CN107151223A - Purposes of the one class N- alkyl-indol class compounds in anti-influenza virus medicament is prepared - Google Patents

Purposes of the one class N- alkyl-indol class compounds in anti-influenza virus medicament is prepared Download PDF

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CN107151223A
CN107151223A CN201610136876.8A CN201610136876A CN107151223A CN 107151223 A CN107151223 A CN 107151223A CN 201610136876 A CN201610136876 A CN 201610136876A CN 107151223 A CN107151223 A CN 107151223A
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alkyl
monosubstituted
substitutions
halogen
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CN107151223B (en
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石建功
郭颖
徐成博
陈勍
陈明华
霸明宇
朱承根
唐克
蒋建东
郭家梅
郭庆兰
林生
杨永春
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The invention discloses a class as led to the Benzazole compounds shown in formula (I), and application of its pharmaceutically acceptable salt in anti-influenza virus medicament or health products is prepared；And disclose the preparation method of such compound and application of the pharmaceutical composition in anti-influenza virus medicament or health products is prepared containing such compound.

Description

Purposes of the one class N- alkyl-indol class compounds in anti-influenza virus medicament is prepared
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), it is non- Structural proteins (Non-structural protein1, NS1；Non-structural protein 2,NS2).Strains of influenza viruses It is numerous, is divided into influenza A virus according to the antigenic difference of virus envelope protein hemagglutinin HA and neuraminidase NA many Kind of hypotype, has 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 is spread out The compositions such as biology, tryptamines ketone, 2,4 (1H, 3H)-quinoline azoles diketone, adenosine have certain antitumor, antibacterial and antiviral respectively Deng pharmacological activity[20~22]；The compositions such as syringic acid, salicylic acid, ortho-aminobenzoic acid, benzoic acid and 4 (3H)-quinazolones have significantly The effects such as antiendotoxin, suppression TNF α and NO releases[23-30], and suppress the activity of 5-LO or reduce cell secretion in vain The effect of triolefin B (4) level[31~33].Yet with the limitation of sample size and Pharmacological Evaluation model, most compounds are not Determination of activity evaluation is carried out, has particularly reported that content and activity intensity of compound etc. are difficult to and isatis root extract and separated It is anti-a variety of viral strongly active corresponding that position is shown.The antiviral activity in isatis root extract is into subhead as can be seen here Before be not fully understood.
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 alkyl-substituted labyrinth derivative[39], but it is not found Have AntiHIV1 RT activity and anti-influenza virus activity.
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36) Wang Xiaoliang, Chen Minghua, Wang Fang, Bu Pengbin, woods life *, Zhu Chenggen, Li Yuhuan, Jiang Jiandong, stone are made contributions Radix Isatidis The chemical constitution study CHINA JOURNAL OF CHINESE MATERIA MEDICAs 2013,38,1172-1182. of water extract
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38)T.Wan g,Z.Yin,Z.Zhan g,J.A.Bender,Z.Yan g,g.Johnson,Z.Yan g, L.M.Zadjura,C.J.D’Arienzo,D.D.Parker,C.gesenber g,g.A.Yamanaka,Y.-F.gon g,H.- T.Ho,H.Fan g,N.Zhou,B.V.McAuliffe,B.J.E g gers,L.Fan,B.Nowicka-Sans, I.B.Dicker,Q.gao,R.J.Colonno,P.-F.Lin,N.A.Meanwell and J.F.Kadow,Inhibitors of human immunodeficiency virus type 1(HIV-1)attachment.5.an evolution from indole to azaindoles leadin g to the discovery of1-(4-benzoylpiperazin-1-yl)- 2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione(BMS-488043),a dru g candidate that demonstrates antiviral activity in HIV-1infected subjects,J.Med.Chem.,2009,52(23),7778–7787
39)WUCHERPFENNIG KAI W[US]；NICHOLSON MELISSA JOY[NZ]；XING XUECHAO [US]；STEIN ROSS L[US]；CUNY GREGORY[US],WO2008121836(A1)
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,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, Position, contraposition are monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
X is selected from substituted or unsubstituted C1-16Alkyl；Wherein described substituent is optionally by following substituent group：OH、C1-6 Alkyl, C1-6Alkoxy, halogen, NH2、NO2, cyano group, carboxyl, phenyl, C1-6Unsaturated alkyl, C3-6Cycloalkyl, C1-6Alcoxyl acyl Base；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl；
Z is selected from carbon atom or nitrogen-atoms.
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 halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, Position, contraposition are monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
X is selected from substituted or unsubstituted C1-16Alkyl；Wherein described substituent is optionally by following substituent group：OH、C1-6 Alkyl, C1-6Alkoxy, halogen, NH2、NO2, cyano group, carboxyl, phenyl, C1-6Unsaturated alkyl, C3-6Cycloalkyl, C1-6Alcoxyl acyl Base；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
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
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, Position, contraposition are monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
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
Wherein,
X is selected from substituted or unsubstituted C1-16Alkyl；Wherein described substituent is optionally by following substituent group：OH、C1-6 Alkyl, C1-6Alkoxy, halogen, NH2、NO2, cyano group, carboxyl, phenyl, C1-6Unsaturated alkyl, C3-6Cycloalkyl, C1-6Alcoxyl acyl Base；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
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
Wherein,
X is selected from substituted or unsubstituted C1-16Alkyl；Wherein described substituent is optionally by following substituent group：OH、C1-6 Alkyl, C1-6Alkoxy, halogen, NH2、NO2, cyano group, carboxyl, phenyl, C1-6Unsaturated alkyl, C3-6Cycloalkyl, C1-6Alcoxyl acyl Base；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
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
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, Position, contraposition are monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
X is selected from substituted or unsubstituted C1-16Alkyl；Wherein described substituent is optionally by following substituent group：OH、C1-6 Alkyl, C1-6Alkoxy, halogen, NH2、NO2, cyano group, carboxyl, phenyl, C1-6Unsaturated alkyl, C3-6Cycloalkyl, C1-6Alcoxyl acyl Base；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IB1) Thing and its pharmaceutically acceptable salt
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, Position, contraposition are monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IB2) Thing and its pharmaceutically acceptable salt
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, Position, contraposition are monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IB3) Thing and its pharmaceutically acceptable salt
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, Position, contraposition are monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IB4) Thing and its pharmaceutically acceptable salt
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, Position, contraposition are monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IB5) Thing and its pharmaceutically acceptable salt
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, Position, contraposition are monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IB6) Thing and its pharmaceutically acceptable salt
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, Position, contraposition are monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IB7) Thing and its pharmaceutically acceptable salt
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, Position, contraposition are monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IB8) Thing and its pharmaceutically acceptable salt
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, Position, contraposition are monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IB9) Thing and its pharmaceutically acceptable salt
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, Position, contraposition are monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IB10) Thing and its pharmaceutically acceptable salt
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, Position, contraposition are monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IB11) Thing and its pharmaceutically acceptable salt
Wherein,
X is selected from substituted or unsubstituted C1-16Alkyl；Wherein described substituent is optionally by following substituent group：OH、C1-6 Alkyl, C1-6Alkoxy, halogen, NH2、NO2, cyano group, carboxyl, phenyl, C1-6Unsaturated alkyl, C3-6Cycloalkyl, C1-6Alcoxyl acyl Base；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to chemical combination shown in formula (IB12) Thing and its pharmaceutically acceptable salt
Wherein,
X is selected from substituted or unsubstituted C1-16Alkyl；Wherein described substituent is optionally by following substituent group：OH、C1-6 Alkyl, C1-6Alkoxy, halogen, NH2、NO2, cyano group, carboxyl, phenyl, C1-6Unsaturated alkyl, C3-6Cycloalkyl, C1-6Alcoxyl acyl Base；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
It is preferred that formula (I) compound and its pharmaceutically acceptable salt include but is not limited to formula (I), (IA), (IA2), (IA3), (IB), (IB11), the compound shown in (IB12) and its pharmaceutically acceptable salt,
Wherein X is selected from substituted or unsubstituted C1-6Alkyl；Wherein described substituent is optionally by following substituent group：OH、 C1-6Alkyl, C1-6Alkoxy, halogen, NH2、NO2, cyano group, carboxyl, phenyl, C1-6Unsaturated alkyl, C3-6Cycloalkyl, C1-6Alcoxyl Acyl group；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
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, X, Y, Z definition is as described in the first aspect of the invention
Substituted 3- indole-carboxylic acids (formula 1) carry out N- substitution reactions in the basic conditions, obtain N- alkylates formula 2, Formula 2 carries out amidation process from different amine again and obtains target product formula 3.
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 to1-16During alkyl ", its refer to carbon number for 1,2,3,4,5,6,7,8,9,10,11, 12nd, 13,14,15,16 alkyl, can include C2-16Alkyl, C2-10Alkyl, C3-8Alkyl, C2-6Alkyl, C3-5The expressions such as alkyl The group of subrange, and preferred specific group such as ethyl, n-propyl, isopropyl, normal-butyl, n-pentyl, n-hexyl, secondary Butyl, the tert-butyl group, further preferred normal-butyl；" the C for example referred to1-6During alkyl ", it is 1,2,3,4,5,6 that it, which refers to carbon number, Alkyl, C can be included1-5Alkyl, C1-4Alkyl, C2-5Alkyl, C2-4Alkyl, C2-3Alkyl, C3-5The subrange of the expressions such as alkyl Group, and preferred specific group such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, the tert-butyl group.
As mentioned by the present invention, term " C3-6Cycloalkyl ", it refers to the cycloalkyl that carbon number is 3,4,5,6, can wrapped Include C3-5Cycloalkyl, C3-4Cycloalkyl, C4-6Cycloalkyl, C4-5Cycloalkyl, C5-6Cycloalkyl, 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 " C1-6Alkoxy ", it refers to the alkoxy that carbon number is 1,2,3,4,5,6, can With including C1-5Alkoxy, C1-2Alkoxy, C2-4Alkoxy, C2-3Alkoxy, C3-4The 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 " C1-6Alkoxy acyl ", it refers to the alcoxyl acyl that carbon number is 1,2,3,4,5,6 Base, can include C1-5Alkoxy acyl, C1-3Alkoxy acyl, C2-5Alkoxy acyl, C2-3Alkoxy acyl, C3-4Alkoxy 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 " C1-6Unsaturated alkyl ", it refers to the insatiable hunger that carbon number is 1,2,3,4,5,6 And alkyl, C can be included1-5Unsaturated alkyl, C1-4Unsaturated alkyl, C2-5Unsaturated alkyl, C2-4Unsaturated 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.
