CN109384783A - Novel heterocyclic compounds and its medical usage as resisiting influenza virus inhibitor - Google Patents
Novel heterocyclic compounds and its medical usage as resisiting influenza virus inhibitor Download PDFInfo
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- CN109384783A CN109384783A CN201710674187.7A CN201710674187A CN109384783A CN 109384783 A CN109384783 A CN 109384783A CN 201710674187 A CN201710674187 A CN 201710674187A CN 109384783 A CN109384783 A CN 109384783A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
The present invention provides one kind to be related to heterocyclic compound or its pharmaceutically acceptable salt and preparation method thereof shown in formula (I) and the application in the drug that preparation treats or prevents influenza A.These compounds can inhibit the transcription and synthesis of Influenza Virus RNA, be a kind of PB2 inhibitor.
Description
Technical field
The invention belongs to medicinal chemistry arts more particularly to heterocycle compounds, heterocyclic compound salts and its preparation side
The application of method and the drug as treatment and prevention influenza virus.
Background technique
Influenza is a kind of potential fatal communicable disease, has very high morbidity and mortality, causes to medical system
Very big burden.There is the population infection influenza virus of 5-20% every year, and cause other complication such as breathing or heart, in the world
Cause hundreds of thousands of them dead in range every year, when flu outbreak may cause millions of people's death, and the influenza in 20th century produces shockingly
Hair once caused tens of millions of people dead.These popular influenzas are all influenza virus mutations in animals, are passed from animal species
Caused by being multicast to the mankind.
Influenza virus belongs to the RNA virus of orthomyxoviridae family (orthomyxoviridae), including 5 kinds: A type disease
Poison, Type B virus, c-type virus, Isavirus and Thogoto virus.A type virus is a kind of virus propagated from birds to the mankind,
There is very high pathogenicity rate, and extensive popular, causes serious consequence.According to the different serotypes of A type influenza, it is divided into different
Influenza virus.Such as H1N1 causes spanish influenza in 1918, H2N2 causes the Asia influenza of nineteen fifty-seven, and H3N2 causes 1968
The Mao flu in year, the influenza type that H5N1 is -2008 years 2007.There is also H1N2, H7N7, H9N2, H7N2, H7N3,
H10N7 etc..The Type B influenza almost single-minded infection mankind, and it is mutated slow, genetic diversity is low, and Type B influenza is caused to be difficult greatly
Scale is popular.
A type and Type B influenza virus are closely similar in structure, virion 80-120nm.Its genome is not single
The nucleic acid of segment, but the negative justice RNA of 7 or 8 segments.11 kinds of the genome encoding protein of A type influenza 8: hemagglutinin
(HA), neuraminidase (NA), nucleoprotein (NP), M1, M2, NS1, NS2, PA, PB1, PB1-F2 and PB2.HA and NA is virus
High molecular weight protein outside particle.HA is the agglutinin that mediate retroviral combination target cell and viral genome enter target cell, NA ginseng
With the release of progeny virus, therefore these albumen all can serve as exploitation influenza inhibitor targeting proteins.
The method for the treatment of influenza is vaccine inoculation or antiviral drugs at present.Since the vaccine in each season is the master of current year
Bacterial strain is wanted, so very weak to the patient or the elderly's curative effect that infect other than main bacterial strain.In addition influenza virus mutant quickly, epidemic disease
Seedling needs annual update.If flu outbreak, producing enough vaccines is also a kind of very big challenge.
The antiviral drugs of present standard is neuraminidase inhibitor, such as Oseltamivir and Zanamivir.This
A little drugs can be used for treating the patient of influenza A and influenza B infection, but neuraminidase inhibitor answers treated as soon as possible, it is necessary to
Within 48 hours.Neuraminidase inhibitor may not have effect to the patient of severe, and in addition neuraminidase inhibitor is resistance to
Pharmacological property is also generated drug resistance to neuraminidase inhibitor by concern, such as H5N1 influenza virus.Clinically, neuraminic acid
The curative effect of enzyme inhibitor has a question.Therefore it needs to develop completely new mechanism and high-efficiency low-toxicity and is mutated high anti-of threshold
Flu pharmaceutical, to meet the needs of clinical and potential flu outbreak.
The polymerase of influenza virus includes three subunits, PB1, PB2 and PA, these three subunits are responsible for answering for 8 RNA segments
System and transcription.These three subunits are all the targets of drug development.When synthesizing virus mRNA, varial polymerases pass through " cap-
Area of the snatching " mechanism using-mRNA before host as the primer of transcription, in PB2 subunit just comprising this mechanism
Domain, for combining the m7GTP of m-RNA precursor.PB2 inhibitor for this region is the resisiting influenza virus of a completely new mechanism
Compound has huge clinical value.
Existing PB2 inhibitor is only effective to influenza A, and efficiently inhibits known clinical serotype,
Such as H1N1 and H5N1 etc..PB2 inhibitor inhibits the transcription and synthesis of viral RNA, and neuraminidase inhibitor does not have RNA
Effect.In addition neuraminidase inhibitor is effective to the crowd of low virus infection, and PB2 inhibitor has guarantor to all MIO
Shield effect, indication PB2 inhibitor also have good protective effect to patient with severe symptoms.With neuraminidase inhibitor only 48
Effectively different in hour, PB2 inhibitor is still effective at 120 hours.According to two kinds of inhibitor to inhibition situation viral in lung
Analysis, whether neuraminidase inhibition effectively has a question, but PB2 inhibitor has apparent inhibiting effect.So exploitation
Novel PB2 inhibitor, substituting or combining existing neuraminidase inhibitor is clinical urgent demand.
