CN112521386A

CN112521386A - Polycyclic pyridone compound with antiviral effect and pharmaceutical composition and application thereof

Info

Publication number: CN112521386A
Application number: CN201910884399.7A
Authority: CN
Inventors: 周雨恬; 刘建波
Original assignee: Individual
Current assignee: Individual
Priority date: 2019-09-19
Filing date: 2019-09-19
Publication date: 2021-03-19
Anticipated expiration: 2039-09-19
Also published as: CN112521386B

Abstract

The invention discloses a polycyclic pyridone compound with antiviral effect, which is characterized in that: containing a pyridone heterocyclic compound represented by the formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a crystal thereof,

Description

Polycyclic pyridone compound with antiviral effect and pharmaceutical composition and application thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to a novel compound serving as an influenza virus replication inhibitor or used for treating or preventing HIV infection in individuals, a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound and the pharmaceutical composition thereof in treating influenza or treating or preventing HIV infection in the individuals. More specifically, the compounds of the present invention may be used as inhibitors of influenza virus RNA polymerase or integrase inhibitors for the treatment or prevention of HIV infection in an individual.

Background

Orthomyxoviruses have a negative-sense single-stranded RNA genome and replicate in the nucleus of infected cells because they lack the mechanism to produce cap structures to produce their own mRNA. Members of the orthomyxovirus family have an RNA-dependent RNA polymerase with nicking nuclease activity that cleaves a portion of the capped 5' end of cellular mRNA; the RNA polymerase then uses the cleavage product as a primer for the synthesis of viral mRNA. This process is called cap snatching. This endonuclease has been recognized as a promising target for the development of antiviral drugs effective against orthomyxoviruses. ACS, chem.letters,2014, vol.5,61-64 inhibitors of this endonuclease have been disclosed, for example, in WO2015038660 and US20150072982, WO2010147068 and US20130197219, which report that these inhibitors are useful for treating influenza infection in mammals.

The orthomyxovirus family includes influenza a, influenza B and influenza C (all of which can infect humans), as well as several other viruses that do not normally infect humans. Unusual for viruses, nucleic acids whose genomes are not single fragments; in contrast, the genome contains segmented antisense RNA of 7 or 8 segments. The influenza a genome encodes 11 proteins: hemagglutinin (H), neuraminidase (N), Nucleoprotein (NP), M1, M2, NS1, NS2(NEP), PA, PB1, PB1-F2, and PB 2. H and N are macromolecular glycoproteins outside the virion. HA is a lectin that mediates binding of the virus to the target cell and entry of the viral genome into the target cell, while NA is involved in the release of progeny virus from infected cells by cleaving sugars that bind to mature viral particles. Therefore, these proteins have been targets for antiviral drugs. Moreover, these proteins are antigens of antibodies that 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, H5N 1.

Influenza a is the most virulent of these pathogens in humans, and usually accounts for the majority of severe influenza cases during the typical influenza season. Influenza is an acute respiratory infectious disease caused by infection with influenza virus, and it is estimated that as many as 29 to 65 million people die of influenza every year worldwide, despite the widespread use of vaccines to reduce the incidence of influenza; in china, tens of millions of people become infected with influenza each year, which is accompanied by high morbidity and mortality. The traditional Chinese medicine composition is a particularly important disease in high-risk groups such as infants, old people and the like, and the complication rate of pneumonia is high in the old people, and the old people account for most of death caused by influenza. Antiviral therapies effective in treating influenza, particularly influenza a, are therefore highly desirable. Anti-influenza drugs commonly used on the market today are: such as cinnamyl (Symmetrel, trade name: Amantadine) or Rimantadine hydrochloride (Flumadine, trade name: Rimantadine) which inhibits the uncoating process of viruses, Oseltamivir (Oseltamivir, trade name: Tamiflu) or Zanamivir (Zanamivir, trade name: relesate (renza)) which is a neuraminidase inhibitor that inhibits the budding release of viruses from cells. However, there is a need for the development of anti-influenza drugs having a novel mechanism, because of concerns about the occurrence of drug-resistant strains, side effects, and the worldwide pandemic of new influenza viruses having high pathogenicity or lethality.

Retroviruses, known as the Human Immunodeficiency Virus (HIV), and in particular the strains known as the HIV type 1 (HIV-1) virus and the HIV type 2 (HIV-2) virus, are the causative agents of complex diseases involving progressive destruction of the immune system (acquired immunodeficiency syndrome; aids) and degeneration of the central and peripheral nervous systems. A common feature of retroviral replication is the insertion of + proviral DNA into the host cell genome by the virally encoded integrase, an essential step in HIV replication in human T lymphocytes and monocyte-like cells. Integration is thought to be mediated by integrase through three steps: assembly of the stable nucleoprotein complex with viral DNA sequences; the two nucleotides are cleaved from the 3 'end of the linear proviral DNA and covalently linked to the recessed 3' OH end of the proviral DNA at a staggered cut created at the host target site. The fourth step of the process, repair of the gap created by the synthesis, can be accomplished by cellular enzymes.

Nucleotide sequencing of HIV shows the presence of the pol gene in one open reading frame [ Ratner, l.et al, Nature,313,277(1985) ]. Amino acid sequence homology provides evidence that pol sequences encode reverse transcriptase, integrase, and HIV protease [ Toh, h.et al, EMBO j.4,1267 (1985); power, m.d. et al, Science,231,1567 (1986); pearl, l.h.et al, Nature,329,351 (1987). All three of these enzymes have been shown to be essential for HIV replication.

Several antiviral compounds that are inhibitors of HIV replication are known to be effective agents for the treatment of AIDS and similar diseases, including reverse transcriptase inhibitors such as Azidothymidine (AZT) and efavirenz, and protease inhibitors such as indinavir and nelfinavir. The compounds of the present invention are inhibitors of HIV integrase and inhibitors of HIV replication.

Disclosure of Invention

The invention provides a novel compound serving as an influenza virus RNA polymerase inhibitor, in particular to a novel compound serving as a cap-dependent endonuclease inhibitor of influenza virus, and application of the compound and a composition thereof in preparing a medicament for preventing, treating or relieving virus infection diseases of patients. Compared with the existing similar compounds, the compound of the invention not only can well inhibit influenza virus, but also has lower cytotoxicity, better in vivo pharmacokinetic property and in vivo pharmacodynamic property. Therefore, compared with the existing similar compounds, the compound provided by the invention has better drugability.

The invention also provides a class of compounds that are inhibitors of HIV integrase and inhibitors of HIV replication. The compound of the invention not only can well inhibit HIV virus, but also has lower cytotoxicity, better in vivo pharmacokinetic property and in vivo pharmacodynamic property. Therefore, compared with the existing similar compounds, the compound provided by the invention has better drugability.

In one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,

wherein:

(1) x is selected from the group consisting of a hydrogen atom, a single bond, a halogen (F, Cl, Br or I), a cyano group, an alkynyl group, an alkyl group, a five-membered heteroaromatic ring, a six-membered heteroaromatic ring and N (R)⁴)C(O)-；

(2) Y is selected from a single bond or C₁-C₃An alkylene group;

(3)Y¹selected from O or S;

(4)Y²and Y³Are respectively selected from N, C and CH;

(5)R⁰is selected from C₆-C₁₀Aryl, 5 or 6 membered monocyclic heteroaryl and 9 or 10 membered bicyclic heteroaryl; said C is₆-C₁₀Aryl, the 5-or 6-membered monocyclic heteroaryl and the 9-or 10-membered bicyclic heteroaryl may have up to three R⁵A substituent group;

(6)R¹selected from hydrogen, cyano, alkynyl, hydroxyl, halogen (F, Cl, Br or I), carboxyl, ester group, amide group, sulfonamide group; or, R¹Selected from the group consisting of unsubstituted or substituted: c_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkanethiol, hydrazinoacyl, C_1-6Alkylcarbonyl group, C_1-6Alkylaminocarbonyl radical, C_1-6Alkylcarbonylamino, C_1-6Alkyloxycarbonyl, C_1-6Alkylsulfinyl radical, C_1-6Alkylamino carbonylamino group, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, C_3-6Cycloalkylamino radical, C_3-6Cycloalkanemercapto group, C_3-6Cycloalkanecarbonyl group, C_3-6Cycloalkylamino carbonyl group, C_3-6Cycloalkanecarbonylamino group, C_3-6Cycloalkylamino carbonylamino group, C_4-8Heterocycloalkyl radical, C_4-8Heterocyclic alkoxy radical, C_4-8Heterocyclic alkylamino radical, C_4-8Heterocycloalkylmercapto group, C_4-8Heterocycloalkylcarbonyl radical, C_4-8Heterocycloalkylaminocarbonyl radical, C_5-10Aryl radical, C_5-10Heteroaryl group, C_5-10Aryloxy radical, C_5-10Aryloxyalkyl radical, C_5-10Arylamine group, C_5-10Aromatic mercapto group, C_5-10Aryl carbonyl group, C_1-6Hydrocarbyl sulfone group, C_1-6Alkyl sulfonylamino group, C_3-6Cycloalkyl sulfone group, C_3-6Cycloalkylsulfonylamino, C_5-10Aryl sulfone group, C_5-10Arylsulfonylamino, aminooxalylamino, aminooxalyl, C_5-10Arylaminocarbonyl radicals or C_5-10Arylaminocarbonylamino; or, X and R¹Are linked and form C together with the carbon to which they are linked_5-10Carbocyclic ring, C_5-10Heterocycle, C_5-10Aromatic ring, C_5-10A heteroaromatic ring;

(7)R²independently H, halogen (F, Cl, Br, I), CN, NO₂Oxo (═ O), -C (═ O) OH, -C (═ O) OCH₃、-C(＝O)NH₂、-OH、-OCH₃、-OCH₂CH₃、-OCF₃、-OCHF₂、-OCH₂CF₃、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoroethyl, alkynyl, cyclopropylalkynyl, methoxypropynyl, hydroxypropynyl, acetoxypropynyl, propenyl, cyclopropylvinyl, methoxypropenyl, hydroxypropenyl, acetoxypropenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxiranyl, azetidinyl, oxetanyl;

(8)R³independently H, halogen (F, Cl, Br, I), CN, NO₂Oxo (═ O), -C (═ O) OH, -C (═ O) OCH₃、-C(＝O)NH₂、-OH、-OCH₃、-OCH₂CH₃、-OCF₃、-OCHF₂、-OCH₂CF₃、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoroethyl, alkynyl, cyclopropylalkynyl, methoxypropynyl, hydroxypropynyl, acetoxypropynyl, propenyl, cyclopropylvinyl, methoxypropenyl, hydroxypropenyl, acetoxypropenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, phenyl, naphthyl, furanyl, benzofuranyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, benzimidazolyl, benzopyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1, 3, 5-triazinyl, thiazolyl, thienyl, benzothienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, etc, Purinyl, quinolinyl or isoquinolinyl, wherein said methyl, ethyl, n-propyl, isopropyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinylPiperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, naphthyl, furanyl, benzofuranyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, benzimidazolyl, benzopyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1, 3, 5-triazinyl, thiazolyl, thienyl, benzothienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolinyl and isoquinolinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from halo (F, Cl, Br, I), CN, NO₂、OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy;

or any two R taken together with the carbon or nitrogen atom to which they are attached form a cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, oxirane, azetidine, oxetane, pyrrolidine, piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholine, thiomorpholine, benzene, furan, pyrrole, pyridine, pyrazole, imidazole, triazole, tetrazole, oxazole, oxadiazole, 1, 3, 5-triazine, thiazole, thiophene, pyrazine, pyridazine, or pyrimidine, wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, oxirane, azetidine, oxetane, pyrrolidine, piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholine, thiomorpholine, benzene, furan, pyrrole, pyridine, pyrazole, imidazole, triazole, tetrazole, oxazole, oxadiazole, 1, 3, 5-triazine, thiazole, imidazole, triazole, tetrazole, Thiophene, pyrazine, pyridazine and pyrimidine are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from halogen (F, Cl, Br, I), CN, NO₂、OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy.

