Compounds that mimic RNA structures, their preparation methods, and pharmaceutical applications

Abstract

This invention belongs to the field of medicinal chemistry and discloses a compound with a mimicking RNA structure represented by Formula I, its preparation method, and its pharmaceutical use in the preparation of antiviral drugs. Formula I

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to a compound that mimics the structure of RNA, its preparation method, and its pharmaceutical uses. Background Technology

[0002] The concept of liquid-liquid phase separation (LLPS) can be traced back to the late 19th century when Wilson et al. observed the phenomenon of "protoplasmic phase separation" during cell division. However, modern research only made a breakthrough in 2009 when Brangwynne et al. discovered that the dynamic behavior of P granules in Caenorhabditis elegans embryos conformed to droplet fusion characteristics, providing the earliest and most convincing evidence that LLPS plays a crucial role in tissue and cell structure. Phase-separation-based partitioning driven by multivalent interactions provides a mechanism for the formation of highly dynamic, reversible, membrane-free organelles. Subsequently, this principle was applied to antiviral research, leading to new strategies for regulating viral protein phase separation. Following this, numerous studies have revealed the universality of phase separation in gene expression regulation, chromatin organization, and signal transduction.

[0003] Recent research indicates that LLPS viruses play a crucial role in their life cycle. For example, during the influenza virus's invasion and uncoating phase, it utilizes the host's LLPS-related protein dissociation pathway: ubiquitin chains on the capsid are recognized by HDAC6, generating mechanical force through the host aggregate processing mechanism, causing the capsid to dissociate and release vRNPs; subsequently, the vRNPs bind to the LLPS regulator TNPO1, causing the matrix protein M1 carrying a PY-NLS-like motif to detach, ultimately allowing the dissociated vRNPs to enter the nucleus and initiate viral genome replication. Similarly, during viral replication, after the viral genome enters the cytoplasm or nucleus, it relies on various host factors for replication. Many RNA viruses depend on cytoplasmic compartmentalization to promote genome synthesis and replication, inducing the formation of membraneless organelles. These high-density structures maximize viral RNA transcription efficiency by concentrating the required RNA and protein components. Stress granules (SGs) are membraneless organelles formed in the cytoplasm through liquid-liquid phase separation; their main components are polyadenylated mRNA and various RNA-binding proteins, and their composition varies greatly depending on cell type and inducing factors. Viral infection-induced stress particles are formed through activation of dsRNA-dependent protein kinase (PKR). PKR phosphorylates the eukaryotic translation initiation factor eIF2α to inhibit translation, temporally blocking viral replication. Therefore, many viruses have evolved strategies to interfere with stress particles, such as isolating stress particle proteins at viral replication sites. West Nile virus prevents stress particle assembly while simultaneously promoting RNA synthesis. This suggests that LLPS-based strategies, while enhancing viral replication, are often intertwined with evading the host's innate immune response. Vaccine virus isolates stress particle components within its DNA replication factory, blocking the host response and assisting in coordinating transcription and translation. Furthermore, during viral assembly, after replication, the viral genome is packaged into viral particles and released. RNA viruses typically utilize membraneless organelles for capsid assembly. Inclusion bodies mediate genome packaging through RNA sequence and structure specificity by co-localizing viral RNA with the N protein. SARS-CoV-2 can induce viral particle assembly through inclusion body hardening. The fluidity of condensates is regulated by the phosphorylation state of the SR-enriched region of the N protein: high phosphorylation produces liquid condensates that promote transcription, while low phosphorylation increases condensate density to achieve RNA packaging. This phenomenon indicates that agglomerate mobility is crucial in inducing a switch between viral transcription and genome packaging, revealing that mutations at potential phosphorylation sites of the N protein can alter viral fitness, infectivity, and virulence. The LLPS mechanism of influenza virus ensures the complete packaging of genome segments. The aggregation of influenza virus vRNPs is mediated by phase-separated inclusion bodies, which promote the assembly of the genome core complex by increasing the concentration of vRNPs at specific sites. Common types of vRNPs are competitively packaged into viral particles.Finally, in the viral budding stage, the budding of enveloped viruses from host cells marks the final stage of the viral life cycle, during which the viral core acquires an outer lipid envelope derived from the host cell membrane. However, the composition of the viral envelope differs significantly from that of the cell membrane, a result of active remodeling at the viral assembly site, a process that also relies on LLPS (Liquid Liquid Phase Sorting). For example, HIV employs an active sorting strategy to increase local membrane curvature and selectively enrich specific host proteins and lipids. Envelope composition is crucial for viral adaptability, influencing survival and infectivity. Sorting is mediated by the viral Ga protein. At the assembly site, Ga protein polymerizes with lipid molecules, increasing cholesterol and sphingomyelin concentrations to form a liquid-ordered (Lo) lipid phase. Acyl chain proteins, due to their higher affinity for the Lo phase, are enriched into the viral envelope, while proteins that prefer the lipid-disordered phase are actively rejected. Therefore, proteins with dual-membrane anchoring exhibit opposite lipid phase preferences, demonstrating temporal sorting behavior and accumulating only in the late stages of assembly.

[0004] Meanwhile, LLPS also play an important role in viral innate immune sensing and escape. Inclusion bodies formed by LLPS are frequently used to evade the innate immune system and bypass antiviral defense pathways. For example, inclusion bodies can protect viral nucleic acids from recognition by nucleic acid sensors; this strategy is widespread in Nipah virus, respiratory syncytial virus, measles virus, and SARS-CoV-2. The size of measles virus inclusion bodies is regulated by the phosphorylation level of the P protein and is a crucial factor determining viral replication efficiency. Larger inclusion bodies and more pronounced gelation state are more effective at evading immune system recognition, thereby promoting viral replication. SARS-CoV-2's N protein localizes to stress particles and isolates G3BP1 / 2, weakening the stress response and preventing stress particle generation and innate immune activation. Respiratory syncytial virus (RSV) inclusion bodies isolate OGT and phosphorylated p38 MAPK, inhibiting stress particle assembly and NF-κB signaling. The N protein of respiratory syncytial virus (RSV) can isolate the pattern recognition receptor MDA5 and its downstream adaptor protein MAVS into viral inclusion bodies, thereby blocking their interaction and signal transduction, and ultimately weakening the interferon-mediated innate immune response. In the late stage of RSV infection, the viral polymerase switches from transcription to replication and triggers the formation of stress granules, indicating that RSV promotes its own replication by means of stress granules at a specific stage of its life cycle.

[0005] In summary, LLPS (Limited Limiting PS) mediated by the interaction of virus-associated proteins and RNA is a common mechanism for replication in various RNA viruses. Inhibiting viral LLPS can disrupt the formation of viral replication factories and block viral proliferation. Furthermore, targeting LLPS is independent of viral enzyme active sites, making it difficult for viruses to escape through single-point mutations, thus creating a high resistance barrier. Therefore, intervening in viral LLPS is an ideal broad-spectrum antiviral strategy. Currently, researchers have discovered some antiviral compounds by screening for inhibition of viral disordered proteins and RNA LLPS, mainly including small molecule compounds, peptides, and nucleic acid analogs. However, how to rationally design compounds to inhibit viral disordered proteins and RNA LLPS remains to be explored. Summary of the Invention

[0006] This invention utilizes natural polyphenol building blocks to construct compounds that mimic the structure of RNA, thereby inhibiting the liquid-liquid phase separation of viral proteins and RNA, and thus designing compounds with antiviral activity.

[0007] According to one aspect of the invention, an object of the invention is to provide a compound representing a structure mimicking RNA, and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers, and solvates thereof:

[0008] Formula I Wherein, A is a linking group, which can chemically connect to the skeletal building blocks of gallic acid, selected from substituted or unsubstituted C4-C10 cycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 5- to 20-membered heteroaryl containing 1-3 heteroatoms selected from N, O, and S, substituted or unsubstituted 5- to 10-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O, and S, substituted or unsubstituted C4-C10 cycloalkyl, C1-C6 alkyl, substituted... The alkyl group may be an unsubstituted C6-C20 aryl C1-C6 alkyl group, a substituted or unsubstituted 5- to 14-membered heteroaryl C1-C6 alkyl group containing 1-3 heteroatoms selected from N, O, and S, or a substituted or unsubstituted 5- to 10-membered heterocyclic alkyl C1-C6 alkyl group containing 1-3 heteroatoms selected from N, O, and S, wherein “substituted” means having 1 to 3 substituents, each independently selected from hydroxyl, amino, nitro, halogen atom, C1-C6 alkyl, or C1-C6 alkoxy. n is an integer selected from 1 to 3; M and W are each independently selected from oxygen or nitrogen atoms; R is selected from hydrogen atom, C1-C6 alkyl acyl, C6-C10 aryl acyl, C3-C8 cycloalkyl acyl, C3-C8 cycloalkylC1-C6 alkyl acyl, or 5- to 10-membered heteroaryl acyl with 1-3 heteroatoms selected from N, O, and S. Its function is to form a prodrug with phenolic hydroxyl groups, thereby improving the membrane permeability and environmental stability of the molecule.