Summary of the invention
Technical problem to be solved by the invention is to provide a kind of novel heterocyclic compounds, such compound shows potent
Inhibit the activity of influenza virus, and there are outstanding pharmacokinetic properties, there is very strong druggability.
In order to solve the above technical problems, the present invention adopts the following technical scheme that:
What the present invention described has heterocyclic compound or its isomers, officinal salt, solvate or knot shown in formula (I)
It is brilliant.In some embodiments of the present invention, isomers and other chemistry with structure representated by formula (I) are also provided
Protection form is sour prodrug forms, ester and other pro-drugs for example including chemical hydrolysis or biodegrade.The present invention provides
Heterocyclic compound, have formula (I) structure,
Wherein, R1Replace alkyl, the alkoxy of C1~C6, C1~C6 selected from halogen, the alkyl of C1~C6, C1~C6
Substituted alkoxy, amino, substituted-amino, acylamino-, cyano, the aryl of C6-C10, the substituted aryl of C6-C10, C4~C10
Heteroaryl, the heteroaryl of C4~C10, RAThe naphthenic base of X-, C3~C6 cycloalkyloxy and C3~C6, the substitution alkyl,
Substituent group in substituted alkoxy, substituted-amino and substituted aryl independently is one or more and selected from fluorine atom, hydroxyl, C1
The alkyl of~C6, the alkoxy of C1~C6, cyano or carboxyl, the amide groups include C1~C6 alkyl amide, C3~C6 cycloalkanes
The aromatic amide of amide groups or C6-C10；The RAR in X-ASelected from alkyl, heteroaryl or aryl, X O, N or S；
R2Selected from carboxyl ,-CONHSO2Rb、-CONHSO2NHRb、-SO2NH2、-SO2NHRbAnd-SO2NHCORb, the RbChoosing
From the alkyl of C1~C8, C1~C8 replace alkyl, the naphthenic base of C3~C6, the aryl of C6-C10, C4~C10 heteroaryl,
The heteroaryl of the substituted heteroaryl of C4~C10, C4-C10, wherein replace alkyl, the substituent group in substituted heteroaryl be one or
Multiple fluorine atoms；
R3、R4It is independently selected from alkyl, replaces alkyl, aryl, substituted aryl and naphthenic base or R3And R4Form carbocyclic ring；R5It is selected from
Alkyl replaces alkyl, aryl, substituted aryl and naphthenic base, wherein the substitution in substitution alkyl, substituted aryl, substituted heteroaryl
Base independently is one or more and selected from fluorine atom, chlorine atom, hydroxyl or alkoxy；
Z1、Z2、Z3、Z4、Z5It is independently selected from N or CRc, RcSelected from H, F, Cl, Br, CN, NH2、CONH2、COCH3、OCHF2、
OCH3、CF3, the alkyl of C1~C8, the naphthenic base of C3~C6, the aryl of C6~C10, the heteroaryl of C4~C10, C1~C8 take
The substituted heteroaryl of substituted alkyl, the substituted aryl of C6~C10 or C4~C10, wherein replacing alkyl, substituted aryl, replacing heteroaryl
Substituent group in base independently is one or more and selected from fluorine atom, hydroxyl, alkyl, naphthenic base, alkoxy, cyano or carboxylic
Base；
Z6Selected from N or CRd, RdFor H, F or Cl.
In logical formula (I), remove except active hydrogen, all hydrogen atoms can separately be replaced by deuterium.
In embodiment, substituent group is selected from some groups of listed option.In some embodiments, Z5Selected from N,
R1Substitution alkyl, the alkoxy of C1~C3, the halogenated alkoxy of C1~C3, amino, second of alkyl, C1~C3 selected from C1~C3
Acylamino-, the naphthenic base of C3~C6, the heteroaryl of C4~C10 or C6~C10 aryl.In further embodiment, R1
The alkoxy of alkyl, C1~C3 selected from C1~C3, amino, the naphthenic base of C3~C6, C4~C10 heteroaryl or C6~C10
Aryl.It is furthermore preferred that R1Selected from methyl, amino, cyclopropane or substituted heteroaryl.
In some embodiments, R2Selected from carboxyl；Z5Selected from CRc, RcSelected from H, F, Cl, Br, CN, NH2、CONH2、
COCH3、OCHF2、OCH3、CF3, the alkyl of C1~C8, the naphthenic base of C3~C6, the heteroaryl of the aryl of C6~C10, C4~C10
Substitution alkyl, the substituted aryl of C6~C10 or the substituted heteroaryl of C4~C10 of base, C1~C8, substituent group are selected from one or more
A fluorine atom, hydroxyl, alkyl, alkoxy, cyano, carboxyl, R1Selected from halogen, the substitution alkane of the alkyl of C1~C3, C1~C3
Base, the alkoxy of C1~C3, the halogenated alkoxy of C1~C3, amino, acetylamino, the naphthenic base of C3~C5, C4~C10 it is miscellaneous
The aryl of aryl or C6~C10.In further some embodiments, Rc is selected from H, F, Cl, CN, CONH2, C1~C8 alkane
The substituted heteroaryl of base, C4~C10, R1Selected from methyl or F.In further some embodiments, Rc be selected from H, F, CN,
CONH2, methyl, C4~C10 substituted heteroaryl, R1It is methyl.
It is some be R in embodiment1For the substitution alkyl of C1~C3, and the substituent group in the substitution alkyl of C1~C3 is
Hydroxyl or halogen.
According to a preferred aspect of the present invention, R3、R4Be independently selected from the alkyl of C1~C8, the naphthenic base of C3~C6, C6~
The aryl or R of C103And R4Form carbocyclic ring；R5The aryl of the naphthenic base of alkyl, C3~C6 selected from C1~C8, C6~C10；R3、
R4、R5Contain 0,1 or 2 ring in the group that carbon atom connected to them is constituted.