(9)R⁴Independently is H or C₁-C₆An alkyl group;

(10)R⁵independently selected from C₁-C₆Alkyl, halogen, -OR⁶，-SR⁶，C₁-C₆Haloalkyl, C₁-C₆Hydroxyalkyl, -O- (C)₁-C₆Haloalkyl), -CN, -NO₂，-N(R⁶)₂，-C(O)OR⁷，-C(O)N(R⁷)₂And NHC (O) R⁷；

(11)R⁶Independently is H or C₁-C₆An alkyl group;

(12)R⁷independently selected from H, C₁-C₆Alkyl, - (C)₁-C₆Alkylene) -O- (C)₁-C₆Alkyl) and C₃-C₇A cycloalkyl group;

(13) ring a is an unsubstituted, one or more substituents (m is 0, 1, 2, 3,4 or 5) monocyclic, spiro, fused, bridged or polycyclic ring, which may be carbocyclic or a heterocyclic ring containing O, S, N; ring A is a saturated or unsaturated ring, and substituent R on ring A²Independently selected from H, cyano, alkynyl, hydroxyl, halogen (F, Cl, Br or I), carboxyl, ester group, amido, sulfonamide, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkanethiol, hydrazinoacyl, C_1-6Alkylcarbonyl group, C_1-6Alkylaminocarbonyl radical, C_1-6Alkylcarbonylamino, C_1-6Alkyloxycarbonyl, C_1-6Alkylsulfinyl radical, C_1-6Alkylamino carbonylamino group, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, C_3-6Cycloalkylamino radical, C_3-6Cycloalkanemercapto group, C_3-6Cycloalkanecarbonyl group, C_3-6Cycloalkylamino carbonyl group, C_3-6Cycloalkanecarbonylamino group, C_3-6Cycloalkylamino carbonylamino group, C_4-8Heterocycloalkyl radical, C_4-8Heterocyclic alkoxy radical, C_4-8Heterocyclic alkylamino radical, C_4-8Heterocycloalkylmercapto group, C_4-8Heterocycloalkylcarbonyl radical, C_4-8Heterocycloalkylaminocarbonyl radical, C_5-10Aryl radical, C_5-10Heteroaryl group, C_5-10Aryloxy radical, C_5-10Aryloxyalkyl radical, C_5-10Arylamine group, C_5-10Aromatic mercapto group, C_5-10Aryl carbonyl group, C_1-6Hydrocarbyl sulfone group, C_1-6Alkyl sulfonylamino group, C_3-6Cycloalkyl sulfone group, C_3-6Cycloalkylsulfonylamino, C_5-10Aryl sulfoneBase, C_5-10Arylsulfonylamino, aminooxalylamino, aminooxalyl, C_5-10Arylaminocarbonyl radicals or C_5-10Arylaminocarbonylamino;

(14) ring B is H or an unsubstituted, one or more substituents (n is 0, 1, 2, 3,4 or 5) bicyclic, tricyclic, tetracyclic, pentacyclic or hexacyclic ring system of 10 to 30 atoms, wherein the 10 to 30 atom bicyclic, tricyclic, tetracyclic, pentacyclic or hexacyclic ring system is a carbocyclic, heterocyclic, aromatic or heteroaromatic ring; substituent R on ring B³Independently selected from H, cyano, alkynyl, hydroxyl, halogen (F, Cl, Br or I), carboxyl, ester group, amido, sulfonamide, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkanethiol, hydrazinoacyl, C_1-6Alkylcarbonyl group, C_1-6Alkylaminocarbonyl radical, C_1-6Alkylcarbonylamino, C_1-6Alkyloxycarbonyl, C_1-6Alkylsulfinyl radical, C_1-6Alkylamino carbonylamino group, C_1-6Alkyl carbonyl oxygen, C_1-6Haloalkyl, C_2-6Substituted alkenyl, C_2-6Substituted alkynyl, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, C_3-6Cycloalkylamino radical, C_3-6Cycloalkanemercapto group, C_3-6Cycloalkanecarbonyl group, C_3-6Cycloalkylamino carbonyl group, C_3-6Cycloalkanecarbonylamino group, C_3-6Cycloalkylamino carbonylamino group, C_4-8Heterocycloalkyl radical, C_4-8Heterocyclic alkoxy radical, C_4-8Heterocyclic alkylamino radical, C_4-8Heterocycloalkylmercapto group, C_4-8Heterocycloalkylcarbonyl radical, C_4-8Heterocycloalkylaminocarbonyl radical, C_5-10Aryl radical, C_5-10Heteroaryl group, C_5-10Aryloxy radical, C_5-10Aryloxyalkyl radical, C_5-10Arylamine group, C_5-10Aromatic mercapto group, C_5-10Aryl carbonyl group, C_1-6Hydrocarbyl sulfone group, C_1-6Alkyl sulfonylamino group, C_3-6Cycloalkyl sulfone group, C_3-6Cycloalkylsulfonylamino, C_5-10Aryl sulfone group, C_5-10Arylsulfonylamino, aminooxalylamino, aminooxalyl, C_5-10Arylaminocarbonyl groupsRadical or C_5-10Arylaminocarbonylamino;

(15) p is H, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_3-8Carbocyclyl, C_3-8carbocyclyl-C_1-4Alkylene, heterocyclic group consisting of 3 to 8 atoms, (heterocyclic group consisting of 3 to 8 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms, (heteroaryl of 5 to 10 atoms) -C_1-4Alkylene, -C (═ O) -R^P1、-C(＝O)-L-R^P1、-C(＝O)-L-O-R^P1、-C(＝O)-L-O-L-O-R^P1、-C(＝O)-L-O-C(＝O)-R^P1、-C(＝O)-NR^P1R^P2、-C(＝O)-O-R^P1、-S(＝O)₂-R^P1、-P(＝O)-(R^P3)(R^P4)、-C(＝O)-O-L-O-R^P1、-C(＝N⁺R^P1R^P1)(-NR^P1R^P1)、R^P1-O-C_1-4Alkylene radical, R^P1-O-L-O-C_1-4Alkylene radical, R^P1-(C＝O)-O-C_1-4Alkylene radical, R^P1-O-(C＝O)-C_1-4Alkylene radical, R^P1-O-(C＝O)-NR^P2-C_1-4Alkylene radical, R^P1-O-(C＝O)-O-C_1-4Alkylene, NR^P1R^P2-O-(C＝O)-O-C_1-4Alkylene radical, R^P1-O-L-O-(C＝O)-O-C_1-4Alkylene, NR^P1R^P1-L-O-(C＝O)-O-C_1-4Alkylene radical, R^P1-O-L-NR^P2-(C＝O)-O-C_1-4Alkylene, NR^P1R^P1-L-N(R^P2)-(C＝O)-O-C_1-4Alkylene radical, R^P1-O-L-O-L-O-(C＝O)-O-C_1-4Alkylene group, (HO)₂P(＝O)-C_1-4Alkylene, (BnO)₂P(＝O)-C_1-4Alkylene or R^P1-(C＝O)-NR^P2-L-O-(C＝O)-O-C_1-4Alkylene, wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_3-8Carbocyclyl, C_3-8carbocyclyl-C_1-4Alkylene, heterocyclic group consisting of 3 to 8 atoms, (heterocyclic group consisting of 3 to 8 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms and (heteroaryl of 5 to 10 atoms) -C_1-4Each alkylene is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from halogen (F, Cl, Br or I), oxo (═ O), CN, NO₂、-OR^b、-NR^cR^d、-C(＝O)R^a、-O(C＝O)R^a、-C(＝O)OR^b、C_1-6Alkyl radical, R^bO-C_1-4Alkylene, -NR^cR^dC(＝O)R^aOr R^cR^dN-C_1-4An alkylene group;

each L is independently C_1-6Alkylene or C_2-6An alkenylene group;

each R^P1Independently is C_1-6Alkyl radical, C_3-8Carbocyclyl, C_3-8carbocyclyl-C_1-4Alkylene, heterocyclyl consisting of 3 to 8 atoms, (heterocyclyl consisting of 3 to 8 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms, (heteroaryl of 5 to 10 atoms) -C_1-4Alkylene radical, C_1-6Alkylamino radical, C_1-6Alkylthio or C_1-6Alkylsilyl group, wherein said C_1-6Alkyl radical, C_3-8Carbocyclyl, C_3-8carbocyclyl-C_1-4Alkylene, heterocyclyl consisting of 3 to 8 atoms, (heterocyclyl consisting of 3 to 8 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms, (heteroaryl of 5 to 10 atoms) -C_1-4Alkylene radical, C_1-6Alkylamino and C_1-6Alkylthio is each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from halogen (F, Cl, Br or I), oxo (═ O), CN, NO₂、-OR^b、-NR^cR^d、-C(＝O)R^a、-O(C＝O)R^a、-C(＝O)OR^b、C_1-6Alkyl radical, R^bO-C_1-4Alkylene, -NR^cR^dC(＝O)R^aOr R^cR^dN-C_1-4An alkylene group;

each R^P2Independently is H or C_1-6An alkyl group;

each R^P3And R^P4Independently is C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_3-8Carbocyclyloxy, C_3-8Carbocyclylamino, heterocyclyloxy of 3 to 8 atoms, heterocyclylamino of 3 to 8 atoms, C_6-10Aryloxy radical, C_6-10Arylamino, heteroaryloxy of 5 to 10 atoms or heteroarylamino of 5 to 10 atoms, wherein said C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_3-8Carbocyclyloxy, C_3-8Carbocyclylamino, heterocyclyloxy of 3 to 8 atoms, heterocyclylamino of 3 to 8 atoms, C_6-10Aryloxy radical, C_6-10Arylamino, heteroaryloxy of 5-10 atoms and heteroarylamino of 5-10 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from halo (F, Cl, Br or I), oxo (═ O), CN, NO₂、-OR^b、-NR^cR^d、-C(＝O)R^a、-O(C＝O)R^a、-C(＝O)OR^b、C_1-6Alkyl radical, R^bO-C_1-4Alkylene, -NR^cR^dC(＝O)R^aOr R^cR^dN-C_1-4An alkylene group;

or R^P3、R^P4And together with the phosphorus atom to which they are attached, form a 3-8 atom heterocyclic ring or a 5-10 atom heteroaromatic ring, wherein the 3-8 atom heterocyclic ring and the 5-10 atom heteroaromatic ring are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from halogen (F, Cl, Br, or I), oxo (═ O), CN, NO₂、-OR^b、-NR^cR^d、-C(＝O)R^a、-O(C＝O)R^a、-C(＝O)OR^b、C_1-6Alkyl radical, R^bO-C_1-4Alkylene, -NR^cR^dC(＝O)R^aOr R^cR^dN-C_1-4An alkylene group;

each R^a、R^b、R^cAnd R^dIndependently is H, C_1-6Haloalkyl, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Carbocyclyl, C_3-6carbocyclyl-C_1-4Alkylene, heterocyclic group consisting of 3 to 6 atoms, (heterocyclic group consisting of 3 to 6 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms or (heteroaryl of 5 to 10 atoms) -C_1-4Alkylene, wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Carbocyclyl, C_3-6carbocyclyl-C_1-4Alkylene, heterocyclic group consisting of 3 to 6 atoms, (heterocyclic group consisting of 3 to 6 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms and (heteroaryl of 5 to 10 atoms) -C_1-4Each alkylene is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from halogen (F, Cl, Br or I), CN, OH, NH₂、NO₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy or C_1-6An alkylamino group;

or R^c、R^dAnd together with the nitrogen atom to which they are attached, form a 3-6 atom heterocyclic ring or a 5-8 atom heteroaromatic ring, wherein the 3-6 atom heterocyclic ring and the 5-8 atom heteroaromatic ring are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from halogen (F, Cl, Br, or I), CN, OH, NH₂、NO₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy or C_1-6An alkylamino group.

In some embodiments, the compound has a structure as shown in formula (Ia), (Ib), or (Ic):

in still other embodiments, the compound has a structure according to formula (Id), (Ie), (If), or (Ig):

in some embodiments, ring a is a saturated or unsaturated monocyclic, spirocyclic, fused, bridged, or polycyclic ring of 5 to 20 atoms, wherein the saturated or unsaturated monocyclic, spirocyclic, fused, bridged, or polycyclic ring system of 5 to 20 atoms is a carbocyclic ring, a heterocyclic ring containing O, S, N, an aromatic ring, a heteroaromatic ring containing O, S, N.

In other embodiments, ring a has the following sub-structures, but is in no way limited to these:

in still other embodiments, ring B is R²Or has the following sub-structure:

in other embodiments, each R is³Independently H, halogen (F, Cl, Br, I), CN, NO₂Oxo (═ O), -C (═ O) OH, -C (═ O) OCH₃、-C(＝O)NH₂、-OH、-OCH₃、-OCH₂CH₃、-OCF₃、-OCHF₂、-OCH₂CF₃、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoroethyl, alkynyl, cyclopropylalkynyl, methoxypropynyl, hydroxypropynyl, acetoxypropynyl, propenyl, cyclopropylvinyl, methoxypropenyl, hydroxypropenyl, acetoxypropenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, phenyl, naphthyl, furanyl, benzofuranyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, benzimidazolyl, benzopyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1, 3, 5-triazinyl, thiazolyl, thienyl, benzothienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, etc, Purinyl, quinolinyl, or isoquinolinyl, wherein said methyl, ethyl, n-propyl, isopropyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, phenyl, naphthyl, furyl, benzofuranyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, benzimidazolyl, benzopyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1, 3, 5-triazinyl, thiazolyl, thienyl, benzothienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolinyl, and isoquinolinyl are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from halo (F, N-propyl, I-propyl, F, O, Cl, Br, I), CN, NO₂、OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy;

or any two R taken together with the carbon or nitrogen atom to which they are attached form cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, oxirane, azetidine, oxetane, pyrrolidine, piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholine, thiofuranMorpholine, benzene, furan, pyrrole, pyridine, pyrazole, imidazole, triazole, tetrazole, oxazole, oxadiazole, 1, 3, 5-triazine, thiazole, thiophene, pyrazine, pyridazine or pyrimidine, wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, ethylene oxide, azetidine, oxetane, pyrrolidine, piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholine, thiomorpholine, benzene, furan, pyrrole, pyridine, pyrazole, imidazole, triazole, tetrazole, oxazole, oxadiazole, 1, 3, 5-triazine, thiazole, thiophene, pyrazine, pyridazine and pyrimidine are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from halogen (F, Cl, Br, I), CN, NO, pyrazine, pyridazine and pyrimidine₂、OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy.

