Perinaphthenone compounds and their uses

Abstract

The present invention discloses a perinaphthenone compound and its use, which can bind to E3 ubiquitin ligase 3 motif 25 (TRIM25), promote pathogen recognition by TRIM25, and induce proteasome-dependent ubiquitination degradation of pathogen proteins, and is a promising ligand for TRIM25, and can realize a wider range of applications, such as the production of PROTAC molecules, so that the perinaphthenone compound has great potential for research and development value and future applications.

Description

[Technical field]

[0001] The present invention relates to the technical field of medicine, in particular to perinaphthenone compounds and their uses, for example in the manufacture of drugs for the prevention and / or treatment of diseases, in the regulation of target ubiquitination levels as ligands of E3 ubiquitin ligase 3 motif protein 25 (tripartite motif 25, TRIM25), and in the manufacture of protein degradation targeting chimeras (PROTACs). [Background technology]

[0002] In recent years, cell therapy, immunotherapy, gene editing technology, etc. have been rapidly developed. Proteolysis-targeting chimeras (PROTACs) are an emerging direction in the field of drug research and development, which can directly induce the degradation of substrate proteins via the ubiquitin-proteasome proteolytic pathway in vivo, and have attracted widespread attention from researchers.

[0003] The mechanism of action of PROTACs is to link a small molecule inhibitor and an E3 ubiquitin ligase ligand with a linker to form a complex that targets and induces protein degradation. In vivo, the inhibitor portion of this bifunctional molecule recognizes the target protein, and the ligand portion of E3 recognizes the E3 ubiquitin ligase, bringing the target protein and the E3 ubiquitin ligase into close spatial proximity, transferring ubiquitin on the E3 ubiquitin-conjugating enzyme to the target protein, ubiquitinating the target protein, and then degrading the target protein via the ubiquitin-proteasome pathway.

[0004] To expand the scope of application of PROTAC in drug discovery, finding small molecule ligands for E3 ubiquitin ligase is an important advance. In 2008, Craig et al. reported a PROTAC (SCHNEEKLOTH AR, PUCHEAULT M, TAE HS,et al.Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics.Bioorganic & medicinal chemistry letters,2008, 18(22) : 5904-5908) that linked nutlin, a ligand of E3 ubiquitin ligase (MDM2), and an androgen receptor inhibitor. Crews et al. designed and engineered ligands for the E3 ubiquitin ligase (VHL) and discovered a VHL ligand with high affinity (BUCKLEY DL, GUSTAFSON JL, VAN MOLLE I, et al. Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1alpha. Angewandte Chemie, 2012, 51(46): 11463-11467).In 2015, Bradner and Crews research teams reported methods to design dual-function molecules dBET1 and ARV-825 using a ligand (a domide drug) for E3 ubiquitin ligase (CRBN) and an inhibitor of BRD4, JQ1, respectively (WINTER GE, BUCKLEY DL, PAULK J,et al.DRUG DEVELOPMENT.Phthalimide conjugation as a strategy for in vivo target protein degradation.Science,2015,348(6241) : 1376-1381, LU J,QIAN Y,ALTIERI M,et al.Hijacking the E3 ubiquitin ligase cereblon to efficiently target brD4.Chemistry & biology,2015,22(6) : 755-763).

[0005] Although PROTAC technology is developing rapidly, it still faces many challenges in the application process; for example, there are relatively few ligands for E3 ubiquitin ligases.

[0006] E3 ubiquitin ligase tripartite motif 25 (TRIM25) is a member of the tripartite protein family among E3 ubiquitin ligases. Currently, there are few reports on TRIM25 ligands, and there have been no reports of PROTACs using TRIM25 ligands. Summary of the Invention [Problem to be solved by the invention]

[0007] As a result of research, the inventors have discovered a perinaphthenone compound that can bind to E3 ubiquitin ligase 3 motif 25 (TRIM25) in vitro, promote the recognition of PA protein by TRIM25, and induce proteasome-dependent ubiquitination degradation of PA protein. The compound is therefore promising as a ligand for E3 ubiquitin ligase TRIM25 and can be used in a wider range of applications, such as in the production of PROTAC molecules, and therefore has great potential for research and development value and future applications. [Means for solving the problem]

[0008] In a first aspect of the invention, there is provided a compound having the structure: TIFF2024545831000002.tif43170 (where One-site or two-site valence bonds TIFF2024545831000003.tif3170 represents a single bond or a double bond, and 1 and 2 are not double bonds at the same time. R 1 ~R 18 are independently H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -CN, -NO 2 , -COR A , -C(O)OR A , -OCOR A , -C(O)NR A R B , -CH=NR A , -OR A , -OC(O)R A , -S(O) t -R A , -S(O) t -NR A R B , -NR A R B , -NR A C(O)R B and optionally, where H on each group is selected from halogen, -CN, -CF 3 , -NO 2 , -CHO, -COOH, -C(O)NH2 , -OH, -OC(O)H, -SH, -S(O) 2 H, -NH 2 and optionally substituted with one or more groups selected from R 19 and R 20 is independently selected from H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, and heterocyclylalkyl, and optionally, where H on each group is selected from substituted or unsubstituted heterocyclyl, halogen, -CN, -NO 2 , -COR A , -C(O)OR A , -C(O)NR A R B , -CH=NR A , -OR A , -OC(O)R A , -S(O) t -R A , -S(O) t -NR A R B , -NR A R B , -NR A C(O)R B or R 19 and R 20 together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl or heterocyclyl, or R 17 and R 19 together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl or heterocyclyl; t is selected from 0, 1, and 2; Each R A and R B are each independently selected from H, alkyl, cycloalkyl, alkenyl, aryl, heterocyclyl, and halogen. Specifically, R 1 ~R 18are independently H, C1-10 alkyl, C1-10 haloalkyl (e.g., fluoroalkyl, e.g., trifluoromethyl), C1-10 alkenyl, C3-6 cycloalkyl, C4-10 cycloalkylalkyl, phenyl, 4- to 6-membered heterocycloalkyl, halogen, -CN, -NO 2 , -CHO, -CO(C1-10 alkyl), -COOH, -C(O)O(C1-10 alkyl), -C(O)NH 2 , -C(O)N(C1-10 alkyl)(C1-10 alkyl), -OH, -O(C1-10 alkyl), -OC(O)H, -OC(O)(C1-10 alkyl), -SH, -S(C1-10 alkyl), -S(O) 2 H, -S(O) 2 (C1-10 alkyl), -NH 2 , -N(C1-10 alkyl)(C1-10 alkyl), -NHC(O)H, -N(C1-10 alkyl)C(O)(C1-10 alkyl).

[0009] More specifically, R 1 -OH, -O(C1-10 alkyl), -SH, -S(C1-10 alkyl), -S(O) 2 H, -S(O) 2 (C1-10 alkyl), and in some embodiments of the present invention, R 1 is -OH.

[0010] More specifically, R 2 is H, halogen, -CN, -CF 3 , -NO 2 , -CHO, -COOH, -C(O)NH 2 , -NH 2 In some embodiments of the present invention, R 2 is H.

[0011] More specifically, R 3is selected from C1-10 alkyl, C1-10 haloalkyl (e.g. fluoroalkyl, e.g. trifluoromethyl), C1-10 alkenyl, C3-6 cycloalkyl, C4-10 cycloalkylalkyl, in particular C1-10 alkyl, e.g. C1-6 alkyl, C1-3 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl), and in some embodiments of the present invention, R 3 is methyl.

[0012] More specifically, R 4 -OH, -O(C1-10 alkyl), -SH, -S(C1-10 alkyl), -S(O) 2 H, -S(O) 2 (C1-10 alkyl), and in some embodiments of the present invention, R 4 is -OH.

[0013] More specifically, R 5 is selected from H, C1-10 alkyl, C1-10 haloalkyl (e.g. fluoroalkyl, e.g. trifluoromethyl), C1-10 alkenyl, C3-6 cycloalkyl, C4-10 cycloalkylalkyl, in particular C1-10 alkyl, e.g. C1-6 alkyl, C1-3 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl), and in some embodiments of the present invention, R 5 is methyl, and in some further embodiments of the present invention, R 5 is H.

[0014] More specifically, R 6 -OH, -O(C1-10 alkyl), -SH, -S(C1-10 alkyl), -S(O) 2 H, -S(O) 2 (C1-10 alkyl), and in some embodiments of the present invention, R 6 is -OH.

[0015] More specifically, R 7 -OH, -O(C1-10 alkyl), -SH, -S(C1-10 alkyl), -S(O) 2 H, -S(O)2 (C1-10 alkyl), and in some embodiments of the present invention, R 7 is -OH.

[0016] More specifically, R 8 , R 9 , R 11 , R 12 , R 13 , R 15 , R 16 are independently H, halogen, -CN, -CF 3 , -NO 2 , -CHO, -COOH, -C(O)NH 2 , -NH 2 In some embodiments of the present invention, R 8 , R 9 , R 11 , R 12 , R 13 , R 15 , R 16 are all H.

[0017] More specifically, R 10 and R 14 is independently selected from C1-10 alkyl, C1-10 haloalkyl (e.g., fluoroalkyl, e.g., trifluoromethyl), C1-10 alkenyl, C3-6 cycloalkyl, C4-10 cycloalkylalkyl, particularly C1-6 alkyl, such as C1-3 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), and in some embodiments of the present invention, R 10 and R 14 are all methyl.

[0018] More specifically, R 17 is H, -OH, -O(C1-10 alkyl), -SH, -S(C1-10 alkyl), -S(O) 2 H, -S(O) 2 (C1-10 alkyl), and in some embodiments of the present invention, R 17 is H, and in some other embodiments of the present invention, R 17 is -OH.

[0019] More specifically, R 18 is H, C1-10 alkyl, C1-10 haloalkyl (e.g., fluoroalkyl, e.g., trifluoromethyl), halogen, -CN, -CF 3 , -NO 2 , -CHO, -CO(C1-10 alkyl), -COOH, -C(O)O(C1-10 alkyl), -C(O)NH 2 , -C(O)N(C1-10 alkyl)(C1-10 alkyl), -OH, -O(C1-10 alkyl), -OC(O)H, -OC(O)(C1-10 alkyl), -SH, -S(C1-10 alkyl), -S(O) 2 H, -S(O) 2 (C1-10 alkyl), -NH 2 , -N(C1-10 alkyl)(C1-10 alkyl), -NHC(O)H, -N(C1-10 alkyl)C(O)(C1-10 alkyl), optionally where one or more H on each group is selected from halogen, -CN, -CF 3 , -NO 2 , -CHO, -CO(C1-10 alkyl), -COOH, -C(O)O(C1-10 alkyl), -C(O)NH 2 , -C(O)N(C1-10 alkyl)(C1-10 alkyl), -OH, -O(C1-10 alkyl), -OC(O)H, -OC(O)(C1-10 alkyl), -SH, -S(C1-10 alkyl), -S(O) 2 H, -S(O) 2 (C1-10 alkyl), -NH 2 , -N(C1-10 alkyl)(C1-10 alkyl), -NHC(O)H, -N(C1-10 alkyl)C(O)(C1-10 alkyl), more specifically, R 18 is selected from H, C1-6 alkyl, C1-6 haloalkyl (e.g., fluoroalkyl, e.g., trifluoromethyl), C1-6 hydroxy-substituted alkyl (C1-6 alkyl with one or more hydroxy substitutions, e.g., hydroxymethyl), -CHO, -CO(C1-10 alkyl), -COOH, -C(O)O(C1-10 alkyl), and in some embodiments of the present invention, R 18is H, methyl, ethyl, n-propyl, isopropyl, -CH 2 OH, -COOH, -COOCH 3 , -CHO.

