CN104447585B

CN104447585B - Pyrazine compounds and combinations thereof thing and purposes

Info

Publication number: CN104447585B
Application number: CN201410674909.5A
Authority: CN
Inventors: 张健存; 任青云; 刘辛昌; 罗慧超; 张英俊
Original assignee: Guangdong HEC Pharmaceutical
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2014-11-20
Filing date: 2014-11-20
Publication date: 2016-08-24
Anticipated expiration: 2034-11-20
Also published as: CN104447585A

Abstract

The present invention relates to a kind of pyrazine compounds and as the purposes of medicine, the especially application in preparing the medicine preventing and treating various influenza virus.Particularly, the present invention relates to logical compound shown in formula (I) or its stereoisomer, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug, each variable is defined as in the description.The invention still further relates to the salt purposes as medicine of logical compound shown in formula (I) or its stereoisomer, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug, especially as being used for preventing and treating the purposes of the medicine of influenza virus.

Description

Pyrazine compounds and combinations thereof thing and purposes

Technical field

The present invention relates to a kind of pyrazine compounds and the purposes as medicine thereof, it is anti-that the compounds of this invention is applicable to preparation The purposes of virus drugs.The invention still further relates to comprise the pharmaceutical composition of these compounds, and be directed to use with described compound, It is used alone or uses with other drug combination, prevent and treat the application of various virus, especially prevent and treat influenza disease The application of poison.

Background technology

Influenza (influenza is called for short influenza) is the ARI that influenza virus causes, and is also a kind of The disease that infectiousness is strong, spread speed is fast.Its mainly by the spittle in air, interpersonal contact or with contaminated thing The contact transmission of product.Typical clinical symptoms are: anxious high heat, overall pain, the most weak and slight respiratory symptom.Typically Autumn and winter season is its high-incidence season, and caused complication and the phenomena of mortality are the most serious.

Research to anti-influenza virus medicament in recent years achieves greater advance, and different anti-influenza virus medicaments is in preventing and treating Effect in influenza is different.M2 ionophorous protein inhibitor (such as Buddha's warrior attendant gastral cavity amine and Rimantadine) is that the influenza listed the earliest is faced Bed medicine, but also exist resistance strain ratio increase and to Type B influenza virus unit effect property limitation.Neuraminic acid It is to explore the breakthrough in resisiting influenza virus grass drug research at present that enzyme inhibitor is succeeded in developing, sick to first, influenza B Poison all has inhibitory activity, such as, first medication when Oseltamivir is to prevent and treat bird flu and occur Human Influenza popular, But, in recent years, researcher all over the world is found that H1N1, H5N1, H3N2 that Oseltamivir creates resistance successively And Type B influenza virus.Other anti-influenza virus medicament roots the most all have preferably to the inhibitory action of virus and disease-resistant Poison application prospect, but often need demonstration further.

Owing to the extensively application clinically of existing medicine makes influenza virus morph, these medicines are created not Drug resistance with degree.The most novel anti-influenza virus medicament research and development are very urgent.

The invention provides a kind of novel antiviral compound, various viruses, especially influenza virus are had pre-by it Anti-effect and therapeutic action.

Summary of the invention

The present invention relates to a kind of novel pyrazine compounds and its pharmaceutical composition, and each in preparation prevention and treatment Plant virus, the especially purposes in influenza virus medicine.

On the one hand, the present invention relates to a kind of compound, it is the compound as shown in formula (I), or its stereoisomer, several What isomers, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,

Wherein, R¹For C_6-10Aryl or-NHC (=O)-C_6-10Aryl；

R²For hydrogen ,-CN, F, Cl, Br, I, C_1-3Alkyl, C_1-3Alkoxyl, hydroxyl, amino or C_1-3Alkylamino；With

N is 0,1 or 2；

Wherein, described C_6-10Aryl or-NHC (=O)-C_6-10C in aryl_6-10Aryl can the most optionally by 1,2 or 3 are selected from hydrogen, hydroxyl, C_1-3Alkyl, amino, F, Cl, Br, I, C_1-3The substituent of alkoxyl is replaced.

In some embodiments, wherein

R¹For phenyl or-NHC (=O)-phenyl；With

R²For hydrogen ,-CN, F, Cl, Br, I, methyl, ethyl, methoxyl group, ethyoxyl, hydroxyl, amino, N-methylamino, N-second Amino or N, N-dimethylamino；

Wherein, the phenyl in described phenyl or-NHC (=O)-phenyl can the most optionally by 1,2 or 3 selected from hydrogen, Hydroxyl, methyl, ethyl, amino, F, Cl, Br, I, methoxyl group, the substituent of ethyoxyl are replaced.

The present invention relates to compound or its stereoisomer of one of, geometric isomer, dynamic isomer, Nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug,

On the one hand, present invention also offers a kind of pharmaceutical composition containing compound of the present invention, this drug regimen Thing contains compound of the present invention, and pharmaceutically acceptable carrier, excipient, diluent, assistant agent, medium or Combinations thereof.

In certain embodiments, it further comprises other anti-influenza virus medicament, wherein said anti influenza Virus drugs be Peramivir, zanamivir, Oseltamivir, that Ni Na meter Wei, Favipiravir, amantadine, Rimantadine, Ah Than Dorr, Ribavirin, Si Tafulin, ingavirin (Ingavirin), GR-217029 or a combination thereof.

On the other hand, present invention also offers described compound or described pharmaceutical composition preparation for preventing, processing, Treat or alleviate the purposes in patient's influenza virus medicine.

Preparation that another aspect of the present invention relates to the compound that formula (I) is comprised, the method separating and purifying.

The present invention also comprises compound and the stereoisomer thereof of the present invention, geometric isomer, dynamic isomer, and nitrogen aoxidizes The application of thing, hydrate, solvate, metabolite, or its pharmaceutically acceptable salt, is used for producing medical product and effectively presses down Influenza virus processed, the compound of the present invention is producing the application effectively suppressed in influenza virus.The compound of the present invention is used equally It is used for alleviating in producing a kind of pharmaceuticals, stops, control or treat patient's influenza infection.The present invention comprises drug regimen Thing, this pharmaceutical composition includes the compound representated by formula (I) and at least one pharmaceutically acceptable carrier, assistant agent or dilution Consumption is effectively treated needed for the combination of agent.

The present invention comprises the disease of effective influenza virus, or the method sensitive to this illness equally, and the method comprises use Representated by formula (I), patient is treated by the therapeutically effective amount of compound.

Unless other aspects show, all of stereoisomer of compound of the present invention, geometric isomer, tautomerism Body, nitrogen oxides, hydrate, solvate, metabolite, salt and pharmaceutically acceptable prodrug broadly fall into the model of the present invention Enclose.

Specifically, salt is pharmaceutically acceptable salt.Term " pharmaceutically acceptable " includes that material or composition must Must be to be suitable for chemistry or toxicology, relevant with other components of composition preparation and the mammal for treating.

The salt of the compound of the present invention also includes intermediate or formula (I) for preparing or purify compound shown in formula (I) The salt of the enantiomter that shown compound separates, but it is not necessarily pharmaceutically acceptable salt.