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 0.03 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 0.64 μM, excellent In clinical first-line drug Ribavirin, prevent in anti-influenza A virus A/ Hubei Hong Shan/50/2005 (H1N1), A type A/ capital 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 aspect it is excellent In clinical 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 methyl 2- [2- (1- ethyl -1H- indol-3-yls) acetamido] benzoic ether
The first step, weighs heteroauxin (1.05g), adds stirring and dissolving in DMF (5mL), is cooled to 0~5 DEG C of stirring；Plus Enter 60% sodium hydride (0.72g), stir 10min, add bromoethane (0.98g), 0~5 DEG C of reaction 0.5h is slowly increased to room temperature anti- Answer 2h；Add ethyl acetate (40mL), water (40mL)；6N hydrochloric acid solution 10mL are added dropwise in quick stirring, 2mim, 5min is stirred； Split-phase, aqueous phase is extracted with ethyl acetate (20mL), split-phase, combined ethyl acetate phase；Saturated aqueous common salt (30mL) is added quickly to stir 5min, split-phase are mixed, 50 DEG C of removal of solvent under reduced pressure of ethyl acetate phase obtain first step product crude product 2- (1- ethyl -1H- indoles -3- Base) acetic acid.
Second step, first step product 2- (1- ethyl -1H- indol-3-yls) acetic acid is added in dichloromethane (20mL) and stirred, EDCI (1.27g), stirring and dissolving are added at room temperature；Methyl anthranilate (1g) is 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； Organic phase is through pillar layer separation, with ethyl acetate-light petrol (1:5) elute, obtain light yellow solid methyl -2- (2- (1- second Base -1H- indol-3-yls) acetylamino) benzoic ether (1.1g).1H NMR(400MHz,acetone-d6):δ10.89(1H, Brs, N-H), 8.75 (1H, d, J=7.6Hz, H-3 '), 7.89 (1H, d, J=8.0Hz, H-6 '), 7.55 (2H, m, H-4,4 '), 7.42 (2H, m, H-2,7), 7.15 (1H, t, J=7.6Hz, H-6), 7.04 (2H, m, H-5,5 '), 4.27 (2H, m, H-10), 3.87 (2H, s, H-8), 3.70 (3H, s, H-8 '), 1.49 (3H, t, J=7.2Hz, H-11)；13C NMR(400MHz, acetone-d6):δ171.2(C-9),168.5(C-7’),142.3(C-2’),137.3(C-7a),135.0(C-4’),131.5 (C-6’),129.0(C-3a),128.4(C-2),123.0(C-5’),122.3(C-6),120.6(C-4),119.8(C-3’), 119.5(C-5),116.0(C-1’),110.3(C-7),107.8(C-3),52.5(C-8’),41.4(C-10),35.9(C-8), 15.8(C-11)；(+)-HR-ESIMS m/z 337.1546[M+H]+(calcd for C20H20N2O3,337.1507)。
Embodiment 2：The preparation of methyl 2- [2- (1- propyl group -1H- indol-3-yls) acetamido] benzoic ether
The first step, weighs heteroauxin (1.05g), adds stirring and dissolving in DMF (5mL), is cooled to 0~5 DEG C of stirring；Plus Enter 60% sodium hydride (0.72g), stir 10min, add N-Propyl Bromide (1.1g), 0~5 DEG C of reaction 0.5h is slowly increased to room temperature anti- Answer 2h；Add ethyl acetate (40mL), water (40mL)；6N hydrochloric acid solution 10mL are added dropwise in quick stirring, 2mim, 5min is stirred； Split-phase, aqueous phase is extracted with ethyl acetate (20mL), split-phase, combined ethyl acetate phase；Saturated aqueous common salt (30mL) is added quickly to stir 5min, split-phase are mixed, 50 DEG C of removal of solvent under reduced pressure of ethyl acetate phase obtain first step product crude product 2- (1- propyl group -1H- indoles -3- Base) acetic acid.
Second step, first step product 2- (1- propyl group -1H- indol-3-yls) acetic acid is added in dichloromethane (20mL) and stirred, EDCI (1.27g), stirring and dissolving are added at room temperature；Methyl anthranilate (1g) is 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； Organic phase is through pillar layer separation, with ethyl acetate-light petrol (1:5) elute, obtain light yellow solid methyl -2- (2- (1- third Base -1H- indol-3-yls) acetylamino) benzoic ether (1.15g).1H NMR(400MHz,acetone-d6):δ10.90(1H, S, N-H), 8.76 (1H, d, J=8.4Hz, H-3 '), 7.89 (1H, d, J=8.0Hz, H-6 '), 7.54 (2H, m, H-4,4 '), 7.44 (1H, d, J=8.0Hz, H-7), 7.39 (1H, s, H-2), 7.15 (1H, t, J=7.6Hz, H-6), 7.04 (2H, m, H-5, 5 '), 4.19 (2H, t, J=7.2Hz, H-10), 3.92 (2H, s, H-8), 3.70 (3H, s, H-8 '), 1.92 (2H, m, H-11), 0.96 (3H, t, J=7.2Hz, H-12)；13C NMR(400MHz,acetone-d6):δ171.2(C-9),168.5(C-7’), 142.4(C-2’),137.7(C-7a),135.0(C-4’),131.5(C-6’),129.0(C-3a),128.9(C-2),123.0 (C-5’),122.3(C-6),120.6(C-4),119.7(C-3’),119.5(C-5),116.0(C-1’),110.5(C-7), 107.7(C-3),52.5(C-8’),48.3(C-10),36.0(C-8),24.4(C-11),11.7(C-12)；(+)-HR-ESIMS m/z 351.1713[M+H]+(calcd for C21H22N2O3,351.1664)。
Embodiment 3：The preparation of N- (3- chloropyridine -4- bases) -2- (1- ethyl -1H- indol-3-yls) acetamide
The first step, weighs heteroauxin (1.05g), adds stirring and dissolving in DMF (5mL), is cooled to 0~5 DEG C of stirring；Plus Enter 60% sodium hydride (0.72g), stir 10min, add bromoethane (0.98g), 0~5 DEG C of reaction 0.5h is slowly increased to room temperature anti- Answer 2h；Add ethyl acetate (40mL), water (40mL)；6N hydrochloric acid solution 10mL are added dropwise in quick stirring, 2min, 5min is stirred； Split-phase, aqueous phase is extracted with ethyl acetate (20mL), split-phase, combined ethyl acetate phase；Saturated aqueous common salt (30mL) is added quickly to stir 5min, split-phase are mixed, 50 DEG C of removal of solvent under reduced pressure of ethyl acetate phase obtain first step product crude product 2- (1- ethyl -1H- indoles -3- Base) acetic acid.
Second step, first step product 2- (1- ethyl -1H- indol-3-yls) acetic acid is added in dichloromethane (20mL) and stirred, EDCI (1.27g), stirring and dissolving are added at room temperature；The chloro- 4-aminopyridines of 3- (0.9g) are added, DMAP (0.15g) is stirred at room temperature React 3h；Add water (10mL) and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, point Phase；Organic phase is through pillar layer separation, with ethyl acetate-light petrol (1:3) elute, obtain light yellow solid N- (3- chloropyridines -4- Base) -2- (1- ethyl -1H- indol-3-yls) acetamide (1.1g).1H NMR(500MHz,acetone-d6):δ8.62(1H, Brs, N-H), 8.36 (3H, m, H-2 ', 5 ', 6 '), 7.63 (1H, d, J=8.0Hz, H-4), 7.45 (2H, m, H-2,7), 7.20 (1H, t, J=7.5Hz, H-6), 7.07 (1H, t, J=7.5Hz, H-5), 4.25 (2H, m, H-1 "), 3.99 (2H, s, H-8), 1.42 (3H, t, J=6.4Hz, H-2 ")；13C NMR(500MHz,acetone-d6):δ171.2(C-9),149.81(C-2’), 149.78(C-6’),142.4(C-4’),137.2(C-7a),128.6(C-3’),128.1(C-6),122.7(C-2),120.1 (C-5’),120.0(C-3a),119.6(C-4),114.7(C-5),110.5(C-7),107.7(C-3),41.4(C-1”), 34.9(C-8),15.8(C-2”)；(+)-HR-ESIMS m/z 313.0984[M+H]+(calcd for C17H16ClN3O, 313.0982)。
Embodiment 4：The preparation of N- (3- chloropyridine -4- bases) -2- (1- propyl group -1H- indol-3-yls) acetamide
The first step, weighs heteroauxin (1.05g), adds stirring and dissolving in DMF (5mL), is cooled to 0~5 DEG C of stirring；Plus Enter 60% sodium hydride (0.72g), stir 10min, add N-Propyl Bromide (1.1g), 0~5 DEG C of reaction 0.5h is slowly increased to room temperature anti- Answer 2h；Add ethyl acetate (40mL), water (40mL)；6N hydrochloric acid solution 10mL are added dropwise in quick stirring, 2min, 5min is stirred； Split-phase, aqueous phase is extracted with ethyl acetate (20mL), split-phase, combined ethyl acetate phase；Saturated aqueous common salt (30mL) is added quickly to stir 5min, split-phase are mixed, 50 DEG C of removal of solvent under reduced pressure of ethyl acetate phase obtain first step product crude product 2- (1- propyl group -1H- indoles -3- Base) acetic acid.