[0020] In one embodiment of the present invention, R 19 has the following structure: TIFF2024545831000004.tif21170 (where TIFF2024545831000005.tif3170 represents a single or double bond, R 21 ~R 24 are independently H, C1-10 alkyl, C1-10 haloalkyl (e.g., fluoroalkyl, e.g., trifluoromethyl), C1-10 alkenyl, C3-6 cycloalkyl, C4-10 cycloalkylalkyl, phenyl, 4- to 6-membered heterocycloalkyl, halogen, -CN, -NO 2 , -CHO, -CO(C1-10 alkyl), -COOH, -C(O)O(C1-10 alkyl), -C(O)NH 2 , -C(O)N(C1-10 alkyl)(C1-10 alkyl), -OH, -O(C1-10 alkyl), -OC(O)H, -OC(O)(C1-10 alkyl), -SH, -S(C1-10 alkyl), -S(O) 2 H, -S(O) 2 (C1-10 alkyl), -NH 2 , -N(C1-10 alkyl)(C1-10 alkyl), -NHC(O)H, -N(C1-10 alkyl)C(O)(C1-10 alkyl), or R 21 ~R 24 two of these together with the intermediate carbon atom form a substituted or unsubstituted cycloalkyl or heterocyclyl; If TIFF2024545831000006.tif3170 represents a double bond, R 24 does not exist, R 25 and R 26are independently selected from C1-10 alkyl, C1-10 haloalkyl (e.g., fluoroalkyl, e.g., trifluoromethyl), C1-10 alkenyl, C3-6 cycloalkyl, C4-10 cycloalkylalkyl, phenyl, and 4- to 6-membered heterocycloalkyl. Specifically, R 25 and R 26 is independently selected from C1-10 alkyl, e.g., C1-6 alkyl, C1-3 alkyl, and in some embodiments of the present invention, R 25 and R 26 are all methyl.

[0021] In some embodiments of the present invention, R 21 is H.

[0022] In some embodiments of the present invention, R 19 teeth, The file is TIFF2024545831000007.tif23170.

[0023] Specifically, R 24 is selected from -OH, -O(C1-10 alkyl), or R 23 and R 24 together with the carbon atoms between them form a substituted or unsubstituted cycloalkyl or heterocyclyl.

[0024] Specifically, R 22 is selected from H, -OC(O)H, -OC(O)(C1-10 alkyl), for example, -OC(O)CH 3 It is.

[0025] Specifically, R 23 is selected from H, -OH, -O(C1-10 alkyl), -SH, -S(C1-10 alkyl), for example, H or -OH.

[0026] In some other embodiments of the present invention, R 20 and R 22 together with the carbon atom between them form a heterocyclyl.

[0027] In some other embodiments of the present invention, R 20 and R 23 together with the carbon atom between them form a heterocyclyl.

[0028] Specifically, the above R 19 In the definition of heterocyclyl, heterocycloalkyl is defined as heterocycloalkyl, such as 4- to 6-membered heterocycloalkyl, in particular oxygen-containing 5- to 6-membered heterocycloalkyl, such as TIFF2024545831000008.tif19170, where R C are one or more individual substituents on the ring, and are C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxy-substituted alkyl, C1-10 alkenyl, halogen, -CN, -NO 2 , -CHO, -CO(C1-10 alkyl), -COOH, -C(O)O(C1-10 alkyl), -C(O)NH 2 , -C(O)N(C1-10 alkyl)(C1-10 alkyl), -OH, -O(C1-10 alkyl), -OC(O)H, -OC(O)(C1-10 alkyl), -SH, -S(C1-10 alkyl), -S(O) 2 H, -S(O) 2 (C1-10 alkyl), -NH 2 , -N(C1-10 alkyl)(C1-10 alkyl), -NHC(O)H, -N(C1-10 alkyl)C(O)(C1-10 alkyl).

[0029] Specifically, R C is one or more individual substituents on the ring, and is selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxy-substituted alkyl, C1-6 alkenyl, halogen, -CN, -NO 2 , -CHO, -COOH, -C(O)NH 2 , —OH, —OC(O)H, —SH, and in some embodiments of the present invention, R C is one or more individual substituents on the ring and is selected from methyl, ethyl, n-propyl, isopropyl.

[0030] In some embodiments of the present invention, R 19 teeth, Selected from TIFF2024545831000009.tif21170.

[0031] In some embodiments of the present invention, R 20 is H.

[0032] In some embodiments of the present invention, R 19 and R 20 are groups together with the carbon atom to which they are attached. Form TIFF2024545831000010.tif21170.

[0033] In some embodiments of the present invention, the valence bond at site 1 is a double bond and the valence bond at site 2 is a single bond.

[0034] In some further embodiments of the present invention, the valence bond at site 1 is a single bond and the valence bond at site 2 is a double bond.

[0035] In some further embodiments of the present invention, the valence bond at site 1 is a single bond and the valence bond at site 2 is a single bond.

[0036] Specifically, the compound may have the following structure: TIFF2024545831000011.tif38170 (where R 1 , R 4 , R 5 , R 6 , R 7 , R 17 , R 18 , R 19 , R 20 has a corresponding definition in the present invention.

[0037] More specifically, the compound may have the structure: TIFF2024545831000012.tif38170 (where R 1 , R4 , R 5 , R 6 , R 17 , R 18 , R 19 , R 20 has a corresponding definition in the present invention.

[0038] More specifically, the compound may have the structure: TIFF2024545831000013.tif31170 (where R 5 , R 17 , R 18 , R 19 , R 20 has a corresponding definition in the present invention.

[0039] More specifically, the compound may be selected from the following structures: TIFF2024545831000014.tif81170

[0040] In an embodiment of the invention, the compound has the following structure: TIFF2024545831000015.tif241170TIFF2024545831000016.tif25170

[0041] Preferably, it does not contain the following compounds: TIFF2024545831000017.tif128170

[0042] In a second aspect of the invention there is provided a pharma- ceutically acceptable salt, ester, stereoisomer, prodrug or solvate of a compound according to the first aspect.

[0043] Specifically, a stereoisomer of the compound may have the following structure: TIFF2024545831000018.tif36170

[0044] More specifically, a stereoisomer of the compound may have the following structure: TIFF2024545831000019.tif37170

[0045] In some embodiments of the invention, the stereoisomer of the compound has the following structure: TIFF2024545831000020.tif236170TIFF2024545831000021.tif24170

[0046] Specifically, the compounds according to the first aspect of the present invention and the pharma- ceutically acceptable salts, esters, stereoisomers, prodrugs, and solvates according to the second aspect of the present invention can be produced by any suitable method known to a person skilled in the art, such as chemical synthesis, semi-synthesis, microbial fermentation, or animal or plant extraction. For example, they can be produced by extracting and isolating a fermentation product of a microorganism (e.g., Aspergillus iizukae CPCC 401321, deposit number CGMCC No. 22467), or by modifying the chemical structure (and performing a physical treatment step) of a compound obtained by extraction and separation (semi-synthesis), or they can be produced from chemical raw materials having a relatively simple chemical structure through a series of chemical synthesis and physical treatment steps (total synthesis).

[0047] In some embodiments of the present invention, the method for producing the compound according to the first aspect of the present invention may comprise a step of extracting or isolating a fermentation product of a microorganism (e.g., Aspergillus iizukae CPCC 401321 having the deposit number CGMCC No. 22467), and further, the method may comprise a step of modifying the chemical structure of the compound obtained by the extraction or separation.

[0048] In some further embodiments of the present invention, a method for producing a compound according to the first aspect of the present invention may comprise producing said compound from chemical raw materials having a relatively simple chemical structure through a series of chemical synthesis and physical processing steps (total synthesis).

[0049] In a third aspect of the invention, there is provided a pharmaceutical composition comprising a compound according to the first aspect of the invention, or a pharma- ceutically acceptable salt, ester, stereoisomer, prodrug, solvate according to the second aspect of the invention, and one or more pharma- ceutically acceptable auxiliary materials.

[0050] Specifically, the pharmaceutical composition may be in any suitable dosage form, such as tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, oral preparations, granules, pills, powders, ointments, elixirs, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, and patches, but is not limited thereto. Oral dosage forms such as capsules, tablets, oral liquids, granules, pills, powders, elixirs, and ointments are preferred.

[0051] Specifically, the pharma- ceutically acceptable auxiliary materials may be, but are not limited to, adhesives, fillers, diluents, tableting agents, lubricants, disintegrants, coloring agents, flavoring agents, and wetting agents, etc. Suitable fillers may be, for example, cellulose, mannotol, lactose, and other similar fillers, suitable disintegrants may be, for example, starch, polyvinylpyrrolidone, and starch derivatives such as sodium starch glycolate, suitable lubricants may be, for example, magnesium stearate, and suitable wetting agents may be, for example, sodium lauryl sulfate.

[0052] Specifically, the pharmaceutical composition may further comprise one or more other ingredients selected from an inosine monophosphate dehydrogenase (IMPDH) inhibitor, an interferon inducer, an M2 ion channel protein inhibitor, and a neuraminidase inhibitor.

[0053] Specifically, the inosine monophosphate dehydrogenase inhibitor may be, for example, ribavirin.

[0054] Specifically, the interferon inducer may be, for example, arbidol hydrochloride.

[0055] Specifically, the M2 ion channel protein inhibitor may be, for example, amantadine hydrochloride or rimantadine hydrochloride.

[0056] Specifically, the neuraminidase inhibitor may be, for example, oseltamivir phosphate, oseltamivir, zanamivir, or peramivir.

[0057] In a fourth aspect of the invention there is provided the use of a compound according to the first aspect of the invention or a pharma- ceutically acceptable salt, ester, stereoisomer, prodrug, solvate according to the second aspect, or a pharmaceutical composition according to the third aspect, in the manufacture of a pharmaceutical composition for the prevention and / or treatment of a disease.

[0058] In one embodiment of the present invention, the disease is a disease caused by a pathogen infection.

[0059] Specifically, the pathogens include viruses, such as Adenoviridae (e.g., adenovirus), Herpesviridae (e.g., HSV1 (oral herpes), HSV2 (genital herpes), VZV (varicella), EBV (Epstein-Barr virus), CMV (cytomegalovirus)), Poxviridae (e.g., smallpox virus, vaccinia, etc.), Papilloviridae (e.g., papilloma virus), Parvoviridae (e.g., B19 virus), Hepadnaviridae (e.g., hepatitis B virus), poliovirus, and the like. Maviridae (e.g., polyomavirus), Reoviridae (e.g., reovirus, rotavirus), Picornaviridae (e.g., enterovirus, foot-and-mouth disease virus), Caliciviridae (e.g., Norwalk virus, hepatitis E virus), Togaviridae (e.g., rubella virus), Arenaviridae (e.g., lymphocytic choriomeningitis virus), Retroviridae (HIV-1, HIV-2, HTLV-1), Flaviviridae (e.g., dengue virus, Zika virus, Japanese encephalitis virus, Chikungunya virus, Yellow fever virus, Hepatitis C virus, West Nile virus), Orthomyxoviridae (e.g. influenza virus (e.g. influenza A virus, influenza B virus, influenza C virus, etc.)), Paramyxoviridae (e.g. human parainfluenza virus type 1 (HPV), HPV type 2, HPV type 3, HPV type 4, Sendai virus, mumps virus, measles virus, respiratory syncytial virus, Newcastle disease virus), Bunyaviridae (e.g. , California Encephalitis Virus, Hantavirus), Rhabdoviridae (e.g., Rabies Virus), Filoviridae (e.g., Ebola Virus, Marburg Virus), Coronaviridae (e.g., HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, SARS-CoV-2), Astrocyte Virus (e.g., Astrovirus), Bornaviridae (e.g., Bornavirus).

[0060] In some embodiments of the invention, the virus is an influenza virus, such as one or more of influenza A virus, influenza B virus, and influenza C virus, in particular influenza A virus.

[0061] Specifically, the influenza A virus may be an influenza A virus of the H1N1 subtype, H2N2 subtype, H3N2 subtype, H5NI subtype, H7N9 subtype, or H9N2 subtype.

[0062] Specifically, diseases caused by the above-mentioned viral infections include, but are not limited to, influenza, SARS, COVID-19, viral hepatitis (e.g., hepatitis A, hepatitis B, hepatitis C, hepatitis D, etc.), AIDS, rabies, dengue fever, Ebola virus disease, etc.

[0063] In another embodiment of the present invention, the disease is a tumor.

[0064] Specifically, the above tumors are malignant tumors, including, but not limited to, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, kidney cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer (small cell lung cancer, non-small cell lung cancer), melanoma, gastric cancer, gastroesophageal adenocarcinoma, esophageal cancer, small intestine cancer, cardia cancer, bladder cancer, anal cancer, gallbladder cancer, bile duct cancer, teratoma, and cardiac tumors, in particular lung cancer (e.g., non-small cell lung cancer), prostate cancer, liver cancer, breast cancer, gastric cancer, and colorectal cancer.

