Pyridone derivative and application thereof

Abstract

The invention relates to a pyridone derivative as shown in a formula (I) or a stereoisomer thereof, a prodrug of the pyridone derivative, a pharmaceutically acceptable salt, a pharmaceutical composition containing the formula (I), and application of the pyridone derivative or the stereoisomer thereof, the prodrug of the pyridone derivative, the pharmaceutically acceptable salt and the pharmaceutical composition in preparation of a medicine for preventing and / or treating HIV (Human Immunodeficiency Virus) infection. The compound disclosed by the invention has remarkable anti-HIV virus activity, relatively low solubility and very low clearance rate, is suitable for developing a long-acting injection prevention and treatment scheme, and is used for preparing a medicine of an HIV virus integrase inhibitor or a medicine composition containing the medicine so as to benefit patients infected by HIV viruses.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a class of pyridone derivatives or their stereoisomers, various prodrugs of pyridone derivatives, pharmaceutically acceptable salts and pharmaceutical compositions containing formula (I) and their use as antiviral drugs, particularly for the preparation of drugs for the prevention and / or treatment of HIV infection. Background Technology

[0002] HIV is a deadly infectious disease virus. Through its direct or indirect effects, it causes damage to a large number of CD4+ T lymphocytes, leading to cellular immune dysfunction, causing severe infections and tumors, and eventually progressing to acquired immunodeficiency syndrome (AIDS).

[0004] In the development of antiviral drugs, reverse transcriptase, protease, and integrase are important drug targets. Among approved HIV drugs, effective antiviral agents have been demonstrated, and combination regimens of these drugs have achieved sustained viral load suppression in most infected individuals. However, due to viral mutations and long-term use of existing drugs, resistance to combination therapies still develops, ultimately leading to treatment failure. Furthermore, the combined use of multiple drugs places higher demands on drug interaction and safety evaluation studies in patients. Long-acting drugs can significantly improve patient adherence compared to daily dosing regimens; at the same time, low-frequency dosing can improve the convenience of treatment for patients in some underdeveloped areas or special populations. Therefore, there is an urgent need to develop new drugs to address the issues of drug resistance, safety, and patient adherence in current treatments.

[0005] Among the commonly used antiviral drugs, integrase strand transfer inhibitors (INSTIs) have advantages such as good safety and tolerability, rapid inhibition of viral replication, strong antiviral activity, and a high genetic resistance barrier, making them one of the most effective antiviral drugs currently available. As antiviral drugs introduced in recent years, INSTIs are gradually expanding their use globally; however, HIV-infected individuals require long-term medication, and as treatment duration increases, drug resistance gradually emerges.

[0006] To effectively limit the occurrence of drug resistance during treatment, overcome existing drug-resistant strains, and improve the convenience of drug use and patient compliance, this invention provides a compound as shown in formula (I). This compound has high antiviral activity and good long-acting drug properties, including pharmacokinetic characteristics such as low clearance, low solubility, and good permeability. Combined with the development of long-acting formulation processes, it can ensure that the drug maintains an effective exposure dose and a stable antiviral level in vivo for a long time. Summary of the Invention

[0007] The purpose of this invention is to provide a class of pyridone derivatives or their stereoisomers, prodrugs of pyridone derivatives, pharmaceutically acceptable salts, and pharmaceutical compositions containing formula (I), or to provide a class of deuterated pyridone derivatives or their stereoisomers, various prodrugs of deuterated pyridone derivatives, pharmaceutically acceptable salts, and pharmaceutical compositions containing formula (I), possessing broad-spectrum anti-HIV activity. These compounds can highly inhibit clinically resistant strains induced by existing anti-HIV drugs with different and similar mechanisms, and also exhibit good inhibitory activity against cross-resistant clinically resistant strains. Furthermore, the compounds of this invention have a high resistance barrier, and when used in combination with other anti-HIV drugs, even with long-term treatment, this combination therapy can almost completely suppress viral escape and mutation. Replacing hydrogen atoms with deuterium atoms in the drug molecules of this invention, although with only minor structural changes, results in deuterated compounds that significantly improve the pharmacokinetic characteristics and reduce the toxicity of the drug compounds. More importantly, to improve patient compliance, these deuterated compounds have longer half-lives and lower metabolic rates, making them suitable for developing long-acting anti-HIV drugs. The amide-based deuterated alkyl compounds of this invention significantly reduce the dealkylation process in drug metabolism, thereby prolonging the metabolic time and increasing drug exposure. This invention, through N-alkyl compounds of deuterated amides, can significantly improve the physicochemical properties of drugs, such as lower clearance rates and good permeability. Compounds with these characteristics are suitable for developing long-acting compositions or single drugs, thus allowing patients to move away from daily oral treatment regimens and instead use injection regimens every three or six months, greatly improving treatment convenience and patient compliance. In the future, this treatment regimen can also be extended to the more promising indication of HIV infection prevention. For antiviral drugs, treatment is one option, but prevention also has a broad market. The development of long-acting drugs provides a vast market for HIV infection prevention. In summary, this invention provides a method for improving the stability of compounds using deuterated drugs. These compounds exhibit low clearance rates, exposure durations of several months, and extremely long half-lives, demonstrating excellent drug-like properties. Using these pyridone derivatives, prodrugs, and pharmaceutical compositions as antiviral drugs, alone or in combination, can conveniently and effectively treat patients or prevent HIV infection.

[0008] To achieve the above objectives, the present invention adopts the following technical solution:

[0009] A pyridone derivative or its stereoisomer, a prodrug of a pyridone derivative, or a pharmaceutically acceptable salt, wherein the pyridone derivative has the structure shown in formula (I):

[0010]

[0011] in:

[0012] (1) R1 is selected from the following groups, whether unsubstituted or substituted: C 1-20 Alkyl, deuterated C 1-20 Alkyl, C 3-6 cycloalkyl, deuterated C 3-6 Cycloalkyl and alkynyl-substituted C 1-20 alkyl and alkynyl substituted C 3-6 Cycloalkyl and alkynyl-substituted C 3-6 Heterocyclic alkyl, C 3-10 cycloalkyl C 1-10 Alkyl, C 2-8 Heterocyclic C 1-10 Alkyl; the substituent used for substitution is one or more selected from the following groups: halogen (e.g., F, Cl, Br, I), C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, C 6-10 Aryl, C 3-10 heteroaryl, C 1-6 Alkyl sulfone group, C 1-6 alkyl mercapto, cyano, or hydroxyl;

[0013] (2) Each R2 is independently selected from halogens (e.g., F, Cl, Br, I), cyano, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 2-6 Alkyne group; n is 1, 2, 3 or 4;

[0014] (3)R 3a R 3b Independently selected from H, D, C 1-6 Alkyl, deuterated C 1-6 alkyl;

[0015] (4) Q is selected from amides, unsubstituted or substituted 4-6 membered heterocycles; the substituents used for substitution are selected from one or more of the following groups: halogens, C1-2 Alkyl, halogenated C 1-2 Alkyl, C 1-6 Alkyl, cyano, or oxo;

[0016] (5) X and Y are independently selected from CH or N;

[0017] (6) A is absent, or A is selected from unsubstituted or substituted 5-10 membered heterocyclic groups or 5-10 membered carbocyclic groups; the substituent used for substitution is one or more selected from the following groups: halogen (e.g., F, Cl, Br, I), cyano, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkyne group, hydroxyl group, oxo group, exocyclic double bond, halogenated exocyclic double bond, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-3 Alkyl group; wherein, when it contains two substituents, the two substituents are connected together with A to form a spirocyclic, fused, or bridged ring;

[0018] When A is absent, R1 is connected to Y and together with N connected to R1, they form a 3-20 elemental heterocycle;

[0019] (7)C 3-6 Heterocyclic alkyl, C 2-8 Heterocyclic, C 3-10 The heteroatoms in heteroaryl, 4-6 membered heterocycles, 5-10 membered heterocyclic groups, and 3-20 membered heterocycles are independently selected from one or more of O, S, N, -SO2-, Se, and oxo.

[0020] In some embodiments of the present invention, X is N and Y is CH.

[0021] In some embodiments of the present invention, when A is absent, both X and Y are CH.

[0022] In some embodiments of the present invention, the chirality of the carbon atom connected to ring A and Y is selected from the S configuration, R configuration, or R / S configuration, where the R / S configuration is shown in formula (I), and the S and R configurations are shown in formulas (Ia) and (Ib), respectively:

[0023]

[0024] In some embodiments of the present invention, A is selected from unsubstituted and substituted 5-10 membered heterocycles, and the substituents used for substitution are selected from one or more of the following groups: F, Cl, Br, methyl, deuterated methyl, ethyl, deuterated ethyl, trifluoromethyl, difluoromethyl, cyclopropyl, methoxy, ethoxy, propoxy, butoxy, halomethoxy, haloethoxy, halopropoxy, halobutoxy, ethynyl, propynyl, oxo, exocyclic double bond, haloexocyclic double bond, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl.

[0025] In some embodiments of the present invention, the pyridone derivative has the structure shown in formula (IA):

[0026]

[0027] In equation (IA), R1, R2, n, and R 3a R 3b The definitions are the same as before; W is selected from O, CH2, oxo, exocyclic double bond, and halogenated exocyclic double bond; R4 is absent or selected from C. 1-3 Alkyl, deuterated C 1-3 Alkyl; R5 and R6 are independently selected from H, methyl, deuterated methyl, ethyl, deuterated ethyl, ethynyl, propynyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, or R5 and R6 are connected together and form a bridged ring with the ring containing W.

[0028] In some embodiments of the present invention, in formula (IA), Selected from unsubstituted and substituted groups:

[0029]

[0030] In some embodiments of the present invention, R1 is selected from the following groups that are either unsubstituted or substituted: C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, deuterated C 3-6 cycloalkyl, C 2-4 alkynyl C 1-6 Alkyl, C 2-4 alkynyl halogenated C 1-6 Alkyl, C 2-4 alkynyl C 3-6 cycloalkyl, C 2-4 alkynyl halogenated C 3-6 cycloalkyl, C 2-4 alkynyl C 3-6Heterocyclic alkyl groups.

[0031] Further, R1 is selected from the following groups, either unsubstituted or substituted: methyl, ethyl, propyl, butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, deuterated n-butyl, deuterated isobutyl, cyclopropyl, deuterated cyclopropyl, ethynylmethyl, ethynylethyl, ethynylpropyl, ethynyl halomethyl, ethynyl haloethyl, ethynyl halopropyl, ethynyl C 3-6 cycloalkyl and ethynyl halogenated C 3-6 cycloalkyl, ethynyl C 3-6 Heterocyclic alkyl, wherein the substituents used for substitution are selected from one or more of the following groups: F, Cl, Br, methyl, ethyl, methoxy, ethoxy, fluoromethyl, fluoroethyl, cyclopropyl, hydroxy.

[0032] In some embodiments of the present invention, R1 is selected from...

[0033]

[0034] In some embodiments of the present invention, the pyridone derivatives have the structure shown in formula (IB):

[0035]

[0036] In equation (IB), R2, n, and R 3a R 3b The definitions are the same as before; E is CH or N; R7 and R8 are independently selected from H, halogen, cyano, hydroxyl, C. 1-6 Alkyl, halogenated C 1-6 Alkyl or C 2-6 Alkyne group; m and p are independently 1, 2, or 3.

[0037] In some embodiments of the present invention, Q is selected from amides, or from unsubstituted or substituted five-membered heterocycles.

[0038] Further, Q is selected from amides, and the carbonyl carbon in the amide is attached to a carbon on the pyridinone; or, Q is selected from...

[0039] In some embodiments of the present invention, R2 is selected from F, Cl, Br, hydroxyl, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, fluoroethyl, ethynyl, and n is 1, 2 or 3.

[0040] In some embodiments of the present invention, R 3a R 3b Selected independently from H or D.

[0041] In some embodiments of the present invention, the prodrug refers to a compound that is metabolized into the original drug by chemical methods or by enzymes in vivo; further, the group containing the shielded hydroxyl group includes the following structure: (H, C 6-20 OC(=O)-、C 6-20 C(=O)-、C 6-20 C(=O)-、C 6-20 C(=O)-、C 6-20 OCH2O-、 In some embodiments of the present invention, the pyridone derivatives have the structure shown in formula (IC).

[0042]

[0043] Where: R1, R2, n, R 3a R 3b The definitions of X and X are the same as before.

[0044] In this invention, the heterocyclic or carbocyclic groups in the pyridone derivatives include monocyclic, bicyclic, and polycyclic compounds. The bicyclic and polycyclic compounds include fused rings, bridged rings, and spirocyclic compounds, for example, including but not limited to monocyclic, bicyclic, and polycyclic compounds that can be 5-10 members. When two substituents are present, the two substituents, depending on whether the carbon atoms they are attached to are the same or different, can form a spirocyclic, fused ring, or bridged ring together with A.

[0045] In some embodiments, R1 is selected from deuterated alkyl groups or deuterated C groups. 3-6 Cycloalkyl.

[0046] In some embodiments, R1 is selected from deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, deuterated cyclopropyl, deuterated isobutyl or deuterated n-butyl.

[0047] In some embodiments, R1 is selected from C containing an alkynyl group. 1-20 Alkyl groups, halogenated C groups containing alkynyl groups 1-20 alkyl and alkynyl substituted C 3-6 Cycloalkyl and alkynyl-substituted C 3-6 Heterocyclic alkyl

[0048] In some embodiments, A is selected from substituted and unsubstituted 5-10 membered heterocycles, wherein A is preferred.

[0049] The substituents are selected from one or more of the following groups: halogen (F, Cl, Br), methyl, trifluoromethyl, difluoromethyl, cyclopropyl, C 1-6 alkoxy or halogenated C1-6 Alkoxy, C 2-6 Alkyne group, oxo, exocyclic double bond, halogenated exocyclic double bond or C 1-6 Alkoxy C 1-3 Alkyl group. In some embodiments of compounds of formula (I), the substituted group is independently selected from H, deuterium, halogen (F, Cl, Br, I), cyano, hydroxyl, amide, carboxyl, oxy, alkynyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkoxy, halogenated C 3-6 Cycloalkoxy, C 2-6 Heterocyclic alkyl, C 1-6 Alkoxy, C 6-10 Aryl, C 3-10 heteroaryl, C 1-6 Alkyl sulfone group, C 1-6 Alkyl mercapto; heteroatoms are selected from oxygen, nitrogen, sulfur, and -SO2-.

[0050] In some embodiments, the alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc., C 1-6 Alkyl groups refer to compounds with 1-6 carbon atoms, C 1-20 Alkyl groups are those with 1 to 20 carbon atoms.

[0051] In some implementations, halogenated C 1-6 Alkyl groups can be obtained by substituting one or more hydrogen atoms from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc., using F, Cl, Br, or I.

[0052] In some implementations, C 2-6 The alkynyl group can be ethynyl, propynyl, butynyl, penynyl, etc.

