wherein described monosubstituted ortho position selected from amide groups, meta, align it is monosubstituted； It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions.

It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IA4) Thing and its pharmaceutically acceptable salt

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to compound shown in formula (IB) And its pharmaceutically acceptable salt

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to compound shown in formula (IC) And its pharmaceutically acceptable salt

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

Technical solution of the present invention second aspect is to provide the preparation method of compound described in first aspect, its can by with Lower step and method synthesis is obtained：

Wherein R, n, Y, Z definition is as described in the first aspect of the invention

Substituted 3- indole-carboxylic acids (formula 1) carry out amidation process with various amine and obtain formula 2, during formula 2 is obtained by reduction Mesosome formula 3；Substituted indoles (formula 4) obtains formula 5 with acyl chloride reaction, then obtains formula 6 from different amine progress amidation process, then Formula 7 is obtained by reduction；Intermediate formula 3 and formula 7 obtain object formula 8 through peroxidating and N- substitutions, then through indoles 2- take In generation, obtains object formula 9.

The third aspect of technical solution of the present invention, which is to provide, contains compound described in first aspect and its pharmaceutically acceptable Salt pharmaceutical composition, indole derivatives of the invention and its pharmaceutically may be used that the pharmaceutical composition contains therapeutically effective amount The salt of receiving, and optional contain pharmaceutical carrier.Wherein described pharmaceutical carrier refers to the conventional pharmaceutical carrier of pharmaceutical field；Should Pharmaceutical composition can be prepared according to method well known in the art.Can be by by the compounds of this invention and its pharmaceutically acceptable salt Combined with one or more pharmaceutically acceptable solids or liquid excipient and/or assistant agent, be made and used suitable for human or animal Any formulation.The content of the compounds of this invention and its pharmaceutically acceptable salt in its pharmaceutical composition is usually 0.1- 95% percentage by weight.

The compounds of this invention and its pharmaceutically acceptable salt or pharmaceutical composition containing it can be in a unit Administration, method of administration can be enteron aisle or non-bowel, and such as oral, intravenous injection, intramuscular injection, hypodermic injection, nasal cavity, oral cavity are glued Film, eye, lung and respiratory tract, skin, vagina, rectum etc..

Form of administration can be liquid dosage form, solid dosage forms or semisolid dosage form.Liquid dosage form can be solution (including True solution and colloidal solution), emulsion (including o/w types, w/o types and emulsion), supensoid agent, injection (including liquid drugs injection, powder-injection And transfusion), eye drops, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet (including ordinary tablet, enteric coatel tablets, lozenge, Dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet), capsule (including hard shell capsules, soft capsule, capsulae enterosolubilis), granule, dissipate Agent, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, spray etc.；Semisolid dosage form can be ointment, gel Agent, paste etc..

It is sustained release preparation, control that the compounds of this invention and its pharmaceutically acceptable salt, which can be made ordinary preparation, also be made, Release formulation, targeting preparation and various particulate delivery systems.

In order to which the compounds of this invention and its pharmaceutically acceptable salt are made into tablet, it can widely use known in this field Various excipient, including diluent, binder, wetting agent, disintegrant, lubricant, glidant.Diluent can be starch, Dextrin, sucrose, glucose, lactose, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate Deng；Wetting agent can be water, ethanol, isopropanol etc.；Adhesive can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline cellulose, mucialga of arabic gummy, gelatine size, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl Cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrant can be dried starch, crystallite fibre Tie up element, low-substituted hydroxypropyl cellulose, PVPP, Ac-Di-Sol, sodium carboxymethyl starch, carbon Sour hydrogen sodium and citric acid, polyoxyethylene sorbitol fatty acid ester, dodecyl sodium sulfate etc.；Lubricant and glidant can be Talcum powder, silica, stearate, tartaric acid, atoleine, polyethylene glycol etc..

Tablet can also be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets, or double Synusia and multilayer tablet.

, can be by active ingredient the compounds of this invention and its pharmaceutically acceptable in order to which administration unit is made into capsule Salt is mixed with diluent, glidant, and mixture is placed directly within hard shell capsules or soft capsule.Also can be by the active ingredient present inventionization Compound and its pharmaceutically acceptable salt are first made particle or micropill with diluent, binder, disintegrant, then be placed in hard shell capsules or In soft capsule.Each diluent, binder, wetting for preparing the compounds of this invention and its pharmaceutically acceptable salt tablet Agent, disintegrant, glidant kind can also be used for preparing the capsule of the compounds of this invention and its pharmaceutically acceptable salt.

For the compounds of this invention and its pharmaceutically acceptable salt are made into injection, can with water, ethanol, isopropanol, Propane diols or their mixture as solvent simultaneously add appropriate solubilizer commonly used in the art, cosolvent, pH adjustments agent, osmotic pressure Conditioning agent.Solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin etc.；PH adjustment agent can be phosphorus Hydrochlorate, acetate, hydrochloric acid, sodium hydroxide etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, vinegar Hydrochlorate etc..Freeze drying powder injection is such as prepared, mannitol, glucose etc. can be also added as proppant.

In addition, if desired, colouring agent, preservative, spices, flavouring or other additions can also be added into pharmaceutical preparation Agent.

To reach medication purpose, strengthen therapeutic effect, medicine of the invention or pharmaceutical composition known can be given with any Prescription method is administered.

Therefore, exist it is a further object of the present invention to provide indole derivatives of the present invention and its pharmaceutically acceptable salt Application in pharmacy and field of health care products, particularly indole derivatives and its pharmaceutically acceptable salt of the present invention are preparing use Application in antiviral drug, indole derivatives of the invention and its pharmaceutically acceptable salt, which can be used for preparing, treats The medicine and health products of the disease as caused by virus, particularly anti HIV-1 virus and resisiting influenza virus.

It is used to treat by the composition of the indole derivatives and its pharmaceutically acceptable salt of the present invention or the present invention During above-mentioned disease, its dosage can refer to consumption when being treated using indole derivatives；By the present invention indoles Derivative or the composition of the present invention are used as health products, or when being added into health products, its consumption should be less than common therapeutic dose.

Present inventor has performed substantial amounts of drug study, it was demonstrated that the indole derivatives of the present invention, which have, suppresses HIV diseases The effect that poison and resisiting influenza virus are replicated, has good treatment to the disease as caused by inhibition of HIV and resisiting influenza virus Effect, and can be used as or add health products, be conducive to improving health, improve immunity.

The dosage of the compounds of this invention pharmaceutical composition is according to the property and serious journey to be prevented or treated disease The individual instances of degree, patient or animal, method of administration and formulation etc. can have large-scale change.In general, the present inventionization The daily Suitable dosage ranges of compound are 0.001-150mg/Kg body weight, preferably 0.1-100mg/Kg body weight, are more preferably 1-60mg/Kg body weight, most preferably 2-30mg/Kg body weight.Above-mentioned dosage with a dosage unit or can be divided into several dosage lists Position administration, this depends on the clinical experience of doctor and including the dosage regimen with other treatment means.

The compound or composition of the present invention can individually be taken, or merge with other treatment medicine or symptomatic drugs and use. When the compound of the present invention exists with other medicines to act synergistically, its dosage should be adjusted according to actual conditions.

The fourth aspect of technical solution of the present invention is to provide compound described in first aspect and its pharmaceutically acceptable salt With application of the third aspect described pharmaceutical composition in inverase or health products is prepared.

5th aspect of technical solution of the present invention is to provide compound described in first aspect and its pharmaceutically acceptable salt With application of the third aspect described pharmaceutical composition in anti-influenza virus medicament or health products is prepared.

Detailed description of the invention：

It is further described to various aspects of the present invention with feature below.

All documents recited in the present invention, their full content is incorporated herein by reference, and if these are literary Offer expressed implication with it is of the invention inconsistent when, be defined by the statement of the present invention.In addition, the various terms that use of the present invention and Phrase has well known to a person skilled in the art general sense, nonetheless, the present invention remain desirable at this to these terms and Phrase is described in more detail and explained that the term and phrase referred to is if any inconsistent with common art-recognized meanings, with institute's table of the present invention The implication stated is defined.Here is the definition of a variety of terms used in the present invention, and these definition are suitable for the application entire disclosure Term used, unless otherwise indicated in concrete condition.

As mentioned by the present invention, term " halogen ", " halogen ", " halogen atom ", " halo " etc. represent fluorine, chlorine, bromine or iodine, It is preferred that chlorine or bromine.

The definition of the various groups of the compounds of this invention presented below, in addition to separately defining, they will in specification and right Ask in book and uniformly use.

As mentioned by the present invention, term " alkyl " refers to that it can be straight with the alkyl for specifying number carbon number The alkyl of chain or the side chain, " C for example referred to_1-6During alkyl ", it refers to the alkyl that carbon number is 1,2,3,4,5,6, can include C_1-5Alkyl, C_1-4Alkyl, C_2-5Alkyl, C_2-4Alkyl, C_2-3Alkyl, C_3-5The group of the subrange of the expressions such as alkyl, and preferably Specific group such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, the tert-butyl group；As mentioned by the present invention, Term " C_1-16Alkyl ", it refers to the alkyl that carbon number is 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16, can With including C_1-10Alkyl, C_1-6Alkyl, C_2-10Alkyl, C_2-6Alkyl, C_3-4The group of the subrange of the expressions such as alkyl, and preferred Specific group such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, the tert-butyl group, n-pentyl, isopentyl；

As mentioned by the present invention, term " C_3-6Cycloalkyl ", it refers to the cycloalkyl that carbon number is 3,4,5,6, can wrapped Include C_3-5Cycloalkyl, C_3-4Cycloalkyl, C_4-6Cycloalkyl, C_4-5Cycloalkyl, C_5-6Cycloalkyl, etc. the subrange of expression group, and It is preferred that specific group such as cyclopropane base, pentamethylene base and cyclohexyl.

As mentioned by the present invention, term " C_1-6Alkoxy ", it refers to the alkoxy that carbon number is 1,2,3,4,5,6, can With including C_1-5Alkoxy, C_1-3Alkoxy, C_2-5Alkoxy, C_2-3Alkoxy, C_3-4The group of the subrange of the expressions such as alkoxy, And specific group preferably such as methoxyl group, ethyoxyl, n-propyl epoxide, isopropyl epoxide, normal-butyl epoxide, sec-butyl oxygen Base, tert-butyl group epoxide；

As mentioned by the present invention, term " C_1-6Alkanoyl ", it refers to the alkanoyl that carbon number is 1,2,3,4,5,6, can With including C_1-5Alkanoyl, C_1-3Alkanoyl, C_2-4Alkanoyl, C_2-3Alkanoyl, C_3-4The group of the subrange of the expressions such as alkanoyl, And specific group preferably such as formoxyl, acetyl group, positive propiono, iso-propionyl, positive bytyry, secondary bytyry, tertiary fourth Acyl group；

As mentioned by the present invention, term " C_1-6Alkoxy acyl ", it refers to the alcoxyl acyl that carbon number is 1,2,3,4,5,6 Base, can include C_1-5Alkoxy acyl, C_1-3Alkoxy acyl, C_2-5Alkoxy acyl, C_2-3Alkoxy acyl, C_3-4Alkoxy acyl etc. is represented Subrange group, and preferred specific group such as methoxy acyl group, ethoxy acyl group；

As mentioned by the present invention, term " C_1-6Unsaturated alkyl ", it refers to the insatiable hunger that carbon number is 1,2,3,4,5,6 And alkyl, C can be included_1-5Unsaturated alkyl, C_1-4Unsaturated alkyl, C_2-5Unsaturated alkyl, C_2-4Unsaturated alkane The group of the subrange of the expressions such as base, and preferred specific group for example vinyl, acetenyl, isopropenyl, isopropynyl, Isobutenyl, isopentene group, 1,4- dibutene bases；

As mentioned by the present invention, pyridine radicals is with 2,3,4 linked with parent nucleus, preferably 4 are connected with parent nucleus.

Advantageous effects：

The present inventor passes through the side of activity tracking during the study of active components to traditional Chinese medicine Radix Isatidis Method isolated methyl -2- [2- (1- methoxies that there is notable anti HIV-1 virus and resisiting influenza virus to act on from Radix Isatidis Base -1H- indol-3-yls) acetamide] benzoic ether.Carried out on this basis methyl -2- [2- (1- methoxyl group -1H- indoles - 3- yls) acetamide] benzoic ether synthesis and derivatization modification, and the antiviral activity of this kind of compound has been carried out further Evaluation, confirm the effect of their anti HIV-1 virus and resisiting influenza virus, such compound is to wild and resistance HIV diseases Poison and influenza virus, which are replicated, has strong inhibitory activity.Wherein to the IC of inhibition of HIV inhibitory activity highest compound₅₀Value can be with 0.01 μM is reached, and such compound also has preferable activity to NVP and efavirenz drug-resistant type inhibition of HIV；Convection current The IC of Influenza Virus A/Puerto Rico/8/1934 (H1N1) inhibitory activity highest compound₅₀Value can reach 1.9 μM, be better than Clinical first-line drug Ribavirin, in anti-influenza A virus A/ Hubei Hong Shan/50/2005 (H1N1), A type A/ capital anti-262/ 95 (H1N1), A type A/ capital prevent/359/95 (H3N2) and B-mode B/ Jiangxi it is newly-built/BV/39/2008 infection activities in terms of be better than face Bed first-line drug Tamiflu.

Embodiment

The following examples can further illustrate the present invention, but do not limit the invention in any way.

Embodiment 1：The preparation of 2- (1- hydroxyl -1H- indol-3-yls)-N- phenyl acetamides

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；Aniline (0.62g) is added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N hydrochloric acid fast Speed stirring 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of organic phase is removed under reduced pressure Solvent, obtains pale red crude brown oil 2- (1H- indol-3-yls)-N- phenyl acetamides.

Second step, 2- (1H- indol-3-yls)-N- phenyl acetamides are dissolved in trifluoroacetic acid (10mL), add triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), saturated sodium bicarbonate aqueous solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic phase, add saturation food Salt solution (30mL) stirs 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil crude product 2- (indoles Quinoline -3- bases)-N- phenyl acetamides.

3rd step, 2- (indoline -3- bases)-N- phenyl acetamides are dissolved in (50mL) methanol, are cooled to 15~20 DEG C of stirrings, plus Enter in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise, completion of dropping, 15~20 DEG C of reaction 1h；Add Dichloromethane (200mL), water (200mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with dichloromethane (100mL × 2), is closed And organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Organic phase through pillar layer separation, with ethyl acetate- Petroleum ether (1:5) elute, obtain yellow gum thing 2- (1- hydroxyl -1H- indol-3-yls)-N- phenyl acetamides (0.64g).¹H NMR(400MHz,acetone-d₆):δ10.26(1H,s,N-H),9.31(1H,s,N-OH),7.69(3H,m,H-4,2’,6’), 7.50 (1H, d, J=8.0Hz, H-7), 7.41 (1H, s, H-2), 7.28 (3H, m, H-6,3 ', 5 '), 7.11 (2H, m, H-5, 4’),3.87(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ170.7(C-9),139.9(C-1’),134.9(C- 7a),129.41(C-3’),129.37(C-5’),125.3(C-2),124.5(C-3a),124.3(C-6),122.6(C-4’), 120.3(C-2’),120.2(C-6’),119.8(C-5),119.6(C-4),109.1(C-7),104.9(C-3),34.6(C- 8)；(+)-HR-ESIMS m/z 267.1136[M+H]⁺(calcd for C₁₆H₁₄N₂O₂,267.1089)。

Embodiment 2：The preparation of ethyl -2- [2- (1- hydroxyl -1H- indol-3-yls) acetamide] benzoic ether

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；Ethyl o-aminobenzoate (1.09g) is added, reaction 3h is stirred at room temperature in DMAP (0.15g)； Add 2N hydrochloric acid and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；Organic phase 40 DEG C of removal of solvent under reduced pressure, obtain pale red crude brown oil ethyl -2- [2- (1H- indol-3-yls) acetamide] benzoic acid Ester.

Second step, ethyl -2- [2- (1H- indol-3-yls) acetamide] benzoic ether is dissolved in trifluoroacetic acid (10mL), plus Enter triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), unsaturated carbonate Hydrogen sodium water solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic phase, Add saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil thick Product ethyl -2- [2- (indoline -3- bases) acetamide] benzoic ether.

3rd step, ethyl -2- [2- (indoline -3- bases) acetamide] benzoic ether is dissolved in (50mL) methanol, is cooled to 15 ~20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL), completion of dropping, 15~20 are added dropwise DEG C reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) are extracted, and merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Organic phase is through column chromatography Separation, with ethyl acetate-light petrol (1:5) elute, obtain yellow gum thing ethyl -2- [2- (1- hydroxyl -1H- indol-3-yls) Acetamide] benzoic ether (0.71g).¹H NMR(400MHz,acetone-d₆):δ10.99(1H,brs,N-H),10.21(1H, S, N-OH), 8.71 (1H, d, J=8.4Hz, H-3 '), 7.95 (1H, d, J=8.0Hz, H-6 '), 7.59 (1H, d, J=8.0Hz, H-4), 7.53 (1H, t, J=7.6Hz, H-4 '), 7.48 (1H, s, H-2), 7.42 (1H, d, J=8.0Hz, H-7), 7.17 (1H, T, J=7.6Hz, H-6), 7.05 (2H, m, H-5,5 '), 4.22 (2H, q, H-8 '), 3.86 (2H, s, H-8), 1.28 (3H, t, H- 9’)；¹³C NMR(400MHz,acetone-d₆):δ170.8(C-9),168.2(C-7’),142.4(C-2’),134.9(C-4’, 7a),131.5(C-6’),125.8(C-2),124.7(C-3a),123.1(C-6),122.8(C-4’),120.7(C-5), 120.0(C-3’),119.6(C-4),116.4(C-1’),109.2(C-7),104.2(C-3),61.9(C-8’),35.8(C- 8),14.3(C-9’)；(+)-HR-ESIMS m/z 339.1353[M+H]⁺(calcd for C₁₉H₁₈N₂O₄,339.1300)。

Embodiment 3：The preparation of methyl -3- [2- (1- hydroxyl -1H- indol-3-yls) acetamide] -4- methyl benzoic acid esters

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；4- methyl -3- amino-benzoic acid methyl esters (1.09g) are added, DMAP (0.15g) is stirred at room temperature React 3h；Add 2N hydrochloric acid and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase； 40 DEG C of removal of solvent under reduced pressure of organic phase, obtain pale red crude brown oil methyl -3- [2- (1H- indol-3-yls) acetamide] - 4- methyl benzoic acid esters.

Second step, methyl -3- [2- (1H- indol-3-yls) acetamide] -4- methyl benzoic acid esters are dissolved in trifluoroacetic acid In (10mL), triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h are added；Reaction solution recycling design, adds ethyl acetate (30mL), saturated sodium bicarbonate aqueous solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), Split-phase；Merge organic phase, add saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, are obtained To dark brown oil crude product methyl -3- [2- (indoline -3- bases) acetamide] -4- methyl benzoic acid esters.

3rd step, methyl -3- [2- (indoline -3- bases) acetamide] -4- methyl benzoic acid esters are dissolved in (50mL) methanol, drop Temperature adds in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise to 15~20 DEG C of stirrings, completion of dropping, 15~20 DEG C of reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane Alkane (100mL × 2) is extracted, and merges organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Organic phase is through post color Spectrum separation, with ethyl acetate-light petrol (1:5) elute, obtain yellow gum thing methyl -3- [2- (1- hydroxyl -1H- indoles -3- Base) acetamide] -4- methyl benzoic acid esters (0.69g).¹H NMR(400MHz,acetone-d₆):δ10.27(1H,brs,N-H), 8.53(1H,s,N-OH),8.34(1H,s,H-2’),7.63(2H,m,H-4,5’),7.41(2H,m,H-2,7),7.18(2H,m, H-6,6 '), 7.04 (1H, t, J=7.2Hz, H-5), 3.85 (2H, s, H-8), 3.82 (3H, s, H-8 '), 2.04 (3H, s, H- 9’)；¹³C NMR(400MHz,acetone-d₆):δ170.8(C-9),166.9(C-7’),137.4(C-3’),136.8(C- 4’),135.0(C-7a),131.2(C-6’),129.1(C-1’),126.5(C-5’),125.6(C-2’),125.3(C-2), 124.4(C-3a),122.8(C-6),120.0(C-5),119.6(C-4),109.2(C-7),104.7(C-3),52.2(C- 8’),34.1(C-8),17.9(C-9’)；(+)-HR-ESIMS m/z 339.1353[M+H]⁺(calcd for C₁₉H₁₈N₂O₄, 339.1300)。

Embodiment 4：The preparation of 2- (1- hydroxyl -1H- indol-3-yls)-N- (4- methoxyl group -2- aminomethyl phenyls) acetamide

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；3- methyl -4- aminoanisoles (0.9g) are added, reaction is stirred at room temperature in DMAP (0.15g) 3h；Add 2N hydrochloric acid and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；It is organic 40 DEG C of removal of solvent under reduced pressure of phase, obtain rufous grease crude product 2- (1H- indol-3-yls)-N- (4- methoxyl group -2- methylbenzenes Base) acetamide.

Second step, 2- (1H- indol-3-yls)-N- (4- methoxyl group -2- aminomethyl phenyls) acetamide is dissolved in trifluoroacetic acid In (10mL), triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h are added；Reaction solution recycling design, adds ethyl acetate (30mL), saturated sodium bicarbonate aqueous solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), Split-phase；Merge organic phase, add saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, are obtained To dark brown oil crude product 2- (indoline -3- bases)-N- (4- methoxyl group -2- aminomethyl phenyls) acetamide.

3rd step, 2- (indoline -3- bases)-N- (4- methoxyl group -2- aminomethyl phenyls) acetamide is dissolved in (50mL) methanol, drop Temperature adds in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise to 15~20 DEG C of stirrings, completion of dropping, 15~20 DEG C of reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane Alkane (100mL × 2) is extracted, and merges organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Organic phase is through post color Spectrum separation, with ethyl acetate-light petrol (1:5) elute, obtain yellow gum thing 2- (1- hydroxyl -1H- indol-3-yls)-N- (4- Methoxyl group -2- aminomethyl phenyls) acetamide (0.8g).¹H NMR(400MHz,CD₃OD-d₄):δ 7.57 (1H, d, J=7.6Hz, H- 6 '), 7.34 (1H, d, J=8.0Hz, H-4), 7.25 (1H, s, H-2), 7.11 (2H, m, H-5,6 '), 7.00 (1H, t, J= 7.6Hz,H-6),6.64(2H,m,H-3’,5’),3.73(2H,s,H-8),3.66(3H,s,H-7’),1.96(3H,s,H-8’) ；¹³C NMR(400MHz,CD₃OD-d₄):δ173.7(C-9),159.4(C-4’),136.1(C-1’),135.6(C-7a), 129.7(C-2’),128.2(C-2),125.7(C-6’),124.8(C-3a),123.0(C-6),120.1(C-5),119.6(C- 4),116.6(C-5’),112.4(C-3’),109.4(C-7),104.8(C-3),55.7(C-8’),34.0(C-8),18.1(C- 7’)；(+)-HR-ESIMS m/z 311.1401[M+H]⁺(calcd for C₁₈H₁₈N₂O₃,311.1351)。

Embodiment 5：The preparation of N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；O-chloraniline (0.84g) is added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N salt Sour quick stirring 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of decompressions of organic phase Solvent is removed, pale red crude brown oil N- (2- chlorphenyls) -2- (1H- indol-3-yls) acetamide is obtained.

Second step, N- (2- chlorphenyls) -2- (1H- indol-3-yls) acetamide is dissolved in trifluoroacetic acid (10mL), adds three Ethylsilane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), saturated sodium bicarbonate The aqueous solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic phase, add Saturated aqueous common salt (30mL) stirs 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil crude product N- (2- chlorphenyls) -2- (indoline -3- bases) acetamide.

3rd step, N- (2- chlorphenyls) -2- (indoline -3- bases) acetamide is dissolved in (50mL) methanol, is cooled to 15~20 DEG C stirring, adds in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise, completion of dropping, and 15~20 DEG C anti- Answer 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase with dichloromethane (100mL × 2) extract, merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Organic phase is used through pillar layer separation Ethyl acetate-light petrol (1:5) elute, obtain yellow gum thing N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) second Acid amides (0.76g).¹H NMR(400MHz,acetone-d₆):δ 8.44 (1H, brs, N-H), 8.28 (1H, d, J=8.4Hz, H- 6 '), 7.64 (1H, d, J=8.0Hz, H-3 '), 7.51 (1H, s, H-2), 7.44 (1H, d, J=8.0Hz, H-4), 7.32 (1H, D, J=8.0Hz, H-7), 7.23 (2H, m, H-4 ', 5 '), 7.05 (2H, m, H-5,6), 3.91 (2H, s, H-8)；¹³C NMR (400MHz,acetone-d₆):δ170.2(C-9),136.1(C-1’),135.1(C-7a),129.8(C-3’),128.3(C- 5’),125.8(C-4’),125.5(C-2),124.5(C-3a),123.9(C-2’),123.0(C-6),122.8(C-6’), 120.2(C-5),119.6(C-4),109.3(C-7),104.4(C-3),34.6(C-8)；(+)-HR-ESIMS m/z 301.0746[M+H]⁺(calcd for C₁₆H₁₃ClN₂O₂,302.0636)。

Embodiment 6：The preparation of N- (4- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；Parachloroanilinum (0.84g) is added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N salt Sour quick stirring 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of decompressions of organic phase Solvent is removed, pale red crude brown oil N- (4- chlorphenyls) -2- (1H- indol-3-yls) acetamide is obtained.

Second step, N- (4- chlorphenyls) -2- (1H- indol-3-yls) acetamide is dissolved in trifluoroacetic acid (10mL), adds three Ethylsilane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), saturated sodium bicarbonate The aqueous solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic phase, add Saturated aqueous common salt (30mL) stirs 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil crude product N- (4- chlorphenyls) -2- (indoline -3- bases) acetamide.

3rd step, N- (4- chlorphenyls) -2- (indoline -3- bases) acetamide is dissolved in (50mL) methanol, is cooled to 15~20 DEG C stirring, adds in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise, completion of dropping, and 15~20 DEG C anti- Answer 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase with dichloromethane (100mL × 2) extract, merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Organic phase is used through pillar layer separation Ethyl acetate-light petrol (1:5) elute, obtain off-white powder N- (4- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) second Acid amides (0.79g).¹H NMR(300MHz,acetone-d₆):δ10.09(1H,brs,N-H),9.24(1H,s,N-OH),7.59 (3H, m, H-4,3 ', 5 '), 7.34 (2H, m, H-2,7), 7.23 (2H, d, J=8.7Hz, H-2 ', 6 '), 7.13 (1H, t, J= 7.5Hz, H-6), 6.98 (1H, t, J=7.5Hz, H-5), 3.75 (2H, s, H-8)；¹³C NMR(400MHz,acetone-d₆):δ 170.8(C-9),138.8(C-1’),134.9(C-7a),129.3(C-2’,6’),128.5(C-4’),125.3(C-6), 124.5(C-3a),122.6(C-2),121.7(C-3’,5’),119.8(C-5),119.6(C-4),109.1(C-7),104.6 (C-3),34.5(C-8)；(+)-HR-ESIMS m/z301.0746[M+H]⁺(calcd for C₁₆H₁₃ClN₂O₂, 302.0636)。

Embodiment 7：The preparation of 2- (1- hydroxyl -1H- indol-3-yls)-N- (4- nitrobenzophenones) acetamide

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；Paranitroanilinum (0.91g) is added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N Hydrochloric acid quickly stirs 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of organic phase subtracts Pressure removes solvent, obtains crude brown oil 2- (1H- indol-3-yls)-N- (4- nitrobenzophenones) acetamide.

Second step, 2- (1H- indol-3-yls)-N- (4- nitrobenzophenones) acetamide is dissolved in trifluoroacetic acid (10mL), is added Triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), unsaturated carbonate hydrogen Sodium water solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic phase, plus Enter saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil crude product 2- (indoline -3- bases)-N- (4- nitrobenzophenones) acetamide.

3rd step, 2- (indoline -3- bases)-N- (4- nitrobenzophenones) acetamide is dissolved in (50mL) methanol, it is cooled to 15~ 20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL), completion of dropping, 15~20 DEG C are added dropwise React 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) extract, merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Organic phase through pillar layer separation, With ethyl acetate-light petrol (1:3) elute, obtain yellow gum thing 2- (1- hydroxyl -1H- indol-3-yls)-N- (4- nitrobenzene Base) acetamide (0.72g).¹H NMR(400MHz,acetone-d₆):δ10.15(1H,brs,N-H),9.74(1H,s,N-OH), 8.16 (2H, d, J=8.8Hz, H-3 ', 5 '), 7.87 (2H, d, J=9.2Hz, H-2 ', 6 '), 7.61 (1H, d, J=8.0Hz, H- 4), 7.39 (2H, m, H-2,7), 7.17 (1H, t, J=7.6Hz, H-5), 3.87 (2H, s, H-8)；¹³C NMR(400MHz, acetone-d₆):δ171.1(C-9),146.2(C-4’),143.7(C-1’),135.0(C-7a),125.5(C-3’,5’), 125.4(C-3a),124.6(C-2),122.8(C-6),119.9(C-4),119.7(C-2’,6’),119.6(C-5),109.1 (C-7),104.4(C-3),34.8(C-8)；(+)-HR-ESIMS m/z 312.0993[M+H]⁺(calcd for C₁₆H₁₃N₃O₄,312.0940)。

Embodiment 8：The preparation of methyl -2- [3- (1- hydroxyl -1H- indol-3-yls) propionamide] benzoic ether

The first step, weighs indolepopionic acid (1.13g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；Methyl anthranilate (1g) is added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N hydrochloric acid quickly stirs 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of organic phase Removal of solvent under reduced pressure, obtains pale red crude brown oil methyl -2- [3- (1H- indol-3-yls) propionamide] benzoic ether.

Second step, methyl -2- [3- (1H- indol-3-yls) propionamide] benzoic ether is dissolved in trifluoroacetic acid (10mL), plus Enter triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), unsaturated carbonate Hydrogen sodium water solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic phase, Add saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil thick Product methyl -2- [3- (indoline -3- bases) propionamide] benzoic ether.

3rd step, methyl -2- [3- (indoline -3- bases) propionamide] benzoic ether is dissolved in (50mL) methanol, is cooled to 15 ~20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL), completion of dropping, 15~20 are added dropwise DEG C reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) are extracted, and merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Organic phase is through column chromatography Separation, with ethyl acetate-light petrol (1:5) elute, obtain yellow gum thing methyl -2- [3- (1- hydroxyl -1H- indol-3-yls) Propionamide] benzoic ether (0.62g).¹H NMR(400MHz,acetone-d₆):δ10.97(1H,brs,N-H),9.99(1H,s, N-OH), 8.72 (1H, d, J=8.4Hz, H-3 '), 8.00 (1H, d, J=8.0Hz, H-6 '), 7.59 (2H, m, H-4,4 '), 7.36 (1H, d, J=8.0Hz, H-7), 7.24 (1H, s, H-2), 7.13 (2H, m, H-5,6), 7.01 (1H, t, J=7.6Hz, H- 5 '), 3.89 (3H, s, H-8 '), 3.15 (2H, t, J=7.2Hz, H-8a), 2.82 (2H, t, J=7.2Hz, H-8)；¹³C NMR (400MHz,acetone-d₆):δ 171.7(C-9),169.1(C-7’),142.5(C-2’),135.2(C-4’),131.6(C- 6’),124.4(C-3a),124.0(C-2,7a),123.1(C-5’),122.5(C-5),120.9(C-3’),119.5(C-6), 119.4(C-4),115.9(C-1’),110.5(C-3),109.0(C-7),52.8(C-8’),39.7(C-8),21.3(C-8a)； (+)-HR-ESIMS m/z 339.1346[M+H]⁺(calcd for C₁₉H₁₈N₂O₄,339.1300)。

Embodiment 9：The preparation of methyl -2- [4- (1- hydroxyl -1H- indol-3-yls) butyramide] benzoic ether

The first step, weighs indolebutyric acid (1.22g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；Methyl anthranilate (1g) is added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N hydrochloric acid quickly stirs 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of organic phase Removal of solvent under reduced pressure, obtains pale red crude brown oil methyl -2- [4- (1H- indol-3-yls) butyramide] benzoic ether.

