Divaricate saposhnikovia acid derivative, salt, stereoisomer and solvate thereof, and preparation method and application thereof

Abstract

The invention relates to the technical field of medicinal chemistry, in particular to a radix saposhnikoviae oxalic acid derivative and salt, stereoisomer and solvate thereof as well as a preparation method and application thereof, the structure of the radix saposhnikoviae oxalic acid derivative is as shown in formula (I), X1 is O, S, NR2 or CR3R4; r1, R2, R3 and R4 are respectively and independently H, OH, NH2, COOH, substituted or unsubstituted C1-10 alkyl groups, C1-10 alkoxy groups, C3-20 cycloalkyl groups, C5-20 heterocycloalkyl groups, C5-30 aryl groups and C5-30 heteroaryl groups, # imgabs 0, # R11, R12, R13, R14, R15 and R16 are respectively and independently H, OH, NH2, COOH, substituted or unsubstituted C1-10 alkyl groups and # imgabs 1 #. The radix saposhnikoviae oxalic acid derivative disclosed by the invention can be used for resisting viruses and cancers. # imgabs2 #

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical chemistry, and in particular to a oxalic acid derivative and its salts, stereoisomers and solvates, and preparation methods and applications thereof. The structure of the oxalic acid derivative is shown in formula (I). Background Art

[0002] Parsnips (Anisomeles indica (L.) Kuntze (Labiatae)), also known as fish needle grass, is classified in the Lamiaceae family and is an annual or biennial herb. As a medicinal plant with a long history, parsnips have been widely used to treat a variety of diseases since ancient times. It has the effects of relieving fever, removing rheumatism, strengthening the stomach, detoxifying and relieving pain. It is often used by the people to relieve symptoms such as fever caused by cold, abdominal pain, vomiting, rheumatic bone pain and eczema.

[0003] In order to fully explore and exert the medical value of traditional Chinese medicine, it is essential to deeply study its intrinsic chemical composition. Through the systematic analysis of the chemical components of traditional Chinese medicine, people can reveal its complex pharmacodynamic relationship, thus providing a scientific basis for the modernization and standardization of traditional Chinese medicine. In addition, the discovery and research of active ingredients can promote the development of new drugs and enhance the application potential of traditional Chinese medicine in modern medicine. For example, through separation and purification technology, specific components with antiviral, anti-tumor, anti-inflammatory and other effects can be extracted, thereby developing more precise and effective drugs.

[0004] Anisomelic acid (AA), also known as anacardiaceae, is a compound isolated from anacardiaceae. This compound has certain antiviral activity against SARS-CoV-2 virus, with a half inhibitory concentration (IC50) of 4.3mM. In order to better exert the antiviral potential of anacardiaceae and improve its pharmacological activity, it is necessary to modify its structure. Summary of the invention

[0005] Based on this, one or more embodiments of the present application provide a oxalic acid derivative and its salt, stereoisomer and solvate, and its preparation method and application. Such oxalic acid derivative has the potential to be developed and prepared into antiviral drugs and anticancer drugs.

[0006] The technical solution of this application includes the following contents:

[0007] A compound having a structure as shown in formula (I), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

[0008]

[0009] X1 is O, S, NR2 or CR3R4;

[0010] R1, R2, R3 and R4 are independently H, OH, NH2, COOH, substituted or unsubstituted C 1～10 Alkyl, substituted or unsubstituted C 1～10 Alkoxy, substituted or unsubstituted C 3～20 Cycloalkyl, substituted or unsubstituted C 5～20 Heterocycloalkyl, substituted or unsubstituted C 5～30 Aryl, substituted or unsubstituted C 5～30 Heteroaryl,

[0011] R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are independently H, OH, NH2, COOH, substituted or unsubstituted C 1～10 alkyl,

[0012]

[0013] R 21 and R 22 are independently H, OH, NH2, COOH, substituted or unsubstituted C 1～10 Alkyl or

[0014] R 31 , R 32 and R 33 are independently H, OH, NH2, COOH or substituted or unsubstituted C 1～10 alkyl;

[0015] Y1, Y2 and Y3 are each independently absent or (CH2) n ;

[0016] n is an integer selected from 1-10.

[0017] In one embodiment, R1 is OH, NH2, COOH, substituted or unsubstituted C 1～10 Alkyl, substituted or unsubstituted C 1～10 Alkoxy, substituted or unsubstituted C 3～20 Cycloalkyl, substituted or unsubstituted C 5～20 Heterocycloalkyl, substituted or unsubstituted C 5～30 Aryl, substituted or unsubstituted C 5～30 Heteroaryl.

[0018] In one embodiment, R1 and R2 are independently H or

[0019] R 11 , R 12 and R 13 are independently H, COOH,

[0020] R 21 and R 22 are independently COOH, substituted or unsubstituted C 1～10 Alkyl or

[0021] In one embodiment, Y1 is absent or is (CH2) n1 ;

[0022] Y2 does not exist or is (CH2) n2 ;

[0023] Y3 does not exist or is (CH2) n3 ;

[0024] n1, n2 and n3 are each independently selected from integers of 1-10.

[0025] In one embodiment, R1 and R2 are independently H,

[0026] R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are independently H, OH, NH2, COOH or substituted or unsubstituted C 1～10 alkyl.

[0027] In one embodiment, R1 is substituted or unsubstituted C 5～6 Heterocycloalkyl, further, R1 is selected from or

[0028] R1 is substituted or unsubstituted C 6～10 Aryl or C 5～10 Heteroaryl, further, R1 is selected from or

[0029] R1 is Further, R1 is selected from or

[0030] R1 is Further, R1 is selected from

[0031] q1, q2, q3, q4, q5 and q6 are independently selected from 0, 1, 2, 3 or 4;

[0032] R a1 and R a2 are independently H or C 1-3 alkyl.

[0033] In one embodiment, X1 is S or NR2,

[0034] Furthermore, R2 is H.

[0035] In one embodiment, R1, R2, R3 and R4 are independently H, OH, NH2, COOH, substituted or unsubstituted C 1～10 Alkyl, substituted or unsubstituted C 3～20 Cycloalkyl, substituted or unsubstituted C 5～30 The aromatic group

[0036] Furthermore, R 13 is COOH.

[0037] In one embodiment, the substituted or unsubstituted C 1～10 Substitution in alkyl refers to C 1～10 At least one hydrogen atom in the alkyl group is replaced by R b1 replace;

[0038] Substituted or unsubstituted C 1～10 Substitution in the alkoxy group refers to C 1～10 At least one hydrogen atom in the alkoxy group is replaced by R b2 replace;

[0039] Substituted or unsubstituted C 3～20 Substitution in cycloalkyl refers to C 3～20 At least one hydrogen atom in the cycloalkyl group is replaced by R b3 replace;

[0040] Substituted or unsubstituted C 5～30 The substitution of the aromatic ring refers to C 5～30 At least one hydrogen atom in the aromatic ring is replaced by R b4 replace;

[0041] R b1 , R b2 , R b3 and R b4 Each occurrence is independently selected from CN, OH, COOH, NO2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, C2-6 Alkenyl, C 2-6 Alkynyl, NR c1 R c2 、C(=O)NR c3 R c4 、C(=O)OC 1-6 Alkyl, -CHO, OC(=O)C 1-6 Alkyl and S(=O)(=O)C 1-6 At least one of the alkyl groups;

[0042] R c1 , R c2 , R c3 and R c4 are independently H or C 1-3 alkyl.

[0043] In one embodiment, the compound has a structure as shown in formula (I-1):

[0044]

[0045] A method for preparing the compound described in any of the above technical solutions comprises the following steps:

[0046]

[0047] Reacting compound 1 with compound R1-Y1-X1-H to obtain the compound represented by formula (I);

[0048] Wherein, R1, Y1 and X1 are the same as defined in any of the above technical solutions.

[0049] A pharmaceutical composition comprises at least one of the above-mentioned compounds or pharmaceutically acceptable salts, stereoisomers or solvates thereof, and pharmaceutically acceptable excipients.

[0050] Use of the compound described above or a pharmaceutically acceptable salt, stereoisomer or solvate thereof in the preparation of an antiviral drug.

[0051] A use of the compound described above or a pharmaceutically acceptable salt, stereoisomer or solvate thereof in the preparation of an anticancer drug; further, the cancer includes cancer caused by a virus; further, the cancer includes cervical cancer caused by human papillomavirus.

