Preparation of an anti-influenza a virus compound and uses thereof

Abstract

The application provides preparation and use of an anti-influenza A virus compound, in particular, the application provides a compound shown in the following formula I, or a pharmaceutically acceptable salt thereof. The application firstly finds that the compound has anti-influenza A virus activity, and provides a method for synthesizing the compound in one step, which is high in atomic efficiency, economical in steps and easy in raw material acquisition.

Description

Technical Field

[0001] This invention relates to the field of pharmaceuticals, specifically to the application of a hydroxyoxime macrolide compound and its preparation method. Background Technology

[0002] Influenza, caused by influenza viruses (IVs), is an acute respiratory infection primarily affecting the mouth, throat, bronchi, and even lungs. Symptoms include sudden high fever, sore throat, cough, runny nose, and muscle and joint pain; severe cases can lead to death. Statistics from the World Health Organization at the end of 2018 showed that respiratory illnesses caused by seasonal influenza alone cause 290,000 to 650,000 deaths globally each year. The four major influenza outbreaks in history, along with the annual outbreaks and epidemics of seasonal and novel influenza strains, indicate that influenza viruses pose a persistent threat to human health.

[0003] Influenza viruses belong to the Orthomyxoviridae family and are highly mutated and pathogenic RNA viruses. Based on differences in nucleoprotein and matrix protein antigenic determinants, influenza viruses can be classified into four subtypes: A, B, C, and D. Among them, influenza A viruses are prone to antigenic mutation and have caused numerous global pandemics. Although vaccination remains the primary preventative strategy for controlling influenza infection, vaccine development is time-consuming and struggles to address rapidly evolving mutants. Therefore, the development of anti-influenza drugs remains a pressing issue in this field. Summary of the Invention

[0004] The purpose of this invention is to provide a class of compounds that resist influenza A virus, as well as their preparation methods and uses.

[0005] A first aspect of the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof:

[0006]

[0007] in,

[0008] Ar is selected from the following group: phenyl, naphthyl, biphenyl, 5-7 heteroaryl;

[0009] R 1 R 2 and R 3 Each is independently selected from the group consisting of: hydrogen, halogen, cyano, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C6 ester, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5-15 heteroaryl; or -CHR3- is absent;

[0010] Linker has the structure shown in the following formula:

[0011] -L1-(L2) m -L3-;

[0012] Where m is 1, 2, 3, 4, 5 or 6;

[0013] L1 is selected from the following group: chemical bond, -O-, -CO-, -CONH-, -CH2-, or -SO2-;

[0014] L2 is selected from the group consisting of: substituted or unsubstituted phenyl groups, substituted or unsubstituted 5-7-membered heteroaryl groups, substituted or unsubstituted 5-7-membered heterocyclic groups, substituted or unsubstituted C1-C6 alkylene groups (preferably C1-C4 alkylene groups), -O-, -CO-, -NH-, substituted or unsubstituted C2-C6 alkenyl groups (preferably C2-C4 alkenyl groups, more preferably C2-C3 alkenyl groups);

[0015] L3 is selected from the following group: -O-, -CO-, -CONH-, -CH2-, or -SO2-;

[0016] Wherein, any “substitution” refers to one or more (preferably 1, 2, 3 or 4) hydrogen atoms on a group being replaced by a substituent selected from the group consisting of: halogen, -CN, halo-C1-C4 alkyl (e.g., -CF3), hydroxyl, amino, methanesulfonyl, -NH-C6-C10 aryl, -NH-5-12 heteroaryl, C1-C4 alkyl, C3-C8 cycloalkyl, C1-C7 alkoxy, C6-C10 aryl, C6-C10 aryl-C1-C4 alkyl-, C6-C10 aryl-C1-C4 alkoxy-, C1-C4 alkylthio, 5-12 heteroaryl, C2-C4 ester, or amino acid residue (i.e., a group formed by losing one molecule of water during the condensation of a natural amino acid).

[0017] The heterocyclic group and the heteroaryl group each have 1 to 3 (preferably 1, 2 or 3) heteroatoms selected from N, O and S on their heterocycles.

[0018] In another preferred embodiment, R 1 It is an unsubstituted or C6-C20 aryl group (such as phenyl or naphthyl) with 1 to 3 (preferably 1, 2 or 3) substitutions.

[0019] In another preferred embodiment, R 1It is a C6-C20 aryl group (such as phenyl, naphthyl) having 1-3 (preferably 1, 2 or 3) substituted or unsubstituted groups, wherein the substituent is a halogen, -CN, halo-C1-C4 alkyl (such as -CF3), cyano, hydroxyl, amino, C1-C4 alkyl, C3-C8 cycloalkyl, C1-C7 alkoxy, C6-C12 aryl, C6-C12 aryl-C1-C4 alkyl-, C6-C12 aryl-C1-C4 alkoxy-, C1-C4 alkylthio, 5-12 heteroaryl, C2-C4 ester group, or amino acid residue.

[0020] In another preferred embodiment, the R 1 Selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C3-C8 cycloalkyl groups; wherein the substitution refers to one or more H atoms on the group being substituted by a substituent selected from the group consisting of: halogen, -CN, halo-C1-C4 alkyl (e.g., -CF3), hydroxyl, amino, C1-C4 alkyl, C3-C8 cycloalkyl, C1-C7 alkoxy, C6-C12 aryl, or 5-12 heteroaryl.

[0021] In another preferred embodiment, the R 2 Selected from the following group: hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C4 ester, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5-15 heteroaryl.

[0022] In another preferred embodiment, the R 2 Selected from the following group: hydrogen, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4 ester, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5-15 heteroaryl.

[0023] In another preferred embodiment, R 2 Selected from the following group: hydrogen, -CF3, methyl, substituted or unsubstituted phenyl, -COOMe.

[0024] In another preferred embodiment, the R 3 Selected from the group consisting of hydrogen, substituted or unsubstituted C1-C10 alkyl groups, or -CHR3- not present.

[0025] In another preferred embodiment, the compound of formula I has the structure shown in formula II:

[0026]

[0027] In another preferred embodiment, R1 is a C6-C20 aryl group (such as phenyl or naphthyl) having 1-3 (preferably 1 or 2) substituted or unsubstituted groups, wherein the substituents are halogens, F, Br, -CF3, cyano, hydroxyl, amino, C1-C4 alkyl, C3-C8 cycloalkyl, C1-C7 alkoxy, C6-C12 aryl, C6-C12 aryl-C1-C4 alkyl-, C6-C12 aryl-C1-C4 alkoxy-, C1-C4 alkylthio, 5-12 heteroaryl, C2-C4 ester group,

[0028] In another preferred embodiment, the Linker is a structure selected from the group consisting of:

[0029]

[0030] In another preferred embodiment, the compound of formula I is selected from the group consisting of:

[0031]

[0032]

[0033] A second aspect of the present invention provides a method for preparing a compound of formula I as described in the first aspect of the present invention, the method comprising steps (1), (2), or (3):

[0034] (1) Under the action of a catalyst, silver salt and first base reagent, compound C1 reacts with compound C2 via a carbon-hydrogen bond active reaction to generate compound I.

[0035]

[0036] (2) Under the action of a catalyst, silver salt, and a first base reagent, compound C3 reacts with compound C4 via a carbon-hydrogen bond reactive reaction to generate compound I; wherein, R 3 For H;

[0037]

[0038] (3) Under the action of a catalyst, silver salt and first base reagent, compound C3 reacts with compound C4 via a carbon-hydrogen bond active reaction to generate compound I; wherein, -CHR3- is not present.

[0039]

[0040] In another preferred embodiment, in step (1), the catalyst is a dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer ([Cp*RhCl2]2).

[0041] In another preferred embodiment, in step (1), the silver salt is silver hexafluoroantimonate (AgSbF6).

[0042] In another preferred embodiment, in step (1), the first alkali reagent is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, silver carbonate, or combinations thereof.

[0043] In another preferred embodiment, in step (1), the first alkali reagent is silver carbonate.

[0044] In another preferred embodiment, in step (1), the reaction is carried out in a solvent-free environment and in a first solvent.

[0045] In another preferred embodiment, the first solvent is selected from the group consisting of methanol, tetrahydrofuran, dioxane, chloroform, dichloromethane, 1,2-dichloroethane, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, or hexamethylphosphoric triamine, or combinations thereof.

[0046] In another preferred embodiment, in step (1), the reaction temperature is 20-100°C, more preferably 40-100°C, and even more preferably 60-90°C.

[0047] In another preferred embodiment, in step (1), the reaction time is 6-36 h, more preferably 8-24 h, more preferably 16-24 h, and most preferably 20-24 h.

[0048] In another preferred embodiment, in step (1), the molar ratio of the C1 compound to the silver salt is 1:0.05-2, more preferably 1:0.05-1, and even more preferably 1:0.1-0.5.

[0049] In another preferred embodiment, in step (1), the molar ratio of the silver salt to the first alkaline reagent is 1:0.5-10.

[0050] In another preferred embodiment, in step (1), the molar ratio of the silver salt to the catalyst is 0.5-20:1, more preferably 1-15:1, more preferably 1-10:1, and even more preferably 2-6:1.

[0051] In another preferred embodiment, in step (1), the molar ratio of the catalyst to the first base reagent is 1:2-40.

[0052] In another preferred embodiment, in step (1), the molar ratio of the C1 compound to the C1 compound is 1:1-5, more preferably 1:1-3, and even more preferably 1:1-2.

[0053] A third aspect of the present invention provides a pharmaceutical composition comprising: (a) a compound of formula I as described in the first aspect of the present invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier.

[0054] A fourth aspect of the invention provides the use of the compound as described in the first aspect of the invention for preparing a pharmaceutical composition, wherein the pharmaceutical composition is used to treat or prevent diseases or symptoms caused by influenza A virus.

[0055] In another preferred embodiment, the disease or symptom is influenza A, or cytopathic effect (CPE) caused by influenza A virus (cell rounding, degeneration, and shedding).

[0056] In another preferred embodiment, the pharmaceutical composition is also used to improve cell viability.

[0057] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0058] Appendix Figure 1 The compound exhibits anti-influenza A virus activity.