[0065] In particular, the subject for the drug may be a mammal (eg, a human, monkey, ape, pig, cow, or sheep) or an avian (domestic fowl such as chickens, ducks, or geese, or a wild bird).

[0066] In a fifth aspect of the present invention, there is provided the use of a compound as shown below and pharma- ceutically acceptable salts, esters, stereoisomers, prodrugs or solvates thereof, as a ligand for the E3 ubiquitin ligase TRIM25, in modulating target ubiquitination levels, in the manufacture of a protein degradation targeting chimera (PROTAC). TIFF2024545831000022.tif44170 (where One-site or two-site valence bonds TIFF2024545831000023.tif3170 represents a single bond or a double bond, and 1 and 2 are not double bonds at the same time. R 1 ~R 18 are independently H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -CN, -NO 2 , -COR A , -C(O)OR A , -OCOR A , -C(O)NR A R B , -CH=NR A , -OR A , -OC(O)R A , -S(O) t -R A , -S(O) t -NR A R B , -NR A R B , -NR A C(O)R B and optionally, where H on each group is selected from halogen, -CN, -CF 3 , -NO 2 , -CHO, -COOH, -C(O)NH 2 , -OH, -OC(O)H, -SH, -S(O) 2 H, -NH 2 may be substituted with one or more groups selected from:

[0067] R 19 and R 20is independently selected from H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, and heterocyclylalkyl, and optionally, where H on each group is selected from substituted or unsubstituted heterocyclyl, halogen, -CN, -NO 2 , -COR A , -C(O)OR A , -C(O)NR A R B , -CH=NR A , -OR A , -OC(O)R A , -S(O) t -R A , -S(O) t -NR A R B , -NR A R B , -NR A C(O)R B or R 19 and R 20 together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl or heterocyclyl, or R 17 and R 19 together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl or heterocyclyl; t is selected from 0, 1, and 2; Each R A and R B are each independently selected from H, alkyl, cycloalkyl, alkenyl, aryl, heterocyclyl, and halogen.

[0068] Specifically, each group has the corresponding definition as set out in the first aspect of the invention.

[0069] In particular, the target is a target protein for degradation, which may be the body's own protein or a foreign protein such as a viral protein.

[0070] In one embodiment of the present invention, the regulation of the ubiquitination level includes promoting PA protein ubiquitination, promoting binding of PA protein to E3 ubiquitin ligase TRIM25, and acting as a ligand for E3 ubiquitin ligase TRIM25. In some embodiments of the invention, in the above uses, the compound has the following structure: TIFF2024545831000024.tif227170TIFF2024545831000025.tif117170

[0071] In some embodiments of the invention, in the above uses, the stereoisomer of the compound has the following structure: TIFF2024545831000026.tif235170TIFF2024545831000027.tif48170

[0072] Specifically, in the above uses, the PROTAC has the following structure: TIFF2024545831000028.tif6170 (wherein SMI is a small molecule inhibitor moiety (which may be formed of any suitable small molecule inhibitor of a target known in the art), E 3 L is a ligand portion of an E3 ubiquitin ligase (e.g., a structural portion formed by the compound described above or a pharma- ceutically acceptable salt, stereoisomer, ester, prodrug, or solvate thereof), and ... 3 L is a bond or linking group.

[0073] In a sixth aspect of the invention, there is provided a PROTAC having the structure: TIFF2024545831000029.tif10170 (where SMI is a small molecule inhibitor moiety, E 3 L is a ligand moiety for an E3 ubiquitin ligase and is formed by a compound according to the sixth aspect of the invention or a pharma- ceutically acceptable salt, stereoisomer, ester, prodrug or solvate thereof; L is SMI and E 3L is a bond or linking group.

[0074] In particular, the SMI may be formed with a small molecule inhibitor of any suitable target known in the art.

[0075] In a seventh aspect of the present invention, there is provided a method for producing a PROTAC, the method comprising using a compound according to the sixth aspect of the present invention or a pharma-ceutically acceptable salt, stereoisomer, ester, prodrug or solvate thereof.

[0076] In an eighth aspect of the present invention, there is provided an Aspergillus deposited at the Center for Ordinary Microorganisms of the China Commission on Microbial Species Depositary (Address: No. 3, Hall 1, Beichen West Road, Chaoyang District, Beijing, China, Institute of Microbiology, Chinese Academy of Sciences) on July 8, 2021, with the deposit number CGMCC No. 22467, and with the taxonomic name Aspergillus iizukae. In a ninth aspect of the present invention, there is provided a method for preventing and / or treating a disease, comprising administering to a subject in need thereof an effective amount of a compound according to the first aspect of the present invention or a pharma- ceutically acceptable salt, stereoisomer, ester, prodrug, solvate thereof, a pharmaceutical composition according to the third aspect of the present invention, or a PROTAC according to the sixth aspect of the present invention.

[0077] Specifically, the above-mentioned disease may be a disease caused by pathogen infection, such as influenza, SARS, COVID-19, viral hepatitis (e.g., hepatitis A, hepatitis B, hepatitis C, hepatitis D, etc.), AIDS, rabies, dengue fever, Ebola virus disease, etc., or a tumor, such as breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, kidney cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer (small cell lung cancer, non-small cell lung cancer), melanoma, gastric cancer, gastroesophageal adenocarcinoma, esophageal cancer, small intestine cancer, cardia cancer, bladder cancer, anal cancer, gallbladder cancer, bile duct cancer, teratoma, and cardiac tumor.

[0078] In particular, the subject may be a mammal (eg, a human, a monkey, ape, pig, cow, or sheep) or an avian (domestic fowl such as a chicken, duck, or goose, or a wild bird).

[0079] In a tenth aspect of the present invention, there is provided a method of modulating target ubiquitination levels comprising administering to a subject in need thereof an effective amount of a compound according to the first aspect of the present invention or a pharma- ceutically acceptable salt, stereoisomer, ester, prodrug or solvate thereof, a pharmaceutical composition according to the third aspect of the present invention or a PROTAC according to the sixth aspect of the present invention.

[0080] The present invention provides perinaphthenone compounds that can bind to TRIM25, promote the recognition of pathogen proteins (e.g., viruses) by TRIM25, and induce proteasome-dependent ubiquitination degradation of pathogens, and are therefore promising ligands for the E3 ubiquitin ligase TRIM25, and can be used in a wider range of applications, such as the preparation of PROTAC molecules, and therefore have great potential for research and development value and future applications.

[0081] Storage information for the biomaterial of the present invention is as follows:

[0082] Aspergillus, Aspergillus iizukae CPCC 401321 (deposited at the Center of Ordinary Microorganisms of the China Commission on Microbial Species Depositary (Address: No. 3, Hall 1, Beichen West Road, Chaoyang District, Beijing, China) on July 8, 2021, with the deposit number CGMCC No. 22467 and the classification name Aspergillus iizukae.) [Brief description of the drawings]

[0083] [Figure 1] The 1H-NMR spectrum of compound C1 is shown. [Diagram 2] The 13C-NMR spectrum of compound C1 is shown. [Diagram 3] The 1H-NMR spectrum of compound C2 is shown. [Figure 4] 13C-NMR spectrum of compound C2 [Diagram 5] The 1H-NMR spectrum of compound C3 is shown. [Figure 6]The 13C-NMR spectrum of compound C3 is shown. [Figure 7] 1 shows the HSQC spectrum of compound C3. [Figure 8] 1 shows the HMBC spectrum of compound C3. [Figure 9] The 1H-1H COSY spectrum of compound C3 is shown. [Figure 10] The NOESY spectrum of compound C3 is shown. [Figure 11] The 1H-NMR spectrum of compound C4 is shown. [Figure 12] The 13C-NMR spectrum of compound C4 is shown. [Figure 13] 1 shows the HSQC spectrum of compound C4. [Figure 14] 1 shows the HMBC spectrum of compound C4. [Figure 15] The 1H-1H COSY spectrum of compound C4 is shown. [Figure 16] The NOESY spectrum of compound C4 is shown. [Figure 17] The 1H-NMR spectrum of compound C5 is shown. [Figure 18] The 13C-NMR spectrum of compound C5 is shown. [Figure 19] 1 shows the HSQC spectrum of compound C5. [Figure 20] 1 shows the HMBC spectrum of compound C5. [Figure 21] The 1H-1H COSY spectrum of compound C5 is shown. [Figure 22] The NOESY spectrum of compound C5 is shown. [Diagram 23] The 1H-NMR spectrum of compound C6 is shown. [Figure 24] The 13C-NMR spectrum of compound C6 is shown. [Diagram 25] 1 shows the HSQC spectrum of compound C6. [Figure 26] 1 shows the HMBC spectrum of compound C6. [Figure 27]The 1H-1H COSY spectrum of compound C6 is shown. [Figure 28] The NOESY spectrum of compound C6 is shown. [Figure 29] The 1H-NMR spectrum of compound C7 is shown. [Diagram 30] The 13C-NMR spectrum of compound C7 is shown. [Diagram 31] 1 shows the HSQC spectrum of compound C7. [Diagram 32] 1 shows the HMBC spectrum of compound C7. [Diagram 33] The 1H-1H COSY spectrum of compound C7 is shown. [Diagram 34] The NOESY spectrum of compound C7 is shown. [Diagram 35] The 1H-NMR spectrum of compound C8 is shown. [Diagram 36] The 13C-NMR spectrum of compound C8 is shown. [Figure 37] HSQC spectrum of compound C8. [Figure 38] 1 shows the HMBC spectrum of compound C8. [Figure 39] The 1H-1H COSY spectrum of compound C8 is shown. [Diagram 40] The NOESY spectrum of compound C8 is shown. [Diagram 41] The 1H-NMR spectrum of compound C9 is shown. [Diagram 42] 13C-NMR spectrum of compound C9. [Diagram 43] 1 shows the HSQC spectrum of compound C9. [Diagram 44] 1 shows the HMBC spectrum of compound C9. [Diagram 45] The 1H-1H COSY spectrum of compound C9 is shown. [Figure 46] The NOESY spectrum of compound C9 is shown. [Figure 47] 1H-NMR spectrum of compound C10 is shown. [Figure 48]13C-NMR spectrum of compound C10. [Figure 49] 1 shows the HSQC spectrum of compound C10. [Figure 50] 1 shows the HMBC spectrum of compound C10. [Figure 51] The 1H-1H COSY spectrum of compound C10 is shown. [Figure 52] 1H-NMR spectrum of compound C11 is shown. [Figure 53] 13C-NMR spectrum of compound C11. [Figure 54] 1 shows the HSQC spectrum of compound C11. [Figure 55] 1 shows the HMBC spectrum of compound C11. [Figure 56] The 1H-1H COSY spectrum of compound C11 is shown. [Figure 57] 1H-NMR spectrum of compound C12 is shown. [Figure 58] The 13C-NMR spectrum of compound C12 is shown. [Figure 59] 1 shows the HSQC spectrum of compound C12. [Figure 60] 1 shows the HMBC spectrum of compound C12. [Figure 61] The 1H-1H COSY spectrum of compound C12 is shown. [Figure 62] The NOESY spectrum of compound C12 is shown. [Figure 63] 1H-NMR spectrum of compound C13 is shown. [Figure 64] The 13C-NMR spectrum of compound C13 is shown. [Figure 65] 1 shows the HSQC spectrum of compound C13. [Figure 66] 1 shows the HMBC spectrum of compound C13. [Figure 67] The 1H-1H COSY spectrum of compound C13 is shown. [Figure 68] The NOESY spectrum of compound C13 is shown. [Figure 69] 1H-NMR spectrum of compound C14 is shown. [Figure 70] The 13C-NMR spectrum of compound C14 is shown. [Figure 71] 1 shows the HSQC spectrum of compound C14. [Figure 72] 1 shows the HMBC spectrum of compound C14. [Figure 73] The 1H-1H COSY spectrum of compound C14 is shown. [Figure 74] The NOESY spectrum of compound C14 is shown. [Figure 75] 1 shows the experimental results regarding the effects of compounds C1 to C14 on the expression of influenza virus PA protein. [Figure 76] 1 shows the experimental results of downregulation of PA protein degradation pathway by compound C1. [Figure 77] 1 shows the experimental results of PA polyubiquitination induction by compound C1. [Figure 78] 1 shows the results of an experiment in which compound C1 induces PA degradation by recognizing the E3 ligase TRIM25. [Figure 79] 1 shows the results of an experiment in which compound C1 promotes the interaction between TRIM25 and PA. [Figure 80] 1 shows the results of an experiment in which compounds bind to TRIM25 in vitro. [Figure 81] 1 shows the results of experiments on the ability of compounds to bind to PA in vitro. [Figure 82] 1 shows the results of an experiment in which compound C1 promotes the polyubiquitination level of PA protein in vitro. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0084] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0085] The term "alkyl" refers to a straight or branched chain hydrocarbon group containing no unsaturated bonds, which is connected to the rest of the molecule by a single bond. As used herein, alkyl generally contains 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms (i.e., C1-10 alkyl), and preferably 1-6 carbon atoms (i.e., C1-6 alkyl). Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isoamyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, and the like. When alkyl is substituted with cycloalkyl, it becomes "cycloalkylalkyl", such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like. When alkyl is substituted with aryl, it becomes "aralkyl", such as benzyl, diphenylmethyl, or phenethyl. When the alkyl is substituted with a heterocyclyl, it becomes a "heterocyclylalkyl."