[0052] The present application obtains a series of oxalic acid derivatives with better antiviral activity by structural modification of oxalic acid, which have the potential to be used in the development of new antiviral drugs and are improved in at least one aspect such as target specificity, drug activity, pharmacokinetics and reduction of side effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] In order to more clearly illustrate the specific implementation methods of the present application or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0054] Figure 1 The synthetic route of Compound 2, Compound 3, Compound 4 and Compound 5 in Example 1 of the present application;

[0055] Figure 2 The synthetic route of Compound 6, Compound 7, Compound 8 and Compound 9 in Example 1 of the present application;

[0056] Figure 3 The synthetic route of compound 10, compound 11, compound 12 and compound 13 in Example 1 of the present application;

[0057] Figure 4 The synthetic route of compound 14, compound 15, compound 16 and compound 17 in Example 1 of the present application;

[0058] Figure 5 The synthetic route of Compound 18, Compound 19, Compound 20 and Compound 21 in Example 1 of the present application;

[0059] Figure 6 The synthetic route of Compound 22, Compound 23 and Compound 24 in Example 1 of the present application;

[0060] Figure 7 The test results of RD cytotoxicity of compound 4 in Example 3 of the present application;

[0061] Figure 8 The enterovirus EV-D68 inhibition results of compound 4 in Example 3 of the present application;

[0062] Fig. 9 This is the protective result of compound 4 in Example 3 of the present application against newborn mice infected with enterovirus EV-D68. DETAILED DESCRIPTION

[0063] In order to facilitate the understanding of the present invention, the present invention will be described more comprehensively below, and preferred embodiments of the present invention are provided. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0064] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items.

[0065] Explanation of terms

[0066] Definitions and General Terms

[0067] Unless stated otherwise, the following terms used in the specification and claims have the following meanings.

[0068] "Aromatic group", "aryl group", "aromatic radical", "aromatic" and "aromatic ring system" have the same meaning and are interchangeable.

[0069] "Heteroaryl", "heteroaromatic group", "heteroaromatic" and "heteroaromatic ring system" have the same meaning and are interchangeable.

[0070] A "heteroatom" is a non-carbon atom, and may be a N atom, an O atom, a S atom, or the like.

[0071] The "substituted" means that a hydrogen atom in a substituted group is replaced by a substituent.

[0072] "Substituted or unsubstituted" means that the defined group may be substituted or unsubstituted. When the defined group is substituted, it is understood that the defined group may be substituted with one or more substituents.

[0073] "Alkyl" refers to a monovalent residue formed by a saturated aliphatic hydrocarbon group losing a hydrogen atom, including straight-chain and branched-chain groups. 1-10 Alkyl refers to an alkyl group containing 1 to 10 carbon atoms. Non-limiting examples of alkyl groups in the present application include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl. C1-C4 alkyl refers to an alkyl group containing 1 to 4 carbon atoms. In one embodiment, the C1-C4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or sec-butyl.

[0074] "Alkoxy" refers to a group having a structure of -O-alkyl, i.e., an alkyl group as defined above is connected to an adjacent group via an oxygen atom. Non-limiting examples of alkoxy in the present application include: methoxy (-O-CH or -OMe), ethoxy (-O-CHCH or -OEt) and tert-butoxy (-OC(CH) or -OtBu).

[0075] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent in which all the ring atoms are carbon, and may be a monocyclic alkyl, a spirocyclic alkyl, or a bridged cycloalkyl. 3-10 Cycloalkyl refers to a cycloalkyl containing 3 to 10 carbon atoms. Non-limiting examples of alkyl in the present application include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. In addition, "cycloalkyl" may also contain one or more double bonds, and representative examples of cycloalkyl containing double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl and cyclobutadienyl.

[0076] "Heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, preferably nitrogen or oxygen heteroatoms; but excluding the ring part of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. 5-20 Heterocycloalkyl refers to a ring containing 5 to 20 ring atoms, at least one of which is a heteroatom; preferably, the heterocyclyl ring contains 5 to 6 ring atoms, 1 to 2 of which are heteroatoms. In one embodiment, the heterocyclyl is dihydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or homopiperazinyl, etc.

[0077] "Aryl" refers to an aromatic hydrocarbon group derived from an aromatic ring compound by removing a hydrogen atom. It can be a monocyclic aromatic group, a condensed aromatic group, or a polycyclic aromatic group. For polycyclic rings, at least one is an aromatic ring system. 6～30 Aryl refers to an aromatic group having 6 to 30 ring atoms. Non-limiting examples of aromatic groups in the present application include: benzene, biphenyl, naphthalene, anthracene, phenanthrene, diphenylene, triphenylene and derivatives thereof. It is understood that multiple aromatic groups may also be interrupted by short non-aromatic units (e.g. <10% non-H atoms, such as C, N or O atoms), such as acenaphthene, fluorene, or 9,9-diarylfluorene, triarylamine, diaryl ether system should also be included in the definition of aromatic group.

[0078] "Heteroaryl" means that at least one carbon atom in an aryl group is replaced by a non-carbon atom, and the non-carbon atom may be a nitrogen atom, an oxygen atom, a sulfur atom, etc. 5～30Heteroaryl refers to a heteroaryl having 5 to 30 ring atoms, and the heteroaryl is optionally further substituted. Non-limiting examples of heteroaryl in the present application include furan, benzofuran, thiophene, benzothiophene, pyrrole, pyrazole, triazole, imidazole, oxazole, oxadiazole, thiazole, tetrazole, indole, carbazole, pyrroloimidazole, pyrrolopyrrole, thienopyrrole, thienothiophene, furopyrrole, furofuran, thienofuran, benzisoxazole, benzisothiazole, benzimidazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, quinoline, isoquinoline, o-naphthyridine, quinoxaline, phenanthridine, primary pyridine, quinazoline and quinazolinone.

[0079] "Halogen" or "halo" refers to F, Cl, Br or I.

[0080] In this application, when the configuration of a chiral carbon atom is not indicated, it should be understood to include any configuration acceptable in the art;

[0081] The compounds of the present application may exist in unsolvated forms and solvated forms containing pharmaceutically acceptable solvents (such as water, ethanol, etc.), ie, they include both solvated and unsolvated forms.

[0082] “*” indicates the attachment site.

[0083] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0084] The excipients contained in the composition may be one or more buffers, stabilizers, anti-adherents, surfactants, wetting agents, lubricants, emulsifiers, binders, suspending agents, disintegrants, fillers, adsorbents, coatings (enteric or sustained-release), preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, aromas, flavoring agents and other known additives.

[0085] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to an organic or inorganic salt of a pharmaceutically acceptable compound.

[0086] When the compound is acidic or includes sufficiently acidic bioisosteres, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Such salts are derived from inorganic bases containing aluminum, ammonium, calcium, copper, iron, iron, lithium, magnesium, manganese salts, manganese, potassium, sodium, octane, etc. Specific embodiments include ammonium, calcium, magnesium, potassium and sodium salts. Salts are derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N.sup.1-dibenzylethylenediamine, ethylenediamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, meglumine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0087] When the compound is alkaline or includes a sufficiently alkaline bioisostere, the salt can be prepared from a pharmaceutically acceptable non-toxic acid, including inorganic and organic acids. Such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, sulfuric acid, succinic acid, tartaric acid, p-toluenesulfonic acid, etc. Specific embodiments include citric acid, hydrobromic acid, hydrochloric acid, phosphoric acid, sulfuric acid, maleic acid, tartaric acid, etc. Other exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, phosphate, acid phosphate, isonicotinic acid, lactic acid, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, fumarate, maleate, gentisinate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (e.g., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)).

[0088] In addition, the pharmaceutical preparation containing the compound can be a tablet, capsule, oral liquid, pill, granule, powder, ointment, patch, suppository, buccal tablet, eye drop, eye ointment, eye ointment, ear drop, spray, aerosol, inhalant, injection, etc.

[0089] The term "therapeutically effective amount" refers to the amount of an effective compound or pharmaceutical agent, the minimum amount necessary to ameliorate, cure or treat one or more symptoms of a disease or disorder.

[0090] In addition, the compounds and pharmaceutical compositions described herein can be administered alone or in combination with other medicaments. For combined treatment with more than one active agent, when the active agent is in a separate dosage formulation, the active agent can be administered separately or in combination. In addition, the administration of one medicament can be performed before, at the same time, or after the administration of another medicament. When administered in combination with other medicaments, the "effective amount" of the second medicament will depend on the type of drug used.

[0091] The compound or pharmaceutical composition of the present application may also be included in a kit.

[0092] It should be noted that the reagents whose specific sources are not indicated in this application are conventional reagents purchased from the market.

[0093] In one aspect of the present application, a compound having a structure as shown in formula (I) is provided, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof:

[0094]

[0095] Further, it has a structure as shown in formula (I-1):

[0096]

[0097] X1 is O, S, NR2 or CR3R4;

[0098] R1, R2, R3 and R4 are independently H, OH, NH2, COOH, substituted or unsubstituted C 1～10 Alkyl, substituted or unsubstituted C 1～10 Alkoxy, substituted or unsubstituted C 3～20 Cycloalkyl, substituted or unsubstituted C 5～20 Heterocycloalkyl, substituted or unsubstituted C 5～30 Aryl, substituted or unsubstituted C 5～30 Heteroaryl,

[0099] R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are independently H, OH, NH2, COOH, substituted or unsubstituted C 1～10 alkyl,

[0100]

[0101] R 21 and R 22 are independently H, OH, NH2, COOH, substituted or unsubstituted C1～10 Alkyl or

[0102] R 31 , R 32 and R 33 are independently H, OH, NH2, COOH or substituted or unsubstituted C 1～10 alkyl;

[0103] Y1, Y2 and Y3 are each independently absent or (CH2) n ;

[0104] n is an integer selected from 1-10.