Second step, first step product 2- (1- propyl group -1H- indol-3-yls) acetic acid is added in dichloromethane (20mL) and stirred, EDCI (1.27g), stirring and dissolving are added at room temperature；The chloro- 4-aminopyridines of 3- (0.9g) are added, DMAP (0.15g) is stirred at room temperature React 3h；Add water (10mL) and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, point Phase；Organic phase is through pillar layer separation, with ethyl acetate-light petrol (1:3) elute, obtain light yellow solid N- (3- chloropyridines -4- Base) -2- (1- propyl group -1H- indol-3-yls) acetamide (1.2g).1H NMR(400MHz,acetone-d6):δ8.58(1H, Brs, N-H), 8.37 (3H, m, H-2 ', 5 ', 6 '), 7.63 (1H, d, J=8.0Hz, H-4), 7.47 (1H, d, J=8.4Hz, H- 7), 7.42 (1H, s, H-2), 7.19 (1H, t, J=7.6Hz, H-6), 7.07 (1H, t, J=7.6Hz, H-5), 4.18 (2H, t, J =6.8Hz, H-1 "), 3.99 (2H, s, H-8), 1.86 (2H, m, H-2 "), 0.90 (3H, t, J=7.2Hz, H-3 ")；13C NMR (400MHz,acetone-d6):δ171.2(C-9),149.8(C-2’,6’),142.4(C-4’),137.6(C-7a),128.8 (C-2),128.5(C-3a),122.6(C-6),120.1(C-5),120.0(C-3’),119.6(C-4),114.7(C-5’), 110.7(C-7),107.4(C-3),48.3(C-1”),34.9(C-8),24.3(C-2”),11.6(C-3”)；(+)-HR-ESIMS m/z 327.114[M+H]+(calcd for C18H19ClN3O,327.1138)。
Embodiment 5：The preparation of N- (3- chloropyridine -4- bases) -2- (1- isopropyl -1H- indol-3-yls) acetamide
The first step, weighs heteroauxin (1.05g), adds stirring and dissolving in DMF (5mL), is cooled to 0~5 DEG C of stirring；Plus Enter 60% sodium hydride (0.72g), stir 10min, add 2- N-Propyl Bromides (1.1g), 0~5 DEG C of reaction 0.5h is slowly increased to room temperature React 2h；Add ethyl acetate (40mL), water (40mL)；6N hydrochloric acid solution 10mL, stirring are added dropwise in quick stirring, 2min 5min；Split-phase, aqueous phase is extracted with ethyl acetate (20mL), split-phase, combined ethyl acetate phase；Add saturated aqueous common salt (30mL) fast Speed stirring 5min, split-phase, 50 DEG C of removal of solvent under reduced pressure of ethyl acetate phase obtain first step product crude product 2- (1- isopropyl -1H- Yin Diindyl -3- bases) acetic acid.
Second step, first step product 2- (1- isopropyl -1H- indol-3-yls) acetic acid is added to be stirred in dichloromethane (20mL) Mix, EDCI (1.27g), stirring and dissolving are added at room temperature；Add the chloro- 4-aminopyridines of 3- (0.9g), DMAP (0.15g), room temperature Stirring reaction 3h；Add 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 is through pillar layer separation, with ethyl acetate-light petrol (1:3) elute, obtain light yellow solid N- (3- Chloropyridine -4- bases) -2- (1- isopropyl -1H- indol-3-yls) acetamide (1.2g).1H NMR(500MHz,acetone-d6): δ 8.56 (1H, brs, N-H), 8.36 (3H, m, H-2 ', 5 ', 6 '), 7.62 (1H, d, J=8.0Hz, H-4), 7.57 (1H, s, H- 2), 7.50 (1H, d, J=8.0Hz, H-7), 7.19 (1H, t, J=7.5Hz, H-6), 7.07 (1H, t, J=7.5Hz, H-5), 4.81 (1H, m, H-1 "), 3.99 (2H, s, H-8), 1.53 (6H, d, J=6.5Hz, H-2 ", 3 ")；13C NMR(500MHz, acetone-d6):δ171.2(C-9),149.81(C-2’),149.78(C-6’),142.3(C-4’),137.1(C-7a), 128.5(C-3’),124.7(C-2),122.6(C-6),120.2(C-5’),120.0(C-3’),119.5(C-4),114.6(C- 5),110.7(C-7),107.9(C-3),47.8(C-1”),35.1(C-8),22.9(C-2”,3”)；(+)-HR-ESIMS m/z 327.1144[M+H]+(calcd for C18H19ClN3O,327.1138)。
Embodiment 6：The preparation of N- (3- chloropyridine -4- bases) -2- (1- butyl -1H- indol-3-yls) acetamide
The first step, weighs heteroauxin (1.05g), adds stirring and dissolving in DMF (5mL), is cooled to 0~5 DEG C of stirring；Plus Enter 60% sodium hydride (0.72g), stir 10min, add NBB (1.2g), 0~5 DEG C of reaction 0.5h is slowly increased to room temperature anti- Answer 2h；Add ethyl acetate (40mL), water (40mL)；6N hydrochloric acid solution 10mL are added dropwise in quick stirring, 2min, 5min is stirred； Split-phase, aqueous phase is extracted with ethyl acetate (20mL), split-phase, combined ethyl acetate phase；Saturated aqueous common salt (30mL) is added quickly to stir 5min, split-phase are mixed, 50 DEG C of removal of solvent under reduced pressure of ethyl acetate phase obtain first step product crude product 2- (1- butyl -1H- indoles -3- Base) acetic acid.
Second step, first step product 2- (1- butyl -1H- indol-3-yls) acetic acid is added in dichloromethane (20mL) and stirred, EDCI (1.27g), stirring and dissolving are added at room temperature；The chloro- 4-aminopyridines of 3- (0.9g) are added, DMAP (0.15g) is stirred at room temperature React 3h；Add water (10mL) and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, point Phase；Organic phase is through pillar layer separation, with ethyl acetate-light petrol (1:3) elute, obtain light yellow solid N- (3- chloropyridines -4- Base) -2- (1- butyl -1H- indol-3-yls) acetamide (1.3g).1H NMR(400MHz,acetone-d6):δ8.57(1H, Brs, N-H), 8.37 (3H, m, H-2 ', 5 ', 6 '), 7.62 (1H, d, J=8.0Hz, H-4), 7.47 (1H, d, J=8.4Hz, H- 7), 7.43 (1H, s, H-2), 7.19 (1H, t, J=7.6Hz, H-6), 7.07 (1H, t, J=7.6Hz, H-5), 4.22 (2H, t, J =6.8Hz, H-1 "), 3.99 (2H, s, H-8), 1.82 (2H, m, H-2 "), 1.32 (2H, m, H-3 "), 0.91 (3H, t, J= 7.6Hz,H-4”)；13C NMR(400MHz,acetone-d6):δ171.2(C-9),149.8(C-2’,6’),142.4(C-4’), 137.5(C-7a),128.8(C-2),128.5(C-3a),122.6(C-6),120.1(C-5),120.0(C-3’),119.5(C- 4),114.7(C-5’),110.8(C-7),107.4(C-3),46.4(C-1”),34.9(C-8),33.2(C-2”),20.7(C- 3”),14.0(C-4”)；(+)-HR-ESIMS m/z 341.1294[M+H]+(calcd for C19H21ClN3O,341.1295)。
Embodiment 7：The preparation of N- (3- chloropyridine -4- bases) -2- (1- isobutyl group -1H- indol-3-yls) acetamide
The first step, weighs heteroauxin (1.05g), adds stirring and dissolving in DMF (5mL), is cooled to 0~5 DEG C of stirring；Plus Enter 60% sodium hydride (0.72g), stir 10min, add 2- methyl N-Propyl Bromide (1.2g), 0~5 DEG C of reaction 0.5h is slowly increased to React at room temperature 2h；Add ethyl acetate (40mL), water (40mL)；6N hydrochloric acid solution 10mL, stirring are added dropwise in quick stirring, 2min 5min；Split-phase, aqueous phase is extracted with ethyl acetate (20mL), split-phase, combined ethyl acetate phase；Add saturated aqueous common salt (30mL) fast Speed stirring 5min, split-phase, 50 DEG C of removal of solvent under reduced pressure of ethyl acetate phase obtain first step product crude product 2- (1- isobutyl group -1H- Yin Diindyl -3- bases) acetic acid.
Second step, first step product 2- (1- isobutyl group -1H- indol-3-yls) acetic acid is added to be stirred in dichloromethane (20mL) Mix, EDCI (1.27g), stirring and dissolving are added at room temperature；Add the chloro- 4-aminopyridines of 3- (0.9g), DMAP (0.15g), room temperature Stirring reaction 3h；Add 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 is through pillar layer separation, with ethyl acetate-light petrol (1:3) elute, obtain light yellow gum thing N- (3- chloropyridine -4- bases) -2- (1- isobutyl group -1H- indol-3-yls) acetamide (1.3g).1H NMR(400MHz,acetone- d6):δ 8.57 (1H, brs, N-H), 8.37 (3H, m, H-2 ', 5 ', 6 '), 7.62 (1H, d, J=7.6Hz, H-4), 7.47 (1H, D, J=8.4Hz, H-7), 7.41 (1H, s, H-2), 7.19 (1H, t, J=7.2Hz, H-6), 7.07 (1H, t, J=7.2Hz, H- 5), 4.01 (2H, m, H-8,1 "), 2.21 (1H, m, H-2 "), 0.92 (6H, d, J=6.4Hz, H-3 ", 4 ")；13C NMR (400MHz,acetone-d6):δ170.5(C-9),149.0(C-2’,6’),141.6(C-4’),137.2(C-7a),128.6 (C-2),127.7(C-3a),121.9(C-6),119.34(C-5),119.26(C-3’),118.8(C-4),114.0(C-5’), 110.2(C-7),106.6(C-3),53.4(C-1”),34.2(C-8),29.7(C-2”),19.6(C-3”,4”)；(+)-HR- ESIMS m/z 341.1298[M+H]+(calcd for C19H20ClN3O,341.1295)。
Embodiment 8：The preparation of 2- [1- (sec-butyl) -1- hydrogen-indol-3-yl]-N- (3- chloropyridine -4- bases) acetamide
The first step, weighs heteroauxin (1.05g), adds stirring and dissolving in DMF (5mL), is cooled to 0~5 DEG C of stirring；Plus Enter 60% sodium hydride (0.72g), stir 10min, add 2- NBBs (1.2g), 0~5 DEG C of reaction 0.5h is slowly increased to room temperature React 2h；Add ethyl acetate (40mL), water (40mL)；6N hydrochloric acid solution 10mL, stirring are added dropwise in quick stirring, 2min 5min；Split-phase, aqueous phase is extracted with ethyl acetate (20mL), split-phase, combined ethyl acetate phase；Add saturated aqueous common salt (30mL) fast Speed stirring 5min, split-phase, 50 DEG C of removal of solvent under reduced pressure of ethyl acetate phase obtain first step product crude product 2- (1- sec-butyl -1H- Yin Diindyl -3- bases) acetic acid.
