Pyridinone derivatives, pharmaceutical compositions thereof and use as antiviral agents

Abstract

The application discloses a pyridinone derivative or a stereoisomer thereof, a pharmaceutical composition thereof and application thereof as an antiviral drug, and further relates to a piperidinone compound shown in formula (I) or a stereoisomer thereof, a prodrug of the piperidinone compound, a pharmaceutically acceptable salt and a pharmaceutical composition containing the formula (I) for preparing a drug for preventing or treating HIV virus infection. The compound of the application has significant anti-HIV virus activity, and is suitable for developing long-acting prevention and treatment schemes for oral administration and injection.

Description

Technical Field

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

[0002] The HIV virus, through its direct or indirect effects, 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), also known as AIDS.

[0003] Highly active antiretroviral therapy (HAART) for HIV-1 infection can effectively reduce viral load and significantly delay disease progression, but these long-term treatments may lead to the emergence of HIV strains resistant to current therapies. Therefore, developing novel antiretroviral drugs to combat existing clinically resistant HIV strains has become a new clinical need.

[0004] New HIV treatment regimens, including features such as increased efficacy, long-acting pharmacokinetics, low solubility, low clearance, and / or other properties, offer patients the option of long-term treatment. Therefore, if new HIV therapies allow patients to receive oral formulations once a week or once a month, or inject smaller effective doses monthly or for longer periods, patient adherence could be improved. These improvements, in turn, can optimize drug exposure and limit the development of drug resistance.

[0005] Drug interactions are also an important consideration for HIV patients. Treatment decisions become complex when patients are taking multiple anti-HIV medications and also need to treat other conditions. New standard-of-care treatments for HIV require the fewest types of drugs and the lowest possible doses to suppress HIV and reduce drug interactions.

[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 present invention aims to provide a class of pyridone derivatives or their stereoisomers, prodrugs of pyridone derivatives, pharmaceutically acceptable salts, and pharmaceutical compositions containing formula (I). These compounds exhibit potent anti-HIV activity and are expected to show good activity against existing clinically resistant strains. Further research indicates that these pyridone derivatives possess long-acting pharmacokinetic characteristics such as low clearance, low solubility, and good permeability, allowing them to be used in long-acting oral or injectable formulations, significantly improving patient compliance. The long-acting and high-activity nature of these compounds makes them potentially capable of raising the threshold for drug resistance.

[0008] Furthermore, based on an understanding of compound pharmacokinetics, this invention provides deuterated compounds with excellent activity. Deuteration modification of drugs can be one of the technical means to increase drug exposure in vivo, reduce the concentration of adverse drug metabolites, and improve efficacy. However, due to the highly complex metabolic processes in vivo, the pharmacokinetic properties of drugs are influenced by many factors. With appropriate selection of specific deuteration sites, the increased binding strength imparted by deuterium can positively influence the metabolic characteristics of drugs, improving efficacy and reducing toxicity.

[0009] To achieve the above objectives, the present invention adopts the following technical solution: A pyridone derivative or its stereoisomer, a prodrug of a pyridone derivative, or a pharmaceutically acceptable salt thereof, wherein the pyridone derivative has the structure shown in formula (I): , in: (1) Each R1 is independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl or halogenated C 1-6 Alkyl group; n is 1, 2, 3 or 4; (2) R2 and R3 are independently selected from H, D or C 1-6 alkyl; (3) Q is selected from amides, unsubstituted or substituted 4-6 membered heteroaryl rings; wherein the substituent used for substitution is selected from one, two or more of the following groups: halogen, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy or deuterated C 1-6 Alkoxy; (4) X is CH or N; (5) A is selected from 6-20 saturated heterocyclic groups or 6-20 unsaturated heterocyclic groups; the 6-20 saturated heterocyclic groups and 6-20 unsaturated heterocyclic groups are single rings, double rings or multiple rings, the double ring is a fused ring, a bridged ring or a spiral ring composed of two rings, the multiple ring includes 3 or more rings, and the rings in the multiple ring are connected by one, two or more of the connection methods of fused rings, bridged rings and spiral rings; (6) Each R4 is independently selected from H, D, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, halogenated, deuterated C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkyl, C 3-8 cycloalkyl, C 3-6 cycloalkyl C 1-6 Alkyl, C 1-6 Alkyl mercapto, halogenated C 1-6 Alkyl mercapto, halogen, cyano, oxo, unsubstituted or substituted 5-10 membered alicyclic or heterocyclic, where m is 1, 2, 3, 4 or 5; Alternatively, when m equals or is greater than 2, any two independent R4 groups are connected to the same or different carbon atoms and form an unsubstituted or substituted spirocyclic or fused ring with A, wherein the spirocyclic or fused ring independently comprises a carbocyclic or heterocyclic ring; wherein the substituents used for substitution are selected from one, two or more of the following groups: halogen, cyano, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy or deuterated C 1-6 Alkoxy; (7) P is selected from H or a group that shields the hydroxyl group; (8) Y is selected from CH, CD, N, CF or CCl; (9) The heteroatoms in the 4-6 membered heteroaromatic ring group, 5-10 membered aliphatic heteroaromatic ring group, and 5-10 membered heteroaromatic ring group are independently selected from one, two or more of O, S, Se, N, -SO2- and oxo; The heteroatoms in the 6-20 saturated heterocyclic groups and 6-20 unsaturated heterocyclic groups are all nitrogen, or independently contain nitrogen and one, two or more of O, S, -SO2- and oxo.

[0010] Furthermore, when Y is selected from CH, the pyridone derivative has the following structure: The definitions of R1, n, R2, R2, Q, P, X, A, R4, and m are the same as before.

[0011] In some embodiments of the present invention, A is selected from... , , , , , , , , or .

[0012] In some embodiments of the present invention Selected from , , , , , , , , , , or .

[0013] In some embodiments of the present invention, each R4 independently represents H, D, methyl, ethyl, propyl, deuterated methyl, deuterated ethyl, deuterated propyl, trifluoromethyl, difluoromethyl, monofluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, hydroxyl, methyl mercapto, ethyl mercapto, propyl mercapto, fluoromethyl mercapto, fluoroethyl mercapto, fluoropropyl mercapto, fluorine, chlorine, or bromine.

[0014] In some embodiments of the invention, when there are 2, 3, 4, or 5 R4s, two of the R4s form rings with their respective connected carbon atoms of the same or different carbon groups, the rings being selected from... , , , , , , or .

[0015] Furthermore, according to certain aspects of the invention, when X is N, for , Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; Alternatively, when X is N, and R2 and R3 are both selected from D, for , Selected from , , or .

[0016] In some embodiments of the present invention, when X is CH and R2 and R3 are H, for , Selected from , , , or .

[0017] In some embodiments of the present invention, when X is CH and R2 and R3 are D, for , Selected from , , , , , or .

[0018] In some embodiments of the present invention, Q is selected from amides, or from unsubstituted or substituted five-membered heterocycles.

[0019] 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... , , , , , or .

[0020] In some embodiments of the present invention, the pyridone derivatives have the structure shown in formula (IA), formula (IB), or formula (IC): , , ; In equations (IA), (IB), or (IC): R1, n, R2, R3, P, X, and Y are defined as before; R 11 R 12 R 13 R 14 R 15 R 16 Independently selected from H, D, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkyl, C 3-8 cycloalkyl, C 3-6 cycloalkyl C 1-6 Alkyl, C 1-6 Alkyl mercapto, halogenated C 1-6 Alkyl mercapto, halogen, or cyano; Or R 11 R 12 The carbon atoms connected to each other and together form a 3-6 membered carbon ring, or an unsubstituted or substituted 3-12 membered heterocycle. The substituents used for substitution are one, two or more selected from the following groups: halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl C 1-6 Alkyl or halogenated C 1-6 Alkyl mercapto; Or R 13 R 14 The carbon atoms connected to each other and together form a 3-6 membered carbon ring, or an unsubstituted or substituted 3-12 membered heterocycle. The substituents used for substitution are one, two or more selected from the following groups: halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6Alkoxy, C 3-6 cycloalkyl C 1-6 Alkyl or halogenated C 1-6 Alkyl mercapto; Or R 15 R 16 The carbon atoms connected to each other together form an unsubstituted or substituted 4-6 membered heterocycle, wherein the substituents used for substitution are one, two or more selected from the following groups: halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl C 1-6 Alkyl or halogenated C 1-6 Alkyl mercapto; The heteroatoms in the 3-12 membered heterocycles and 4-6 membered heterocycles are independently selected from one, two or more of O, S, N, -SO2- and oxo.

[0021] In some embodiments, the pyridone derivatives have the structures shown in formula (I-A1), formula (I-B1), or formula (I-C1): , , ; In formula (I-A1), formula (I-B1), or formula (I-C1): R1, n, R2, R3, P, X, Y, R 11 R 12 R 13 R 14 R 15 R 16 The definition is the same as before.

[0022] Furthermore, R 11 R 12 Independently selected from H, D, methyl, ethyl, propyl, deuterated methyl, deuterated ethyl, deuterated propyl, trifluoromethyl, difluoromethyl, monofluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, methoxy, ethoxy, propoxy, or hydroxyl, and R 11 R 12 Not both H; Or, R 11 R 12 The carbon atoms connected to each other and together form unsubstituted or substituted groups as follows: , or The substituents used in the substitution are selected from one, two or more of the following groups: fluorine, chlorine, bromine, methyl, ethyl, propyl, trifluoromethyl, difluoromethyl, monofluoromethyl, fluoroethyl, fluoropropyl, methoxy, ethoxy, propoxy, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, fluoromethyl mercapto, fluoroethyl mercapto, or fluoropropyl mercapto.

[0023] Furthermore, R 13 R 14 Independently selected from H, D, methyl, ethyl, propyl, deuterated methyl, deuterated ethyl, deuterated propyl, trifluoromethyl, difluoromethyl, monofluoromethyl, fluoroethyl, fluoropropyl, methoxy, ethoxy, propoxy, or hydroxy, and R 13 R 14 Not both H; Or, R 13 R 14 The carbon atoms connected to and jointly connected to each other constitute unsubstituted or substituted groups such as cyclopropyl, cyclobutyl, oxacyclobutyl, cyclopentyl, and cyclohexyl. The substituents used for substitution are selected from one, two, or more of the following groups: fluorine, chlorine, bromine, methyl, ethyl, propyl, trifluoromethyl, or difluoromethyl.

[0024] Furthermore, R 15 R 16 The carbon atoms connected to each other and to which they are connected together form the following unsubstituted or substituted groups: The substituents used for substitution are selected from one, two or more of the following groups: fluorine, chlorine, bromine, methyl, ethyl, propyl, trifluoromethyl or difluoromethyl.

[0025] In some embodiments of the present invention, the pyridone derivatives have the structure shown in formula (ID): , In formula (ID), R1, n, R2, R3, P, X, Y, R 11 R 12 The definition is the same as before; Z is a bond, CH2, O or S, and E is CH2, CH2CH2, O or S, and Z and E are not both O or S.

[0026] In some embodiments of the present invention, the pyridone derivatives have the structure shown in formula (IE) or formula (IF): , , In equations (IE) and (IF), the definitions of R1, n, P, and X are the same as before, and R... 11 R 12R 13 R 14 Independently selected from H, D, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkyl, C 3-8 cycloalkyl, C 3-6 cycloalkyl C 1-6 Alkyl, C 1-6 Alkyl mercapto, halogenated C 1-6 Alkyl mercapto, halogen, cyano, or R 11 and R 12 Or R 13 and R 14 The carbon atoms that are connected to each other and together form unsubstituted or substituted spiroheterocyclic groups or spirocycloalkyl groups.

[0027] In some embodiments of the present invention, each R1 is independently selected from F, Cl, Br, hydroxyl, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, or fluoroethyl.

[0028] According to certain aspects of the invention, the substituted groups are independently selected from H, deuterium, halogens (F, Cl, Br, I), cyano, hydroxyl, amide, carboxyl, oxo, 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 or C 1-6 Alkyl mercapto; heteroatoms are selected from oxygen, nitrogen, sulfur, se, oxo or -SO2-.

[0029] 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, or 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.

[0030] In some implementations, halogenated C 1-6Alkyl groups can be obtained by substituting one, two or more hydrogens of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl or isohexyl with one, two or more of F, Cl, Br or I.

[0031] 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, or isohexyloxy. 1-6 Alkoxy groups refer to alkoxy groups with 1 to 6 carbon atoms.

[0032] In some embodiments, the haloalkoxy group includes, but is not limited to, the hydrogen that can be obtained by substituting one, two or more of F, Cl, Br, I with methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy, isopentoxy, n-hexyloxy or isohexyloxy.

