CN113880831A - A kind of pyrazine dione derivative and use thereof - Google Patents

Abstract

The invention belongs to the field of medicine, in particular to a pyrazine dione derivative and use thereof, its compound and its pharmaceutically acceptable salts and solvates include hydrates, polycrystals, prodrugs, co-crystals and tautomers , Stereoisomer, more specifically, the compounds described in the present invention can be used as anti-influenza drugs with CEN inhibitory effect.

Description

A kind of pyrazine dione derivative and use thereof

Field of Invention

The invention belongs to the field of medicine, in particular to a pyrazine dione derivative and use thereof. More specifically, the compounds of the present invention can be used as anti-influenza drugs with CEN inhibitory effect.

Background technique

Unusually for a virus, its genome is not a single segment of nucleic acid; instead, the genome contains seven or eight segments of negative-sense RNA. The influenza A genome encodes 11 proteins: hemagglutinin (H), neuraminidase (N), nucleoprotein (NP), M1, M2, NS1, NS2 (NEP), PA, PB1, PB1-F2, and PB2 . H and N are macromolecular glycoproteins on the outside of the virus particle. HA is a lectin that mediates viral binding to target cells and entry of the viral genome into target cells, while NA is involved in the release of progeny virus from infected cells by cleaving sugars bound to mature viral particles. Therefore, these proteins have become targets of antiviral drugs. Furthermore, these proteins are antigens for which antibodies can be produced. Influenza A viruses are classified into subtypes based on antibody responses to H and N, forming the basis for the distinction between H and N in, for example, H5N1.

Due to the small size of the influenza virus genome, the synthesis of its required proteins relies on the translation system of the host cell. Therefore, the messenger RNA (mRNA) of influenza virus needs to have both a 5' cap (CAP) structure and a 3'-poly(A) tail structure that can be recognized by the host cell translation system. Among them, the 5' cap structure is "snatched" from the 5' end of the host cell precursor mRNA by the endonuclease activity of the PA subunit in the influenza virus RNA polymerase complex. This method, called "CAP-snatching", captures the CAP cap structure of the host mRNA for transcription of the virus's own mRNA, which is necessary for the initiation of influenza virus transcription.

Because "CAP-snatching" is a key link in the replication cycle of influenza virus, and because there is no similar mechanism and corresponding protease in host cells, inhibitors against "CAP-snatching" endonuclease can selectively block The transcription process of influenza virus does not affect the host cells, that is, it has cap-dependent endonuclease (CEN) inhibition. Thus, this mechanism becomes a potential anti-influenza drug target.

At present, the existing means of preventing and treating influenza virus infection are mainly influenza vaccination and the use of anti-influenza virus drugs. Influenza vaccination is the main preventive method and is highly effective, but it has the major disadvantage that it must be injected once a year and is less effective in immunocompromised and high-risk adults and young children. In addition, if the predicted influenza vaccine type is incorrect, the efficacy of the vaccine will be reduced to 25%. Therefore, anti-influenza virus drugs are the first-line regimen for the treatment of influenza.

So far, the anti-influenza virus drugs approved by FDA for clinical use are roughly divided into two categories: 1) M2 ion channel blockers, including amantadine and rimantadine; 2) neuraminidase inhibitors, mainly including Seltamivir and zanamivir, as well as peramivir and lanamivir, which have been approved in several countries. In addition, currently only the anti-influenza drugs approved for marketing in Japan are the RNA inhibitors favipiravir and Xofluza. Because the current circulating influenza viruses are all resistant to amantadine drugs (the S31N mutation in the viral NS gene), amantadine drugs are no longer the first choice for the prevention and treatment of influenza recommended by WHO. Neuraminidase inhibitors are the main antiviral treatment options for influenza patients. However, researchers have successively discovered H1N1, H5N1, H3N2 and B-type drug-resistant strains that are resistant to oseltamivir, indicating that they are resistant to oseltamivir. The drug situation still deserves our attention.

Therefore, research and development of novel mechanisms such as anti-influenza drugs with CEN inhibition remains very urgent for scientists. Documents 1-5 report the structure and structure-activity relationship of flutamide and 2,4-dioxobutyric acid derivatives as CEN inhibitors. CN201080036154 discloses the synthesis of 3-hydroxy-4-pyridone derivatives as CEN inhibitors, the antiviral effect, especially the biological activity of inhibiting the proliferation of influenza virus. CN201680027747 discloses the synthesis of aza-pyridone compounds as CEN inhibition and methods of alleviating and/or treating diseases and/or disorders including influenza virus infection. WO2017072341A1 discloses the application of pyrimidinone derivatives as CEN inhibitors in the field of antiviral. The compound series disclosed by the above three patents all have a common 2-piperazinone structure, and the present patent has invented novel 5-hexahydropyridazinone derivatives, their synthesis and as an anti-influenza with CEN inhibitory effect Use of drugs.

literature:

1. Tetrahedron Lett 1995, 36(12), 2005;

2. Tetrahedron Lett 1995, 36(12), 2009.

3. Antimicrobial Agents And Chemotherapy, Dec.1994, p.2827－2837

4. Antimicrobial Agents And Chemotherapy, May 1996, p.1304-1307

5. J. Med. Chem. 2003, 46, 1153-1164

SUMMARY OF THE INVENTION

The present invention provides a new class of compounds as influenza virus RNA polymerase inhibitors, more specifically, the present invention provides a new class of compounds of general formula I with CEN inhibitory effect, such compounds and compositions thereof can A medicament for preventing, treating, treating or alleviating a patient's viral infection is prepared.

In one aspect, the present invention relates to a compound, which is a compound represented by general formula I and pharmaceutically acceptable salts and solvates thereof, including hydrates, polycrystals, prodrugs, co-crystals, tautomers, stereoisomers isomer,

Wherein, R ₁ : H or, -C(=O)Y ₁ , -C(=O)-OY ₁ , -(CH ₂ )-O-(C=O)-Y ₁ , -(CH ₂ ) -O-(C=O)-OY ₁ ,

-(CHCH ₃ )-O-(C=O)-Y ₁ and -(CHCH ₃ )-O-(C=O)-OY ₁ ;

Y ₁ is optionally substituted C _1-10 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, mono substituted amino groups, disubstituted amino groups, and -C(R ^* ) _2NHR ^** ; and each R ^* and R ^** is independently hydrogen or optionally substituted _C1-6 alkyl;

R ₂ and R ₃ : can be independently H, C _1-6 alkyl, -C(O)-C _1-6 alkyl, halogen, -CF ₃ , -CN, -COOR ^* , -OR ^* , -( CH ₂ )qNR ^* R ^** ,-C(O)-NR ^* R ^** ; R ₂ and R ₃ can be connected to form a ring to form optionally substituted cycloalkyl, optionally substituted heterocyclyl and optionally Substituted cycloalkenyl; R ^* and R ^** are independently H and optionally substituted C _1-6 alkyl; q is 0-6;

R ₄ or R ₆ is the structure shown below

R ₇ and R ₈ are optionally substituted aryl, and optionally substituted heteroaryl; wherein the substituents are independent C _1-6 alkyl, -C(O)-

_C1-6 alkyl, halogen, _-CF3 , -CN, -COOR ^* , -OR ^* , -( _CH2 )qNR ^* R ^** , -C(O)-NR ^* R ^** ; R ^* and R ^** is independently H and optionally substituted C _1-6 alkyl, and q is 0-6;

_R7 and _R8 can be linked to form the structure shown below:

wherein n and m can be independently 0-3, Q is CR ^* R ^** , NR ^* , O, S, SO, SO2 _; R ^* and R ^** are independently H and optionally substituted C _1-6 alkyl ;

R ₅ : is H, or selected from optionally substituted C _1-8 alkyl, optionally substituted C _2-8 alkenyl, optionally substituted heterocyclyl, optionally substituted C _3-8 cycloalkyl , optionally substituted aryl, and optionally substituted heteroaryl; wherein the substituents can be independent C _1-6 alkyl groups,