Second step, methyl -2- [4- (1H- indol-3-yls) butyramide] benzoic ether is dissolved in trifluoroacetic acid (10mL), plus Enter triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), unsaturated carbonate Hydrogen sodium water solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic phase, Add saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil thick Product methyl -2- [4- (indoline -3- bases) butyramide] benzoic ether.

3rd step, methyl -2- [4- (indoline -3- bases) butyramide] benzoic ether is dissolved in (50mL) methanol, is cooled to 15 ~20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL), completion of dropping, 15~20 are added dropwise DEG C reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) are extracted, and merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Organic phase is through column chromatography Separation, with ethyl acetate-light petrol (1:5) elute, obtain yellow gum thing methyl -2- [4- (1- hydroxyl -1H- indol-3-yls) Butyramide] benzoic ether (0.67g).¹H NMR(400MHz,acetone-d₆):δ10.97(1H,brs,N-H),10.00(1H, S, N-OH), 8.72 (1H, d, J=8.4Hz, H-3 '), 8.01 (1H, d, J=8.0Hz, H-6 '), 7.57 (2H, m, H-4,4 '), 7.38 (1H, d, J=8.0Hz, H-7), 7.22 (1H, s, H-2), 7.13 (2H, m, H-6,5 '), 7.01 (1H, t, J=7.2Hz, H-5), 3.90 (3H, s, H-8 '), 2.83 (2H, s, H-8b), 2.51 (2H, t, J=7.6Hz, H-8), 2.10 (2H, m, H-8a) ；¹³C NMR(400MHz,acetone-d₆):δ172.2(C-9),169.2(C-7’),142.6(C-2’),135.3(C-7a), 135.2(C-4’),131.6(C-6’),124.7(C-3a),124.0(C-2),123.0(C-5’),122.5(C-5),120.8 (C-3’),119.6(C-6),119.4(C-4),115.8(C-3),111.2(C-1’),109.0(C-7),52.8(C-8’), 38.3(C-8),26.8(C-8b),24.9(C-8a)；(+)-HR-ESIMS m/z 353.1508[M+H]⁺(calcd for C₂₀H₂₀N₂O₄,353.1457)。

Embodiment 10：The preparation of 2- (1- methoxyl group -1H- indol-3-yls)-N- phenyl acetamides

3rd step, 2- (indoline -3- bases)-N- phenyl acetamides are dissolved in (50mL) methanol, are cooled to 15~20 DEG C of stirrings, plus Enter in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise, completion of dropping, 15~20 DEG C of reaction 1h；Add Dichloromethane (200mL), water (200mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with dichloromethane (100mL × 2), is closed And organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing 2- (1- hydroxyl -1H- indoles -3- Base) dichloromethane of-N- phenyl acetamides mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain brown solid 2- (1- first Oxy-1 H- indol-3-yls)-N- phenyl acetamides (498mg).¹H NMR(400MHz,acetone-d₆):δ9.16(1H,brs, NH-1), 7.64 (3H, m, H-4,2 ', 6 '), 7.46 (1H, s, H-2), 7.42 (1H, d, J=8.4Hz, H-7), 7.23 (3H, m, H-6,3’,5’),7.04(2H,m,H-5,4’),4.05(3H,s,OMe-10),3.79(2H,s,H-8)；¹³C NMR(400MHz, acetone-d₆):δ169.9(C-9),140.4(C-1’),133.4(C-7a),129.4(C-3’,5’),124.9(C-3a), 124.1(C-2),123.4(C-6),123.2(C-4’),120.4(C-5),120.2(C-2’,6’),120.1(C-4),109.0 (C-7),106.6(C-3),66.1(C-10),34.6(C-8)；(+)-HR-ESIMS m/z 281.1287[M+H]⁺(calcd for C₁₇H₁₇N₂O₂,281.1285)。

Embodiment 11：The preparation of methyl 2- [2- (1- methoxyl group -1H- indol-3-yls) acetamide] benzoic ether

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；Methyl anthranilate (1g) is added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N hydrochloric acid quickly stirs 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of organic phase Removal of solvent under reduced pressure, obtains pale red crude brown oil methyl -2- [2- (1H- indol-3-yls) acetamide] benzoic ether.

Second step, methyl -2- [2- (1H- indol-3-yls) acetamide] benzoic ether is dissolved in trifluoroacetic acid (10mL), plus Enter triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), unsaturated carbonate Hydrogen sodium water solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic phase, Add saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil thick Product methyl -2- [2- (indoline -3- bases) acetamide] benzoic ether.

3rd step, methyl -2- [2- (indoline -3- bases) acetamide] benzoic ether is dissolved in (50mL) methanol, is cooled to 15 ~20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL), completion of dropping, 15~20 are added dropwise DEG C reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) are extracted, and merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing methyl- The dichloromethane of 2- [2- (1- hydroxyl -1H- indol-3-yls) acetamide] benzoic ether mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain pale yellow crystals methyl- 2- [2- (1- methoxyl group -1H- indol-3-yls) acetamide] benzoic ether (406mg).¹H NMR(400MHz,acetone-d₆):δ 10.92 (1H, brs, NH-1), 8.75 (1H, d, J=8.8Hz, H-3 '), 7.90 (1H, d, J=8.4Hz, H-6 '), 7.56 (3H, M, H-2,4,4 '), 7.46 (1H, d, J=8.4Hz, H-7), 7.21 (1H, t, J=7.6Hz, H-6), 7.06 (2H, m, H-5, 5’),4.19(3H,s,H-10),3.87(2H,s,H-8),3.72(3H,s,H-8’)；¹³C NMR(400MHz,acetone-d₆): δ170.7(C-9),168.7(C-7’),142.3(C-2’),135.0(C-4’),133.4(C-7a),131.5(C-6’),124.8 (C-2),124.2(C-3a),123.3(C-5’),123.1(C-6),120.6(C-4,3’),119.8(C-5),116.0(C- 1’),109.0(C-7),105.1(C-3),66.4(C-10),52.5(C-8’),35.6(C-8)；(+)-HR-ESIMS m/z 339.1342[M+H]⁺(calcd for C₁₉H₁₉N₂O₄,339.1339)。

Embodiment 12：The preparation of methyl 3- [2- (1- methoxyl group -1H- indol-3-yls) acetamide] benzoic ether

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；Gavaculine methyl esters (1g) is added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N hydrochloric acid quickly stirs 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of organic phase Removal of solvent under reduced pressure, obtains pale red crude brown oil methyl -3- [2- (1H- indol-3-yls) acetamide] benzoic ether.

Second step, methyl -3- [2- (1H- indol-3-yls) acetamide] benzoic ether is dissolved in trifluoroacetic acid (10mL), plus Enter triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), unsaturated carbonate Hydrogen sodium water solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic Phase, adds saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil Crude product methyl -3- [2- (indoline -3- bases) acetamide] benzoic ether.

3rd step, methyl -3- [2- (indoline -3- bases) acetamide] benzoic ether is dissolved in (50mL) methanol, is cooled to 15 ~20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL), completion of dropping, 15~20 are added dropwise DEG C reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) are extracted, and merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing methyl- The dichloromethane of 3- [2- (1- hydroxyl -1H- indol-3-yls) acetamide] benzoic ether mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain brown solid methyl- 3- [2- (1- methoxyl group -1H- indol-3-yls) acetamide] benzoic ether (435mg).¹H NMR(400MHz,acetone-d₆):δ 9.37 (1H, brs, NH-1), 8.29 (1H, s, H-2 '), 7.89 (1H, d, J=8.0Hz, H-4 '), 7.67 (2H, d, J= 7.6Hz, H-4,6 '), 7.48 (1H, s, H-2), 7.40 (2H, m, H-7,5 '), 7.21 (1H, t, J=7.6Hz, H-6), 7.06 (1H, t, J=7.6Hz, H-5), 4.09 (3H, s, OMe-10), 3.84 (3H, s, OMe-8 '), 3.83 (2H, s, H-8)；¹³C NMR (400MHz,acetone-d₆):δ170.2(C-9),167.0(C-7’),140.6(C-3’),133.4(C-7a),131.6(C- 1’),129.7(C-2’),124.9(C-6’),124.86(C-3a),124.4(C-2),123.5(C-6),123.2(C-5’), 120.9(C-4’),120.5(C-5),120.1(C-4),109.0(C-7),106.3(C-3),66.2(C-10),52.3(C- 8’),34.6(C-8)；(+)-HR-ESIMS m/z 339.1347[M+H]⁺(calcd for C₁₉H₁₉N₂O₄,339.1339)。

Embodiment 13：The preparation of methyl 4- [2- (1- methoxyl group -1H- indol-3-yls) acetamide] benzoic ether

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；Methyl p-aminobenzoate (1g) is added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N hydrochloric acid quickly stirs 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of organic phase Removal of solvent under reduced pressure, obtains pale red crude brown oil methyl -4- [2- (1H- indol-3-yls) acetamide] methyl benzoate.

Second step, methyl -4- [2- (1H- indol-3-yls) acetamide] methyl benzoate is dissolved in trifluoroacetic acid (10mL), Add triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), saturated carbon Sour hydrogen sodium water solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic Phase, adds saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil Crude product methyl -4- [2- (indoline -3- bases) acetamide] methyl benzoate.

3rd step, methyl -4- [2- (indoline -3- bases) acetamide] methyl benzoate is dissolved in (50mL) methanol, is cooled to 15~20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) are added dropwise, completion of dropping, 15~ 20 DEG C of reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) are extracted, and merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing methyl- The dichloromethane of 4- [2- (1- hydroxyl -1H- indol-3-yls) acetamide] methyl benzoate mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain light yellow solid methyl- 4- [2- (1- methoxyl group -1H- indol-3-yls) acetamide] methyl benzoate (500mg).¹H NMR(400MHz,acetone- d₆):δ 9.52 (1H, brs, NH-1), 7.92 (2H, d, J=8.4Hz, H-3 ', 5 '), 7.76 (2H, d, J=8.4Hz, H-2 ', 6 '), 7.65 (1H, d, J=8.0Hz, H-4), 7.46 (1H, s, H-2), 7.41 (1H, d, J=8.0Hz, H-7), 7.21 (1H, t, J=7.6Hz, H-6), 7.07 (1H, t, J=7.6, H-5), 4.06 (3H, s, OMe-10), 3.84 (2H, s, H-8), 3.83 (3H, s,OMe-8’)；¹³C NMR(400MHz,acetone-d₆):δ170.5(C-9),166.7(C-7’),144.5(C-4’),133.3 (C-7a),131.1(C-3’,5’),125.6(C-1’),124.8(C-3a),123.5(C-2),123.2(C-6),120.5(C- 5),120.1(C-4),119.3(C-2’,6’),109.0(C-7),106.1(C-3),66.1(C-10),52.0(C-8’),34.7 (C-8)；(+)-HR-ESIMS m/z 339.1344[M+H]⁺(calcd for C₁₉H₁₉N₂O₄,339.1339)。

Embodiment 14：The preparation of ethyl 2- [2- (1- methoxyl group -1H- indol-3-yls) acetamide] benzoic ether

3rd step, ethyl -2- [2- (indoline -3- bases) acetamide] benzoic ether is dissolved in (50mL) methanol, is cooled to 15 ~20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL), completion of dropping, 15~20 are added dropwise DEG C reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) are extracted, and merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing ethyl- The dichloromethane of 2- [2- (1- hydroxyl -1H- indol-3-yls) acetamide] benzoic ether mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain brown solid ethyl- 2- [2- (1- methoxyl group -1H- indol-3-yls) acetamide] benzoic ether (423mg).¹H NMR(400MHz,acetone-d₆): δ 11.00 (1H, brs, NH-1), 8.76 (1H, d, J=8.4Hz, H-3 '), 7.92 (1H, d, J=8.0Hz, H-6 '), 7.60 (1H, s, H-2), 7.59 (1H, d, J=9.2Hz, H-4), 7.53 (1H, t, J=8.0Hz, H-4 '), 7.46 (1H, d, J= 8.0Hz, H-7), 7.21 (1H, t, J=7.6Hz, H-6), 7.06 (2H, t, J=7.2Hz, H-5,5 '), 4.18 (5H, t, J= 10.0Hz,OMe-10,OCH₂CH₃), -8 ' 3.87 (2H, s, H-8), 1.25 (3H, t, J=6.8Hz, OCH₂CH₃-9’)；¹³C NMR (400MHz,acetone-d₆):δ170.7(C-9),168.2(C-7’),142.4(C-2’),134.9(C-4’),133.3(C- 7a),131.5(C-6’),124.8(C-3a),124.2(C-2),123.3(C-6),123.0(C-4’),120.6(C-5), 120.5(C-3’),119.8(C-4),116.2(C-1’),109.0(C-7),105.1(C-3),66.4(C-10),61.9(C- 8’),35.7(C-8),14.3(C-9’)；(+)-HR-ESIMS m/z 353.1504[M+H]⁺(calcd for C₂₀H₂₁N₂O₄, 353.1496)。

Embodiment 15：The preparation of methyl 3- [2- (1- methoxyl group -1H- indol-3-yls) acetamide] -4- methyl benzoic acid esters

3rd step, methyl -3- [2- (indoline -3- bases) acetamide] -4- methyl benzoic acid esters are dissolved in (50mL) methanol, drop Temperature adds in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise to 15~20 DEG C of stirrings, completion of dropping, 15~20 DEG C of reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane Alkane (100mL × 2) is extracted, and merges organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing first The dichloromethane of base -3- [2- (1- hydroxyl -1H- indol-3-yls) acetamide] -4- methyl benzoic acid esters mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain white solid methyl -3- [2- (1- methoxyl group -1H- indol-3-yls) acetamide] -4- methyl benzoic acid esters (500mg).¹H NMR(400MHz, acetone-d₆):δ 8.47 (1H, brs, NH-1), 8.39 (1H, s, H-2 '), 7.68 (1H, d, J=8.0Hz, H-5 '), 7.64 (1H, d, J=7.6Hz, H-4), 7.55 (1H, s, H-2), 7.45 (1H, d, J=8.0Hz, H-7), 7.23 (2H, t, J= 7.6Hz, H-6,6 '), 7.09 (1H, t, J=7.6Hz, H-5), 4.11 (3H, s, OMe-10), 3.87 (2H, s, H-8), 3.83 (3H,s,H-8’),2.11(3H,s,H-9’)；¹³C NMR(400MHz,acetone-d₆):δ170.0(C-9),167.0(C- 7’),137.8(C-3’),136.5(C-4’),133.4(C-7a),131.2(C-6’),129.3(C-5’),126.3(C-2’), 125.1(C-1’),124.8(C-3a),123.7(C-2),123.4(C-6),120.6(C-5),120.1(C-4),109.1(C- 7),106.4(C-3),66.2(C-10),52.2(C-8’),34.2(C-8),17.9(C-9’)；(+)-HR-ESIMS m/z 353.1503[M+H]⁺(calcd for C₂₀H₂₁N₂O₄,353.1496)。

Embodiment 16：The preparation of 2- (1- methoxyl group -1H- indol-3-yls)-N- (2- methoxyphenyls) acetamide

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；O-aminoanisole (0.81g) is added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N hydrochloric acid quickly stirs 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of organic phase Removal of solvent under reduced pressure, obtains pale red crude brown oil 2- (1H- indol-3-yls)-N- (2- methoxyphenyls) acetamide.

Second step, 2- (1H- indol-3-yls)-N- (2- methoxyphenyls) acetamide is dissolved in trifluoroacetic acid (10mL), plus Enter triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), unsaturated carbonate Hydrogen sodium water solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic phase, Add saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil thick Product 2- (indoline -3- bases)-N- (2- methoxyphenyls) acetamide.

3rd step, 2- (indoline -3- bases)-N- (2- methoxyphenyls) acetamide is dissolved in (50mL) methanol, is cooled to 15 ~20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL), completion of dropping, 15~20 are added dropwise DEG C reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) are extracted, and merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing 2- (1- Hydroxyl -1H- indol-3-yls) dichloromethane of-N- (2- methoxyphenyls) acetamide mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain orange jelly 2- (1- Methoxyl group -1H- indol-3-yls)-N- (2- methoxyphenyls) acetamide (654mg).¹H NMR(400MHz,acetone-d₆):δ 8.43 (1H, brs, NH-1), 8.33 (1H, d, J=7.6Hz, H-6 '), 7.67 (1H, d, J=7.6Hz, H-3 '), 7.56 (1H, S, H-2), 7.47 (1H, d, J=8.0Hz, H-4), 7.24 (1H, t, J=7.6Hz, H-5 '), 7.10 (1H, t, J=7.6Hz, H- 4 '), 6.96 (1H, t, J=8.0Hz, H-6), 6.87 (2H, m, H-5,7), 4.13 (3H, s, OMe-10), 3.86 (2H, s, H- 8),3.64(3H,s,OMe-7’)；¹³C NMR(400MHz,acetone-d₆):δ169.5(C-9),149.1(C-2’),133.4 (C-7a),129.1(C-1’),124.7(C-3a),124.2(C-2),123.7(C-6’),123.4(C-6),121.3(C-3’), 120.7(C-5),120.13(C-5’),120.09(C-4),111.2(C-4’),109.1(C-7),106.4(C-3),66.3(C- 10),56.0(C-7’),34.8(C-8)；(+)-HR-ESIMS m/z 311.1397[M+H]⁺(calcd for C₁₈H₁₉N₂O₃, 311.1396)。

Embodiment 17：The preparation of 2- (1- methoxyl group -1H- indol-3-yls)-N- (3- methoxyphenyls) acetamide

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；M-Anisidine (0.81g) is added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N hydrochloric acid quickly stirs 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of organic phase Removal of solvent under reduced pressure, obtains pale red crude brown oil 2- (1H- indol-3-yls)-N- (3- methoxyphenyls) acetamide.

Second step, 2- (1H- indol-3-yls)-N- (3- methoxyphenyls) acetamide is dissolved in trifluoroacetic acid (10mL), plus Enter triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), unsaturated carbonate Hydrogen sodium water solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic phase, Add saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil thick Product 2- (indoline -3- bases)-N- (3- methoxyphenyls) acetamide.

3rd step, 2- (indoline -3- bases)-N- (3- methoxyphenyls) acetamide is dissolved in (50mL) methanol, is cooled to 15 ~20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL), completion of dropping, 15~20 are added dropwise DEG C reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) are extracted, and merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing 2- (1- Hydroxyl -1H- indol-3-yls) dichloromethane of-N- (3- methoxyphenyls) acetamide mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain light brown jelly 2- (1- methoxyl group -1H- indol-3-yls)-N- (3- methoxyphenyls) acetamide (643mg).¹H NMR(400MHz,acetone- d₆):δ 9.30 (1H, brs, NH-1), 7.66 (1H, d, J=8.0Hz, H-6 '), 7.46 (1H, s, H-2), 7.41 (2H, d, J= 6.8Hz, H-4,7), 7.20 (1H, t, J=7.6Hz, H-6), 7.13 (2H, m, H-2 ', 5 '), 7.06 (1H, t, J=7.6Hz, H- 5), 6.59 (1H, d, J=6.8Hz, H-4 '), 4.08 (3H, s, OMe-10), 3.78 (2H, s, H-8), 3.72 (3H, s, OMe- 7’)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),160.9(C-3’),141.6(C-1’),133.3(C- 7a),130.1(C-6’),124.9(C-3a),123.4(C-6),123.1(C-2),120.4(C-5),120.2(C-4),112.3 (C-5’),109.5(C-7),108.9(C-4’),106.6(C-2’),105.9(C-3),66.1(C-10),55.4(C-7’), 34.6(C-8)；(+)-HR-ESIMS m/z 311.1399[M+H]⁺(calcd for C₁₈H₁₉N₂O₃,311.1396)。

Embodiment 18：The preparation of 2- (1- methoxyl group -1H- indol-3-yls)-N- (4- methoxyphenyls) acetamide

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；Paraphenetidine (0.81g) is added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N hydrochloric acid quickly stirs 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of organic phase Removal of solvent under reduced pressure, obtains pale red crude brown oil 2- (1H- indol-3-yls)-N- (4- methoxyphenyls) acetamide.

Second step, 2- (1H- indol-3-yls)-N- (4- methoxyphenyls) acetamide is dissolved in trifluoroacetic acid (10mL), plus Enter triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), unsaturated carbonate Hydrogen sodium water solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic phase, Add saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil thick Product 2- (indoline -3- bases)-N- (4- methoxyphenyls) acetamide.

3rd step, 2- (indoline -3- bases)-N- (4- methoxyphenyls) acetamide is dissolved in (50mL) methanol, is cooled to 15 ~20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL), completion of dropping, 15~20 are added dropwise DEG C reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) are extracted, and merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing 2- (1- Hydroxyl -1H- indol-3-yls) dichloromethane of-N- (4- methoxyphenyls) acetamide mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain light yellow solid 2- (1- Methoxyl group -1H- indol-3-yls)-N- (4- methoxyphenyls) acetamide (612mg).¹H NMR(400MHz,acetone-d₆):δ 9.02 (1H, brs, NH-1), 7.66 (1H, d, J=8.0Hz, H-4), 7.52 (2H, d, J=8.8Hz, H-2 ', 6 '), 7.45 (1H, s, H-2), 7.41 (1H, d, J=8.0Hz, H-7), 7.20 (1H, t, J=7.6Hz, H-6), 7.06 (1H, t, J= 7.6Hz, H-5), 6.82 (2H, d, J=8.8Hz, H-3 ', 5 '), 4.08 (3H, s, OMe-10), 3.75 (2H, s, H-8), 3.73 (3H,s,OMe-4’)；¹³C NMR(400MHz,acetone-d₆):δ169.5(C-9),156.7(C-4’),133.5(C-1’), 133.4(C-7a),124.9(C-3a),123.4(C-2),123.2(C-6),121.7(C-2’,6’),120.4(C-5),120.2 (C-4),114.5(C-3’,5’),108.9(C-7),106.7(C-3),66.1(C-10),55.6(C-7’),34.5(C-8)； (+)-HR-ESIMS m/z 311.1398[M+H]⁺(calcd for C₁₈H₁₉N₂O₃,311.1396)。

Embodiment 19：The system of 2- (1- methoxyl group -1H- indol-3-yls)-N- (4- methoxyl group -2- aminomethyl phenyls) acetamide It is standby

3rd step, 2- (indoline -3- bases)-N- (4- methoxyl group -2- aminomethyl phenyls) acetamide is dissolved in (50mL) methanol, drop Temperature adds in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise to 15~20 DEG C of stirrings, completion of dropping, 15~20 DEG C of reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane Alkane (100mL × 2) is extracted, and merges organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing 2- The dichloromethane of (1- hydroxyl -1H- indol-3-yls)-N- (4- methoxyl group -2- aminomethyl phenyls) acetamide mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain off-white powder 2- (1- Methoxyl group -1H- indol-3-yls)-N- (4- methoxyl group -2- aminomethyl phenyls) acetamide (408mg).¹H NMR(400MHz, acetone-d₆):δ 8.28 (1H, brs, NH-1), 7.69 (1H, d, J=6.8Hz, H-6 '), 7.53 (1H, s, H-2), 7.44 (2H,s,H-4,7),7.24(1H,s,H-6),7.10(1H,s,H-5),6.71(2H,s,H-3’,5’),4.11(3H,s,OMe- 10),3.81(2H,s,H-8),3.73(3H,s,H-7’),2.04(3H,s,H-8’)；¹³C NMR(400MHz,acetone-d₆): δ169.7(C-9),157.9(C-4’),133.7(C-1’),133.4(C-7a),130.5(C-2’),126.5(C-2),124.8 (C-3a),123.6(C-6’),123.3(C-6),120.5(C-5),120.2(C-4),116.2(C-5’),111.8(C-3’), 109.0(C-7),106.8(C-3),66.2(C-10),55.5(C-8’),34.1(C-8),18.1(C-7’)；(+)-HR-ESIMS m/z 325.1554[M+H]⁺(calcd for C₁₉H₂₁N₂O₃,325.1547)。

Embodiment 20：The preparation of N- (2- chlorphenyls) -2- (1- methoxyl group -1H- indol-3-yls) acetamide

3rd step, N- (2- chlorphenyls) -2- (indoline -3- bases) acetamide is dissolved in (50mL) methanol, is cooled to 15~20 DEG C stirring, adds in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise, completion of dropping, and 15~20 DEG C anti- Answer 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase with dichloromethane (100mL × 2) extract, merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing N- (2- chlorphenyls)- The dichloromethane of 2- (1- hydroxyl -1H- indol-3-yls) acetamide mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain khaki solid N- (2- Chlorphenyl) -2- (1- methoxyl group -1H- indol-3-yls) acetamide (414mg).¹H NMR(400MHz,acetone-d₆):δ8.46 (1H, brs, NH-1), 8.29 (1H, d, J=8.0Hz, H-6 '), 7.67 (1H, d, J=8.0Hz, H-3 '), 7.61 (1H, s, H- 2), 7.47 (1H, d, J=8.0Hz, H-4), 7.33 (1H, d, J=8.0Hz, H-7), 7.26 (2H, m, H-4 ', 5 '), 7.10 (1H, t, J=7.6Hz, H-6), 7.05 (1H, t, J=8.0Hz, H-5), 4.12 (3H, s, OMe-10), 3.925 (2H, s, H- 8)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),136.1(C-1’),133.4(C-7a),129.9(C-3’), 128.3(C-5’),125.5(C-4’),124.7(C-3a),123.9(C-2),123.5(C-6),122.9(C-2’,6’), 120.8(C-5),120.0(C-4),109.1(C-7),105.8(C-3),66.3(C-10),34.5(C-8)；(+)-HR-ESIMS m/z 315.0905[M+H]⁺(calcd for C₁₇H₁₆ClN₂O₂,315.0895)。

Embodiment 21：The preparation of N- (3- chlorphenyls) -2- (1- methoxyl group -1H- indol-3-yls) acetamide

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；M-chloroaniline (0.84g) is added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N salt Sour quick stirring 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of decompressions of organic phase Solvent is removed, pale red crude brown oil N- (3- chlorphenyls) -2- (1H- indol-3-yls) acetamide is obtained.

Second step, N- (3- chlorphenyls) -2- (1H- indol-3-yls) acetamide is dissolved in trifluoroacetic acid (10mL), adds three Ethylsilane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), saturated sodium bicarbonate The aqueous solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic phase, add Saturated aqueous common salt (30mL) stirs 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil crude product N- (3- chlorphenyls) -2- (indoline -3- bases) acetamide.

3rd step, N- (3- chlorphenyls) -2- (indoline -3- bases) acetamide is dissolved in (50mL) methanol, is cooled to 15~20 DEG C stirring, adds in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise, completion of dropping, and 15~20 DEG C anti- Answer 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase with dichloromethane (100mL × 2) extract, merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing N- (3- chlorphenyls)- The dichloromethane of 2- (1- hydroxyl -1H- indol-3-yls) acetamide mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain orange jelly N- (3- Chlorphenyl) -2- (1- methoxyl group -1H- indol-3-yls) acetamide (436mg).¹H NMR(400MHz,acetone-d₆):δ9.33 (1H, brs, NH-1), 7.89 (1H, s, H-2 '), 7.64 (1H, d, J=8.0Hz, H-6 '), 7.44 (3H, m, H-2,4,7), 7.26 (1H, t, J=8.0Hz, H-6), 7.21 (1H, t, J=8.0Hz, H-5 '), 7.06 (2H, m, H-5,4 '), 4.09 (3H, s, OMe-10),3.80(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ170.3(C-9),141.7(C-1’), 134.6(C-3’),133.3(C-7a),130.9(C-2’),124.8(C-3a),123.9(C-2),123.5(C-6’),123.2 (C-6),120.5(C-5),120.1(C-5’),119.9(C-4’),118.3(C-4),109.0(C-7),106.2(C-3), 66.2(C-10),34.6(C-8)；(+)-HR-ESIMS m/z 315.0897[M+H]⁺(calcd for C₁₇H₁₆ClN₂O₂, 315.0895)。

Embodiment 22：The preparation of N- (4- chlorphenyls) -2- (1- methoxyl group -1H- indol-3-yls) acetamide

3rd step, N- (4- chlorphenyls) -2- (indoline -3- bases) acetamide is dissolved in (50mL) methanol, is cooled to 15~20 DEG C stirring, adds in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise, completion of dropping, and 15~20 DEG C anti- Answer 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase with dichloromethane (100mL × 2) extract, merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing N- (4- chlorphenyls)- The dichloromethane of 2- (1- hydroxyl -1H- indol-3-yls) acetamide mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain light yellow solid N- (4- Chlorphenyl) -2- (1- methoxyl group -1H- indol-3-yls) acetamide (384mg).¹H NMR(400MHz,acetone-d₆):δ9.30 (1H, brs, NH-1), 7.65 (3H, d, J=8.4Hz, H-4,3 ', 5 '), 7.46 (1H, s, H-2), 7.41 (1H, d, J= 8.4Hz, H-7), 7.27 (2H, d, J=8.4Hz, H-2 ', 6 '), 7.21 (1H, t, J=7.6Hz, H-6), 7.06 (1H, t, J= 7.6Hz,H-5),4.08(3H,s,OMe-10),3.79(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ170.1 (C-9),139.2(C-1’),133.3(C-7a),129.3(C-2’,6’),128.4(C-4’),124.8(C-3a),123.5(C- 6),123.2(C-2),121.6(C-3’,5’), 120.5(C-5),120.1(C-4),109.0(C-7),106.3(C-3), 66.2(C-10),34.6(C-8)；(+)-HR-ESIMS m/z315.0905[M+H]⁺(calcd for C₁₇H₁₆ClN₂O₂, 315.0895)。

Embodiment 23：The preparation of 2- (1- methoxyl group -1H- indol-3-yls)-N- p-methylphenyl acetamides

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；4- methylanilines (0.71g) are added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N Hydrochloric acid quickly stirs 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of organic phase subtracts Pressure removes solvent, obtains yellow oil crude product 2- (1H- indol-3-yls)-N- p-methylphenyl acetamides.

Second step, 2- (1H- indol-3-yls)-N- p-methylphenyl acetamides are dissolved in trifluoroacetic acid (10mL), add three Ethylsilane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), saturated sodium bicarbonate The aqueous solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic phase, add Saturated aqueous common salt (30mL) stirs 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil crude product 2- (indoline -3- bases)-N- p-methylphenyl acetamides.

3rd step, 2- (indoline -3- bases)-N- p-methylphenyl acetamides are dissolved in (50mL) methanol, are cooled to 15~20 DEG C stirring, adds in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise, completion of dropping, and 15~20 DEG C anti- Answer 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase with dichloromethane (100mL × 2) extract, merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing 2- (1- hydroxyls -1H- Indol-3-yl) dichloromethane of-N- p-methylphenyl acetamides mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain yellow solid 2- (1- first Oxy-1 H- indol-3-yls)-N- p-methylphenyls acetamide (490mg).¹H NMR(400MHz,acetone-d₆):δ9.11 (1H, brs, NH-1), 7.66 (1H, d, J=8.0Hz, H-4), 7.51 (2H, d, J=8.4Hz, H-2 ', 6 '), 7.44 (1H, s, H-2), 7.41 (1H, d, J=8.4Hz, H-7), 7.21 (1H, t, J=8.0Hz, H-6), 7.06 (3H, t, H-5,3 ', 5 '), 4.06(3H,s,OMe-10),3.77(2H,s,H-8),2.24(3H,s,H-7’)；¹³C NMR(400MHz,acetone-d₆):δ 169.7(C-9),137.8(C-7a),133.3(C-1’),129.8(C-2’,6’),124.9(C-3a),123.4(C-6), 123.1(C-4’),120.4(C-5),120.2(C-3’,5’),108.9(C-7),106.7(C-3),66.1(C-10),34.6 (C-8),20.7(C-7’)；(+)-HR-ESIMS m/z 295.245[M+H]⁺(calcd for C₁₈H₁₉N₂O₂,295.1441)。

Embodiment 24：The preparation of N- (3,4- 3,5-dimethylphenyls) -2- (1- methoxyl group -1H- indol-3-yls) acetamide

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；3,4- dimethylanilines (0.8g) are added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N hydrochloric acid quickly stirs 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of organic phase Removal of solvent under reduced pressure, obtains yellow oil crude product N- (3,4- 3,5-dimethylphenyl) -2- (1H- indol-3-yls) acetamide.