[0033] In some implementations, deuterated C 1-6 Alkyl, deuterated C 1-6 The alkoxy group can be replaced by one, two, three or more deuterium atoms, respectively. 1-6 Alkyl, C 1-6 Hydrogen is obtained from alkoxy groups.

[0034] 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. There can be one, two or more heteroatoms, and it can be a monocyclic, bicyclic or polycyclic ring, wherein the heteroatoms are nitrogen, oxygen, sulfur and oxo, etc. The carbocyclic group is a pure carbon ring without heteroatoms, and it can be a monocyclic, bicyclic or polycyclic ring, and can contain double bonds or not. For example, it can be a saturated carbocyclic group or an unsaturated carbocyclic group.

[0035] In some implementations, C 3-6 cycloalkyl, C 3-8 The cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0036] In some embodiments of the present invention, n is 1, 2 or 3.

[0037] In some embodiments of the present invention, R2 and R3 are independently selected from H or D.

[0038] In some embodiments of the present invention, the hydroxyl-shielding group includes C 6-20 OC(=O)-、C 6-20 C(=O)-、C 6-20 OCH2O-、 , , , , , or .

[0039] Furthermore, the shielding hydroxyl group includes CH3C. x H 2x OC(=O)-, CH3C x H 2x C(=O)-、CH3C x H 2x OCH2O-、 or x is 5-20, for example, it can be 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.

[0040] 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 through the metabolism of a group containing a shielding hydroxyl group.

[0041] In some embodiments of the present invention Selected from: , , , , , , , , , , , , , , , , , , , , , , , , or .

[0042] According to certain aspects of the present invention, the pyridone derivatives or their stereoisomers are selected from the following compounds: .

[0043] Another technical solution provided by the present invention: a pharmaceutical composition containing the above-mentioned pyridone derivatives or their stereoisomers, a prodrug of a pyridone derivative, and a pharmaceutically acceptable salt.

[0044] Further, the pharmaceutical composition is an antiviral pharmaceutical composition, further comprising one or more therapeutic agents, wherein the one or more therapeutic agents are anti-HIV 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.

[0045] Another technical solution provided by the present invention: the use of the above-mentioned pyridone derivatives or their stereoisomers, prodrugs of pyridone derivatives, pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions in the preparation of a medicament for the prevention and / or treatment of viral infectious diseases; further, the medicament for the prevention and / or treatment of viral infectious diseases has a long-lasting effect, and the medicament for the prevention and / or treatment of viral infectious diseases includes oral formulations, injectable formulations, or topical formulations.

[0046] Another technical solution provided by the present invention: the use of the above-mentioned pyridone derivatives or their stereoisomers, prodrugs of pyridone derivatives, pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions in the preparation of a medicament for the prevention and / or treatment of HIV infection; further, the medicament for the prevention and / or treatment of HIV infection has a long-lasting effect, and the medicament for the prevention and / or treatment of HIV infection includes oral formulations, injectable formulations, or topical formulations.

[0047] Another technical solution provided by the present invention: an intermediate for preparing the above-mentioned pyridone derivatives or their stereoisomers, prodrugs of pyridone derivatives, and pharmaceutically acceptable salts, wherein the intermediate has the structure shown in formula (Ⅳ), formula (Ⅴ), formula (Ⅵ) or formula (Ⅶ): , , ; The definitions of R1, n, R2, R3, R4, X, and Q are the same as before; R 11 R 12 R 13 R 14 The definition is the same as before; R 17 It is an H or hydroxyl protecting group.

[0048] Furthermore, in some embodiments of the present invention, the intermediate has the structure shown in formula (Ⅳ-1), formula (Ⅳ-2), formula (Ⅴ-1), formula (Ⅴ-2), formula (Ⅴ-3), formula (Ⅵ-1), or formula (Ⅶ-1): , , , , , , .

[0049] According to certain aspects of the invention, the intermediate is selected from the following compounds: , , , , , , , , , , , , , , , .

[0050] The present invention further provides a method for preparing the pyridone derivative or its stereoisomer as shown in (I) of the present invention, comprising the following steps: ; Synthesis of compound B: Paraformaldehyde is added to an ACN / DCE solution of intermediate A, and the mixture is heated to 20-80°C with the addition of acetic acid and trifluoroacetic acid. The reaction is carried out under sealed conditions (e.g., for 0.5-5 hours). After cooling to room temperature, the reaction solution is concentrated to remove the solvent, and DMF, potassium carbonate, and benzyl bromide are added. The mixture is stirred at 20-100°C for 1-20 hours. After cooling to room temperature, the reaction solution is diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The intermediate B is purified by silica gel column chromatography (using a petroleum ether solution containing 20-33% ethyl acetate) to obtain intermediate B. This step is a polymerization reaction; paraformaldehyde reacts with the amino group of the amide under strong acid to remove water molecules. The reaction is carried out in aprotic solvents, not limited to dichloromethane and acetonitrile; other suitable aprotic solvents include DMF, toluene, and chloroform. Under strong acid, benzyl ether will lose the benzyl group, requiring reaction with benzyl bromide or benzyl chloride in the presence of a base to reprotect the hydroxyl group. This step can be applied to reactions that synthesize ethers from hydroxyl groups, such as those involving NaH, cesium carbonate, and potassium phosphate. Phase transfer catalysts can also be used to promote the reaction.

[0051] Synthesis of compounds C and D: Intermediate B is dissolved in DCE, bubbled under nitrogen for 10 minutes, then HOVEYDA-GRUBBS II is added, and bubbling under nitrogen continues (bubbling time can be, for example, 1-20 minutes). The mixture is then stirred overnight at 50-100°C under nitrogen protection. The reaction solution is cold-concentrated, and purified by a plate (e.g., using a petroleum ether solution of 33% ethyl acetate) to obtain intermediates C and D. For this olefin metathesis reaction, the catalyst can be either a Grubbs-Hoveyda catalyst or a Schrock catalyst, selected according to the structure of the substrate. The reaction is carried out in an aprotic solvent, with reaction temperatures ranging from room temperature to 145-155°C, and the reaction time also varies depending on the substrate.

[0052] Synthesis of target molecules isomer-1 or isomer-2: Intermediate C or D and LiCl were added to DMF and stirred overnight at 50-120°C under nitrogen protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Preparative column purification yielded the off-white solid compound isomer-1 or isomer-2. Besides lithium chloride, other methods for removing the benzyl protecting group include: TsOH, magnesium bromide, TFA, and catalytic hydrogenation.

[0053] The present invention also provides the pyridone derivatives or stereoisomers thereof, various prodrugs of pyridone derivatives, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof containing formula (I), wherein one or more of the therapeutic agents are used in an effective therapeutic dose for HIV patients or for the prevention of HIV infection.

[0054] The present invention also provides administration routes for the pyridone derivatives or their stereoisomers, various prodrugs of pyridone derivatives, pharmaceutically acceptable salts and pharmaceutical compositions containing formula (I), wherein the administration routes include oral, intravenous, subcutaneous or intramuscular injection and various transdermal administration methods.

[0055] The present invention also provides the pyridone derivatives or stereoisomers thereof, various prodrugs of pyridone derivatives, pharmaceutically acceptable salts thereof and pharmaceutical compositions thereof containing formula (I), or pharmaceutical compositions thereof in the preparation of a drug for treating patients with HIV infection or preventing people at risk of HIV infection.

[0056] The pharmaceutically acceptable carriers in the above-mentioned pharmaceutical compositions include pharmaceutically acceptable diluents, excipients, fillers, binders, disintegrants, absorption enhancers, surfactants, lubricants, flavorings, or sweeteners.

[0057] 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.

[0058] All of the above-mentioned dosage forms of drugs can be prepared using conventional methods in the pharmaceutical field.

[0059] 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 for the treatment of infections or complications caused by HIV or for the prevention of HIV infection in people at risk of infection.

[0060] The pharmaceutical composition of the present invention may be composed of the following proportions: 5%-95% of the compounds of this invention Lactose 1%-60% Starch 0-20% Microcrystalline cellulose 1%-40% Sodium carboxymethyl starch 1%-5% Polyethylene glycol (PEG6000) 0-10% Magnesium stearate 1%-5%.

[0061] Due to the implementation of the above technical solutions, the present invention has the following advantages compared with the prior art: This invention provides a class of pyridone derivatives that have potent anti-HIV activity. These compounds exhibit high activity, low toxicity, low solubility, and very low clearance, and can be used to develop treatment regimens for long-acting injectable anti-HIV drugs.

[0062] This invention provides deuterated compounds with excellent activity. By rationally selecting deuterated compounds modified at specific sites, the increased binding strength imparted by deuterium can positively influence the metabolic properties of drugs, improve drug efficacy, and reduce drug toxicity.

[0063] Terminology Definition 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] The term "crystallization" refers to the various solid forms formed by the compounds described in this invention, including crystalline and amorphous forms.

[0068] The term "hydrocarbon group" refers to saturated alkyl, alkenylalkyl, and alkynylalkyl groups.

[0069] 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: .

[0070] 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.

[0071] The term "ring" refers to both carbon rings and heterocycles. "Carbocyclic group" or "carbon ring" refers to a carbon cyclic group having 3-20 carbon atoms, preferably 3-16, and more preferably 4-12, 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 from O, S, and N within the ring. The term "ring" includes monocyclic, bridged, spirocyclic, fused, and polycyclic rings.

[0072] 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, two, 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.

[0073] The term "aryl" refers to two types: carbocyclic aryl and heteroaryl.

[0074] 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.

[0075] 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 selected independently 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.

[0076] The term "halogen" refers to fluorine, chlorine, bromine, and iodine, with fluorine, chlorine, and bromine being preferred.

[0077] 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.

[0078] The term "halogenated alkyl" refers to an alkyl group that is substituted by at least one halogen atom.

[0079] The term "heterocyclic group" refers to a cyclic group containing at least one heteroatom, such as nitrogen, oxygen, sulfur, sulfoxide, or sulfone. Heterocyclic groups include monocyclic and polycyclic groups. Detailed Implementation

[0080] 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.

[0081] The abbreviations of the compound names used in the examples are as follows:

[0082] The present invention will be further described below with reference to specific embodiments: Compound Synthesis Example 1: Synthesis of Compound I-1

[0083] The reaction route is shown below:

[0084] Synthesis of intermediate 2: N-tert-Butoxycarbonyl-L-alanine (10 g, 52.85 mmol) and DIPEA (6.1 g, 47.60 mmol) were dissolved in DCM (150 mL); the solution was cooled to 0 °C and stirred for 10 min. EDCI (12.2 g, 63.42 mmol) and HOBT (8.6 g, 63.42 mmol) were added sequentially. After stirring at 0 °C for 10 min, dimethylhydroxylamine hydrochloride (6.19 g, 63.42 mmol) and DIPEA (8.2 g, 63.42 mmol) were added. The solution was stirred at 0 °C for 1 hour and then stirred overnight at room temperature under nitrogen protection. The reaction solution was diluted with dichloromethane (150 mL), washed sequentially with water (100 mL × 3), saturated brine (150 mL), and dried over anhydrous sodium sulfate. The solution was purified by silica gel column chromatography (PE / EA = 4 / 1–3 / 1) to obtain a white solid intermediate 2 (9.7 g, 78%). MS: [MH] + 233.10; 1 HNMR (400MHz, CDCl3): δ5.31-5.15 (m, 1H), 4.77-4.56(m, 1H), 3.76 (s, 3H), 3.20(s, 3H), 1.43 (s, 9H), 1.31 (d, J= 6.8Hz, 3H).

[0085] Synthesis of intermediate 3: At 0°C, lithium aluminum hydride (784.2 mg, 20.66 mmol) was added in four batches to a dry THF (50 mL) solution of intermediate 2 (4.0 g, 17.22 mmol). The mixture was stirred for 1 hour under nitrogen protection, quenched dropwise with saturated potassium hydrogen sulfate aqueous solution at 0°C, diluted with ethyl acetate (50 mL), and stirred at room temperature for 30 minutes. The mixture was extracted with ethyl acetate (30 mL × 2), the organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain intermediate 3 (2.9 g, 60%). 1 HNMR (400MHz, DMSO- d6): δ 9.42 (s, 1H), 7.32 (d, J= 6.0Hz, 1H), 3.90-3.80 (m, 1H), 1.39 (s, 9H), 1.12 (d, J= 7.2Hz, 3H).

[0086] Synthesis of intermediate 4: KHMDS / THF (1M, 4.6 mL, 4.60 mmol) was added to a suspension of dried THF (10 mL) containing MePPh3Br (1.73 g, 4.85 mmol), and stirred at room temperature for 1 hour under nitrogen protection. The reaction solution was cooled to -78 °C, and a THF solution of intermediate 3 (500 mg, 2.89 mmol) in 3 mL was added dropwise. After the addition was complete, the temperature was slowly raised to room temperature and stirred for 2 hours. The reaction solution was quenched successively at 0 °C with methanol and saturated ammonium chloride solution, extracted with ethyl acetate (10 mL × 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (EA / PE: 2.5~5%) to obtain intermediate 4 (190 mg, 38%). 1 HNMR (400MHz, CDCl3): δ5.88-5.76(m, 1H), 5.19-5.02(m, 2H), 4.55-4.35(m, 1H), 4.31-4.13(m, 1H), 1.45(s, 9H), 1.21 (d, J=6.8Hz, 3H).

