CN102206172A

CN102206172A - Substituted diaryl compound and preparation method and antiviral application thereof

Info

Publication number: CN102206172A
Application number: CN2010102754768A
Authority: CN
Inventors: 蒋建东; 李卓荣; 李艳萍; 李玉环; 彭宗根; 郝兰虎; 仲兆金
Original assignee: Institute of Medicinal Biotechnology of CAMS and PUMC
Current assignee: Institute of Medicinal Biotechnology of CAMS and PUMC
Priority date: 2010-03-30
Filing date: 2010-09-08
Publication date: 2011-10-05
Anticipated expiration: 2030-09-08
Also published as: CN102206172B

Abstract

本发明提供一组如通式(I)取代双芳基化合物或其药学上可接受的盐，还提供了其制备方法，通过构效关系以及活性化合物的作用机制研究，筛选获得一类新的以细胞因子为靶点的广谱抗病毒化合物及其药用盐，该类化合物不仅具有显著的抗广泛病毒的活性，还具有低毒，药学性质好等优点。

The present invention provides a group of substituted bisaryl compounds such as general formula (I) or pharmaceutically acceptable salts thereof, and also provides a preparation method thereof, through the study of the structure-activity relationship and the mechanism of action of the active compound, and screening to obtain a new class of A broad-spectrum antiviral compound targeting cytokines and a medicinal salt thereof, the compound not only has significant anti-viral activity, but also has the advantages of low toxicity and good pharmaceutical properties.

Description

One group replaces bi-aromatic compounds and preparation method thereof and antiviral application

Technical field

The present invention relates to one group and replace bi-aromatic compounds, also relate to the preparation method of described compound and, the especially application in hepatitis virus resisting, preventing respiratory viruses and enterovirus and the AIDS virus resisting at broad-spectrum antiviral.

Background technology

At present, the antiviral of Ying Yonging clinically, its action target spot is viral protein, and mechanism of action is for suppressing duplicating or the intrusion of blocking virus of virus.Virus is " target that moves ", relies on constantly variation to escape medicine and attacks.The medicine that with the viral protein is target spot all causes virus variation and resistance, has become global problem.Equally, 6 medicines of the treatment hepatitis B of clinical application at present, except that Interferon, rabbit, its structure type is nucleoside analog, and action target spot is viral protein DNA polymerase, can produce serious resistance problem behind the long-term prescription, causes the treatment failure.Multiple medicines combined utilization (drug cocktail therapy (treatment)) can reduce patient's virus load greatly, and slow down resistance and take place, but the final still unavoidable resistance that takes place; The new listing kind has certain advantage on the overriding resistance strain, but along with the prolongation of clinical duration of service, resistance still can't be avoided.Therefore, tackling viral resistance is the current major subjects that will solve.In addition, the virus disease that some RNA viruses (as Coxsackie virus, influenza virus and EV71 virus etc.) cause still lacks effective clinical treatment medicine, therefore, be badly in need of some convenient, effective and less new drugs of side effect of exploitation at present, use with the treatment that replenishes existing antiviral.

Ratified still do not have the listing of new anti-virus medicine so far after Interferon, rabbit and the ribavirin combined utilization treatment hepatitis C from 1998, and Interferon, rabbit and ribavirin combined utilization result of treatment are limited, nearly half patient no response after combination therapy is arranged, simultaneously a lot of patients can not tolerate the side effect of this conjoint therapy, as anaemia, fatigue, dysthymia disorders etc., and very high recurrence rate is arranged.Therefore, be badly in need of some convenient, effective and less new drugs of side effect of exploitation at present, to replenish existing treatment plan.

Along with deepening continuously of virusology and RESEARCH ON CELL-BIOLOGY, lot of research shows, in the very long process of organic evolution, host cell generally forms the defense system at Different Kinds of Pathogens virus, and virus also can form specific antagonism mechanism, realizes the inhibiting escape of host cell.Between virus and the host cell interdependence and mutually antagonism relation, particularly virus replication relevant cell factor become at present in the world in the Medical Biology basic and applied research direction in forward position and field with the fastest developing speed the most.

The contriver is in the broad-spectrum antiviral medicament screening study, find and confirm to replace bi-aromatic compounds and have the activity that wide spectrum suppresses virus, especially suppress the effect of hepatitis B and hepatitis c viral replication, inhibition Respirovirus and enterovirus and AIDS virus resisting.The action target spot of invention compound may be different from existing antiviral, and latter's multiaction is in viral enzyme, and compound of the present invention then may be based on novel cell mechanism and bring into play the broad-spectrum disease resistance toxic action.The report that domestic and international pertinent literature is arranged is not seen in compound of the present invention and effect thereof up to now.Development is the novel antiviral compound of target spot at cytokine, is expected to make a breakthrough for solving the virus drug resistance problem, thereby provides more effective New-type wide-spectrum antiviral for clinical.

Summary of the invention

Main purpose of the present invention is, imitate research by the structure that replaces bi-aromatic compounds to a group, and the study on mechanism of active compound, what screening acquisition one class was new is the broad-spectrum antiviral compound and the pharmaceutical salts thereof of target spot with the cytokine, this compounds not only has significant broad-spectrum disease resistance cytotoxic activity, also has low toxicity, advantage such as pharmaceutical properties is good.

In order to achieve the above object, the present invention adopts following technical scheme:

The invention provides one group and replace bi-aromatic compounds or its pharmaceutical salts, have structure shown in the following general formula (I):

Wherein:

X representative-C (O)-,-CH ₂C (O)-,-OCH ₂C (O)-,-S (O)-,-S (O) ₂-,-C (OH) (R ₁₀)-or-CH (R ₁₀)-, Y representative-O-,-S-,-CH (R ₁₁)-,-N (R ₁₂)-or singly-bound; Described R ₁₀, R ₁₁Represent hydrogen, alkyl, aralkyl, aryloxyalkyl group or fragrant sulfane base, R ₁₂Represent hydrogen, alkyl, halo alkyl, acyl group, hydroxy alkylene, hydrocarbyl amino, alkylsulfonyl.

Wherein, when X representative-C (O)-,-CH ₂C (O)-,-OCH ₂C (O)-time, Y representative-O-,-CH (R ₁₁)-,-N (R ₁₂)-or singly-bound; When X representative-S (O)-,-S (O) ₂-time, Y representative-O-or-N (R ₁₂)-; As X representative-C (OH) (R ₁₀)-time, Y representative-CH (R ₁₁)-or singly-bound; As X representative-CH (R ₁₀)-time, Y representative-O-,-S-or-N (R ₁₂)-.

Perhaps, when X representative-C (O)-,-CH ₂C (O)-,-OCH ₂C (O)-,-S (O) ₂-,-C (OH) (R ₁₀)-or-CH (R ₁₀)-, Y representative-N (R ₁₂)-,-O-,-S-,-CH (R ₁₁)-or singly-bound.

In preferred embodiment of the present invention, X representative-C (O)-or-S (O) ₂-, Y representative-O-or-NH-.

W ₁, W ₂, W ₃, W ₄, W ₅Each represents independently carbon atom, nitrogen-atoms, Sauerstoffatom or a sulphur atom, and has at least 4 to exist simultaneously in the molecule arbitrarily, and at least 1 is represented carbon atom; When W represented heteroatoms, there was not substituting group in this position;

Described W ₁, W ₂, W ₃, W ₄And W ₅With R ₃, R ₄Or R ₅Form and replace or unsubstituted phenyl ring, pyridine ring, pyrazine ring, pyrimidine ring, thiazole ring, furan nucleus or pyrrole ring, more preferably phenyl ring, pyrimidine ring, thiazole ring or furan nucleus;

Work as R ₁, R ₂, R ₃, R ₄, R ₅Can be the same or different when independently existing separately, represent hydrogen, alkyl, halo alkyl, hydroxy alkylene, halogen, nitro, cyano group, acyl group, carboxyl, sulfonic group, phosphate, aryl, heteroaryl, C (O) OR respectively ₁₃, CONR ₁₃R ₁₄, S (O) ₂NR ₁₃R ₁₄, SR ₁₃, OR ₁₄Or NR ₁₃R ₁₄, described R ₁₃, R ₁₄Represent respectively hydrogen, alkyl, cyclic hydrocarbon radical, heterocycle alkyl, aryl, heteroaryl, alkylsulfonyl, acyl group,

Or

Wherein, preferred, R ₁, R ₂, R ₃, R ₄, R ₅Represent hydrogen, alkyl, halo alkyl, halogen, nitro, aryl, CONR respectively ₁₃R ₁₄, S (O) ₂NR ₁₃R ₁₄, SR ₁₃, OR ₁₄Or NR ₁₃R ₁₄, described R ₁₃, R ₁₄Represent the aryl of hydrogen, alkyl, aryl, benzsulfamide replacement, aryl, acyl group or the alkylsulfonyl that para toluene sulfonamide replaces respectively, hydrogen, alkyl, halo alkyl, halogen, nitro,-oxyl or NR ₁₃R ₁₄, described R ₁₃, R ₁₄Represent hydrogen, alkyl or acyl group respectively;

In preferred embodiment of the present invention, preferred, described R ₁, R ₂, R ₃, R ₄, R ₅Represent hydrogen, alkyl, nitro, aryl, SR respectively ₁₃, OR ₁₄Or NR ₁₃R ₁₄, described R ₁₃, R ₁₄Represent hydrogen, alkyl, aryl, acyl group or alkylsulfonyl respectively;

Perhaps, R ₃And R ₄Or R ₄And R ₅Can interconnect, condense formation five yuan or hexa-atomic aromatic shape structure M with parent nucleus, its constitutional features allows to contain 0-3 heteroatoms suc as formula shown in (IIa and IIb) in the skeleton of M, and the position that allows on chemical theory may be connected with one or more identical or different substituent R ₁₅, in addition, heteroatoms is represented nitrogen, oxygen or sulphur;

Preferred described M and parent nucleus are formed jointly and are replaced or unsubstituted benzothiazole, cumarone, indoles, quinoline or naphthyridines etc. described R ₁₅Represent halogen, amino, nitro, C1-C6 alkyl, C1-C6 alkoxyl group or sulfonamido;

Z ₁, Z ₂, Z ₃, Z ₄, Z ₅Each represents independently a carbon atom or a nitrogen-atoms, and has at least 4 to exist simultaneously in the molecule arbitrarily, and at least one represents carbon atom; When Z represented nitrogen-atoms, there was not substituting group in this position;

Described Z ₁, Z ₂, Z ₃, Z ₄And Z ₅With R ₆, R ₇, R ₈And R ₉Form and replace or unsubstituted phenyl ring, pyridine ring, pyrazine ring, pyrimidine ring, thiazole ring, furan nucleus, pyrrole ring, imidazole ring or triazole ring, more preferably phenyl ring, pyridine ring, pyrimidine ring, thiazole ring or triazole ring; Described R ₆, R ₇, R ₈And R ₉Can be the same or different when independently existing separately, represent the aryl of hydrogen, alkyl, halo alkyl, hydroxy alkylene, halogen, nitro, amino, alkyl amino, hydroxyl, cyano group,-oxyl, acyl group, amido, ester group, carboxyl, sulfonic group, phosphate, aryl, benzsulfamide replacement, aryl, heteroaryl, the CONR that para toluene sulfonamide replaces respectively ₁₆R ₁₇, S (O) ₂NR ₁₆R ₁₇, SR ₁₆, OR ₁₇Or NR ₁₆R ₁₇Deng;

Described R ₁₆, R ₁₇Represent hydrogen, alkyl, cyclic hydrocarbon radical, heterocycle alkyl, aryl, heteroaryl, alkylsulfonyl, acyl group respectively, in addition, R ₁₆With R ₁₇Also can connect into the azepine ring texture;

In addition, R ₆And R ₇, R ₇And R ₈Or R ₈And R ₉All may be interconnected to form with parent nucleus thick and five yuan of the fragrance of structure shown in IIIa, IIIb and IIIc or six-membered cyclic structure N, allow to contain 0-3 heteroatoms in the skeleton of N, and the position that allows may be connected with one or more identical or different substituent R on chemical theory ₁₅, in addition, heteroatoms is represented nitrogen, oxygen or sulphur

Preferred N and parent nucleus are formed jointly and are replaced or unsubstituted benzothiazole, cumarone, indoles, purine, quinoline or naphthyridines etc. described R ₁₅Represent hydrogen, alkyl,-oxyl, halogen, oxo, acyl group, amido, sulfonamido replace;

Wherein, preferred described Z ₁, Z ₂, Z ₃, Z ₄And Z ₅With R ₆, R ₇, R ₈And R ₉Form and replace or unsubstituted phenyl ring, pyrimidine ring or pyridine ring described R ₆, R ₇, R ₈And R ₉Represent the aryl of hydrogen, alkyl, aryl, benzsulfamide replacement, aryl, halo alkyl, halogen, the CONR that para toluene sulfonamide replaces respectively ₁₆R ₁₇, S (O) ₂NR ₁₆R ₁₇, SR ₁₆, OR ₁₇Or NR ₁₆R ₁₇, described R ₁₆, R ₁₇Represent hydrogen, alkyl, aryl or alkylsulfonyl respectively.