[0105] In one embodiment, n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0106] Preferably, the oxalic acid derivatives of the present application are used to prepare anti-EV-D68 virus drugs.

[0107] In one embodiment, R1 is OH, NH2, COOH, substituted or unsubstituted C 1～10 Alkyl, substituted or unsubstituted C 1～10 Alkoxy, substituted or unsubstituted C 3～20 Cycloalkyl, substituted or unsubstituted C 5～20 Heterocycloalkyl, substituted or unsubstituted C 5～30 Aryl, substituted or unsubstituted C 5～30 Heteroaryl.

[0108] In one embodiment, R1 and R2 are independently H or

[0109] R 11 , R 12 and R 13 are independently H, COOH,

[0110] R 21 and R 22 are independently COOH, substituted or unsubstituted C 1～10 Alkyl or

[0111] In one embodiment, Y1 is absent or is (CH2) n1 ;

[0112] Y2 does not exist or is (CH2) n2 ;

[0113] Y3 does not exist or is (CH2) n3 ;

[0114] n1, n2 and n3 are each independently selected from integers of 1-10.

[0115] In one embodiment, R1 and R2 are independently H,

[0116] R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are independently H, OH, NH2, COOH or substituted or unsubstituted C 1～10 alkyl.

[0117] In one embodiment, R1 is substituted or unsubstituted C 5～6 Heterocycloalkyl, further, R1 is selected from or

[0118] R1 is substituted or unsubstituted C 6～10 Aryl or C 5～10 Heteroaryl, further, R1 is selected from or

[0119] R1 is Further, R1 is selected from or

[0120] R1 is Further, R1 is selected from

[0121] q1, q2, q3, q4, q5 and q6 are independently selected from 0, 1, 2, 3 or 4;

[0122] R a1 and R a2 are independently H or C 1-3 alkyl.

[0123] In one embodiment, R1 is

[0124] In one embodiment, X1 is S or NR2,

[0125] Furthermore, R2 is H.

[0126] In one embodiment, R1, R2, R3 and R4 are independently H, OH, NH2, COOH, substituted or unsubstituted C 1～10 Alkyl, substituted or unsubstituted C 3～20Cycloalkyl, substituted or unsubstituted C 5～30 The aromatic group

[0127] Furthermore, R 13 is COOH.

[0128] In one embodiment, the substituted or unsubstituted C 1～10 Substitution in alkyl refers to C 1～10 At least one hydrogen atom in the alkyl group is replaced by R b1 replace;

[0129] Substituted or unsubstituted C 1～10 Substitution in the alkoxy group refers to C 1～10 At least one hydrogen atom in the alkoxy group is replaced by R b2 replace;

[0130] Substituted or unsubstituted C 3～20 Substitution in cycloalkyl refers to C 3～20 At least one hydrogen atom in the cycloalkyl group is replaced by R b3 replace;

[0131] Substituted or unsubstituted C 5～30 The substitution of the aromatic ring refers to C 5～30 At least one hydrogen atom in the aromatic ring is replaced by R b4 replace;

[0132] R b1 , R b2 , R b3 and R b4 Each occurrence is independently selected from CN, OH, COOH, NO2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, NR c1 R c2 、C(=O)NR c3 R c4 、C(=O)OC 1-6 Alkyl, -CHO, OC(=O)C 1-6 Alkyl and S(=O)(=O)C 1-6 At least one of the alkyl groups;

[0133] R c1 , R c2 , R c3 and R c4 are independently H or C 1-3 alkyl.

[0134] In one embodiment, the compound as shown in formula (I) comprises:

[0135]

[0136]

[0137] In another aspect of the present application, there is provided a method for preparing the compound described above, comprising the following steps:

[0138]

[0139] Compound 1 is reacted with compound R1-Y1-X1-H to obtain the compound represented by formula (I). R1, Y1 and X1 are the same as defined in any of the above technical solutions.

[0140] In another aspect of the present application, a pharmaceutical composition is provided, comprising at least one of the above-mentioned compounds or pharmaceutically acceptable salts, stereoisomers or solvates thereof, and pharmaceutically acceptable excipients.

[0141] In another aspect of the present application, there is provided a use of the compound described above or a pharmaceutically acceptable salt, stereoisomer or solvate thereof in the preparation of an antiviral drug.

[0142] In another aspect of the present application, there is provided a use of the compound described above or a pharmaceutically acceptable salt, stereoisomer or solvate thereof in the preparation of an anticancer drug; further, the cancer includes cancer caused by a virus; further, the cancer includes cervical cancer caused by human papillomavirus.

[0143] The present application obtains a series of oxalic acid derivatives with antiviral potential by structural modification of oxalic acid, which have the potential to be used in the development of new antiviral drugs and are improved in at least one aspect such as target specificity, drug activity, pharmacokinetics and reduction of side effects.

[0144] The following are some specific embodiments.

[0145] Example 1

[0146] This example provides the synthesis and structural characterization of various fangfeng acid derivatives and their salts. The synthetic routes are shown in Figures 1 to 6 , the synthesis steps are as follows:

[0147] 1.1 Preparation of compound 2

[0148] At room temperature, the natural product Anisomelic acid (Compound 1) (66 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (1 mL), and then glutathione (73.7 mg, 0.24 mmol, 1.2 eq) and triethylamine (64.8 mg, 0.64 mmol, 3.2 eq) were added. Stirring was carried out at room temperature overnight, and saturated ammonium chloride solution (2 mL) was added to the system, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (3×2 mL), and the combined organic phase was washed with saturated sodium chloride (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then dissolved in methanol (1 mL), and reverse phase preparation (0.1% TFA water and 0.1% TFA acetonitrile) was performed by HPLC, and the fraction was lyophilized overnight, Compound 2 (96.9 mg, 76%).

[0149] 1 H NMR(400MHz, Methanol-d4)δ5.92–5.79(m,1H),5.28(dq,J=9.4,1.4Hz,1H),5.13–5.04( m,1H),4.63(dd,J=8.8,5.3Hz,1H),4.03(t,J=6.4Hz,1H),3.94(d,J=2.8Hz,2H),3.08(dd ,J=13.9,5.4Hz,1H),3.00(dd,J=4.7,1.4Hz,2H),2.94–2.83(m,1H),2.82–2.73(m,2H), 2.71–2.55(m,3H),2.39–2.12(m,9H),2.11–2.05(m,2H),1.85–1.66(m,5H),1.57(s,3H).

[0150] ESI-MS m / z calculated value 637.2669, found value 638.5 (M+1) + and 636.8(M-1)-.

[0151] 1.2 Preparation of compound 3

[0152] At room temperature, the natural product Anisomelic acid (Compound 1) (66 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (1 mL), and then cysteine ​​glycine (39.2 mg, 0.24 mmol, 1.2 eq) and triethylamine (64.8 mg, 0.64 mmol, 3.2 eq) were added. The mixture was stirred overnight at room temperature, and a saturated ammonium chloride solution (2 mL) was added to the system to separate the organic phase. The aqueous phase was extracted with dichloromethane (3×2 mL), and the combined organic phase was washed with saturated sodium chloride (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then dissolved in methanol (1 mL). The reverse phase preparation (0.1% TFA water and 0.1% TFA acetonitrile) was directly performed by HPLC, and the fraction was lyophilized overnight to obtain Compound 3 (86.4 mg, 85%).

[0153] 1 H NMR (400MHz, Methanol-d4) δ5.84 (dd, J=7.4, 6.0Hz, 1H), 5.28 (dq, J=9.4, 1.4Hz, 1H), 5 .14–5.05(m,1H),4.92(dd,J=9.4,8.3Hz,3H),4.12(dd,J=8.6,5.0Hz,1H),4.09–3.94( m,2H),3.19(dd,J=14.7,5.1Hz,1H),3.11–2.97(m,2H),2.95–2.77(m,3H),2.71–2.58( m,1H),2.42–2.20(m,7H),2.18–2.01(m,2H),1.84–1.70(m,5H),1.58(d,J=1.3Hz,3H).

[0154] ESI-MS m / z calculated value 508.2243, found value 509.4 (M+1) + and 507.7(M-1) - .