[0087] Synthesis of intermediate 5: Add HCl / 1,4-dioxane (4M, 2mL) to a 2mL solution of intermediate 4 (190mg, 1.11mmol) in DCM, and stir overnight at room temperature. The reaction solution was concentrated to give intermediate 5 (100mg, 84%) as an off-white solid. 1 HNMR (400MHz, CDCl3): δ8.26(br, 3H), 5.95-5.84 (m, 1H), 5.36-5.22(m,2H), 3.85-3.67(m, 1H), 1.28 (d, J=6.8Hz, 3H).

[0088] Synthesis of intermediate 7: Intermediate 6 (10 g, 31.42 mmol) and acetic acid (754.7 mg, 12.57 mmol) were added to toluene (70 mL). Under nitrogen protection, the mixture was heated to 65 °C, and a solution of tert-butyl hydrazide carbamate (4.57 g, 34.56 mmol) and toluene (30 mL) was added dropwise. After the addition was complete, the mixture was stirred overnight at 65 °C. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with Hexane / EA = 1 / 1 and dried to give a pale yellow solid intermediate 7 (11.2 g, 82%). MS: [MH] + 433.45; 1 HNMR (400MHz, DMSO- d6 ): δ 11.13 (br, 1H), 8.35 (s,1H), 7.43-7.29 (m, 5H), 5.10 (s, 2H), 3.76 (s, 6H), 1.41 (s, 9H).

[0089] Synthesis of intermediate 8: 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) under ice bath conditions, and stirred overnight at room temperature. The solution was concentrated at room temperature to remove most of the THF / MeOH, adjusted to pH 5 with 2N hydrochloric acid, filtered, the filter cake was washed with water, and dried overnight to obtain a pale yellow solid intermediate 8 (10.1 g, 93%). MS: [MH] + 419.55; 1 HNMR (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).

[0090] Synthesis of intermediate 9: Intermediate 8 (7.0 g, 16.73 mmol), EDCI (6.4 g, 33.46 mmol), and HOBT (2.94 g, 21.75 mmol) were added to DMF (100 mL), and the mixture was stirred at room temperature for 60 minutes. The reaction mixture was cooled to 0 °C, and a solution of (2,4,6-trifluorophenyl)methane-d2-amine (2.7 g, 16.73 mmol) in DMF (20 mL) was added dropwise. The mixture was stirred overnight at room temperature under nitrogen protection. The reaction mixture was diluted with ethyl acetate (300 mL), washed successively with water (100 mL × 3), saturated brine (200 mL), and dried over anhydrous sodium sulfate. The solution was purified by silica gel column chromatography (25-50% ethyl acetate in petroleum ether solution) to give intermediate 9 (7.4 g, 74%) as a white solid. MS: [MH] + 564.45; 1 HNMR (400MHz, DMSO- d6 ): δ 11.28 (brs, 1H), 10.07(t,J=5.6Hz, 1H), 8.41 (s, 1H), 7.42-7.30 (m, 5H), 7.22 (t, J =7.2Hz, 2H), 5.13(s, 2H), 3.77 (s, 3H), 1.41 (s, 9H).

[0091] Synthesis of intermediate 10: 3-Buten-2-ol (513.7 mg, 7.12 mmol) and triphenylphosphine (1.59 g, 6.05 mmol) were added to a dry THF (100 mL) solution of intermediate 9 (2.0 g, 3.56 mmol). The reaction solution was cooled to 0 °C, and DIAD (1.22 g, 6.05 mmol) was added dropwise under nitrogen protection. After the addition was complete, the mixture was stirred overnight at 35 °C. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (10-25% ethyl acetate in petroleum ether solution) to obtain a colorless oily intermediate 10 (2.0 g, 90%). MS: [MH] + 618.75; 1 HNMR (400MHz, DMSO- d6): δ 10.09-10.00 (m, 1H), 8.47-8.33 (m, 1H), 7.42-7.31 (m, 5H), 7.23 (t, J=8.4Hz, 2H), 5.95-5.80 (m, 1H), 5.28-5.05 (m, 4H), 4.81-4.68 (m, 1H), 3.79-3.71 (m, 3H), 1.37 (s, 9H), 1.21-1.16 (m, 3H).

[0092] Synthesis of intermediate 11: LiOH·H₂O (818.1 mg, 19.49 mmol) was added to a MeOH / H₂O (18 mL / 9 mL) solution of intermediate 10 (2.0 g, 3.25 mmol), and the reaction mixture was stirred overnight at 40 °C. The reaction mixture was concentrated at 45 °C to remove most of the MeOH, and the pH was adjusted to 6 with 2N hydrochloric acid. The mixture was filtered, the filter cake was washed with water, and dried to obtain a white solid intermediate 11 (1.2 g, 61%). MS: [MH] + 604.55.

[0093] Synthesis of intermediate 12: Intermediate 11 (2.0 g, 3.32 mmol), intermediate 5 (536.5 mg, 4.99 mmol), and DIPEA (2.57 g, 19.92 mmol) were added to DMF (30 mL), and the mixture was cooled to 0 °C before adding HATU (1.9 g, 4.99 mmol). The mixture was stirred overnight at room temperature under nitrogen protection. The reaction mixture was diluted with ethyl acetate (90 mL), washed successively with water (30 mL × 3), and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was purified by silica gel column chromatography (15-25% ethyl acetate in petroleum ether solution) to obtain a pale yellow oily intermediate 12 (1.17 g, 54%). MS: [MH] + 657.90; 1 HNMR (400MHz, DMSO- d6): δ 10.21-10.12 (m, 1H), 8.92-8.79 (m, 1H), 8.35-8.29 (m, 1H), 7.45-7.30 (m, 5H), 7.22 (t, J=8.4Hz, 2H), 6.15-5.87 (m, 1H), 5.81-5.70 (m, 1H), 5.29-4.92 (m, 6H), 4.67-4.33 (m, 2H), 1.46-1.38 (m, 9H), 1.38-1.27 (m, 3H), 1.13-1.06 (m, 3H).

[0094] Synthesis of intermediate 13: 4M HCl / 1,4-dioxane was added to a 3 mL solution of intermediate 12 (430 mg, 0.66 mmol) in DCM and stirred overnight at room temperature. The reaction mixture was concentrated to dryness, and 10 mL of ethyl acetate and 5 mL of saturated sodium bicarbonate solution were added. The aqueous phase was extracted with ethyl acetate (8 mL × 2), and the organic phase was washed with 10 mL of saturated brine and dried over anhydrous sodium sulfate. The solution was purified by silica gel column chromatography (20–33% ethyl acetate in petroleum ether solution) to give a reddish-brown oily solid intermediate 13 (340 mg, 93%). MS: [MH] + 557.45; 1 HNMR (400 MHz, CDCl3): δ 10.17 (t, J =4.8 Hz, 1H), 8.51 (d, J=2.4 Hz, 1H), 7.38-7.33 (m, 5H), 7.19-7.12 (m, 1H), 6.99-6.89 (m, 1H), 6.67 (t, J=8.0Hz, 2H), 5.69-5.52 (m, 2H), 5.42-5.23 (m, 2H), 5.19-4.83(m, 4H), 4.54-4.45 (m, 1H), 3.33-3.22 (m, 1H), 1.12-1.06 (m, 6H).

[0095] Synthesis of intermediate 14: Paraformaldehyde (37.4 mg, 1.08 mmol) was added to an ACN / DCE (3 mL / 3 mL) solution of intermediate 13 (300 mg, 0.54 mmol), and the mixture was heated to 88 °C. Acetic acid (0.15 mL) and trifluoroacetic acid (0.15 mL) were then added, and the mixture was reacted under sealed conditions for 1 hour. After cooling to room temperature, the reaction solution was concentrated to remove the solvent, and DMF (6 mL), potassium carbonate (447.9 mg, 3.25 mmol), and benzyl bromide (416.4 mg, 2.44 mmol) were added. The mixture was stirred at 70 °C for 3 hours. After cooling to room temperature, the reaction solution was diluted with ethyl acetate (25 mL), washed successively with water (6 mL × 3), saturated brine (10 mL), and dried over anhydrous sodium sulfate. The solution was purified by silica gel column chromatography (using a petroleum ether solution containing 20–33% ethyl acetate) to obtain a pale yellow oily solid intermediate 14 (155 mg, 43%). MS: [MH] + 569.80; 1 HNMR (400 MHz, CDCl3): δ 10.28-10.17 (m, 1H), 8.51-8.36 (m, 1H), 7.56 (d, J=6.8 Hz, 2H), 7.36-7.27 (m, 5H), 6.67 (t, J=8.0 Hz, 2H), 5.90-5.60 (m, 2H), 5.44-5.20 (m, 6H), 4.51-4.37 (m, 2H), 1.35-1.27 (m, 6H).

[0096] Synthesis of intermediate 15: Intermediate 14 (125 mg, 0.22 mmol) was dissolved in DCE (10 mL), bubbled under nitrogen for 10 minutes, and then HOVEYDA-GRUBBS II (27.6 mg, 0.044 mmol) was added. Bubbling under nitrogen continued for 5 minutes, followed by stirring overnight at 80°C under nitrogen protection. The reaction solution was concentrated by cold and purified by a preparative plate (33% ethyl acetate in petroleum ether solution) to obtain a light brown solid intermediate 15 (41 mg, 36%). MS: [MH] + 541.55; 1HNMR (400 MHz, CDCl3): δ 10.25 (t, J=4.8 Hz, 1H), 8.54 (s, 1H), 7.56-7.49 (m, 2H), 7.37-7.28 (m, 3H), 6.67 (t, J=8.0 Hz, 2H), 5.62-5.45 (m, 3H), 5.39-5.32 (m, 1H), 5.22 (d, J=10.4 Hz, 1H), 4.86 (d, J=10.0 Hz, 1H), 4.13 (d, J=10.0 Hz, 1H), 3.81-3.70 (m, 1H), 1.38 (d, J=6.8 Hz,3H), 1.29 (d, J = 7.6 Hz, 3H).

[0097] Synthesis of compound I-1: Trifluoroacetic acid (1 mL) was added to a solution of intermediate 15 (41 mg, 0.076 mmol) and toluene (1 mL), and stirred overnight at room temperature. The reaction solution was concentrated to obtain a crude product, which was purified by preparative column chromatography to give a white solid compound I-1 (25 mg, 73%). MS: [MH] + 451.45; 1 HNMR (400MHz, CD3CN): δ 10.19-10.00(m, 1H), 8.44-8.27 (m, 1H), 6.90-6.75 (m, 2H), 5.63 (d, J=11.2Hz, 1H), 5.43-5.27 (m, 2H), 4.96 (d, J=14.0Hz, 1H), 4.65-4.47 (m, 1H), 3.81-3.72 (m, 1H), 1.40-1.21 (m, 6H).

[0098] Example 2: Synthesis of two stereoisomers of compound I-10

[0099] The reaction route is shown below:

[0100] Synthesis of intermediate 17: Intermediate 16 (5.0 g, 24.85 mmol), N,O-dimethylhydroxylamine hydrochloride (2.67 g, 27.33 mmol), and DIPEA (16.03 g, 124.24 mmol) were added to DMF (30 mL), and the mixture was cooled to 0 °C before adding HATU (11.33 g, 29.82 mmol). The mixture was stirred overnight at room temperature under nitrogen protection. The reaction solution was diluted with ethyl acetate (300 mL), washed successively with water (150 mL × 3), saturated brine (150 mL), and dried over anhydrous sodium sulfate. The solution was purified by silica gel column chromatography (15-25% ethyl acetate in petroleum ether solution) to give intermediate 17 (4.9 g, 80%), a pale yellow solid. MS: [MH] + 245.00; 1 HNMR (400 MHz, CDCl3): δ 3.74 (s, 3H), 3.18 (s, 3H), 1.44 (s, 11H), 1.05-1.02 (m, 2H).