Second step, N- (3,4- 3,5-dimethylphenyl) -2- (1H- indol-3-yls) acetamide is dissolved in trifluoroacetic acid (10mL), Add triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), saturated carbon Sour hydrogen sodium water solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic Phase, adds saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil Crude product N- (3,4- 3,5-dimethylphenyls) -2- (indoline -3- bases) acetamide.

3rd step, N- (3,4- 3,5-dimethylphenyl) -2- (indoline -3- bases) acetamide is dissolved in (50mL) methanol, is cooled to 15~20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) are added dropwise, completion of dropping, 15~ 20 DEG C of reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) are extracted, and merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing N- (3, 4- 3,5-dimethylphenyls) dichloromethane of -2- (1- hydroxyl -1H- indol-3-yls) acetamide mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain light brown jelly N- (3,4- 3,5-dimethylphenyls) -2- (1- methoxyl group -1H- indol-3-yls) acetamide (497mg).¹H NMR(400MHz, acetone-d₆):δ 8.99 (1H, brs, NH-1), 7.66 (1H, d, J=8.0Hz, H-4), 7.45 (1H, s, H-2), 7.41 (1H, d, J=8.0Hz, H-7), 7.38 (1H, s, H-2 '), 7.35 (1H, d, J=8.0Hz, H-6 '), 7.20 (1H, t, J= 7.6Hz, H-6), 7.06 (1H, t, J=7.6Hz, H-5), 6.99 (1H, d, J=8.0Hz, H-5 '), 4.08 (3H, s, OMe- 10),3.76(2H,s,H-8),2.16(3H,s,H-7’),2.15(3H,s,H-8’)；¹³C NMR(400MHz,acetone-d₆): δ169.6(C-9),138.1(C-1’),137.3(C-3’),133.4(C-7a),132.0(C-4’),130.4(C-5’),124.9 (C-3a),123.4(C-2),123.2(C-6),121.4(C-2’),120.4(C-5),120.2(C-6’),117.7(C-4), 108.9(C-7),106.7(C-3),66.1(C-10),34.6(C-8),19.9(C-7’),19.1(C-8’)；(+)-HR-ESIMS m/z 309.1601[M+H]⁺(calcd for C₁₉H₂₀N₂O₂,309.1598)。

Embodiment 25：The preparation of N- (3,5- 3,5-dimethylphenyls) -2- (1- methoxyl group -1H- indol-3-yls) acetamide

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；3,5- dimethylanilines (0.8g) are added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Plus Enter 2N hydrochloric acid and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；Organic phase 40 DEG C removal of solvent under reduced pressure, obtains yellow oil crude product N- (3,5- 3,5-dimethylphenyl) -2- (1H- indol-3-yls) acetamide.

Second step, N- (3,5- 3,5-dimethylphenyl) -2- (1H- indol-3-yls) acetamide is dissolved in trifluoroacetic acid (10mL), Add triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), saturated carbon Sour hydrogen sodium water solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic Phase, adds saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil Crude product N- (3,5- 3,5-dimethylphenyls) -2- (indoline -3- bases) acetamide.

3rd step, N- (3,5- 3,5-dimethylphenyl) -2- (indoline -3- bases) acetamide is dissolved in (50mL) methanol, is cooled to 15~20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) are added dropwise, completion of dropping, 15~ 20 DEG C of reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) are extracted, and merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing N- (3, 5- 3,5-dimethylphenyls) dichloromethane of -2- (1- hydroxyl -1H- indol-3-yls) acetamide mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain off-white powder N- (3, 5- 3,5-dimethylphenyls) -2- (1- methoxyl group -1H- indol-3-yls) acetamide (553mg).¹H NMR(400MHz,acetone- d₆):δ 9.00 (1H, brs, NH-1), 7.66 (1H, d, J=8.0Hz, H-4), 7.46 (1H, s, H-2), 7.41 (1H, d, J= 8.0Hz, H-7), 7.25 (2H, s, H-2 ', 6 '), 7.20 (1H, t, J=7.6Hz, H-6), 7.06 (1H, t, J=7.6Hz, H- 5),6.66(1H,s,H-4’),4.08(3H,s,OMe-10),3.77(2H,s,H-8),2.20(6H,s,H-7’,8’)；¹³C NMR (400MHz,acetone-d₆):δ169.7(C-9),140.2(C-1’),138.8(C-3’,5’),133.4(C-7a),125.7 (C-2),124.9(C-3a),123.4(C-5),123.2(C-4’),120.4(C-5),120.2(C-4),117.9(C-2’, 6’),108.9(C-7),106.7(C-3),66.1(C-10),34.7(C-8),21.4(C-7’,8’)；(+)-HR-ESIMS m/z 309.1608[M+H]⁺(calcd for C₁₉H₂₀N₂O₂,309.1598)。

Embodiment 26：The preparation of 2- (1- methoxyl group -1H- indol-3-yls)-N- o-methyl-benzene yl acetamides

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；2-aminotoluene (0.71g) is added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N Hydrochloric acid quickly stirs 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of organic phase subtracts Pressure removes solvent, obtains yellow oil crude product 2- (1H- indol-3-yls)-N- o-methyl-benzene yl acetamides.

Second step, 2- (1H- indol-3-yls)-N- o-methyl-benzene yl acetamides are dissolved in trifluoroacetic acid (10mL), add three Ethylsilane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), saturated sodium bicarbonate The aqueous solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic phase, plus Enter saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil crude product 2- (indoline -3- bases)-N- o-methyl-benzene yl acetamides.

3rd step, 2- (indoline -3- bases)-N- o-methyl-benzene yl acetamides are dissolved in (50mL) methanol, are cooled to 15~20 DEG C stirring, adds in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise, completion of dropping, and 15~20 DEG C anti- Answer 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase with dichloromethane (100mL × 2) extract, merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing 2- (1- hydroxyls -1H- Indol-3-yl) dichloromethane of-N- o-methyl-benzene yl acetamides mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain white solid 2- (1- first Oxy-1 H- indol-3-yls)-N- o-methyl-benzenes yl acetamide (354mg).¹H NMR(400MHz,acetone-d₆):δ8.33 (1H, brs, NH-1), 7.72 (1H, d, J=8.0Hz, H-6 '), 7.68 (1H, d, J=8.0Hz, H-4), 7.54 (1H, s, H- 2), 7.45 (1H, d, J=7.6Hz, H-7), 7.24 (1H, t, J=7.6Hz, H-6), 7.10 (3H, m, H-3 ', 4 ', 5 '), 6.99 (1H, t, J=7.6Hz, H-5), 4.10 (3H, s, OMe-10), 3.84 (2H, s, H-8), 2.01 (3H, s, H-7 ')；¹³C NMR (400MHz,acetone-d₆):δ169.7(C-9),137.6(C-1’),133.4(C-7a),131.0(C-6’),130.7(C- 2’),126.9(C-3’),125.4(C-5’),124.8(C-3a),124.1(C-2),123.6(C-4’),123.3(C-6), 120.6(C-5),120.1(C-4),109.0(C-7),106.6(C-3),66.2(C-10),34.3(C-8),17.7(C-7’)； (+)-HR-ESIMS m/z 295.1447[M+H]⁺(calcd for C₁₈H₁₉N₂O₂,295.1441)。

Embodiment 27：The preparation of 2- (1- methoxyl group -1H- indol-3-yls)-N- neighbour's ethylphenyl acetamides

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；2- MEAs (0.8g) are added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N salt Sour quick stirring 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of decompressions of organic phase Solvent is removed, the adjacent ethylphenyl acetamides of yellow oil crude product 2- (1H- indol-3-yls)-N- are obtained.

Second step, 2- (1H- indol-3-yls)-N- neighbour's ethylphenyl acetamides are dissolved in trifluoroacetic acid (10mL), add three Ethylsilane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), saturated sodium bicarbonate The aqueous solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic phase, add Saturated aqueous common salt (30mL) stirs 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil crude product 2- (indoline -3- bases)-N- neighbour's ethylphenyl acetamides.

3rd step, 2- (indoline -3- bases)-N- neighbour's ethylphenyl acetamides are dissolved in (50mL) methanol, are cooled to 15~20 DEG C stirring, adds in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise, completion of dropping, and 15~20 DEG C anti- Answer 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase with dichloromethane (100mL × 2) extract, merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing 2- (1- hydroxyls -1H- Indol-3-yl) dichloromethane of the adjacent ethylphenyl acetamides of-N- mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain off-white powder 2- (1- Methoxyl group -1H- indol-3-yls) the adjacent ethylphenyl acetamides (513mg) of-N-.¹H NMR(400MHz,acetone-d₆):δ8.20 (1H, brs, NH-1), 7.76 (1H, d, J=8.0Hz, H-6 '), 7.68 (1H, d, J=8.0Hz, H-4), 7.57 (1H, s, H- 2), 7.46 (1H, d, J=7.6Hz, H-7), 7.25 (1H, t, J=7.6Hz, H-6), 7.11 (3H, m, H-3 ', 4 ', 5 '), 7.03 (1H, t, J=6.8Hz, H-5), 4.12 (3H, s, OMe-10), 3.84 (2H, s, H-8), 2.33 (2H, q, J=7.6Hz, H- 7 '), 0.85 (3H, t, J=7.6Hz, H-8 ')；¹³C NMR(400MHz,acetone-d₆):δ169.8(C-9),136.8(C- 1’),136.4(C-2’),133.4(C-7a),129.4(C-5’),126.9(C-3’),125.7(C-4’),124.7(C-3a), 124.4(C-2),123.7(C-6’),123.5(C-6),120.7(C-5),120.1(C-4),109.1(C-7),106.5(C- 3),66.3(C-10),34.4(C-8),24.7(C-7’),14.3(C-8’)；(+)-HR-ESIMS m/z 309.1601[M+H]⁺ (calcd for C₁₉H₂₀N₂O₂,309.1598)。

Embodiment 28：The preparation of N- (2- fluorophenyls) -2- (1- methoxyl group -1H- indol-3-yls) acetamide

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；Adjacent fluoroaniline (0.73g) is added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N salt Sour quick stirring 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of decompressions of organic phase Solvent is removed, rufous grease crude product N- (2- fluorophenyls) -2- (1H- indol-3-yls) acetamide is obtained.

Second step, N- (2- fluorophenyls) -2- (1H- indol-3-yls) acetamide is dissolved in trifluoroacetic acid (10mL), adds three Ethylsilane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), saturated sodium bicarbonate The aqueous solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic phase, add Saturated aqueous common salt (30mL) stirs 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil crude product N- (2- fluorophenyls) -2- (indoline -3- bases) acetamide.

3rd step, N- (2- fluorophenyls) -2- (indoline -3- bases) acetamide is dissolved in (50mL) methanol, is cooled to 15~20 DEG C stirring, adds in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise, completion of dropping, and 15~20 DEG C anti- Answer 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase with dichloromethane (100mL × 2) extract, merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing N- (2- fluorophenyls)- The dichloromethane of 2- (1- hydroxyl -1H- indol-3-yls) acetamide mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain off-white color crystal N- (2- Fluorophenyl) -2- (1- methoxyl group -1H- indol-3-yls) acetamide (330mg).¹H NMR(400MHz,acetone-d₆):δ8.83 (1H, brs, NH-1), 8.22 (1H, t, J=8.0Hz, H-5 '), 7.68 (1H, d, J=8.0Hz, H-3 '), 7.52 (1H, s, H- 2), 7.44 (1H, d, J=8.0Hz, H-4), 7.22 (1H, t, J=7.6Hz, H-6), 7.09 (4H, m, H-7,4 ', 5 ', 6 '), 4.09(3H,s,OMe-10),3.91(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ170.1(C-9),133.4 (C-7a),125.2(C-1’),125.14(C-3’),125.09(C-2’),124.8(C-3a),123.5(C-2),123.4(C- 5’),123.3(C-6),120.5(C-5),120.1(C-4),115.8(C-4’),115.6(C-6’),109.0(C-7),106.3 (C-3),66.2(C-10),34.3(C-8)；(+)-HR-ESIMS m/z 299.1193[M+H]⁺(calcd for C₁₇H₁₆FN₂O₂,299.119)。

Embodiment 29：The preparation of N- (2- bromophenyls) -2- (1- methoxyl group -1H- indol-3-yls) acetamide

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；O-bromoaniline (1.2g) is added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N hydrochloric acid Quick stirring 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of decompressions of organic phase are removed Solvent is removed, rufous grease crude product N- (2- bromophenyls) -2- (1H- indol-3-yls) acetamide is obtained.

Second step, N- (2- bromophenyls) -2- (1H- indol-3-yls) acetamide is dissolved in trifluoroacetic acid (10mL), adds three Ethylsilane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), saturated sodium bicarbonate The aqueous solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic phase, add Saturated aqueous common salt (30mL) stirs 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil crude product N- (2- bromophenyls) -2- (indoline -3- bases) acetamide.

3rd step, N- (2- bromophenyls) -2- (indoline -3- bases) acetamide is dissolved in (50mL) methanol, is cooled to 15~20 DEG C stirring, adds in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise, completion of dropping, and 15~20 DEG C anti- Answer 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase with dichloromethane (100mL × 2) extract, merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing N- (2- bromophenyls)- The dichloromethane of 2- (1- hydroxyl -1H- indol-3-yls) acetamide mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain yellow solid N- (2- bromines Phenyl) -2- (1- methoxyl group -1H- indol-3-yls) acetamide (240mg).¹H NMR(400MHz,acetone-d₆):δ8.32 (1H, brs, NH-1), 8.27 (1H, d, J=8.0Hz, H-6 '), 7.66 (1H, d, J=8.0Hz, H-3 '), 7.64 (1H, s, H- 2), 7.49 (1H, d, J=7.6Hz, H-4), 7.47 (1H, d, J=8.0Hz, H-7), 7.32 (1H, t, J=8.0Hz, H-6), 7.25 (1H, t, J=7.6Hz, H-5 '), 7.10 (1H, t, J=7.6Hz, H-4 '), 6.99 (1H, t, J=8.0Hz, H-5), 4.13(3H,s,OMe-10),3.91(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),137.2 (C-1’),133.4(C-7a),133.2(C-5’),129.0(C-3’),126.0(C-6’),124.7(C-3a),124.0(C- 2),123.6(C-6),122.9(C-4’),120.9(C-5),120.0(C-4),114.2(C-2’),109.1(C-7),105.6 (C-3),66.4(C-10),34.6(C-8)；(+)-HR-ESIMS m/z359.0403[M+H]⁺(calcd for C₁₇H₁₅BrN₂O₂,359.039)。

Embodiment 30：The preparation of N- (2- iodophenyls) -2- (1- methoxyl group -1H- indol-3-yls) acetamide

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；Adjacent Iodoaniline (1.45g) is added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N salt Sour quick stirring 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of decompressions of organic phase Solvent is removed, crude brown oil N- (2- iodophenyls) -2- (1H- indol-3-yls) acetamide is obtained.

Second step, N- (2- iodophenyls) -2- (1H- indol-3-yls) acetamide is dissolved in trifluoroacetic acid (10mL), adds three Ethylsilane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), saturated sodium bicarbonate The aqueous solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic phase, add Saturated aqueous common salt (30mL) stirs 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil crude product N- (2- iodophenyls) -2- (indoline -3- bases) acetamide.

3rd step, N- (2- iodophenyls) -2- (indoline -3- bases) acetamide is dissolved in (50mL) methanol, is cooled to 15~20 DEG C stirring, adds in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise, completion of dropping, and 15~20 DEG C anti- Answer 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase with dichloromethane (100mL × 2) extract, merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing N- (2- iodophenyls)- The dichloromethane of 2- (1- hydroxyl -1H- indol-3-yls) acetamide mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain brown solid N- (2- Iodophenyl) -2- (1- methoxyl group -1H- indol-3-yls) acetamide (252mg).¹H NMR(400MHz,acetone-d₆):δ8.17 (1H, d, J=8.4Hz, H-6 '), 8.13 (1H, brs, NH-1), 7.72 (1H, d, J=7.6Hz, H-3 '), 7.65 (2H, d, J= 8.0Hz, H-2,4), 7.47 (1H, d, J=8.4Hz, H-7), 7.33 (1H, t, J=8.0Hz, H-4 '), 7.25 (1H, t, J= 8.0Hz, H-5 '), 7.10 (1H, t, J=7.6Hz, H-6), 6.83 (1H, t, J=7.6Hz, H-5), 4.14 (3H, s, OMe- 10),3.89(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),139.8(C-1’,5’), 133.5(C-7a),129.7(C-3’),126.7(C-4’),124.7(C-3a),124.2(C-2),123.6(C-6),122.7 (C-2’,6’),120.9(C-5),120.1(C-4),109.2(C-7),105.4(C-3),66.5(C-10),34.6(C-8)； (+)-HR-ESIMS m/z 407.0269[M+H]⁺(calcd for C₁₇H₁₆IN₂O₂,407.0251)。

Embodiment 31：The preparation of 2- (1- methoxyl group -1H- indol-3-yls)-N- (4- nitrobenzophenones) acetamide

3rd step, 2- (indoline -3- bases)-N- (4- nitrobenzophenones) acetamide is dissolved in (50mL) methanol, it is cooled to 15~ 20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL), completion of dropping, 15~20 DEG C are added dropwise React 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) extract, merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing 2- (1- hydroxyls- 1H- indol-3-yls) dichloromethane of-N- (4- nitrobenzophenones) acetamide mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain yellow solid 2- (1- first Oxy-1 H- indol-3-yls)-N- (4- nitrobenzophenones) acetamide (506mg).¹H NMR(400MHz,acetone-d₆):δ9.76 (1H, brs, NH-1), 8.17 (2H, d, J=9.2Hz, H-3 ', 5 '), 7.88 (2H, d, J=8.8Hz, H-2 ', 6 '), 7.64 (1H, d, J=7.6Hz, H-4), 7.49 (1H, s, H-2), 7.42 (1H, d, J=8.0Hz, H-7), 7.21 (1H, t, J= 7.6Hz, H-6), 7.07 (1H, t, J=7.2Hz, H-5), 4.09 (3H, s, OMe-10), 3.88 (2H, s, H-8)；¹³C NMR (400MHz,acetone-d₆):δ170.8(C-9),146.3(C-4’),143.8(C-1’),133.3(C-7a),125.5(C- 3’,5’),124.8(C-3a),123.6(C-2),123.3(C-6),120.5(C-5),120.1(C-4),119.7(C-2’, 6’),109.0(C-7),105.8(C-3),66.2(C-10),34.7(C-8)；(+)-HR-ESIMS m/z 326.1144[M+H ]⁺(calcd for C₁₇H₁₆N₃O₄,326.1135)。

Embodiment 32：The preparation of N- (3,5- Dimethoxyphenyls) -2- (1- methoxyl group -1H- indol-3-yls) acetamide

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；3,5- dimethoxyanilines (1g) are added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N hydrochloric acid quickly stirs 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of organic phase Removal of solvent under reduced pressure, obtains pale red crude brown oil N- (3,5- Dimethoxyphenyl) -2- (1H- indol-3-yls) acetyl Amine.

Second step, N- (3,5- Dimethoxyphenyl) -2- (1H- indol-3-yls) acetamide is dissolved in trifluoroacetic acid (10mL) In, add triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), satisfies With sodium bicarbonate aqueous solution (30mL), 15min, split-phase are quickly stirred；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge Organic phase, adds saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark-brown oil Shape thing crude product N- (3,5- Dimethoxyphenyls) -2- (indoline -3- bases) acetamide.

3rd step, N- (3,5- Dimethoxyphenyl) -2- (indoline -3- bases) acetamide is dissolved in (50mL) methanol, cooling To 15~20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL), completion of dropping, 15 is added dropwise ~20 DEG C of reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) are extracted, and merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing N- (3, 5- Dimethoxyphenyls) dichloromethane of -2- (1- hydroxyl -1H- indol-3-yls) acetamide mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain off-white powder N- (3, 5- Dimethoxyphenyls) -2- (1- methoxyl group -1H- indol-3-yls) acetamide (497mg).¹H NMR(400MHz,acetone- d₆):δ 9.19 (1H, brs, NH-1), 7.65 (1H, d, J=8.0Hz, H-4), 7.44 (1H, s, H-2), 7.41 (1H, d, J= 8.0Hz, H-7), 7.21 (1H, t, J=7.6Hz, H-5), 7.06 (1H, t, J=7.6Hz, H-4), 6.92 (2H, d, J= 1.2Hz,H-2’,6’),6.20(1H,s,H-4’),4.07(3H,s,OMe-10),3.78(2H,s,H-8),3.70(6H,s,H- 7’,8’)；¹³C NMR(400MHz,acetone-d₆):δ170.0(C-9),161.9(C-3’,5’),141.9(C-1’),133.3 (C-7a),124.8(C-3a),123.4(C-6),123.2(C-2),120.4(C-5),120.2(C-4),108.9(C-7), 106.5(C-3),98.4(C-2’,6’),96.2(C-4’),66.1(C-10),55.4(C-7’,8’),34.7(C-8)；(+)- HR-ESIMS m/z 341.1506[M+H]⁺(calcd for C₁₉H₂₁N₂O₄,341.1496)。

Embodiment 33：The preparation of 2- (1- methoxyl group -1H- indol-3-yls)-N- (3,4,5- trimethoxyphenyls) acetamide

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；3,4,5- trimethoxy-anilines (1.21g) are added, reaction is stirred at room temperature in DMAP (0.15g) 3h；Add 2N hydrochloric acid and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；It is organic 40 DEG C of removal of solvent under reduced pressure of phase, obtain pale red crude brown oil 2- (1H- indol-3-yls)-N- (3,4,5- trimethoxy-benzenes Base) acetamide.

Second step, 2- (1H- indol-3-yls)-N- (3,4,5- trimethoxyphenyl) acetamide is dissolved in trifluoroacetic acid In (10mL), triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h are added；Reaction solution recycling design, adds ethyl acetate (30mL), saturated sodium bicarbonate aqueous solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), Split-phase；Merge organic phase, add saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, are obtained To dark brown oil crude product 2- (indoline -3- bases)-N- (3,4,5- trimethoxyphenyls) acetamide.

3rd step, 2- (indoline -3- bases)-N- (3,4,5- trimethoxyphenyl) acetamide is dissolved in (50mL) methanol, drop Temperature adds in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise to 15~20 DEG C of stirrings, completion of dropping, 15~20 DEG C of reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane Alkane (100mL × 2) is extracted, and merges organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing 2- The dichloromethane of (1- hydroxyl -1H- indol-3-yls)-N- (3,4,5- trimethoxyphenyls) acetamide mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain off-white powder 2- (1- Methoxyl group -1H- indol-3-yls)-N- (3,4,5- trimethoxyphenyls) acetamide (230mg).¹H NMR(400MHz, acetone-d₆):δ 9.12 (1H, brs, NH-1), 7.65 (1H, d, J=8.0Hz, H-7), 7.45 (1H, s, H-2), 7.42 (1H, d, J=8.0Hz, H-4), 7.21 (1H, t, J=7.6Hz, H-6), 7.06 (1H, t, J=7.6Hz, H-5), 7.03 (2H, s,H-2’,6’),4.09(3H,s,OMe-10),3.78(2H,s,H-8),3.72(6H,s,H-7’,9’),3.65(3H,s,H- 8’)；¹³C NMR(400MHz,acetone-d₆):δ169.8(C-9),154.2(C-3’,5’),136.4(C-4’),133.4(C- 7a),124.9(C-3a),123.4(C-2),123.2(C-6),120.4(C-4),120.2(C-5),109.0(C-7),106.6 (C-3),98.0(C-2’,6’),66.2(C-10),60.5(C-8’),56.2(C-7’,9’),34.7(C-8)；(+)-HR- ESIMS m/z 371.1613[M+H]⁺(calcd for C₂₀H₂₃N₂O₅,371.1601)。

Embodiment 34：The preparation of 2- (1- methoxyl group -1H- indol-3-yls)-N- (pyridin-3-yl) acetamide

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；3- aminopyridines (0.62g) are added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N Hydrochloric acid quickly stirs 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of organic phase subtracts Pressure removes solvent, obtains crude brown oil 2- (1H- indol-3-yls)-N- (pyridin-3-yl) acetamide.

Second step, 2- (1H- indol-3-yls)-N- (pyridin-3-yl) acetamide is dissolved in trifluoroacetic acid (10mL), is added Triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), unsaturated carbonate hydrogen Sodium water solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic phase, plus Enter saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil crude product 2- (indoline -3- bases)-N- (pyridin-3-yl) acetamide.

3rd step, 2- (indoline -3- bases)-N- (pyridin-3-yl) acetamide is dissolved in (50mL) methanol, is cooled to 15~20 DEG C stirring, adds in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise, completion of dropping, and 15~20 DEG C anti- Answer 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase with dichloromethane (100mL × 2) extract, merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing 2- (1- hydroxyls -1H- Indol-3-yl) dichloromethane of-N- (pyridin-3-yl) acetamide mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:3) elute, obtain dark brown solid 2- (1- methoxyl group -1H- indol-3-yls)-N- (pyridin-3-yl) acetamide (156mg).¹H NMR(400MHz,acetone-d₆):δ 9.42 (1H, brs, NH-1), 8.73 (1H, s, H-2 '), 8.24 (1H, d, J=4.4Hz, H-6 '), 8.12 (1H, d, J= 8.4Hz, H-4 '), 7.65 (1H, d, J=8.0Hz, H-4), 7.48 (1H, s, H-2), 7.42 (1H, d, J=8.0Hz, H-7), 7.26 (1H, dd, J=8.4,4.8Hz, H-5 '), 7.21 (1H, t, 7.6Hz, H-6), 7.07 (1H, t, 7.6Hz, H-5), 4.08 (3H,s,OMe-10),3.84(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ170.5(C-9),145.2(C- 2’),141.9(C-6’),136.9(C-3’),133.3(C-7a),127.0(C-4’),124.8(C-3a),124.2(C-2), 123.5(C-5’),123.2(C-3),120.5(C-5),120.1(C-4),109.0(C-7),106.1(C-3),66.2(C- 10),34.4(C-8)；(+)-HR-ESIMS m/z 282.1242[M+H]⁺(calcd for C₁₆H₁₆N₃O₂,282.1237)。

Embodiment 35：The preparation of 2- (1- methoxyl group -1H- indol-3-yls)-N- (pyridin-4-yl) acetamide

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；4-aminopyridine (0.62g) is added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N Hydrochloric acid quickly stirs 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of organic phase subtracts Pressure removes solvent, obtains crude brown oil 2- (1H- indol-3-yls)-N- (pyridin-4-yl) acetamide.

Second step, 2- (1H- indol-3-yls)-N- (pyridin-4-yl) acetamide is dissolved in trifluoroacetic acid (10mL), is added Triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), unsaturated carbonate hydrogen Sodium water solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic phase, plus Enter saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil crude product 2- (indoline -3- bases)-N- (pyridin-4-yl) acetamide.

3rd step, 2- (indoline -3- bases)-N- (pyridin-4-yl) acetamide is dissolved in (50mL) methanol, is cooled to 15~20 DEG C stirring, adds in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise, completion of dropping, and 15~20 DEG C anti- Answer 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase with dichloromethane (100mL × 2) extract, merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing 2- (1- hydroxyls -1H- Indol-3-yl) dichloromethane of-N- (pyridin-4-yl) acetamide mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:3) elute, obtain dark brown solid 2- (1- Methoxyl group -1H- indol-3-yls)-N- (pyridin-4-yl) acetamide (169mg).¹H NMR(400MHz,acetone-d₆):δ 9.59 (1H, brs, NH-1), 8.39 (2H, d, J=5.6Hz, H-2 ', 6 '), 7.63 (1H, d, J=8.0Hz, H-4), 7.59 (2H, d, J=5.6Hz, H-3 ', 5 '), 7.47 (1H, s, H-2), 7.42 (1H, d, J=8.0Hz, H-7), 7.21 (1H, t, J= 7.6Hz, H-6), 7.06 (1H, t, J=7.6Hz, H-5), 4.09 (3H, s, OMe-10), 3.84 (2H, s, H-8)；¹³C NMR (400MHz,acetone-d₆):δ171.0(C-9),151.2(C-2’,6’),146.9(C-4’),133.3(C-7a),124.8 (C-3a),123.5(C-2),123.2(C-6), 120.5(C-5),120.1(C-4),114.1(C-3’,5’),109.0(C- 7),105.8(C-3),66.2(C-10),34.7(C-8)；(+)-HR-ESIMS m/z 282.1243[M+H]⁺(calcd for C₁₆H₁₆N₃O₂,282.1237)。

Embodiment 36：The preparation of 2- (1- methoxyl group -1H- indol-3-yls)-N- (pyridine -2- bases) acetamide

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；PA (0.62g) is added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Add 2N Hydrochloric acid quickly stirs 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of organic phase subtracts Pressure removes solvent, obtains crude brown oil 2- (1H- indol-3-yls)-N- (pyridine -2- bases) acetamide.

Second step, 2- (1H- indol-3-yls)-N- (pyridine -2- bases) acetamide is dissolved in trifluoroacetic acid (10mL), is added Triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), unsaturated carbonate hydrogen Sodium water solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic phase, plus Enter saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil crude product 2- (indoline -3- bases)-N- (pyridine -2- bases) acetamide.

3rd step, 2- (indoline -3- bases)-N- (pyridine -2- bases) acetamide is dissolved in (50mL) methanol, is cooled to 15~20 DEG C stirring, adds in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise, completion of dropping, and 15~20 DEG C anti- Answer 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase with dichloromethane (100mL × 2) extract, merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing 2- (1- hydroxyls -1H- Indol-3-yl) dichloromethane of-N- (pyridine -2- bases) acetamide mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:3) elute, obtain dark brown solid 2- (1- Methoxyl group -1H- indol-3-yls)-N- (pyridine -2- bases) acetamide (173mg).¹H NMR(300MHz,acetone-d₆):δ 9.36(1H,brs,NH-1),8.22(2H,m,H-3’,6’),7.70(2H,m,H-4,4’),7.52(1H,s,H-2),7.43 (1H, d, J=7.8Hz, H-7), 7.22 (1H, t, J=7.5Hz, H-6), 7.08 (1H, t, J=7.5Hz, H-5), 7.01 (1H, Dd, J=7.2,4.5Hz, H-5 '), 4.07 (3H, s, OMe-10), 3.93 (2H, s, H-8)；¹³C NMR(300MHz,acetone- d₆):δ170.5(C-9),153.1(C-2’),148.7(C-6’),138.7(C-3’),133.3(C-7a),124.8(C-3a), 123.6(C-2),123.3(C-6),120.5(C-5),120.2(C-4’),120.1(C-4),114.1(C-5’),109.0(C- 7),106.1(C-3),66.2(C-10),34.5(C-8)；(+)-HR-ESIMS m/z 282.1239[M+H]⁺(calcd for C₁₆H₁₆N₃O₂,282.1237)。

Embodiment 37：The preparation of N- (3- chloropyridine -4- bases) -2- (1- methoxyl group -1H- indol-3-yls) acetamide

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；The chloro- 4-aminopyridines of 3- (0.85g) are added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Plus Enter deionized water (20mL) and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase； 40 DEG C of removal of solvent under reduced pressure of organic phase, obtain pale red crude brown oil N- (3- chloropyridine -4- bases) -2- (1H- indoles -3- Base) acetamide.

Second step, N- (3- chloropyridine -4- bases) -2- (1H- indol-3-yls) acetamide is dissolved in trifluoroacetic acid (10mL), Add triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), saturated carbon Sour hydrogen sodium water solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic Phase, adds saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil Crude product N- (3- chloropyridine -4- bases) -2- (indoline -3- bases) acetamide.