In some more specific preferred embodiments, R3、R4、R5It is independently selected from the alkyl of C1~C6 or replaces alkyl, C3
The naphthenic base of~C6 replaces alkyl.Wherein R3、R4、R5Such as it is independently selected from methyl, ethyl, isopropyl, propyl, cyclopropyl, fluorine
For methyl, chloromethyl, fluoroethyl groups, Chloroethyl etc..
One of preferred embodiment according to the present invention, Z1、Z2、Z3In one or two be N.For example, Z1、Z2It is simultaneously N.
According to a preferred aspect of the present invention, Z1For N.
Preferably, lead in formula (I), R2For carboxyl.
Preferably, lead in formula (I), Z4For CH.
According to the present invention, typical heterocyclic compound is following compounds: formula (I-1), formula (I-2), formula (I-3), formula (I-
4), formula (I-5), formula (I-6), formula (I-7), formula (I-8), formula (I-9), formula (I-10), formula (I-11), formula (I-12), formula (I-
13), formula (I-14), formula (I-15), formula (I-16), formula (I-17), formula (I-18), formula (I-19), formula (I-20), formula (I-21),
Formula (I-22), formula (I-23), formula (I-24), formula (I-25), formula (I-26), formula (I-27), formula (I-28), formula (I-29), formula (I-
30), formula (I-31), formula (I-32), formula (I-33), formula (I-34), formula (I-35), formula (I-36), formula (I-37), formula (I-38),
Formula (I-39), formula (I-40), formula (I-41), formula (I-42), formula (I-43), formula (I-44), formula (I-45), formula (I-46), formula (I-
47), formula (I-48), formula (I-49), formula (I-50), (I-51), formula (I-52), formula (I-53), formula (I-54), formula (I-55), formula
(I-56), (I-57), formula (I-58), formula (I-59), formula (I-60) or formula (I-61), (I-62), formula (I-63), formula (I-64),
(I-65), formula (I-66), (I-67), formula (I-68),
The present invention also provides the preparation methods of heterocyclic compound shown in the logical formula (I) of the present invention, lead to R in formula (I)2For carboxylic
Base, the preparation method include:
(1) coupling reaction occurs for formula Int-1 compound and Formulas I nt-2 compound, obtains Formulas I nt-3 compound；
(2) acid or basic hydrolysis occurs for formula Int-3 compound；
In above-mentioned formula, Z1、Z2、Z3、Z4、Z5、Z6、R1、R3、R4、R5As defined above, P, which is represented, in Formulas I nt-1 compound protects
Protect base, such as p-toluenesulfonyl, 2- (trimethylsilyl) ethoxymethyl, THP trtrahydropyranyl or trityl.
The present invention also provides a kind of heterocyclic compound salts, have formula (II) structure,
Wherein, R1~R5And Z1~Z6It is as defined above.Acid is pharmaceutically acceptable acid.These can be at the acid of salt
Including phosphoric acid, hydrochloric acid, sulfuric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, cream
Acid, nitric acid, sulfonic acid, p-methyl benzenesulfonic acid, malic acid or methanesulfonic acid.
Heterocyclic compound and heterocyclic compound salts of the invention shows the potent activity for inhibiting influenza virus, and has outstanding
Pharmacokinetic properties, have very strong druggability.In addition, the substituent group at such compound heterocyclic nitrogen atom ortho position will block
P450 oxidation site reduces the unstability of compound metabolism, improves the bioavilability of compound and reduces clinical medicine
Dosage.The compound of these high activities will be with neuraminidase inhibitor, PA endonuclease enzyme inhibitor or other antiviral drugs
Object drug combination, the drug or composition for clinically providing rapid healing influenza infection or flu-prevention infection show potent suppression
The activity of influenza virus processed, and there are outstanding pharmacokinetic properties, there is very strong druggability.In addition, such compound is miscellaneous
The substituent group at theheterocyclic nitrogen atom ortho position will block P450 oxidation site, reduce the unstability of compound metabolism, improve compound
Bioavilability and the dosage for reducing clinical medicine.The compound of these high activities will be with neuraminidase inhibitor, PA nucleic acid
Inscribe enzyme inhibitor or other Tamiflu drug combinations clinically provide rapid healing influenza infection or flu-prevention sense
The drug or composition of dye.
The present invention is furthermore provided comprising one or more heterocyclic compounds provided by the invention, its isomers, its medicine
The pharmaceutical composition of the acceptable salt of object or its solvate.In some embodiments, the composition further includes that drug can connect
Diluent, excipient or the adhesive received.It is some be in embodiment, described pharmaceutical composition also includes one or more treatments
Agent, the therapeutic agent are selected from neuraminidase inhibitor, PA endonuclease enzyme inhibitor or other Tamiflu.
The present invention provides the heterocyclic compound or its isomers, officinal salt, hydrate, solvate, crystallizations
Or application of the pharmaceutical composition containing the heterocyclic compound in the drug that preparation treats or prevents influenza virus.
Preferably, the present invention provides the heterocyclic compounds or its isomers, officinal salt, hydrate, solvent to close
Object, crystallization or the pharmaceutical composition containing the heterocyclic compound are preparing the application in the Tamiflu such as PB2 inhibitor.
The present invention also provides described pharmaceutical composition in preparation for treating or preventing in influenza infection drug simultaneously
Application and using described pharmaceutical composition treat or prevent influenza infection patient disease method.
Pharmaceutical composition according to the present invention, wherein the compounds of this invention preferably exists with therapeutically effective amount.
Acceptable carrier in aforementioned pharmaceutical compositions Chinese pharmacology, such as pharmaceutically acceptable diluent, excipients, filling
Agent, adhesive, disintegrating agent, sorbefacient, surfactant, lubricant, flavouring agent, sweetener etc..