Described in more than defining:

" alkyl " can be meant the alkyl or cycloalkyl of carbonatoms at the straight or branched of 1-8, for example, methyl, ethyl, sec.-propyl, n-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, n-hexyl, isohexyl etc. or its corresponding cycloalkyl.The low alkyl group of C1-C6 more preferably.

" aryl " is meant the aromatic hydrocarbons part and can be substituted or be substituted; aromatic hydrocarbons is selected from phenyl, naphthyl, xenyl, tetralyl, phenanthryl, fluorenyl, acenaphthenyl or phenanthrylene etc., the halogen of described replacement unit of being meant or multidigit, alkyl, hydroxyl, nitro, amino, acyl group,-oxyl, CONH ₂, CONH (alkyl), CON (alkyl) ₂, trifluoromethyl, trifluoromethoxy, sulfonic group, SO ₂NH ₂, SO ₂NH (alkyl), SO ₂N (alkyl) ₂, SO ₂N (cyclic hydrocarbon radical), ester group, itrile group, oxygen aryl, sulphur aryl or alkylaryl etc.; The preferred aryl groups substituting group comprises: alkyl, halogen, nitro, amino, CONH ₂,-oxyl, trifluoromethyl, SO ₂NH (alkyl), itrile group, oxygen aryl, sulphur aryl or alkylaryl;

" heteroaryl " can be meant and be substituted or unsubstituted aromatic heterocycle system (monocycle or dicyclo), wherein fragrant heterocyclic moiety is selected from N, O or S heteroatomic five yuan or six-ring for containing 1-4, and include but not limited to: as furans, thiophene, indoles, oxazole, thiazole, imidazoles, pyridine, pyrimidine, pyrazine, pyrroles, pyrazoles, 1,2, monocycle aroma systems such as 4-triazole or condense the Bicyclic system that forms by benzene, pyridine, pyrimidine or pyridazine and other five yuan or hexa-member heterocycle are as thionaphthene, cumarone, benzoglyoxaline and quinazoline etc.; The halogen of described replacement unit of being meant or multidigit, alkyl, hydroxyl, nitro, amino, acyl group,-oxyl, CONH ₂, CONH (alkyl), CON (alkyl) ₂, trifluoromethyl, trifluoromethoxy, sulfonic group, SO ₂NH ₂, SO ₂NH (alkyl), SO ₂N (alkyl) ₂, SO ₂N (cyclic hydrocarbon radical), ester group, itrile group, oxygen aryl, sulphur aryl or alkylaryl etc.; The preferred aryl groups substituting group comprises: alkyl, halogen, nitro, amino, CONH ₂,-oxyl, trifluoromethyl, SO ₂NH (alkyl), itrile group, oxygen aryl, sulphur aryl or alkylaryl;

"-oxyl " can be the alkoxyl group of carbonatoms at 1-8, for example, methoxyl group, oxyethyl group, isopropoxy, positive propoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, positive hexyloxy, different hexyloxy etc.The lower alkoxy of C1-C6 more preferably.

" acyl group " can be hydrocarbon substituted acyl or aryl-acyl or the heteroaryl acyl group with 1-8 carbon; for example formyl radical, ethanoyl, sec.-propyl acyl group, n-propyl acyl group, allyl group acyl group, cyclopropyl acyl group, normal-butyl acyl group, isobutyl-acyl group, sec-butyl acyl group, tertiary butyl acyl group, n-pentyl acyl group, isopentyl acyl group, n-hexyl acyl group, isohexyl acyl group, phenyl acyl group, tolyl acyl group, 2-pyridine acyl etc. can also be halo alkyl substituted acyl.More preferably the low alkyl group substituted acyl of C1-C6 or halo alkyl substituted acyl.

" ester group " can be hydrocarbon ester appended (alkyl acyloxy) or the aryl ester group with 1-8 carbon, for example methanoyl, acetoxyl group, sec.-propyl acyloxy, n-propyl acyloxy, allyl group acyloxy, cyclopropyl acyloxy, normal-butyl acyloxy, isobutyl-acyloxy, sec-butyl acyloxy, tertiary butyl acyloxy, n-pentyl acyloxy, isopentyl acyloxy, n-hexyl acyloxy, isohexyl acyloxy, phenyl acyloxy, tolyl acyloxy etc.The low alkyl group ester appended of C1-C6 (alkyl acyloxy) more preferably.

" amido " can be that the hydrocarbon with 1-8 carbon replaces amido or aryl amido, for example methyl amido, ethyl amido, sec.-propyl amido, n-propyl amido, allyl group amido, cyclopropyl amido, normal-butyl amido, isobutyl-amido, sec-butyl amido, tertiary butyl amido, n-pentyl amido, isopentyl amido, n-hexyl amido, isohexyl amido, phenyl amido, tolyl amido etc.More preferably the low alkyl group of C1-C6 replaces amido.

" halo " or " halogen " can be fluorine, chlorine, bromine or iodine.

" alkylsulfonyl " can be hydrocarbon substituted sulphonyl or the aryl sulfonyl with 1-8 carbon, for example methyl sulphonyl, ethylsulfonyl, sec.-propyl alkylsulfonyl, n-propyl alkylsulfonyl, allyl group alkylsulfonyl, cyclopropyl alkylsulfonyl, normal-butyl alkylsulfonyl, isobutyl-alkylsulfonyl, sec-butyl alkylsulfonyl, tertiary butyl alkylsulfonyl, n-pentyl alkylsulfonyl, isopentyl alkylsulfonyl, n-hexyl alkylsulfonyl, isohexyl alkylsulfonyl, phenyl sulfonyl, tolylsulfonyl-base etc.In better embodiment of the present invention, be preferably the substituted phenyl sulfonyl base, described replacement is that alkyl, amino, nitro, halogen, the hydroxyl of unit or multidigit replaces.

In the substituting group of replacement bi-aromatic compounds of the present invention or its pharmaceutical salts structural formula, the alkyl in described halo alkyl, carbonyl alkyl, hydroxy alkylene, the hydrocarbyl amino is the alkyl of C1-C6.

Pharmaceutical salts of the present invention is that the replacement bi-aromatic compounds according to above-mentioned definition general formula (I) comprises that also the product of salt-forming reaction takes place for itself and acid, and promptly its pharmacy acceptable salt comprises inorganic acid salt, example hydrochloric acid salt, hydrobromate or vitriol etc.; Organic acid salt is as acetate, lactic acid salt, succinate, fumarate, maleate, Citrate trianion, benzoate, mesylate or paratolunitrile salt etc.

The preferred representative compounds of the present invention comprises following compound, wherein:

(A) have structure shown in the following general formula (IV):

Wherein: X representative-C (O)-,-S (O) ₂-,-S (O)-,-CH (OH)-or-CH ₂-, Y representative-O-,-CH ₂-,-N (R ₁₂)-; Described R ₁₂Represent the phenyl sulfonyl of hydrogen, replacement or the phenyl acyl group of replacement, described replacement is that C1-C6 alkyl, C1-C6 alkoxyl group, amino, nitro, the C1-C6 alkyl amido of unit or multidigit replaces;

R ₂Be amino, nitro, C1-C6 alkyl acyloxy or NR ₁₃R ₁₄, described R ₁₃, R ₁₄Represent respectively hydrogen, C1-C6 alkyl, C1-C6 alkyl acyl, halo C1-C6 alkyl acyl,

R ₃For hydrogen, C1-C6 alkyl, C1-C6 alkoxyl group ,-S (O) ₂NH ₂Or phenyl-S-;

R ₆, R ₇, R ₈And R ₉Can be the same or different when independently existing separately, represent the aryl of hydrogen, halogen, nitro, amino, C1-C6 alkyl, C1-C6 alkoxyl group, benzsulfamide replacement, aryl, halo C1-C6 alkyl or the methylthio group that para toluene sulfonamide replaces respectively, or R ₇With R ₈Common composition-O-CH ₂-CH ₂-O-.

The preferred compound of the present invention comprises those compounds of (A), wherein:

(B) X representative-C (O)-,-S (O) ₂-,-S (O)-, Y representative-O-or-NH-;

R ₂Be amino, nitro or NR ₁₃R ₁₄, described R ₁₃, R ₁₄Represent hydrogen, C1-C6 alkyl acyl, trifluoroacetyl group respectively;

R ³Be hydrogen, C1-C6 alkyl, C1-C6 alkoxyl group;

R ₆, R ₇, R ₈And R ₉Represent H, halogen or C1-C6 alkoxyl group independently of one another.

The preferred compound of the present invention comprises those compounds of (B), wherein:

(C) X representative-C (O)-,-S (O) ₂-, Y representative-O-or-NH-;

R ₂Be amino, nitro or NR ₁₃R ₁₄, described R ₁₃R during for hydrogen ₁₄Be propionyl or trifluoroacetyl group, or R ₁₃And R ₁₄Be propionyl;

R ₃Be methyl or methoxy;

R ₆, R ₇, R ₈And R ₉Represent H, halogen or methoxyl group independently of one another.

In preferred embodiment of the present invention, the part of compounds in the general formula (IV) especially has the activity of anti HIV-1 virus, wherein

(D) X representative-C (O)-, Y representative-O-or-NH-;

R ₂Be amino or NHR ₁₄, described R ₁₄Be propionyl or trifluoroacetyl group;

R ₃Be methoxyl group;

Perhaps the preferred compound of the present invention comprises following compound, wherein

(E) have structure shown in the following logical formula V:

Wherein: X representative-C (O)-,-S (O) ₂-,-S (O)-, Y representative-N (R ₁₂)-; Described R ₁₂Represent the phenyl acyl group of hydrogen or replacement, described replacement is that nitro, C1-C6 alkoxyl group, the C1-C6 alkyl amido of unit or multidigit replaces;

R ₂Be amino, nitro or NHR ₁₃, described R ₁₃Represent C1-C6 alkyl acyl or halo C1-C6 alkyl acyl;

R ₃Be hydrogen, C1-C6 alkyl, C1-C6 alkoxyl group;

Q1 is selected from

The preferred compound of the present invention comprises those compounds of (E), wherein:

X representative-C (O)-,-S (O) ₂-, Y representative-NH-;

R ₂Be NO ₂

R ₃Be the C1-C6 alkyl;

Q1 is

(G) have structure shown in the following general formula (VI):

Wherein: X representative-C (O)-,-S (O) ₂-or-S (O)-, Y representative-NH-

R ₆, R ₇, R ₈And R ₉Can be the same or different aryl, aryl, the C1-C6 alkoxyl group that para toluene sulfonamide replaces, preferably chlorine or the methoxyl group of representing hydrogen, halogen, benzsulfamide to replace respectively when independently existing separately;

Q2 is selected from and replaces or unsubstituted pyridine base or thienyl, and described replacement is replaced by nitro or methylthio group list.

(H) have structure shown in the following general formula (VII):

Wherein, X representative-C (O)-,-S (O) ₂-or-S (O)-, Y representative-NH-;

Q1 and Q2 are selected from respectively and replace or unsubstituted pyridine base, pyrimidyl, thienyl or benzofuryl, and described replacement is replaced by halogen or aminoacyl.

The present invention also provides the preparation method of described replacement bi-aromatic compounds or its pharmaceutical salts, can determine initiator and reactant according to the structure design of the X in the purpose compound, Y, specifically can carry out according to five kinds of methods:

Method one: the X of formula (I) compound is-C (O)-,-CH ₂C (O)-or-OCH ₂C (O)-, Y is-O-,-N (R ₁₂)-time, adopt following route method synthetic: with A and condensing agent (as, I-hydroxybenzotriazole, HOBT; N, N '-DIC, DIC etc.) be dissolved in the polar aprotic solvent (as: N, dinethylformamide) by the suitable proportion mixing, add B behind the stirring 0.5-5h, to react under the room temperature, separation and purification gets product

Wherein, X=-C (O)-,-CH ₂C (O)-or-OCH ₂C (O)-; Y=-O-or-N (R ₁₂)-; Other substituting group definition is the same;

Method two: the X of formula (I) compound is-C (O)-,-CH ₂C (O)-,-OCH ₂C (O)-,-S (O) ₂-or-S (O)-time, Y is-O-,-N (R ₁₂)-time, also can adopt following method synthetic: with A with suitable halide reagent (as, thionyl chloride, phosphorus pentachloride etc.) be converted into acyl chlorides, doing under the condition of acid binding agent with alkali (as, triethylamine), in the aprotic, polar solution of B, slowly add the gained acyl chlorides under the low temperature, finish, reply room temperature to reacting completely, separation and purification obtains target compound;

Wherein, X=-C (O)-,-CH ₂C (O)-,-OCH ₂C (O)-,-S (O) ₂-or-S (O)-; Y=-O-or-N (R ₁₂)-; Other substituting group definition is the same;

Method three: the X of formula (I) compound is-C (OH) (R ₁₀)-, Y is-CH (R ₁₁)-or during singly-bound, adopt following method synthetic: the halohydrocarbon that will contain (mix) aryl is made Grignard reagent or directly under the catalysis of (as, butyllithium etc.) of metal organic bases, with aryl ketones (aldehyde) reaction generation 2-diaryl alcohol class target compound;

Method four: the X of formula (I) compound is-C (O)-, Y is-CH (R ₁₁)-or during singly-bound, the synthetic method of employing is: diaryl secondary alcohol class target compound is generated diaryl ketone class target compound through the peroxychromic acid oxidation;

Method five: the X of formula (I) compound is-CH (R ₁₀)-, Y is-O-,-N (R ₁₂)-or-during S-, adopt following method synthetic: A is generated halides by halogen (as bromine) generation reaction, in polar aprotic solvent (as, methylene dichloride), obtain target compound with the B condensation under alkalescence (as, the Anhydrous potassium carbonate) condition;

Wherein, Y=O, N (R ₁₂) or S; G represents chlorine, bromine or iodine; Other substituting group definition is the same.

