CN102206172B - Substituted diaryl compound and preparation method and antiviral application thereof - Google Patents

Abstract

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

A group of substituted biaryl compounds and their preparation method and antiviral application

technical field

The present invention relates to a group of substituted biaryl compounds, and also relates to the preparation method of the compounds and the application in broad-spectrum anti-virus, especially anti-hepatitis virus, anti-respiratory virus, enterovirus and anti-AIDS virus.

Background technique

At present, the antiviral drugs used clinically all target viral proteins, and the mechanism of action is to inhibit the replication of the virus or block the invasion of the virus. Viruses are "moving targets" that rely on continuous mutation to evade drug attacks. Drugs targeting viral proteins all cause virus mutation and drug resistance, which has become a worldwide problem. Similarly, the 6 drugs currently clinically used to treat hepatitis B, except for interferon, are all nucleoside analogues in structure, and all target viral protein DNA polymerase, and severe drug resistance will occur after long-term use problems, leading to treatment failure. The combined application of multiple drugs (cocktail therapy) can greatly reduce the viral load of patients and slow down the occurrence of drug resistance, but drug resistance will inevitably occur in the end; new marketed varieties will have certain advantages in resisting drug-resistant strains, but with the time of clinical use The extension of drug resistance is still inevitable. Therefore, dealing with viral drug resistance is the main issue to be solved at present. In addition, the viral diseases caused by some RNA viruses (such as Coxsackie virus, influenza virus and EV71 virus, etc.) still lack effective clinical treatment drugs. Therefore, it is urgent to develop some new drugs that are more convenient, effective and have fewer side effects. Therapeutic applications to complement existing antiviral agents.

Since the combined application of interferon and ribavirin was approved for the treatment of hepatitis C in 1998, there are still no new antiviral drugs on the market, and the combined treatment of interferon and ribavirin has limited therapeutic effects, and nearly half of the patients have no symptoms after combined treatment. At the same time, many patients cannot tolerate the side effects of the combination therapy, such as anemia, fatigue, depression, etc., and have a high recurrence rate. Therefore, there is an urgent need to develop new drugs that are more convenient, effective and have fewer side effects to supplement existing treatment options.

With the continuous deepening of virology and cell biology research, a large number of research results have shown that in the long process of biological evolution, host cells generally form a defense system against different pathogenic viruses, and viruses will also form specific antagonistic mechanisms. Achieve escape from host cell inhibition. The interdependence and mutual antagonism between viruses and host cells, especially the cytokines related to viral replication, has become the most cutting-edge direction and the fastest-growing field in the international basic and applied research of medical biology.

In the broad-spectrum antiviral drug screening research, the inventors found and confirmed that substituted bisaryl compounds have broad-spectrum antiviral activity, especially inhibiting the replication of hepatitis B and hepatitis C viruses, inhibiting respiratory viruses and enteroviruses and antiviral activity. The role of HIV. The target of the compound of the invention may be different from the existing antiviral drugs, which mostly act on viral enzymes, while the compound of the present invention may exert a broad-spectrum antiviral effect based on a novel cellular mechanism. The compounds of the present invention and their effects have not been reported so far in relevant literature at home and abroad. The development of new antiviral compounds targeting cytokines is expected to make a breakthrough in solving the problem of viral drug resistance, so as to provide more effective new broad-spectrum antiviral drugs for clinical practice.

Contents of the invention

The main purpose of the present invention is to screen and obtain a new class of broad-spectrum antiviral compounds and their drugs with cytokines as targets through the structure-activity research of a group of substituted bisaryl compounds and the research on the mechanism of action of active compounds. With salt, this type of compound not only has significant broad-spectrum antiviral activity, but also has the advantages of low toxicity and good pharmaceutical properties.

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

The present invention provides a group of substituted bisaryl compounds or pharmaceutically acceptable salts thereof, which have the 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 ₁₂ represents hydrogen, hydrocarbyl, halogenated hydrocarbyl, acyl, hydroxyhydrocarbyl, aminohydrocarbyl, sulfonyl.

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 )-.

Alternatively, 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.

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

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;

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;

When R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ exist independently, they can be the same or different, representing hydrogen, hydrocarbon group, halogenated hydrocarbon group, hydroxy hydrocarbon group, halogen, nitro, cyano, acyl, carboxyl, Sulfonic acid group, phosphoric acid group, aryl group, heteroaryl group, 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, heterocyclic hydrocarbon group, aryl group, heteroaryl group, sulfonyl group, acyl group, or

Among them, preferably, R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ represent hydrogen, hydrocarbon group, halogenated hydrocarbon group, halogen, nitro group, aryl group, 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, aryl group, aryl group substituted by benzenesulfonamide, aryl group substituted by p-toluenesulfonamide, acyl group or sulfonyl group , hydrogen, hydrocarbyl, halogenated hydrocarbyl, halogen, nitro, hydrocarbyloxy or NR ₁₃ R ₁₄ , said R ₁₃ and R ₁₄ represent hydrogen, hydrocarbyl or acyl respectively;

In a preferred embodiment of the present invention, more preferably, 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 , the R ₁₃ and R ₁₄ respectively represent hydrogen, hydrocarbon group, aryl group, acyl group or sulfonyl group;

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

Preferably, said M and the mother nucleus together form a substituted or unsubstituted benzothiazole, benzofuran, indole, quinoline or naphthyridine, etc., and said _R represents halogen, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy or sulfonylamino;

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

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, amino, hydrocarbylamino, hydroxyl, cyano, hydrocarbyloxy, acyl, amido, ester, carboxyl, sulfonic acid, Phosphate, aryl, benzenesulfonamide substituted aryl, p-toluenesulfonamide substituted aryl, 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;

In addition, 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 fused with the mother nucleus, such as the aromatic five-membered or six-membered ring structure shown in IIIa, IIIb and IIIc N , N's skeleton is allowed to contain 0-3 heteroatoms, and one or more identical or different substituents R ₁₅ may be attached to the positions allowed by the chemical theory. In addition, the heteroatoms represent nitrogen, oxygen or sulfur

Preferably, N and the mother nucleus jointly form substituted or unsubstituted benzothiazole, benzofuran, indole, purine, quinoline or naphthyridine, etc., and the R ₁₅ represents hydrogen, hydrocarbyl, hydrocarbyloxy, halogen, oxo, Acyl, amido, sulfonylamino substitution;

Among them, preferably 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 or pyridine ring, and the R ₆ , R ₇ , R ₈ and R ₉ 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.

As stated in the definition above:

"Hydrocarbyl" may refer to a straight-chain or branched alkyl or cycloalkyl group with 1-8 carbon atoms, for example, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl , sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc. or their corresponding cycloalkyl groups. More preferably, it is a C1-C6 lower alkyl group.

"Aryl" refers to an aromatic hydrocarbon moiety and may be substituted or unsubstituted. The aromatic hydrocarbon is selected from phenyl, naphthyl, biphenyl, tetrahydronaphthyl, phenanthrenyl, fluorenyl, acenaphthyl or phenanthrenyl, etc., so The substitution refers to a unit or multiple positions of halogen, hydrocarbon group, hydroxyl group, nitro group, amino group, acyl group, hydrocarbon group, CONH ₂ , CONH(hydrocarbyl group), CON(hydrocarbyl group) ₂ , trifluoromethyl group, trifluoromethoxy group , sulfonic acid group, SO ₂ NH ₂ , SO ₂ NH (hydrocarbyl), SO ₂ N (hydrocarbyl) ₂ , SO ₂ N (cycloalkyl), ester, nitrile, oxyaryl, thioaryl or hydrocarbyl aryl etc.; preferred aryl substituents include: hydrocarbyl, halogen, nitro, amino, _CONH2 , hydrocarbyloxy, trifluoromethyl, _SO2NH (hydrocarbyl), nitrile, oxyaryl, thioaryl or hydrocarbyl Aryl;

"Heteroaryl" may refer to a substituted or unsubstituted aromatic heterocyclic ring system (monocyclic or bicyclic), wherein the aromatic heterocyclic ring part is a five-membered or Six-membered rings, and include but not limited to: monocyclic aromatic systems such as furan, thiophene, indole, oxazole, thiazole, imidazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, 1,2,4-triazole, etc. Or a bicyclic aromatic system formed by condensing benzene, pyridine, pyrimidine or pyridazine with other five-membered or six-membered heterocyclic rings, such as benzothiophene, benzofuran, benzimidazole and quinazoline; the substitution means Single or multiple positions of halogen, hydrocarbyl, hydroxyl, nitro, amino, acyl, alkoxy, CONH ₂ , CONH(hydrocarbyl), CON(hydrocarbyl) ₂ , trifluoromethyl, trifluoromethoxy, sulfonic acid , SO ₂ NH ₂ , SO ₂ NH (hydrocarbyl), SO ₂ N (hydrocarbyl) ₂ , SO ₂ N (cyclohydrocarbyl), ester, nitrile, oxygen aryl, sulfur aryl or hydrocarbyl aryl, etc.; preferred Aryl substituents include: hydrocarbyl, halogen, nitro, amino, _CONH2 , hydrocarbyloxy, trifluoromethyl, _SO2NH (hydrocarbyl), nitrile, oxyaryl, thioaryl or hydrocarbylaryl;

"Hydroxyl" can be an alkoxy group with 1-8 carbon atoms, for example, methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, isobutoxy, sec- Butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy, etc. More preferably, it is a C1-C6 lower alkoxy group.