[0086] The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing at least two carbon atoms, at least one unsaturated bond, and linked to the rest of the molecule by a single bond. As used herein, alkenyl generally contains 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms (i.e., C1-10 alkenyl), preferably 1-6 carbon atoms (i.e., C1-6 alkenyl). Examples of alkenyl include, but are not limited to, vinyl, 1-methyl-vinyl, 1-propenyl, 2-propenyl, or butenyl.

[0087] The term "cycloalkyl" refers to an alicyclic hydrocarbon, and as used herein, cycloalkyl typically contains 1 to 4 single and / or fused rings and contains 3 to 18 carbon atoms, preferably 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms (e.g., C3-10 cycloalkyl, C3-6 cycloalkyl), such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or adamantyl.

[0088] The term "aryl" refers to a functional group or substituent derived from a simple aromatic ring, including single-ring aryl groups and / or fused-ring aryl groups, e.g., 1-3 single or fused rings, having 6-18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms. As used herein, aryl generally refers to aryl having 1-2 single or fused rings, having 6-12 carbon ring atoms (i.e., C6-12 aryl), where the H on the carbon atom may be substituted with a group such as alkyl, halogen, etc. Examples of said aryl include, but are not limited to, phenyl, p-methylphenyl, naphthyl, biphenyl, indenyl, etc.

[0089] The term "halogen" refers to bromine, chlorine, iodine or fluorine.

[0090] The term "heterocyclyl" refers to a 3-18 membered non-aromatic ring group containing 2-17 carbon atoms and 1-10 heteroatoms. Heterocyclyls may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems and may include fused, spirocyclic, or bridged ring systems. Heterocyclyls may be partially saturated (heteroaryl) or fully saturated (heterocycloalkyl). Suitable heteroaryls in the compounds of the present invention contain one, two or three heteroatoms, the heteroatoms being selected from N, O or S atoms, and the heteroaryls include, for example, coumarin, including 8-coumarin, quinolinyl, including 8-quinolinyl, isoquinolinyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzfurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridyl.Suitable heterocycloalkyls in the compounds of the present invention contain one, two or three heteroatoms, the heteroatoms being selected from N, O or S atoms, and the heterocycloalkyls are, for example, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, oxathianyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxiranyl, thiirane, azepinyl, o- ... These include xoazepanyl, diazepinyl, triazepinyl, 1,2,3,6-tetrahydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, and quinozinyl.

[0091] The pharma- ceutically acceptable salts of the present invention include acid addition salts and alkali addition salts.

[0092] The acid addition salts include, but are not limited to, salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphonic acid, and salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids. Thus, these salts include, but are not limited to, sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, iodate, acetate, propionate, octanoate, isobutyrate, ethylene glycolate, malonate, succinate, octanoate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, and mesylate salts, as well as salts of amino acids such as arginate, gluconate, galacturonate, and the like. Acid addition salts can be prepared in a conventional manner by contacting the free alkali form with a sufficient amount of the desired acid to form the salt. The free alkali form can be regenerated by contacting the salt form with an alkali, which can be separated as conventional.

[0093] The alkali addition salts of the present invention refer to salts formed with metals or amines, such as hydroxides of alkali metals or alkaline earth metals, or organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucosamine, and procaine. The alkali addition salts can be prepared in a conventional manner by contacting the free acid form with a sufficient amount of the desired alkali to form the salt. The free acid form can be regenerated by contacting the salt form with an acid, and the free acid can be isolated in a conventional manner.

[0094] The stereoisomers of the present invention exist in the form of enantiomers, diastereomers, and geometric isomers. Some compounds of the present invention have a cyclic hydrocarbon group, which may be substituted at one or more carbon atoms, and in this case, all of its geometric forms, including cis and trans, and mixtures thereof, are within the scope of the present invention. The cyclic hydrocarbon group includes alicyclic hydrocarbon groups and aryl, where the alicyclic hydrocarbon group may be a non-aromatic monocyclic, fused, bridged, or spiro-cyclic saturated or unsaturated cyclic hydrocarbon group, and the aryl may be, for example, phenyl, naphthyl, phenanthrenyl, biphenyl, etc.

[0095] The solvate of the present invention refers to the physical bond between the compound of the present invention and one or more solvent molecules. This physical bond includes various degrees of ionic bonds and covalent bonds, including hydrogen bonds. In some cases, the solvate can be separated, for example, when one or more solvent molecules are incorporated into the lattice of a crystalline solid. The solvate includes solution-phase and separable solvates. Representative solvates include ethanol solvates, methanol solvates, etc.

[0096] The prodrug of the present invention refers to a form of the compound of formula I that is suitable for administration to a patient, does not have excessive toxicity, irritation, allergies, etc., and is effective for its intended application, including acetal, ester, and zwitterion forms. The prodrug is converted in vivo, for example by hydrolysis in blood, to give the parent compound.

[0097] The "patient" or "subject" of the present invention may be used interchangeably herein and refer to any animal or cells thereof that are treated according to the methods described herein, whether ex vivo or in situ. Specifically, the animal includes mammals, such as rats, mice, guinea pigs, rabbits, dogs, monkeys or humans, particularly humans.

[0098] The "treatment" in the present invention refers to preventing, curing, reversing, alleviating, reducing, minimizing, suppressing, arresting and / or halting one or more clinical symptoms of the disease after the onset of the disease.

[0099] The term "prevention" in the present invention refers to avoiding, minimizing, or making difficult the onset or progression of a disease by treatment before the onset of the disease.

[0100] The disclosures of various publications, patents and published patent specifications cited herein are hereby incorporated by reference in their entireties.

[0101] The technical solutions of the present invention will be described below clearly and completely with reference to the embodiments of the present invention, but it is obvious that the described embodiments are only some of the embodiments of the present invention, and are not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative labor belong to the protection scope of the present invention. Example 1: Production of Aspergillus iizukae CPCC 401321 fermentation culture

[0102] Aspergillus iizukae CPCC 401321, a strain with high perinaphthenone production (its accession number is CGMCC No. 22467), was cultured on a PDA slant at 28°C for 7 days, and then a mycelium fragment was selected and inoculated into a 500-ml Erlenmeyer flask containing 100 ml of PDB seed medium, and cultured with shaking at 28-30°C for 5 days to obtain a seed solution. Next, 10 ml of the seed solution was placed in a 500-ml Erlenmeyer flask containing rice medium (100 g of rice was placed in a 500-ml Erlenmeyer flask, immersed in 100 ml of deionized water, and sterilized at 121°C for 20 minutes to obtain a rice medium) and cultured at 28°C for 20 days to obtain a solid fermentation culture of Aspergillus iizukae CPCC 401321. Example 2: Preparation of ethyl acetate extract of Aspergillus iizukae CPCC 401321 fermentation culture

[0103] 10 kg of the solid fermentation culture of Aspergillus iizukae CPCC 401321 obtained in Example 1 was collected, stirred and crushed with a glass rod, 20 L of ethyl acetate was added, and extraction was performed three times for 30 minutes each using ultrasonic waves at room temperature. The ethyl acetate extracts were combined and rotary evaporated in a rotary evaporator (temperature 40°C) to remove the ethyl acetate in the collected liquid, and the resulting product was the ethyl acetate extract of the fermentation culture of Aspergillus iizukae CPCC 401321. Example 3: Separation of ethyl acetate extract