[0059] Appendix Figure 2 The compound improves the cytopathic effect (CPE) induced by influenza A virus. Detailed Implementation

[0060] Through long-term and in-depth research, the inventors unexpectedly developed a compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof, which exhibits anti-influenza A virus activity. Furthermore, this application also provides a method for preparing a compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof, and a method for preparing such a compound. The method for preparing the compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof involves a rhodium-catalyzed carbon-hydrogen bond activation reaction. This method represents the first one-step preparation of a multi-substituted type I compound, characterized by high atom efficiency, economical steps, and readily available raw materials. Prior to this, other methods could not easily and quickly obtain compounds of formula I. Based on this, the inventors completed this invention.

[0061] the term

[0062] In this invention, the halogen is F, Cl, Br or I.

[0063] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0064] In this invention, the term "C1-C10 alkyl" refers to a straight-chain or branched alkyl group having 1 to 10 carbon atoms, and includes, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl; preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

[0065] In this invention, the term "C1-C7 alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 7 carbon atoms, and includes, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

[0066] In this invention, the term "C2-C6 alkenyl" refers to a straight-chain or branched alkenyl group having 2 to 6 carbon atoms and containing a double bond, and includes, without limitation, vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl groups.

[0067] In this invention, the term "C2-C6 alkenyl" refers to a divalent group formed by the loss of a hydrogen atom from a C2-C6 alkenyl group.

[0068] In this invention, the term "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms on a ring, and non-limitingly includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, etc. The terms "C3-C7 cycloalkyl" and "C3-C6 cycloalkyl" have similar meanings.

[0069] In this invention, the term "C3-C10 cycloalkenyl" refers to a cyclic alkenyl group having 3 to 10 carbon atoms on a ring, and non-limitingly includes cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and cyclodecylene, etc. The term "C3-C7 cycloalkenyl" has a similar meaning.

[0070] In this invention, the terms "aromatic ring" and "aryl" have the same meaning, and preferably "aryl" refers to "C6-C12 aryl" or "C6-C10 aryl". The term "C6-C12 aryl" refers to an aromatic cyclic group with 6 to 12 carbon atoms that does not contain heteroatoms on the ring, such as phenyl or naphthyl. The term "C6-C10 aryl" has a similar meaning.

[0071] In this invention, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning, referring to a heteroaryl group containing one or more heteroatoms. Heteroatoms referred to herein include oxygen, sulfur, and nitrogen. Examples include furanyl, thiophene, pyridinyl, pyrazolyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted; unless otherwise specified, preferred heteroaryl groups are 5-12 membered heteroaryl groups, more preferably 5-7 membered heteroaryl groups.

[0072] In this invention, the term "3-12 membered heterocyclic group" refers to a saturated or unsaturated 3-12 membered cyclic group containing 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen, such as dioxanepentyl. The term "3-7 membered heterocyclic group" has a similar meaning.

[0073] In this invention, the term "substitution" refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is either the substituent described accordingly above or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Cyclic substituents, such as heterocyclic alkyl groups, may be attached to another ring, such as a cycloalkyl group, thereby forming a spirobicyclic system, for example, where the two rings share a common carbon atom. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible. The substituents are, for example (but not limited to): C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3- to 12-membered heterocyclic groups, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C1-8 aldehyde, C2-10 acyl, C2-10 ester, amino, alkoxy, C1-10 sulfonyl, etc.

[0074] Macrolides with anti-influenza A virus activity

[0075] This invention provides a class of hydroxyoxime macrolide compounds, which are compounds with 15 to 24-membered rings linked by lactams. The core structure is prepared by rhodium-catalyzed C-H bond activation of different hydroxyoxime precursors and various five-membered ring oxazolone compounds. Testing has shown that these compounds exhibit excellent anti-influenza A virus activity.

[0076] In this invention, exemplary macrocyclic lactam compounds have the structure shown in the following formula:

[0077]

[0078] in,

[0079] Ar is selected from the following group: phenyl, naphthyl, biphenyl, 5-7 membered heteroaryl;

[0080] R 1 R 2 and R 3 Each is independently selected from the group consisting of: hydrogen, halogen, cyano, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C6 ester, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5-15 heteroaryl; or -CHR3- is absent;

[0081] Linker has the structure shown in the following formula:

[0082] -L1-(L2) m -L3-;

[0083] Where m is 1, 2, 3, 4, 5 or 6;

[0084] L1 is selected from the following group: chemical bond, -O-, -CO-, -CONH-, -CH2-, or -SO2-;

[0085] L2 is selected from the group consisting of: substituted or unsubstituted phenyl groups, substituted or unsubstituted 5-7-membered heteroaryl groups, substituted or unsubstituted 5-7-membered heterocyclic groups, substituted or unsubstituted C1-C6 alkylene groups (preferably C1-C4 alkylene groups), -O-, -CO-, -NH-, substituted or unsubstituted C2-C6 alkenyl groups (preferably C2-C4 alkenyl groups, more preferably C2-C3 alkenyl groups);

[0086] L3 is selected from the following group: -O-, -CO-, -CONH-, -CH2-, or -SO2-;

[0087] Wherein, any “substitution” refers to one or more (preferably 1, 2, 3 or 4) hydrogen atoms on a group being replaced by a substituent selected from the group consisting of: halogen, -CN, halo-C1-C4 alkyl (e.g., -CF3), hydroxyl, amino, methanesulfonyl, -NH-C6-C10 aryl, -NH-5-12 heteroaryl, C1-C4 alkyl, C3-C8 cycloalkyl, C1-C7 alkoxy, C6-C10 aryl, C6-C10 aryl-C1-C4 alkyl-, C6-C10 aryl-C1-C4 alkoxy-, C1-C4 alkylthio, 5-12 heteroaryl, C2-C4 ester, or amino acid residue (i.e., a group formed by losing one molecule of water during the condensation of a natural amino acid).

[0088] The heterocyclic group and the heteroaryl group each have 1 to 3 (preferably 1, 2 or 3) heteroatoms selected from N, O and S on their heterocycles.

[0089] Pharmaceutical Compositions and Administration

[0090] Because the compounds of the present invention have excellent anti-influenza A virus activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate diseases associated with influenza A virus infection, especially influenza A.

[0091] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-3000 mg (active dose range 3-30 mg / kg) of the compound of the present invention per dose, more preferably, 10-2000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0092] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0093] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0094] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0095] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0096] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0097] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0098] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0099] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0100] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0101] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0102] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 6–600 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0103] Compared with the prior art, the main advantages of the present invention include:

[0104] The hydroxyoxime macrolides, or their isomers, or pharmaceutically acceptable salts discovered in this invention, possess anti-influenza A virus activity. Furthermore, this application provides a method for preparing such compounds, or their isomers, or pharmaceutically acceptable salts, achieving, for the first time, a one-step preparation of multi-substituted hydroxyoxime macrolides. This method features high atom efficiency, economical steps, and readily available raw materials. Previously, other methods could not rapidly obtain hydroxyoxime macrolides. The anti-influenza A virus activity of this type of structure is reported for the first time, representing a fundamental innovation with significant academic value and application prospects.

[0105] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0106] compound 1¹H NMR spectral data were measured using a Varian Mercury-400MHz or Varian Mercury-500MHz NMR spectrometer. EI-MS was performed using a Finnigan MAT 95 mass spectrometer, and ESI-MS was performed using a Finnigan LCQ Deca mass spectrometer. Rapid column chromatography was performed on silica gel H (10–40 μM). Reagent purification was performed according to Purification of Laboratory Chemicals; DD Perrin; WLF Armarego and DR Perrin Eds., Pergamon Press: Oxford, 1980.

[0107] Unless otherwise specified, the reagents and methods used in this invention are those well known in the art.

[0108] Example 1

[0109]

[0110] Reaction conditions:

[0111]

[0112] Experimental Method: Under air atmosphere, macrolide precursor 1' (0.2 mmol, 2.0 mol%), dioxazolone 1' (0.1 mmol, 1.0 mol%), [Cp*RhCl2]2 (0.005 mmol, 5 mol%), AgSbF6 (0.02 mmol, 20 mol%), and Ag2CO3 (0.02 mmol, 20 mol%) were added sequentially to a screw-capped pressure-resistant tube. Immediately afterwards, 10 mL of dichloroethane solution was added and thoroughly mixed. The reaction system was stirred at 80 °C for 24 hours. After the reaction was complete as monitored by TLC, the reaction system was cooled to room temperature, filtered through diatomaceous earth to remove metals and other solid impurities, and then the solvent was removed by rotary evaporation. Finally, the target product 1 was purified by column chromatography. It was a white solid with a reaction yield of 46%.

[0113] 1H NMR(500MHz,Chloroform-d)δ7.68(d,J=7.9Hz,1H),7.51(td,J=7.6,1.5Hz,1H),7.46–7.39(m,3H),7.35(td,J=7.7,1.5Hz, 2H),7.08(ddd,J=8.2,2.7,0.9Hz,1H),6.32(t,J=6.2Hz,1H),5.00–4.81(m,1H),4.25(dt,J=11.5,4.6Hz,1H),4.15–4.03(m, 1H), 3.76 (s, 3H), 3.63 (dd, J = 13.1, 4.7Hz, 1H), 3.39 (dd, J = 13.5, 6.8Hz, 1H), 3.31 (dd, J = 13.2, 10.9Hz, 1H), 2.99 (dd, J = 13. 6,5.6Hz,1H),2.74(dt,J=13.0,8.5Hz,1H),2.07(ddd,J=12.6,7.4,4.2Hz,1H),1.71–1.59(m,4H),1.10(s,3H),0.99(s,3H).

[0114] 13 C NMR(126MHz,Chloroform-d)δ196.81,168.43,163.83,158.56,137.32,136.50,133.03,130.74,130.07,128.94,128.42,127.04,126.5 6(q,J=280.7Hz),121.63,121.36,113.39,66.99,61.41,47.65,42.58(q,J=28.2Hz),41.17,40.41,27.72,25.04,24.75,23.38,23.06.

[0115] 19 F NMR (471MHz, Chloroform-d) δ-68.05 (d, J = 8.9Hz).

[0116] HRMS(ESI)calcd.for C27H30F3N2O4[MH]-:503.2163,found:503.2150.

[0117] Example 2

[0118]

[0119] For the synthesis method of compound 1, see compound 1, white solid, yield 45%.