[0009] Preferably, A is a linking group selected from substituted or unsubstituted C6-C10 cycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 6- to 20-membered heteroaryl containing one or two heteroatoms selected from N and O, substituted or unsubstituted 5- to 10-membered heterocycloalkyl containing one or two heteroatoms selected from N and O, substituted or unsubstituted C6-C10 cycloalkyl C1-C3 alkyl, substituted or unsubstituted C6-C20 aryl C1-C3 alkyl, substituted or unsubstituted 5- to 14-membered heteroaryl C1-C3 alkyl containing one or two heteroatoms selected from N and O, and substituted or unsubstituted 5- to 10-membered heterocycloalkyl C1-C3 alkyl containing one or two heteroatoms selected from N and O. The term "substituted" refers to the presence of one to three substituents, each independently selected from hydroxyl and C1-C3 alkoxy groups.

[0010] More preferably, A is a linking group selected from substituted or unsubstituted C6-C8 cycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 6- to 18-membered heteroaryl containing one or two heteroatoms selected from N and O, substituted or unsubstituted 5- to 10-membered heterocycloalkyl containing one or two heteroatoms selected from N and O, substituted or unsubstituted C6-C10 cycloalkyl C1-C2alkyl, substituted or unsubstituted C6-C20 aryl C1-C2alkyl, substituted or unsubstituted 5- to 14-membered heteroaryl C1-C2alkyl containing one or two heteroatoms selected from N and O, and substituted or unsubstituted 5- to 10-membered heterocycloalkyl C1-C2alkyl containing one or two heteroatoms selected from N and O. The term "substituted" refers to the presence of one to three substituents, each independently selected from hydroxyl, methoxy, ethoxy, and propoxy.

[0011] More preferably, A is selected from the following structures, where * represents the connection position of W or M: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; .

[0012] Preferably, n is an integer selected from 1 or 2.

[0013] Preferably, R is selected from hydrogen atom, C1-C6 alkyl acyl, C6-C10 aryl acyl, C4-C6 cycloalkyl acyl, C4-C6 cycloalkylC1-C3 alkyl acyl, and 5- to 8-membered heteroaryl acyl with one or two heteroatoms selected from N and O; Preferably, R is selected from hydrogen atom, C1-C6 alkyl acyl, phenyl acyl, C5-C6 cycloalkyl acyl, C5-C6 cycloalkylC1-C2 alkyl acyl, and 5- to 6-membered heteroaryl acyl with one or two heteroatoms selected from N and O; Preferably, R is selected from acetyl, propionyl, isopropionyl, cyclopropionyl, cyclobutylmethyl, butyryl, isobutyryl, valeryl, cyclopentanoyl, hexanoyl, cyclohexanoyl, benzoyl, pyridine-2-acyl, pyridine-3-acyl, and pyridine-4-acyl.

[0014] Furthermore, the compounds of the RNA-mimicking structure represented by Formula I according to the present invention, and their pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers, and solvates, are preferably derived from the compounds in the following examples: .

[0015] According to another aspect of the invention, another object of the invention is to provide a method for synthesizing compounds of formula I that mimic RNA structures, as well as pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers, and solvates thereof, via the following synthetic route:

[0016] 1) Gallic acid is first reacted with acyl chloride (R-Cl) to prepare intermediate 1; 2) Intermediate 1 and M n -AW reaction to form an ester or amide, yielding the compound shown in Formula I; the method for forming the ester or amide can be to prepare an acyl chloride from intermediate 1, and then react with M. n -AW reaction; it can also be intermediate 1 and M. n-AW undergoes condensation in the presence of condensing agents, including N,N-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), O-benzotriazole-tetramethylurea hexafluorophosphate (HBTU), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), etc.

[0017] According to another aspect of the invention, the invention provides a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of a compound of the invention represented by Formula I with a mimicking RNA structure, and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers, and solvates thereof, as well as pharmaceutically acceptable excipients.

[0018] According to another aspect of the invention, another object of the invention is to provide the use of compounds representing RNA-mimicking structures of Formula I, and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers, and solvates thereof, or said pharmaceutical compositions, in the preparation of antiviral drugs.

[0019] Preferably, the virus includes RNA viruses such as influenza virus, coronavirus, respiratory syncytial virus, and herpes simplex virus (VSV).

[0020] According to another aspect of the invention, another object of the invention is to provide an antiviral method comprising administering to a patient in need a therapeutically effective amount of a compound of the invention represented by Formula I that mimics an RNA structure, and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers, and solvates, or said pharmaceutical compositions thereof. Attached Figure Description

[0021] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0022] Figures 1a to 1r The results of the cytotoxicity experiment were used to test the compounds in Example 1.

[0023] Figures 2a to 2l The test results were used to evaluate the anti-PR8 virus activity of the compounds in Example 2.

[0024] Figures 3a to 3lThe test results were used to evaluate the anti-VSV virus activity of the compounds in Example 3.

[0025] Figures 4a to 4c The test results of the phase separation inhibition experiment of the compound in Example 4 were used to test the results. Detailed Implementation

[0026] The present invention will now be described in detail. Before proceeding with the description, it should be understood that the terminology used in this specification and the appended claims should not be construed as limited to its general or dictionary meaning, but rather should be interpreted according to the meaning and concept corresponding to the technical aspects of the invention, based on the principle that the inventors are allowed to appropriately define the terms for the best interpretation. Therefore, the description presented herein is merely a preferred example for illustrative purposes and is not intended to limit the scope of the invention. It should be understood that other equivalents or modifications can be obtained from it without departing from the spirit and scope of the invention.

[0027] In this document, the terms “comprising,” “including,” “having,” “containing,” or any other similar terms are open-ended conjunctions intended to cover non-exclusive inclusions. For example, a composition or article containing a plurality of elements is not limited to those listed herein, but may also include other elements not explicitly listed but typically inherent to the composition or article. Furthermore, unless explicitly stated to the contrary, the term “or” is inclusive, not exclusive. For example, the condition “A or B” is satisfied in any of the following cases: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); A and B are both true (or exist). Moreover, in this document, the terms “comprising,” “including,” “having,” and “containing” should be interpreted as specifically disclosed and simultaneously cover closed or semi-closed conjunctions such as “composed of” and “substantially composed of.”

[0028] In this document, all features or conditions defined in the form of numerical ranges or percentage ranges are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible secondary ranges and individual values ​​within those ranges, particularly integer values. For example, a range description of "1 to 8" should be considered as specifically disclosing all secondary ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly secondary ranges defined by all integer values, and should be considered as specifically disclosing individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, 8, etc. Unless otherwise specified, the foregoing interpretation applies to all content throughout this invention, regardless of its scope.

[0029] If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that this document has specifically disclosed all ranges consisting of any upper or preferred value of that range and the lower or preferred value of that range, regardless of whether such ranges are separately disclosed. Furthermore, when a range of numerical values ​​is mentioned herein, unless otherwise stated, the range shall include its endpoints and all integers and fractions within the range.

[0030] In this document, numerical values ​​are to be understood as having a precision with significant digits, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover a range from 39.50 to 40.49.

[0031] In this document, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that subgroups of all elements within a Markush group or option list, or any individual element, can also be used to describe the invention. For example, if X is described as "selected from the group consisting of X1, X2, and X3," it also indicates that the claim that X is X1 and the claim that X is X1 and / or X2 have been fully described. Furthermore, when Markush groups or alternative terms are used to describe features or examples of the invention, those skilled in the art should understand that any combination of subgroups of all elements within a Markush group or option list, or any combination of individual elements, can also be used to describe the invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2, and X3," and Y is described as "selected from the group consisting of Y1, Y2, and Y3," it indicates that the claim that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 has been fully described.

[0032] definition As used herein, “compounds of the present invention” refers to amide compounds represented by Formula 1 and their pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers and solvates.

[0033] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 8 carbon atoms ("C..."). 1-8 Alkyl group). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C6”). 1-6 Alkyl group). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C1”). 1-5 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C”). 1-4 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C”). 1-3 Alkyl group (“alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C”). 1-2Alkyl group (“C1 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C1 alkyl”). 2-6 Alkyl group). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl), and hexyl (C6) (e.g., n-hexyl). Further examples of alkyl groups include n-heptyl (C7), etc.

[0034] "Alkoxy" indicates the unit valence. O Alkyl group, wherein the alkyl moiety has a specified number of carbon atoms. In this disclosure, the alkoxy group typically contains 1... 6 carbon atoms (“C 1-6 Alkoxy groups, such as methoxy, ethoxy, isopropoxy, tert-butyloxy, etc.