The present invention also provides a kind of anti-viral pharmaceutical compositions on the other hand, and it comprises that above-mentioned replacement bi-aromatic compounds or its pharmaceutical salts for the treatment of significant quantity are activeconstituents, and contains one or more pharmaceutically acceptable pharmaceutical excipients.Pharmaceutical composition provided by the invention can be according to the various form of administration of the conventional production method preparation of pharmaceutical field, and activeconstituents is mixed with one or more carriers, is made into required formulation then.For example the mixture of compound itself or itself and pharmaceutically acceptable vehicle, thinner etc. can be prepared into combination of oral medication with the form of tablet, capsule, granule, powder or syrup with the mixture of compound itself or itself and pharmaceutically useful vehicle, thinner etc. with the form oral administration of tablet, capsule, granule, powder or syrup or with the non-oral administration of the form of injection, or be prepared into non-combination of oral medication with the form of injection.

Pharmaceutical composition of the present invention preferably contains the activeconstituents that weight ratio is 0.1%-99.5%, most preferably contains the activeconstituents that weight ratio is 0.5%-99.5%.

Above-mentioned preparation can be by conventional pharmaceutical methods preparation.The example of available medicinal adjuvant comprises vehicle (for example carbohydrate derivative such as lactose, sucrose, glucose, mannitol and Sorbitol Powder; Starch derivative such as W-Gum, potato starch, dextrin and carboxymethyl starch; Derivatived cellulose such as crystalline cellulose, hydroxypropylcellulose, carboxymethyl cellulose, calcium carboxymethylcellulose, Xylo-Mucine; Gum arabic; Dextran; Silicate derivative such as metasilicic acid magnalium; Phosphate derivative such as calcium phosphate; Carbonate derivative such as lime carbonate; Sulfate-derivatives such as calcium sulfate etc.); Tackiness agent (for example gelatin, polyvinylpyrrolidone and polyoxyethylene glycol); Disintegrating agent (for example derivatived cellulose such as Xylo-Mucine, polyvinylpyrrolidone); Lubricant (for example talcum, calcium stearate, Magnesium Stearate, spermaceti, boric acid, Sodium Benzoate, leucine), stablizer (methyl p-hydroxybenzoate, propylparaben etc.); Correctives (for example Chang Yong sweeting agent, acidic flavoring agent and spices etc.); Thinner and injection liquid solvent (for example water, ethanol and glycerine etc.).

The present invention also provides described one group of application that replaces bi-aromatic compounds or its pharmaceutical salts and described anti-viral pharmaceutical compositions in the broad-spectrum antiviral field, especially the application in treatment hepatitis B and hepatitis c virus infection comprises the combined utilization with other antiviral chemotherapeutics.

The present invention also provides the pharmacodynamic experiment research of described compound.Adopt the HepG2.2.15 cell cultures,, measure the restraining effect of compound hbv replication with the qPCR method with the toxicity of CPE method mensuration compound pair cell; Adopt the Huh7.5 cell cultures,, measure the restraining effect that compound infects HCV with the qRT-PCR method with the toxicity of MTT staining mensuration compound pair cell.Measurement result sees Table 2.

The present invention also adopts the MT-4P24 antigen method, has measured the anti-HIV-1 activity of invention compound, the results are shown in Table 3.The compounds of this invention is also inhibited to HIV.

The present invention also provides described one group to replace the application in treatment Respirovirus and enterovirus infection of bi-aromatic compounds or its pharmaceutical salts and described anti-viral pharmaceutical compositions, comprises the combined utilization with other antiviral chemotherapeutics.

The present invention also provides the pharmacodynamic experiment research of described compound.The employing mdck cell is cultivated, and the toxicity of usefulness CPE method mensuration compound pair cell and compound are to the restraining effect of influenza virus, and measurement result sees Table 4; Employing Vero cell cultures uses the CPE method to measure the toxicity of compound pair cell and compound is viral to EV71 and the restraining effect of Coxsackie virus, and measurement result sees Table 4.

Above result of study preliminary identification The compounds of this invention or its pharmaceutical salts suppress aspect hepatitis virus and the HIV, in the effect that suppresses aspect Respirovirus and the enterovirus.Because its broad-spectrum disease resistance toxic action is based on novel cell mechanism, have that treatment back is difficult for producing resistance, having with other antiviral that potential combination therapy effect, security are better etc. may advantage, for this product is laid a good foundation as the Application and Development of broad-spectrum antiviral medicament.

Embodiment

Following examples can further help those skilled in the art to understand the present invention, but do not limit the present invention in any way.

＜embodiment 1 〉Synthesizing of (3-propionamido-4-anisole) formyl (3 ', 4 ', 5 '-trimethoxy-benzene) amine (1)

In the flask of 25ml; with 3-amino-4-methoxybenzoic acid (1.0g; 6mmol) be dissolved in exsiccant THF (tetrahydrofuran (THF)) after; (1.2ml 12mmol) obtains yellow transparent solution, nitrogen protection to add triethylamine; stir; (0.78ml 9mmol), dropwises the back and recovers room temperature reaction naturally to wherein dripping propionyl chloride under the ice-water bath condition.Filtering reacting liquid is gone up the silicagel column separation and is obtained 3-propionamido-4-methoxybenzoic acid 1.3g (yield 67%) behind the filtrate evaporate to dryness.

With above-mentioned product 100mg (0.45mmol) under the ice-water bath condition with HOBT 136mg (0.6mmol), DIC0.1ml (0.8mmol) is blended among the dry DMF, N ₂Protection adds 3,4 behind the stirring 30min, and 5-trimethoxy-aniline 72mg (mmol) returns to stirred overnight at room temperature naturally.Evaporated under reduced pressure reaction solution, resistates acetic acid ethyl dissolution after-filtration adopts silicagel column to separate and obtains compound 1 120mg (yield 68%) behind the filtrate evaporate to dryness, ¹H NMR data see Table 1.

＜embodiment 2 〉Synthesizing of (3-propionamido-4-anisole) formyl (4 '-chlorinated benzene) amine (2)

With 3-amino-4-methoxybenzoic acid, propionyl chloride and p-Chlorobenzoic acid amide is starting raw material, according to embodiment 1 similar approach, synthetic obtains compound 2, yield 23%, ¹H NMR data see Table 1.

＜embodiment 3 〉Synthesizing of (3-trifluoroacetamido-4-anisole) formyl (4 '-chlorinated benzene) amine (4)

With 3-amino-4-methoxybenzoic acid, trifluoroacetic anhydride and p-Chlorobenzoic acid amide is starting raw material, according to embodiment 1 similar approach, synthetic obtains compound 4, yield 26%, ¹H NMR data see Table 1.

＜embodiment 4 〉Synthesizing of (3-amino-4-anisole) formyl (3 ', 4 ', 5 '-trimethoxy benzene) amine (5)

With 3-amino-4-methoxybenzoic acid, (BOC) ₂O and 3,4,5-trimethoxy-aniline are starting raw material, according to embodiment 1 similar approach, synthetic obtain compound 5, yield 18%, ¹H NMR data see Table 1.

＜embodiment 5 〉Synthesizing of (3-propionamido-4-anisole) formylaniline (6)

With 3-amino-4-methoxybenzoic acid, propionyl chloride and aniline is starting raw material, according to embodiment 1 similar approach, synthetic obtains compound 6, yield 34%, ¹H NMR data see Table 1.

＜embodiment 6 〉Synthesizing of (3-propionamido-4-first hydrogen base benzene) formyl-(4 '-methylbenzene) amine (7)

With 3-amino-4-methoxybenzoic acid, propionyl chloride with to monomethylaniline is starting raw material, according to embodiment 1 similar approach, syntheticly obtains compound 7, yield 32%, ¹H NMR data see Table 1.

＜embodiment 7 〉Synthesizing of (3-propionamido-4-anisole) formyl-(4 '-trifluoromethylbenzene) amine (8)

With 3-amino-4-methoxybenzoic acid, propionyl chloride and p-trifluoromethylaniline is starting raw material, according to embodiment 1 similar approach, synthetic obtains compound 8, yield 38%, ¹H NMR data see Table 1.

＜embodiment 8 〉Synthesizing of (3-propionamido-4-anisole) formyl-(2 '-chlorinated benzene) amine (9)

With 3-amino-4-methoxybenzoic acid, propionyl chloride and 2-chloroaniline is starting raw material, according to embodiment 1 similar approach, synthetic obtains compound 9, yield 32%, ¹H NMR data see Table 1.

＜embodiment 9 〉Synthesizing of (3-propionamido-4-anisole) formyl (4 '-fluorobenzene) amine (10)

With 3-amino-4-methoxybenzoic acid, propionyl chloride and para-fluoroaniline is starting raw material, according to embodiment 1 similar approach, synthetic obtains compound 10, yield 35%, ¹H NMR data see Table 1.

＜embodiment 10 〉Synthesizing of (3-propionamido-4-anisole) formyl (4 '-bromobenzene) amine (11)

With 3-amino-4-methoxybenzoic acid, propionyl chloride and para-bromoaniline is starting raw material, according to embodiment 1 similar approach, synthetic obtains compound 11, yield 16%, ¹H NMR data see Table 1.

＜embodiment 11 〉Synthesizing of (3-propionamido-4-anisole) formyl-(3 '-chlorinated benzene) amine (12)

With 3-amino-4-methoxybenzoic acid, propionyl chloride and 3-chloroaniline is starting raw material, according to embodiment 1 similar approach, synthetic obtains compound 12, yield 31%, ¹H NMR data see Table 1.

＜embodiment 12 〉Synthesizing of (3-propionamido-4-anisole) formyl-(2 ', 4 '-dichlorobenzene) amine (13)

With 3-amino-4-methoxybenzoic acid, propionyl chloride and 2,4 dichloro aniline is starting raw material, according to embodiment 1 similar approach, synthetic obtains compound 13, yield 30%, ¹H NMR data see Table 1.

＜embodiment 13 〉Synthesizing of (3-(N-Cbz-valyl) amino-4-anisole) formylaniline (16)

With 3-amino-4-methoxybenzoic acid, (BOC) ₂O, aniline and N-Cbz-Xie Ansuan are starting raw material, according to embodiment 1 similar approach, synthetic obtain compound 16, yield 30%, ¹H NMR data see Table 1.

＜embodiment 14 〉Synthesizing of (3-valyl amino-4-anisole) formylaniline (18)

16 to be starting raw material, hydrogenation removes protection, syntheticly obtains compound 18, yield 90%, ¹H NMR data see Table 1.

＜embodiment 15 〉Synthesizing of (3-(2 '-bromine propionyl) amino-4-anisole) formylaniline (22)

With 3-amino-4-methoxybenzoic acid, 2-bromo propionyl chloro and aniline is starting raw material, according to embodiment 1 similar approach, synthetic obtains compound 22, yield 37%, ¹H NMR data see Table 1.

＜embodiment 16 〉Synthesizing of (3-(2 '-chlorine propionyl) amino-4-anisole) formylaniline (23)

With 3-amino-4-methoxybenzoic acid, 2-chlorpromazine chloride and aniline is starting raw material, according to embodiment 1 similar approach, synthetic obtains compound 23, yield 35%, ¹H NMR data see Table 1.

＜embodiment 17 〉Synthesizing of (3-trifluoroacetamido-4-anisole) formyl-4 '-5-trifluoromethylaniline (24)

With 3-amino-4-methoxybenzoic acid, trifluoroacetic anhydride and p-trifluoromethylaniline is starting raw material, according to embodiment 1 similar approach, synthetic obtains compound 24, yield 30%, ¹H NMR data see Table 1.