[0120] 1 1H NMR (500 MHz, Chloroform-d) δ 7.55 (d, J = 8.0 Hz, 1H), 7.45 (dt, J = 7.7, 1.2 Hz, 1H), 7.42–7.40 (m, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.33–7.30 (m, 1H), 7.22 (d, J = 1.9 Hz, 1H), 7.08 (ddd, J = 8.2, 2.7, 0.9 Hz, 1H), 6.23 (t, J = 6.1 Hz, 1H), 4.96–4.77 (m, 1H), 4.26 (dt, J = 11.5, 4.5 Hz, 1H), 4.07 (ddd, J = 11.9, 7.2, 5.3 Hz, 1H), 3.78 (s, 3H), 3.64 (dd, J = 13.0, 4.7 Hz, 1H), 3.39 (dd, J = 13.5, 7.1 Hz, 1H), 3.26 (dd, J = 13.1, 11.0 Hz, 1H), 2.97–2.89 (m, 1H), 2.75 (dt, J = 12.8, 8.4 Hz, 1H), 2.35 (s, 3H), 2.07 (ddd, J = 12.9, 7.3, 4.0 Hz, 1H), 1.70–1.60 (m, 4H), 1.10 (s, 3H), 0.98 (s, 3H).

[0121] 13 13C NMR (126 MHz, Chloroform-d) δ 196.98, 168.46, 163.78, 158.52, 138.35, 137.20, 136.51, 131.48, 130.08, 129.82, 128.80, 127.62, 126.60 (q, J = 280.4 Hz), 121.63, 121.41, 113.32, 66.92, 61.40, 47.50, 42.33 (q, J = 28.2 Hz), 41.14, 40.50, 27.70, 25.03, 24.75, 23.42, 23.07, 21.09.

[0122] 19 19F NMR (471 MHz, Chloroform-d) δ -68.28 (d, J = 9.0 Hz).

[0123] HRMS (ESI) calcd. for [M-H] - C 28 H 32 F3N2O4: 517.2320, found: 517.2308.

[0124] Example 3

[0125]

[0126] For the synthesis method of compound 1, see compound 1, white solid, yield 42%.

[0127] 1 H NMR(500MHz,Chloroform-d)δ7.63(dd,J=8.5,2.1Hz,1H),7.56(d,J=2.1Hz,1H),7.55–7.52(m,1H),7.45–7.43(m,1H),7.39–7.35(m ,2H),7.09(ddd,J=8.1,2.6,0.9Hz,1H),6.32(t,J=6.0Hz,1H),4.87(ddt,J=11.4,9.1,4.1Hz,1H),4.27(d,J=11.8Hz,1H),4.09(d,J =6.0Hz,1H),3.81(s,3H),3.79–3.74(m,1H),3.68(dd,J=13.3,4.3Hz,1H),3.36(dd,J=13.5,7.0Hz,1H),3.21(dd,J=13.2,11.4Hz,1 H),2.85(dd,J=13.5,5.3Hz,1H),2.82–2.73(m,1H),2.06(ddd,J=12.9,7.0,4.0Hz,1H),1.71–1.56(m,3H),1.10(s,3H),1.00(s,3H).

[0128] 13 C NMR (126MHz, Chloroform-d) δ196.50,166.73,163.69,158.51,139.21,136.29,133.75,131.92,130.59,130.18,130.04,126.23 (q, J=2 80.6Hz),122.49,122.20,121.39,112.80,66.94,61.63,47.68,42.24(q,J=28.5Hz),41.01,40.09,27.59,25.28,24.72,23.44,23.13.

[0129] 19 F NMR (471MHz, Chloroform-d) δ-68.35 (d, J = 8.4Hz).

[0130] HRMS(ESI)calcd.for[MH] - C27 H 29 BrF3N2O4:581.1268,found:581.1261.

[0131] Example 4

[0132]

[0133] For the synthesis method of compound 1, see compound 1, white solid, yield 43%.

[0134] 1 H NMR(500MHz,Chloroform-d)δ7.45(dt,J=7.5,1.2Hz,2H),7.40(dd,J=2.7,1.5Hz,1H),7.34(t,J=7.9Hz,1H),7.31(d,J=7.8Hz,1H),7.15 –7.12(m,1H),7.07(ddd,J=8.2,2.6,0.9Hz,1H),6.25(t,J=6.2Hz,1H),5.05–4.83(m,1H),4.25(dt,J=11.4,4.6Hz,1H),4.07(ddd,J=11.8 ,7.3,5.0Hz,1H),3.77(s,3H),3.63(dd,J=13.0,4.8Hz,1H),3.37(dd,J=13.5,6.8Hz,1H),3.29(dd,J=13.1,10.8Hz,1H),2.97(dd,J=13. 5,5.6Hz,1H),2.74(dt,J=13.0,8.5Hz,1H),2.42(s,3H),2.06(ddd,J=12.4,7.4,4.1Hz,1H),1.78–1.58(m,4H),1.09(s,3H),0.97(s,3H).

[0135] 13 C NMR(151MHz,Chloroform-d)δ196.51,167.95,163.34,158.04,140.48,136.02,133.92,132.50,129.56,129.09,128.64,126.56,126.13(q ,J=280.8Hz),121.19,120.93,112.83,66.48,60.95,47.09,41.85(q,J=27.9Hz),40.69,39.95,27.19,24.58,24.24,22.90,22.58,21.11.

[0136] 19F NMR (471MHz, Chloroform-d) δ-68.02 (d, J = 9.4Hz).

[0137] HRMS(ESI)calcd.for[MH] - C 28 H 32 F3N2O4:517.2320,found:517.2309.

[0138] Example 5

[0139]

[0140] For the synthesis method of compound 1, see compound 1, white solid, yield 42%.

[0141] 1 H NMR(500MHz,Chloroform-d)δ7.67(d,J=1.5Hz,1H),7.43(dd,J=2.6,1.6Hz,1H),7.41(dt,J=7.7,1.2Hz,1H),7.34–7.28( m,2H),7.05(ddd,J=8.2,2.7,0.9Hz,1H),6.22(t,J=6.2Hz,1H),4.96(tt,J=9.6,4.7Hz,1H),4.22(dt,J=11.1,4.7Hz,1H), 4.08(dt,J=11.4,5.8Hz,1H),3.78(s,3H),3.54(dd,J=13.1,5.3Hz,1H),3.45–3.35(m,2H),3.11(dd,J=13.5,6.1Hz,1H),2 .73(dt,J=16.8,6.2Hz,1H),2.08(ddd,J=12.6,7.7,4.1Hz,1H),1.74–1.62(m,4H),1.35(s,9H),1.10(s,3H),1.02(s,3H).

[0142] 13C NMR(126MHz,Chloroform-d)δ197.01,168.42,163.77,158.61,153.98,136.74,134.18,132.95,129.88,126.78,126.71(q,J=280.8Hz),126.1 8,125.14,121.26,121.07,113.91,67.20,61.42,47.56,42.63(q,J=27 .4Hz),41.33,40.58,34.94,31.08,27.87,24.90,24.81,23.34,23.10.

[0143] 19 F NMR (471MHz, Chloroform-d) δ-67.79 (d, J=9.1Hz).

[0144] HRMS(ESI)calcd.for[MH] - C 31 H 38 F3N2O4:559.2789,found:559.2780.

[0145] Example 6

[0146]

[0147] For the synthesis method of compound 1, see compound 1, white solid, yield 32%.

[0148] 11H NMR (500 MHz, Chloroform-d) δ 7.90 (s, 1H), 7.61 (dd, J = 8.1, 1.8 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.42 (dt, J = 7.7, 1.2 Hz, 1H), 7.38 (dd, J = 2.7, 1.5 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.09 (ddd, J = 8.2, 2.7, 0.9 Hz, 1H), 6.42 (t, J = 6.2 Hz, 1H), 5.07–4.82 (m, 1H), 4.23 (dt, J = 11.9, 4.8 Hz, 1H), 4.09 (dt, J = 12.1, 6.0 Hz, 1H), 3.76 (s, 3H), 3.67 (dd, J = 13.6, 4.1 Hz, 1H), 3.39 (dd, J = 13.5, 6.2 Hz, 1H), 3.32 (dd, J = 13.6, 11.3 Hz, 1H), 3.09 (dd, J = 13.5, 6.1 Hz, 1H), 2.80–2.62 (m, 1H), 2.17–1.99 (m, 1H), 1.76–1.51 (m, 4H), 1.11 (s, 3H), 1.01 (s, 3H).

[0149] 13 13C NMR (151 MHz, Chloroform-d) δ 195.69, 166.75, 163.49, 158.08, 140.42, 135.78, 133.89, 132.14 (q, J = 32.8 Hz), 129.68, 127.59 (q, J = 280.1 Hz), 127.06, 125.37, 124.88 (q, J = 3.6 Hz), 122.90 (q, J = 272.9 Hz), 121.95, 120.86, 112.20, 66.64, 61.01, 47.32, 42.01 (q, J = 28.4 Hz), 40.67, 39.20, 27.13, 24.78, 24.25, 22.75, 22.73.

[0150] 19 19F NMR (471 MHz, Chloroform-d) δ -62.99, -68.21 (d, J = 8.9 Hz).

[0151] HRMS (ESI) calcd. for [M-H] - C 28 H 29 F6N2O4: 571.2037, found: 571.2023.

[0152] Example 7

[0153]

[0154] For the synthesis method of compound 1, see compound 1, white solid, yield 40%.

[0155] 1 H NMR(500MHz,Chloroform-d)δ7.69(d,J=7.9Hz,1H),7.51(dd,J=7.6,1.4Hz,1H),7.49–7.45(m,1H),7.43(dd,J=7.8,1.4Hz,1H),7.37 (d,J=2.0Hz,1H),7.33(td,J=7.5,1.2Hz,1H),6.85(d,J=8.4Hz,1H),6.46(t,J=6.1Hz,1H),4.98(ddt,J=12.5,9.3,4.6Hz,1H),4.41– 4.28(m,1H),4.16(dt,J=9.8,6.1Hz,1H),3.93(s,3H),3.75(s,3H),3.68(dd,J=13.1,2.9Hz,1H),3.31(dd,J=13.4,6.1Hz,1H),3.19( t,J=12.8Hz,1H),3.00(dd,J=13.4,6.2Hz,1H),2.88–2.74(m,1H),2.07–1.95(m,1H),1.60(d,J=5.6Hz,4H),1.09(s,3H),0.98(s,3H).