[0035] "Cycloalkyl" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C"). 3-10 A group consisting of a cycloalkyl group and a non-aromatic cycloalkyl group with zero heteroatoms. An example C 3-6 Cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. As shown in the foregoing examples, in some embodiments, the cycloalkyl group is a monocyclic (“monocyclic cycloalkyl”) or contains a fused ring, bridged ring, or spirocyclic system, such as a bicyclic system (“bicyclic cycloalkyl”), and may be saturated or may be partially unsaturated. “Cycloalkyl” also includes ring systems in which the cycloalkyl group as defined above is fused with one or more aryl or heteroaryl groups at the junction point on the carbon ring, and in this case, the carbon number continues to refer to the number of carbons in the carbon ring system. Unless otherwise stated, each instance of a cycloalkyl group is optionally substituted independently, i.e., unsubstituted or substituted by one or more substituents.

[0036] "Heterocyclic alkyl" refers to a group having a four- to eight-membered non-aromatic ring system having a ring carbon atom and one to three ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("four- to eight-membered heterocyclic group"). In heterocyclic groups containing one or more nitrogen atoms, the linkage can be a carbon atom or a nitrogen atom, provided that the valence allows. Heterocyclic alkyl can be monocyclic ("monocyclic heterocyclic alkyl group") or fused, bridged, or spirocyclic, such as bicyclic ("bicyclic heterocyclic alkyl"), and can be saturated or partially unsaturated. Heterocyclic bicyclic systems can contain one or more heteroatoms in one or both rings. "Heterocyclic alkyl" also includes ring systems in which the linkage of a heterocycle as defined above with one or more carbocyclic groups is on the carbocyclic group or the heterocycle, or ring systems in which the linkage of a heterocycle as defined above with one or more aryl or heteroaryl groups is on the heterocycle, and in this case, the number of ring members continues to refer to the number of ring members in the heterocyclic system.

[0037] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system. 6-14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has 6 ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms (“C”). 14 "Aryl" (e.g., anthracene). "Aryl" also includes ring systems in which the aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the groups or linkages are on the aromatic ring, and in this case, the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system.

[0038] "Heteroaryl" refers to a group having a five- to eight-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 π electrons shared in a cyclic array) having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("five- to eight-membered heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the linkage can be a carbon atom or a nitrogen atom, provided the valence allows. Heteroaryl bicyclic systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes a ring system in which the heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the linkage is on the heteroaryl ring, and in this case, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes a ring system in which a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the connection point is on the aryl or heteroaryl ring, and in this case, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system.

[0039] The invention includes all possible geometric isomers of compounds within its scope, such as Z and E isomers (cis and trans isomers), and all possible optical isomers of the compounds of the invention, such as diastereomers and enantiomers. Additionally, the invention includes individual isomers and any mixtures thereof within its scope, such as racemic mixtures. Individual isomers can be obtained using the corresponding isomer form of the starting material, or they can be separated according to conventional separation methods after the preparation of the final compound. For the separation of optical isomers, such as enantiomers, from mixtures thereof, conventional resolution methods, such as stepwise crystallization or preparative chiral chromatography, can be applied.

[0040] The invention includes all possible solvates of compounds within its scope, wherein the solvent in "solvate" includes Class III solvents as defined in the pharmacopoeia and mixtures of Class III solvents and water: pentane, formic acid, acetic acid, diethyl ether, acetone, anisole, 1-propanol, 2-propanol, 1-butanol, 2-butanol, pentanol, butyl acetate, tributylmethyl ethyl ether, isopropyl acetate, methyl ethyl ketone, dimethyl sulfoxide, isopropylbenzene, ethyl acetate, ethyl formate, isobutyl acetate, methyl acetate, 3-methyl-1-butanol, methyl isobutyl ketone, 2-methyl-1-propanol, propyl acetate. The compounds of the present invention, or pharmaceutically acceptable salts thereof, may exist as hydrates, solvates, or prodrugs. Therefore, hydrates, solvates, or prodrugs of the compounds of the present invention, or pharmaceutically acceptable salts thereof, are also included within the scope of the present invention.

[0041] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0042] The term "pharmaceuticalally acceptable excipient" refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention, without interfering with the biological activity of the active substance, and without toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, transdermal penetration enhancers, etc. Their formulations are well known to those skilled in the art of cosmetics or topical pharmaceuticals.

[0043] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts (i.e., pharmaceutically acceptable salts) can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples include inorganic acid salts and organic acid salts, wherein the inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and the organic acids include, for example, benzoic acid, 2-hydroxyethanesulfonic acid, aminosulfonic acid, benzenesulfonic acid, phenylacetic acid, mandelic acid, etc. Malonic acid, propionic acid, oxalic acid, p-aminobenzenesulfonic acid, p-toluenesulfonic acid, polygalacturonic acid, fumaric acid, pantothenic acid, fumaric acid, glutamic acid, succinic acid, methanesulfonic acid, tartaric acid, ascorbic acid, phthalic acid, maleic acid, citric acid, malic acid, glucohepose, gluconic acid, ethanesulfonic acid, lactic acid, lactose, dodecyl sulfonic acid, dihydroxynaphthyl acid, salicylic acid, succinic acid, phosphorous acid, etc.; acetic acid, edetate, glycolic acid, acetic acid, ethanesulfonic acid, isobutyric acid, stearic acid, and similar acids; also including salts of amino acids (such as arginine), and salts of organic acids such as glucuronic acid. Certain specific compounds of this invention contain basic and acidic functional groups, thus they can be converted into any base or acid addition salt. The parent form of the compound differs from its various salt forms in certain physical properties, such as different solubilities in polar solvents.

[0044] A typical formulation is prepared by mixing the compound represented by formula (I) of the present invention with excipients, diluents or excipients. Suitable carriers, diluents or excipients are well known to those skilled in the art and include substances such as carbohydrates, waxes, water-soluble and / or expandable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water and the like.

[0045] The specific excipients, diluents, or excipients used will depend on the manner and purpose of use of the compound according to the invention. Solvents are generally selected based on those deemed safe and effective for administration to mammals by those skilled in the art. Generally, safe solvents are non-toxic aqueous solvents such as water, as well as other non-toxic solvents that are soluble in or miscible with water. Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (such as PEG400, PEG300), etc. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavorings, or other known additives to manufacture or use the drug in an acceptable form.

[0046] These pharmaceutical compositions may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavorings, or other known additives to make or use the pharmaceutical composition in an acceptable form.

[0047] The term "treatment" refers to reversing, alleviating, delaying the onset of the disease described herein, or inhibiting its development. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to susceptible subjects before the onset of symptoms (e.g., based on a history of symptoms and / or based on exposure to a pathogen) to delay or prevent the occurrence of the disease. Treatment may also continue after symptoms have subsided, for example, to delay or prevent recurrence.

[0048] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the quantity required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0049] The term "substituted" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, which can include deuterium and hydrogen variants, provided that the valence state of the specific atom is normal and the substituted compound is stable. When the substituent is a ketone group (i.e., =O), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on aromatic groups.

[0050] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0051] The following embodiments are merely examples illustrating implementations of the present invention and do not constitute any limitation on the present invention. Those skilled in the art will understand that modifications made without departing from the spirit and concept of the present invention fall within the protection scope of the present invention. Unless otherwise specified, the reagents and instruments used in the following embodiments are commercially available products.

[0052] Example Unless otherwise specified, the experimental methods described in the following examples are conventional methods.

[0053] Unless otherwise specified, all materials and reagents used in the following examples are commercially available. ¹H-NMR and ¹³C-NMR measurements were performed using an LSI-IST / JNM-ECA400 NMR spectrometer, with TMS as an internal standard. Coupling constants (J) were recorded in Hz. Electrospray ionization mass spectrometry (ESI-MS) was performed on an LSI-IST-003 / G6230A ion trap mass spectrometer. GF254 fluorescent plates were used for thin-layer chromatography. All chemical reagents used in the compound preparation experiments were chemically pure or analytically pure and were used without further purification.

[0054] Example 1: (7,7'-dimethoxy-[4,4'-biphenyl[d][1,3]dioxane]-5,5'-diyl)bis(methylene)bis[3,4,5tris(acetoxy)benzoate (YKW-0818) 1) Synthesis of intermediate (1)

[0055] Gallic acid (3.26 g, 19.1 mmol) was added to a 100 mL three-necked flask under argon protection. Acetic anhydride (12 mL, 115.1 mmol) was slowly added dropwise under ice-salt bath conditions. After the reaction was completed, concentrated sulfuric acid was added to the catalytic amount. The mixture was then refluxed in an oil bath at 75 °C for 3 h. After the reaction was monitored by TLC until it was complete, the mixture was cooled to room temperature. The reaction solution was then slowly poured into a beaker containing 60 mL of ice water and allowed to stand until the solid precipitated. The solid was filtered and dried to obtain 4.51 g of white solid powder (intermediate 1), with a yield of 79.6%. 1 H NMR (400 MHz, DMSO- d 6) δ 13.38 (s, 1H), 7.78 (d, J = 1.2 Hz, 2H), 2.36 (d, J = 1.3 Hz, 3H), 2.32(d, J = 1.3 Hz, 6H). 2) Synthesis of (7,7'-dimethoxy-[4,4'-biphenyl[d][1,3]dioxane]-5,5'-diyl)bis(methylene)bis[3,4,5tris(acetoxy)benzoate