[0053] In some embodiments, the alkoxy group includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy, isopentoxy, n-hexyloxy, isohexyloxy, etc., C 1-6 Alkoxy groups refer to alkoxy groups with 1 to 6 carbon atoms.

[0054] In some embodiments, the halogenated alkoxy group includes, but is not limited to, the hydrogen that can be obtained by substituting one or more of the following: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy, isopentoxy, n-hexyloxy, isohexyloxy, etc.

[0055] In some implementations, deuterated C 1-20 Alkyl, deuterated C 3-6 The cycloalkyl group can be substituted with one, two, three or more deuterium atoms, respectively. 1-20 Alkyl, C 3-6 Hydrogen is obtained from cycloalkyl groups.

[0056] In some embodiments, the heterocyclic group includes alicyclic heterocyclic groups containing heteroatoms and heteroaromatic cyclic groups containing heteroatoms, etc., for example, it can be a saturated heterocyclic group or an unsaturated heterocyclic group, and there can be one, two or more heteroatoms, and it can be monocyclic, bicyclic or polycyclic, wherein the heteroatoms are nitrogen, oxygen, sulfur, oxo, etc. The carbocyclic group is a pure carbon ring without heteroatoms, and it can be monocyclic, bicyclic or polycyclic, and can contain double bonds or not, for example, it can be a saturated carbocyclic group or an unsaturated carbocyclic group.

[0057] In some implementations, C 3-6 The cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0058] In some embodiments, the pyridone derivatives are selected from the following compounds:

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069] The present invention further provides a method for preparing the novel pyridone derivative or its stereoisomer as shown in (I) of the present invention, comprising the following steps:

[0070]

[0071] Synthesis of compound B:

[0072] Compound A was dissolved in DMF at room temperature, and intermediate 5-(hydroxymethyl)tetrahydrofuran-2-yl)methyl methanesulfonate, a phase transfer catalyst, and a base were added sequentially. The reaction mixture was then stirred overnight at -100°C under nitrogen protection. The reaction solution was cooled to room temperature and diluted with ethyl acetate, followed by washing with water and saturated brine sequentially. After drying with anhydrous sodium sulfate, the crude product was concentrated and purified by silica gel column chromatography and preparative plate analysis with a petroleum ether solution containing 33% ethyl acetate and 33% dichloromethane to obtain a white solid B.

[0073] The phase transfer catalyst is selected from TBAI, TBABr, TBAHSO4, and various crown ethers; the base includes organic and inorganic bases, with organic bases selected from triethylamine, DIPEA, DBU, pyridine, etc.; and inorganic bases selected from sodium carbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium bicarbonate, etc. In addition to using Ms as the leaving group, other leaving groups include Ts, bromine, chlorine, iodine, etc. Furthermore, besides this SN2 reaction, the Mitsunobu reaction and the corresponding amino group generating a Schiff base followed by reduction can also yield the alkylated compound.

[0074] Synthesis of compound C:

[0075] At room temperature, intermediate B was dissolved in acetonitrile, and 2-iodobenzoic acid was added. The reaction solution was stirred overnight at -100°C under nitrogen protection. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was concentrated to obtain a crude product, which was purified by passing it through a silica gel column with a petroleum ether solution containing 33% ethyl acetate and 33% dichloromethane to obtain a light yellow oil intermediate C.

[0076] Besides IBX oxidation, other mild oxidizing agents such as Dess-Martin Periodinane (DMP) and PySO3 can also be used in this reaction.

[0077] Synthesis of compound D:

[0078] At room temperature, p-toluenesulfonic acid was added to a 1,2-dichloroethane solution of intermediate C. The reaction mixture was stirred at 0-80°C for 1 hour to overnight under nitrogen protection. The reaction mixture was cooled to room temperature and neutralized to a pH of approximately 8 with a saturated sodium bicarbonate aqueous solution; then extracted with ethyl acetate; the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Purification using a preparative column yielded a pink solid compound D. Many methods for removing the benzyl protecting group, such as lithium halides, magnesium bromide, TFA, and catalytic hydrogenation, are suitable for this reaction.

[0079] The present invention also provides an intermediate for preparing the above-described pyridone derivatives or their stereoisomers, prodrugs of pyridone derivatives, and pharmaceutically acceptable salts, wherein the intermediate has the structure shown in formula (VI), formula (VII), or formula (VIII):

[0080] In equation (VI), R1, R2, n, and R 3a R 3b The definitions of X, Y, and A are the same as before, and R9 is a hydroxyl protecting group;

[0081] In equation (VII), R1, R2, n, and R 3a R 3b The definitions are the same as before, R9 is a hydroxyl protecting group, R 10 For H, The definitions of R4, R5, W, and R6 are the same as before;

[0082] In equation (VIII), R2, n, and R 3a R 3b The definitions are the same as before, R 11 The protecting group can be hydrogen or hydroxyl. Further, the hydroxyl protecting group can be Bn (benzyl).

[0083] Furthermore, the intermediate is compound B, compound C, or their stereoisomers or racemates.

[0084]

[0085] Furthermore, the intermediate is selected from the following compounds:

[0086]

[0087] The present invention also provides a pharmaceutical composition comprising a pyridone derivative or its stereoisomer as described above, a prodrug of a pyridone derivative, and a pharmaceutically acceptable salt; further, the pharmaceutical composition is an antiviral pharmaceutical composition, further comprising one or more therapeutic agents selected from the following categories: nucleoside or nucleotide reverse transcriptase inhibitors, non-nucleoside or nucleotide reverse transcriptase inhibitors, HIV protease inhibitors, HIV capsid inhibitors, CXCR4 inhibitors, GP41 inhibitors, GP120 inhibitors, CCR5 inhibitors, HIV latency reversal (or awakening) agents, capsid polymerization inhibitors, HIV bNAbs, TLR 7, 8 or 9 agonists, and PK enhancers or other anti-HIV agents.

[0088] The present invention also provides the use of the above-described pyridone derivatives or their stereoisomers, pyridone derivative prodrugs, pharmaceutically acceptable salts, or the above-described pharmaceutical compositions in the preparation of medicaments for the prevention and / or treatment of viral infectious diseases.

[0089] The present invention also provides the use of the above-described pyridone derivatives or their stereoisomers, prodrugs of pyridone derivatives, pharmaceutically acceptable salts, or the above-described pharmaceutical compositions in the preparation of medicaments for the prevention and / or treatment of HIV viral infection; further, the pharmaceutical composition has a long-acting effect, and the pharmaceutical composition includes oral formulations, injectable formulations, or topical formulations.

[0090] The pharmaceutical composition according to the invention, wherein the compound of the invention is preferably present in a therapeutically effective amount.

[0091] The pharmaceutically acceptable carriers in the above-mentioned pharmaceutical compositions include pharmaceutically acceptable diluents, excipients, fillers, binders, disintegrants, absorption enhancers, surfactants, lubricants, flavorings, sweeteners, etc.

[0092] The pharmaceutical products prepared using the compounds of this invention as active ingredients can take various forms, such as tablets, powders, capsules, granules, oral liquids, and injectable formulations. The preferred dosage form of the pharmaceutical composition is tablets, capsules, or injections.

[0093] All of the above-mentioned dosage forms of drugs can be prepared using conventional methods in the pharmaceutical field.

[0094] The present invention also provides the use of the compounds of the present invention in the preparation of prevention or treatment of viral infections, preferably wherein the viral infections are infections and complications caused by HIV.

[0095] The pharmaceutical composition of the present invention may be composed of the following proportions:

[0096] Compounds of the present invention 5-95%

[0097] Lactose 1-60%

[0098] Starch 0-20%

[0099] Microcrystalline cellulose 1-40%

[0100] Sodium carboxymethyl starch 1-5%

[0101] Polyethylene glycol (PEG6000) 0-10%

[0102] Magnesium stearate 1-5%.

[0103] Due to the implementation of the above technical solutions, the present invention has the following advantages compared with the prior art:

[0104] This invention provides a class of deuterated pyridinone derivatives or their stereoisomers that, by improving the oxidative dealkylation effect of compound metabolism, exhibit low solubility and very low clearance, and are used to develop long-acting anti-HIV treatment regimens.

[0105] This invention provides a class of pyridone derivatives containing an alkynyl group. The synthesized compounds have strong HIV inhibitory activity, and their long-acting drug physicochemical properties make them promising for clinical application.

[0106] Furthermore, given that the compounds of this invention have highly efficient HIV-inhibiting activity, they can be used in combination with other anti-HIV drugs with different mechanisms of action, such as nucleoside analogs, protease inhibitors, non-nucleoside reverse transcriptase inhibitors, HIV capsid inhibitors, and broadly neutralizing antibodies, to develop long-acting treatment regimens that require injections every three months or every six months. These regimens can be used clinically to prevent or treat HIV-infected patients, thereby improving patient compliance and the rate of participation in treatment.

[0107] Terminology Definition

[0108] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0109] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule. This includes cis-trans isomers, enantiomers, and conformational isomers. All stereoisomers are within the scope of this invention. The compounds of this invention can be individual stereoisomers or mixtures of other isomers, such as racemates, or mixtures of all other stereoisomers.

[0110] The term "salt" refers to a pharmaceutically acceptable salt formed by the compound of the present invention with an acid, which may be an organic or inorganic acid, specifically selected from: phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid, or analogs thereof.

[0111] The term "solvent" refers to the form of the compounds of this invention that form solid or liquid complexes by coordination with solvent molecules. Hydrates are a specific form of solvate in which coordination with water occurs. Within the scope of this invention, hydrates are preferred solvates.

[0112] The term "crystallization" refers to the various solid forms formed by the compounds described in this invention, including crystalline and amorphous forms.

[0113] The term "hydrocarbon group" refers to saturated alkyl, alkenylalkyl, and alkynylalkyl groups.

[0114] The term "saturated alkyl" refers to a straight-chain, branched, or cyclic saturated or unsaturated substituent mainly composed of carbon and hydrogen. Preferably, it has 1-20 carbon atoms, more preferably 1-12 carbon atoms. The term "alkyl" refers to a straight-chain, branched, or cyclic saturated hydrocarbon group. Alkyl groups specifically include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, n-hexyl, isohexyl, 2,2'-methylbutyl and 2,3'-dimethylbutyl, 16-alkyl, and 18-alkyl. The term "C 1-20 Alkyl refers to a straight-chain, branched, or cyclic saturated hydrocarbon group containing 1-20 carbon atoms. Alkyl groups include substituted and unsubstituted alkyl groups. When an alkyl group is substituted, the substituent can be substituted at any usable connection point, and the substituent can be monosubstituted or polysubstituted. Substituents are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, deuterium, halogen, thiol, hydroxyl, nitro, carboxyl, ester, cyano, cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and oxo. In naming, the substituent is usually placed before the alkyl group, for example, C10. 1-3 Alkoxy C 3-8 cycloalkyl C 1-6 Alkyl refers to C 1-6 Alkyl groups, which are C 3-8 Cycloalkyl substitution, and the C 3-8 Cycloalkyl groups are also C 1-3 Alkoxy substitution, for example: the structural formula of methoxycyclobutylmethyl is:

[0115]

[0116] The terms "alkenyl" and "alkynyl" refer to straight-chain, branched, or cyclic unsaturated hydrocarbon groups containing double and triple bonds, respectively, preferably with 2-20 carbon atoms, more preferably 2-12 carbon atoms. Alkenyl and alkynyl groups include substituted and unsubstituted alkenyl and alkynyl groups. When substituted, the substituent can be substituted at any usable linker, and the substituent can be monosubstituted or polysubstituted. The substituent is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, deuterium, halogen, thiol, hydroxyl, nitro, carboxyl, ester, cyano, cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and oxo. In nomenclature, the substituent is usually placed before the alkenyl or alkynyl group.

[0117] The term "ring" refers to both carbon rings and heterocycles. "Carbocyclic group" or "carbon ring" refers to a carbon cyclic group having 3 to 20 carbon atoms, preferably 3 to 16, and more preferably 4 to 12, including cycloalkyl, cycloalkenyl, aryl, bicyclic carbon rings, and polycyclic carbon cyclic groups. "Heterocyclic group" or "heterocycle" includes heteroaryl, non-aromatic heterocyclic groups, bicyclic heterocyclic groups, and polycyclic heterocyclic groups having one or more identical or different heteroatoms chosen arbitrarily from O, S, and N within the ring. The term "ring" includes monocyclic, bridged, spirocyclic, fused, and polycyclic rings.

[0118] The term "cycloalkyl" refers to a saturated and / or partially unsaturated monocyclic or polycyclic cycloalkyl group. A monocyclic group may include 3-10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, etc. Polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups. Cycloalkyl groups include unsubstituted and substituted groups. Substituents are selected from one or more substituent groups, including but not limited to the following groups, independently selected from alkyl, cycloalkyl, alkoxy, halogen, carboxyl, ester, amino, amide, hydroxy, cyano, nitro, aryl, and heteroaryl groups.

[0119] The term "aryl" refers to two types: carbocyclic aryl and heteroaryl.

[0120] The term "carbocyclic aryl" refers to an aromatic group consisting of a 6-10 member, all-carbon monocyclic or polycyclic ring, including phenyl, naphthalene, biphenyl, etc. Aryl groups can be substituted or unsubstituted. Substituents are independently selected from alkyl, cycloalkyl (cyclopropane, cyclobutane, and cyclopentane, etc.), alkenyl, alkynyl, azide, amino, deuterium, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, alkylsilyl, etc.

[0121] The term "heteroaryl" refers to a group in a heteroaromatic system containing 1-10 heteroatoms. Heteroatoms include oxygen, sulfur, nitrogen, phosphorus, etc. Monoheterocyclic groups include, but are not limited to, furan, thiophene, pyrrole, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-thiadiazole, oxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, pyridine, pyrimidine, pyrazine, tetrahydrofuran, tetrahydropyrrole, piperidine, piperazine, morpholine, isoxazoline, etc. Fused heterocyclic groups include, but are not limited to, quinoline, isoquinoline, indole, benzofuran, benzothiophene, purine, acridine, carbazole, fluorene, chromone, fluorenone, quinoxaline, 3,4-dihydronaphthone, dibenzofuran, hydrogenated dibenzofuran, benzoxazolyl, etc. Heteroaryl groups can be substituted or unsubstituted. The substituents are independently selected from alkyl, cycloalkyl (cyclopropane, cyclobutane, and cyclopentane, etc.), alkenyl, alkynyl, azide, amino, deuterium, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, alkylsilyl, etc.

[0122] The term "halogen" refers to fluorine, chlorine, bromine, and iodine, with fluorine, chlorine, and bromine being preferred.