"Acyl" can be a hydrocarbon-substituted acyl or aryl acyl or heteroaryl acyl group having 1 to 8 carbons, such as formyl, acetyl, isopropyl acyl, n-propyl acyl, allyl acyl, cyclopropyl Acyl, n-butylacyl, isobutylacyl, sec-butylacyl, tert-butylacyl, n-pentylacyl, isopentylacyl, n-hexylacyl, isohexylacyl, phenylacyl, tolylacyl, 2- Pyridoyl, etc., may also be a halogenated hydrocarbon group instead of an acyl group. More preferably, it is a C1-C6 lower alkyl-substituted acyl group or a halogenated hydrocarbon group-substituted acyl group.

"Ester group" may be a hydrocarbon-substituted ester group (hydrocarbyl acyloxy) or aryl ester group having 1-8 carbons, such as formyloxy, acetoxy, isopropyloxy, n-propylacyl Oxygen, allyl acyloxy, cyclopropyl acyloxy, n-butyryl acyloxy, isobutyryl acyloxy, sec-butyryl acyloxy, tert-butyl acyloxy, n-pentyl acyloxy group, isopentyl acyloxy group, n-hexyl acyloxy group, isohexyl acyloxy group, phenyl acyloxy group, tolyl acyloxy group, etc. More preferred is a C1-C6 lower alkyl-substituted ester group (hydrocarbyl acyloxy).

"Acylamino" can be a hydrocarbon-substituted amido or arylamido having 1 to 8 carbons, such as methylamido, ethylamido, isopropylamido, n-propylamido, allylamido Amino, cyclopropylamido, n-butylamido, isobutylamido, sec-butylamido, tert-butylamido, n-pentylamido, isopentylamido, n-hexylamido, isohexyl Acyl amido, phenyl amido, tolyl amido, etc. More preferably, it is a C1-C6 lower alkyl-substituted amido group.

"Halo" or "halogen" may be fluoro, chloro, bromo or iodo.

"Sulfonyl" can be a hydrocarbon-substituted sulfonyl or arylsulfonyl group with 1-8 carbons, such as methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, n-propylsulfonyl, allylsulfonyl Acyl, cyclopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, n-hexylsulfonyl, isohexyl Sulfonyl, phenylsulfonyl, tolylsulfonyl, etc. In a preferred embodiment of the present invention, it is preferably substituted phenylsulfonyl, and said substitution is substituted by single or multiple hydrocarbon groups, amino groups, nitro groups, halogen groups, and hydroxyl groups.

In the substituent of the substituted biaryl compound or its pharmaceutically acceptable salt structure formula of the present invention, the hydrocarbon group in the halogenated hydrocarbon group, carbonyl hydrocarbon group, hydroxy hydrocarbon group, and amino hydrocarbon group is a C1-C6 hydrocarbon group.

The pharmaceutically acceptable salt of the present invention is a substituted bisaryl compound of the general formula (I) according to the above definition and also includes the product of its salt-forming reaction with an acid, i.e. its pharmaceutically acceptable salt, including inorganic acid salt, such as salt salt, hydrobromide or sulfate, etc.; organic acid salts, such as acetate, lactate, succinate, fumarate, maleate, citrate, benzoate, methanesulfonate salt or p-toluate, etc.

Preferred representative compounds of the invention include compounds wherein:

(A) has the 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 amino, nitro, C1-C6 alkyl acyloxy or NR ₁₃ R ₁₄ , and R ₁₃ and R ₁₄ respectively represent hydrogen, C1-C6 alkyl, C1-C6 alkyl acyl, halogenated C1- C6 alkyl acyl,

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 methylthio, or R ₇ and R ₈ jointly form -O-CH ₂ -CH ₂ -O-.

Preferred compounds of the invention include those of (A) wherein:

(B) 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.

Preferred compounds of the invention include those of (B) wherein:

(C) X represents -C(O)-, -S(O) ₂ -, Y represents -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.

In a preferred embodiment of the present invention, some compounds in the general formula (IV) especially have anti-HIV virus activity, wherein

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

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

R ₃ is methoxy;

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

Or preferred compounds of the present invention include the following compounds, wherein

(E) has the 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 hydrogen, C1-C6 alkyl, C1-C6 alkoxy;

Q1 selected from

Preferred compounds of the invention include those of (E) wherein:

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

R ₂ is NO ₂ ;

R ₃ is C1-C6 alkyl;

Q1 is

Or preferred compounds of the present invention include the following compounds, wherein

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

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

R ₆ , R ₇ , R ₈ and R ₉ can be the same or different when they exist independently, and represent hydrogen, halogen, aryl substituted by benzenesulfonamide, aryl substituted by p-toluenesulfonamide, 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.

Or preferred compounds of the present invention include the following compounds, wherein

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

Among them, X represents -C(O)-, -S(O) ₂ - or -S(O)-, 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.

The present invention also provides a preparation method for the substituted bisaryl compound or a pharmaceutically acceptable salt thereof. The starting material and the reactant can be determined according to the structural design of X and Y in the target compound. Specifically, five methods can be followed:

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 as defined above;

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 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 then 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 )-; other substituents are as defined above;

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 ) generation of halides, in a polar aprotic solvent (such as dichloromethane), condensation 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 above.

Another aspect of the present invention also provides an antiviral pharmaceutical composition, which includes a therapeutically effective amount of the above-mentioned substituted bisaryl compound or a pharmaceutically acceptable salt thereof as an active ingredient, and contains one or more pharmaceutically acceptable drugs Use accessories. The pharmaceutical composition provided by the present invention can be in various dosage forms prepared according to conventional production methods in the field of pharmacy, for example, mixing the active ingredient with one or more carriers, and then making it into the desired dosage form. For example, the compound itself or its mixture with pharmaceutically acceptable excipients, diluents, etc. can be administered orally in the form of tablets, capsules, granules, powders or syrups, or administered parenterally in the form of injections. It is prepared as an oral pharmaceutical composition in the form of tablet, capsule, granule, powder or syrup by itself or its mixture with pharmaceutically acceptable excipients, diluents, etc., or as a parenteral pharmaceutical composition in the form of injection thing.

The pharmaceutical composition of the present invention preferably contains 0.1%-99.5% by weight of the active ingredient, most preferably contains 0.5%-99.5% by weight of the active ingredient.

The above preparations can be prepared by conventional pharmaceutical methods. Examples of usable pharmaceutical adjuvants include excipients (e.g. carbohydrate derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, dextrin and carboxymethyl starch; Cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium; gum arabic; dextran; silicate derivatives such as magnesium metasilicate aluminum; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, etc.); binders (such as gelatin, polyvinylpyrrolidone and polyethylene glycol); disintegrants ( For example, cellulose derivatives such as sodium carboxymethylcellulose, polyvinylpyrrolidone); lubricants (such as talc, calcium stearate, magnesium stearate, spermaceti, boric acid, sodium benzoate, leucine), stabilizers ( Methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, etc.); flavoring agents (such as commonly used sweeteners, sour agents, and spices, etc.); diluents and solvents for injections (such as water, ethanol, glycerin, etc.) .

The present invention also provides the application of the group of substituted biaryl compounds or their pharmaceutically acceptable salts and the antiviral pharmaceutical composition in the field of broad-spectrum antiviral, especially in the treatment of hepatitis B and C virus infection, including Combined application with other antiviral chemotherapy drugs.