[0155] 1.3 Preparation of compound 4

[0156] At room temperature, the natural product Anisomelic acid (Compound 1) (66 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (1 mL), and then L-cysteine ​​(29.1 mg, 0.24 mmol, 1.2 eq) and triethylamine (44.5 mg, 0.44 mmol, 2.2 eq) were added. The mixture was stirred overnight at room temperature, and a saturated ammonium chloride solution (2 mL) was added to the system to separate the organic phase. The aqueous phase was extracted with dichloromethane (3×2 mL), and the combined organic phase was washed with saturated sodium chloride (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then dissolved in methanol (1 mL). The reverse phase preparation (0.1% TFA water and 0.1% TFA acetonitrile) was directly performed by HPLC, and the fraction was lyophilized overnight to obtain Compound 4 (65.9 mg, 73%).

[0157] 1 H NMR (600MHz, Methanol-d4) δ5.79(t,J=6.8Hz,1H),5.25(d,J=9.4Hz,1H),4.86(dd,J=9.4,8.0Hz,1H),4.18(dd,J=7.8,4.3Hz,1H),3.29–3 .22(m,2H),3.05–2.93(m,3H),2.79–2.73(m,1H),2.68–2.56(m,1H), 2.34–2.15(m,7H),2.11–1.97(m,2H),1.79–1.67(m,5H),1.54(s,3H).

[0158] ESI-MS m / z calculated value 451.2029, found value 452.4 (M+1) + and 452.6(M-1) - .

[0159] 1.4 Preparation of compound 5

[0160] At room temperature, the natural product Anisomelic acid (Compound 1) (66 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (1 mL), and then N-acetyl-L-cysteine ​​(39.2 mg, 0.24 mmol, 1.2 eq) and triethylamine (64.8 mg, 0.64 mmol, 3.2 eq) were added. The mixture was stirred overnight at room temperature, and a saturated ammonium chloride solution (2 mL) was added to the system to separate the organic phase. The aqueous phase was extracted with dichloromethane (3×2 mL), and the combined organic phases were washed with saturated sodium chloride (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then dissolved in methanol (1 mL). The reverse phase preparation (0.1% TFA water and 0.1% TFA acetonitrile) was directly performed by HPLC, and the fraction was lyophilized overnight to obtain Compound 5 (84.8 mg, 86%).

[0161] 1 H NMR(400MHz, Methanol-d4)δ5.84(t,J=6.6Hz,1H),5.30(dd,J=9.3,1.5Hz,1H), 5.08(td,J=6.7,1.7Hz,1H),4.61(dd,J=8.5,4.7Hz,1H),3.13(dd,J=13.8,4.7Hz ,1H),2.98(d,J=4.8Hz,2H),2.83(dd,J=13.8,8.5Hz,2H),2.78–2.60(m,2H),2. 42–2.16(m,8H),2.13–2.05(m,2H),2.02(s,3H),1.82–1.69(m,5H),1.58(s,3H).

[0162] ESI-MS m / z calculated value 493.2134, found value 494.4 (M+1) + and 492.5(M-1) - .

[0163] 1.5 Preparation of compound 6

[0164] At room temperature, the natural product Anisomelic acid (Compound 1) (66 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (1 mL), and then ethanethiol (14.9 mg, 0.24 mmol, 1.2 eq) and triethylamine (24.3 mg, 0.24 mmol, 1.2 eq) were added, stirred overnight at room temperature, saturated ammonium chloride solution (2 mL) was added to the system, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (3×2 mL), and the combined organic phase was washed with saturated sodium chloride (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then dissolved in dichloromethane (0.5 mL), and separated by thin layer chromatography (petroleum ether / ethyl acetate = 1 / 1, Rf = 0.6) to obtain Compound 6 (72.9 mg, 93%).

[0165] 1 H NMR(400MHz,Chloroform-d)δ5.95(t,J=6.5Hz,1H),5.29–5.22(m,1H),5.06–4.98(m,1H),4.76(dd,J=9.3,7.1Hz,1H),3.03–2.74 (m,4H),2.64–2.49(m,4H),2.49–2.38(m,1H),2.36–2.17(m,7H),2.07(t,J=5.4Hz,2H),1.83–1.63(m,6H),1.57(d,J=1.2Hz,3H).

[0166] ESI-MS m / z calculated value 392.2021, found value 393.3 (M+1) + and 391.6(M-1) - .

[0167] 1.6 Preparation of compound 7

[0168] At room temperature, the natural product Anisomelic acid (Compound 1) (66 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (1 mL), and then 4-toluene thiophenol (29.8 mg, 0.24 mmol, 1.2 eq) and triethylamine (24.3 mg, 0.24 mmol, 1.2 eq) were added, stirred overnight at room temperature, saturated ammonium chloride solution (2 mL) was added to the system, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (3×2 mL), and the combined organic phase was washed with saturated sodium chloride (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then dissolved in dichloromethane (0.5 mL) and separated by thin layer chromatography (petroleum ether / ethyl acetate = 1 / 1, R f=0.6), to give compound 7 (80.8 mg, 89%).

[0169] 1 H NMR (400MHz, Methanol-d4) δ7.31(d,J=8.1Hz,2H),7.14(d,J=7.9Hz,2H),5.79(t,J=6.7Hz,1H),5.30(d,J=7.8Hz,1H),5.02–4.97(m,1H),4.86(dd,J =9.4,7.3Hz,1H),3.37–3.25(m,2H),2.91–2.77(m,1H),2.77–2.64(m,2H), 2.43–2.14(m,11H),2.04(t,J=6.2Hz,2H),1.80–1.64(m,5H),1.50(s,3H).

[0170] ESI-MS m / z calculated value 454.2178, found value 455.4 (M+1) + and 453.5(M-1) - .

[0171] 1.7 Preparation of compound 8

[0172] At room temperature, the natural product Anisomelic acid (Compound 1) (66 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (1 mL), and then 3-mercaptopropionic acid (25.4 mg, 0.24 mmol, 1.2 eq) and triethylamine (44.5 mg, 0.44 mmol, 2.2 eq) were added. The mixture was stirred overnight at room temperature, and a saturated ammonium chloride solution (2 mL) was added to the system to separate the organic phase. The aqueous phase was extracted with dichloromethane (3×2 mL), and the combined organic phase was washed with saturated sodium chloride (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then dissolved in methanol (1 mL). The reverse phase preparation (0.1% TFA water and 0.1% TFA acetonitrile) was directly performed by HPLC, and the fraction was freeze-dried overnight to obtain Compound 8 (64.5 mg, 74%).

[0173] 1H NMR(400MHz, Methanol-d4)δ5.84(t,J=6.6Hz,1H),5.32(dq,J=9.5,1.4Hz,1H),5.13–5.05(m,1H),4.87(s,1H),3.02–2.90 (m,2H),2.88–2.68(m,5H),2.59(t,J=6.9Hz,2H),2.42–2.17(m,7H),2.09(t,J=6.0Hz,2H),1.84–1.70(m,5H),1.58(s,3H).

[0174] ESI-MS m / z calculated value 436.1920, found value 437.4 (M+1) + and 435.6(M-1) - .

[0175] 1.8 Preparation of compound 9

[0176] At room temperature, the natural product Anisomelic acid (Compound 1) (66 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (1 mL), and then 2-tert-butyloxycarbonylaminoethanethiol (42.6 mg, 0.24 mmol, 1.2 eq) and triethylamine (24.3 mg, 0.24 mmol, 1.2 eq) were added, stirred overnight at room temperature, saturated ammonium chloride solution (2 mL) was added to the system, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (3×2 mL), and the combined organic phase was washed with saturated sodium chloride (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, then dissolved in dichloromethane (0.5mL), separated by thin layer chromatography (petroleum ether / ethyl acetate = 1 / 1, Rf = 0.6), and the fraction was concentrated and used directly in the next step. The first step product was dissolved in an ethyl acetate solution of hydrochloric acid (2M, 0.5mL), stirred at room temperature for 30 minutes, and a saturated sodium bicarbonate solution (2mL) was added to the system to separate the organic phase. The aqueous phase was extracted with dichloromethane (3×2mL), and the combined organic phase was washed with saturated sodium chloride (5mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, then dissolved in methanol (1mL), and directly subjected to reverse phase preparation (0.1% TFA water and 0.1% TFA acetonitrile) by HPLC. The fraction was lyophilized overnight to obtain compound 9 (52.9mg, 65%).

[0177] 1H NMR (400MHz, Methanol-d4) δ5.83 (dd, J=7.4, 5.9Hz, 1H), 5.28 (dq, J=9.4, 1.4Hz, 1H), 5.08 (td, J=6.6, 1.8Hz, 1H), 4.90 (s, 1H), 3.17 (t, J=6. 8Hz,2H),3.00(t,J=4.6Hz,2H),2.92–2.77(m,4H),2.70–2.58(m,1H), 2.40–2.20(m,7H),2.16–2.02(m,2H),1.84–1.73(m,5H),1.58(s,3H).

[0178] ESI-MS m / z calculated value 407.2130, found value 408.4 (M+1) + and 406.6(M-1) - .