[0123] The term "deuterium" is an isotope of hydrogen, with an atomic mass twice that of hydrogen and a stronger bond to carbon. "Deuteration" and "deuterium" indicate that hydrogen is replaced with deuterium at a specified position. A "deuterated substituent" is a substituent in which at least one hydrogen atom is replaced by deuterium enriched in a specified percentage.

[0124] The term "halogenated alkyl" refers to an alkyl group that is substituted by at least one halogen atom.

[0125] The term "heterocyclic group" refers to a cyclic group containing at least one heteroatom, such as nitrogen, oxygen, sulfur, or thiocyanate. Heterocyclic groups include monocyclic and polycyclic groups. Detailed Implementation

[0126] The following examples are intended to provide a more comprehensive understanding of the invention by those skilled in the art, but do not limit the invention in any way. The structures of all compounds have been determined... 1 Determined by H NMR or MS.

[0127] The abbreviations of the compound names used in the examples are as follows:

[0128] Dioxane: 1,4-Dioxane;

[0129] DMSO: Dimethyl sulfoxide;

[0130] TEA: Triethylamine;

[0131] TBAF: Tetrabutylammonium fluoride;

[0132] NBS: N-bromosuccinimide;

[0133] TFA: Trifluoroacetic acid;

[0134] LiOH H2O: Lithium hydroxide monohydrate;

[0135] PyBop: Benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate;

[0136] EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;

[0137] HOBT: 1-Hydroxybenzotriazole;

[0138] TEMPO: 2,2,6,6-Tetramethylpiperidine oxide;

[0139] TBAB: Tetrabutylammonium bromide;

[0140] Trost ligand(R,R): (1R,2R)-(+)-1,2-diaminocyclohexyl-N,N'-bis(2'-diphenylphosphobenzoyl); Pd2(dba)3: tridibenzylacetone dipalladium;

[0141] TBAI: Tetrabutylammonium iodide;

[0142] NIS: N-iodosuccinimide;

[0143] DMAP: 4-Dimethylaminopyridine;

[0144] m-CPBA: m-chloroperoxybenzoic acid;

[0145] TBAOH: Tetrabutylammonium hydroxide;

[0146] DIPEA: Diisopropylethylamine;

[0147] TLC: Thin-layer chromatography.

[0148] The present invention will be further described below with reference to specific embodiments:

[0149] Compound Synthesis

[0150] Example 1: Synthesis of compound IV-17

[0151]

[0152] The reaction route is shown below:

[0153]

[0154] Synthesis of intermediate 3:

[0155] Intermediate 1 (15 g, 87.14 mmol) was added to a solution of DCM (100 mL) and DMF (5 drops), and the mixture was cooled to 0-5 °C. Oxaloyl chloride (4.57 g, 34.56 mmol) in DCM (50 mL) was slowly added dropwise. The reaction mixture was stirred at room temperature for 1 hour, concentrated to remove the solvent, diluted with DCM (80 mL), and concentrated again. This process was repeated three times to obtain the crude product. In another 250 mL three-necked flask, intermediate 2 (14.97 g, 113.29 mmol), DCM (100 mL), and triethylamine (17.60 g, 174.29 mmol) were added. The mixture was cooled to 0-5 °C, and the previously prepared crude DCM (50 mL) solution was slowly added dropwise. The mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with DCM (100 mL), then washed successively with water (100 mL x 3) and saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product purified by silica gel column chromatography (9-33% ethyl acetate in petroleum ether solution). Concentration yielded a yellow oily substance, which was left at room temperature overnight. A solid precipitated; 15 mL of petroleum ether was added, and the mixture was stirred for 1 hour. Filtration yielded a white solid intermediate 3 (11 g, 44%). MS: [M+H] + 186.75; 1 HNMR (400MHz, CDCl3): δ7.52-7.48 (m, 1H), 7.36-7.30 (m, 1H), 6.90-6.81 (m, 2H), 6.51 (s, 1H), 3.58 (s, 2H), 1.45 (s, 9H).

[0156] Synthesis of intermediate 4:

[0157] Lawson's reagent (18.37 g, 45.41 mmol) was added to a THF (100 mL) solution of intermediate 3 (10.0 g, 34.93 mmol), and the mixture was stirred at 50 °C for 4 hours. The reaction solution was cooled to room temperature, quenched with saturated sodium bicarbonate solution (150 mL), extracted with ethyl acetate (200 mL), and the organic phase was washed with brine (100 mL) and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (9-14% ethyl acetate in petroleum ether solution) to give a colorless oily intermediate 4 (9.3 g, 88%). 1 HNMR (400MHz, DMSO-d6): δ11.82(s,1H),9.38-9.36(m,1H),7.45-7.39(m,1H),7.21-7.15(m,1H),7.08-7.03(m,1H),3.88(s,2H),1.40(s,9H).

[0158] Synthesis of intermediate 5:

[0159] At room temperature, intermediate 4 (9.3 g, 30.76 mmol) was dissolved in 4 M HCl / 1,4-dioxane (100 mL) and stirred at room temperature for 2 hours. The mixture was filtered, and the filter cake was dissolved in water (150 mL). The solution was cooled to 0-5 °C and neutralized to approximately pH 8 with saturated sodium bicarbonate solution while stirring. The reaction mixture was extracted with ethyl acetate (200 mL), and the organic phase was washed successively with water (100 mL x 2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Hexane (20 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was then filtered to obtain a white solid intermediate 5 (5.8 g, 93%). 1 HNMR (400MHz, CDCl3): δ8.44-8.40(m,1H),7.39-7.33(m,1H),6.93-6.82(m,2H),4.84-4.75(m,2H),4.03-4.02(m,2H).

[0160] Synthesis of intermediate 7:

[0161] A solution of intermediate 6 (10 g, 31.42 mmol) and acetic acid (754.7 mg, 12.57 mmol) in toluene (70 mL) was heated to 65 °C under nitrogen protection, and a solution of intermediate 2 (4.57 g, 34.56 mmol) in toluene (30 mL) was slowly added dropwise. The mixture was stirred overnight at 65 °C. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with Hex / EA = 1 / 1 and dried to give a pale yellow solid, intermediate 7 (11.2 g, 82%). MS: [M+H] + 433.45; 1 HNMR (400MHz, DMSO-d6): δ11.13(br,1H),8.35(s,1H),7.43-7.29(m,5H),5.10(s,2H),3.76(s,6H),1.41(s,9H).

[0162] Synthesis of intermediate 8:

[0163] At 0 °C, LiOH H₂O (2.28 g, 54.4 mmol) was added to a THF / MeOH / H₂O (60 mL / 30 mL / 30 mL) solution of intermediate 7 (11.2 g, 25.9 mmol). The reaction mixture was then heated to room temperature and stirred overnight. The reaction mixture was concentrated at 25 °C to remove most of the THF / MeOH, then acidified with 2N hydrochloric acid to approximately pH 5. After filtration, the filter cake was washed with water and finally dried overnight to obtain a pale yellow solid intermediate 8 (10.1 g, 93%). MS: [M+H] + 419.55; 1HNMR (400MHz, DMSO-d6): δ14.87(br,1H),11.47(br,1H),8.81(s,1H),7.47-7.29(m,5H),5.22(s,2H),3.79(s,3H),1.42(s,9H).

[0164] Synthesis of intermediate 9:

[0165] At room temperature, intermediate 8 (6.0 g, 14.34 mmol), intermediate 5 (4.35 g, 21.51 mmol), DIPEA (5.55 g, 43.02 mmol), and PyBop (8.95 g, 17.21 mmol) were sequentially added to DCM (60 mL) solution, and stirred at room temperature for 3 hours under nitrogen protection. The reaction solution was diluted with DCM (150 mL), then washed sequentially with water (100 mL x 2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (14-33% ethyl acetate in petroleum ether solution) to give a white solid intermediate 9 (3.2 g, 37%). MS: [M+H] + 603.10; 1 HNMR (400MHz, CDCl3): δ13.58(s 1H),10.81-10.64(m,1H),8.47(s,1H),7.97(s,1H),7.45-7.30(m,6H), 6.91-6.92(m,2H),5.33(s,2H),4.12(s,2H),3.76(s,3H),1.43(s,9H).

[0166] Synthesis of intermediate 10:

[0167] Intermediate 9 (3.4 g, 5.64 mmol) and 50% T3P (7.18 g, 11.28 mmol) in ethyl acetate (34 mL) were heated under reflux for 20 min, concentrated to give the crude product, and purified by silica gel column chromatography (25-50% ethyl acetate in petroleum ether solution) to give colorless oily intermediate 10 (2.5 g, 75%). MS: [M+H] + 585.10; 1 HNMR (400MHz, CDCl3): δ9.35-9.29(m,1H),9.06(s,1H),7.42-7.28(m,6H),6.87-6.83(m,2H),5.33(s,2H),4.46(s,2H),3.83(s,3H),1.46(s,9H).

[0168] Synthesis of intermediate 11:

[0169] LiOH H2O (855.3 mg, 21.38 mmol) was added to a MeOH / H2O (30 mL / 15 mL) solution of intermediate 10 (2.5 g, 4.28 mmol). The reaction mixture was heated to 50 °C and stirred for 2 days. The reaction mixture was concentrated at 45 °C to remove most of the MeOH, then acidified with 2N hydrochloric acid to approximately pH 6. After filtration, the filter cake was washed with water and finally dried to obtain a white solid, intermediate 11 (2.1 g, 86%). MS: [M+H] + 571.15; 1 HNMR (400MHz, DMSO-d6): δ8.49(s,1H),7.58-7.50(s,1H),7.38-7.26(m,5H),7.14-7.10(m,1H),5.03(s,2H),4.49(s,2H),1.44(s,9H).

[0170] Synthesis of intermediate 13:

[0171] Under ice bath conditions, intermediate 12 (28.6 mg, 0.36 mmol), EDCI (67.1 mg, 0.36 mmol), HOBT (35.5 g, 0.26 mmol), and TEA (53.0 mg, 0.53 mmol) were sequentially added to a DMF (4 mL) solution of intermediate 11 (100 mg, 0.18 mmol), and stirred overnight at room temperature under nitrogen protection. The reaction solution was diluted with ethyl acetate (20 mL), then washed sequentially with water (8 mL x 3), saturated brine (15 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (50-100% ethyl acetate in petroleum ether solution) to give a white solid intermediate 13 (68 mg, 64%). MS: [M+H] + 603.80; 1 HNMR (400MHz, CDCl3): δ8.81(s,1H),8.76(br,1H),7.38-7.28(m,6H),6.89-6.82(m,2H),6.64(br,1H),5.37(s,2H),4.48(s,2H),1.44(s,9H).

[0172] Synthesis of intermediate 15:

[0173] Intermediate 14 (28.0 mg, 0.13 mmol) and K₂CO₃ (32.5 mg, 0.24 mmol) were added sequentially to a DMF (2 mL) solution of intermediate 13 (68 mg, 0.11 mmol), and stirred overnight at room temperature under nitrogen protection. The reaction solution was diluted with ethyl acetate (15 mL), then washed sequentially with water (6 mL x 3), saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by passing it through a preparative agar plate and then purified with 50% ethyl acetate in petroleum ether to obtain a white solid intermediate 15 (64 mg, 78%). MS: [M+H] + 731.80; 1 HNMR (400MHz, CDCl3): δ8.64(s,1H),7.41-7.29(m,7H),6.89-6.81(m,2H),5.86(br,1H),5.51(d,J=11.2Hz,1H),5.18(d,J=10.8Hz,1H ), 4.84 (t, J = 4.8Hz, 1H), 4.48 (s, 2H), 3.96-3.91 (m, 2H), 3.85-3.80 (m, 2H), 3.64-3.60 (m, 1H), 1.76-1.66 (m, 4H), 1.47-1.41 (m, 11H).

[0174] Synthesis of compound IV-17:

[0175] At room temperature, 1 mL of 1,4-dioxane (64 mg, 0.087 mmol) of intermediate 15 was added to 4 M HCl / 1,4-dioxane, and the mixture was stirred for 1 hour. The reaction solution was concentrated to obtain a crude product, which was purified by HPLC-preparative column chromatography to give a white solid compound IV-17 (21 mg, 50%). MS: [M+H] + 479.05; 1 HNMR (400MHz, CD3OD): δ8.79(s,1H),7.50-7.41(m,1H),7.05-6.95(m,2H),5.32(t,J=2.8Hz,1H),4.49(s,2H),3.28-3.20 (m,1H),3.17-3.11(m,1H),2.46-2.37(m,1H),2.14-2.03(m,1H),1.99-1.84(m,2H),1.79-1.69(m,1H),1.54-1.41(m,1H).

[0176] Example 2: Synthesis of compound IV-20

[0177]

[0178] The reaction route is shown below:

[0179]

[0180] Synthesis of intermediate 16:

[0181] Hydrochloric acid / 1,4-dioxane (2 mL) was added to a solution of intermediate 3 (500 mg, 1.75 mmol) in dichloromethane (2 mL). The mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC and LCMS until the starting material was completely reacted. The solution was then concentrated to give a white solid intermediate 16 (372 mg, 96%). MS: [M+H] + 186.90; 1 HNMR (400MHz, DMSO-d6): δ11.35(s,1H),10.5(s,2H),7.47-7.41(m,1H),7.25(t,J=10.0Hz,1H), 7.75(t,J=12.0Hz,1H),3.66(s,2H).

[0182] Synthesis of intermediate 18:

[0183] A methanol (10 mL) solution of intermediate 8 (2 g, 4.78 mmol) and an aqueous solution of intermediate 17 (10 mL of ethylamine) were added to a thick-walled, pressure-resistant flask, sealed, and reacted at 100 °C for 3 hours. The reaction mixture was concentrated to obtain a crude product, which was then purified by silica gel column chromatography (50% ethyl acetate in petroleum ether solution ~ 50% ethyl acetate in dichloromethane solution) to obtain an orange solid intermediate 18 (1.6 g, 78%). MS: [M+H] + 432.10; 1 HNMR (400MHz, DMSO-d6): δ15.28(s,1H),11.40(s,1H),8.86(s,1H),8.70(s,1H),7. 43-7.33(m,5H),5.19(s,2H),3.22-3.15(m,2H),1.44(s,9H),1.02(t,J=7.2Hz,3H).

[0184] Synthesis of intermediate 19:

[0185] Intermediate 18 (1.6 g, 3.71 mmol), intermediate 14 (2.33 g, 11.14 mmol), and potassium carbonate (1.54 g, 11.14 mmol) were added to N,N-dimethylformamide (20 mL), and the mixture was reacted overnight at room temperature. The reaction solution was adjusted to pH 7-8 with 2M hydrochloric acid, extracted with ethyl acetate (20 mL), and the organic phase was washed with water (70 mL x 3) and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by column chromatography (25-50% ethyl acetate in petroleum ether solution ~ 10% methanol in dichloromethane solution) to give a pale yellow oily intermediate 19 (2.1 g, 82%). MS: [M+H] + 688.45; 1 HNMR (400MHz, DMSO-d6): δ8.68(t,J=5.6Hz,1H),8.21(s,1H),7.41-7.32(m,5H),5.09(s,2H), 4.78-4.75(m,2H),4.18(t,J=6.4Hz,2H),3 .88-3.66(m,9H),3.53-3.45(m,1H),3.21-3.13(m,2H),1.73-1.66(m,2H),1.63-1.55(m,6H),1.49-1.31(m,13H),1.01(t,J=7.2Hz,3H).