The invention also provides the pharmacodynamic experimental research of the compound. HepG2.2.15 cells were cultured, the toxicity of the compound to the cells was determined by the CPE method, and the inhibitory effect of the compound on HBV replication was determined by the qPCR method; Huh7.5 cells were cultured, and the toxicity of the compound to the cells was determined by the MTT staining method, and the qRT- The inhibitory effect of the compound on HCV infection was determined by PCR method. The measurement results are shown in Table 2.

The present invention also uses the MT-4P24 antigen method to measure the anti-HIV-1 activity of the inventive compound, and the results are shown in Table 3. The compounds of the present invention also have inhibitory effect on HIV.

The present invention also provides the application of the group of substituted biaryl compounds or their pharmaceutically acceptable salts and the antiviral pharmaceutical composition in the treatment of respiratory virus and enterovirus infection, including the combined application with other antiviral chemotherapeutic drugs .

The invention also provides the pharmacodynamic experimental research of the compound. Adopt MDCK cell culture, measure the toxicity of compound to cell and the inhibitory effect of compound to influenza virus with CPE method, measure the result and see Table 4; Adopt Vero cell culture, measure the toxicity of compound to cell and compound to EV71 virus and Ke Saatchi virus inhibitory effect, assay result is shown in Table 4.

The above research results preliminarily verified the effect of the compound of the present invention or its pharmaceutically acceptable salt on inhibiting hepatitis virus and HIV, and on inhibiting respiratory virus and enterovirus. Because its broad-spectrum antiviral effect is based on a new type of cellular mechanism, it has possible advantages such as not easy to produce drug resistance after treatment, has potential combined therapeutic effect with other antiviral drugs, and has better safety. The development and application of drugs has laid the foundation.

Detailed ways

The 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.

<Example 1> Synthesis of (3-propionylamino-4-methoxyphenyl)formyl (3',4',5'-trimethoxyphenyl)amine (1)

In a 25ml flask, after dissolving 3-amino-4-methoxybenzoic acid (1.0g, 6mmol) in dry THF (tetrahydrofuran), triethylamine (1.2ml, 12mmol) was added to obtain a yellow transparent solution, nitrogen Protected, stirred, and propionyl chloride (0.78ml, 9mmol) was added dropwise thereto under ice-water bath conditions, and the reaction at room temperature was naturally restored after the dropwise addition was completed. The reaction solution was filtered, and the filtrate was evaporated to dryness and separated on a silica gel column to obtain 1.3 g of 3-propionylamino-4-methoxybenzoic acid (yield 67%).

Mix 100mg (0.45mmol) of the above product with 136mg (0.6mmol) of HOBT, 0.1ml (0.8mmol) of DIC in dry DMF under the condition of ice-water bath, under _N2 protection, add 3,4,5-trimethoxy after stirring for 30min Base aniline 72 mg (mmol), naturally return to room temperature and stir overnight. The reaction solution was evaporated to dryness under reduced pressure, the residue was dissolved in ethyl acetate and filtered. After the filtrate was evaporated to dryness, it was separated by silica gel column to obtain 120 mg of compound 1 (yield 68%). See Table 1 for ¹ H NMR data.

<Example 2> Synthesis of (3-propionylamino-4-methoxyphenyl)formyl (4'-chlorophenyl)amine (2)

Using 3-amino-4-methoxybenzoic acid, propionyl chloride and p-chloroaniline as starting materials, according to the method similar to Example 1, Compound 2 was synthesized with a yield of 23%. ^{The 1} H NMR data are shown in Table 1.

<Example 3> Synthesis of (3-trifluoroacetamido-4-methoxyphenyl)formyl (4'-chlorophenyl)amine (4)

Using 3-amino-4-methoxybenzoic acid, trifluoroacetic anhydride and p-chloroaniline as starting materials, according to the method similar to Example 1, compound 4 was synthesized with a yield of 26%. ¹ H NMR data are shown in Table 1 .

<Example 4> Synthesis of (3-amino-4-methoxyphenyl)formyl (3',4',5'-trimethoxyphenyl)amine (5)

Using 3-amino-4-methoxybenzoic acid, (BOC) ₂ O and 3,4,5-trimethoxyaniline as starting materials, according to the method similar to Example 1, compound 5 was synthesized with a yield of 18% , see Table 1 for ¹ H NMR data.

<Example 5> Synthesis of (3-propionylamino-4-methoxybenzene)carboxanilide (6)

Using 3-amino-4-methoxybenzoic acid, propionyl chloride and aniline as starting materials, according to the method similar to Example 1, Compound 6 was synthesized with a yield of 34%. Table 1 shows ^{the 1} H NMR data.

<Example 6> Synthesis of (3-propionylamino-4-methylhydrophenyl)formyl-(4'-methylphenyl)amine (7)

Using 3-amino-4-methoxybenzoic acid, propionyl chloride and p-methylaniline as starting materials, according to the method similar to Example 1, compound 7 was synthesized with a yield of 32%. Table 1 shows ^{the 1} H NMR data.

<Example 7> Synthesis of (3-propionylamino-4-methoxyphenyl)formyl-(4'-trifluoromethylphenyl)amine (8)

Using 3-amino-4-methoxybenzoic acid, propionyl chloride and p-trifluoromethylaniline as starting materials, according to the method similar to Example 1, compound 8 was synthesized with a yield of 38%. ^{The 1} H NMR data are shown in the table 1.

<Example 8> Synthesis of (3-propionylamino-4-methoxyphenyl)formyl-(2'-chlorophenyl)amine (9)

Using 3-amino-4-methoxybenzoic acid, propionyl chloride and 2-chloroaniline as starting materials, according to the method similar to Example 1, Compound 9 was synthesized with a yield of 32%. ^{The 1} H NMR data are shown in Table 1.

<Example 9> Synthesis of (3-propionylamino-4-methoxyphenyl)formyl (4'-fluorophenyl)amine (10)

Using 3-amino-4-methoxybenzoic acid, propionyl chloride and p-fluoroaniline as starting materials, according to the method similar to Example 1, compound 10 was synthesized with a yield of 35%. Table 1 shows ^{the 1} H NMR data.

<Example 10> Synthesis of (3-propionylamino-4-methoxyphenyl)formyl (4'-bromophenyl)amine (11)

Using 3-amino-4-methoxybenzoic acid, propionyl chloride and p-bromoaniline as starting materials, according to the method similar to Example 1, compound 11 was synthesized with a yield of 16%. See Table 1 for ¹ H NMR data.

<Example 11> Synthesis of (3-propionylamino-4-methoxyphenyl)formyl-(3'-chlorophenyl)amine (12)

Using 3-amino-4-methoxybenzoic acid, propionyl chloride and 3-chloroaniline as starting materials, compound 12 was synthesized according to the method similar to Example 1, with a yield of 31%. Table 1 shows ^{the 1} H NMR data.

<Example 12> Synthesis of (3-propionylamino-4-methoxyphenyl)formyl-(2',4'-dichlorophenyl)amine (13)

Using 3-amino-4-methoxybenzoic acid, propionyl chloride and 2,4-dichloroaniline as starting materials, according to the method similar to Example 1, compound 13 was synthesized with a yield of 30%. For ¹ H NMR data, see Table 1.

<Example 13> Synthesis of (3-(N-Cbz-valyl)amino-4-methoxybenzene)carboxanilide (16)

Using 3-amino-4-methoxybenzoic acid, (BOC) ₂ O, aniline and N-Cbz-valine as starting materials, according to the method similar to Example 1, compound 16 was synthesized with a yield of 30%. See Table 1 for ¹ H NMR data.

<Example 14> Synthesis of (3-valylamino-4-methoxybenzene)carboxanilide (18)

Using 16 as the starting material, deprotection by hydrogenation, the compound 18 was synthesized with a yield of 90%. ^{The 1} H NMR data are shown in Table 1.

<Example 15> Synthesis of (3-(2'-bromopropionyl)amino-4-methoxybenzene)carboxanilide (22)

Using 3-amino-4-methoxybenzoic acid, 2-bromopropionyl chloride and aniline as starting materials, compound 22 was synthesized according to the method similar to Example 1 with a yield of 37%. ^{The 1} H NMR data are shown in Table 1.