[0179] 1.9 Preparation of compound 10

[0180] At room temperature, the natural product Anisomelic acid (Compound 1) (66 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (1 mL), and then 3-mercapto-1-propanol (22.1 mg, 0.24 mmol, 1.2 eq) and triethylamine (24.3 mg, 0.24 mmol, 1.2 eq) were added. The mixture was stirred overnight at room temperature, and a saturated ammonium chloride solution (2 mL) was added to the system to separate the organic phase. The aqueous phase was extracted with dichloromethane (3×2 mL), and the combined organic phases were washed with saturated sodium chloride (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then dissolved in methanol (1 mL). The reverse phase preparation (0.1% TFA water and 0.1% TFA acetonitrile) was directly performed by HPLC, and the fraction was lyophilized overnight to obtain Compound 10 (59.9 mg, 71%).

[0181] 1 H NMR (600MHz, Methanol-d4) δ5.83(t,J=6.6Hz,1H),5.30(d,J=9.3Hz,1H),5.09(t,J=6.8Hz,1H),4.87(dd,J=9.4,7.6Hz,1H),3.63(t,J=6.3Hz,2H),2 .97–2.89(m,2H),2.88–2.81(m,1H),2.73–2.58(m,4H),2.42–2.30(m,4H) ,2.30–2.16(m,3H),2.09(t,J=6.0Hz,2H),1.83–1.68(m,7H),1.58(s,3H).

[0182] ESI-MS m / z calculated value 422.2127, found value 423.4 (M+1) + and 421.6(M-1) - .

[0183] 1.10 Preparation of compound 11

[0184] At room temperature, the natural product Anisomelic acid (Compound 1) (66 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (1 mL), and then 1-(3-aminopropyl) pyrrolidine (30.7 mg, 0.24 mmol, 1.2 eq) and triethylamine (24.3 mg, 0.24 mmol, 1.2 eq) were added. The mixture was stirred overnight at room temperature, and a saturated ammonium chloride solution (2 mL) was added to the system to separate the organic phase. The aqueous phase was extracted with dichloromethane (3×2 mL), and the combined organic phases were washed with saturated sodium chloride (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then dissolved in methanol (1 mL). The reverse phase preparation (0.1% TFA water and 0.1% TFA acetonitrile) was directly performed by HPLC, and the fraction was lyophilized overnight to obtain Compound 11 (78.8 mg, 86%).

[0185] 1 H NMR (400MHz, Methanol-d4) δ5.81(dd,J=7.4,5.9Hz,1H),5.27(dd,J=9.7,1.9Hz,1H),5.03(d,J=4.1Hz,1H),4.99(d,J=9.0Hz,1H),3.93(s,4H),3.60– 3.32(m,4H),3.25(dt,J=24.7,7.5Hz,5H),3.01–2.82(m,2H),2.62(ddd,J= 17.3,9.3,4.9Hz,1H),2.44–1.96(m,11H),1.87–1.68(m,5H),1.57(s,3H).

[0186] ESI-MS m / z calculated value 458.3145, found value 459.4 (M+1) + and 457.6(M-1) - .

[0187] 1.11 Preparation of compound 12

[0188] At room temperature, the natural product Anisomelic acid (Compound 1) (66 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (1 mL), and then 4-(3-aminopropyl)morpholine (34.6 mg, 0.24 mmol, 1.2 eq) and triethylamine (24.3 mg, 0.24 mmol, 1.2 eq) were added. The mixture was stirred overnight at room temperature, and a saturated ammonium chloride solution (2 mL) was added to the system to separate the organic phase. The aqueous phase was extracted with dichloromethane (3×2 mL), and the combined organic phases were washed with saturated sodium chloride (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then dissolved in methanol (1 mL). The reverse phase preparation (0.1% TFA water and 0.1% TFA acetonitrile) was directly performed by HPLC, and the fraction was freeze-dried overnight to obtain Compound 16 (83.5 mg, 88%).

[0189] 1 H NMR (400MHz, Methanol-d4) δ5.81(dd,J=7.4,5.9Hz,1H),5.27(dd,J=9.7,1.9Hz,1H),5.03(d,J=4.1Hz,1H),4.99(d,J=9.0Hz,1H),3.93(s,4H),3.60– 3.32(m,4H),3.25(dt,J=24.7,7.5Hz,5H),3.01–2.82(m,2H),2.62(ddd,J= 17.3,9.3,4.9Hz,1H),2.44–1.96(m,11H),1.87–1.68(m,5H),1.57(s,3H).

[0190] ESI-MS m / z calculated value 474.3094, found value 475.3 (M+1) + and 473.6(M-1) - .

[0191] 1.12 Preparation of compound 13

[0192] At room temperature, the natural product Anisomelic acid (Compound 1) (66 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (1 mL), and then 2-(2-aminoethyl)pyridine (29.3 mg, 0.24 mmol, 1.2 eq) and triethylamine (24.3 mg, 0.24 mmol, 1.2 eq) were added. The mixture was stirred overnight at room temperature, and a saturated ammonium chloride solution (2 mL) was added to the system to separate the organic phase. The aqueous phase was extracted with dichloromethane (3×2 mL), and the combined organic phases were washed with saturated sodium chloride (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then dissolved in methanol (1 mL). The reverse phase preparation (0.1% TFA water and 0.1% TFA acetonitrile) was directly performed by HPLC, and the fraction was lyophilized overnight to obtain Compound 13 (76.9 mg, 85%).

[0193] 1 H NMR (400MHz, Methanol-d4) δ8.71(dd,J=5.4,1.8Hz,1H),8.24(td,J=7.9,1.7Hz,1H),7.77(d,J=8.0Hz,1H),7.71(dd,J=7.8,5.2Hz,1H),5.81(t,J=6.6Hz,1 H),5.28(d,J=9.5Hz,1H),5.01(t,J=9.0Hz,2H),3.69–3.37(m,7H),3.07–2.82 (m,2H),2.67–2.57(m,1H),2.43–1.95(m,9H),1.87–1.72(m,5H),1.57(s,3H).

[0194] ESI-MS m / z calculated value 452.2675, found value 453.3 (M+1) + and 451.6(M-1) - .

[0195] 1.13 Preparation of compound 14

[0196] At room temperature, the natural product Anisomelic acid (Compound 1) (66 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (1 mL), and then 1-(3-aminopropyl) imidazole (30.0 mg, 0.24 mmol, 1.2 eq) and triethylamine (24.3 mg, 0.24 mmol, 1.2 eq) were added. The mixture was stirred overnight at room temperature, and a saturated ammonium chloride solution (2 mL) was added to the system to separate the organic phase. The aqueous phase was extracted with dichloromethane (3×2 mL), and the combined organic phases were washed with saturated sodium chloride (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then dissolved in methanol (1 mL). The reverse phase preparation (0.1% TFA water and 0.1% TFA acetonitrile) was directly performed by HPLC, and the fraction was lyophilized overnight to obtain Compound 14 (76.5 mg, 84%).

[0197] 1 H NMR(400MHz, Methanol-d4)δ9.00(d,J=1.6Hz,1H),7.69(t,J=1.7Hz,1H),7.60(t ,J=1.7Hz,1H),5.80(dd,J=7.4,5.9Hz,1H),5.27(d,J=9.4Hz,1H),4.99(t,J=9.0 Hz,3H),4.42(t,J=7.1Hz,2H),3.40–3.30(m,2H),3.19(t,J=7.8Hz,2H),3.03–2. 80(m,2H),2.69–2.56(m,1H),2.44–1.95(m,11H),1.86–1.69(m,5H),1.56(s,3H).

[0198] ESI-MS m / z calculated value 455.2784, found value 456.4 (M+1) + and 454.6(M-1) - .

[0199] 1.14 Preparation of compound 15

[0200] At room temperature, the natural product Anisomelic acid (Compound 1) (66 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (1 mL), and then L-serine (42.1 mg, 0.40 mmol, 2.0 eq) and triethylamine (60.7 mg, 0.60 mmol, 3.0 eq) were added. The mixture was stirred overnight at room temperature, and a saturated ammonium chloride solution (2 mL) was added to the system to separate the organic phase. The aqueous phase was extracted with dichloromethane (3×2 mL), and the combined organic phase was washed with saturated sodium chloride (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then dissolved in methanol (1 mL). The reverse phase preparation (0.1% TFA water and 0.1% TFA acetonitrile) was directly performed by HPLC, and the fraction was lyophilized overnight to obtain Compound 15 (61.8 mg, 71%).

[0201] 1 H NMR(600MHz, Methanol-d4)δ5.82(dd,J=7.5,5.8Hz,1H),5.30(dd,J=9.3,2.0Hz,1H),5.10–5.04(m,1H),5.02( t,J=9.0Hz,1H),4.12(d,J=3.9Hz,1H),4.09(d,J=3.9Hz,2H),3.53(dd,J=12.5,4.6Hz,1H),3.42(t,J=11.9Hz, 1H),2.97(td,J=11.0,4.6Hz,1H),2.93–2.84(m,1H),2.68–2.59(m,1H),2.44–2.34(m,2H),2.33–2.26(m,2H), 2.25–2.15(m,3H),2.14–2.07(m,1H),2.04–1.96(m,1H),1.82(d,J=1.3Hz,3H),1.81–1.76(m,2H),1.58(s,3H).