Using the compounds of this invention as drug prepared by active constituent can be tablet, pulvis, capsule, granula, oral solution with
And the diversified forms such as ejection preparation.The dosage form of pharmaceutical composition is preferably tablet, capsule or injection.
The drug of above-mentioned various dosage forms can be prepared by the conventional method of pharmaceutical field.
The present invention also provides purposes of the compounds of this invention in preparation prevention or treatment virus infection, preferably wherein
Virus infection is influenza infection.
Pharmaceutical composition composition of the invention can be made of lower proportion:
Due to the implementation of above technical scheme, there is following advantage in the present invention compared with prior art:
The present invention provides novel heterocyclic compound, the heterocyclic compounds and existing widely applied neuraminidase
Inhibitor relatively has big advantage, these compounds show as potent influenza A inhibitor, effective to inhibit virus
The duplication and synthesis of RNA.These compounds still have potent protection to make 120 hours patients of patient with severe symptoms and influenza infection
With, and neuraminidase inhibitor is only effective within 48 hours, and invalid to the patient of influenza severe infections.This kind of heterocyclic compound
Object has potent PB2 inhibitory activity, and reduces the fat-soluble of compound, reduce compound in blood plasma and albumin or
The binding force of hemoglobin has very strong druggability so such compound has excellent pharmacokinetic properties.
Further, in the structure of the pyrimidine ring of certain compounds according to the present invention, nitrogen-atoms is removed or in nitrogen original
The hydrogen atom at sub- ortho position is replaced by methyl, methoxyl group or amino etc., these substituent groups will block the oxidation site of P450, reductionization
The metabolism unstability for closing object, the dosage for being conducive to the bioavilability for improving drug and reducing clinical medicine.
The compound of the present invention individually or with neuraminidase inhibitor, PA endonuclease enzyme inhibitor or other anti influenzas
Combination therapies, the reserve drug for treating the influenza patient of clinic or for preventing big influenza.
Term definition
Unless otherwise defined, all technical and scientific terms used herein has and common skill of the art
The normally understood identical meaning of art personnel.
Term " isomers " refers to the isomers as caused by the spatially arrangement mode difference of atom in molecule.Including suitable
Trans isomer, enantiomter and conformer.All stereoisomers all belong to the scope of the present invention.Chemical combination of the invention
Object can be the mixing such as racemic modification or all other stereoisomer of independent stereoisomer or other isomers
Mixing.
Term " salt " refers to the pharmaceutically acceptable salt that compound of the present invention and acid are formed, and the acid can be with
It is organic acid or inorganic acid, specifically can be selected from: phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, almond
Acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-methyl benzenesulfonic acid, malic acid, Loprazolam or its analog.
Term " solvate " refers to form the present inventionization of the complex of solid-state or liquid by being coordinated with solvent molecule
Close the form of object.Hydrate is the special shape of solvate, wherein being coordinated with water.Within the scope of the present invention, solvent closes
Object is preferably hydrate.
Term " crystallization " refers to the various solid forms that compound of the present invention is formed, including crystal form, amorphous.
Term " alkyl " refers to straight chain, branch or cricoid saturation or the unsaturated substituent group being mainly made of carbon and hydrogen.
It is preferred that 1-20 carbon atom, more preferable 1-12 carbon atom.Term " alkyl " refers to the saturated hydrocarbyl of straight chain, branch.Alkyl tool
Body includes methyl, ethyl, n-propyl, isopropyl, cyclopropyl, normal-butyl, isobutyl group, tert-butyl, cyclobutyl, n-pentyl, isoamyl
Base, neopentyl, cyclohexyl, n-hexyl, isohesyl, 2,2 ,-methyl butyl and 2,3- dimethylbutyl, 16- alkyl, 18- alkyl.
Term " C1-20 alkyl " refers to the straight chain containing 1-20 carbon atom, branched saturated hydrocarbon group.Replace alkyl to refer to be substituted with a substituent
Alkyl.When alkyl is substituted, substituent group can replace on any workable tie point, and substituent group can be monosubstituted
Or it is polysubstituted.Substituent group it is independent selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, deuterium, halogen, mercaptan,
Hydroxyl, nitro, carboxyl, ester group, cyano, naphthenic base, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, oxygen
Generation, before substituent group is usually placed in alkyl in name.
Term " alkenyl " and " alkynyl " refer respectively to straight chain, branch or the cricoid unsaturated hydrocarbons containing double bond and three keys
Base, preferably 2-20 carbon atom, more preferable 2-12 carbon atom.Alkenyl, alkynyl include alkenyl, alkynes replacing and not replacing
Base.When substituted, substituent group can replace on any workable tie point, and substituent group can be monosubstituted or take more
Generation.Substituent group is independent to be selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, deuterium, halogen, mercaptan, hydroxyl, nitre
Base, carboxyl, ester group, cyano, naphthenic base, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, oxo are being named
When substituent group be usually placed in front of alkenyl, alkynyl.
Term " naphthenic base " refers to the unsaturated monocycle of saturation and/or part or polycyclic cyclic hydrocarbon radical.Monocycle may include 3-10 carbon
Atom.The non-limiting example of monocyclic naphthenes base includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexene
Base, cyclohexadienyl, suberyl etc..Polycyclic naphthene base includes the naphthenic base of loop coil, condensed ring and bridged ring.Naphthenic base includes unsubstituted
Base and contain substituent group.Substituent group is selected from one or more substituent groups, includes but are not limited to following group, independent to be selected from
Alkyl, naphthenic base, alkoxy, halogen, carboxyl, ester group, amino, amide groups, hydroxyl, cyano, nitro, aryl, heteroaryl.