<Example 16> Synthesis of (3-(2'-chloropropionyl)amino-4-methoxybenzene)carboxanilide (23)

Using 3-amino-4-methoxybenzoic acid, 2-chloropropionyl chloride and aniline as starting materials, according to the method similar to Example 1, compound 23 was synthesized with a yield of 35%. See Table 1 for ¹ H NMR data.

<Example 17> Synthesis of (3-trifluoroacetamido-4-methoxybenzene)formyl-4'-trifluoromethylaniline (24)

Using 3-amino-4-methoxybenzoic acid, trifluoroacetic anhydride and p-trifluoromethylaniline as starting materials, according to the method similar to Example 1, compound 24 was synthesized with a yield of 30%, ¹ H NMR data See Table 1.

<Example 18> Synthesis of (3-(2'-bromopropionyl)amino-4-methoxyphenyl)formyl-(4'-trifluoromethylphenyl)amine (25)

Using 3-amino-4-methoxybenzoic acid, 2-bromopropionyl chloride and p-trifluoromethylaniline as starting materials, compound 25 was synthesized according to the method similar to Example 1, with a yield of 30%, ¹ H NMR See Table 1 for the data.

<Example 19> Synthesis of (3-propionylamino-4-methoxybenzene)formyloxy-(3',4',5'-trimethoxy)benzene (34)

Using 3-amino-4-methoxybenzoic acid, propionyl chloride and 3,4,5-trimethoxyaniline as starting materials, according to the method similar to Example 1, compound 34 was synthesized with a yield of 21%, ¹ H See Table 1 for NMR data.

<Example 20> Synthesis of (3-propionylamino-4-methoxyphenyl)formyl-(4'-methoxyphenyl)amine (35)

Using 3-amino-4-methoxybenzoic acid, propionyl chloride and 4-methoxyaniline as starting materials, according to the method similar to Example 1, compound 35 was synthesized with a yield of 25%. ^{The 1} H NMR data are shown in the table 1.

<Example 21> Synthesis of (3-trifluoroacetamido-4-methoxybenzene)formyl (3',4',5'-trimethoxy)amine (36)

Using 3-amino-4-methoxybenzoic acid, trifluoroacetic anhydride and 3,4,5-trimethoxyaniline as starting materials, according to the method similar to Example 1, compound 36 was synthesized with a yield of 27%. See Table 1 for ¹ H NMR data.

<Example 22> Synthesis of (3-propionylamino-4-methoxybenzene)formyloxy-(4'-methoxy)benzene (39)

Using 3-amino-4-methoxybenzoic acid, propionyl chloride and 4-methoxyphenol as starting materials, according to the method similar to Example 1, compound 39 was synthesized with a yield of 25%. ^{The 1} H NMR data are shown in the table 1.

<Example 23> Synthesis of (3-amino-4-methoxybenzene)formyloxy-(3',4',5'-trimethoxy)benzene (40)

Using 3-amino-4-methoxybenzoic acid, (BOC) ₂ O and 3,4,5-trimethoxyphenol as starting materials, according to the method similar to Example 1, compound 40 was synthesized with a yield of 21% , see Table 1 for ¹ H NMR data.

<Example 24> Synthesis of (3-trifluoroacetyl-4-methoxybenzene)formyloxy-(3',4',5'-trimethoxy)benzene (41)

Using 3-amino-4-methoxybenzoic acid, trifluoroacetic anhydride and 3,4,5-trimethoxyphenol as starting materials, according to the method similar to Example 1, compound 41 was synthesized with a yield of 24%, See Table 1 for ¹ H NMR data.

<Example 25> Synthesis of (3-trifluoroacetyl-4-methoxybenzene)formyloxy-(4'-methoxy)benzene (42)

Using 3-amino-4-methoxybenzoic acid, trifluoroacetic anhydride and 4-methoxyphenol as starting materials, according to the method similar to Example 1, compound 42 was synthesized with a yield of 24%, ¹ H NMR data See Table 1.

<Example 26> Synthesis of (3-propionylamino-4-methoxyphenyl)formyl-(3'-methylthiophenyl)amine (45)

Using 3-amino-4-methoxybenzoic acid, propionyl chloride and 3-methylthioaniline as starting materials, according to the method similar to Example 1, compound 45 was synthesized with a yield of 21%. ^{The 1} H NMR data are shown in the table 1.

<Example 27> Synthesis of (3-propionylamino-4-methoxyphenyl)formyl-(3',4'-dioxyethylenephenyl)amine (46)

Using 3-amino-4-methoxybenzoic acid, propionyl chloride and 3,4-dioxyethyleneaniline as starting materials, according to the method similar to Example 1, compound 46 was synthesized with a yield of 26%, ¹ H NMR See Table 1 for the data.

<Example 28> Synthesis of 3-amino-4-methoxybenzanilide (67)

Using 3-amino-4-methoxybenzoic acid, (BOC) ₂ O and aniline as starting materials, according to the method similar to Example 1, compound 67 was synthesized with a yield of 29%. See Table 1 for ¹ H NMR data.

<Example 29> Synthesis of (3-propionylamino-4-methoxybenzene)sulfonyl (4'-chlorophenyl)amine (33)

3-nitro-4-methoxybenzenesulfonic acid (5.0 g, 21 mmol) was dissolved in SOCl ₂ , heated to reflux for 3 hours, and thionyl chloride was evaporated under normal pressure to obtain crude benzenesulfonyl chloride;

Then take p-chloroaniline (1.0g, 7.8mmol) and dissolve it in dichloromethane, add triethylamine (2ml, 20mmol), under ice-water bath conditions, gradually add crude product benzenesulfonyl chloride (3.5g) therein, and stir after adding Half an hour later, the room temperature was naturally restored, and the mixture was stirred until the reaction was complete. The reaction solution was adsorbed on silica gel, and the product was separated by column chromatography to obtain 1.6 g of 3-nitro-substituent.

The above nitro compound (0.5 g) was dissolved in methanol, 10% Pd/C was added, hydrogenated and reduced at medium pressure, the raw material disappeared after 5 hours, filtered, and the filtrate was evaporated to dryness to obtain 0.42 g of 3-amino substituent; the 3-amino The substituent was acylated with propionyl chloride in dichloromethane under the condition of triethylamine as an acidic agent to obtain 330.47 g of the target compound.

<Example 30> Synthesis of (3-dipropionylamino-4-methoxybenzene)sulfonyl (3',4',5'-trimethoxyphenyl)amine (3)

Using 3-nitro-4-methoxybenzenesulfonic acid, thionyl chloride, 3,4,5-trimethoxyaniline and propionyl chloride as starting materials, compound 3 was synthesized according to a method similar to Example 29, See Table 1 for ¹ H NMR data.

<Example 31> Synthesis of (3-nitro-4-methylbenzene)sulfonyl-3'-(2'-chloro-5'-picoline)amine (14)

Using 3-nitro-4-methylbenzenesulfonic acid and 2-chloro-3-amino-5-picoline as starting materials, according to the method similar to Example 29, compound 14 was synthesized, and ^{the 1} H NMR data are shown in the table 1.

<Example 32> Synthesis of (3-nitro-4-methylbenzene)sulfonyloxy-4'-methoxybenzene (15)

Using 3-nitro-4-methylbenzenesulfonic acid and 4-methoxyphenol as starting materials, according to the method similar to Example 29, compound 15 was synthesized. ^{The 1} H NMR data are shown in Table 1.

<Example 33> Synthesis of (3-propionylamino-4-methylbenzene)sulfonyloxy-4'-methoxybenzene (17)

Using 3-nitro-4-methylbenzenesulfonic acid, 4-methoxyphenol and propionyl chloride as starting materials, compound 17 was synthesized according to the method similar to Example 29. Table 1 shows ^{the 1} H NMR data.

<Example 34> Synthesis of (3-nitro-4-methylbenzene)sulfonyl-2'-(4',6'-dimethoxypyrimidine)amine (19)

Using 3-nitro-4-methylbenzenesulfonic acid and 2-amino-4,6-dimethoxypyridine as starting materials, according to the method similar to Example 29, compound 19 was synthesized, and ^{the 1} H NMR data are shown in the table 1.

<Example 35> Synthesis of (3-amino-4-methylbenzene)sulfonyl-2'-(4',6'-dimethoxypyrimidine)amine (20) Using compound 19 as raw material, palladium carbon Catalyst, hydrogenation reduction to obtain 20, ¹ H NMR data are shown in Table 1.