[0101] Synthesis of intermediate 18: Intermediate 17 (4.9 g, 20.06 mmol) was dissolved in THF (50 mL) under nitrogen protection, and 1 M LiAlH4 / THF solution (24 mL, 24.07 mmol) was slowly added at -5 °C. The mixture was stirred at -5 °C to -10 °C for 60 minutes. The reaction was quenched by slow dropwise addition of KHSO4 solution at -5 °C to -10 °C. The mixture was diluted with ethyl acetate (200 mL), washed successively with water (100 mL × 3), and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The solution was purified by silica gel column chromatography (using petroleum ether solution containing 15% ethyl acetate) to give intermediate 18 (2.7 g, 72%) as a white solid. 1 HNMR (400 MHz, CDCl3): δ 9.17 (s, 1H), 5.21-5.11 (m, 1H), 1.51-1.48(m, 2H), 1.46(s, 9H), 1.33-1.28(m, 2H).

[0102] Synthesis of intermediate 19: Under nitrogen protection at 0°C, KHMDS (23.3 mL, 23.32 mmol) was added dropwise to a THF (20 mL) solution of MePPh3Br (8.75 g, 24.49 mmol), and the mixture was stirred at room temperature for 60 minutes. The reaction solution was cooled to -78°C, and a THF (20 mL) solution of intermediate 18 (2.7 g, 14.58 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction was quenched dropwise with methanol and ammonium chloride solution, diluted with ethyl acetate (100 mL), and then washed successively with water (50 mL × 3), saturated brine (50 mL), and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (using petroleum ether solution containing 5% ethyl acetate) to obtain a colorless oily intermediate 19 (2.5 g, 93%). 1 HNMR (400 MHz, CDCl3): δ 5.47-5.40 (m, 1H), 5.08-4.99 (m, 2H), 1.45 (s, 9H), 1.08 (s, 2H), 0.91 (s, 2H).

[0103] Synthesis of intermediate 20: 4M HCl / 1,4-dioxane (25 mL) was added to a DCM (10 mL) solution of intermediate 19 (2.5 g, 13.64 mmol), and the mixture was stirred overnight at room temperature. The solution was concentrated, and the DCM (30 mL) was replaced three times to give a white solid intermediate 20 (1.5 g, 92%). 1 HNMR (400 MHz, DMSO- d6 ): δ 8.78 (s, 3H), 5.68-5.61 (m, 1H), 5.22-5.14 (m, 2H), 1.26-1.23 (m, 2H), 0.97-0.94 (m, 2H).

[0104] Synthesis of intermediate 21: Intermediate 8 (4.0 g, 9.56 mmol), EDCI (3.67 g, 19.13 mmol), and HOBT (1.68 g, 12.44 mmol) were added to DMF (50 mL), and the mixture was stirred at room temperature for 60 minutes. The reaction mixture was cooled to 0 °C, and a DMF (10 mL) solution of 2,4,6-trifluorobenzylamine (1.54 g, 9.56 mmol) was added dropwise. The mixture was stirred overnight at room temperature under nitrogen protection. The reaction mixture was diluted with ethyl acetate (200 mL), washed successively with water (100 mL × 3), saturated brine (100 mL), and dried over anhydrous sodium sulfate. The solution was purified by silica gel column chromatography (25–50% ethyl acetate in petroleum ether solution) to give intermediate 21 (3.6 g, 67%) as a white solid. MS: [MH] + 562.65.

[0105] Synthesis of intermediate 22: 3-Buten-2-ol (0.80 mg, 11.04 mmol) and triphenylphosphine (2.46 g, 9.38 mmol) were added to a dry THF (100 mL) solution of intermediate 21 (3.0 g, 5.52 mmol). The reaction mixture was cooled to 0 °C, and DIAD (1.90 g, 9.38 mmol) was added dropwise under nitrogen protection. After the addition was complete, the mixture was stirred overnight at 35 °C. The reaction mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography (10-25% ethyl acetate in petroleum ether solution) to obtain a colorless oily intermediate 22 (4.0 g, 95%). MS: [MH] + 616.55.

[0106] Synthesis of intermediate 23: LiOH·H₂O (252 mg, 6 mmol) was added to a MeOH / H₂O (8 mL / 4 mL) solution of intermediate 22 (600 mg, 1 mmol), and the reaction mixture was stirred overnight at 40 °C. The reaction mixture was concentrated at 45 °C to remove most of the MeOH, the pH was adjusted to 6 with 2N hydrochloric acid, filtered, the filter cake was washed with water, and dried to obtain a white solid intermediate 23 (320 mg, 55%). MS: [MH] + 602.65; 1 HNMR (400MHz, DMSO- d6): δ10.67-10.53(m, 1H), 8.02(s,1H), 7.48 (d, J=7.6Hz, 2H), 7.37-7.27 (m, 3H), 7.21 (t, J=8.4Hz, 2H), 6.39-5.93 (m, 1H), 5.22-5.09 (m, 2H), 4.99-4.90 (m, 2H), 4.68-4.35 (m, 3H), 1.44-1.28 (m, 12H).

[0107] Synthesis of intermediate 24: Intermediate 23 (1.0 g, 1.66 mmol), intermediate 20 (218.7 mg, 1.83 mmol), DIPEA (1.07 g, 8.31 mmol), and HATU (758.0 mg, 1.99 mmol) were added to DMF (5 mL) and stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (80 mL), washed successively with water (40 mL × 3), saturated brine (40 mL), and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (15% ethyl acetate in petroleum ether solution) yielded a colorless oily intermediate 24 (750 mg, 68%). MS: [MH] + 668.00; 1 HNMR (400 MHz, CDCl3): δ 10.27-10.26 (m, 1H), 8.33 (d, J=4.4Hz, 1H), 7.44-7.35 (m, 5H), 6.70 (t, J=8.4Hz, 2H), 6.25 (d, J=20.4Hz, 1H), 6.11-5.93 (m, 1H), 5.49-5.38(m, 2H), 5.32-5.21 (m,2H), 5.1-5.06(m, 2H), 4.97-4.92 (m, 1H), 4.78-4.38 (m, 3H), 1.50-1.48 (m, 9H), 1.33-1.30(m, 2H), 5.69-5.52 (m, 3H), 0.98-0.86 (m, 4H).

[0108] Synthesis of intermediate 25: 10% H2SO4 (15 mL) was added to a 1,4-dioxane (24 mL) solution of intermediate 24 (750 mg, 1.12 mmol), and the mixture was stirred overnight at 50 °C. The reaction solution was concentrated, diluted with ethyl acetate (120 mL), washed successively with saturated sodium bicarbonate aqueous solution (80 mL) and saturated saline solution (50 mL), and dried over anhydrous sodium sulfate. The solution was purified by silica gel column chromatography (15–33% ethyl acetate in petroleum ether solution) to give intermediate 25 (475 mg, 74%), a pale orange-yellow solid. MS: [MH] + 567.80; 1 HNMR (400 MHz, CDCl3): δ 10.25 (s, 1H), 8.53 (s,1H), 7.39-7.36 (m, 5H), 7.12-7.06 (m, 1H), 6.67 (t, J=8.0Hz, 2H), 5.65-5.56(m, 1H), 5.48-5.41 (m, 2H), 5.22 (d, J=10.8Hz, 1H), 5.07-5.00 (m, 3H), 4.87(d, J=16.8Hz, 1H), 4.71-4.62 (m, 2H), 3.30-3.28 (m, 1H), 1.10 (d, J=6.8Hz,3H), 0.98-0.90 (m, 2H), 0.79-0.71 (m, 2H).

[0109] Synthesis of intermediate 26: Paraformaldehyde (158.8 mg, 1.76 mmol) and PPTS (351.8 mg, 1.4 mmol) were added to a DCE (20 mL) solution of intermediate 25 (200 mg, 0.35 mmol) and stirred overnight at 85 °C. The reaction solution was cooled to room temperature, neutralized to pH 7-8 with saturated sodium bicarbonate aqueous solution, extracted with DCM (10 mL × 3), washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The solution was purified by preparative stenosis (using 25% ethyl acetate and 25% dichloromethane in petroleum ether) to give intermediate 26 (155 mg, 50%) as a white solid. MS: [MH] + 579.80; 1HNMR (400 MHz, CDCl3): δ 10.29 (t, J=5.2Hz, 1H), 8.40 (s, 1H), 7.54-7.50 (m, 2H), 7.34-7.27 (m, 3H), 6.67 (t, J=8.0Hz, 2H), 5.88-5.76 (m, 1H), 5.74-5.64 (m, 1H), 5.41-5.31 (m, 2H), 5.22-4.92 (m, 4H), 4.73-4.45 (m, 4H), 3.71-3.60 (m, 1H), 1.20-1.02 (m, 7H).

[0110] Synthesis of intermediates 27 & 28: Intermediate 26 (170 mg, 0.29 mmol) was dissolved in DCE (80 mL), bubbled under nitrogen for 10 minutes, and then 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-yl[2-(isopropoxy-5-(N,N-dimethylaminesulfonyl)phenyl]methylruthenium dichloride (43.1 mg, 0.059 mmol) was added. Bubbling under nitrogen continued for 5 minutes. The mixture was sealed and stirred overnight at 80°C under nitrogen protection. The reaction solution was cooled to room temperature and concentrated to obtain the crude product. The crude product was purified by stencil (33% ethyl acetate in petroleum ether solution) to obtain light brown solids: Intermediate 27 (50 mg) and Intermediate 28 (60 mg) (total: 67%). MS: [MH] + 551.10; (Intermediate 27): 1 HNMR (400 MHz, CDCl3): δ 10.37 (t, J=5.2Hz, 1H), 8.58 (s, 1H), 7.54-7.49 (m, 2H), 7.35-7.28 (m, 3H), 6.67 (t, J=8.0Hz, 2H), 5.48 (d, J=10.4Hz,1H), 5.29-5.15 (m, 3H), 4.76 (d, J=14.4Hz, 1H), 4.66 (d, J=5.6Hz, 2H), 4.35(d, J=10Hz, 1H), 4.03-3.93 (m, 1H), 2.08-1.99 (m, 1H), 1.44 (d, J=6.8Hz, 3H),1.42-1.36 (m, 1H), 0.97-0.90 (m, 1H), 0.79-0.72 (m, 1H); (Intermediate 28): 1 HNMR (400 MHz, CDCl3): δ 10.37 (t, J=5.2Hz, 1H), 8.55 (s, 1H), 7.56-7.50 (m, 2H), 7.35-7.28 (m, 3H), 6.67 (t, J=8.0Hz, 2H), 5.47 (d, J=10.4Hz,1H), 5.35-5.22 (m, 2H), 5.21 (d, J=10.4Hz, 1H), 4.71-4.59 (m, 4H), 4.58-4.50(m, 1H), 1.80-1.71 (m, 1H), 1.46-1.39 (m, 1H), 1.25 (d, J=7.2Hz, 3H), 1.01-0.94 (m, 1H), 0.80-0.72 (m, 1H).

[0111] Synthesis of compounds I-10-1 and I-10-2: Trifluoroacetic acid (0.5 mL) was added to a solution of intermediate 27 (50 mg, 0.071 mmol) and toluene (1 mL), and stirred overnight at room temperature. The reaction solution was concentrated to obtain a crude product, which was purified by preparative column chromatography to give a white solid compound I-10-1 (29.2 mg, 70%). MS: [MH] + 461.40; 1 HNMR (400 MHz, DMSO- d6 ): δ 10.33 (t, J=5.6Hz, 1H),8.29 (s, 1H), 7.20 (t, J=8.8Hz, 2H), 5.34-5.21 (m, 2H), 4.91-4.80 (m, 2H), 4.56 (d, J=5.6Hz, 2H), 4.12-4.03 (m, 1H), 1.82-1.74 (m, 1H), 1.37 (d, J=6.8Hz, 3H), 1.36-1.30 (m, 1H), 1.05-0.98 (m, 1H), 0.78-0.70 (m, 1H).

[0112] Trifluoroacetic acid (0.5 mL) was added to a solution of intermediate 28 (60 mg, 0.11 mmol) and toluene (1 mL), and stirred overnight at room temperature. The reaction solution was concentrated to obtain a crude product, which was purified by preparative column chromatography to give a pink solid compound I-10-2 (8.2 mg, 70%). MS: [MH]+ 461.35; 1 HNMR (400 MHz, DMSO- d6 ): δ 10.31 (t, J=5.6Hz, 1H), 8.30 (s, 1H), 7.21 (t, J=8.4Hz, 2H), 5.45-5.37 (m, 1H), 5.27-5.19 (m, 1H), 5.04 (d, J=14.4Hz, 1H), 4.85 (d, J=14.4Hz, 1H), 4.65-4.53 (m, 3H), 1.58-1.48(m, 1H), 1.40-1.32 (m, 1H), 1.11 (d, J=7.2Hz, 3H), 1.09-1.03 (m, 1H), 0.76-0.66 (m, 1H).