Second step, first step product 2- (1- sec-butyl -1H- indol-3-yls) acetic acid is added to be stirred in dichloromethane (20mL) Mix, EDCI (1.27g), stirring and dissolving are added at room temperature；Add the chloro- 4-aminopyridines of 3- (0.9g), DMAP (0.15g), room temperature Stirring reaction 3h；Add 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 is through pillar layer separation, with ethyl acetate-light petrol (1:3) elute, obtain light yellow gum thing 2- [1- (sec-butyl) -1- hydrogen-indol-3-yl]-N- (3- chloropyridine -4- bases) acetamide (1.2g).1H NMR(500MHz, acetone-d6):δ 8.53 (1H, brs, N-H), 8.37 (3H, m, H-2 ', 5 ', 6 '), 7.61 (1H, d, J=8.0Hz, H-4), 7.55 (1H, s, H-2), 7.52 (1H, d, J=8.0Hz, H-7), 7.19 (1H, t, J=7.5Hz, H-6), 7.06 (1H, t, J= 7.5Hz, H-5), 4.56 (1H, m, H-1 "), 4.00 (2H, s, H-8), 1.91 (2H, m, H-2 "), 1.52 (3H, d, J=6.5Hz, H-4 "), 0.82 (3H, t, J=6.5Hz, H-3 ")；13C NMR(500MHz,acetone-d6):δ171.2(C-9),149.9(C- 2’),149.8(C-6’),142.4(C-4’),137.8(C-7a),128.3(C-3a),125.2(C-2),122.6(C-6), 120.2(C-5’),120.0(C-3’),119.5(C-4),114.6(C-5),110.8(C-7),108.0(C-3),53.8(C- 1”),35.1(C-8),30.7(C-4”),21.3(C-2”),11.2(C-3”)；(+)-HR-ESIMS m/z341.1304[M+H]+ (calcd for C19H20ClN3O,341.1295)。
Embodiment 9：The preparation of N- (3- chloropyridine -4- bases) -2- [1- (Cvclopropvlmethvl) -1H- indol-3-yls] acetamide
The first step, weighs heteroauxin (1.05g), adds stirring and dissolving in DMF (5mL), is cooled to 0~5 DEG C of stirring；Plus Enter 60% sodium hydride (0.72g), stir 10min, add bromomethyl cyclopropane (1.2g), 0~5 DEG C of reaction 0.5h is slowly increased to React at room temperature 2h；Add ethyl acetate (40mL), water (40mL)；6N hydrochloric acid solution 10mL, stirring are added dropwise in quick stirring, 2min 5min；Split-phase, aqueous phase is extracted with ethyl acetate (20mL), split-phase, combined ethyl acetate phase；Add saturated aqueous common salt (30mL) fast Speed stirring 5min, split-phase, 50 DEG C of removal of solvent under reduced pressure of ethyl acetate phase obtain first step product crude product 2- (the third methyl isophthalic acid of 1- rings H- Indol-3-yl) acetic acid.
Second step, first step product 2- (1- rings the third Methyl-1H-indole -3- bases) acetic acid is added in dichloromethane (20mL) Stirring, adds EDCI (1.27g), stirring and dissolving at room temperature；Add the chloro- 4-aminopyridines of 3- (0.9g), DMAP (0.15g), room Warm stirring reaction 3h；Add 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 is through pillar layer separation, with ethyl acetate-light petrol (1:3) elute, obtain light yellow solid N- (3- Chloropyridine -4- bases) -2- [1- (Cvclopropvlmethvl) -1H- indol-3-yls] acetamide (1.2g).1H NMR(500MHz, acetone-d6):δ 8.60 (1H, brs, N-H), 8.37 (3H, m, H-2 ', 5 ', 6 '), 7.63 (1H, d, J=8.0Hz, H-4), 7.49 (2H, m, H-2,7), 7.20 (1H, t, J=7.5Hz, H-6), 7.07 (1H, t, J=7.5Hz, H-5), 4.07 (2H, d, J =7.0Hz, H-1 "), 4.00 (2H, s, H-8), 1.29 (1H, m, H-2 "), 0.54 (2H, m, H-3 "), 0.41 (2H, m, H-4 ") ；13C NMR(500MHz,acetone-d6):δ171.2(C-9),149.78(C-2’),149.76(C-6’),142.4(C-4’), 137.7(C-7a),128.54(C-2),128.50(C-3a),122.7(C-6),120.11(C-5),120.06(C-3’), 119.5(C-4),114.7(C-5’),110.7(C-7),107.5(C-3),50.8(C-1”),35.0(C-8),12.2(C-2”), 4.3(C-3”,4”)；(+)-HR-ESIMS m/z 339.1141[M+H]+(calcd for C19H18ClN3O,339.1138)。
Embodiment 10：The system of 2- (1- butyl -2- methyl isophthalic acids-hydrogen-indol-3-yl)-N- (3- chloropyridine -4- bases) acetamide It is standby
The first step, weighs 2 methyl indole acetic acid (1.13g), adds stirring and dissolving in DMF (5mL), is cooled to 0~5 DEG C Stirring；60% sodium hydride (0.72g) is added, 10min is stirred, NBB (1.2g) is added, 0~5 DEG C of reaction 0.5h is slowly increased to React at room temperature 2h；Add ethyl acetate (40mL), water (40mL)；6N hydrochloric acid solution 10mL, stirring are added dropwise in quick stirring, 2min 5min；Split-phase, aqueous phase is extracted with ethyl acetate (20mL), split-phase, combined ethyl acetate phase；Add saturated aqueous common salt (30mL) fast Speed stirring 5min, split-phase, 50 DEG C of removal of solvent under reduced pressure of ethyl acetate phase obtain first step product crude product 2- (1- butyl -2- methyl - 1H- indol-3-yls) acetic acid.
Second step, first step product 2- (1- butyl -2- Methyl-1H-indole -3- bases) acetic acid adds dichloromethane (20mL) Middle stirring, adds EDCI (1.27g), stirring and dissolving at room temperature；The addition chloro- 4-aminopyridines of 3- (0.9g), DMAP (0.15g), Reaction 3h is stirred at room temperature；Add 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 is through pillar layer separation, with ethyl acetate-light petrol (1:3) elute, obtain light yellow gum thing 2- (1- butyl -2- methyl isophthalic acids-hydrogen-indol-3-yl)-N- (3- chloropyridine -4- bases) acetamide (1.4g).1H NMR(500MHz, acetone-d6):δ 8.39 (1H, brs, N-H), 8.35 (3H, m, H-2 ', 5 ', 6 '), 7.55 (1H, d, J=8.0Hz, H-4), 7.41 (1H, d, J=8.0Hz, H-7), 7.14 (1H, t, J=7.5Hz, H-6), 7.04 (1H, t, J=7.5Hz, H-5), 4.20 (2H, t, J=7.5Hz, H-1 "), 3.94 (2H, s, H-8), 2.50 (3H, s, H-2a), 1.74 (2H, m, H-2 "), 1.39 (2H, M, H-3 "), 0.94 (3H, t, J=7.5Hz, H-4 ")；13C NMR(500MHz,acetone-d6):δ171.1(C-9),149.8 (C-2’),149.7(C-6’),142.3(C-4’),137.3(C-7a),135.9(C-3a),128.4(C-2),122.0(C-6), 120.2(C-5’),119.8(C-3’),118.4(C-4),114.5(C-5),110.2(C-7),104.2(C-3),43.6(C- 1”),34.2(C-8),33.1(C-2a),20.8(C-2”),14.1(C-3”),10.3(C-4”)；(+)-HR-ESIMS m/z 355.1458[M+H]+(calcd for C20H22ClN3O,355.1451)。
Embodiment 11：The preparation of N- (3- chloropyridine -4- bases) -2- (1- amyl group -1H- indol-3-yls) acetamide
The first step, weighs heteroauxin (1.05g), adds stirring and dissolving in DMF (5mL), is cooled to 0~5 DEG C of stirring；Plus Enter 60% sodium hydride (0.72g), stir 10min, add bromo pentane silane (1.4g), 0~5 DEG C of reaction 0.5h is slowly increased to room temperature anti- Answer 2h；Add ethyl acetate (40mL), water (40mL)；6N hydrochloric acid solution 10mL are added dropwise in quick stirring, 2min, 5min is stirred； Split-phase, aqueous phase is extracted with ethyl acetate (20mL), split-phase, combined ethyl acetate phase；Saturated aqueous common salt (30mL) is added quickly to stir 5min, split-phase are mixed, 50 DEG C of removal of solvent under reduced pressure of ethyl acetate phase obtain first step product crude product 2- (1- amyl group -1H- indoles -3- Base) acetic acid.