[0104] (1) The ethyl acetate extract (250 g) of Example 2 was dissolved in an ethyl acetate-methanol mixed solution, and then separated by silica gel column chromatography. The silica gel used in the silica gel column chromatography was silica gel H, the size of the silica gel column used was 12 x 40 cm, and the column volume was 4522 mL. In the elution step used in the silica gel column chromatography, linear gradient elution was performed as follows. The mobile phase used was a mixture of petroleum ether and acetone, and the volume ratio of petroleum ether to acetone in the mobile phase of the linear gradient elution was linearly decreased from 4:1 to 1:1. From the start of the elution process, 275 fractions of 500 ml each (200 ml / fraction) of eluate were collected in succession, and were labeled F.1, F.2, F.3, F.4, ..., F.275. The fractions were combined under guidance of TLC detection, and finally, F.1-5 (a mixture of fractions F.1 to F.5, the same applies below), F.6, F.7-11, F.12-23 were collected. , Fr.24-26, Fr.27-29, Fr.30-44, Fr.45-51, Fr.52-67, Fr.68-77, Fr.78-91, Fr.92-99, Fr.100-11 5, 19 combined components were obtained: Fr.116-127, Fr.128-137, Fr.138-196, Fr.197-227, Fr.228-258, and Fr.259-275. (2) The supernatants of Fr.12-23 obtained in step (1) were combined and subjected to Sephadex LH-20 gel column chromatography. The size of the gel column used was 3 × 120 cm, and in the elution step used, methanol was used as the mobile phase to elute. From the start of the elution step, 25 fractions of 30 ml per tube (30 ml / fraction) were collected continuously, and were labeled as tube.1, tube.2, tube.3, …, tube.25. Tubes 5-9 (Tube.5-Tube.9 were mixed to obtain components called tubes 5-9) were separated by preparative high-performance liquid chromatography (separated by RP-C18 liquid-phase preparative separation). The packing used in this preparative high-performance liquid chromatography separation was octadecylsilane-bonded silica gel packing, the particle size of the packing was 5 μm, and the column used in this preparative high-performance liquid chromatography separation had a diameter of 8 mm and a height of 250 mm. The mobile phase was a mixture of methanol and water (containing 0.05% formic acid), the volume ratio of methanol to water in the mobile phase was 90:10, and the flow rate was 4.0 ml / min. R The elution peaks at (retention times) of 16.0 min, 18.0 min, and 19.9 min were collected, and methanol and water were removed by rotary evaporation using a rotary evaporator (temperature: 50° C.), to obtain 80.5 mg of compound C3, 39.1 mg of compound C4, and 4.1 mg of compound C5 in this order. (3) MCI column chromatography was performed on Fr. 92-99 obtained in step (1). The size of the MCI column used was 2 x 30 cm, and in the elution process used, a mixture of methanol and water in a volume ratio of 90:10 was used as the mobile phase, and 20 fractions of 40 ml per tube (40 ml / fraction) were collected continuously from the start of the elution process, and these were labeled as tube.1, tube.2, tube.3, …, tube.20. Sephadex LH-20 gel column chromatography was performed on tubes 5-9 (a mixture of fractions from tube.5 to tube.9). The size of the gel column used was 2 x 80 cm, and in the elution process used, methanol was used as the mobile phase, and 25 fractions of 20 ml per tube (20 ml / fraction) were collected continuously from the start of the elution process, and these were labeled as tube.1′, tube.2′, tube.3′, …, tube.25′. Tubes 2'-5' (a mixture of Tube.2'-Tube.5') were separated by preparative high performance liquid chromatography (RP-C18 liquid phase separation). The packing used in this preparative high performance liquid chromatography separation was octadecylsilane-bonded silica gel packing, the particle size of the packing was 5 μm, and the column used in this preparative high performance liquid chromatography separation had a diameter of 8 mm and a height of 250 mm. The mobile phase was a mixture of methanol and water (containing 0.05% formic acid), and the volume ratio of methanol to water in the mobile phase was 85:15. The flow rate was 4.0 mL / min. RThe elution peaks with retention times of 11.8 min, 12.5 min, and 17.7 min were collected, and methanol and water were removed by rotary evaporation using a rotary evaporator (temperature 50°C), obtaining 21.6 mg of compound C9, 10.6 mg of compound C10, and 102.9 mg of compound C6 in this order. Sephadex LH-20 gel column chromatography was performed on tubes 11 to 15 (a mixture of fractions from tube.11 to tube.15). The size of the gel column used was 2 x 80 cm, and in the elution process used, methanol was used as the mobile phase, and 15 fractions of 20 ml per tube (20 ml / fraction) of the eluate were collected continuously from the start of the elution process, and were labeled tube.1", tube. 2", tube.3", ..., tube.15". Tubes 2"-8" (a mixture of fractions from tube.2"-tube.8") were separated by preparative high performance liquid chromatography (RP-C18 liquid phase separation). The packing used in this preparative high performance liquid chromatography separation was octadecylsilane-bonded silica gel packing, the particle size of the packing was 5 μm, and the column used in this preparative high performance liquid chromatography separation had a diameter of 8 mm and a height of 250 mm. The mobile phase was a mixture of methanol and water (containing 0.05% formic acid), and the volume ratio of methanol to water in the mobile phase was 87:13. The flow rate was 4.0 mL / min. R The elution peaks at (retention times) of 17.2 min, 19.4 min, and 21.1 min were collected, and methanol and water were removed by rotary evaporation using a rotary evaporator (temperature 50° C.), yielding 40.5 mg of compound C6, 28.2 mg of compound C8, and 425.6 mg of compound C7 in this order. MCI column chromatography was performed on Fr. 228-258 obtained in step (1). The size of the MCI column used was 6 x 18 cm, and in the elution process used, a mixture of methanol and water in a volume ratio of 80:20 was used as the mobile phase, and 39 fractions of 100 ml per tube (100 ml / fraction) of the eluate were collected continuously from the start of the elution process, and were labeled tube.1, tube.2, tube.3, ..., tube.39. ODS column chromatography was performed on tubes 16-39 (a mixture of fractions from tube.16 to tube.39). The size of the ODS column used was 5.5 × 28 cm, and in the elution process used, a mixture of methanol and water in a volume ratio of 75:25 was used as the mobile phase, and 50 fractions of 100 ml per tube (100 ml / fraction) of the eluate were collected continuously from the start of the elution process, and were labeled as tube.1′, tube.2′, tube.3′, …, tube.50′. Tubes 34-45 (a mixture of fractions Tube.34′-Tube.55′) were rotary evaporated in a rotary evaporator (temperature 50°C) to remove methanol and water, and 1.25 g of compound C1 was obtained. Tubes 31-33 (a mixture of fractions Tube.31′-Tube.33′) were separated by preparative high-performance liquid chromatography (separated by RP-C18 liquid-phase preparative). The packing used in this preparative high-performance liquid chromatography separation was octadecylsilane-bonded silica gel packing, the particle size of the packing was 5 μm, and the column used in this preparative high-performance liquid chromatography separation had a diameter of 8 mm and a height of 250 mm. The mobile phase was a mixture of methanol and water (containing 0.05% formic acid), and the volume ratio of methanol to water in the mobile phase was 73:27. The flow rate was 4.5 mL / min. R The peak eluted at 14.0 min (retention time) was collected, and methanol and water were removed by rotary evaporation using a rotary evaporator (temperature 50° C.) to obtain 14.4 mg of compound C11. MCI column chromatography was performed on Fr.30-44 obtained in step (1). The size of the MCI column used was 3 x 23 cm, and in the elution process used, a mixture of methanol and water in a volume ratio of 90:10 was used as the mobile phase, and 20 fractions of 50 ml per tube (50 ml / fraction) were collected continuously from the start of the elution process, and these were labeled as tube.1, tube.2, tube.3, …, tube.20. Sephadex LH-20 gel column chromatography was performed on tubes 7-20 (a mixture of tube.7-tube.20 fractions). The size of the gel column used was 2 x 80 cm, and in the elution process used, methanol was used as the mobile phase, and 18 fractions of 20 ml per tube (20 ml / fraction) were collected continuously from the start of the elution process, and these were labeled as tube.1′, tube.2′, tube.3′, …, tube.18′. Tubes 2'-6' (a mixture of tube.2'-tube.6' fractions) were separated by preparative high performance liquid chromatography (RP-C18 liquid phase separation). The packing used in this preparative high performance liquid chromatography separation was octadecylsilane-bonded silica gel packing, the particle size of the packing was 5 μm, and the column used in this preparative high performance liquid chromatography separation had a diameter of 8 mm and a height of 250 mm. The mobile phase was a mixture of methanol and water (containing 0.05% formic acid), and the volume ratio of methanol to water in the mobile phase was 84:16. The flow rate was 4.5 mL / min. R The elution peaks at (retention times) 20.0 min, 23.7 min, 30.4 min, and 33.7 min were collected, and methanol and water were removed by rotary evaporation using a rotary evaporator (temperature 50°C), yielding 3.2 mg of compound C14, 33.5 mg of compound C13, 152.3 mg of compound C12, and 206.1 mg of compound C2, in this order. Compounds C1 to C14 are all brown gel-like solids, and are easily soluble in solvents such as methanol, ethanol, and DMSO, but are poorly soluble in water. Compounds C1 to C14 have Rf values ​​of 0.4 to 0.8 in a chloroform-methanol-water (volume ratio 70:15:2) solvent system for silica gel thin layer chromatography, and show prominent fluorescent coloring at 254 nm and 365 nm, with vanillin sulfate coloring brown red. Example 4: Structural Identification