If the compound of the present invention is alkaline, the most conceivable salt can by provide on document any suitably Method prepares, and such as, uses inorganic acid, example hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid etc..Or use organic Acid, such as acetic acid, maleic acid, butanedioic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, malic acid, Lactic acid citric acid, Oxalic acid, glycolic and salicylic acid；Pyrans saccharic acid, such as glucuronic acid and galacturonic acid；Alpha-hydroxy acid, such as citric acid and winestone Acid；Amino acid, such as asparatate and glutamic acid；Aromatic acid, such as benzoic acid and cinnamic acid；Sulfonic acid, such as p-methyl benzenesulfonic acid, benzene Sulfonic acid, methanesulfonic acid, ethyl sulfonic acid, TFMS etc. or combinations thereof.

If the compound of the present invention is acid, the most conceivable salt can be prepared by suitable method, e.g., Use inorganic base or organic base, such as ammonia (primaquine, parahelium, tertiary ammonia), alkali metal hydroxide, ammonium, N⁺(R¹⁴)₄Salt and alkaline earth gold Belong to hydroxide, etc..Suitably salt includes, but is not limited to, the organic salt obtained from amino acid, such as glycine and essence ammonia Acid, ammonia, such as primaquine, parahelium and tertiary ammonia, N⁺(R¹⁴)₄Salt, such as R¹⁴It is H, C_1-4Alkyl, C_6-10Aryl, C_6-10Aryl C_1-4Alkyl Deng, and ring-type ammonia, such as piperidines, morpholine and piperazine etc., and obtain inorganic salts from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium. Also the amine cation that suitable, nontoxic ammonium, quaternary ammonium salt and gegenions are formed is included, such as halide, hydroxide, carboxylation Thing, hydrosulphate, phosphoric acid compound, nitric acid compound, C_1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.

Detailed description of the invention book

Definition and general terms

Certain embodiments of the present invention be will now be described in more detail, and the example is by the structural formula enclosed and chemical formula explanation.This Invention intention contains all of replacement, amendment and equivalent technical solutions, and they are included in such as the present invention of claim definition In the range of.Those skilled in the art will appreciate that many similar with the described herein or method of equivalent and material can be used in reality Trample the present invention.The present invention is not limited to method described herein and material.At the document combined, patent and similar material one Or many different from the application or conflicting in the case of (include but not limited to defined term, term application, described Technology, etc.), be as the criterion with the application.

It will further be appreciated that some feature of the present invention, for clearly visible, carry out in multiple independent embodiments Describe but it also may provide in combination in single embodiment.Otherwise, the various features of the present invention, for brevity, Single embodiment is described but it also may individually or with the sub-portfolio being arbitrarily suitable for provide.

Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood that identical implication.The all patents that the present invention relates to and public publication are integrally incorporated this by reference Bright.

Unless otherwise indicated, it should apply following definition used herein.For purposes of the present invention, chemical element with Periodic table of elements CAS version, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle can be joined Examine " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Description in Wiley&Sons, New York:2007, entire contents is incorporated herein by.

Context except as otherwise noted or has significantly conflict, article used herein " ", " one (kind) " " described " is intended to include " at least one " or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.Such as, " component " refers to one or more component, it is possible to have more than one Component be taken into account in the embodiment of described embodiment and use or use.

Term used in the present invention " study subject " refers to animal.The most described animal is mammal.Tested right As, the most also refer to primate (the such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, little Mouse, fish, bird etc..In certain embodiments, described study subject is primate.In other embodiments, described it is subject to Try liking people.

The present invention says that the term " patient " of use refers to people's (including adult and children) or other animals.Implement at some In scheme, " patient " refers to people.

It is open language that term " comprises ", i.e. includes the content specified by the present invention, but is not precluded from otherwise Content.

Stereochemical definitions used in the present invention and rule typically follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York；and Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley&Sons, Inc., New York, 1994.

Many organic compounds exist with optical active forms, and i.e. they have and make the plane of linearly polarized light rotate Ability.When describing optically active compound, prefix D and L or R and S is used to represent that molecule is about one or more hand The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols rotated for linearly polarized light caused by appointed compound, Wherein (-) or l represent that compound is left-handed.Prefix for (+) or the compound of d be dextrorotation.A kind of concrete alloisomerism Body is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50:50 mixture of enantiomter Be referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereoselectivity or stereospecificity time, May occur in which this situation.

Come into the open any asymmetric atom (such as, carbon etc.) of compound of the present invention can be enriched with racemic or enantiomer Presented in, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration aspect there is at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer Excess.

According to starting material and the selection of method, the compounds of this invention can with in possible isomers or they Mixture, the such as form of racemic modification and non-enantiomer mixture (this depends on the quantity of asymmetric carbon atom) is deposited ?.Optically active (R)-or (S)-isomers can use chiral synthon or chiral reagent to prepare, or use routine techniques to tear open Point.If compound contains a double bond, substituent may be E or Z configuration；If containing dibasic cycloalkanes in compound Base, the substituent of cycloalkyl may have cis or trans configuration.

The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties Pure or the purest geometric isomer, enantiomter, diastereoisomer, such as, by chromatography and/or fractional crystallization Method.

By known method, the racemic modification of any gained end-product or intermediate can be passed through those skilled in the art The method being familiar with splits into optical antipode, e.g., by separating its diastereoisomeric salt obtained.Racemic product Thing can also be separated by chiral chromatogram, e.g., uses the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomers can be prepared by asymmetric syntheses, such as, refers to Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2^ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。

As described in the invention, the compound of the present invention can optionally be replaced by one or more substituents, as General formula compound above, the particular compound of the present invention, or as example special inside embodiment, subclass, and institute of the present invention The compounds comprised.Should be appreciated that term " optionally substituted " and term " substituted or non-substituted " can exchange use.One For as, term " substituted ", represent that the one or more hydrogen atoms in given structure are replaced by concrete substituent.Unless its He shows aspect, and an optional substituted radical can replace in each commutable position of group.When given knot In structure formula, more than one position can be selected from one or more substituents of concrete group and replaced, then substituent can be identical Or differently replace in each position.Wherein said substituent it may be that but be not limited to: hydrogen, hydroxyl, C_1-3Alkyl, ammonia Base, F, Cl, Br, I, C_1-3Alkoxyl etc..

At each several part of this specification, the come into the open substituent of compound of the present invention is open according to radical species or scope.Special Not pointing out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.Such as, term “C_1-6Alkyl " refer in particular to individually disclosed methyl, ethyl, C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkyl.

At each several part of the present invention, describe connection substituent.When this structure clearly needs linking group, for this Ma Kushi variable cited by group is interpreted as linking group.Such as, if this structure needs linking group and for this The Ma Kushi group definition of variable lists " alkyl " or " aryl ", then it should be understood that should " alkyl " or " aryl " represent respectively The alkylidene group connected or arylene group.

Terminology used in the present invention " alkyl " or " alkyl group ", represent containing 1 to 20 carbon atom, saturated straight chain or Side chain univalent hydrocarbyl group, wherein, the substituent institute that described alkyl group can optionally be described by one or more present invention Replace.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1- 12 carbon atoms；In another embodiment, alkyl group contains 1-6 carbon atom；In yet another embodiment, alkyl group Containing 1-4 carbon atom；The most in one embodiment, alkyl group contains 1-3 carbon atom.

The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH₃), ethyl (Et ,-CH₂CH₃), n-pro-pyl (n- Pr、-CH₂CH₂CH₃), isopropyl (i-Pr ,-CH (CH₃)₂), normal-butyl (n-Bu ,-CH₂CH₂CH₂CH₃), isobutyl group (i-Bu ,- CH₂CH(CH₃)₂), sec-butyl (s-Bu ,-CH (CH₃)CH₂CH₃), the tert-butyl group (t-Bu ,-C (CH₃)₃), n-pentyl (- CH₂CH₂CH₂CH₂CH₃), etc..