-C(O) _-C1-6 alkyl, halogen, _-CF3 , -CN, -COOR ^* , -OR ^* , -( _CH2 )qNR ^* R ^** , -C(O)-NR ^* R ^** , where R ^* and R ^**

independently H and optionally substituted C _1-6 alkyl, q is 0-6;

In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of the compound of the present invention, which is a compound represented by general formula I and pharmaceutically acceptable salts and solvates thereof, including hydrated compounds, polycrystals, prodrugs, co-crystals, tautomers, stereoisomers,

in,

R ₁ : is H;

R ₂ and R ₃ : can be independently H, C _1-6 alkyl, -C(O)-C _1-6 alkyl, halogen, -CF ₃ , -CN, -COOR ^* , -OR ^* ;

R ₂ and R ₃ can form optionally substituted cycloalkyl, optionally substituted heterocyclyl and optionally substituted cycloalkenyl, and R ^* is independently H and optionally substituted C _1-6 alkyl;

R ₄ or R ₆ is the structure shown below

R ₇ and R ₈ are optionally substituted aryl groups, and optionally substituted heteroaryl groups, which can be linked to form the structures shown below:

wherein n and m can be independently 0-3, Q is CR ^* R ^** , NR ^* , O, S, SO, SO2 _; R ^* and R ^** are independently H and optionally substituted C _1-6 alkyl ;

R ₅ : is H, or selected from optionally substituted C _1-8 alkyl, optionally substituted C _2-8 alkenyl, optionally substituted heterocyclyl, optionally substituted C _3-8 cycloalkyl Or R ₅ and R ₆ can form optionally substituted cycloalkyl, optionally substituted heterocyclyl; wherein the substituents can be independent C _1-6 alkyl, -C(O)-C _1-6 alkane base, halogen, -CF ₃ , -CN, -COOR ^* , -OR ^* , R ^* is independently H and optionally substituted C _1-6 alkyl;

In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of the compound of the present invention, which is a compound represented by general formula I and pharmaceutically acceptable salts and solvates thereof, including hydrated compounds, polycrystals, prodrugs, co-crystals, tautomers, stereoisomers,

Wherein, R ₁ : is H;

R ₂ and R ₃ : can be independently H, C _1-6 alkyl, -C(O)-C _1-6 alkyl, halogen, -CF ₃ , -CN;

R ₄ or R ₆ is the structure shown below

R ₇ and R ₈ are optionally substituted aryl groups, and optionally substituted heteroaryl groups, which can be linked to form the structures shown below:

where n and m can be independently 0-3, and Q is O, S, SO, SO ₂ ;

R ₅ : is H, or optionally substituted C _1-8 alkyl, optionally substituted C _2-8 alkenyl, optionally substituted heterocyclyl, optionally substituted C _3-8 cycloalkyl; wherein Substituents can be independent C _1-6 alkyl, -C(O)-C _1-6 alkyl, halogen, -CF ₃ , -CN;

On the other hand, the present invention provides a pharmaceutical composition comprising an effective amount of the compound of the present invention, which is a compound represented by general formula I and pharmaceutically acceptable salts and solvates thereof, including hydrated compounds, polycrystals, prodrugs, co-crystals, tautomers, stereoisomers,

Wherein, R ₁ : is H;

R ₂ and R ₃ : can be independently C _1-6 alkyl, halogen, -CF ₃ , -CN;

R ₄ or R ₆ is the structure shown below

R ₇ and R ₈ are optionally substituted aryl groups, and optionally substituted heteroaryl groups, which can be linked to form the structures shown below:

Among them, n and m can be independently 0-3, and Q is O, S;

R ₅ : is H, or selected from optionally substituted C _1-8 alkyl, optionally substituted C _2-8 alkenyl, optionally substituted heterocyclyl, optionally substituted C _3-8 cycloalkyl ; Wherein the substituents can be independent C _1-6 alkyl, -C(O)-C _1-6 alkyl, halogen, -CF ₃ , -CN;

In some embodiments of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, adjuvant, vehicle or a combination thereof.

In some embodiments, the pharmaceutical compositions provided herein further comprise one or more other therapeutic agents.

In other embodiments, the other therapeutic agent is selected from anti-influenza agents or vaccines.

In other embodiments, the pharmaceutical composition may be in liquid, solid, semi-solid, gel or spray form.

In other embodiments, the pharmaceutical composition of the present invention may include one or more drugs that inhibit the replication of influenza virus infection, selected from the group consisting of neuraminidase inhibitors, M2 protein inhibitors, polymerase inhibitors, PB ₂ Inhibitors, immunomodulators.

In other embodiments, the pharmaceutical composition of the present invention, wherein the other therapeutic agent involved is Amantadine, Rimantadine, Oseltamivir, Zanamivir ), Peramivir, Laninamivir, Laninamivir Octanoate, Favipiravir, Arbidol, Ribavirin ), beraprost (Beraprost), staphylofrin, ingavirin (Ingavirin), influenza enzyme (Fludase), drugs with CAS No. 1422050-75-6, JNJ-872, S-033188, influenza vaccine (FluMist , Quadrivalent, Quadrivalent) or a combination thereof.

In another aspect, the present invention provides the use of the compound or the pharmaceutical composition in the preparation of a medicament, wherein the medicament is used to prevent, alleviate or treat a viral infectious disease in a patient.

In some embodiments, the viral infection is an influenza virus infection.

In other embodiments, the present invention provides the use of the compound or the pharmaceutical composition in the manufacture of a medicament for inhibiting the RNA polymerase of influenza virus.

In other embodiments, the present invention provides use of the compound or the pharmaceutical composition in the manufacture of a medicament for inhibiting cap-dependent endonuclease (CEN).

Unless otherwise specified, the present invention includes all compounds of the present invention and their pharmaceutically acceptable salts, solvates including hydrates, polycrystals, prodrugs, co-crystals, tautomers, stereoisomers.

In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that a substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal to be treated with it.

The compounds of the present invention also include the form of their salts, which are not necessarily pharmaceutically acceptable salts, but which can be used in the preparation and/or purification of the compounds of the present invention and/or in the isolation of isomers of the compounds of the present invention. Intermediate.

The compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents, including water; thus, the present invention also includes solvated and unsolvated forms thereof.

On the other hand, the compounds of the present invention may contain several asymmetric centers or in the form of racemic mixtures generally described. The present invention further includes racemic mixtures, partially racemic mixtures, and separated enantiomers and diastereomers.

The compounds of the present invention may exist in one form of possible isomers, rotamers, atropisomers, tautomers, or mixtures thereof, and the present invention may further include isomers of the compounds of the present invention isomers, rotamers, atropisomers, mixtures of tautomers, or partial mixtures of isomers, rotamers, atropisomers, tautomers, or separated Isomers, rotamers, atropisomers, tautomers.

In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds encompassed by formula I.

The foregoing has outlined only certain aspects of the invention, but is not limited to these aspects. These and other aspects are described in more detail below.

Detailed Description of the Invention

Definitions and General Terms

Unless otherwise indicated, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, and unless otherwise indicated, all patent publications cited throughout this disclosure are by reference It is incorporated into the present invention in its entirety.

As used herein, the articles "a", "an" and "said" are intended to include "at least one" or "one or more" unless stated otherwise or otherwise clearly contradicted by context. Thus, as used herein, these articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in the implementation of the described embodiments.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. A subject also refers to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "patient" refer to animals (eg, birds or mammals such as chickens, quails, or turkeys), particularly "mammals" including non-primates (eg, cows, pigs, etc.) , horses, sheep, rabbits, guinea pigs, rats, cats, dogs and mice) and primates (eg, monkeys, chimpanzees and humans), more particularly humans. In one embodiment, the subject is a non-human animal, such as a domestic animal (eg, horse, cow, pig, or sheep) or a pet (eg, dog, cat, guinea pig, or rabbit). In other embodiments, "patient" refers to a human.

All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers, and mixtures thereof such as racemic mixtures, are also encompassed by the present invention within the range. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes d and l or (+) and (-) are symbols used to designate the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method Spin body.