In still other embodiments, wherein each P is independently H, C_1-4Alkyl radical, C_2-6Alkenyl radical, C_3-8Carbocyclyl, C_3-6carbocyclyl-C_1-2Alkylene, heterocyclic group consisting of 3 to 6 atoms, (heterocyclic group consisting of 3 to 6 atoms) -C_1-2Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-2Alkylene, heteroaryl of 5 to 10 atoms, (heteroaryl of 5 to 10 atoms) -C_1-2Alkylene, -C (═ O) -R^P1、-C(＝O)-L-R^P1、-C(＝O)-L-O-R^P1、-C(＝O)-L-O-L-O-R^P1、-C(＝O)-L-O-C(＝O)-R^P1、-C(＝O)-NR^P1R^P2、-C(＝O)-O-R^P1、-S(＝O)₂-R^P1、-P(＝O)-(R^P3)(R^P4)、-C(＝O)-O-L-O-R^P1、-C(＝N⁺R^P1R^P1)(-NR^P1R^P1)、R^P1-O-C_1-4Alkylene radical, R^P1-O-L-O-C_1-2Alkylene radical, R^P1-(C＝O)-O-C_1-2Alkylene radical, R^P1-O-(C＝O)-C_1-2Alkylene radical, R^P1-O-(C＝O)-NR^P2-C_1-2Alkylene radical, R^P1-O-(C＝O)-O-C_1-2Alkylene, NR^P1R^P2-O-(C＝O)-O-C_1-2Alkylene oxideRadical, R^P1-O-L-O-(C＝O)-O-C_1-2Alkylene, NR^P1R^P1-L-O-(C＝O)-O-C_1-2Alkylene radical, R^P1-O-L-NR^P2-(C＝O)-O-C_1-2Alkylene, NR^P1R^P1-L-N(R^P2)-(C＝O)-O-C_1-2Alkylene radical, R^P1-O-L-O-L-O-(C＝O)-O-C_1-2Alkylene group, (HO)₂P(＝O)-C_1-2Alkylene, (BnO)₂P(＝O)-C_1-2Alkylene or R^P1-(C＝O)-NR^P2-L-O-(C＝O)-O-C_1-2Alkylene, wherein said C_1-4Alkyl radical, C_2-4Alkenyl radical, C_3-6Carbocyclyl, C_3-6carbocyclyl-C_1-2Alkylene, heterocyclic group consisting of 3 to 8 atoms, (heterocyclic group consisting of 3 to 8 atoms) -C_1-2Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-2Alkylene, heteroaryl of 5 to 10 atoms and (heteroaryl of 5 to 10 atoms) -C_1-2Each alkylene is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from halogen (F, Cl, Br or I), oxo (═ O), CN, NO₂、-OR^b、-NR^cR^d、-C(＝O)R^a、-O(C＝O)R^a、-C(＝O)OR^b、C_1-4Alkyl radical, R^bO-C_1-2Alkylene, -NR^cR^dC(＝O)R^aOr R^cR^dN-C_1-2An alkylene group;

each L is independently C_1-6An alkylene group;

each R^P1Independently is C_1-4Alkyl radical, C_3-6Carbocyclyl, C_3-6carbocyclyl-C_1-2Alkylene, heterocyclyl consisting of 3 to 6 atoms, (heterocyclyl consisting of 3 to 6 atoms) -C_1-2Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-2Alkylene, heteroaryl of 5 to 10 atoms, (heteroaryl of 5 to 10 atoms) -C_1-2Alkylene radical, C_1-4Alkylamino or C_1-4Alkylthio group wherein said C_1-4Alkyl radical, C_3-6Carbocyclyl, C_3-6carbocyclyl-C_1-2Alkylene, heterocyclyl consisting of 3 to 6 atoms, (heterocyclyl consisting of 3 to 6 atoms) -C_1-2Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-2Alkylene, heteroaryl of 5 to 10 atoms, (heteroaryl of 5 to 10 atoms) -C_1-2Alkylene radical, C_1-4Alkylamino or C_1-4Alkylthio is each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from halogen (F, Cl, Br or I), oxo (═ O), CN, NO₂、-OR^b、-NR^cR^d、-C(＝O)R^a、-O(C＝O)R^a、-C(＝O)OR^b、C_1-6Alkyl radical, R^bO-C_1-4Alkylene, -NR^cR^dC(＝O)R^aOr R^cR^dN-C_1-4An alkylene group;

each R^P2Independently is H or C_1-4An alkyl group;

each R^P3And R^P4Independently is C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_3-6Carbocyclyloxy, C_3-6Carbocyclylamino, heterocyclyloxy of 3 to 6 atoms, heterocyclylamino of 3 to 6 atoms, C_6-10Aryloxy radical, C_6-10Arylamino, heteroaryloxy of 5 to 10 atoms or heteroarylamino of 5 to 10 atoms, wherein said C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_3-6Carbocyclyloxy, C_3-6Carbocyclylamino, heterocyclyloxy of 3 to 6 atoms, heterocyclylamino of 3 to 6 atoms, C_6-10Aryloxy radical, C_6-10Arylamino, heteroaryloxy of 5-10 atoms and heteroarylamino of 5-10 atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from halo (F, Cl, Br or I), oxo (═ O), CN, NO₂、-OR^b、-NR^cR^d、-C(＝O)R^a、-O(C＝O)R^a、-C(＝O)OR^b、C_1-6Alkyl radical, R^bO-C_1-4Alkylene, -NR^cR^dC(＝O)R^aOr R^cR^dN-C_1-4An alkylene group;

or R^P3、R^P4And together with the phosphorus atom to which they are attached, form a 3-6 atom heterocyclic ring or a 5-6 atom heteroaromatic ring, wherein the 3-6 atom heterocyclic ring and the 5-6 atom heteroaromatic ring are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from halogen (F, Cl, Br, or I), oxo (═ O), CN, NO₂、-OR^b、-NR^cR^d、-C(＝O)R^a、-O(C＝O)R^a、-C(＝O)OR^b、C_1-4Alkyl radical, R^bO-C_1-4Alkylene, -NR^cR^dC(＝O)R^aOr R^cR^dN-C_1-4An alkylene group;

in other embodiments, each R is^a、R^b、R^cAnd R^dIndependently H, methyl, ethyl, trifluoromethyl, trifluoroethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, 3-6 atom heterocyclyl, phenyl or 5-10 atom heteroaryl, wherein said methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, 3-6 atom heterocyclyl, phenyl and 5-10 atom heteroaryl are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, CN, OH, NH₂、NO₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy;

or R^c、R^dAnd together with the nitrogen atom to which they are attached, form a 3-6 atom heterocyclic ring or a 5-6 atom heteroaromatic ring, wherein said 3-6 atom heterocyclic ring and 5-6 atom heteroaromatic ring are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, CN, OH, NH₂、NO₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy.

In other embodiments, P is independently H or the following group:

in some embodiments, X is selected from the group consisting of a hydrogen atom, a single bond, a five-membered heteroaromatic ring, a six-membered heteroaromatic ring, and N (R)⁴) C (O) -; wherein the five-membered heteroaromatic ring is selected from the following subformulas:

in other embodiments, R⁰Is selected from C₆-C₁₀Aryl, 5 or 6 membered monocyclic heteroaryl and 9 or 10 membered bicyclic heteroaryl; said C is₆-C₁₀Aryl, the 5-or 6-membered monocyclic heteroaryl and the 9-or 10-membered bicyclic heteroaryl may have up to three R⁵A substituent group; wherein the 5 or 6 membered monocyclic heteroaryl is selected from the following subformulae:

in other embodiments, the present invention relates to a compound, or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a crystal thereof, of one of the following structures, wherein the compound is selected from the group consisting of, but in no way limited to:

in still other embodiments, the present invention relates to a compound, or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a crystal thereof, wherein the compound is selected from the following structures, but is by no means limited to:

in another aspect, the invention provides the use of the compound or the pharmaceutical composition for the manufacture of a medicament for the prevention, treatment or alleviation of a viral infectious disease in a patient.

In some embodiments, the pharmaceutical composition is an antiviral pharmaceutical composition, optionally further comprising one or more therapeutic agents selected from neuraminidase inhibitors, nucleosides, PB2 inhibitors, PB1 inhibitors, M2 inhibitors or other anti-influenza drugs, and the like. The application of one or more combinations in the pharmaceutical composition in preparing a medicament for preventing and/or treating viral infectious diseases, wherein the viral infectious diseases are infectious diseases caused by HIV. The antiviral pharmaceutical composition comprises at least one therapeutic agent.

In some embodiments, the invention also relates to application of the compound shown in the formula (I), the stereoisomer, the pharmaceutically acceptable salt, the solvate or the crystal or the pharmaceutical composition thereof in preparing a medicament for preventing and/or treating viral infectious diseases, wherein the viral infectious diseases are preferably infectious diseases caused by influenza A or influenza B.

In some embodiments, the present invention further relates to the use of a compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt, solvate or crystal thereof, or a pharmaceutical composition thereof, for the manufacture of an antiviral medicament, preferably a medicament or agent that inhibits influenza cap-dependent endonuclease activity; or the antiviral drug is an HIV inhibiting drug or agent.

Unless otherwise indicated, the present invention encompasses stereoisomers, geometric isomers, tautomers, solvates, hydrates, metabolites, salts and pharmaceutically acceptable prodrugs of all of the compounds of the present invention.

In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. The compounds of the present invention also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for the preparation and/or purification of the compounds of the present invention and/or for the isolation of enantiomers of the compounds of the present invention.

Pharmaceutically acceptable acid addition salts may be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheophylline, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogen phosphate, dihydrogenphosphate, Polysilonolactates, propionates, stearates, succinates, sulfosalicylates, tartrates, tosylates and trifluoroacetates.

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 of 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 including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include, for example, isopropylamine, benzathine (benzathine), choline salts (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine, and tromethamine. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of pharmaceutical salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) may find some additional lists of suitable salts.

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

On the other hand, the compounds of the invention may contain several asymmetric centers or their racemic mixtures as generally described. The invention further comprises racemic mixtures, partial racemic mixtures and isolated enantiomers and diastereomers.

The compound of the present invention may exist in one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, and the present invention may further comprise the isomers, rotamers, atropisomers, tautomers or mixtures thereof, or partial mixtures or separated isomers, rotamers, atropisomers, tautomers of the compound of the present invention.

In the present invention, for convenience of description, the compound represented by the formula (I) of the present invention, a stereoisomer, a pharmaceutically acceptable salt, a solvate thereof, or any combination thereof, is hereinafter collectively referred to as a compound according to the present invention, in some places.

The pharmaceutical composition according to the invention, wherein the compound according to the invention is preferably present in a therapeutically effective amount.

In some embodiments, the above-described pharmaceutical compositions of the present invention generally comprise pharmaceutically acceptable carriers, such as pharmaceutically acceptable diluents, excipients, fillers, binders, disintegrants, absorption enhancers, surfactants, lubricants, flavoring agents, sweeteners, and the like.

Further, in some embodiments, the pharmaceutical composition of the present invention may be in any suitable dosage form, and specifically may be in the form of tablets, powders, capsules, granules, oral liquids, injections, powders, suppositories, pills, creams, pastes, gels, powders, inhalants, suspensions, dry suspensions, patches, lotions, nano-formulations, and the like. The dosage form of the pharmaceutical composition is preferably tablets, capsules or injections.

The medicaments in various dosage forms can be prepared by the conventional method in the pharmaceutical field.

In a specific embodiment, the pharmaceutical composition according to the present invention may consist of, for example, the following ratios (mass ratios):

Detailed Description

The present invention will be further described with reference to the following examples.

Example 1:

synthesis of intermediate tricyclic compound:

references Collection of Czechloroslavak Chemical Communications,49(8), 1800-9; 1984; 47(1), 65-71; 1982. the provided methods synthesize the following tricyclic compounds:

example 2:

synthesis of Compound a-57

Preparation of Compound a-52 a-51(4.08g, 10mmol) was dissolved in anhydrous tetrahydrofuran (70mL) followed by addition of sodium borohydride (0.38g, 10mmol) at 0 deg.C and stirring of the mixture for 5 hours. The reaction mixture was concentrated under reduced pressure, acidified to pH 4 with 0.5M potassium hydrogen sulfate and extracted with ethyl acetate. The combined extracts were washed with brine and dried over anhydrous magnesium sulfate, the solvent was evaporated, and it was purified through a silica gel column, washed with benzene: acetone (20: 1) solvent system gave a mixture of diastereomer a-52, 2.91 g, 71% yield. LCMS (ESI) M/z ([ M +1 ]]⁺)411.1。

Preparation of Compound a-53 Compound a-52(250mg, 0.61mmol) was dissolved in trifluoroacetic acid (5.0 mL). After 1 hour, the trifluoroacetic acid was evaporated to dryness under reduced pressure. The residue was washed with diethyl ether, dissolved in methanol (10mL), and triethylamine (85. mu.L, 0.61mmol) was added and allowed to react at room temperature for 24 hours. The methanol was then evaporated and the crude product was purified by silica gel column chromatography over ethyl acetate: methanol (15: 1) solvent system elution provided compound a-53(51 mg, 32% yield). 1H NMR (400MHz, DMSO-d)₆)δppm:2.08(dd,1H,J＝17.6Hz,J＝5.6Hz),2.51(dd,1H,J＝17.4Hz,J＝5.2Hz),2.92(m,1H),3.36(m,1H),3.58(m,1H),3.81(m,1H),5.05(s,2H),5.20(d,1H,J＝4.4Hz,OH),7.33(m,1H,lactam NH),7.34–7.40(m,5H),7.45(d,1H,J＝7.2Hz)。

