CN110317211A - Substituted polycyclic pyridone compound and prodrug thereof - Google Patents

Substituted polycyclic pyridone compound and prodrug thereof Download PDF

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Publication number
CN110317211A
CN110317211A CN201910675084.1A CN201910675084A CN110317211A CN 110317211 A CN110317211 A CN 110317211A CN 201910675084 A CN201910675084 A CN 201910675084A CN 110317211 A CN110317211 A CN 110317211A
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compound
compounds
deuterium
hydrogen
prodrug
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CN110317211B (en
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王义汉
刘志强
李焕银
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Shenzhen Targetrx Inc
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Shenzhen Targetrx Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Abstract

The invention provides a deuterium-substituted polycyclic pyridone compound, a prodrug thereof, a composition containing the compound and application of the composition. The compounds and compositions of the present invention exhibit cap-dependent endonuclease inhibitory activity and have superior pharmacokinetic properties.

Description

A kind of substituted polycyclic pyridinone compounds and its prodrug
Technical field
The present invention relates to a kind of substituted polycyclic pyridinone compounds and its prodrug and include the composition of the compound And application thereof.More particularly it relates to (((12aR) -12- (fluoro- 6,11- bis- of (11S) -7,8- bis- that certain deuteriums replace Diphenyl hydrogen simultaneously (B, E) thiepin -11- base) -6,8- dioxo -3,4,6,8,12,12a- hexahydro -1H- (1,4) oxazines (3,4- C) pyrido (2,1-F) (1,2,4) triazine -7- base) oxygroup) methyl carbonic acid methyl esters and its female medicine, the compound that these deuteriums replace And combinations thereof show cap dependence endonuclease (Cap-dependent endonuclease) inhibitory activity, and these The compound that deuterium replaces has more excellent pharmacokinetic property.
Background technique
It is anxious as caused by the infection of influenza virus that influenza, which is referred to as influenza (influenza or flu), Property respiratory infectious disease, has become the highest viral infection disease of lethality.The old man of over-65s, 2 years old youngster below Virgin and crowd with chronic respiratory disease and cardiovascular disease is easier that influenza complications occur, therefore is the high-risk of influenza Crowd.In 20th century, there are extensive flu outbreak three times, spanish influenza in 1918, nineteen fifty-seven Asia influenza and nineteen sixty-eight perfume Port influenza.Wherein, spanish influenza (H1N1) is destructive, and death toll has been more than the World War I, has infected generation The population on boundary 30% causes at least 20,000,000 people death.Other flu outbreaks twice are H2N2 and H3N2 type influenza disease respectively Caused by poison, although scale is smaller, up to a hundred people's death is also resulted in.The one plant of novel Influenza A H1N1 occurred in 2009 Virus causes the first time flu outbreak of 21 century, and research finds that the gene of this virus contains the mankind, pig and birds It is a kind of recombinant virus etc. the gene order of a variety of influenza viruses.In short several months, which spreads to rapidly complete Ball causes great fear.The World Health Organization will guard against by three-level, repeatedly be promoted, until being highest six grades.
Influenza virus is divided into first, second, third (also referred to as A, B, C) according to the difference of nucleoprotein and stromatin antigenic characteristic Three types.The host range of influenza A virus is most wide, can infect people, pig, horse and birds, and pathogenicity is strong, Neng Gouyin World's flu outbreak is played, it is maximum to the harm of the mankind；Influenza B virus main infection people and pig, pathogenecity is lower, energy Influenza is caused locally to break out；Influenza virus C only infects the crowd of infant and hypoimmunity, seldom causes prevalence, harm It is relatively small.
Medicine is emitted as influenza, it is well known mainly to have: (1) amantadine (Amantadine) and Rimantadine It (Rimantadine) is the two kinds of anti-influenza virus medicaments relatively to early go public, the main M2 ion channel for passing through blocking virus, suppression Virus uncoating processed and play antivirus action.(2) Oseltamivir phosphate (Oseltamivir Phosphate, trade name: Tamiflu (Tamiflu), Roche development), (Zanamivir, trade name: Yi Lewei (Relenza), GlaxoSmithKline PLC is ground zanamivir System), it is neuraminidase inhibitor, curative effect with higher and preferable safety and tolerance, are the head of current anti influenza Select drug.However, there is the problem of appearance of endurance strain, side effect, and there are pathogenicity or the higher novel prevalence of lethal Sexuality emits virosphere and the misgivings such as is very popular, and the influenza therefore it is desirable to develop new mechanism out emits medicine.
About the cap dependence endonuclease as the enzyme for being originated from influenza virus, since it is for virus multiplication For be necessary, and the virus-specific enzymatic activity not having with host, so think the cap dependence endonuclease Enzyme is suitable for the object that influenza emits medicine.The cap dependence restriction endonuclease of influenza virus is before generating with host mRNA Body be substrate and include cap structure 9~13 bases (base of cap structure is simultaneously not included in above-mentioned base quantity) piece The endonuclease activity of section.The segment is functioned as the introduction of viral RNA polymerase, is used for encoded viral proteins MRNA synthesis.I.e., it is believed that inhibit the substance of cap dependence endonuclease by inhibiting the synthesis of virus mRNA to inhibit The synthesis of virus protein, as a result inhibits virus multiplication.
Baloxavir Marboxil (also known as S-033188, chemical name are (((12aR) -12- ((11S) -7,8- bis- Fluoro- 6,11- dihydro-dibenzo (B, E) thiepin -11- base) -6,8- dioxo -3,4,6,8,12,12a- hexahydro -1H- (1,4) Oxazines (3,4-C) pyrido (2,1-F) (1,2,4) triazine -7- base) oxygroup) methyl carbonic acid methyl esters, have following structure) be Japanese Shionogi Seiyaku Kabushiki Kaisha (Shionogl&Co., Ltd) exploitation a pioneering (first-in-class), single dose are real The property tested oral drugs, it is intended to inhibit cap dependence endonuclease in influenza virus, play the role of suppressing virus replication.2016 Years 2 months, the development rights in area other than Japan and TaiWan, China were assigned to Roche by the wild justice of salt.Baloxavir Marboxil is In on 2 23rd, 2018 in Japan by accelerating examination & approval and successfully listing A type for treating adult and child patient and B-mode Influenza, trade name Xofluza.In June, 2018, Roche announce that U.S. FDA has accepted the new drug of Baloxavir Marboxil Apply and be granted by preferential examination qualification, it is contemplated that examination will be made on December 24th, 2018 and determined.Clinical test shows Baloxavir Marboxil only needs single dose (40 or 80mg every time takes 1 day once a day) to be administered, and just can be reduced influenza The duration of symptom, and virus shedding is substantially reduced in one day, compared to Oseltamivir, (each 75mg, one day is secondary, takes 5 days) there is more powerful Anti-viral Treatment, first day after receiving treatment, 50% or more patient (including children) is in vivo Virus titer drop to detection limit hereinafter, in addition to this, it is also highly effective to swin flu (H5N1 or H7N9).
Known poor absorption, distribution, metabolism and/or excretion (ADME) property are to lead to many drug candidate clinical tests The main reason for failure.The many drugs currently listed are also due to poor ADME property limits their application range.Medicine The tachymetabolism of object will lead to many drugs that can efficiently treat disease originally fallen from internal metabolite clearance due to too fast and It is difficult to patent medicine.Frequently or high dose medication is although it is possible to solve the problems, such as that drug is quickly removed, but this method can be brought such as The problems such as side effect caused by patient dependence is poor, high dose is taken medicine and treatment cost rise.In addition, the drug of tachymetabolism Patient may be made to be exposed in undesirable toxicity or reactive metabolin.
Although Baloxavir Marboxil can effectively treat influenza, there are still serious clinics in the field Unmet demand is found to have with good oral administration biaavailability and has the new compound of druggability still to have challenge The work of property.Therefore, this field, which still needs to exploitation, has inhibition cap dependence endonuclease activity and/or preferably medicine for power Compound, the present invention provides such compounds.
Summary of the invention
Against the above technical problems, the invention discloses a kind of polycyclic Pyridione derivatives that novel deuterium replaces and its Prodrug and the composition comprising the compound and application thereof have and preferably inhibit cap dependence endonuclease activity, special It is not that there is preferably pharmacokinetics performance and/or oral administration biaavailability.
In this regard, the invention adopts the following technical scheme:
The first aspect of the present invention provides formula (I) compound:
Wherein,
P is selected from H or-C (R11R12)OC(O)OC(R13R14R15)；
Y1、Y2、Y3、Y4、Y5、Y6、Y7And Y8It is each independently selected from hydrogen or deuterium；
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14And R15It is each independently selected from hydrogen or deuterium；
Additional conditions are that above compound at least contains a D-atom；
Or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvent chemical combination Object.
On the other hand, the present invention provides contain the compounds of this invention or its tautomer, stereoisomer, preceding The pharmaceutical composition of medicine, pharmaceutically acceptable salt, crystal form, hydrate or solvated compounds and pharmaceutically acceptable excipient Object.In a particular embodiment, the compounds of this invention or its tautomer, stereoisomer, prodrug, pharmaceutically acceptable Salt, crystal form, hydrate or solvated compounds are provided in described pharmaceutical composition with effective quantity.In a particular embodiment, originally Invention compound or its tautomer, stereoisomer, prodrug, pharmaceutically acceptable salt, crystal form, hydrate or solvation Object is closed to provide with therapeutically effective amount.In a particular embodiment, the compounds of this invention or its tautomer, stereoisomer, Prodrug, pharmaceutically acceptable salt, crystal form, hydrate or solvated compounds are provided with prevention effective dose.
On the other hand, the present invention provides a kind of pharmaceutical composition as described above or its tautomer, solid are different The preparation method of structure body, prodrug, pharmaceutically acceptable salt, crystal form, hydrate or solvated compounds, comprising the following steps: will Pharmaceutically acceptable excipient and the compounds of this invention or its pharmaceutically acceptable salt, crystal form, hydrate or solvent chemical combination Object is mixed, to form pharmaceutical composition.
On the other hand, the present invention provides a kind of pharmaceutical compositions, and it includes the compounds of this invention or its tautomerisms Body, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds inhibit with neural amino acid enzyme Agent, RNA Dependent RNA polymerase inhibitors, M2 protein inhibitor, PB2Cap binding inhibitors, anti-HA antibody or immune Make the combination of medication.
On the other hand, the present invention provides a kind of the compounds of this invention or its tautomers, stereoisomer, preceding Medicine, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds be used to prepare treatment and prevention with by with cap according to Rely the purposes in the drug of disease caused by the virus of property endonuclease.
On the other hand, the invention further relates to provide one kind in subject treat and/or prevent with by being relied on cap The method of disease caused by the virus of property endonuclease, this method includes the present invention to snibject's therapeutically effective amount Compound or its pharmaceutically acceptable salt, crystal form, hydrate or solvated compounds or pharmaceutical composition.In specific embodiment In, it is oral, subcutaneous, intravenously or intramuscularly interior that the compound is administered.In a particular embodiment, chemical combination described in long term administration Object.
The present invention further provides a kind of cure of influenza infectious disease using prodrug compound or preventive treatment, And the above compound of effect is emitted with influenza.The present invention further provides a kind of female chemical combination of prodrug compound Object.The parent compound system emits agent or the intermediate of the prodrug compound as influenza.
The compound of the present invention has the activity for inhibiting cap dependence endonuclease.Preferred compound is prodrug, Since it becomes the parent compound with the inhibitory activity to cap dependence endonuclease, conduct in vivo upon administration The therapeutic agent and/or prophylactic of influenza infectious disease and it is useful.
By subsequent specific embodiment, embodiment and claim, other objects and advantages of the present invention will be for this Field technical staff is apparent.
Definition
Herein, unless otherwise instructed, " deuterated " refers to one or more hydrogen in compound or group replaced deuterium；Deuterium In generation, can be a substitution, two replace, polysubstituted or full substitution.Term " one or more deuterated " and " one or many deuterated " It is used interchangeably.