[0056] Intermediate 1 (500 mg, 1.67 mmol) was dissolved in 10 mL of ultra-dry dichloromethane, and a catalytic amount of DMF was added. Oxaloyl chloride (183 μl) was slowly added dropwise under ice-salt bath conditions, and the reaction was carried out at room temperature for 3 h. After the reaction was completed, the solvent was evaporated to obtain a white solid powder, which was dissolved in ultra-dry dichloromethane and slowly added dropwise to a solution containing 4,4'-dimethoxy-5,6,5',6'-bis(methylenedioxybiphenyl)-2,2'-diethanol (275 mg, 0.76 mmol) and ultra-dry triethylamine (352 μl, 2.53 mmol) in anhydrous dichloromethane. The reaction was carried out at room temperature for two hours, and the reaction was completed under TLC monitoring. The organic layer was washed successively with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (dichloromethane: petroleum ether = 3:1) to obtain the target product, a white solid powder of 527 mg, with a yield of 75.6%. 1 H NMR (400 MHz, CDCl3) δ 7.70 (s, 4H), 6.71 (s, 2H), 5.90 (s, 2H), 5.81 (s, 2H), 5.07 (s, 4H), 3.92 (s, 6H), 2.28 (d, J = 5.7 Hz, 18H). ESI-MS m / z 941.33 [M+Na]+ . Example 2: (7,7'-dimethoxy-[4,4'-biphenyl[d][1,3]dioxane]-5,5'-ylidene)bis(methylene)bis(3,4,5-trihydroxybenzoate) (YKW-0819)

[0057] The compound from Example 1 (300 mg, 0.326 mmol) was placed in a round-bottom flask and dissolved in 15 mL of methanol. Hydrazine hydrate (98%) (342 μl, 2.15 mmol) was slowly added dropwise under an ice-salt bath. The reaction was maintained at 0 °C for 0.5 h. The reaction was detected by TLC to indicate completion. The pH was adjusted to weakly acidic with glacial acetic acid under an ice bath. The reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow oil, 107 mg, with a yield of 49.83%. 1 H NMR (400 MHz, DMSO) δ 9.23(s, 4H), 8.92 (s, 2H), 6.87 (d, J = 3.3 Hz, 6H), 5.96 (s, 2H), 5.70 (s, 2H), 4.98- 4.77 (m, 4H), 3.86 (s, 6H). ESI-MS m / z 665.04 [MH] ¯ . Example 3: [1,1'-Biphenyl]-4,4'-Dimethylbis(methylene)bis[3,4,5-tris(acetoxy)benzoic acid] ester YKW-0831

[0058] Using [1,1'-biphenyl]-4,4'-dimethyldiethanol as the raw material, and following the synthesis method of Example 1, 457 mg of white solid powder was obtained, with a yield of 72%. 1 H NMR (400 MHz, CDCl3) δ 7.83 (s, 4H), 7.61 (d, J = 8.0Hz, 4H), 7.49 (d, J = 8.0 Hz, 4H), 5.38 (s, 4H), 2.29 (d, J = 3.2 Hz, 18H). ESI-MS m / z 941.2 [M+Na] + . Example 4: [1,1'-Biphenyl]-4,4'-Dimethylbis(methylene)bis(3,4,5-trihydroxybenzoate) YKW-0833

[0059] Using YKW-0831 as raw material, and following the synthesis method in Example 2, 98 mg of a buttery substance was obtained, with a yield of 49.8%. 1 H NMR (400 MHz, DMSO) δ 11.97 (s, 1H), 9.30 (s, 4H), 8.97 (s, 2H), 7.68 (d, J = 8.2 Hz, 4H), 7.52 (d, J = 8.1 Hz, 4H), 7.05 (s, 4H), 6.02 (q, J = 6.5 Hz, 2H), 3.20 (s, 2H), 1.93 (s, 3H), 1.61 (d, J = 6.5 Hz, 6H). ESI-MS m / z 545.20 [MH] - . Example 5: [1,1'-Biphenyl]-4,4'-Diylbis(ethane-1,1-diyl)bis[3,4,5-tris(acetoxy)benzoate]YKW-0835

[0060] Using 1,1'-([1,1'-biphenyl]-4,4'-diyl)bis(ethanol-1-ol) as the starting material, and following the synthesis method in Example 1, 749 mg of white powder was obtained, with a yield of 73%. 1 H NMR (400 MHz, CDCl3) δ 7.87 (s, 4H),7.61 (d, J = 8.0 Hz, 4H), 7.51 (d, J = 8.0 Hz, 4H), 6.19 (q, J = 6.5 Hz, 2H), 2.34 (s, 18H), 1.73 (d, J = 6.5 Hz, 6H). ESI-MS m / z 821.34 [M+Na] + . Example 6: [1,1'-Biphenyl]-4,4'-Dimethylbis(ethane-1,1-dimethyl)bis(3,4,5-trihydroxybenzoate) YKW-0837

[0061] Using YKW-0835 as raw material, and following the synthesis method in Example 2, 158 mg of a yellow oily substance was obtained, with a yield of 62.2%. 1 H NMR (400 MHz, DMSO) δ 9.30 (s, 4H), 8.97 (s, 2H), 7.68 (d, J = 8.2Hz, 4H), 7.52 (d, J = 8.1 Hz, 4H), 7.05 (s, 4H), 6.02 (q, J = 6.5 Hz, 2H), 1.61(d, J = 6.5 Hz, 6H). ESI-MS m / z 545.20 [MH] - . Example 7: [1,1'-binaphthyl]-2,2'-dimethylbis[3,4,5-tris(acetoxy)benzoate]YKW-0839

[0062] Using [1,1'-binaphthyl]-2,2'-diol as the raw material, and following the synthesis method in Example 1, 958 mg of a white solid powder was obtained, with a yield of 82%. 1 H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.9 Hz, 2H), 7.95 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.9 Hz, 2H), 7.49 (ddd, J = 8.1, 5.7, 2.2 Hz, 2H),7.43 – 7.35 (m, 8H), 2.29 (d, J = 2.9 Hz, 18H). ESI-MS m / z 865.34 [M+Na] + . Example 8: 5-(((3,4,5-trihydroxybenzoyl)oxy)methyl)-1,3-phenylenebis[3,4,5-tris(acetoxy)benzoate] YKW-0948

[0063] Using 3-hydroxybenzyl alcohol as a raw material, and following the synthesis method in Example 1, 507 mg of a white powder was obtained, with a yield of 69%. 1 H NMR (400 MHz, DMSO) δ 8.01 (d, J = 1.2 Hz, 2H), 7.86 (d, J = 1.2 Hz, 2H), 7.54 (t, J = 7.9 Hz, 1H), 7.50 – 7.43 (m, 2H), 7.38 – 7.31 (m, 1H), 5.44(s, 2H), 2.35 (dd, J = 18.5, 10.6 Hz, 18H). ESI-MS m / z 703.53 [M+Na] + . Example 9: 3-((3,4,5-trihydroxybenzoyl)oxy)benzyl-3,4,5-trihydroxybenzoate YKW-0847

[0064] Using YKW-08948 as raw material, a pale yellow oily substance was obtained by following the synthesis method in Example 2, yielding 127 mg, with a yield of 56.8%.

[0065] 1 H NMR (400 MHz, DMSO) δ 9.29 (s, 6H), 7.57 (dd, J = 7.6, 1.7 Hz, 1H), 7.47 (td, J = 7.7, 1.8 Hz, 1H), 7.39 – 7.34 (m, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.13 (s, 2H), 6.96 (s, 2H), 5.20 (s, 2H). ESI-MS m / z 452.14 [M+Na] + . Example 10: (5-Methyl-2-((3,4,5-trihydroxybenzoyl)oxy)-1,3-phenylene)bis(methylene)bis[3,4,5-tris(acetoxy)benzoate] YKW-0849

[0066] Using (2-hydroxy-5-methyl-1,3-phenylene)diethanol as a raw material, and following the synthesis method in Example 1, 702 mg of solid powder was obtained, with a yield of 83.2%. 1 H NMR (400 MHz, CDCl3) δ 7.90 (s, 2H), 7.74 (s,4H), 7.32 (s, 2H), 5.28 (d, J = 12.6 Hz, 4H), 2.40 (s, 3H), 2.28 (q, J = 3.8Hz, 27H). ESI-MS m / z 1026.2 [M+Na] + . Example 11: (5-Methyl-2-((3,4,5-trihydroxybenzoyl)oxy)-1,3-phenylene)bis(methylene)bis(3,4,5-trihydroxybenzoate)YKW-0850

[0067] Using YKW-0849 as raw material, a pale yellow oily substance was obtained by following the synthesis method in Example 2, yielding 143 mg, with a yield of 54.5%. 1 H NMR (400 MHz, DMSO) δ 9.15 (s, 9H), 7.38 (s, 2H), 7.12 (s, 2H), 6.95 (s, 4H), 5.12 (s, 4H), 2.40 (s, 3H). ESI-MS m / z 647.2 [M+Na] + . Example 12: 5-(((3,4,5-trihydroxybenzoyl)oxy)methyl)-1,3-phenylenebis[3,4,5-tris(acetoxy)benzoate] YKW-0901