[0186] Synthesis of intermediate 20:

[0187] Intermediate 19 (2.1 g, 3.06 mmol) was dissolved in tetrahydrofuran (20 mL), and 2M sodium hydroxide aqueous solution (3 mL, 6.11 mmol) was added. The mixture was stirred at room temperature for two hours. The reaction solution was adjusted to pH 7-8 with 2M hydrochloric acid and extracted with ethyl acetate (20 mL). The organic phase was washed with water (30 mL x 2), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography in a solution of 25-50% ethyl acetate in petroleum ether and 10% methanol in dichloromethane to obtain a pale yellow oily intermediate 20 (1.25 g, 73%). MS: [M+H] + 560.25; 1 HNMR (400MHz, DMSO-d6): δ15.12(s,1H),8.85(t,J=5.6Hz,1H),8.80(s,1H),7.43-7.35(m,5H),5.23-5.16(m,2H) , 4.77-4.74(m,1H),3.87-3.54(m,7H),3.25-3.14(m,2H),1.66-1.52(m,5H),1.41(s,9H),1.02(t,J=7.2Hz,3H).

[0188] Synthesis of intermediate 21:

[0189] Hydrochloric acid / 1,4-dioxane (2 mL) was added to a 1,4-dioxane (2 mL) solution of intermediate 20 (880 mg, 1.57 mmol), and the mixture was stirred overnight at 50 °C. The reaction solution was concentrated to obtain intermediate 21, a pale yellow oily crude product (600 mg). MS: [M+H] + 308.00.

[0190] Synthesis of intermediate 22:

[0191] Intermediate 21 (600 mg, 1.95 mmol), benzyl bromide (668 mg, 3.91 mmol), and cesium carbonate (1.27 g, 3.91 mmol) were added to N,N-dimethylformamide (8 mL). The mixture was stirred at room temperature for two hours. After the reaction was complete as monitored by TLC, the reaction solution was adjusted to pH 7-8 with 1 M hydrochloric acid. Ethyl acetate (10 mL) was added for extraction. The organic phase was washed with water (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain 700 mg of crude intermediate 22, a pale pink oil. MS: [M+H] + 488.15.

[0192] Synthesis of intermediate 23:

[0193] Intermediate 22 (700 mg, 1.44 mmol) was dissolved in tetrahydrofuran (4 mL), and 2M sodium hydroxide aqueous solution (1.4 mL, 2.88 mmol) was added. The mixture was stirred at room temperature for two hours. The pH of the reaction solution was adjusted to 7-8 with 2M hydrochloric acid. Extraction was performed with ethyl acetate (20 mL). The organic phase was washed with water (30 mL x 2), dried over anhydrous sodium sulfate, and the crude product was purified by silica gel column chromatography (33-50% ethyl acetate in petroleum ether solution to 50% ethyl acetate in dichloromethane solution) to give intermediate 23 as a pale pink solid (210 mg, 33% yield in three steps). MS: [M+H] + 398.05; 1 HNMR (400MHz, DMSO-d6): δ15.53(s,1H),8.59(s,1H),7.57-7.56(m,2H),7.41-7.31(m,3H),5.24-5.13(m,3H),4.19-4.10(m,1H),3. 24-2.99(m,3H),2.28-2.24(m,1H),1.93-1.84(m,1H),1.81-1.76(m,2H),1.62-1.59(m,1H),1.35-1.24(m,1H),1.1(t,J=7.2Hz,3H).

[0194] Synthesis of intermediate 24:

[0195] Intermediate 23 (210 mg, 0.53 mmol), intermediate 16 (176 mg, 0.79 mmol), N,N-diisopropylethylamine (205 mg, 1.59 mmol), and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (330 mg, 0.64 mmol) were sequentially added to dichloromethane (8 mL). The mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC and LCMS, the reaction solution was concentrated to obtain the crude product. This crude product was then purified by preparative chromatography (using a dichloromethane solution of 50% ethyl acetate) to obtain intermediate 24 as a pale yellow solid (210 mg, 70%). MS: [M+H] + 566.15; 1 HNMR (400MHz, DMSO-d6): δ11.97-11.96(m,1H),10.98-10.97(m,1H),8.4 3(s,1H),7.58-7.56(m,2H),7.46-7.18(m,5H),7.08-7.03(m,1H),5.23- 5.08(m,3H),4.18-4.11(m,1H),3.24-3.00(m,4H),2.34-2.24(m,1H),1. 92-1.73(m,4H),1.62-1.59(m,1H),1.38-1.28(m,1H),1.10-0.99(m,4H).

[0196] Synthesis of compound IV-20:

[0197] Intermediate 24 (180 mg, 0.32 mmol) was dissolved in dry toluene (2 mL), and Woolins Reagent (170 mg, 0.32 mmol) was added. The mixture was heated to 110 °C and stirred overnight. The solid was filtered off, and the filtrate was concentrated to obtain the crude product. Preparative HPLC yielded a yellow solid compound IV-20 (4 mg, 3%). MS: [M+H] + 522.00; 1 HNMR (400MHz, CD3OD): δ8.83(s,1H),7.49-7.43(m,1H),7.30-7.20(m,1H),7.03-6.96(m,2H),5.32(s,1H),4.58(s ,5H),4.48(s,1H),3.27-3.22(m,2H),3.16-3.13(m,1H),2.43-2.40(m,1H),2.20-1.87(m,3H),1.76-1.44(m,2H).

[0198] Example 3: Synthesis of Compound IV-2

[0199]

[0200] The reaction route is shown below:

[0201]

[0202] Synthesis of intermediate 26:

[0203] Under nitrogen protection, intermediate 25 (5.0 g, 67.49 mmol), TEMPO (526.6 mg, 3.37 mmol), and iodobenzoylbenzene (17.82 g, 80.99 mmol) were added to DCM (250 mL). After cooling to 0 °C, ytterbium trifluoromethanesulfonate (837.3 mg, 13.50 mmol) was added. The reaction was carried out at 0 °C for 1 hour, and the reaction solution was filtered. The filtrate was concentrated at 20 °C to obtain crude orange oily intermediate 26 (18 g). 1 HNMR (400MHz, CDCl3): δ8.96 (d, J = 6.4Hz, 1H), 3.37-3.34 (m, 1H), 3.17-3.13 (m, 1H), 3.04-3.02 (m, 1H).

[0204] Synthesis of intermediate 28:

[0205] At room temperature, ((1,3-dioxane-2-yl)methyl)triphenylphosphonium bromide (37.67 g, 87.74 mmol) was dissolved in dry tetrahydrofuran (150 mL) under nitrogen protection. 60% sodium hydroxide (7.02 g, 175.49 mmol) was added in portions over 10 minutes. After reacting at room temperature for 30 minutes, a tetrahydrofuran solution of intermediate 26 (18 g, 67.49 mmol) was added dropwise to the reaction mixture. The reaction was continued at room temperature for 3 hours. TLC monitoring showed the reaction was complete. The mixture was cooled to 0°C, and the reaction solution was quenched with ice water (50 mL). Extraction was performed with ethyl acetate (200 mL). The organic layer was washed successively with water (100 mL x 2) and saturated brine (80 mL). After drying with anhydrous sodium sulfate, the crude product was concentrated and purified by silica gel column chromatography (5% ethyl acetate in petroleum ether solution) to obtain a yellow oily intermediate 28 (2.0 g, two steps). (yield: 20.8%) 1 HNMR (400MHz, CDCl3): δ5.77-5.68(m,1H),5.36-5.29(m,1H),4.05-4.01(m,2H) ),3.96-3.91(m,2H),3.79-3.75(m,1H),3.03-3.00(m.1H),2.68-2.66(m,1H).

[0206] Synthesis of intermediate 30:

[0207] Intermediate 11 (2.0 g, 3.51 mmol) was dissolved in DMF (80 mL). Intermediate 29 (ethylamine hydrochloride, 571.6 mg, 7.01 mmol), EDCI (1.34 g, 7.01 mmol), HOBT (710.4 mg, 5.26 mmol), and DIPEA (1.81 g, 14.02 mmol) were added at 0 °C. The reaction mixture was then heated to 60 °C and stirred overnight. After TLC monitoring showed complete reaction of the starting material, the reaction solution was diluted with ethyl acetate (300 mL), washed successively with water (250 mL x 3) and saturated brine (200 mL). The crude product was dried over anhydrous sodium sulfate and concentrated. Purification was then performed by silica gel column chromatography (using 25-50% ethyl acetate in petroleum ether solution) to obtain a yellow solid intermediate 30 (1.0 g, 45%). MS: [M+H] + 598.15; 1 HNMR (400MHz, CDCl3): δ8.79(s,1H),8.77(s,1H),7.36(s,5H),7.33-7.29(m,1H),6.87-6.83(m,2H) , 6.68-6.65(m,1H),5.37(s,2H),4.47(s,2H),3.26-3.19(m,2H),1.45(s,9H),1.00(t,J=7.2Hz,3H).

[0208] Synthesis of intermediate 31:

[0209] Intermediate 30 (500 mg, 0.86 mmol) and TBAB (556.2 mg, 1.73 mmol) were dissolved in dry acetonitrile. After purging with nitrogen for 10 minutes, Trost ligand(R,R) (81.9 mg, 0.104 mmol) and Pd2(dba)3 (39.5 mg, 0.043 mmol) were added, and nitrogen purging was continued for another 10 minutes. Intermediate 28 (306.5 mg, 2.16 mmol) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Trost ligand(R,R) (81.9 mg, 0.104 mmol) and Pd2(dba)3 (39.5 mg, 0.043 mmol) were added again, and after purging with nitrogen for 10 minutes, intermediate 28 (306.5 mg, 2.16 mmol) was slowly added dropwise to the reaction solution, and the mixture was stirred at room temperature overnight. TLC monitoring showed that after the reactants were fully reacted, the crude product was concentrated and purified by silica gel column chromatography (15-33% ethyl acetate in petroleum ether solution) to give a yellow solid intermediate 31 (520 mg, 81%). MS: [M+H] + 740.20; 1HNMR (400MHz, CDCl3): δ8.85 (s, 1H), 7.48 (d, J = 4.8Hz, 1H), 7.36 (s, 5H), 7.33- 7.29(m,1H),7.03-7.01(m,1H),6.87-6.82(m,2H),5.74-5.68(m,1H),5.46-5.3 2(m,3H),.5.12(d,J=5.2Hz,1H),4.47(s,2H),4.18-4.02(m,2H),3.82-3.73(m ,3H), 3.72-3.68(m,1H),3.29-3.23(m,2H),1.45(s,9H),1.03(t,J=7.2Hz,3H).

[0210] Synthesis of intermediate 32:

[0211] Intermediate 31 (200 mg, 0.27 mmol) was dissolved in methanol (20 mL), and platinum dioxide (60 mg) was added. The mixture was then purged with hydrogen three times and stirred at room temperature for 1 hour. LCMS monitoring was performed, and platinum dioxide was added as needed until the reaction was complete. The reaction solution was filtered and concentrated to obtain a crude product, which was purified using a 5% methanol-dichloromethane solution to obtain an orange solid intermediate 32 (85 mg, 42%). 1 HNMR (400MHz, CDCl3): δ8.93(s,1H),7.38(s,5H),7.33-7.29(m,1H),7.24(d,J =3.2Hz,1H),6.87-6.81(m,3H),5.42-5.32(m,2H),4.83(t,J=4.0Hz,1H),4.47 (s,2H),4.05-4.01(m,1H),3.96-3.90(m,3H),3.85-3.79(m,2H),3.29-3.17(m ,3H),1.81-1.65(m,2H),1.53-1.47(m,1H),1.33(s,9H),1.02(t,J=7.2Hz,3H).

[0212] Synthesis of intermediate 33:

[0213] Intermediate 32 (340 mg, 0.458 mmol) was dissolved in 1,4-dioxane (15 mL), cooled to 0 °C, and then slowly added with 4 M HCl / 1,4-dioxane (15 mL). The mixture was stirred overnight at room temperature. LC-MS and TLC were performed until the starting material was completely reacted. The reaction solution was concentrated under reduced pressure. DMF (3.5 mL), potassium carbonate (379.5 mg, 2.75 mmol), and benzyl bromide (352.8 mg, 2.06 mmol) were added to the concentrated residue, followed by stirring at 40 °C for 2 hours. LC-MS showed complete reaction of the starting material. The solution was diluted with ethyl acetate (60 mL), washed successively with water (30 mL x 2) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by plate testing with a 24% methanol dichloromethane solution to obtain a white solid intermediate 33 (300 mg, 63%). MS: [M+H] + 580.05; 1 HNMR (400MHz, CDCl3): δ8.83-8.81(m,1H),7.62-7.60(m,2H),7.36-7.28(m,4H),6.86-6.81(s,2H),5.44(d,J=10.0Hz,1H), 5.32(d,J=10 .0Hz,1H),5.09-5.08(m,1H),4.43(s,2H),3.81-3.74(m,3H),3.48-3.40(m,2H),2.34-2.27(m,1H),2.23-2.02(m,3H),1.27-1.23(m,4H).

[0214] Synthesis of intermediate 34:

[0215] Dys-Martin reagent (273.2 mg, 0.64 mmol), sodium bicarbonate (67.4 mg, 0.80 mmol), and intermediate 33 (186 mg, 0.32 mmol) were added to DCM (10 mL). The reaction mixture was stirred at 30 °C for 3 hours. Dys-Martin reagent (273.2 mg, 0.64 mmol) was then added, and the mixture was stirred at 30 °C for another 3 hours. LC-MS showed complete conversion of the starting materials. The reaction mixture was filtered to obtain a filtrate. The filtrate was concentrated and purified three times using preparative chromatography (DCM:EA = 1:1) to obtain a yellow solid intermediate 34 (29 mg, 15%). MS: [M + H + H₂O] + 596.05.

[0216] Synthesis of intermediate 35:

[0217] Intermediate 34 (13 mg, 0.023 mmol) was dissolved in methanol (1 mL), cooled to 0 °C, and potassium carbonate (6.2 mg, 0.045 mmol) and dimethyl (2-oxomylidenepropyl)phosphonate (5.2 mg, 0.027 mmol) were added. The mixture was then naturally heated to room temperature and stirred overnight. The reaction solution was diluted with ethyl acetate (15 mL), and then washed successively with water (8 mL x 2) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (33% ethyl acetate in dichloromethane solution) to give intermediate 35 (6.2 mg, 48%) as a yellow solid. MS: [M+H] + 573.95.