3rd step, N- (3- chloropyridine -4- bases) -2- (indoline -3- bases) acetamide is dissolved in (50mL) methanol, is cooled to 15 ~20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL), completion of dropping, 15~20 are added dropwise DEG C reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) are extracted, and merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing N- (3- Chloropyridine -4- bases) dichloromethane of -2- (1- hydroxyl -1H- indol-3-yls) acetamide mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain brown solid N- (3- chlorine Pyridin-4-yl) -2- (1- methoxyl group -1H- indol-3-yls) acetamide (340mg).¹H NMR(400MHz,acetone-d₆):δ 8.69 (1H, brs, NH-1), 8.42 (1H, s, H-2 '), 8.36 (2H, m, H-5 ', 6 '), 7.66 (1H, d, J=8.0Hz, H-4), 7.63 (1H, s, H-2), 7.47 (1H, d, J=8.0Hz, H-7), 7.25 (1H, t, J=7.6Hz, H-6), 7.10 (1H, t, J= 7.6Hz,H-5),4.12(3H,s,H-10),4.01(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ170.9(C- 9),149.9(C-2’),149.8(C-6’),142.5(C-4’),133.3(C-7a),124.5(C-3a),123.9(C-2), 123.6(C-3),120.9(C-5),120.2(C-3’),119.9(C-4),115.1(C-5’),109.2(C-7),105.2(C- 3),66.4(C-10),34.6(C-8)；(+)-HR-ESIMS m/z316.086[M+H]⁺(calcd for C₁₆H₁₅ClN₃O₂, 316.0847)。

Embodiment 38：The preparation of N- (3- bromopyridine -4- bases) -2- (1- methoxyl group -1H- indol-3-yls) acetamide

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；The bromo- 4-aminopyridines of 3- (1.14g) are added, reaction 3h is stirred at room temperature in DMAP (0.15g)； Add deionized water (20mL) and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, point Phase；40 DEG C of removal of solvent under reduced pressure of organic phase, obtain rufous grease crude product N- (3- bromopyridine -4- bases) -2- (1H- indoles -3- Base) acetamide.

Second step, N- (3- bromopyridine -4- bases) -2- (1H- indol-3-yls) acetamide is dissolved in trifluoroacetic acid (10mL), Add triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), saturated carbon Sour hydrogen sodium water solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic Phase, adds saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil Crude product N- (3- bromopyridine -4- bases) -2- (indoline -3- bases) acetamide.

3rd step, N- (3- bromopyridine -4- bases) -2- (indoline -3- bases) acetamide is dissolved in (50mL) methanol, is cooled to 15 ~20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL), completion of dropping, 15~20 are added dropwise DEG C reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) are extracted, and merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing N- (3- Bromopyridine -4- bases) dichloromethane of -2- (1- hydroxyl -1H- indol-3-yls) acetamide mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain brown solid N- (3- bromines Pyridin-4-yl) -2- (1- methoxyl group -1H- indol-3-yls) acetamide (319mg).¹H NMR(400MHz,acetone-d₆):δ 8.51 (1H, brs, NH-1), 8.38 (1H, d, J=5.6Hz, H-6 '), 8.33 (1H, d, J=5.6Hz, H-5 '), 7.65 (2H, D, J=9.2Hz, H-2,4), 7.48 (1H, d, J=8.0Hz, H-7), 7.26 (1H, t, J=7.6Hz, H-6), 7.11 (1H, t, J =7.6Hz, H-5), 4.14 (3H, s, OMe-10), 3.99 (2H, s, H-8)；¹³C NMR(400MHz,acetone-d₆):δ 170.8(C-9),152.5(C-2’),150.3(C-6’),143.5(C-4’),133.4(C-7a),124.5(C-3a),124.1 (C-2),123.7(C-3),121.0(C-5),119.9(C-3’),115.3(C-4),110.9(C-5’),109.2(C-7), 104.9(C-3),66.5(C-10),34.7(C-8)；(+)-HR-ESIMS m/z 360.0345[M+H]⁺(calcd for C₁₆H₁₅BrN₃O₂,360.0342)。

Embodiment 39：The preparation of methyl 2- [3- (1- methoxyl group -1H- indol-3-yls) propionamide] benzoic ether

3rd step, methyl -2- [3- (indoline -3- bases) propionamide] benzoic ether is dissolved in (50mL) methanol, is cooled to 15 ~20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL), completion of dropping, 15~20 are added dropwise DEG C reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) are extracted, and merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing methyl- The dichloromethane of 2- [3- (1- hydroxyl -1H- indol-3-yls) propionamide] benzoic ether mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain orange jelly methyl- 2- [3- (1- methoxyl group -1H- indol-3-yls) propionamide] benzoic ether (147mg).¹H NMR(400MHz,acetone-d₆):δ 10.95 (1H, brs, NH-1), 8.72 (1H, d, J=8.8Hz, H-3 '), 7.99 (1H, d, J=8.0Hz, H-6 '), 7.64 (1H, D, J=7.6Hz, H-4), 7.58 (1H, t, J=7.6Hz, H-4 '), 7.38 (1H, d, J=8.4Hz, H-7), 7.35 (1H, s, H- 2), 7.19 (1H, t, J=7.6Hz, H-6), 7.11 (1H, t, J=7.6Hz, H-5), 7.05 (1H, t, J=7.6Hz, H-5 '), 4.03 (3H, s, OMe-10), 3.89 (3H, s, OMe-8 '), 3.15 (2H, t, J=7.6Hz, H-8a), 2.83 (2H, t, J= 7.6Hz,H-8)；¹³C NMR(400MHz,acetone-d₆):δ171.6(C-9),169.1(C-7’),142.5(C-2’), 135.2(C-4’),133.6(C-7a),131.6(C-6’),124.7(C-3a),123.1(C-2,5’),122.1(C-5), 120.9(C-3’),120.2(C-6),119.8(C-4),115.9(C-1’),111.9(C-3),109.0(C-7),65.9(C- 10),52.8(C-8’),39.5(C-8),21.4(C-8a)；(+)-HR-ESIMS m/z353.1513[M+H]⁺(calcd for C₂₀H₂₁N₂O₄,353.1496)。

Embodiment 40：The preparation of methyl 2- [4- (1- methoxyl group -1H- indol-3-yls) butyramide] benzoic ether

Second step, methyl -2- [4- (1H- indol-3-yls) butyramide] benzoic ether is dissolved in trifluoroacetic acid (10mL), plus Enter triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), unsaturated carbonate Hydrogen sodium water solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic Phase, adds saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil Crude product methyl -2- [4- (indoline -3- bases) butyramide] benzoic ether.

3rd step, methyl -2- [4- (indoline -3- bases) butyramide] benzoic ether is dissolved in (50mL) methanol, is cooled to 15 ~20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL), completion of dropping, 15~20 are added dropwise DEG C reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) are extracted, and merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Obtain containing methyl- The dichloromethane of 2- [4- (1- hydroxyl -1H- indol-3-yls) butyramide] benzoic ether mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (10mL), room Warm lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain yellow gum thing methyl- 2- [4- (1- methoxyl group -1H- indol-3-yls) butyramide] benzoic ether (102mg).¹H NMR(400MHz,acetone-d₆):δ 10.97 (1H, brs, NH-1), 8.73 (1H, d, J=8.4Hz, H-3 '), 8.01 (1H, d, J=8.0Hz, H-6 '), 7.59 (2H, M, H-4,4 '), 7.39 (1H, d, J=8.0Hz, H-7), 7.33 (1H, s, H-2), 7.18 (1H, t, J=7.6Hz, H-6), 7.12 (1H, t, J=7.6Hz, H-5 '), 7.04 (1H, t, J=7.6Hz, H-5), 4.06 (3H, s, OMe-10), 3.91 (3H, s, OMe- 8 '), 2.83 (2H, t, J=6.0Hz, H-8b), 2.52 (2H, t, J=7.6Hz, H-8), 2.11 (2H, m, H-8a)；¹³C NMR (400MHz,acetone-d₆):δ172.0(C-9),169.2(C-7’),142.6(C-2’),135.2(C-4’),133.7(C- 7a),131.6(C-6’),124.9(C-3a),123.0(C-2,5’),122.0(C-5),120.8(C-3’),120.1(C-6), 120.0(C-4),115.8(C-1’),112.5(C-3),109.0(C-7),65.8(C-10),52.8(C-8’),38.2(C-8), 26.6(C-8b),24.9(C-8a)；(+)-HR-ESIMS m/z 367.166[M+H]⁺(calcd for C₂₁H₂₃N₂O₄, 367.1652)。

Embodiment 41：The preparation of methyl 2- [2- (1,5- dimethoxy -1H- indol-3-yls) acetamide] benzoic ether

The first step, weighs 5-methoxyindoleacetic acid (0.5g), adds the stirring that suspended in dichloromethane (20mL), at room temperature Add EDCI (0.52g), stirring and dissolving；Methyl anthranilate (0.41g) is added, reaction is stirred at room temperature in DMAP (0.1g) 3h；Add 2N hydrochloric acid and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；It is organic 40 DEG C of removal of solvent under reduced pressure of phase, obtain yellow oil crude product methyl -2- [2- (5- methoxyl group -1H- indol-3-yls) acetamide] Benzoic ether.

Second step, methyl -2- [2- (5- methoxyl group -1H- indol-3-yls) acetamide] benzoic ether is dissolved in trifluoroacetic acid In (10mL), triethyl silicane (0.7g), 60 DEG C of back flow reaction 3h are added；Reaction solution recycling design, adds ethyl acetate (20mL), saturated sodium bicarbonate aqueous solution (20mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (20mL), Split-phase；Merge organic phase, add saturated aqueous common salt (20mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, are obtained To dark brown oil crude product methyl -2- [2- (5- methoxy-Indole quinoline -3- bases) acetamide] benzoic ether.

3rd step, methyl -2- [2- (5- methoxy-Indole quinoline -3- bases) acetamide] benzoic ether is dissolved in (25mL) methanol, 15~20 DEG C of stirrings are cooled to, adds in the sour sodium (0.15g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (5mL) is added dropwise, drip Finish, 15~20 DEG C of reaction 1h；Dichloromethane (100mL) is added, water (100mL) quickly stirs 10min, split-phase；Aqueous phase dichloro Methane (50mL × 2) is extracted, and merges organic phase；It is organic to be added to saturated aqueous common salt (100mL) washing, split-phase；Obtain containing first The dichloromethane of base -2- [2- (1- hydroxy-5-methyl Oxy-1 H- indol-3-yls) acetamide] benzoic ether mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (5mL), room temperature Lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain light brown jelly methyl- 2- [2- (1,5- dimethoxy -1H- indol-3-yls) acetamide] benzoic ether (40mg).¹H NMR(400MHz,acetone- d₆):δ 10.94 (1H, brs, NH-1), 8.75 (1H, d, J=8.4Hz, H-3 '), 7.92 (1H, d, J=7.6Hz, H-6 '), 7.55 (2H, m, H-2,4 '), 7.36 (1H, d, J=8.8Hz, H-7), 7.09 (2H, m, H-4,5 '), 6.87 (1H, dd, J= 8.8,2.0Hz,H-6),4.18(3H,s,OMe-10),3.83(2H,s,H-8),3.77(3H,s,OMe-5a),3.74(3H,s, H-7’)；¹³C NMR(400MHz,acetone-d₆):δ170.8(C-9),168.7(C-7’),155,6(C-5),142.3(C- 2’),135.1(C-4’),131.6(C-6’),128.7(C-7a),125.4(C-2),124.8(C-3a),123.1(C-6), 120.7(C-3’),116.1(C-1’),113.7(C-4),110.0(C-7),104.6(C-3),101.5(C-5’),66.4(C- 10),55.9(C-5a),52.6(C-8’),35.7(C-8)；(+)-HR-ESIMS m/z 369.1453[M+H]⁺(calcd for C₂₀H₂₀N₂O₅,369.1445)。

Embodiment 42：The preparation of N- (2- chlorphenyls) -2- (1,5- dimethoxy -1H- indol-3-yls) acetamide

The first step, weighs 5-methoxyindoleacetic acid (0.5g), adds the stirring that suspended in dichloromethane (20mL), at room temperature Add EDCI (0.52g), stirring and dissolving；O-chloraniline (0.41g) is added, reaction 3h is stirred at room temperature in DMAP (0.1g)；Add 2N Hydrochloric acid quickly stirs 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of organic phase subtracts Pressure removes solvent, obtains yellow oil crude product N- (2- chlorphenyls) -2- (5- methoxyl group -1H- indol-3-yls) acetamide.

Second step, N- (2- chlorphenyls) -2- (5- methoxyl group -1H- indol-3-yls) acetamide is dissolved in trifluoroacetic acid (10mL) In, add triethyl silicane (0.7g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (20mL), saturation Sodium bicarbonate aqueous solution (20mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (20mL), split-phase；It is associated with Machine phase, adds saturated aqueous common salt (20mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark-brown oily Thing crude product N- (2- chlorphenyls) -2- (5- methoxy-Indole quinoline -3- bases) acetamide.

3rd step, N- (2- chlorphenyls) -2- (5- methoxy-Indole quinoline -3- bases) acetamide is dissolved in (25mL) methanol, cooling To 15~20 DEG C of stirrings, add in the sour sodium (0.15g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (5mL), completion of dropping, 15 is added dropwise ~20 DEG C of reaction 1h；Dichloromethane (100mL) is added, water (100mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (50mL × 2) are extracted, and merge organic phase；It is organic to be added to saturated aqueous common salt (100mL) washing, split-phase；Obtain containing N- (2- Chlorphenyl) dichloromethane of -2- (1- hydroxy-5-methyl Oxy-1 H- indol-3-yls) acetamide mutually places stand-by.

4th step, what the 3rd step was obtained organic is added to 2N trimethyl silane diazomethane hexane solutions (5mL), room temperature Lucifuge reacts 24h；Separated through silica gel column chromatography, with ethyl acetate-light petrol (1:5) elute, obtain brown solid N- (2- chlorine Phenyl) -2- (1,5- dimethoxy -1H- indol-3-yls) acetamide (88mg).¹H NMR(400MHz,acetone-d₆):δ 8.45 (1H, brs, NH-1), 8.29 (1H, d, J=8.4Hz, H-6 '), 7.56 (1H, s, H-2), 7.37 (1H, d, J=8.8Hz, H-3 '), 7.34 (1H, d, J=8.0Hz, H-7), 7.28 (1H, t, J=8.0Hz, H-4 '), 7.20 (1H, d, J=1.2Hz, H- 4), 7.05 (1H, t, J=7.6Hz, H-5 '), 6.90 (1H, dd, J=8.8,1.6Hz, H-6), 4.09 (3H, s, OMe-10), 3.88(2H,s,H-8),3.77(3H,s,OMe-5a)；¹³C NMR(400MHz,acetone-d₆):δ170.0(C-9),155.7 (C-5),136.1(C-7a),129.9(C-6’),128.8(C-1’),128.4(C-6),125.5(C-3’),125.3(C-3a), 124.5(C-2),122.8(C-4’),113.9(C-4),110.6(C-2’),110.1(C-7),105.3(C-3),101.7(C- 5’),66.3(C-10),55.9(C-5a),34.6(C-8)；(+)-HR-ESIMS m/z 345.1003[M+H]⁺(calcd for C₁₈H₁₈ClN₂O₃,345.1)。

Embodiment 43：The preparation of methyl 2- [2- (1- ethyoxyl -1H- indol-3-yls) acetamide] benzoic ether

3rd step, methyl -2- [2- (indoline -3- bases) acetamide] benzoic ether is dissolved in (50mL) methanol, is cooled to 15 ~20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL), completion of dropping, 15~20 are added dropwise DEG C reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) are extracted, and merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Organic phase is removed under reduced pressure Solvent, obtains methyl -2- [2- (1- hydroxyl -1H- indol-3-yls) acetamide] benzoic ether crude product.

4th step, methyl -2- [2- (1- hydroxyl -1H- indol-3-yls) acetamide] benzoic ether, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in bromoethane (0.98g)；Reaction solution is added Ethyl acetate (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is merged Organic phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, uses acetic acid Ethyl ester-petroleum ether (1:5) elute, obtain light pink gum methyl -2- [2- (1- ethyoxyl -1H- indol-3-yls) acetamide] Benzoic ether (510mg)；¹H NMR(400MHz,acetone-d₆):δ 10.93 (1H, brs, NH-1), 8.75 (1H, d, J= 8.4Hz, H-3 '), 7.90 (1H, d, J=8.4Hz, H-6 '), 7.56 (3H, m, H-2,4,4 '), 7.46 (1H, d, J=8.4Hz, ), H-7 7.21 (1H, t, J=7.6Hz, H-6), 7.06 (2H, m, H-5,5 '), 4.43 (2H, q, J=6.8Hz, H-1 "), 3.87 (2H, s, H-8), 3.71 (3H, s, H-8 '), 1.43 (3H, t, J=6.8Hz, H-2 ")；¹³C NMR(400MHz,acetone- d₆):δ170.2(C-9),168.0(C-7’),141.7(C-2’),134.4(C-4’),133.5(C-7a),130.9(C-6’), 124.4(C-2),124.1(C-3a),122.6(C-5’),122.5(C-6),120.0(C-3’),119.9(C-4),119.1(C- 5),115.4(C-1’),108.7(C-7),104.2(C-3),74.3(C-1”),51.9(C-8’),35.1(C-8),13.6(C- 2”)；(+)-HR-ESIMS m/z 353.1502[M+H]⁺(calcd for C₂₀H₂₁N₂O₄,353.1496)。

Embodiment 44：The preparation of N- (2- chlorphenyls) -2- (1- ethyoxyl -1H- indol-3-yls) acetamide

3rd step, N- (2- chlorphenyls) -2- (indoline -3- bases) acetamide is dissolved in (50mL) methanol, is cooled to 15~20 DEG C stirring, adds in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise, completion of dropping, and 15~20 DEG C anti- Answer 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase with dichloromethane (100mL × 2) extract, merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Organic phase removal of solvent under reduced pressure, is obtained To N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide crude product.

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in bromoethane (0.98g)；Reaction solution adds ethyl acetate (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), merges organic phase, plus Enter saturated aqueous common salt (50mL), quickly stir 10min, split-phase；Organic phase is separated through silica gel column chromatography, uses ethyl acetate-pet Ether (1:5) elute, obtain pink solid N- (2- chlorphenyls) -2- (1- ethyoxyl -1H- indol-3-yls) acetamide (498mg).¹H NMR(400MHz,acetone-d₆):δ 8.44 (1H, brs, NH-1), 8.30 (1H, d, J=8.4Hz, H-6 '), 7.67 (1H, D, J=8.0Hz, H-3 '), 7.60 (1H, s, H-2), 7.47 (1H, d, J=8.0Hz, H-4), 7.32 (1H, d, J=8.0Hz, H- 7), 7.25 (2H, m, H-4 ', 5 '), 7.09 (1H, t, J=7.6Hz, H-6), 7.04 (1H, t, J=7.6Hz, H-5), 4.35 (2H, q, J=7.2Hz, H-1 "), 3.93 (2H, s, H-8), 1.38 (3H, t, H-2 ")；¹³C NMR(400MHz,acetone- d₆):δ169.9(C-9),136.0(C-1’),134.0(C-7a),129.8(C-5’),125.5(C-3’),124.7(C-2), 124.5(C-3a),123.4(C-6,4’),122.8(C-2’,6’),120.7(C-5),119.9(C-4),109.3(C-7), 105.4(C-3),74.7(C-1”),34.5(C-8),14.1(C-2”)；(+)-HR-ESIMS m/z 329.106[M+H]⁺ (calcd for C₁₈H₁₈ClN₂O₂,329.1051)。

Embodiment 45：The preparation of methyl 2- [2- (1- propoxyl group -1H- indol-3-yls) acetamide] benzoic ether

4th step, methyl -2- [2- (1- hydroxyl -1H- indol-3-yls) acetamide] benzoic ether, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in N-Propyl Bromide (1.1g)；Reaction solution adds second Acetoacetic ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is merged organic Phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, with ethyl acetate- Petroleum ether (1:5) elute, obtain light pink solid methyl -2- [2- (1- propoxyl group -1H- indol-3-yls) acetamide] benzoic acid Ester (523mg).¹H NMR(400MHz,acetone-d₆):δ 10.92 (1H, brs, NH-1), 8.75 (1H, d, J=8.4Hz, H- 3 '), 7.90 (1H, d, J=8.4Hz, H-6 '), 7.56 (3H, m, H-2,4,4 '), 7.46 (1H, d, J=8.0Hz, H-7), 7.21 (1H, t, J=7.6Hz, H-6), 7.06 (2H, m, H-5,5 '), 4.34 (2H, t, J=6.4Hz, H-1 "), 3.87 (2H, s, H- 8), 3.72 (3H, s, H-8 '), 1.86 (2H, m, H-2 "), 1.10 (3H, t, J=7.6Hz, H-3 ")；¹³C NMR(400MHz, acetone-d₆):δ170.8(C-9),168.6(C-7’),142.3(C-2’),135.0(C-4’),133.9(C-7a),131.5 (C-6’),124.9(C-2),124.7(C-3a),123.2(C-5’),123.1(C-6),120.6(C-3’),120.5(C-4), 119.7(C-5),116.0(C-1’),109.2(C-7),104.9(C-3),80.8(C-1”),52.5(C-8’),35.7(C-8), 22.3(C-2”),10.6(C-3”)；(+)-HR-ESIMS m/z367.1664[M+H]⁺(calcd for C₂₁H₂₃N₂O₄, 367.1652)。

Embodiment 46：The preparation of N- (2- chlorphenyls) -2- (1- propoxyl group -1H- indol-3-yls) acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in N-Propyl Bromide (1.1g)；Reaction solution adds ethyl acetate (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), merges organic phase, plus Enter saturated aqueous common salt (50mL), quickly stir 10min, split-phase；Organic phase is separated through silica gel column chromatography, uses ethyl acetate-pet Ether (1:5) elute, obtain pink solid N- (2- chlorphenyls) -2- (1- propoxyl group -1H- indol-3-yls) acetamide (511mg).¹H NMR(400MHz,acetone-d₆):δ 8.44 (1H, brs, NH-1), 8.30 (1H, d, J=8.4Hz, H-6 '), 7.67 (1H, D, J=8.0Hz, H-3 '), 7.61 (1H, s, H-2), 7.47 (1H, d, J=8.0Hz, H-4), 7.33 (1H, d, J=8.0Hz, H- 7), 7.26 (2H, m, H-4 ', 5 '), 7.09 (1H, t, J=7.6Hz, H-6), 7.04 (1H, t, J=7.6Hz, H-5), 4.26 (2H, t, J=6.8Hz, H-1 "), 3.92 (2H, s, H-8), 1.81 (2H, m, H-2 "), 1.07 (3H, t, J=7.6Hz, H-3 ") ；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),136.1(C-1’),133.9(C-7a),129.9(C-5’), 128.3(C-3’),125.5(C-3a,4), 124.6(C-2),123.5(C-6,2’),122.8(C-6’),120.7(C-5), 119.9(C-4),109.3(C-7),105.5(C-3),80.7(C-1”),34.6(C-8),22.3(C-2”),10.5(C-3”)； (+)-HR-ESIMS m/z 343.1221[M+H]⁺(calcd for C₁₉H₂₀ClN₂O₂,343.1208)。

Embodiment 47：The preparation of N- (3- chloropyridine -4- bases) -2- (1- propoxyl group -1H- indol-3-yls) acetamide

3rd step, N- (3- chloropyridine -4- bases) -2- (indoline -3- bases) acetamide is dissolved in (50mL) methanol, is cooled to 15 ~20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL), completion of dropping, 15~20 are added dropwise DEG C reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) are extracted, and merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Organic phase is removed under reduced pressure Solvent, obtains N- (3- chloropyridine -4- bases) -2- (1- hydroxyl -1H- indol-3-yls) acetamide crude product.

4th step, N- (3- chloropyridine -4- bases) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in N-Propyl Bromide (1.1g)；Reaction solution adds second Acetoacetic ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is merged organic Phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, with ethyl acetate- Petroleum ether (1:5) elute, obtain white solid N- (3- chloropyridine -4- bases) -2- (1- propoxyl group -1H- indol-3-yls) acetamide (445mg)。¹H NMR(400MHz,acetone-d₆):δ8.66(1H,brs,NH-1),8.42(1H,s,H-2’),8.36(2H, M, H-5 ', 6 '), 7.65 (1H, d, J=8.0Hz, H-4), 7.63 (1H, s, H-2), 7.47 (1H, d, J=8.0Hz, H-7), 7.24 (1H, t, J=7.6Hz, H-6), 7.10 (1H, t, J=7.6Hz, H-5), 4.26 (2H, t, J=6.8Hz, H-1 "), 4.00 (2H,s,H-8),1.81(2H,m,H-2”),1.08(3H,t,H-3”)；¹³C NMR(400MHz,acetone-d₆):δ170.9 (C-9),149.9(C-2’),149.8(C-6’),142.5(C-4’),133.8(C-7a),124.7(C-2),124.5(C-3a), 123.5(C-6),120.8(C-5),119.9(C-4),115.0(C-5’),114.9(C-3’),109.3(C-7),104.9(C- 3),80.8(C-1”),34.7(C-8),22.3(C-2”), 10.5(C-3”)；(+)-HR-ESIMS m/z 344.1166[M+H ]⁺(calcd for C₁₈H₁₉ClN₃O₂,344.116)。

Embodiment 48：The preparation of N- (3- fluorine pyridin-4-yl) -2- (1- propoxyl group -1H- indol-3-yls) acetamide

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；3- fluorine-4-aminopyridines (0.9g) are added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Plus Enter water (10mL) and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；Organic phase 40 DEG C of removal of solvent under reduced pressure, obtain pale red crude brown oil N- (3- fluorine pyridin-4-yl) -2- (1H- indol-3-yls) acetyl Amine.

Second step, N- (3- fluorine pyridin-4-yl) -2- (1H- indol-3-yls) acetamide is dissolved in trifluoroacetic acid (10mL), Add triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), saturated carbon Sour hydrogen sodium water solution (30mL), quickly stirs 15min, split-phase；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge organic Phase, adds saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark brown oil Crude product N- (3- fluorine pyridin-4-yl) -2- (indoline -3- bases) acetamide.

3rd step, N- (3- fluorine pyridin-4-yl) -2- (indoline -3- bases) acetamide is dissolved in (50mL) methanol, is cooled to 15 ~20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL), completion of dropping, 15~20 are added dropwise DEG C reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) are extracted, and merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Organic phase is removed under reduced pressure Solvent, obtains crude product N- (3- fluorine pyridin-4-yl) -2- (1- hydroxyl -1H- indol-3-yls) acetamide.

4th step, N- (3- fluorine pyridin-4-yl) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in N-Propyl Bromide (1.1g)；Reaction solution adds second Acetoacetic ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is merged organic Phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, with ethyl acetate- Petroleum ether (1:3) elute, obtain red brown solid N- (3- fluorine pyridin-4-yl) -2- (1- propoxyl group -1H- indol-3-yls) acetyl Amine (203mg).¹H NMR(400MHz,acetone-d₆):δ9.29(1H,brs,NH-1),8.36(2H,m,H-2’,6’),8.28 (1H, d, J=6.4Hz, H-5 '), 7.65 (1H, d, J=8.0Hz, H-4), 7.52 (1H, s, H-2), 7.43 (1H, d, J= 7.6Hz, H-7), 7.21 (1H, t, J=7.6Hz, H-6), 7.07 (1H, t, J=7.6Hz, H-5), 4.24 (2H, t, J= 6.4Hz,H-1”),3.98(2H,s,H-8),1.79(2H,m,H-2”),1.07(3H,t,H-3”)；¹³C NMR(400MHz, acetone-d₆):δ171.1(C-9),147.45(C-2’),147.39(C-6’),138.0(C-3’),137.8(C-3’), 133.8(C-4’),124.7(C-7a),124.3(C-2),123.3(C-6),120.5(C-5),120.0(C-4),115.6(C- 5’),110.6(C-3a),109.2(C-7),105.4(C-3),80.6(C-1”),34.4(C-8),22.3(C-2”),10.5(C- 3”)；(+)-HR-ESIMS m/z 327.1386[M+H]⁺(calcd for C₁₈H₁₈FN₃O₂,327.1383)。

Embodiment 49：The preparation of N- (the chloro- 5- aminomethyl phenyls of 2-) -2- (1- propoxyl group -1H- indol-3-yls) acetamide

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), adds at room temperature EDCI (1.27g), stirring and dissolving；5- methyl -2- chloroanilines (0.93g) are added, reaction 3h is stirred at room temperature in DMAP (0.15g)；Plus Enter 2N hydrochloric acid and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；Organic phase 40 DEG C removal of solvent under reduced pressure, obtains pale red crude brown oil N- (the chloro- 5- aminomethyl phenyls of 2-) -2- (1H- indol-3-yls) acetyl Amine.

Second step, N- (the chloro- 5- aminomethyl phenyls of 2-) -2- (1H- indol-3-yls) acetamide is dissolved in trifluoroacetic acid (10mL) In, add triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), satisfies With sodium bicarbonate aqueous solution (30mL), 15min, split-phase are quickly stirred；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge Organic phase, adds saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark-brown oil Shape thing crude product N- (the chloro- 5- aminomethyl phenyls of 2-) -2- (indoline -3- bases) acetamide.

3rd step, N- (the chloro- 5- aminomethyl phenyls of 2-) -2- (indoline -3- bases) acetamide is dissolved in (50mL) methanol, is cooled to 15~20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) are added dropwise, completion of dropping, 15~ 20 DEG C of reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) are extracted, and merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Organic phase is removed under reduced pressure Solvent, obtains crude product N- (the chloro- 5- aminomethyl phenyls of 2-) -2- (1- hydroxyl -1H- indol-3-yls) acetamide.

4th step, N- (the chloro- 5- aminomethyl phenyls of 2-) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in N-Propyl Bromide (1.1g)；Reaction solution adds second Acetoacetic ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is merged organic Phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, with ethyl acetate- Petroleum ether (1:5) elute, obtain off-white powder N- (the chloro- 5- aminomethyl phenyls of 2-) -2- (1- propoxyl group -1H- indol-3-yls) second Acid amides (519mg).¹H NMR(400MHz,acetone-d₆):δ8.37(1H,brs,NH-1),8.14(1H,s,H-6’),7.66 (1H, d, J=8.0Hz, H-3 '), 7.60 (1H, s, H-2), 7.46 (1H, d, J=8.4Hz, H-4 '), 7.24 (1H, t, J= 7.6Hz, H-6), 7.18 (1H, d, J=8.0Hz, H-4), 7.09 (1H, t, J=7.6Hz, H-5), 6.85 (1H, d, J= 8.0Hz, H-7), 4.25 (2H, t, J=6.8Hz, H-1 "), 3.91 (2H, s, H-8), 2.27 (3H, s, H-7 '), 1.81 (2H, m, H-2 "), 1.07 (3H, t, J=7.6Hz, H-3 ")；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),138.4(C- 1’),135.6(C-5’),133.9(C-7a),129.4(C-3’),126.1(C-4’),124.6(C-3a),124.5(C-6’), 123.4(C-6),123.2(C-2’),120.7(C-5),119.9(C-4),109.2(C-7),105.5(C-3),80.7(C- 1”),34.6(C-8),22.3(C-7’),21.2(C-2”),10.5(C-3”)；(+)-HR-ESIMS m/z 357.1365[M+H ]⁺(calcd for C₂₀H₂₁ClN₂O₂,357.1364)。

Embodiment 50：The preparation of 2- (1- propoxyl group -1H- indol-3-yls)-N- [2- (trifluoromethyl) phenyl] acetamide

The first step, weighs heteroauxin (1.05g), adds the stirring that suspended in dichloromethane (20mL), is cooled to 0~5 DEG C Stirring；Oxalyl chloride (1.15g) is added in 5min, one is instilled and drips DMF, is slowly increased to react at room temperature 1h；By 25 DEG C of decompressions of reaction solution Remove, obtain 2- (1H- indol-3-yls) chloroacetic chloride.

Second step, 2- (1H- indol-3-yls) chloroacetic chloride adds dichloromethane (20mL), and stirring and dissolving is cooled to 0~5 DEG C Stirring；2- 5-trifluoromethylanilines (0.97g) are added, triethylamine (1.2g) is slowly increased to react at room temperature 1h；Add 2N hydrochloric acid (20mL) quickly stirs 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, split-phase；40 DEG C of organic phase Removal of solvent under reduced pressure, obtains pale red crude brown oil 2- (1H- indol-3-yls)-N- [2- (trifluoromethyl) phenyl] acetyl Amine.