Herein, unless otherwise instructed, " non-deuterated compound " refers to ratio containing D-atom not higher than the same position of natural deuterium The compound of cellulose content (0.015%).
Term " pharmaceutically acceptable salt " refers to, in reliable medical judgment scope, is suitble to and people and lower animal Tissue contact without excessive toxicity, irritation, allergy etc., and match with reasonable benefit/hazard ratio Those salt.Pharmaceutically acceptable salt is well known in the art.For example, Berge et al. is in J.Pharmaceutical The pharmaceutically acceptable salt being described in detail in Sciences (1977) 66:1-19.The compounds of this invention it is pharmaceutically acceptable Salt include the salt derived from suitable inorganic and organic bronsted lowry acids and bases bronsted lowry.
The compounds of this invention can be amorphous or crystal form.In addition, the compounds of this invention can be with one or more Crystal form exists.Therefore, the present invention includes all amorphous or crystal form of the compounds of this invention within its scope.Term " crystal form " refers to the different arrangement modes of chemicals molecule, normally behave as medicine material in the solid state there are shapes Formula.A kind of drug can exist with a variety of crystal-form substances states, and the different crystal forms of same drug, dissolution and absorption in vivo can Can be different, thus can dissolution to preparation and release have an impact.
Term " crystal form " refers to the different arrangement modes of chemicals molecule, normally behaves as medicine material in solid state Under existence form.A kind of drug can exist with a variety of crystal-form substances states, the different crystal forms of same drug, in vivo molten Solution and absorb may be different, thus can dissolution to preparation and release have an impact.
As used herein, term " subject " includes but is not limited to: people is (that is, the sex of any age group, example Such as, pediatric subject (for example, baby, children and adolescents) or Adult human subjects (for example, young adult, the adult in middle age or Old adult)) and/or inhuman animal, for example, mammal, for example, primate (for example, machin, rhesus macaque), Ox, pig, horse, sheep, goat, rodent, cat and/or dog.In some embodiments, subject is people.In other realities It applies in scheme, subject is non-human animal.
" disease ", " obstacle " and " illness " interchangeably in this specification uses.
Unless otherwise noted, terms used herein " treatment " include subject with disease specific, obstacle or disease The effect occurred when disease, it reduces disease, the severity of obstruction and illness, or postpones or slow down disease, obstruction and illness Development (" therapeutic treatment "), further include that subject starts with the effect occurred before disease specific, obstacle or disease (" prophylactic treatment ").
In general, " effective quantity " of compound refers to the quantity for being enough to cause target organism to react.As the common skill in this field As art personnel understand, the effective quantity of the compounds of this invention can change according to following factors: for example, biology mesh The age health condition and symptom of mark, the pharmacokinetics of compound, the disease treated, mode of administration and subject.Have Effect amount includes treatment and prevention property therapeutically effective amount.
Unless otherwise noted, " therapeutically effective amount " of compound used herein is in treatment disease, obstacle or disease It is enough to provide the helpful quantity for the treatment of during disease, or prolongs one or more symptoms related with disease, obstruction and illness Late or minimize.The therapeutically effective amount of compound refer to be used alone or with other therapies associated with therapeutic agent quantity, it Treatment benefit is provided during treatment disease, obstruction and illness.Term " therapeutically effective amount " may include improve overall therapeutic, Reduce or avoid disease or illness symptom the cause of disease or enhance other therapeutic agents therapeutic efficacy quantity.
Unless otherwise noted, " prevention effective dose " of compound used herein be enough to prevent disease, obstacle or The quantity of illness, or be enough to prevent the quantity of one or more symptoms related with disease, obstruction and illness, or prevent disease, barrier Hinder or illness recurrence quantity.The prevention effective dose of compound refer to be used alone or with other medicaments associated with therapeutic agent number Amount, it provides prevention benefit during preventing disease, obstruction and illness.Term " prevention effective dose " may include improving always The quantity of body prevention, or the quantity of the other prevention efficiency for preventing medicaments of enhancing.
" combination " and relational language, which refer to, is administered either simultaneously or sequentially therapeutic agent of the invention.For example, the compounds of this invention The unit dosage forms that can be separated with another therapeutic agent are administered either simultaneously or sequentially, or are in single unit dose together with another therapeutic agent Type is administered simultaneously.
Specific embodiment
Compound
So-called " prodrug " in this specification refers to formula (II) compound represented or its pharmacy in reaction equation below Upper acceptable salt, expression is under physiological condition in vivo by by drug metabolic enzyme, hydrolase, gastric acid, intestinal bacterium It is converted into formula (III) compound represented Deng caused decomposition reaction, to show cap dependence endonuclease (CEN) compound of inhibitory activity, and/or CPE inhibitory effect.
(in formula, each symbol is identical as above-mentioned implication)
Prodrug shown in the formula (II) more preferably indicates: bioavilability and/or AUC (the blood medicine when vivo medicine-feeding The area that concentration curve surrounds time shaft) and/or Cmax(the blood concentration peak occurred after administration) is compared with formula (III) institute The compound that the compound shown is improved.
Therefore, the prodrug efficiently absorbed in stomach and/or intestines etc. after being administered to living body (for example, oral administration) to In vivo, it is converted into formula (III) compound represented thereafter, therefore preferably shows compared with compound shown in formula (III) more High treatment and/or preventive effect.
The present invention provides formula (I) compound or its tautomer, stereoisomer, prodrug, crystal form, can pharmaceutically connect Salt, hydrate or the solvated compounds received:
Wherein,
P is selected from H or-C (R11R12)OC(O)OC(R13R14R15)；
Y1、Y2、Y3、Y4、Y5、Y6、Y7And Y8It is each independently selected from hydrogen or deuterium；
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14And R15It is each independently selected from hydrogen or deuterium；
Additional conditions are that above compound at least contains a D-atom.
As the preferred embodiments of the invention, it is same that deuterium isotopic content of the deuterium in deuterated position is at least greater than natural deuterium Position cellulose content 0.015%, is preferably greater than 30%, even more preferably greater than 50%, even more preferably greater than 75%, even more preferably greater than 95%, Even more preferably greater than 99%.
Specifically, Y in the present invention1、Y2、Y3、Y4、Y5、Y6、Y7、Y8、R1、R2、R3、R4、R5、R6、R7、 R8、R9、R10、 R11、R12、R13、R14And R15, deuterium isotopic content is at least 5%, even more preferably greater than 10% in each deuterated position, even more preferably greater than 15%, even more preferably greater than 20%, even more preferably greater than 15%, even more preferably greater than 25%, even more preferably greater than 30%, even more preferably greater than 35%, even more preferably greater than 40%, even more preferably greater than 45%, even more preferably greater than 50%, even more preferably greater than 55%, even more preferably greater than 60%, even more preferably greater than 65%, even more preferably greater than 70%, even more preferably greater than 75%, even more preferably greater than 80%, even more preferably greater than 85%, even more preferably greater than 90%, even more preferably greater than 95%, even more preferably greater than 99%.
As the preferred embodiments of the invention, at least contains a D-atom in the compound of formula (I), more preferably contain Two D-atoms, more preferably containing there are three D-atom, more preferably containing there are four D-atoms, more preferably containing there are five D-atoms, more The D-atom containing there are six goodly, more preferably contains seven D-atoms, more preferably contains eight D-atoms, more preferably contains nine deuteriums Atom more preferably contains ten D-atoms, more preferably contains 11 D-atoms, more preferably contains 12 D-atoms, more preferably Ground contains 13 D-atoms, more preferably contains 14 D-atoms, more preferably contains 15 D-atoms, more preferably contains ten Six D-atoms more preferably contain 17 D-atoms, more preferably contain 18 D-atoms, more preferably contain 19 deuterium originals Son more preferably contains 20 D-atoms, more preferably contains 21 D-atoms, more preferably contains 22 D-atoms, More preferably contain 23 D-atoms.
In a particular embodiment, " Y1、Y2、Y3、Y4、Y5、Y6、Y7And Y8It is each independently selected from hydrogen or deuterium " it include Y1Choosing From hydrogen or deuterium, Y2Selected from hydrogen or deuterium, Y3Selected from hydrogen or deuterium, and so on, until Y8Technical solution selected from hydrogen or deuterium.More specifically Ground, including Y1For hydrogen or Y1For deuterium, Y2For hydrogen or Y2For deuterium, Y3For hydrogen or Y3For deuterium, and so on, until Y8For hydrogen or Y8For deuterium Technical solution.
In another embodiment, " R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14And R15Respectively From independently selected from hydrogen or deuterium " it include R1Selected from hydrogen or deuterium, R2Selected from hydrogen or deuterium, R3Selected from hydrogen or deuterium, and so on, until R15 Technical solution selected from hydrogen or deuterium.More specifically, including R1For hydrogen or R1For deuterium, R2For hydrogen or R2For deuterium, R3For hydrogen or R3For deuterium, And so on, until R15For hydrogen or R15For the technical solution of deuterium.
It is preferably carried out in scheme at one, the present invention relates to a kind of compound of formula (I) or its tautomer, stands Body isomers, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, wherein P is selected from H or-C (R11R12) OC(O)OC(R13R14R15), Y1-Y8For hydrogen, and R1-R15As defined above, additional conditions are that the compound at least contains one D-atom.
Be preferably carried out in scheme at another, the present invention relates to a kind of compound of formula (I) or its tautomer, Stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, wherein P is selected from H or-C (R11R12)OC(O)OC(R13R14R15), Y1-Y8For hydrogen, and R1-R15As defined above, additional conditions are R7-R15At least one of It is deuterium.
Be preferably carried out in scheme at another, the present invention relates to a kind of compound of formula (I) or its tautomer, Stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, wherein P is selected from H or-C (R11R12)OC(O)OC(R13R14R15), Y1-Y8For hydrogen, R1And R2For hydrogen, and R3-R15It is each independently selected from hydrogen or deuterium, additional strip Part is that the compound at least contains a D-atom.
Be preferably carried out in scheme at another, the present invention relates to a kind of compound of formula (I) or its tautomer, Stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, wherein P is selected from H or-C (R11R12)OC(O)OC(R13R14R15), Y1-Y8For hydrogen, R1And R2For hydrogen, and R3-R15It is each independently selected from hydrogen or deuterium, additional strip Part is R7-R15At least one of be deuterium.
Be preferably carried out in scheme at another, the present invention relates to a kind of compound of formula (I) or its tautomer, Stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, wherein P is selected from H or-C (R11R12)OC(O)OC(R13R14R15), Y1-Y8For hydrogen, R1-R2And R4-R6For hydrogen, and R3、R7-R15Be each independently selected from hydrogen or Deuterium, additional conditions are that the compound at least contains a D-atom.
Be preferably carried out in scheme at another, the present invention relates to a kind of compound of formula (I) or its tautomer, Stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, wherein P is selected from H or-C (R11R12)OC(O)OC(R13R14R15), Y1-Y8For hydrogen, R1-R2And R4-R6For hydrogen, and R3、R7-R15Be each independently selected from hydrogen or Deuterium, additional conditions are R7-R15At least one of be deuterium.
In another more preferably embodiment, R7-R10It is identical.
In another more preferably embodiment, R7-R10It is deuterium.
In another more preferably embodiment, R7-R10It is hydrogen.
In another more preferably embodiment, R11-R12It is identical.
In another more preferably embodiment, R11-R12It is deuterium.
In another more preferably embodiment, R11-R12It is hydrogen.
In another more preferably embodiment, R13-R15It is identical.
In another more preferably embodiment, R13-R15It is deuterium.
In another more preferably embodiment, R13-R15It is hydrogen.
Be preferably carried out in scheme at another, the present invention relates to a kind of compound of formula (I) or its tautomer, Stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, wherein P is selected from H or-C (R11R12)OC(O)OC(R13R14R15), Y1-Y8For hydrogen, R1-R2And R4-R6For hydrogen, R3For deuterium, and R7-R15It is each independently selected from Hydrogen or deuterium.