Term " alkoxyl " represents that alkyl group is connected with molecule remainder by oxygen atom, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom.An embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom；? In another embodiment, alkoxy base contains 1-3 carbon atom.Described alkoxy base can be the most one or more The substituent that the present invention describes is replaced.

The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH₃), ethyoxyl (EtO ,- OCH₂CH₃), 1-propoxyl group (n-PrO, n-propoxyl group ,-OCH₂CH₂CH₃), 2-propoxyl group (i-PrO, i-propoxyl group ,-OCH (CH₃)₂), 1-butoxy (n-BuO, n-butoxy ,-OCH₂CH₂CH₂CH₃), 2-methyl-l-propoxyl group (i-BuO, i-fourth oxygen Base ,-OCH₂CH(CH₃)₂), etc..

Term " alkyl amino " or " alkylamino " include " N-alkyl amino " and " N, N-dialkyl amido ", wherein amino base Group is separately replaced by one or two alkyl group.Some of them embodiment is, alkyl amino is one or two C_1-6The alkylamino group of the lower level that alkyl is connected on nitrogen-atoms.Other embodiment is, alkyl amino is C_1-3's The alkylamino group of lower level.Suitably alkylamino group can be alkyl monosubstituted amino or dialkyl amido, such reality Example includes, but is not limited to, N-methylamino, N-ethylamino, N, N-dimethylamino, etc..

Term " aryl " represents containing 6-14 annular atoms, or 6-12 annular atoms, or the monocycle of 6-10 annular atoms, double Ring and the carbocyclic ring system of three rings, wherein, at least one member ring systems is aromatic, and it is individual former that each of which member ring systems comprises 3-7 Molecular ring, and have one or more attachment point to be connected with the remainder of molecule.Term " aryl " can be with term " fragrance Ring " exchange use.The example of aromatic yl group can include phenyl, 2,3-dihydro-1H-indenyl, naphthyl and anthracene.Described aromatic yl group The substituent that can be optionally described by one or more present invention replaces.

Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

Unless other aspects show, structural formula described in the invention includes that all of isomeric forms is (as mapping is different Structure, diastereo-isomerism, and geometrical isomerism (or conformational isomerism)): such as contain R, S configuration of asymmetric center, (Z) of double bond, (E) isomers, and (Z), the rotamer of (E).Therefore, the single three-dimensional chemical isomer of the compound of the present invention or it is right Reflect isomers, diastereoisomer, or the mixture of geometric isomer (or rotamer) and broadly fall into the scope of the present invention.

Unless other aspects show, structural formula described in the invention and described compound include all of isomerism Form (such as enantiomerism, diastereo-isomerism, geometrical isomerism or conformational isomerism), nitrogen oxides, hydrate, solvate, metabolism Product, pharmaceutically acceptable salt and prodrug.Therefore, the single three-dimensional chemical isomer of the compound of the present invention, enantiomerism Body, diastereoisomer, geometric isomer, rotamer, nitrogen oxides, hydrate, solvate, metabolite, pharmacy The compound of upper acceptable salt and prodrug falls within the scope of the present invention.It addition, unless other aspects show, the present invention is retouched The structural formula of the compound stated includes the enriched isotope of one or more different atom.

Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo. Such conversion is hydrolyzed in blood by pro-drug or is that precursor structure is affected through enzymatic conversion in blood or tissue.This Bright pro-drug compounds can be ester, and in existing invention, ester can have phenyl ester class, aliphatic as pro-drug (C_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as in the present invention one Compound comprises hydroxyl, i.e. can be acylated the compound obtaining prodrug form.Other prodrug form includes Phosphate, if these phosphate compounds are that the di on parent obtains.About complete the begging for of pro-drug Discuss and be referred to documents below: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。

" metabolite " refers to that concrete compound or its salt is in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified by technology known to art, and its activity can be retouched by such as the present invention Adopt as stating and experimentally characterize.Such product can be by passing through oxidation, reduction, water to drug compound Solving, amidated, desamido-effect, esterification, degreasing, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes compound Metabolite, be fully contacted metabolite produced by a period of time including by the compound of the present invention and mammal.

The definition of neutral body of the present invention chemistry and the use of convention are typically referenced to documents below: S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons, Inc., New York, the compound of 1994. present invention can comprise asymmetric center or chiral centre, therefore There is different stereoisomers.The all of stereoisomeric forms in any ratio of compound of the present invention, include, but not limited to, diastereomeric Body, enantiomter, atropisomer, and their mixture, such as racemic mixture, constitute the part of the present invention. A lot of organic compounds all exist with optical active forms, and i.e. they are had the ability the plane of Plane of rotation polarised light.Light is being described When learning reactive compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) use Name the symbol that compound linearly polarized light rotates, (-) or l refer to that compound is left-handed, prefix (+) or d refer to chemical combination Thing is dextrorotation.The chemical constitution of these stereoisomers is identical, but their stereochemical structure is different.Specific vertical Body isomers can be enantiomer, and the mixture of isomers is commonly referred to enantiomeric mixture.The enantiomer mixing of 50:50 Thing is referred to as racemic mixture or racemic modification, and this may cause not having stereoselectivity or three-dimensional fixed in chemical reaction process Tropism.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomters, lack light Learn activity.

Stereoisomer " refer to that there is identical chemical constitution, but the change that atom or group spatially arrangement mode is different Compound.Stereoisomer includes enantiomter, diastereoisomer, rotamer (rotational isomer), geometric isomer (cis/trans) isomers, atropisomer, etc..

Term " dynamic isomer " or " tautomeric form " refer to that the isomer of the structure of different-energy is permissible Converted mutually by low energy barrier.Such as proton tautomer (the most prototropic dynamic isomer) includes being migrated by proton Change, such as keto-enol and the isomerization of imine-enamine.Valence (chemical valence) dynamic isomer includes Reassemble into the change of bonding electron.

" chirality " is that have can not the molecule of overlapping character with its mirror image；And " achirality " refer to can be overlapping with its mirror image Molecule.

" enantiomter " refer to two of a compound can not be overlapping but be mutually the isomers of mirror.

" diastereoisomer " refers to two or more chiral centre and the alloisomerism of its molecule mirror image the most each other Body.Diastereoisomer has different physical propertys, such as fusing point, boiling point, spectral quality and reactivity.Diastereoisomer mixes Compound can be separated by high resolution analysis operation such as electrophoresis and chromatogram, such as HPLC.

" pharmaceutically acceptable salt " used in the present invention refers to organic salt and the inorganic salts of the compound of the present invention.Medicine On, acceptable salt is known to us at art, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. it is described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Additive method such as ion-exchange obtain these salt.Other pharmaceutically acceptable salts include adipate, alginates, resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2-hydroxy-ethanesulfonic acid Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalene sulphur Hydrochlorate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionic acid salt, bitter taste Hydrochlorate, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through The salt that suitable alkali obtains includes alkali metal, alkaline-earth metal, ammonium and N⁺(C_1-4Alkyl)₄Salt.The present invention is also intended to contemplate any The quaternary ammonium salt that the compound of the group of comprised N is formed.Water solubility or oil-soluble or dispersion product can be turned into by quaternary ammonium With obtaining.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt farther includes to fit When, nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulfuric acid Compound, phosphoric acid compound, nitric acid compound, C_1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.