[0113] Example 3: Synthesis of Compound I-31

[0114] The reaction route is shown below:

[0115] Synthesis of intermediate 30: 1M vinyl magnesium bromide (36 mL, 35.95 mmol) was added dropwise to a dry THF (30 mL) solution of cyclopropaneformaldehyde (2.0 g, 28.53 mmol) at -78 °C. After addition, the mixture was stirred for 15 minutes and then stirred at 0 °C for 1 hour. The solution was quenched at 0 °C with saturated brine (20 mL), extracted with n-hexane (30 mL × 2), and the organic phase was washed with saturated brine (60 mL) and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (10-20% ethyl acetate in petroleum ether solution) yielded a pale yellow oil intermediate 30 (1.67 g, 60%). 1 HNMR(400 MHz, CDCl3): δ 6.03-5.88 (m, 1H), 5.31-5.22 (m, 1H), 5.17-5.07(m, 1H), 3.54-3.43 (m, 1H), 1.05-0.94 (m, 1H), 0.6-0.49(m, 2H), 0.41-0.22(m, 2H).

[0116] Synthesis of intermediate 31: Under nitrogen protection, intermediate 30 (1.18 g, 2.10 mmol), intermediate 21 (241.3 mg, 2.46 mmol), and triphenylphosphine (2.2 g, 8.40 mmol) were dissolved in dry THF (30 mL). The solution was cooled to 0 °C, and DIAD (1.7 g, 8.40 mmol) was added dropwise. After the addition was complete, the solution was stirred for 15 minutes and then stirred overnight at 80 °C. The crude product was concentrated and purified by silica gel column chromatography (using 10% ethyl acetate in petroleum ether) to obtain a pale yellow oil intermediate 31 (1.1 g, 81%). MS: [MH] + 642.50; 1 HNMR (400 MHz, CDCl3): δ 10.24-10.13 (m, 1H), 8.61-8.25 (m, 1H), 7.41-7.29 (m, 5H), 6.68 (t, J=7.6Hz, 2H), 5.93-5.63 (m, 0.38H),5.55-5.42 (m, 0.72H), 5.37-4.93 (m, 5H), 4.76-4.56 (m, 2H), 4.41-4.31 (m,0.6H), 4.05-3.80 (m, 1H), 3.66-3.56 (m, 1H), 1.40 (s, 9H), 1.12-0.83 (m,0.64H), 0.74-0.63 (m, 2H), 0.60-0.51 (m, 0.56H), 0.41-0.13 (m, 2H).

[0117] Synthesis of intermediate 32: LiOH H2O (392.5 mg, 9.35 mmol) was added to a THF / MeOH / H2O (10 mL / 5 mL / 5 mL) solution of intermediate 31 (1.0 g, 1.56 mmol) at 0 °C, and stirred overnight at 35 °C. After cooling to room temperature, the pH was adjusted to 6 with 2N hydrochloric acid, and the mixture was extracted with DCM (20 mL × 3). The organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (3.3–10% methanol in dichloromethane solution) yielded a pale yellow solid intermediate 32 (528 mg, 54%). MS: [MH] + 628.82; 1HNMR (400 MHz, CDCl3): δ 10.33-10.22 (m, 1H), 8.44-8.13 (m, 1H), 7.46-7.35 (m, 2H), 7.25-7.16 (m, 3H), 6.71-6.61 (m, 2H), 6.02-5.41 (m, 1H), 5.28-4.97 (m, 3.6H), 4.75-4.50 (m, 2H), 4.45-4.31 (m, 0.5H), 4.05-3.74 (m, 1H), 1.35-1.27 (m, 9H), 1.02-0.80 (m, 1H), 0.70-0.40 (m, 2H), 0.35-0.02 (m, 2H).

[0118] Synthesis of intermediate 33: Under nitrogen protection, intermediate 32 (580 mg, 0.92 mmol), intermediate 5 (149.2 mg, 1.39 mmol), and DIPEA (715.2 mg, 5.54 mmol) were added to DMF (10 mL), cooled to 0°C, and HATU (526.7 mg, 1.39 mmol) was added. The mixture was stirred overnight at room temperature. The solution was diluted with ethyl acetate (30 mL), washed successively with water (10 mL × 3), and saturated brine (20 mL), and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (10-25% ethyl acetate in petroleum ether solution) yielded a pale yellow solid, intermediate 33 (533 mg, 84%). MS: [MH] + 681.60; 1 HNMR (400 MHz, CDCl3): δ 10.29-10.15 (m, 1H), 8.52-8.23 (m, 1H), 7.45-7.28(m, 5H), 6.67(d, J=8.0Hz, 2H), 6.15-5.50 (m, 3H), 5.42-4.97 (m, 5H), 4.79-4.33 (m, 4H), 4.00-3.73 (m, 1H), 1.50-1.40 (m, 9H), 1.24-1.02 (m, 4H), 0.72-0.26 (m, 4H).

[0119] Synthesis of intermediate 34: 10% H2SO4 (15 mL) was added to a 1,4-dioxane (10 mL) solution of intermediate 33 (530 mg, 0.78 mmol), and the mixture was stirred at 50 °C for two nights. The solution was neutralized to pH 7-8 with saturated sodium bicarbonate solution, extracted with DCM (15 mL × 3), and the organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (20-33% ethyl acetate in petroleum ether solution) yielded a pale yellow solid intermediate 34 (120 mg, 26.5%). MS: [MH] + 581.85; 1 HNMR (400 MHz, CDCl3): δ 10.32-10.21 (m, 1H), 8.56 (d, J=6.0Hz, 1H), 7.38-7.31 (m, 5H), 7.24 (t, J=2.8Hz, 1H), 8.07 (t, J=9.2Hz, 1H), 6.68 (t, J =8.0 Hz, 2H), 5.76-5.50 (m, 2H), 5.47-5.21 (m, 2H), 5.13-4.99 (m, 3H), 5.84(t, J=16.8 Hz, 1H), 4.67 (d, J=5.6 Hz, 2H), 4.54-4.44 (m, 1H), 2.39-2.26 (m,1H), 1.11-1.01 (m, 3H), 0.87-0.77 (m, 1H), 0.51-0.42 (m, 2H), 0.05-0.00 (m,2H).

[0120] Synthesis of intermediate 35: Intermediate 34 (105 mg, 0.18 mmol), paraformaldehyde (81.5 mg, 0.90 mmol), and PPTS (181.9 mg, 0.72 mmol) were dissolved in DCE (10 mL) and stirred overnight at 85 °C under nitrogen protection. The reaction solution was cooled to room temperature, neutralized to pH 7-8 with saturated sodium bicarbonate aqueous solution, extracted with DCM (15 mL × 3), and the organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The solution was purified by preparative stencil (33% ethyl acetate in petroleum ether solution) to obtain a pale yellow solid intermediate 35 (100 mg, 90%). MS: [MH] + 593.10; 1HNMR (400 MHz, CDCl3): δ 10.35 (t, J =5.6 Hz, 1H), 8.55 (s, 1H), 7.61-7.55 (m, 2H), 7.36-7.27 (m, 3H), 6.67 (t, J=8.0 Hz, 2H), 5.87-5.68 (m, 2H), 5.41-5.15 (m, 7H), 4.73-4.60 (m, 2H), 4.58-4.48 (m, 1H), 4.46-4.29 (m, 1H), 2.81-2.62 (m, 1H), 1.32-1.25 (m, 3H), 0.86-0.71 (m, 1H),0.58-0.43 (m, 1H), 0.37-0.20 (m, 1H), 0.12-0.03 (m, 1H), -0.20~-0.38 (m, 1H).

[0121] Synthesis of intermediate 36: Intermediate 35 (91 mg, 0.15 mmol) was dissolved in DCE (50 mL), bubbled under nitrogen for 10 minutes, and then 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-yl[2-(isopropoxy-5-(N,N-dimethylaminesulfonyl)phenyl]methylruthenium dichloride (22.5 mg, 0.031 mmol) was added. Bubbling under nitrogen was continued for 5 minutes, and the mixture was sealed and stirred overnight at 80°C under nitrogen protection. After cooling to room temperature, the solution was concentrated and purified by a petroleum ether solution of 33% ethyl acetate to give intermediate 36 (32 mg, 37%), a pale yellow solid. MS: [MH] + 565.45.

[0122] Synthesis of compound I-31: Intermediate 36 (32 mg, 0.057 mmol) and LiCl (24 mg, 0.57 mmol) were dissolved in DMF (3 mL) and stirred overnight at 90 °C under nitrogen protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate (15 mL), washed successively with water (6 mL × 3), saturated brine (10 mL), and dried over anhydrous sodium sulfate. Preparative column purification yielded a white solid compound I-31 (23.8 mg, 61.4%). MS: [MH] + 475.10; 1HNMR (400 MHz, CD3OD): δ 8.58 (s, 1H), 6.90 (t, J=8.4 Hz, 2H), 5.79-5.66 (m, 2H), 5.40-5.30 (m, 1H), 5.17 (d, J=14.4 Hz, 1H),4.73-4.60 (m, 3H), 2.87-2.79 (m, 1H), 1.37 (d, J=7.2 Hz, 3H), 1.34-1.28 (m,1H), 0.72-0.53 (m, 2H), 0.09-0.02 (m, 1H), -0.11~-0.19 (m, 1H).

[0123] Example 4: Synthesis of compound I-34

[0124] The reaction route is shown below:

[0125] Synthesis of intermediate 38: Under nitrogen protection at -78°C, DMSO (4.08 g, 52.2 mmol) was added dropwise to a DCM (10 mL) solution of oxalyl chloride (2.65 g, 20.9 mmol), and the mixture was stirred for 15 minutes. Then, a dichloromethane solution (4 mL) of intermediate 37 (1.5 g, 17.4 mmol) was added dropwise, and the mixture was stirred at -78°C for 1 hour after the addition was complete. TEA (8.79 g, 87.0 mmol) was added dropwise at -78°C, and the mixture was slowly brought to room temperature after the addition was complete. The mixture was diluted with water (20 mL), extracted with dichloromethane (15 mL × 3), and the organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The mixture was concentrated below 10°C to obtain the crude product intermediate 38 (4 g, containing solvent). 1 HNMR (400 MHz, CDCl3): δ 9.80 (t, J=2.4 Hz, 1H), 2.32-2.27 (m, 2H), 1.00-0.93 (m, 1H), 0.64-0.58 (m, 2H), 0.20-0.14 (m, 2H).

[0126] Synthesis of intermediate 39: 1M vinyl magnesium bromide (5.9 mL, 5.90 mmol) was added dropwise to a dry THF (10 mL) solution of intermediate 38 (1.0 g, 11.89 mmol) under nitrogen protection at -78°C. The mixture was stirred at -78°C for 15 minutes and then at 0°C for 1 hour. The solution was quenched with saturated brine (10 mL) at 0°C, extracted with n-hexane (15 mL × 2), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated below 25°C. Purification by silica gel column chromatography (20% ethyl acetate in petroleum ether solution) yielded a colorless oil intermediate 39 (220 mg, 16.5%). 1 HNMR (400 MHz, CDCl3): δ 5.98-5.88 (m, 1H), 5.29-5.22 (m, 1H), 5.14-5.08 (m, 1H), 4.26-4.19 (m, 1H), 1.49-1.39 (m, 2H), 0.81-0.71 (m, 1H), 0.53-0.43 (m, 2H), 0.15-0.05 (m, 2H).

[0127] Synthesis of intermediate 40: Intermediate 39 (339.6 mg, 3.03 mmol), intermediate 21 (1.0 g, 1.78 mmol), and triphenylphosphine (1.87 g, 7.12 mmol) were dissolved in dry toluene (20 mL). Under nitrogen protection and after cooling to 0 °C, DIAD (1.44 g, 7.12 mmol) was added dropwise. After the addition was complete, stirring was continued for 15 minutes, followed by stirring overnight at 80 °C. The reaction mixture was concentrated to obtain the crude product, which was purified by silica gel column chromatography (using 10% ethyl acetate in petroleum ether) to obtain a pale yellow oil intermediate 40 (920 mg, 78%). MS: [MH] + 656.40; 1 HNMR (400 MHz, CDCl3): δ 10.25-10.15 (m, 1H), 8.37(d, J=14.4 Hz, 1H), 7.42-7.29 (m, 5H), 6.68 (t, J=8.0 Hz, 2H), 5.86-5.68 (m,1H), 5.30-4.95 (m, 6H), 4.73-4.58 (m, 2H), 4.43-4.28 (m, 1H), 3.71 (s, 3H), 1.39 (s, 9H), 0.65-0.40 (m, 3H), 0.15-0.04 (m, 2H).