<Example 36> Synthesis of (3-propionylamino-4-methylbenzene)sulfonyl-2'-(4',6'-dimethoxypyrimidine)amine (21)

Using compound 20 as a raw material, it was acylated with propionyl chloride to obtain 21. The ¹ H NMR data are shown in Table 1.

<Example 37> Synthesis of (3-nitro-4-methylbenzene)sulfonyl-(3'-methylthiophenyl)amine (43)

Using 3-nitro-4-methylbenzenesulfonic acid and 3-methylthioaniline as starting materials, according to the method similar to Example 29, compound 43 was synthesized. ^{The 1} H NMR data are shown in Table 1.

<Example 38> Synthesis of (3-nitro-4-methylbenzene)sulfonyl (3',4',5'-trimethoxyphenyl)amine (47)

Using 3-nitro-4-methylbenzenesulfonic acid and 3,4,5-trimethoxyaniline as starting materials, compound 47 was synthesized according to the method similar to Example 29. ^{The 1} H NMR data are shown in Table 1.

<Example 39> Synthesis of (3-amino-4-methylbenzene)sulfonyl (3',4',5'-trimethoxyphenyl)amine (48)

Using 47 as the starting material and palladium carbon as the catalyst, compound 48 was synthesized by hydrogenation. ^{The 1} H NMR data are shown in Table 1.

<Example 40> Synthesis of (3-propionylamino-4-methylbenzene)sulfonyl (3',4',5'-trimethoxyphenyl)amine (49)

Using 48 and propionyl chloride as starting materials, according to the acylation method in Example 29, compound 49 was synthesized. ^{The 1} H NMR data are shown in Table 1.

<Example 41> Synthesis of (3-methylamino-4-methylbenzene)sulfonyl (3',4',5'-trimethoxyphenyl)amine (50)

Using 48 and methyl iodide as starting materials and triethylamine as an acid-binding agent, compound 50 was synthesized by halogenation reaction. ^{The 1} H NMR data are shown in Table 1.

<Example 42> Synthesis of (3-acetylamino-4-methylbenzene)sulfonyl (3',4',5'-trimethoxyphenyl)amine (51)

Using 48 and acetyl chloride as starting materials, according to the acylation method in Example 29, compound 51 was synthesized. ^{The 1} H NMR data are shown in Table 1.

<Example 43> Synthesis of (3-nitro-4-methylbenzene)sulfonyl (4'-chlorophenyl)amine (54)

Using 3-nitro-4-methylbenzenesulfonic acid and p-chloroaniline as starting materials, compound 54 was synthesized according to the method similar to Example 29. ^{The 1} H NMR data are shown in Table 1.

<Example 44> Synthesis of (3-N,N'-propionylamino-4-methylbenzene)sulfonyl (4'-chlorophenyl)amine (57)

Using 54 and propionyl chloride as starting materials, according to the similar reduction and acylation methods of Example 29, compound 57 was synthesized. ^{The 1} H NMR data are shown in Table 1.

<Example 45> Synthesis of (3-nitro-4-methylbenzene)sulfonyl 3'-triazolamide (58)

Using 3-nitro-4-methylbenzenesulfonic acid and 3-aminotriazole as starting materials, according to the method similar to Example 29, compound 58 was synthesized. ^{The 1} H NMR data are shown in Table 1.

<Example 46> Synthesis of N,N'-(3-nitro-4-methylbenzene)sulfonyl-(4'-chlorophenyl)amine (62)

Using 3-nitro-4-methylbenzenesulfonic acid and p-chloroaniline as starting materials, according to the method similar to Example 29, compound 62 was synthesized when the excess of sulfonyl chloride was three times in the second step reaction, ¹ H NMR See Table 1 for the data.

<Example 47> Synthesis of N,N'-(3-nitro-4-methylbenzene)sulfonyl-(3'-methylthiophenyl)amine (63)

Using 3-nitro-4-methylbenzenesulfonic acid and 3-methylthioaniline as starting materials, according to the method similar to Example 46, compound 63 was synthesized. ^{The 1} H NMR data are shown in Table 1.

<Example 48> Synthesis of (3-propionylamino-4-methoxyphenyl)formyl-4'-aminopyrimidine (52)

3-nitro-4-methoxybenzoic acid (5.0 g, 25 mmol) was dissolved in SOCl ₂ , heated to reflux for 3 hours, and thionyl chloride was evaporated under normal pressure to obtain crude benzoyl chloride;

Then take 4-aminopyrimidine (1.0g, 10mmol) and dissolve it in dichloromethane, add triethylamine-milliliter, under the condition of ice-water bath, add crude product benzoyl chloride 3.8g to it gradually, after adding, stir for half an hour and then recover naturally Stir at room temperature until the reaction is complete, the reaction solution is adsorbed on silica gel, and the product is separated by column chromatography to obtain 2.2 g of 3-nitro substituted product.

The above nitro compound (0.5 g) was dissolved in methanol, 10% Pd/C was added, hydrogenated and reduced at medium pressure, the raw material disappeared after 5 hours, filtered, and the filtrate was evaporated to dryness to obtain 0.43 g of 3-amino substituent; the 3-amino The substituent was acylated with propionyl chloride in dichloromethane under the condition of triethylamine as an acidic agent, and the reaction solution was separated by column chromatography to obtain 520.51 g of the target product.

<Example 49> Synthesis of (3-propionylamino-4-methoxyphenyl)formyl-2'-(4',6'-dimethoxypyrimidine)amine (26)

Using 28 as the starting material, compound 26 was synthesized by propionylation according to the method of Example 48. ^{The 1} H NMR data are shown in Table 1.

<Example 50> Synthesis of (3-nitro-4-methoxyphenyl)formyl-2'-(4',6'-dimethoxypyrimidine)amine (27)

Using 3-nitro-4-methoxybenzoic acid and 2-amino-4,6-dimethoxypyrimidine as starting materials, compound 27 was synthesized according to the method of Example 48. ^{The 1} H NMR data are shown in Table 1.

<Example 51> Synthesis of (3-amino-4-methoxyphenyl)formyl-2'-(4',6'-dimethoxypyrimidine)amine (28)

Using 27 as the starting material, compound 28 was synthesized according to the hydrogenation reduction method in Example 48. ^{The 1} H NMR data are shown in Table 1.

<Example 52> (3-(2"-bromopropionyl)amino-4-methoxyphenyl)formyl-2'-(4',6'-dimethoxypyrimidine)amine (29) synthesis

Using 28 as the starting material, compound 29 was synthesized by acylation according to the method of Example 48. ^{The 1} H NMR data are shown in Table 1.

<Example 53> Synthesis of (3-nitro-4-methoxyphenyl)formyl-(4'-nitrophenyl)amine (30)

Using 3-nitro-4-methoxybenzoic acid and p-nitroaniline as starting materials, compound 30 was synthesized according to the method of Example 48. ^{The 1} H NMR data are shown in Table 1.

<Example 54> Synthesis of (3-amino-4-methoxyphenyl)formyl-(4'-aminophenyl)amine (31)

Using 30 as the starting material, compound 31 was synthesized according to the hydrogenation method in Example 48. ^{The 1} H NMR data are shown in Table 1.

<Example 55> Synthesis of (3-propionylamino-4-methoxyphenyl)formyl-(4'-aminophenyl)amine (32)

Using 31 as the starting material, compound 32 was synthesized according to the acylation method of Example 48. ^{The 1} H NMR data are shown in Table 1.

<Example 56> Synthesis of (3-nitro-4-methoxyphenyl)formyl-(4'-trifluoromethylphenyl)amine (37)

Using 3-nitro-4-methoxybenzoic acid and p-trifluoromethylaniline as starting materials, compound 37 was synthesized according to the method of Example 48. ^{The 1} H NMR data are shown in Table 1.

<Example 57> Synthesis of (3-nitro-4-methoxyphenyl)formyl-2'-(4'-cyanopyridinium)amine (38)

Using 3-nitro-4-methoxybenzoic acid and 2-amino-5-cyanopyridine as starting materials, compound 38 was synthesized according to the method of Example 48. ^{The 1} H NMR data are shown in Table 1.

<Example 58> Synthesis of N,N'-(3-nitro-4-methoxyphenyl)formyl-2'-(4'-cyanopyridinium)amine (44)

Using 3-nitro-4-methoxybenzoic acid and 2-amino-5-cyanopyridine as starting materials, compound 44 is easily synthesized when the amount of acid chloride added exceeds three times the amount of heteroarylamine. ¹ See Table 1 for H NMR data.