" hydrate " of the present invention refers to that solvent molecule is the associated matter that water is formed.

" nitrogen oxides " of the present invention refers to when compound is containing several amine functional group, can be by 1 or former more than the nitrogen of 1 Son oxidation forms N-oxide.The particular example of N-oxide is N-oxide or the N-oxidation of nitrogen heterocyclic ring nitrogen-atoms of tertiary amine Thing.Available oxidant such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) process corresponding amine formation N-oxide and (see Advanced Organic Chemistry, Wiley Interscience, the 4th edition, Jerry March, pages).Especially It is that N-oxide can be prepared (Syn.Comm.1977,7,509-514) by the method for L.W.Deady, such as the most molten in inertia In agent such as dichloromethane, amines is made to react with m-chloroperoxybenzoic acid (MCPBA).

" solvate " of the present invention refers to the association that the compound of one or more solvent molecule and the present invention is formed Thing.The solvent forming solvate includes, but is not limited to, water, isopropanol, ethanol, methyl alcohol, dimethyl sulfoxide, ethyl acetate, second Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated matter that water is formed.

Any disease or illness " treated " in term as used in the present invention, and some embodiment middle fingers improve disease wherein Disease or illness (i.e. slow down or stop or palliate a disease or the development of its at least one clinical symptoms).In other embodiments In, " treatment " refers to relax or improve at least one body parameter, including the body parameter may not discovered by patient.At another In a little embodiments, " treatment " refers to (such as stablize perceptible symptom) from health or physiologically (such as stablize health Parameter) or above-mentioned two aspect regulation disease or illnesss.In other embodiments, " treat " and refer to prevention or postpone disease or disease The outbreak of disease, occur or deteriorate.

Any structural formula that the present invention is given be also intended to represent these compounds not by isotope enrichment form and with The form of position element enrichment.The compound of isotope enrichment has the structure of the formula description that the present invention provides, except one or many Individual atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes in the compounds of this invention can be introduced Including the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, as²H,³H,¹¹C,¹³C,¹⁴C,¹⁵N,¹⁷O,¹⁸O,¹⁸F,³¹P,³²P,³⁵S,³⁶Cl and¹²⁵I。

On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, such as, and its In there is radio isotope, as³H,¹⁴C and¹⁸Those compounds of F, or wherein there is non radioactive isotope, as²H and¹³C.The compound of such isotope enrichment can be used for metabolism research and (uses¹⁴C), kinetics research (uses such as²H or³H), detection or imaging technique, such as positron emission tomography (PET) or include medicine or substrate tissue measure of spread SPECT (SPECT), or can be used in the radiotherapy of patient.¹⁸The compound of F enrichment to PET or It is especially desirable for SPECT research.Compound shown in the formula (I) of isotope enrichment can be ripe by those skilled in the art Embodiment and the preparation process suitable isotope labeling reagent of described use in the routine techniques known or the present invention substitute former Carry out used unmarked reagent to prepare.

On the other hand, the present invention relates to prepare the intermediate of the compound that formula (I) is comprised.

On the other hand, the preparation that the present invention relates to the compound that formula (I) is comprised, the method separating and purifying.

On the other hand, the present invention provides a kind of pharmaceutical composition, and described pharmaceutical composition comprises the compounds of this invention, pharmacy Upper acceptable carrier, excipient, diluent, assistant agent, solvent, or combinations thereof.At some embodiments, pharmaceutical composition Can be liquid, solid, semi-solid, gel or spray-type.

Additionally, higher isotope particularly deuterium is (i.e.,²H or D) replacement can provide some treat advantage, these advantages are Brought by metabolic stability is higher.Such as, Half-life in vivo increases or volume requirements reduces or therapeutic index obtains improving band Come.Should be appreciated that the deuterium in the present invention is seen as the substituent of formula (I) compound.Can determine by the isotope enrichment factor The concentration of justice such higher isotope particularly deuterium.Term used in the present invention " the isotope enrichment factor " refers to specified same Ratio between isotope abundance and the natural abundance of position element.If the substituent of the compounds of this invention is designated as deuterium, this change Compound for each D-atom specified, have at least 3500 (each specify the deuterium of 52.5% at D-atom to mix), at least 4000 (deuterium of 60% mixes), at least 4500 (deuterium of 67.5% mixes), at least 5000 (deuterium of 75% mixes), at least 5500 The deuterium of 82.5% (mix), at least 6000 (deuterium of 90% mixes), at least 6333.3 (deuterium of 95% mixes), at least 6466.7 (deuterium of 97% mixes), at least 6600 (deuterium of 99% mixes) or the isotope enrichment of at least 6633.3 (deuterium of 99.5% mixes) The factor.The pharmaceutically useful solvate of the present invention includes that wherein recrystallisation solvent can be the substituted such as D of isotope₂O, acetone-d₆、 DMSO-d₆Those solvates.

The compounds of this invention and pharmaceutical composition, preparation and administration

Described pharmaceutical composition comprises the compound of any present invention.This pharmaceutical composition can also comprise further Pharmaceutically acceptable carrier, excipient, diluent, assistant agent, medium or a combination thereof.

Described pharmaceutical composition comprises the medicine of resisiting influenza virus further.The medicine of described resisiting influenza virus can be to appoint Other of the compounds of this invention it are different from for the medicine of anti influenza known to He.For example, it is possible to be Peramivir, Zha Na meter Wei, Oseltamivir, that Ni Na meter Wei, Favipiravir, amantadine, Rimantadine, arbidol, Ribavirin, Si Tafulin, Ingavirin (Ingavirin), GR-217029 or a combination thereof.

When can be used for treatment, the compounds of this invention of therapeutically effective amount, especially formula (I) compound and pharmaceutically may be used The salt accepted can give as unprocessed chemicals, and the active component being alternatively arranged as pharmaceutical composition provides.Therefore, this Bright content also provides for pharmaceutical composition, and this pharmaceutical composition includes this compounds of this invention of therapeutically effective amount, especially formula (I) Compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers, diluent or excipient.Herein The term " therapeutically effective amount " used refers to be enough to demonstrate that significant patient benefit's (such as viral load minimizing) is each The total amount of active component.When using single active component individually dosed, this term only refers to this composition.When combination application, No matter this term then refers to combination, when being sequentially or simultaneously administered, all cause the combined amount of the active component of result for the treatment of.The present invention Compound, especially formula (I) compound and pharmaceutically acceptable salt thereof are described above.From compatible with other compositions of preparation and To its recipient harmless in the sense that from the point of view of, carrier, diluent or excipient must be acceptable.According to present invention On the other hand, also providing for the method for preparing pharmaceutical preparation, the method includes the compounds of this invention, and especially formula (I) is changed Compound or its pharmaceutically acceptable salt mix with one or more pharmaceutically acceptable carriers, diluent or excipient.This The term " pharmaceutically acceptable " that used of invention refers to such compound, raw material, composition and/or formulation, they In the range of rational medicine judges, it is adaptable to patient tissue contacts and without excessive toxicity, excitant, allergy or with rationally The symmetrical other problems of interests/Hazard ratio and complication, and be effective to given application.