Depending on the choice of starting materials and methods, the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, for example, as pure optical isomers, or as mixtures of isomers, such as racemic and non-isomeric isomers. A mixture of enantiomers, depending on the number of asymmetric carbon atoms. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be of E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl may be cis or trans (cis- or trans-) structure.

The term "stereoisomers" refers to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, etc. .

A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association in which the solvent molecule is water.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups including hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods such as ion exchange method described in books and literature these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lacturonate, Lactate, Laurate, Lauryl Sulfate, Malonate, Malonate, Mesylate, 2-Naphthalenesulfonate, Nicotinate, Nitrate, Oleate, Palmitate, Pamoate, Pectate, Persulfate, 3 - Phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates quaternary ammonium salts formed from any compound containing an N-group. Water- or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that resist the formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, _{C1 -8} Sulfonates and aromatic sulfonates.

The term "prodrug" as used in the present invention refers to the conversion of a compound into a compound of formula (I) in vivo. Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue. The prodrug compounds of the present invention can be esters. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, carbonate esters , carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to give the compound in prodrug form. Other prodrug forms include phosphates, such as these phosphates are phosphorylated by the hydroxyl group on the parent.

Any asymmetric atom (eg, carbon, etc.) of the compounds of the present invention may exist in a racemic or enantiomerically enriched form, eg, (R)-, (S)-, (R,R)-, (S, Exist in the S)-, (S,R)- or (R,S)- configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 70% enantiomeric excess in the (R)- or (S)-configuration 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. Substituents on atoms with unsaturated double bonds may exist in the form -(Z)- or -(E)-, if possible.

As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or as in the Examples, subclasses, and subclasses encompassed by the present invention. a class of compounds. It is to be understood that the terms "optionally substituted" and "unsubstituted or substituted with" and "substituted or unsubstituted" are used interchangeably. The terms "optionally,""optional," or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances in which the event or circumstance occurs, and instances in which it does not occur or situation. In general, the term "optionally" whether or not preceded by the term "substituted" means that one or more hydrogen atoms in a given structure are unsubstituted or substituted with a specified substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents can be substituted identically or differently at each position. The substituents described therein can be, but are not limited to, F, Cl, Br, I, CN, N ₃ , OH, NH ₂ , NO ₂ , oxo (=O), C _1-12 alkyl, C _{1 -6} haloalkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-12 cycloalkyl, C _3-12 cycloalkyl -C _1-4 alkylene, C _3-12 carbocyclyl, C _3-12 carbocyclyl-C _1-4 alkylene, heterocyclyl composed of 3-12 atoms, (3-12 atoms composed of heterocyclyl)-C _1-4 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, 5-16 atoms composed of heteroaryl or (5 -Heteroaryl consisting of 16 atoms)-C _1-4 alkylene.

In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed in terms of group type or scope. Specifically, the invention includes each and every independent subcombination of each member of these group species and ranges. For example, the term " _C1-6 alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, _C4 alkyl, _C5 alkyl and _C6 alkyl; the term "5-10 atoms consists _of "Heteroaryl" specifically refers to the independently disclosed heteroaryl groups consisting of 5 atoms, heteroaryl groups consisting of 6 atoms, heteroaryl groups consisting of 7 atoms, heteroaryl groups consisting of 8 atoms, and heteroaryl groups consisting of 9 atoms. The heteroaryl group and the 10-atom heteroaryl group.

The term "alkyl" as used in the present invention means a saturated straight or branched chain monovalent hydrocarbon radical containing 1 to 20 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl , 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2- Methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, n-octyl, etc., wherein the alkyl group Groups may independently be unsubstituted or substituted with one or more of the substituents described herein.

As used herein, the term "alkyl" and its prefix "alk" include both straight and branched saturated carbon chains.

The term "cycloalkyl" refers to a saturated, monocyclic, bicyclic or tricyclic ring system having one or more points of attachment to the remainder of the molecule, containing from 3 to 6 ring carbon atoms. In some embodiments, a cycloalkyl group is a ring system containing 3-6 ring carbon atoms, eg, a _C3-6 cycloalkyl group; in some embodiments, a cycloalkyl group is a ring system containing 5-6 ring carbon atoms Ring systems such as _C5-6 cycloalkyl; examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., and the cycloalkyl Groups may independently be unsubstituted or substituted with one or more of the substituents described herein.

The term "heterocyclyl", used alone or as part of "heterocyclylalkyl" or "heterocyclylalkoxy", refers to a saturated or partially unsaturated, non- Aromatic monocyclic, bicyclic or tricyclic ring systems, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms, wherein the heterocyclic group is non-aromatic and does not contain any aromatic rings, and the ring system There is one or more junction points to the rest of the molecule. The terms "heterocyclyl" and "heterocycle" are used interchangeably herein. The term "heterocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems. Bicyclic heterocyclyls include bridged bicyclic heterocyclyls, fused bicyclic heterocyclyls, and spirobicyclic heterocyclyls. In some embodiments, heterocyclyl is a ring system of 3-8 ring atoms; in other embodiments, heterocyclyl is a ring system of 3-6 ring atoms; in other embodiments, Heterocyclyl is a ring system of 5-7 ring atoms; in other embodiments, heterocyclyl is a ring system of 5-8 ring atoms; in other embodiments, heterocyclyl is 6- Ring systems of 8 ring atoms; in other embodiments, heterocyclyl is a ring system of 5-6 ring atoms; in other embodiments, heterocyclyl is a ring system of 4 ring atoms In other embodiments, heterocyclyl is a ring system of 5 ring atoms; in other embodiments, heterocyclyl is a ring system of 6 ring atoms; in other embodiments, heterocyclyl is a ring system of 7 ring atoms; in other embodiments, a heterocyclyl group is a ring system of 8 ring atoms.

Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl , pyrazolinyl, pyrazolidine, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide ring Amyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl , Dioxanyl, Dithianyl, Thioxanyl, Homopiperazinyl, Homopiperidinyl, Oxepanyl, Thiepanyl. Examples of heterocyclyl groups where the _-CH2- group is substituted with -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidine Keto, 3,5-dioxopiperidyl, pyrimidinedione. Examples of the oxidized sulfur atom in the heterocyclyl group include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl. Bridged heterocyclyl groups include, but are not limited to, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2. 1] Octy, etc. The heterocyclyl group may be optionally substituted with one or more substituents described herein.

The term "aryl" may be used alone or as part of an "arylalkyl" or "arylalkoxy" group to mean containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 Monocyclic, bicyclic, and tricyclic aromatic carbocyclic ring systems of 3 ring atoms, wherein at least one ring system is aromatic, each ring contains 3 to 7 ring atoms, and has one or more points of attachment to The rest of the molecule is connected. The term "aryl" may be used interchangeably with the term "aromatic ring" or "aromatic ring", e.g. aryl may include phenyl, naphthyl and anthracenyl. The aryl groups may independently be unsubstituted or substituted with one or more of the substituents described herein.

The term "heteroaryl" may be used alone or as part of "heteroarylalkyl" or "heteroarylalkoxy" to mean containing 5-16 ring atoms, or containing 5-14 ring atoms, or Monocyclic, bicyclic and tricyclic aromatic systems containing 5-12 ring atoms, or containing 5-10 ring atoms, or containing 5-8 ring atoms, or containing 5-7 ring atoms, or containing 5 - a monocyclic ring system of 6 ring atoms, wherein at least one ring system is aromatic and at least one ring contains one or more heteroatoms, wherein each ring contains 5-7 ring atoms, while the heteroatoms Aryl groups have one or more points of attachment to the rest of the molecule. When a _-CH2- group is present in a heteroaryl group, the _-CH2- group can optionally be replaced by -C(=O)-. Unless otherwise specified, the heteroaryl group can be attached to the remainder of the molecule (eg, the host structure in the formula) through any reasonable site (which can be C in CH, or N in NH). The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic". In some embodiments, a heteroaryl group is a heteroaryl group consisting of 5-14 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl group consisting of 5-12 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, Heteroaryl is a heteroaryl group consisting of 5-10 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N; in other embodiments, heteroaryl is a heteroaryl group containing 1, A heteroaryl group consisting of 5-8 atoms of 2, 3 or 4 heteroatoms independently selected from O, S and N; in other embodiments, the heteroaryl group is composed of 1, 2, 3 or 4 Heteroaryl groups consisting of 5-7 atoms of heteroatoms selected from O, S and N; in other embodiments, heteroaryl groups containing 1, 2, 3 or 4 atoms independently selected from O, S and N Heteroaryl groups consisting of 5-6 atoms of heteroatoms; in other embodiments, heteroaryl groups are 5 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N In other embodiments, a heteroaryl group is a 6-atom heteroaryl group containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.