LCMS(ESI)m/z([M+1]⁺)265.1。

Preparation of compound a-55 compound a-53(264 mg, 1.0mmol) was dissolved in ethyl acetate (10ml), palladium on carbon (10%, 10mg) was added, after shaking on a hydrogenation apparatus for 8 hours, the catalyst was removed by filtration, then the solvent was removed under reduced pressure and dried under high vacuum to give compound a-54. A-54 was dissolved in methyl formate (5mL) and heated at reflux for 48 h, the solvent was removed under reduced pressure and dried under high vacuum for 24 h. The crude product was dissolved in dichloromethane (3mL), cooled to 0 deg.C, and triethylamine (2.5mmol) and POCl were added₃(1.0 mol). After the addition was complete, the ice bath was removed and the solution was warmed to room temperature and reacted for 5 hours. Sodium carbonate solution (20%) was added, stirred for 30 min, aqueous layer was added, aqueous layer was extracted twice with dichloromethane, combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo, and crude product a-55(95 mg, 68% yield) was purified by flash chromatography. LCMS (ESI) M/z ([ M +1 ]]⁺)141.1。

Preparation of a-56 Compound a-55(210 mg, 1.5mmol) was dissolved in 8ml of anhydrous tetrahydrofuran and cooled to-78 ℃. To the solution was added dropwise a 2.5M n-butyllithium-hexane solution (0.72 ml, 1.8mmol), and the mixture was stirred at-78 ℃ for 2 hours. A solution of allyl chloroformate (216 mg, 1.8mmol) in THF (0.4 ml) was added dropwise to the reaction mixture, stirred at-78 ℃ for 2 hours, and the reaction solution was quenched with saturated aqueous ammonium chloride, warmed to room temperature, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain compound a-56(265 mg, yield 79%). LCMS (ESI) M/z ([ M +1 ]]⁺)225.1。

Preparation of a-57 to a solution of compound a-56(224 mg, 1.0mmol) in THF (4.0 mL) was added a 1M DIBAL-H hexane solution (1.4 mL, 1.4 mmol) and the mixture was stirred at-78 deg.C for 1 hour. After the reaction solution was quenched with acetone, an aqueous solution of sodium potassium tartrate was added, stirred and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was dissolved in 5ml of methanol at room temperature, and p-toluenesulfonic acid monohydrate (19 mg, 0.1 mmol) was added and stirred overnight. The reaction solution was quenched with aqueous sodium bicarbonate, concentrated, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain compound a-57.

Example 3:

synthesis of Compound a-65

Preparation of Compound 3-Furomethylamine a-59 to 30mL of 28% aqueous ammonia were added aldehyde a-58(0.96g,10mmol) and 5% Raney nickel. The mixture was hydrogenated at 50psi for 14 h at room temperature, then the mixture was filtered through celite, extracted with dichloromethane (2X 10mL), and dried over anhydrous sodium sulfate. The drying agent was removed and the resulting solution was filtered and used without further purification.

Preparation of Compound a-61

Compound a-59(0.97g, 10.0mmol) was dissolved in dichloromethane (20 ml). Chloroacetyl chloride (0.40ml,5.0mmol) was slowly added dropwise at 0 deg.C and stirred for 30 min, then at room temperature for another 3 h. The reaction mixture was diluted with 30ml of ethyl acetate, and washed with 2N hydrochloric acid, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. To the crude product a-60 was added anhydrous tetrahydrofuran (25mL), (Boc)₂O (2.01g, 9.23mmol) and DMAP (113mg, 0.92mmol), the reaction mixture was stirred at room temperature for 48 hours, after concentration, the crude product was purified by column chromatography (hexane/ethyl acetate 10/1 to 2/1) to give compound a-61(0.75g, yield 55%). LCMS (ESI) M/z ([ M +1 ]]⁺)274.1。

Preparation of Compound a-62 in a reaction flask under nitrogen atmosphere, Pd (dba)₂(58.0mg，0.1mmol，10mol％)，L^*(230mg，0.2mmol，20mol％)，a-61(274mg,1.0mmol)，AdCO₂H (18.0mg, 0.1mmol, 10 mol%) and cesium carbonate (490mg, 1.5mmol) were added to toluene (10ml), followed by stirring at 110 ℃ overnight. After cooling to room temperature, the reaction mixture was purified by silica gel chromatography eluting with (hexane/EtOAc 10/1 to 1/1) to give β -lactam product a-62(83mg, yield 35%).

LCMS(ESI)m/z([M+1]⁺)238.1。

Preparation of Compound a-63 Compound a-62(238mg, 1.0mmol) was dissolved in 4M HCl in ethyl acetate (2mL) and stirred at room temperature for 2 h. The solvent of the reaction solution was distilled off under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the resulting residue to conduct extraction with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under the reduced pressure to obtain compound a-63(125mg, yield 91%). LC-MS 138.1(M +1)⁺。

Synthesis of a-64, LC-MS:222.1(M +1) according to the preparation method of a-56⁺。

Synthesis of a-65, LC-MS:238.1(M +1) according to the preparation of a-57⁺。

The following compounds were synthesized in a similar manner:

example 4:

synthesis of Compounds a-105

Preparation of Compounds a-102

To a solution of compound a-101(24.6g, 100mmol) in DMF (300mL) was added iodomethane (28.16g, 179.6mmol) and DBU (22.63mL, 150mmol) and stirred at room temperature overnight. The reaction solution was poured into a 10% ammonium chloride aqueous solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under the reduced pressure to obtain compound a-102(24.18g, yield 94%).

¹H NMR(400MHz,Chloroform-d)δ7.74(d,J＝5.6Hz,1H),7.51–7.42(m,2H),7.41–7.31(m,3H),6.48(d,J＝5.6Hz,1H),5.32(s,2H),3.87(s,3H).

¹³C NMR(101MHz,CDCl₃)δ176.17,160.27,154.06,149.04,146.00,136.11,128.93,128.49,128.40,117.75,74.68,53.03.

LC-MS:261.1(M+1)⁺。

Preparation of Compounds a-103

Pyridinium p-toluenesulfonate (41.1g, 164mmol) and NH₂NHBoc (10.8g, 82.1mmol) was added to a solution of compound a-102(14.2g, 54.6mmol) in DMA (150mL) and the reaction stirred at 60 ℃ overnight. The reaction solution was added to water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution and a saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography (hexane/ethyl acetate ═ 3:1 to 1:2) to obtain compound a-103(14.6g, yield 71%).

¹H NMR(400MHz,Chloroform-d)δ7.48–7.37(m,2H),7.38–7.21(m,4H),6.38(dt,J＝7.8,1.4Hz,1H),5.30(s,1H),5.28–5.22(m,2H),3.76(s,3H),1.45(s,9H).

LC-MS:375.1(M+1)⁺。

Preparation of Compounds a-104

Compound a-103(14.0g, 37.4mmol) was dissolved in 4M HCl in ethyl acetate (200mL) and stirred at room temperature for 4 hours. The solvent of the reaction solution was distilled off under reduced pressure, and a saturated aqueous sodium hydrogencarbonate solution was added to the resulting residue to conduct extraction with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain compound a-104(9.12g, yield 89%). LC-MS 275.1(M +1)⁺。

Preparation of Compounds a-105

To a solution of compound a-104(696mg, 2.54mmol) and compound a-65(710mg, 3.0mmol) in acetonitrile (16mL) under nitrogen was added tin tetrachloride (446uL, 3.8mmol) and stirred at-25 ℃ for 50 min. The reaction solution was quenched with saturated aqueous sodium bicarbonate, dichloromethane was added, stirring was performed at room temperature, filtration was performed through celite, and the filtrate was extracted with dichloromethane. The obtained organic layer was washed with saturated brine, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure, and the obtained compound was dissolved in THF (16ml), morpholine (2.20 ml, 25.4 mmol), tetrakistriphenylphosphine palladium (292 mg, 0.254 mmol), and the mixture was stirred at room temperature for 2 hours. Diethyl ether (35 ml) was added to the reaction solution, and the precipitated solid was collected by filtration, and the dried solid compound was subjected to chiral column HPLC separation and purification to give the single isomer compound a-105(322 mg, yield 35%).

LCMS:364.1(M+1)^+，。

The following compounds were synthesized in a similar manner:

example 5:

synthesis of Compound b-6

Preparation of Compound b-5

To compound b-4(1.37g, 5.0mmol) and cyclohexanone (590mg, 6.02mmol) was added toluene (100mL) under nitrogen and heated under reflux with the trap for 8 h. The solvent was distilled off under reduced pressure to give a crude product, which was purified by silica gel column chromatography (dichloromethane/methanol ═ 50:1 to 20:1) to give compound b-4(1.5g, yield 85%).¹H NMR(400MHz,Chloroform-d)δ7.45–7.38(m,2H),7.37–7.25(m,3H),6.97(d,J＝7.6Hz,1H),6.52(d,J＝7.6Hz,1H),5.34(s,2H),3.73(s,3H),2.44(dd,J＝7.4,5.3Hz,2H),2.22(t,J＝6.2Hz,2H),1.87–1.78(m,2H),1.77–1.62(m,4H).LCMS：355.1(M+1)⁺。

Preparation of Compound b-6

Compound b-5(354mg, 1.0mmol) was dissolved in anhydrous tetrahydrofuran (5mL) under nitrogen and ice was usedWater was cooled and LiHMDS (1.5mL,1M in THF,1.5mmol) was added dropwise. After the dropwise addition, the temperature was slowly raised to 60 ℃ and stirred for 3 hours. After cooling to room temperature, the reaction was quenched by addition of a saturated ammonium chloride solution, extracted with ethyl acetate, the organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane/methanol ═ 30:1 to 20:1) to obtain compound b-6(232mg, yield 72%).¹H NMR(400MHz,Chloroform-d)δ10.6(s,1H),8.06(d,J＝7.9Hz,1H),7.54–7.45(m,2H),7.43–7.33(m,3H),6.84(d,J＝7.9Hz,1H),5.56(s,2H),2.73–2.66(m,2H),2.58(t,J＝6.3Hz,2H),1.88–1.69(m,4H)。LCMS：323.1(M+1)⁺。

The following b series compounds are synthesized by a similar method by taking a-104 as an intermediate

Example 6:

synthesis of Compound I-1 and Compound I-367

Compound b-6(166mg, 0.5mmol) and a-10(158mg, 0.6mmol) were added to a solution of 50 wt% ethyl propylphosphonic anhydride acetate (T3P) (0.9 g). Methanesulfonic acid (65. mu.L, 1.0mmol) was added to the reaction solution at room temperature, and stirred at 70 ℃ for 4 hours. Water was added to the reaction solution under ice-cooling, and extraction was performed with ethyl acetate. The organic layer was washed with water and an 8% aqueous solution of sodium hydrogencarbonate, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Chiral compound I-1 was isolated by chiral column chromatography (50mg, yield 21%). LCMS: 479.1(M +1)⁺。

Preparation of Compound I-367

Compound I-1(100mg,0.21mmol) and P₂S₅(69mg,0.31mmol) 1ml pyridine was added and stirred in an oil bath preheated to 100 ℃ for 25 minutes. The solvent was removed under reduced pressure, and C18 column chromatography (acetonitrile/water) was performed to concentrate to give Compound I-367(37mg, yield 37%).

LCMS：495.2(M+1)⁺。

Referring to the preparation method of the compound I-1, the intermediates a-106 to a-117 and b-6 to b-28 are used as raw materials to react with the tricyclic compounds a-10 to a-25, so as to synthesize the following compounds:

example 7:

synthesis of Compound VII-1

Preparation of Compound c-2

To a cooled solution of potassium tert-butoxide (1.15g, 10.34mmol) in tetrahydrofuran (25mL) at 0 ℃ was added dropwise ethyl isocyanoacetate (1g, 10.34mmol) over 20 minutes. Stirred at room temperature for 30 minutes. A solution of compound 1-c (2.26 g; 8.62mmol) in tetrahydrofuran (25mL) was then added dropwise over 30 minutes, followed by stirring at room temperature overnight. After completion of the reaction, the reaction mixture was quenched with crushed ice and then extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water (3X 50mL) then brine (2X 50mL), dried over anhydrous sodium sulfate and concentrated to give the crude product. Ethanol (200mL) solution of crude product in hydrogenation unit with 10% Pd-C (C: (A-B)) (1g) Hydrogenation was carried out at 50psi pressure for 18 hours. The reaction mass was filtered through celite and washed with ethanol. The combined filtrate and washings were concentrated in vacuo and the resulting crude product was refluxed with hydrochloric acid (35%) (70mL) for 16 h. The reaction mixture was then co-distilled 2 times with toluene, washed with ether to remove organic impurities and concentrated in vacuo to give 1.96g of product, which was separated by HPLC with chiral column to give compound c-2(913mg, 33%), LCMS: 322.2(M +1)⁺。

Preparation of Compound c-3

To a solution of compound c-2(0.64g, 2.0mmol) in methanol (10mL) was added dropwise chlorotrimethylsilane (0.43g, 4.0mmol) at 0 ℃ under an argon atmosphere, and the mixture was stirred at room temperature overnight. At 0 deg.C, Boc was added sequentially₂O (0.65g,3.0mmol) and triethylamine (0.41mL,3.0mmol), followed by stirring at room temperature overnight. After completion of the reaction, most of the solvent was removed under reduced pressure, and the reaction mixture was quenched with crushed ice and then extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give compound c-3(731mg, 84%). LCMS: 436.1(M +1)⁺。