Pharmaceutical preparation can be in unit dosage forms, and each UD contains the active component of scheduled volume.The change of present invention The dosage level of compound is between about 0.01 mg/kg (mg/kg) body weight/day and about 250 mg/kg body weight/day, excellent Selected introductions, between about 0.05mg/kg body weight/day and about 100mg/kg body weight/day, usually are used for preventing or treating with monotherapy The disease of influenza virus mediation.Generally can be by every day about 1 to about 5 time or the medicine giving present invention as continuous infusion Composition.This kind of dose regimen can be used as long-term or short-term therapy.Mix with carrier material to prepare the active component of single formulation Amount by according to disease to be treated, the order of severity of disease, administration time, method of administration, the discharge rate of compound used therefor, Treatment time and patient age, sex, body weight and situation and change.Preferably unit dosage forms is containing hereinbefore active component Daily dose or divided dose or the unit dosage forms of its appropriate fraction.The available low dose being already clearly below compound optimal dose starts Treatment.Hereafter, escalated dose is carried out with less increment until reaching optimum efficiency in this case.It is said that in general, it is the most preferable To give the concentration level of compound be generally effective result can be provided any harmful without regard to causing at anti-virus aspect Or poisonous side effect.

When the composition of present invention comprise the compound of present invention and one or more other treatment medicines or During the combination of prophylactic agent, the dosage level of compound and other medicine, generally in monotherapy scheme, accounts for normal administration The about 10-150% of dosage, more preferably accounts for the about 10-80% of bio-occlusion pharmaceutical quantities.Pharmaceutical preparation is suitable to by any suitable way Footpath is administered, such as by oral (including oral cavity or sublingual), rectum, nose, locally (include oral cavity, sublingual or percutaneous), vagina or Parenteral (in including subcutaneous, intracutaneous, intramuscular, joint, in intrasynovial, breastbone, in sheath, in focus, intravenous or corium bet Penetrate or infusion) approach.This kind of preparation can be prepared, such as by by active component and load by any known method of art of pharmacy Body or excipient mixing.Preferred oral is administered or drug administration by injection.

The pharmaceutical preparation being suitable to oral administration is provided by independent unit, such as capsule or tablet；Powder or granule； Solution in aqueous or non-aqueous liquid or supensoid agent；Edible foam formulations or foaming preparations (whip)；Or oil-in-water breast Liquor or water in oil emulsion liquor.

For example, for oral administration in the form of a tablet or capsule, active medicine component can with pharmaceutically can connect The oral, non-toxic inert carrier (such as ethanol, glycerine, water etc.) being subject to mixes mutually.By compound powder being broken into suitable fine chi Very little, and with by as pulverize pharmaceutical carrier (edible carbohydrate such as such as starch or mannitol etc.) mixing prepare powder.Also Flavouring, preservative, dispersant and colouring agent can be there is.

By preparing pulverulent mixture as above, and it is loaded in the gelatin shell of shaping, prepares capsule.At dress Before filling out operation, can be by glidant and lubricant (such as colloidal silica, talcum powder, magnesium stearate, calcium stearate or solid-state Polyethylene glycol) it is added in pulverulent mixture.Also can add when the lower capsule of clothes by improve medicine utilizability disintegrant or Solubilizer (such as agar, calcium carbonate or sodium carbonate).

When needing in addition or be required, it is possible to suitable adhesive, lubricant, disintegrant and colouring agent are mixed mixture In.Suitably adhesive includes starch, gelatin, natural sugar (such as glucose or beta lactose), corn sweetener, natural and synthesis Natural gum (such as gum arabic, tragacanth or mosanom), carboxymethylcellulose calcium, polyethylene glycol etc..For these formulations Lubricant includes enuatrol, sodium chloride etc..Disintegrant includes, but are not limited to starch, methylcellulose, agar, bentonite, xanthan Glue etc..Such as, by making pulverulent mixture, pelletize or pre-compressing tablet, add lubricant and disintegrant, tabletted, thus make Piece agent.By the compound suitably pulverized and diluent as described above or base-material, optional and adhesive (such as carboxymethyl fibre Dimension element, alginates, gelatin or polyvinylpyrrolidone), dissolve inhibitor (such as paraffin), absorption accelerator (quaternary salt) and/or Absorbent (such as bentonite, kaolin or Dicalcium Phosphate) mixes, and prepares pulverulent mixture.Useful binders (such as syrup, shallow lake Slurry, mucialga of arabic gummy (acadiamucilage) or cellulosic material or polymeric material solution) pressurize and sieve, by powder after wetting Shape granulating mixture.The alternative pelletized is, can be by pulverulent mixture by tablet press machine, and result is the best by formation Agglomerate smashes and makes particle.Can be by adding stearic acid, stearate, talcum powder or mineral oil make particle lubrication to prevent from gluing On the punch die of tablet press machine.Then by the mixture tabletted through lubrication.The compound of present invention also can be with free stream Dynamic inert carrier mixing, it is not necessary to just can tabletted by granulation or pre-tableting step.Can provide transparent or opaque by The protectiveness bag that shellac seal coat, sugar-coat or polymeric material clothing and wax polishing clothing (polish coating of wax) form Clothing material.Can be added to dyestuff in these coating materials distinguish different UDs.

Oral liquid such as solution, syrup and elixir can be prepared with dosage unit form, thus specified rate contains There is the compound of scheduled volume.Syrup can be prepared by being dissolved in the suitably seasoned aqueous solution by compound, and elixir can lead to Cross use non-toxic vehicle to prepare.Also can add solubilizer and emulsifying agent (such as ethoxylated isostearyl alcohols and polyoxyethylene mountain Pears alcohol ether), preservative, flavoring additive (such as peppermint oil or natural sweetener or saccharin or other artificial sweeteners) etc..

If appropriate, the dosage unit preparations microencapsulation of oral administration can be used for.Also preparation can be made and prolong Time or sustained release, such as by coating or be embedded in the microparticle material such as polymer, wax.

The compounds of this invention, especially formula (I) compound and pharmaceutically acceptable salt thereof can pass medicine system with liposome System gives, such as small unilamellar vesicle, big unilamellar liposome and multilamellar liposome.Liposome can (such as courage be solid by multiple phosphatide Alcohol, octadecylamine or phosphatid ylcholine) constitute.

The compounds of this invention, especially formula (I) compound and pharmaceutically acceptable salt thereof also can be by using monoclonal Antibody passs medicine as single carrier (compound molecule is coupled).Compound also can with as can target medicine carrier can Soluble polymer coupling.This base polymer can include polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropyhnethacrylamide Phenol, polyhydroxyethylaspart or the polyethylene-oxide polylysine replaced by palmitoyl residues.Additionally, compound can With a class Biodegradable polymeric coupling, for reaching the controlled release of medicine, this base polymer such as PLA, poly-ε-oneself in Ester, poly butyric, poe, polyacetals, poly-dihydropyran, polybutylcyanoacrylate and the cross-linked copolymer of hydrogel or Amphipathic nature block polymer.

The pharmaceutical preparation being suitable to percutaneous dosing can be as discrete patch (discrete patch) to protect in a long time Hold and recipient's epidermis close contact.Such as, active component can be passed medicine by by electro-ionic osmosis patch, generally can be found in Pharmaceutical Research 1986,3(6),318。

The pharmaceutical preparation being suitable to topical can be made into ointment, cream, supensoid agent, lotion, powder, solution, paste Agent, gel, spray, aerosol, oil formulation or transdermal patch.

The pharmaceutical preparation being suitable to rectally can be as suppository or as enema offer.