[0128] Synthesis of intermediate 41: LiOH H2O (341.8 mg, 8.14 mmol) was added to a THF / MeOH / H2O (6 mL / 3 mL / 3 mL) solution of intermediate 40 (890 mg, 1.36 mmol) at 0 °C, and stirred overnight at 35 °C. The reaction solution was cooled to room temperature, adjusted to pH 6 with 2N hydrochloric acid, extracted with DCM (15 mL × 3), and the organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (3.3–10% methanol in dichloromethane solution) yielded a pink solid intermediate 41 (530 mg, 61%). MS: [MH] + 642.50; 1 HNMR (400 MHz, DMSO- d6 ): δ 10.68-10.51 (m, 1H), 8.15-7.94 (m, 1H), 7.49 (d, J=7.6 Hz, 2H), 7.37-7.27 (m, 3H), 7.21 (t, J=8.4Hz, 2H), 6.24-5.82 (m, 1H), 5.33-5.17 (m, 2H), 5.02-4.89 (m, 2H), 4.52 (d, J=5.6 Hz, 2H), 4.47-4.02 (m, 2H), 1.72-1.56 (m, 1H), 1.46-1.29 (m, 9H), 0.62-0.50 (m, 1H), 0.45-0.03 (m, 4H).

[0129] Synthesis of intermediate 42: Intermediate 41 (530 mg, 0.83 mmol), intermediate 5 (133.3 mg, 1.24 mmol), and DIPEA (639.3 mg, 4.96 mmol) were added to DMF (10 mL), cooled to 0°C, and then HATU (471.1 mg, 1.24 mmol) was added. The mixture was stirred overnight at room temperature under nitrogen protection. The solution was diluted with ethyl acetate (30 mL), washed successively with water (10 mL × 3), and saturated brine (20 mL), and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (12.5% ​​ethyl acetate in petroleum ether solution) yielded a white solid intermediate 42 (380 mg, 66%). MS: [MH] + 596.60; 1 HNMR (400 MHz, DMSO- d6): δ 10.26 (t, J=4.8 Hz, 1H), 8.93-8.76 (m, 1H), 8.45-8.18 (m, 1H), 7.44-7.29 (m, 5H), 7.23 (t, J=8.4 Hz, 2H), 6.13-5.65 (m, 3H), 5.42-4.88 (m, 6H), 4.60-4.40 (m, 3H), 4.15-4.03 (m,1H), 1.61-1.35 (m, 10H), 1.13-1.06 (m, 3H), 0.61-0.47 (m, 1H), 0.46-0.01 (m,4H).

[0130] Synthesis of intermediate 43: A 4M HCl / 1,4-dioxane solution was added to a 4 mL solution of DCM containing intermediate 42 (400 mg, 0.58 mmol), and the mixture was stirred at room temperature for 5 hours. The solution was neutralized to pH 7-8 with saturated sodium bicarbonate solution, extracted with DCM (10 mL × 3), and the organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (20-25% ethyl acetate in petroleum ether solution) yielded a white solid intermediate 43 (250 mg, 73%). MS: [MH] + 595.55; 1 HNMR (400 MHz, CDCl3): δ 10.32-10.23 (m, 1H), 8.51 (d, J=1.2 Hz, 1H), 7.37-7.33 (m, 5H), 7.27 (d, J=3.6 Hz, 1H), 6.86 (t, J=8.0Hz, 1H), 6.68 (t, J =8.0 Hz, 2H), 5.72-5.53 (m, 2H), 5.47-5.35 (m, 1H), 5.24-5.06 (m, 3H), 5.03-4.98 (m, 1H), 4.88-4.81 (m, 1H), 4.72-4.62 (m, 2H), 4.56-4.47 (m, 1H), 3.30-3.21 (m, 1H), 1.54-1.47 (m, 1H), 1.19-1.04 (m, 4H), 0.66-0.55 (m, 1H), 0.48-0.40 (m, 2H), 0.08-0.00 (m, 2H).

[0131] Synthesis of intermediate 44: Intermediate 43 (250 mg, 0.42 mmol), paraformaldehyde (189.0 mg, 2.10 mmol), and PPTS (422.6 mg, 1.68 mmol) were dissolved in DCE (25 mL) and stirred overnight at 85 °C under nitrogen protection. After cooling to room temperature, the solution was neutralized to pH 7-8 with saturated sodium bicarbonate solution, extracted with DCM (10 mL × 3), and the organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (20%–33% ethyl acetate in petroleum ether solution) yielded a white solid intermediate 44 (210 mg, 82%). MS: [MH] + 607.25; 1 HNMR (400 MHz, CDCl3): δ 10.39-10.25 (m, 1H), 8.45-8.30 (m, 1H), 7.60-7.53 (m, 2H), 7.36-7.26 (m, 4H), 6.67 (t, J=8.0 Hz, 2H),6.01-5.75 (m, 1H), 5.72-5.60 (m, 1H), 5.45-4.95 (m, 7H), 4.71-4.61 (m, 2H),4.55-4.34 (m, 2H), 3.68-3.51 (m, 1H), 1.38-1.18 (m, 4H), 0.64-0.37 (m, 3H), 0.12-0.10 (m, 2H).

[0132] Synthesis of intermediate 45: Intermediate 44 (210 mg, 0.35 mmol) was dissolved in DCE (100 mL), bubbled under nitrogen for 10 minutes, and then 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-yl[2-(isopropoxy-5-(N,N-dimethylaminesulfonyl)phenyl]methylruthenium dichloride (50.7 mg, 0.069 mmol) was added. Bubbling under nitrogen continued for 5 minutes. The mixture was sealed and stirred overnight at 80°C under nitrogen protection. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature and directly concentrated to obtain the crude product. The crude product was purified by passing it through a preparative plate with a petroleum ether solution containing 25% ethyl acetate to obtain an off-white solid intermediate 45 (94 mg, 47%). MS: [MH] + 579.55; 1HNMR (400 MHz, CDCl3): δ 10.37 (t, J=6.0 Hz, 1H),8.56 (s, 1H), 7.56-7.50 (m, 2H), 7.37-7.29 (m, 3H), 6.67 (t, J=8.0 Hz, 2H),5.70-5.45 (m, 4H), 5.23 (d, J =10.4 Hz, 1H), 4.82 (d, J =14.4 Hz, 1H), 4.72-4.61 (m, 2H), 4.17 (d, J =14.4 Hz, 1H), 3.72-3.68 (m, 1H), 1.77-1.67 (m, 1H),1.57-1.48 (m, 1H), 1.30 (d, J=7.2 Hz, 3H), 0.75-0.65 (m, 1H), 0.62-0.47 (m, 2H), 0.22-0.13 (m, 1H), 0.09-0.02 (m, 1H).

[0133] Synthesis of compound I-34: Intermediate 45 (94 mg, 0.16 mmol) and LiCl (68.9 mg, 1.62 mmol) were dissolved in DMF (3 mL) and stirred overnight at 90 °C under nitrogen protection. After cooling to room temperature, the mixture was diluted with ethyl acetate (15 mL), washed successively with water (6 mL × 3) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Preparative column purification yielded a pink solid compound I-34 (43.8 mg, 55.2%). MS: [MH] + 489.30; 1 HNMR (400 MHz, CD3OD): δ 8.51 (s, 1H), 6.90 (t, J=8.4 Hz, 2H), 5.77-5.70 (m, 1H), 5.64-5.57 (m, 1H), 5.46-5.36 (m, 1H), 5.08(d, J=14.4 Hz, 1H), 4.73-4.64 (m, 3H), 3.88-3.80 (m, 1H), 1.74-1.55 (m, 2H), 1.38 (d, J=7.6 Hz, 3H), 0.96-0.85 (m, 1H), 0.62-0.50 (m,2H), 0.24-0.09 (m,2H).

[0134] Example 5: Synthesis of two stereoisomers of compound I-11

[0135] The reaction route is shown below:

[0136] Synthesis of intermediate 46: 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), stirred at room temperature for 1 hour, cooled to 0°C, and HATU (1.03 g, 7.18 mmol) was added. The mixture was stirred overnight at room temperature under nitrogen protection. It was diluted with ethyl acetate (90 mL), washed with water (100 mL × 3), saturated brine (50 mL), and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (20-50% ethyl acetate in petroleum ether solution) yielded a white solid intermediate 46 (2.86 g, 75%). MS: [MH] + 544.15; 1 HNMR (400 MHz, DMSO- d6 ): δ 11.08 (s, 1H), 10.18(t, J=8 Hz, 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=8 Hz, 2H), 3.78 (s, 3H), 1.42 (s, 9H).

[0137] Synthesis of intermediate 47: Intermediate 46 (3.0 g, 5.52 mmol), 3-buten-2-ol (796 mg, 11.04 mmol), and triphenylphosphine (2.46 g, 9.38 mmol) were added to dry THF (40 mL), cooled to 0 °C, and DIAD (1.9 g, 9.38 mmol) was added dropwise under nitrogen protection. The mixture was stirred overnight at 35 °C. The reaction solution was concentrated to obtain the crude product, which was purified by silica gel column chromatography (14-17% ethyl acetate in petroleum ether solution) to obtain a colorless oily intermediate 47 (4.3 g). Note: Contains DIAD. MS: [MH] + 598.45.

[0138] Synthesis of intermediate 48: Intermediate 47 (4.3 g, 7.20 mmol) and LiOH H2O (1.82 g, 43.22 mmol) were added to MeOH / H2O (40 mL / 20 mL), and stirred overnight at 40 °C. The reaction solution was concentrated at 45 °C to remove most of the MeOH, adjusted to pH 6 with 2N hydrochloric acid, filtered, and the filter cake was washed with water and dried to give a pinkish solid intermediate 48 (3.0 g, two-step yield: 93%). MS: [MH] + 594.84.

[0139] Synthesis of intermediate 49: Intermediate 48 (3.0 g, 5.14 mmol), intermediate 20 (674 mg, 5.66 mmol), and DIPEA (3.3 g, 25.73 mmol) were added to DMF (30 mL), cooled to 0°C, and HATU (2.35 g, 6.17 mmol) was added in portions. The mixture was stirred at room temperature for 3 hours under nitrogen protection. The solution was diluted with ethyl acetate (90 mL), washed successively with water (30 mL × 3), and saturated brine (50 mL), and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (12-20% ethyl acetate in petroleum ether solution) yielded a pale pink solid, intermediate 49 (2.8 g, 84%). MS: [MH] + 649.20; 1 HNMR (400 MHz, DMSO- d6 ): δ 10.26-10.23 (m, 1H), 9.19-9.11 (m, 1H), 8.36-8.35 (m, 1H), 7.45-7.33 (m, 6H), 7.29-7.23 (m, 1H), 7.11-7.06 (m, 1H), 6.16-5.87 (m, 1H), 5.43-5.36 (m, 1H), 5.27-5.16 (m, 3H), 5.19-4.97 (m, 2H), 4.79-4.76 (m, 1H), 4.54 (d, J=5.6 Hz, 2H), 1.44-1.43 (m,9H), 1.36-1.28 (m, 4H), 0.93-0.76 (m, 4H).

[0140] Synthesis of intermediate 50: Intermediate 49 (1.0 g, 1.54 mmol) was dissolved in DCM (5 mL), and 4M HCl / 1,4-dioxane (5 mL) was added. The mixture was stirred at room temperature for 3 hours. The pH was adjusted to 6 with saturated sodium bicarbonate solution, and ethyl acetate (20 mL × 2) was added. The aqueous layer was separated, and the organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The solution was purified by silica gel column chromatography (14% ethyl acetate + 14% dichloromethane ~ 25% ethyl acetate + 25% dichloromethane in petroleum ether) to give intermediate 50 (380 mg, 45%) as a white solid. MS: [MH] + 549.05; 1 HNMR (400 MHz, DMSO- d6 ): δ 10.49-10.47 (m, 1H),9.00 (s, 1H), 8.46 (s, 1H), 7.45-7.23 (m, 7H), 7.11-7.03 (m, 2H), 5.78-5.69(m, 1H), 5.43-5.37 (m, 1H), 5.27-5.22 (m, 1H), 5.11-4.99 (m, 4H), 4.84-4.81(m, 1H), 4.54 (d, J=5.6 Hz, 2H), 3.81-3.72 (m, 1H), 1.07-1.06 (m, 3H), 0.93-0.85 (m, 4H).

[0141] Synthesis of intermediate 51: Intermediate 50 (650 mg, 1.19 mmol), paraformaldehyde (534 mg, 5.93 mmol), and PPTS (1.19 g, 4.74 mmol) were added to DCE (20 mL) and stirred overnight at 85 °C. The reaction mixture was cooled to room temperature, quenched with water, extracted with DCM (20 mL × 3), and the organic phase was washed with saturated sodium bicarbonate aqueous solution (30 mL) and dried over anhydrous sodium sulfate. The mixture was purified by silica gel column chromatography (14% ethyl acetate and 14% dichloromethane in petroleum ether solution) and preparative HPLC to give intermediate 51 (159 mg, 24%) as a white solid. MS: [MH] + 561.55; 1 HNMR (400 MHz, DMSO- d6): δ 10.33-10.30 (m, 1H), 8.31-8.26 (m, 1H), 7.56-7.53 (m, 2H), 7.45-7.27 (m, 6H), 7.11-7.06 (m, 1H), 5.82-5.67 (m, 2H), 5.12-4.98 (m, 4H), 4.55-4.54 (m, 2H), 1.49-0.84 (m, 10H).