<Example 59> Synthesis of (3-nitro-4-methoxybenzene)formyl-4'-pyrimidinamine (53)

Using 3-nitro-4-methoxybenzoic acid and 4-aminopyrimidine as starting materials, according to the method similar to Example 48, compound 53 was synthesized. ^{The 1} H NMR data are shown in Table 1.

<Example 60> Synthesis of (3-propionylamino-4-methoxybenzene)formyl-2'-(4'-cyanopyridinium)amine (55)

Using 3-nitro-4-methoxybenzoic acid and 2-amino-5-cyanopyridine as starting materials, compound 55 was synthesized according to the method similar to Example 48. ^{The 1} H NMR data are shown in Table 1.

<Example 61> Synthesis of N,N'-(3-propionylamino-4-methoxybenzene)formyl-2'-(4'-cyanopyridinium)amine (56)

Using 44 as the starting material, compound 56 was synthesized through hydrogenation reduction and acylation. ^{The 1} H NMR data are shown in Table 1.

<Example 62> Synthesis of 1-(3'-nitro-4'-methoxy)phenyl-2-(3", 4", 5"-trimethoxy)phenylethanol (61)

Put 200mg of magnesium wire in 15ml of anhydrous tetrahydrofuran solution, raise the temperature to 65 degrees, add 5 drops of benzyl bromide (0.5ml) in tetrahydrofuran solution and a small amount of iodine dropwise, continue to add benzyl bromide dropwise after initiation, and keep the slight boiling temperature after dropping After 5 hours until a large amount of magnesium silk was consumed, 1g of 3-nitro-4methoxy-acetophenone tetrahydrofuran solution was added dropwise, refluxed for 8 hours, and 25% ammonium chloride solution was added to terminate the reaction, and the target product 61 was obtained by column chromatography , ¹ H NMR data are shown in Table 1, (yield 20%).

<Example 63> Synthesis of (3-nitro-4-methoxybenzene)formylmethylene-(3',4',5'-trimethoxy)benzene (59)

Slowly add 10ml of 20% chromic acid solution dropwise to 200mg of compound 61 in acetone under ice-bath conditions, and react overnight at room temperature after dropping, the next day the reaction solution is extracted with water and ethyl acetate, the organic layer is concentrated and separated on a column to obtain the target compound 59 , ¹ H NMR data are shown in Table 1, (yield 31%).

<Example 64> Synthesis of (3-amino-4-methoxybenzene)formylmethylene-(3',4',5'-trimethoxy)benzene (60)

The above-mentioned nitro compound 59 (0.1g) was dissolved in methanol, 10% Pd/C was added, hydrogenated and reduced at medium pressure, the raw material disappeared after 5 hours, filtered, and the filtrate was evaporated to dryness to obtain 600.062g of 3-amino substituent; ¹ H NMR See Table 1 for the data.

<Example 65> Synthesis of (3-nitro-4-methoxybenzene)methyleneamino-(3',4',5'-trimethoxy)benzene (64)

Dissolve 3-nitro-4-methoxytoluene (5g, 30mmol) in carbon tetrachloride, add NBS to it, add a small amount of sulfur, heat to reflux, return to room temperature after 8 hours, and depressurize the reaction solution Evaporate to dryness, dissolve the residue with dichloromethane, wash with water, dilute hydrochloric acid solution, and water successively, dry the organic layer with anhydrous sodium sulfate, and evaporate the solvent to obtain crude 3-nitro-4-methoxytoluene bromide;

Dissolve 3,4,5-trimethoxyaniline (0.4g, 2.4mmol) in dichloromethane, add 0.25ml of triethylamine, and slowly add about 1.0g of the crude bromotoluene to it under ice-water bath conditions, add Return to room temperature and stir overnight. The next day, the reaction solution is washed with water, dilute acid solution, and dilute alkali solution. The organic layer is dried, concentrated and separated on a silica gel column to obtain pure (3-nitro-4-methoxybenzene) methylene Amino-3',4',5'-trimethoxybenzene 640.42g (yield: 55%); see Table 1 for ¹ H NMR data.

<Example 66> Synthesis of (3-amino-4-methoxybenzene)methyleneamino-3',4',5'-trimethoxybenzene (65)

The above-mentioned nitro compound 64 (0.15g) was dissolved in methanol, 10% Pd/C was added, hydrogenated and reduced at medium pressure, the raw material disappeared after 5 hours, filtered, and the filtrate was evaporated to dryness to obtain 650.10g of 3-amino substituent (yield: 73%); see Table 1 for ¹ H NMR data.

<Example 67> Synthesis of (3-propionylamino-4-methoxybenzene)methyleneamino-3',4',5'-trimethoxybenzene (66)

The 3-amino substituent 65 was acylated with propionyl chloride in dichloromethane under the condition of triethylamine as an acidic agent and separated by column to obtain 0.10 g of the target compound 66 (yield: 85%). See Table 1 for ¹ H NMR data.

<Example 68> Synthesis of (3-propionylamino-4-methoxybenzene)formylmethylene-(3',4',5'-trimethoxy)benzene (68)

The 3-amino substituent 60 was dissolved in dichloromethane, acylated with propionyl chloride under the condition of triethylamine as an acidic agent, and separated by a column to obtain 0.065 g of the target compound 68. See Table 1 for ¹ H NMR data.

<Example 69> Synthesis of N, N'-p-toluenesulfonyl-(4,4'-biphenyldi)amine (69)

Using 4,4'-biphenylenediamine and p-toluenesulfonyl chloride as raw materials, compound 69 was synthesized according to the method similar to the second step of Example 29. ^{The 1} H NMR data are shown in Table 1.

<Example 70> Synthesis of two (N, N'-di-p-toluenesulfonyl)-(4,4'-biphenyldi)amine (70)

Using 4,4'-biphenylenediamine and p-toluenesulfonyl chloride as raw materials, according to the method similar to the second step of Example 29, compound 70 was obtained while compound 69 was synthesized. See Table 1 for ¹ H NMR data.

<Example 71> Synthesis of 2-nitrophenoxyacetyl-(4'-sulfonyl-(1"-piperidine)aminophenyl)amine (71)

Using p-nitrobenzenesulfonic acid and piperidine as starting materials, synthesize p-nitrobenzenesulfonylpiperidinamine according to a method similar to Example 29; Sulfonylpiperidinamine; Finally, using p-nitrophenoxyacetic acid and p-aminobenzenesulfonylpiperidinamine as raw materials, compound 71 was synthesized according to a method similar to that in Example 48. ^{The 1} H NMR data are shown in Table 1.

<Example 72> Synthesis of 2-aminophenoxyacetyl-(4'-sulfonyl-(1"-piperidine)aminophenyl)amine (72)

Using compound 71 as the starting material, compound 72 was obtained by reduction according to the method of catalytic hydrogenation similar to that of Example 48. ^{The 1} H NMR data are shown in Table 1.

<Example 73> Synthesis of 2-acetylaminophenoxyacetyl-(4'-sulfonyl-(1"-piperidine)aminophenyl)amine (73)

Using compound 72 and acetyl chloride as starting materials, compound 73 was obtained by reduction according to the similar acylation method of Example 48. ^{The 1} H NMR data are shown in Table 1.

<Example 74> Synthesis of 4-sulfonylaminobenzoyl-(4'-chlorophenyl)amine (74)

Using p-sulfonylaminobenzoic acid and p-chloroaniline as starting materials, according to the similar condensation method of Example 1, compound 74 was synthesized. ^{The 1} H NMR data are shown in Table 1.

<Example 75> Synthesis of 4-phenylthiobenzoyl-(4'-chlorophenyl)amine (75)

Using p-phenylthiobenzoic acid and p-chloroaniline as starting materials, according to the similar condensation method of Example 1, compound 75 was synthesized. ^{The 1} H NMR data are shown in Table 1.

<Example 76> Synthesis of 6-chloronicotinoyl-(-4'-pyrimidine)amine (76)

Using 6-chloronicotinoyl chloride and 4-aminopyrimidine as starting materials, compound 76 was synthesized according to the method similar to Example 48. ^{The 1} H NMR data are shown in Table 1.