[0156] 13 C NMR(126MHz,Chloroform-d)δ195.16,168.36,163.81,154.26,147.22,137.74,133.03,130.57,128.88,128.39,128.34,127.06,126.69(q ,J=280.6Hz),123.53,112.16,110.46,67.56,61.43,56.14,47.74,42.49(q,J=28.2Hz),41.07,39.12,27.08,25.66,24.36,23.29,23.18.

[0157] 19 F NMR (471MHz, Chloroform-d) δ-68.63 (d, J=9.4Hz).

[0158] HRMS(ESI)calcd.for[MH] - C28 H 32 F3N2O5:533.2269,found:533.2256.

[0159] Example 8

[0160]

[0161] For the synthesis method of compound 1, see compound 1, white solid, yield 31%.

[0162] 1 H NMR(500MHz,Chloroform-d)δ7.68(d,J=7.9Hz,1H),7.47(td,J=7.7,1.5Hz,1H),7.43–7.39(m,2H),7.36(dd,J=7.7,1.4Hz,1H),7.31(t,J=7.9Hz,1H),7.2 7(d,J=1.1Hz,1H),7.26–7.23(m,2H),7.22–7.16(m,1H),7.13–7.09(m,2H),7 .05(ddd,J=8.2,2.6,1.0Hz,1H),6.30(t,J=6.2Hz,1H),4.92(ddd,J=10.7,9.0 ,4.5Hz,1H),4.24(dt,J=11.4,4.7Hz,1H),4.08(ddd,J=11.9,7.3,4.5Hz,1H) ,3.98(t,J=6.5Hz,2H),3.60(dd,J=13.2,4.5Hz,1H),3.42–3.28(m,2H),3.02 (dd,J=13.5,5.7Hz,1H),2.82–2.73(m,1H),2.62(td,J=7.5,3.2Hz,2H),2.15 –2.07(m,1H),1.96–1.84(m,2H),1.75–1.67(m,4H),1.11(s,3H),1.02(s,3H).

[0163] 13C NMR(126MHz,Chloroform-d)δ196.76,168.39,163.70,158.55,141.71,137. 34,136.53,133.09,130.71,130.04,128.92,128.39,126.97,126.59(q,J=28 0.8Hz),125.87,121.66,121.33,113.21,72.89,67.00,47.71,42.52(q,J=28 .4,27.8Hz),41.28,40.29,32.27,30.75,27.88,25.11,24.82,23.45,23.19.

[0164] 19 F NMR (471MHz, Chloroform-d) δ-68.14 (d, J=9.3Hz).

[0165] HRMS(ESI)calcd.for[MH] - C 35 H 38 F3N2O4:607.2789,found:607.2778.

[0166] Example 9

[0167]

[0168] For the synthesis method of compound 1, see compound 1, white solid, yield 47%.

[0169] 11H NMR (500 MHz, Chloroform-d) δ 8.12 (s, 1H), 7.93 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.61–7.51 (m, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.42 (t, J = 2.0 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.06 (dd, J = 8.2, 2.6 Hz, 1H), 6.46 (t, J = 6.2 Hz, 1H), 5.02 (ddt, J = 14.4, 9.4, 4.6 Hz, 1H), 4.21 (dt, J = 11.5, 4.5 Hz, 1H), 4.07 (ddd, J = 11.8, 7.4, 4.8 Hz, 1H), 3.79 (s, 3H), 3.73 (dd, J = 13.4, 4.9 Hz, 1H), 3.51–3.39 (m, 2H), 3.05 (dd, J = 13.4, 5.6 Hz, 1H), 2.75 (dt, J = 12.7, 8.1 Hz, 1H), 2.09 (ddd, J = 12.2, 7.5, 3.6 Hz, 1H), 1.72–1.58 (m, 4H), 1.16 (s, 3H), 1.04 (s, 3H).

[0170] 13 13C NMR (151 MHz, Chloroform-d) δ 196.41, 168.20, 163.42, 158.06, 136.07, 134.51, 133.28, 131.55, 129.60, 129.57, 128.43, 127.69, 127.41, 127.36, 126.94, 126.58, 126.27 (q, J = 280.3 Hz), 121.02, 120.84, 113.02, 66.53, 61.01, 47.16, 41.96 (q, J = 27.8 Hz), 40.80, 40.74, 27.24, 24.63, 24.37, 22.89, 22.63.

[0171] 19 19F NMR (471 MHz, Chloroform-d) δ -68.01 (d, J = 9.6 Hz).

[0172] HRMS (ESI) calcd. for [M-H] - C 31 H 32 F3N2O4: 553.2320, found: 553.2307.

[0173] Example 10

[0174]

[0175] For the synthesis method of compound 1, see compound 1, white solid, yield 41%.

[0176] 1 H NMR(500MHz,Chloroform-d)δ8.13(s,1H),7.79–7.70(m,1H),7.51(dd,J=7.5,1.5Hz,1H),7.46(d,J=7.8Hz,1H),7.41–7.34(m,2H),7.33–7.2 7(m,2H),7.16–7.11(m,1H),4.90(ddd,J=11.8,9.6,2.6Hz,1H),4.67(d,J=14.7Hz,1H),4.46(d,J=14.7Hz,1H),3.93(dd,J=13.2,9.4Hz,1H),3 .77(s,3H),3.75–3.67(m,1H),3.61(dd,J=18.4,2.5Hz,1H),3.54–3.34(m,3H),2.53(td,J=12.2,3.8Hz,1H),2.02(ddt,J=12.5,8.2,4.5Hz,1H ),1.89(td,J=12.2,4.5Hz,1H),1.82–1.72(m,1H),1.58(qt,J=12.4,4.1Hz,1H),1.45(ddt,J=15.6,9.2,3.0Hz,1H),1.36(s,3H),1.15(s,3H).

[0177] 13 C NMR(126MHz,Chloroform-d)δ194.36,169.37,165.07,140.38,140.07,135.93,133.85,130.98,129.79,128.37,127.94,127.54,127.41,1 27.06(q,J=280.2Hz),126.49,125.55,70.45,70.21,61.50,47.21,42.17,40.15(q,J=27.6Hz),39.45,30.96,26.69,25.79,25.72,22.22.

[0178] 19 F NMR (471MHz, Chloroform-d) δ-68.34 (d, J=9.6Hz).

[0179] HRMS(ESI)calcd.for[MH] - C 28 H 32 F3N2O4:517.2320,found:517.2306.

[0180] Example 11

[0181]

[0182] For the synthesis method of compound 1, see compound 1, white solid, yield 41%.

[0183] 1 H NMR(500MHz,Chloroform-d)δ8.61(t,J=1.9Hz,1H),8.15(dt,J=7.8,1.3Hz,1H),7.97(dt,J=7.9,1.4Hz,1H),7.60–7.49(m,2H),7.46 (dd,J=7.7,1.5Hz,1H),7.40(td,J=7.7,1.5Hz,1H),7.31(td,J=7.6,1.2Hz,1H),6.57(dd,J=9.3,3.6Hz,1H),5.31(td,J=10.1,3.4Hz, 1H),4.51(dt,J=10.7,3.3Hz,1H),4.07(td,J=10.5,3.5Hz,1H),3.85(dd,J=13.4,9.1Hz,1H),3.81(s,3H),3.65–3.51(m,2H),3.45(dd ,J=13.4,3.6Hz,1H),2.60(td,J=11.6,5.9Hz,1H),2.06–1.97(m,1H),1.94–1.81(m,3H),1.79–1.69(m,1H),1.43(s,3H),1.16(s,3H).

[0184] 13 C NMR(126MHz,Chloroform-d)δ194.28,168.97,165.19,164.89,138.75,135.79,134.50,133.55,131.46,131.34,130.57,130.28,128.98,1 28.44,128.10,127.35,127.10(q,J=279.5Hz),64.71,61.52,47.04,4 2.05,39.97(q,J=27.6Hz),39.96,29.23,26.20,25.48,23.47,21.98.

[0185] 19 F NMR (471MHz, Chloroform-d) δ-67.82 (d, J=9.4Hz).

[0186] HRMS(ESI)calcd.for[MH] - C 28 H 30 F3N2O5:531.2112,found:531.2097.

[0187] Example 12

[0188]

[0189] For the synthesis method of compound 1, see compound 1, white solid, yield 37%.

[0190] 1 H NMR(500MHz,Chloroform-d)δ8.20(d,J=2.0Hz,1H),7.86(dd,J=7.8,1.8Hz,2H),7.56–7.47(m,3H),7.40(td,J=7.6,1.5Hz,1H),7.33(td, J=7.8,1.8Hz,2H),7.28(t,J=2.1Hz,1H),7.20(dd,J=7.7,1.3Hz,1H),7.02(dd,J=7.7,4.6Hz,1H),6.91(dd,J=8.1,2.5Hz,1H),4.99(pd,J =9.8,9.1,2.8Hz,1H),4.22(t,J=6.5Hz,2H),3.89–3.76(m,2H),3.70(s,3H),3.58(dd,J=17.6,3.5Hz,1H),3.48(dd,J=13.4,4.6Hz,1H),2 .56–2.39(m,1H),2.33(ddd,J=12.4,10.5,4.3Hz,1H),1.83(dhept,J=11.8,7.7,6.1Hz,3H),1.73–1.59(m,1H),1.32(s,3H),1.19(s,3H).

[0191] 13C NMR(126MHz,Chloroform-d)δ195.63,169.20,164.52,159.28,141.00,140.58, 139.22,136.34,133.10,131.43,130.13,130.04,129.16,128.22,127.83,127.7 6,126.90,126.86(q,J=280.3Hz),126.66,118.84,117.09,112.50,68.03,61.3 6,47.52,41.66,40.58(q,J=27.6Hz),39.61,29.29,26.25,24.71,23.41,23.28.

[0192] 19 F NMR (471MHz, Chloroform-d) δ-68.28 (d, J=9.7Hz).

[0193] HRMS(ESI)calcd.for[MH] - C 33 H 34 F3N2O4:579.2476,found:579.24762.