3rd step, 2- (1H- indol-3-yls)-N- [2- (trifluoromethyl) phenyl] acetamide is dissolved in trifluoroacetic acid (10mL) In, add triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, adds ethyl acetate (30mL), satisfies With sodium bicarbonate aqueous solution (30mL), 15min, split-phase are quickly stirred；Aqueous phase is extracted with ethyl acetate (30mL), split-phase；Merge Organic phase, adds saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of removal of solvent under reduced pressure of organic phase, obtain dark-brown oil Shape thing crude product 2- (indoline -3- bases)-N- [2- (trifluoromethyl) phenyl] acetamide.

4th step, 2- (indoline -3- bases)-N- [2- (trifluoromethyl) phenyl] acetamide is dissolved in (50mL) methanol, cooling To 15~20 DEG C of stirrings, add in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL), completion of dropping, 15 is added dropwise ~20 DEG C of reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane (100mL × 2) are extracted, and merge organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Organic phase is removed under reduced pressure Solvent, obtains crude product 2- (1- hydroxyl -1H- indol-3-yls)-N- [2- (trifluoromethyl) phenyl] acetamide.

5th step, 2- (1- hydroxyl -1H- indol-3-yls)-N- [2- (trifluoromethyl) phenyl] acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in N-Propyl Bromide (1.1g)；Reaction solution adds second Acetoacetic ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is merged organic Phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, with ethyl acetate- Petroleum ether (1:5) elute, obtain light purple solid 2- (1- propoxyl group -1H- indol-3-yls)-N- [2- (trifluoromethyl) phenyl] Acetamide (95mg).¹H NMR(400MHz,acetone-d₆):δ 8.30 (1H, brs, NH-1), 8.11 (1H, d, J=8.4Hz, H-6 '), 7.61 (4H, m, H-2,4,3 ', 5 '), 7.46 (1H, d, J=8.4Hz, H-7), 7.29 (1H, t, J=7.6Hz, H- 4 '), 7.24 (1H, t, J=7.6Hz, H-6), 7.09 (1H, t, J=7.6Hz, H-5), 4.26 (2H, t, J=6.8Hz, H-1 "), 3.90 (2H, s, H-8), 1.83 (2H, m, H-2 "), 1.08 (3H, t, J=7.6Hz, H-3 ")；¹³C NMR(600MHz, acetone-d₆):δ170.2(C-9),136.8(C-1’),133.9(C-7a),133.7(C-5’),126.8(q,C-7’), 126.2(C-3’),125.7(C-2’),125.6(C-5’),125.5(C-6’),124.6(C-2),123.9(C-3a),123.4 (C-6),120.7(C-5),119.8(C-4),109.2(C-7),105.2(C-3),80.8(C-1”),34.3(C-8),22.3 (C-2”),10.5(C-3”)；(+)-HR-ESIMS m/z377.1477[M+H]⁺(calcd for C₂₀H₂₀F₃N₂O₂, 377.1473)。

Embodiment 51：The preparation of 2- (the chloro- 1- propoxyl group -1H- indol-3-yls of 2-)-N- (2- chlorphenyls) acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in N-Propyl Bromide (1.1g)；Reaction solution adds ethyl acetate (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), merges organic phase, plus Enter saturated aqueous common salt (50mL), quickly stir 10min, split-phase；Organic phase is separated through silica gel column chromatography, uses ethyl acetate-pet Ether (1:5) elute, obtain white solid N- (2- chlorphenyls) -2- (1- propoxyl group -1H- indol-3-yls) acetamide (570mg).

5th step, N- (2- chlorphenyls) -2- (1- propoxyl group -1H- indol-3-yls) acetamide (200mg) adds dichloromethane Alkane (10mL) stirring and dissolving, 25 DEG C of stirrings of room temperature, adds NCS (86mg), and reaction 2h is stirred at room temperature, is separated through silica gel column chromatography, With ethyl acetate-light petrol (1:5) elute, obtain yellow solid 2- (the chloro- 1- propoxyl group -1H- indol-3-yls of 2-)-N- (2- chlorine Phenyl) acetamide (150mg).¹H NMR(400MHz,acetone-d₆):δ 8.46 (1H, brs, NH-1), 8.22 (1H, d, J= 8.0Hz, H-6 '), 7.68 (1H, d, J=7.6Hz, H-4), 7.48 (1H, d, J=8.0Hz, H-3 '), 7.37 (1H, d, J= 8.0Hz, H-7), 7.28 (2H, t, 7.6Hz, H-4 ', 5 '), 7.15 (1H, t, J=7.6Hz, H-6), 7.08 (1H, t, J= 7.6Hz, H-5), 4.29 (2H, t, J=6.4Hz, H-1 "), 3.94 (2H, s, H-8), 1.89 (2H, m, H-2 "), 1.12 (3H, t, J=7.2Hz, H-3 ")；¹³C NMR(400MHz,acetone-d₆):δ168.6(C-9),136.0(C-1’),133.9(C-7a), 129.9(C-5’),128.4(C-3’),125.8(C-3a,4’),124.1(C-6),124.0(C-2’),123.6(C-2), 123.4(C-6’),121.9(C-5),119.7(C-4),109.5(C-7),104.2(C-3),80.9(C-1”),33.2(C-8), 22.3(C-2”),10.6(C-3”)；(+)-HR-ESIMS m/z 377.0816[M+H]⁺(calcd for C₁₉H₁₉Cl₂N₂O₂, 377.0818)。

Embodiment 52：The preparation of 2- (the chloro- 1- propoxyl group -1H- indol-3-yls of 2-)-N- (3- chloropyridine -4- bases) acetamide

4th step, N- (3- chloropyridine -4- bases) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in N-Propyl Bromide (1.1g)；Reaction solution adds second Acetoacetic ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is merged organic Phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, with ethyl acetate- Petroleum ether (1:3) elute, obtain white solid N- (3- chloropyridine -4- bases) -2- (1- propoxyl group -1H- indol-3-yls) acetamide (445mg)。

5th step, N- (3- chloropyridine -4- bases) -2- (1- propoxyl group -1H- indol-3-yls) acetamide (200mg) is added Dichloromethane (10mL) stirring and dissolving, 25 DEG C of stirrings of room temperature, adds NCS (86mg), reaction 2h is stirred at room temperature, through silica gel column chromatography Separation, with ethyl acetate-light petrol (1:3) elute, obtain yellow solid 2- (the chloro- 1- propoxyl group -1H- indol-3-yls of 2-)-N- (3- chloropyridine -4- bases) acetamide (102mg).¹H NMR(400MHz,acetone-d₆):δ8.74(1H,brs,NH-1),8.47 (1H, s, H-2 '), 8.37 (1H, d, J=5.6Hz, H-6 '), 8.31 (1H, d, J=5.6Hz, H-5 '), 7.66 (1H, d, J= 8.0Hz, H-4), 7.48 (1H, d, J=8.0Hz, H-7), 7.29 (1H, t, J=7.6Hz, H-6), 7.16 (1H, t, J= 7.6Hz, H-5), 4.30 (2H, t, J=6.4Hz, H-1 "), 4.04 (2H, s, H-8), 1.89 (2H, m, H-2 "), 1.12 (3H, t, H-3”)；¹³C NMR(400MHz,acetone-d₆):δ169.6(C-9),150.0(C-2’),149.8(C-6’),142.5(C- 4’),133.8(C-7a),124.1(C-6),123.9(C-2),121.9(C-5),119.6(C-4),115.4(C-5’),109.5 (C-7),103.6(C-3),80.9(C-1”),33.3(C-8),22.2(C-2”),10.6(C-3”)；(+)-HR-ESIMS m/z 377.0712[M+H]⁺(calcd for C₁₈H₁₈Cl₂N₃O₂,377.0698)。

Embodiment 53：The preparation of 2- (the bromo- 1- propoxyl group -1H- indol-3-yls of 2-)-N- (2- chlorphenyls) acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in N-Propyl Bromide (1.1g)；Reaction solution adds ethyl acetate (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), merges organic phase, plus Enter saturated aqueous common salt (50mL), quickly stir 10min, split-phase；Organic phase is separated through silica gel column chromatography, uses ethyl acetate-pet Ether (1:5) elute, obtain white solid N- (2- chlorphenyls) -2- (1- propoxyl group -1H- indol-3-yls) acetamide (570mg)；

5th step, N- (2- chlorphenyls) -2- (1- propoxyl group -1H- indol-3-yls) acetamide (200mg) adds dichloromethane Alkane (10mL) stirring and dissolving, 25 DEG C of stirrings of room temperature, adds NBS (115mg), and reaction 2h is stirred at room temperature, is separated through silica gel column chromatography, With ethyl acetate-light petrol (1:5) elute, obtain light yellow solid 2- (the bromo- 1- propoxyl group -1H- indol-3-yls of 2-)-N- (2- Chlorphenyl) acetamide (192mg).¹H NMR(300MHz,acetone-d₆):δ8.40(1H,brs,NH-1),8.25(1H,d,J =8.1Hz, H-6 '), 7.69 (1H, d, J=7.8Hz, H-4), 7.49 (1H, d, J=8.1Hz, H-3 '), 7.36 (1H, dd, J= 8.1,1.5Hz, H-7), 7.27 (2H, m, H-4 ', 5 '), 7.10 (2H, m, H-5,6), 4.29 (2H, t, J=6.6Hz, H-1 "), 3.93 (2H, s, H-2), 1.90 (2H, m, H-2 "), 1.13 (3H, t, J=7.5Hz, H-3 ")；¹³C NMR(300MHz, acetone-d₆):δ168.6(C-9),135.9(C-1’),134.7(C-7a),129.9(C-5’),128.4(C-3’),125.8 (C-3a,4’),124.7(C-2),124.0(C-6),123.1(C-6’),121.7(C-5),119.6(C-4),112.3(C- 2’),109.5(C-7),107.1(C-3),80.8(C-1”),34.3(C-8),22.3(C-2”),10.7(C-3”)；(+)-HR- ESIMS m/z 421.0308[M+H]⁺(calcd for C₁₉H₁₈BrClN₂O₂, 421.0313)。

Embodiment 54：The preparation of 2- (the chloro- 1- propoxyl group -1H- indol-3-yls of 5-)-N- (3- chloropyridine -4- bases) acetamide

The first step, weighs 5- chloro-indoles (1.51g), adds absolute ether (30mL) stirring and dissolving, is cooled to 0~5 DEG C and stirs Mix, oxalyl chloride (1.9g) is added dropwise in 5min, completion of dropping is warmed to room temperature 20~25 DEG C of stirring reaction 2h.By reaction solution, 25 DEG C subtract Pressure removes solvent, obtains brown oil 2- (the chloro- 1H- indol-3-yls of 5-) -2- carbonyl chloroacetic chlorides.

Second step, 2- (the chloro- 1H- indol-3-yls of 5-) -2- carbonyls chloroacetic chloride adds dichloromethane (20mL) stirring and dissolving, It is cooled to 0~5 DEG C of stirring.The chloro- 4-aminopyridines of 3- (1.28g) are added, triethylamine (1.5g) is slowly increased to react at room temperature 2h. 0~5 DEG C of stirring 30min is cooled to, filtering, filter cake is washed with dichloromethane (5mL)；40 DEG C of forced air dryings obtain faint yellow solid 2- (the chloro- 1H- indol-3-yls of 5-)-N- (3- chloropyridine -4- bases) -2- carbonyls acetamide (2.0g).

3rd step, 2- (the chloro- 1H- indol-3-yls of 5-)-N- (3- chloropyridine -4- bases) -2- carbonyls acetamide adds methanol (20mL) stirring and dissolving, is cooled to 10~15 DEG C of stirrings, adds sodium borohydride (1g), is slowly increased to react at room temperature 30min.30℃ Removal of solvent under reduced pressure, adds ethyl acetate (20mL), and water (20mL) quickly stirs 5min, split-phase；Aqueous phase ethyl acetate (20mL) is extracted, split-phase；Combined ethyl acetate phase, adds saturated aqueous common salt (20mL) and quickly stirs 5min, split-phase；Ethyl acetate 45 DEG C of removal of solvent under reduced pressure of phase, obtain light yellow oil crude product 2- (the chloro- 1H- indol-3-yls of 5-)-N- (3- chloropyridines -4- Base) -2- hydroxyl acetamides.

4th step, 2- (the chloro- 1H- indol-3-yls of 5-)-N- (3- chloropyridine -4- bases) -2- hydroxyl acetyl that the 3rd step is obtained Amine is dissolved in trifluoroacetic acid (10mL), adds triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution recycling design, plus Enter ethyl acetate (30mL), saturated sodium bicarbonate aqueous solution (30mL) quickly stirs 15min, split-phase；Aqueous phase ethyl acetate (30mL) is extracted, split-phase；Merge organic phase, add saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of decompressions of organic phase Solvent is removed, dark brown oil crude product 2- (the chloro- indoline -3- bases of 5-)-N- (3- chloropyridine -4- bases) acetamide is obtained thick Product.

5th step, 2- (the chloro- indoline -3- bases of 5-)-N- (3- chloropyridine -4- bases) acetamide is dissolved in (50mL) methanol, drop Temperature adds in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise to 15~20 DEG C of stirrings, completion of dropping, 15~20 DEG C of reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase dichloromethane Alkane (100mL × 2) is extracted, and merges organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；Organic phase decompression is removed Solvent is removed, 2- (the chloro- 1- hydroxyls -1H- indol-3-yls of 5-)-N- (3- chloropyridine -4- bases) acetamide crude product is obtained.

6th step, 2- (the chloro- 1- hydroxyls -1H- indol-3-yls of 5-)-N- (3- chloropyridine -4- bases) acetamide adds drying DMF (8mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in N-Propyl Bromide (1.65g)；Reaction solution adds Enter ethyl acetate (50mL), water (50mL) quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is merged Organic phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, uses acetic acid Ethyl ester-petroleum ether (1:5) elute, obtain brown solid 2- (the chloro- 1- propoxyl group -1H- indol-3-yls of 5-)-N- (3- chlorine pyrroles Pyridine -4- bases) acetamide (102mg).¹H NMR(400MHz,acetone-d₆):δ8.76(1H,brs,NH-1),8.45(1H,s, H-2 '), 8.38 (1H, d, J=5.6Hz, H-6 '), 8.33 (1H, d, J=5.2Hz, H-5 '), 7.72 (1H, s, H-4), 7.68 (1H, s, H-2), 7.48 (1H, d, J=8.4Hz, H-7), 7.22 (1H, d, J=8.8Hz, H-6), 4.28 (2H, t, J= 6.8Hz, H-1 "), 4.02 (2H, s, H-8), 1.81 (2H, m, H-2 "), 1.07 (3H, t, J=6.4Hz, H-3 ")；¹³C NMR (600MHz,acetone-d₆):δ170.7(C-9),150.0(C-6’),149.8(C-5’),142.6(C-4’),132.2(C- 7a),126.16(C-2),125.6(C-3a),123.6(C-6),120.4(C-5),119.6(C-4),115.36(C-2’), 115.29(C-3’),110.8(C-7),105.0(C-3),81.1(C-1”),34.3(C-8),22.3(C-2”),10.5(C- 3”)；(+)-HR-ESIMS m/z 378.0784[M+H]⁺(calcd for C₁₈H₁₈Cl₂N₃O₂,378.0771)。

Embodiment 55：N- (3- chloropyridine -4- bases) -2- (4- methoxyl group -1- propoxyl group -1H- indol-3-yls) acetamide Prepare

The first step, weighs 4- methoxy-Indoles (1.47g), adds absolute ether (30mL) stirring and dissolving, is cooled to 0~5 DEG C stirring, oxalyl chloride (1.9g) is added dropwise in 5min, completion of dropping is warmed to room temperature 20~25 DEG C of stirring reaction 2h.By reaction solution 25 DEG C removal of solvent under reduced pressure, obtains brown oil 2- (4- methoxyl group -1H- indol-3-yls) -2- carbonyl chloroacetic chlorides.

Second step, it is molten that 2- (4- methoxyl group -1H- indol-3-yls) -2- carbonyls chloroacetic chloride adds dichloromethane (20mL) stirring Solution, is cooled to 0~5 DEG C of stirring.The chloro- 4-aminopyridines of 3- (1.28g) are added, triethylamine (1.5g) is slowly increased to room temperature reaction 2h.0~5 DEG C of stirring 30min is cooled to, filtering, filter cake is washed with dichloromethane (5mL)；40 DEG C of forced air dryings obtain faint yellow Solid 2- (4- methoxyl group -1H- indol-3-yls)-N- (3- chloropyridine -4- bases) -2- carbonyls acetamide (2.0g).

3rd step, 2- (4- methoxyl group -1H- indol-3-yls)-N- (3- chloropyridine -4- bases) -2- carbonyls acetamide adds first Alcohol (20mL) stirring and dissolving, is cooled to 10~15 DEG C of stirrings, adds sodium borohydride (1g), is slowly increased to react at room temperature 30min.30 DEG C removal of solvent under reduced pressure, adds ethyl acetate (20mL), and water (20mL) quickly stirs 5min, split-phase；Aqueous phase ethyl acetate (20mL) is extracted, split-phase；Combined ethyl acetate phase, adds saturated aqueous common salt (20mL) and quickly stirs 5min, split-phase；Ethyl acetate 45 DEG C of removal of solvent under reduced pressure of phase, obtain light yellow oil crude product 2- (4- methoxyl group -1H- indol-3-yls)-N- (3- chloropyridines - 4- yls) -2- hydroxyl acetamides.

4th step, 2- (4- methoxyl group -1H- indol-3-yls)-N- (3- chloropyridine -4- bases) -2- hydroxyls that the 3rd step is obtained Acetamide is dissolved in trifluoroacetic acid (10mL), adds triethyl silicane (1.74g), 60 DEG C of back flow reaction 3h；Reaction solution reclaims molten Agent, adds ethyl acetate (30mL), and saturated sodium bicarbonate aqueous solution (30mL) quickly stirs 15min, split-phase；Aqueous phase acetic acid Ethyl ester (30mL) is extracted, split-phase；Merge organic phase, add saturated aqueous common salt (30mL) stirring 10min, split-phase；50 DEG C of organic phase Removal of solvent under reduced pressure, obtains dark brown oil crude product 2- (4- Methoxv-indole quinoline -3- bases)-N- (3- chloropyridine -4- bases) second Crude amide.

5th step, 2- (4- Methoxv-indole quinoline -3- bases)-N- (3- chloropyridine -4- bases) acetamide is dissolved in (50mL) first Alcohol, is cooled to 15~20 DEG C of stirrings, adds in the sour sodium (0.3g) of tungstate dihydrate, 5min and 30% hydrogen peroxide (10mL) is added dropwise, be added dropwise Finish, 15~20 DEG C of reaction 1h；Dichloromethane (200mL) is added, water (200mL) quickly stirs 10min, split-phase；Aqueous phase uses two Chloromethanes (100mL × 2) is extracted, and merges organic phase；It is organic to be added to saturated aqueous common salt (200mL) washing, split-phase；It is organic to subtract each other Pressure removes solvent, obtains 2- (the chloro- 1- hydroxyls -1H- indol-3-yls of 5-)-N- (3- chloropyridine -4- bases) acetamide crude product.

6th step, 2- (4- methoxyl group -1- hydroxyl -1H- indol-3-yls)-N- (3- chloropyridine -4- bases) acetamide adds dry Dry DMF (8mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in N-Propyl Bromide (1.65g)；Reaction solution Ethyl acetate (50mL) is added, water (50mL) quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is closed And organic phase, saturated aqueous common salt (50mL) is added, 10min, split-phase is quickly stirred；Organic phase is separated through silica gel column chromatography, uses second Acetoacetic ester-petroleum ether (1:5) elute, obtain brown solid 2- (4- methoxyl group -1- propoxyl group -1H- indol-3-yls)-N- (3- Chloropyridine -4- bases) acetamide (110mg).¹H NMR(400MHz,acetone-d₆):δ8.65(1H,brs,NH-1),8.37 (3H, m, H-2 ', 5 ', 6 '), 7.45 (1H, s, H-2), 7.15 (1H, t, J=8.0Hz, H-6), 7.06 (1H, d, J=8.4Hz, ), H-7 6.59 (1H, d, J=6.8Hz, H-1 "), 4.00 (2H, s, H-1 "), 3.91 (3H, s, H-4a), 1.79 (2H, m, H- 2 "), 1.06 (3H, t, J=7.6Hz, H-3 ")；¹³C NMR(400MHz,acetone-d₆):δ171.4(C-9),155.1(C- 4),149.9(C-2’),149.8(C-6’),142.7(C-4’),135.5(C-7a),124.8(C-2),123.5(C-6), 114.8(C-5),114.7(C-3a),114.0(C-3’),104.4(C-3a),102.8(C-5’),101.1(C-7),80.8(C- 1”),55.9(C-4a),36.7(C-8),22.2(C-2”),10.5(C-3”)；(+)-HR-ESIMS m/z 373.12[M+H]⁺ (calcd for C₁₉H₂₀ClN₃O₃,373.1193)。

Embodiment 56：The preparation of methyl 2- [2- (1- isopropoxy -1H- indol-3-yls) acetamide] benzoic ether

4th step, methyl -2- [2- (1- hydroxyl -1H- indol-3-yls) acetamide] benzoic ether, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in bromo propane (1.1g)；Reaction solution adds Enter ethyl acetate (50mL), water (50mL) quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is merged Organic phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, uses acetic acid Ethyl ester-petroleum ether (1:5) elute, obtain violet gum thing methyl -2- [2- (1- isopropoxy -1H- indol-3-yls) acetamide] Benzoic ether (495mg).¹H NMR(400MHz,acetone-d₆):δ 10.93 (1H, brs, NH-1), 8.75 (1H, d, J= 8.4Hz, H-3 '), 7.91 (1H, d, J=8.0Hz, H-6 '), 7.55 (3H, m, H-2,4,4 '), 7.45 (1H, d, J=8.0Hz, H-7), 7.20 (1H, t, J=7.6Hz, H-5 '), 7.06 (2H, m, H-5,6), 4.71 (1H, m, H-1 "), 3.99 (2H, s, H- 8),3.71(3H,s,H-8’),1.42(3H,s,H-2”),1.40(3H,s,H-3”)；¹³C NMR(400MHz,acetone-d₆): δ170.8(C-9),168.6(C-7’),142.4(C-2),135.0(C-4’),134.8(C-7a),131.5(C-6’),125.9 (C-2),124.7(C-3a),123.2(C-6),123.1(C-5’),120.6(C-5),120.4(C-3’),119.6(C-4), 116.0(C-1’),109.6(C-7),104.7(C-3),81.2(C-1”),52.6(C-8’),35.8(C-8),21.4(C-2”, 3”)；(+)-HR-ESIMS m/z 367.1656[M+H]⁺(calcd for C₂₁H₂₃N₂O₄,367.1652)。

Embodiment 57：The preparation of N- (2- chlorphenyls) -2- (1- isopropoxy -1H- indol-3-yls) acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in bromo propane (1.1g)；Reaction solution adds acetic acid second Ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), merges organic phase, Saturated aqueous common salt (50mL) is added, 10min, split-phase is quickly stirred；Organic phase is separated through silica gel column chromatography, with ethyl acetate-stone Oily ether (1:5) elute, obtain light pink solid N- (2- chlorphenyls) -2- (1- isopropoxy -1H- indol-3-yls) acetamide (480mg)。¹H NMR(400MHz,acetone-d₆):δ 8.42 (1H, brs, NH-1), 8.32 (1H, d, J=8.0Hz, H-6 '), 7.66 (1H, d, J=8.0Hz, H-3 '), 7.58 (1H, s, H-2), 7.46 (1H, d, J=8.0Hz, H-4), 7.27 (3H, m, H- 7,4 ', 5 '), 7.09 (1H, t, J=7.6Hz, H-6), 7.04 (1H, t, J=7.6Hz, H-5), 4.61 (1H, m, H-1 "), 3.93 (2H,s,H-8),1.36(3H,s,H-2”),1.35(3H,s,H-3”)；¹³C NMR(400MHz,acetone-d₆):δ170.0 (C-9),136.0(C-1’),134.7(C-7a),129.8(C-3’),128.3(C-5’),125.5(C-4’),125.4(C-3), 124.5(C-3a),123.4(C-2),122.7(C-2’,6’),120.6(C-5),119.8(C-4),109.7(C-7),105.2 (C-3),81.1(C-1”),34.6(C-8),21.2(C-2”,3”)；(+)-HR-ESIMS m/z 343.1227[M+H]⁺ (calcd for C₁₉H₂₀ClN₂O₂,343.1208)。

Embodiment 58：The preparation of N- (2- chlorphenyls) -2- (1- butoxy -1H- indol-3-yls) acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in n-bromide butane (1.23g)；Reaction solution adds acetic acid second Ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), merges organic phase, Saturated aqueous common salt (50mL) is added, 10min, split-phase is quickly stirred；Organic phase is separated through silica gel column chromatography, with ethyl acetate-stone Oily ether (1:5) elute, obtain violet solid N- (2- chlorphenyls) -2- (1- butoxy -1H- indol-3-yls) acetamide (560mg)。¹H NMR(400MHz,acetone-d₆):δ 8.43 (1H, brs, NH-1), 8.30 (1H, d, J=8.4Hz, H-6 '), 7.66 (1H, d, J=8.0Hz, H-4), 7.61 (1H, s, H-2), 7.46 (1H, d, J=8.0Hz, H-3 '), 7.33 (1H, d, J= 8.0Hz, H-7), 7.26 (2H, m, H-4 ', 5 '), 7.09 (1H, t, J=7.6Hz, H-6), 7.04 (1H, t, J=7.6Hz, H- 5), 4.30 (2H, t, J=6.4Hz, H-1 "), 3.92 (2H, s, H-8), 1.78 (2H, m, H-2 "), 1.56 (2H, m, H-3 "), 0.98 (3H, t, J=7.2Hz, H-4 ")；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),136.1(C-1’), 133.9(C-7a),129.9(C-5’),128.4(C-3’),125.5(C-3a,4),124.6(C-2),123.5(C-6,2’), 122.8(C-6’),120.7(C-5),120.0(C-4),109.2(C-7),105.5(C-3),79.0(C-1”),34.6(C-8), 31.0(C-2”),19.7(C-3”),14.1(C-4”)；(+)-HR-ESIMS m/z 357.1373[M+H]⁺(calcd for C₂₀H₂₂ClN₂O₂,357.1364)。

Embodiment 59：The preparation of 2- (1- butoxy -1H- indol-3-yls)-N- (3- chloropyridine -4- bases) acetamide

4th step, N- (3- chloropyridine -4- bases) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in NBB (1.2g)；Reaction solution adds second Acetoacetic ester (50 mL), water (50mL) quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is associated with Machine phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, uses acetic acid second Ester-petroleum ether (1:5) elute, obtain light yellow gum thing 2- (1- butoxy -1H- indol-3-yls)-N- (3- chloropyridines -4- Base) acetamide (440mg).¹H NMR(400MHz,acetone-d6):δ8.66(1H,brs,N-H),8.42(1H,s,H-2’), 8.36 (2H, m, H-5 ', 6 '), 7.64 (2H, m, H-2,4), 7.47 (1H, d, J=8.4Hz, H-7), 7.25 (1H, t, J= 7.6Hz, H-6), 7.10 (1H, t, J=7.6Hz, H-5), 4.31 (2H, t, J=7.2Hz, H-1 "), 4.00 (2H, s, H-8), 1.78 (2H, s, H-2 "), 1.54 (2H, m, H-3 "), 0.98 (3H, t, J=7.6Hz, H-4 ")；¹³C NMR(400MHz, acetone-d6):δ170.9(C-9),149.9(C-2’),149.8(C-6’),142.5(C-4’),133.9(C-7a),124.7 (C-2),124.5(C-3’),123.6(C-6),120.8(C-5’),119.9(C-4),115.03(C-3a),114.96(C-5), 109.3(C-7),104.9(C-3),79.1(C-1”),34.7(C-8),31.0(C-2”),19.7(C-3”),14.1(C-4”)； (+)-HR-ESIMS m/z 357.1249[M+H]⁺(calcd for C₁₉H₂₁ClN₃O₂,357.1244)。

Embodiment 60：The preparation of N- (2- chlorphenyls) -2- (1- amoxy -1H- indol-3-yls) acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in positive bromo pentane silane (1.36g)；Reaction solution adds acetic acid second Ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), merges organic phase, Saturated aqueous common salt (50mL) is added, 10min, split-phase is quickly stirred；Organic phase is separated through silica gel column chromatography, with ethyl acetate-stone Oily ether (1:8) elute, obtain violet gum thing N- (2- chlorphenyls) -2- (1- amoxy -1H- indol-3-yls) acetamide (549mg)。 ¹H NMR(400MHz,acetone-d₆):δ 8.43 (1H, brs, NH-1), 8.30 (1H, d, J=8.4Hz, H- 6 '), 7.66 (1H, d, J=8.0Hz, H-4), 7.61 (1H, s, H-2), 7.46 (1H, d, J=8.0Hz, H-3 '), 7.33 (1H, D, J=8.0Hz, H-7), 7.26 (2H, m, H-4 ', 5 '), 7.07 (2H, m, H-5,6), 4.30 (2H, t, J=6.4Hz, H-1 "), 3.92 (2H, s, H-8), 1.80 (2H, m, H-2 "), 1.51 (2H, m, H-3 "), 1.41 (2H, m, H-4 "), 0.93 (3H, t, J= 7.2Hz,H-5”)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),136.1(C-1’),133.9(C-7a), 129.9(C-5’),128.4(C-3’),125.5(C-3a,4),124.6(C-2),123.5(C-6,2’),122.8(C-6’), 120.7(C-5),120.0(C-4),109.3(C-7),105.5(C-3),79.3(C-1”),34.6(C-8),28.70(C-2”), 28.68(C-3”),23.1(C-4”),14,2(C-5”)；(+)-HR-ESIMS m/z 371.1528[M+H]⁺(calcd for C₂₁H₂₄ClN₂O₂,371.1521)。

Embodiment 61：The preparation of N- (3- chloropyridine -4- bases) -2- [1- (amoxy) -1H- indol-3-yls] acetamide

4th step, N- (3- chloropyridine -4- bases) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in bromo pentane silane (1.2g)；Reaction solution adds second Acetoacetic ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is merged organic Phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, with ethyl acetate- Petroleum ether (1:5) elute, obtain light yellow gum thing 2- (1- amoxy -1H- indol-3-yls)-N- (3- chloropyridine -4- bases) second Acid amides (450mg).¹H NMR(400MHz,acetone-d6):δ8.66(1H,brs,N-H),8.42(1H,s,H-2’),8.36 (2H, m, H-5 ', 6 '), 7.64 (2H, m, H-2,4), 7.47 (1H, d, J=8.4Hz, H-7), 7.25 (1H, t, J=7.6Hz, H- 6), 7.10 (1H, t, J=7.6Hz, H-5), 4.31 (2H, t, J=7.2Hz, H-1 "), 4.00 (2H, s, H-8), 1.81 (2H, s, H-2 "), 1.45 (2H, m, H-3 ", 4 "), 0.93 (3H, t, J=7.2Hz, H-5 ")；¹³C NMR(400MHz,acetone-d6):δ 170.9(C-9),149.9(C-2’),149.8(C-6’),142.5(C-4’),133.9(C-7a),124.7(C-2),124.5 (C-3’),123.6(C-6),120.8(C-5’),119.9(C-4),115.0(C-3a),109.3(C-7),104.9(C-3), 79.4(C-1”),34.7(C-8),28.69(C-2”),28.68(C-3”),23.1(C-4”),14.2(C-5”)；(+)-HR- ESIMS m/z 371.141[M+H]⁺(calcd for C₂₀H₂₃ClN₃O₂,371.1401)。