[0068] Using 1,3,5-phenylpyrogallol as a raw material, a gray powder of 789 mg was obtained by following the synthesis method in Example 1, with a yield of 78.5%. 1 H NMR (400 MHz, DMSO) δ 7.93 (s, 4H), 7.86 (s, 2H) 7.13-7.23 (m, 3H), 5.41 (s, 2H). 2.33 (s, 18H), 2.06 (s, 9H). ESI-MS m / z 619.17 [M+Na] + . Example 13: 5-(((3,4,5-trihydroxybenzoyl)oxy)methyl)-1,3-phenylenebis(3,4,5-trihydroxybenzoate)YKW-0902

[0069] Using YKW-0901 as raw material, a brown powder of 120 mg was obtained by following the synthesis method in Example 2, with a yield of 45.6%. 1 H NMR (400 MHz, DMSO) δ 9.17 (s, 9H), 7.24 (d, J = 2.1 Hz, 2H), 7.20 (d, J =2.2 Hz, 1H), 7.13 (s, 4H), 7.02 (s, 2H), 5.31 (s, 2H). ESI-MS m / z 619.17 [M+Na] + . Example 14: 1,3-Phenylidene bis(methylene)bis[3,4,5-tris(acetoxy)benzoic acid] ester YKW-1307

[0070] Using 1,3-benzyldiethanol as a raw material, and following the synthesis method of Example 1, 765 mg of a white solid powder was obtained, with a yield of 82.3%. 1 H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 3.0 Hz, 4H), 7.48 - 7.39 (m,4H), 5.36 (d, J = 3.0 Hz, 4H), 2.29 (q, J = 3.6 Hz, 18H). ESI-MS m / z 717.26 [M+Na] + . Example 15: 1,3-Phenylidene bis(methylene)bis(3,4,5-trihydroxybenzoate) YKW-0904

[0071] Using YKW-1307 as raw material, a solid pale yellow powder was obtained by following the synthesis method in Example 2, with a yield of 970 mg and a yield of 89.8%. 1 H NMR (400 MHz, DMSO) δ 8.94 (s, 1H), 7.47 (d, J= 24.8 Hz, 4H), 7.00(s, 4H), 5.28 (s, 4H). ESI-MS m / z 465.15 [M+Na] + . Example 16: 1,2-Phenylidene bis(methylene)bis[3,4,5-tris(acetoxy)benzoate] YKW-0905

[0072] Using 1,2-benzyldiethanol as a raw material, a white solid powder was obtained by following the synthesis method in Example 1, with a yield of 783 mg and a yield of 90.3%. 1 H NMR (400 MHz, CDCl3) δ 7.80 (s, 4H), 7.48 (dd, J = 5.6, 3.4 Hz, 2H), 7.38 (dd, J = 5.6, 3.4 Hz, 2H), 5.51 (s, 4H), 2.29 (d, J = 4.0 Hz, 18H). ESI-MS m / z 717.21 [M+Na] + . Example 17: 1,2-Phenylidene bis(methylene)bis(3,4,5-trihydroxybenzoate) YKW-0906

[0073] Using YKW-0905 as raw material, 185 mg of solid white powder was obtained by following the synthesis method in Example 2, with a yield of 65%. 1 H NMR (400 MHz, DMSO) δ 7.52 (dt, J = 7.4, 3.7 Hz, 2H), 7.43 (dd, J = 5.7,3.4 Hz, 2H), 7.00 (s, 4H), 5.40 (s, 4H). ESI-MS m / z 465.15 [M+Na] + . Example 18: 4-Methoxy-3-((3,4,5-trihydroxybenzoyl)oxy)benzyl[3,4,5-tris(acetoxy)benzoate] YKW-0907

[0074] Using 5-hydroxymethyl-2-methoxyphenol as a raw material, and following the synthesis method in Example 1, 852 mg of a solid white powder was obtained, with a yield of 85%. 1 H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 1.2 Hz, 2H), 7.84 (d, J =1.3 Hz, 2H), 7.35 (dd, J = 8.4, 2.0 Hz, 1H), 7.24 (s, 1H), 7.04 (d, J = 8.3 Hz,1H), 5.32 (s, 2H), 3.86 (d, J = 1.3 Hz, 3H), 2.38 - 2.31 (m, 18H). ESI-MS m / z 733.56 [M+Na] + . Example 19: (6-Methyl-5-((3,4,5-trihydroxybenzoyl)oxy)pyridine-3,4-diyl)bis(methylene)bis[3,4,5-tris(acetoxy)benzoate YKW-1046

[0075] Using 5-hydroxy-6-methylpyridine-3,4-dimethyl)diethanol as a raw material, and following the synthesis method in Example 1, 892 mg of a white solid powder was obtained, with a yield of 93%. 1 H NMR (400 MHz, DMSO) δ 8.54 (s, 1H), 7.82 (s,6H), 4.98 (s, 2H), 4.80 (s, 2H), 2.44 (s, 3H), 2.36 (s, 9H), 2.33 (s, 18H).ESI-MS m / z: 1027.05 [M+Na] + . Example 20: 2-((3,4,5-trihydroxybenzoyl)oxy)benzyl[3,4,5-tris(acetoxy)benzoate] YKW-0947

[0076] Using 2-hydroxybenzyl alcohol as a raw material, and following the synthesis method in Example 1, 7786 mg of a white solid powder was obtained, with a yield of 85%. 1H NMR (400 MHz, DMSO) δ 7.96 (s, 2H), 7.69 (s, 2H), 7.70 - 7.64 (m,1H), 7.58 - 7.50 (m, 1H), 7.46 - 7.37 (m, 2H), 5.42 (s, 2H), 2.39 (s, 3H),2.37 - 2.29 (m, 15H). ESI-MS m / z 703.24 [M+Na] + . Example 21: 2-Methoxy-4-((3,4,5-trihydroxybenzoyl)oxy)methyl)phenyl[3,4,5-tris(acetoxy)benzoate] YKW-0949

[0077] Using 4-(hydroxymethyl)-2-methoxyphenol as a raw material, and following the synthesis method in Example 1, 682 mg of a white solid powder was obtained, with a yield of 90%. 1 H NMR (400 MHz, DMSO) δ 8.00 (s, 2H), 7.87 (s, 2H), 7.38 -7.28 (m, 2H), 7.15 (dd, J = 8.1, 1.8 Hz, 1H), 5.40 (s, 2H), 3.81 (s, 3H), 2.35(dd, J = 18.8, 8.4 Hz, 18H). ESI-MS m / z 733.26 [M+Na] + . Example 22: 2-Methoxy-4-((3,4,5-trihydroxybenzoyl)oxy)methyl)phenyl-3,4,5-trihydroxybenzoate YKW-0955

[0078] Using YKW-0949 as raw material, 122 mg of white solid powder was obtained by following the synthesis method in Example 2, with a yield of 48.6%. 1 H NMR (400 MHz, DMSO) δ 9.31 (t, J = 48.9 Hz, 6H), 7.28 – 7.18 (m, 2H), 7.09 (d, J = 8.7 Hz, 3H), 7.02 (s, 2H), 5.26 (s, 2H), 3.79 (s, 3H). ESI-MSm / z 481.15 [M+Na] + . Example 23: 2-(3,4,5-trihydroxybenzoamide)benzyl[3,4,5-tris(acetoxy)benzoate]YKW-0919

[0079] Using 2-hydroxymethylaniline as a raw material, and following the synthesis method of Example 1, 893 mg of solid powder was obtained, with a yield of 88.3%. 1 H NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 7.98 - 7.91 (m, 3H), 7.83 (dd, J = 11.4, 1.7 Hz, 2H), 7.54 - 7.46 (m, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 5.40 - 5.34 (m, 2H), 2.35 - 2.29 (m, 18H). ESI-MS m / z: 702.23[M+Na] + . Example 24: 1,3-Cyclohexanediol bis(3,4,5-trihydroxybenzoate) YKW-0958

[0080] Using 1,3-cyclohexanediol as a raw material, 728 mg of a white solid powder was obtained by following the synthesis method in Example 1, with a yield of 88.6%. 1 H NMR (400 MHz, DMSO) δ 7.82 (d, J = 8.2 Hz, 4H), 5.05 (tt, J = 9.9, 4.5 Hz, 2H), 2.34 (d, J = 16.2 Hz, 18H), 2.08 (q, J = 8.2 Hz, 2H), 1.93 (s,1H), 1.89 (s, 1H), 1.75 (q, J = 11.3 Hz, 1H), 1.47 (t, J = 10.1 Hz, 3H). ESI-MS m / z: 695.12 [M+Na] + . Example 25: 2-(3,4,5-trihydroxybenzoamide)benzyl-3,4,5-trihydroxybenzoate YKW-1006