[0194] Example 13

[0195]

[0196] For the synthesis method of compound 1, see compound 1, white solid, yield 33%.

[0197] 1H NMR(500MHz,Chloroform-d)δ8.54(d,J=1.4Hz,1H),7.80(d,J=1.4Hz,1H),7.76(t,J=2.1Hz,1H),7.54(d,J=7.9Hz,1H),7.48(td,J=7.6,1.6Hz,1H),7.44(dd,J=7.6,1.5Hz,1H),7.38(td,J=7.4,1.3Hz,1H),7.31(t,J=7.9Hz,1H),7.21(ddd,J=7.7,1.7,0.9Hz,1H),6.83(ddd,J=8.1,2.5,0.9Hz,1H),6.03(dd,J=9.6,3.5Hz,1H),5.10–4.93(m,1H),4.33–4.19(m,1H),4.13–3.99(m,2H),3.88(s,3H),3.65–3.54(m,1H),3.30(dd,J=13.5,11.4Hz,1H),2.91–2.79(m,1H),2.66–2.47(m,2H),1.92–1.84(m,2H),1.80(dt,J=11.9,4.9Hz,1H),1.74–1.65(m,1H),1.21(s,3H),1.14(s,3H).

[0198] 13 C NMR(126MHz,Chloroform-d)δ190.19,169.17,164.16,159.37,143.36,143.25,137.66,135.87,132.94,130.74,129.74,128.87,128.82,128.59,127.18,126.27(q,J=280.2Hz),118.03,115.34,111.93,68.37,61.43,47.55,43.10(q,J=27.7Hz),41.80,41.69,28.72,26.48,24.83,24.22,23.18.

[0199] 19 F NMR(471MHz,Chloroform-d)δ-67.15(d,J=9.2Hz).

[0200] HRMS(ESI)calcd.for[M-H] - C 31 H 32 F3N2O4S:585.2040,found:585.2034.

[0201] Example 14

[0202]

[0203] For the synthesis method of compound 1, white solid, yield 26%.

[0204] 1H NMR(500MHz,Chloroform-d)δ7.91(d,J=1.7Hz,1H),7.84(dt,J=7.7,1.4Hz,1H),7.66(dt,J=8.0,1.3Hz,1H),7.57–7.54(m,1H),7.52(dt,J=7.2,3. 1Hz,1H),7.48(t,J=7.7Hz,1H),7.35(d,J=3.5Hz,3H),7.10(t,J=8.2Hz,1 H),6.53(ddd,J=8.3,2.4,0.9Hz,1H),6.43(ddd,J=8.1,2.4,0.9Hz,1H),6 .37(t,J=2.3Hz,1H),5.30–5.03(m,2H),4.77(ddq,J=19.0,9.4,4.6,4.0H z,1H),3.92–3.76(m,4H),3.65(s,3H),3.61(dd,J=18.2,4.1Hz,1H),3.52 (dd,J=13.5,5.1Hz,1H),2.29(td,J=12.1,5.2Hz,1H),2.17–2.07(m,1H), 1.73(td,J=6.7,3.0Hz,2H),1.61–1.50(m,2H),1.23(s,3H),1.17(s,3H).

[0205] 13 C NMR(126MHz,Chloroform-d)δ195.86,169.10,164.28,159.99,158.96,139.45,13 8.73,136.05,132.87,131.20,130.02,129.88,129.29,128.71,128.45,127.77,1 26.89,126.71,126.50(q,J=280.5Hz),109.40,107.66,101.86,69.59,67.18,61. 20,47.44,41.87,40.59(q,J=28.1Hz),38.75,28.96,25.41,24.16,23.52,22.97.

[0206] 19F NMR (471MHz, Chloroform-d) δ-69.00 (d, J = 8.3Hz).

[0207] HRMS(ESI)calcd.for[MH] - C 34 H 36 F3N2O5:609.2582,found:609.2576.

[0208] Example 15

[0209]

[0210] For the synthesis method of compound 1, see compound 1, white solid, yield 33%.

[0211] 1 H NMR(500MHz,Chloroform-d)δ7.56–7.49(m,2H),7.48–7.43(m,2H),7.41–7.34(m,5H),7.33–7 .27(m,2H),7.21–7.14(m,2H),5.19(s,2H),4.75(ddd,J=11.3,9.2,3.3Hz,1H),4.55–4.41(m,2 H),3.80–3.72(m,2H),3.69(s,3H),3.57–3.49(m,2H),3.34(t,J=6.2Hz,2H),2.23(dq,J=11.7, 5.7Hz,1H),2.17–2.00(m,1H),1.63–1.56(m,2H),1.52–1.44(m,2H),1.19(s,3H),1.15(s,3H).

[0212] 13 C NMR(126MHz,Chloroform-d)δ195.37,169.11,164.17,158.67,139.56,139.03,1 37.18,136.81,131.24,129.80,128.64,128.55,128.36,127.26,126.77,126.56( q, J=279.6Hz),126.31,126.05,121.47,121.00,114.24,72.55,69.85,69.32,61. 26,47.38,41.63,40.63(q,J=27.7Hz),38.68,30.32,26.05,24.44,23.57,23.13.

[0213] 19F NMR (471MHz, Chloroform-d) δ-68.99 (d, J=8.3Hz).

[0214] HRMS(ESI)calcd.for[MH] - C 35 H 38 F3N2O5:623.2738,found:623.2733.

[0215] Example 16

[0216]

[0217] Reaction conditions:

[0218]

[0219] Experimental Methods: Under air atmosphere, macrolide precursor 16' (0.2 mmol, 2.0 mol%), dioxazolone 16' (0.1 mmol, 1.0 mol%), [Cp*RhCl2]2 (0.005 mmol, 5 mol%), AgSbF6 (0.02 mmol, 20 mol%), and AgOAc (0.02 mmol, 20 mol%) were added sequentially to a screw-capped pressure-resistant tube. Immediately afterwards, 10 mL of dichloromethane solution was added and thoroughly mixed. The reaction system was stirred at 80 °C for 24 hours. After the reaction was complete as monitored by TLC, the reaction system was cooled to room temperature, filtered through diatomaceous earth to remove metals and other solid impurities, and then the solvent was removed by rotary evaporation. Finally, the differentiated product 16 was purified by column chromatography, with a reaction yield of 26%.

[0220] 1 H NMR(500MHz,Chloroform-d)δ7.39–7.30(m,2H),7.26–7.18(m,2H),6.46(q,J=1.7Hz,1H),5.97(t,J=5.3Hz,1H),5.68(q,J=1.2Hz,1H),3.91–3.86(m ,2H),3.85(s,2H),3.75(s,3H),3.57(d,J=5.8Hz,2H),2.37(t,J=6.8Hz,2 H),1.52(dt,J=10.0,6.8Hz,2H),1.45(tt,J=8.0,2.9Hz,2H),1.25(s,6H).

[0221] 13C NMR(126MHz,Chloroform-d)δ169.89,167.07,163.38,138.44,136.70,136.64,129.93,129. 27,128.12,126.38,126.36,65.10,61.24,48.07,42.11,35.63,27.63,25.33,23.95,23.69.

[0222] HRMS[ESI]calcd.for[M+H] + C 21 H 29 N2O4:373.2122, found:373.2128.

[0223] Example 17

[0224]

[0225] For the synthesis method of compound 16, white solid, yield 28%.

[0226] 1 H NMR(500MHz,Chloroform-d)δ7.15(d,J=1.9Hz,1H),7.13(dd,J=7.8,1.8Hz,1H ),7.08(d,J=7.9Hz,1H),6.44(q,J=1.8Hz,1H),5.94(t,J=5.5Hz,1H),5.65(q,J =1.3Hz,1H),3.95–3.86(m,2H),3.79(d,J=1.2Hz,2H),3.76(s,3H),3.56(d,J= 5.8Hz,2H),2.37(t,J=6.8Hz,2H),2.33(s,3H),1.58–1.42(m,4H),1.25(s,6H).

[0227] 13 C NMR(126MHz,Chloroform-d)δ170.08,167.15,163.45,138.60,136.57,136.06,133.38,130.63, 129.05,128.07,127.01,65.05,61.24,48.04,42.06,35.19,27.68,25.31,23.99,23.67,20.90.

[0228] HRMS[ESI]calcd.for[M+H] + C 22 H 31N2O4:387.2278, found:387.2277.

[0229] Example 18

[0230]

[0231] For the synthesis method of compound 16, white solid, yield 30%.

[0232] 1 H NMR(500MHz,Chloroform-d)δ7.52(dd,J=8.1,1.7Hz,1H),7.48(d,J=8.0Hz,1H),7.44(d,J=1.7Hz,1H),6.55(q,J=1.6Hz,1H),6.04(t,J=6.0Hz,1H),5.75(q ,J=1.3Hz,1H),3.95–3.89(m,2H),3.86(s,2H),3.75(s,3H),3.59(d,J=5.9Hz, 2H), 2.39 (t, J = 6.7Hz, 2H), 1.58–1.46 (m, 2H), 1.47–1.40 (m, 2H), 1.25 (s, 6H).

[0233] 13 C NMR (126MHz, Chloroform-d) δ168.57,166.46,163.24,139.95,137.93,137.27,131.95(q,J=32.38),130.57,126.88,124.83(q,J= 3.84), 123.66 (q, J = 272.49), 123.56 (q, J = 3.93), 122.57, 120.40, 65.23, 61.29, 47.97, 42.26, 35.59, 27.53, 25.36, 23.83, 23.70.

[0234] HRMS[ESI]calcd.for[M+H] + C 22 H 28 F3N2O4:441.1996,found:441.2003.

[0235] Example 19

[0236]

[0237] For the synthesis method of compound 16, white solid, yield 30%.

[0238] 1H NMR(500MHz,Chloroform-d)δ7.56–7.50(m,2H),7.48–7.39(m,5H),7.39–7.33(m,1H),6.49(q,J=1.8Hz,1H),6.02(t,J=5.7Hz,1H), 5.72(q,J=1.3Hz,1H),3.95–3.86(m,4H),3.76(s,3H),3.59(d,J=5.7Hz,2H),2.38(t,J=6.8Hz,2H),1.58–1.43(m,4H),1.26(s,6H).