Be preferably carried out in scheme at another, the present invention relates to a kind of compound of formula (I) or its tautomer, Stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, wherein P is selected from H or-C (R11R12)OC(O)OC(R13R14R15), Y1-Y8For hydrogen, R1-R2And R4-R6For hydrogen, R3For deuterium, and R7-R15It is each independently selected from Hydrogen or deuterium, additional conditions are R7-R15At least one of be deuterium.
Be preferably carried out in scheme at another, the present invention relates to a kind of compound of formula (I) or its tautomer, Stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, wherein P is selected from-C (R11R12) OC(O)OC(R13R14R15), Y1-Y8For hydrogen, R1-R2And R4-R6For hydrogen, R3For deuterium, and R7-R15Be each independently selected from hydrogen or Deuterium.
Be preferably carried out in scheme at another, the present invention relates to a kind of compound of formula (I) or its tautomer, Stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, wherein P is selected from-C (R11R12) OC(O)OC(R13R14R15), Y1-Y8For hydrogen, R1-R2And R4-R6For hydrogen, R3For deuterium, and R7-R15Be each independently selected from hydrogen or Deuterium, additional conditions are R7-R15At least one of be deuterium.
Be preferably carried out in scheme at another, the present invention relates to a kind of compound of formula (I) or its tautomer, Stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, wherein P is selected from H or-C (R11R12)OC(O)OC(R13R14R15), Y1-Y8For hydrogen, R1-R2And R4-R6For hydrogen, R7-R10For deuterium, and R3、R11-R15It is respectively independent Ground is selected from hydrogen or deuterium.
Be preferably carried out in scheme at another, the present invention relates to a kind of compound of formula (I) or its tautomer, Stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, wherein P is selected from-C (R11R12) OC(O)OC(R13R14R15), Y1-Y8For hydrogen, R1-R2And R4-R6For hydrogen, R7-R10For deuterium, and R3、R11-R15It is each independently selected from Hydrogen or deuterium.
Be preferably carried out in scheme at another, the present invention relates to a kind of compound of formula (I) or its tautomer, Stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, wherein P is selected from H or-C (R11R12)OC(O)OC(R13R14R15), Y1-Y8For hydrogen, R1-R2And R4-R6For hydrogen, R3And R7-R10For deuterium, and R11-R15Respectively solely On the spot it is selected from hydrogen or deuterium.
Be preferably carried out in scheme at another, the present invention relates to a kind of compound of formula (I) or its tautomer, Stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, wherein P is selected from-C (R11R12) OC(O)OC(R13R14R15), Y1-Y8For hydrogen, R1-R2And R4-R6For hydrogen, R3And R7-R10For deuterium, and R11-R15It selects each independently From hydrogen or deuterium.
Be preferably carried out in scheme at another, the present invention relates to a kind of compound of formula (I) or its tautomer, Stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, wherein P is selected from H or-C (R11R12)OC(O)OC(R13R14R15), Y1-Y8For hydrogen, R1-R2And R4-R6For hydrogen, R13-R15For deuterium, and R3、R7-R12It is respectively independent Ground is selected from hydrogen or deuterium.
Be preferably carried out in scheme at another, the present invention relates to a kind of compound of formula (I) or its tautomer, Stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, wherein P is selected from H or-C (R11R12)OC(O)OC(R13R14R15), Y1-Y8For hydrogen, R1-R2And R4-R6For hydrogen, R3And R13-R15For deuterium, and R7-R12Respectively solely On the spot it is selected from hydrogen or deuterium.
Be preferably carried out in scheme at another, the present invention relates to a kind of compound of formula (I) or its tautomer, Stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, wherein P is selected from-C (R11R12) OC(O)OC(R13R14R15), Y1-Y8For hydrogen, R1-R2And R4-R6For hydrogen, R13-R15For deuterium, and R3、R7-R12It is each independently selected from Hydrogen or deuterium.
Be preferably carried out in scheme at another, the present invention relates to a kind of compound of formula (I) or its tautomer, Stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, wherein P is selected from-C (R11R12) OC(O)OC(R13R14R15), Y1-Y8For hydrogen, R1-R2And R4-R6For hydrogen, R3And R13-R15For deuterium, and R7-R12It selects each independently From hydrogen or deuterium.
Be preferably carried out in scheme at another, the present invention relates to a kind of compound of formula (I) or its tautomer, Stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, wherein P is selected from H or-C (R11R12)OC(O)OC(R13R14R15), Y1-Y8For hydrogen, R1-R2And R4-R6For hydrogen, R7-R10And R13-R15For deuterium, and R3And R11- R12It is each independently selected from hydrogen or deuterium.
Be preferably carried out in scheme at another, the present invention relates to a kind of compound of formula (I) or its tautomer, Stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, wherein P is selected from-C (R11R12) OC(O)OC(R13R14R15), Y1-Y8For hydrogen, R1-R2And R4-R6For hydrogen, R7-R10And R13-R15For deuterium, and R3And R11-R12Respectively Independently selected from hydrogen or deuterium.
Be preferably carried out in scheme at another, the present invention relates to a kind of compound of formula (I) or its tautomer, Stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, wherein P is selected from H or-C (R11R12)OC(O)OC(R13R14R15), Y1-Y8For hydrogen, R1-R2And R4-R6For hydrogen, R3、R7-R10And R13-R15For deuterium, and R11- R12It is each independently selected from hydrogen or deuterium.
Be preferably carried out in scheme at another, the present invention relates to a kind of compound of formula (I) or its tautomer, Stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds, wherein P is selected from-C (R11R12) OC(O)OC(R13R14R15), Y1-Y8For hydrogen, R1-R2And R4-R6For hydrogen, R3、R7-R10And R13-R15For deuterium, and R11-R12Respectively solely On the spot it is selected from hydrogen or deuterium.
As the preferred embodiments of the invention, the compound is following any structure or its is pharmaceutically acceptable Salt, but it is not limited to having structure:
The compounds of this invention may include one or more asymmetric centers, and therefore may exist multiple stereoisomers shape Formula, for example, enantiomter and/or diastereomeric form.For example, the compounds of this invention can be individual enantiomerism Body, diastereoisomer or geometric isomer (such as cis and trans isomer), or can be the mixture of stereoisomer Form, the mixture including raceme mixture and rich in one or more stereoisomers.Isomers can pass through ability Method known to field technique personnel is separated from mixture, which comprises chiral high pressure liquid chromatography (HPLC) and The formation and crystallization of chiral salt；Or preferred isomers can be prepared by asymmetric syntheses.
It will be understood by those skilled in the art that organic compound can form compound with solvent, occur in the solvent Reaction is precipitated or is crystallized out from the solvent.These compounds are known as " solvate ".When solvent is water, compound claims For " hydrate ".Present invention encompasses all solvates of the compounds of this invention.
Term " solvate " refers to the compound or its salt combined with solvent usually formed by solvolysis reaction Form.This physical association may include hydrogen bonding.Conventional solvents include including water, methanol, ethyl alcohol, acetic acid, DMSO, THF, Ether etc..Compound as described herein can be prepared into, for example, crystal form, and can be completely solvated.Suitable solvate includes Pharmaceutically acceptable solvate and further comprise stoichiometry solvate and non-stoichiometric solvate.? Under some cases, the solvate will be separated, for example, when in the lattice of one or more solvent molecules incorporation crystalline solid When." solvate " includes the solvate and separable solvate of solution state.Representative solvate includes water Close object, ethanolates and methanol solvate.
Term " hydrate " refers to the compound combined with water.In general, including the moisture in the hydrate of compound The ratio of the compound molecule number determines in subnumber and the hydrate.Therefore, such as general formula R x can be used in the hydrate of compound H2O is represented, and wherein R is the number that the compound and x are greater than 0.Given compound can form over a kind of hydrate type, packet It includes, for example, (x is greater than 0 and the number less than 1, for example, semihydrate (R for monohydrate (x 1), rudimentary hydrate 0.5H2O)) and polyhydrate (x is number greater than 1, for example, dihydrate (R2H2) and hexahydrate (R6H O2O))。
The compounds of this invention can be amorphous or crystal form (polymorphic).In addition, the compounds of this invention can be with one Kind or a variety of crystal forms exist.Therefore, the present invention includes all amorphous of the compounds of this invention or crystallization within its scope Form.Term " polymorph " refers to crystal form (or its salt, hydrate or the solvent of the compound of particular crystal stacked arrangement Close object).All polymorphs element composition having the same.Different crystal forms usually has different X-ray diffractions Figure, infrared spectroscopy, fusing point, density, hardness, crystal shape, photoelectric property, stability and solubility.Recrystallization solvent, crystallization speed Rate, storage temperature and other factors can lead to a kind of crystal form and are dominant.The various polymorphs of compound can be in different items Pass through crystallization preparation under part.
The invention also includes the compound of isotope labelling, it is those of described but one or more that they are equal to formula (I) Atom is replaced by the atom that atomic mass or mass number are different from the common atomic mass or mass number of nature.It can introduce The example of isotope in the compounds of this invention includes the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, respectively for example2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F and36Cl.It is other same containing above-mentioned isotope and/or other atoms The compounds of this invention, its pro-drug and the compound of position element or the pharmaceutically acceptable salt of the pro-drug all belong to In the scope of the present invention.The compounds of this invention of certain isotope labellings, such as introducing radioactive isotope (such as3H and14C) Those of can be used for drug and/or substrate tissue measure of spread.Tritium, i.e.3H and carbon-14, i.e.14C isotope be it is particularly preferred, Because they are easy preparation and detection.In turn, replaced by heavier isotope, such as deuterium, i.e.2H, since metabolic stability is higher Benefit in treatment can be provided, such as extend Half-life in vivo or reduce volume requirements, thus may be in some cases Preferably.The formula (I) compound and its pro-drug of the present invention of isotope labelling can generally be prepared, and carry out following streams When technique disclosed in journey and/or embodiment and preparation example, heterotope is replaced with the reagent for the isotope labelling being easy to get The reagent of label.
Pharmaceutical composition, preparation and kit
On the other hand, the present invention provides pharmaceutical compositions, and it includes the compounds of this invention (also known as " active groups Point ") and pharmaceutically acceptable excipient.In some embodiments, described pharmaceutical composition includes a effective amount of active group Point.In some embodiments, described pharmaceutical composition includes the active component of therapeutically effective amount.In some embodiments, Described pharmaceutical composition includes the active component of prevention effective dose.
Refer to the pharmacology that will not destroy the compound prepared together for pharmaceutically acceptable excipient of the invention Active non-toxic carriers, adjuvant or mediator.It can be used for pharmaceutically acceptable carrier, adjuvant or the matchmaker in the present composition Agent includes but is not limited to, ion-exchanger, aluminium oxide, aluminum stearate, lecithin, haemocyanin (such as human serum albumin), Buffer substance (such as phosphate), glycine, sorbic acid, potassium sorbate, the partial glyceride mixture of saturated vegetable fatty acid, water, Salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, silica gel, magnesium trisilicate, poly- second Alkene pyrrolidone, the substance based on cellulose, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxy Propylene-block polymer, polyethylene glycol and lanolin.
The invention also includes kit (for example, drug packages).Provided kit may include the compounds of this invention, Other therapeutic agents, and containing the compounds of this invention, other therapeutic agents the first and second containers (for example, bottle, ampoule bottle, Bottle, syringe and/or dispersible packaging or other suitable containers).In some embodiments, the kit provided can be with Include optionally third container, contains the pharmaceutical excipient for dilute or suspend the compounds of this invention and/or other therapeutic agents. In some embodiments, the compounds of this invention in the first container and second container is provided and other therapeutic agents combine to be formed One unit dosage forms.