[0202] ESI-MS m / z calculated value 435.2257, found value 436.3 (M+1) + and 434.6(M-1) - .

[0203] 1.15 Preparation of compound 16

[0204] At room temperature, the natural product Anisomelic acid (Compound 1) (66 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (1 mL), and then threonine (47.6 mg, 0.40 mmol, 2.0 eq) and triethylamine (60.7 mg, 0.60 mmol, 3.0 eq) were added. The mixture was stirred overnight at room temperature, and a saturated ammonium chloride solution (2 mL) was added to the system to separate the organic phase. The aqueous phase was extracted with dichloromethane (3×2 mL), and the combined organic phase was washed with saturated sodium chloride (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then dissolved in methanol (1 mL). The reverse phase preparation (0.1% TFA water and 0.1% TFA acetonitrile) was directly performed by HPLC, and the fraction was lyophilized overnight to obtain Compound 16 (64.7 mg, 72%).

[0205] 1 H NMR (600MHz, Methanol-d4) δ5.82 (dd, J=7.4, 5.9Hz, 1H), 5.30 (d, J=9.4Hz, 1H), 5.06 (t, J=5.7Hz, 1H), 5.01 (t, J = 9.0Hz, 1H), 4.22 (p, J = 6.4Hz, 1H), 3.89 (d, J = 6.2Hz, 1H), 3.51 (dd, J = 12.7, 4.8Hz, 1H),3.44(dd,J=12.6,11.2Hz,1H),3.01(td,J=10.9,4.8Hz,1H),2.93–2.80(m,1H),2.68–2.59(m ,1H),2.44–1.92(m,10H),1.82(s,3H),1.78(q,J=6.1Hz,2H),1.57(s,3H),1.42(d,J=6.4Hz,3H).

[0206] ESI-MS m / z calculated value 449.2414, found value 450.3 (M+1) + and 448.6(M-1) - .

[0207] 1.16 Preparation of compound 17

[0208] At room temperature, the natural product Anisomelic acid (Compound 1) (66 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (1 mL), and then L-lysine (35.1 mg, 0.24 mmol, 1.2 eq) and triethylamine (44.5 mg, 0.44 mmol, 2.2 eq) were added. The mixture was stirred overnight at room temperature, and a saturated ammonium chloride solution (2 mL) was added to the system to separate the organic phase. The aqueous phase was extracted with dichloromethane (3×2 mL), and the combined organic phase was washed with saturated sodium chloride (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then dissolved in methanol (1 mL). The reverse phase preparation (0.1% TFA water and 0.1% TFA acetonitrile) was directly performed by HPLC, and the fraction was lyophilized overnight to obtain Compound 17 (74.3 mg, 78%).

[0209] 1 H NMR (400MHz, Methanol-d4) δ5.81(t,J=6.6Hz,1H),5.27(d,J=9.0Hz,1H),4.99(dd,J=9.1,5.1Hz,2H),3.98(t,J=6.4Hz,1H),3.47–3.32( m,1H),3.13(dq,J=10.9,4.2,3.3Hz,1H),3.06–2.79(m,3H),2.69–2.55(m,1H),2.42–1.91(m,11H),1.85–1.69(m,8H),1.68–1.48(m,6H).

[0210] ESI-MS m / z calculated value 476.2886, found value 477.5 (M+1) + and 475.7(M-1) - .

[0211] 1.17 Preparation of compound 18

[0212] At room temperature, the natural product Anisomelic acid (Compound 1) (66 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (1 mL), and then aspartic acid (53.2 mg, 0.40 mmol, 2.0 eq) and triethylamine (101.2 mg, 1.0 mmol, 5.0 eq) were added. The mixture was stirred overnight at room temperature, and a saturated ammonium chloride solution (2 mL) was added to the system to separate the organic phase. The aqueous phase was extracted with dichloromethane (3×2 mL), and the combined organic phase was washed with saturated sodium chloride (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then dissolved in methanol (1 mL). The reverse phase preparation (0.1% TFA water and 0.1% TFA acetonitrile) was directly performed by HPLC, and the fraction was lyophilized overnight to obtain Compound 18 (66.7 mg, 72%).

[0213] 1 H NMR (600MHz, Methanol-d4) δ5.82(t,J=6.7Hz,1H),5.30(d,J=9.4Hz,1H),5.06(t,J=6.6Hz,1H),5.02(t,J=9.0Hz,1H),4.24(dd,J=6.4,4.3Hz,1H),3.5 5–3.46(m,2H),3.12(qd,J=18.4,5.3Hz,2H),2.99–2.82(m,2H),2.68–2.61( m,1H),2.44–1.96(m,10H),1.82(s,3H),1.79(q,J=6.2Hz,2H),1.58(s,3H).

[0214] ESI-MS m / z calculated value 463.2206, found value 464.3 (M+1) + and 462.6(M-1) - .

[0215] 1.18 Preparation of compound 19

[0216] At room temperature, the natural product Anisomelic acid (Compound 1) (66 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (1 mL), and then adenine (40.5 mg, 0.30 mmol, 1.5 eq) and triethylamine (50.6 mg, 0.50 mmol, 2.5 eq) were added. The mixture was stirred overnight at room temperature, and a saturated ammonium chloride solution (2 mL) was added to the system to separate the organic phase. The aqueous phase was extracted with dichloromethane (3×2 mL), and the combined organic phase was washed with saturated sodium chloride (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then dissolved in methanol (1 mL). The reverse phase preparation (0.1% TFA water and 0.1% TFA acetonitrile) was directly performed by HPLC, and the fraction was lyophilized overnight to obtain Compound 19 (33.5 mg, 36%).

[0217] 1 H NMR (400MHz, Methanol-d4) δ8.40(s,1H),8.31(s,1H),5.69(t,J=6.7Hz,1H),5.11(d,J=9.4Hz,1H),4.93(s,1H),4.62(qd,J=14.5,6.5Hz ,2H),3.13(dt,J=9.2,6.4Hz,1H),2.85–2.72(m,1H),2.71–2.58(m,1H),2.39–2.00(m,10H),1.77(s,3H),1.74–1.68(m,2H),1.46(s,3H).

[0218] ESI-MS m / z calculated value 465.2376, found value 466.4 (M+1) + and 464.7(M-1) - .

[0219] 1.19 Preparation of compound 20

[0220] At room temperature, the natural product Anisomelic acid (Compound 1) (66 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (1 mL), and then 6-mercaptopurine (monohydrate) (51.1 mg, 0.30 mmol, 1.5 eq) and triethylamine (50.6 mg, 0.50 mmol, 2.5 eq) were added. The mixture was stirred overnight at room temperature, and a saturated ammonium chloride solution (2 mL) was added to the system to separate the organic phase. The aqueous phase was extracted with dichloromethane (3×2 mL), and the combined organic phase was washed with saturated sodium chloride (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then dissolved in methanol (1 mL). The reverse phase preparation (0.1% TFA water and 0.1% TFA acetonitrile) was directly performed by HPLC, and the fraction was lyophilized overnight to obtain Compound 20 (63.7 mg, 66%).

[0221] 1 H NMR (400MHz, Methanol-d4) δ8.48(s,1H),8.15(s,1H),5.78(t,J=6.7Hz,1H),5.41(dd,J=13.8,7.3Hz,1H),5.25(d,J=9.6Hz,1H),4.96–4.92(m ,2H),3.35(t,J=7.8Hz,1H),2.74(q,J=6.2,5.6Hz,2H),2.45–2.07(m,8 H), 2.00 (t, J = 6.2Hz, 2H), 1.77 (s, 3H), 1.74–1.63 (m, 2H), 1.38 (s, 3H).

[0222] ESI-MS m / z calculated value 482.1988, found value 483.4 (M+1) + and 481.6(M-1) - .

[0223] 1.20 Preparation of compound 21

[0224] At room temperature, the natural product Anisomelic acid (Compound 1) (66 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (1 mL), and then cytosine (33.3 mg, 0.30 mmol, 1.5 eq) and triethylamine (50.6 mg, 0.50 mmol, 2.5 eq) were added. The mixture was stirred overnight at room temperature, and a saturated ammonium chloride solution (2 mL) was added to the system to separate the organic phase. The aqueous phase was extracted with dichloromethane (3×2 mL), and the combined organic phase was washed with saturated sodium chloride (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then dissolved in methanol (1 mL). The reverse phase preparation (0.1% TFA water and 0.1% TFA acetonitrile) was directly performed by HPLC, and the fraction was lyophilized overnight to obtain Compound 21 (37 mg, 42%).