[0105] (1) Compounds C1 and C2 The spectral data of compounds C1 and C2 are shown in Table 1. 1 H NMR and 13 The C NMR spectra are shown in Figures 1 to 4, respectively. The structures of compounds C1 and C2 are shown in Table 6. Table 1. Nuclear magnetic data of compounds C1 and C2 ( 1 H NMR 600 MHz, 13 C NMR 150 MHz, DMSO-d 6 ) TIFF2024545831000030.tif249170TIFF2024545831000031.tif118170(2) Compound C3 HRESIMS (negative ion) ion peak of compound C3: m / z 573.2825 [MH] - The molecular formula is C 35 H 42 O 7 It was shown that. 1 H NMR (Figure 5), 13 A comprehensive analysis of the C NMR (Figure 6) and HSQC spectra (Figure 7) revealed that the compound contains two ketone carbonyls, one aldehyde carbonyl, 18 olefinic carbons, and 14 sp 3It is presumed to contain hybrid carbon. In the hydrogen spectrum, characteristic signals were observed: δ 14.33 (1H, s), 13.11 (1H, s), 9.29 (1H, s), 6.83 (1H, s), 6.50 (1H, t, J = 7.3 Hz), 5.05 (1H, t, J = 7.2 Hz), 4.94 (1H, t, J = 6.8 Hz), 4.81 (1H, t, J = 7.8 Hz), 2.83 (3H, s), 2.56 (2H, d, J = 7.9 Hz), 2.14 (3H, s), 1.57 (3H, s), 1.49 (3H, s), 1.44 (3H, s), 1.28 (3H, s). The above characteristic signals are similar to those of compound C2. Detailed comparison of the nuclear magnetic signals of compounds C3 and C2 showed that both have the same perinaphthenone three-membered ring structure, except for the diterpene branched chain. In the HMBC spectrum (Figure 8), the following related signals were observed: δ 1.28 (H-35) is related to δ 115.4 (C-17), 139.4 (C-18), and 39.2 (C-19); δ 1.44 (H-34) is related to 124.4 (C-21), 133.3 (C-22), and 37.4 (C-23); δ 9.29 (H-33) is related to δ 155.2 (C-25), 142.1 (C-26), and 23.5 (C-27); and δ 5.05 (H-29) is related to δ 23.5 ( δ6.50 (H-25) is related to δ26.9 (C-24), 23.5 (C-27), and 194.9 (C-33); δ4.94 (H-21) is related to δ38.2 (C-19), 37.4 (C-23), and 15.3 (C-34); and δ4.81 (H-17) is related to δ39.2 (C-19), and 15.5 (C-35). 1 H- 1In the H COSY spectrum (Figure 9), the following related signals were observed: δ 4.81 (H-17) is related to δ 2.56 (H-16), δ 4.94 (H-21) is related to δ 1.56 (H-20), δ 1.56 (H-20) is related to δ 1.64 (H-19), δ 6.50 (H-25) is related to δ 2.36 (H-24), δ 2.36 (H-24) is related to δ 2.02 (H-23), δ 5.05 (H-29) is related to δ 1.93 (H-28), and δ 1.93 (H-28) is related to δ 2.14 (H-27). 1 H- 1 The related signals of H COSY confirmed the planar structure of the diterpene branched chain. In the NOESY spectrum (Figure 10), the following related signals were observed: δ 4.81 (H-17) related to δ 1.64 (H-19), δ 4.94 (H-21) related to δ 2.02 (H-23), and δ 6.50 (H-25) related to δ 9.29 (H-33), which revealed that the configurations of 17(18)-ene, 21(22)-ene, and 25(26)-ene were E-, E-, and E-, respectively. Since it has the same biosynthetic pathway as compounds C1 and C2, the absolute configuration of the C-1 position of compound C3 was also determined to be S-configuration. Finally, compound C3 was identified to have the structure shown in Table 6, and its nuclear magnetic signal assignments are specifically shown in Table 2. (3) Compound C4 HRESIMS (negative ion) ion peak of compound C4: m / z 573.2838 [MH] - The molecular formula is C 35 H 42 O 7 It was shown that. 1 H NMR (Figure 11), 13 A comprehensive analysis of the C NMR (Figure 12) and HSQC spectra (Figure 13) revealed that the compound contains two ketone carbonyls, 18 olefinic carbons, and 15 sp 3 It is presumed that it contains hybrid carbon. The nuclear magnetic signal of compound C4 is substantially the same as that of compound C2, except for the C-25 to C-28 structural fragment. 1 H- 1In the H COSY spectrum (FIG. 15), H-29 is related to H-28, and taking into account the HSQC related signals, the signal δ H 4.43 and δ C 75.1 was found to be assigned to the C-28 position, and it was determined from the signal chemical shift value that C-28 was oxidized. In the HMBC spectrum (Figure 14), the following related signals were found. H-25 (δ 4.26, 4.06) was related to C-25 (δ 119.0) and C-26 (δ 138.8), and H-25 (δ 4.26, 4.06) was related to C-28 (δ 75.1), which indicated that C-28 and C-33 were linked by an ether bond. In the NOESY spectrum (Figure 16), δ 5.17 (H-25) was related to δ 2.50 (H-27), demonstrating that the 25(26)-ene configuration was E-. Since it has the same biosynthetic pathway as compounds C1 and C2, it was determined that the C-1 position configuration of compound C4 was S-configuration. Finally, compound C4 was identified to have the structure shown in Table 6, and the nuclear magnetic signal assignments thereof are specifically shown in Table 2. (4) Compound C5 HRESIMS (negative ion) ion peak of compound C5: m / z 617.3372 [MH] - The molecular formula is C 37 H 46 O 8 It was shown that. 1 H NMR (Figure 17), 13 A comprehensive analysis of the C NMR (Figure 18) and HSQC spectra (Figure 19) revealed that the compound contains two ketone carbonyls, one ester carbonyl, 18 olefinic carbons, and 16 sp 3It is presumed that it contains hybrid carbon. The nuclear magnetic signals of compound C5 are similar to most of the nuclear magnetic signals of compound C2, but the C-25 to C-30 structural fragments are different. In the HMBC spectrum (Figure 20), δ1.54 (H-33) is related to 106.0 (C-5), 130.1 (C-26), and 44.6 (C-27), δ1.62 (H-31) is related to 123.7 (C-29), 135.9 (C-30), and 25.2 (C-31), and δ1.65 (H-32) is related to δ123.7 (C-29), 135.9 (C-30), and 18.0 (C-32). 1 H- 1 In the H COSY spectrum (Figure 21), δ 5.50 (H-28) was found to be related to δ 2.2, 2.06 (H-27), and 5.07 (H-29), respectively, and the above evidence confirmed the C-25-C-30 framework structure. In the HMBC spectrum, δ 5.50 (H-28) was found to be related to δ 169.3 (-COCH 3 ) and δ 1.91 (-COCH 3 ) is δ169.3 (-COCH 3 ), proving that one acetyl group was linked to the C-28 position. In the NOESY spectrum (Figure 22), the following related signals were observed: δ 4.82 (H-17) related to δ 1.64 (H-19), δ 4.87 (H-21) related to δ 1.83 (H-23), and δ 5.05 (H-25) related to δ 2.20 (H-27), which confirmed that the configurations of 17(18)-ene, 21(22)-ene, and 25(26)-ene were E-, E-, and E-, respectively. Since it has the same biosynthetic pathway as compounds C1 and C2, it was found that the C-1 position configuration of compound C5 was also S-configuration. Finally, compound C5 was identified to have the structure shown in Table 6, and its nuclear magnetic signal assignments are specifically shown in Table 2. Table 2. Nuclear magnetic data of compounds C3 to C5 ( 1 H NMR 600 MHz, 13 C NMR 150 MHz, DMSO-d 6 ) TIFF2024545831000032.tif248170TIFF2024545831000033.tif166170(5) Compound C6 HRESIMS (negative ion) ion peak of compound C6: m / z 593.3115 [MH] - The molecular formula is C 35 H 46 O 8 It was shown that. 1 H NMR (Figure 23), 13 A comprehensive analysis of the C NMR (Figure 24) and HSQC spectra (Figure 25) revealed that the compound contains two ketone carbonyls, 16 olefinic carbons, and 17 sp 3 It is assumed that hybrid carbon is included. The nuclear magnetic signals of compound C6 were substantially identical to those of compound C1 except for the C-26 position. In the HMBC spectrum (Figure 26), the following related signals were observed: δ 5.04 (H-25) related to δ 36.5 (C-27), 15.9 (C-33), and δ 1.53 (H-33) related to δ 123.2 (C-25), 135.0 (C-26), 36.5 (C-27), indicating one methyl substitution at the C-26 position. In the NOESY spectrum (Figure 28), δ 5.04 (H-25) related to δ 1.85 (H-27), demonstrating that the configuration of 25(26)-ene is E-. Since compound C6 has the same biosynthetic pathway as compounds C1 and C2, it was determined that the configurations of C-1 and C-29 positions of compound C6 are S and R, respectively. Finally, compound C6 was identified as having the structure shown in Table 6, and the nuclear magnetic signal assignments are specifically shown in Table 3. (6) Compound C7 HRESIMS (negative ion) ion peak of compound C7: m / z 649.3383 [MH] - The molecular formula is C 38 H 50 O 9 It was shown that. 1 H NMR (Figure 29), 13A comprehensive analysis of the C NMR (Figure 30) and HSQC spectra (Figure 31) revealed that the compound contains two ketone carbonyls, 16 olefinic carbons, and 20 sp 3 We hypothesize that it contains hybrid carbons. The nuclear magnetic signals of compound C7 were virtually identical to those of compound C1, except for the C-28-C-32 structural fragment on the diterpene branched chain. Compound C7 has three more carbon atoms than compound C1, including one oxidized quaternary carbon δ 105.6 (C-1′) and two methyl carbon signals δ 28.4 (C-2′) [δ 1.29 (3H, s, H-2′)] and δ 26.7 (C-3′) [δ 1.21 (3H, s, H-3′)]. In the HMBC spectrum (Figure 46), δ 1.29 (H-2') is related to δ 105.6 (C-1') and 26.7 (C-3'), and δ 1.21 (H-3') is related to δ 105.6 (C-1') and 28.4 (C-2'), indicating that C-1' is substituted with two methyls. Also, the large chemical shift of C-1' indicates that it is substituted with two oxygen atoms. HMBC related signals: δ 1.15 (H-31) is related to δ 79.4 (C-30) and 82.1 (C-29), and δ 0.98 (H-32) is related to 79.4 (C-30) and 82.1 (C-29). 1 H- 1 Considering the H COSY-related signals, δ 3.61 (H-29) is related to δ 2.04 (H-28), and δ 2.04 (H-28) is related to δ 2.19 (H-27a) and 2.00 (H-27b), and the structure of the C-28 to C-32 fragment was further confirmed. From the large chemical shifts of C-29 and C-30 and the degree of unsaturation of compound C7, it was determined that C-1′ is linked to C-29 and C-30 by an ether bond, and finally, a five-membered ring structural fragment is constituted. Since it has the same biosynthetic pathway as compounds C1 and C2, it was determined that the absolute configuration of the C-1 position of compound C7 is S configuration. Finally, compound C7 was identified to have the structure shown in Table 6, and the assignment of its nuclear magnetic signals is specifically shown in Table 3. (7) Compound C8 HRESIMS (negative ion) ion peak of compound C8: m / z 663.3114 [MH] -The molecular formula is C 38 H 48 O 10 It was shown that. 1 H NMR (Figure 35), 13 A combined analysis of the C NMR (Figure 36) and HSQC spectra (Figure 37) revealed that the compound contains two ketone carbonyls, one ester carbonyl, 16 olefinic carbons, and 19 sp 3 It is presumed that it contains hybrid carbon. The nuclear magnetic signal of compound C8 is substantially the same as that of compound C7, except for the C-26 position on the diterpene branched chain. In the HMBC spectrum (Figure 38), δ 6.60 (H-25) is related to δ 23.6 (C-27), 37.8 (C-23), and 168.2 (C-33), which indicates that the C-26 position is substituted with one carboxy (-COOH). In the NOESY spectrum (Figure 40), δ 2.34 (H-27) is related to δ 2.20 (H-24), which demonstrates that the configuration of 25(26)-ene is E-. Since it has the same biosynthetic pathway as compounds C1 and C2, it was determined that the absolute configuration of the C-1 position of compound C8 is also S-configuration. Finally, compound C8 was identified as the structure shown in Table 6, and the assignment of its nuclear magnetic signals is specifically shown in Table 3. Table 3. Nuclear magnetic data of compounds C6 to C8 ( 1 H NMR 600 MHz, 13 C NMR 150 MHz, DMSO-d 6 ) TIFF2024545831000034.tif248170TIFF2024545831000035.tif248170TIFF2024545831000036.tif88170(8) Compound C9 HRESIMS (negative ion) ion peak of compound C9: m / z 609.3343 [MH] - The molecular formula is C 35 H 46 O 9 It was shown that. 1 H NMR (Figure 41), 13A combined C NMR (Figure 42) and HSQC spectrum (Figure 43) revealed that the compound contains two ketone carbonyls, 16 olefinic carbons, and 17 sp 3 It is presumed that it contains hybrid carbon. The nuclear magnetic signal of compound C9 is almost similar to that of compound C1, except for the C-24 to C-29 structural fragment. In the HMBC spectrum (Figure 44), δ1.00 (H-31) is related to δ85.9 (C-29) and 69.8 (C-30), δ0.99 (H-33) is related to δ74.5 (C-25), 84.9 (C-26), and 34.3 (C-27), δ3.13 (H-25) is related to δ35.9 (C-23), 84.9 (C-26), and 34.3 (C-27), 1 H- 1 In the H COSY spectrum (Figure 45), δ 3.57 (H-29) was found to be related to δ 1.71 (H-28), δ 1.71 (H-28) was found to be related to δ 1.91, 1.45 (H-27), δ 3.13 (H-25) was found to be related to δ 1.56, 1.19 (H-24), and δ 1.56, 1.19 (H-24) was found to be related to δ 2.07, 1.85 (H-24), and the above evidence confirmed the structure of C-24 to C-29 in compound C9. In the NOESY spectrum (Figure 46), δ 0.99 (H-33) was found to be related to δ 3.57 (H-29), and the relative configuration of the C-26 and C-29 substituents was confirmed. Finally, compound C9 was identified as the structure shown in Table 6, and the nuclear magnetic signal assignments are specifically shown in Table 4. (9) Compound C10 HRESIMS (negative ion) ion peak of compound C10: m / z 609.3343 [MH] - The molecular formula is C 35 H 46 O 9 It was shown that the nuclear magnetic signal of compound C10 is substantially identical to that of C9, and it is assumed that both have the same planar structure. 1 H NMR (Figure 47), 13 C NMR (Figure 48) and HSQC spectrum (Figure 49), 1 H- 1A comprehensive analysis of H COSY (Figure 50) and HMBC spectrum (Figure 51) proved the above conclusion. A detailed comparison of the nuclear magnetic signals of compounds C10 and C9 showed that the structures of C-26 to C-29 were slightly different in both, and the relative configuration of the C-26 and C-29 substituents in compound C10 (different from compound C9) was estimated. Finally, compound C10 was identified as having the structure shown in Table 6, and its nuclear magnetic signal assignments are specifically shown in Table 4. (10) Compound C11 HRESIMS (negative ion) ion peak of compound C11: m / z 595.2946 [MH] - The molecular formula is C 34 H 44 O 9 It was shown that. 1 H NMR (Figure 52), 13 A combined analysis of the C NMR (Figure 53) and HSQC spectra (Figure 54) revealed that the compound contains two ketone carbonyls, 16 olefinic carbons, and 16 sp 3It is presumed that it contains hybrid carbon. Compound C11 has a nuclear magnetic signal very similar to that of C1, but a detailed comparison shows that both diterpene branched chain structures are the same, with only subtle differences in the perinaphthenone three-membered ring structure. In the hydrogen spectrum of compound C11, there is one less C-14 methyl hydrogen signal (at about δ 2.13) than in the hydrogen spectrum of compound C1, and one more aromatic hydrogen signal (δ 6.31) present in the form of a single peak, indicating that there is no methyl substitution at C-12 in the compound C11 structure. In the HMBC spectrum (Figure 55), δ 13.78 (13-OH) was related to δ 101.7 (C-3), 99.1 (C-12), and 167.0 (C-13), and δ 6.32 (H-12) was related to δ 101.7 (C-3), 112.6 (C-10), which further substantiated the above conclusion. Since it has the same biosynthetic pathway as compounds C1 and C2, it was estimated that the configurations of C-1 and C-29 in the compound C11 structure are S and R configurations, respectively, and the configurations of 17(18)-ene, 21(22)-ene, and 25(26)-ene are E-, E-, and Z-, respectively. Finally, compound C11 was identified as the structure shown in Table 6, and its nuclear magnetic signal assignments are specifically shown in Table 4. Table 4. Nuclear magnetic data of compounds C9 to C11 ( 1 H NMR 600 MHz, 13 C NMR 150 MHz, DMSO-d 6 ) TIFF2024545831000037.tif249170TIFF2024545831000038.tif127170(11) Compound C12 HRESIMS (negative ion) ion peak of compound C12: m / z 589.2827 [MH] - The molecular formula is C 35 H 42 O 8 It was shown that. 1 H NMR (Figure 57), 13A combined analysis of the C NMR (Figure 58) and HSQC spectra (Figure 59) revealed that the compound contains two ketone carbonyls, one ester carbonyl, 18 olefinic carbons, and 14 sp 3 It is presumed that it contains hybrid carbon. Compound C12 has a nuclear magnetic signal very similar to that of C2, but a detailed comparison shows that the only difference between the two is the substituent at C-26. In the HMBC spectrum (Figure 60), δ 5.70 (H-25) is related to δ 34.3 (C-27), 38.4 (C-23), and 168.7 (C-33), which confirmed that the C-26 position of compound C12 was substituted with one carboxy (-COOH). In the NOESY spectrum (Figure 62), δ 5.70 (H-25) is related to δ 2.11 (H-27), which demonstrated that the 25(26)-ene configuration is E-. In the structure of compound C12, the configurations at other positions are the same as those of compound C2. Finally, compound C12 was identified as the structure shown in Table 6, and the nuclear magnetic signal assignments are specifically shown in Table 5. (12) Compound C13 HRESIMS (negative ion) ion peak of compound C13: m / z 591.2969 [MH] - The molecular formula is C 35 H 42 O 7 It was shown that. 1 H NMR (Figure 63), 13 A combined analysis of the C NMR (Figure 64) and HSQC spectra (Figure 65) revealed that the compound contains two ketone carbonyls, 16 olefinic carbons, and 17 sp 3It is presumed that it contains hybrid carbon. Compound C13 has a nuclear magnetic signal similar to that of C1, but a detailed comparison shows that the C-25~C-29 structural fragments are different between the two. In the HMBC spectrum (Figure 66), H-33 (δ 4.26, 4.06) is related to C-25 (δ 119.0) and C-26 (δ 138.8), H-33 (δ 4.49, 3.63) is related to C-28 (δ 84.1), and H-33 (δ 3.06) is related to C-28 (δ 66.1), which demonstrates that C-29 and C-30 are linked by an ether bond to form a six-membered ring structure. In the NOESY spectrum (Figure 68), δ 5.12 (H-25) is related to δ 2.50 (H-27), and δ 4.49 (H-33) is related to δ 1.99 (H-24), which demonstrates that the 25(26)-ene configuration is Z-. The configurations of the other positions of the structure are the same as those of compound C1. Finally, compound C13 was identified as the structure shown in Table 6, and its nuclear magnetic signal assignments are specifically shown in Table 5. (13) Compound C14 HRESIMS (negative ion) ion peak of compound C14: m / z 591.3248 [MH] - The molecular formula is C 35 H 44 O 8 It was shown that. 1 H NMR (Figure 69), 13 A combined C NMR (Figure 70) and HSQC spectrum (Figure 71) revealed that the compound contains two ketone carbonyls, 16 olefinic carbons, and 17 sp 3 It is presumed that it contains hybrid carbon. The nuclear magnetic signal of compound C14 is almost similar to that of compound C1, except for the C-24~C-29 structural fragment. In the HMBC spectrum (Figure 72), δ1.03 (H-31) is related to δ84.6 (C-29) and 70.0 (C-30), δ1.20 (H-33) is related to δ137.2 (C-25), 81.9 (C-26), and 37.0 (C-27), 1 H- 1In the H COSY spectrum (Figure 73), δ 3.60 (H-29) was found to be related to δ 1.78, 1.70 (H-28), δ 1.78, 1.70 (H-28) was found to be related to δ 1.76, 1.75 (H-27), and δ 5.39 (H-24) was found to be related to δ 5.41 (H-25) and δ 2.53 (H-23), respectively, and the above evidence confirmed the structure of C-24 to C-29 in compound C14. In the NOESY spectrum (Figure 74), δ 5.41 (H-25) was found to be related to δ 2.53 (H-23), which demonstrated that the configuration of 24(25)-ene is E-. Finally, compound C14 was identified to have the structure shown in Table 6, and the nuclear magnetic signal assignments are specifically shown in Table 5. Table 5. Nuclear magnetic data of compounds C12 to C14 ( 1 H NMR 600 MHz, 13 C NMR 150 MHz, DMSO-d 6 ) TIFF2024545831000039.tif248170TIFF2024545831000040.tif156170Table 6. Structures of compounds C1 to C14 TIFF2024545831000041.tif246170TIFF2024545831000042.tif94170Example 5: Effects of compounds C1 to C14 on PA protein