[0218] Synthesis of compound IV-2:

[0219] Intermediate 35 (15 mg, 0.026 mmol) and lithium chloride (11.1 mg, 0.261 mmol) were added to DMF (2 mL) and stirred at 90 °C for 8 hours. The reaction mixture was diluted with ethyl acetate (20 mL), and then washed successively with water (8 mL x 2) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. Preparative chromatography purification yielded a white solid compound IV-2 (8.9 mg, 64%). MS: [M+H] + 484.25; 1 HNMR (400MHz, CDCl3): δ8.93-8.92(m,1H),7.35-7.29(m,1H),6.88-6.83(m,2H),5.24-2.23(m,1H),4.48(s,2H),4.14-4.10( m,1H),3.73-3.64(m,1H),3.60-3.51(m,1H),2.57(d,J=2.0Hz,1H),2.49-2.40(m,4H),2.32-2.27(m,1H),1.30-1.25(m,3H).

[0220] Example 4: Synthesis of Compound III-9

[0221]

[0222] The reaction route is shown below:

[0223]

[0224] Synthesis of intermediate 37:

[0225] Under nitrogen protection, a suspension of lithium aluminum hydride (4.75 g, 125.2 mmol) in THF (200 mL) was cooled to 0 °C, and a THF solution of intermediate 36 (9.0 g, 56.9 mmol) (100 mL) was added dropwise. After the addition was complete, the mixture was refluxed for 3 hours. After TLC monitoring showed that the reaction of the starting materials was complete, the reaction solution was cooled to 0 °C, and water (4.8 mL), 15% NaOH (4.8 mL), and water (14.4 mL) were added dropwise in sequence. After stirring at room temperature for 30 minutes, the mixture was filtered. The filter cake was washed with DCM / MeOH = 10 / 1, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (2.5-10% methanol in dichloromethane solution) to obtain colorless oil intermediate 37 (7.6 g, 95%). 1 HNMR (400MHz, CDCl3): δ3.55 (d, J=6.8Hz, 4H), 2.25-2.08 (m, 2H), 2.01-1.91 (m, 1H), 1.83-1.71 (m, 2H), 1.41-1.32 (m, 2H), 0.98-0.88 (m, 1H).

[0226] Synthesis of intermediate 38:

[0227] Under nitrogen protection, intermediate 37 (500 mg, 3.84 mmol) and TEA (775.7 mg, 7.68 mmol) were dissolved in DCM (10 mL); cooled to 0 °C, MsCl (461.9 mg, 4.03 mmol) was added dropwise, and the mixture was stirred overnight at room temperature. The reaction solution was diluted with dichloromethane (15 mL), washed successively with water (6 mL * 2) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (25% ethyl acetate in petroleum ether solution) to obtain colorless oil intermediate 38 (230 mg, 28.7%). 1 HNMR (400MHz, CDCl3): δ4.14(d,J=6.8Hz,2H),3.56(d,J=6.4Hz,2H),3.01(s,3H),2.42-2.31(m,1 H), 2.25-2.14(m,1H),2.05-1.98(m,2H),1.88-1.75(m,2H),1.45-1.39(m,2H),1.05-0.96(m,1H).

[0228] Synthesis of intermediate 40:

[0229] Under nitrogen protection, a tetrahydrofuran (10 mL) solution of intermediate 39 (2.5 g, 10.12 mmol) was cooled to 0 °C, and a borane tetrahydrofuran complex (15 mL, 15.18 mmol) was added. The reaction mixture was heated to 50 °C and stirred for three hours. The reaction mixture was then cooled to 0 °C, and a saturated ammonium chloride solution (15 mL) and a 2 M hydrochloric acid solution (10 mL) were added. The mixture was stirred at room temperature for one hour. Dichloromethane was added for extraction, and intermediate 40 was retained in the aqueous phase and proceeded directly to the next step. MS: [M+H] + 251.75.

[0230] Synthesis of intermediate 41:

[0231] Add tetrahydrofuran (10 mL), potassium carbonate (4.2 g, 30.35 mmol), and di-tert-butyl dicarbonate (3.3 g, 15.18 mmol) to an aqueous solution of intermediate 40 (10.12 mmol), stir overnight at room temperature, extract with ethyl acetate (100 mL), wash the organic phase with saturated brine (50 mL), dry with anhydrous sodium sulfate, and concentrate to obtain crude product; purify by silica gel column chromatography (4-5% ethyl acetate in petroleum ether solution) to give white solid intermediate 41 (1.7 g, two-step yield 48%). 1 HNMR (400MHz, DMSO-d6): δ7.73-7.69(m,1H),7.43(t,J=8Hz,1H),7.30-7.26(m,1H),6.99(t,J=7.6Hz,1H),4.17(d,J=6.0Hz,2H),1.38(s,9H).

[0232] Synthesis of intermediate 43:

[0233] Intermediate 41 (1.7 g, 4.84 mmol), intermediate 42 (814 mg, 5.81 mmol), cuprous iodide (92 mg, 0.48 mmol), triethylamine (978 mg, 9.68 mmol), and tetrakis(triphenylphosphine)palladium (560 mg, 0.48 mmol) were added to 1,2-dichloroethane (20 mL), heated to 50 °C, and stirred overnight. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (3-4% ethyl acetate in petroleum ether solution) to obtain a yellow oily intermediate 43 (1.66 g, 90%). 1 HNMR (400MHz, DMSO-d6): δ7.39-7.35(m,1H),7.31-7.26(m,1H),7.03(t,J=7.6Hz,1H), 4.92(m,1H),4.34-4.33(m,2H),1.43(m,9H),1.05(t,J=7.8Hz,9H),0.71-0.65(m,6H).

[0234] Synthesis of intermediate 44:

[0235] Intermediate 43 (1.66 g, 4.41 mmol) was dissolved in trifluoroacetic acid (10 mL) in dichloromethane (10 mL); the mixture was stirred at room temperature for 2 hours, concentrated at 45 °C to obtain the crude product, adjusted to pH 7–8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (10 mL), washed with saturated brine, dried, and purified by silica gel column chromatography (50%–100% ethyl acetate in dichloromethane solution) to give a yellow oily intermediate 44 (670 mg, 58%). MS: [M+H] + 264.00; 1 HNMR (400MHz, CDCl3): δ7.38-7.36(m,2H),7.08-7.04(m,1H),3.91(s,2H),3.89(s,2H),1.06(t,J=8.0Hz,9H),0.72-0.66(m,6H).

[0236] Synthesis of intermediate 46:

[0237] Intermediate 8 (2 g, 4.78 mmol), intermediate 45 (methylamine aqueous solution, 10 mL), and methanol (10 mL) were added to a pressure-resistant sealed tube. The mixture was heated to 100 °C and stirred for three hours. The reaction solution was cooled to room temperature, and the solution was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (3%–6% methanol in dichloromethane solution) to obtain a white solid intermediate 46 (1.39 g, 70%). MS: [M+H] + 418.30; 1 HNMR (400MHz, DMSO-d6): δ15.29(s,1H),11.43(s,1H),8.77-8.76(m,1H),8.6 9(s,1H),7.40-7.35(m,5H),5.18(s,2H),2.71(d,J=4.8Hz,3H),1.43(s,9H).

[0238] Synthesis of intermediate 47:

[0239] Intermediate 46 (77 mg, 1.85 mmol), HOBT (325 mg, 2.41 mmol), and EDCI (711 mg, 3.70 mmol) were added to DMF (8 mL). After stirring at room temperature for 1 hour, the reaction solution was cooled to 0°C. A DMF solution of intermediate 44 (560 mg, 2.13 mmol) in 1 mL was added dropwise to the reaction solution, and the mixture was left to stand overnight at room temperature. The reaction solution was diluted with water (90 mL), extracted with ethyl acetate (30 mL x 3), and the organic layer was washed with water (30 mL x 3). The residue was dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (14-30% ethyl acetate in petroleum ether solution) to give intermediate 47 (670 mg, 45%) as a white solid. MS: [M+H] + 663.30.

[0240] Synthesis of intermediate 48:

[0241] Intermediate 47 (670 mg, 0.89 mmol), intermediate 38 (346 mg, 1.60 mmol), potassium carbonate (229 mg, 1.66 mmol), and potassium iodide (69 mg, 0.41 mmol) were added to N,N-dimethylformamide (8 mL), and stirred at 100 °C for 5 hours. The reaction mixture was quenched with water (90 mL), extracted with ethyl acetate (30 mL x 3), and the organic phase was washed with water (30 mL x 3) and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (16-50% ethyl acetate in petroleum ether solution) to give a light buttery intermediate 48 (280 mg, 36%). MS: [M+H] + 775.35.

[0242] Synthesis of intermediate 49:

[0243] Intermediate 48 (280 mg, 0.36 mmol) was dissolved in dichloromethane (10 mL), and Desmartin (614 mg, 1.45 mmol) was added at 0 °C. The reaction mixture was then stirred overnight at room temperature. The solid was filtered off, and the filtrate was washed with water (10 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by passing it through a preparative plate and then purified with 33% ethyl acetate in petroleum ether to give an off-white solid, intermediate 49 (180 mg, 43%). MS: [M+H] + 659.20.

[0244] Synthesis of compound III-9:

[0245] Intermediate 49 (90 mg, 0.14 mmol) was dissolved in 1,4-dioxane (1 mL), and hydrochloric acid / 1,4-dioxane (1 mL) was added. The mixture was reacted overnight at 50 °C. The reaction solution was concentrated, and a white solid compound III-9 (10 mg, 15%) was obtained by preparative HPLC. MS: [M+H]+ 451.05; 1 HNMR (400MHz, DMSO-d6): δ12.11(s,1H),10.35-10.32(m,1H),8.33(s,1H),7.46 (t,J=6.0Hz,1H),7.40-7.37(m,1H),7.18(t,J=7.6Hz.1H)4.91-4.90(m,1H),4. 57(t,J=6.8Hz,2H),4.49(s,1H),3.12-3.10(m,1H),3.05-2.99(m,4H),2.79-2. 75(m,1H),2.27(s,1H),1.95-1.94(m,1H),1.78-1.59(m,4H),1.42-1.39(m,1H).

[0246] Example 5: Synthesis of Compound II-14

[0247]

[0248] The reaction route is shown below:

[0249]

[0250] Synthesis of intermediate 52:

[0251] Intermediate 50 (100 g, 1.09 mol) and cuprous bromide (215.2 mg, 0.0015 mol) were dissolved in toluene (250 mL). The mixture was heated to 90 °C, and intermediate 51 (toluene of tert-butyl peroxide, 50 mL) was added dropwise over approximately 1 hour. The mixture was stirred at 90 °C for another hour. The reaction mixture was then cooled to room temperature and washed successively with saturated brine (100 mL x 3), 10% sodium hydroxide aqueous solution (100 mL x 3), and saturated brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and then concentrated to obtain a light yellow oil intermediate 52 (10 g, 14.4%) (the product contains the solvent toluene). 1 HNMR (400MHz, CDCl3): δ6.65 (t, J = 2.4Hz, 2H), 6.61-6.57 (m, 2H), 3.78 (br, 1H), 3.42-3.37 (m, 2H), 1.14 (s, 9H).

[0252] Synthesis of intermediate 53:

[0253] Intermediate 52 (5.0 g, 30.44 mmol) was dissolved in acetic acid (50 mL); cooled to 0 °C, acetic anhydride (11.2 g, 409.6 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. The mixture was then cooled to 0 °C again, and the reaction solution was added to pre-cooled perchloric acid (7.0 mL). The mixture was stirred for 2 minutes and extracted with dichloromethane (50 mL * 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated at low temperature (25 °C) to obtain the crude product. The crude product was purified by silica gel column chromatography (1% ethyl acetate in petroleum ether solution) to obtain a light yellow oil intermediate 53 (4.9 g, 98%). 1 HNMR (400MHz, CDCl3): δ6.71 (t, J = 2.4Hz, 2H), 6.61-6.56 (m, 2H), 4.57 (br, 1H), 3.63-3.58 (m, 2H), 1.98 (s, 3H).

[0254] Synthesis of intermediate 54:

[0255] Under nitrogen protection, a suspension of lithium aluminum hydride (3.64 g, 95.88 mmol) in diethyl ether (160 mL) was cooled to 0 °C, and a solution of intermediate 53 (9.0 g, 59.93 mmol) in diethyl ether (40 mL) was added dropwise. The mixture was stirred at 0 °C for 5 minutes, then heated to room temperature and stirred for 2 hours. The mixture was cooled to 0 °C again, and water was slowly added dropwise to quench the reaction. The mixture was extracted with diethyl ether (100 mL * 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated at low temperature (25 °C) to obtain the crude product. The crude product was purified by silica gel column chromatography (16.7% ethyl acetate in petroleum ether solution) to obtain a light yellow oil intermediate 54 (4.9 g, 71%). 1 HNMR (400MHz, CDCl3): δ5.97 (t, J = 2.0 Hz, 2H), 3.61-3.55 (m, 1H), 2.57-2.51 (m, 2H), 1.85-1.76 (m, 2H), 1.54 (d, J = 4.8Hz, 1H), 1.06-1.00 (m, 2H).

[0256] Synthesis of intermediate 55:

[0257] A solution of oxalyl chloride (6.5 g, 51.20 mmol) in dichloromethane (40 mL) was cooled to -78 °C. A solution of DMSO (8.0 g, 102.40 mmol) in dichloromethane (8 mL) was added dropwise. After stirring at -78 °C for 10 minutes, a solution of intermediate 54 (4.7 g, 42.67 mmol) in dichloromethane (10 mL) was added dropwise. After stirring at -78 °C for 1 hour, triethylamine (21.5 g, 213.35 mmol) was added. After the addition was complete, the mixture was slowly brought to room temperature. The reaction solution was quenched with an appropriate amount of water. The mixture was extracted with dichloromethane (50 mL * 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated at low temperature (25 °C) to obtain the crude product. The crude product was purified by silica gel column chromatography (16.7% ethyl acetate in petroleum ether solution) to obtain a light yellow oil intermediate 55 (4.0 g, 71%). 1 HNMR (400MHz, CDCl3): δ6.53 (t, J = 2.4Hz, 2H), 2.84-2.80 (m, 2H), 1.99-1.95 (m, 2H), 1.23-1.19 (m, 2H).