The pharmaceutical preparation (wherein carrier is solid) being suitable to nose administration includes that particle diameter is such as 20-500 micrometer range Dust base, by being administered in snuffing mode, is i.e. quickly sucked from close to the dust base container of nose by nasal passage.Wherein carry Body is liquid, be adapted as nasal mist or appropriate formulation that nasal drop is administered includes aqueous solution agent or the oil of active component Property solution.

Be suitable to the pharmaceutical preparation by inhalation and include minuteness particle pulvis (dust) or mist agent (mist), can use not Dosage compresed gas aerosol, nebulizer, insufflator or other matters with type metering deliver the device of aerosol spray Middle preparation.

The pharmaceutical preparation being suitable to vagina administration can be with vaginal plug, vagina plug, cream, creme, gel, paste, foam Agent or spray provide.

Be suitable to the pharmaceutical preparation of parenteral and include aqueous and non-aqueous sterile injection solution and aqueous and non-aqueous Sterile suspensions, aqueous and non-aqueous sterile injection solution can contain antioxidant, buffer, bacteriostatic agent and make described preparation The solute isotonic with receptor's blood waiting, aqueous and non-aqueous sterile suspensions can include suspending agent and thickener.Preparation is permissible UD or multi-dose container provide, and the peace such as sealed is triumphant and bottle, and under the conditions of freeze-drying (being lyophilized) can be saved in, Only need to add sterile liquid carrier, such as water for injection before use.The injection solution and the supensoid agent that face used time configuration can be by Prepared by sterile powder injection, granule and tablet.

It will be appreciated that in addition to the composition being particularly mentioned above, preparation also includes relevant with described preparation type Other composition commonly used in the art, this kind of preparation being for example suitable for oral administration can include flavouring.

The compounds of this invention and the purposes of pharmaceutical composition

The feature of the pharmaceutical composition of the present invention includes the compound of formula (I), the compound listed by the present invention, or implements The compound of example 1-2, and pharmaceutically acceptable carrier, assistant agent, or excipient.In the composition of the present invention, compound can be effective The ability of suppression influenza virus, it is adaptable to the prevention of influenza virus and treatment.

Comprise the compounds of this invention or the methods for the treatment of of pharmaceutical composition administration, farther include that patient is administered other and resist The medicine of influenza, thus, it is possible to the medicine of the compound of the present invention Yu other anti influenza to be carried out therapeutic alliance, wherein said anti- The medicine of influenza be Peramivir, zanamivir, Oseltamivir, that Ni Na meter Wei, Favipiravir, amantadine, Rimantadine, Arbidol, Ribavirin, Si Tafulin, ingavirin (Ingavirin), GR-217029 or a combination thereof.

And comprise the compounds of this invention or the methods for the treatment of of pharmaceutical composition administration, comprise other antiviral drugs further The administration of thing, wherein, other Tamiflu can be with the compounds of this invention or its pharmaceutical composition administering drug combinations, of the present inventionization Compound or pharmaceutical composition are as single formulation, or separate compound or pharmaceutical composition are as a part for multi-form.Its He can be administered simultaneously with the compounds of this invention or not be administered simultaneously Tamiflu.The situation of the latter, administration can stagger into Row as carried out for 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month or 2 months.

The compound of the present invention or " effective dose " of pharmaceutically acceptable composition or " effective dose " refer to process or Alleviate the effective dose that one or more present invention is previously mentioned the severity of illness.The method according to the invention, compound and combination Thing can be any dosage and any method of administration is efficiently used for the order of severity that processes or palliate a disease.Required standard Situation according to patient is changed by true amount, and this depends on race, the age, the general condition of patient, the order of severity of infection, Special factor, administering mode, etc..Compound or composition can with one or more other therapeutic agents administering drug combinations, as The present invention is discussed.

The general synthetic method of this compound

Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent such as formula (I).Following reaction scheme and embodiment are used for being further illustrated by this The content of invention.

Those skilled in the art will realize that: chemical reaction described in the invention can be used to prepare perhaps suitably Other compounds of many present invention, and it is considered as the model in the present invention for other method of the compound of preparing the present invention Within enclosing.Such as, the synthesis according to the compound of those non-illustrations of the present invention can be successfully by those skilled in the art Completed by method of modifying, as group is disturbed in suitable protection, by utilizing reagent known to other except described in the invention , or reaction condition is made the amendment of some routines.It addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applicable to the preparation of other compounds of the present invention.

The embodiments described below, unless other aspects show all of temperature and are set to degree Celsius.Reagent is bought in business Product supplier such as Ling Kai medicine, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, the most not through being further purified, unless other aspects show during use.General reagent is from Shantou Chemical plant, western Gansu Province, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Qingdao is risen Dragon chemical reagent Co., Ltd, and Haiyang Chemical Plant, Qingdao is commercially available.

Anhydrous tetrahydro furan is to be dried to obtain through metallic sodium backflow.Anhydrous methylene chloride and chloroform are to return through calcium hydride Fluidized drying obtains.Ethyl acetate, DMA and petroleum ether are to be dried in advance through anhydrous sodium sulfate to use.

Hereinafter reaction is usually and overlaps a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects Show), reaction bulb the most suitable rubber stopper, substrate is squeezed into by syringe.Glassware is all dried.

Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.NMR spectrum with CDC1₃Or DMSO-d₆For solvent (report in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) as reference standard. When multiplet occurs when, the abbreviation by following for use: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of Doublets, quartet), dt (doublet of triplets, double triplets).Coupling constant, represents with hertz (Hz).

By outfit G1312A binary pump and a G1316A TCC, (column temperature is maintained at 30 to Algorithm (MS) data DEG C) the spectrometer of Agilent6320 series LC-MS measure, G1329A automatic sampler and G1315B DAD detector Being applied to analyze, ESI source is applied to LC-MS spectrometer.

Algorithm (MS) data are by being equipped with G1311A quaternary pump and G1316A TCC (column temperature is maintained at 30 DEG C) The spectrometer of Agilent 6120 series LC-MS measure, G1329A automatic sampler and G1315D DAD detector should For analyzing, ESI source is applied to LC-MS spectrometer.

Both the above spectrometer is provided with Agilent Zorbax SB-C18 post, and specification is 2.1 × 30mm, 5 μm.Note Beam is long-pending is to be determined by sample concentration；Flow velocity is 0.6mL/min；The peak value of HPLC is by 210nm and 254nm UV-Vis wavelength records reading.Flowing be mutually 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure water-soluble Liquid (phase B).Condition of gradient elution is as shown in table 1:

Table 1

Time (min)	A(CH₃CN, 0.1%HCOOH)	B(H₂O, 0.1%HCOOH)
			0-3	5-100	95-0

3-6	100	0
			6-6.1	100-5	0-95
6.1-8	5	95

Compound is purified and is evaluated by Agilent 1100 series of high efficiency liquid chromatogram (HPLC), wherein UV detection At 210nm and 254nm, Zorbax SB-C18 post, specification is 2.1 × 30mm, 4 μm, 10 minutes, and flow velocity is 0.6mL/min, (0.1% aqueous formic acid) of (the 0.1% formic acid acetonitrile solution) of 5-95%, column temperature is maintained at 40 DEG C.