<Example 77> Synthesis of 2-methylthionicotinoyl-(-3',4',5'-trimethoxyphenyl)ester (77)

Using 2-methylthionicotinoyl chloride and 3,4,5-trimethoxyphenol as starting materials, according to the method similar to Example 48, compound 77 was synthesized. ^{The 1} H NMR data are shown in Table 1.

<Example 78> Synthesis of (3'-methylbenzothiophen-2-yl)acetyl-(4"-chlorophenyl)amine (78)

Using 2-(3-methyl)benzothiopheneacetic acid and p-chloroaniline as starting materials, compound 78 was synthesized according to the method similar to Example 48. ^{The 1} H NMR data are shown in Table 1.

<Example 79> Synthesis of 5-chlorobenzofuran-2-formyl- (4' -formylaminothiophene)-2-amine (79)

Using 2-carboxy-5-chloro-benzofuran and 2-amino-4-formylaminothiophene as starting materials, compound 79 was synthesized according to a method similar to Example 48. ^{The 1} H NMR data are shown in Table 1.

<Example 80> Synthesis of 5-nitrothiophene-2-formyl- (4' -chlorophenyl)amine (80)

Using 2-carboxy-5-nitrothiophene and p-chloroaniline as starting materials, according to the method similar to Example 48, compound 80 was synthesized. ^{The 1} H NMR data are shown in Table 1.

<Example 81> Synthesis of 3-propionyloxy-4-methoxybenzoyl- (3 ', 4 ', 5'-trimethoxyphenyl)amine (81)

Using 3-hydroxy-4-methoxybenzoic acid, propionyl chloride and 3,4,5-trimethoxyaniline as starting materials, compound 81 was synthesized according to a method similar to Example 1, and ^{the 1} H NMR data are shown in the table 1.

<Example 82> Synthesis of 3-nitro-benzenesulfinyl-(3',4',5'-trimethoxyphenyl)amine (84)

Using 3-nitro-benzenesulfinyl chloride and 3,4,5-trimethoxyaniline as starting materials, compound 84 was synthesized according to the method similar to Example 29. ^{The 1} H NMR data are shown in Table 1.

<Example 83> Synthesis of 3-amino-benzenesulfinyl-(3',4',5'-trimethoxyphenyl)amine (83)

Using 84 as the starting material, according to the similar reduction method of Example 29, compound 83 was synthesized. ^{The 1} H NMR data are shown in Table 1.

<Example 84> Synthesis of 3-propionylamino-benzenesulfinyl-(3',4',5'-trimethoxyphenyl)amine (82)

Using 83 and propionyl chloride as starting materials, according to the similar acylation method of Example 29, compound 82 was synthesized. ^{The 1} H NMR data are shown in Table 1.

<Example 85> Synthesis of (3-amino-4-methoxyphenyl)formyl-4'-pyrimidinamine (85)

Using (3-nitro-4-methoxyphenyl)formyl-4'-pyrimidinamine as raw material, Compound 85 was synthesized according to the hydrogenation reduction method in Example 48. ^{The 1} H NMR data are shown in Table 1.

As a non-limiting example, the substituted bisaryl compound described in the present invention can be selected from the following specific compounds:

Table 1 Invention compound

<Example 85> , inhibition of HBV activity experiment

After the HepG2.2.15 cell culture flask is full of cells, it is digested and prepared to 200,000 cells per ml, inoculated into a 96-well culture plate, 100 μl per well, and cultured at 37°C with 5% CO ₂ for 24 hours. After the cells grow into a single layer, proceed experiment. After the compound samples of the present invention were formulated into different concentrations with culture medium, they were added to 96-well cell culture plates and cultured at 37° C. with 5% CO ₂ . The cells were cultured until the third day and observed with an inverted microscope. Cytopathies were recorded, 4 for complete destruction; 3 for 75%; 2 for 50%; 1 for 25%; 0 for no lesion. Calculate the half toxic concentration (TC ₅₀ ) and the maximum non-toxic concentration (TC ₀ ) according to the Reed-Muench method. The cells in the plate were extracted with a small amount of rapid DNA extraction kit, primers were added, and the level of intracellular DNA (HVB Ct value) and the level of the intracellular control gene GAPDH (GAPDH Ct value). The percent inhibition was calculated according to the following formula. Inhibition percentage%=1/2^((HBV Ct _{cell control} -HBV Ct _{drug group} )/(GAPDH Ct _{cell control} -GAPDHCt _{drug group} )×100%, half inhibitory concentration (IC ₅₀ ) was calculated by Reed-Muench method.

The results are listed in Table 2.

<Example 86> , Inhibition of HCV Activity Determination Experiment

Toxicity of compounds to Huh7.5 cells: 1×10 ⁵ /mL Huh7.5 cells were inoculated into 100 μL of 96-well cell culture plates, and cultured in an incubator at 37°C, 5% CO ₂ and saturated humidity for 6 hrs, Add different concentrations of the compound liquid of the present invention and the positive control drug (α-interferon) respectively, after continuing to cultivate for 96hrs, add 10 μ L of 5mg/mL MTT to each well, continue to cultivate for 4 hours, after lysing with DMSO, place in a microplate reader Measure the OD 570nm value above, compare with the OD value of the cell control group, calculate the toxicity inhibition rate of each concentration to the cells, and use the Reed-Muench method to calculate the half toxic concentration of the drug to the cells.

Anti-HCV activity of the compound in cell culture: 1×10 ⁵ /mL Huh7.5 cells were inoculated into 100 μL in a 96-well cell culture plate, and cultured in an incubator at 37°C, 5% CO ₂ and saturated humidity for 6 hrs, While infecting Huh7.5 cells with the virus solution containing the recombinant full-gene HCV virus particles, add different concentrations of the compound solution of the present invention or the positive control drug respectively, and after continuing to cultivate for 96hrs, extract the total RNA in the cells respectively, and quantify it with a one-step method The content of HCV RNA in the cells was measured by RT-PCR, and compared with the RNA level of the virus control group, the inhibitory rate of each concentration to HCV was calculated, and the half effective concentration of the drug inhibiting HCV was calculated by the Reed-Muench method. See Table 2 for the results.

The inhibitory activity of table 2 inventive compound to HBV and HCV

<Example 87>, HIV-1 inhibitory activity assay experiment

Add 8 different dilution concentrations of the compound of the present invention and the positive control solution to the 96-well cell culture, repeat each dilution for ² wells, and set up the cell control; 96-well cell culture plate. They were cultured in an incubator at 37°C, 5% CO ₂ and saturated humidity, and the cytopathic changes were observed every day. According to the operating steps provided by the HIV-1P24 antigen kit, measure the HIV-1P24 antigen content in the cell culture supernatant on the 4th day (96 hours) after adding the drug, and calculate the inhibitory activity of the drug on the virus. The initial concentration of the compound of the present invention is 1 μg/ ml, see Table 3 for the measurement results. The concentration of the control drug zidovudine was 0.15 ng/ml, and its assay result was IC ₅₀ <0.0005 μM.

The anti-HIV activity of table 3 invention compound

NO. x Y R ₂ R ₃ R ₆ R ₇ R ₈ R _{9 IC50} (μM) 1 CO NH COCH ₂ CH ₃ OCH ₃ h OCH ₃ OCH ₃ OCH ₃ 0.058 5 CO NH h OCH ₃ h OCH ₃ OCH ₃ OCH ₃ 0.073 36 CO NH COCF ₃ OCH ₃ h OCH ₃ OCH ₃ OCH ₃ ＜0.032 35 CO NH COCH ₂ CH ₃ OCH ₃ h h OCH ₃ h 0.053 2 CO NH COCH ₂ CH ₃ OCH ₃ h h Cl h 0.041 67 CO NH h OCH ₃ h h h h ＜0.0566 34 CO o COCH ₂ CH ₃ OCH ₃ h OCH ₃ OCH ₃ OCH ₃ 0.077 40 CO o h OCH ₃ h OCH ₃ OCH ₃ OCH ₃ 0.166 41 CO o COCF ₃ OCH ₃ h OCH ₃ OCH ₃ OCH ₃ 0.128 39 CO o COCH ₂ CH ₃ OCH ₃ h h OCH ₃ h 0.091

<Example 88> , anti-EV71 virus and coxsackie (Coxaskies) virus activity assay

Vero cell species 96-well culture plate, infect virus (EV71 virus, Coxsackie A16, B3 or B6 virus) about 100TCID ₅₀ after 24 hours, absorb for 2 hours, discard virus liquid, add the compound sample containing different concentrations of the present invention and positive The maintenance solution of the contrast drug ribavirin (RBV), and the virus control without drug addition and the cell control without virus infection were set at the same time. ), using the Reed-Muench method to calculate the half inhibitory concentration (IC ₅₀ ) of the sample to the virus respectively, the IC ₅₀ of the contrast drug RBV to the three strains of Coxsackie virus was 412.26 μg/ml, and the compound results of the present invention are listed in Table 4.