[0106] 2.5×10 5A 6-well plate was seeded with 2 ml of HEK 293T cell suspension per well at 1.5 ml / mL. When the cells had grown to 80%, the HEK 293T cell group was transfected with 500 ng pHW2000-PA plasmid per well. Four hours after transfection, the medium was replaced with DMEM medium containing 10% fetal bovine serum (FBS). One group was added with 2 μL of 5.00 mM test compound per well, and the other group was cultured with DMSO (dimethyl sulfoxide) as a negative control for 24 hours. The medium was discarded, and 80 μL of RIPA lysis solution was added to each well. The lysis solution was transferred to a 1.5 ml EP tube and dissolved on ice for 20 minutes. 20 μL of 5X protein loading buffer was added to each tube and boiled in a 100 °C metal bath for 30 minutes. The expression level of PA protein was detected using Western Blot. The detection results are shown in Figure 75. In addition, HEK293T cells were transfected with pHW2000-PA-Luc plasmid and treated with different concentrations of compounds. The expression level of Luc protein was detected after 24 h, and the EC 50 The values ​​were calculated (Table 7). Table 7. EC values ​​of compounds that degrade influenza virus PA protein 50 result TIFF2024545831000043.tif56170 Example 6: Effective inhibition of PA protein degradation by compound C1 by the protease inhibitor MG132

[0107] HEK239T cells were transfected with pHW183-PA plasmid and treated with different concentrations of compound C1 (2μM and 10μM), and the expression of PA protein was observed by adding the lysosomal inhibitor ConA (Concanavalin A) or the proteasome inhibitor MG-132 at the same time. As a result, the expression level of PA protein was almost completely restored by treatment with the proteasome inhibitor MG-132 (Figure 76A), while the recovery of PA protein was hardly affected by treatment with the lysosomal inhibitor ConA (Figure 76B), indicating that the degradation of PA protein by compound C1 was mainly carried out via the proteasome pathway. Example 7: Promotion of ubiquitination level of PA protein by compound C1

[0108] HEK293T cells were transfected with PA and myc-CW7 ubiquitin plasmid, and treated with different concentrations of compound C1 3.5 h after transfection, and incubated with MG-132 8 h before receiving cells. 24 h after cell transfection, samples were received and captured with PA protein antibody, and Western Blotting was used to detect the expression level of ubiquitinated PA protein. The test results showed that compound C1 promoted the polyubiquitination level of PA protein (Figure 77). Example 8: Discovery of E3 ubiquitin ligase TRIM25 using surface plasmon resonance (SPR) technology

[0109] SPR technology is a classical method for detecting the binding of small molecules and proteins, and its advantages are that it does not require molecular labeling of the sample, i.e., it does not change the properties of small molecules, and it has high sensitivity. Its basic principle is to first fix small molecules to the chip surface, continuously flow cell lysate onto the chip surface in the form of a solution, and record the changes in the molecular concentration on the chip surface during the binding and dissociation process of small molecules and proteins by LC-MS liquid chromatography mass spectrometry, thereby monitoring the interaction of small molecules and proteins in real time. SPR technology was used to detect proteins involved in the polyubiquitination of PA protein. As a result of the test, this experiment obtained seven host proteins involved in protein polyubiquitination, including KEAP1, HERC5, RBP2, UBA7, TRIM25, ISG15, and UB2E2. Only TRIM25 has a significant effect on the anti-influenza activity of compound C1 after knockdown (Figure 78A). By overexpressing TRIM25 in a TRIM25 knockout cell line, the anti-influenza activity of compound C1 was restored to normal cell levels (Figure 78B). Example 9: Promotion of interaction between TRIM25 and PA by compound C1

[0110] HEK293T cells were transfected with PA and TRIM25 plasmids, and 3.5 h after transfection, different concentrations of compound C1 were added and treated, and MG-132 was added and incubated 8 h before receiving the cells. 24 h after cell transfection, samples were received and captured with TRIM25 protein antibody, and the expression level of ubiquitinated PA protein was detected by Western Blotting. The test results showed that compound C1 promoted the interaction of TRIM25 and PA protein (Figure 79). Example 10: Direct binding of compounds C1-C14 to TRIM25 and PA proteins

[0111] To further study the mechanism by which compound C1 degrades PA protein, the present inventors used biofilm layer surface interference technology (BLI) to detect the binding ability of the compounds to TRIM25 protein and PA protein. As a result of the test, compounds C1 to C14 all bound to TRIM25 protein, with KD values ​​of 12 to 43 μM (Figure 80). This result suggests that the binding ability of the compounds to TRIM25 is directly related to the function of inducing PA degradation. At the same time, the above compounds also have the ability to bind PA in vitro, for example, compounds C1 and C2 can bind to PA protein, with KD values ​​of 11 μM and 58 μM, respectively (Figure 81). The above results suggest that such compounds can recruit TRIM25 to PA by binding to TRIM25 and PA, and further induce its ubiquitination and degradation. Example 11: In vitro promotion of ubiquitination levels of PA protein by compound C1

[0112] The results of in vitro ubiquitination assay showed that compound C1 could promote the polyubiquitination level of PA protein in vitro (Figure 82). Example 12: Anti-influenza virus activity

[0113] (1)Cell culture Human embryonic kidney epithelial cells 293T and 293T-derived cell line 293T-Gluc were cultured in DMEM medium containing 10% fetal bovine serum (FBS). (2) Preparation of recombinant influenza A viruses 1.8 x 10 cells in a 10 cm cell culture dish 6 293T cells and 0.6 × 10 6MDCK cells were inoculated at a ratio of 3:1. After 24 h of incubation, eight plasmids (pHW181-PB2, pHW182-PB1, pHW183-PA, pHW184-HA, pHW185-NP, pHW186-NA, pHW187-M, pHW188-NS) of influenza A virus (IAV) A / WSN / 33 (H1N1) were transfected using the transfection reagent Lipofectamine2000 at a transfection amount of 1.2 μg, and 40 μl was used per dish according to the instruction manual. 6 h after transfection, the medium was replaced with fresh DMEM medium. 24 h after transfection, TPCK-trypsin was added at a final concentration of 1 μg / mL. After 48 h, the supernatant was collected, centrifuged at 1000 rpm for 5 min to remove cell debris, filtered through a 0.45 μM filter membrane, and aliquoted to obtain the A / WSN / 33 (H1N1) recombinant influenza virus, which was then stored in a -80°C refrigerator. Among them, the influenza A virus (IAV) eight plasmid reverse genetic system was donated by Dr. Robert G. Webster and is named pHW181-PB2, pHW182-PB1, pHW183-PA, pHW184-HA, pHW185-NP, pHW186-NA, pHW187-M, and pHW188-NS (Hoffmann, E., G.Neumann, et al. A DNA transfection system for generation of influenza A virus from eight plasmids[J]. Proc Natl AcadSci USA, 2000, 97:6108-6113). (3)EC using 293T-Gluc cells 50 measurement 293T-Gluc cells (Gao Q, Wang Z, Liu Z, et al. A cell-based high-throughput approach to identify inhibitors of influenza A virus[J]. Acta Pharmaceutica Sinica B, 2014, 4(4): 301-306) were plated in a 96-well plate at 2.5 × 10 cells per well. 4 The cells were inoculated and cultured in 100 μl of DMEM culture medium containing 10% FBS. 24 h after plating the cells, 1 μl of gradient-diluted test compound (test compound dissolved in DMSO (dimethyl sulfoxide) and diluted with DMSO) was added per well. 1 h after adding the test compound, virus infection was performed at MOI 0.25. After 24 h, 10 μl of the supernatant was collected to detect the Gluc protein content and EC 50 was calculated (the concentration required to inhibit the virus by 50%). The experiment was repeated three times. Gasussia luciferase activity detection 250μg of the substrate Coelenterazine-h freeze-dried powder was dissolved in 600μL of absolute ethanol to prepare a substrate mother solution with a concentration of 1.022mM, which was stored at -20℃. Before measurement, the mother solution was diluted with PBS at a ratio of 1:60 to prepare the substrate working solution. The working solution was allowed to stand at room temperature for 30 minutes to stabilize, and since the substrate becomes unstable when exposed to light, it is necessary to avoid light throughout the entire process. 10μL of the cell culture supernatant (cell supernatant after 24 hours of culture after transfection in the above Western Blot experiment) was collected in a white opaque 96-well plate and analyzed using a microplate reader Centro XS. 3 Using an LB 960 autosampler, the substrate working solution incubated under light was added to each well at an injection volume of 60 μL per well, and the signal was collected continuously for 0.5 seconds, and the measurement results were expressed in Relative Light Units (RLU). Three parallel experiments were performed. The experimental data were Represented as TIFF2024545831000044.tif4170. Plots and statistical analysis were performed using GraphPad Prism 5.0. (4) Cell activity measurement CCK-8 (Cell Counting Kit-8) kit is a rapid and sensitive test kit based on WST-8 (water-soluble tetrazolium salt, chemical name: 2-(2-methyloxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfobenzene)-2H-tetrazolium monosodium salt), which is widely applied to cell proliferation and cytotoxicity. WST-8 is a compound similar to MTT, which can be reduced by dehydrogenase in mitochondria in the presence of electron-binding reagent to generate orange formazan. The more the cell proliferation, the faster the color, and the greater the cytotoxicity, the lighter the color. For the same cells, the color intensity and the cell number are in a linear relationship. The light absorption value can be measured at a wavelength of 450 nm by an enzyme-linked immunosorbent assay device to indirectly reflect the number of live cells. 2.5 × 10 293T-Gluc cells per well 4 The cells were seeded in a 96-well plate and cultured in 100 μl of DMEM culture medium containing 10% FBS. 24 h after plating the cells, 1 μl of gradient-diluted test compound (test compound dissolved in DMSO and diluted with DMSO) was added per well, and a blank control (100 μl of DMEM medium only), a positive control (1 μl of Ribavirin added), and a negative control (1 μl of DMSO added) were simultaneously set up and incubated at 37°C for 48 h. The 96-well plate was removed, and 10 μl of CCK-8 was added per well. After 1-2 hours of incubation at 37°C, the optical absorption value at a wavelength of 450 nm of each well was measured using an Enspire2300 multifunction microplate reader, and the half cytotoxic concentration of CCK-8 was determined. 50 (refers to the concentration of drug that kills 50% of cells) was calculated. The experiment was repeated three times. Table 8. Anti-IAV activity results of compounds TIFF2024545831000045.tif101170

[0114] From this, it can be seen that compounds C1 to C14 all have good anti-type A influenza virus activity, although to different degrees, and their anti-influenza virus EC 50 The CC values ​​of these compounds ranged from 0.45 to 2.22 μM. 50 All values ​​were greater than 100 μM. Therefore, the perinaphthenone compound exhibited the characteristics of having a strong antiviral activity and low cytotoxicity.