[0081] Using YKW-0919 as raw material, and following the synthesis method of Example 2, 145 mg of solid powder was obtained, with a yield of 50%. 1 HNMR (400 MHz, DMSO) δ 9.81 (s, 1H), 9.30 (s, 2H), 9.16 (s, 2H), 9.00 (s, 1H),8.84 (s, 1H), 7.48 (d, J = 7.5 Hz, 1H), 7.44 - 7.25 (m, 3H), 6.99 (d, J = 5.3Hz, 4H), 5.21 (s, 2H). ESI-MS m / z: 450.15 [M+Na] + . Example 26: 2-((3,4,5-trihydroxybenzoyl)oxy)benzyl-3,4,5-trihydroxybenzoate YKW-1007

[0082] Using YKW-0947 as the raw material, and following the synthesis method in Example 2, 135 mg of a white solid powder was obtained, with a yield of 72%. ¹H NMR (400 MHz, DMSO) δ 9.15 (brs, 6H), 7.56 (dd, J = 7.7, 1.7 Hz, 1H), 7.45 (td, J = 7.8, 1.8 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.11 (s, 2H), 6.94 (s, 2H), 5.18 (s, 2H). ESI-MS m / z 451.13 [M+Na] + . Example 27: 1,3,5-Phosphothine tris(3,4,5-tris(acetoxy)benzoic acid) ester YKW-1036

[0083] Using 1,3,5-phenylpyrogallol as the raw material, and following the synthesis method of Example 1, 769 mg of solid powder was obtained, with a yield of 78%. 1H NMR (400 MHz, DMSO) δ 8.00 (d, J = 1.1 Hz, 6H), 7.44 (d, J = 1.0 Hz, 3H), 2.36 (s, 9H), 2.32 (s, 18H). ESI-MS m / z 983.02 [M+Na] + . Example 28: N,N'-((1s,4s)-cyclohexane-1,4-diyl)bis[3,4,5-tris(acetoxy)benzoate] YKW-1025

[0084] Using 2,4-cyclohexanediamine as a raw material, and following the synthesis method in Example 1, 789 mg of solid powder was obtained, with a yield of 89%. 1 H NMR (400 MHz, DMSO- d6 ) δ 8.25 (d, J = 6.2 Hz, 2H), 7.73 (s, 4H), 3.88(s, 1H), 3.34 (s, 3H), 2.32 (d, J = 5.4 Hz, 18H), 1.85 (dd, J = 12.0, 6.5 Hz,3H), 1.68 - 1.60 (m, 3H). ESI-MS m / z 693.3 [M+Na] + . Example 29: N, N'-((1s,4s)-cyclohexane-1,4-diyl)bis(3,4,5-trihydroxybenzamide)YKW-1028

[0085] Using YKW-1025 as raw material and following the synthesis method of Example 2, 152 mg of brown blocky solid was obtained, with a yield of 72.1%. 1 H NMR (400 MHz, DMSO) δ 8.98 (s, 4H), 8.64 (s, 2H), 7.55 (d, J = 6.7Hz, 2H), 6.86 (s, 4H), 3.87 - 3.80 (m, 2H), 1.80 (dd, J = 11.3, 6.1 Hz, 4H), 1.59 (td, J= 10.0, 6.3 Hz, 4H). ESI-MS m / z : 419.21 [M+H] + . Example 30: 1,4-Phenylidene bis(methylene)bis[3,4,5-tris(acetoxy)benzoic acid] ester YKW-1029

[0086] Using 1,4-benzyldiethanol as a raw material, and following the synthesis method of Example 1, 856 mg of a white solid powder was obtained, with a yield of 85.6%. 1 H NMR (400 MHz, CDCl3) δ 7.81 (s, 4H), 7.43 (s, 4H), 5.34 (s, 4H), 2.29 (d, J = 3.2 Hz, 18H). ESI-MS m / z: 717.26 [M+Na] + . Example 31: 1,4-Phenylidene bis(methylene)bis(3,4,5-trihydroxybenzoate) YKW-1030

[0087] Using YKW-1029 as raw material, and following the synthesis method in Example 2, 120 mg of a yellow oily substance was obtained, with a yield of 67.3%. 1 H NMR (400 MHz, DMSO) δ 9.26 (s, 4H), 8.94 (s, 2H), 7.46 (s, 4H), 6.98 (s, 4H), 5.25 (s, 4H). ESI-MS m / z 465.16 [M+Na] + . Example 32: [1,1'-binaphthyl]-2,2'-dimethylbis(3,4,5-trihydroxybenzoic acid) ester YKW-1033

[0088] Using YKW-0839 as raw material and following the synthesis method in Example 2, 149 mg of white solid powder was obtained, with a yield of 70.6%. 1 H NMR (400 MHz, DMSO) δ 9.16 (s, 6H), 8.08 (d, J = 9.0 Hz, 2H), 8.00(d, J = 8.2 Hz, 2H), 7.56 (d, J= 8.9 Hz, 2H), 7.47 (t, J = 7.8 Hz, 2H), 7.33(ddd, J = 8.3, 6.8, 1.3 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H), 6.70 (s, 4H). ESI-MS m / z 591.4 [M+H] + . Example 33: (1s,4s)-cyclohexane-1,4-dimethylbis[3,4,5-tris(acetoxy)benzoic acid] ester YKW-1034

[0089] Using 1,4-cyclohexanediol as a raw material, and following the synthesis method of Example 1, 900 mg of a white solid powder was obtained, with a yield of 90.3%. 1 H NMR (400 MHz, DMSO) δ 7.81 (s, 4H), 5.76 (s, 2H), 2.33 (d, J = 12.0Hz, 18H), 2.08 (d, J = 9.1 Hz, 4H), 1.75 (q, J = 7.5 Hz, 4H). MS m / z 695.42 [M+Na] + . Example 34: [1,1'-Biphenyl]-2,2'-Dihydroxybis[3,4,5-Tris(acetoxy)benzoic acid] ester YKW-1035

[0090] Using [1,1'-biphenyl]-2,2'-diol as the raw material, and following the synthesis method in Example 1, 856 mg of a white solid powder was obtained, with a yield of 89%. 1 H NMR (400 MHz, DMSO) δ 7.67 (s, 4H), 7.50 - 7.31 (m, 8H), 2.32 (d, J = 16.9 Hz, 18H). ESI-MS m / z 765.26 [M+Na] + . Example 35: [1,1'-Biphenyl]-2,2'-Dimethylbis(3,4,5-trihydroxybenzoic acid) ester YKW-1039

[0091] Using YKW-1035 as raw material and following the synthesis method of Example 2, 156 mg of a yellow oily substance was obtained, with a yield of 56.3%. 1 H NMR (400 MHz, DMSO) δ 9.31 (s, 4H), 9.13 (s, 2H), 7.42 - 7.34 (m,2H), 7.34 - 7.21 (m, 6H), 6.94 (s, 4H). ESI-MS m / z 514.00 [M+Na] + . Example 36: 1,3,5-Phosphoryl tris(3,4,5-trihydroxybenzoic acid) ester YKW-1040

[0092] Using YKW-1036 as raw material, and following the synthesis method in Example 2, 75 mg of a pale yellow powder was obtained, with a yield of 45.6%. 1 H NMR (400 MHz, DMSO) δ 9.34 (brs, 9H) 7.07-7.14 (m, 9H). ESI-MS m / z 604.97 [M+Na] + . Example 37: 4-Methoxy-3-((3,4,5-trihydroxybenzoyl)oxy)benzyl benzoate YKW-1042

[0093] Using YKW-0907 as raw material and following the synthesis method in Example 2, 154 mg of brown solid powder was obtained, with a yield of 63.2%. 1 H NMR (400 MHz, DMSO) δ 9.41 (s, 2H), 9.28 (s, 2H), 9.13 (s, 1H), 8.95 (s, 1H), 7.34 (dd, J = 8.4, 2.1 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.17 (d, J =8.5 Hz, 1H), 7.09 (s, 2H), 6.97 (s, 2H), 5.19 (s, 2H), 3.77 (s, 3H). ESI-MS m / z: 481.00 [M+Na] + . Example 38: (6-Methyl-5-((3,4,5-trihydroxybenzoyl)oxy)pyridine-3,4-diyl)bis(methylene)bis(3,4,5-trihydroxybenzoate)YKW-1047

[0094] Using YKW-0933 as raw material, the product was synthesized according to the method in Example 2, yielding a brown solid of 152 mg, with a yield of 59.6%. 1 HNMR (400 MHz, DMSO) δ 9.46 (s, 2H), 9.32 (s, 3H), 9.24 (s, 2H), 9.03 (s, 2H), 8.57 (s, 1H), 7.14 (s, 2H), 6.98 (s, 2H), 6.85 (s, 2H), 5.48 (s, 2H), 5.27(s, 2H), 2.35 (s, 3H). ESI-MS m / z 648.10 [M+Na] + . Example 39: (1s,4s)-cyclohexane-1,4-dimethylbis(3,4,5-trihydroxybenzoic acid) ester YKW-1050