Pharmaceutical composition provided by the invention can be administered by many approach, including but not limited to: oral administration, stomach External administration, inhalation, local administration, rectally, nasal-cavity administration, oral administration, vagina administration, by implant administration or Other administration modes.For example, parenteral administration used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular Administration, intra-articular administration, intraarterial delivery, synovial membrane intracavitary administration, administration in breastbone, administration in meninges, intralesional administration, Injection or infusion techn with encephalic.
In general, giving a effective amount of compound provided in this article.According to related situation, including treated illness, choosing The administration route selected, the compound actually given, age, weight and the response of individual patient, patient symptom severity, etc. Deng can determine the amount for the compound actually given by doctor.
When for when preventing illness of the present invention, giving in the subject this paper institute formed among the illness danger The compound of offer will be typically based on the suggestion of doctor and be administered under doctor's supervision, and dosage level is as described above.In formation Subject among the danger of specific illness generally includes the subject with the family history of the illness, or passes through heredity examination It tests or screens and determine subject especially those of sensitive to the formation illness.
Various medications can be used, further deliver pharmaceutical composition of the invention.For example, in some embodiments In, it can be with inject administration pharmaceutical composition, for example, in order to improve the concentration of compound in blood quickly to effective level. Bolus dose depends on the target systemic levels of active component, for example, intramuscular or subcutaneous bolus dose keeps active component slow On The Drug Release, and being directly delivered to the injecting of vein (for example, by IV intravenous drip) can more rapidly deliver, so that active The concentration of component in blood is quickly increased to effective level.In other embodiments, it can be given in the form of continuous infusion Pharmaceutical composition, for example, by IV intravenous drip, to provide the active component of Css in subject's body.In addition, In other embodiments, the pharmaceutical composition of bolus dose can be given first, then continuous infusion.
Orally administered composition can be using bulk liquids solution or suspension or bulk powder form.However, more generally, in order to Convenient for the administration of accurately dosage, the composition is provided in a unit.Term " unit dosage forms ", which refers to, to be suitable for as people The physical discrete unit of the dosage unit of class patient and other mammals, each unit include predetermined quantity, be suitable for generate The active material of required therapeutic effect and suitable pharmaceutical excipient.Typical unit dosage form includes liquid composition Ampoule or syringe, or pill, tablet, capsule in solid composite prefilled, measure in advance etc..? In this composition, the compound is usually less component (about 0.1 to about 50 weight %, or preferably from about 1 to about 40 weight Measure %), remainder is the various carriers or excipient and processing aid useful for form of medication needed for being formed.
For oral dose, representative scheme is a daily oral dose.Using these dosage mode of administration, often A dosage provides about 0.01 to about 50mg/kg the compounds of this invention, and preferred dosage respectively provides about 10 to about 40mg/kg, especially about 10 are to about 30mg/kg.
In order to provide with using the similar blood level of injection dosage, or than using the lower blood level of injection dosage, Generally select transdermal dosage compositions, quantity is about 0.01 to about 20% weight, preferably approximately 0.1 to about 20% weight, preferably About 0.1 to about 10% weight, and more preferably from about 0.5 to about 15% weight.
Liquid form suitable for oral administration may include suitable aqueous or nonaqueous carrier and buffer, suspending agent and divide Powder, colorant, flavoring agent, etc..Solid form may include, for example, any following component, or the chemical combination with similarity Object: adhesive, for example, microcrystalline cellulose, bassora gum or gelatin；Excipient, for example, starch or lactose, disintegrating agent, for example, brown Alginic acid, Primogel or cornstarch；Lubricant, for example, magnesium stearate；Glidant, for example, colloidal silicon dioxide；Sweetener, For example, sucrose or saccharin；Or flavoring agent, for example, peppermint, gaultherolin or orange flavoring.
The composition of injectable will be typically based in the Sterile Saline or phosphate buffered saline (PBS) or this field of injectable The excipient of known other injectables.As previously mentioned, in such a composition, reactive compound is typically less group Point, often about 0.05 to 10% weight, remainder is the excipient etc. of injectable.
Transdermal composition is typically formulated as to topical ointments or cream containing active component.When being formulated as ointment When agent, active component is typically combined with paraffin or ointment bases miscible with water.Alternatively, active component can be with such as water packet Oil type emulsifiable paste matrix is formulated as cream together.This preparation capable of permeating skin is it is well known in the art that and generally including for being promoted Other components of the stable Cutaneous permeation of active component or preparation.All this known preparation capable of permeating skin and component are included in this In the range of invention provides.
The compounds of this invention can also be given by transcutaneous device.Therefore, reservoir (reservoir) can be used in percutaneous dosing Or porous film type or the patch of many kinds of solids matrix are realized.
Above-mentioned component for the oral composition given, inject or administered locally to is only representative.Other materials And processing technology etc. is set forth in Remington's Pharmaceutical Sciences, 17th edition, 1985, In the 8th part of Mack Publishing Company, Easton, Pennsylvania, it is incorporated by reference herein The document.
The compounds of this invention can also be given with sustained release form, or give from sustained release administration system.It represents The description of the sustained release materials of property can be found in Remington's Pharmaceutical Sciences.
The invention further relates to the pharmaceutically acceptable preparations of the compounds of this invention.In one embodiment, the system Agent includes water.In another embodiment, the preparation includes cyclodextrine derivatives.The most common cyclodextrin be respectively by 6, 7 and 8 α-Isosorbide-5-Nitrae-connection glucose unit composition α-, β-and gamma-cyclodextrin optionally include in the saccharide part of connection One or more substituent groups comprising but be not limited to: methylation, hydroxy alkylated, acylation and sulfoalkyl ether replaces.? In some embodiments, the cyclodextrin is sulfoalkyl ether beta-cyclodextrin, for example, sulfobutyl ether beta-cyclodextrin, also referred to as Captisol.See, e.g., U.S.5,376,645.In some embodiments, the preparation includes six propyl-beta-cyclodextrins (for example, in water, 10-50%).
Indication
As used herein, term " the compounds of this invention " refers to formula (I) compound represented.The term further includes and formula (I) Tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or the solvated compounds of compound.
The compounds of this invention is anti-influenza virus medicament, has the inhibitory activity to dependence endonuclease, so can For treating and/or preventing epidemic infectious diseases.
Influenza virus is negative adopted single strand RNA virus, and is a member of family, orthomyxoviridae family.There is influenza disease in 3 at present Poison: influenza virus A, influenza virus B and influenzavirus C.Influenza virus A have from host cell lipid film, it includes from Virus surface hemagglutinin outstanding, neuraminidase and M2 protein.According to hemagglutinin (H or HA) and neuraminidase (N) Influenza virus A is further classified.About 16 kinds of H antigens (H1 to H16) and 9 kinds of N antigen (N1 to N9).Influenza virus A packet Include several hypotypes, including H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N7, H7N9, H9N2 and H10N7.The heterotrimer that influenza virus polymerase is made of following 3 kinds of subunits: Polymerase acid (PA), polymerase alkali 1 (PB1) and polymerase alkali 2 (PB2).In the nucleus of infected cell, this polymerase It is responsible for the duplication and transcription of viral RNA.PA subunit includes endonuclease activity position.The endonuclease activity cutting of PA is thin Born of the same parents mRNA, subsequent cell mRNA are used as primer by PB1 subunit and synthesize for virus mRNA.
In some embodiments, a effective amount of the compounds of this invention or pharmaceutical composition as described herein can be used for treating With/improve influenza infection.In other embodiments, a effective amount of the compounds of this invention or medicine group as described herein Closing object can be used for flu-prevention virus infection.
In some embodiments, a effective amount of the compounds of this invention or pharmaceutical composition as described herein can be used for inhibiting The duplication of influenza virus.In other embodiments, a effective amount of the compounds of this invention or pharmaceutical composition as described herein It can be used for inhibiting influenza polymerase complex.In other embodiments, a effective amount of the compounds of this invention or described herein Pharmaceutical composition can be used for inhibiting and/or reducing the activity of cap dependence endonuclease.In other embodiments, have The compounds of this invention of effect amount or pharmaceutical composition as described herein can be used for inhibiting and/or reducing endonuclease cutting mRNA Ability.
In some embodiments, the influenza infection can be influenza A virus infection.In other embodiments In, the influenza infection can be influenza B virus infection.In other embodiments, the influenza infection can To be influenza C virus infection.In some embodiments, the compounds of this invention can be used for treating and/or alleviating one kind of influenza Or a variety of hypotypes.For example, the compounds of this invention can be used for treating H1N1 and/or H3N2.Additionally or alternatively, the compounds of this invention It can be used for treating H2N2, H5N1 and/or H7N9.In some embodiments, the compounds of this invention is effective against more than a kind The influenza of hypotype.For example, the compounds of this invention is effective against the influenza of 2,3,4 and/or 5 kind or more.
In some embodiments, a effective amount of the compounds of this invention or pharmaceutical composition comprising the compounds of this invention can For treating and/or alleviating the infection of the upper respiratory tract as caused by (directly and/or indirectly) influenza infection.In some implementations In scheme, a effective amount of the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be used for treating and/or alleviating The lower respiratory channel virus infection as caused by (directly and/or indirectly) influenza infection.In some embodiments, effective quantity The compounds of this invention or pharmaceutical composition comprising the compounds of this invention can be used for treating and/or alleviating influenza infection One or more symptoms are (for example, cough, throat pain, headache, nasal obstruction, fever or aversion to cold, muscle or joint are to pain, fatigue Deng).In some embodiments, a effective amount of the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be used for Treatment and/or alleviation capillary bronchitis as caused by influenza infection and/or tracheobronchitis.In some embodiments In, a effective amount of the compounds of this invention or the pharmaceutical composition comprising the compounds of this invention can be used for treating and/or alleviating due to Pneumonia caused by influenza infection.
In some embodiments, a effective amount of the compounds of this invention or pharmaceutical composition comprising the compounds of this invention can For mitigating the severity of one or more symptoms of influenza infection.The example of symptom include, but are not limited to it is following, fever, Shiver with cold, cough, sore-throat, rhinorrhea, nasal obstruction, DOMS, physical distress, headache, fatigue, vomiting and/or diarrhea.
In some embodiments, the effective quantity of the compounds of this invention effectively can make virus titer be reduced to reduced levels Amount, for example, about 10E4TCID50/mL (TCID=tissue culture infection dose) is to about 10E3TCID50/mL or to about 100TCID50/mL or to about 10TCID50/mL.In some embodiments, the effective quantity of the compounds of this invention are as follows: with give Virus load before formula (I) compound is compared, and the amount of virus load is effectively reduced.For example, wherein in the change for giving formula (I) Virus load is detected before closing object, and is detected again after being started using the therapeutic scheme of the compound of formula (I) (for example, treatment 1-2 days after beginning).In some embodiments, the effective quantity of the compounds of this invention, which can be, effectively reduces virus load To the amount for being below about 10E4TCID50/mL.In some embodiments, the effective quantity of the compounds of this invention are as follows: in giving construction (I) the virus load before compound is compared, and the virus titer in effective nose/pharynx for realizing individual or nasal douche sample is such as The reduced amount of lower range: reducing about 1.5-log to about 2.5-log or reduces about 3-log to about 4-log.For example, wherein existing Virus load is detected before giving the compound of formula (I), and virus load is detected before the compound using formula (I), and (for example, treatment starts latter 1-2 days) is detected after starting using the therapeutic scheme of the compound of formula (I) again.
In some embodiments, compared with the individual of untreated, the compounds of this invention can produce one or more lifes Total quality health living, such as compared with the individual of untreated, disease duration greatly reduces, disease severity reduces, The time for being restored to the time reduction of normal health and normal activity and mitigating one or more symptoms of virus infection subtracts It is few.In some embodiments, compared with the individual of untreated, the compounds of this invention can cause related with virus infection one The reduction of the length and/or severity of kind or a variety of symptoms.In some embodiments, compared with the individual of untreated, The compounds of this invention can cause it is related with virus infection, include but is not limited to tympanitis (ear inflammation) sinusitis, bronchitis With the reduction of one or more complications of pneumonia.