The use of brief word below runs through the present invention:

BOC, Boc tert-butoxycarbonyl

CDC1₃Deuterochloroform

H₂O water

H₂O₂Hydrogen peroxide

EtOAc ethyl acetate

UL microlitre

ML, m milliliter

N₂Nitrogen

Pd/C palladium/carbon

PE petroleum ether (60 90 DEG C)

DCM dichloromethane

MeOH methyl alcohol

DMSO dimethyl sulfoxide

DMSO-d₆Deuterated dimethyl sulfoxide

K₂CO₃Potassium carbonate

KF potassium fluoride

POCl₃POCl3

KF potassium fluoride

SOCl₂Thionyl chloride

Pd/C palladium/carbon

NaOH NaOH

DMF N,N-dimethylformamide

DIPEA diisopropylethylamine

H hour

TBAF tetrabutyl ammonium fluoride

HPLC high performance liquid chromatography

MS mass spectrum

Synthetic schemes

Synthetic method 1

Compound (d) can be prepared by synthetic method 1, wherein n, R¹、R²There is implication of the present invention, change Compound (a) obtains target compound by a step necleophilic reaction with compound (b) under alkali such as triethylamine, potassium carbonate etc. acts on C (), compound (c) obtains target compound (d) in alkalescence next step reaction of condition such as potassium carbonate effect.

The synthesis of intermediate: 3,6-bis-Calmazine-2-formonitrile HCN

The synthesis of step 1:6-bromo-3-HYDROXYPYRAZINE-2-formamide

2,6-lutidines (4.2mL, 35.97mmol, 1eq.) is joined 3-HYDROXYPYRAZINE-2-formamide (5g, 36.0mmol, 1eq.) and DMF (50mL) solution of TBAB (19g, 39.6mmol, 1.1eq.) in.Mixture is in room Stir 17h under temperature, after having reacted, add the sodium chloride solution of 10%, then filter.Solid 30mL water and the 30mL collected EtOAc mixed solution dilutes and stirs ten minutes, and the organic phase of separation saturated aqueous common salt (20mL x 2) washs, then with anhydrous Sodium sulphate is dried, reduced pressure concentration, obtains residue silica gel column chromatography (eluant, eluent: PE/EtOAc (V/V)=2/1) purifying and obtains white Look solid-like title compound (4g, 51%).

MS:(ESI,pos.ion)m/z:219.2[M+1]⁺.

The synthesis of step 2:6-bromo-3-chloropyrazine-2-formonitrile HCN

At 0 DEG C, by POCl₃(5.3mL, 57.3mmol, 3.5eq.) and DIPEA (11.4mL, 65.5mmol, 4eq.) add In chlorobenzene (70mL) solution of 6-bromo-3-HYDROXYPYRAZINE-2-formamide (3.57g, 16.4mmol, 1eq.), reactant mixture Being heated to 100 DEG C of stirring 17h to have reacted, then reduced pressure concentration, residue is through with silica gel column chromatography (eluant, eluent: PE/EtOAc (V/ V)=10/1) purifying obtains white solid title compound (2.2g, 62%).

The synthesis of step 3:3,6-bis-Calmazine-2-formonitrile HCN

By KF (5.7g, 98.44mmol, 3.7eq.) and NBu₄Br (1.72g, 5.3mmol, 0.2eq.) join 10mL without In water DMSO, mixture 100 DEG C stir 1h, be then cooled to 70 DEG C, add 6-bromo-3-chloropyrazine-2-formonitrile HCN (5.8g, 26.6mmol, 1eq.) anhydrous toluene solution 20mL, gained reactant mixture stirs 3h at this temperature.After having reacted, add 10mL water, the organic phase of separation saturated aqueous common salt 20mL washs, and adds concentrated hydrochloric acid and regulates to pH about 1.6, and organic phase is used again Saturated nacl aqueous solution 20mL washs, and is dried with anhydrous sodium sulfate, then reduced pressure concentration, and residue purifies through silica gel column chromatography and (washes De-agent: PE/EtOAc (V/V)=30/1) obtain white solid title compound (1.85g, 49%).

¹H NMR(400MHz,CDCl₃):δ8.34-8.31(d,1H).

The fluoro-3-of embodiment 1:6-((2-(2-hydroxy benzenes methylamino) ethyl) amino) pyrazine-2-formamide

The synthesis of step 1:2-nipagin A

2 hydroxybenzoic acid (10g, 72mmol, 1eq.) is dissolved in EtOH (31.5mL), at 0 DEG C, is added dropwise over the concentrated sulfuric acid (0.5mL, 9.39mmol), reactant liquor is heated to 85 DEG C of reaction 16h.After having reacted, concentration of reaction solution, residue 20mL water is dilute Release, extract with dichloromethane (20mL x 2), then be dried with anhydrous sodium sulfate, be concentrated under reduced pressure to give colorless oil target compound (5.77g, 48%).

MS:(ESI,pos.ion)m/z:167.1[M+1]⁺.

The synthesis of step 2:N-(2-amino-ethyl)-2-Hydroxylbenzamide

2 hydroxybenzoic acid ethyl ester (3g, 18.05mmol, 1eq.) and ethylenediamine (1.21mL, 18.1mmol, 1eq.) mixed Compound reacts stirring 15h at 110 DEG C, after having reacted, by reactant liquor reduced pressure concentration, residue silica gel column chromatography (eluant, eluent is: DCM/MeOH=20/1) purifying obtains colorless oil title compound (118mg, 4%).

MS:(ESI,pos.ion)m/z:181.2[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ9.02(br,1H),7.85-7.82(d,1H),7.34-7.32(m,1H), 6.86-6.79(m,2H),3.33-3.30(t,2H),2.75-2.71(t,2H),1.42-1.25(m,6H).

The synthesis of step 3:N-(2-((3-cyano group-5-Calmazine-2-base) amino) ethyl)-2-Hydroxylbenzamide

N-(2-amino-ethyl)-2-Hydroxylbenzamide (110mg, 0.61mmol, 1.0eq.) is dissolved in anhydrous THF (8mL), in, 3 are added, anhydrous THF (2mL) solution of 6-bis-Calmazine-2-formonitrile HCN (86mg, 0.61mmol, 1.0eq.), instead Answering liquid to be stirred at room temperature 3h, after having reacted, reduced pressure concentration, residue purifies (eluant, eluent: PE/EtOAc (V/ through silica gel column chromatography V)=3/1) white solid title compound (108mg, 59%) is obtained.

MS:(ESI,pos.ion)m/z:302.3[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ12.54(br,1H),8.88(br,1H),8.46-8.44(d,1H),7.79- 7.77(m,2H),7.39-7.37(t,1H),6.90-6.86(m,2H),3.60-3.52(t,2H),3.50-3.47(t,2H).

The synthesis of the fluoro-3-of step 4:6-((2-(2-Hydroxylbenzamide base) ethyl) amino) pyrazine-2-formamide

By N-(2-((3-cyano group-5-Calmazine-2-base) amino) ethyl)-2-Hydroxylbenzamide (50mg, 0.17mmol, 1eq.) it is dissolved in DMSO (2mL), more gradually add K₂CO₃(9mg, 0.06mmol, 0.4eq.) and H₂O₂(75mg, 0.66mmol, 4eq.), reactant mixture is stirred at room temperature 4h, after having reacted, adds the dilution of 20mL water, and uses EtOAc (20mL x 2) extracts, and the organic phase of merging saturated nacl aqueous solution (20mL x 2) washs, and is dried with anhydrous sodium sulfate, mistake Filter reduced pressure concentration.Residue purifies through silica gel column chromatography (eluant, eluent: PE/EtOAc (V/V)=2/1) and obtains white solid mark Topic compound (43mg, 81%).