＜embodiment 18 〉Synthesizing of (3-(2 '-bromine propionyl) amino-4-anisole) formyl-(4 '-trifluoromethylbenzene) amine (25)

With 3-amino-4-methoxybenzoic acid, 2-bromo propionyl chloro and p-trifluoromethylaniline is starting raw material, according to embodiment 1 similar approach, synthetic obtains compound 25, yield 30%, ¹H NMR data see Table 1.

＜embodiment 19 〉Synthesizing of (3-propionamido-4-anisole) methanoyl-(3 ', 4 ', 5 '-trimethoxy) benzene (34)

With 3-amino-4-methoxybenzoic acid, propionyl chloride and 3,4, the 5-trimethoxy-aniline is a starting raw material, according to embodiment 1 similar approach, synthetic obtains compound 34, yield 21%, ¹H NMR data see Table 1.

＜embodiment 20 〉Synthesizing of (3-propionamido-4-anisole) formyl-(4 '-anisole) amine (35)

With 3-amino-4-methoxybenzoic acid, propionyl chloride and 4-anisidine is starting raw material, according to embodiment 1 similar approach, synthetic obtains compound 35, yield 25%, ¹H NMR data see Table 1.

＜embodiment 21 〉Synthesizing of (3-trifluoroacetamido-4-anisole) formyl (3 ', 4 ', 5 '-trimethoxy) amine (36)

With 3-amino-4-methoxybenzoic acid, trifluoroacetic anhydride and 3,4, the 5-trimethoxy-aniline is a starting raw material, according to embodiment 1 similar approach, synthetic obtains compound 36, yield 27%, ¹H NMR data see Table 1.

＜embodiment 22 〉Synthesizing of (3-propionamido-4-anisole) methanoyl-(4 '-methoxyl group) benzene (39)

With 3-amino-4-methoxybenzoic acid, propionyl chloride and 4-methoxyphenol is starting raw material, according to embodiment 1 similar approach, synthetic obtains compound 39, yield 25%, ¹H NMR data see Table 1.

＜embodiment 23 〉Synthesizing of (3-amino-4-anisole) methanoyl-(3 ', 4 ', 5 '-trimethoxy) benzene (40)

With 3-amino-4-methoxybenzoic acid, (BOC) ₂O and 3,4,5-trimethoxy phenol is starting raw material, according to embodiment 1 similar approach, synthetic obtains compound 40, yield 21%, ¹H NMR data see Table 1.

＜embodiment 24 〉Synthesizing of (3-trifluoroacetyl group-4-anisole) methanoyl-(3 ', 4 ', 5 '-trimethoxy) benzene (41)

With 3-amino-4-methoxybenzoic acid, trifluoroacetic anhydride and 3,4,5-trimethoxy phenol is starting raw material, according to embodiment 1 similar approach, synthetic obtains compound 41, yield 24%, ¹H NMR data see Table 1.

＜embodiment 25 〉Synthesizing of (3-trifluoroacetyl group-4-anisole) methanoyl-(4 '-methoxyl group) benzene (42)

With 3-amino-4-methoxybenzoic acid, trifluoroacetic anhydride and 4-methoxyphenol is starting raw material, according to embodiment 1 similar approach, synthetic obtains compound 42, yield 24%, ¹H NMR data see Table 1.

＜embodiment 26 〉Synthesizing of (3-propionamido-4-anisole) formyl-(3 '-methylthio phenyl) amine (45)

With 3-amino-4-methoxybenzoic acid, propionyl chloride and 3-methylthio group aniline is starting raw material, according to embodiment 1 similar approach, synthetic obtains compound 45, yield 21%, ¹H NMR data see Table 1.

＜embodiment 27 〉Synthesizing of (3-propionamido-4-anisole) formyl-(3 ', 4 '-dioxy ethylene group benzene) amine (46)

With 3-amino-4-methoxybenzoic acid, propionyl chloride and 3,4-dioxy ethylene aniline is starting raw material, according to embodiment 1 similar approach, synthetic obtains compound 46, yield 26%, ¹H NMR data see Table 1.

＜embodiment 28 〉Synthesizing of 3-amino-4-methoxybenzoyl aniline (67)

With 3-amino-4-methoxybenzoic acid, (BOC) ₂O and aniline are starting raw material, according to embodiment 1 similar approach, synthetic obtain compound 67, yield 29%, ¹H NMR data see Table 1.

＜embodiment 29 〉Synthesizing of (3-propionamido-4-anisole) sulphonyl (4 '-chlorinated benzene) amine (33)

(5.0g 21mmol) is dissolved in SOCl with 3-nitro-4-methoxy benzenesulfonic acid ₂In, reflux 3 hours, normal pressure steams and removes thionyl chloride, obtains the benzene sulfonyl chloride crude product;

Get p-Chlorobenzoic acid amide (1.0g again, 7.8mmol) be dissolved in the methylene dichloride, add triethylamine (2ml, 20mmol), under the ice-water bath condition, to wherein adding crude product benzene sulfonyl chloride (3.5g) gradually, finish and stir after half an hour recovery room temperature naturally, be stirred to and react completely, the reaction solution silica gel adsorption, the column chromatography for separation product obtains 3-nitro substituent 1.6 grams.

(0.5g) is dissolved in the methyl alcohol with above-mentioned nitro-compound, adds 10%Pd/C, middle pressure hydro-reduction, and raw material disappears after 5 hours, filters, and the filtrate evaporate to dryness obtains the amino substituent 0.42g of 3-; The amino substituent of this 3-is done at triethylamine under the condition of acid-binding agent in methylene dichloride, carries out acidylate with propionyl chloride and obtains target compound 330.47g.

＜embodiment 30 〉Synthesizing of (3-two propionamido-4-anisole) sulphonyl (3 ', 4 ', 5 '-trimethoxy-benzene) amine (3)

With 3-nitro-4-methoxy benzenesulfonic acid, thionyl chloride, 3,4,5-trimethoxy-aniline and propionyl chloride are starting raw material, according to embodiment 29 similar approach, and the synthetic compound 3 that obtains, ¹H NMR data see Table 1.

＜embodiment 31 〉Synthesizing of (3-nitro-4-methyl benzene) sulphonyl-3 '-(2 '-chloro-5 '-picoline) amine (14)

With 3-nitro-4-methyl Phenylsulfonic acid and 2-chloro-3-amino-5-picoline is starting raw material, according to embodiment 29 similar approach, and the synthetic compound 14 that obtains, ¹H NMR data see Table 1.

＜embodiment 32 〉Synthesizing of (3-nitro-4-methyl benzene) sulphonyl oxygen-4 '-anisole (15)

With 3-nitro-4-methyl Phenylsulfonic acid and 4-methoxyphenol is starting raw material, according to embodiment 29 similar approach, and the synthetic compound 15 that obtains, ¹H NMR data see Table 1.

＜embodiment 33 〉Synthesizing of (3-propionamido-4-methylbenzene) sulphonyl oxygen-4 '-anisole (17)

With 3-nitro-4-methyl Phenylsulfonic acid and 4-methoxyphenol, propionyl chloride is a starting raw material, according to embodiment 29 similar approach, and the synthetic compound 17 that obtains, ¹H NMR data see Table 1.

＜embodiment 34 〉Synthesizing of (3-nitro-4-methyl benzene) sulphonyl-2 '-(4 ', 6 '-dimethoxypyridin) amine (19)

With 3-nitro-4-methyl Phenylsulfonic acid and 2-amino-4, the 6-dimethoxy-pyridine is a starting raw material, according to embodiment 29 similar approach, and the synthetic compound 19 that obtains, ¹H NMR data see Table 1.

＜embodiment 35 〉The synthetic of (3-amino-4-methylbenzene) sulphonyl-2 '-(4 ', 6 '-dimethoxypyridin) amine (20) is raw material with compound 19, and palladium carbon is made catalyzer, and hydro-reduction obtains 20, ¹H NMR data see Table 1.

＜embodiment 36 〉Synthesizing of (3-propionamido-4-methylbenzene) sulphonyl-2 '-(4 ', 6 '-dimethoxypyridin) amine (21)

With compound 20 is raw material, obtains 21 with the propionyl chloride acidylate, ¹H NMR data see Table 1.

＜embodiment 37 〉Synthesizing of (3-nitro-4-methyl benzene) sulphonyl-(3 '-methylthio phenyl) amine (43)

With 3-nitro-4-methyl Phenylsulfonic acid and 3-methylthio group aniline is starting raw material, according to embodiment 29 similar approach, and the synthetic compound 43 that obtains, ¹H NMR data see Table 1.

＜embodiment 38 〉Synthesizing of (3-nitro-4-methyl benzene) sulphonyl (3 ', 4 ', 5 '-trimethoxy-benzene) amine (47)

With 3-nitro-4-methyl Phenylsulfonic acid, 3,4, the 5-trimethoxy-aniline is a starting raw material, according to embodiment 29 similar approach, and the synthetic compound 47 that obtains, ¹H NMR data see Table 1.

＜embodiment 39 〉Synthesizing of (3-amino-4-methylbenzene) sulphonyl (3 ', 4 ', 5 '-trimethoxy-benzene) amine (48)

47 to be starting raw material, make catalyzer with palladium carbon, the synthetic compound 48 that obtains of hydrogenation, ¹H NMR data see Table 1.

＜embodiment 40 〉Synthesizing of (3-propionamido-4-methylbenzene) sulphonyl (3 ', 4 ', 5 '-trimethoxy-benzene) amine (49)

With 48 and propionyl chloride be starting raw material, according to the process for acylating among the embodiment 29, the synthetic compound 49 that obtains, ¹H NMR data see Table 1.

＜embodiment 41 〉Synthesizing of (3-methylamino--4-methylbenzene) sulphonyl (3 ', 4 ', 5 '-trimethoxy-benzene) amine (50)

With 48 and methyl iodide be starting raw material, be acid binding agent with the triethylamine, by the synthetic compound 50 that obtains of halogenating reaction, ¹H NMR data see Table 1.

＜embodiment 42 〉Synthesizing of (3-acetylaminohydroxyphenylarsonic acid 4-methylbenzene) sulphonyl (3 ', 4 ', 5 '-trimethoxy-benzene) amine (51)

With 48 and Acetyl Chloride 98Min. be starting raw material, according to the process for acylating among the embodiment 29, the synthetic compound 51 that obtains, ¹H NMR data see Table 1.

＜embodiment 43 〉Synthesizing of (3-nitro-4-methyl benzene) sulphonyl (4 '-chlorinated benzene) amine (54)

With 3-nitro-4-methyl Phenylsulfonic acid, p-Chlorobenzoic acid amide is starting raw material, according to embodiment 29 similar approach, and the synthetic compound 54 that obtains, ¹H NMR data see Table 1.

＜embodiment 44 〉Synthesizing of (3-N, N '-propionamido-4-methylbenzene) sulphonyl (4 '-chlorinated benzene) amine (57)

With 54 and propionyl chloride be starting raw material, according to embodiment 29 similar reduction and process for acylating, the synthetic compound 57 that obtains, ¹H NMR data see Table 1.

＜embodiment 45 〉Synthesizing of (3-nitro-4-methyl benzene) sulphonyl 3 '-triazole amine (58)

With 3-nitro-4-methyl Phenylsulfonic acid, the amino triazole of 3-is starting raw material, according to embodiment 29 similar approach, and the synthetic compound 58 that obtains, ¹H NMR data see Table 1.

＜embodiment 46 〉N, N '-(3-nitro-4-methyl benzene) sulphonyl-(4 '-chlorinated benzene) amine (62) synthetic

With 3-nitro-4-methyl Phenylsulfonic acid and p-Chlorobenzoic acid amide is starting raw material, according to embodiment 29 similar approach, in the second step reaction, when excessive three times of SULPHURYL CHLORIDE, synthesize and obtain compound 62, ¹H NMR data see Table 1.

＜embodiment 47 〉N, N '-(3-nitro-4-methyl benzene) sulphonyl-(3 '-methylthio phenyl) amine (63) synthetic

With 3-nitro-4-methyl Phenylsulfonic acid and 3-methylthio group aniline is starting raw material, according to embodiment 46 similar approach, and the synthetic compound 63 that obtains, ¹H NMR data see Table 1.

＜embodiment 48 〉Synthesizing of (3-propionamido-4-anisole) formyl-4 '-aminopyrimidine (52)

(5.0g 25mmol) is dissolved in SOCl with 3-nitro-4-methoxybenzoic acid ₂In, reflux 3 hours, normal pressure steams and removes thionyl chloride, obtains the Benzoyl chloride crude product;

Get 4-aminopyrimidine (1.0g again, 10mmol) be dissolved in the methylene dichloride, add triethylamine-milliliter, under the ice-water bath condition, to wherein adding crude product Benzoyl chloride 3.8g gradually, finish and stir after half an hour recovery room temperature naturally, be stirred to and react completely, reaction solution silica gel adsorption, column chromatography for separation product obtain 3-nitro substituent 2.2 grams.