In other embodiments, the heteroaryl group includes, but is not limited to, the following monocyclic groups: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazole base, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl , 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazine base), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5H-tetrazolyl, 2H-tetrazolyl), triazolyl (such as 2-triazolyl, 5-triazolyl azolyl, 4H-1,2,4-triazolyl, 1H-1,2,4-triazolyl, 1,2,3-triazolyl), 2-thienyl, 3-thienyl, pyrazole bases (such as 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl azolyl, 1,3,4-oxadiazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, Pyrazinyl, 1,3,5-triazinyl; also including, but in no way limited to, the following bi- or tricyclic groups: indolinyl, 1,2,3,4-tetrahydroisoquinoline Linyl, 4,5,6,7-tetrahydrobenzofuranyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinoline group (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), Phenoxthiyl, dibenzimidazolyl, dibenzofuranyl, dibenzothienyl, the heteroaryl groups are optionally substituted with one or more of the substituents described herein.

As used herein, the term "pharmaceutically acceptable carrier" includes any solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (eg, antibacterial, antifungal), isotonic agents, Salts, pharmaceutical stabilizers, binders, excipients, dispersants, lubricants, sweeteners, flavoring agents, coloring agents, or combinations thereof, such carriers are known to those skilled in the art. Except in the event that any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.

The term "effective amount" of a compound of the present invention refers to that amount that elicits the expected biological response. In the present invention, the expected biological response is to inhibit influenza virus replication, reduce the amount of influenza virus or reduce or improve the severity, duration, progression or onset of influenza virus infection, prevent the spread of influenza virus infection, and prevent symptoms associated with influenza virus infection. Recurrence, evolution, onset or progression, or enhancement or enhancement of the prophylactic or therapeutic effect of another anti-influenza infection therapy used. The exact amount of compound administered to a subject will depend on the mode of administration, the type and severity of the infection, and the characteristics of the subject, such as health, age, sex, weight, and tolerance to the drug. The skilled artisan will be able to determine appropriate dosages based on these and other factors. When administered in combination with other antiviral agents, such as an anti-influenza drug, the "effective amount" of the second agent will depend on the type of drug used. Appropriate dosages of approved agents are known and can be adjusted by the skilled artisan depending on the condition of the subject, the type of condition being treated, and the amount of the compound of the invention used. In cases where the amount is not clearly indicated, the effective amount should be taken. For example, the compounds of the present invention can be administered to a subject in a dose range of about 0.01-100 mg/body weight/day for therapeutic or prophylactic treatment.

The term "treatment" as used herein refers to both therapeutic and prophylactic treatment. For example, therapeutic treatment includes reducing or ameliorating the progression, severity and/or progression of an influenza virus-mediated condition as a result of administration of one or more therapies (eg, one or more therapeutic agents (eg, compounds and compositions of the invention) or duration, or amelioration of one or more symptoms (in particular, one or more discernible symptoms) of an influenza virus-mediated condition. In certain embodiments, therapeutic treatment comprises amelioration of an influenza virus-mediated condition At least one measurable physical parameter of . In other embodiments, the therapeutic treatment comprises inhibiting an influenza virus-mediated condition physically by, for example, stabilizing discernible symptoms or physiologically, or both by, for example, stabilizing a physical parameter In other embodiments, therapeutic treatment includes reducing or stabilizing influenza virus-mediated infection. Antiviral drugs may be used in the community to treat people already suffering from influenza to reduce the severity of symptoms and reduce the number of days they are sick .

In other embodiments, the present invention relates to one of the following compounds or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof , but in no way limited to these compounds: 4-(10,11-Dihydro-5H-dibenzo[a,d][7]rotaxen-5-yl)-9-hydroxy-2-isopropyl-1H -pyrido[1,2-a]pyrazine-1,3,8(2H,4H)-trione.

In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of the compound of the present invention.

In some embodiments of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, adjuvant, vehicle or a combination thereof.

In some embodiments, the pharmaceutical compositions provided herein further comprise a second drug.

In other embodiments, the second drug is one or more drugs that inhibit the replication of influenza virus infection, selected from the group consisting of neuraminidase inhibitors, M2 protein inhibitors, polymerase inhibitors, PB2 inhibitors, Namivir, oseltamivir, peramivir, laninamivir, laninamivir capnoate, favipiravir, immunomodulators, beraprost, ribavirin.

In another aspect, the present invention provides the use of the compound or the pharmaceutical composition in the manufacture of a medicament for preventing, treating, treating or alleviating a viral infectious disease in a patient.

In some embodiments, the viral infection is an influenza virus infection.

In other embodiments, the present invention provides the use of the compound or the pharmaceutical composition in the manufacture of a medicament for inhibiting the RNA polymerase of influenza virus.

In other embodiments, the present invention provides use of the compound or the pharmaceutical composition in the manufacture of a medicament for inhibiting cap-dependent endonuclease (CEN).

In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that a substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal to be treated with it.

The compounds of the present invention also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts, and which can be used for the preparation and/or purification of the compounds of the present invention and/or for the isolation of the compounds of the present invention enantiomeric intermediates.

Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids such as acetates, aspartates, benzoates, benzenesulfonates, bromides/hydrobromides, bicarbonates/ Carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorophylline, citrate, ethanedisulfonate, fumarate, glucoheptonate, gluconate Sugar, glucuronate, hippurate, hydroiodate/iodide, isethionate, lactate, lacturonate, lauryl sulfate, malate, maleate acid salt, malonate, mandelate, mesylate, methosulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalic acid Salt, Palmitate, Pamoate, Phosphate/Hydrogen Phosphate/Dihydrogen Phosphate, Polygalactonate, Propionate, Stearate, Succinate, Sulfosalicylates, Tartrate , tosylate and trifluoroacetate.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid , ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, etc.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from Groups I to XII of the Periodic Table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include primary, secondary and tertiary amines, substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include, for example, isopropylamine, benzathine penicillin, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moieties, using conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (eg, Na, Ca, Mg or K hydroxide, carbonate, bicarbonate, etc.), or by The free base forms of these compounds are prepared by reaction with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of the two. Generally, where appropriate, the use of non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile is required.

Furthermore, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents, including water; thus, the present invention is intended to include both solvated and unsolvated forms.

Compositions, Formulations and Administration of Compounds of the Invention

The present invention provides a pharmaceutical composition comprising a compound represented by formula (I), formula (I-a) or (I-b) or a stereoisomer thereof, a racemic or non-racemic mixture of isomers or A pharmaceutically acceptable salt or solvate thereof. The pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, diluent, adjuvant or vehicle, and optionally, other therapeutic and/or prophylactic ingredients. In some embodiments, the pharmaceutical composition comprises an effective amount of at least one pharmaceutically acceptable carrier, diluent, adjuvant or vehicle.

A pharmaceutically acceptable carrier may contain inert ingredients that do not unduly inhibit the biological activity of the compound. A pharmaceutically acceptable carrier should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic, or free from other adverse reactions or side effects once administered to a patient. Standard pharmaceutical techniques can be employed.