[0095] Using YKW-1034 as raw material, and following the synthesis method of Example 2, 200 mg of a yellow oily substance was obtained, with a yield of 86%. 1 H NMR (400 MHz, DMSO) δ 9.14 (d, J = 98.1 Hz, 6H), 6.97 (s, 4H), 4.94 (s,2H), 2.09 - 1.90 (m, 4H), 1.80 - 1.55 (m, 4H). ESI-MS m / z 443.10 [M+Na] + . Example 40: [2,2'-Bipyridine]-5,5'-bis(methylene)bis[3,4,5-tris(acetoxy)benzoate]YKW-1304

[0096] Using [2,2'-bipyridine]-5,5'-dimethyldiethanol as the raw material, and following the synthesis method of Example 1, 825 mg of white solid powder was obtained, with a yield of 85.9%. 1 H NMR (400 MHz, DMSO) δ 8.71 (s, 2H), 8.44 (s, 2H) 7.67 (s, 4H), 7.50 - 7.31 (m, 8H), 2.32 (d, J = 16.9 Hz, 18H). ESI-MS m / z 795.29 [M+Na] + . Example 41: Synthesis of [2,2'-bipyridine]-4,4'-diyldi(methylene)bis[3,4,5-tris(acetoxy)benzoic acid] ester YKW-1305

[0097] Using [2,2'-bipyridine]-4,4'-dimethyldiethanol as the raw material, and following the synthesis method in Example 1, 756 mg of a white solid powder was obtained, with a yield of 89.6%. 1 H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 5.0 Hz, 2H),8.45 (s, 2H), 7.87 (d, J = 1.4 Hz, 4H), 7.37 (d, J = 5.0 Hz, 2H), 5.45 (s, 4H), 2.31 (t, J = 1.9 Hz, 18H). ESI-MS m / z 795.29 [M+Na] + . Example 42: [2,2'-Bipyridine]-6,6'-Dimethylbis(methylene)[3,4,5-tris(acetoxy)benzoic acid] ester YKW-1306

[0098] Using [2,2'-bipyridine]-6,6'-dimethyldiethanol as the raw material, and following the synthesis method of Example 1, 823 mg of white solid powder was obtained, with a yield of 84.6%. 1 H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 5.0 Hz, 2H),8.45 (s, 2H), 7.87 (d, J = 1.4 Hz, 4H), 7.37 (d, J = 5.0 Hz, 2H), 5.45 (s, 4H).ESI-MS m / z 795.29 [M+Na] + . Example 43: [2,2'-Bipyridine]-5,5'-Dimethylbis(methylene)bis(3,4,5-trihydroxybenzoic acid) ester YKW-1320

[0099] Using YKW-1304 as raw material, and following the synthesis method in Example 2, 100 mg of white solid powder was obtained, with a yield of 68.9%. 1 H NMR (400 MHz, DMSO) δ 9.17 (s, 6H), 8.78 (d, J = 2.2 Hz, 2H), 8.43(d, J = 8.2 Hz, 2H), 8.02 (dd, J = 8.2, 2.2 Hz, 2H), 7.00 (s, 4H), 5.36 (s,4H). ESI-MS m / z 521.2 [M+H] + . Example 44: [2,2'-Bipyridine]-6,6'-Dimethylbis(methylene)bis(3,4,5-trihydroxybenzoic acid) ester YKW-1321

[0100] Using YKW-1306 as raw material and following the synthesis method in Example 2, 123 mg of white solid powder was obtained, with a yield of 75.9%. 1 H NMR (400 MHz, DMSO) δ 9.23 (s, 6H), 8.34 – 8.26 (m, 2H), 7.99 (t, J =7.8 Hz, 2H), 7.51 (d, J = 7.7 Hz, 2H), 7.06 (s, 4H), 5.42 (s, 4H). ESI-MS m / z 544.19 [M+Na] + . Example 45: [2,2'-Bipyridine]-5,5'-Dimethylbis(methylene)bis(3,4,5-trihydroxybenzoic acid) ester YKW-1325

[0101] Using [2,2'-bipyridine]-5,5'-dimethyldiethanol as the starting material, and following the synthesis method of Example 2, 100 mg of white powder was obtained, with a yield of 67.3%. 1 H NMR (400 MHz, DMSO) δ 8.70 (d,J = 5.0 Hz, 2H), 8.41(s, 2H), 7.48 (dd, J = 5.0, 1.6 Hz, 2H), 7.04 (s, 4H), 5.41 (s, 4H). ESI-MS m / z 521.20 [M+H] + . Example 46: N,N'-([1,1'-biphenyl]-2,2'-diyl)bis(3,4,5-trihydroxybenzoyl)amine YKW-1329

[0102] Using [1,1'-biphenyl]-2,2'-diamine as the raw material, and following the synthesis method of Example 2, 89 mg of a brown oily substance was obtained, with a yield of 63%. 1 H NMR (400 MHz, DMSO) δ 10.25 (s, 6H), 9.19 (s, 2H), 7.66 - 7.59(m, 2H), 7.37 (td, J = 7.7, 1.6 Hz, 2H), 7.21 (td, J = 7.5, 1.3 Hz, 2H), 7.10(dd, J = 7.6, 1.6 Hz, 2H), 6.73 (s, 4H). ESI-MS m / z : 490.19 [M+H] + . Example 47: 4-(3,4,5-trihydroxybenzoyl)aminobenzyl alcohol (3,4,5-trihydroxybenzoic acid) ester YKW-1048

[0103] Using 4-hydroxymethylaniline as a raw material, and following the synthesis method in Example 2, 124 mg of a pale yellow powder was obtained, with a yield of 57%.

[0104] 1 H NMR (400 MHz, DMSO) δ 9.98 (s, 1H), 9.29 (s, 2H), 9.18 (s, 2H), 8.97 (s, 1H), 8.84 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 6.96 (d, J= 5.5 Hz, 4H), 5.19 (s, 2H). ESI-MS m / z 450.09 [M+Na] + . General information for test examples Test materials and methods Influenza A virus (A / Puerto Rico / 8 / 34, PR8) was preserved at the Vector Biology and Biosafety Research Laboratory of the Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences; recombinant vesicular stomatitis virus (VSV-GFP) was preserved at the Biomedical Analysis Center of the Academy of Military Medical Sciences; canine kidney (Madin-Darby canine kidney, MDCK) cells were preserved at the Vector Biology and Biosafety Research Laboratory of the Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences; and human non-small cell lung cancer H1299 cells (H1299-N-mGFP cells) were preserved.

[0105] Test Example 1: Compound Cytotoxicity Test Test method: (1) Cell culture: Resuscitate the target cells, culture them at 37 ℃ and 5% CO2 until the logarithmic growth phase, and then passage them for use.

[0106] (2) Cell digestion and counting: Logarithmic growth phase cells were digested with trypsin, collected by centrifugation and made into a suspension, and counted by trypan blue staining.

[0107] (3) Cell seeding: 1.5 × 10⁶ cells per well of a 96-well plate. 4 One live cell was placed in each well with PBS added to the outermost well and incubated until the cells adhered to the surface.

[0108] (4) Treatment of test compounds: Accurately weigh each compound to be tested and calculate the required volume of DMSO according to the formula: mass = concentration × volume × molecular weight; prepare a 10 mM stock solution. Based on the stock solution, set up 8 final concentration gradients for the compounds, namely 5, 10, 20, 40, 80, and 160 μM. Take a sterile EP tube, add 500 μL of DMEM complete medium to each tube, and then add the corresponding volume of the compound stock solution. Mix thoroughly to prepare culture media for different concentrations of the compounds. Remove the original culture media from the 96-well plate with a sterile pipette, add sterile PBS to rinse each well once, discard the PBS, and then add the prepared culture media for different concentrations of the compounds to the corresponding wells in sequence (100 μL / well); at the same time, set up a blank control group (NT group), add ordinary DMEM complete medium (100 μL) to each well in the first column of the 96-well plate, without adding any drugs. After the dosing was completed, the 96-well plate was placed in a 37 ℃, 5% CO2 constant temperature incubator and incubated for 24 h.

[0109] (6) MTS detection: After incubation for 24 h, remove the 96-well plate from the incubator and use a sterile pipette to remove the culture medium from each well. Prepare the test solution in advance according to the ratio of basal culture medium to MTS reagent (5:1), and add 100 μL of test solution to each well; place the 96-well plate with the test solution in a 37 ℃, 5% CO2 constant temperature incubator and incubate in the dark (1-4 h) until the color of the control group well solution reaches the appropriate depth.

[0110] (6) OD value detection and cell viability calculation: After incubation, the absorbance (OD value) of each well at a wavelength of 490 nm was detected using an ELISA reader. This ELISA reader can automatically subtract the OD value of the background control group and directly output the actual OD value of the sample. The cell viability calculation formula is as follows: Cell viability (%) = (OD value of the test compound experimental group) / (OD value of the solvent control group) × 100%, where the solvent control group is the NT group (pure culture medium group).

[0111] Cytotoxicity test results as follows Figures 1a to 1n As shown.