Embodiment 62：The preparation of N- (2- chlorphenyls) -2- (1- hexyloxy -1H- indol-3-yls) acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (8mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in N- Hexyl Bromide (1.48g)；Reaction solution adds acetic acid second Ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), merges organic phase, Saturated aqueous common salt (50mL) is added, 10min, split-phase is quickly stirred；Organic phase is separated through silica gel column chromatography, with ethyl acetate-stone Oily ether (1:8) elute, obtain light brown jelly N- (2- chlorphenyls) -2- (1- hexyloxy -1H- indol-3-yls) acetamide (530mg)。 ¹H NMR(400MHz,acetone-d₆):δ 8.43 (1H, brs, NH-1), 8.30 (1H, d, J=8.4Hz, H- 6 '), 7.66 (1H, d, J=8.0Hz, H-4), 7.61 (1H, s, H-2), 7.46 (1H, d, J=8.0Hz, H-3 '), 7.33 (1H, D, J=8.0Hz, H-7), 7.26 (2H, m, H-4 ', 5 '), 7.09 (1H, t, J=7.6Hz, H-6), 7.04 (1H, t, J= 7.6Hz, H-5), 4.30 (2H, t, J=6.4Hz, H-1 "), 3.92 (2H, s, H-8), 1.80 (2H, m, H-2 "), 1.53 (2H, m, H-3 "), 1.35 (4H, m, H-4 ", 5 "), 0.90 (3H, t, J=6.4Hz, H-6 ")；¹³C NMR(400MHz,acetone-d₆): δ169.9(C-9),136.1(C-1’),133.9(C-7a),129.9(C-5’),128.4(C-3’),125.5(C-3a,4), 124.6(C-2),123.5(C-6,2’),122.8(C-6’),120.7(C-5),120.0(C-4),109.3(C-7),105.5 (C-3),79.3(C-1”),34.6(C-8),32.3(C-2”),29.0(C-3”),26.2(C-4”),23.2(C-5”),14.2 (C-6”)；(+)-HR-ESIMS m/z 385.1678[M+H]⁺(calcd for C₂₂H₂₆ClN₂O₂,385.1677)。

Embodiment 63：The preparation of N- (2- chlorphenyls) -2- (1- Oxy-1 in heptan H- indol-3-yls) acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (8mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in positive heptyl bromide (1.6g)；Reaction solution adds ethyl acetate (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), merges organic phase, plus Enter saturated aqueous common salt (50mL), quickly stir 10min, split-phase；Organic phase is separated through silica gel column chromatography, uses ethyl acetate-pet Ether (1:8) elute, obtain light brown jelly N- (2- chlorphenyls) -2- (1- Oxy-1 in heptan H- indol-3-yls) acetamide (580mg)。 ¹H NMR(400MHz,acetone-d₆):δ 8.43 (1H, brs, NH-1), 8.30 (1H, d, J=8.4Hz, H- 6 '), 7.66 (1H, d, J=8.0Hz, H-4), 7.61 (1H, s, H-2), 7.46 (1H, d, J=8.0Hz, H-3 '), 7.33 (1H, D, J=8.0Hz, H-7), 7.26 (2H, m, H-4 ', 5 '), 7.07 (2H, m, H-5,6), 4.30 (2H, t, J=6.4Hz, H-1 "), 3.92(2H,s,H-8),1.81(2H,m,H-2”),1.53(2H,m,H-3”),1.34(6H,m,H-4”,5”,6”),0.88(3H, T, J=6.0Hz, H-7 ")；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),136.1(C-1’),133.9(C- 7a),129.9(C-5’),128.4(C-3’),125.5(C-3a,4),124.6(C-2),123.5(C-6,2’),122.8(C- 6’),120.7(C-5),120.0(C-4),109.3(C-7), 105.5(C-3),79.3(C-1”),34.6(C-8),32.4(C- 2”),29.8(C-3”),29.0(C-4”),26.5(C-5”),23.2(C-6”),14.3(C-7”)；(+)-HR-ESIMS m/z 399.184[M+H]⁺(calcd for C₂₃H₂₈ClN₂O₂,399.1834)。

Embodiment 64：The preparation of N- (2- chlorphenyls) -2- (1- octyloxy -1H- indol-3-yls) acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (8mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in positive bromo spicy silane (1.72g)；Reaction solution adds acetic acid second Ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), merges organic phase, Saturated aqueous common salt (50mL) is added, 10min, split-phase is quickly stirred；Organic phase is separated through silica gel column chromatography, with ethyl acetate-stone Oily ether (1:10) elute, obtain light brown jelly N- (2- chlorphenyls) -2- (1- octyloxy -1H- indol-3-yls) acetamide (602mg)。 ¹H NMR(400MHz,acetone-d₆):δ 8.43 (1H, brs, NH-1), 8.30 (1H, d, J=8.4Hz, H- 6 '), 7.66 (1H, d, J=8.0Hz, H-4), 7.61 (1H, s, H-2), 7.46 (1H, d, J=8.0Hz, H-3 '), 7.33 (1H, D, J=8.0Hz, H-7), 7.26 (2H, m, H-4 ', 5 '), 7.07 (2H, m, H-5,6), 4.31 (2H, t, J=6.4Hz, H-1 "), 3.92(2H,s,H-8),1.81(2H,m,H-2”),1.53(2H,m,H-3”),1.32(8H,m,H-4”,5”,6”,7”),0.88 (3H, t, J=6.4Hz, H-8 ")；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),136.1(C-1’),133.9 (C-7a),129.9(C-5’),128.4(C-3’),125.5(C-3a,4),124.6(C-2),123.5(C-6,2’),122.8 (C-6’),120.7(C-5),120.0(C-4),109.3(C-7),105.5(C-3),79.3(C-1”),34.6(C-8),32.5 (C-2”),30.1(C-3”),29.9(C-4”),29.0(C-5”),26.5(C-6”),23.3(C-7”),14.3(C-8”)；(+)- HR-ESIMS m/z 413.1996[M+H]⁺(calcd for C₂₄H₃₀ClN₂O₂,413.199)。

Embodiment 65：The preparation of N- (2- chlorphenyls) -2- (1- nonyl epoxide -1H- indol-3-yls) acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (8mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in positive bromononane (1.84g)；Reaction solution adds acetic acid second Ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), merges organic phase, Saturated aqueous common salt (50mL) is added, 10min, split-phase is quickly stirred；Organic phase is separated through silica gel column chromatography, with ethyl acetate-stone Oily ether (1:5) elute, obtain light yellow solid N- (2- chlorphenyls) -2- (1- nonyl epoxide -1H- indol-3-yls) acetamide (660mg)。 ¹H NMR(400MHz,acetone-d₆):δ 8.43 (1H, brs, NH-1), 8.30 (1H, d, J=8.4Hz, H- 6 '), 7.66 (1H, d, J=8.0Hz, H-4), 7.61 (1H, s, H-2), 7.46 (1H, d, J=8.0Hz, H-3 '), 7.33 (1H, D, J=8.0Hz, H-7), 7.26 (2H, m, H-4 ', 5 '), 7.09 (1H, t, J=7.6Hz, H-6), 7.05 (1H, t, J= 7.6Hz, H-5), 4.30 (2H, t, J=6.4Hz, H-1 "), 3.92 (2H, s, H-8), 1.80 (2H, m, H-2 "), 1.53 (2H, m, H-3 "), 1.33 (10H, m, H-4 ", 5 ", 6 ", 7 ", 8 "), 0.87 (3H, t, J=6.4Hz, H-9 ")；¹³C NMR(400MHz, acetone-d₆):δ169.9(C-9),136.1(C-1’),133.9(C-7a),129.9(C-5’),128.4(C-3’),125.5 (C-3a,4),124.6(C-2),123.5(C-6,2’),122.7(C-6’),120.7(C-5),120.0(C-4),109.3(C- 7),105.5(C-3),79.3(C-1”),34.6(C-8),32.5(C-2”),30.2(C-3”),30.1(C-4”),29.9(C- 5”),29.0(C-6”),26.5(C-7”),23.3(C-8”),14.3(C-9”)；(+)-HR-ESIMS m/z 427.2158[M+ H]⁺(calcd for C₂₅H₃₂ClN₂O₂,427.2147)。

Embodiment 66：The preparation of N- (2- chlorphenyls) -2- (1- decyloxy -1H- indol-3-yls) acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (10mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in positive bromo-decane (2g)；Reaction solution adds ethyl acetate (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), merges organic phase, plus Enter saturated aqueous common salt (50mL), quickly stir 10min, split-phase；Organic phase is separated through silica gel column chromatography, uses ethyl acetate-pet Ether (1:10) elute, obtain lilac jelly N- (2- chlorphenyls) -2- (1- decyloxy -1H- indol-3-yls) acetamide (689mg)。 ¹H NMR(400MHz,acetone-d₆):δ 8.42 (1H, brs, NH-1), 8.30 (1H, d, J=8.4Hz, H- 6 '), 7.66 (1H, d, J=8.0Hz, H-4), 7.61 (1H, s, H-2), 7.46 (1H, d, J=8.0Hz, H-3 '), 7.33 (1H, D, J=8.0Hz, H-7), 7.26 (2H, m, H-4 ', 5 '), 7.07 (2H, m, H-5,6), 4.30 (2H, t, J=6.4Hz, H-1 "), 3.92(2H,s,H-8),1.81(2H,m,H-2”),1.53(2H,m,H-3”),1.32(12H,m,H-4”,5”,6”,7”,8”, 9 "), 0.87 (3H, t, J=6.4Hz, H-10 ")；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),136.1(C- 1’),133.9(C-7a),129.9(C-5’),128.4(C-3’),125.5(C-3a,4),124.6(C-2),123.5(C-6, 2’),122.7(C-6’),120.7(C-5),120.0(C-4),109.3(C-7),105.5(C-3),79.3(C-1”),34.6 (C-8),32.6(C-2”),30.2(C-3”,4”),30.1(C-5”),30.0(C-6”),29.0(C-7”),26.5(C-8”), 23.3(C-9”),14.3(C-10”)；(+)-HR-ESIMS m/z441.2309[M+H]⁺(calcd for C₂₆H₃₄ClN₂O₂, 441.2303)。

Embodiment 67：The preparation of N- (2- chlorphenyls) -2- (1- tetradecyloxyaniline -1H- indol-3-yls) acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (10mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in bromotetradecane (2.5g)；Reaction solution adds acetic acid second Ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), merges organic phase, Saturated aqueous common salt (50mL) is added, 10min, split-phase is quickly stirred；Organic phase is separated through silica gel column chromatography, with ethyl acetate-stone Oily ether (1:10) elute, obtain brown solid N- (2- chlorphenyls) -2- (1- tetradecyloxyaniline -1H- indol-3-yls) acetamide (690mg)。¹H NMR(400MHz,acetone-d₆):δ 8.42 (1H, brs, NH-1), 8.30 (1H, d, J=8.4Hz, H-6 '), 7.66 (1H, d, J=8.0Hz, H-4), 7.61 (1H, s, H-2), 7.46 (1H, d, J=8.0Hz, H-3 '), 7.33 (1H, d, J= 8.0Hz, H-7), 7.26 (2H, m, H-4 ', 5 '), 7.07 (2H, m, H-5,6), 4.30 (2H, t, J=6.4Hz, H-1 "), 3.92 (2H,s,H-8),1.81(2H,m,H-2”),1.53(2H,m,H-3”),1.35(20H,m,H-4”,5”,6”,7”,8”,9”, 10 ", 11 ", 12 ", 13 "), 0.87 (3H, t, J=6.4Hz, H-14 ")；¹³C NMR(400MHz,acetone-d₆):δ169.3 (C-9),135.5(C-1’),133.3(C-7a),129.2(C-5’),127.8(C-3’),124.9(C-3a,4),124.0(C- 2),122.8(C-6,2’),122.1(C-6’),120.1(C-5),119.3(C-4),108.7(C-7),104.9(C-3),78.7 (C-1”),33.9(C-8),32.0(C-2”),29.8(C-3”,4”),29.71(C-5”),29.65(C-6”),29.6(C-7”), 29.5(C-8”),29.4(C-9”,10”),28.4(C-11”),25.9(C-12”),22.7(C-13”),13.7(C-14”)； (+)-HR-ESIMS m/z 497.2944[M+H]⁺(calcd for C₃₀H₄₂ClN₂O₂,497.2929)。

Embodiment 68：The preparation of N- (2- chlorphenyls) -2- (1- hexadecane epoxide -1H- indol-3-yls) acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (10mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in bromohexadecane (2.5g)；Reaction solution adds acetic acid second Ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), merges organic phase, Saturated aqueous common salt (50mL) is added, 10min, split-phase is quickly stirred；Organic phase is separated through silica gel column chromatography, with ethyl acetate-stone Oily ether (1:10) elute, obtain brown solid N- (2- chlorphenyls) -2- (1- hexadecane epoxide -1H- indol-3-yls) acetamide (717mg)。¹H NMR(400MHz,acetone-d₆):δ 8.43 (1H, brs, NH-1), 8.32 (1H, d, J=8.4Hz, H-6 '), 7.67 (1H, d, J=8.0Hz, H-4), 7.62 (1H, s, H-2), 7.47 (1H, d, J=8.0Hz, H-3 '), 7.34 (1H, d, J= 8.0Hz, H-7), 7.27 (2H, m, H-4 ', 5 '), 7.10 (1H, t, J=7.6Hz, H-6), 7.06 (1H, t, J=7.6Hz, H- 5), 4.31 (2H, t, J=6.4Hz, H-1 "), 3.93 (2H, s, H-8), 1.82 (2H, m, H-2 "), 1.54 (2H, m, H-3 "), 1.36 (24H, m, H-4 ", 5 ", 6 ", 7 ", 8 ", 9 ", 10 ", 11 ", 12 ", 13 ", 14 ", 15 "), 0.88 (3H, t, J=6.4Hz, H- 16”)；¹³C NMR(300MHz,acetone-d₆):δ169.3(C-9),135.5(C-1’),133.3(C-7a),129.2(C- 5’),127.7(C-3’),124.8(C-3a,4),124.0(C-2),122.8(C-6,2’),122.1(C-6’),120.1(C- 5),119.3(C-4),108.6(C-7),104.9(C-3),78.7(C-1”),34.0(C-8),32.0(C-2”),29.8(C- 3”,4”,5”,6”,7”,8”),29.6(C-9”),29.4(C-10”,11”,12”),28.4(C-13”),25.9(C-14”), 22.7(C-15”),13.7(C-16”)；(+)-HR-ESIMS m/z525.3255[M+H]⁺(calcd for C₃₂H₄₆ClN₂O₂, 525.3242)。

Embodiment 69：The preparation of 2- [1- (two grades of butoxy) -1H- indol-3-yls]-N- (2- chlorphenyls) acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in 2- NBBs (1.24g)；Reaction solution adds acetic acid second Ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), merges organic phase, Saturated aqueous common salt (50mL) is added, 10min, split-phase is quickly stirred；Organic phase is separated through silica gel column chromatography, with ethyl acetate-stone Oily ether (1:5) elute, obtain yellow solid 2- [1- (two grades of butoxy) -1H- indol-3-yls]-N- (2- chlorphenyls) acetamide (515mg)。 ¹H NMR(400MHz,acetone-d₆):δ 8.41 (1H, brs, NH-1), 8.29 (1H, d, J=9.4Hz, H- 6 '), 7.65 (1H, d, J=8.0Hz, H-4), 7.59 (1H, s, H-2), 7.46 (1H, d, J=8.0Hz, H-3 '), 7.33 (1H, D, J=8.0Hz, H-7), 7.28 (1H, t, J=7.6Hz, H-4 '), 7.23 (1H, t, J=7.6Hz, H-5 '), 7.07 (2H, m, ), H-5,6 4.43 (1H, m, H-1 "), 3.92 (2H, s, H-8), 1.76 (3H, m, H-2 "), 1.32 (2H, d, J=6.4Hz, H- 4 "), 1.07 (3H, t, J=2.6Hz, H-3 ")；¹³C NMR(400MHz,acetone-d₆):δ170.0(C-9),136.1(C- 1’),134.8(C-7a),129.9(C-5’),128.4(C-3’),125.6(C-4),125.5(C-3a),124.6(C-2), 123.4(C-6,2’),122.7(C-6’),120.6(C-5),119.9(C-4),109.7(C-7),105.3(C-3),86.0(C- 1”),34.6(C-8),28.5(C-4”),18.8(C-2”),9.9(C-3”)；(+)-HR-ESIMS m/z 357.1376[M+H]⁺ (calcd for C₂₀H₂₁ClN₂O₂,357.1364)。

Embodiment 70：The preparation of N- (2- chlorphenyls) -2- (1- isobutoxy -1H- indol-3-yls) acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in 2- methyl N-Propyl Bromide (1.24g)；Reaction solution adds second Acetoacetic ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is merged organic Phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, with ethyl acetate- Petroleum ether (1:5) elute, obtain yellow solid N- (2- chlorphenyls) -2- (1- isobutoxy -1H- indol-3-yls) acetamide (552mg)。¹H NMR(400MHz,acetone-d₆):δ 8.43 (1H, brs, NH-1), 8.29 (1H, d, J=9.4Hz, H-6 '), 7.66 (1H, d, J=8.0Hz, H-4), 7.62 (1H, s, H-2), 7.46 (1H, d, J=8.0Hz, H-3 '), 7.34 (1H, d, J= 8.0Hz, H-7), 7.26 (2H, m, H-4 ', 5 '), 7.08 (2H, m, H-5,6), 4.09 (2H, t, J=6.8Hz, H-1 "), 3.92 (2H, s, H-8), 2.15 (1H, m, H-2 "), 1.14 (6H, d, J=6.8Hz, H-3 ", 4 ")；¹³C NMR(400MHz,acetone- d₆):δ169.9(C-9),136.1(C-1’),133.7(C-7a),129.9(C-5’),128.4(C-3’),125.5(C-3a, 4),124.6(C-2’),124.5(C-2),123.5(C-6),122.8(C-6’),120.7(C-5),120.0(C-4),109.2 (C-7),105.6(C-3),85.5(C-1”),34.6(C-8),28.3(C-2”),19.3(C-3”,4”)；(+)-HR-ESIMS m/z 357.1369[M+H]⁺(calcd for C₂₀H₂₂ClN₂O₂,357.1364)。

Embodiment 71：The preparation of N- (3- chloropyridine -4- bases) -2- (1- isobutoxy -1H- indol-3-yls) acetamide

4th step, N- (3- chloropyridine -4- bases) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in bromine iso-butane (1.2g)；Reaction solution is added Ethyl acetate (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is associated with Machine phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, uses acetic acid second Ester-petroleum ether (1:5) elute, obtain light yellow gum thing 2- (1- isobutoxy -1H- indol-3-yls)-N- (3- chloropyridines -4- Base) acetamide (435mg).¹H NMR(400MHz,acetone-d6):δ8.67(1H,brs,N-H),8.42(1H,s,H-2’), 8.36 (2H, m, H-5 ', 6 '), 7.65 (2H, m, H-2,4), 7.47 (1H, d, J=8.4Hz, H-7), 7.25 (1H, t, J= 7.6Hz, H-6), 7.10 (1H, t, J=7.6Hz, H-5), 4.08 (2H, t, J=6.8Hz, H-1 "), 4.00 (2H, s, H-8), 2.13 (1H, m, H-2 "), 1.09 (6H, d, J=6.8Hz, H-3 ", 4 ")；¹³C NMR(400MHz,acetone-d6):δ170.9 (C-9),149.9(C-2’),149.8(C-6’),142.5(C-4’),133.7(C-7a),124.6(C-2),124.5(C-3a), 123.6(C-6),120.8(C-5),119.9(C-4),115.0(C-5’),109.3(C-7),105.0(C-3),85.5(C- 1”),34.6(C-8),28.3(C-2”),19.3(C-3”,4”)；(+)-HR-ESIMS m/z 357.1245[M+H]⁺(calcd for C₁₉H₂₁ClN₃O₂,357.1244)。

Embodiment 72：The preparation of N- (2- chlorphenyls) -2- [1- (2- pentanes epoxide) -1H- indol-3-yls] acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in 3- methyl NBB (1.36g)；Reaction solution adds second Acetoacetic ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is merged organic Phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, with ethyl acetate- Petroleum ether (1:5) elute, obtain light brown jelly N- (2- chlorphenyls) -2- [1- (2- pentanes epoxide) -1H- indol-3-yls] Acetamide (610mg).¹H NMR(400MHz,acetone-d₆):δ 8.43 (1H, brs, NH-1), 8.29 (1H, d, J=9.4Hz, H-6 '), 7.66 (1H, d, J=8.0Hz, H-4), 7.62 (1H, s, H-2), 7.46 (1H, d, J=8.0Hz, H-3 '), 7.33 (1H, d, J=8.0Hz, H-7), 7.26 (2H, m, H-4 ', 5 '), 7.07 (2H, m, H-5,6), 4.35 (2H, t, J=6.8Hz, H- 1 "), 3.92 (2H, s, H-8), 1.89 (1H, m, H-3 "), 1.72 (2H, q, J=13.6,6.8Hz, H-2 "), 0.98 (6H, d, J =6.8Hz, H-4 ", 5 ")；¹³C NMR(400MHz,acetone-d₆):δ170.0(C-9),136.1(C-1’),133.9(C- 7a),129.9(C-5’),128.4(C-3’),125.5(C-3a,4),124.6(C-2),123.5(C-6’),122.8(C-6, 2’),120.7(C-5),120.0(C-4),109.3(C-7),105.6(C-3),77.9(C-1”),37.7(C-8),34.6(C- 3”),25.8(C-2”),22.8(C-4”,5”)；(+)-HR-ESIMS m/z 371.1534[M+H]⁺(calcd for C₂₁H₂₄ClN₂O₂,371.1521)。

Embodiment 73：The preparation of N- (3- chloropyridine -4- bases) -2- (1- isoamoxy -1H- indol-3-yls) acetamide

4th step, N- (3- chloropyridine -4- bases) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in 3- methyl NBB (1.36g)；Reaction Liquid adds ethyl acetate (50mL), and water (50mL) quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), Merge organic phase, add saturated aqueous common salt (50mL), quickly stir 10min, split-phase；Organic phase is separated through silica gel column chromatography, is used Ethyl acetate-light petrol (1:3) elute, obtain light yellow gum thing N- (3- chloropyridine -4- bases) -2- (1- isoamoxy -1H- Indol-3-yl) acetamide (480mg).¹H NMR(400MHz,acetone-d6):δ8.66(1H,brs,N-H),8.42(1H, S, H-2 '), 8.36 (2H, m, H-5 ', 6 '), 7.65 (2H, m, H-2,4), 7.47 (1H, d, J=8.0Hz, H-7), 7.25 (1H, T, J=7.6Hz, H-6), 7.10 (1H, t, J=7.6Hz, H-5), 4.35 (2H, t, J=6.8Hz, H-1 "), 4.00 (2H, s, H- 8), 1.89 (1H, m, H-3 "), 1.72 (2H, m, H-2 "), 0.98 (6H, d, J=6.8Hz, H-4 ", 5 ")；¹³C NMR(400MHz, acetone-d6):δ170.9(C-9),149.9(C-2’),149.8(C-6’),142.5(C-4’),133.8(C-7a),124.7 (C-2),124.5(C-3’),123.6(C-6),120.8(C-5’),119.9(C-5),115.0(C-4),109.3(C-7), 105.0(C-3),77.9(C-1”),37.7(C-3”),34.7(C-8),25.7(C-2”),22.8(C-4”,5”)；(+)-HR- ESIMS m/z 371.1406[M+H]⁺(calcd for C₂₀H₂₃ClN₃O₂,371.1401)。

Embodiment 74：The preparation of N- (2- chlorphenyls) -2- (1- pentamethylene Oxy-1 H- indol-3-yls) acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in bromocyclopentane (1.4g)；Reaction solution adds acetic acid second Ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), merges organic phase, Saturated aqueous common salt (50mL) is added, 10min, split-phase is quickly stirred；Organic phase is separated through silica gel column chromatography, with ethyl acetate-stone Oily ether (1:5) elute, obtain brown solid N- (2- chlorphenyls) -2- (1- pentamethylene Oxy-1 H- indol-3-yls) acetamide (429mg)。¹H NMR(400MHz,acetone-d₆):δ 8.41 (1H, brs, NH-1), 8.30 (1H, d, J=8.4Hz, H-6 '), 7.65 (1H, d, J=8.0Hz, H-4), 7.63 (1H, s, H-2), 7.45 (1H, d, J=8.4Hz, H-3 '), 7.33 (1H, d, J= 8.0Hz, H-7), 7.28 (1H, t, J=7.6Hz, H-4 '), 7.23 (1H, t, J=7.6Hz, H-5 '), 7.07 (2H, m, H-5, 6),5.00(1H,m,H-1”),3.92(2H,s,H-8),1.83(8H,m,H-2”,3”,4”,5”)；¹³C NMR(400MHz, acetone-d₆):δ170.0(C-9),136.1(C-1’),134.5(C-7a),129.9(C-5’),128.4(C-3’),125.5 (C-3a,4),125.2(C-2),124.5(C-2’),123.5(C-6),122.7(C-6’),120.7(C-5),119.9(C-4), 109.5(C-7),105.3(C-3),90.9(C-1”),34.6(C-8),31.9(C-2”,5”),24.1(C-3”,4”)；(+)- HR-ESIMS m/z 369.1363[M+H]⁺(calcd for C₂₁H₂₂ClN₂O₂,369.1364)。

Embodiment 75：The preparation of N- (3- chloropyridine -4- bases) -2- (1- cyclopentyloxy -1H- indol-3-yls) acetamide

4th step, N- (3- chloropyridine -4- bases) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in bromocyclopentane (1.4g)；Reaction solution adds Enter ethyl acetate (50mL), water (50mL) quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is merged Organic phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, uses acetic acid Ethyl ester-petroleum ether (1:3) elute, obtain light yellow gum thing N- (3- chloropyridine -4- bases) -2- (1- cyclopentyloxy -1H- indoles - 3- yls) acetamide (405mg).¹H NMR(400MHz,acetone-d6):δ8.64(1H,brs,N-H),8.41(1H,s,H- 2 '), 8.36 (2H, m, H-5 ', 6 '), 7.64 (2H, m, H-2,4), 7.46 (1H, d, J=8.0Hz, H-7), 7.24 (1H, t, J= 7.6Hz, H-6), 7.09 (1H, t, J=7.6Hz, H-5), 5.01 (1H, m, H-1 "), 4.00 (2H, s, H-8), 1.83 (8H, m, H-2”,3”,4”,5”)；¹³C NMR(400MHz,acetone-d6):δ171.0(C-9),149.9(C-2’),149.8(C- 6’),142.5(C-4’),134.5(C-7a),125.3(C-2),124.4(C-3’),123.6(C-6),120.8(C-5’), 119.8(C-4),115.0(C-3a),109.5(C-7),104.7(C-3),90.9(C-1”),34.7(C-8),31.9(C-2”, 5”),24.1(C-3”,4”)；(+)-HR-ESIMS m/z369.1249[M+H]⁺(calcd for C₂₀H₂₁ClN₃O₂, 369.1244)。

Embodiment 76：The preparation of N- (3- chloropyridine -4- bases) -2- (1- methylbutoxy group -1H- indol-3-yls) acetamide

4th step, N- (3- chloropyridine -4- bases) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in 2- methybutanes (1.4g)；Reaction solution adds Enter ethyl acetate (50mL), water (50mL) quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is merged Organic phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, uses acetic acid Ethyl ester-petroleum ether (1:3) elute, obtain light yellow solid N- (3- chloropyridine -4- bases) -2- (1- methylbutoxy group -1H- indoles - 3- yls) acetamide (610mg).¹H NMR(500MHz,acetone-d6):δ8.65(1H,brs,N-H),8.41(1H,s,H- 2 '), 8.35 (2H, m, H-5 ', 6 '), 7.64 (2H, m, H-2,4), 7.46 (1H, d, J=8.0Hz, H-7), 7.25 (1H, t, J= 7.5Hz, H-6), 7.10 (1H, t, J=7.5Hz, H-5), 4.15 (2H, m, H-1 "), 4.00 (2H, s, H-8), 1.93 (1H, m, H-2 "), 1.64 (1H, m, H-3 "), 1.33 (1H, m, H-3 "), 1.09 (3H, d, J=7.0Hz, H-5 "), 0.97 (3H, t, J= 7.0Hz,H-4”)；¹³C NMR(500MHz,acetone-d6):δ170.9(C-9),149.9(C-2’),149.8(C-6’), 142.5(C-4’),133.7(C-7a),124.5(C-2),123.6(C-6),120.8(C-3a),119.9(C-5),115.0(C- 4),109.3(C-7),107.7(C-3),84.1(C-1”),34.8(C-8),34.7(C-2”),26.6(C-3”),16.6(C- 5”),11.5(C-4”)；(+)-HR-ESIMS m/z 371.14[M+H]⁺(calcd for C₂₀H₂₂ClN₃O₂,371.1401)。

Embodiment 77：N- (3- chloropyridine -4- bases) -2- [1- (3,3- dimethyl butyrates epoxide) -1H- indol-3-yls] acetyl The preparation of amine

4th step, N- (3- chloropyridine -4- bases) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in 3,3- dimethylbutanes (1.5g)；Reaction Liquid adds ethyl acetate (50mL), and water (50mL) quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), Merge organic phase, add saturated aqueous common salt (50mL), quickly stir 10min, split-phase；Organic phase is separated through silica gel column chromatography, is used Ethyl acetate-light petrol (1:3) elute, obtain light yellow solid N- (3- chloropyridine -4- bases) -2- [1- (3,3- dimethyl butyrate oxygen Base) -1H- indol-3-yls] acetamide (480mg).¹H NMR(400MHz,acetone-d6):δ8.67(1H,brs,N-H), 8.42 (1H, s, H-2 '), 8.36 (2H, m, H-5 ', 6 '), 7.66 (2H, m, H-2,4), 7.47 (1H, d, J=8.4Hz, H-7), 7.25 (1H, t, J=7.6Hz, H-6), 7.10 (1H, t, J=7.6Hz, H-5), 4.39 (2H, t, J=7.2Hz, H-1 "), 4.00 (2H, s, H-8), 1.80 (2H, t, J=7.2Hz, H-2 "), 0.99 (9H, s, H-4 ", 5 ", 6 ")；¹³C NMR(400MHz, acetone-d6):δ170.9(C-9),149.9(C-2’),149.8(C-6’),142.5(C-4’),133.8(C-7a),124.7 (C-2),124.5(C-6),123.6(C-5),120.8(C-4),119.9(C-3a),115.0(C-5’),109.4(C-7), 104.9(C-3),77.0(C-1”),42.0(C-2”),34.7(C-8),29.9(C-4”,5”,6”)；(+)-HR-ESIMS m/z 385.1554[M+H]⁺(calcd for C₂₁H₂₄ClN₃O₂,385.1557)。

Embodiment 78：N- (3- chloropyridine -4- bases) -2- [1- (2- ethyl-butoxies) -1H- indol-3-yls] acetamide Prepare

4th step, N- (3- chloropyridine -4- bases) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in 2- ethylbutanes (1.5g)；Reaction solution adds Enter ethyl acetate (50mL), water (50mL) quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is merged Organic phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, uses acetic acid Ethyl ester-petroleum ether (1:3) elute, obtain light yellow solid N- (3- chloropyridine -4- bases) -2- (1- ethyl-butoxy -1H- indoles - 3- yls) acetamide (615mg).¹H NMR(500MHz,acetone-d6):δ8.66(1H,brs,N-H),8.36(3H,m,H- 2 ', 5 ', 6 '), 7.65 (2H, m, H-2,4), 7.46 (1H, d, J=8.0Hz, H-7), 7.25 (1H, t, J=7.5Hz, H-6), 7.10 (1H, t, J=7.5Hz, H-5), 4.22 (2H, m, H-1 "), 4.00 (2H, s, H-8), 1.71 (1H, m, H-2 "), 1.57 (4H,m,H-3”,5”),0.98(6H,m,H-4”,6”)；¹³C NMR(500MHz,acetone-d6):δ170.9(C-9),149.9 (C-2’),149.8(C-6’),142.5(C-4’),133.7(C-7a),124.53(C-2),124.47(C-6),123.6(C- 5),120.8(C-4),119.9(C-3a),115.0(C-4),109.2(C-7),105.0(C-3),81.6(C-1”),41.1(C- 2”),34.7(C-8),23.9(C-3”,5”),11.4(C-4”,6”)；(+)-HR-ESIMS m/z 385.1562[M+H]⁺ (calcd for C₂₁H₂₄ClN₃O₂,385.1557)。