[0142] Synthesis of intermediates 52 and 53: Intermediate 51 (159 mg, 0.28 mmol) was dissolved in DCE (20 mL), bubbled under nitrogen for 10 minutes, and then Janssen reagent (41 mg, 0.056 mmol) was added to the reaction solution. Bubbling under nitrogen continued for 5 minutes, and the mixture was stirred overnight at 80°C under a sealed nitrogen atmosphere. The reaction solution was cooled to room temperature and concentrated to obtain the crude product. Purification using a preparative agar plate (25% ethyl acetate and 25% dichloromethane in petroleum ether solution) yielded pale yellow oil intermediates 52 (35 mg) and 53 (35 mg) (total yield: 46%). MS: [MH] + 533.75 (Intermediate 52); MS: [MH] + 533.50 (intermediate 53).

[0143] Synthesis of compounds I-11-1 and I-11-2: Intermediate 52 (35 mg, 0.066 mmol) was dissolved in toluene (1 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred overnight at room temperature. The reaction solution was concentrated to obtain the crude product, which was purified by preparative HPLC to obtain an off-white solid I-11-1 (15 mg, 50%). MS: [MH] + 443.05; 1 HNMR (400 MHz, CD3OD): δ 8.49 (s, 1H), 7.45-7.37(m, 1H), 6.98-6.93 (m, 2H), 5.33 (s, 2H), 5.02-4.99 (m, 2H), 4.62 (s, 2H), 4.10-4.05 (m, 1H), 2.20-2.03 (m, 2H), 1.48 (d, J=7.2 Hz, 3H), 1.13-1.07 (m,1H), 0.91-0.79 (m, 2H).

[0144] Intermediate 53 (35 mg, 0.066 mmol) was dissolved in toluene (1 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred overnight at room temperature. The reaction solution was concentrated to obtain a crude product, which was purified by preparative HPLC to give an off-white solid I-11-2 (12 mg, 40%). MS: [MH] + 443.65; 1 HNMR (400 MHz, DMSO- d6 ): δ 10.28-10.27 (m, 1H), 8.33 (s, 1H), 7.45-7.40 (m, 1H), 7.25 (t, J=8 Hz, 1H), 7.08 (t, J=8 Hz, 1H), 5.44-5.41 (m, 1H), 5.26-5.23 (m, 1H), 5.08-5.05 (m, 1H), 4.88-4.85 (m, 1H), 4.65-4.50 (m, 2H), 1.58-1.51 (m, 1H), 1.40-1.35 (m, 1H), 1.24 (s, 1H), 1.13-1.08 (m, 3H), 0.75-0.70 (m, 1H).

[0145] Example 6: Synthesis of Compound II-23

[0146] The reaction route is shown below:

[0147] Synthesis of intermediate 54: Intermediate 38 (2.0 g, 11.61 mmol) and triethylamine (1.17 g, 11.61 mmol) were added to dichloromethane (20 mL), cooled to 15 °C, and hydroxylamine hydrochloride (806.8 mg, 11.61 mmol) was added in three portions. The mixture was stirred at 15 °C for 30 minutes under nitrogen protection. The reaction solution was concentrated at 20 °C to obtain a crude product. The crude product was slurried with petroleum ether (20 mL), filtered, and the filter cake was washed with petroleum ether. The filtrate was collected and concentrated, and purified by silica gel column chromatography (25% ethyl acetate in petroleum ether solution) to obtain colorless oil intermediate 54 (700 mg, 60%). 1HNMR (400 MHz, CDCl3): δ 7.48 (t, J=6.0 Hz, 1H), 6.89-6.78 (m, 1H), 2.10 (t, J=6.0 Hz, 2H), 0.88-0.78 (m, 1H), 0.55-0.49 (m, 2H), 0.18-0.12 (m,2H).

[0148] Synthesis of intermediate 56: Benzyl chloroformate (25.2 g, 147.7 mmol) was added dropwise to a solution of D-allyl glycine (10.0 g, 86.78 mmol) and sodium bicarbonate (20.4 g, 243.2 mmol) in 267 mL of water. The mixture was stirred overnight at room temperature. The pH was adjusted to 2 with saturated potassium bisulfate solution, and the mixture was extracted with dichloromethane (150 mL × 3). The organic phase was washed with saturated brine (300 mL) and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (5% methanol in dichloromethane solution) yielded a light red oil intermediate 56 (13 g, 60%). MS: [MH] + 250.25; 1 HNMR (400 MHz, CDCl3): δ 7.43-7.27 (m, 5H), 5.80-5.63 (m, 1H), 5.28 (d, J=8.0 Hz, 1H), 5.21-5.07 (m, 4H), 4.53-4.43 (m, 1H),3.68-2.49 (m, 2H).

[0149] Synthesis of intermediate 57: At -10°C, TEA (1.90 g, 18.86 mmol) and isobutyl chloroformate (2.83 g, 20.74 mmol) were added dropwise to a THF (50 mL) solution of intermediate 56 (4.7 g, 18.86 mmol), and the mixture was stirred at 0°C–5°C for 2 hours. The triethylamine salt was removed by filtration, and the filter cake was washed with tetrahydrofuran (20 mL). The filtrate was cooled to 0°C, and an aqueous solution of sodium borohydride (1.5 g, 39.60 mmol) (10 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. The pH was adjusted to approximately 5 with a saturated potassium bisulfate solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (150 mL) and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (25%–50% ethyl acetate in petroleum ether solution) yielded a white solid intermediate 57 (2.1 g, 48%). MS: [MH] + 236.00; 1HNMR (400 MHz, CDCl3): δ 7.40-7.28 (m, 5H), 5.85-5.72 (m, 1H), 5.17-5.07 (m, 4H), 4.99-4.85 (m, 1H), 3.84-3.59 (m, 3H), 2.40-2.15 (m, 3H).

[0150] Synthesis of intermediate 58: Oxaloyl chloride (7.0 g, 54.90 mmol) was dissolved in dichloromethane (120 mL), and the solution was cooled to -78 °C. A solution of DMSO (11.0 g, 140.26 mmol) in dichloromethane (20 mL) was added dropwise. After stirring at -78 °C for 10 minutes, a solution of intermediate 57 (11.0 g, 46.75 mmol) in dichloromethane (20 mL) was added dropwise. Stirring was continued at -78 °C for 1 hour. Triethylamine (23.6 g, 233.75 mmol) was added dropwise, and the mixture was slowly brought to room temperature after the addition was complete. A suitable amount of water was added to the reaction mixture. The aqueous phase was extracted with dichloromethane (80 mL × 2), and the organic phase was washed with saturated brine (150 mL) and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (20%–33% ethyl acetate in petroleum ether solution) yielded a pale yellow oil intermediate 58 (8.2 g, 75%). MS: [MH] + 234.00; 1 HNMR (400 MHz, CDCl3): δ 9.61 (s, 1H), 7.42-7.27(m, 5H), 5.77-5.64 (m, 1H), 5.40-5.28 (m, 1H), 5.21-5.05 (m, 4H), 4.42-4.31(m, 1H), 3.70-2.47 (m, 2H).

[0151] Synthesis of intermediate 59: Under nitrogen protection, intermediate 5 (2.1 g, 19.33 mmol) and acetic acid (1 drop) were added to a MeOH (50 mL) solution of intermediate 58 (4.1 g, 17.58 mmol), and stirred at room temperature for 1 hour. After cooling to 0°C, sodium cyanoborohydride (1.3 g, 21.10 mmol) was added in portions, and the mixture was stirred overnight at room temperature. The mixture was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (50 mL × 3), and the organic phase was washed with saturated brine (150 mL) and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (20% ethyl acetate in petroleum ether solution) yielded a pale yellow oil intermediate 59 (2.6 g, 51%). MS: [MH]+ 289.65; 1 HNMR (400 MHz, CDCl3): δ 7.40-7.28 (m, 5H), 5.83-5.55 (m, 2H), 5.15-4.99 (m, 6H), 3.83-3.73 (m, 1H), 3.21-3.06 (m, 1H), 2.72-2.58 (m, 2H), 2.35-2.24 (m, 2H), 1.13 (d, J=6.4 Hz, 3H).

[0152] Synthesis of intermediate 60: Intermediate 59 (2.6 g, 9.02 mmol) and potassium carbonate (2.5 g, 18.04 mmol) were added to 1,4-dioxane / water (20 mL / 20 mL), cooled to 0 °C, and benzyl chloroformate (2.3 g, 13.52 mmol) was added dropwise. After the addition was complete, the mixture was slowly brought to room temperature and stirred overnight. The reaction solution was extracted with ethyl acetate (40 mL × 3), and the organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (6.7% ethyl acetate in petroleum ether solution) yielded colorless oil intermediate 60 (2.7 g, 71%). MS: [MH] + 423.80; 1 HNMR (400 MHz, CDCl3): δ 7.40-7.27 (m, 10H), 6.00-5.48 (m, 2H), 5.21-4.96 (m, 8H), 4.67-4.45 (m, 1H), 3.97-3.76 (m, 1H), 3.57-3.21 (m, 1H), 3.20-3.03 (m, 1H), 2.41-2.10 (m, 2H), 1.33-1.24 (m, 3H).

[0153] Synthesis of intermediate 61: Intermediate 60 (6.1 g, 14.44 mmol) was dissolved in DCM (100 mL), bubbled under nitrogen for 10 minutes, then Grubbs II (1.2 g, 1.44 mmol) was added, and bubbling under nitrogen continued for 5 minutes. The mixture was then heated to 40°C and stirred for 3 hours. The reaction solution was cooled to room temperature and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (5%–10% ethyl acetate in petroleum ether solution) to obtain a light yellow oil intermediate 61 (3.1 g, 54%). MS: [MH] + 395.40; 1HNMR (400 MHz, CDCl3): δ 7.42-7.27 (m, 9H), 7.24-7.16 (m, 1H), 6.33 (d, J=8.4Hz, 1H), 5.70-5.50 (m, 1H), 5.37-4.89 (m, 6H), 4.12-3.93 (m, 1H), 3.75-3.61 (m, 1H), 3.55-3.44 (m, 1H), 2.41-2.16 (m, 2H), 1.22-1.14 (m, 3H).

[0154] Synthesis of intermediate 62: Intermediate 61 (2.5 g, 6.35 mol) was dissolved in TFA (25 mL), stirred at 95 °C for 3 hours. After cooling to room temperature, the solution was concentrated to obtain brown oil intermediate 62 (3.5 g), which was used directly in the next reaction. MS: [MH] + 127.05 [M+H] + ; 1 HNMR (400 MHz, CD3OD): δ 6.12-6.02 (m, 1H),5.75-5.68 (m, 1H), 4.18-4.07 (m, 1H), 3.86-3.76 (m, 1H), 3.63-3.53 (m, 1H),3.49-3.41 (m, 1H), 2.80-2.66 (m, 2H), 1.49 (d, J=7.2 Hz, 3H).

[0155] Synthesis of intermediate 63: Intermediate 62 (3.5 g, 6.35 mmol), intermediate 6 (2.0 g, 6.35 mmol), and sodium bicarbonate (5.3 g, 63.5 mmol) were added to MeOH / H2O (120 mL / 12 mL) and stirred at 60 °C for 6 hours. The reaction solution was concentrated to remove methanol, diluted with saturated ammonium chloride, extracted with dichloromethane / methanol (10 / 1, 50 mL × 3), and the organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (5% methanol in dichloromethane solution) yielded a pale yellow solid intermediate 63 (1.6 g, 64%). MS: [MH] + 395.45; 1HNMR (400 MHz, CDCl3): δ 8.13 (s, 1H), 7.64-7.57 (m, 2H), 7.37-7.27 (m, 3H), 6.54 (d, J=10.4 Hz, 1H), 5.58-5.43 (m, 3H), 5.15 (d,J=10.4 Hz, 1H), 4.39 (t, J=7.6 Hz, 1H), 3.92 (s, 3H), 3.76-3.69 (m, 1H), 3.38(d, J= 14.4 Hz, 1H), 2.89-2.77 (m, 1H), 2.52-2.41 (m, 1H), 1.27 (d, J=7.2 Hz, 3H).