(0.5g) is dissolved in the methyl alcohol with above-mentioned nitro-compound, adds 10%Pd/C, middle pressure hydro-reduction, and raw material disappears after 5 hours, filters, and the filtrate evaporate to dryness obtains the amino substituent 0.43g of 3-; The amino substituent of this 3-is done at triethylamine to carry out acidylate with propionyl chloride under the condition of acid-binding agent in methylene dichloride, and reaction solution uses column chromatography and obtains target compound 520.51g.

＜embodiment 49 〉Synthesizing of (3-propionamido-4-anisole) formyl-2 '-(4 ', 6 '-dimethoxypyridin) amine (26)

28 being starting raw material, be combined to by the method propionyl of embodiment 48 and obtain compound 26, ¹H NMR data see Table 1.

＜embodiment 50 〉Synthesizing of (3-nitro-4-anisole) formyl-2 '-(4 ', 6 '-dimethoxypyridin) amine (27)

With 3-nitro-4-methoxybenzoic acid and 2-amino-4,6 dimethoxypyridin is starting raw material, by the synthetic compound 27 that obtains of the method for embodiment 48, ¹H NMR data see Table 1.

＜embodiment 51 〉Synthesizing of (3-amino-4-anisole) formyl-2 '-(4 ', 6 '-dimethoxypyridin) amine (28)

27 to be starting raw material, by the synthetic compound 28 that obtains of the hydro-reduction method of embodiment 48, ¹H NMR data see Table 1.

＜embodiment 52 〉(3-(2 "-bromo propionyl) amino-4-anisole) formyl-2 '-(4 ', 6 '-dimethoxypyridin) amine (29) synthetic

28 to be starting raw material, by the synthetic compound 29 that obtains of the method acidylate of embodiment 48, ¹H NMR data see Table 1.

＜embodiment 53 〉Synthesizing of (3-nitro-4-anisole) formyl-(4 '-oil of mirbane) amine (30)

With 3-nitro-4-methoxybenzoic acid and p-Nitroaniline is starting raw material, by the synthetic compound 30 that obtains of the method for embodiment 48, ¹H NMR data see Table 1.

＜embodiment 54 〉Synthesizing of (3-amino-4-anisole) formyl-(4 '-amino-benzene) amine (31)

30 to be starting raw material, by the synthetic compound 31 that obtains of the method for hydrogenation of embodiment 48, ¹H NMR data see Table 1.

＜embodiment 55 〉Synthesizing of (3-propionamido-4-anisole) formyl-(4 '-amino-benzene) amine (32)

31 to be starting raw material, by the synthetic compound 32 that obtains of the process for acylating of embodiment 48, ¹H NMR data see Table 1.

＜embodiment 56 〉Synthesizing of (3-nitro-4-anisole) formyl-(4 '-trifluoromethylbenzene) amine (37)

With 3-nitro-4-methoxybenzoic acid and p-trifluoromethylaniline is starting raw material, by the synthetic compound 37 that obtains of the method for embodiment 48, ¹H NMR data see Table 1.

＜embodiment 57 〉Synthesizing of (3-nitro-4-anisole) formyl-2 '-(4 '-itrile group pyridine) amine (38)

With 3-nitro-4-methoxybenzoic acid and 2-amino-5-itrile group pyridine is starting raw material, by the synthetic compound 38 that obtains of the method for embodiment 48, ¹H NMR data see Table 1.

＜embodiment 58 〉N, N '-(3-nitro-4-anisole) formyl-2 '-(4 '-itrile group pyridine) amine (44) synthetic

With 3-nitro-4-methoxybenzoic acid and 2-amino-5-itrile group pyridine is starting raw material, the easily synthetic compound 44 that obtains when the acyl chlorides add-on for preparing surpasses the triplication of assorted arylamine, ¹H NMR data see Table 1.

＜embodiment 59 〉Synthesizing of (3-nitro-4-anisole) formyl-4 '-PYRIMITHAMINE (53)

With 3-nitro-4-methoxybenzoic acid and 4-aminopyrimidine is starting raw material, according to embodiment 48 similar approach, and the synthetic compound 53 that obtains, ¹H NMR data see Table 1.

＜embodiment 60 〉Synthesizing of (3-propionamido-4-anisole) formyl-2 '-(4 '-itrile group pyridine) amine (55)

With 3-nitro-4-methoxybenzoic acid and 2-amino-5-itrile group pyridine is starting raw material, according to embodiment 48 similar approach, and the synthetic compound 55 that obtains, ¹H NMR data see Table 1.

＜embodiment 61 〉N, N '-(3-propionamido-4-anisole) formyl-2 '-(4 '-itrile group pyridine) amine (56) synthetic

44 to be starting raw material, through hydro-reduction and the synthetic compound 56 that obtains of acidylate, ¹H NMR data see Table 1.

＜embodiment 62 〉1-(3 '-nitro-4 '-methoxyl group) phenyl-2-(3 ", 4 ", 5 "-trimethoxy) phenylethyl alcohol (61) synthetic

With 200mg magnesium silk as in the 15ml anhydrous tetrahydrofuran solution, be warming up to 65 degree, drip the tetrahydrofuran solution and the micro iodine of bromobenzyl (0.5ml) to Dropwise 5 wherein, cause the back and continue to drip bromobenzyl, drip to finish and keep little temperature 5 hours of boiling, drip 1g 3-nitro-4 methoxyl groups-methyl phenyl ketone tetrahydrofuran solution again to magnesium silk mass consumption, refluxed 8 hours, add 25% ammonium chloride solution termination reaction, column chromatography for separation obtains target compound 61 ¹H NMR data see Table 1, (yield 20%).

＜embodiment 63 〉Synthesizing of (3-nitro-4-anisole) formyl methylene-(3 ', 4 ', 5 '-trimethoxy) benzene (59)

In the acetone soln of 200mg compound 61, slowly drip 20% chromic acid solution 10ml under the condition of ice bath, drip a complete room temperature reaction and spend the night, next day reaction solution water and ethyl acetate extraction, organic layer concentrates the back upper prop to be separated and obtains target compound 59, ¹H NMR data see Table 1, (yield 31%).

＜embodiment 64 〉Synthesizing of (3-amino-4-anisole) formyl methylene-(3 ', 4 ', 5 '-trimethoxy) benzene (60)

Above-mentioned nitro-compound 59 (0.1g) is dissolved in the methyl alcohol, adds 10%Pd/C, middle pressure hydro-reduction, raw material disappears after 5 hours, filters, and the filtrate evaporate to dryness obtains the amino substituent 600.062g of 3-; ¹H NMR data see Table 1.

＜embodiment 65 〉Synthesizing of (3-nitro-4-anisole) methylene amino-(3 ', 4 ', 5 '-trimethoxy) benzene (64)

With 3-nitro-4-methoxy toluene (5g, 30mmol) be dissolved in the tetracol phenixin,, add a small amount of sulphur to wherein adding NBS, be heated to backflow, after 8 hours, return to room temperature, the reaction solution evaporated under reduced pressure, resistates dissolves the back water with methylene dichloride, dilute hydrochloric acid solution, water washs successively, and organic layer steams to desolventize after with anhydrous sodium sulfate drying and obtains crude product 3-nitro-4-methoxyl group toluene bromide;

Get 3,4,5-trimethoxy-aniline (0.4g, 2.4mmol) be dissolved in the methylene dichloride, add triethylamine 0.25ml, under the ice-water bath condition, slowly, finish the recovery stirred overnight at room temperature, reaction solution next day water successively to wherein adding the about 1.0g of above-mentioned crude product toluene bromide, dilute acid soln, dilute alkaline soln, washing, concentrating upward after the organic layer drying, the silicagel column separation obtains pure product (3-nitro-4-anisole) methylene amino-3 ', 4 ', 5 '-trimethoxy-benzene 640.42g (yield: 55%); ¹H NMR data see Table 1.

＜embodiment 66 〉(3-amino-4-anisole) methylene amino-3 ', 4 ', 5 '-trimethoxy-benzene (65) synthetic

Above-mentioned nitro-compound 64 (0.15g) is dissolved in the methyl alcohol, adds 10%Pd/C, middle pressure hydro-reduction, raw material disappears after 5 hours, filters, and the filtrate evaporate to dryness obtains the amino substituent 650.10g of 3-(yield: 73%); ¹H NMR data see Table 1.

＜embodiment 67 〉(3-propionamido-4-anisole) methylene amino-3 ', 4 ', 5 '-trimethoxy-benzene (66) synthetic

The amino substituent 65 of this 3-is done at triethylamine under the condition of acid-binding agent in methylene dichloride, carries out the separation of acidylate rear pillar with propionyl chloride and obtains target compound 66 0.10g (yield: 85%). ¹H NMR data see Table 1.

＜embodiment 68 〉Synthesizing of (3-propionamido-4-anisole) formyl methylene-(3 ', 4 ', 5 '-trimethoxy) benzene (68)

The amino substituent 60 of 3-is dissolved in the methylene dichloride, does at triethylamine under the condition of acid-binding agent, carry out acidylate and obtain target compound 68 0.065g with the post separation with propionyl chloride, ¹H NMR data see Table 1.

＜embodiment 69〉N, N '-tolysulfonyl-(4,4 '-biphenyl two) amine (69) synthetic

With 4,4 '-benzidine and Tosyl chloride are raw material, according to embodiment similar method of 29 second step, and the synthetic compound 69 that obtains, ¹H NMR data see Table 1.

＜embodiment 70〉two (N, N '-two tolysulfonyl)-(4,4 '-biphenyl two) amine (70) synthetic

With 4,4 '-benzidine and Tosyl chloride are raw material, according to embodiment 29 second similar method of step, obtain compound 70 synthetic when obtaining compound 69, ¹H NMR data see Table 1.

＜embodiment 71 〉2-oil of mirbane oxygen acetyl-(4 '-sulphonyl-(1 "-piperidines) amino-benzene) amine (71) synthetic

With p-nitrophenyl sulfonic acid and piperidines is starting raw material, according to the synthetic p-nitrophenyl sulphonyl piperylhydrazine that obtains of embodiment 29 similar approach; Method reduction with similar catalytic hydrogenation among the embodiment 48 obtains the sulfanilyl-piperylhydrazine again; Be raw material with p-nitrophenyl fluoroacetic acid and sulfanilyl-piperylhydrazine at last, according to the synthetic compound 71 that obtains of similar method among the embodiment 48, ¹H NMR data see Table 1.

＜embodiment 72 〉2-amino-benzene oxygen acetyl-(4 '-sulphonyl-(1 "-piperidines) amino-benzene) amine (72) synthetic

With compound 71 is starting raw material, reduce according to the method for embodiment 48 similar catalytic hydrogenations and obtain compound 72, ¹H NMR data see Table 1.

＜embodiment 73 〉2-acetyl amino phenyl oxygen acetyl-(4 '-sulphonyl-(1 "-piperidines) amino-benzene) amine (73) synthetic

With compound 72 and Acetyl Chloride 98Min. is starting raw material, obtains compound 73 according to embodiment 48 similar process for acylating reduction, ¹H NMR data see Table 1.

＜embodiment 74 〉Synthesizing of 4-sulfonamido benzoyl-(4 '-chlorobenzene) amine (74)

To be starting raw material to sulfonyl-benzoic acid and p-Chlorobenzoic acid amide, according to embodiment 1 similar method of condensing, the synthetic compound 74 that obtains, ¹H NMR data see Table 1.

＜embodiment 75 〉Synthesizing of 4-thiophenyl benzoyl-(4 '-chlorobenzene) amine (75)

To be starting raw material to thiophenyl phenylformic acid and p-Chlorobenzoic acid amide, according to embodiment 1 similar method of condensing, the synthetic compound 75 that obtains, ¹H NMR data see Table 1.

＜embodiment 76 〉Synthesizing of 6-chloronicotinoyl-(4 '-pyrimidine) amine (76)

With 6-chloronicotinoyl chloride and 4-aminopyrimidine is starting raw material, according to embodiment 48 similar methods, and the synthetic compound 76 that obtains, ¹H NMR data see Table 1.

＜embodiment 77 〉Synthesizing of 2-methylthio group nicotinoyl-(3 ', 4 ', 5 '-trimethoxy-benzene) ester (77)

With 2-methylthio group nicotinoyl chlorine and 3,4,5-trimethoxy phenol is starting raw material, according to embodiment 48 similar methods, and the synthetic compound 77 that obtains, ¹H NMR data see Table 1.

＜embodiment 78 〉(3 '-methylbenzene thiophthene-2-yl) acetyl-(4 "-chlorinated benzene) amine (78) synthetic

With 2-(3-methyl) thionaphthene acetate and p-Chlorobenzoic acid amide is starting raw material, according to embodiment 48 similar methods, and the synthetic compound 78 that obtains, ¹H NMR data see Table 1.

＜embodiment 79 〉5-chloro-benzofuran-2-formyl- (4'-formamido group thiophene)-2-amine (79) synthetic

With 2-carboxyl-5-chloro-cumarone and 2-amino-4-formamido group thiophene is starting raw material, according to embodiment 48 similar methods, and the synthetic compound 79 that obtains, ¹H NMR data see Table 1.