Embodiment 79：The preparation of N- (2- chlorphenyls) -2- (1- allyloxy -1H- indol-3-yls) acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in propylene iodine (1.5g)；Reaction solution adds ethyl acetate (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), merges organic phase, plus Enter saturated aqueous common salt (50mL), quickly stir 10min, split-phase；Organic phase is separated through silica gel column chromatography, uses ethyl acetate-pet Ether (1:5) elute, obtain brown solid N- (2- chlorphenyls) -2- (1- allyloxy -1H- indol-3-yls) acetamide (395mg)。 ¹H NMR(400MHz,acetone-d₆):δ 8.42 (1H, brs, NH-1), 8.29 (1H, d, J=8.0Hz, H- 6 '), 7.66 (1H, d, J=8.0Hz, H-4), 7.60 (1H, s, H-2), 7.47 (1H, d, J=8.0Hz, H-3 '), 7.33 (1H, D, J=8.0Hz, H-7), 7.26 (2H, m, H-4 ', 5 '), 7.07 (2H, m, H-5,6), 6.19 (1H, m, H-2 "), 5.36 (2H, M, H-3 "), 4.80 (2H, d, J=6.8Hz, H-1 "), 3.91 (2H, s, H-8)；¹³C NMR(400MHz,acetone-d₆):δ 169.9(C-9),136.1(C-1’),134.1(C-7a),133.1(C-2”),129.9(C-5’),128.3(C-3’),125.5 (C-3a,4),124.9(C-2),124.6(C-2’),123.5(C-6),122.8(C-6’),121.5(C-3”),120.8(C- 5),119.9(C-4),109.5(C-7),105.5(C-3),79.8(C-1”),34.6(C-8)；(+)-HR-ESIMS m/z 341.1051[M+H]⁺(calcd for C₁₉H₁₈ClN₂O₂,341.1051)。

Embodiment 80：The system of 2- [1- (allyloxy) -1- hydrogen-indol-3-yl]-N- (3- fluorine pyridin-4-yl) acetamide It is standby

4th step, N- (3- fluorine pyridin-4-yl) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in bromopropene (1.1g)；Reaction solution adds second Acetoacetic ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is merged organic Phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, with ethyl acetate- Petroleum ether (1:3) elute, obtain red brown solid 2- [1- (allyloxy) -1- hydrogen-indol-3-yl]-N- (3- fluorine pyridines -4- Base) acetamide (224mg).¹H NMR(400MHz,acetone-d₆):δ9.25(1H,brs,NH-1),8.35(2H,m,H-2’, 6 '), 8.27 (1H, d, J=6.4Hz, H-5 '), 7.65 (1H, d, J=8.0Hz, H-4), 7.52 (1H, s, H-2), 7.44 (1H, D, J=8.4Hz, H-7), 7.22 (1H, t, J=7.6Hz, H-6), 7.08 (1H, t, J=7.6Hz, H-5), 6.18 (1H, m, H- 2 "), 5.34 (2H, m, H-3 "), 4.78 (2H, d, J=6.8Hz, H-1 "), 3.97 (2H, s, H-8)；¹³C NMR(400MHz, acetone-d₆):δ171.1(C-9),147.41(C-2’),147.36(C-6’),137.9(C-3’),137.8(C-3’), 133.8(C-4’),133.0(C-2”),124.6(C-7a),124.5(C-2),123.3(C-6),121.5(C-4),120.5(C- 5),120.0(C-3”),115.43(C-5’),115.35(C-3a),109.3(C-7),105.3(C-3),79.7(C-1”), 34.3(C-8)；(+)-HR-ESIMS m/z 325.1229[M+H]⁺(calcd for C₁₈H₁₇FN₃O₂,325.1227)。

Embodiment 81：The system of 2- [1- (alkene butoxy) -1- hydrogen-indol-3-yl]-N- (3- chloropyridine -4- bases) acetamide It is standby

4th step, N- (3- chloropyridine -4- bases) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in the bromo- 3- butylene (1.3g) of 1-；Reaction solution Ethyl acetate (50mL) is added, water (50mL) quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is closed And organic phase, saturated aqueous common salt (50mL) is added, 10min, split-phase is quickly stirred；Organic phase is separated through silica gel column chromatography, uses second Acetoacetic ester-petroleum ether (1:3) elute, obtain light yellow solid 2- [1- (alkene butoxy) -1- hydrogen-indol-3-yl]-N- (3- chlorine Pyridin-4-yl) acetamide (520mg).¹H NMR(400MHz,acetone-d6):δ8.67(1H,brs,N-H),8.42(1H, S, H-2 '), 8.35 (2H, m, H-5 ', 6 '), 7.65 (2H, m, H-2,4), 7.48 (1H, d, J=8.0Hz, H-7), 7.25 (1H, T, J=7.6Hz, H-6), 7.10 (1H, t, J=7.6Hz, H-5), 5.96 (1H, m, H-3 "), 5.19 (2H, m, H-4 "), 4.37 (2H, t, J=6.4Hz, H-1 "), 4.00 (2H, s, H-8), 2.57 (2H, m, H-2 ")；¹³C NMR(400MHz,acetone- d6):δ170.9(C-9),149.9(C-2’),149.8(C-6’),142.5(C-4’),135.0(C-3”),133.9(C-7a), 124.7(C-2),124.5(C-4”),123.6(C-6),120.9(C-3a),119.9(C-5),117.8(C-4),115.0(C- 5’),109.4(C-7),105.1(C-3),78.2(C-1”),34.7(C-8),34.3(C-2”)；(+)-HR-ESIMS m/z 355.1096[M+H]⁺(calcd for C₁₉H₁₉ClN₃O₂,355.1088)。

Embodiment 82：N- (3- chloropyridine -4- bases) -2- [1- (2- amyl group -4- alkene -1- bases epoxide) -1H- indol-3-yls] The preparation of acetamide

4th step, N- (3- chloropyridine -4- bases) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in the bromo- 4- amylenes (1.4g) of 1-；Reaction solution Ethyl acetate (50mL) is added, water (50mL) quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is closed And organic phase, saturated aqueous common salt (50mL) is added, 10min, split-phase is quickly stirred；Organic phase is separated through silica gel column chromatography, uses second Acetoacetic ester-petroleum ether (1:3) elute, obtain light yellow gum thing N- (3- chloropyridine -4- bases) -2- [1- (2- amyl group -4- alkene -1- Base epoxide) -1H- indol-3-yls] acetamide (540mg).¹H NMR(400MHz,acetone-d6):δ8.66(1H,brs,N- H), 8.42 (1H, s, H-2 '), 8.35 (2H, m, H-5 ', 6 '), 7.64 (2H, m, H-2,4), 7.48 (1H, d, J=8.0Hz, H- 7), 7.25 (1H, t, J=7.6Hz, H-6), 7.10 (1H, t, J=7.6Hz, H-5), 5.88 (1H, m, H-4 "), 5.05 (2H, m, H-5 "), 4.32 (2H, t, J=6.8Hz, H-1 "), 4.00 (2H, s, H-8), 2.30 (2H, m, H-3 "), 1.90 (2H, m, H- 2”)；¹³C NMR(400MHz,acetone-d6):δ170.9(C-9),149.9(C-2’),149.8(C-6’),142.5(C- 4’),138.6(C-4”),133.8(C-7a),124.6(C-2),124.5(C-5”),123.6(C-6),120.8(C-3a), 119.9(C-5),115.7(C-4),115.0(C-5’),109.3(C-7),105.0(C-3),78.6(C-1”),34.7(C-8), 30.6(C-3”),28.2(C-2”)；(+)-HR-ESIMS m/z 369.1259[M+H]⁺(calcd for C₂₀H₂₀ClN₃O₂, 369.1244)。

Embodiment 83：N- (3- chloropyridine -4- bases) -2- [1- (2- hexyl -5- alkene -1- bases epoxide) -1H- indol-3-yls] The preparation of acetamide

4th step, N- (3- chloropyridine -4- bases) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in the bromo- 5- hexenes (1.6g) of 1-；Reaction solution Ethyl acetate (50mL) is added, water (50mL) quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is closed And organic phase, saturated aqueous common salt (50mL) is added, 10min, split-phase is quickly stirred；Organic phase is separated through silica gel column chromatography, uses second Acetoacetic ester-petroleum ether (1:3) elute, obtain light yellow gum thing N- (3- chloropyridine -4- bases) -2- [1- (2- hexyl -5- alkene -1- Base epoxide) -1H- indol-3-yls] acetamide (580mg).¹H NMR(400MHz,acetone-d6):δ8.69(1H,brs,N- H), 8.42 (1H, s, H-2 '), 8.36 (2H, m, H-5 ', 6 '), 7.65 (2H, m, H-2,4), 7.47 (1H, d, J=8.0Hz, H- 7), 7.25 (1H, t, J=7.6Hz, H-6), 7.10 (1H, t, J=7.6Hz, H-5), 5.84 (1H, m, H-5 "), 4.98 (2H, m, H-6 "), 4.31 (2H, t, J=6.4Hz, H-1 "), 4.00 (2H, s, H-8), 2.13 (2H, m, H-4 "), 1.81 (2H, m, H- 2”),1.62(2H,m,H-3”)；¹³C NMR(400MHz,acetone-d6):δ170.9(C-9),149.9(C-2’),149.8 (C-6’),142.5(C-4’),139.2(C-2),133.7(C-7a),124.6(C-6”),124.4(C-3a),123.5(C-6), 120.8(C-5),120.1(C-3’),119.9(C-4),115.2(C-5”),115.0(C-5’),109.3(C-7),104.9(C- 3),79.1(C-1”),34.6(C-8),34.1(C-4”),28.4(C-2”),25.8(C-3”)；(+)-HR-ESIMS m/z 383.1406[M+H]⁺(calcd for C₂₁H₂₃ClN₃O₂,383.1401)。

Embodiment 84：2- [1- (butyl -3- alkynes -1- bases epoxide) -1- hydrogen-indol-3-yl]-N- (3- chloropyridine -4- bases) The preparation of acetamide

4th step, N- (3- chloropyridine -4- bases) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in the bromo- 3- butine (1.2g) of 1-；Reaction solution Ethyl acetate (50mL) is added, water (50mL) quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is closed And organic phase, saturated aqueous common salt (50mL) is added, 10min, split-phase is quickly stirred；Organic phase is separated through silica gel column chromatography, uses second Acetoacetic ester-petroleum ether (1:3) elute, obtain light yellow gum thing 2- [1- (butyl -3- alkynes -1- bases epoxide) -1- hydrogen-indoles -3- Base]-N- (3- chloropyridine -4- bases) acetamide (490mg).¹H NMR(400MHz,acetone-d6):δ8.69(1H,brs,N- H), 8.42 (1H, s, H-2 '), 8.35 (2H, m, H-5 ', 6 '), 7.66 (2H, m, H-2,4), 7.58 (1H, d, J=8.0Hz, H- 7), 7.26 (1H, t, J=7.6Hz, H-6), 7.11 (1H, t, J=7.6Hz, H-5), 4.42 (2H, t, J=6.4Hz, H-1 "), 4.01(2H,s,H-8),2.70(2H,m,H-2”),2.56(1H,m,H-4”)；¹³C NMR(400MHz,acetone-d6):δ 170.9(C-9),150.0(C-2’),149.8(C-6’),142.5(C-4’),134.2(C-7a),124.8(C-2),124.6 (C-3’),123.7(C-6),121.0(C-5’),119.9(C-4),115.1(C-3a),109.5(C-7),105.5(C-3), 81.1(C-3”),76.9(C-1),71.7(C-4”),34.6(C-8),19.0(C-2”)；(+)-HR-ESIMS m/z 353.0935[M+H]⁺(calcd for C₁₉H₁₇ClN₃O₂,353.0931)。

Embodiment 85：2- [1- (butyl -2- alkynes -1- bases epoxide) -1- hydrogen-indol-3-yl]-N- (3- chloropyridine -4- bases) The preparation of acetamide

4th step, N- (3- chloropyridine -4- bases) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in the bromo- 2- butine (1.2g) of 1-；Reaction solution Ethyl acetate (50mL) is added, water (50mL) quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is closed And organic phase, saturated aqueous common salt (50mL) is added, 10min, split-phase is quickly stirred；Organic phase is separated through silica gel column chromatography, uses second Acetoacetic ester-petroleum ether (1:3) elute, obtain light yellow gum thing 2- [1- (butyl -2- alkynes -1- bases epoxide) -1- hydrogen-indoles -3- Base]-N- (3- chloropyridine -4- bases) acetamide (416mg).¹H NMR(400MHz,acetone-d6):δ8.69(1H,brs,N- H), 8.43 (1H, s, H-2 '), 8.36 (2H, m, H-5 ', 6 '), 7.65 (2H, m, H-2,4), 7.52 (1H, d, J=8.0Hz, H- 7), 7.25 (1H, t, J=7.6Hz, H-6), 7.10 (1H, t, J=7.6Hz, H-5), 4.90 (2H, s, H-1 "), 4.00 (2H, s, H-8),1.79(3H,s,H-4”)；¹³C NMR(400MHz,acetone-d6):δ170.9(C-9),150.0(C-2’),149.8 (C-6’),142.6(C-4’),134.3(C-7a),125.2(C-2),124.5(C-3’),123.6(C-6),121.0(C-5’), 120.3(C-5),119.8(C-4),115.0(C-3a),109.8(C-7),105.2(C-3),86.9(C-2”),74.2(C- 3”),68.9(C-1”),34.6(C-8),3.4(C-4”)；(+)-HR-ESIMS m/z 353.0942[M+H]⁺(calcd for C₁₉H₁₆ClN₃O₂,353.0931)。

Embodiment 86：The preparation of N- (2- chlorphenyls) -2- [1- (3- chlorine propoxyl group) -1H- indol-3-yls] acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in 3- chlorobromopropanes (1.4g)；Reaction solution adds acetic acid second Ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), merges organic phase, Saturated aqueous common salt (50mL) is added, 10min, split-phase is quickly stirred；Organic phase is separated through silica gel column chromatography, with ethyl acetate-stone Oily ether (1:5) elute, obtain yellow gum thing N- (2- chlorphenyls) -2- [1- (3- chlorine propoxyl group) -1H- indol-3-yls] acetyl Amine (450mg).¹H NMR(400MHz,acetone-d₆):δ 8.47 (1H, brs, NH-1), 8.29 (1H, d, J=8.4Hz, H- 6 '), 7.68 (1H, d, J=8.0Hz, H-4), 7.62 (1H, s, H-2), 7.50 (1H, d, J=8.0Hz, H-3 '), 7.33 (1H, D, J=8.0Hz, H-7), 7.26 (2H, m, H-4 ', 5 '), 7.11 (1H, t, J=7.6Hz, H-6), 7.04 (1H, t, J= 7.6Hz, H-5), 4.46 (2H, t, J=6.0Hz, H-1 "), 3.93 (2H, s, H-8), 3.88 (2H, t, J=6.4Hz, H-3 "), 2.28(2H,m,H-2”)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),136.0(C-1’),133.8(C- 7a),129.8(C-5’),128.3(C-3’),125.5(C-3a,4),124.6(C-2’),124.5(C-2),123.6(C-6), 122.9(C-6’),120.8(C-5),120.0(C-4),109.2(C-7),105.9(C-3),75.8(C-1”),42.0(C- 3”),34.5(C-8),31.9(C-2”)；(+)-HR-ESIMS m/z 377.0824[M+H]⁺(calcd for C₁₉H₁₉Cl₂N₂O₂,377.0818)。

Embodiment 87：2- [1- (3- chlorine propoxyl group) -1- hydrogen-indol-3-yl]-N- (3- chloropyridine -4- bases) acetamide Prepare

4th step, N- (3- chloropyridine -4- bases) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in trimethylene chlorobromide (1.3g)；Reaction Liquid adds ethyl acetate (50mL), and water (50mL) quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), Merge organic phase, add saturated aqueous common salt (50mL), quickly stir 10min, split-phase；Organic phase is separated through silica gel column chromatography, is used Ethyl acetate-light petrol (1:3) elute, obtain light yellow gum thing 2- [1- (3- chlorine propoxyl group) -1- hydrogen-indol-3-yl]-N- (3- chloropyridine -4- bases) acetamide (452mg).¹H NMR(400MHz,acetone-d6):δ8.69(1H,brs,N-H),8.42 (1H, s, H-2 '), 8.35 (2H, m, H-5 ', 6 '), 7.65 (2H, m, H-2,4), 7.51 (1H, d, J=8.4Hz, H-7), 7.26 (1H, t, J=7.6Hz, H-6), 7.11 (1H, t, J=7.6Hz, H-5), 4.47 (2H, t, J=6.4Hz, H-1 "), 4.01 (2H, S, H-8), 3.88 (2H, t, J=6.4Hz, H-3 "), 2.28 (2H, m, H-2 ")；¹³C NMR(400MHz,acetone-d6):δ 170.8(C-9),149.9(C-2’),149.7(C-6’),142.4(C-4’),133.8(C-7a),124.5(C-2),123.7 (C-6),120.9(C-5’),120.2(C-3a),119.9(C-5),115.1(C-4),109.3(C-7),105.2(C-3), 75.8(C-1”),42.0(C-8),34.6(C-3”),31.9(C-2”)；(+)-HR-ESIMS m/z 377.0707[M+H]⁺ (calcd for C₁₈H₁₈Cl₂N₃O₂,377.0698)。

Embodiment 88：2- [1- (4- neoprenes epoxide) -1- hydrogen-indol-3-yl]-N- (3- chloropyridine -4- bases) acetamide Prepare

4th step, N- (3- chloropyridine -4- bases) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in the chloro- 1- NBBs (1.4g) of 4-；Reaction Liquid adds ethyl acetate (50mL), and water (50mL) quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), Merge organic phase, add saturated aqueous common salt (50mL), quickly stir 10min, split-phase；Organic phase is separated through silica gel column chromatography, is used Ethyl acetate-light petrol (1:3) elute, obtain light yellow gum thing 2- [1- (4- neoprenes epoxide) -1- hydrogen-indol-3-yl]-N- (3- chloropyridine -4- bases) acetamide (465mg).¹H NMR(400MHz,acetone-d6):δ8.70(1H,brs,N-H),8.43 (1H, s, H-2 '), 8.36 (2H, m, H-5 ', 6 '), 7.67 (2H, m, H-2,4), 7.49 (1H, d, J=8.4Hz, H-7), 7.27 (1H, t, J=7.6Hz, H-6), 7.11 (1H, t, J=7.6Hz, H-5), 4.38 (2H, t, J=6.4Hz, H-1 "), 4.02 (2H, S, H-8), 3.73 (2H, t, J=6.4Hz, H-4 "), 2.02 (4H, m, H-2 ", 3 ")；¹³C NMR(400MHz,acetone-d6): δ170.9(C-9),149.9(C-2’),149.8(C-6’),142.5(C-4’),133.8(C-7a),124.7(C-2),124.5 (C-3’),123.6(C-6),120.9(C-5’),120.3(C-5),119.9(C-4),115.1(C-3a),109.3(C-7), 105.1(C-3),78.6(C-1”),45.5(C-4”),34.6(C-8),29.9(C-2”),26.5(C-3”)；(+)-HR-ESIMS m/z 391.0858[M+H]⁺(calcd for C₁₉H₁₉Cl₂N₃O₂,391.0854)。

Embodiment 89：The preparation of N- (2- chlorphenyls) -2- (1- Cyanomethoxy -1H- indol-3-yls) acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in chloroacetonitrile (0.68g)；Reaction solution adds ethyl acetate (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), merges organic phase, plus Enter saturated aqueous common salt (50mL), quickly stir 10min, split-phase；Organic phase is separated through silica gel column chromatography, uses ethyl acetate-pet Ether (1:5) elute, obtain brown solid N- (2- chlorphenyls) -2- (1- Cyanomethoxy -1H- indol-3-yls) acetamide (315mg)。 ¹H NMR(400MHz,acetone-d₆):δ 8.56 (1H, brs, NH-1), 8.24 (1H, d, J=8.4Hz, H- 6 '), 7.70 (2H, d, J=6.8Hz, H-2,4), 7.57 (1H, d, J=8.0Hz, H-3 '), 7.35 (1H, d, J=8.4Hz, H- 7), 7.28 (2H, m, H-4 ', 5 '), 7.16 (1H, t, J=7.6Hz, H-5), 5.33 (2H, s, H-10), 3.96 (2H, s, H-2) ；¹³C NMR(400MHz,acetone-d₆):δ169.6(C-9),136.0(C-1’),135.0(C-7a),129.9(C-5’), 128.3(C-3’),125.7(C-4’),125.2(C-3a),125.1(C-2),124.2(C-6,2’),123.3(C-11), 121.7(C-6’),120.2(C-5),116.4(C-4),109.8(C-7),108.1(C-3),63.5(C-10),34.3(C-8)； (+)-HR-ESIMS m/z 340.0844[M+H]⁺(calcd for C₁₈H₁₅ClN₃O₂,340.0847)。

Embodiment 90：The system of N- (3- chloropyridine -4- bases) -2- [1- (Cyanomethoxy) -1H- indol-3-yls] acetamide It is standby

4th step, N- (3- chloropyridine -4- bases) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in bromoacetonitrile (0.9g)；Reaction solution adds second Acetoacetic ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is merged organic Phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, with ethyl acetate- Petroleum ether (1:3) elute, obtain light yellow solid N- (3- chloropyridine -4- bases) -2- [1- (Cyanomethoxy) -1H- indoles -3- Base] acetamide (670mg).¹H NMR(400MHz,acetone-d6):δ8.80(1H,brs,N-H),8.44(1H,s,H-2’), 8.35 (2H, m, H-5 ', 6 '), 7.72 (1H, s, H-2), 7.69 (1H, d, J=8.0Hz, H-4), 7.57 (1H, d, J=8,4Hz, H-7), 7.30 (1H, t, J=7.6Hz, H-6), 7.16 (1H, t, J=7.6Hz, H-5), 5.35 (2H, s, H-1 "), 4.05 (2H, s,H-8)；¹³C NMR(400MHz,acetone-d6):δ170.6(C-9),150.0(C-2’),149.7(C-6’),142.5(C- 4’),134.9(C-7a),125.2(C-2),125.1(C-2”),124.2(C-6),121.8(C-5),120.2(C-4),116.4 (C-3’),115.3(C-5’),109.9(C-7),107.4(C-3),63.6(C-1”),34.4(C-8)；(+)-HR-ESIMS m/ z 340.0731[M+H]⁺(calcd for C₁₇H₁₄ClN₄O₂,340.0727)。

Embodiment 91：The preparation of N- (2- chlorphenyls) -2- [1- (3- hydroxy propyloxy groups) -1H- indol-3-yls] acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (8mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in 3- hydroxyls N-Propyl Bromide (1.25g)；Reaction solution adds second Acetoacetic ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is merged organic Phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, with ethyl acetate- Petroleum ether (1:5) elute, obtain light brown jelly N- (2- chlorphenyls) -2- [1- (3- hydroxy propyloxy groups) -1H- indoles -3- Base] acetamide (340mg).¹H NMR(400MHz,acetone-d₆):δ 8.49 (1H, brs, NH-1), 8.32 (1H, d, J= 8.4Hz, H-6 '), 7.70 (1H, d, J=8.0Hz, H-4), 7.65 (1H, s, H-2), 7.53 (1H, d, J=8.4Hz, H-3 '), 7.37 (1H, d, J=8.0Hz, H-7), 7.29 (2H, m, H-4 ', 5 '), 7.13 (1H, t, J=7.6Hz, H-6), 7.08 (1H, t, J=7.6Hz, H-5), 4.47 (2H, t, J=6.8Hz, H-1 "), 3.96 (2H, s, H-8), 3.83 (3H, H-3 " ,-OH), 2.04 (2H,m,H-2”)；¹³C NMR(400MHz,acetone-d₆):δ170.0(C-9),136.0(C-1’),133.9(C-7a), 129.9(C-5’),128.3(C-3’),125.5(C-3a,4’),124.6(C-2),123.5(C-6’),122.9(C-6,2’), 120.7(C-5),119.9(C-4),109.3(C-7),105.5(C-3),76.4(C-1”),58.7(C-3”),34.5(C-8), 32.3(C-2”)；(+)-HR-ESIMS m/z 359.1165[M+H]⁺(calcd for C₁₉H₂₀ClN₂O₃,359.1157)。

Embodiment 92：N- (3- chloropyridine -4- bases) -2- [1- (3- hydroxy propyloxy groups) -1H- indol-3-yls] acetamide Prepare

4th step, N- (3- chloropyridine -4- bases) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in 3- bromopropyl alcohols (1.0g)；Reaction solution is added Ethyl acetate (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is associated with Machine phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, uses acetic acid second Ester-petroleum ether (1:3) elute, obtain light yellow gum thing N- (3- chloropyridine -4- bases) -2- [1- (3- hydroxy propyloxy groups) -1H- Indol-3-yl] acetamide (150mg).¹H NMR(400MHz,acetone-d6):δ8.70(1H,brs,N-H),8.42(1H, S, H-2 '), 8.36 (2H, m, H-5 ', 6 '), 7.65 (2H, m, H-2,4), 7.51 (1H, d, J=8.0Hz, H-7), 7.24 (1H, T, J=7.6Hz, H-6), 7.10 (1H, t, J=7.6Hz, H-5), 4.44 (2H, t, J=6.4Hz, H-1 "), 4.01 (2H, s, H- 8),3.79(2H,t,H-3”),2.00(2H,m,H-2”)；¹³C NMR(400MHz,acetone-d6):δ170.9(C-9), 149.9(C-2’),149.8(C-6’),142.3(C-4’),133.7(C-7a),124.6(C-2),124.4(C-3a),123.5 (C-6),120.7(C-5),119.8(C-4),115.0(C-3’),114.9(C-5’),109.3(C-7),104.8(C-3), 76.4(C-1”),58.4(C-3”),34.6(C-8),32.1(C-2”)；(+)-HR-ESIMS m/z 359.104[M+H]⁺ (calcd for C₁₈H₁₉ClN₃O₃,359.1037)。

Embodiment 93：N- (3- fluorine pyridin-4-yl) -2- [1- (3- hydroxy propyloxy groups) -1H- indol-3-yls] acetamide Prepare

4th step, N- (3- fluorine pyridin-4-yl) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in bromopropyl alcohol (1.2g)；Reaction solution adds second Acetoacetic ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is merged organic Phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, with ethyl acetate- Petroleum ether (1:3) elute, obtain red brown solid N- (3- fluorine pyridin-4-yl) -2- [1- (3- hydroxy propyloxy groups) -1H- indoles - 3- yls] acetamide (120mg).¹H NMR(400MHz,acetone-d₆):δ9.31(1H,brs,NH-1),8.35(2H,m,H- 2 ', 6 '), 8.27 (1H, d, J=5.2Hz, H-5 '), 7.65 (1H, d, J=8.0Hz, H-4), 7.53 (1H, s, H-2), 7.46 (1H, d, J=8.0Hz, H-7), 7.21 (1H, t, J=7.6Hz, H-6), 7.07 (1H, t, J=7.6Hz, H-5), 4.41 (2H, T, J=6.0Hz, H-1 "), 3.98 (2H, s, H-8), 3.79 (3H, m, H-3 ", H-OH), 1.99 (2H, m, H-2 ")；¹³C NMR (400MHz,acetone-d₆):δ171.1(C-9),147.42(C-2’),147.37(C-6’),138.0(C-3’),137.8 (C-3’),133.8(C-4’),124.7(C-7a),124.3(C-2),123.2(C-6),120.5(C-4),120.0(C-5), 115.6(C-5’),109.3(C-7),105.4(C-3),76.3(C-1”),58.7(C-3”),34.4(C-8),32.3(C-2”)； (+)-HR-ESIMS m/z 343.133[M+H]⁺(calcd for C₁₈H₁₉FN₃O₃,343.1332)。

Embodiment 94：N- (3- chloropyridine -4- bases) -2- [1- (cyclo propyl methoxy) -1H- indol-3-yls] acetamide Prepare

4th step, N- (3- chloropyridine -4- bases) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in bromomethyl cyclopropane (1.2g)；Reaction solution Ethyl acetate (50mL) is added, water (50mL) quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is closed And organic phase, saturated aqueous common salt (50mL) is added, 10min, split-phase is quickly stirred；Organic phase is separated through silica gel column chromatography, uses second Acetoacetic ester-petroleum ether (1:5) elute, obtain light yellow gum thing N- (3- chloropyridine -4- bases) -2- [1- (cyclo propyl methoxy) - 1H- indol-3-yls] acetamide (105mg).¹H NMR(300MHz,acetone-d₆):δ8.62(1H,brs,NH-1),8.39 (1H, s, H-2 '), 8.36 (2H, s, H-5 ', 6 '), 7.63 (1H, d, J=8.1Hz, H-4), 7.54 (1H, s, H-2), 7.51 (1H, d, J=8.4Hz, H-7), 7.20 (1H, t, J=7.8Hz, H-6), 7.07 (1H, t, J=8.1Hz, H-5), 4.11 (2H, D, J=6.9Hz, H-1 "), 4.00 (2H, s, H-8), 0.87 (1H, m, H-2 "), 0.58 (2H, m, H-3 "), 0.44 (2H, m, H- 4”)；¹³C NMR(600MHz,acetone-d₆):δ171.3(C-9),149.9(C-5’,6’),142.5(C-4’),137.8(C- 7a),128.62(C-2’),128.57(C-3’),122.7(C-2),120.1(C-6),119.5(C-5),114.73(C-4), 114.66(C-3a),110.8(C-7),107.6(C-3),50.9(C-1”),35.0(C-8),12.2(C-2”),4.2(C-3”, 4”)；(+)-HR-ESIMS m/z 356.1156[M+H]⁺(calcd for C₁₉H₁₉ClN₃O₂,356.116)。

Embodiment 95：N- (3- fluorine pyridin-4-yl) -2- [1- (cyclo propyl methoxy) -1H- indol-3-yls] acetamide Prepare

4th step, N- (3- fluorine pyridin-4-yl) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in bromopropyl alcohol (1.2g)；Reaction solution adds second Acetoacetic ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is merged organic Phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, with ethyl acetate- Petroleum ether (1:3) elute, obtain red brown solid N- (3- fluorine pyridin-4-yl) -2- [1- (cyclo propyl methoxy) -1H- indoles - 3- yls] acetamide (650mg).¹H NMR(400MHz,acetone-d₆):δ9.28(1H,brs,NH-1),8.35(2H,m,H- 2 ', 6 '), 8.28 (1H, d, J=5.2Hz, H-5 '), 7.65 (1H, d, J=8.0Hz, H-4), 7.53 (1H, s, H-2), 7.46 (1H, d, J=8.0Hz, H-7), 7.20 (1H, t, J=7.6Hz, H-6), 7.06 (1H, t, J=7.6Hz, H-5), 4.08 (2H, D, J=7.2Hz, H-1 "), 3.98 (2H, s, H-8), 1.20 (1H, m, H-2 "), 0.57 (2H, m, H-3 "), 0.28 (2H, m, H- 4”)；¹³C NMR(400MHz,acetone-d₆):δ171.1(C-9),147.44(C-2’),147.39(C-6’),138.0(C- 3’),137.8(C-3’),133.9(C-4’),124.64(C-7a),124.58(C-2),123.2(C-6),120.4(C-5), 119.9(C-4),115.6(C-5’),109.4(C-7),105.4(C-3),83.5(C-1”),34.4(C-8),10.2(C-2”), 3.6(C-3”,4”)；(+)-HR-ESIMS m/z339.1384[M+H]⁺(calcd for C₁₉H₁₉FN₃O₂,339.1383)。

Embodiment 96：N- (3- chloropyridine -4- bases) -2- [1- (3- Cyano-propoxies) -1H- indol-3-yls] acetamide Prepare

4th step, N- (3- chloropyridine -4- bases) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in the bromo- 4- butyronitrile (1.2g) of 1-；Reaction solution Ethyl acetate (50mL) is added, water (50mL) quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is closed And organic phase, saturated aqueous common salt (50mL) is added, 10min, split-phase is quickly stirred；Organic phase is separated through silica gel column chromatography, uses second Acetoacetic ester-petroleum ether (1:3) elute, obtain light yellow gum thing N- (3- chloropyridine -4- bases) -2- [1- (3- Cyano-propoxies) - 1H- indol-3-yls] acetamide (170mg).¹H NMR(400MHz,acetone-d6):δ8.70(1H,brs,N-H),8.42 (1H, s, H-2 '), 8.35 (2H, m, H-5 ', 6 '), 7.67 (2H, m, H-2,4), 7.52 (1H, d, J=8,4Hz, H-7), 7.26 (1H, t, J=7.6Hz, H-6), 7.11 (1H, t, J=7.6Hz, H-5), 4.45 (2H, t, J=6.0Hz, H-1 "), 4.01 (2H, s,H-8),2.78(2H,m,H-3”),2.19(2H,m,H-2”)；¹³C NMR(400MHz,acetone-d6):δ170.8(C-9), 149.9(C-2’),149.8(C-6’),142.5(C-4’),133.8(C-7a),124.6(C-2),123.7(C-6),121.0 (C-3a),120.3(C-3’),120.04(C-4”),119.96(C-5),115.1(C-4),109.3(C-7),105.4(C-3), 77.2(C-1”),34.6(C-8),25.1(C-3”),14.2(C-2”)；(+)-HR-ESIMS m/z 368.1044[M+H]⁺ (calcd for C₁₉H₁₈ClN₄O₂,368.104)。