[0225] 1 H NMR (400MHz, Methanol-d4) δ7.95 (d, J=7.7Hz, 1H), 6.04 (d, J=7.6Hz, 1H), 5.81 (t, J= 6.7Hz,1H),5.29(d,J=9.3Hz,1H),5.05(t,J=6.5Hz,1H),4.93(d,J=7.6Hz,1H),4.18( dd,J=14.0,4.8Hz,1H),3.99(dd,J=14.0,9.1Hz,1H),2.93(td,J=9.3,4.8Hz,1H),2.8 9–2.77(m,1H),2.73–2.59(m,1H),2.40–2.07(m,9H),1.87–1.74(m,5H),1.57(s,3H).

[0226] ESI-MS m / z calculated value 441.2264, found value 442.4 (M+1) + and 440.7(M-1) - .

[0227] 1.21 Preparation of compound 22

[0228] At room temperature, the natural product Anisomelic acid (Compound 1) (66 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (1 mL), and then 4-thiouracil (38.4 mg, 0.30 mmol, 1.5 eq) and triethylamine (50.6 mg, 0.50 mmol, 2.5 eq) were added. The mixture was stirred overnight at room temperature, and a saturated ammonium chloride solution (2 mL) was added to the system to separate the organic phase. The aqueous phase was extracted with dichloromethane (3×2 mL), and the combined organic phase was washed with saturated sodium chloride (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then dissolved in methanol (1 mL). The reverse phase preparation (0.1% TFA water and 0.1% TFA acetonitrile) was directly performed by HPLC, and the fraction was lyophilized overnight to obtain Compound 22 (59.6 mg, 65%).

[0229] 1 H NMR (400MHz, Methanol-d4) δ7.41(d,J=7.4Hz,1H),6.32(d,J=7.4Hz,1H),5.81(t,J=6.7Hz,1H),5.29(d,J=9.5Hz,1H),5.08–4.98(m,1H),4.93 (dd,J=9.5,6.8Hz,1H),4.11–3.91(m,2H),2.92(td,J=8.2,6.0Hz,1H), 2.79–2.70(m,2H),2.45–2.03(m,10H),1.82–1.71(m,5H),1.53(s,3H).

[0230] ESI-MS m / z calculated value 458.1875, found value 459.3 (M+1) + and 457.6(M-1) - .

[0231] 1.22 Preparation of compound 23

[0232] At room temperature, the natural product Anisomelic acid (Compound 1) (66 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (1 mL), and then 2-mercapto-6-hydroxypurine (50.5 mg, 0.30 mmol, 1.5 eq) and triethylamine (50.6 mg, 0.50 mmol, 2.5 eq) were added. The mixture was stirred overnight at room temperature, and a saturated ammonium chloride solution (2 mL) was added to the system to separate the organic phase. The aqueous phase was extracted with dichloromethane (3×2 mL), and the combined organic phases were washed with saturated sodium chloride (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then dissolved in methanol (1 mL). The reverse phase preparation (0.1% TFA water and 0.1% TFA acetonitrile) was directly performed by HPLC, and the fraction was lyophilized overnight to obtain Compound 23 (61.8 mg, 62%).

[0233] 1 H NMR (400MHz, Methanol-d4) δ8.39(s,1H),5.66(t,J=6.7Hz,1H),5.29(d,J=9.5Hz,1H),4.93(dd,J=9.5,7.1Hz,2H),3.83–3.67( m,2H),2.97(dt,J=8.9,5.7Hz,1H),2.71(q,J=6.3Hz,2H),2.38–2.01(m,8H),2.00–1.84(m,3H),1.82–1.64(m,5H),1.47(s,3H).

[0234] ESI-MS m / z calculated value 498.1937, found value 499.4 (M+1) + and 497.4(M-1) - .

[0235] 1.23 Preparation of compound 24

[0236] At room temperature, the natural product Anisomelic acid (Compound 1) (66 mg, 0.2 mmol, 1.0 eq) was dissolved in methanol (1 mL), and then L-cysteine ​​(29.1 mg, 0.24 mmol, 1.2 eq) and triethylamine (44.5 mg, 0.44 mmol, 2.2 eq) were added. The mixture was stirred overnight at room temperature, and a saturated ammonium chloride solution (2 mL) was added to the system to separate the organic phase. The aqueous phase was extracted with dichloromethane (3×2 mL), and the combined organic phase was washed with saturated sodium chloride (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and then dissolved in methanol (1 mL). The reverse phase preparation (0.1% TFA water and 0.1% TFA acetonitrile) was directly performed by HPLC, and the fraction was freeze-dried overnight to obtain Compound 4 (23.5 mg, 26%).

[0237] 1 H NMR (400MHz, DMSO-d6) δ12.34(s,2H),8.38(s,2H),5.57(dd,J=8.8,4.3Hz,1H),5.42 (d,J=10.0Hz,1H),4.96(dd,J=10.1,2.8Hz,1H),4.91(dd,J=9.1,4.9Hz,1H),4.22–4 .14(m,1H),3.27–3.19(m,1H),3.14–2.82(m,5H),2.70(dd,J=13.1,10.1Hz,1H),2.4 0–2.31(m,1H),2.27–2.00(m,7H),1.97–1.89(m,1H),1.80–1.60(m,5H),1.54(s,3H).

[0238] ESI-MS m / z calculated value 451.2029, found value 452.3 (M+1) + and 452.5(M-1) - .

[0239] Example 2

[0240] This example provides the use of each compound prepared in Example 1 above in the preparation of a drug that inhibits enterovirus EV-D68. Unless otherwise specified, the materials and consumables listed in this example can be obtained from commercial channels. Cells and viruses are from the cell and microbial resource library of ATCC or other relevant institutions, and plasmid vectors are from Addgene, independent construction or academic material exchange. The experimental method of this example is a standard molecular biology, cell biology or virology operating procedure, which can be easily understood and operated by researchers in the field. The specific steps are as follows:

[0241] Step 1: Experiment on the inhibitory effect of drugs on enterovirus EV-D68

[0242] Step 1.1: Normal RD cells were seeded in 6-well plates (8×10 5 / well), cultured overnight;

[0243] Step 1.2: When the cells grew to about 70% of the confluence, they were infected with enterovirus EV-D68 (MOI = 0.01) and cultured at 37°C. After 2 hours, the culture medium containing the virus was discarded, and culture medium containing different concentrations of drugs was added, and cultured at 37°C for 48 hours;

[0244] Step 1.3: Collect cells and verify by immunoblotting. The immunoblotting experiment used EV-D68 virus VP1 and Tubulin antibodies, horseradish peroxidase-conjugated mouse and rabbit secondary antibodies, and ECL color development substrate for color development.

[0245] The anti-EV-D68 activity of each drug is shown in Table 1.

[0246] Table 1 Anti-EV-D68 Virus Activity EC of Anisomelic Acid Derivatives 50 μM.

[0247] serial number <![CDATA[EC 50 ]]> 1 + 2 + 3 ++ 4 +++ 5 +++ 6 ++ 7 ++ 8 ++ 9 No 10 + 11 No 12 No 13 No 14 No 15 + 16 ++ 17 No 18 + 19 ++ 20 + 21 No 22 +++ 23 ++ 24 +++

[0248] In Table 1, "+++" means <1 μM, "++" means 1-10 μM; "+" means 10-100 μM, and "No" means <100 μM showed no activity.

[0249] Example 3

[0250] This example shows the detection process and results of the inhibition of enterovirus EV-D68 replication in cells by compound 4 (AA-Cys) prepared in Example 1. The materials and consumables listed in this example can be obtained from commercial channels unless otherwise specified. Cells and viruses are from the cell and microbial resource library of ATCC or other relevant institutions, and plasmid vectors are from Addgene, independent construction or academic material exchange. The experimental method of this example is a standard molecular biology, cell biology or virology operating procedure, which can be easily understood and operated by researchers in the field. The specific steps are as follows:

[0251] Step 1: Toxicity test of compound 4 (AA-Cys) on RD cells

[0252] Step 1.1. Normal RD cells (from ATCC, CCL-136) were counted and seeded in 96-well plates (2×10 4 pcs / hole);

[0253] Step 1.2, the next day, the compound 4 (AA-Cys) stock solution was diluted with cell culture medium to prepare different concentration gradients (0.01, 0.1, 1, 10, 100, 200, 400, 800 μM), and 100 μl was added to the cell culture wells from which the supernatant was discarded. Three replicate wells were set up for each concentration, and a control well without drug addition was set up at the same time, and cultured at 37°C;

[0254] Step 1.3: After 48 hours, add 10 μl of CCK-8 detection reagent (Biyuntian) and continue to culture for 1.5-2 hours;

[0255] Step 1.4, select 450nm wavelength, detect the light absorption value of each well on the enzyme-linked immunosorbent assay reader, record the results, and calculate the cell survival rate.