Term " aryl " refers to the full carbon monocycle of 6-10 member or polycyclic aromatic group, including phenyl, Nai Ji, xenyl etc..Virtue
Base can be substituted and unsubstituted.Substituent group is independent to be selected from alkyl, naphthenic base (cyclopropyl alkyl, cyclobutane base and ring penta
Alkyl etc.), alkenyl, alkynyl, nitrine, amino, deuterium, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl are nitro, miscellaneous
Naphthenic base, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, alkyl silyl etc..
Term " heteroaryl " refers to the group comprising 1-10 heteroatomic miscellaneous aroma systems.Hetero atom includes oxygen, sulphur, nitrogen,
Phosphorus etc..Wherein single heterocycle includes but is not limited to furans, thiophene, pyrroles, thiazole, imidazoles, 1,2,3- triazole, tri- nitrogen of 1,2,4-
Azoles, 1,2,3- thiadiazoles, oxazole, 1,2,4- oxadiazoles, 1,3,4- oxadiazoles, pyridine, pyrimidine, pyridazine, pyrazine, tetrahydrofuran,
Nafoxidine, piperidines, piperazine, morpholine, isoxazoline etc..Condensed hetero ring base includes but is not limited to quinoline, isoquinolin, indoles, benzo
Furans, benzothiophene, purine, acridine, carbazole, fluorenes, chromene ketone, Fluorenone, quinoxaline, 3,4- dihydro naphthalenone, dibenzofurans, hydrogen
Change dibenzofurans, benzoxazolyl etc..Heteroaryl can be substituted and unsubstituted.Substituent group is independent to be selected from substituent group
It is independent selected from alkyl, naphthenic base (cyclopropyl alkyl, cyclobutane base and pentamethylene base etc.), alkenyl, alkynyl, nitrine, amino, deuterium,
Alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle
Alkoxy, cycloalkylthio, heterocycle alkylthio group, alkyl silyl etc..
Term " halogen " refers to fluorine, chlorine, bromine, iodine, preferably fluorine, chlorine, bromine.
Term " deuterium " is the isotope of hydrogen, and atomic mass is 2 times of the latter, and the combination of carbon is stronger.Deuterate "and" deuterium " table
Show that hydrogen is replaced by deuterium in designated position.One " substituent group of deuterate " is substituent group, and wherein at least one hydrogen is by with specified
The deuterium of percentage enrichment replaces.
Term " halogenated alkyl " refers to the alkyl at least replaced by a halogen atom.
Term " heterocycle " refers to that wherein hetero atom is nitrogen, oxygen, sulphur, sulphur at least containing a heteroatomic cyclic group
Deng.Heterocycle includes single heterocycle and more heterocycles.
Specific embodiment
Following embodiment can make those skilled in the art that the present invention be more fully understood, but not limit this in any way
Invention.The structure of all compounds passes through1H NMR or MS are determined.
The compound name abbreviation used in embodiment is as follows:
DCM: methylene chloride
EtOAc: ethyl acetate
THF: tetrahydrofuran
DME: glycol dimethyl ether
1,4-Dioxane:1,4- dioxane
Pd2(dba)3: tris(dibenzylideneacetone) dipalladium
Bis- diphenylphosphine -9,9- dimethyl the oxa-s of Xantphos:4,5- are feared
TBuONa: sodium tert-butoxide
TsCl: paratoluensulfonyl chloride
DIPEA: diisopropylethylamine
Pd(dppf)Cl2: [bis- (diphenylphosphino) ferrocene of 1,1'-] palladium chloride
MCPBA: metachloroperbenzoic acid
X-phos:2- dicyclohexyl phosphorus -2,4,6- tri isopropyl biphenyl
Combined with specific embodiments below, the present invention is described further:
Embodiment 1: ((the fluoro- 2- of 5- (fluoro- 1H- pyrrolo- [2,3-b] pyridin-3-yl of 5-) -6- methyl is phonetic by preparation (R) -3-
Pyridine -4- base) amino) -4,4- dimethyl valeric acid (I-1)
The preparation of compound 2: N- bromo-succinimide (NBS, 5.29g, 29.7mmol) is added to compound 1
It reacts in methylene chloride (100mL) solution of (4.50g, 33mmol) and at room temperature 19 hours, saturation is added after reaction
Solution of sodium bisulfite (200ml), liquid separation, organic layer washs with 20% sodium hydroxide solution, and anhydrous sodium sulfate is dry, mistake
Filter, filter vacuum are concentrated to get crude product 4.62g.
The preparation of compound 3: compound 2 (4.40g, 20.4mmol) is dissolved in the dry DMF of 30mL, and sodium hydrogen is added
It (1.30g, 32.6mol) and stirs 30 minutes.Then paratoluensulfonyl chloride (TsCl, 5.78g, 30.6mmol) is added and reacts 4
Hour.It is poured into mixture of ice and water after reaction, solid, filtering, filter cake petroleum ether, crude product acetic acid second is precipitated
Ester is recrystallized to give 3.10g compound 3.Yield: 42.1%.
The preparation of compound 4: compound 3 (1.50g, 4.05mmol), duplex pinacol borate (3.089g,
12.16mmol), Pd (dppf) Cl2 (0.296g, 0.41mmol) and potassium acetate (1.193g, 12.16mmol) are added to 25mL1,
In 4- dioxane, nitrogen is bubbled the oxygen in removing system, and mixture is heated to reflux 19 hours, is spin-dried for, crude product is dissolved in acetic acid
Ethyl ester (150ml) crosses column with silicagel pad, and product is recrystallized with methyl tertiary butyl ether(MTBE) (4.5ml) and petroleum ether (15ml)
0.605g product.Yield: 35.9%.