In some embodiments, relative to level before the treatment of individual, the compounds of this invention can cause virus replication to subtract It is at least 1,2,3,4,5,10,15,20,25,75,100 times or more few, as being measured after therapeutic scheme starts.
After a period of time, infectious agent can develop to it is one or more treatment and drug resistance.Term as used herein is " anti- Pharmacological property " refers to the virus strains to one or more therapeutic agent display delays, reduction and/or zero reaction.For example, using disease-resistant After toxic agent treatment, compared with the amount of the virus load reduction shown by the individual for infecting non-drug-fast strain, drug-resistant pathogen is infected The virus load of the individual of poison can be reduced to smaller extent.In some embodiments, can to infected resist it is one or more not Individual with the influenza virus of anti influenza medicament (for example, amantadine and/or Oseltamivir) gives the compounds of this invention.One In a little embodiments, the compounds of this invention can be given to the individual for the influenza virus for having infected anti-M2 protein inhibitor.Some In embodiment, compared with influenza strain resists the development of other flu pharmaceuticals, but when use the compounds of this invention treatment individual, resist The development of pharmacological property influenza strain postpones.
In some embodiments, compared with the individual percentage for undergoing the complication treated using Oseltamivir, this hair Bright compound can reduce the individual percentage of complication of the experience from influenza infection.For example, using the compound of formula (I) The percentage of the Individual Experience complication for the treatment of is few 10% using individual that Oseltamivir is treated, 20%, 30%, 40%, 60%, 70%, 80% and 90%.
In some embodiments, the individual percentage of the Baloxavir marboxil complication treated is used with experience It compares, the compounds of this invention can reduce the individual percentage of complication of the experience from influenza infection.For example, using formula (I) individual that the percentage of the Individual Experience complication of compound treatment is treated using Baloxavir marboxil is few 10%, 20%, 30%, 40%, 60%, 70%, 80% and 90%.
Conjoint therapy
In some embodiments, the compounds of this invention, or the pharmaceutical composition including compound described herein can be with one Kind or a variety of additional pharmaceutical agent combinations use.In some embodiments, the compounds of this invention can exist at present with one or more Treat the use of pharmaceutical agent combinations used in the routine care standard of influenza.For example, the additional medicament can be amantadine (gold Rigid alkane -1- amine, Symmetrel), rimantadine (Flumadine), zanamivir (Relenza) and Oseltamivir (Tamiflu).Treatment for influenza, additional medicament includes but is not limited to: neuraminidase inhibitor, M2 albumen inhibit Agent, polymerase inhibitors, PB2 inhibitor, Peramivir, La Nina's rice Wei, Favipiravir, La Nina's rice Wei caprylate, influenza Enzyme (DAS181, NexBio), ADS-8902 (amantadine HCl/ Oseltamivir/Ribavirin, Adamas Pharmaceuticals), immunomodulator (for example, I type interferon), beraprost, Ribavirin etc..
In some embodiments, the compounds of this invention can be combined with one or more additional medicaments with single medicine Object is administered together.In some embodiments, the compounds of this invention can with one or more additional medicaments as two kinds or More kinds of individual pharmaceutical composition administrations.For example, the compounds of this invention can be administered with a kind of pharmaceutical composition, and at least A kind of additional medicament can be administered with second of pharmaceutical composition.It is if there is at least two additional medicaments, then described additional The one or more of medicament may be present in the first pharmaceutical composition comprising the compounds of this invention and other are additional At least one of medicament may be present in second of pharmaceutical composition.The compounds of this invention and one or more additional medicaments Order of administration is alterable.In some embodiments, the compounds of this invention can be given before all additional medicaments.At other In embodiment, the compounds of this invention can be given before at least one additional medicament.It is still in other embodiments, originally Invention compound can be administered simultaneously with one or more additional medicaments.Still still in other embodiments, it can give The compounds of this invention is given after at least one additional medicament.In some embodiments, all additional medicines can given The compounds of this invention is given after agent.
In some embodiments, the combination that the compounds of this invention combines one or more additional medicaments can lead to cumulative Effect.In some embodiments, the combination that the compounds of this invention combines one or more additional medicaments can lead to collaboration effect It answers.In some embodiments, the combination that the compounds of this invention combines one or more additional medicaments can lead to strong association Same effect.In some embodiments, the combination that the compounds of this invention combines one or more additional medicaments is not antagonism.
As used herein, term " antagonism " is meant: compared with the summation of compound activity in combination, when individually surveying (single compound is used as) when the activity of fixed each compound, and the activity of compound combination is lower.As used herein, term " synergistic effect " is meant: when individually measuring the activity of each compound, the activity of compound combination is greater than compound in combination Independent active summation.As used herein, term " additive effect " is meant: when individually measuring the activity of each compound, The activity of compound combination is approximately equal to the independent active summation of compound in combination.
Using with one or more additional medicament (including its pharmaceutically acceptable salt and prodrug) groups as described above The potential advantage of the compounds of this invention of conjunction may is that and work as in the compound or its pharmaceutically acceptable salt for being free of formula (I) In the case where give one or more additional medicaments (including its pharmaceutically acceptable salt and prodrug) Shi Shixian identical treatment As a result amount required for is compared, and the one or more additional of morbid state disclosed herein (for example, influenza) is effectively treated Amount required for medicament (including its pharmaceutically acceptable salt and prodrug) decreases.For example, when with administered as monotherapy Realize the amount phase of medicament (including its pharmaceutically acceptable salt and prodrug) additional required for identical virus load is reduced Than, additional medicament (including its pharmaceutically acceptable salt and prodrug) as described above when with the compounds of this invention combination medicine-feeding When amount can be less.Using with one or more as described above additional medicaments (including its pharmaceutically acceptable salt and Prodrug) combination the compounds of this invention another potential advantage is that: with barrier phase when giving compound with monotherapy Than the more Gao Ping to form drug-resistant pathogen toxic bacterial strain can be established using two or more compounds with different role mechanism Barrier.
The method for preparing the compounds of this invention
Known organic synthesis technology can be used to prepare for the compounds of this invention (including its salt), and can be according to a variety of possible conjunctions At any one of approach (those of in all schemes as follows) Lai Hecheng.The reaction for being used to prepare the compounds of this invention can close It is carried out in suitable solvent, the technical staff of organic synthesis field is readily able to select solvent.Suitable solvent can reacted Temperature (for example, in temperature that solvent freezes in temperature to solvent boiling point temperature range) under with initial substance (reactant), in Mesosome or product do not react substantially.Set reaction can carry out in the mixture of a kind of solvent or more than one solvents.Technology Personnel can select the solvent for specific reaction step according to specific reaction step.
The preparation of the compounds of this invention can be related to the protection and removal protection of different chemical groups.Those skilled in the art can It easily determines whether to need to protect and remove protection and the selection of suitable protecting base.The chemical property of protecting group can be found in example Such as Wuts and Greene, Protective Groups in Organic Synthesis, the 4th edition, John Wiley&Sons: New Jersey, (2006) are incorporated herein by reference in their entirety.
The compounds of this invention can be reacted by the racemic mixture of compound with optically active resolving agent to be formed it is a pair of non- Enantiomter compound separates diastereoisomer and recycles the enantiomer of optical purity, is prepared into its single alloisomerism Body.The non-enantiomer derivative of the compounds of this invention can be used to carry out when Chiral Separation, the compound (example that can preferentially dissociate Such as, crystallization of diastereomeric salt).Diastereomer has dramatically different physical property (for example, fusing point, boiling point, solubility, reaction Property etc.), and separation can be readily derived by the advantage of these dissimilarities.Diastereomer can preferably pass through base by chromatography It is separated in separation/fractionation technology of the difference of solubility.Then by will not racemization any practical means, recycling light Pure enantiomer is learned, together with resolution reagent.The technology of compound stereoisomer is obtained suitable for splitting since racemic mixture More detailed description be found in Jean Jacques, Andre Collet, Samue1H.Wilen, " enantiomer, raceme and Split " (" Enantiomers, Racemates and Resolutions "), John Wiley And Sons, Inc., 1981.
Reaction can be monitored according to any suitable method known in the art.For example, spectrum means (such as nuclear-magnetism can be passed through Resonance (NMR) spectroscopic methodology (such as1H or13C), infrared (IR) spectroscopic methodology, spectrophotometry (for example, UV- visible light), mass spectrum (MS)) it or by chromatographic process (such as high performance liquid chromatography (HPLC) or thin-layered chromatography (TLC)) to monitor product is formed.
In common synthetic method and embodiment, the meaning respectively abridged is as described below.
Boc: tert-butoxycarbonyl
DBU: diazabicycloundecene
DMA:N, N- dimethyl acetamide
DMF:N, dinethylformamide
NMP:N- methyl pyrrolidone
THF: tetrahydrofuran
OBn: benzyloxy
T3P: propyl phosphonous acid acid anhydride
PPT: para-methylbenzenepyridinsulfonate sulfonate
MSA: methanesulfonic acid
ACN: acetonitrile
MTBE: methyl tertiary butyl ether(MTBE)
Formula (I) compound of the present invention can be by being prepared as following reaction route 1:
Reaction route 1
Wherein R3、R7-R15It is each independently selected from hydrogen or deuterium, and R3、R7-R15It is not all hydrogen.
Formula (C) compound can by formula (A) compound and formula (B) compound in suitable condensing agent (for example, propyl phosphoric acid Acid anhydride (T3P), methanesulfonic acid or p-methyl benzenesulfonic acid), suitable solvent is (for example, DMF, DMA, NMP, THF, ethyl acetate, acetic acid fourth Ester, dioxane equal solvent or these mixed solvent) and suitable alkali (such as sodium carbonate, potassium carbonate, cesium carbonate etc.) exist Lower reaction.The temperature range reacted at about 10 DEG C to 80 DEG C carries out, and can need to complete in about 1-24 hours.Formula (I-1) compound can It is left away and is synthesized (for example, using protective Groups in from formula (C) compound by blocking group Bn Organic Synthesis, Theodora W Green (progress of usual method documented by John Wiley&Sons etc.).Formula (I-2) compound can be by formula (I-1) compound and formula (D) compound in suitable alkali (such as sodium carbonate, potassium carbonate, carbonic acid Caesium etc.) in the presence of using hydroxyl be converted into the usual method of ether (for example, Protective Groups in can be applied Organic Synthesis,Theodora W Green(John Wiley&Sons)、Prog.Med,5:2157-2161 (1985) and side documented by Supplied by The British Library-" The word ' s Knowledge " etc. Method) and obtain formula (I-2) compound.
Formula (A-1) compound can be prepared by following reaction route 2:
Reaction route 2
The preparation route and synthetic method of formula (A-1) compound and formula (E-1) disclose in WO2017/221869A1.
Formula (A-2) compound can be prepared by following reaction route 3:
Reaction route 3
The preparation route and the same formula of synthetic method (A-1) compound of formula (A-2) compound, difference deuterated compound F-2 replaces compound F-1.
Formula (B-1) compound and formula (B-2) compound can be prepared by following reaction route 4:
Reaction route 4
The preparation route and synthetic method of formula (B-1) compound disclose in WO2017/221869A1.Formula (B-2) is changed The contract method and formula (B-1) compound for closing object are the difference is that final step is substituted with deuterated metallic reducing agent NaBH4。
The preparation of midbody compound 9
Synthetic route is as follows:
The synthesis of step 1 compound 3
Compound 1 (2.0g, 1.05mmol) and compound 2 (2.3g, 1.7mmol) are added in DMA (20ml) solution, Solution is heated to 40 DEG C, is then slowly added into sodium tert-butoxide (1.6g, 1.6mmol), is stirred to react at 40 DEG C 3 hours, is reacted It is cooled to room temperature after completely, it is about 7 that acetic acid tune pH value, which is then slowly added dropwise, and 10ml water is added, and is extracted with methylene chloride (50ml × 3) It taking, merges organic phase, anhydrous sodium sulfate is dry, concentrate progress post separation (eluant, eluent: petrol ether/ethyl acetate (v/v)= 10:1), white solid 2.1g, yield 72% are obtained.