[0239] 13 C NMR(126MHz,Chloroform-d)δ169.75,167.02,163.40,142.77,140.18,138.40,137.24,135.46,129.47,128. 85,127.82,127.19,126.92,126.88,125.12,65.17,61.27,48.14,42.11,35.67,27.70,25.36,24.01,23.74.

[0240] HRMS[ESI]calcd.for[MH] - C 27 H 31 N2O4:447.2289, found:447.2274.

[0241] Example 20

[0242]

[0243] For the synthesis method of compound 16, white solid, yield 31%.

[0244] 1 H NMR(500MHz,Chloroform-d)δ7.44(dd,J=7.7,1.3Hz,1H),7.19–7.09(m,2H),6.51(d,J=1.6Hz,1H),5.85(t,J=6.0Hz,1H),5.67 (d,J=1.4Hz,1H),3.94(t,J=4.8Hz,2H),3.77(s,3H),3.75(s,2H),3.65(d,J=5.9Hz,2H),1.69–1.52(m,4H),1.33-1.24(m,8H).

[0245] 13C NMR(126MHz,Chloroform-d)δ167.62,166.70,162.91,138.28,138.17,137.29,130.88,130.3 1,130.13,126.22,119.70,65.13,61.27,47.63,41.85,36.02,27.48,25.30(m),23.66,23.60.

[0246] HRMS[ESI]calcd.for[MH] - C 21 H 26 BrN2O4:449.1081,found:449.1074.

[0247] Example 21

[0248]

[0249] For the synthesis method of compound 16, white solid, yield 36%.

[0250] 1 H NMR(500MHz,Chloroform-d)δ7.89–7.80(m,2H),7.78–7.71(m,1H),7.61(s,1H),7 .49(tt,J=6.9,5.3Hz,2H),6.55(d,J=1.7Hz,1H),6.15(t,J=5.8Hz,1H),5.77(d,J =1.7Hz,1H),3.95(s,2H),3.87–3.81(m,2H),3.71(s,3H),3.63(d,J=5.8Hz,2H),2 .38(t,J=6.9Hz,2H),1.52(dt,J=10.1,6.8Hz,2H),1.44–1.35(m,2H),1.28(s,6H).

[0251] 13 C NMR(126MHz,Chloroform-d)δ169.89,167.15,163.36,138.35,135.74,133.90,133.77,131.38,129.32,127. 77,127.68,127.20,126.88,126.26,125.94,65.08,61.25,48.05,42.38,35.72,27.50,25.48,23.90,23.75.

[0252] HRMS[ESI]calcd.for[M+H]+ C 25 H 31 N2O4:423.2278, found:423.2289.

[0253] Example 22

[0254]

[0255] For the synthesis method of compound 16, white solid, yield 32%.

[0256] 1 H NMR(500MHz,Chloroform-d)δ7.24–7.20(m,2H),7.15(dd,J=8.3,1.6Hz,1H),7.11(d,J=7.9Hz, 1H),6.88(t,J=2.0Hz,1H),6.84–6.77(m,2H),6.49(t,J=6.4Hz,1H),6.32(q,J=1.2Hz,1H),5.4 7(d,J=1.6Hz,1H),5.13(s,2H),4.09(t,J=5.7Hz,2H),3.83(s,2H),3.74(s,3H),3.50(d,J=6.4 Hz, 2H), 2.33 (s, 3H), 2.28–2.20 (m, 2H), 1.75 (q, J = 6.1Hz, 2H), 1.69–1.59 (m, 2H), 1.09 (s, 6H).

[0257] 13 C NMR(126MHz,Chloroform-d)δ169.81,166.55,164.22,159.04,139.63,137.70,137.10,136.35,133.13,130.56,130.52,129 .39,127.96,127.48,119.97,115.38,114.00,67.19,65.84,61.33,47.13,41.86,35.03,28.89,25.30,23.79,22.63,20.96.

[0258] HRMS[ESI]calcd.for[M+H] + C 29 H 37 N2O5: 493.2697, found: 493.2703.

[0259] Example 23

[0260]

[0261] For the synthesis method of compound 16, white solid, yield 33%.

[0262] 1 H NMR(500MHz,Chloroform-d)δ7.30(d,J=1.9Hz,1H),7.15(dt,J=7.9,1.4Hz,1H),7.04(d ,J=7.9Hz,1H),6.63(s,1H),6.34(q,J=1.3Hz,1H),5.33(q,J=1.7Hz,1H),4.32–4.15(m,2 H),3.74(d,J=1.6Hz,2H),3.71(s,3H),3.56(d,J=5.9Hz,2H),2.35(s,3H),2.26(t,J=6. 8Hz,2H),1.65(dd,J=6.5,4.7Hz,2H),1.60–1.52(m,2H),1.42–1.32(m,2H),1.15(s,6H).

[0263] 13 C NMR(126MHz,Chloroform-d)δ169.94,166.74,164.07,139.77,137.78,136.55,131.36,130.41,129 .88,128.65,127.58,64.01,61.26,47.52,41.60,35.11,28.32,26.12,25.88,25.30,24.74,20.95.

[0264] HRMS[ESI]calcd.for[M+H] + C 23 H 33 N2O4:401.2435, found:401.2431.

[0265] Example 24

[0266]

[0267] For the synthesis method of compound 16, white solid, yield 31%.

[0268] 1H NMR(500MHz,Chloroform-d)δ7.63–7.54(m,2H),7.54–7.51(m,1H),7.50(d,J=2.0Hz ,1H),7.47–7.41(m,2H),7.27(d,J=8.0Hz,1H),6.50(d,J=1.7Hz,1H),6.05(t,J=5.9H z,1H),5.71(q,J=1.2Hz,1H),3.96–3.88(m,2H),3.85(s,2H),3.73(s,3H),3.61(d,J= 5.9Hz,2H),2.39(t,J=6.7Hz,2H),1.57–1.52(m,2H),1.51–1.42(m,2H),1.26(s,6H).

[0269] 13 C NMR(126MHz,Chloroform-d)δ169.67,167.00,163.38,138.84,138.15,137.45,135.94,132.05,129.58, 128.75,128.58,128.25,124.77,121.95,65.17,61.30,47.97,42.30,35.45,27.55,25.41,23.88,23.67.

[0270] HRMS[ESI]calcd.for[M+H] + C 27 H 32 BrN2O4:527.1540,found:527.1544.

[0271] Example 25

[0272]

[0273] Reaction conditions:

[0274]

[0275] Experimental methods:

[0276] Step 1: Take a dry reaction flask and dissolve compound 24 (1 mmol, 1 equivalent), Pd(dppf)Cl2 (15 mol%), B2Pin2 (2.0 equivalent), and KOAc (3.0 equivalent) in a 1,4-dioxane solution. After completely purging with nitrogen, seal the reaction system and react at 90°C for 2–3 hours. After the reaction is complete, purify by column chromatography to obtain phenylboronic acid ester 24'.

[0277] Step 2: Take a dry reaction flask and dissolve compound 24' (1 mmol, 1 equivalent), 6-chloro-2-(methanesulfonyl)-N-phenylpyrimidine-4-amino (compound 24', 1.3 equivalent), Pd(PPh3)4 (10 mol%), and sodium carbonate (3.0 equivalent) in a mixed solution of 1,4-dioxane and water (v / v = 10 / 1). After fully purging with nitrogen, seal the reaction system and react overnight at 90°C. After the reaction is complete, purify by column chromatography to obtain product 25.

[0278] Product 25 was a white solid, with a two-step yield of 68%.

[0279] 1 H NMR(500MHz,Chloroform-d)δ8.08–7.91(m,2H),7.71–7.63(m,2H),7.60(d,J=2.0Hz,1H),7.56(dd,J=8.2, 2.2Hz,2H),7.47(t,J=7.8Hz,2H),7.42(d,J=7.9Hz,2H),7.29(dd,J=7.8,4.8Hz,2H),7.18(s,1H),6.50(d,J =1.7Hz,1H),6.10(t,J=5.9Hz,1H),5.71(d,J=1.7Hz,1H),3.93(t,J=5.0Hz,2H),3.86(s,2H),3.72(s,3H),3 .62(d,J=5.9Hz,2H),3.42(s,3H),2.39(t,J=6.6Hz,2H),1.64–1.56(m,2H),1.56–1.43(m,2H),1.26(s,6H).

[0280] 13 C NMR(126MHz,Chloroform-d)δ169.73,166.97,166.05,163.99,163.38,162.70,142.73,138.14,138.09,137.49,137.06,136.37,134.78,129 .89,129.65,128.85,128.47,127.78,127.37,126.18,124.95,123.01, 65.19,61.31,48.02,42.32,38.95,35.50,27.56,25.42,23.89,23.67.

[0281] HRMS[ESI]Calcd for[M+H] + C 38 H 42N5O6S:696.2850,Found:696.2847.

[0282] Example 26

[0283]

[0284] Reaction conditions:

[0285]

[0286] Experimental Method: Under air atmosphere, macrolide precursor 26' (0.2 mmol, 2.0 mol%), dioxazolone 26' (0.1 mmol, 1.0 mol%), [Cp*RhCl2]2 (0.005 mmol, 5 mol%), AgSbF6 (0.02 mmol, 20 mol%), and AgOAc (0.04 mmol, 40 mol%) were added sequentially to a screw-capped pressure-resistant tube. Immediately afterwards, 5 mL of tetrachloroethane solution was added and thoroughly mixed. The reaction system was stirred at 80 °C for 24 hours. After the reaction was complete as monitored by TLC, the reaction system was cooled to room temperature, filtered through diatomaceous earth to remove metals and other solid impurities, and then the solvent was removed by rotary evaporation. Finally, the target product 26 was purified by column chromatography. It was a white solid with a reaction yield of 30%.

[0287] 1 H NMR(500MHz,Chloroform-d)δ7.83(d,J=16.0Hz,1H),7.47(d,J=7.8Hz,1H),7.40(td,J=8.0,5.5Hz,1H),7. 25–7.24(m,1H),7.14(t,J=8.6Hz,1H),6.91(d,J=2.5Hz,1H),6.83(dd,J=8.3,2.5Hz,1H),6.47(dd,J=15.9 ,0.9Hz,1H),6.47(dd,J=15.9,0.9Hz,1H),6.36(t,J=6.6Hz,1H),5.23(s,2H),4.11(t,J=5.5Hz,2H),3.72( s,3H),3.61(d,J=6.5Hz,2H),2.42–2.00(m,2H),1.75(p,J=6.1Hz,2H),1.66(q,J=7.1Hz,2H),1.04(s,6H).