The preparation of compound 6: methyl magnesium bromide solution (1M, 15ml, 15mmol) is added in the anhydrous THF of 10mL and cooling
To 0 DEG C, compound 5 (1.67g, 10mmol) is added into this solution and is stirred 1 hour at 15 DEG C.Then it is added and contains I2
After charging, solution of sodium bisulfite washing, ethyl acetate extraction is added in the THF solution (6ml) of (2.54g, 10mmol)
(50ml × 3), organic phase merge, and saturated common salt washing is filtered after anhydrous sodium sulfate is dry, and filter vacuum is concentrated to get crude product
0.620g。
The preparation of compound 8: compound 6 (0.62g, 3.43mmol), 7 (0.67g, 3.43mmol) and triethylamine
(1.14g, 13.02mmol) is dissolved in the mixed solvent of 15mL tetrahydrofuran and 0.8mL ethyl alcohol, is heated to reflux 5 hours, reaction terminates
After be spin-dried for, crude product chromatographs to obtain 0.46g compound 8 by column.Yield: 32.2%.
The preparation of compound 9: compound 4 (0.30g, 1.0mmol), compound 8 (0.46g, 1.1mmol), sodium carbonate
(0.32g, 3.0mmol), Pd2(dba)3(46mg, 0.05mmol) and X-phos (0.12g, 0.25mmol) are added to 15mL2- first
The in the mixed solvent of base tetrahydrofuran and 3mL water, nitrogen are bubbled 10 minutes, are then heated to reflux 19 hours.It is cold after reaction
But it to room temperature, is spin-dried for, crude product obtains 0.43g solid through column chromatography (PE:EA=20:1-8:1).Yield: 77.1%.
The preparation of compound 10: compound 9 (0.40g, 0.73mmol) is dissolved in 2mL acetonitrile, be added 1mL 4N HCl (g)/
Then Isosorbide-5-Nitrae-dioxane solution is heated to 120 DEG C in closed reactor and reacts 2.5 hours, is spin-dried for, crude product is dissolved in 20mL
Methylene chloride is added saturated sodium bicarbonate solution and stirs 10 minutes, and (20mL × 2) are extracted with dichloromethane in then liquid separation, water layer,
Merge organic layer, is spin-dried for after anhydrous sodium sulfate is dry, crude product is prepared plate and purifies to obtain 0.080g compound 10.Yield:
27.4%.
The preparation of compound I-1: compound 10 (72mg, 0.18mmol) is dissolved in 6mL THF, and the water of 1N lithium hydroxide is added
Solution (0.5ml, 0.5mmol) is heated to 65 DEG C in closed container and reacts 3 hours, 1N hydrochloric acid is then added and adjusts pH=6,
Ethyl acetate extracts (20ml × 3), merges organic phase, is concentrated after dry, crude product is obtained through column chromatography (DCM:MeOH=20:1)
45mg product.Yield: 64.8%.
1H NMR(400MHz,CDCl3)δ:10.99(br,1H),8.27-8.25(m,1H),7.88(s,1H),7.59(s,
1H),4.93-4.87(m,1H),4.79-4.71(m,1H),2.74(dd,1H,J1=12.0Hz, J2=1.6Hz), 2.39 (s,
3H), 2.33 (d, 1H, J=10.8Hz), 1.08 (s, 9H)；ESI-MS m/z 390.2(M+H)+。
Embodiment 2: preparation (R) -3- ((the fluoro- 2- of 5- (fluoro- 1H- pyrrolo- [2,3-b] pyridin-3-yl of 5-) pyrimidine-4-yl)
Amino) -4,4- dimethyl-N-(methyl sulphonyl) pentanamide (I-65)
The preparation of compound 11: compound 4 (1.40g, 3.36mmol), the chloro- 4- sulfidomethyl -5-FU of 2- (0.50g,
2.80mmol), Pd2 (dba) 3 (0.26g, 0.28mmol), X-phos (0.67g, 1.4mmol) and sodium carbonate (0.89g,
It 8.40mmol) is dissolved in 25mL glycol dimethyl ether and 5mL water, nitrogen is bubbled the oxygen in 30 minutes removing systems, is heated to reflux
It 19 hours, is cooled to room temperature, reaction solution is poured into 100mL water, filter, filter cake is washed with water, and then uses recrystallized from acetonitrile
Obtain 1.10g product.Yield: 75.7%.
The preparation of compound 12: at 0 DEG C, into methylene chloride (15mL) solution of compound 11 (0.60g, 1.39mmol)
Metachloroperbenzoic acid (MCPBA, 85%, 0.71g, 3.48mmol) is added portionwise, after charging, is stirred 3 hours at 0 DEG C.
The dilution of 30mL methylene chloride is added after reaction, is then washed 3 times with 15% wet chemical, and use saturated salt solution
It washes, is spin-dried for after anhydrous sodium sulfate is dry, crude product obtains sulfoxide 0.110g and sulfone by column chromatography (PE:EA=5:1-1:1)
0.106g。
The preparation of compound 14: compound 13 (0.60g, 2.45mmol), Methanesulfomide (0.23g, 2.45mmol) and
DMAP (55mg, 0.49mmol) is stirred 5 minutes in 10mL methylene chloride, and EDC.HCl (0.47g, 2.45mmol) then is added
And it is stirred at room temperature 2 hours.0.5N hydrochloric acid (15ml) is added after reaction, liquid separation, organic layer is washed with saturated common salt, anhydrous
Sodium sulphate dries, filters, and filter vacuum is concentrated to get crude product 0.789g.
The preparation of compound 15: compound 14 (0.79g, 2.45mmol) is dissolved in 10mL methylene chloride, and TFA is added
It (0.38ml) and is stirred at room temperature 19 hours, vacuum concentration obtains 0.99g grease.