The synthesis of step 2 compound 4
Compound 3 (2.0g, 7.2mmol) is added in ethyl alcohol (10ml) and water (10ml), solution is heated to 60 DEG C, Then hydrazine hydrate (0.7g, 14.3mmol) is added, is stirred to react 4 hours at 60 DEG C, slowly add 20% hydrogen-oxygen after fully reacting again Changing sodium water solution tune pH is about 13, is extracted with methylene chloride (100ml × 3), and organic phase is merged, and anhydrous sodium sulfate is dry, concentration, Concentrate is directly thrown in next step.
The synthesis of step 3 compound 6
Successively by compound 5 (5.0g, 20.5mmol), iodomethane (3.5g, 24.4mmol), DBU (6.3g, 40.7mmol) It is added into DMF (20ml) liquid, which reacts 20h at room temperature, 80ml water is then added, then with ethyl acetate (60ml × 3) it extracts, merges organic phase, anhydrous sodium sulfate is dry, and concentrate carries out post separation (eluant, eluent: petrol ether/ethyl acetate (v/v)=5:1), obtain yellow solid 3.6g, yield 69%.
The synthesis of step 4 compound 7
Successively by compound 6 (0.5g, 1.8mmol), para-methylbenzenepyridinsulfonate sulfonate (1.38g, 5.5mmol), NH2NHBoc (0.36 g, 2.7mmol) is added into DMA (10ml) liquid, and 15h is reacted at 60 DEG C, 20ml water is then added, then with acetic acid second Ester (30ml × 3) extraction merges organic phase, and anhydrous sodium sulfate is dry, and concentrate carries out post separation (eluant, eluent: petroleum ether/acetic acid Ethyl ester (v/v)=4:1), obtain yellow solid 0.6g, yield 80%.
The synthesis of step 5 compound 8
Successively by compound 7 (1.0g, 2.7mmol), compound 4 (0.8g, 5.3mmol), it is added to THF (20ml) liquid In, 2 drop DBU are then added dropwise, which reacts 20h at 60 DEG C, is then spin-dried for reaction solution, is added 20ml water, then with acetic acid second Ester (30ml × 3) extraction merges organic phase, and anhydrous sodium sulfate is dry, and concentrate carries out post separation (eluant, eluent: petroleum ether/acetic acid Ethyl ester (v/v)=4:1), obtain solid 0.7g, yield 54%.
The synthesis of step 6 compound 9
Successively compound 8 (1.5g, 3.1mmol), methanesulfonic acid (0.43g, 4.5mmol) are added to acetonitrile (20ml) liquid In, which reacts 5h at 60 DEG C, is then spin-dried for reaction solution, 20ml water is added, then extracted with ethyl acetate (30ml × 3), Merging organic phase, anhydrous sodium sulfate is dry, and concentrate carries out post separation (eluant, eluent: petrol ether/ethyl acetate (v/v)=1:2), Obtain solid 0.5g, yield 51%.
The preparation of midbody compound 17
Synthetic route is as follows:
The synthesis of step 1 compound 11
Under the conditions of 0 DEG C, by LiAlD4(7.2g, 170.9mmol) be slowly added into compound 10 (10.0g, In tetrahydrofuran (150ml) solution 85.6mmol), reaction solution is warming up to back flow reaction 10h again after adding.After fully reacting It is cooled to 0 DEG C, then plus water quenching reaction, diatomite filtering are directly spin-dried for filtrate, obtain liquid 4.4g, directly throw next step.
The synthesis of step 2 compound 13
Successively by compound 12 (5.0g, 34.0mmol), compound 11 (4.4g, 68.0mmol), nine water ferric nitrates (1.3g, 3.4mmol) is added into toluene (40ml) liquid, which reacts 15h at 115 DEG C, and 20ml water is then added, It being extracted again with ethyl acetate (50ml × 3), merges organic phase, anhydrous sodium sulfate is dry, concentrate progress post separation (eluant, eluent: Petrol ether/ethyl acetate (v/v)=5:1), obtain white solid 3.9g, yield 59%.
The synthesis of step 3 compound 14
Compound 13 (4.0g, 21.0mmol) and compound 2 (4.6g, 34mmol) are added in DMA (20ml) solution, Solution is heated to 40 DEG C, is then slowly added into sodium tert-butoxide (3.2g, 3.2mmol), is stirred to react at 40 DEG C 3 hours, is reacted It is about 7 that acetic acid tune pH value is slowly added dropwise after completely again, and 10ml water is added, is extracted with methylene chloride (50ml × 3), merges organic Phase, anhydrous sodium sulfate is dry, and concentrate carries out post separation (eluant, eluent: petrol ether/ethyl acetate (v/v)=10:1), obtains white Color solid 3.7g, yield 63%.
The synthesis of step 4 compound 15
Compound 14 (2.0g, 7.2mmol) is added in ethyl alcohol (10ml) and water (10ml), solution is heated to 60 DEG C, hydrazine hydrate (0.7g, 14.3mmol) then is added, is stirred to react 4 hours at 60 DEG C, slowly adds 20% hydrogen after fully reacting again Aqueous solution of sodium oxide tune pH value is about 13, is extracted with methylene chloride (100ml × 3), and organic phase is merged, and anhydrous sodium sulfate is dry, Concentration, concentrate are directly thrown in next step.
The synthesis of step 5 compound 16
Successively compound 7 (1.0g, 2.7mmol) and compound 15 (0.8g, 5.3mmol) are added to THF (20ml) liquid In, 2 drop DBU are then added dropwise, which reacts 20h at 60 DEG C, is then spin-dried for reaction solution, is added 20ml water, then with acetic acid second Ester (30ml × 3) extraction merges organic phase, and anhydrous sodium sulfate is dry, and concentrate carries out post separation (eluant, eluent: petroleum ether/second Acetoacetic ester (v/v)=4:1), obtain solid 0.8g, yield 60%.
The synthesis of step 6 compound 17
Successively compound 16 (1.0g, 2.1mmol) and methanesulfonic acid (0.3g, 3.0mmol) are added to acetonitrile (20ml) liquid In, which reacts 5h at 60 DEG C, is then spin-dried for reaction solution, 20ml water is added, then extracted with ethyl acetate (30ml × 3), Merging organic phase, anhydrous sodium sulfate is dry, and concentrate carries out post separation (eluant, eluent: petrol ether/ethyl acetate (v/v)=1:2), Obtain solid 0.45g, yield 68%.
The preparation of midbody compound 23
Synthetic route is as follows:
The synthesis of step 1 compound 19
Under nitrogen protection, compound L DA (35ml, 70mmol) is added into anhydrous THF (50ml) liquid, solution drop To after -40 DEG C, be then added dropwise again in the tetrahydrofuran solution of compound 18 (5g, 31.6mmol), after adding at such a temperature after Continuous reaction 1.5h, is then slowly added into DMF (5.74g, 78.5mmol) into above-mentioned reaction solution again, adds hydrochloric acid after adding (34ml, 6 mol/L), are stirred for ten minutes, then are extracted with ethyl acetate (50ml × 3), merge organic phase, and anhydrous sodium sulfate is dry It is dry, it is concentrated to get yellow liquid 6g.
The synthesis of step 2 compound 20
Benzenethiol (3.9g, 35.4mmol) and d-camphorsulfonic acid (1.6g, 5.0mmol) are added to above compound 6 Toluene solution in, 4h is then stirred to react at 60 DEG C, after fully reacting, 0 DEG C when cooling, sodium hydroxide is then added (10ml, 2mol/L) is being washed with water then with toluene extraction (20ml × 3) extraction, merges organic phase, and anhydrous sodium sulfate is dry Dry, concentration, concentrate is directly thrown in next step.
The synthesis of step 3 compound 21
Alchlor (5.52g, 41.4mmol) is added in toluene (30ml), solution is cooled to 0 DEG C, then by four Tetramethyldisiloxane (5.56g, 41.4mmol) is slowly added dropwise in above-mentioned solution, then at room temperature by compound 20 again slowly It is added in above-mentioned solution, reacts 3h after adding at room temperature, slowly add 15% sulfuric acid (35ml) again after fully reacting, then use second Acetoacetic ester (50ml × 3) extraction merges organic phase, and anhydrous sodium sulfate is dry, and concentration is dry, then is beaten with petroleum ether, obtains white Solid 7g, 79%.
The synthesis of step 4 compound 22
Compound 21 (7.0g, 25.0mmol) is added in polyphosphoric acids (30ml), solution is warming up to 120 DEG C, it should At a temperature of react 3h, slowly reaction solution is poured into ice water again after fully reacting, then with ethyl acetate (60ml × 3) extract, Merging organic phase, anhydrous sodium sulfate is dry, and concentration is dry, then is beaten with petroleum ether, obtain white solid 5g, 77%.
The synthesis of step 5 compound 23
Under the conditions of 40 DEG C, by NaBH4(0.4g, 11.5mmol) is added to the isopropyl of compound 22 (2.0g, 7.6mmol) In alcohol alcohol (20ml) solution, reaction 1h is then proceeded to.Then it is reacted with the hydrochloric acid of 1M, methylene chloride (30ml × 2) extraction, Merge organic phase, anhydrous sodium sulfate, which dries, filters, to be spin-dried for, and gray solid product 1.8g is obtained.
The synthesis of midbody compound 24
Using following synthetic route:
Under the conditions of 40 DEG C, by NaBD4(0.5g, 11.5mmol) is added to the isopropyl of compound 22 (2.0g, 7.6mmol) In alcohol alcohol (20ml) solution, reaction 1h is then proceeded to.Then it is reacted with the hydrochloric acid of 1M, methylene chloride (30ml × 2) extraction, Merge organic phase, anhydrous sodium sulfate, which dries, filters, to be spin-dried for, and gray solid product 1.8g is obtained.
(((12aR) -12- (fluoro- 6,11- dihydro-dibenzo (B, the E) thiepin -11- base-of (11S) -7,8- two of embodiment 1 11-d) -6,8- dioxo -3,4,6,8,12,12a- hexahydro -1H- (1,4) oxazines (3,4-C) pyrido (2,1-F) (1,2,4) Triazine -7- base) oxygroup) methyl carbonic acid methyl esters (compound T-1) preparation
Synthetic route is as follows
The synthesis of step 1 compound 25
Successively by compound 9 (0.5g, 1.5mmol), compound 24 (0.45g, 1.5mmol) and T3P (0.73g, It 2.3mmol) is added into ethyl acetate (6ml) liquid, then adds methanesulfonic acid (0.29g, 3.0mmol), which exists, 6 h are reacted at 70 DEG C, 10ml water are then added, then extracted with ethyl acetate (20ml × 3), are merged organic phase, anhydrous sodium sulfate Dry, concentrate carries out post separation (eluant, eluent: petrol ether/ethyl acetate (v/v)=1:2), obtains white solid 0.6g, yield 69%.
The synthesis of step 2 compound 26
Compound 25 (0.6g, 1.0mmol) and lithium chloride (0.23g, 5.0mmol) are added in DMA (10ml), it will be molten Liquid is warming up to 80 DEG C, reacts 3h at this temperature, again slowly pours into reaction solution in ice water after fully reacting, then uses ethyl acetate (20 ml × 3) extraction merges organic phase, and anhydrous sodium sulfate is dry, and concentration is dry, then is beaten with MTBE, obtains white solid 0.4g, yield 81%.