Preparation of Compound c-4

Compound c-3(872mg,2.0mmol) was dissolved in 12 ml of methanol/tetrahydrofuran (1:1) and then sodium borohydride (0.11g, 3.0mmol) was added and the reaction mixture stirred at room temperature for 2 hours. The reaction was then quenched with water (30mL), the suspension was extracted with ethyl acetate, and the organic layers were combined, dried and filtered. The filtrate was evaporated to dryness and then dissolved in 10ml of dichloromethane, Dess-Martin periodinane (1.48g, 3.49mmol) and sodium bicarbonate (0.37g, 3.49mmol) were added, the resulting mixture was stirred at room temperature for two hours, the mixture was concentrated and purified by silica gel column chromatography (n-hexane/ethyl acetate 8/1 to 1:1) to give the product c-4(615mg, 76%). LCMS: 406.1(M +1)⁺。

Preparation of Compound c-5

Compound c-4(1.15g, 3mmol), 3-amino-1-propanol (379mg, 5.05mmol) and anhydrous sodium sulfate (3.26g, 22.4mmol) were added to toluene (40ml) and stirred at room temperature for 5 hours. The obtained crude product was subjected to silica gel column chromatography (Hexane/EtOAc, 2/1 to 1/2, v/v) to afford product c-5(1.22g, 89%). LCMS: 463.1(M +1)⁺。

Preparation of Compound c-6

Compound a-101(2.46 g, 10.0Mmol) was dissolved in tetrahydrofuran (40ml), and 1-hydroxybenzotriazole (1.65 g, 12.2Mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.80 g, 14.6Mmol), compound c-5(4.63 g, 10.0Mmol) and N, N-diisopropylethylamine (2.55 ml, 14.6Mmol) were added and stirred at room temperature for 12 hours. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, a saturated sodium bicarbonate solution and water in this order, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting compound was dissolved in a 4N hydrochloric acid/ethyl acetate solution (45 ml) at room temperature and stirred for 2 hours. The solvent was distilled off under reduced pressure, ethanol was added, the reaction was basified with saturated aqueous sodium carbonate solution, stirred for 2 hours, followed by extraction with chloroform, the organic layer was dried over sodium sulfate, the solvent was removed under reduced pressure, and silica gel column chromatography (dichloromethane/methanol 40/1 to 10/1) gave compound c-6(3.60 g, yield 61%). LCMS: 591.2(M +1)⁺。

Preparation of Compound c-7

Compound c-6(1.18g, 2.0mmol) the resulting crude product was added to toluene (10mL) and stirred at 100 ℃ for 3 h. After removing the solvent under reduced pressure, the resulting crude product was purified by silica gel column chromatography (dichloromethane/methanol ═ 40/1 to 10/1) and then separated by HPLC with a chiral column to give pure isomer c-7(332mg, yield 29%). LCMS: 573.1(M +1)⁺。

Preparation of Compound VII-1

Compound c-7(286mg, 0.5mmol) was dissolved in N, N-dimethylacetamide (3ml), and lithium chloride (210mg, 5.0mmol) was added, heated to 80 ℃ and stirred for 3 hours. After cooling to room temperature, 30ml of ethyl acetate were added, washed twice with water (5ml of X2), the organic phase was filtered over anhydrous sodium sulfate, the solvent was removed under reduced pressure and purified by C18 reverse column (acetonitrile/water) to give compound VII-1(193 mg, 80% yield). LCMS: 483.1(M+1)⁺。

Referring to the synthesis of compound VII-1, the following compounds can be synthesized:

example 8:

synthesis of Compound IX-39

Preparation of Compound d-1

Methyl iodide (370mg,2.6mmol) was added dropwise to a suspension of b-6(645mg,2.0mmol) and cesium carbonate in dimethylformamide (20ml) at 0 ℃ and the reaction mixture was stirred at room temperature for 24 hours. Saturated ammonium chloride solution was added, extraction was performed with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure, followed by vacuum concentration to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane/methanol ═ 30:1 to 20:1) to obtain compound d-1(417mg, 62%). LCMS: 337.2(M +1)⁺。

Preparation of Compound d-2

N-bromosuccinimide (145mg, 0.81mmol) was added to a solution of d-1(182mg, 0.54mmol) in acetonitrile (10 mL). The mixture was stirred at 25 ℃ for 3 hours, cooled to room temperature, quenched by addition of saturated ammonium chloride solution, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure, followed by vacuum concentration to give a crude product, which was purified by silica gel column chromatography (dichloromethane/methanol ═ 30:1 to 20:1) to give compound d-2(163mg, 73%). LCMS: 415.1(M +1)⁺。

Preparation of Compound d-4

To a solution of compound d-2(500mg, 1.2mmol) in DMF (3ml) under nitrogen was added compound d-3(860mg, 1.8mmol) and PdCl₂(dppf) (88mg, 0.12mmol) and the reaction mixture was stirred at 110 ℃ for 1 h. Subjecting the obtained product to reactionThe solution was cooled to room temperature, diluted with ethyl acetate (50ml), a saturated aqueous solution of potassium fluoride (50ml) was added, and the mixture was stirred overnight. The precipitated insoluble matter was filtered and separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed three times with water and dried over sodium sulfate, and then the solvent was distilled off. The crude product was purified by silica gel column chromatography. Elution first with hexane/ethyl acetate (1:1, v/v) and then with ethyl acetate gave compound d-4(525mg, yield 80%). LCMS: 546.3(M +1)⁺。

Preparation of Compound IX-39

Compound d-4(273mg, 0.5mmol) was dissolved in N, N-dimethylacetamide (3ml), and lithium chloride (210mg, 5.0mmol) was added thereto, and the mixture was heated to 80 ℃ and stirred for 3 hours. After cooling to room temperature, 30ml of ethyl acetate were added, washed twice with water (5ml of X2), the organic phase was filtered over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by C18 reverse column (acetonitrile/water) to give Compound IX-39(187mg, 82% yield). LCMS: 456.1(M +1)⁺。

Example 9:

synthesis of Compound IX-36

Preparation of Compound d-7

Using d-5 as raw material, synthesizing compound d-6 by using the method for synthesizing b-6. LCMS: 456.1(M +1)⁺. And then methylated to give compound d-7. LCMS: 395.3(M +1)⁺。

Preparation of Compound d-8

To compound d-7(1.97g,5mmol) were added methanol (25ml) and 2M aqueous lithium hydroxide (25ml,50mmol), the reaction mixture was stirred at room temperature for 2 hours and LCMS followed the reaction to completion. Neutralizing with 2M hydrochloric acid to pH6 under ice water cooling, extracting with ethyl acetate, washing the organic layer with saturated brine, drying with anhydrous magnesium sulfate, distilling under reduced pressure to remove the solvent, and vacuum concentrating to obtain crude product, and purifying with silica gel column chromatography (dichloromethane/methanol ═ 30:1 to 10:1) to obtainTo compound d-8(1.69g, 89%). LCMS: 381.2(M +1)⁺。

Preparation of Compound d-10

To a solution of compound d-8(198mg, 0.52mmol) in DMF (5ml) under ice-cooling were added triethylamine (263mg, 2.60mmol) and ethyl chloroformate (169mg, 1.56 mmol). After stirring at the same temperature for 10 minutes, compound d-9(287mg, 1.56mmol) and dimethylaminopyridine (6mg, 0.05mmol) were added, and the mixture was stirred at the same temperature for 1 hour. To the resulting reaction solution was added water, and after washing with ethyl acetate 3 times, the aqueous layer was extracted with chloroform 2 times. The combined extracts were dried over sodium sulfate and the solvent was distilled off to give the crude product which was purified by silica gel column chromatography (chloroform/methanol ═ 30:1 to 10:4) to give compound d-10(114mg, 40%). LCMS: 547.3(M +1)⁺。

Preparation of Compound IX-36

Compound d-10(110mg, 0.2mmol) was dissolved in N, N-dimethylacetamide (1ml), and lithium chloride (84mg, 2.0mmol) was added thereto, and the mixture was heated to 80 ℃ and stirred for 3 hours. After cooling to room temperature, 30ml of ethyl acetate were added, washed twice with water (5ml of X2), and the organic phase was filtered over anhydrous sodium sulfate, the solvent was removed under reduced pressure and purified by C18 reverse phase column (acetonitrile/water) to give compound IX-36(70.3mg, 77% yield). LCMS: 457.1(M +1)⁺。

Example 10:

synthesis of Compound IX-1

Preparation of Compound d-12

To a solution of compound d-8(148mg, 0.39mmol) in DMF (2mL) was added (2, 4-difluorophenyl) methylamine d-11(84.4mg, 0.59mmol), 4-methylmorpholine (158mg, 1.56mmol) in that order. ) And HATU (223mg, 0.59 mmol). The reaction was stirred at room temperature for 16 hours. The reaction solution was purified by C18 reverse phase column (0-100% 0.05% TFA in ACN/0.05% aqueous TFA) to give compound d-12(168mg, 85% yield). LCMS: 506.3(M +1)⁺。

Preparation of Compound IX-1

Compound d-12(101mg, 0.2mmol) was dissolved in N, N-dimethylacetamide (1ml), and lithium chloride (84mg, 2.0mmol) was added thereto, and the mixture was heated to 80 ℃ and stirred for 3 hours. After cooling to room temperature, 30ml of ethyl acetate were added, washed twice with water (5ml of X2), the organic phase was filtered over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by C18 reverse column (acetonitrile/water) to give Compound IX-1(60.6mg, 73% yield). LCMS: 416.1(M +1)⁺。

The following compounds were synthesized in a similar manner:

example 11:

synthesis of Compound X-1

Preparation of Compound e-2

3, 4-dihydro-2H-pyran-1 (120mL, 112g, 1.32mol) was added to a 2L round bottom flask followed by TMEDA (138mL, 107g, 0.92 mol). After cooling to 0 ℃ a 2.5M solution of n-butyllithium in hexane (370mL, 0.92mol) was added slowly over 15 minutes. During the addition, the clear pale yellow solution turned off-white and a white solid precipitated, and the solution turned dark yellow to orange in color. The reaction was stirred at 0 ℃ for an additional 45 minutes during which time the solution became bright, opaque orange. The reaction was then warmed to room temperature and stirred for 20 hours. Anhydrous THF (600mL) was then added, at which point the solution turned reddish brown. After cooling again to 0 °, paraformaldehyde (90g, 2.96mol) is added in portions slowly with vigorous stirring, initially ≈ 1g, then ≈ 2g, then ≈ 4g, etc., with a pause of about 5 minutes between additions to prevent exotherms. Finish addingAfter paraformaldehyde, the reaction was allowed to warm gradually to room temperature over 20 hours, at which time the solution turned milky white, opaque and pale yellow. The reaction was slowly quenched with saturated sodium bicarbonate solution at room temperature. Ammonium chloride solution (200mL) was added and stirred for 15 minutes. The mixture was then diluted with 500mL of diethyl ether. The organic layer was separated, poured into an aqueous solution of copper sulfate (250g in 700mL of water), and stirred vigorously for 30 minutes. The organic layer was then decanted, washed with saturated aqueous sodium bicarbonate (3 × 50mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The crude product was purified by vacuum distillation and e-2 was collected as a clear colorless oil with aromatic costustoot in 72g yield, 68% yield.¹H NMR(400MHz,C₆D₆)δ4.74(t,J＝3.8Hz,1H),4.00-3.94(broad s,3H),3.76(app t,J＝5.1Hz,2H),1.78(app q,J＝6.4,4.0Hz,2H),1.47(app quintet,J＝5.2Hz,4.4Hz,2H)；¹³C NMR(100MHz,C₆D₆)δ154.7,97.1,66.7,63.6,23.3,20.8。

Preparation of Compound e-4

(3, 4-dihydro-2H-pyran-6-yl) methanol e-2(4.6g, 40.4mmol, 1.0 equiv.) was dissolved in dichloromethane (125mL) and cooled to 0 ℃. Triethylamine (8.43mL, 60.5mmol, 1.5 equiv.) was added to the top, followed by dropwise addition of methanesulfonyl chloride (3.75mL, 1.2 equiv.). The resulting mixture was stirred at 0 ℃ for 2 hours, then triethylamine (3.94mL, 0.7 eq.) and methanesulfonyl chloride (1.56mL, 0.5 eq.) were added. The mixture was stirred at 0 ℃ for a further 1 hour. After a period of time, water was added and the product was extracted with dichloromethane, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. To the crude mesylate thus obtained was added DMF (75mL) and water (7.5 mL). Sodium azide (3.15g, 48.4mmol, 1.2 equivalents) was then added to the above solution and the mixture was stirred at room temperature for 16 hours. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with water and brine (3 times), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a volume of about 75 ml. To the resulting solution was added triphenylphosphine (9.7g, 37mmol), THF (100mL) and water (10 mL). The resulting mixture was heated at 60 ℃ for 2 hours. The product was extracted with ethyl acetate, and the organic layer was washed with water and brine, and dried over anhydrous sodium sulfateDried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by distillation under reduced pressure (85 ℃, 0.1mm Hg) to give compound e-4 in a yield of 2.3g (50.4%).¹H NMR(400MHz,CDCl₃)δ(ppm)：4.59(t,J＝3.6Hz,1H),3.97(apt,J＝5.4Hz,2H),3.10(s,2H),2.00-1.95(m,2H),1.80-1.73(m,2H)；¹³CNMR 8(100.6MHz,CDCl₃)δ(ppm)154.9,95.3,66.2,45.0,22.3,19.9。