Second step, first step product 2- (1- amyl group -1H- indol-3-yls) acetic acid is added in dichloromethane (20mL) and stirred, EDCI (1.27g), stirring and dissolving are added at room temperature；The chloro- 4-aminopyridines of 3- (0.9g) are added, DMAP (0.15g) is stirred at room temperature React 3h；Add water (10mL) and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirring 10min, point Phase；Organic phase is through pillar layer separation, with ethyl acetate-light petrol (1:3) elute, obtain light yellow gum thing N- (3- chloropyridines- 4- yls) -2- (1- amyl group -1H- indol-3-yls) acetamide (1.3g).1H NMR(400MHz,acetone-d6):δ8.57(1H, Brs, N-H), 8.36 (3H, m, H-2 ', 5 ', 6 '), 7.62 (1H, d, J=8.0Hz, H-4), 7.46 (2H, m, H-2,7), 7.19 (1H, t, J=7.6Hz, H-6), 7.07 (1H, t, J=7.6Hz, H-5), 4.23 (2H, t, J=7.2Hz, H-1 "), 3.99 (2H, S, H-8), 1.85 (2H, s, H-2 "), 1.32 (4H, m, H-3 ", 4 "), 0.85 (3H, t, J=6.4Hz, H-5 ")；13C NMR (400MHz,acetone-d6):δ171.3(C-9),149.8(C-2’,6’),142.4(C-4’),137.6(C-7a),128.8 (C-2),128.5(C-3a),122.7(C-6),120.1(C-5,3’),119.6(C-4),114.7(C-5’),110.7(C-7), 107.5(C-3),46.7(C-1”),35.0(C-8),30.8(C-2”),29.7(C-3”),23.0(C-4”),14.2(C-5”)； (+)-HR-ESIMS m/z 355.1458[M+H]+(calcd for C20H23ClN3O,355.1451)。
Embodiment 12：The preparation of N- (3- chloropyridine -4- bases) -2- (1- isopentyl -1H- indol-3-yls) acetamide
The first step, weighs heteroauxin (1.05g), adds stirring and dissolving in DMF (5mL), is cooled to 0~5 DEG C of stirring；Plus Enter 60% sodium hydride (0.72g), stir 10min, add 3- methyl NBB (1.4g), 0~5 DEG C of reaction 0.5h is slowly increased to React at room temperature 2h；Add ethyl acetate (40mL), water (40mL)；6N hydrochloric acid solution 10mL, stirring are added dropwise in quick stirring, 2min 5min；Split-phase, aqueous phase is extracted with ethyl acetate (20mL), split-phase, combined ethyl acetate phase；Add saturated aqueous common salt (30mL) fast Speed stirring 5min, split-phase, 50 DEG C of removal of solvent under reduced pressure of ethyl acetate phase obtain first step product crude product 2- (1- isopentyl -1H- Yin Diindyl -3- bases) acetic acid.
Second step, first step product 2- (1- isopentyl -1H- indol-3-yls) acetic acid is added to be stirred in dichloromethane (20mL) Mix, EDCI (1.27g), stirring and dissolving are added at room temperature；Add the chloro- 4-aminopyridines of 3- (0.9g), DMAP (0.15g), room temperature Stirring reaction 3h；Add 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 is through pillar layer separation, with ethyl acetate-light petrol (1:3) elute, obtain light yellow gum thing N- (3- chloropyridine -4- bases) -2- (1- isopentyl -1H- indol-3-yls) acetamide (1.4g).1H NMR(500MHz,acetone- d6):δ 8.65 (1H, brs, N-H), 8.45 (3H, m, H-2 ', 5 ', 6 '), 7.71 (1H, d, J=8.0Hz, H-4), 7.54 (2H, M, H-2,7), 7.28 (1H, t, J=7.5Hz, H-6), 7.15 (1H, t, J=7.5Hz, H-5), 4.34 (2H, m, H-1 "), 4.07 (2H, s, H-8), 1.83 (2H, m, H-2 "), 1.70 (1H, m, H-3 "), 1.05 (6H, d, J=6.5Hz, H-4 ", 5 ")；13C NMR (500MHz,acetone-d6):δ171.2(C-9),149.8(C-2’,6’),142.4(C-4’),137.5(C-7a),128.7 (C-3a),128.6(C-2),122.7(C-6),120.1(C-5),120.0(C-3’),119.6(C-4),114.7(C-5’), 110.6(C-7),107.6(C-3),45.0(C-1”),39.9(C-2”),35.0(C-8),26.4(C-3”),22.7(C-4”, 5”)；(+)-HR-ESIMS m/z 355.1455[M+H]+(calcd for C20H22ClN3O,355.1451)。
Embodiment 13：The preparation of N- (3- chloropyridine -4- bases) -2- [1- (methyl butyl) -1H- indol-3-yls] acetamide
The first step, weighs heteroauxin (1.05g), adds stirring and dissolving in DMF (5mL), is cooled to 0~5 DEG C of stirring；Plus Enter 60% sodium hydride (0.72g), stir 10min, add 2- methyl NBB (1.4g), 0~5 DEG C of reaction 0.5h is slowly increased to React at room temperature 2h；Add ethyl acetate (40mL), water (40mL)；6N hydrochloric acid solution 10mL, stirring are added dropwise in quick stirring, 2min 5min；Split-phase, aqueous phase is extracted with ethyl acetate (20mL), split-phase, combined ethyl acetate phase；Add saturated aqueous common salt (30mL) fast Speed stirring 5min, split-phase, 50 DEG C of removal of solvent under reduced pressure of ethyl acetate phase obtain first step product crude product 2- [1- (2- methyl fourths Base) -1H- indol-3-yls] acetic acid.
Second step, first step product 2- [1- (2- methyl butyls) -1H- indol-3-yls] acetic acid adds dichloromethane Stirred in (20mL), EDCI (1.27g), stirring and dissolving are added at room temperature；Add the chloro- 4-aminopyridines of 3- (0.9g), DMAP (0.15g), is stirred at room temperature reaction 3h；Add water (10mL) and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirs 10min, split-phase；Organic phase is through pillar layer separation, with ethyl acetate-light petrol (1:3) elute, obtain light yellow Solid N- (3- chloropyridine -4- bases) -2- [1- (methyl butyl) -1H- indol-3-yls] acetamide (1.4g).1H NMR (400MHz,acetone-d6):δ 8.61 (1H, brs, N-H), 8.42 (3H, m, H-2 ', 5 ', 6 '), 7.67 (1H, d, J= 7.6Hz, H-4), 7.51 (1H, d, J=8.4Hz, H-7), 7.45 (1H, s, H-2), 7.24 (1H, t, J=7.2Hz, H-6), 7.12 (1H, t, J=7.2Hz, H-5), 4.14 (4H, m, H-8,1 "), 2.05 (1H, m, H-2 "), 1.36 (2H, m, H-3 "), 0.94(6H,m,H-4”,5”)；13C NMR(400MHz,acetone-d6):δ171.2(C-9),149.8(C-2’,6’),142.4 (C-4’),137.9(C-7a),129.4(C-2),128.4(C-3a),122.7(C-6),120.1(C-5),120.0(C-3’), 119.5(C-4),114.7(C-5’),110.9(C-7),107.3(C-3),52.7(C-1”),36.8(C-2”),35.0(C-8), 27.6(C-5”),17.3(C-3”),11.5(C-4”)；(+)-HR-ESIMS m/z355.1458[M+H]+(calcd for C20H22ClN3O,355.1451)。
Embodiment 14：The system of N- (3- chloropyridine -4- bases) -2- (1- isopentyl -2- Methyl-1H-indole -3- bases) acetamide It is standby
The first step, weighs 2 methyl indole acetic acid (1.13g), adds stirring and dissolving in DMF (5mL), is cooled to 0~5 DEG C Stirring；60% sodium hydride (0.72g) is added, 10min is stirred, NBB (1.2g) is added, 0~5 DEG C of reaction 0.5h is slowly increased to React at room temperature 2h；Add ethyl acetate (40mL), water (40mL)；6N hydrochloric acid solution 10mL, stirring are added dropwise in quick stirring, 2min 5min；Split-phase, aqueous phase is extracted with ethyl acetate (20mL), split-phase, combined ethyl acetate phase；Add saturated aqueous common salt (30mL) fast Speed stirring 5min, split-phase, 50 DEG C of removal of solvent under reduced pressure of ethyl acetate phase obtain first step product crude product 2- (1- isopentyl -2- first Base -1H- indol-3-yls) acetic acid.
Second step, first step product 2- (1- isopentyl -2- Methyl-1H-indole -3- bases) acetic acid adds dichloromethane Stirred in (20mL), EDCI (1.27g), stirring and dissolving are added at room temperature；Add the chloro- 4-aminopyridines of 3- (0.9g), DMAP (0.15g), is stirred at room temperature reaction 3h；Add water (10mL) and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirs 10min, split-phase；Organic phase is through pillar layer separation, with ethyl acetate-light petrol (1:3) elute, obtain light yellow Jelly N- (3- chloropyridine -4- bases) -2- (1- isopentyl -2- Methyl-1H-indole -3- bases) acetamide (1.4g).1H NMR (500MHz,acetone-d6):δ 8.35 (4H, m, N-H, H-2 ', 5 ', 6 '), 7.55 (1H, d, J=7.0Hz, H-4), 7.40 (1H, d, J=8.5Hz, H-7), 7.14 (1H, t, J=7.5Hz, H-6), 7.04 (1H, t, J=7.5Hz, H-5), 4.21 (2H, T, J=8.0Hz, H-1 "), 3.94 (2H, s, H-8), 2.50 (3H, s, H-2a), 1.74 (1H, m, H-3 "), 1.63 (2H, m, H- 2 "), 1.00 (6H, d, J=6.5Hz, H-4 ", 5 ")；13C NMR(500MHz,acetone-d6):δ171.1(C-9),149.8 (C-2’),149.7(C-6’),142.3(C-4’),137.1(C-7a),135.8(C-2),128.4(C-3’),122.0(C-6), 120.2(C-5’),119.8(C-3a),118.5(C-4),114.5(C-4),110.0(C-7),104.3(C-3),42.3(C- 1”),39.7(C-2a),34.1(C-8),26.8(C-3”),22.8(C-2”),10.3(C-4”,5”)；(+)-HR-ESIMS m/z 369.1608[M+H]+(calcd for C21H24ClN3O,369.1608)。
Embodiment 15：N- (3- chloropyridine -4- bases) -2- [1- (3,3- dimethylbutyls) -1H- indol-3-yls] acetamide Preparation
The first step, weighs heteroauxin (1.05g), adds stirring and dissolving in DMF (5mL), is cooled to 0~5 DEG C of stirring；Plus Enter 60% sodium hydride (0.72g), stir 10min, add 3,3- dimethyl NBB (1.5g), 0~5 DEG C is reacted 0.5h, slowly It is warmed to room temperature reaction 2h；Add ethyl acetate (40mL), water (40mL)；6N hydrochloric acid solution 10mL are added dropwise in quick stirring, 2min, Stir 5min；Split-phase, aqueous phase is extracted with ethyl acetate (20mL), split-phase, combined ethyl acetate phase；Add saturated aqueous common salt (30mL) quickly stirs 5min, split-phase, and 50 DEG C of removal of solvent under reduced pressure of ethyl acetate phase obtain first step product crude product 2- [1- (2- T-butylethyl) -1H- indol-3-yls] acetic acid.