[0288] 13C NMR(126MHz,Chloroform-d)δ165.56,164.63,163.79,159.05(d,J=247.5Hz),140.89(d,J=2.5Hz),138.01,134.98(d,J=3.4Hz),130.87(d,J=8.4Hz) ,129.41,122.42(d,J=3.1Hz),121.69,120.05,117.10(d,J=22.5Hz),116. 04,112.88,66.01,65.59,61.45,47.04,41.70,28.48,25.03,23.54,21.40.

[0289] HRMS[ESI]Calcd for[M+H] + C27H32FN2O5:483.2290,Found:483.2302.

[0290] Example 27

[0291]

[0292] For the synthesis method of compound 16, white solid, yield 33%.

[0293] 1 H NMR(500MHz,Chloroform-d)δ7.20(s,1H),7.13(d,J=8.0Hz,1H),7.09(d,J=7.9Hz,1H),6.43(d,J=1.6Hz,1H),6. 22(dd,J=9.4,4.0Hz,1H),5.67(s,1H),4.00(d,J=16.2Hz,1H),3.97–3.86(m,2H),3.82–3.78(m,1H),3.77(s,3H), 3.66(d,J=16.2Hz,1H),3.29(td,J=13.1,12.5,4.0Hz,1H),2.84(td,J=11.6,4.4Hz,1H),2.74(dqd,J=11.1,6.9,4 .0Hz,1H),2.33(s,3H),1.90(dt,J=12.5,4.7Hz,1H),1.61–1.41(m,3H),1.37–1.22(m,1H),1.14(d,J=6.9Hz,3H).

[0294] 13C NMR(126MHz,Chloroform-d)δ169.73,167.09,162.07,138.71,135.88,135.59,134.69,130.90, 128.74,128.22,127.25,64.73,61.25,41.80,38.07,35.35,27.77,25.92,23.05,20.90,17.81.

[0295] HRMS[ESI]calcd.for[M+H] + C 21 H 29 N2O4:373.2122, found:373.2124.

[0296] Example 28

[0297]

[0298] For the synthesis method of compound 16, white solid, yield 22%.

[0299] 1 H NMR(500MHz,Chloroform-d)δ7.52(t,J=5.6Hz,2H),7.45(s,1H),6.55(t,J=1.2Hz,1H),6.30(dd, J=9.2,3.8Hz,1H),5.78(s,1H),4.07(d,J=16.4Hz,1H),4.03–3.91(m,2H),3.83–3.76(m,1H),3.76 (s,3H),3.72(d,J=16.4Hz,1H),3.31(td,J=13.3,12.5,3.8Hz,1H),2.91–2.79(m,1H),2.80–2.64 (m,1H),1.91(dt,J=12.5,4.4Hz,1H),1.56–1.45(m,3H),1.31–1.20(m,1H),1.15(d,J=6.8Hz,3H).

[0300] 13C NMR(126MHz,Chloroform-d)δ168.23,166.37,161.82,139.17,138.94,137.36,132.16(d,J=32.8Hz),130.32,127.06,124.9 8(d,J=3.7Hz),123.64(d,J=272.6Hz),123.43(d,J=3.8Hz),64.87,61.31,41.72,37.98,35.69,27.72,25.76,23.06,17.74.

[0301] HRMS[ESI]calcd.for[M+H] + C 21 H 26 F3N2O4:427.1839,found:427.1845.

[0302] Example 29

[0303]

[0304] For the synthesis method of compound 16, white solid, yield 36%.

[0305] 1 H NMR(500MHz,Chloroform-d)δ7.92(s,1H),7.84(d,J=7.7Hz,1H),7.75(d,J=7.8Hz,1H),7.61(s,1H),7.49(ddd,J=13.4,7.6,3 .9Hz,2H),6.60–6.50(m,1H),6.48–6.34(m,1H),5.78(s,1H),4.11(d,J=16.3Hz,1H),4.02(ddd,J=13.1,9.2,4.0Hz,1H),3.93( td,J=11.1,1.8Hz,1H),3.85(d,J=16.4Hz,1H),3.73(s,3H),3.73–3.69(m,1H),3.44–3.19(m,1H),2.85(td,J=11.9,4.6Hz,1H) ,2.76(dqd,J=11.0,6.9,3.8Hz,1H),1.89(dt,J=12.5,4.8Hz,1H),1.58–1.39(m,3H),1.29–1.19(m,1H),1.16(d,J=6.9Hz,3H).

[0306] 13C NMR(126MHz,Chloroform-d)δ169.57,167.05,161.92,138.50,134.80,134.77,133.91,131.28,129.00,127. 79,127.65,127.34,127.05,126.41,126.25,64.74,61.26,41.69,38.14,35.80,27.69,25.88,23.10,17.81.

[0307] HRMS[ESI]calcd.for[M+H] + C 24 H 29 N2O4:409.2122, found:409.2123.

[0308] Example 30

[0309]

[0310] For the synthesis method of compound 16, white solid, yield 29%.

[0311] 1 H NMR(500MHz,Chloroform-d)δ7.36(dd,J=8.1,5.7Hz,1H),6.99–6.82(m,2H),6.50(d,J=1.6Hz,1H),5.96(t,J=4.9Hz,1H),5.71(d,J= 1.5Hz,1H),4.01–3.87(m,2H),3.83(s,2H),3.75(s,3H),3.55(d,J=5.8Hz,2H),2.38(t,J=6.7Hz,2H),1.58–1.39(m,4H),1.24(s,6H).

[0312] 13 C NMR(126MHz,Chloroform-d)δ169.03,166.69,163.52(d,J=249.6Hz).163.33,140.16(d,J=7.4Hz),137.80,132.81(d,J=3.2Hz),129. 99,128.30(d,J=8.6Hz),115.29(d,J=22.6Hz),113.35(d,J=21.8Hz),65.26,61.27,48.10,42.17,35.64,27.59,25.37,23.93,23.74.

[0313] HRMS[ESI]Calcd for[M+H] + C 21 H 28 FN2O4:391.2028,Found:391.2037.

[0314] Example 31

[0315]

[0316] For the synthesis of compound 16, a white solid with a yield of 35%, please refer to Compound 16.

[0317] 1 H NMR(500MHz,Chloroform-d)δ7.23–7.15(m,1H),7.13–7.04(m,1H),6.35(d,J=1.2Hz,1H),6.01(t,J=5.8Hz,1H),5.60(t,J=1.4Hz,1H), 4.13(t,J=5.1Hz,2H),3.91(d,J=1.7Hz,2H),3.74(s,3H),3.49(d,J=5.8Hz,2H),2.33(t,J=6.5Hz,2H),1.65–1.54(m,4H),1.19(s,6H).

[0318] 13 C NMR(126MHz,Chloroform-d)δ167.85(d,J=1.74Hz),166.25,163.57,151.33(d,J=252.0Hz),149.77(d,J=249.7Hz),137.20,134.06(d,J=3.7Hz) ,128.28,126.96(d,J=12.5Hz),123.33(dd,J=7.1,4.4Hz),115.47(d,J= 17.6Hz),64.54,61.31,48.12,41.51,29.74,28.24,25.05,24.33,22.86.

[0319] HRMS[ESI]Calcd for[M+H] + C 21 H 27 F2N2O4:409.1933,Found:409.1936.

[0320] Example 32

[0321]

[0322] For the synthesis method of compound 16, white solid, yield 30%.

[0323] 1 H NMR(500MHz,Chloroform-d)δ7.92(dd,J=7.9,1.7Hz,1H),7.84(d,J=1.6Hz,1H),7.44 (d,J=7.9Hz,1H),6.55(d,J=1.6Hz,1H),6.04(t,J=5.9Hz,1H),5.77(q,J=1.3Hz,1H), 3.90(s,3H),3.89(d,J=5.5Hz,2H),3.85(s,2H),3.74(s,3H),3.58(d,J=5.9Hz,2H),2 .38(t,J=6.8Hz,2H),1.52(dp,J=9.9,4.6,3.1Hz,2H),1.47–1.39(m,2H),1.25(s,6H).

[0324] 13 C NMR(126MHz,Chloroform-d)δ169.02,166.72,166.42,163.25,140.65,137.46,137.23,131.48,130 .42,129.07,127.87,126.55,65.17,61.27,52.37,47.95,42.24,35.59,27.51,25.35,23.83,23.71.

[0325] HRMS[ESI]Calcd for[M+H] + C 23 H 31 N2O6:431.2177, Found:431.2180.

[0326] Example 33

[0327]

[0328] For the synthesis method of compound 16, white solid, yield 27%.

[0329] 1H NMR(500MHz,Chloroform-d)δ7.91(dd,J=7.9,1.7Hz,1H),7.85(s,1H),7.47(d,J=7.9Hz,1H),6.54(d,J=1.5Hz,1H),6. 31(dd,J=9.0,3.8Hz,1H),5.78(s,1H),4.09–4.02(m,1H),4.00–3.96(m,1H),3.95–3.92(m,1H),3.90(s,3H),3.80–3.7 7(m,1H),3.75(s,3H),3.72(d,J=16.3Hz,1H),3.30(ddd,J=13.2,11.3,3.8Hz,1H),2.85(td,J=11.8,4.4Hz,1H),2.73( ddt,J=11.2,7.0,3.5Hz,1H),1.90(dt,J=12.6,4.5Hz,1H),1.52–1.39(m,3H),1.30–1.18(m,1H),1.15(d,J=6.9Hz,3H).

[0330] 13 C NMR(126MHz,Chloroform-d)δ168.64,166.62,166.39,161.86,139.65,138.45,137.59,131.68,130 .11,129.23,127.73,126.72,64.80,61.28,52.36,41.70,38.00,35.70,27.70,25.77,23.06,17.74.

[0331] HRMS[ESI]Calcd for[M+H] + C 22 H 29 N2O6:417.2020, Found:417.2009.