Preparation of Compound e-6

Pyridinium p-toluenesulfonate (41.1g, 164mmol) and e-4(9.3g, 82.1mmol) were added to a solution of compound 4-5(17.4g, 54.6mmol) in DMA (150mL) and the reaction was stirred at 60 ℃ overnight. The reaction solution was added to water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution and a saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography (hexane/ethyl acetate ═ 3:1 to 1:2) to obtain compound e-6(16.9g, yield 75%). LCMS: 414.1(M +1)⁺。

Preparation of Compound e-7

Compound e-6(1.24g, 3.0mmol) was dissolved in anhydrous tetrahydrofuran (15mL) under a nitrogen atmosphere and cooled with ice water, LiHMDS (4.5mL,1M in THF,4.5mmol) was added dropwise. After the dropwise addition, the temperature was slowly raised to 60 ℃ and stirred for 3 hours. After cooling to room temperature, the reaction was quenched by addition of saturated ammonium chloride solution, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane/methanol ═ 30:1 to 20:1) to obtain compound e-7(881mg, yield 77%). LCMS: 382.3(M +1)⁺。

Preparation of Compound e-8

To compound e-7(1.91g,5mmol) were added methanol (25ml) and 2M aqueous lithium hydroxide (25ml,50mmol), the reaction mixture was stirred at room temperature for 2 hours and LCMS followed the reaction to completion. Neutralizing with 2M hydrochloric acid to pH6 under ice water cooling, extracting with ethyl acetate, washing the organic layer with saturated brine, drying over anhydrous magnesium sulfate, distilling off the solvent under reduced pressure, and concentrating under vacuum to obtain crude product, which is subjected to silica gel column chromatography (dichloromethane/methanol)Purification of 30:1 to 10:1) gave compound e-8(1.52g, 83%). LCMS: 368.3(M +1)⁺。

Preparation of Compound e-9

To a solution of compound e-8(144mg, 0.39mmol) in DMF (2mL) were added (2, 4-difluorophenyl) methylamine d-11(84.4mg, 0.59mmol), 4-methylmorpholine (158mg, 1.56mmol) and HATU (223mg, 0.59mmol) in that order. The reaction was stirred at room temperature for 18 hours. The reaction solution was purified by C18 reverse phase column (0-100% 0.05% TFA in ACN/0.05% aqueous TFA) to give compound e-9(156mg, 81% yield). LCMS: 493.3(M +1)⁺。

Preparation of Compound X-1

Compound e-9(98.5mg, 0.2mmol) was dissolved in N, N-dimethylacetamide (1ml), and lithium chloride (84mg, 2.0mmol) was added thereto, and the mixture was heated to 80 ℃ and stirred for 3 hours. After cooling to room temperature, 30ml of ethyl acetate were added, washed twice with water (5ml of X2), the organic phase was filtered over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by C18 reverse column (acetonitrile/water) to give Compound X-1(55.5mg, 69% yield). LCMS: 403.2(M +1)⁺。

Example 12:

synthesis of Compound X-21

Preparation of Compound e-10

To a solution of the compound e-8(191mg, 0.52mmol) in DMF (5ml) under ice-cooling were added triethylamine (263mg, 2.60mmol) and ethyl chloroformate (169mg, 1.56 mmol). After stirring at the same temperature for 10 minutes, compound d-9(287mg, 1.56mmol) and dimethylaminopyridine (6mg, 0.05mmol) were added, and the mixture was stirred at the same temperature for 1 hour. To the resulting reaction solution was added water, and after washing with ethyl acetate 3 times, the aqueous layer was extracted with chloroform 2 times. The combined extracts were dried over sodium sulfate and the solvent was distilled off to give a crude product which was purified by silica gel column chromatography (chloroform/methanol ═ 30:1 to 10:4) to give compound e-10(119.3mg, 43%). LCMS: 534.3(M +1)⁺。

Preparation of Compound X-21

Compound e-10(107mg, 0.2mmol) was dissolved in N, N-dimethylacetamide (1ml), and lithium chloride (84mg, 2.0mmol) was added thereto, and the mixture was heated to 80 ℃ and stirred for 3 hours. After cooling to room temperature, 30ml of ethyl acetate was added, washed twice with water (5ml of X2), the organic phase was filtered over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by C18 reverse column (acetonitrile/water) to give Compound X-21(63.8mg, 72% yield). LCMS: 444.1(M +1)⁺。

The following compounds were synthesized in a similar manner:

example 13:

synthesis of Compounds XI-1a and XI-1b

Preparation of Compound f-2

Compound f-1(715mg, 3.70mmol), 2- (1-aminocyclopropyl) -1-ethanol (373mg, 3.69mmol) and sodium sulfate (1.91g, 13.4mmol) were added to toluene (25ml), and the mixture was stirred at room temperature for 1 hour. Boc addition at room temperature₂O (804mg, 3.69mmol), stirred directly for 18 h. Further Boc was added at room temperature₂O (400mg, 1.72mmol), stirred directly for 48 h. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (n-hexane/ethyl acetate, 1:1, v/v) to obtain compound f-2(1.02g, 71%).

LCMS：391.1(M+1)⁺。

Preparation of Compound f-3

To ethanol (20ml) was added compound f-2 (78)0mg, 2.0mmol) and palladium-activated carbon (10%, 200mg), under a hydrogen atmosphere, at room temperature for 2 hours. After filtration through celite, the solvent was concentrated under reduced pressure to give compound f-3(510 mg). LCMS: 257.1(M +1)⁺。

Preparation of Compound f-5

To toluene (8ml) were added f-4(664mg, 2.0mmol) and f-3(512mg, 2.0mmol), and the mixture was stirred at 100 ℃ for 3 hours. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (n-hexane/ethyl acetate 3/1 to 1/2) to obtain compound f-5(912mg, 80%). LCMS: 571.2(M +1)⁺。

Preparation of Compound f-6

To compound f-5(570mg, 1.0mmol) was added 4N HCl (ethyl acetate solution, 4 ml). After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. Toluene (10ml) and 2- (1-aminocyclopropyl) -1-ethanol (322mg, 3.19mmol) were then added, and the mixture was stirred at 80 ℃ for 15 minutes. The solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (dichloromethane/methanol, 100/1 to 10/1) to obtain compound f-6(225mg, 53%). LCMS: 425.1(M +1)⁺。

Preparation of Compound f-7

Compound f-6(352mg, 0.83mmol) was dissolved in ethanol (3ml) and THF (6ml), and a 2N aqueous solution of sodium hydroxide (1.69ml, 3.38mmol) was added thereto, followed by stirring at room temperature for 1 hour. 2N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate and dried over sodium sulfate. The solvent was concentrated under reduced pressure to give compound f-7(187mg, 57%). LCMS: 397.1(M +1)⁺。

Preparation of Compound f-8

The compound f-7(396mg, 1.0mmol), (2, 4-difluorophenyl) methylamine (143mg, 1.0mmol), diisopropylethylamine (0.52mL, 3.0mmol) and HATU (380mg, 1.0mmol) were added to DMF (5mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added ethyl acetate (50mL), washed with water (10mL X2), the organic layer was dried over sodium sulfate, the solvent was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (dichloromethane/methanol, 100/1 to 10/1) to give compound f-8(250mg, 48%). LCMS: 522.1(M+1)⁺。

Preparation of Compounds XI-1a and XI-1b

Trifluoroacetic acid (6ml) was added to the compound f-8(250mg, 0.48mmol), and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the pH was adjusted to 6 with saturated sodium bicarbonate, extracted with chloroform, and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (dichloromethane/methanol, 100/1 to 10/1) and further separated by HPLC with a chiral column to give compound XI-1a (66mg, 33%) and compound XI-1b (71mg, 34%). LCMS: 432.1(M +1)⁺。

Example 14:

synthesis of Compounds XI-31a and XI-31b

Preparation of Compound f-9

1, 1-carbonyldiimidazole (164mg, 1.0mmol) and f-7(396mg, 1.0mmol) were added to 10mL of N, N-dimethylacetamide, followed by N, N-diisopropylethylamine (0.18mL), 1.1 mmol). The mixture was stirred at room temperature for 2h, 2- (2, 4-difluorobenzene) acetohydrazide (186mg, 1.0mmol) was added, and the mixture was heated to 60 ℃ for 2 h. The mixture was cooled to room temperature, diluted with water, extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, and after concentration, the resulting crude product was purified by silica gel column chromatography (dichloromethane/methanol, 100/1 to 10/1) to give compound f-9(391mg, 73%). LCMS: 537.1(M +1)⁺。

Preparation of Compound f-10

F-9(220mg, 0.41mmol) was suspended in 4mL of 1, 4-dihexacyclo and phosphorus pentasulfide (183mg, 0.83mmol) was added in one portion. The mixture was stirred at room temperature for 15 minutes and heated to 40 ℃ for 1 hour. The mixture was cooled to room temperature and poured into ice water and stirred until all the ice had melted. The mixture was extracted with dichloromethane, the combined organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/methanol, 100/1 to 1)0/1) to give compound f-10(143mg, 62%). LCMS: 563.1(M +1)⁺。

Preparation of Compounds XI-31a and XI-31b

Trifluoroacetic acid (4ml) was added to the compound f-10(140mg, 0.25mmol), and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the pH was adjusted to 6 with saturated sodium bicarbonate, extracted with chloroform, and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting crude product was purified by silica gel column chromatography (dichloromethane/methanol, 100/1 to 10/1) and further separated by HPLC with a chiral column to give compound XI-31a (34mg, 29%) and compound XI-31b (40mg, 34%). LCMS: 473.1(M +1)⁺。

The following compounds were synthesized in a similar manner:

example 15:

synthesis of prodrug Compound IV-1

Compound I-1(480mg, 1mmol), DMA (10ml) was added and stirred, chloromethyl methyl carbonate (240mg), potassium carbonate (290mg), potassium iodide (170mg) were added, and the mixture was warmed to 50 ℃ and stirred for 6 hours. Then DMA (1ml) was added and stirring was continued for 6 hours. The reaction solution was cooled to room temperature, DMA (2ml) was added thereto, stirred at 50 ℃ for 5 minutes, and filtered. 1N hydrochloric acid water (5ml) and water (2ml) were added dropwise to the filtrate at 0-5 ℃ and stirred for 1 hour. The solid was filtered and dried at 60 ℃ under reduced pressure to give prodrug compound IV-1(494mg) in 87% yield. LCMS:567.2(M +1)⁺。

The following prodrug compounds can be synthesized in a similar manner.

Biological evaluation

Determination of Cap-dependent Endonuclease (CEN) inhibitory Activity

1) Preparation of the substrate

30mer RNAs (5 ' -pp- [ m2 ' -0] GAA UAU (-Cy3) GCA UCA CUA GUA AGCUUU GCU CUA-BHQ2-3 ') obtained by diphosphorylating G at the 5' -end and methoxylating the hydroxyl group at the 2 ' -end, labeling U at the 6-position from the 5' -end with Cy3 and labeling U at the 3' -end with BHQ2 were purchased and added with a cap structure (product m7G [ 5' ] -ppp- [ 5' ] [ m2 ' -0] GAA UAU (-Cy3) GCA UCA CUA GUA AGC UUUGCU CUA (-BHQ2) -3 ') using the ScripCap system. The resulting mixture was separated and purified by a modified polyacrylamide gel electrophoresis method and used as a substrate.

2) Preparation of enzymes

RNPs were prepared from virus particles according to the protocol (ref: VIROLOGY (1976)73, 327-338 LGA M. ROCHOVASNKY). Specifically, 200 μ L of 1x10 will be used³PFU/mL A/WSN/33 virus was inoculated into 10-day-old, grown chicken eggs, cultured at 37 ℃ for 2 days, and allantoic fluid was recovered from the eggs. Virus particles were purified by ultracentrifugation using 20% sucrose, dissolved using TritonX-100 and lysolecithin, and then subjected to ultracentrifugation using a 30-70% glycerol density gradient to collect RNP fractions (50-70% glycerol fractions) for use as an enzyme solution (containing about 1nM of PB 1. PB 2. PA complex).

3) Enzymatic reaction

2.5. mu.L of an enzymatic reaction solution (composition: 53mM Tris hydrochloride (pH7.8), 1mM magnesium chloride, 1.25mM dithiothreitol, 80mM NaCl, 12.5% glycerol, 0.15. mu.L of an enzyme solution) was dispensed onto a 384-well plate made of polypropylene. Then, 0.5. mu.L of DMSO was added to 0.5. mu.L of the test compound solution serially diluted with DMSO, the Positive Control (PC) and the Negative Control (NC), and mixed well. Then, 2. mu.L of a substrate solution (1.4nM substrate RNA, 0.05% Tween20) was added to the reaction mixture to initiate a reaction, the reaction mixture was incubated at room temperature for 60 minutes, and then 1. mu.L of the reaction mixture was added to 10. mu.L of a highly purified formamide solution (containing GeneScan120LizSize Standard as a size marker (manufactured by Applied Biosystem (ABI)) to terminate the reaction. NC is a reaction which was previously stopped by adding EDTA (4.5mM) before the reaction was started (the labeling concentration was all at the final concentration).

4) Inhibition rate (IC)₅₀Value) determination

The solution after the reaction was terminated was heated at 85 ℃ for 5 minutes, quenched on ice for 2 minutes, and then analyzed with ABIPRIZM3730Genetic Analyzer (Gene Analyzer). The peak of the cap-dependent endonuclease product was quantified by analysis software ABI Genemapper, and the CEN reaction inhibition ratio (%) of the test compound was determined using the fluorescence intensities of PC and NC as 0% inhibition and 100% inhibition, respectively, and then IC was determined by curve fitting software₅₀The value is obtained.