As described in the present invention, the pharmaceutical composition or pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, adjuvant or excipient, as used in the present invention, including suitable of the target dosage form, any solvent, diluent, liquid excipient, dispersant, suspending agent, surfactant, isotonicity agent, thickener, emulsifier, preservative, solid binder or lubricant, etc. . Except for conventional carrier vehicles that are incompatible with the compounds of the present invention, for example, would produce adverse biological effects or adversely interact with any other component of the pharmaceutically acceptable composition, any conventional carrier vehicles and their Use is also contemplated by the present invention.

Some examples of substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum albumin), buffer substances (eg, Tween 80 , phosphate, glycine, sorbic acid or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g. protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride or zinc salts) , silica gel, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, methylcellulose, hydroxypropylmethylcellulose, lanolin, sugars (eg. lactose, glucose and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate), powdered tragacanth, malt, Gels, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol or polyethylene glycol) ethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution (Ringer'ssolution), ethanol and phosphate buffers, and other non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate) as well as colorants, release agents, coatings, Sweetening and flavoring agents, preservatives and antioxidants can also be present in the compositions.

The compounds or compositions of the present invention may be administered by any suitable means, orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powder, ointment, or drops) depending on the severity of the infection being treated. ), oral administration of the above-described compounds and pharmaceutically acceptable compositions to humans or other animals as an oral or nasal spray and the like.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate Esters, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, poly Fatty acid esters of ethylene glycol and sorbitan and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents, such as sterile injectable aqueous or oily suspensions. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids, such as octadecenoic acid, are used in the preparation of injectables.

Injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter or by the addition of bactericides in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of a compound or composition of the present invention, it is often desirable to slow the absorption of the compound by subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous substances. The rate of absorption of the compound then depends on its rate of dissolution, which in turn depends on crystal size and form. Alternatively, delayed absorption of a parenterally administered compound is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolic acid. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.

Oral solid dosage forms include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or bulking agents such as starch, lactose, sucrose , glucose, mannitol and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerin, d) disintegrants , e.g. agar - agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution blockers, e.g. paraffin, f) absorption accelerators, e.g. quaternary ammonium compounds, g) Wetting agents such as cetyl alcohol and glyceryl monostearate, h) absorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sulfuric acid Sodium lauryl esters and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents.

Similar types of solid compositions can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical art. They may optionally contain opacifying agents and may also be of a compositional nature so as to release only the active ingredient, optionally in a delayed manner, or preferably, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes. Similar types of solid compositions can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

The active compounds may also be presented in microencapsulated form with one or more of the above-described excipients. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings, release controlled coatings and others well known in the pharmaceutical art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose or starch. In general, such dosage forms may also contain additional substances in addition to inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents. They may optionally contain opacifying agents and may also be of a compositional nature so as to release only the active ingredient, optionally in a delayed manner, or preferably, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes.

Dosage forms for topical or transdermal administration of the compounds of this invention include ointments, ointments, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Under sterile conditions, the active compound is combined with a pharmaceutically acceptable carrier and any required preservatives or buffers that may be required. Ophthalmic formulations, ear drops and eye drops are also contemplated within the scope of the present invention. Additionally, the present invention contemplates the use of dermal patches with the added advantage of providing controlled delivery of compounds to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

The compositions described herein may also be administered orally, parenterally, topically, rectally, nasally, bucally, vaginally, or via an implanted kit by inhalation spray. The term "parenteral" as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In particular, the composition is administered orally, intraperitoneally or intravenously.

Sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated using techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as octadecenoic acid and its glyceride derivatives are used in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in polyoxyethylated forms. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersants which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms can also be used for formulation purposes.

The pharmaceutical compositions of the present invention may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral administration, common carriers include, but are not limited to, lactose and starch. Lubricants, such as magnesium stearate, are also usually added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. Certain sweetening, flavoring, or coloring agents may also be added, if desired.

For topical administration, the pharmaceutical composition can be formulated as a suitable ointment containing the active components suspended or dissolved in one or more carriers. Carriers suitable for topical administration of the compounds of this invention include, but are not limited to, mineral oil, petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated as a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water .

For ophthalmic use, the pharmaceutical compositions are formulated as micronized suspensions in isotonic pH adjusted sterile saline, or particularly as solutions in isotonic pH adjusted sterile saline, with or without preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition can be formulated as an ointment, such as petrolatum.

Pharmaceutical compositions can also be administered by nasal vaporized spray or inhalation. This composition is prepared according to techniques well known in the pharmaceutical art and prepared as a solution in saline using benzyl alcohol and other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and/or other conventional solubilizing or dispersing agents solution.

The compounds used in the methods of the present invention can be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form can be presented as a single daily dose or as one of multiple daily doses (eg, about 1-4 or more times per day). When multiple daily doses are used, the unit dosage form can be the same or different for each dose.

In summary, the present invention provides the use of the compound or the pharmaceutical composition in the preparation of a medicament for inhibiting cap-dependent endonuclease (CEN). The compounds of the present invention are suitable for preparing medicines in various dosage forms, and can be widely used for the treatment of seasonal influenza, avian influenza, swine influenza and influenza virus mutant strains resistant to Tamiflu.

In addition to their therapeutic benefits in humans, the compounds and pharmaceutical compositions of the present invention can be used in veterinary treatment of mammals in pets, introduced breeds, and farm animals. Examples of other animals include horses, dogs and cats. Herein, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.

Compared with the existing similar compounds, the compounds of the present invention can not only inhibit influenza virus well, but also have lower cytotoxicity, better in vivo agent kinetic properties and in vivo pharmacodynamic properties. Therefore, the compounds provided by the present invention have better druggability than existing similar compounds.

Detailed ways

To illustrate the invention, the following examples are set forth. It is to be understood, however, that the invention is not limited to these examples, but merely provides methods of practicing the invention.

In this specification, if there is any difference between chemical name and chemical structure, the structure will prevail.

In general, the compounds of the present invention can be prepared by the methods described in the present invention, wherein the substituents are as defined in formula I unless otherwise specified. The following reaction schemes and examples serve to further illustrate the content of the present invention.

The following examples are intended to illustrate the present invention, but not to limit the scope of the present invention.

Preparation Examples

In the following preparation examples, the inventors take some of the compounds of the present invention as examples to describe the preparation process of the compounds of the present invention in detail.

Example 1: 4-(10,11-Dihydro-5H-dibenzo[a,d][7]rotaxen-5-yl)-9-hydroxy-2-isopropyl-1H-pyrido[ Preparation of 1,2-a]pyrazine-1,3,8(2H,4H)-trione (Compound 1)

Obtained by the following reaction:

experiment procedure:

Compound 1a (100g, 480mmol, 1.00eq) was dissolved in the reaction flask with methanol (1L), the temperature was lowered to 0-5°C, NaBH ₄ (36.3g, 960mmol, 2.00eq) was added to the reaction system, after the addition of materials , and the system was stirred at 0 to 5 °C for 2 hours. TLC (petroleum ether:ethyl acetate = 10:1, R _f (R1) = 0.4) spot plate monitoring compound 1 to complete the reaction. The reaction solution was poured into 800 mL of water, filtered, and the filter cake was concentrated to obtain compound 1b (100 g, 476 mmol, white solid, the structure was confirmed by NMR), and the crude product was directly used in the next step. ¹ H NMR: (400MHz, CDCl ₃ ) δ 7.54-7.43 (m, 2H), 7.26-7.14 (m, 6H), 5.97 (d, J=2.8Hz, 1H), 3.52-3.37 (m, 2H) , 3.21-3.06 (m, 2H), 2.36-2.23 (m, 1H).

Compound 1b (100g, 476mmol, 1.00eq) was dissolved in a reaction flask with dichloromethane (1L), cooled to 0-5°C, SOCl ₂ (113g, 951mmol, 69.0mL, 2.00eq) was added to the reaction system, After the addition of materials, the system was stirred at 20-30°C for 12 hours. Without detection, the reaction solution was concentrated, washed with petroleum ether (200 mL) after concentration, filtered, and the filter cake was concentrated to obtain compound 1c (105 g, 459 mmol, 96.5% yield, pink solid, structure confirmed by NMR).