＜embodiment 80 〉5-nitrothiophene-2-formyl- (4'-chlorinated benzene) amine (80) is synthetic

With 2-carboxyl-5-nitrothiophene and p-Chlorobenzoic acid amide is starting raw material, according to embodiment 48 similar methods, and the synthetic compound 80 that obtains, ¹H NMR data see Table 1.

＜embodiment 81 〉3-propionyloxy-4-methoxybenzoyl- (3', 4', 5 '-trimethoxy-benzene) amine (81) synthetic

With 3-hydroxyl-4-methoxybenzoic acid, propionyl chloride and 3,4,5-trimethoxy-aniline are starting raw material, according to embodiment 1 similar method, and the synthetic compound 81 that obtains, ¹H NMR data see Table 1.

＜embodiment 82 〉Synthesizing of 3-nitro-phenylsulfinyl-(3 ', 4 ', 5 '-trimethoxy-benzene) amine (84)

With 3-nitro-phenylsulfinyl chlorine, 3,4, the 5-trimethoxy-aniline is a starting raw material, according to embodiment 29 similar approach, and the synthetic compound 84 that obtains, ¹H NMR data see Table 1.

＜embodiment 83 〉Synthesizing of 3-amino-phenylsulfinyl-(3 ', 4 ', 5 '-trimethoxy-benzene) amine (83)

84 to be starting raw material, according to embodiment 29 similar method of reducing, the synthetic compound 83 that obtains, ¹H NMR data see Table 1.

＜embodiment 84 〉Synthesizing of 3-propionamido-phenylsulfinyl-(3 ', 4 ', 5 '-trimethoxy-benzene) amine (82)

With 83 and propionyl chloride be starting raw material, according to embodiment 29 similar process for acylating, the synthetic compound 82 that obtains, ¹H NMR data see Table 1.

＜embodiment 85 〉Synthesizing of (3-amino-4-anisole) formyl-4 '-PYRIMITHAMINE (85)

With (3-nitro-4-anisole) formyl-4 '-PYRIMITHAMINE is raw material, by the synthetic compound 85 that obtains of the hydro-reduction method of embodiment 48, ¹H NMR data see Table 1.

As the indefiniteness example, replacement bi-aromatic compounds of the present invention can be selected from following particular compound:

Table 1 invention compound

＜embodiment 85 〉, suppress the HBV activity experiment

After the HepG2.2.15 Tissue Culture Flask covers with cell,, be mixed with every milliliter of 200,000 cells, inoculate 96 well culture plates, every hole 100 μ l, 37 ℃ of 5%CO through digestion ₂Cultivated 24 hours, cell experimentizes after growing up to individual layer.After the The compounds of this invention sample is mixed with different concns with nutrient solution, add 96 porocyte culture plates, 37 ℃ of 5%CO ₂Cultivate, cell cultures to the was the cytotoxicity index with the inverted microscope observation with cytopathy (CPE) in 3 days.The record cytopathy, completely destroy is 4; 75% is 3; 50% is 2; 25% is 1; Anosisly become 0.Press the Reed-Muench method and calculate the poisonous concentration (TC of half ₅₀) and maximal non-toxic concentration (TC ₀).The plate inner cell extracts DNA in the cell with a small amount of rapid extraction DNA test kit, adds primer, with qPCR test kit and the level (HVB Ct value) of the interior DNA of iQ5 quantitative PCR instrument detection by quantitative cell and the level (GAPDH Ct value) of cell internal reference gene GAPDH.Calculate the inhibition percentage by following formula.Suppress percentage %=1/2^ ((HBV Ct _{The cell contrast}-HBV Ct _{The medicine group})/(GAPDH Ct _{The cell contrast}-GAPDHCt _{The medicine group}) * 100% is with Reed-Muench method calculation of half inhibitory concentration (IC ₅₀).

The result lists table 2 in.

＜embodiment 86 〉, suppress HCV determination of activity experiment

Compound is to the toxicity of Huh7.5 cell: 1 * 10 ⁵/ mL Huh7.5 cell inoculation 100 μ L are in 96 porocyte culture plates, in 37 ℃, 5%CO ₂After cultivating 6hrs in the incubator under the saturated humidity condition, the The compounds of this invention soup and the positive control drug (alpha-interferon) that add different concns respectively, after continuing to cultivate 96hrs, every hole adds the MTT of 10 μ L 5mg/mL, continues to cultivate 4 hours, after the DMSO cracking, on microplate reader, measure OD 570nm value, compare with cell control group OD value, calculate the toxicity inhibiting rate of every concentration pair cell, calculate the poisonous concentration of half of medicine pair cell with the Reed-Muench method.

Compound is anti-HCV activity in cell cultures: 1 * 10 ⁵/ mL Huh7.5 cell inoculation 100 μ L are in 96 porocyte culture plates, in 37 ℃, 5%CO ₂After cultivating 6hrs in the incubator under the saturated humidity condition, when dying the Huh7.5 cell with the viral liquid inductance that contains the full gene HCV virion of recombinating, the The compounds of this invention soup or the positive control drug that add different concns respectively, after continuing to cultivate 96hrs, extract total RNA in the cell respectively, measure the content of HCV RNA in the cell with the single stage method quantitative RT-PCR, compare with virus control group rna level, calculate the inhibiting rate of every concentration, calculate the medium effective concentration that medicine suppresses the HCV effect with the Reed-Muench method to HCV.The result is referring to table 2.

Table 2 invention compound is to the inhibition activity of HBV and HCV

＜embodiment 87 〉, suppress HIV-1 determination of activity experiment

Add the The compounds of this invention soup and the positive control soup of 8 different weaker concns in 96 porocytes are cultivated, each extent of dilution repeats 2 holes, establishes the cell contrast; Again with 2 * 10 ⁵Cell/ml 100 μ l are inoculated in the pastille 96 porocyte culture plates.Put 37 ℃, 5%CO ₂With cultivate in the saturated humidity incubator, every day the observation of cell pathology.The operation steps that provides by the HIV-1P24 antigenic reagent box, the 4th day (96 hours) cells and supernatant HIV-1P24 antigenic content after the mensuration dosing, calculate the inhibition activity of medicine to virus, the The compounds of this invention initial concentration is 1 μ g/ml, and measurement result is referring to table 3.The concentration of contrast medicine Qi Duofu pyridine is 0.15ng/ml, its measurement result IC ₅₀＜0.0005 μ M.

The HIV (human immunodeficiency virus)-resistant activity of table 3 invention compound

NO.

X

Y

R ₂

R ₃

R ₆

R ₇

R ₈

R ₉

IC ₅₀(μM)

1

CO

NH

COCH ₂CH ₃

OCH ₃

H

OCH ₃

0.058

5

CO

NH

H

OCH ₃

H

OCH ₃

0.073

36

CO

NH

COCF ₃

OCH ₃

H

OCH ₃

＜0.032

35

CO

NH

COCH ₂CH ₃

OCH ₃

H

OCH ₃

H

0.053

2

CO

NH

COCH ₂CH ₃

OCH ₃

H

Cl

H

0.041

67

CO

NH

H

OCH ₃

H

＜0.0566

34

CO

O

COCH ₂CH ₃

OCH ₃

H

OCH ₃

0.077

40

CO

O

H

OCH ₃

H

OCH ₃

0.166

41

CO

O

COCF ₃

OCH ₃

H

OCH ₃

0.128

39

CO

O

COCH ₂CH ₃

OCH ₃

H

OCH ₃

H

0.091

＜embodiment 88 〉, anti-EV71 virus and COxsackie (Coxaskies) virus activity measure

Vero cell kind 96 well culture plates, 24 hours about 100TCID of postoperative infection virus (EV71 virus, COxsackie A16, B3 or B6 virus) ₅₀Adsorbed 2 hours, abandon viral liquid, the liquid of keeping that adds the The compounds of this invention sample contain different concns and positive control drug ribavirin (RBV), establish the virus control of not dosing and the cell contrast of virus-free infection simultaneously, treat that virus control group lesion degree (CPE) observes the cytopathy degree (CPE) of respectively organizing when reaching 4+, with the Reed-Muench method respectively calculation sample to the half-inhibition concentration (IC of virus ₅₀), contrast medicine RBV is to the IC of three strain Coxsackie viruss ₅₀Be 412.26 μ g/ml, the The compounds of this invention result lists table 4 in.

＜embodiment 89 〉, anti-influenza virus activity measures

Mdck cell is inoculated 96 well culture plates, puts 5%CO ₂, cultivated 24 hours for 37 ℃.Mdck cell adds the about 100TCID of influenza virus (A/H1N1, A/H3N2 or B/13/79 type) ₅₀, 37 ℃ of absorption hypsokinesis in 2 hours venom of preventing or cure a disease adds the liquid of keeping of different dilution The compounds of this invention or positive control drug ribavirin respectively.Establish the cell contrast of the virus control of not dosing and virus-free infection simultaneously, 37 ℃ of cultivations treat that virus control group lesion degree (CPE) observes the cytopathy degree (CPE) of respectively organizing (about 36 hours) when reaching 4+, calculate each sample resisiting influenza virus half-inhibition concentration (IC ₅₀), contrast medicine RBV is to the IC of influenza virus A/H1N1, A/H3N2 or B/13/79 type ₅₀Be respectively 1.43,1.71 and 5.75 μ g/ml, the The compounds of this invention result is referring to table 4.

Table 4 invention compound is to the inhibition activity of many strain virus

* ND represents undetermined.

As can be seen from Table 4, wherein there are 49 compounds that at least 3 strains are had and suppress active; Have 55 compounds in the above-mentioned two big viroids at least each 1 strain have simultaneously and suppress active; There are 34 compounds that at least 1 strain virus in the above 4 strain gi tract viruses is demonstrated the vitro inhibition activity; There are 54 compounds that at least 1 influenzae strain virus is had and suppress active.As seen this compounds generally has antiviral activity.

Claims

1. Substituted bisaryl compounds have a structure shown in the following general formula (I):

in:

X stands for -C(O)-, -CH ₂ C(O)-, -OCH ₂ C(O)-, -S(O)-, -S(O) ₂ -, -C(OH)(R ₁₀ )- or -CH(R ₁₀ )-, Y represents -O-, -S-, -CH(R ₁₁ )-, -N(R ₁₂ )- or a single bond; said R ₁₀ , R ₁₁ represents hydrogen, Hydrocarbyl, aralkyl, aryloxyalkyl or arylsulfanyl, _R represents hydrogen, hydrocarbyl, halogenated hydrocarbyl, acyl, hydroxyhydrocarbyl, aminohydrocarbyl, sulfonyl;

W ₁ , W ₂ , W ₃ , W ₄ , and W ₅ each represent an independent carbon atom, nitrogen atom, oxygen atom or sulfur atom, and at least four of them exist simultaneously in any molecule, and at least one of them represents a carbon atom, When W represents a heteroatom, there is no substituent at this position;

When R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ exist independently, they can be the same or different, representing hydrogen, hydrocarbyl, halogenated hydrocarbyl, hydroxyhydrocarbyl, halogen, nitro, cyano, acyl, sulfonyl , carboxyl, sulfonic acid, phosphoric acid, aryl, heteroaryl, C(O)OR ₁₃ , CONR ₁₃ R ₁₄ , S(O) ₂ NR ₁₃ R ₁₄ , SR ₁₃ , OR ₁₄ or NR ₁₃ R ₁₄ , The R ₁₃ and R ₁₄ respectively represent hydrogen, hydrocarbon group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, sulfonyl group, acyl group, or

Alternatively, R ₃ and R ₄ or R ₄ and R ₅ can be connected to each other to form a five-membered or six-membered aromatic ring structure M fused to the mother nucleus, and its structural characteristics are as shown in formula (IIa and IIb), and M 0-3 heteroatoms are allowed in the skeleton, and one or more identical or different substituents R ₁₅ may be attached to the chemically allowed positions. In addition, the heteroatoms represent nitrogen, oxygen or sulfur

Z ₁ , Z ₂ , Z ₃ , Z ₄ , and Z ₅ each represent an independent carbon atom, nitrogen atom, oxygen atom or sulfur atom, and at least four of them exist simultaneously in any molecule, and at least one represents a carbon atom; when When Z represents a heteroatom, there is no substituent at this position;

The R ₆ , R ₇ , R ₈ and R ₉ can be the same or different when they exist independently, and represent hydrogen, hydrocarbyl, halogenated hydrocarbyl, hydroxyhydrocarbyl, halogen, nitro, amino, hydrocarbylamino, hydroxyl, cyano , alkoxy, acyl, amido, ester, carboxyl, sulfonic acid, phosphoric acid, aryl, aryl substituted with benzenesulfonamide, aryl substituted with p-toluenesulfonamide, heteroaryl, CONR ₁₆ R ₁₇ , S(O) ₂ NR ₁₆ R ₁₇ , SR ₁₆ , OR ₁₇ or NR ₁₆ R ₁₇ etc.;

The R ₁₆ and R ₁₇ respectively represent hydrogen, hydrocarbon group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, sulfonyl group, and acyl group. In addition, R ₁₆ and R ₁₇ can also be connected to form a nitrogen-heterocyclic structure;

Alternatively, R ₆ and R ₇ , R ₇ and R ₈ or R ₈ and R ₉ may be connected to each other to form a structure condensed with the mother nucleus, such as the aromatic ring structure N shown in IIIa, IIIb and IIIc, in the skeleton of N It is allowed to contain 0-3 heteroatoms, and there may be one or more identical or different substituents R ₁₅ in the positions allowed by the chemical theory. In addition, the heteroatoms represent nitrogen, oxygen or sulfur

Wherein, R ₁₅ represents hydrogen, hydrocarbyl, halogenated hydrocarbyl, hydrocarbyloxy, halogen, oxo, acyl, amido, sulfonic acid or sulfonamido, etc.