Confirmation test of CPE-inhibiting Effect

< materials >

1) 2% FCS E-MEM (prepared by adding kanamycin and FCS to MEM (minimum essential Medium))

2) 0.5% BSA E-MEM (prepared by adding kanamycin and BSA to MEM (minimum essential Medium))

3) HBSS (Hanks balanced salt solution)

4) MDBK cells: the number of cells was adjusted to an appropriate number with 2% FCS E-MEM (3X 10)⁵/mL)。

5) MDCK cells: the cells were washed 2 times with HBSS and then adjusted to the appropriate cell number with 0.5% BSA E-MEM (5X 10)⁵/mL)。

6) Trypsin solution

Trypsin (SIGMA) from porcine pancreas was dissolved in PBS (-) and filtered through a 0.45 μm filter.

7) Enzyme-linked immunosorbent assay (ELISA) instrument

8) WST-8 kit

9) 10% SDS solution

< procedure flow >

1) Dilution and dispensing of test sample

2% FCS E-MEM was used for MDBK cells, and 0.5% BSA E-MEM was used for MDCK cells. The same culture medium was used for dilution of virus, cell and test sample. Test samples were diluted in culture medium to an appropriate concentration in advance, and 2-to 5-fold serial dilutions (50. mu.L/well) were prepared in a 96-well plate. Two blocks for measuring influenza resistance and cytotoxicity were prepared. Triplicate assays were performed for each drug. .

In the case of MDCK cells, trypsin was added to the cells to a final concentration of 3. mu.g/mL only for measurement of anti-influenza activity.

2) Dilution and dispensing of influenza Virus

Influenza virus culture medium was diluted to an appropriate concentration in advance, and each was dispensed into a 96-well plate to which test samples were added at 50. mu.L/well. The culture medium was dispensed at 50. mu.L/well into the plate for measuring cytotoxicity.

3) Dilution and dispensing of cells

Cells adjusted to an appropriate number of cells were dispensed into a 96-well plate containing a test sample at 100. mu.L/well.

Mixed with a plate mixer (plate mixer) and cultured in a CO2 incubator. The cells were cultured for 3 days for both influenza resistance and cytotoxicity.

4) Dispensing of WST-8

The 96-well plate cultured for 3 days was observed under a microscope with the naked eye, and the supernatant was removed from the plate without sucking the cells.

The WST-8 kit was diluted 10-fold with a culture medium, and the WST-8 solution was dispensed into each well at 100. mu.L each.

Mixing with a hole plate mixer, and then culturing in a CO2 incubator for 1-3 hours.

After the plate for measuring anti-influenza activity was cultured, 10. mu.L of 10% SDS solution was dispensed into each well, and the virus was inactivated.

5) Measurement of absorbance

For the mixed 96-well plate, absorbance was measured at 450nm/620nm of two wavelengths using EnVision.

< calculation of values of measurement items >

The calculation was performed using Microsoft Excel program based on the following calculation formula.

50% inhibitory concentration of influenza-infected cell death (EC)₅₀) Is calculated by

EC₅₀＝10^Z

Z＝(50％-High％)/(High％-Low％)x{log(High conc.)-log(Low conc.)}+

log(High conc.)

The results of measurement of the test substances (example compounds) as the parent compounds are shown in table 1.

TABLE 1 CPE inhibition test results

0.1nM≤+++++≤1nM<++++≤10nm≤+++≤50nM

A≥100μM≥B≥50μM≥C≥10μM≥D≥1μM

From the above results, it is clear that all the compounds showed very high CPE-inhibiting effect, and many of the compounds showed CPE-inhibiting effect more than twice that of S-033188A, and toxicity was 5 times or even 10 times less than that of S-033188A. Thus, the compounds of the examples may be prepared for use as prophylactic/therapeutic agents for symptoms/diseases induced by influenza virus infection.

Bioavailability (BA) assay

Experimental materials and method for oral absorbability study

(1) Animals were used: rats were used.

(2) Feeding conditions are as follows: the rats were allowed free intake of solid feed and sterilized tap water.

(3) Setting of application amount and grouping: oral administration and intravenous administration are carried out using a prescribed administration amount. The group is set as follows. (variation in the amount of each compound to be administered)

Orally administered at 1-30 mg/kg (n is 2-3)

Intravenous administration of 0.5 to 10mg/kg (n is 2 to 3)

(4) Preparation of an application liquid: oral administration is administered as a solution or suspension. Intravenous administration is administered in a solubilized manner.

(5) The application method comprises the following steps: oral administration is forced into the stomach by an oral feeding tube. Intravenous administration is from the tail vein by means of a syringe with a needle.

(6) Evaluation items: blood was collected over time and drug concentrations in plasma were determined using LC/MS/MS.

(7) Statistical analysis: for the concentration change in plasma, the area under the concentration-time curve (AUC) in plasma was calculated using a non-linear least squares procedure, and the Bioavailability (BA) was calculated from the AUC of the oral administration group and the intravenous administration group.

The measurement results using rat measurement are shown in table 2 below.

TABLE 2 bioavailability of parent compounds and prodrugs

From the above results, it is clear that the prodrug has improved bioavailability compared to the parent compound in most cases. Therefore, the compound of the present invention is superior to S-033188A/S-033188B in oral absorbability, and can be used as a pharmaceutical drug for treating and/or preventing symptoms and/or diseases caused by infection with influenza virus, and it is expected that the administration dose can be made smaller and the side effects can be made lower.

anti-HIV Activity assay

Test samples were subjected to a series of two-fold dilutions in 96-well plates (50 μ L/well). Two plates were prepared for measurement of anti-HIV activity and for measurement of cytotoxicity. Duplicate measurements were performed for each agent. 2.5X 10^5/mL of MT-4 cell suspension was dispensed at 100. mu.L/well onto 96-well plates containing the test samples. HIV virus solution was dispensed at 50. mu.L/well into the containing assaySamples and cells in 96-well plates. To the plate for measuring cytotoxicity, the culture solution was dispensed at 50. mu.L/well. Mixing with a plate mixer, and then mixing in CO₂Culturing in an incubator for 4 days. The 96-well plate cultured for 4 days was observed with the naked eye and a microscope, and it was confirmed that there was no problem in the proliferation and inhibition of the virus in the wells of the positive control and the negative control. Mu.l of MTT (3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide) solution was dispensed into each well.

Reacting at CO₂The incubation was carried out in an incubator for 1 hour. Remove 150 μ L of supernatant from each well so that the cells are not aspirated. To this, 150. mu.l of cell lysis solution was added, followed by thorough mixing by a plate mixer until all cells were lysed. The mixed 96-well plates were measured by a microplate reader at two wavelengths of 560nm/690 nm. Based on the following calculation formula, the 50% HIV inhibitory concentration (EC50) was calculated.

EC50＝10Z

Z＝(50％-Low％)/(High％-Low％)×{log(High conc.)-log(Low conc.)}+log(Low conc.)

Based on the following calculation formula, the 50% cytotoxic concentration (CC50) was calculated.

CC50＝10Z

The Selectivity Index (SI) was calculated based on the following calculation formula.

SI＝CC 50/EC 50

TABLE 3 HIV inhibition test results

As is apparent from the above results, all the compounds showed a high HIV inhibitory effect, and therefore, the compounds of the examples can be prepared as preventive/therapeutic agents for symptoms/diseases induced by HIV viral infection.

Claims

1. A polycyclic pyridone compound having an antiviral action, characterized in that: containing a pyridone heterocyclic compound represented by the following formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a crystal thereof,

wherein:

(1) x is selected from the group consisting of a hydrogen atom, a single bond, a halogen, a cyano group, an alkynyl group, an alkyl group, a five-membered heteroaromatic ring, a six-membered heteroaromatic ring and N (R)⁴)C(O)-；

(2) Y is selected from a single bond or C₁-C₃An alkylene group;

(3)Y¹selected from O or S;

(4)Y²and Y³Respectively selected from N, C, CH;

(5)R⁰is selected from C₆-C₁₀Aryl, 5 or 6 membered monocyclic heteroaryl, 9 or 10 membered bicyclic heteroaryl; said C is₆-C₁₀Aryl, the 5-or 6-membered monocyclic heteroaryl and the 9-or 10-membered bicyclic heteroaryl may have up to three R⁵A substituent group;

(6)R¹selected from hydrogen, cyano, alkynyl, hydroxyl, halogen, carboxyl, ester group, amido and sulfonamide; or, R¹Selected from the group consisting of unsubstituted or substituted: c_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkanethiol, hydrazinoacyl, C_1-6Alkylcarbonyl group, C_1-6Alkylaminocarbonyl radical, C_1-6Alkylcarbonylamino, C_1-6Alkyloxycarbonyl, C_1-6Alkylsulfinyl radical, C_1-6Alkylamino carbonylamino group, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, C_3-6Cycloalkylamino radical, C_3-6Cycloalkanemercapto group, C_3-6Cycloalkanecarbonyl group, C_3-6Cycloalkylamino carbonyl group, C_3-6Cycloalkanecarbonylamino group, C_3-6Cycloalkylamino carbonylamino group, C_4-8Heterocycloalkyl radical, C_4-8Heterocyclic alkoxy radical, C_4-8Heterocyclic alkylamino radical, C_4-8Heterocycloalkylmercapto group, C_4-8A heterocycloalkylcarbonyl group,C_4-8Heterocycloalkylaminocarbonyl radical, C_5-10Aryl radical, C_5-10Heteroaryl group, C_5-10Aryloxy radical, C_5-10Aryloxyalkyl radical, C_5-10Arylamine group, C_5-10Aromatic mercapto group, C_5-10Aryl carbonyl group, C_1-6Hydrocarbyl sulfone group, C_1-6Alkyl sulfonylamino group, C_3-6Cycloalkyl sulfone group, C_3-6Cycloalkylsulfonylamino, C_5-10Aryl sulfone group, C_5-10Arylsulfonylamino, aminooxalylamino, aminooxalyl, C_5-10Arylaminocarbonyl group, C_5-10Arylaminocarbonylamino; or, X and R¹Are linked and form C together with the carbon to which they are linked_5-10Carbocyclic ring, C_5-10Heterocycle, C_5-10Aromatic ring, C_5-10A heteroaromatic ring;

(7)R²independently of each other H, halogen, CN, NO₂Oxo (═ O), -C (═ O) OH, -C (═ O) OCH₃、-C(＝O)NH₂、-OH、-OCH₃、-OCH₂CH₃、-OCF₃、-OCHF₂、-OCH₂CF₃、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoroethyl, alkynyl, cyclopropylalkynyl, methoxypropynyl, hydroxypropynyl, acetoxypropynyl, propenyl, cyclopropylvinyl, methoxypropenyl, hydroxypropenyl, acetoxypropenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxiranyl, azetidinyl or oxetanyl;

(8)R³independently of each other H, halogen, CN, NO₂Oxo (═ O), -C (═ O) OH, -C (═ O) OCH₃、-C(＝O)NH₂、-OH、-OCH₃、-OCH₂CH₃、-OCF₃、-OCHF₂、-OCH₂CF₃、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoroethyl, alkynyl, cyclopropylalkynyl, methoxypropynyl, hydroxypropynyl, acetoxypropynyl, propenyl, cyclopropylvinyl, methoxypropenyl, hydroxypropenyl, acetoxypropenyl, cyclopropyl, cyclobutyl, cyclopentylCyclohexyl, cycloheptyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, phenyl, naphthyl, furanyl, benzofuranyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, benzimidazolyl, benzpyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1, 3, 5-triazinyl, thiazolyl, thienyl, benzothienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolinyl, or isoquinolinyl, wherein said methyl, ethyl, n-propyl, isopropyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, Morpholinyl, phenyl, naphthyl, furyl, benzofuryl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, benzimidazolyl, benzopyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 1, 3, 5-triazinyl, thiazolyl, thienyl, benzothienyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolyl, purinyl, quinolinyl, isoquinolinyl, each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from halogen, CN, NO₂、OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy;

or any two R taken together with the carbon or nitrogen atom to which they are attached form a cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, oxirane, azetidine, oxetane, pyrrolidine, piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholine, thiomorpholine, benzene, furan, pyrrole, pyridine, pyrazole, imidazole, triazole, tetrazole, oxazole, oxadiazole, 1, 3, 5-triazine, thiazole, thiophene, pyrazine, pyridazine, or pyrimidine, wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, oxirane, azetidine, oxetane, pyrrolidine, piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholine, thiomorpholine, benzene, furan, pyrrole, pyridine, pyrazole, imidazole, triazole, tetrazoleOxazole, oxadiazole, 1, 3, 5-triazine, thiazole, thiophene, pyrazine, pyridazine, pyrimidine are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from halogen, CN, NO₂、OH、-NH₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy;

(9)R⁴independently is H or C₁-C₆An alkyl group;

(11)R⁶Independently is H or C₁-C₆An alkyl group;