[0332] Example 34

[0333]

[0334] For the synthesis method of compound 16, white solid, yield 46%.

[0335] 1H NMR(500MHz,Chloroform-d)δ7.41(dd,J=8.2,5.7Hz,1H),6.91(td,J=8.1,4.0Hz,2H),6.50(d,J=1.5Hz,1H),6.24(dd,J=9.5, 4.0Hz,1H),5.72(d,J=1.6Hz,1H),4.08(d,J=16.3Hz,1H),3.97(td,J=11.0,1.6Hz,1H),3.91(td,J=9.0,4.5Hz,1H),3.79(dt, J=11.3,3.7Hz,1H),3.76(s,3H),3.67(d,J=16.4Hz,1H),3.27(ddd,J=13.2,11.4,3.9Hz,1H),2.93–2.80(m,1H),2.74(ddp,J= 10.0,7.0,3.5,3.0Hz,1H),1.89(dt,J=12.5,4.5Hz,1H),1.59–1.38(m,2H),1.26(qt,J=9.9,2.8Hz,1H),1.14(d,J=6.9Hz,3H).

[0336] 13 C NMR (126MHz, Chloroform-d) δ168.66, 166.58, 163.71 (d, J = 249.9Hz), 161.96, 141.51 (d, J = 7.6Hz), 137.95, 131.86 (d, J = 2.8Hz), 129. 63,128.61(d,J=8.7Hz),115.48(d,J=22.4Hz),113.18(d,J=21.7Hz),64.90,61.26,41.83,37.98,35.77,27.73,25.91,23.12,17.76.

[0337] HRMS[ESI]Calcd for[M+H] + C 20 H 26 FN2O4:377.1871,Found:377.1871.

[0338] Example 35

[0339]

[0340] For the synthesis method of compound 16, white solid, yield 36%.

[0341] 1H NMR(500MHz,Chloroform-d)δ7.19–7.10(m,1H),7.10–6.90(m,1H),6.32(s,1H),6.37 –6.27(m,1H),5.75(d,J=1.8Hz,1H),4.16–3.99(m,3H),3.91(d,J=15.8Hz,1H),3.85–3 .76(m,1H),3.76(s,3H),3.34–3.24(m,1H),2.83–2.75(m,1H),2.74–2.63(m,1H),2.0 1(dt,J=13.5,5.4Hz,1H),1.65–1.51(m,3H),1.44–1.35(m,1H),1.13(d,J=7.0Hz,3H).

[0342] 13 C NMR(126MHz,Chloroform-d)δ167.53,166.27,162.11,151.58(d,J=252.4Hz),151.47(d,J=252.1Hz),137.02,133.46(d,J=3.1Hz),12 8.76, 128.32 (d, J = 11.7Hz), 122.70 (dd, J = 6.9, 4.6Hz), 115.05 (d, J = 17.4Hz), 63.91, 61.37, 42.06, 37.68, 29.60, 25.36, 21.83, 17.45.

[0343] HRMS[ESI]Calcd for[M+H] + C 20 H 25 F2N2O4:395.1777,Found:395.1777.

[0344] Example 36

[0345]

[0346] For the synthesis method of compound 16, white solid, yield 32%.

[0347] 1H NMR(500MHz,Chloroform-d)δ7.25(d,J=7.9Hz,1H),7.03(dd,J=7.8,1.7Hz,1 H),6.99(s,1H),6.46(d,J=1.7Hz,1H),5.96–5.88(m,1H),5.68(d,J=1.7Hz,1H ),3.93–3.86(m,2H),3.83(s,2H),3.75(s,3H),3.54(d,J=5.6Hz,2H),2.36(t, J=6.8Hz,2H),2.30(s,3H),1.55–1.48(m,2H),1.48–1.41(m,2H),1.24(s,6H).

[0348] 13 C NMR(101MHz,Chloroform-d)δ170.03,167.16,163.37,139.96,138.55,136.63,133.84,129.15, 128.83,126.99,126.38,65.12,61.22,48.16,41.98,35.44,27.73,25.31,24.03,23.72,21.40.

[0349] HRMS[ESI]calcd.for[M+H] + C 22 H 31 N2O4:387.2278, found:387.2275.

[0350] Example 37

[0351]

[0352] For the synthesis method of compound 16, white solid, yield 40%.

[0353] 1H NMR(500MHz,Chloroform-d)δ7.31–7.27(m,1H),7.14(td,J=9.3,7.7Hz,1H ),6.50(s,1H),6.31(s,1H),5.30–5.10(m,1H),4.38–4.26(m,2H),3.82(q,J =1.9Hz,2H),3.70(s,3H),3.53(d,J=6.0Hz,2H),2.24(t,J=7.0Hz,2H),1.77 –1.68(m,2H),1.54(dd,J=10.6,6.8Hz,3H),1.43–1.36(m,2H),1.12(s,6H).

[0354] 13 C NMR(126MHz,Chloroform-d)δ167.69(d,J=1.8Hz),165.97,164.18,151.11(dd,J=250.7,12.4Hz),149.02(dd,J=248.6,11.6Hz),137.68,135.39–135.23( m),126.40,124.81(d,J=13.4Hz),124.44(dd,J=6.8,4.5Hz),116.09(d,J=17 .4Hz),64.26,61.30,47.70,41.55,29.17,28.01,26.41,25.86,25.69,24.56.

[0355] HRMS[ESI]Calcd for[M+H] + C 22 H 29 F2N2O4:423.2090,Found:423.2095.

[0356] Example 38

[0357]

[0358] For the synthesis method of compound 16, white solid, yield 37%.

[0359] 1H NMR(500MHz,Chloroform-d)δ7.95(dd,J=8.0,1.7Hz,1H),7.84(d,J=1.6Hz,1H), 7.54(d,J=8.0Hz,1H),6.81(s,1H),6.40(q,J=1.1Hz,1H),5.43(q,J=1.5Hz,1H),4 .25–4.17(m,2H),3.91(s,3H),3.82(s,2H),3.70(s,3H),3.57(d,J=5.8Hz,2H),2. 27(t,J=6.7Hz,2H),1.63(dt,J=11.7,6.2Hz,2H),1.37–1.29(m,1H),1.16(s,6H).

[0360] 13 C NMR(126MHz,Chloroform-d)δ168.86,166.47,164.00,141.91,138.89,135.31,131.13,130.85,128 .35,128.19,127.98,63.94,61.23,52.29,47.65,41.58,35.50,28.45,25.87,25.79,25.13,24.79.

[0361] HRMS[ESI]Calcd for[M+H] + C 24 H 33 N2O6:445.2333, Found:445.2342.

[0362] Pharmacological Example 1: Anti-influenza A virus activity

[0363] MDCK cells (ATCC, CCL-34) were seeded in 96-well plates at a density of 10,000 cells per well. After incubation at 37°C in a 5% CO2 incubator for 24 hours, different concentrations of the compound were added and incubated for 1 hour. Then, influenza A virus H1N1 A / Puerto Rico / 8 / 34 (A / PR / 8 / 34) (0.025 TCID50) was added, and the cells were cultured for a total of 3 days. Virus control, cell control, and sample groups were included. After 3 days of culture, viral RNA was extracted from the supernatant and quantified using a probe-based one-step real-time PCR method. A synthetic RNA oligosaccharide dilution was used as a standard to achieve absolute quantification of viral RNA, and the EC50 of the compound was calculated. 50(Half-maximal inhibitory concentration). Simultaneously, the in vitro cytotoxicity of the compound was determined using the MTT assay. In short, after co-culturing the compound with MDCK cells for 3 days, MDCK cells in each well were incubated for 2 hours with 100 μl of MTT (3-(4,5-dimethylthiazolyl)-2,5-diphenyl-2-tetraazole bromide) reagent (final concentration 2.5 mg / mL). Cells were then lysed with lysis buffer containing 10% sodium dodecyl sulfate (SDS) and 50% N,N-dimethylformamide (pH 7.2). The compound's CCC was calculated by measuring the methylbenzan content, which was proportional to the number of viable cells, by reading the absorbance at 570 nm. 50 (Median lethal concentration).

[0364] Pharmacological Example 2: Assay of Influenza A Virus Cytopathic Effect (CPE)

[0365] MDCK cells were seeded in 6-well plates at a density of 600,000 cells per well. After incubation at 37°C in a 5% CO2 incubator for 24 hours, a compound at a final concentration of 20 μM was added and incubated for 1 hour. Influenza A virus H1N1 (2.5 TCID50) was then added, and the cells were cultured for a total of 3 days. Virus control, cell control, and sample groups were included. After 3 days, cell viability and morphology were observed under a microscope. The results showed that the compound significantly improved the cytopathic effect (CPE) induced by influenza A virus (cell rounding, degeneration, and detachment) and increased cell survival.

[0366] The experimental results of pharmacological examples 1 and 2 are shown in Table 1 below.

[0367] Table 1. Anti-influenza A virus activity of compounds

[0368]

[0369]

[0370] Note: CC 50 The effect of the sample drug on the growth of MDCK cells was measured at a 50% lethal concentration.

[0371] EC 50 The concentration at which the sample inhibits H1N1 RNA copy by 50% is given.

[0372] SI is the bioselectivity coefficient for a sample. An SI value greater than 2 indicates effectiveness, and a higher value is better.

[0373] NA: Inactive; -: Cannot be calculated

[0374] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound represented by Formula I, or a pharmaceutically acceptable salt thereof: Formula I in, The compound has a structure selected from the group consisting of: 。 2. A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof: 。 3. The method for preparing the compound of formula I as described in claim 1, characterized in that, The method includes steps (1) or (2): (1) Under the action of a catalyst, silver salt and first base reagent, compound C1 reacts with compound C2 via a carbon-hydrogen bond active reaction to generate compound I; (2) under the action of a catalyst, a silver salt and a first base reagent, the compound of formula C3 reacts with the compound of formula C4 via a carbon-hydrogen bond activation reaction to generate the compound of formula I; wherein R 3 is H; 。 4. A pharmaceutical composition, characterized in that, The composition comprises: (a) a compound as described in any one of claims 1-2, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier.

5. Use of the compound according to any one of claims 1-2 for the preparation of a pharmaceutical composition for the treatment or prevention of diseases or symptoms caused by influenza A virus.

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