2. The substituted bisaryl compound as claimed in claim 1, wherein when X represents -C(O)-, -CH ₂ C(O)-, -OCH ₂ C(O)-, Y represents -O- , -CH(R ₁₁ )-, -N(R ₁₂ )- or a single bond; when X represents -S(O)-, -S(O) ₂ -, Y represents -O- or -N(R ₁₂ )-; when X represents -C(OH)(R ₁₀ )-, Y represents -CH(R ₁₁ )- or a single bond; when X represents -CH(R ₁₀ )-, Y represents -O-,- S- or -N(R ₁₂ )-; said R ₁₀ , R ₁₁ represents hydrogen, hydrocarbon group, aralkyl group, R ₁₂ represents hydrogen, hydrocarbon group, acyl group, sulfonyl group;

Said W ₁ , W ₂ , W ₃ , W ₄ and W ₅ and R ₃ , R ₄ or R ₅ form a substituted or unsubstituted benzene ring, pyridine ring, pyrazine ring, pyrimidine ring, thiazole ring, furan ring or Pyrrole ring, more preferably benzene ring, pyrimidine ring, thiazole ring or furan ring; said R ₁ , R ₂ , R ₃ , R ₄ , R ₅ each independently represent hydrogen, hydrocarbon group, halogenated hydrocarbon group, halogen, nitric acid group, aryl group, C(O)NR ₁₃ R ₁₄ , S(O) ₂ NR ₁₃ R ₁₄ , SR ₁₃ , OR ₁₄ or NR ₁₃ R ₁₄ , where R ₁₃ and R ₁₄ represent hydrogen, hydrocarbon group and aryl group respectively , acyl or sulfonyl;

The Z ₁ , Z ₂ , Z ₃ , Z ₄ and Z ₅ and R ₆ , R ₇ , R ₈ and R ₉ form a substituted or unsubstituted benzene ring, pyridine ring, pyrazine ring, pyrimidine ring, thiazole ring, Furan ring, pyrrole ring, imidazole ring or triazole ring, more preferably benzene ring, pyridine ring, pyrimidine ring, thiazole ring or triazole ring; said R ₆ , R ₇ , R ₈ and R ₉ can be the same when they exist independently It can also be different, representing hydrogen, hydrocarbyl, halogenated hydrocarbyl, hydroxyhydrocarbyl, halogen, nitro, hydrocarbylamino, cyano, acyl, aryl, aryl substituted by benzenesulfonamide, aryl substituted by p-toluenesulfonamide, C(O)NR ₁₆ R ₁₇ , S(O) ₂ NR ₁₆ R ₁₇ , SR ₁₆ , OR ₁₇ or NR ₁₆ R ₁₇ , where R ₁₆ and R ₁₇ respectively represent hydrogen, hydrocarbon group, aryl group, acyl group or sulfonyl group , In addition, R ₁₆ and R ₁₇ can also be connected to form a nitrogen heterocyclic structure.

3. The substituted bisaryl compound as claimed in claim 2, wherein when X represents -C(O)-, -CH ₂ C(O)-, -OCH ₂ C(O)-, -S(O) ₂ -, -C(OH)(R ₁₀ )- or -CH(R ₁₀ )-, Y represents -N(R ₁₂ )-, -O-, -S-, -CH(R ₁₁ )- or a single bond; Preferably, X represents -C(O)- or -S(O) ₂ -, Y represents -O- or -NH-; said R ₁₀ , R ₁₁ represents hydrogen, hydrocarbon group, aralkyl group, R ₁₂ represents hydrogen , hydrocarbon group, acyl group, sulfonyl group;

The R ₁ , R ₂ , R ₃ , R ₄ and R ₅ represent hydrogen, hydrocarbon group, nitro group, aryl group, SR ₁₃ , OR ₁₄ or NR ₁₃ R ₁₄ respectively, and the R ₁₃ and R ₁₄ represent hydrogen, Hydrocarbyl, aryl, acyl or sulfonyl;

The Z ₁ , Z ₂ , Z ₃ , Z ₄ and Z ₅ and R ₆ , R ₇ , R ₈ and R ₉ form a substituted or unsubstituted benzene ring, pyrimidine ring, triazole ring, pyridine ring or thiazole ring, The R ₆ , R ₇ , R ₈ and R ₉ respectively represent hydrogen, hydrocarbon group, aryl group, aryl group substituted by benzenesulfonamide, aryl group substituted by p-toluenesulfonamide, halogenated hydrocarbon group, halogen, CONR ₁₆ R ₁₇ , S(O) ₂ NR ₁₆ R ₁₇ , SR ₁₆ , OR ₁₇ or NR ₁₆ R ₁₇ , where R ₁₆ and R ₁₇ respectively represent hydrogen, hydrocarbon group, aryl group or sulfonyl group.

4. The substituted bisaryl compound as claimed in claim 1, wherein: X represents -C(O)-, -S(O) ₂ -, -S(O)-, -CH(OH)- or -CH ₂ -; Y represents -O-, -CH ₂ -, -N(R ₁₂ )-; the R ₁₂ represents hydrogen, substituted or unsubstituted phenylsulfonyl, and the substitution is single or multiple C1- C6 alkyl, C1-C6 alkoxy, amino, nitro, halogen, C1-C6 alkyl amido;

The R ₃ and R ₄ or R ₄ and R ₅ are connected to each other to form a five-membered or six-membered aromatic ring structure M fused to the core, and its structural characteristics are as shown in formula (IIa and IIb), preferably the M and the mother nucleus together form a substituted or unsubstituted benzothiazole, benzofuran, indole, quinoline or naphthyridine, etc., and the R ₁₅ represents halogen, amino, nitro, C1-C6 alkyl, C1-C6 Alkoxy or sulfonylamino;

The substitution is substituted by halogen, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy or -S(O) ₂ NH ₂ ;

5. The substituted bisaryl compound as claimed in claim 1, wherein: X represents -C(O)-, -S(O) ₂ -, -S(O)-, -CH(OH)- or -CH ₂ -; Y represents -O-, -CH ₂ -, -N(R ₁₂ )-; the R ₁₂ represents hydrogen, substituted or unsubstituted phenylsulfonyl, and the substitution is single or multiple C1- C6 alkyl, C1-C6 alkoxy, amino, nitro, halogen, C1-C6 alkyl amido;

The R ₆ and R ₇ , R ₇ and R ₈ or R ₈ and R ₉ may be connected to each other to form a structure condensed with the parent nucleus such as the aromatic ring structure N shown in IIIa, IIIb and IIIc, and N is preferably connected to the parent nucleus The nucleus together constitutes substituted or unsubstituted benzothiazole, benzofuran, indole, purine, quinoline or naphthyridine, etc., and the R ₁₅ represents hydrogen, alkyl, alkoxy, halogen, oxo, acyl, amido , sulfonylamino substitution;

6. The substituted bisaryl compound as claimed in claim 1 has a structure shown in the following general formula (IV):

Among them: X stands for -C(O)-, -S(O) ₂ -, -S(O)-, -CH(OH)- or -CH ₂ -, Y stands for -O-, -CH ₂ -, - N(R ₁₂ )-; the R ₁₂ represents hydrogen, substituted phenylsulfonyl or substituted phenylacyl, and the substitution is C1-C6 alkyl, C1-C6 alkoxy, amino in one or more positions , Nitro, C1-C6 alkylamido substituted;

R ₂ is hydrogen, amino, nitro, C1-C6 alkyl acyloxy or NR ₁₃ R ₁₄ , and R ₁₃ and R ₁₄ represent hydrogen, C1-C6 alkyl, C1-C6 alkyl acyl, halogenated C1-C6 alkyl acyl,

or

R ₃ is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, -S(O) ₂ NH ₂ or phenyl-S-;

R ₆ , R ₇ , R ₈ and R ₉ can be the same or different when they exist independently, and represent hydrogen, halogen, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, benzenesulfonamide substituted Aryl, aryl substituted by p-toluenesulfonamide, halogenated C1-C6 alkyl or phenyl-S-, or R ₇ and R ₈ together form -O-CH ₂ -CH ₂ -O-.

7. The substituted bisaryl compound of claim 6, wherein:

X represents -C(O)-, -S(O) ₂ -, -S(O)-, Y represents -O- or -NH-;

R ₂ is amino, nitro or NR ₁₃ R ₁₄ , and R ₁₃ and R ₁₄ respectively represent hydrogen, C1-C6 alkyl acyl, trifluoroacetyl;

R ₃ is hydrogen, C1-C6 alkyl, C1-C6 alkoxy;

R ₆ , R ₇ , R ₈ and R ₉ each independently represent H, halogen or C1-C6 alkoxy.

8. The substituted bisaryl compound of claim 7, wherein:

X stands for -C(O)- or -S(O) ₂ -; Y stands for -O- or -NH-;

R ₂ is amino, nitro or NR ₁₃ R ₁₄ , when R ₁₃ is hydrogen, R ₁₄ is propionyl or trifluoroacetyl, or both R ₁₃ and R ₁₄ are propionyl;

R ₃ is methyl or methoxy;

R ₆ , R ₇ , R ₈ and R ₉ each independently represent H, halogen or methoxy.

9. Substituted bisaryl compounds as claimed in claim 8, wherein

X stands for -C(O)-, Y stands for -O- or -NH-;

R ₂ is amino or NHR ₁₄ , and said R ₁₄ is propionyl or trifluoroacetyl;

R ₃ is methoxy;

10. The substituted bisaryl compound as claimed in claim 1 has a structure shown in the following general formula (V):

Wherein: X represents -C(O)-, -S(O) ₂ -, -S(O)-, Y represents -N(R ₁₂ )-; said R ₁₂ represents hydrogen or substituted phenylacyl, and The above substitution is substituted by unit or multiple nitro, C1-C6 alkoxy, C1-C6 alkylamido;

R ₂ is amino, nitro or NHR ₁₃ , said R ₁₃ represents C1-C6 alkyl acyl or halogenated C1-C6 alkyl acyl;

R ₃ is C1-C6 alkyl, C1-C6 alkoxy;

Q1 selected from

11. The substituted bisaryl compound of claim 10, wherein:

X stands for -C(O)-, -S(O) ₂ - or -S(O)-, Y stands for -NH-;

R ₂ is NO ₂ ;

R ₃ is C1-C6 alkyl;

12. The substituted bisaryl compound as claimed in claim 1, has the structure shown in the following general formula (VI):

Among them: X stands for -C(O)-, -S(O) ₂ -, -S(O)-, Y stands for -NH-;

R ₆ , R ₇ , R ₈ and R ₉ may be the same or different when they exist independently, and represent hydrogen, halogen, C1-C6 alkoxy, preferably chlorine or methoxy;

Q2 is selected from substituted or unsubstituted pyridyl or thienyl, said substitution being monosubstituted by nitro or methylthio.

13. The substituted bisaryl compound as claimed in claim 1, has the structure shown in the following general formula (VII):

Among them, X represents -C(O)-, -S(O) ₂ -, Y represents -NH-;

Q1 and Q2 are respectively selected from substituted or unsubstituted pyridyl, pyrimidyl, thienyl or benzofuryl, and the substitution is substituted by halogen or aminoacyl.