<Example 89> , anti-influenza virus activity assay

MDCK cells were inoculated into 96-well culture plates, and cultured at 37° C. for 24 hours in 5% CO ₂ . Add about 100 TCID ₅₀ of influenza virus (type A/H1N1, A/H3N2 or B/13/79) to MDCK cells, absorb at 37°C for 2 hours, pour off the virus solution, and add different dilutions of the compound of the present invention or positive control drug Bavirin maintenance solution. At the same time, a virus control without drug addition and a cell control without virus infection were set up, cultivated at 37°C until the degree of pathological changes (CPE) of the virus control group (CPE) reached 4+, observed the degree of pathological changes (CPE) of each group (about 36 hours), and calculated the Anti-influenza virus half inhibitory concentration (IC ₅₀ ), the IC ₅₀ of the control drug RBV to influenza virus A/H1N1, A/H3N2 or B/13/79 type is 1.43, 1.71 and 5.75 μg/ml, the results of the compound of the present invention can be found in Table 4.

The inhibitory activity of table 4 inventive compound to multiple strains of virus

*ND means not determined.

As can be seen from Table 4, 49 compounds have inhibitory activity to at least 3 strains; 55 compounds have inhibitory activity to at least 1 strain in the above-mentioned two major classes of viruses; 34 compounds have inhibitory activity to the above two types of viruses At least one of the four gastrointestinal viruses showed inhibitory activity in vitro; 54 compounds showed inhibitory activity against at least one influenza virus. It can be seen that these compounds generally have antiviral activity.

Claims (12)

1. replacement bi-aromatic compounds or its pharmaceutical salts with structure shown in following logical formula IV are preparing the application in broad-spectrum antiviral medicament, and described virus is hepatitis B virus, hepatitis C virus, Respirovirus or enterovirus:

Wherein: X representative-C (O)-, Y represents-N (R ₁₂)-; Described R ₁₂represent hydrogen, the phenyl sulfonyl of replacement or the phenylacyl of replacement, described replacement is the C1-C6 alkyl of unit or multidigit, C1-C6 alkoxyl group, amino, nitro, C1-C6 alkyl amido replaced;

R ₂for NR ₁₃r ₁₄, described R ₁₃, R ₁₄represent respectively hydrogen, C1-C6 alkyl, C1-C6 alkyl acyl, halo C1-C6 alkyl acyl, or

R ₃for methoxyl group;

R ₆, R ₇, R ₈and R ₉to can be the same or different when independently existing separately, represent hydrogen respectively, aryl, halo C1-C6 alkyl or phenyl-S-that aryl that halogen, nitro, amino, C1-C6 alkyl, C1-C6 alkoxyl group, benzsulfamide replace, para toluene sulfonamide replace, or R ₇with R ₈common composition-O-CH ₂-CH ₂-O-.

2. apply as claimed in claim 1, wherein:

X represent-C (O)-, Y representative-NH-;

R ₂for NR ₁₃r ₁₄, described R ₁₃, R ₁₄represent hydrogen, C1-C6 alkyl acyl, trifluoroacetyl group respectively;

R ₃for methoxyl group;

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

3. apply as claimed in claim 2, wherein:

X represent-C (O)-, Y representative-NH-;

R ₂for NR ₁₃r ₁₄, described R ₁₃for R during hydrogen ₁₄for propionyl or trifluoroacetyl group, or R ₁₃and R ₁₄be propionyl;

R ₃for methoxyl group;

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

4. apply as claimed in claim 1, described compound is

(3-propionamido-4-anisole) formyl-(3 ', 4 ', 5 '-trimethoxy-benzene) amine

(3-propionamido-4-anisole) formyl-(4 '-chlorinated benzene) amine

(3-trifluoroacetamido-4-anisole) formyl-(4 '-chlorinated benzene) amine

(3-amino-4-methoxyl benzene) formyl-(3 ', 4 ', 5 '-trimethoxy benzene) amine

(3-propionamido-4-anisole) formylaniline

(3-propionamido-4-anisole) formyl-(4 '-methylbenzene) amine

(3-propionamido-4-anisole) formyl-(4 '-trifluoromethylbenzene) amine

(3-propionamido-4-anisole) formyl-(2 '-chlorinated benzene) amine

(3-propionamido-4-anisole) formyl-(4 '-fluorobenzene) amine

(3-propionamido-4-anisole) formyl-(4 '-bromobenzene) amine

(3-propionamido-4-anisole) formyl-(3 '-chlorinated benzene) amine

(3-propionamido-4-anisole) formyl-(2 ', 4 '-dichlorobenzene) amine

(3-(N-Cbz-valyl) amino-4-methoxyl benzene) formylaniline

(3-valyl amino-4-methoxyl benzene) formylaniline

(3-(2 '-bromine propionyl) amino-4-methoxyl benzene) formylaniline

(3-(2 '-chlorine propionyl) amino-4-methoxyl benzene) formylaniline

(3-trifluoroacetamido-4-anisole) formyl-4 '-5-trifluoromethylaniline

(3-(2 '-bromine propionyl) amino-4-methoxyl benzene) formyl-(4 '-trifluoromethylbenzene) amine

(3-propionamido-4-anisole) methanoyl-(3 ', 4 ', 5 '-trimethoxy) benzene

(3-propionamido-4-anisole) formyl-(4 '-anisole) amine

(3-trifluoroacetamido-4-anisole) formyl-(3 ', 4 ', 5 '-trimethoxy) amine

(3-propionamido-4-anisole) formyl-(3 '-methylthio phenyl) amine

(3-propionamido-4-anisole) formyl-(3 ', 4 '-ethylenedioxy base benzene) amine

3-amino-4-methoxyl benzanilide

(3-propionamido-4-anisole) formyl-4 '-aminopyrimidine

(3-propionamido-4-anisole) formyl-2 '-(4 ', 6 '-dimethoxypyridin) amine

(3-amino-4-methoxyl benzene) formyl-2 '-(4 ', 6 '-dimethoxypyridin) amine

(3-(2 "-bromo propionyl) amino-4-methoxyl benzene) formyl-2 '-(4 ', 6 '-dimethoxypyridin) amine

(3-amino-4-methoxyl benzene) formyl-(4 '-amino-benzene) amine

(3-propionamido-4-anisole) formyl-(4 '-amino-benzene) amine

N, N '-(3-nitro-4-anisole) formyl-2 '-(4 '-itrile group pyridine) amine

(3-propionamido-4-anisole) formyl-2 '-(4 '-itrile group pyridine) amine

N, N '-(3-propionamido-4-anisole) formyl-2 '-(4 '-itrile group pyridine) amine

3-propionyloxy-4-methoxybenzoyl-(3 ', 4 ', 5 '-trimethoxy) aniline

(3-amino-4-methoxyl benzene) formyl-4 '-PYRIMITHAMINE.

5. the application as described in any one of claim 1-4, described pharmaceutical salts refers to that described replacement bi-aromatic compounds, with acid, the product of salt-forming reaction occurs, and comprises inorganic acid salt and organic acid salt.

6. apply as claimed in claim 5, described inorganic acid salt is hydrochloride, hydrobromate or vitriol; Organic acid salt is acetate, lactic acid salt, succinate, fumarate, maleate, Citrate trianion, benzoate, mesylate or paratolunitrile salt.

7. apply as claimed in claim 1, described Respirovirus refers to influenza virus.

8. apply as claimed in claim 7, described influenza virus comprises first, second, the third three type influenza virus and avian influenza virus.

9. apply as claimed in claim 1, described enterovirus refers to Coxsackie virus.

10. apply as claimed in claim 9, described Coxsackie virus comprises coxsackie virus A 16-type, Coxsackie virus type B3 and Coxsackie B virus 6 type.

11. apply as claimed in claim 1, and described enterovirus refers to new enterovirus.

12. apply as claimed in claim 11, and described new enterovirus is EV71 virus.