[0258] Synthesis of intermediate 56:

[0259] Intermediate 55 (4.0 g, 37.0 mmol), ethylene glycol (3.44 g, 55.5 mmol), and p-toluenesulfonic acid hydrate (1.12 g, 5.92 mmol) were added sequentially to toluene (40 mL). After reflux for 5 hours, the mixture was cooled to room temperature and stirred overnight. The reaction solution was diluted with ethyl acetate (70 mL), washed sequentially with saturated sodium bicarbonate aqueous solution (25 mL x 2), saturated brine (60 mL), dried over anhydrous sodium sulfate, and concentrated at low temperature (25 °C) to obtain the crude product. The crude product was purified by silica gel column chromatography (using 5% ethyl acetate in petroleum ether solution) to obtain a pale yellow oil intermediate 56 (1.5 g, 26.7%). 1 HNMR (400MHz, CDCl3): δ6.19 (t, J=6.0Hz, 2H), 3.95-3.90 (m, 2H), 3.87-3.81 (m, 2H), 2.56-2.51 (m, 2H), 1.95-1.90 (m, 2H), 1.01-0.95 (m, 2H).

[0260] Synthesis of intermediate 57:

[0261] Intermediate 56 (5.0 g, 32.85 mmol) was dissolved in tert-butanol (50 mL) and water (50 mL), followed by the addition of potassium osmium tetroxide dihydrate (102.3 mg, 0.33 mmol) and N-methylmorpholine oxide (4.62 g, 39.42 mmol). The mixture was stirred overnight at room temperature. The reaction solution was cooled to 0 °C, and sodium periodate (9.1 g, 42.71 mmol) was added. The mixture was then stirred at room temperature for 2 hours. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL x 2), and the organic phase was washed with saturated brine (60 mL) and dried over anhydrous sodium sulfate. The crude product, light brown oil intermediate 57 (8.0 g crude product), was obtained and used directly in the next step.

[0262] Synthesis of intermediate 58:

[0263] Intermediate 57 (8.0 g crude, 26.3 mmol) was dissolved in methanol (30 mL), cooled to 0 °C, and sodium borohydride (1.5 g, 39.4 mmol) was added in portions. The mixture was stirred at room temperature for 2 hours under nitrogen protection. The reaction solution was quenched with water and concentrated to obtain the crude product, which was purified by silica gel column chromatography (50%–100% ethyl acetate in petroleum ether solution) to give colorless oil intermediate 58 (1.3 g, 26.5%). 1 HNMR (400MHz, CDCl3): δ4.07-3.99(m,4H), 3.71-3.63(m,4H), 2.25-2.18(m,2H), 1.86-1.77(m,2H), 1.67-1.58(m,4H).

[0264] Synthesis of intermediate 59:

[0265] Intermediate 58 (380 mg, 2.02 mmol) was dissolved in DMF (10 mL), and tert-butyldiphenylchlorosilane (1.67 g, 6.06 mmol) and imidazole (825.1 mg, 12.12 mmol) were added sequentially. The mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate (30 mL), washed successively with water (8 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (1%–2% ethyl acetate in petroleum ether solution) to obtain a light yellow oil intermediate 59 (1.3 g, 26.5%). 1HNMR (400MHz, CDCl3): δ7.67-7.63(m,8H),7.41-7.35(m,12H),3.81(t,J=6.4Hz,2H),3.77-3.72(m,2H),3.6 8(t,J=6.4Hz,2H),1.86-1.77(m,2H),2.38-2.28(m,2H),1.89-1.78(m,2H),1.48-1.40(m,2H),1.02(s,18H).

[0266] Synthesis of intermediate 60:

[0267] Intermediate 59 (2.1 g, 3.15 mmol) was dissolved in tetrahydrofuran (40 mL), cooled to 0 °C, and 1 N TBAF (2.5 mL, 2.52 mmol) was added. The mixture was stirred at room temperature for 2.5 hours. The reaction solution was quenched with water, extracted with ethyl acetate (20 mL * 3), and the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (2.5%–10% ethyl acetate in petroleum ether solution) to give a pale yellow oil intermediate 60 (360 mg, 26.8%). 1 HNMR (400MHz, CDCl3): δ7.70-7.64(m,4H),7.46-7.35(m,6H),3.99-3.49(m ,8H),2.31-2.18(m,2H),1.87-1.68(m,2H),1.65-1.45(m,3H),1.04(s,9H).

[0268] Synthesis of intermediate 62:

[0269] Under nitrogen protection, intermediate 46 (4.0 g, 9.59 mmol) was dissolved in DMF (60 mL), followed by the addition of EDCI (3.68 g, 19.18 mmol) and HOBT (1.68 g, 12.47 mmol). The mixture was stirred at room temperature for 1 hour, cooled to 0 °C, and a solution of intermediate 61 (1.68 g, 10.55 mmol) in DMF (10 mL) was added dropwise. The mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate (150 mL), washed successively with water (75 mL x 3), and saturated brine (100 mL). The solution was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. Purification was achieved by silica gel column chromatography (using 33-50% ethyl acetate in petroleum ether) to obtain a white solid intermediate 62 (4.5 g, 80%). MS: [M+H] + 559.05; 1HNMR (400MHz, CDCl3): δ10.25(t,J=6.0Hz,1H),8.59(s,1H),8.47(s,1H),7.40-7.28(m,7H),7.08-7.02 (m,1H),6.59-6.51(m,1H),4.70(d,J=6.0Hz,2H),3.75-3.68(m,2H),2.70(d,J=4.8Hz,3H),1.42(s,9H).

[0270] Synthesis of intermediate 63:

[0271] Under nitrogen protection, intermediate 62 (449.2 mg, 0.80 mmol), intermediate 60 (360 mg, 0.84 mmol), and triphenylphosphine (843.5 mg, 3.22 mmol) were dissolved in dry toluene (10 mL), cooled to 0 °C, and DIAD (650.3 mg, 3.22 mmol) was added dropwise. After the addition was complete, the mixture was stirred at 0 °C for 15 minutes, then heated to 80 °C and stirred overnight. The reaction solution was concentrated to obtain the crude product, which was purified by silica gel column chromatography (20%–33% ethyl acetate in petroleum ether solution) to obtain a light yellow oil intermediate 63 (740 mg, 95%). 1 HNMR (400MHz, CDCl3): δ10.36(t,J=6.0Hz,1H),8.54-8.30(m,1H),7.68-7.61(m,4 H),7.44-7.30(m,13H),7.06(t,J=7.6Hz,1H),5.73(br,1H),5.42-5.34(m,1H),5. 17-5.06(m,1H),4.79-4.65(m,2H),3.95-3.66(m,6H),3.60-3.41(m,2H),2.73-2. 66(m,3H),2.44-2.23(m,2H),1.93-1.75(m,2H),1.41-1.20(m,11H),1.02(s,9H).

[0272] Synthesis of intermediate 64:

[0273] Intermediate 63 (740 mg, 0.77 mmol) was dissolved in tetrahydrofuran (4 mL), and 1 M TBAF / THF was added. The mixture was stirred at room temperature for 4 hours. The reaction solution was quenched in ethyl acetate (10 mL) and saturated water (8 mL). The aqueous phase was extracted with ethyl acetate (8 mL * 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (50%–100% ethyl acetate in petroleum ether solution) to give intermediate 64 (350 mg, 62%), an off-white solid. MS: [M+H] +729.10; 1 HNMR (400MHz, CDCl3): δ10.34(t,J=6.0Hz,1H),8.54-8.31(m,1H),7.39-7 .29(m,7H),7.06(t,J=7.6Hz,1H),5.80-5.62(m,1H),5.44-5.37(m,1H),5. 17-5.07(m,1H),4.77-4.64(m,2H),4.08-3.83(m,5H),3.71-3.47(m,3H),2 .76-2.66(m,3H),2.32-1.96(m,4H),1.94-1.78(m,2H),1.48-1.35(m,9H).

[0274] Synthesis of intermediate 65:

[0275] Under nitrogen protection, intermediate 64 (350 mg, 0.48 mmol) was dissolved in DCM (8 mL), cooled to 0 °C, and Dess-Martin oxidant (1.29 g, 3.05 mmol) was added in three portions, stirred overnight at room temperature. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with dichloromethane, and the filtrate was washed successively with saturated sodium bicarbonate aqueous solution (15 mL * 2), saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (33%–50% ethyl acetate in petroleum ether solution) to give a pale yellow oil intermediate 65 (300 mg, 85%). MS: [M+H] + 727.05; 1 HNMR (400MHz, CDCl3): δ10.34(t,J=6.0Hz,1H),9.64-9.57(m,1H),8.58-8.33(m,1H),7. 40-7.28(m,7H),7.06(t,J=8.0Hz,1H),5.81-5.63(m,1H),5.43-5.38(m,1H),5.16-5.06( m,1H),4.77-4.64(m,2H),4.10-3.73(m,5H),3.63-3.35(m,1H),2.95-2.83(m,1H),2.73- 2.66(m,3H),2.47-2.33(m,1H),2.21-2.10(m,1H),2.03-1.82(m,2H),1.50-1.36(m,9H).

[0276] Synthesis of intermediate 66:

[0277] Under nitrogen protection, toluenesulfonic acid hydrate (440.8 mg, 23.2 mmol) was added to an acetonitrile (20 mL) solution of intermediate 65 (420 mg, 0.58 mmol) and stirred overnight at 30 °C. After cooling the reaction solution to room temperature, it was quenched with ethyl acetate (20 mL) and saturated sodium bicarbonate solution (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL * 2), and the organic phase was washed with saturated brine (30 mL). The solution was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was dissolved in DMF (10 mL), and Cs₂CO₃ (3.78 g, 11.6 mmol) and benzyl bromide (1.98 g, 11.6 mmol) were added sequentially. The mixture was stirred overnight at 40 °C. The reaction solution was diluted with ethyl acetate (30 mL), washed sequentially with water (10 mL * 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (50% ethyl acetate in dichloromethane solution) to give an off-white solid intermediate 66 (120 mg, 34%). MS: [M + H] + 609.00; 1 HNMR (400MHz, CDCl3): δ10.51(t,J=6.4Hz,1H),8.53(s,1H),7.67-7.61(m,2H),7.38-7.28(m,5H),7.04(t,J=7.6Hz,1H),5.34-5.23(m,2H),4.78( d,J=4.0Hz,1H),4.70(d,J=5.6Hz,2H),4.04-3.88(m,4H),3.76-3.71(m,1 H), 3.09(s,3H),3.04-2.99(m,1H),2.47-2.42(m,1H),2.09-1.87(m,5H).

[0278] Synthesis of intermediate 67:

[0279] Intermediate 66 (120 mg, 0.20 mmol) and 4N hydrochloric acid aqueous solution (5 mL) were added to acetone (5 mL) and stirred overnight at 50 °C. After the reaction solution was cooled to room temperature, ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL) were added. The aqueous phase was extracted with ethyl acetate (10 mL * 2), and the organic phase was washed with saturated brine (20 mL). The solution was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was dissolved in DMF (10 mL), and Cs₂CO₃ (1.30 g, 4.0 mmol) and benzyl bromide (684.1 mg, 4.0 mmol) were added sequentially. The solution was stirred overnight at 40 °C. The reaction solution was diluted with ethyl acetate (30 mL), washed sequentially with water (10 mL * 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (33% ethyl acetate and 33% dichloromethane in petroleum ether solution) to obtain a light yellow solid intermediate 67 (95.4 mg, 85%). MS: [M+H] + 565.00; 1 HNMR (400MHz, CDCl3): δ10.42 (t, J = 6.0Hz, 1H), 8.60 (s, 1H), 7.60-7.55 (m, 2H), 7 .37-7.27(m,5H),7.04(t,J=7.6Hz,1H),5.37(t,J=10.0Hz,1H),5.24(d,J=10.0Hz ,1H),4.96(d,J=4.0Hz,1H),4.71(d,J=6.0Hz,2H),3.73(d,J=10.0Hz,1H),3.40-3 .34(m,1H),3.16(s,3H),2.84-2.78(m,1H),2.45-2.39(m,1H),2.27-1.99(m,4H).

[0280] Synthesis of intermediate 68:

[0281] Methyltriphenylphosphine bromide (126.5 mg, 0.35 mmol) was suspended in dried tetrahydrofuran (4 mL); potassium tert-butoxide (39.7 mg, 0.35 mmol) was added; the mixture was stirred at 45 °C until the yellow solution turned pale yellow turbidity; a tetrahydrofuran solution of intermediate 67 (5 mg, 0.0088 mmol) (1 mL) was added; the mixture was heated to 50 °C and stirred for 20 minutes. The reaction solution was cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, and extracted with ethyl acetate (8 mL * 3); the organic phase was washed with saturated brine (15 mL) and dried over anhydrous sodium sulfate; the crude product was concentrated and purified by preparative plate (33% ethyl acetate and 33% dichloromethane in petroleum ether solution) to give a white solid intermediate 68 (30 mg, 30%). MS:

[0282] [M+H]+ 563.55; 1 HNMR (400MHz, CDCl3): δ10.49 (t, J = 6.0Hz, 1H), 8.54 (s, 1H), 7.62-7.57 (m, 2H), 7 .37-7.27(m,5H),7.04(t,J=7.6Hz,1H),5.35(t,J=10.0Hz,1H),5.24(d,J=10.0Hz ,1H),5.07(s,1H),5.02(s,1H),4.72-4.68(m,3H),3.35(d,J=9.2Hz,1H),3.15(s ,3H),3.15-3.11(m,1H),3.07-3.01(m,1H),2.67-2.62(m,1H),2.05-1.80(m,4H).

[0283] Synthesis of compound II-14:

[0284] Under nitrogen protection, intermediate 68 (30 mg, 0.053 mmol) and LiCl (22.5 mg, 0.53 mmol) were dissolved in DMF (2 mL) and stirred overnight at 90 °C. The reaction solution was cooled to room temperature, diluted with ethyl acetate (15 mL), washed successively with water (6 mL x 3), and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC to obtain a white solid compound II-14 (19 mg, 73%). MS: [M+H] + 473.35; 1 HNMR (400MHz, CD3OD): δ8.49(s,1H), 7.39(t,J=8.0Hz,1H), 7.34(t,J=6.4Hz,1H), 7.13(t,J=7.6Hz,1H), 5.10(s,2H), 5.02(d,J=4. 0Hz,1H),4.69(s,2H),3.37-3.33(m,2H),3.25-3.21(m,1H),3.20(s,3H),2.71-2.65(m,1H),2.12-2.03(m,2H),1.93-1.82(m,2H).

[0285] Example 6: Synthesis of Compound II-13

[0286]

[0287] The reaction route is shown below:

[0288]

[0289] Synthesis of compound II-13:

[0290] Intermediate 67 (45 mg, 0.080 mmol) was dissolved in 4M hydrochloric acid aqueous solution (3 mL) and acetone (3 mL) and stirred overnight at 50 °C. The reaction solution was cooled to room temperature, neutralized to pH 8 with saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate (10 mL * 3). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC to give a light pink solid compound II-13 (25.3 mg, 67%). MS: [MH] + 474.90; 1 HNMR (400MHz, CD3OD): δ8.59(s,0.3H),8.47(s,0.7H),7.40(t,J=7.6Hz,1H),7.34(t,J=6.4 Hz,1H),7.13(t,J=7.6Hz,1H),5.32(d,J=4.4Hz,0.3H),5.04(d,J=3.6Hz,0.7H),4.69(s,2H ),3.76-3.68(m,1H),3.54-3.46(m,0.4H),3.23-3.17(m,3H),3.12-3.06(m,0.6H),3.00-2. 94(m,0.3H),2.90-2.83(m,0.7H),2.41-2.24(m,1H),2.12-2.06(m,1H),2.02-1.72(m,3H).