The preparation of compound 16: compound 15 (0.110g, 0.25mmol), compound 12 (0.099g, 0.30mmol) and
Diisopropyl ethyl amine (95mg, 0.74mmol) is heated to reflux about 2 hours in 12mL acetonitrile, is then transferred to closed reactor,
It is reacted 2 hours in 110 DEG C of heating.It is spin-dried for after reaction, crude product is dissolved in 50mL methylene chloride, is successively washed with water and saturated common salt
Washing, anhydrous sodium sulfate dry, filter, and filtrate is spin-dried for, and crude product is prepared plate and purifies to obtain 0.018g compound 16.Yield:
12.1%.
The preparation of compound I-65: compound 16 (18mg, 0.030mmol) is dissolved in 2mL acetonitrile, and 1mL 4NHCl is added
(g) then/Isosorbide-5-Nitrae-dioxane solution is heated to 120 DEG C in closed reactor and reacts 2.5 hours, is spin-dried for, crude product is dissolved in
20mL methylene chloride is added saturated sodium bicarbonate solution and stirs 10 minutes, and (20mL is extracted with dichloromethane in then liquid separation, water layer
× 2), merge organic layer, be spin-dried for after anhydrous sodium sulfate is dry, crude product is prepared plate and purifies to obtain 4mg compound I-65.Yield:
29.9%.
1H NMR(400MHz,CDCl3)δ:9.47(brs,1H),8.55-8.53(m,1H),8.22-8.13(m,2H),
8.07 (d, 1H, J=3.2Hz) 7.51-7.33 (m, 1H), 5.60-5.52 (m, 1H), 4.88-4.77 (m, 1H), 3.73-3.62
(m,1H),3.15-3.05(m,1H),2.88(s,3H),2.86-2.77(m,1H),2.67-2.59(m,1H),1.04(s,9H)；
ESI-MS m/z453.2(M+H)+
The research of 3. Bioactivity of embodiment and Study of cytotoxicity
Untested compound: the compound of the present invention: compound I-1, compound I-65；Control compound: VX-787.
The test method of Bioactivity research: it is thin that mdck cell with the density kind of 2,000 cell per wells is entered into 384 holes
In born of the same parents' culture plate, 37 DEG C are subsequently placed at, 5%CO2Overnight incubation in incubator.It is added separately to after second day diluted chemical compound thin
In hilum (3 times of doubling dilutions, 8 test concentrations points), influenza virus A/PR/8/34 (H1N1) strain is then with every hole 2*TCID90
It is added in cell culture well, DMSO final concentration of 0.5% in culture medium.Cell plates are placed in 37 DEG C, 5%CO25 are cultivated in incubator
It.Cell activity is detected using cell viability detection kit CCK8 after culture 5 days.Initial data is soft with GraphPadPrism
Part carries out non linear fit analysis to the inhibiting rate and cytotoxicity of compound, obtains EC50It is worth (result is referring to table 1).
The research method of Study of cytotoxicity: the cytotoxicity assay of compound is parallel with Assay of Antiviral Activity to be carried out,
In addition to virus is not added, other experiment conditions are consistent with antiviral activity experiment.Cell viability detection reagent is used after culture 5 days
Box CCK8 detects cell activity.Initial data calculates (result is referring to table 1) for Compound Cytotoxicity (CC50).
Inhibitory activity and toxicity of 1. compound of table for influenza virus A/PR/8/34 (H1N1)
Conclusion: compound I-1 has an activity of outstanding inhibition H1N1, and activity is lower than 10nM, and with very low thin
Cellular toxicity.
The above description of the embodiment is only used to help understand the method for the present invention and its core ideas.It should be pointed out that pair
For those skilled in the art, without departing from the principle of the present invention, the present invention can also be carried out
Some improvements and modifications, these improvements and modifications also fall within the scope of protection of the claims of the present invention.
Claims (10)
1. heterocyclic compound shown in logical formula (I), stereoisomer, officinal salt, hydrate, solvate or crystallization,
Wherein, R1The substitution for replacing alkyl, the alkoxy of C1~C6, C1~C6 selected from halogen, the alkyl of C1~C6, C1~C6
Alkoxy, amino, substituted-amino, acylamino-, the heteroaryl of cyano, the aryl of C6-C10, the substituted aryl of C6-C10, C4~C10
Base, the heteroaryl of C4~C10, RAThe naphthenic base of X-, C3~C6 cycloalkyloxy and C3~C6, the substitution alkyl replace
Substituent group in alkoxy, substituted-amino and substituted aryl independently is one or more and selected from fluorine atom, hydroxyl, C1~C6
Alkyl, C1~C6 alkoxy, cyano or carboxyl, the amide groups includes C1~C6 alkyl amide, C3~C6 cycloalkanes amide
The aromatic amide of base or C6-C10；The RAR in X-ASelected from alkyl, heteroaryl or aryl, X O, N or S；
R2Selected from carboxyl ,-CONHSO2Rb、-CONHSO2NHRb、-SO2NH2、-SO2NHRbAnd-SO2NHCORb, the RbSelected from C1
The alkyl of~C8, the substitution alkyl of C1~C8, the naphthenic base of C3~C6, the aryl of C6-C10, the heteroaryl of C4~C10, C4~
The heteroaryl of the substituted heteroaryl of C10, C4-C10, wherein alkyl, the substituent group in substituted heteroaryl is replaced to be one or more
Fluorine atom；
R3、R4It is independently selected from alkyl, replaces alkyl, aryl, substituted aryl and naphthenic base or R3And R4Form carbocyclic ring；R5Selected from alkane
Base replaces alkyl, aryl, substituted aryl and naphthenic base, wherein the substituent group in substitution alkyl, substituted aryl, substituted heteroaryl
It independently is one or more and selected from fluorine atom, chlorine atom, hydroxyl or alkoxy；
Z1、Z2、Z3、Z4、Z5It is independently selected from N or CRc, RcSelected from H, F, Cl, Br, CN, NH2、CONH2、COCH3、OCHF2、OCH3、
CF3, the alkyl of C1~C8, the naphthenic base of C3~C6, the aryl of C6~C10, the heteroaryl of C4~C10, C1~C8 substitution alkane
The substituted heteroaryl of base, the substituted aryl of C6~C10 or C4~C10, wherein in substitution alkyl, substituted aryl, substituted heteroaryl
Substituent group independently be one or more and selected from fluorine atom, hydroxyl, alkyl, naphthenic base, alkoxy, cyano or carboxyl；
Z6Selected from N or CRd, wherein RdFor H, F or Cl；
In logical formula (I), remove except active hydrogen, all hydrogen atoms can separately be replaced by deuterium.