Remarks: Because the activity of the product is too high, it can be decomposed in the presence of water, and neither TLC or LCMS can display the product well. ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.39 (d, J=7.0 Hz, 2H), 7.34-7.28 (m, 2H), 7.26-7.19 (m, 4H), 6.14 (s, 1H), 3.90 -3.72(m,2H),3.10-2.91(m,2H)

Potassium tert-butoxide (64.3g, 572mmol, 1.46eq) was dissolved in the reaction flask with THF (1050mL), cooled to 0-5°C, stirred for 0.25 hours, and compound 1c (105g, 393mmol, 1.00% was added to the reaction system) eq), the system was stirred at 0 to 5 °C for 0.5 hours, and the compound 2-((diphenylmethylene)amino)ethyl acetate (91.6 g, 401 mmol, 1.02 eq) was added to the reaction system at -5 to 5 °C. ), the system was stirred at 0 °C for 3 hours, and the target m/z was generated by LCMS monitoring. The reaction solution was poured into saturated aqueous ammonium chloride solution (1500 mL) at 0-5 °C, extracted with ethyl acetate (500 mL*2), the organic phases were combined and concentrated to obtain compound 1d (150 g, yellow oil), the crude product used directly in the next step.

Compound 1d (150g, 326mmol, 1.00eq) was dissolved in the reaction flask with THF (900mL), and CITRIC ACID (599g, 936mmol, 600mL, 30% purity, 2.87eq) was added to the reaction system. Stir at 80-90 degreeC for 1 hour. TLC (petroleum ether:ethyl acetate=1:1) spot plate monitoring compound 4 reaction complete and new spot formation. The reaction solution was concentrated, diluted with 500 mL of water, and then the impurities were extracted with 200 mL of methyl tert-butyl ether. The pH of the aqueous phase was adjusted to 7-8 with solid sodium carbonate, and then extracted with 2-MeTHF (500 mL*2), and the organic phase was dried. Concentrated, the crude product was separated and purified by column chromatography (SiO ₂ , petroleum ether:ethyl acetate=1:1) to obtain compound 1e (34.0 g, 115 mmol, 35.3% yield, yellow solid, the structure was confirmed by NMR). ¹ H NMR: (400 MHz, CDCl ₃ ) δ 7.26-7.06 (m, 8H), 4.22 (d, J=10.3 Hz, 1H), 3.93-3.84 (m, 2H), 3.82-3.72 (m, 1H) ,3.57-3.45(m,2H),3.05-2.91(m,2H),0.91(t,J=7.2Hz,3H)

Compound 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylate ethyl ester (18.6g, 67.8mmol, 1.00eq) was dissolved in a reaction flask with NMP (300mL), and added to the reaction system Compound 1e (30.1 g, 102 mmol, 1.50 eq) and PPTS (51.1 g, 2035 mmol, 3.00 eq) were added. After the addition of materials, the system was stirred at 140-145 °C for 1 hour. LCMS monitoring has target m/z generation. The reaction solution was poured into water (1200 mL), then extracted with ethyl acetate (500 mL*2), the organic phase was washed with saturated aqueous NaCl solution (300 mL*5), and the organic phase was dried and spin-dried. The crude product was separated and purified by column chromatography (SiO ₂ , petroleum ether:ethyl acetate=1:1) to obtain compound 1f (6.5 g, 11.78 mmol, 17.37% yield, red oil, the structure was confirmed by NMR). ¹ H NMR: (400 MHz, CDCl ₃ ) δ 8.35 (d, J=7.9 Hz, 1H), 7.35-7.29 (m, 4H), 7.22-7.13 (m, 7H), 6.96 (br t, J=7.4 Hz,1H),6.79-6.70(m,1H),6.66(d,J=7.9Hz,1H),5.37(d,J=11.2Hz,1H),5.18(d,J=10.9Hz,1H), 4.86(d,J=11.0Hz,1H),4.42(d,J=11.2Hz,1H),4.28-4.18(m,1H),4.04-3.96(m,1H),3.87- 3.74(m,2H) , 3.43-3.30 (m, 2H), 3.05-2.93 (m, 2H), 1.11 (t, J=7.2Hz, 3H), 0.85-0.80 (m, 3H).

Compound 1f (5.50g, 9.97mmol, 1.00eq), MeOH (27.5mL), NaOH (598mg, 15.0mmol, 1.50eq) and H ₂ O (11mL) were added to the reaction flask together, and the system was at 20-30 degrees Stir for 2 hours. TLC (petroleum ether:ethyl acetate=1:2, R _f (R1)=0.50) spot plate monitoring compound 1f complete reaction and new spot formation. The reaction solution was concentrated, diluted with water (50 mL), then adjusted to pH 1-2 with 1N dilute hydrochloric acid, extracted with ethyl acetate (50 mL), and the organic phase was concentrated. LCMS showed target m/z generation. The crude product was slurried with MTBE (30 mL) at 20-30° C. for half an hour, filtered, and the filter cake was concentrated to obtain compound 1 g (4.50 g, 8.59 mmol, 86.2% yield, red solid, structure confirmed by NMR). ¹ H NMR: (400MHz, DMSO-d ₆ )δ8.61(br d, J=7.6Hz, 1H), 7.35-7.13(m, 12H), 7.04-7.01(m, 1H), 6.42(br d, J=7.7Hz, 1H), 5.10(br d, J=11.2Hz, 1H), 4.94-4.80(m, 3H), 4.28-4.16(m, 1H), 4.13-3.95(m, 1H), 3.25( br s, 2H), 2.97-2.88 (m, 2H), 1.11-1.06 (m, 3H).

Compound 1g (3.50g, 6.68mmol, 1.00eq), DMF (35mL), propan-2-amine (593mg, 10.0mmol, 861uL, 1.5.00eq), DIEA (1.04g, 8.02mmol, 1.40mL, 1.20eq) ) and HATU (3.05g, 8.02mmol, 1.20eq) were added to the reaction flask together, and the system was stirred at 20 to 30 degrees for 1 hour. TLC (petroleum ether:ethyl acetate=1:2, R _f (R1)=0.01)) spot plate monitoring compound 1g complete reaction and new spot formation. The reaction solution was poured into water (140 mL), filtered, and the filter cake was concentrated. LCMS showed target m/z generation. The filter cake was concentrated to obtain compound 1h (3.50 g, crude, red solid, structure confirmed by NMR). ¹ H NMR: (400MHz, DMSO-d ₆ )δ8.66(br d, J=7.9Hz, 1H), 7.30-7.11(m, 12H), 6.97-6.91(m, 1H), 6.32(d, J =7.8Hz,1H),4.95-4.78(m,4H),4.40-4.25(m,1H),4.23-4.07(m,1H),1.09(t,J=7.1Hz,3H),0.90(d, J=6.6Hz, 3H), 0.54 (d, J=6.6Hz, 3H).

Compound 1h (3.50g, 6.20mmol, 1.00eq), KOH (695mg, 12.4mmol, 2.00eq), THF (17.5mL), _H2O (17.5mL) and MeOH (7mL) were added to the reaction flask together, The system was stirred at 20-30 degrees for 1 hour. TLC (petroleum ether:ethyl acetate=1:2, _Rf (R1)=0.50) point plate to monitor the completion of the reaction of compound 8 and the formation of new points. LCMS showed target m/z generation. The reaction solution was concentrated, diluted with water (20 mL), the impurities were extracted with MTBE (10 mL*2), the pH of the aqueous phase was adjusted to 2～3 with 1N dilute hydrochloric acid, filtered, and the filter cake was concentrated to obtain compound 1i (1.80 g, 3.35 mmol, 54.1% yield, yellow solid, structure confirmed by NMR). ¹ H NMR: (400MHz, DMSO-d ₆ )δ8.63-8.51 (m, 2H), 7.31 (br d, J=4.4Hz, 5H), 7.22-7.06 (m, 8H), 6.99-6.92 (m ,1H),6.32(d,J＝7.7Hz,1H),5.43(br d,J＝11.6Hz,1H),5.08(d,J＝11.0Hz,1H),4.91-4.72(m,2H), 3.99-3.82 (m, 1H), 3.56-3.48 (m, 1H), 2.94-2.86 (m, 2H), 1.06-0.95 (m, 6H).