The synthesis of step 3 compound 27
Successively by compound 26 (0.3g, 0.61mmol), methyl chloromethyl ester (0.15g, 1.3mmol), potassium carbonate (0.2g, 1.22mmol), potassium iodide (0.1g, 0.61mmol) are added into DMA (6ml) liquid, which exists, anti-at 50 DEG C 6h is answered, 10ml water is then added, then extracted with ethyl acetate (20ml × 3), merges organic phase, anhydrous sodium sulfate is dry, concentration Liquid carries out post separation (eluant, eluent: DCM/MeOH (v/v)=20:1), obtains white solid 0.21g.
The synthesis of step 4 compound T-1
The compound 27 of 0.21g is dissolved in 20mL methanol, (instrument: SFC-80 is prepared using following condition (Thar,Waters)；Chiral column: OJ-H 20*250mm, 10um (Daicel)；Column temperature: 35 DEG C；Mobility: CO2/ methanol (contains 0.2% ammonia methanol)=87/13；Flow velocity: 80g/min；Column pressure: 100bar；Detection wavelength: 214nm；Circulation time: 6.0min； Each sampling volume: 1.0mL), four isomers are obtained, chiral analysis (instrument: Agilent is carried out using following condition 1200；Chiral column: IG 4.6 × 250mm, 5um (Decial)；Column temperature: 25 DEG C；Mobile phase: n-hexane (contains 0.1 diethylamine): Ethyl alcohol (containing 0.1% diethylamine)=60:40；Flow velocity: 1.0mL/min；Detection wavelength: 214nm；Sample volume: 15uL), wherein protecting Staying time=35.65min is compound T-1, white compound 45mg.LC-MS:m/z=573.2 (M+1)+,UV 214；1H NMR(500MHz,CDCl3)δ/ppm:7.14-7.08(m,4H), 7.03-7.00(m,1H),6.89-6.87(m,1H),6.83- 6.81 (m, 1H), 5.99 (s, 2H), 5.87 (d, J=7.5Hz, 1H), 5.27 (dd, J=14.0 Hz, J=2.5Hz, 1H), 4.63 (dd, J=14.0Hz, J=2.5Hz, 1H), 4.51 (dd, J=10.0Hz, J=2.5Hz, 1H), 4.06 (d, J=14.0 Hz, 1H), 3.93 (dd, J=11.0Hz, J=3.0Hz, 1H), 3.86 (s, 3H), 3.76 (dd, J=11.0Hz, J=3.0Hz, 1H), 3.55 (t, J=10. 5Hz, 1H), 3.46-3.41 (m, 1H), 2.96-2.91 (m, 1H)
(((12aR) -12- (fluoro- 6,11- dihydro-dibenzo (B, the E) thiepin -11- base-of (11S) -7,8- two of embodiment 2 11-d) -6,8- dioxo -3,4,6,8,12,12a- hexahydro -1H- (1,4) oxazines (3,4-C) pyrido (2,1-F) (1,2,4) Triazine -7- base -3,3,4,4-d4) oxygroup) and methyl carbonic acid methyl esters (compound T-2) preparation
Synthetic route is as follows
The synthesis of step 1 compound 28
Successively by compound 17 (0.5g, 1.5mmol), compound 24 (0.45g, 1.5mmol) and T3P (0.73g, It 2.3mmol) is added into ethyl acetate (6ml) solution, then adds methanesulfonic acid (0.29g, 3.0mmol), the reaction solution 6h is being reacted at 70 DEG C, 10ml water is then added, then extracted with ethyl acetate (20ml × 3), is merged organic phase, anhydrous slufuric acid Sodium is dry, and concentrate carries out post separation (eluant, eluent: petrol ether/ethyl acetate (v/v)=1:2), obtains white solid 0.55g, Yield 60%.
The synthesis of step 2 compound 29
Compound 28 (0.5g, 0.86mmol) and lithium chloride (0.2g, 4.3mmol) are added in DMA (10ml), it will be molten Liquid is warming up to 80 DEG C, reacts 3h at this temperature, again slowly pours into reaction solution in ice water after fully reacting, then uses ethyl acetate (20 ml × 3) extraction merges organic phase, and anhydrous sodium sulfate is dry, and concentration is dry, then is beaten with MTBE, obtains white solid 0.33g, 78%.
The synthesis of step 3 compound 30
Successively by compound 29 (0.33g, 0.67mmol), methyl chloromethyl ester (0.20g, 1.4mmol), potassium carbonate (0.25g, 1.4mmol) and potassium iodide (0.1g, 0.67mmol) are added into DMA (6ml) solution, which exists, at 50 DEG C 6h is reacted, 10ml water is then added, then extracted with ethyl acetate (20ml × 3), merges organic phase, anhydrous sodium sulfate is dry, dense Contracting liquid carries out post separation (eluant, eluent: DCM/MeOH (v/v)=20:1), obtains white solid 0.25g.
The synthesis of step 4 compound T-2
The compound 30 of 0.25g is dissolved in 25mL methanol, (instrument: SFC-80 is prepared using following condition (Thar,Waters)；Chiral column: OJ-H 20*250mm, 10um (Daicel)；Column temperature: 35 DEG C；Mobility: CO2/ methanol (contains 0.2% ammonia methanol)=87/13；Flow velocity: 80g/min；Column pressure: 100bar；Detection wavelength: 214nm；Circulation time: 6.0min； Each sampling volume: 1.0mL), four isomers are obtained, chiral analysis (instrument: Agilent is carried out using following condition 1200；Chiral column: IG 4.6 × 250mm, 5um (Decial)；Column temperature: 25 DEG C；Mobile phase: n-hexane (contains 0.1 diethylamine): Ethyl alcohol (containing 0.1% diethylamine)=60:40；Flow velocity: 1.0mL/min；Detection wavelength: 214nm；Sample volume: 15uL), wherein protecting Staying time=36.53min is compound T-2, white compound 50mg.LC-MS:m/z=577.3 (M+1)+,UV 214；1H NMR(500MHz,CDCl3)δ/ppm:7.14-7.08(m,4H), 7.03-7.00(m,1H),6.89-6.87(m,1H),6.83- 6.81 (m, 1H), 5.99 (s, 2H), 5.87 (d, J=7.5Hz, 1H), 5.27 (dd, J=14.0 Hz, J=2.5Hz, 1H), 4.51 (dd, J=10.0Hz, J=2.5Hz, 1H), 4.06 (d, J=14.0Hz, 1H), 3.93 (dd, J=11.0Hz, J=3.0 Hz, 1H), 3.86 (s, 3H), 3.55 (t, J=10.5Hz, 1H), 3.12-3.08 (m, 1H)
(((the 12aR) -12- (fluoro- 6,11- dihydro-dibenzo (B, the E) thiepin -11- base of (11S) -7,8- two)-of embodiment 3 6,8- dioxo -3,4,6,8,12,12a- hexahydro -1H- (1,4) oxazines (3,4-C) pyrido (2,1-F) (1,2,4) triazine -7- Base) oxygroup) methyl carbonic acid (methyl-d3) ester (compound T-3) preparation
Synthetic route is as follows
Step 1 compound carbonic acid (methyl-d3) chloromethyl ester synthesis
Deuterated methanol (1.0g, 28.7mmol) and triethylamine (3.4g, 34.2mmol) are added to methylene chloride (30ml) In, solution is cooled to 0 DEG C, then chloro-methyl-chloroformate (3.7g, 28.7mmol) is slowly added drop-wise in above-mentioned solution, then 3h is reacted at room temperature, water (10ml) is quenched after fully reacting, DCM (20ml) extraction merges organic phase, and anhydrous sodium sulfate is dry Dry, concentration is dry, obtains liquid 2.8g, yield 78%.
The synthesis of step 2 compound 31
Successively by compound 9 (0.8g, 2.45mmol), compound 23 (0.65g, 2.45mmol) and T3P (1.2g, It 3.7mmol) is added into ethyl acetate (6ml) solution, then adds methanesulfonic acid (0.45g, 4.9mmol), which exists 6h is reacted at 70 DEG C, 10ml water is then added, then extracted with ethyl acetate (20ml × 3), is merged organic phase, anhydrous sodium sulfate is dry Dry, concentrate carries out post separation (eluant, eluent: petrol ether/ethyl acetate (v/v)=1:2), obtains white solid 0.9g, yield 64%.
The synthesis of step 3 compound 32
Compound 31 (0.9g, 1.57mmol) and lithium chloride (0.33g, 7.85mmol) are added in DMA (10ml), it will Solution is warming up to 80 DEG C, reacts 3h at this temperature, again slowly pours into reaction solution in ice water after fully reacting, then uses acetic acid second Ester (20 ml × 3) extraction merges organic phase, and anhydrous sodium sulfate is dry, and concentration is dry, then is beaten with MTBE, obtains white solid 0.6g, 79%.
The synthesis of step 4 compound 33
Successively by compound 32 (0.6g, 1.2mmol), carbonic acid (methyl-d3) chloromethyl ester (0.3g, 2.4mmol), potassium carbonate (0.4g, 2.4mmol) and potassium iodide (0.2g, 1.2mmol) are added into DMA (6ml) liquid, which reacts at 50 DEG C Then 6h is added 10ml water, then is extracted with ethyl acetate (20ml × 3), merge organic phase, anhydrous sodium sulfate is dry, concentrate It carries out post separation (eluant, eluent: DCM/MeOH (v/v)=20:1), obtains white solid 0.55g.
The synthesis of step 5 compound T-3
0.55g compound 33 is dissolved in 50mL methanol, prepared using following condition (instrument: SFC-80 (Thar, Waters)；Chiral column: OJ-H 20*250mm, 10um (Daicel)；Column temperature: 35 DEG C；Mobility: CO2/ methanol (contains 0.2% ammonia Methanol)=87/13；Flow velocity: 80g/min；Column pressure: 100bar；Detection wavelength: 214nm；Circulation time: 6.0min；Each sample introduction Volume: 1.0mL), four isomers are obtained, chiral analysis (instrument: Agilent 1200 is carried out using following condition；Chiral column: IG 4.6×250mm,5um (Decial)；Column temperature: 25 DEG C；Mobile phase: n-hexane (contains 0.1 diethylamine): ethyl alcohol (contains 0.1% Diethylamine)=60:40；Flow velocity: 1.0mL/min；Detection wavelength: 214nm；Sample volume: 15uL), wherein retention time= 37.24min is compound T-3, white solid 100mg.LC-MS:m/z=575.0 (M+1)+,UV 214；1H NMR (500MHz,CDCl3)δ/ppm:7.14-7.08(m,4H), 7.03-7.00(m,1H),6.89-6.87(m,1H),6.83- 6.81 (m, 1H), 5.99 (s, 2H), 5.87 (d, J=7.5Hz, 1H), 5.33 (s, 1H), 5.27 (dd, J=14.0Hz, J= 2.5Hz, 1H), 4.63 (dd, J=14.0Hz, J=2.5Hz, 1H), 4.51 (dd, J=10.0Hz, J=2.5Hz, 1H), 4.06 (d, J=14.0Hz, 1H), 3.93 (dd, J=11.0Hz, J=3.0Hz, 1H), 3.76 (dd, J=11.0Hz, J=3.0Hz, 1H), 3.55 (t, J=10.5Hz, 1H), 3.46-3.41 (m, 1H), 2.96-2.91 (m, 1H)
(((12aR) -12- (fluoro- 6,11- dihydro-dibenzo (B, the E) thiepin -11- base-of (11S) -7,8- two of embodiment 4 11-d) -6,8- dioxo -3,4,6,8,12,12a- hexahydro -1H- (1,4) oxazines (3,4-C) pyrido (2,1-F) (1,2,4) Triazine -7- base) oxygroup) methyl carbonic acid (methyl-d3) ester (compound T-4) preparation
Synthetic route is as follows
The synthesis of step 1 compound 34
Successively by compound 26 (0.5g, 1.01mmol), carbonic acid (methyl-d3) chloromethyl ester (0.26g, 2.06mmol), carbon Sour potassium (0.28 g, 2.06mmol) and potassium iodide (0.1g, 1.01mmol) are added into DMA (6ml) liquid, which exists, and 50 6h is reacted at DEG C, 10ml water is then added, then extracted with ethyl acetate (20ml × 3), is merged organic phase, anhydrous sodium sulfate is dry Dry, concentrate carries out post separation (eluant, eluent: DCM/MeOH (v/v)=20:1), obtains white solid 0.4g.