(13) ring a is monocyclic, spiro, bicyclic, bridged, or polycyclic, unsubstituted, one or more substituents with m being 0, 1, 2, 3,4, or 5, and may be carbocyclic or a heterocyclic ring containing O, S, N; ring A is a saturated or unsaturated ring, and substituent R on ring A²Independently selected from H, cyano, alkynyl, hydroxyl, halogen, carboxyl, ester group, amido, sulfonamide and C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkanethiol, hydrazinoacyl, C_1-6Alkylcarbonyl group, C_1-6Alkylaminocarbonyl radical, C_1-6Alkylcarbonylamino, C_1-6Alkyloxycarbonyl, C_1-6Alkylsulfinyl radical, C_1-6Alkylamino carbonylamino group, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, C_3-6Cycloalkylamino radical, C_3-6Cycloalkanemercapto group, C_3-6Cycloalkanecarbonyl group, C_3-6Cycloalkylamino carbonyl group, C_3-6Cycloalkanecarbonylamino group, C_3-6Cycloalkylamino carbonylamino group, C_4-8Heterocycloalkyl radical, C_4-8Heterocyclic alkoxy radical, C_4-8Heterocyclic alkylamino radical, C_4-8Heterocycloalkylmercapto group, C_4-8Heterocycloalkylcarbonyl radical, C_4-8Heterocycloalkylaminocarbonyl radical, C_5-10Aryl radical, C_5-10Heteroaryl group, C_5-10Aryloxy radical, C_5-10Aryloxyalkyl radical, C_5-10Arylamine group, C_5-10Aromatic mercapto group, C_5-10Aryl carbonyl group, C_1-6Hydrocarbyl sulfone group, C_1-6Alkyl sulfonylamino group, C_3-6Cycloalkyl sulfone group, C_3-6Cycloalkylsulfonylamino, C_5-10Aryl sulfone group, C_5-10Arylsulfonylamino, aminooxalylamino, aminooxalyl, C_5-10Arylaminocarbonyl group, C_5-10Arylaminocarbonylamino;

(14) ring B is H or an unsubstituted, one or more substituents with n being 0, 1, 2, 3,4 or 5, bicyclic, tricyclic, tetracyclic, pentacyclic or hexacyclic ring system of 10 to 30 atoms, wherein the bicyclic, tricyclic, tetracyclic, pentacyclic or hexacyclic ring system of 10 to 30 atoms is a carbocyclic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring; substituent R on ring B³Independently selected from H, cyano, alkynyl, hydroxyl, halogen, carboxyl, ester group, amido, sulfonamide and C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkanethiol, hydrazinoacyl, C_1-6Alkylcarbonyl group, C_1-6Alkylaminocarbonyl radical, C_1-6Alkylcarbonylamino, C_1-6Alkyloxycarbonyl, C_1-6Alkylsulfinyl radical, C_1-6Alkylamino carbonylamino group, C_1-6Alkyl carbonyl oxygen, C_1-6Haloalkyl, C_2-6Substituted alkenyl, C_2-6Substituted alkynyl, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, C_3-6Cycloalkylamino radical, C_3-6Cycloalkanemercapto group, C_3-6Cycloalkanecarbonyl group, C_3-6Cycloalkylamino carbonyl group, C_3-6Cycloalkanecarbonylamino group, C_3-6Cycloalkylamino carbonylamino group, C_4-8Heterocycloalkyl radical, C_4-8Heterocyclic alkoxy radical, C_4-8Heterocyclic alkylamino radical, C_4-8Heterocycloalkylmercapto group, C_4-8Heterocycloalkylcarbonyl radical, C_4-8Heterocycloalkylaminocarbonyl radical, C_5-10Aryl radical, C_5-10Heteroaryl group, C_5-10Aryloxy radical, C_5-10Aryloxyalkyl radical, C_5-10Arylamine group, C_5-10Aromatic mercapto group, C_5-10Aryl carbonyl group, C_1-6Hydrocarbyl sulfone group, C_1-6Alkyl sulfonylamino group, C_3-6Cycloalkyl sulfone group, C_3-6Cycloalkylsulfonylamino, C_5-10Aryl sulfone group, C_5-10Arylsulfonylamino, aminooxalylamino, aminooxalyl, C_5-10Arylaminocarbonyl group, C_5-10Arylaminocarbonylamino;

(15) p is H, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_3-8Carbocyclyl, C_3-8carbocyclyl-C_1-4Alkylene, heterocyclic group consisting of 3 to 8 atoms, (heterocyclic group consisting of 3 to 8 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms, (heteroaryl of 5 to 10 atoms) -C_1-4Alkylene, -C (═ O) -R^P1、-C(＝O)-L-R^P1、-C(＝O)-L-O-R^P1、-C(＝O)-L-O-L-O-R^P1、-C(＝O)-L-O-C(＝O)-R^P1、-C(＝O)-NR^P1R^P2、-C(＝O)-O-R^P1、-S(＝O)₂-R^P1、-P(＝O)-(R^P3)(R^P4)、-C(＝O)-O-L-O-R^P1、-C(＝N⁺R^P1R^P1)(-NR^P1R^P1)、R^P1-O-C_1-4Alkylene radical, R^P1-O-L-O-C_1-4Alkylene radical, R^P1-(C＝O)-O-C_1-4Alkylene radical, R^P1-O-(C＝O)-C_1-4Alkylene radical, R^P1-O-(C＝O)-NR^P2-C_1-4Alkylene radical, R^P1-O-(C＝O)-O-C_1-4Alkylene, NR^P1R^P2-O-(C＝O)-O-C_1-4Alkylene radical, R^P1-O-L-O-(C＝O)-O-C_1-4Alkylene, NR^P1R^P1-L-O-(C＝O)-O-C_1-4Alkylene radical, R^P1-O-L-NR^P2-(C＝O)-O-C_1-4Alkylene, NR^P1R^P1-L-N(R^P2)-(C＝O)-O-C_1-4Alkylene radical, R^P1-O-L-O-L-O-(C＝O)-O-C_1-4Alkylene group, (HO)₂P(＝O)-C_1-4Alkylene, (BnO)₂P(＝O)-C_1-4Alkylene or R^P1-(C＝O)-NR^P2-L-O-(C＝O)-O-C_1-4Alkylene, wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_3-8Carbocyclyl, C_3-8carbocyclyl-C_1-4Alkylene, heterocyclic group consisting of 3 to 8 atoms, (heterocyclic group consisting of 3 to 8 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms and (heteroaryl of 5 to 10 atoms) -C_1-4Each alkylene is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from halo, oxo (═ O), CN, NO₂、-OR^b、-NR^cR^d、-C(＝O)R^a、-O(C＝O)R^a、-C(＝O)OR^b、C_1-6Alkyl radical, R^bO-C_1-4Alkylene, -NR^cR^dC(＝O)R^a、R^cR^dN-C_1-4An alkylene group;

each L is independently C_1-6Alkylene or C_2-6An alkenylene group;

each R^P1Independently is C_1-6Alkyl radical, C_3-8Carbocyclyl, C_3-8carbocyclyl-C_1-4Alkylene, heterocyclyl consisting of 3 to 8 atoms, (heterocyclyl consisting of 3 to 8 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms, (heteroaryl of 5 to 10 atoms) -C_1-4Alkylene radical, C_1-6Alkylamino radical, C_1-6Alkylthio or C_1-6Alkylsilyl group, wherein said C_1-6Alkyl radical, C_3-8Carbocyclyl, C_3-8carbocyclyl-C_1-4Alkylene, heterocyclyl consisting of 3 to 8 atoms, (heterocyclyl consisting of 3 to 8 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms, (heteroaryl of 5 to 10 atoms) -C_1-4Alkylene radical, C_1-6Alkylamino and C_1-6Alkylthio is each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from halogen (F, Cl, Br or I), oxo (═ O), CN, NO₂、-OR^b、-NR^cR^d、-C(＝O)R^a、-O(C＝O)R^a、-C(＝O)OR^b、C_1-6Alkyl radical, R^bO-C_1-4Alkylene, -NR^cR^dC(＝O)R^a、R^cR^dN-C_1-4An alkylene group;

each R^P2Independently is H or C_1-6An alkyl group;

or R^P3、R^P4And together with the phosphorus atom to which they are attached, form a 3-8 atom heterocycle or a 5-10 atom heteroaryl ring, wherein the 3-8 atom heterocycle and the 5-10 atom heteroaryl ring are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from halogen, oxo (═ O), CN, NO₂、-OR^b、-NR^cR^d、-C(＝O)R^a、-O(C＝O)R^a、-C(＝O)OR^b、C_1-6Alkyl radical, R^bO-C_1-4Alkylene, -NR^cR^dC(＝O)R^aOr R^cR^dN-C_1-4An alkylene group;

each R^a、R^b、R^cAnd R^dIndependently is H, C_1-6Haloalkyl, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Carbocyclyl, C_3-6carbocyclyl-C_1-4Alkylene, heterocyclic group consisting of 3 to 6 atoms, (heterocyclic group consisting of 3 to 6 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms or (heteroaryl of 5 to 10 atoms) -C_1-4Alkylene, wherein said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Carbocyclyl, C_3-6carbocyclyl-C_1-4Alkylene, heterocyclic group consisting of 3 to 6 atoms, (heterocyclic group consisting of 3 to 6 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms and (heteroaryl of 5 to 10 atoms) -C_1-4Each alkylene is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from halogen, CN, OH, NH₂、NO₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy or C_1-6An alkylamino group;

or R^c、R^dTogether with the nitrogen atom to which they are attached, form a heterocyclic ring of 3 to 6 atoms or a heteroaromatic ring of 5 to 8 atoms, which isWherein said 3-6 atom heterocycle and 5-8 atom heteroaryl ring are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halogen, CN, OH, NH₂、NO₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy or C_1-6An alkylamino group;

the halogen is F, Cl, Br or I.

2. An antiviral polycyclic pyridone compound according to claim 1, wherein: wherein the compound of formula (I) has a structure as shown in formula (Ia), (Ib), or (Ic):

wherein X, Y1, P, R¹、R²、R³Ring A and ring B are as defined in (1) to (15) in formula I.

3. An antiviral polycyclic pyridone compound according to claim 1, wherein: wherein the compound of formula (I) has a structure according to formula (Id), (Ie), (If) or (Ig):

x, Y, P, R therein⁰、R²And ring A is as defined for (1) to (15) in formula I.

4. An antiviral polycyclic pyridone compound according to claim 1, 2 or 3, wherein: wherein: (1) ring A is a saturated or unsaturated monocyclic, spiro, fused, bridged or polycyclic ring of 5 to 20 atoms, wherein the saturated or unsaturated monocyclic, spiro, fused, bridged or polycyclic ring system of 5 to 20 atoms is carbocyclic, a heterocyclic ring containing O, S, N, an aromatic ring, a heteroaromatic ring containing O, S, N;

(2) or ring a has the sub-structure:

(3) wherein said ring B is R²Or has the following sub-structure:

(4) wherein said P is independently H or has the following group:

(5) wherein each R is^a、R^b、R^cAnd R^dIndependently H, methyl, ethyl, trifluoromethyl, trifluoroethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, 3-6 atom heterocyclyl, phenyl or 5-10 atom heteroaryl, wherein said methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, 3-6 atom heterocyclyl, phenyl and 5-10 atom heteroaryl are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, CN, OH, NH₂、NO₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy;

or R^c、R^dAnd together with the nitrogen atom to which they are attached, form a 3-6 atom heterocyclic ring or a 5-6 atom heteroaromatic ring, wherein said 3-6 atom heterocyclic ring and 5-6 atom heteroaromatic ring are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, CN, OH, NH₂、NO₂Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy;

(6) x is selected from the group consisting of a hydrogen atom, a single bond, a five-membered heteroaromatic ring, a six-membered heteroaromatic ring, N (R)⁴) C (O) -; wherein the five-membered heteroaromatic ring is selected from the following subformulas:

(7)R⁰is selected from C₆-C₁₀Aryl, 5 or 6 membered monocyclic heteroaryl and 9 or 10 membered bicyclic heteroaryl; said C is₆-C₁₀Aryl, the 5-or 6-membered monocyclic heteroaryl and the 9-or 10-membered bicyclic heteroaryl may have up to three R⁵A substituent group; wherein the 5 or 6 membered monocyclic heteroaryl is selected from the following subformulae:

5. an antiviral polycyclic pyridone compound according to any one of claims 1 to 4, wherein: the compound is selected from the following structures, but is not limited to these compounds:

6. a pharmaceutical composition comprising the antiviral polycyclic pyridone compound of claim 1, characterized in that: the pharmaceutical composition is an antiviral pharmaceutical composition, and optionally comprises one or more therapeutic agents; the therapeutic agent is selected from the following: neuraminidase inhibitors, nucleoside drugs, PB2 inhibitors, PB1 inhibitors, M2 inhibitors, other anti-influenza drugs;

or the therapeutic agent is selected from the following: a second therapeutic agent that is an HIV antiviral agent, an immunomodulator, and an anti-infective agent; wherein the HIV antiviral agent is an antiviral inhibitor selected from the group consisting of HIV protease inhibitors, HIV integrase inhibitors, nucleoside reverse transcriptase inhibitors, CCR5 co-receptor antagonists, non-nucleoside reverse transcriptase.

7. The pharmaceutical composition containing polycyclic pyridone compounds with antiviral action according to claim 6, wherein: the pharmaceutical composition is a pharmaceutical preparation selected from tablets, powders, capsules, granules, oral liquids, injections, powders, suppositories, pills, creams, pastes, gels, powders, inhalants, suspensions, dry suspensions, patches, lotions and nano preparations.

8. Use of one or more combinations of the pharmaceutical compositions of formula (I) according to claim 6 for the preparation of a medicament for the prevention and/or treatment of viral infectious diseases.

9. The use of a pharmaceutical composition containing a polycyclic pyridone compound having an antiviral effect according to claim 8 for the preparation of a medicament for the prophylaxis and/or treatment of viral infectious diseases, characterized in that: the virus infectious disease is an infectious disease caused by HIV; or the virus infectious disease is an infectious disease caused by influenza A and/or influenza B.