Compound 1i (1.20g, 2.24mmol, 1.00eq), DIEA (1.16g, 8.94mmol, 1.56mL, 4.00eq), TFAA (939mg, 4.47mmol, 622uL, 2.00eq) and THF (12mL) were added to the reaction together In the bottle, the system was stirred at 30-40°C for 12 hours. TLC (petroleum ether:ethyl acetate=1:2, _Rf (R1)=0.01)) spot plate monitoring compound 9 remained and new spots were formed. The reaction solution was diluted with ethyl acetate (20 mL), then washed with water (10 mL*2), and the organic phase was dried and concentrated. LCMS showed target m/z generation. The crude product was separated and purified by column chromatography to obtain compound 1j (0.20 g, 386 umol, 17.3% yield, red solid, structure confirmed by NMR). ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 7.53 (d, J=7.1 Hz, 2H), 7.41-7.36 (m, 2H), 7.34-7.30 (m, 1H), 7.22-7.08 (m, 7H),6.90-6.78(m,2H),6.47(d,J=7.6Hz,1H),5.92(d,J=7.5Hz,1H),5.69(d,J=10.1Hz,1H),5.41- 5.20(m, 2H), 4.70-4.54(m, 1H), 3.75- 3.60(m, 1H), 3.46-3.38(m, 1H), 2.95-2.81(m, 2H), 1.29(d, J=6.9 Hz, 3H), 1.18-1.15 (m, 3H).

Compound 1j (0.100g, 193umol, 1.00eq), MeOH (1mL) and Pd/C (10.0mg, 193umol, 10% purity, 1.00eq) were added to the reaction flask together, and the system was placed under a hydrogen balloon atmosphere for 20-30 minutes. Stir at °C for 1 hour. LCMS showed target m/z generation. The reaction solution was filtered, and the filtrate was concentrated. The crude product was separated and purified by reverse phase preparation (column: Phenomenex Synergi C18 150*25*10um; mobile phase: [water (0.225%FA)-ACN]; B%: 40%-70%, 10min) to obtain compound 1 (30.0 mg, 69.9 umol, 36.2% yield, 99.8% purity, yellow solid, structure confirmed by NMR and LCMS, 99.8% purity from HPLC). ¹ H NMR: (400MHz, DMSO-d ₆ ) δ 7.22-7.16 (m, 5H), 7.12-7.03 (m, 1H), 6.91-6.84 (m, 1H), 6.79 (d, J=7.5Hz, 1H),6.59(d,J=7.6Hz,1H),5.82(d,J=7.3Hz,1H),5.71(d,J=10.3Hz,1H),4.77-4.62(m,1H),4.39( d, J=10.4Hz, 1H), 3.76-3.63 (m, 2H), 2.96- 2.82 (m, 2H), 1.34 (d, J=7.0Hz, 3H), 1.18 (d, J=7.0Hz, 3H) ).

Example 2: Screening experiment of compound in vitro anti-influenza virus activity

In the following examples, the inventors took part of the compounds of the present invention as examples to conduct experiments using cytopathic effect (CPE) to detect the antiviral activity of the compounds against influenza virus A/WSN/33 (H1N1) and MDCK cellular toxicity.

The following abbreviations are used throughout this example

English abbreviations English full name Chinese full name ATCC American Tissue Culture Collection American Type Culture Collection CC₅₀ Concentration for 50%Cytotoxicity 50% cytotoxic concentration CCK8 Cell Counting Kit 8 Cell Counting Kit 8 CPE Cytopathic Effect cytopathic effect DMSO Dimethyl Sulfoxide dimethyl sulfoxide EC₅₀ Concentration for 50% of Maximal Effect 50% effective concentration ml Millilitre ml mM Millimolar millimoles per liter MOI Multiplicity Of Infection multiplicity of infection OD Optical Density Optical density μM Mircomolar micromoles per liter μl Mircolitre microliters

1. Test material

1.1 Compounds

Compounds were prepared as 20 mM stock solutions in 100% DMSO solutions. Compounds were tested at 8 concentration points, 4-fold serial dilution, and double wells. The initial test concentrations are shown in Table 1.

Table 1. Compound Information Sheet

1.2 Cell lines

MDCK canine kidney cells were purchased from ATCC. Cells were cultured in EMEM ( Sigma). OptiPRO SFM broth (Gibco) supplemented with 2 mM L-glutamine, 1% non-essential amino acids, 100 U/ml penicillin and 100 μg/ml streptomycin was used as a test broth.

1.3 Virus strains

Influenza virus A/WSN/33 (H1N1) strain was purchased from Virapur.

1.4 Reagents

The main reagent used in this project is the cell viability detection kit CCK8 (Shanghai Liji Bio)

1.5 Instruments

The main instrument used in this project is the microplate reader SpectraMax340PC384 (Molecular Device).

2 Test methods

CPE refers to the phenomenon that the virus proliferates in a large amount in host cells, resulting in cytopathic and even death. The CPE assay is widely used to measure the inhibitory activity of compounds against cytopathic viruses by measuring cell viability. In this study, the CPE assay was used to detect the in vitro inhibitory activity of the compounds against influenza virus A/WSN/33 (H1N1). A summary of the virus experimental methods is shown in Table 2.

Table 2. Experimental methods for antiviral activity

Influenza strains cell Compound treatment time (days)/end point method Positive control compound Detection reagent A/WSN/33(H1N1) MDCK 5/CPE S-033447 CCK8

MDCK cells were seeded into 384-well cell culture plates at a density of 2,000 cells per well and cultured overnight in a 5% _CO2 , 37°C incubator. Compounds (8 concentration points, 4-fold serial dilution, double wells) and virus (MOI = 0.04) were added the next day. The final concentrations of DMSO and trypsin in the cell culture medium were 0.5% and 2.5 μg/ml, respectively. Cells were further cultured at 37°C and 5% CO ₂ for 5 days until the cytopathic rate in virus control wells (cells infected with virus, no compound treatment) reached 80-95%. The cytotoxicity experiment and the antiviral experiment were tested at the same time, and the experimental conditions were the same, but there was no virus infection.

Cell viability was detected using the cell viability assay reagent CCK8. The antiviral activity and cytotoxicity of the compound were expressed by the inhibition rate (%) and cell viability (%) of the compound against the cytopathic effect caused by the virus, respectively. Calculated as follows:

Note: Sample hole: compound treatment hole;

Virus control wells: cells infected with virus, no compound treatment;

Cell control wells: cells, no compound treatment or virus infection;

Medium control wells: Medium only, no cells, viruses or compounds.

Using GraphPad Prism (version 5) software, nonlinear fitting analysis was performed on the inhibition rate and cell viability rate of the compounds, and the EC ₅₀ and CC ₅₀ values of the compounds were obtained.

3 results

Compound anti-influenza virus A/WSN/33 (H1N1) activity and cytotoxicity against MDCK are summarized in Table 3.

Table 3. Test results of anti-influenza virus activity

compound EC₅₀(nM)* CC₅₀(μM) Example 1 60.5 >50

As can be seen from Tables 1 and 2, the experimental results show that the compound series has excellent inhibitory activity against influenza virus A/WSN/33 (H1N1).

In the description of this specification, description with reference to the terms "one embodiment," "some embodiments," "example," "specific example," or "some examples", etc., means specific features described in connection with the embodiment or example , structure, material or feature is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, those skilled in the art may combine and combine the different embodiments or examples described in this specification, as well as the features of the different embodiments or examples, without conflicting each other.

Although the embodiments of the present invention have been shown and described above, it should be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Embodiments are subject to variations, modifications, substitutions and variations.