[0256] The results are as follows Figure 7 As shown, Figure 7 In the figure, the horizontal axis represents the logarithmic value of the concentration of compound 4 (AA-Cys), and the vertical axis represents the inhibition rate percentage of enterovirus D68 (Enterovirus D68, referred to as EV-D68). Figure 7 It can be seen that compound 4 (AA-Cys) has a CC 50 >400μM.

[0257] Step 2: Inhibitory effect of compound 4 (AA-Cys) on enterovirus EV-D68

[0258] Step 2.1: Normal RD cells were seeded in 6-well plates (8×10 5 / well), cultured overnight;

[0259] Step 2.2: When the cells grew to about 70% of the total mass, they were infected with enterovirus EV-D68 (MOI = 0.01) and cultured at 37°C. After 2 hours, the culture medium containing the virus was discarded, and culture medium containing different concentrations (0 nM, 1 nM, 10 nM, 100 nM and 1000 nM) of compound 4 (AA-Cys) was added, recorded as experimental groups with different concentrations of compound 4 (AA-Cys), and cultured at 37°C for 48 hours;

[0260] Step 2.3: Collect cells and verify by immunoblotting. The immunoblotting experiment used EV-D68 virus VP1 and Tubulin antibodies (respectively denoted as Anti-EVD68-VP1 and Anti-Tubulin), horseradish peroxidase-conjugated mouse secondary antibody and rabbit secondary antibody, and ECL color development substrate for color development.

[0261] The results are as follows Figure 8 As shown, Figure 8In the table, AA-Cys (nM) represents the experimental groups to which different concentrations of compound 4 (AA-Cys) were added, and the unit is nM; Anti-EVD68-VP1 is the antibody expression level of the VP1 protein of the EV-D68 virus in each experimental group (the imprint of the target protein); Anti-Tubulin is the antibody of the internal reference protein in each experimental group. Figure 8 It can be seen that compound 4 (AA-Cys) has an inhibitory effect on the infection of enterovirus EV-D68, and the inhibitory effect increases with the increase of the dose of compound 4 (AA-Cys).

[0262] Example 4: Compound 4 (AA-Cys) has a protective effect on newborn mice infected with enterovirus EV-D68

[0263] In order to further explore whether compound 4 (AA-Cys) can affect the survival rate of newborn mice infected with EV-D68 and the symptoms after infection, the present invention carried out animal experiments.

[0264] The antiviral effect of compound 4 (AA-Cys) was evaluated using the EV-D68 neonatal mouse infection model. Male and female mice were mated to obtain neonatal mice. On the first day after birth, the mice were divided into three groups (10 mice in each group), namely, a negative control group (DMEM, 10 μL / mouse), an EV-D68 infection group (10 5.5 TCID 50 mL -1 EV-D68, 10 μL / mouse), EV-D68+Compound 4 (AA-Cys) treatment group (Compound 4 (AA-Cys), 3 mg / kg and 10 5.5 TCID 50 mL -1 EV-D68, 10 μL / mouse), EV-D68 virus was injected intracranially into the suckling mice on day 0, and compound 4 (AA-Cys) was injected intraperitoneally into the suckling mice on days 0, 2, 4, 6, and 8. After injection, the clinical symptoms of the newborn mice were observed and monitored for 10 days.

[0265] The experimental results are as follows Fig. 9 , Fig. 9 A is a line graph of days after infection (days) and body weight (g) of mice in different groups, and B is a line graph of days after infection (days) and survival percentage (%) of mice in different groups; Fig. 9It can be found that the negative control group was healthy within 10 days. The suckling mice in the EV-D68 infection group began to die on the 3rd day, all showed symptoms of front and rear limb paralysis on the 4th day, most of them were on the verge of death, all died on the 5th day, and the survival rate within 5 days was 0%. In the EV-D68+Compound 4 (AA-Cys) treatment group, on the 8th day, 2 mice began to show mild symptoms of front and rear limb paralysis, and 1 died. The survival rate within 7 days was 100%, and the survival rate within 10 days was 90%. The experimental results show that Compound 4 (AA-Cys) can alleviate the clinical symptoms of EV-D68 infected mice, protect mice from lethal damage caused by EV-D68 infection, and increase the survival rate of EV-D68 infected mice.

[0266] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0267] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A compound having a structure as shown in formula (I), or a pharmaceutically acceptable salt, stereoisomer or solvate thereof: X1 is O, S, NR2 or CR3R4; R1, R2, R3 and R4 are independently H, OH, NH2, COOH, substituted or unsubstituted C 1～10 Alkyl, substituted or unsubstituted C 1～10 Alkoxy, substituted or unsubstituted C 3～20 Cycloalkyl, substituted or unsubstituted C 5～20 Heterocycloalkyl, substituted or unsubstituted C 5～30 Aryl, substituted or unsubstituted C 5～30 Heteroaryl, R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are independently H, OH, NH2, COOH, substituted or unsubstituted C 1～10 alkyl, R 21 and R 22 are independently H, OH, NH2, COOH, substituted or unsubstituted C 1～10 Alkyl or R 31 , R 32 and R 33 are independently H, OH, NH2, COOH or substituted or unsubstituted C 1～10 alkyl; Y1, Y2 and Y3 are each independently absent or (CH2) n ; n is an integer selected from 1-10.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, characterized in that: R1 is OH, NH2, COOH, substituted or unsubstituted C 1～10 Alkyl, substituted or unsubstituted C 1～10 Alkoxy, substituted or unsubstituted C 3～20 Cycloalkyl, substituted or unsubstituted C 5～20 Heterocycloalkyl, substituted or unsubstituted C 5～30 Aryl, substituted or unsubstituted C 5～30 Heteroaryl.

3. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, characterized in that: R1 and R2 are independently H or R 11 , R 12 and R 13 are independently H, COOH, R 21 and R 22 are independently COOH, substituted or unsubstituted C 1～10 Alkyl or 4. The compound according to claim 2, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, characterized in that: Y1 does not exist or is (CH2) n1 ; Y2 does not exist or is (CH2) n2 ; Y3 does not exist or is (CH2) n3 ; n1, n2 and n3 are each independently selected from integers of 1-10.

5. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, characterized in that: R1 and R2 are independently H, R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are independently H, OH, NH2, COOH or substituted or unsubstituted C 1～10 alkyl.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, characterized in that: R1 is substituted or unsubstituted C 5～6 Heterocycloalkyl, further, R1 is selected from or R1 is substituted or unsubstituted C 6～10 Aryl or C 5～10 Heteroaryl, further, R1 is selected from or R1 is Further, R1 is selected from or R1 is Further, R1 is selected from q1, q2, q3, q4, q5 and q6 are independently selected from 0, 1, 2, 3 or 4; R a1 and R a2 are independently H or C 1-3 alkyl.

7. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, characterized in that: X1 is S or NR2, Furthermore, R2 is H.

8. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, characterized in that: R1, R2, R3 and R4 are independently H, OH, NH2, COOH, substituted or unsubstituted C 1～10 Alkyl, substituted or unsubstituted C 3～20 Cycloalkyl, substituted or unsubstituted C 5～30 The aromatic group Furthermore, R 13 is COOH.

9. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, characterized in that: Substituted or unsubstituted C 1～10 Substitution in alkyl refers to C 1～10 At least one hydrogen atom in the alkyl group is replaced by R b1 replace; Substituted or unsubstituted C 1～10 Substitution in the alkoxy group refers to C 1～10 At least one hydrogen atom in the alkoxy group is replaced by R b2 replace; Substituted or unsubstituted C 3～20 Substitution in cycloalkyl refers to C 3～20 At least one hydrogen atom in the cycloalkyl group is replaced by R b3 replace; Substituted or unsubstituted C 5～30 The substitution of the aromatic ring refers to C 5～30 At least one hydrogen atom in the aromatic ring is replaced by R b4 replace; R b1 , R b2 , R b3 and R b4 Each occurrence is independently selected from CN, OH, COOH, NO2, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, NR c1 R c2 、C(=O)NR c3 R c4 、C(=O)OC 1-6 Alkyl, -CHO, OC(=O)C 1-6 Alkyl and S(=O)(=O)C 1-6 At least one of the alkyl groups; R c1 , R c2 , R c3 and R c4 are independently H or C 1-3 alkyl.

10. The compound according to any one of claims 1 to 5, characterized in that It has a structure as shown in formula (I-1):

11. A method for preparing a compound according to any one of claims 1 to 10, characterized in that: The following steps are involved: Reacting compound 1 with compound R1-Y1-X1-H to obtain the compound represented by formula (I); wherein R1, Y1 and X1 are as defined in any one of claims 1-10.

12. A pharmaceutical composition, characterized in that The invention comprises at least one of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, stereoisomer or solvate thereof, and a pharmaceutically acceptable excipient.

13. Use of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, stereoisomer or solvate thereof in the preparation of an antiviral drug.

14. Use of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, stereoisomer or solvate thereof in the preparation of an anticancer drug; further, the cancer includes cancer caused by a virus; further, the cancer includes cervical cancer caused by human papillomavirus.

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