2. heterocyclic compound shown in logical formula (I) according to claim 1, stereoisomer, officinal salt, hydration
Object, solvate or crystallization, it is characterised in that: the R1Alkyl, C1~C3 selected from C1~C3 replace alkyl, C1~C3
Alkoxy, the halogenated alkoxy of C1~C3, amino, acetylamino, the naphthenic base of C3~C6, the heteroaryl of C4~C10 or C6~
The aryl of C10；The R2Selected from carboxyl；Z5Selected from N.
3. heterocyclic compound shown in logical formula (I) according to claim 1, stereoisomer, officinal salt, hydration
Object, solvate or crystallization, it is characterised in that: the R1Selected from halogen, substitution alkyl, the C1 of the alkyl of C1~C3, C1~C3
The alkoxy of~C3, the halogenated alkoxy of C1~C3, amino, acetylamino, the naphthenic base of C3~C5, C4~C10 heteroaryl
Or the aryl of C6~C10；
The R2Selected from carboxyl；
Z5Selected from CRc, RcSelected from H, F, Cl, Br, CN, NH2、CONH2、COCH3、OCHF2、OCH3、CF3, C1~C8 alkyl, C3
The naphthenic base of~C6, the aryl of C6~C10, the heteroaryl of C4~C10, C1~C8 replace alkyl, C6~C10 substituted aryl
Or the substituted heteroaryl of C4~C10.
4. heterocyclic compound shown in logical formula (I) according to claim 3, stereoisomer, officinal salt, hydration
Object, solvate or crystallization, it is characterised in that: the R1For the substitution alkyl of C1~C3, and substituent group therein be hydroxyl or
Halogen.
5. heterocyclic compound shown in logical formula (I) according to claim 1, stereoisomer, officinal salt, hydration
Object, solvate or crystallization, it is characterised in that: R3、R4It is independently selected from the alkyl of C1~C8, the naphthenic base of C3~C6, C6~C10
Aryl or R3And R4Form carbocyclic ring；R5The aryl of the naphthenic base of alkyl, C3~C6 selected from C1~C8, C6~C10；R3、R4、R5
Contain 0,1 or 2 ring in the group that carbon atom connected to them is constituted.
6. leading to heterocyclic compound shown in formula (I), stereoisomer, officinal salt, water according to claim 1 or 5
Close object, solvate or crystallization, it is characterised in that: R3、R4、R5It is independently selected from the alkyl of C1~C6 or replaces alkyl, C3~C6
Naphthenic base replaces alkyl.
7. heterocyclic compound shown in logical formula (I) according to claim 6, stereoisomer, officinal salt, hydration
Object, solvate or crystallization, it is characterised in that: R3、R4、R5It is independently selected from methyl, ethyl, isopropyl, propyl, cyclopropyl, fluoro
Methyl, chloromethyl, fluoroethyl groups, Chloroethyl.
8. heterocyclic compound shown in logical formula (I) according to claim 1, stereoisomer, officinal salt, hydration
Object, solvate or crystallization, it is characterised in that: Z1、Z2、Z3In one or two be N.
9. heterocyclic compound shown in logical formula (I) according to claim 1 or 8, stereoisomer, officinal salt, water
Close object, solvate or crystallization, it is characterised in that: Z1For N.
10. heterocyclic compound shown in logical formula (I) according to claim 1, stereoisomer, officinal salt, hydration
Object, solvate or crystallization, which is characterized in that the compound is formula (I-1), formula (I-2), formula (I-3), formula (I-4), formula
(I-5), formula (I-6), formula (I-7), formula (I-8), formula (I-9), formula (I-10), formula (I-11), formula (I-12), formula (I-13), formula
(I-14), formula (I-15), formula (I-16), formula (I-17), formula (I-18), formula (I-19), formula (I-20), formula (I-21), formula (I-
22), formula (I-23), formula (I-24), formula (I-25), formula (I-26), formula (I-27), formula (I-28), formula (I-29), formula (I-30),
Formula (I-31), formula (I-32), formula (I-33), formula (I-34), formula (I-35), formula (I-36), formula (I-37), formula (I-38), formula (I-
39), formula (I-40), formula (I-41), formula (I-42), formula (I-43), formula (I-44), formula (I-45), formula (I-46), formula (I-47),
Formula (I-48), formula (I-49), formula (I-50), (I-51), formula (I-52), formula (I-53), formula (I-54), formula (I-55), formula (I-
56), (I-57), formula (I-58), formula (I-59), formula (I-60) or formula (I-61), (I-62), formula (I-63), formula (I-64), (I-
65) compound shown in, formula (I-66), (I-67) or formula (I-68),
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