[0115] The above are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

[0116] The foregoing embodiments and methods described in the present invention may vary based on the capabilities, experience, and preferences of those skilled in the art.

[0117] Although the present invention recites method steps in a certain order, this is not intended to imply any limitation on the order of the method steps.

Claims

1. A compound having the following structure, or a pharmaceutically acceptable salt, ester, stereoisomer, prodrug or solvate thereof. (Herein, The valence bond at site 1 or site 2 represents a single bond or a double bond, and 1 and 2 are not double bonds simultaneously, R １ to R １８ are independently H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -CN, -NO ２ , -COR Ａ , -C(O)OR Ａ , -OCOR Ａ , -C(O)NR Ａ R Ｂ , -CH=NR Ａ , -OR Ａ , -OC(O)R Ａ , -S(O) ｔ -R Ａ , -S(O) ｔ -NR Ａ R Ｂ , -NR Ａ R Ｂ , -NR Ａ C(O)R Ｂ selected from, and optionally, where H on each group is halogen, -CN, -CF ３ , -NO ２ , -CHO, -COOH, -C(O)NH ２ , -OH, -OC(O)H, -SH, -S(O) ２ H, -NH ２ and may be substituted with one or more groups selected from, R １９ and R ２０ are each independently selected from H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, and optionally, where H on each group is substituted or unsubstituted heterocyclyl, halogen, -CN, -NO ２ , -COR Ａ , -C(O)OR Ａ , -C(O)NR Ａ R Ｂ , -CH=NR Ａ , -OR Ａ , -OC(O)R Ａ , -S(O) ｔ -R Ａ , -S(O) ｔ , -S(O) Ａ -NR Ｂ R Ａ R Ｂ , -NR Ａ C(O)R Ｂ and may be substituted with one or more groups selected from, or R １９ and R ２０ together with the carbon atom to which they are simultaneously attached form a substituted or unsubstituted cycloalkyl or heterocyclyl, or R １７ and R １９ together with the carbon atom to which they are simultaneously attached form a substituted or unsubstituted cycloalkyl or heterocyclyl, t is selected from 0, 1, and 2, Each R Ａ and R Ｂ is independently selected from H, alkyl, cycloalkyl, alkenyl, aryl, heterocyclyl, and halogen.)

2. R １ is selected from -OH, -O(C1-10 alkyl), -SH, -S(C1-10 alkyl), -S(O) ２ H, -S(O) ２ (C1-10 alkyl), R ２ is selected from H, halogen, -CN, -CF ３ , -NO ２ , -CHO, -COOH, -C(O)NH ２ , -NH ２ and is selected from R ３ is selected from C1-10 alkyl, C1-10 haloalkyl, C1-10 alkenyl, C3-6 cycloalkyl, C4-10 cycloalkylalkyl, R ４ is selected from -OH, -O(C1-10 alkyl), -SH, -S(C1-10 alkyl), -S(O) ２ H, -S(O) ２ (C1-10 alkyl), R ５ is selected from H, C1-10 alkyl, C1-10 haloalkyl, C1-10 alkenyl, C3-6 cycloalkyl, C4-10 cycloalkylalkyl, R ６ is selected from -OH, -O(C1-10 alkyl), -SH, -S(C1-10 alkyl), -S(O) ２ H, -S(O) ２ (C1-10 alkyl), R ７ is selected from -OH, -O(C1-10 alkyl), -SH, -S(C1-10 alkyl), -S(O) ２ H, -S(O) ２ (C1-10 alkyl), and the compound according to claim 1, characterized by this.

3. R ８ 、R ９ 、R １１ 、R １２ 、R １３ 、R １５ 、R １６ is independently selected from H, halogen, -CN, -CF ３ , -NO ２ , -CHO, -COOH, -C(O)NH ２ , -NH ２ and the compound according to claim 1, characterized in that.

4. R １０ and R １４ each independently is selected from C1-10 alkyl, C1-10 haloalkyl, C1-10 alkenyl, C3-6 cycloalkyl, C4-10 cycloalkylalkyl, the compound according to claim 1, characterized in that.

5. R １７ is selected from H, —OH, —O(C1-10 alkyl), —SH, —S(C1-10 alkyl), —S(O) ２ H, —S(O) ２ (C1-10 alkyl), and the compound according to claim 1, characterized in that.

6. R １８ is selected from H, C1-10 alkyl, C1-10 haloalkyl, halogen, -CN, -CF ３ , -NO ２ , -CHO, -CO(C1-10 alkyl), -COOH, -C(O)O(C1-10 alkyl), -C(O)NH ２ , -C(O)N(C1-10 alkyl)(C1-10 alkyl), -OH, -O(C1-10 alkyl), -OC(O)H, -OC(O)(C1-10 alkyl), -SH, -S(C1-10 alkyl), -S(O) ２ H, -S(O) ２ (C1-10 alkyl), -NH ２ , -N(C1-10 alkyl)(C1-10 alkyl), -NHC(O)H, -N(C1-10 alkyl)C(O)(C1-10 alkyl), and optionally, one or more H on each group is halogen, -CN, -CF ３ , -NO ２ , -CHO, -CO(C1-10 alkyl), -COOH, -C(O)O(C1-10 alkyl), -C(O)NH ２ , -C(O)N(C1-10 alkyl)(C1-10 alkyl), -OH, -O(C1-10 alkyl), -OC(O)H, -OC(O)(C1-10 alkyl), -SH, -S(C1-10 alkyl), -S(O) ２ H, -S(O) ２ (C1-10 alkyl), -NH ２ , -N(C1-10 alkyl)(C1-10 alkyl), -NHC(O)H, -N(C1-10 alkyl)C(O)(C1-10 alkyl), and is substituted with a group selected therefrom, the compound according to claim 1, characterized in that.

7. R １９ The compound according to claim 1, characterized in that it has the following structure. (Herein, represents a single bond or a double bond, R ２１ to R ２４ are independently H, C1-10 alkyl, C1-10 haloalkyl (such as fluoroalkyl, such as trifluoromethyl), C1-10 alkenyl, C3-6 cycloalkyl, C4-10 cycloalkylalkyl, phenyl, 4- to 6-membered heterocycloalkyl, halogen, -CN, -NO ２ , -CHO, -CO(C1-10 alkyl), -COOH, -C(O)O(C1-10 alkyl), -C(O)NH ２ , -C(O)N(C1-10 alkyl)(C1-10 alkyl), -OH, -O(C1-10 alkyl), -OC(O)H, -OC(O)(C1-10 alkyl), -SH, -S(C1-10 alkyl), -S(O) ２ H, -S(O) ２ (C1-10 alkyl), -NH ２ , -N(C1-10 alkyl)(C1-10 alkyl), -NHC(O)H, -N(C1-10 alkyl)C(O)(C1-10 alkyl), or R ２１ to R ２４ two of which, together with the carbon atoms in between, form a substituted or unsubstituted cycloalkyl or heterocyclyl, When it represents a double bond, R ２４ does not exist, R ２５ and R ２６ are each independently selected from C1-10 alkyl, C1-10 haloalkyl, C1-10 alkenyl, C3-6 cycloalkyl, C4-10 cycloalkylalkyl, phenyl, 4- to 6-membered heterocycloalkyl.)

8. R ２５ and R ２６ are independently selected from C1-10 alkyl, a compound according to claim 7, characterized in that.

9. R ２１ is H, and R ２２ is selected from H, -OC(O)H, -OC(O)(C1-10 alkyl), and R ２３ is selected from H, -OH, -O(C1-10 alkyl), -SH, -S(C1-10 alkyl), and R ２４ is selected from -OH, -O(C1-10 alkyl), or R ２０ and R ２２ together with the carbon atoms therebetween form a heterocyclyl, or R ２０ and R ２３ together with the carbon atoms therebetween form a heterocyclyl, or R ２３ and R ２４ form a heterocyclyl together with the carbon atoms between them, a compound according to claim 7, characterized in that.

10. The compound according to claim 9, wherein the heterocyclyl is selected from the following. (Here, R Ｃ is one or more individual substituents on the ring, selected from C1-10 alkyl, C1-10 haloalkyl, C1-10 hydroxy-substituted alkyl, C1-10 alkenyl, halogen, -CN, -NO ２ , -CHO, -CO(C1-10 alkyl), -COOH, -C(O)O(C1-10 alkyl), -C(O)NH ２ , -C(O)N(C1-10 alkyl)(C1-10 alkyl), -OH, -O(C1-10 alkyl), -OC(O)H, -OC(O)(C1-10 alkyl), -SH, -S(C1-10 alkyl), -S(O) ２ H, -S(O) ２ (C1-10 alkyl), -NH ２ , -N(C1-10 alkyl)(C1-10 alkyl), -NHC(O)H, -N(C1-10 alkyl)C(O)(C1-10 alkyl).)

11. R １９ is selected from, or R １９ and R ２０ together with the carbon atoms to which they are simultaneously attached forms a group selected from, the compound according to claim 1.

12. The compound according to claim 1, wherein the compound is selected from the following structures.

13. The compound according to claim 1, wherein the stereoisomer is selected from the following structures.

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, ester, stereoisomer, prodrug, solvate thereof, and one or more pharmaceutically acceptable auxiliary materials.

15. Use of the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, ester, stereoisomer, prodrug, solvate thereof, in the manufacture of a pharmaceutical composition for preventing and / or treating a disease.

16. The use according to claim 15, wherein the disease is a disease caused by a pathogen infection or a tumor.

17. The disease caused by the pathogen infection is selected from influenza, SARS, COVID-19, viral hepatitis, AIDS, rabies, dengue fever, Ebola virus disease, and / or The tumor is selected from breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, kidney cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer, melanoma, gastric cancer, gastroesophageal adenocarcinoma, esophageal cancer, small intestine cancer, cardiac cancer, anal cancer, gallbladder cancer, cholangiocarcinoma, teratoma, and heart tumor, the use according to claim 16.

18. Use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, ester, stereoisomer, prodrug, solvate thereof as a ligand of E3 ubiquitin ligase TRIM25 or in the manufacture of a chimeric PROTAC targeting proteolysis.

19. The compound is selected from the structures of, characterized in that the use according to claim 18.

20. The stereoisomer is selected from the structures of, characterized in that the use according to claim 18.

21. The PROTAC has the following structure, characterized in that the use according to claim 18. (wherein SMI is a small molecule inhibitor moiety, E ３ L is the ligand part of the E3 ubiquitin ligase, L is a linking or connecting group between SMI and E ３ and L, Here, E ３ L is formed of the compound or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, or solvate thereof.)

22. A PROTAC having the following structure. (wherein SMI is a small molecule inhibitor moiety, E ３ L is the ligand part of the E3 ubiquitin ligase, L is a linking or connecting group between SMI and E ３ and L, Here, E ３ L is formed of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, or solvate thereof.)

23. Aspergillus, with the deposit number of CGMC No. 22467.

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