[0291] Example 7: Synthesis of compound V-1

[0292]

[0293] The reaction route is shown below:

[0294]

[0295] Synthesis of intermediate 70:

[0296] Intermediate 69 (1.0 g, 7.57 mmol) was dissolved in dichloromethane (20 mL), cooled to 0 °C, and then triethylamine (2.1 mL, 15.14 mmol) and methanesulfonyl chloride (823.4 mg, 7.19 mmol) were added dropwise. The mixture was then stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain the crude product, which was purified by silica gel column chromatography (50%–100% ethyl acetate in dichloromethane solution) to give a colorless oily intermediate 70 (420 mg, 26%). MS: [M+H] + 210.90.

[0297] Synthesis of intermediate 72:

[0298] Intermediate 8 (3.0 g, 7.18 mmol), HOBT (1.26 g, 9.33 mmol), and EDCI (2.76 g, 14.35 mmol) were added to DMF (30 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was cooled to 0 °C, and intermediate 71 (1.03 g, 7.18 mmol) was added dropwise. The mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate (90 mL), washed successively with water (100 mL x 3), and saturated brine (50 mL). The solution was dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography (20-50% ethyl acetate in petroleum ether solution) to give intermediate 72 (2.86 g, 75%) as a white solid. MS: [M+H] + 544.15; 1 HNMR (400MHz, DMSO-d6): δ11.08(s,1H),10.18(t,J=8Hz,1H),8.43(s,1H),7.47-7.41(m,1H),7.38-7.32 (m,5H),7.28-7.23(m,1H),7.11-7.05(m,1H),5.15(s,2H),4.56(d,J=8Hz,2H),3.78(s,3H),1.42(s,9H).

[0299] Synthesis of intermediate 73:

[0300] Intermediate 72 (2.85 g, 5.25 mmol) was dissolved in MeOH (15 mL) and H₂O (15 mL), and NaOH (839 mg, 20.99 mmol) was added. The mixture was stirred overnight at 50 °C, concentrated to dryness, and the pH was adjusted to 6-7 with 2 M HCl. A solid precipitated, which was filtered and dried under reduced pressure to obtain a white solid intermediate 73 (2.5 g, 90%). MS: [MH] + 530.05; 1 HNMR (400MHz, DMSO-d6): δ10.99(s,1H),10.53(s,1H),8.12(s,1H),7.49-7 .22(m,7H),7.10-7.05(m,1H),5.01(s,2H),4.54-4.53(m,2H),1.43(s,9H).

[0301] Synthesis of intermediate 75:

[0302] Intermediate 73 (1.16 g, 2.19 mmol), intermediate 74 (385 mg, 3.29 mmol), and EDCI (632 mg, 3.29 mmol) were added to pyridine (10 mL), heated to 50 °C, and stirred overnight. Pyridine was removed by vacuum distillation. Extraction was performed three times with EA (50 mL). The organic layer was washed with citric acid (50 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification was achieved by silica gel column chromatography (using 20%–50% ethyl acetate and 20%–50% dichloromethane in petroleum ether) to give intermediate 75 (960 mg, 74%) as an orange solid. MS: [M+H] + 593.05; 1 HNMR (400MHz, DMSO-d6): δ11.31(s,1H),10.27(t,J=8.8Hz,1H),9.45(s,1H),8.32(s,1H),7.46-7.33(m,6 H),7.28-7.06(m,1H),5.12(s,2H),4.55(d,J=6Hz,2H),1.45(s,9H),1.24-1.14(m,3H),0.91-0.89(m,2H).

[0303] Synthesis of intermediate 76:

[0304] Intermediate 75 (460 mg, 0.77 mmol) was dissolved in DMF (5 mL), and intermediate 70 (244 mg, 1.16 mmol) and K₂CO₃ (214 mg, 1.55 mmol) were added. The reaction mixture was reacted at 100 °C for 4 hours. The reaction solution was cooled to room temperature, quenched with water, and extracted with EA (30 mL x 3). The organic phase was washed with water (30 mL x 3) and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by preparative plate (40% ethyl acetate in petroleum ether solution) to give intermediate 76 (100 mg, 18%) as a white solid. MS: [M+H] + 707.40.

[0305] Synthesis of intermediate 77:

[0306] Intermediate 76 (100 mg, 0.142 mmol) was dissolved in acetonitrile (4 mL), and 2-iodobenzoic acid (79 mg, 0.283 mmol) was added. The mixture was stirred overnight at 50 °C. The solid was removed by filtration, and the filtrate was concentrated to obtain the crude product, which was then purified by preparative plate (50% ethyl acetate in dichloromethane solution).

[0307] A pale yellow oily intermediate 77 (60 mg, 60%) was obtained. MS: [M+H] + 705.55.

[0308] Synthesis of compound V-1:

[0309] Intermediate 77 (60 mg, 0.085 mmol) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (1.5 mL) was added. The mixture was stirred overnight at room temperature. The pH of the reaction solution was adjusted to 6–7 with saturated NaHCO3. The solution was extracted twice with EA (15 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by preparative HPLC to obtain a pale pink solid compound V-1 (10 mg, 22%). MS: [M+H] + 497.00; 1 HNMR (400MHz, DMSO-d6): δ10.28-10.27(m,2H),8.43(s,1H),7.44-7.40(m,1H),7.26(t,J=8Hz,1H),7.09(t,J=8Hz ,1H),5.12-5.06(m,2H),4.81(s,1H),4.63-4.49(m,3H),3.41-3.22(m,3H),2.25-1.89(m,4H),1.59-1.36(m,3H).

[0310] The compounds listed in Table 1 below were synthesized using the same method:

[0311] Table 1

[0312]

[0313] Example 8: Synthesis of Compound I-4

[0314]

[0315] The reaction route is shown below:

[0316]

[0317] Synthesis of intermediate 79:

[0318] Under nitrogen protection, intermediates 73 (855 mg, 1.62 mmol), 78 (160 mg, 2.42 mmol), and EDCI (465 mg, 2.42 mmol) were added to pyridine (10 mL), and the mixture was stirred overnight at 50 °C. The reaction solution was concentrated under reduced pressure to remove pyridine. The residue was diluted with ethyl acetate (20 mL), washed successively with saturated citric acid aqueous solution (8 mL x 3), saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (25%–50% ethyl acetate in petroleum ether solution) to give intermediate 79 (580 mg, 63%), an off-white solid. MS: [M+H] + 578.05; 1HNMR (400MHz, DMSO-d6): δ11.25(br,1H),10.32(t,J=6.0Hz,1H),8.68(s,1H),8.31(s,1H),7.46-7 .29(m,6H),7.29-7.21(m,1H),7.12-7.03(m,1H),5.13(s,2H),4.55(d,J=6.0Hz,2H),1.44(s,9H).

[0319] Synthesis of intermediate 80:

[0320] Under nitrogen protection, intermediates 79 (366.3 mg, 0.63 mmol), 70 (200 mg, 0.95 mmol), TBAI (232.7 mg, 0.63 mmol), and Cs₂CO₃ (410.5 mg, 1.26 mmol) were sequentially added to DMF (8 mL). The mixture was stirred overnight at 70 °C. The reaction solution was cooled to room temperature, diluted with ethyl acetate (20 mL), and then washed sequentially with water (8 mL x 3) and saturated brine (15 mL). The solution was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (using a solution of 33% ethyl acetate and 33% dichloromethane in petroleum ether) to obtain a white solid intermediate 80 (76 mg, 17.3%). MS: [M+H] + 692.65; 1 HNMR (400MHz, CDCl3): δ10.55-10.30(m,1H),8.95-8.70(m,1H),7.45-7.29(m,6H),6.88-6.76(m,2H),5.53-5.33(m,1H),5.04-4.98(m ,1H),4.64(br,2H),4.09-4.02(m,2H),3.99-3.73(m,2H),3.67-3.37(m,2H),1.98-1.86(m,2H),1.81-1.64(m,2H),1.31-1.22(m,9H).

[0321] Synthesis of intermediate 81:

[0322] Under nitrogen protection, 2-iodobenzoic acid (97.1 mg, 0.35 mmol) was added to an acetonitrile solution (4 mL) of intermediate 80 (120 mg, 0.17 mmol). The mixture was stirred overnight at 50 °C. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (using a solution of 33% ethyl acetate and 33% dichloromethane in petroleum ether) to give a pale yellow oil intermediate 81 (102 mg, 85%). MS: [M+H] + 690.55; 1HNMR (400MHz, CDCl3): δ10.29(t,J=4.4Hz,1H),9.70(br,1H),8.64(s,1H),7.43-7.31(m,6H),6.88-6.77(m,2H),5.49-5.33(m,1H), 5.08-5.02(m,1H),4.72-4.52(m,2H),4.45-4.18(m,2H),4.08-3.95(m,1H),3.84-3.68(m,1H),2.24-1.98(m,4H),1.34-1.22(m,9H).

[0323] Synthesis of compound I-4:

[0324] Under nitrogen protection, toluenesulfonic acid (84.9 mg, 0.49 mmol) was added to a solution of intermediate 81 (85 mg, 0.12 mmol) in 1,2-dichloroethane (5 mL). The mixture was stirred at 80 °C for 4 hours. The reaction solution was cooled to room temperature and neutralized to pH 8 with saturated sodium bicarbonate aqueous solution. Extraction was performed with ethyl acetate (10 mL * 3). The organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by preparative HPLC to obtain a pink solid compound I-4 (20 mg, 28%). MS: [M+H] + 482.3; 1 HNMR (400MHz, CD3OD): δ8.43(s,1H),7.47-7.37(m,1H),7.01-6.88(m,2H),5.04-4.98(m,1H),4.94-4.91(m,1H) ),4.62(s,2H),4.54-4.49(m,1H),3.43-3.37(m,1H),3.05-2.99(m,1H),2.30-2.15(m,2H),2.13-2.00(m,2H).

[0325] The compounds listed in Table 2 were synthesized using the same method:

[0326] Table 2

[0327]

[0328] Example 9. In vitro HIV-1 pseudovirus test and cytotoxicity test

[0329] HEK293T cells were seeded at a specific density in microplates and cultured overnight at 37°C and 5% CO2. The next day, the compound and a pseudovirus were added. Cells were set up as controls (no compound treatment or virus infection) and virus-infected cells (cells infected with virus, no compound treatment). The final concentration of DMSO in the cell culture medium was 0.5%. Cells were cultured at 37°C and 5% CO2 for 3 days. Reporter gene expression was detected using a luciferase reporter gene assay. Cytotoxicity assays were performed similarly to antiviral assays, but without virus infection. Cell viability was assessed using CellTiter Glo reagent. Raw data were used to calculate the compound's antiviral activity and cytotoxicity. GraphPad Prism software was used to analyze the compound's dose-response curve and calculate the IC50. 50 and CC 50 The values ​​are shown in Table 3 below.

[0330] Table 3

[0331]

[0332]

[0333] Cabotegravir (positive control):

[0334]

[0335] In vitro PHIV results showed that these unresolved compounds IV-17, IV-20, IV-2, II-13, and V-1 already had good anti-HIV-1 activity and no obvious cytotoxicity. It is predicted that the activity of the dominant conformation after resolution will be at least doubled.

[0336] Example 10. Stability test of human and rat liver microsomes

[0337] Experimental protocol: This experiment was conducted in a 96-well plate. The reaction conditions were: ① Microsomal protein concentration: 0.7 mg / mL ② Compound concentration:

[0338] 1 μM ③ NADPH concentration: 1 mM ④ Phosphate concentration: 100 mM ⑤ Incubation volume: 100 μL ⑥ Acetonitrile concentration: 0.1%. The reaction was terminated by adding a stop solution after incubation for 0 min, 15 min, 30 min, 60 min, and 90 min, respectively. The remaining amount of the compound was detected using a liquid chromatography-mass spectrometry (LC-MS) analyzer. Positive controls were testosterone and diclofenac.

[0339] Data Analysis: Analyte / Internal Standard Peak Area Ratio (A) analyte / A IS The remaining percentage (%Control) will be determined by the instrument, calculated from the A values ​​of the samples at non-zero time points and the sample at time zero. analyte / AIS The ratio was calculated. Ln(%Control) was plotted against incubation time and linearly fitted.

[0340] Scavenging constant (k, min) of the test compound -1 ), elimination half-life (T) 1 / 2 (min) with clearance rate ( The (μl / min / mg) was calculated using the following equation, and the results are shown in Table 4 below.

[0341] k = -slope

[0342]

[0343]

[0344] Table 4

[0345]

[0346] The results showed that compound IV-17 had a low clearance rate, and this compound's properties are suitable for the research and development of long-acting formulations.

[0347] Example 11. Thermodynamic solubility test

[0348] Experimental protocol: Accurately weigh approximately 2 mg of the compound per pH, and add an appropriate volume of PB buffer (pH 7.4) to obtain a solution with a concentration of 2 mg / mL. After sonication for 10 minutes, fix the solution on a shaker and shake at room temperature for 8 hours. After shaking, sonicate for 10 minutes and centrifuge at 13000 rpm for 15 minutes. Transfer 0.1 mL of the supernatant to a new tube, shake and rinse for 5 minutes, then discard the liquid. Transfer another 0.5 mL of the supernatant to a new tube, centrifuge at 13000 rpm for 15 minutes, and collect the supernatant (dilute with water if necessary). Analyze the supernatant by LC-MS / MS. The results are shown in Table 5 below.

[0349] Table 5

[0350] Compound numbering Solubility (μg / ml) Cabotegravir 7.44 IV-17 2.18 IV-2 13.3 II-13 11.0

[0351] The results showed that compounds IV-17, IV-2, and II-13 all had extremely low thermodynamic solubility in pH 7.4 PB buffer, which increased the probability of successful development of long-acting injectable formulations.

[0352] Example 12. Caco2 Permeability Test

[0353] Experimental design and results:

[0354] (1) Preparation of working solutions of control compound and test compound

[0355] The hypotonic control compound (atenolol), hypertonic control compound (propranolol), P-glycoprotein substrate control compound (digoxin), and working solution of the test substance were obtained by diluting the stock solution with transport buffer (HBSS containing 10 mM HEPES, pH = 7.4) to the following final concentrations: working solution of test substance: 10 μM; atenolol: 20 μM; propranolol: 5 μM; digoxin: 10 μM.