[0112] Test Example 2: Anti-influenza virus PR8 activity test experiment Cells: MDCK cells Virus: PR8 Plating medium: DMEM medium + FBS (10%) + antibiotics (1%) Drug-containing culture medium: Viral culture medium + TPCK at a final concentration of 2 μg / ml Operating instructions: 1. Digest MDCK cells, seed them in 96-well plates (8000 cells / well), and culture for 24 hours.

[0113] 2. Wash the adherent cells with physiological saline (once). Prepare the target drug to the target dilution concentration and add 100 μl / well to a 96-well plate.

[0114] 3. Add 10 μl of PR8 virus dilution solution with a final dilution factor of 20,000 and incubate for 48 h.

[0115] 4. Aspirate the culture medium containing the virus and drugs, incubate with MTS for 2 hours, and then test.

[0116] 5. Data Processing: Inhibition rate (%) = (OD value of drug-treated wells - OD value of viral wells) / (OD value of NT wells - OD value of viral wells) * 100% Test results are as follows Figures 2a to 2i As shown.

[0117] Test Example 3: Anti-VSV Virus Activity Test Experiment Test principle: Using African green monkey kidney cells (Vero) as host cells, the green fluorescence signal of recombinant vesicular stomatitis virus with inserted green fluorescent protein (GFP) is measured to measure the inhibition efficiency of the sample.

[0118] Test materials and methods: Viral strain: vesicular stomatitis virus with green fluorescent protein reporter gene (National Center for Biomedical Analysis), cultured and passaged in African green monkey kidney cells (Vero) at -80°C.

[0119] Cell culture medium: MEM medium (CM50011, MACGENE) containing 10% fetal bovine serum (HQ30071-T500, Hongquan Biotechnology).

[0120] Sample preparation: The sample was prepared into a stock solution using DMSO and then diluted with cell culture medium.

[0121] Assay method: Vero cells were seeded at 2×10⁴ / well in 96-well culture plates and incubated at 37°C with 5% CO₂. After 12 h, the culture medium was replaced with culture medium containing the drug or DMSO, and the cells were pretreated for 2 h. Diluted virus suspension was added, and the plates were incubated at 37°C with 5% CO₂. After 24 h, GFP signals were detected using a fluorescence microplate reader at an excitation wavelength of 488 nm and an emission wavelength of 535 nm. The inhibition rate was calculated using the formula: Inhibition rate = 1 - [(fluorescence intensity of the drug group - background fluorescence intensity) / (fluorescence intensity of the DMSO group - background fluorescence intensity)]. Cell viability was assessed using the CCK-8 assay for the drug mock group.

[0122] Test results are as follows Figures 3a to 3i As shown.

[0123] Test Example 4: Compound Suppression Phase Separation Experiment Test method: (1) H1299-N-mGFP cells were seeded in 96-well plates, 8000 cells per well, and cultured overnight in a 37 ℃, 5% CO2 cell culture incubator to allow the cells to adhere naturally. (2) The next day, the cells were pretreated with 1 μM of the compound for 4 hours and the pH was adjusted to 6.8. (4) Hoechst 5000× dilution, added to cell supernatant for nuclear staining for 15 min; (5) The imaging was processed using a Cytation 5 microplate reader, and the imaging results were statistically analyzed.

[0124] Test results are available Figures 4a to 4c .

[0125] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A compound representing a structure mimicking RNA, and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers, and solvates thereof: Formula I in, A is a linking group that can chemically connect to the gallic acid skeleton building blocks. It is selected from substituted or unsubstituted C4-C10 cycloalkyl groups, substituted or unsubstituted C6-C20 aryl groups, substituted or unsubstituted 5- to 20-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, and S, substituted or unsubstituted 5- to 10-membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O, and S, substituted or unsubstituted C4-C10 cycloalkyl groups, C1-C6 alkyl groups, and substituted or Unsubstituted C6-C20 aryl C1-C6 alkyl, substituted or unsubstituted 5- to 14-membered heteroaryl C1-C6 alkyl containing 1-3 heteroatoms selected from N, O, and S, substituted or unsubstituted 5- to 10-membered heterocyclic alkyl C1-C6 alkyl containing 1-3 heteroatoms selected from N, O, and S, wherein "substituted" means containing 1 to 3 substituents, each independently selected from hydroxyl, amino, nitro, halogen atom, C1-C6 alkyl, and C1-C6 alkoxy; n is an integer selected from 1 to 3; M and W are each independently selected from oxygen or nitrogen atoms; R is selected from hydrogen atom, C1-C6 alkyl acyl, C6-C10 aryl acyl, C3-C8 cycloalkyl acyl, C3-C8 cycloalkylC1-C6 alkyl acyl, or 5- to 10-membered heteroaryl acyl with 1-3 heteroatoms selected from N, O, and S. Its function is to form a prodrug with phenolic hydroxyl groups, thereby improving the membrane permeability and environmental stability of the molecule.

2. The compound representing the RNA-mimicking structure according to formula I, and its pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers, and solvates according to claim 1, characterized in that, Preferably, A is a linking group selected from substituted or unsubstituted C6-C10 cycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 6- to 20-membered heteroaryl containing 1 or 2 heteroatoms selected from N and O, substituted or unsubstituted 5- to 10-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O, substituted or unsubstituted C6-C10 cycloalkyl C1-C3 alkyl, substituted or unsubstituted C6-C20 aryl C1-C3 alkyl, substituted or unsubstituted 5- to 14-membered heteroaryl C1-C3 alkyl containing 1 or 2 heteroatoms selected from N and O, and substituted or unsubstituted 5- to 10-membered heterocycloalkyl C1-C3 alkyl containing 1 or 2 heteroatoms selected from N and O. The term "substituted" refers to the presence of 1 to 3 substituents, each independently selected from hydroxyl or C1-C3 alkoxy groups. More preferably, A is a linking group selected from substituted or unsubstituted C6-C8 cycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 6- to 18-membered heteroaryl containing one or two heteroatoms selected from N and O, substituted or unsubstituted 5- to 10-membered heterocycloalkyl containing one or two heteroatoms selected from N and O, substituted or unsubstituted C6-C10 cycloalkyl C1-C2alkyl, substituted or unsubstituted C6-C20 aryl C1-C2alkyl, substituted or unsubstituted 5- to 14-membered heteroaryl C1-C2alkyl containing one or two heteroatoms selected from N and O, and substituted or unsubstituted 5- to 10-membered heterocycloalkyl C1-C2alkyl containing one or two heteroatoms selected from N and O. The term "substituted" refers to the presence of one to three substituents, each independently selected from hydroxyl, methoxy, ethoxy, and propoxy. More preferably, A is selected from the following structures, where * represents the connection position of W or M: ； ； ； ； ; ; ; ; ; ； ； ； ； ； ； ； ； ； ； ； 。 3. The compound representing the RNA-mimicking structure according to formula I, and its pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers, and solvates according to claim 1, characterized in that, n is an integer selected from 1 or 2.

4. The compound representing the RNA-mimicking structure according to formula I, and its pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers, and solvates, as described in claim 1, are characterized in that... Preferably, R is selected from hydrogen atom, C1-C6 alkyl acyl, C6-C10 aryl acyl, C4-C6 cycloalkyl acyl, C4-C6 cycloalkylC1-C3 alkyl acyl, and 5- to 8-membered heteroaryl acyl with one or two heteroatoms selected from N and O; Preferably, R is selected from hydrogen atom, C1-C6 alkyl acyl, phenyl acyl, C5-C6 cycloalkyl acyl, C5-C6 cycloalkylC1-C2 alkyl acyl, and 5- to 6-membered heteroaryl acyl with one or two heteroatoms selected from N and O; Preferably, R is selected from acetyl, propionyl, isopropionyl, cyclopropionyl, cyclobutylmethyl, butyryl, isobutyryl, valeryl, cyclopentanoyl, hexanoyl, cyclohexanoyl, benzoyl, pyridine-2-acyl, pyridine-3-acyl, and pyridine-4-acyl.

5. The compound representing the RNA-mimicking structure according to formula I, and its pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers, and solvates according to claim 1, characterized in that, It is selected from the following compounds: 。 6. A pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of a compound of formula I representing a mimicking RNA structure according to any one of claims 1 to 5, and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers, and solvates thereof, as an active ingredient, and pharmaceutically acceptable excipients.

7. The use of a compound representing a simulated RNA structure according to any one of claims 1 to 5, and its pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers, and solvates, or the use of a pharmaceutical composition according to claim 6 in the preparation of an antiviral drug.

8. The use according to claim 7, characterized in that, The viruses mentioned include RNA viruses such as influenza virus, coronavirus, respiratory syncytial virus, and herpes simplex virus (VSV).

9. An antiviral method comprising administering to a patient in need a therapeutically effective amount of a compound of formula I representing a mimicking RNA structure according to any one of claims 1 to 5, and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers, tautomers, and solvates thereof, or a pharmaceutical composition according to claim 6.

Images