Claims (10)

1. the compound shown in general formula I and its pharmaceutically acceptable salts, solvates include hydrates, polycrystals, prodrugs, co-crystals, tautomers, stereoisomers,

Wherein, R ₁ : H or, -C(=O)Y ₁ , -C(=O)-OY ₁ , -(CH ₂ )-O-(C=O)-Y ₁ , -(CH ₂ ) -O-(C=O)-OY ₁ , -(CHCH ₃ )-O-(C=O)-Y ₁ and -(CHCH ₃ )-O-(C=O)-OY ₁ ; Y ₁ is optionally substituted C _1-10 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, mono substituted amino groups, disubstituted amino groups, and -C(R ^* ) _2NHR ^** ; and each R ^* and R ^** is independently hydrogen or optionally substituted _C1-6 alkyl; R ₂ and R ₃ : can be independently H, C _1-6 alkyl, -C(O)-C _1-6 alkyl, halogen, -CF ₃ , -CN, -COOR ^* , -OR ^* , -( CH ₂ )qNR ^* R ^** ,-C(O)-NR ^* R ^** ; R ₂ and R ₃ can be connected to form a ring to form optionally substituted cycloalkyl, optionally substituted heterocyclyl and optionally Substituted cycloalkenyl; R ^* and R ^** are independently H and optionally substituted C _1-6 alkyl; q is 0-6; R ₄ or R ₆ : H, C _1-3 alkyl, halogen, -CF ₃ , -CN, or selected from the structures shown below

R ₇ and R ₈ are optionally substituted aryl, and optionally substituted heteroaryl; wherein the substituents are independent C _1-6 alkyl, -C(O)-C _1-6 alkyl, halogen, _-CF3 , -CN, -COOR ^* , -OR ^* , -( _CH2 )qNR ^* R ^** , -C(O)-NR ^* R ^** ; R ^* and R ^** are independently H and optionally substituted C _1-6 alkyl, q is 0-6; _R7 and _R8 can be linked to form the structure shown below:

wherein n and m can be independently 0-3, Q is CR ^* R ^** , NR ^* , O, S, SO, SO2 _; R ^* and R ^** are independently H and optionally substituted C _1-6 alkyl ; R ₅ : is H, or selected from optionally substituted C _1-8 alkyl, optionally substituted C _2-8 alkenyl, optionally substituted heterocyclyl, optionally substituted C _3-8 cycloalkyl , optionally substituted aryl, and optionally substituted heteroaryl; wherein the substituents can be independent C _1-6 alkyl, -C(O)-C _1-6 alkyl, halogen, -CF ₃ , -CN, -COOR ^* , -OR ^* , -( _CH2 )qNR ^* R ^** , -C(O)-NR ^* R ^** , where R ^* and R ^** are independently H and optionally substituted _{C1 -6} alkyl, q is 0-6; -( _CH2 )qNR ^* R ^** , -C(O)-NR ^* R ^** , R ^* and R ^** are independently H and optionally substituted _C1-6 alkyl; q is 0-6. 2. according to the compound shown in general formula I and its pharmaceutically acceptable salts, solvates include hydrates, polycrystals, prodrugs, co-crystals, tautomers, stereoisomers, in, R ₁ : is H; R ₂ and R ₃ : can be independently H, C _1-6 alkyl, -C(O)-C _1-6 alkyl, halogen, -CF ₃ , -CN, -COOR ^* , -OR ^* ; R ₂ and R ₃ can form optionally substituted cycloalkyl, optionally substituted heterocyclyl and optionally substituted cycloalkenyl, R ^* is independently H and optionally substituted C _1-6 alkyl; R ₄ or R ₆ : H, or selected from the structures shown below

R ₇ and R ₈ are optionally substituted aryl groups, and optionally substituted heteroaryl groups, which can be linked to form the structures shown below:

wherein n and m can be independently 0-3, Q is CR ^* R ^** , NR ^* , O, S, SO, SO2 _; R ^* and R ^** are independently H and optionally substituted C _1-6 alkyl ; R ₅ : is H, or selected from optionally substituted C _1-8 alkyl, optionally substituted C _2-8 alkenyl, optionally substituted heterocyclyl, optionally substituted C _3-8 cycloalkyl ; wherein the substituents can be independent C _1-6 alkyl, -C(O)-C _1-6 alkyl, halogen, -CF ₃ , -CN, -COOR ^* , -OR ^* , R ^* is independently H and optionally substituted C _1-6 alkyl. 3. according to the compound shown in general formula I and its pharmaceutically acceptable salts, solvates include hydrates, polycrystals, prodrugs, co-crystals, tautomers, stereoisomers, in, R ₁ : is H; R ₂ and R ₃ : can be independently H, C _1-6 alkyl, -C(O)-C _1-6 alkyl, halogen, -CF ₃ , -CN; R ₄ or R ₆ : H, or selected from the structures shown below

R ₇ and R ₈ are optionally substituted aryl groups, and optionally substituted heteroaryl groups, which can be linked to form the structures shown below:

where n and m can be independently 0-3, and Q is O, S, SO, SO ₂ ; R ₅ : optionally substituted C _1-8 alkyl, optionally substituted C _2-8 alkenyl, optionally substituted heterocyclyl, optionally substituted C _3-8 cycloalkyl; wherein the substituents may be independent C _1-6 alkyl, -C(O)-C _1-6 alkyl, halogen, -CF ₃ , -CN. 4. According to the compound shown in general formula I and its pharmaceutically acceptable salts, solvates include hydrates, polycrystals, prodrugs, co-crystals, tautomers, stereoisomers: in, R ₁ : is H; R ₂ and R ₃ : can be independently C _1-6 alkyl, halogen, -CF ₃ , -CN; R ₄ or R ₆ : H, or selected from the structures shown below

R ₇ and R ₈ are optionally substituted aryl groups, and optionally substituted heteroaryl groups, which can be linked to form the structures shown below:

Among them, n and m can be independently 0-3, and Q is O, S; R ₅ : is H, or selected from optionally substituted C _1-8 alkyl, optionally substituted C _2-8 alkenyl, optionally substituted heterocyclyl, optionally substituted C _3-8 cycloalkyl ; wherein the substituents can be independent C _1-6 alkyl, -C(O)-C _1-6 alkyl, halogen, -CF ₃ , -CN. 5. according to the compound shown in general formula I and pharmaceutically acceptable salts, solvates including hydrates, polycrystals, prodrugs, co-crystals, tautomers, stereoisomers, the compounds are specifically :

6. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1-5, and pharmaceutically acceptable salts, solvates thereof including hydrates, polycrystals, Prodrugs, co-crystals, tautomers, stereoisomers, pharmaceutical compositions, and pharmaceutically acceptable carriers, diluents, excipients, or combinations thereof. 7. A method for preventing, alleviating or treating viral infection, the method comprising administering an effective amount of a compound according to any one of claims 1-5, and a pharmaceutically acceptable salt, solvate thereof Including hydrates, polycrystals, prodrugs, co-crystals, tautomers, stereoisomers, and pharmaceutical compositions. 8. A method for preventing, alleviating or treating influenza virus infection, the method comprising administering an effective amount of a compound according to any one of claims 1-5, and a pharmaceutically acceptable salt, solvent thereof Compounds include hydrates, polycrystals, prodrugs, co-crystals, tautomers, stereoisomers, and pharmaceutical compositions. 9. A method for preventing, relieving or treating influenza virus infection with a combined drug, wherein a drug is the compound according to any one of claims 1-5, and pharmaceutically acceptable salts and solvates thereof, including hydrates , polycrystals, prodrugs, co-crystals, tautomers, stereoisomers; other drugs are one or more drugs that inhibit the replication of influenza virus infection, selected from neuraminidase inhibitors, M2 protein inhibitors , polymerase inhibitors, PB ₂ inhibitors, immunomodulators; such as zanamivir, oseltamivir, peramivir, laninamivir, laninamivir capnoate, favipiravir, beraprost , Ribavirin. 10. The compound of any one of claims 1-5, and pharmaceutically acceptable salts, solvates thereof, including hydrates, polycrystals, prodrugs, co-crystals, tautomers, stereoisomers Use in the manufacture of a medicament for the treatment and/or prevention, mitigation or treatment of influenza virus infection.