Second step, first step product 2- [1- (2- t-butylethyls) -1H- indol-3-yls] acetic acid adds dichloromethane Stirred in (20mL), EDCI (1.27g), stirring and dissolving are added at room temperature；Add the chloro- 4-aminopyridines of 3- (0.9g), DMAP (0.15g), is stirred at room temperature reaction 3h；Add water (10mL) and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirs 10min, split-phase；Organic phase is through pillar layer separation, with ethyl acetate-light petrol (1:3) elute, obtain light yellow Solid N- (3- chloropyridine -4- bases) -2- [1- (3,3- dimethylbutyls) -1H- indol-3-yls] acetamide (1.1g).1H NMR (500MHz,acetone-d6):δ 8.57 (1H, brs, N-H), 8.36 (3H, m, H-2 ', 5 ', 6 '), 7.63 (1H, d, J= 8.0Hz, H-4), 7.45 (2H, m, H-2,7), 7.20 (1H, t, J=7.5Hz, H-6), 7.07 (1H, t, J=7.5Hz, H-5), 4.26(2H,m,H-1”),3.98(2H,s,H-8),1.76(2H,m,H-2”),1.04(9H,s,H-4”,5”,6”)；13C NMR (500MHz,acetone-d6):δ171.2(C-9),149.8(C-2’,6’),142.4(C-4’),137.4(C-7a),128.7 (C-3a),128.6(C-2),122.7(C-6),120.1(C-5),120.0(C-3’),119.6(C-4),114.7(C-5’), 110.6(C-7),107.7(C-3),44.6(C-1”),43.4(C-2”),34.9(C-8),30.5(C-3”),29.5(C-4”, 5”,6”)；(+)-HR-ESIMS m/z 369.1611[M+H]+(calcd for C21H24ClN3O,369.1608)。
Embodiment 16：The system of N- (3- chloropyridine -4- bases) -2- [1- (2- ethyl-butyls) -1H- indol-3-yls] acetamide It is standby
The first step, weighs heteroauxin (1.05g), adds stirring and dissolving in DMF (5mL), is cooled to 0~5 DEG C of stirring；Plus Enter 60% sodium hydride (0.72g), stir 10min, add 2- ethyls NBB (1.5g), 0~5 DEG C of reaction 0.5h is slowly increased to React at room temperature 2h；Add ethyl acetate (40mL), water (40mL)；6N hydrochloric acid solution 10mL, stirring are added dropwise in quick stirring, 2min 5min；Split-phase, aqueous phase is extracted with ethyl acetate (20mL), split-phase, combined ethyl acetate phase；Add saturated aqueous common salt (30mL) fast Speed stirring 5min, split-phase, 50 DEG C of removal of solvent under reduced pressure of ethyl acetate phase obtain first step product crude product 2- [1- (2- ethyl fourths Base) -1H- indol-3-yls] acetic acid.
Second step, first step product 2- [1- (2- ethyl-butyls) -1H- indol-3-yls] acetic acid adds dichloromethane Stirred in (20mL), EDCI (1.27g), stirring and dissolving are added at room temperature；Add the chloro- 4-aminopyridines of 3- (0.9g), DMAP (0.15g), is stirred at room temperature reaction 3h；Add water (10mL) and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirs 10min, split-phase；Organic phase is through pillar layer separation, with ethyl acetate-light petrol (1:3) elute, obtain light yellow Crystal N- (3- chloropyridine -4- bases) -2- [1- (2- ethyl-butyls) -1H- indol-3-yls] acetamide (1.2g).1H NMR (500MHz,acetone-d6):δ 8.54 (1H, brs, N-H), 8.37 (3H, m, H-2 ', 5 ', 6 '), 7.62 (1H, d, J= 8.0Hz, H-4), 7.45 (2H, m, H-2,7), 7.19 (1H, t, J=7.5Hz, H-6), 7.07 (1H, t, J=7.5Hz, H-5), 4.12 (2H, d, J=7.5Hz, H-1 "), 3.99 (2H, s, H-8), 1.89 (1H, m, H-2 "), 1.35 (4H, m, H-3 ", 5 "), 0.91 (6H, t, J=7.5Hz, H-4 ", 6 ")；13C NMR(500MHz,acetone-d6):δ171.3(C-9),149.8(C-2’, 6’),142.4(C-4’),137.9(C-7a),129.4(C-2),128.5(C-3a),122.7(C-6),120.1(C-5), 120.0(C-3’),119.6(C-4),114.7(C-5’),110.7(C-7),107.5(C-3),50.2(C-1”),42.5(C- 2”),35.0(C-8),24.0(C-3”,5”),10.9(C-4”,6”)；(+)-HR-ESIMS m/z 369.1611[M+H]+ (calcd for C21H24ClN3O,369.1608)。
Embodiment 17：The system of N- (3- chloropyridine -4- bases) -2- [1- (2- cyano ethyls) -1H- indol-3-yls] acetamide It is standby
The first step, weighs heteroauxin (1.05g), adds stirring and dissolving in DMF (5mL), is cooled to 0~5 DEG C of stirring；Plus Enter 60% sodium hydride (0.72g), stir 10min, add the cyanogen of bromine third (1.2g), 0~5 DEG C of reaction 0.5h is slowly increased to room temperature anti- Answer 2h；Add ethyl acetate (40mL), water (40mL)；6N hydrochloric acid solution 10mL are added dropwise in quick stirring, 2min, 5min is stirred； Split-phase, aqueous phase is extracted with ethyl acetate (20mL), split-phase, combined ethyl acetate phase；Saturated aqueous common salt (30mL) is added quickly to stir 5min, split-phase are mixed, 50 DEG C of removal of solvent under reduced pressure of ethyl acetate phase obtain first step product crude product 2- [1- (2- cyano ethyls) -1H- Indol-3-yl] acetic acid.
Second step, first step product 2- [1- (2- cyano ethyls) -1H- indol-3-yls] acetic acid adds dichloromethane Stirred in (20mL), EDCI (1.27g), stirring and dissolving are added at room temperature；Add the chloro- 4-aminopyridines of 3- (0.9g), DMAP (0.15g), is stirred at room temperature reaction 3h；Add water (10mL) and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirs 10min, split-phase；Organic phase is through pillar layer separation, with ethyl acetate-light petrol (1:3) elute, obtain light yellow Solid N- (3- chloropyridine -4- bases) -2- [1- (2- cyano ethyls) -1H- indol-3-yls] acetamide (0.8g).1H NMR (500MHz,acetone-d6):δ8.63(1H,brs,N-H),8.40(1H,s,H-2’),8.35(2H,s,H-5’,6’),7.66 (1H, d, J=8.0Hz, H-4), 7.57 (1H, d, J=8.0Hz, H-7), 7.51 (1H, s, H-2), 7.23 (1H, t, J= 7.5Hz, H-6), 7.11 (1H, t, J=7.5Hz, H-5), 4.60 (2H, t, J=6.5Hz, H-1 "), 4.02 (2H, s, H-8), 3.04 (2H, t, J=6.5Hz, H-2 ")；13C NMR(500MHz,acetone-d6):δ171.1(C-9),149.8(C-2’), 149.7(C-6’),142.4(C-4’),137.3(C-7a),128.8(C-3”),128.5(C-2),123.1(C-6),120.6 (C-5),120.2(C-3a),119.8(C-4),118.7(C-3’),114.9(C-5’),110.6(C-7),108.8(C-3), 42.6(C-1”),34.8(C-8),19.5(C-2”)；(+)-HR-ESIMS m/z 338.0942[M+H]+(calcd for C18H16ClN4O,338.0934)。
Embodiment 18：The system of N- (3- chloropyridine -4- bases) -2- [1- (3- hydroxypropyls) -1H- indol-3-yls] acetamide It is standby
The first step, weighs heteroauxin (1.05g), adds stirring and dissolving in DMF (5mL), is cooled to 0~5 DEG C of stirring；Plus Enter 60% sodium hydride (0.72g), stir 10min, add 3- bromopropyl alcohols (1.2g), 0~5 DEG C of reaction 0.5h is slowly increased to room temperature React 2h；Add ethyl acetate (40mL), water (40mL)；6N hydrochloric acid solution 10mL, stirring are added dropwise in quick stirring, 2min 5min；Split-phase, aqueous phase is extracted with ethyl acetate (20mL), split-phase, combined ethyl acetate phase；Add saturated aqueous common salt (30mL) fast Speed stirring 5min, split-phase, 50 DEG C of removal of solvent under reduced pressure of ethyl acetate phase obtain first step product crude product 2- [1- (3- hydroxyls third Base) -1H- indol-3-yls] acetic acid.
Second step, first step product 2- [1- (3- hydroxypropyls) -1H- indol-3-yls] acetic acid adds dichloromethane Stirred in (20mL), EDCI (1.27g), stirring and dissolving are added at room temperature；Add the chloro- 4-aminopyridines of 3- (0.9g), DMAP (0.15g), is stirred at room temperature reaction 3h；Add water (10mL) and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirs 10min, split-phase；Organic phase is through pillar layer separation, with ethyl acetate-light petrol (1:3) elute, obtain light yellow Solid N- (3- chloropyridine -4- bases) -2- [1- (3- hydroxypropyls) -1H- indol-3-yls] acetamide (0.4g).1H NMR (500MHz,acetone-d6):δ 8.60 (1H, brs, N-H), 8.39 (3H, m, H-2 ', 5 ', 6 '), 7.64 (1H, d, J= 8.0Hz, H-4), 7.52 (1H, d, J=8.0Hz, H-7), 7.47 (1H, s, H-2), 7.21 (1H, t, J=7.5Hz, H-6), 7.09 (1H, t, J=7.5Hz, H-5), 4.38 (2H, t, J=7.0Hz, H-1 "), 4.01 (2H, s, H-8), 3.59 (2H, m, H- 2”),2.06(3H,m,H-3”,-OH)；13C NMR(500MHz,acetone-d6):δ171.2(C-9),149.8(C-2’,6’), 142.4(C-4’),137.6(C-7a),129.0(C-3’),128.5(C-6),122.7(C-2),120.1(C-5),119.6(C- 4),114.7(C-3a),110.7(C-7),107.5(C-3),59.1(C-1”),43.4(C-3”),34.9(C-8),34.1(C- 2”)；(+)-HR-ESIMS m/z 343.1094[M+H]+(calcd for C18H18ClN3O2,343.1088)。
Embodiment 19：2- [1- (butyl -3- alkene -1- bases) -1- hydrogen-indol-3-yl]-N- (3- chloropyridine -4- bases) acetyl The preparation of amine
The first step, weighs heteroauxin (1.05g), adds stirring and dissolving in DMF (5mL), is cooled to 0~5 DEG C of stirring；Plus Enter 60% sodium hydride (0.72g), stir 10min, add the bromo- 3- butylene (1.3g) of 1-, 0~5 DEG C of reaction 0.5h is slowly increased to room Temperature reaction 2h；Add ethyl acetate (40mL), water (40mL)；6N hydrochloric acid solution 10mL, stirring are added dropwise in quick stirring, 2min 5min；Split-phase, aqueous phase is extracted with ethyl acetate (20mL), split-phase, combined ethyl acetate phase；Add saturated aqueous common salt (30mL) fast Speed stirring 5min, split-phase, 50 DEG C of removal of solvent under reduced pressure of ethyl acetate phase obtain first step product crude product 2- [1- (butyl -3- alkene - 1- yls) -1H- indol-3-yls] acetic acid.