[0356] (2) Culture of Caco2 cells

[0357] Caco-2 cells were seeded and cultured in 24-well Transwell plates. After culture, they should have completely merged and differentiated. The transmembrane resistance was measured using a resistance meter, and only monolayer cells with a transmembrane resistance (TEER) value ≥ 230 ohms·cm were observed. 2 Only cell pores with specific TEER values ​​(ohm·cm) can be used for the penetration test. 2 = Measured resistance (ohms) × Film area (cm²) 2 ).

[0358] (3) Drug penetration test

[0359] a) Remove the Transwell plate from the incubator. Rinse the cell membrane twice with preheated transport buffer and incubate at 37°C for 30 minutes.

[0360] b) Due to the reduced solubility of the compound, the buffer solutions at the dosing and receiving ends were adjusted to HBSS buffer containing 0.1% BSA.

[0361] c) Determine the transport rate of the compound from the top to the base. Add 210 μL of the dosing end solution to each well of the upper chamber (top), then immediately remove 10 μL of the dosing end solution and add it to a new 96-well plate. Mix this with 90 μL of transport buffer and 300 μL of quenching solution (acetonitrile, containing 5 ng / mL verapamil and 50 ng / mL glibenclamide). This sample is used as the initial dosing end sample TA0.

[0362] (A→B). Add 1300 μL of receiver solution to each well of the lower chamber (base end).

[0363] d) Determine the transport rate of the compound from the base end to the top end. Add 1310 μL of the drug-end solution to each well of the lower chamber (base end), then immediately remove 10 μL of the drug-end solution and add it to a 96-well plate, mixing it with 90 μL of transport buffer and 300 μL of quenching solution. This sample is used as the initial drug-end sample TB0 (B→A). Add 200 μL of the receiver end solution to each well of the upper chamber (top end).

[0364] e) The Transwell plates were incubated at 37°C for 120 minutes.

[0365] f) Preparation of drug delivery end sample: After the Transwell plate incubation is completed, 10 μL of drug delivery end solution is transferred to a 96-well plate and mixed with 90 μL of transport buffer solution and 300 μL of quenching solution.

[0366] g) Sample preparation for receiving end: After the Transwell plate incubation is completed, 100 μL of the receiving end solution is transferred to a 96-well plate and mixed with 300 μL of quenching solution.

[0367] h) After centrifuging all samples, transfer the supernatant to a new 96-well plate, mix it with water in a certain proportion, and then perform LC-MS / MS analysis. Each experimental sample is tested in duplicate.

[0368] (4) Data Analysis

[0369] a) Apparent permeability coefficient (P) app cm / s×10 -6 It is calculated using the following formula:

[0370]

[0371] In the formula: C R The concentration at the receiver after incubation

[0372] C D0 Initial concentration at the dosing end

[0373] V R The volume of the solution at the receiving end is 1.3 mL for A→B and 0.2 mL for B→A.

[0374] A represents the area of ​​a single cell membrane (0.33 cm²). 2 )

[0375] T represents the incubation time (7200 seconds).

[0376] b) The efflux ratio is calculated using the following formula:

[0377]

[0378] In the formula: P app(B→A) The apparent permeability coefficient from the base to the tip.

[0379] P app(A→B) The apparent permeability coefficient from the top to the base.

[0380] c) Recovery rate is calculated using the following formula:

[0381]

[0382] In the formula: C R The concentration at the receiver after incubation

[0383] V R The volume of the solution at the receiving end is 1.3 mL for A→B and 0.2 mL for B→A.

[0384] C D Concentration at the dosing end after incubation

[0385] V D The volume of the solution at the administration end is 0.2 mL for A→B and 1.3 mL for B→A.

[0386] C D0 Concentration at the initial dosing point

[0387] d) See Table 6 for parameter standards.

[0388] Table 6

[0389]

[0390] (5) See Table 7 for the data results.

[0391] Table 7

[0392]

[0393]

[0394] According to the parameter standards, the results show that compound IV-17 is similar to cabotegravir, with moderate permeability, making it suitable for the development of long-acting drugs; while compounds IV-2 and II-13 may be substrates for efflux transporters, which may have a certain impact on the absorption of the compounds.

[0395] The above description of the embodiments is only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A pyridone derivative or its stereoisomer, a prodrug of a pyridone derivative, or a pharmaceutically acceptable salt, wherein the pyridone derivative has the structure shown in formula (I): in: (1) R1 is selected from the following groups, whether unsubstituted or substituted: C 1-20 Alkyl, deuterated C 1-20 Alkyl, C 3-6 cycloalkyl, deuterated C 3-6 Cycloalkyl and alkynyl-substituted C 1-20 alkyl and alkynyl substituted C 3-6 Cycloalkyl and alkynyl-substituted C 3-6 Heterocyclic alkyl, C 3-10 cycloalkyl C 1-10 Alkyl, C 2-8 Heterocyclic C 1-10 Alkyl; the substituent used for substitution is one or more selected from the following groups: halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, C 6-10 Aryl, C 3-10 heteroaryl, C 1-6 Alkyl sulfone group, C 1-6 alkyl mercapto, cyano, or hydroxyl; (2) Each R2 is independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 2-6 Alkyne group; n is 1, 2, 3 or 4; (3) R 3a R 3b Independently selected from H, D, C 1-6 Alkyl, deuterated C 1-6 alkyl; (4) Q is selected from amides, unsubstituted or substituted 4-6 membered heterocycles; the substituents used for substitution are selected from one or more of the following groups: halogens, C 1-2 Alkyl, halogenated C 1-2 Alkyl, C 1-6 alkoxy, cyano, or oxo; (5) X and Y are independently selected from CH or N; (6) A is absent, or A is selected from unsubstituted or substituted 5-10 membered heterocyclic groups or 5-10 membered carbocyclic groups; the substituent used for substitution is one or more selected from the following groups: halogen, cyano, C 1-6 Alkyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkyne, hydroxyl, oxo, exocyclic double bond, halogenated exocyclic double bond, C 1-6 Alkoxy or C 1-6 Alkoxy C 1-3 Alkyl group; wherein, when it contains two substituents, the two substituents are connected together with A to form a spirocyclic, fused, or bridged ring; When A is absent, R1 is connected to Y and together with N connected to R1, they form a 3-20 elemental heterocycle; (7)C 3-6 Heterocyclic alkyl, C 2-8 Heterocyclic, C 3-10 The heteroatoms in heteroaryl, 4-6 membered heterocycles, 5-10 membered heterocyclic groups, and 3-20 membered heterocycles are independently selected from one or more of O, S, N, -SO2-, Se, and oxo.

2. The pyridone derivative or its stereoisomer, the prodrug of the pyridone derivative, or the pharmaceutically acceptable salt according to claim 1, characterized in that, X is N, Y is CH.

3. The pyridone derivative or its stereoisomer, the prodrug of the pyridone derivative, or the pharmaceutically acceptable salt according to claim 1, characterized in that, When A does not exist, both X and Y are CH.

4. The pyridone derivative or its stereoisomer, the prodrug of the pyridone derivative, or a pharmaceutically acceptable salt according to claim 1, characterized in that, The chirality of the carbon atom connected to ring A and Y is selected from the S configuration, R configuration, or R / S configuration. The R / S configuration is shown in formula (I), and the S and R configurations are shown in formulas (Ia) and (Ib), respectively.

5. The pyridone derivative or its stereoisomer, the prodrug of the pyridone derivative, or a pharmaceutically acceptable salt according to claim 1, characterized in that, A is selected from unsubstituted and substituted 5-10 membered heterocycles, and the substituents used for substitution are selected from one or more of the following groups: F, Cl, Br, methyl, deuterated methyl, ethyl, deuterated ethyl, trifluoromethyl, difluoromethyl, cyclopropyl, methoxy, ethoxy, propoxy, butoxy, halomethoxy, haloethoxy, halopropoxy, halobutoxy, ethynyl, propynyl, oxo, exocyclic double bond, haloexocyclic double bond, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl.

6. The pyridone derivative or its stereoisomer, the prodrug of the pyridone derivative, or a pharmaceutically acceptable salt according to claim 1, characterized in that, The pyridone derivatives have the structure shown in formula (IA): In equation (IA), R1, R2, n, and R 3a R 3b The definitions are the same as in claim 1; W is selected from O, CH2, oxo, exocyclic double bond, and halogenated exocyclic double bond; R4 is absent or selected from C. 1-3 Alkyl, deuterated C 1-3 Alkyl; R5 and R6 are independently selected from H, methyl, deuterated methyl, ethyl, deuterated ethyl, ethynyl, propynyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, or R5 and R6 are connected together and form a bridged ring with the ring containing W.

7. The pyridone derivative or its stereoisomer, the prodrug of the pyridone derivative, or the pharmaceutically acceptable salt according to claim 6, characterized in that, In formula (IA), Selected from unsubstituted and substituted groups:

8. The pyridone derivative or its stereoisomer, the prodrug of the pyridone derivative, or a pharmaceutically acceptable salt according to any one of claims 1-7, characterized in that, R1 is selected from the following groups, whether unsubstituted or substituted: C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 3-6 cycloalkyl, deuterated C 3-6 cycloalkyl, C 2-4 alkynyl C 1-6 Alkyl, C 2-4 alkynyl halogenated C 1-6 Alkyl, C 2-4 alkynyl C 3-6 cycloalkyl, C 2-4 alkynyl halogenated C 3-6 cycloalkyl, C 2-4 alkynyl C 3-6 Heterocyclic alkyl groups.

9. The pyridone derivative or its stereoisomer, the prodrug of the pyridone derivative, or a pharmaceutically acceptable salt according to claim 8, characterized in that, R1 is selected from the following groups, either unsubstituted or substituted: methyl, ethyl, propyl, butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, deuterated n-butyl, deuterated isobutyl, cyclopropyl, deuterated cyclopropyl, ethynylmethyl, ethynylethyl, ethynylpropyl, ethynyl halomethyl, ethynyl haloethyl, ethynyl halopropyl, ethynyl C 3-6 cycloalkyl and ethynyl halogenated C 3-6 cycloalkyl, ethynyl C 3-6 Heterocyclic alkyl, wherein the substituents used for substitution are selected from one or more of the following groups: F, Cl, Br, methyl, ethyl, methoxy, ethoxy, fluoromethyl, fluoroethyl, cyclopropyl, hydroxy.

10. The pyridinone derivative or its stereoisomer, the prodrug of the pyridinone derivative, or a pharmaceutically acceptable salt according to claim 9, characterized in that, R1 is selected from 11. The pyridinone derivative or its stereoisomer, the prodrug of the pyridinone derivative, or a pharmaceutically acceptable salt according to claim 1, characterized in that, The pyridone derivatives have the structure shown in formula (IB): In equation (IB), R2, n, and R 3a R 3b The definitions are the same as in claim 1; E is CH or N; R7 and R8 are independently selected from H, halogen, cyano, hydroxyl, C. 1-6 Alkyl, halogenated C 1-6 Alkyl or C 2-6 Alkyne group; m and p are independently 1, 2, or 3.

12. The pyridone derivative or its stereoisomer, the prodrug of the pyridone derivative, or a pharmaceutically acceptable salt according to any one of claims 1-7 and 11, characterized in that, Q is selected from amides, or from unsubstituted or substituted five-membered heterocycles.

13. The pyridinone derivative or its stereoisomer, the prodrug of the pyridinone derivative, or a pharmaceutically acceptable salt according to claim 12, characterized in that, Q is selected from amides, and the carbonyl carbon in the amide is attached to a carbon atom on the pyridone; or, Q is selected from...

14. The pyridone derivative or its stereoisomer, the prodrug of the pyridone derivative, or a pharmaceutically acceptable salt according to any one of claims 1-7 and 11, characterized in that, R2 is selected from F, Cl, Br, hydroxyl, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, fluoroethyl, ethynyl, and n is 1, 2, or 3; and / or, R 3a R 3b Selected independently from H or D.

15. The pyridone derivative or its stereoisomer, the prodrug of the pyridone derivative, or a pharmaceutically acceptable salt according to claim 1, characterized in that, The prodrug refers to a compound that is metabolized into the original drug by chemical methods or by enzymes in vivo; further, the hydroxyl-shielding group includes the following structures: H, C 6-20 OC(=O)-、C 6-20 C(=O)-、C 6-20 C(=O)-、C 6-20 C(=O)-、C 6-20 OCH2O-、 16. The pyridone derivative or its stereoisomer, the prodrug of the pyridone derivative, or a pharmaceutically acceptable salt according to claim 1, characterized in that, The pyridone derivatives mentioned above are selected from the following compounds:

17. A pharmaceutical composition comprising a pyridone derivative or its stereoisomer as described in any one of claims 1-16, a prodrug of a pyridone derivative, or a pharmaceutically acceptable salt; further, the pharmaceutical composition is an antiviral pharmaceutical composition, further comprising one or more therapeutic agents selected from the following categories: nucleoside or nucleotide reverse transcriptase inhibitors, non-nucleoside or nucleotide reverse transcriptase inhibitors, HIV protease inhibitors, HIV capsid inhibitors, CXCR4 inhibitors, GP41 inhibitors, GP120 inhibitors, CCR5 inhibitors, HIV latency reversal agents, capsid polymerization inhibitors, HIV bNAbs, TLR 7, 8, or 9 agonists, and PK enhancers or other anti-HIV agents.

18. Use of the pyridone derivative or stereoisomer thereof, the prodrug of the pyridone derivative, the pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 17 in the preparation of a medicament for the prevention and / or treatment of viral infectious diseases.

19. Use of the pyridone derivative or stereoisomer thereof, the prodrug of the pyridone derivative, the pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 17 in the preparation of a medicament for the prevention and / or treatment of HIV viral infection; further, the pharmaceutical composition having a long-acting effect, the pharmaceutical composition comprising an oral formulation, an injectable formulation, or a topical formulation.

20. An intermediate for preparing the pyridone derivative or its stereoisomer, the prodrug of a pyridone derivative, or a pharmaceutically acceptable salt according to any one of claims 1-16, characterized in that, The intermediate has the structure shown in formula (VI), formula (VII), or formula (VIII): In equation (VI), R1, R2, n, and R 3a R 3b The definitions of X, Y, and A are the same as before, and R9 is a hydroxyl protecting group; In equation (VII), R1, R2, n, and R 3a R 3b The definitions are the same as before, R9 is a hydroxyl protecting group, R 10 For H, The definitions of R4, R5, W, and R6 are the same as before; In equation (VIII), R2, n, and R 3a R 3b The definitions are the same as before, R 11 It is a hydrogen or hydroxyl protecting group.

21. The intermediate according to claim 20, characterized in that, The intermediate is compound B, compound C, or their stereoisomers or racemates.

22. An intermediate for preparing the pyridone derivative or its stereoisomer, the prodrug of the pyridone derivative, or a pharmaceutically acceptable salt according to any one of claims 1-16, characterized in that, The intermediate is selected from the following compounds:

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