14. The substituted bisaryl compound of claim 1, which is

(3-propionylamino-4-methoxyphenyl)formyl-(3’,4’,5’-trimethoxyphenyl)amine

(3-propionylamino-4-methoxyphenyl)formyl-(4’-chlorophenyl)amine

(3-Trifluoroacetamido-4-methoxyphenyl)formyl-(4’-chlorophenyl)amine

(3-Amino-4-methoxyphenyl)formyl-(3’,4’,5’-trimethoxyphenyl)amine

(3-propionylamino-4-methoxyphenyl)formanilide

(3-propionylamino-4-methoxyphenyl)formyl-(4’-methylphenyl)amine

(3-propionylamino-4-methoxyphenyl)formyl-(4’-trifluoromethylphenyl)amine

(3-propionylamino-4-methoxyphenyl)formyl-(2’-chlorophenyl)amine

(3-propionylamino-4-methoxyphenyl)formyl-(4’-fluorophenyl)amine

(3-propionylamino-4-methoxyphenyl)formyl-(4’-bromophenyl)amine

(3-propionylamino-4-methoxyphenyl)formyl-(3’-chlorophenyl)amine

(3-propionylamino-4-methoxyphenyl)formyl-(2’,4’-dichlorophenyl)amine

(3-(N-Cbz-valyl)amino-4-methoxyphenyl)carboxanilide

(3-Valylamino-4-methoxyphenyl)formanilide

(3-(2'-Bromopropionyl)amino-4-methoxyphenyl)carboxanilide

(3-(2'-Chloropropionyl)amino-4-methoxyphenyl)carboxanilide

(3-Trifluoroacetamido-4-methoxybenzene)formyl-4’-trifluoromethylaniline

(3-(2'-Bromopropionyl)amino-4-methoxyphenyl)formyl-(4'-trifluoromethylphenyl)amine

(3-propionylamino-4-methoxybenzene)formyloxy-(3',4',5'-trimethoxy)benzene

(3-propionylamino-4-methoxyphenyl)formyl-(4'-methoxyphenyl)amine

(3-Trifluoroacetamido-4-methoxyphenyl)formyl-(3',4',5'-trimethoxy)amine

(3-propionylamino-4-methoxybenzene)formyloxy-(4'-methoxybenzene)

(3-Amino-4-methoxybenzene)formyloxy-(3',4',5'-trimethoxy)benzene

(3-Trifluoroacetyl-4-methoxybenzene)formyloxy-(3',4',5'-trimethoxy)benzene

(3-Trifluoroacetyl-4-methoxybenzene)formyloxy-(4'-methoxybenzene)

(3-propionylamino-4-methoxyphenyl)formyl-(3’-methylthiophenyl)amine

(3-propionylamino-4-methoxyphenyl)formyl-(3’,4’-dioxyethylenephenyl)amine

3-Amino-4-methoxybenzanilide

(3-propionylamino-4-methoxyphenyl)sulfonyl-(4’-chlorophenyl)amine

(3-Dipropionylamino-4-methoxyphenyl)sulfonyl-(3’,4’,5’-trimethoxyphenyl)amine

(3-nitro-4-methylbenzene)sulfonyl-3'-(2'-chloro-5'-methylpyridinium)amine

(3-nitro-4-methylbenzene)sulfonyloxy-4'-methoxybenzene

(3-propionylamino-4-methylbenzene)sulfonyloxy-4'-methoxybenzene

(3-nitro-4-methylbenzene)sulfonyl-2'-(4',6'-dimethoxypyrimidine)amine

(3-Amino-4-methylbenzene)sulfonyl-2'-(4',6'-dimethoxypyrimidine)amine

(3-propionylamino-4-methylbenzene)sulfonyl-2'-(4',6'-dimethoxypyrimidine)amine

(3-nitro-4-methylphenyl)sulfonyl-(3’-methylthiophenyl)amine

(3-nitro-4-methylbenzene)sulfonyl-(3’,4’,5’-trimethoxyphenyl)amine

(3-Amino-4-methylbenzene)sulfonyl-(3’,4’,5’-trimethoxyphenyl)amine

(3-propionylamino-4-methylphenyl)sulfonyl-(3’,4’,5’-trimethoxyphenyl)amine

(3-Methylamino-4-methylbenzene)sulfonyl-(3’,4’,5’-trimethoxyphenyl)amine

(3-Acetamido-4-methylphenyl)sulfonyl-(3’,4’,5’-trimethoxyphenyl)amine

(3-nitro-4-methylbenzene)sulfonyl-(4'-chlorophenyl)amine

(3-N,N'-propionylamino-4-methylphenyl)sulfonyl-(4'-chlorophenyl)amine

(3-nitro-4-methylbenzene)sulfonyl-3'-triazolamide

N,N'-(3-nitro-4-methylbenzene)sulfonyl-(4'-chlorophenyl)amine

N,N'-(3-nitro-4-methylphenyl)sulfonyl-(3'-methylthiophenyl)amine

(3-propionylamino-4-methoxyphenyl)formyl-4’-aminopyrimidine

(3-propionylamino-4-methoxyphenyl)formyl-2'-(4',6'-dimethoxypyrimidine)amine

(3-nitro-4-methoxyphenyl)formyl-2'-(4',6'-dimethoxypyrimidine)amine

(3-Amino-4-methoxyphenyl)formyl-2'-(4',6'-dimethoxypyrimidine)amine

(3-(2”-bromopropionyl)amino-4-methoxyphenyl)formyl-2’-(4’,6’-dimethoxypyrimidine)amine

(3-Nitro-4-methoxyphenyl)formyl-(4’-nitrophenyl)amine

(3-Amino-4-methoxyphenyl)formyl-(4’-aminophenyl)amine

(3-propionylamino-4-methoxyphenyl)formyl-(4’-aminophenyl)amine

(3-Nitro-4-methoxyphenyl)formyl-(4’-trifluoromethylphenyl)amine

(3-Nitro-4-methoxyphenyl)formyl-2'-(4'-cyanopyridinium)amine

N,N'-(3-nitro-4-methoxyphenyl)formyl-2'-(4'-cyanopyridinium)amine

(3-nitro-4-methoxyphenyl)formyl-4'-pyrimidinamine

(3-propionylamino-4-methoxyphenyl)formyl-2'-(4'-cyanopyridinyl)amine

N,N'-(3-propionylamino-4-methoxyphenyl)formyl-2'-(4'-cyanopyridinium)amine

(3-nitro-4-methoxybenzene)formylmethylene-(3',4',5'-trimethoxy)benzene

(3-Amino-4-methoxybenzene)formylmethylene-(3',4',5'-trimethoxy)benzene

(3-propionylamino-4-methoxybenzene)formylmethylene-(3',4',5'-trimethoxy)benzene

(3-nitro-4-methoxybenzene)methyleneamino-(3',4',5'-trimethoxy)benzene

(3-Amino-4-methoxybenzene)methyleneamino-3’,4’,5’-trimethoxybenzene

(3-propionylamino-4-methoxybenzene)methyleneamino-3',4',5'-trimethoxybenzene

1-(3’-propionylamino-4’-methoxy)phenyl-2-(3”, 4”, 5”-trimethoxy)phenylethanol

N,N'-p-toluenesulfonyl-(4,4'-biphenyl)diamine

Bis(N,N'-di-p-toluenesulfonyl)-(4,4'-biphenyl)diamine

2-Nitrophenoxyacetyl-(4’-sulfonyl-(1”-piperidine)aminophenyl)amine

2-Aminophenoxyacetyl-(4’-sulfonyl-(1”-piperidine)aminophenyl)amine

2-Acetamidophenoxyacetyl-(4’-sulfonyl-(1”-piperidine)aminophenyl)amine

4-sulfonylaminobenzoyl-(4’-chlorophenyl)amine

4-Phenylthiobenzoyl-(4’-chlorophenyl)amine

6-Chloronicotinoyl-(-4'-pyrimidine)amine

2-Methylthionicotinoyl-(-3',4',5'-trimethoxyphenyl)ester

5-Nitrothiophene-2-formyl-(4’-chlorophenyl)amine

5-Chlorobenzofuran-2-formyl-(4’-formylaminothiophene)-2-amine

(3’-Methylbenzothiophen-2-yl)acetyl-(4”-chlorophenyl)amine

3-Propionyloxy-4-methoxybenzoyl-(3’,4’,5’-trimethoxy)aniline

3-Propionylamino-phenylsulfinyl-(3’,4’,5’-trimethoxyphenyl)amine

3-Amino-benzenesulfinyl-(3’,4’,5’-trimethoxyphenyl)amine

3-Nitro-benzenesulfinyl-(3’,4’,5’-trimethoxyphenyl)amine

(3-Amino-4-methoxyphenyl)formyl-4'-pyrimidinamine.

15. The pharmaceutically acceptable salt of the substituted bisaryl compound as claimed in claims 1-14, the pharmaceutically acceptable salt refers to the product of the salt-forming reaction between the substituted bisaryl compound and an acid, including inorganic acid salts, such as Hydrochloride, hydrobromide or sulfate, etc.; organic acid salts, such as acetate, lactate, succinate, fumarate, maleate, citrate, benzoate, formazan Sulfonate or p-toluate, etc.

16. the preparation method of the described substituted bisaryl compound of claim 1-15, adopts following method:

Method 1: X of the compound of formula (I) is -C(O)-, -CH ₂ C(O)- or -OCH ₂ C(O)-, Y is -O-, -N(R ₁₂ )- , using the following route to synthesize: mix A with a condensing agent (such as 1-hydroxybenzotriazole, HOBT; N, N'-diisopropylcarbodiimide, DIC, etc.) In an aprotic solvent (such as: N,N-dimethylformamide), after stirring for 0.5-5h, add B, react at room temperature, separate and purify the product

Wherein, X=-C(O)-, -CH ₂ C(O)- or -OCH ₂ C(O)-; Y=-O- or -N(R ₁₂ )-; other substituents are defined as in the claims 1;

Method 2: X of the compound of formula (I) is -C(O)-, -CH ₂ C(O)-, -OCH ₂ C(O)-, -S(O) ₂ - or -S(O)- When Y is -O-, -N(R ₁₂ )-, it can also be synthesized by the following method: A is converted into an acid chloride with an appropriate halogenation reagent (such as thionyl chloride, phosphorus pentachloride, etc.), and the Under the condition of using a base (such as triethylamine) as an acid-binding agent, slowly add the obtained acid chloride to the polar aprotic solution of B at low temperature, after the addition is completed, return to room temperature until the reaction is complete, and separate and purify to obtain the target product;

Wherein, X=-C(O)-, -CH ₂ C(O)-, -OCH ₂ C(O)-, -S(O) ₂ - or -S(O)-; Y=-O- or -N(R ₁₂ )-; the definitions of other substituents are the same as those in claim 1;

Method 3: When X of the compound of formula (I) is -C(OH)(R ₁₀ )-, Y is -CH(R ₁₁ )- or a single bond, the following method is used to synthesize: the halogen containing (hetero)aryl Substitute hydrocarbons to make Grignard reagents or directly react with aryl ketones (aldehydes) under the catalysis of organometallic bases (such as butyllithium, etc.) to generate diaryl alcohols;

Method 4: When X of the compound of formula (I) is -C(O)-, and Y is -CH(R ₁₁ )- or a single bond, the synthesis method adopted is: subjecting the target diaryl secondary alcohol to chromic acid Oxidation produces diaryl ketone targets;

Method 5: When X of the compound of formula (I) is -CH(R ₁₀ )-, and Y is -O-, -N(R ₁₂ )- or -S-, the following method is used for synthesis: A is passed through a halogen (such as bromine ) substitution reaction to generate a halogenated product, in a polar aprotic solvent (such as dichloromethane), condensed with B under basic (such as anhydrous potassium carbonate) conditions to obtain the target object;

Wherein, Y=O, N(R ₁₂ ) or S; G represents chlorine, bromine or iodine; other substituents are as defined in claim 1.

17. An antiviral pharmaceutical composition, containing the substituted biaryl compound or pharmaceutically acceptable salt thereof according to any one of claims 1-15 in a therapeutically effective dose, and containing one or more pharmaceutically acceptable drugs Use accessories.

18. The pharmaceutical composition according to claim 17, wherein the substituted bisaryl compound or a pharmaceutically acceptable salt thereof is used as an active ingredient, and the weight content in the pharmaceutical composition is 0.1%-99.5%.

19. A kind of pharmaceutical preparation for antiviral, is the compound itself or pharmaceutically acceptable salt thereof described in any one of claim 1-15 and the mixture of pharmaceutically acceptable excipient, diluent etc. in tablet, capsule, The form of granule, powder or syrup is made into oral medicine, or the form of injection is made into parenteral medicine.

20. The application of the compound or its pharmaceutically acceptable salt according to any one of claims 1-15 in the preparation of broad-spectrum antiviral drugs, and the viruses include HIV, hepatitis B virus, hepatitis C virus, respiratory virus or enterovirus virus.

21. The application of the pharmaceutical composition according to claim 17 or 18 in the preparation of broad-spectrum antiviral drugs, and the viruses include HIV, hepatitis B virus, hepatitis C virus, respiratory virus or enterovirus.

22. The application as claimed in claim 20 or 21, wherein said respiratory virus refers to influenza virus, including influenza A, B, C and avian influenza viruses.

23. The use according to claim 20 or 21, wherein the enterovirus refers to Coxsackievirus, including Coxsackievirus A16, Coxsackievirus B3 or Coxsackievirus B6.

24. The use according to claim 20 or 21, wherein the enterovirus refers to a new enterovirus, such as EV71 virus. the