Second step, first step product 2- [1- (butyl -3- alkene -1- bases) -1H- indol-3-yls] acetic acid adds dichloromethane Stirred in (20mL), EDCI (1.27g), stirring and dissolving are added at room temperature；Add the chloro- 4-aminopyridines of 3- (0.9g), DMAP (0.15g), is stirred at room temperature reaction 3h；Add water (10mL) and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirs 10min, split-phase；Organic phase is through pillar layer separation, with ethyl acetate-light petrol (1:3) elute, obtain light yellow Solid 2- [1- (butyl -3- alkene -1- bases) -1- hydrogen-indol-3-yl]-N- (3- chloropyridine -4- bases) acetamide (1.0g).1H NMR(400MHz,acetone-d6):δ 8.57 (1H, brs, N-H), 8.38 (3H, m, H-2 ', 5 ', 6 '), 7.62 (1H, d, J= 8.0Hz, H-4), 7.49 (1H, d, J=8.0Hz, H-7), 7.45 (1H, s, H-2), 7.20 (1H, t, J=7.2Hz, H-6), 7.07 (1H, t, J=7.2Hz, H-5), 5.85 (1H, m, H-3 "), 5.03 (2H, m, H-4 "), 4.31 (2H, t, J=7.2Hz, H- 1”),3.98(2H,s,H-8),2.62(2H,m,H-2”)；13C NMR(400MHz,acetone-d6):δ171.2(C-9), 149.9(C-2’),149.8(C-6’),142.4(C-4’),137.6(C-7a),136.0(C-2),128.8(C-3),128.6 (C-3’),122.7(C-6),120.2(C-5),119.6(C-3’),119.6(C-4),117.4(C-5’),114.8(C-3a), 110.7(C-7),107.7(C-3),46.3(C-1”),35.4(C-8),35.0(C-2”)；(+)-HR-ESIMS m/z 339.1145[M+H]+(calcd for C19H19ClN3O,339.1138)。
Embodiment 20：The system of N- (3- chloropyridine -4- bases) -2- [1- (3- cyanopropyls) -1H- indol-3-yls] acetamide It is standby
The first step, weighs heteroauxin (1.05g), adds stirring and dissolving in DMF (5mL), is cooled to 0~5 DEG C of stirring；Plus Enter 60% sodium hydride (0.72g), stir 10min, add bromine fourth cyanogen (1.4g), 0~5 DEG C of reaction 0.5h is slowly increased to room temperature anti- Answer 2h；Add ethyl acetate (40mL), water (40mL)；6N hydrochloric acid solution 10mL are added dropwise in quick stirring, 2min, 5min is stirred； Split-phase, aqueous phase is extracted with ethyl acetate (20mL), split-phase, combined ethyl acetate phase；Saturated aqueous common salt (30mL) is added quickly to stir 5min, split-phase are mixed, 50 DEG C of removal of solvent under reduced pressure of ethyl acetate phase obtain first step product crude product 2- [1- (3- cyanopropyls) -1H- Indol-3-yl] acetic acid.
Second step, first step product 2- [1- (3- cyanopropyls) -1H- indol-3-yls] acetic acid adds dichloromethane Stirred in (20mL), EDCI (1.27g), stirring and dissolving are added at room temperature；Add the chloro- 4-aminopyridines of 3- (0.9g), DMAP (0.15g), is stirred at room temperature reaction 3h；Add water (10mL) and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirs 10min, split-phase；Organic phase is through pillar layer separation, with ethyl acetate-light petrol (1:3) elute, obtain light brown Jelly N- (3- chloropyridine -4- bases) -2- [1- (3- cyanopropyls) -1H- indol-3-yls] acetamide (0.8g).1H NMR (500MHz,acetone-d6):δ8.61(1H,brs,N-H),8.40(1H,s,H-2’),8.35(2H,m,H-5’,6’),7.65 (1H, d, J=8.0Hz, H-4), 7.52 (1H, d, J=8.0Hz, H-7), 7.48 (1H, s, H-2), 7.22 (1H, t, J= 7.5Hz, H-6), 7.10 (1H, t, J=7.5Hz, H-5), 4.40 (2H, t, J=7.0Hz, H-1 "), 4.01 (2H, s, H-8), 2.48 (2H, t, J=7.0Hz, H-3 "), 2.24 (2H, m, H-2 ")；13C NMR(500MHz,acetone-d6):δ171.2(C- 9),149.9(C-2’),149.8(C-6’),142.5(C-4’),137.5(C-7a),128.7(C-4”),128.6(C-2), 122.9(C-6),120.4(C-5),120.2(C-3a),119.8(C-4),114.9(C-5’),110.5(C-7),108.3(C- 3),45.2(C-1”),34.8(C-8),27.1(C-3”),14.8(C-2”)；(+)-HR-ESIMS m/z 352.1093[M+H]+ (calcd for C19H17ClN4O,352.1091)。
Embodiment 21：N- (3- chloropyridine -4- bases) -2- [1- (3- amyl group -4- alkene -1- bases) -1H- indol-3-yls] acetyl The preparation of amine
The first step, weighs heteroauxin (1.05g), adds stirring and dissolving in DMF (5mL), is cooled to 0~5 DEG C of stirring；Plus Enter 60% sodium hydride (0.72g), stir 10min, add the bromo- 4- amylenes (1.4g) of 1-, 0~5 DEG C of reaction 0.5h is slowly increased to room Temperature reaction 2h；Add ethyl acetate (40mL), water (40mL)；6N hydrochloric acid solution 10mL, stirring are added dropwise in quick stirring, 2min 5min；Split-phase, aqueous phase is extracted with ethyl acetate (20mL), split-phase, combined ethyl acetate phase；Add saturated aqueous common salt (30mL) fast Speed stirring 5min, split-phase, 50 DEG C of removal of solvent under reduced pressure of ethyl acetate phase obtain first step product crude product 2- [1- (amyl group -4- alkene - 1- yls) -1H- indol-3-yls] acetic acid.
Second step, first step product 2- [1- (amyl group -4- alkene -1- bases) -1H- indol-3-yls] acetic acid adds dichloromethane Stirred in (20mL), EDCI (1.27g), stirring and dissolving are added at room temperature；Add the chloro- 4-aminopyridines of 3- (0.9g), DMAP (0.15g), is stirred at room temperature reaction 3h；Add water (10mL) and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirs 10min, split-phase；Organic phase is through pillar layer separation, with ethyl acetate-light petrol (1:3) elute, obtain rufous Jelly N- (3- chloropyridine -4- bases) -2- [1- (3- amyl group -4- alkene -1- bases) -1H- indol-3-yls] acetamide (1.3g).1H NMR(500MHz,acetone-d6):δ 8.57 (1H, brs, N-H), 8.36 (3H, m, H-2 ', 5 ', 6 '), 7.63 (1H, d, J= 8.0Hz, H-4), 7.46 (2H, m, H-2,7), 7.20 (1H, t, J=7.5Hz, H-6), 7.07 (1H, t, J=7.5Hz, H-5), 5.84 (1H, m, H-4 "), 4.98 (2H, m, H-5 "), 4.25 (2H, t, J=7.0Hz, H-1 "), 3.99 (2H, s, H-8), 2.09 (2H,m,H-2”),1.95(2H,m,H-3”)；13C NMR(500MHz,acetone-d6):δ171.2(C-9),149.8(C-2’, 6’),142.4(C-4’),138.6(C-2),137.6(C-7a),128.8(C-4”),128.6(C-3a),122.7(C-6), 120.2(C-5),120.0(C-4),119.8(C-3’),115.6(C-5”),114.7(C-5’),110.7(C-7),107.7(C- 3),46.1(C-1”),35.0(C-8),31.5(C-2”)；(+)-HR-ESIMS m/z 353.13[M+H]+(calcd for C20H20ClN3O,353.1295)。
Embodiment 22：N- (3- chloropyridine -4- bases) -2- [1- (hexyl -5- alkene -1- bases) -1H- indol-3-yls] acetamide Preparation
The first step, weighs heteroauxin (1.05g), adds stirring and dissolving in DMF (5mL), is cooled to 0~5 DEG C of stirring；Plus Enter 60% sodium hydride (0.72g), stir 10min, add the bromo- 5- hexenes (1.5g) of 1-, 0~5 DEG C of reaction 0.5h is slowly increased to room Temperature reaction 2h；Add ethyl acetate (40mL), water (40mL)；6N hydrochloric acid solution 10mL, stirring are added dropwise in quick stirring, 2min 5min；Split-phase, aqueous phase is extracted with ethyl acetate (20mL), split-phase, combined ethyl acetate phase；Add saturated aqueous common salt (30mL) fast Speed stirring 5min, split-phase, 50 DEG C of removal of solvent under reduced pressure of ethyl acetate phase obtain first step product crude product 2- [1- (hexyl -5- alkene - 1- yls) -1H- indol-3-yls] acetic acid.