MS:(ESI,pos.ion)m/z:320.2[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ12.53(br,1H),8.92-8.76(br,2H),8.35-8.33(d,1H), 8.03(br,1H),7.79-7.76(d,1H),7.70(br,1H),7.41-7.37(m,1H),6.90-6.85(m,2H),3.70- 3.60(t,2H),3.52-3.48(t,2H).

The fluoro-3-of embodiment 2:6-((4-hydroxybenzyl) amino) pyrazine-2-formamide

The synthesis of the fluoro-3-of step 1:6-((4-hydroxybenzyl) amino) pyrazine-2-formonitrile HCN

4-(amino methyl) phenol (87mg, 0.71mmol, 1eq.) is dissolved in anhydrous THF (8mL), adds 3,6-bis- Calmazine-2-formonitrile HCN (100mg, 0.71mmol, 1eq.), reactant mixture is stirred at room temperature 3h, then reduced pressure concentration, residue Through silica gel chromatography (eluant, eluent: PE/EtOAc (V/V)=3/1) obtain white solid title compound (66mg, 38%).

MS:(ESI,pos.ion)m/z:245.3[M+1]⁺.

The synthesis of the fluoro-3-of step 2:6-((4-hydroxybenzyl) amino) pyrazine-2-formamide

Fluoro-for 6-3-((4-hydroxybenzyl) amino) pyrazine-2-formonitrile HCN (60mg, 0.25mmol, 1eq.) is dissolved in DMSO (2mL) K, is more gradually added₂CO₃(7mg, 0.05mmol, 0.2eq.) and H₂O₂(111mg, 0.98mmol, 4eq.), reactant liquor exists 2.5h is stirred under room temperature.After having reacted, reactant liquor adds the dilution of 20mL water, then extracts (20mL x 2) with EtOAc, merges organic Washing with saturated nacl aqueous solution (20mL x 2) mutually, then be dried with anhydrous sodium sulfate, residue purifies (wash-out through silica gel column chromatography Agent: PE/EtOAc (V/V)=2/1) obtain white solid title compound (64mg, 96%).

MS:(ESI,pos.ion)m/z:263.3[M+1]⁺.

¹H NMR(400MHz,DMSO-d₆):δ9.32(br,1H),8.89-8.87(br,1H),8.37-8.35(d,1H), 8.07-7.69(br,2H),7.20-7.07(d,2H),6.72-6.70(d,2H),4.52-4.49(d,2H).

Anti-influenza virus activity measures

96 orifice plate CPE determination method steps:

Spread 96 orifice plates, 5000 mdck cells of every hole inoculation, 37 DEG C, 5%CO₂, incubated overnight.

By DMSO and serum free medium diluted compounds to suitable concn, DMSO final concentration of 1%.

-80 DEG C of frozen influenza virus H1N1 (A/weiss/43) are diluted with culture medium.

Every hole adds the compound after 50 μ L dilutions and the virus liquid (final MOI=0.01) after 50 μ L dilution.

96 orifice plates are placed in 37 DEG C, 5%CO₂, cultivate 3 days.

Every hole adds 20 μ L MTT, is placed in 37 DEG C, hatches 4 hours.

Measure the first a ceremonial jade-ladle, used in libation amount that MTT is generated by living cells reduction, and the CPE calculating influenza virus mediation accordingly is detected chemical combination The percentage of thing suppression.

96 orifice plates mensuration cytotoxicity steps:

Every hole adds the compound after 50 μ L dilutions and 50 μ L nutrient solutions.

96 orifice plates are placed in 37 DEG C, 5%CO₂, cultivate 3 days.

Every hole adds 20 μ L MTT, is placed in 37 DEG C, 4 hours.

Measure the first a ceremonial jade-ladle, used in libation amount that MTT is generated by living cells reduction, and calculate the cytotoxicity of test compound accordingly.

Data analysis: % inhibiting rate=(OD_T–OD_V)/(OD_C–OD_V) × 100%

% cytotoxicity=OD_T/OD_C× 100%

% activity=% inhibiting rate-% cytotoxicity

OD_T,OD_V, and OD_CRepresent the absorptivity of test compound respectively, and virus-infected controls (without compound ,+1% DMSO), and cell blank comparison (virus-free, without compound ,+1%DMSO)

OD value=OD₅₇₀–OD₆₃₀(MTT)

Table one: part of compounds infected by influenza H1N1 (A/weiss/43) experiment in vitro activity value of the present invention

As seen from the above table, compound involved in the present invention has obvious anti-influenza virus activity.

It will be apparent to one skilled in the art that present invention is not limited to foregoing illustrative embodiment, and And can be embodied in other concrete form without departing from its essential characteristics.It is therefore contemplated that each embodiment is the most all It is considered illustrative and nonrestrictive, should refer to appended claims rather than these embodiments aforementioned, therefore, All changes in the implication of appended claims equivalents and scope are included in herein.

In the description of this specification, reference term " embodiment ", " some embodiments ", " example ", " specifically show Example " or the description of " some examples " etc. means to combine this embodiment or example describes specific features, structure, material or feature It is contained at least one embodiment or the example of the present invention.In this manual, the schematic representation of above-mentioned term is differed Surely identical embodiment or example are referred to.And, the specific features of description, structure, material or feature can be any One or more embodiments or example combine in an appropriate manner.

Although above it has been shown and described that embodiments of the invention, it is to be understood that above-described embodiment is example Property, it is impossible to be interpreted as limitation of the present invention, those of ordinary skill in the art is without departing from the principle of the present invention and objective In the case of above-described embodiment can be changed within the scope of the invention, revise, replace and modification, the scope of the present invention Limited by claim and equivalent thereof.

Claims

1. a compound, it is the compound as shown in formula (I), or its stereoisomer, geometric isomer, dynamic isomer Or pharmaceutically acceptable salt,

Wherein, R¹For phenyl or-NHC (=O)-phenyl；

N is 0,1 or 2；

Wherein, the phenyl in described phenyl or-NHC (=O)-phenyl can the most optionally by 1,2 or 3 selected from hydrogen, hydroxyl, C_1-3Alkyl, amino, F, Cl, Br, I, C_1-3The substituent of alkoxyl is replaced.

2. compound as claimed in claim 1, wherein

R¹For phenyl or-NHC (=O)-phenyl；With

R²For hydrogen ,-CN, F, Cl, Br, I, methyl, ethyl, methoxyl group, ethyoxyl, hydroxyl, amino, N-methylamino, N-ethylamino or N, N-dimethylamino；

3. according to the compound described in any one of claim 1-2, its be the structure of one of or its stereoisomer, Geometric isomer, dynamic isomer or pharmaceutically acceptable salt,

4. a pharmaceutical composition, comprises the arbitrary described compound of claim 1-3, and pharmaceutically acceptable assistant agent.

Pharmaceutical composition the most according to claim 4, wherein said assistant agent be carrier, excipient, diluent or its Meaning combination.

Pharmaceutical composition the most according to claim 4, it further comprises suppression influenza virus medicine, wherein said Anti-influenza virus medicament be Peramivir, zanamivir, Oseltamivir, that Ni Na meter Wei, Favipiravir, amantadine, gold Just ethamine, arbidol, Ribavirin, Si Tafulin, ingavirin (Ingavirin) or a combination thereof.

7. the arbitrary described compound of claim 1-3 or the arbitrary described pharmaceutical composition of claim 4-6 are in preparation Prevent, treat or alleviate the purposes in patient's influenza virus medicine.