The synthesis of step 2 compound T-4
0.4g compound 34 is dissolved in 40mL methanol, prepared using following condition (instrument: SFC-80 (Thar, Waters)；Chiral column: OJ-H 20*250mm, 10um (Daicel)；Column temperature: 35 DEG C；Mobility: CO2/ methanol (contains 0.2% ammonia Methanol)=87/13；Flow velocity: 80g/min；Column pressure: 100bar；Detection wavelength: 214nm；Circulation time: 6.0min；Each sample introduction Volume: 1.0mL), four isomers are obtained, chiral analysis (instrument: Agilent 1200 is carried out using following condition；Chiral column: IG 4.6×250mm,5um (Decial)；Column temperature: 25 DEG C；Mobile phase: n-hexane (contains 0.1 diethylamine): ethyl alcohol (contains 0.1% Diethylamine)=60:40；Flow velocity: 1.0mL/min；Detection wavelength: 214nm；Sample volume: 15uL), wherein retention time= 33.77min is compound T-4, white solid 80mg.LC-MS:m/z=576.3 (M+1)+,UV 214；1H NMR (500MHz,CDCl3)δ/ppm:7.14-7.08(m,4H), 7.03-7.00(m,1H),6.89-6.87(m,1H),6.83- 6.81 (m, 1H), 5.99 (s, 2H), 5.87 (d, J=7.5Hz, 1H), 5.27 (dd, J=14.0 Hz, J=2.5Hz, 1H), 4.63 (dd, J=14.0Hz, J=2.5Hz, 1H), 4.51 (dd, J=10.0Hz, J=2.5Hz, 1H), 4.06 (d, J=14.0 Hz, 1H), 3.93 (dd, J=11.0Hz, J=3.0Hz, 1H), 3.76 (dd, J=11.0Hz, J=3.0Hz, 1H), 3.55 (t, J =10.5Hz, 1H), 3.46-3.41 (m, 1H), 2.96-2.91 (m, 1H)
Biological activity test.
(1) metabolic stability is evaluated
Microsomal assay: people's hepatomicrosome (Human liver microsome, HLM): 0.5mg/mL, Xenotech；Greatly Rat hepatic microsome (Rat liver microsome, RLM): 0.5mg/mL, Xenotech；Coenzyme (NADPH/NADH): 1mM, Sigma Life Science；Magnesium chloride: 5mM, 100mM phosphate buffer (pH 7.4).
The preparation of stock solution: precision weighs the powder of a certain amount of embodiment compound and reference substance compound, is used in combination DMSO is dissolved to 5mM respectively.
The preparation of phosphate buffer (100mM, pH=7.4): take the 150mL prepared in advance 0.5M potassium dihydrogen phosphate and The 0.5M dipotassium hydrogen phosphate solution of 700mL mixes, then adjusts mixed liquor pH value to 7.4 with 0.5M dipotassium hydrogen phosphate solution, uses It is preceding to dilute 5 times with ultrapure water, magnesium chloride is added, phosphate buffer (100mM) is obtained, wherein potassium phosphate containing 100mM, 3.3mM Magnesium chloride, pH 7.4.
It prepares NADPH regenerative system solution and (contains 6.5mM NADP, 16.5mM G-6-P, 3U/mL G-6-P D, 3.3mM Magnesium chloride), using it is preposition in it is wet on ice.
Prepare terminate liquid: the acetonitrile containing 50ng/mL Propranolol Hydrochloride and 200ng/mL orinase (internal standard) is molten Liquid.It takes 25057.5 μ L phosphate buffers (pH7.4) into 50mL centrifuge tube, is separately added into 812.5 μ L people's hepatomicrosomes, mix It is even, obtain the hepatomicrosome dilution that protein concentration is 0.625mg/mL.Take 25057.5 μ L phosphate buffers (pH7.4) extremely In 50mL centrifuge tube, 812.5 μ L SD rat liver microsomes are separately added into, are mixed, the liver that protein concentration is 0.625mg/mL is obtained Microsome dilution.
The incubation of sample: being diluted to 0.25mM for the stock solution of respective compound with the aqueous solution containing 70% acetonitrile respectively, It is spare as working solution.It takes people's hepatomicrosome of 398 μ L or rat liver microsomes dilution that 96 holes are added respectively to be incubated in plate (N=2), it is separately added into the working solution of 2 μ L 0.25mM, mixes.
The measurement of metabolic stability: the terminate liquid of 300 μ L pre-cooling is added in every hole of 96 hole deep-well plates, is placed in ice On, as termination plate.96 holes are incubated for plate and NADPH regenerative system is placed in 37 DEG C of water baths, 100 revs/min of concussions are incubated in advance 5min.80 μ L Incubating Solutions addition termination plate is taken out from the every hole of plate is incubated for, mixes, supplements 20 μ L NADPH regenerative system solution, make For 0min sample.Again to the NADPH regenerative system solution for being incubated for 80 μ L of the every hole addition of plate, starting reaction starts timing.Correspondingization The reaction density for closing object is 1 μM, protein concentration 0.5mg/mL.When reacting 10,30,90min, 100 μ L is respectively taken to react Liquid is added in termination plate, and vortex 3min terminates reaction.Termination plate is centrifuged 10min under the conditions of 5000 × g, 4 DEG C.Take 100 μ L Supernatant is mixed to being previously added in 96 orifice plates of 100 μ L distilled water, carries out sample analysis using LC-MS/MS.
Data analysis: by LC-MS/MS system detection respective compound and interior target peak area, calculate compound with it is interior Mark peak area ratio.Slope is measured by the natural logrithm of the percentage of compound surplus and time mapping, and according to following Formula calculates t1/2And CLint, wherein V/M is equal to 1/ protein concentration.
To the compounds of this invention and its not deuterated compound is test compare simultaneously, evaluates it in people and rat liver microsomes The metabolic stability of body.Using without deuterated compound Baloxavir marboxil as reference substance.In people and rats'liver In microsomal assay, by compareing with without deuterated compound Baloxavir marboxil, the compounds of this invention can be bright It is aobvious to improve metabolic stability.The hepatomicrosome experimental result of representative embodiment compound is as shown in table 1 below.
Table 1:
(2) pharmacokinetics in rats is tested
6 male Sprague-Dawley rats, 7-8 week old, weight about 210g are divided into 2 groups, every group 3, through vein or The compound (oral 10mg/kg) of oral single dosage, compares its pharmacokinetic difference.
Rat is raised using standard feed, gives water.Test is fasted for first 16 hours.Drug is sub- with PEG400 and diformazan Sulfone dissolution.Eye socket blood sampling, the time point of blood sampling are 0.25 hour, 0.5 hour, 1 hour, 2 hours, 4 0.083 hour after administration Hour, 6 hours, 8 hours, 12 hours and 24 hours.
Rat sucks of short duration anesthesia after ether, and eye socket acquires 300 μ L sample of blood in test tube.There is 30 μ L, 1% heparinate in test tube Solution.Before use, test tube is stayed overnight in 60 DEG C of drying.After the last one time point blood specimen collection completion, rat etherization After put to death.
It after blood specimen collection, leniently overturns test tube at least 5 times, is placed on ice after guaranteeing mixing sufficiently immediately.Blood sample is 4 DEG C 5000rpm is centrifuged 5 minutes, and blood plasma is separated with red blood cell.100 μ L blood plasma are sucked out to clean plastic centrifuge with pipettor Guan Zhong indicates title and the time point of compound.Blood plasma is stored in -80 DEG C before being analyzed.Blood plasma is measured with LC-MS/MS The concentration of middle the compounds of this invention.Pharmacokinetic parameter is based on every animal blood concentration in different time points into calculating.
Experiment, which shows the compounds of this invention in animal body, has better pharmacokinetic property, therefore has more preferable Pharmacodynamics and therapeutic effect.
(3) external anti-influenza virus activity Strain: influenza virus A/WSN/33 (H1N1), cell: MDCK；
Application cell lesion (CPE) method tests the antiviral activity of test-compound infected by influenza strain, while measuring thin Cellular toxicity.Compound tests 8 concentration, duplicate hole.Cell viability is detected using CCK-8 reagent.Compound initial concentration is 500nM, final concentration of 0.229nM, 3 times of gradient dilutions.
Mdck cell is inoculated in 384 orifice plates with the density in 2000/hole, in 37 DEG C, 5%CO2Overnight incubation.Second day Compound and virus is added, cell (virus-free infection) and virus-infected controls are set.Cell culture DMSO is final concentration of 0.5%.Cell is in 37 DEG C, 5%CO2Culture 5 days to virus control wells cytopathy variability reach 80-95%.Cytotoxicity experiment with Antiviral breeding is identical, but virus-free infection.Cell viability is detected using CCK-8 reagent, initial data is disease-resistant for compound Cytotoxic activity and cytotoxicity calculate.Using GraphPad Prism software analysis of compounds dose-effect curve and calculate EC50With CC50Value.
To the compounds of this invention and its not deuterated compound is test compare simultaneously, evaluates its antiviral activity and cell Toxicity.The result shows that the compounds of this invention shows higher compared with without deuterated compound Baloxavir marboxil CPE inhibitory effect, therefore the compounds of this invention can more efficiently inhibit cap dependence endonuclease in influenza virus (CDE), to play the role of suppressing virus replication.The antiviral activity of representative embodiment compound and the knot of cytotoxicity Fruit is as shown in table 2 below.
Table 2
Embodiment compound EC50(nM) CC50(nM)
Baloxavir marboxil 10.11 >500
T-1 10.05 >500
T-2 3.54 >500
T-3 6.11 >500
T-4 5.94 >500
The above content is a further detailed description of the present invention in conjunction with specific preferred embodiments, and it cannot be said that Specific implementation of the invention is only limited to these instructions.For those of ordinary skill in the art to which the present invention belongs, exist Under the premise of not departing from present inventive concept, a number of simple deductions or replacements can also be made, all shall be regarded as belonging to of the invention Protection scope.

Claims (10)

1. a kind of formula (I) compound or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, water Close object or solvated compounds:
Wherein,
P is selected from H or-C (R11R12)OC(O)OC(R13R14R15)；
Y1、Y2、Y3、Y4、Y5、Y6、Y7And Y8It is each independently selected from hydrogen or deuterium；
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14And R15It is each independently selected from hydrogen or deuterium；
Additional conditions are that above compound at least contains a D-atom.
2. compound described in claim 1, wherein R7、R8、R9、R10、R11、R12、R13、R14And R15At least one of be deuterium.
3. compound of any of claims 1 or 2, wherein R3It is deuterium.
4. the described in any item compounds of claim 1-3, wherein R7、R8、R9And R10It is deuterium.
5. the described in any item compounds of claim 1-4, wherein R11And R12It is deuterium.
6. the described in any item compounds of claim 1-5, wherein R13、R14And R15It is deuterium.
7. compound described in claim 1 is selected from following formula: compound:
Or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds.
8. a kind of pharmaceutical composition contains pharmaceutically acceptable excipient and of any of claims 1-7ization Close object or its tautomer, stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt, hydrate or solvated compounds.
9. compound of any of claims 1-7 or its tautomer, stereoisomer, prodrug, crystal form, pharmacy Upper acceptable salt, hydrate or solvated compounds or pharmaceutical composition according to any one of claims 8 be used to prepare treatment and/ Or prevention and the purposes in the drug of the disease as caused by the virus with cap dependence endonuclease.
10. purposes as claimed in claim 9, wherein the disease as caused by the virus with cap dependence endonuclease is selected from Flu-A, influenza B or influenza C.
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