Embodiment 97：The preparation of methyl 2- [2- (1- acetoxyl group -1H- indol-3-yls) acetamido] benzoic ether

4th step, methyl -2- [2- (1- hydroxyl -1H- indol-3-yls) acetamide] benzoic ether adds dry methylene chloride (20mL), 0~5 DEG C of stirring, adds chloroacetic chloride (0.94g), triethylamine (1.2g), 0~5 DEG C of stirring reaction 1h；Through silicagel column color Spectrum separation, with ethyl acetate-light petrol (1:4) elute, obtain yellow solid methyl -2- [2- (1- acetoxyl group -1H- indoles - 3- yls) acetamide] benzoic ether (410mg).¹H NMR(400MHz,acetone-d₆):δ10.97(1H,brs,NH-1),8.71 (1H, d, J=8.8Hz, H-3 '), 7.94 (1H, d, J=8.0Hz, H-6 '), 7.67 (1H, d, J=8.4Hz, H-4), 7.55 (1H, t, J=7.6Hz, H-4 '), 7.49 (1H, s, H-2), 7.33 (1H, d, J=8.0Hz, H-7), 7.22 (1H, t, J= 7.6Hz,H-5’),7.10(2H,m,H-5,6),3.90(2H,s,H-8),3.73(3H,s,H-11),2.43(3H,s,H-8’)；¹³C NMR(400MHz,acetone-d₆):δ170.2(C-9),169.4(C-7’),168.7(C-10),142.2(C-2’), 135.5(C-7a),135.0(C-4’),131.6(C-6’),125.9(C-2),125.3(C-3a),123.9(C-5’),123.2 (C-6),121.2(C-5),120.8(C-4),120.0(C-3’),116.3(C-1’),109.4(C-7),107.3(C-3), 52.6(C-11),35.6(C-8),18.0(C-8’)；(+)-HR-ESIMS m/z 367.1287[M+H]⁺(calcd for C₂₀H₁₉N₂O₅,367.1288)。

Embodiment 98：The preparation of N- (2- chlorphenyls) -2- (1- acetoxyl group -1H- indol-3-yls) acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide adds dry methylene chloride (20mL), 0~5 DEG C of stirring, adds chloroacetic chloride (0.94g), triethylamine (1.2g), 0~5 DEG C of stirring reaction 1h；Through silicagel column color Spectrum separation, with ethyl acetate-light petrol (1:4) elute, obtain light yellow solid 3- { 2- [(2- chlorphenyls) amino] -2- acetyl Epoxide } -1H- indoles -1- yl acetamides (480mg).¹H NMR(400MHz,acetone-d₆):δ8.52(1H,brs,NH-1), 8.28 (1H, d, J=8.0Hz, H-6 '), 7.69 (1H, d, J=8.4Hz, H-3 '), 7.51 (1H, s, H-2), 7.34 (2H, d, J =8.4Hz, H-4,7), 7.26 (2H, m, H-4 ', 5 '), 7.14 (1H, t, J=7.6Hz, H-6), 7.06 (1H, t, J=7.6Hz, H-5),3.95(2H,s,H-8),2.42(3H,s,H-11)；¹³C NMR(400MHz,acetone-d₆):δ169.7(C-9), 169.4(C-10),136.1(C-1’),135.3(C-7a),129.9(C-5’),128.3(C-3’),125.8(C-4’),125.6 (C-2),125.1(C-3a),124.0(C-6),123.0(C-2’),121.3(C-6’),120.3(C-4),109.4(C-7), 107.4(C-3),34.4(C-8),18.0(C-11)；(+)-HR-ESIMS m/z 343.0845[M+H]⁺(calcd for C₁₈H₁₆ClN₂O₃,343.0849)。

Embodiment 99：The preparation of methyl 2- [2- (1- benzoyloxy -1H- indol-3-yls) acetamide] benzoic ether

4th step, methyl -2- [2- (1- hydroxyl -1H- indol-3-yls) acetamide] benzoic ether adds dry methylene chloride (20mL), 0~5 DEG C of stirring, adds chlorobenzoyl chloride (1.36g), triethylamine (1.2g), 0~5 DEG C of stirring reaction 1h；Through silicagel column Chromatographic isolation, with ethyl acetate-light petrol (1:5) elute, obtain orange-yellow crystal methyl -2- [2- (1- benzoyloxys -1H- Indol-3-yl) acetamide] benzoic ether (568mg).¹H NMR(400MHz,acetone-d₆):δ11.04(1H,brs,NH- 1), 8.73 (1H, d, J=8.8Hz, H-3 '), 8.25 (2H, d, J=8.0Hz, H-2 ", 6 "), 7.96 (1H, d, J=7.6Hz, H- 6 '), 7.82 (1H, t, J=7.6Hz, H-4 "), 7.73 (1H, d, J=8.0Hz, H-4), 7.67 (3H, m, H-2,3 ", 5 "), 7.57 (1H, t, J=7.6Hz, H-4 '), 7.39 (1H, d, J=8.4Hz, H-7), 7.26 (1H, t, J=7.6Hz, H-5 '), 7.17 (1H, t, J=7.6Hz, H-6), 7.11 (1H, t, J=7.6Hz, H-5), 3.97 (2H, s, H-8), 3.81 (3H, s, H- 8’)；¹³C NMR(400MHz,acetone-d₆):δ169.6(C-9),168.1(C-7’),164.6(C-10),141.6(C- 2’),135.4(C-7a),134.9(C-4’),134.4(C-4”),131.0(C-6’),130.3(C-3”,5”),129.4(C- 2”,6”),126.8(C-1”),125.9(C-2),125.0(C-3a),123.5(C-6),122.6(C-5’),120.9(C-5), 120.2(C-3’),119.6(C-4),115.7(C-1’),109.0(C-7),107.3(C-3),52.0(C-8’),35.0(C- 8)；(+)-HR-ESIMS m/z 429.1452[M+H]⁺(calcd for C₂₅H₂₀N₂O₅,429.1445)。

Embodiment 100：The preparation of N- (2- chlorphenyls) -2- (1- benzoyloxy -1H- indol-3-yls) acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide adds dry methylene chloride (20mL), 0~5 DEG C of stirring, adds chlorobenzoyl chloride (1.36g), triethylamine (1.2g), 0~5 DEG C of stirring reaction 1h；Through silicagel column Chromatographic isolation, with ethyl acetate-light petrol (1:4) elute, obtain yellow crystals 3- { 2- [(2- chlorphenyls) amino] -2- oxygen second Base } -1H- indoles -1- yl benzoic acids esters (530mg).¹H NMR(400MHz,acetone-d₆):δ8.60(1H,brs,NH-1), 8.29 (1H, d, J=8.0Hz, H-6 '), 8.240 (2H, d, J=7.6Hz, H-2 ", 6 "), 7.81 (1H, t, J=7.2Hz, H- 4 "), 7.75 (1H, d, J=8.0Hz, H-3 '), 7.66 (3H, m, H-2,3 ", 5 "), 7.38 (2H, m, H-4,7), 7.28 (2H, m, H-4 ', 5 '), 7.18 (1H, t, J=7.6Hz, H-6), 7.07 (1H, t, J=7.6Hz, H-5), 4.01 (2H, s, H-8)；¹³C NMR(400MHz,acetone-d₆):δ169.7(C-9),165.3(C-10),136.1(C-1’),135.8(C-7a),135.6 (C-4”),130.9(C-2”,6”),130.0(C-3”,5”),129.9(C-5’),128.3(C-3’),127.4(C-1”), 126.3(C-4’),125.6(C-2),125.4(C-3a),124.2(C-6),123.1(C-2’,6’),121.6(C-5),120.2 (C-4),109.6(C-7),108.0(C-3),34.4(C-8)；(+)-HR-ESIMS m/z405.1010[M+H]⁺(calcd for C₂₃H₁₈ClN₂O₃,405.1006)。

Embodiment 101：The preparation of methyl 2- [2- (1- benzyloxy -1H- indol-3-yls) acetamide] benzoic ether

4th step, methyl -2- [2- (1- hydroxyl -1H- indol-3-yls) acetamide] benzoic ether, which is added, dries DMF (5mL), is stirred at room temperature, and adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in cylite (1.5g)；Reaction solution adds second Acetoacetic ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is merged organic Phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, with ethyl acetate- Petroleum ether (1:5) elute, obtain yellow solid methyl -2- [2- (1- benzyloxy -1H- indol-3-yls) acetamide] benzoic ether (521mg)。¹H NMR(400MHz,acetone-d₆):δ 10.93 (1H, brs, NH-1), 8.76 (1H, d, J=8.4Hz, H- 3 '), 7.91 (1H, d, J=8.0Hz, H-6 '), 7.56 (5H, m, H-2,4,4 ', 3 ", 5 "), 7.41 (4H, m, H-7,2 ", 4 ", 6 "), 7.19 (1H, t, J=7.6Hz, H-6), 7.06 (2H, m, H-5,5 '), 5.36 (2H, s, H-10), 3.86 (2H, s, H-8), 3.70(3H,s,H-8’)；¹³C NMR(400MHz,acetone-d₆):δ170.7(C-9),168.7(C-7’),142.3(C- 2’),136.0(C-1”),135.0(C-4’),134.0(C-7a),131.5(C-6’),130.6(C-3”,5”),129.8(C- 4”),129.4(C-2”,6”),125.0(C-2),124.8(C-3a),123.3(C-5’),123.1(C-6),120.6(C-1’, 3’),119.7(C-5),116.0(C-1’),109.4(C-7),105.1(C-3),81.2(C-10),52.6(C-8),35.7(C- 8’)；(+)-HR-ESIMS m/z 415.1666[M+H]⁺(calcd for C₂₅H₂₃N₂O₄,415.1652)。

Embodiment 102：The preparation of N- (2- chlorphenyls) -2- (1- benzyloxy -1H- indol-3-yls) acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (5mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in cylite (1.5g)；Reaction solution adds ethyl acetate (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), merges organic phase, plus Enter saturated aqueous common salt (50mL), quickly stir 10min, split-phase；Organic phase is separated through silica gel column chromatography, uses ethyl acetate-pet Ether (1:5) elute, obtain light pink solid N- (2- chlorphenyls) -2- (1- benzyloxy -1H- indol-3-yls) acetamide (537mg)。 ¹H NMR(300MHz,acetone-d₆):δ 8.43 (1H, brs, NH-1), 8.31 (1H, dd, J=8.4,1.2Hz, H-6’),7.35(1H,m,H-2,4,7,3’,4’,5’),7.07(2H,m,H-5,6),5.28(2H,s,H-10),3.90(2H,s, H-8)；¹³C NMR(300MHz,acetone-d₆):δ169.9(C-9),136.0(C-1’),135.8(C-1”),134.0(C- 7a),130.5(C-2”,6”),129.81(C-6’),129.78(C-4”),129.7(C-3’),129.3(C-3”,5”),128.3 (C-5’),125.5(C-4’),124.8(C-2),124.5(C-3a),123.4(C-6),122.9(C-2’),120.7(C-5), 119.9(C-4),109.4(C-7),105.5(C-3),80.9(C-10),34.5(C-8)；(+)-HR-ESIMS m/z 391.1215[M+H]⁺(calcd for C₂₃H₂₀ClN₂O₂,391.1208)。

Embodiment 103：N- (2- chlorphenyls) -2- { 1- [(4- methoxy-benzyls) epoxide] -1H- indol-3-yls } acetamide Preparation

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (8mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), to methoxyl group cylite (1.8g), and reaction 2h is stirred at room temperature；Reaction solution adds second Acetoacetic ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is merged organic Phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, with ethyl acetate- Petroleum ether (1:5) elute, obtain pale red solid N- (2- chlorphenyls) -2- 1- [(4- methoxy-benzyls) epoxide] -1H- indoles - 3- yls } acetamide (728mg).¹H NMR(400MHz,acetone-d₆):δ 8.39 (1H, brs, NH-1), 8.28 (1H, d, J= 8.0Hz, H-6 '), 7.65 (1H, d, J=8.0Hz, H-4), 7.42 (4H, m, H-2,3 ', 2 ", 6 "), 7.34 (1H, d, J= 8.0Hz, H-7), 7.28 (1H, t, J=8.0Hz, H-4 '), 7.20 (1H, t, J=7.6Hz, H-5 '), 7.07 (2H, m, H-5, 6), 6.91 (2H, d, J=8.4Hz, H-3 ", 5 "), 5.22 (2H, s, H-10), 3.88 (2H, s, H-8), 3.76 (3H, s, OMe- 7”)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),161.3(C-4”),136.1(C-1’),134.0(C- 7a),132.3(C-3”,5”),129.9(C-5’),128.3(C-3’),127.9(C-1”),125.5(C-3a),125.0(C- 4’),124.6(C-6,2’),123.4(C-2),122.9(C-6’),120.7(C-5),119.9(C-4),114.7(C-2”, 6”),109.5(C-7),105.4(C-3),80.6(C-10),55.5(C-7”),34.5(C-8)；(+)-HR-ESIMS m/z 421.1312[M+H]⁺(calcd for C₂₄H₂₂ClN₂O₃,421.1313)。

Embodiment 104：N- (2- chlorphenyls) -2- { 1- [(4- methyl-benzyls) epoxide] -1H- indol-3-yls } acetamide Prepare

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (8mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), to methyl bromide benzyl (1.67g), and reaction 2h is stirred at room temperature；Reaction solution adds second Acetoacetic ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), is merged organic Phase, adds saturated aqueous common salt (50mL), quickly stirs 10min, split-phase；Organic phase is separated through silica gel column chromatography, with ethyl acetate- Petroleum ether (1:5) elute, obtain khaki solid N- (2- chlorphenyls) -2- { 1- [(4- methyl-benzyls) epoxide] -1H- indoles -3- Base } acetamide (605mg).¹H NMR(400MHz,acetone-d₆):δ 8.38 (1H, brs, NH-1), 8.28 (1H, d, J= 8.0Hz, H-6 '), 7.65 (1H, d, J=8.0Hz, H-4), 7.39 (5H, m, H-2,7,3 ', 2 ", 6 "), 7.28 (1H, t, J= 8.0Hz,H-4’),7.20(3H,m,H-5’,3”,5”),7.07(2H,m,H-5,6),5.25(2H,s,H-10),3.88(2H,s, H-8),2.31(3H,s,H-7”)；¹³C NMR(400MHz,acetone-d₆):δ169.3(C-9),139.1(C-4”),135.5 (C-1’),133.4(C-7a),132.3(C-1”),130.1(C-3”,5”),129.4(C-2”,6”),129.3(C-5’), 127.7(C-3’),124.9(C-4’),124.3(C-2),124.0(C-3a),122.8(C-6’),122.3(C-6,2’), 120.1(C-5),119.3(C-4),108.9(C-7),104.9(C-3),80.2(C-10),33.9(C-8),20.6(C-7”)； (+)-HR-ESIMS m/z 405.1359[M+H]⁺(calcd for C₂₄H₂₂ClN₂O₂,405.1364)。

Embodiment 105：The preparation of N- (2- chlorphenyls) -2- (1- benzene ethyoxyl -1H- indol-3-yls) acetamide

4th step, N- (2- chlorphenyls) -2- (1- hydroxyl -1H- indol-3-yls) acetamide, which is added, dries DMF (8mL), room Temperature stirring, adds Anhydrous potassium carbonate (1.66g), and reaction 2h is stirred at room temperature in bromo ethyl phenenyl (1.65g)；Reaction solution adds acetic acid second Ester (50mL), water (50mL), quickly stirs 10min, split-phase；Aqueous phase is extracted with ethyl acetate (25mL × 2), merges organic phase, Saturated aqueous common salt (50mL) is added, 10min, split-phase is quickly stirred；Organic phase is separated through silica gel column chromatography, with ethyl acetate-stone Oily ether (1:5) elute, obtain violet gum thing N- (2- chlorphenyls) -2- (1- benzene ethyoxyl -1H- indol-3-yls) acetamide (566mg)。 ¹H NMR(400MHz,acetone-d₆):δ 8.43 (1H, brs, NH-1), 8.28 (1H, d, J=8.4Hz, H- 6 '), 7.65 (1H, d, J=8.0Hz, H-4), 7.57 (1H, s, H-2), 7.31 (8H, m, 7,3 ', 4 ' 2 ", 3 ", 4 ", 5 ", 6 "), 7.18 (1H, t, H-5 '), 7.06 (2H, m, H-5,6), 4.54 (2H, t, J=6.8Hz, H-10), 3.91 (2H, s, H-8), 3.14 (2H, t, J=6.8Hz, H-11)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),138.8(C-1’),136.1 (C-1”),133.9(C-7a),129.9(C-3”,5”),129.8(C-4”),129.3(C-2”,6”),128.4(C-5’), 127.4(C-3’),125.5(C-4’),124.61(C-2),124.58(C-6’),123.5(C-3a),122.9(C-2’6), 120.8(C-5),119.9(C-4),109.3(C-7),105.7(C-3),79.7(C-10),35.3(C-11),34.5(C-8)； (+)-HR-ESIMS m/z 405.1345[M+H]⁺(calcd for C₂₄H₂₂ClN₂O₂,405.1364)。

Pharmacological evaluation

Experimental example 1, anti HIV-1 virus activity

(1) recombinant virus screening principle

This model applies VSV G/HIV recombinant virus modelling techniques, will express vesicular stomatitis virus coat protein (pNL4-3. can for (Vesicular stomatitis virus glycoprotein, VSV-G) and expression HIV-1 core genes For wild strain or the persister containing mutational site) plasmid co-transfection to 293T cells, the VSV-G and HIV-1 cores of cell expression The heart can be assembled into recombinant virus.The characteristics of recombinant virus is by env, vpr and nef gene knockout in HIV genomes, therefore again Group virion is only capable of Single-infection cell and in the cell reproducible, can be without the ability for repacking and breeding Routine Test Lab is operated；Expressing luciferase gene is introduced at nef genes, can be anti-by determining reporter gene expression Answer HIV levels of replication [Cao Ying jasmine Guo Ying application pseudovirus technical research HIV-1 replication inhibitors Acta Pharmaceutica Sinicas, 2008, 43:253-258.]。

(2) experimental method

The previous day is infected, 293T cells are pressed into cell number 5 × 10⁴/ hole is inoculated into 24 orifice plates.This implementation is dissolved with DMSO Compound or positive drug (NVP or efavirenz) in example.Infection adds testing compound/positive drug in first 15 minutes Thing (final concentration of 0.1%) of DMSO, using DMSO as solvent control, using NVP and efavirenz as positive control.Add Virus stock solution used (is diluted to 0.1-0.5n g p24/mL) by 0.5mL recombinant viruses liquid according to p24 concentration.48h after infection, is removed Culture medium, the cracking of 50 μ L cell pyrolysis liquids (Prome ga) is added per hole, takes 20 μ L product of cell lysis to add to 30 μ L fluorescence In plain zymolyte, mix, the relative activity of luciferase in cell is determined with FB12 fluorescence detectors, the strong and weak reaction of its activity HIV levels of replication is strong and weak, using DMSO as control, the results are shown in Table 1 and table 2.

(3) experimental result

1), to wild HIV replication activities evaluation result

The present invention have studied embodiment compound 1-105 Anti-HIV-1 Actives, as a result find that 57 compounds have compared with high inhibition Wild HIV-1 is active (half-inhibition concentration 10nM~20 μM, table 1), wherein the activity of embodiment 69,81,97,105 and clinic one Line non-nucleoside reverse transcriptase suppresses medicine NVP quite, the activity of embodiment 74,93,95,98,99,104,110 better than how Wei Laping, the results are shown in Table 1 and table 2.

The part of compounds of table 1. suppresses wild HIV-1 replication activities evaluation result in vitro

2), to resistance HIV-1 replication activity evaluation results

HIV-1 is RNA virus, and its reverse transcriptase lacks calibration function, causes the fidelity of the virus replication relatively low, in medicine Under thing selection pressure, mutant drug-resistant strain existence, wild type is then suppressed, so that persister is largely bred, is occurred resistance to Medicine phenomenon, is the difficult point for the treatment of AIDS.Anti-AIDS non-nucleoside reverse transcriptase inhibitor NVP (NVP), draw Wei Pyridine (DLV) and in accordance with the law polyvinyl (EFV) are through the clinical practice of more than ten years, existing resistance strain in patient's body.ETR and RPV respectively at Approval listing in 2009 and 2011.Clinical studies show, patient on medication occurs for both in vivo after 48 weeks The drug-resistant virus of medicine.Therefore lasting research and development are still the weight in antiviral drugs research and development field for the medicine of resistance HIV-1 strains Problem is wanted, the present invention determines 17 target compounds and clinical two kinds of non-nucleoside reverse transcriptases of occurrence probability highest are suppressed Agent medicament-resistant mutation strain HIV-1_RT-K103N(occurrence probability 11%) and HIV-1_RT-Y181CInhibitory activity [Cao of (occurrence probability 3%) Clever jasmine, Li Shaoxiong, Chen Hong, the foundation of Guo Ying non-nucleoside reverse transcriptase inhibitor drug-resistant type HIV-1 Pharmacological Evaluation systems, medicine Learn journal, 2009,44:355-361.], as a result show inhibitory activity and resistance of wherein 14 compounds to two kinds of resistance strains Multiple is superior to NVP (table 2).

The part of compounds of table 2. suppresses resistance HIV-1 replication activity evaluation results in vitro

Experimental example 2, anti-influenza virus activity

(1) preparation of influenza virus：

Acted on for the anti influenza of detection compound, we are prepared for human influenza virus A type A/Puerto Rico/8/1934 (H1N1), 262/95 (H1N1), A type A/ capital anti-/ 359/95 are prevented in A type A/ Hubei Hong Shan/50/2005 (H1N1), A type A/ capital (H3N2), A type A/ Jis prevent/15/90 (H3N2) and B-mode B/ Jiangxi it is newly-built/BV/39/2008, preparation method is as follows：By virus Liquid storage is inoculated with the allantoic cavity and amniotic cavity of instar chicken embryo on the 9th, and 35 DEG C of culture chicken embryos are after 2-3 days, the disease in harvest allantoic fluid and amniotic fluid Poison, is dispensed after centrifugation, -70 DEG C of preservations.From the sensitive cells strain mdck cell (MDCK) of suitable influenza virus growth For virus infected cell, DMEM+0.2%BSA+2 μ g/mlTPCK are viral maintaining liquid, and virus liquid 10 times of gradient dilutions of work are connect Plant in mdck cell, each gradient sets 3 multiple holes, after 37 DEG C are cultivated 3 days, observes cytopathy, and according to Reed-Muench side Method calculates viral median infective dose (TCID₅₀)。

(2) compound suppresses the cytopathy of influenza infection host cell

The previous day is infected, by every hole 3 × 10⁴Mdck cell is inoculated in 96 orifice plates, cell culture medium by the density of individual cell For DMEM+10%FBS (GIBCO), cell culture condition is 37 DEG C, 5%CO₂.The infection same day, mdck cell length to 90-100% Cell culture fluid is discarded after full, cell is washed 2 times with PBS solution (pH7.4), 1 (row is washed with plasma-free DMEM medium Except the interference of serum infected by influenza host cells infected).By influenza virus A type A/Puerto Rico/8/1934 (H1N1), A type A/ Hubei Hong Shan/50/2005 (H1N1), A type A/ capital prevent 262/95 (H1N1), A type A/ Jis prevent/15/90 (H3N2) and B-mode B/ Jiangxi is newly-built/and BV/39/2008 virus liquids are diluted to 100TCID respectively₅₀、316TCID₅₀、100TCID₅₀、100TCID₅₀ And 43TCID₅₀, add in cell hole, while setting the normal cell controls group for being not added with virus and only adding virus, be not added with compound Virus control group, 37 DEG C be incubated 2 hours after discard viral solution, wash 2 times with PBS solution (pH7.4), with serum-free DMEM training Base is supported to wash 1 time.With viral maintaining liquid diluted compounds, per the μ l of hole 100, every group sets 4 multiple holes, 37 DEG C, 5%CO₂Culture 3 days Observation cytopathy (CPE), and the half-inhibition concentration that compound suppresses virus infection is calculated according to Reed-Muench methods afterwards (IC₅₀)。

(3) experimental result

The present invention have studied embodiment compound 1-105 anti-influenza virus activities, as a result find that 65 compounds have stronger Suppress A/Puerto Rico/8/1934 (H1N1) infection activity (1.7 μM of half-inhibition concentration~77 μM, table 3), wherein implementing The activity of example compound 35 and 47 is better than clinical first-line drug Ribavirin.Inventor also measured were this anti-A type stream of 2 compounds 262/95 (H1N1), A type A/ capital anti-/ 359/95 are prevented in Influenza Virus A/ Hubei Hong Shan/50/2005 (H1N1), A type A/ capital (H3N2), A type A/ Jis prevent/15/90 (H3N2) and B-mode B/ Jiangxi it is newly-built/BV/39/2008 infection activities, as a result show, it Activity be superior to clinical first-line drug Tamiflu (table 4).This result shows that such compound not only has to influenza A virus Good inhibitory action, the barrier effect replicated to influenza B virus has wide also superior to existing medicine, i.e., such compound Compose anti influenza effect.

Table 3 compound infected by influenza A/Puerto Rico/8/1934 (H1N1) infection activity evaluation result

Compound infected by influenza A type A/ Hubei Hong Shan/50/2005 (H1N1) of table 4, A type A/ capital anti-262/95 (H1N1), A type A/ capital prevent/359/95 (H3N2), A type A/ Jis prevent/15/90 (H3N2) and B-mode B/ Jiangxi it is newly-built/BV/39/ 2008 infection activity evaluation results

ND:Not detect.

Claims

1. a class Benzazole compounds and its pharmaceutically acceptable salt are preparing prevention, alleviated and/or treatment HIV medicines or guarantor Application in strong product, it is characterised in that described compound is as shown in logical formula (I)：

Wherein,

N is selected from 1,2,3,4 integer；

X is selected from hydrogen, substituted or unsubstituted C_1-16Alkyl, C_3-6Cycloalkyl, C_1-6Alkanoyl, substituted or unsubstituted benzyl, substitution Or unsubstituted benzoyl；Wherein described substituent is optionally by following substituent group：OH、C_1-6Alkyl, C_1-6Alkoxy, halogen Element, NH₂、NO₂, cyano group, carboxyl, phenyl, C_1-6Unsaturated alkyl, C_3-6Cycloalkyl, C_1-6Alkoxy acyl；

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

Z is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridine radicals；Wherein described substituent is optionally by following base Group's substitution：Halogen, C_1-6Alkyl, C_1-6Alkoxy, cyano group, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C_1-6Alkoxy acyl.

2. application according to claim 1, it is characterised in that shown in the compound such as formula (IA)

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

3. application according to claim 2, it is characterised in that shown in the compound such as formula (IA1)

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

R₁To be monosubstituted or polysubstituted, selected from hydrogen, halogen, C_1-6Alkyl, C_1-6Alkoxy, cyano group, trifluoromethyl, nitro, hydroxyl, Amino, carboxyl, C_1-6Alkoxy acyl；Wherein described is monosubstituted monosubstituted selected from ortho position, meta, contraposition；Described polysubstituted choosing From two substitutions, three substitutions, four substitutions, five substitutions.

4. application according to claim 3, it is characterised in that shown in the compound such as formula (IA1a)

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

5. application according to claim 3, it is characterised in that shown in the compound such as formula (IA1b)

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

6. application according to claim 3, it is characterised in that shown in the compound such as formula (IA1c)

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

7. application according to claim 3, it is characterised in that shown in the compound such as formula (IA1d)

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

8. application according to claim 3, it is characterised in that shown in the compound such as formula (IA1e)

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

9. application according to claim 3, it is characterised in that shown in the compound such as formula (IA1f)

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

10. application according to claim 3, it is characterised in that shown in the compound such as formula (IA1g)

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

11. application according to claim 3, it is characterised in that shown in the compound such as formula (IA1h)

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

12. application according to claim 3, it is characterised in that shown in the compound such as formula (IA1i)

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

R₁To be monosubstituted or polysubstituted, selected from hydrogen, halogen, C_1-6Alkyl, C_1-6Alkoxy, cyano group, trifluoromethyl, nitro, hydroxyl, Amino, carboxyl, C_1-6Alkoxy acyl；Wherein described is monosubstituted monosubstituted selected from ortho position, meta, contraposition；Described polysubstituted choosing From two substitutions, three substitutions, four substitutions, five substitutions；

R₁' it is selected from hydrogen, halogen, C_1-6Alkyl, C_1-6Alkoxy.

13. application according to claim 3, it is characterised in that shown in the compound such as formula (IA1j)

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

R₁" it is selected from C_1-6Alkyl, phenyl.

14. application according to claim 2, it is characterised in that shown in the compound such as formula (IA2)

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

R₂To be monosubstituted or polysubstituted, selected from hydrogen, halogen, C_1-6Alkyl, C_1-6Alkoxy, cyano group, trifluoromethyl, nitro, hydroxyl, Amino, carboxyl, C_1-6Alkoxy acyl；The wherein described monosubstituted ortho position selected from amide groups, meta are monosubstituted；It is described to take more In generation, is selected from two substitutions, three substitutions, four substitutions.

15. application according to claim 2, it is characterised in that shown in the compound such as formula (IA2 ')

X is selected from substituted or unsubstituted C_1-6Alkyl；Wherein described substituent is optionally by following substituent group：OH、C_1-6Alkyl, C_1-6Alkoxy, halogen, NH₂、NO₂, cyano group, carboxyl, phenyl, C_1-6Unsaturated alkyl, C_3-6Cycloalkyl, C_1-6Alkoxy acyl；

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

16. application according to claim 14, it is characterised in that shown in the compound such as formula (IA2a)

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

17. application according to claim 14, it is characterised in that shown in the compound such as formula (IA2b)

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

18. application according to claim 14, it is characterised in that shown in the compound such as formula (IA2c)

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

19. application according to claim 14, it is characterised in that shown in the compound such as formula (IA2d)

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

20. application according to claim 14, it is characterised in that shown in the compound such as formula (IA2e)

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

21. application according to claim 2, it is characterised in that shown in the compound such as formula (IA3)

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

R₂To be monosubstituted or polysubstituted, selected from hydrogen, halogen, C_1-6Alkyl, C_1-6Alkoxy, cyano group, trifluoromethyl, nitro, hydroxyl, Amino, carboxyl, C_1-6Alkoxy acyl；The wherein described monosubstituted ortho position selected from amide groups, meta, align it is monosubstituted；Described It is polysubstituted to be selected from two substitutions, three substitutions, four substitutions.

22. application according to claim 2, it is characterised in that shown in the compound such as formula (IA4)

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

23. application according to claim 1, it is characterised in that shown in the compound such as formula (IB)

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

24. application according to claim 1, it is characterised in that shown in the compound such as formula (IC)

Y is selected from hydrogen, halogen, cyano group, carboxyl, C_1-6Alkyl；

25. application according to claim 1, it is characterised in that the compound is selected from following group：

26. the application as described in claim any one of 1-25, it is characterised in that the preparation method of the compound is as follows：

Wherein any one of R, n, Y, Z definition and claim 1-25 are identical

Substituted 3- indole-carboxylic acids (formula 1) carry out amidation process with various amine and obtain formula 2, and formula 2 obtains intermediate by reduction Formula 3；Substituted indoles (formula 4) obtains formula 5 with acyl chloride reaction, then obtains formula 6 from different amine progress amidation process, then passes through Reduction obtains formula 7；Intermediate formula 3 and formula 7 obtain object formula 8 through peroxidating and N- substitutions, then through indoles 2- replace To object formula 9.

27. a kind of application of pharmaceutical composition in preparing prevention, alleviating and/or treating HIV medicines or health products, its feature exists Contain any one of the claim 1-25 of therapeutically effective amount compound and its pharmaceutically acceptable in, the pharmaceutical composition Salt, and pharmaceutically acceptable carrier.