Second step, first step product 2- [1- (hexyl -5- alkene -1- bases) -1H- indol-3-yls] acetic acid adds dichloromethane Stirred in (20mL), EDCI (1.27g), stirring and dissolving are added at room temperature；Add the chloro- 4-aminopyridines of 3- (0.9g), DMAP (0.15g), is stirred at room temperature reaction 3h；Add water (10mL) and quickly stir 10min, split-phase；It is organic to be added to saturated aqueous common salt (10mL) stirs 10min, split-phase；Organic phase is through pillar layer separation, with ethyl acetate-light petrol (1:3) elute, obtain rufous Jelly N- (3- chloropyridine -4- bases) -2- [1- (hexyl -5- alkene -1- bases) -1H- indol-3-yls] acetamide (1.4g).1H NMR(500MHz,acetone-d6):δ 8.56 (1H, brs, N-H), 8.36 (3H, m, H-2 ', 5 ', 6 '), 7.62 (1H, d, J= 8.0Hz, H-4), 7.48 (1H, d, J=8.0Hz, H-7), 7.44 (1H, s, H-2), 7.19 (1H, t, J=7.5Hz, H-6), 7.07 (1H, t, J=7.5Hz, H-5), 5.76 (1H, m, H-5 "), 4.96 (2H, m, H-6 "), 4.25 (2H, t, J=7.0Hz, H- 1”),3.99(2H,s,H-8),2.07(2H,m,H-4”),1.87(2H,m,H-2”),1.43(2H,m,H-3”)；13C NMR (500MHz,acetone-d6):δ171.2(C-9),149.8(C-2’,6’),142.4(C-4’),139.2(C-2),137.6 (C-7a),128.8(C-6”),128.5(C-3a),122.7(C-6),120.1(C-5),120.0(C-4),119.6(C-3’), 115.1(C-5”),114.7(C-5’),110.7(C-7),107.7(C-3),46.5(C-1”),35.0(C-8),34.0(C- 4”),30.6(C-2”),26.9(C-3”)；(+)-HR-ESIMS m/z 367.1456[M+H]+(calcd for C21H22ClN3O,367.1451)。
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 0.1-0.5ng p24/mL) by 0.5mL recombinant viruses liquid according to p24 concentration.48h after infection, removes training Base is supported, 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 fluoresceins In zymolyte, mix, the relative activity of luciferase in cell is determined with FB12 fluorescence detectors, the strong and weak reaction HIV of its activity 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 1-22 Anti-HIV-1 Actives, as a result find that 21 compounds have compared with high inhibition Wild HIV-1 is active (half-inhibition concentration 30nM~9 μM, table 1), and wherein embodiment 14,16 is active with the clinical non-nucleosides of a line Quite, the activity of embodiment 12,13 is better than NVP to class reverse transcriptase inhibitor thing NVP, 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
Example No. IC50(μM) Example No. IC50(μM)
1 8.3 14 0.05
3 1.2 15 0.15
4 0.6 16 0.05
5 5.8 17 0.6
6 0.5 18 9.0
7 0.2 19 0.3
8 0.7 20 0.5
9 0.3 21 0.14
10 0.3 22 0.09
11 0.1 NVP 0.05
12 0.04 Efavirenz 0.001
13 0.03
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 2 target compounds and clinical two kinds of non-nucleoside reverse transcriptases of occurrence probability highest are suppressed Agent medicament-resistant mutation strain HIV-1RT-K103N(occurrence probability 11%) and HIV-1RT-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 times of the two compounds to two kinds of resistance strains Number 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 1-22 anti-influenza virus activities, as a result find that 18 compounds have stronger suppression A/Puerto Rico/8/1934 (H1N1) infection activity (0.64 μM of half-inhibition concentration~65 μM, table 3) processed, wherein embodiment The activity of compound 6,12,15,16 and 21 is better than clinical first-line drug Ribavirin.Inventor also measured were this 5 compounds and resisted 262/95 (H1N1), A type A/ capital anti-/ 359/95 are prevented in influenza A 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 IC50(μM) Compound IC50(μM)
1 54.2 13 2.0
2 65.0 14 0.64
3 3.2 15 1.5
4 5.9 16 1.5
6 5.9 19 1.6
7 2.1 20 2.8
8 2.4 21 1.5
9 2.8 22 1.5
11 5.9 Ribavirin 15.0
12 5.9
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 (22)

1. a class Benzazole compounds and its pharmaceutically acceptable salt are preparing prevention, alleviated and/or treatment influenza virus medicine Application in thing or health products, it is characterised in that described compound is as shown in logical formula (I)：
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, it is meta, right Position is monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
X is selected from substituted or unsubstituted C1-16Alkyl；Wherein described substituent is optionally by following substituent group：OH、C1-6Alkyl, C1-6Alkoxy, halogen, NH2、NO2, cyano group, carboxyl, phenyl, C1-6Unsaturated alkyl, C3-6Cycloalkyl, C1-6Alkoxy acyl；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl；
Z is selected from carbon atom or nitrogen-atoms.
2. application according to claim 1, it is characterised in that shown in the compound such as formula (IA)
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, it is meta, right Position is monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
X is selected from substituted or unsubstituted C1-16Alkyl；Wherein described substituent is optionally by following substituent group：OH、C1-6Alkyl, C1-6Alkoxy, halogen, NH2、NO2, cyano group, carboxyl, phenyl, C1-6Unsaturated alkyl, C3-6Cycloalkyl, C1-6Alkoxy acyl；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
3. application according to claim 2, it is characterised in that shown in the compound such as formula (IA1)
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, it is meta, right Position is monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
4. application according to claim 2, it is characterised in that shown in the compound such as formula (IA2)
Wherein,
X is selected from substituted or unsubstituted C1-16Alkyl；Wherein described substituent is optionally by following substituent group：OH、C1-6Alkyl, C1-6Alkoxy, halogen, NH2、NO2, cyano group, carboxyl, phenyl, C1-6Unsaturated alkyl, C3-6Cycloalkyl, C1-6Alkoxy acyl；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
5. application according to claim 2, it is characterised in that shown in the compound such as formula (IA3)
Wherein,
X is selected from substituted or unsubstituted C1-16Alkyl；Wherein described substituent is optionally by following substituent group：OH、C1-6Alkyl, C1-6Alkoxy, halogen, NH2、NO2, cyano group, carboxyl, phenyl, C1-6Unsaturated alkyl, C3-6Cycloalkyl, C1-6Alkoxy acyl；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
6. application according to claim 2, it is characterised in that shown in the compound such as formula (IB)
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, it is meta, right Position is monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
X is selected from substituted or unsubstituted C1-16Alkyl；Wherein described substituent is optionally by following substituent group：OH、C1-6Alkyl, C1-6Alkoxy, halogen, NH2、NO2, cyano group, carboxyl, phenyl, C1-6Unsaturated alkyl, C3-6Cycloalkyl, C1-6Alkoxy acyl；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
7. application according to claim 4, it is characterised in that shown in the compound such as formula (IB1)
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, it is meta, right Position is monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
8. application according to claim 4, it is characterised in that shown in the compound such as formula (IB2)
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, it is meta, right Position is monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
9. application according to claim 4, it is characterised in that shown in the compound such as formula (IB3)
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, it is meta, right Position is monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
10. application according to claim 4, it is characterised in that shown in the compound such as formula (IB4)
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, it is meta, right Position is monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
11. application according to claim 4, it is characterised in that shown in the compound such as formula (IB5)
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, it is meta, right Position is monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
12. application according to claim 4, it is characterised in that shown in the compound such as formula (IB6)
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, it is meta, right Position is monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
13. application according to claim 4, it is characterised in that shown in the compound such as formula (IB7)
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, it is meta, right Position is monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
14. application according to claim 4, it is characterised in that shown in the compound such as formula (IB8)
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, it is meta, right Position is monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
15. application according to claim 4, it is characterised in that shown in the compound such as formula (IB9)
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, it is meta, right Position is monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
16. application according to claim 4, it is characterised in that shown in the compound such as formula (IB10)
Wherein,
R is monosubstituted or polysubstituted, selected from halogen or C1-6Alkoxy acyl；It is wherein described it is monosubstituted selected from ortho position, it is meta, right Position is monosubstituted；It is described polysubstituted to be selected from two substitutions, three substitutions, four substitutions；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
17. application according to claim 6, it is characterised in that shown in the compound such as formula (IB11)
Wherein,
X is selected from substituted or unsubstituted C1-16Alkyl；Wherein described substituent is optionally by following substituent group：OH、C1-6Alkyl, C1-6Alkoxy, halogen, NH2、NO2, cyano group, carboxyl, phenyl, C1-6Unsaturated alkyl, C3-6Cycloalkyl, C1-6Alkoxy acyl；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
18. application according to claim 6, it is characterised in that shown in the compound such as formula (IB12)
Wherein,
X is selected from substituted or unsubstituted C1-16Alkyl；Wherein described substituent is optionally by following substituent group：OH、C1-6Alkyl, C1-6Alkoxy, halogen, NH2、NO2, cyano group, carboxyl, phenyl, C1-6Unsaturated alkyl, C3-6Cycloalkyl, C1-6Alkoxy acyl；
Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
19. the application according to any one of claim 1,2,4,5,6,17,18, it is characterised in that：
The compound X is selected from substituted or unsubstituted C1-6Alkyl；Wherein described substituent is optionally by following substituent group： OH、C1-6Alkyl, C1-6Alkoxy, halogen, NH2、NO2, cyano group, carboxyl, phenyl, C1-6Unsaturated alkyl, C3-6Cycloalkyl, C1-6Alkane Oxygen acyl group；
The compound Y is selected from hydrogen, halogen, cyano group, carboxyl, C1-6Alkyl.
20. application according to claim 1, it is characterised in that the compound is selected from following group：
21. the application as described in claim any one of 1-20, it is characterised in that the preparation method of the compound is as follows：
Wherein any one of R, X, Y, Z definition and claim 1-20 are identical
Substituted 3- indole-carboxylic acids (formula 1) carry out N- substitution reactions in the basic conditions, obtain N- alkylates formula 2, formula 2 is again Amidation process, which is carried out, from different amine obtains target product formula 3.
22. a kind of application of pharmaceutical composition in preparing prevention, alleviating and/or treating influenza virus medicine or health products, its It is characterised by, any one of claim 1-20 that the pharmaceutical composition contains therapeutically effective amount compound and its pharmaceutically may be used The salt of receiving, and pharmaceutically acceptable carrier.
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