[0156] Synthesis of intermediate 64: Intermediate 63 (4.5 g, 11.40 mmol) was dissolved in MeOH (23 mL), and 2N NaOH aqueous solution (22.8 mL, 45.6 mmol) was added. The mixture was stirred at 60 °C for 1 hour. The mixture was concentrated at 45 °C to remove most of the MeOH, and the pH was adjusted to 6 with 2N hydrochloric acid. The mixture was filtered, the filter cake was washed with water, and dried to obtain a white solid intermediate 64 (3.4 g, 78%). MS: [MH] + 381.30; 1 HNMR (400 MHz, DMSO- d6 ): δ 15.66 (s, 1H), 8.85 (s,1H), 7.54-7.48 (m, 2H), 7.42-7.31 (m, 3H), 5.57-5.43 (m, 2H), 5.40-5.28 (m,2H), 5.15-4.97 (m, 2H), 3.83-3.74 (m, 1H), 3.57 (d, J=14.4 Hz, 1H), 3.03-2.88(m, 1H), 2.35-2.23 (m, 1H), 1.25 (d, J=7.2 Hz, 3H).

[0157] Synthesis of intermediate 65: Intermediate 64 (1.0 g, 2.63 mmol), EDCI (1.0 g, 5.26 mmol), and HOBT (533.0 mg, 3.95 mmol) were added to DMF (15 mL), stirred at room temperature for 60 minutes, cooled to 0°C, and 2,4-difluorobenzylamine (489.2 mg, 3.42 mmol) in DMF (3 mL) was added dropwise. The mixture was stirred at room temperature overnight. It was diluted with ethyl acetate (60 mL), then washed successively with water (20 mL × 3), saturated saline (40 mL), and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (33% ethyl acetate and 33% dichloromethane in petroleum ether) yielded an off-white solid intermediate 65 (730 mg, 46%). MS: [MH] + 506.40; 1 HNMR (400 MHz, DMSO- d6 ): δ 10.48 (t, J =5.6 Hz,1H), 8.65 (s, 1H), 7.52-7.48 (m, 2H), 7.45-7.29 (m, 4H), 7.28-7.21 (m, 1H), 7.11-7.04 (m, 1H), 5.55-5.42 (m, 2H), 5.36-5.28 (m, 2H), 5.03 (d, J=10.4 Hz,1H), 4.99-4.91 (m, 1H), 4.58-4.51 (m, 2H), 3.78-3.70 (m, 1H), 3.53 (d, J=14.4Hz, 1H), 3.01-2.89 (m, 1H), 2.28-2.18 (m, 1H), 1.24 (d, J=7.2 Hz, 3H).

[0158] Synthesis of intermediate 66: Under nitrogen protection, intermediate 65 (1.6 g, 3.17 mmol) and selenium dioxide (3.5 g, 31.7 mmol) were added to 1,4-dioxane (32 mL), and stirred overnight at 105 °C. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate. The filtrate was collected and washed successively with semi-saturated ammonium chloride aqueous solution (25 mL × 2) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (50% ethyl acetate in dichloromethane solution) yielded a gray solid intermediate 66 (850 mg, 51%). MS: [MH] + 520.00; 1HNMR (400 MHz, CDCl3): δ 10.37 (t, J =5.6 Hz, 1H), 8.60 (s, 1H), 7.58-7.52 (m, 2H), 7.42-7.29 (m, 4H), 6.87-6.77 (m, 2H), 6.34-6.26 (m, 1H), 6.08-6.00 (m, 1H), 5.73-5.62 (m, 1H), 5.53 (d, J=12.0 Hz, 1H), 5.09 (d, J=12.0 Hz, 1H), 4.68-4.60 (m, 3H), 3.93 (d, J=12.0 Hz, 1H), 3.58 (d,J=16.0 Hz, 1H), 1.45 (d, J=4.0 Hz, 3H).

[0159] Synthesis of intermediate 67: Intermediate 66 (800 mg, 1.54 mmol) was dissolved in dry tetrahydrofuran (10 mL), cooled to -20 °C, and a tetrahydrofuran solution of 1N methylmagnesium bromide (9.2 mL, 9.20 mmol) was added dropwise. The mixture was stirred at -20 °C for 30 minutes. The reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate (15 mL × 3), and the organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (50% ethyl acetate in petroleum ether solution) yielded a pale yellow solid intermediate 67 (430 mg, 52%). MS: [MH] + 536.05; 1 HNMR (400 MHz, DMSO- d6): δ 10.53 (t, J =5.6 Hz,1H), 8.48 (s, 1H), 7.54-7.49 (m, 2H), 7.46-7.28 (m, 4H), 7.27-7.20 (m, 1H), 7.11-7.03 (m, 1H), 5.58-5.51 (m, 1H), 5.45 (s, 1H), 5.42-5.37 (m, 1H), 5.29(d, J=8.0 Hz, 1H), 5.23-5.16 (m, 1H), 5.01 (d, J=8.0 Hz, 1H), 4.69-4.64 (m,1H), 4.56 (d, J=8.0 Hz, 2H), 3.85-3.77 (m, 1H), 3.58-3.50 (m, 1H), 1.40 (s, 3H), 1.25 (d, J=4.0 Hz, 3H).

[0160] Synthesis of intermediate 68: Platinum dioxide (42.0 mg, 0.19 mmol) was added to a methanol / dichloromethane (9 mL / 3 mL) solution of intermediate 67 (330 mg, 0.62 mmol), purged three times with hydrogen, and then stirred overnight at room temperature under a hydrogen atmosphere. Platinum dioxide was removed by filtration, and the filter cake was washed with DCM / MeOH = 10 / 1. The filtrate was concentrated to give a gray solid intermediate 68 (crude 300 mg), which was used directly in the next step. MS: [MH] + 448.25.

[0161] Synthesis of intermediate 69: Intermediate 68 (300 mg, 0.62 mmol), K₂CO₃ (510.6 mg, 3.70 mmol), and benzyl bromide (526.8 mg, 3.08 mmol) were added to DMF (8 mL) and stirred overnight at 40 °C. The reaction mixture was diluted with ethyl acetate (30 mL), washed successively with water (10 mL × 3), saturated brine (20 mL), and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (50% ethyl acetate in dichloromethane solution) yielded a gray solid intermediate 69 (260 mg, 78%). MS: [MH] + 538.00; 1 HNMR (400 MHz, DMSO- d6): δ 10.54 (t, J=5.6 Hz, 1H), 8.46 (s, 1H), 7.54-7.49 (m, 2H), 7.45-7.29 (m, 4H), 7.27-7.20 (m, 1H), 7.10-7.02 (m, 1H), 5.31 (d, J=12.0 Hz, 1H), 5.09 (s, 1H), 5.01 (d, J=8.0 Hz, 1H), 4.63-4.51 (m, 3H), 4.26-4.21 (m, 1H), 3.65-3.51 (m, 1H), 1.44-1.36 (m, 2H),1.35 (s, 3H), 1.27-1.21 (m, 2H), 1.14 (d, J=8.0 Hz, 3H).

[0162] Synthesis of intermediate 70: Intermediate 69 (310 mg, 0.58 mmol) was dissolved in dry toluene (6 mL), and Martin sulfurane (975.2 mg, 1.45 mmol) was added in a single batch at room temperature. The mixture was stirred at 40 °C for 1 hour. The reaction solution was directly concentrated and purified by silica gel column chromatography (33% ethyl acetate and 33% dichloromethane in petroleum ether solution) to give intermediate 70 (260 mg, 86%) as a yellow solid. MS: [MH] + 520.05; 1 HNMR (400 MHz, CDCl3): δ 10.49 (t, J =5.6 Hz, 1H), 8.45 (s, 1H), 7.60-7.56 (m, 2H), 7.41-7.28 (m, 4H), 6.85-6.76 (m, 2H), 5.54(d, J=12.0 Hz, 1H), 5.19-5.13 (m, 2H), 4.90-4.79 (m, 1H), 4.64 (d, J=4.0 Hz, 2H), 4.61-4.57 (m, 1H), 3.55-3.39 (m, 2H), 2.39-2.15 (m, 2H), 2.01-1.93 (m,1H), 1.37-1.27 (m, 2H), 1.21 (d, J=8.0 Hz, 3H).

[0163] Synthesis of intermediate 71: Under nitrogen protection, NCS (154.2 mg, 1.16 mmol) was added to a DMF (4 mL) solution of intermediate 70 (114.5 mg, 1.16 mmol), and the mixture was stirred at 60 °C for 2 hours. The reaction mixture was cooled to room temperature, and intermediate 54 (120 mg, 0.23 mmol) and triethylamine (233.3 mg, 2.31 mmol) were added. The mixture was stirred overnight at room temperature. The reaction mixture was quenched with a semi-saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate (15 mL × 3), and the organic phase was washed once with water (5 mL × 3), saturated brine (20 mL), and dried over anhydrous sodium sulfate. Purification by silica gel column chromatography (50% ethyl acetate in petroleum ether solution) yielded an off-white solid intermediate 71 (120 mg, 77%). MS: [MH] + 617.50; 1 HNMR (400 MHz, CDCl3): δ 10.38 (t, J=6.0 Hz, 1H), 8.31 (s, 1H), 7.57-7.52 (m, 2H), 7.39-7.29 (m, 4H), 6.87-6.77 (m, 2H), 5.51(d, J=8.0 Hz, 1H), 5.20 (d, J=12.0 Hz, 1H), 4.95-4.81 (m, 1H), 4.70-4.57 (m,2H), 3.98-3.93 (m, 1H), 3.74-3.68 (m, 1H), 3.43-3.65 (m, 1H), 3.17 (d, J=20.0Hz, 1H), 2.67 (d, J=20.0 Hz, 1H), 2.42-2.33 (m, 1H), 2.30-2.23 (m, 1H), 1.98-1.88 (m, 3H), 1.73-1.63 (m, 1H), 1.21 (d, J=8.0 Hz, 3H), 0.99-0.88 (m, 1H), 0.73-0.61 (m, 2H), 0.23-0.13 (m, 2H).

[0164] Synthesis of compound II-23: Trifluoroacetic acid (1 mL) was added to a toluene (3 mL) solution of intermediate 71 (110 mg, 0.18 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated and purified by preparative column chromatography to give a white solid compound II-23 (42.9 mg, 45%). MS: [MH] + 527.45; 1HNMR (400 MHz, CD3OD): δ 8.44 (s, 1H), 7.48-7.37 (m, 1H), 7.03-6.88 (m, 2H), 4.75-4.57 (m, 3H), 4.44 (s, 1H), 3.94-3.77 (m, 2H), 3.05 (d, J=20.0Hz, 1H), 2.71 (d, J=16.0Hz, 1H), 2.41-2.31 (m, 1H), 2.23-2.14 (m, 1H), 2.04-1.90 (m, 3H), 1.68-1.58 (m, 1H), 1.29 (d, J=4.0Hz, 3H),1.02-0.90 (m, 1H), 0.68-0.54 (m, 2H), 0.22-0.12 (m, 2H).

[0165] The compounds listed in Table 1 below were synthesized using the same method: Table 1

[0166] Example 7. In vitro HIV-1 pseudovirus test and cytotoxicity test 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 2.

[0167] Table 2. In vitro cellular antiviral activity of compounds

[0168] Cabotegravir (control compound): .

[0169] In vitro PHIV results showed that all of these tested compounds had good anti-HIV-1 activity, with the most prominent compounds being I-1, I-10-1, I-10-2, I-11-2, I-31, II-2, II-8, II-16, and II-23, and none of these compounds showed significant cytotoxicity.

[0170] Example 8. Stability test of human and rat liver microsomes Experimental protocol: This experiment was conducted in a 96-well plate. The reaction conditions were as follows: ① Microsomal protein concentration: 0.7 mg / mL ② Compound concentration: 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 stop solution after incubation for 0 min, 15 min, 30 min, 60 min, and 90 min, respectively. The remaining amount of compound was detected using liquid chromatography-mass spectrometry (LC-MS). Testosterone and diclofenac were used as positive controls.

[0171] 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 / A IS The ratio was calculated. Ln (%Control) was plotted against incubation time and linearly fitted. The scavenging constant (k, min) of the test compound was determined. -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 3.

[0172] .

[0173] Table 3 Results of the study on the stability of compounds in liver microsomes

[0174] The results showed that compounds I-10-1, I-10-2, I-11-1, I-11-2, and I-31 had relatively low clearance rates when incubated with human and rat liver microsomes. This property of these compounds is suitable for the research and development of long-acting formulations.

[0175] Example 9. Thermodynamic Solubility Test Experimental protocol: Accurately weigh approximately 2 mg of the compound 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 4.

[0176] Table 4. Solubility results of compounds

[0177] The results showed that compounds I-10-2, I-11-1, and I-11-2 all had extremely low thermodynamic solubility in PB buffer at pH 7.4, which increased the probability of successful development of long-acting injectable formulations.

[0178] Example 10. Caco-2 Permeability Test Experimental design and results: (1) Preparation of working solutions of control compound and test compound 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.

[0179] (2) Culture of Caco-2 cells 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) ≥ 230 ohms·cm were observed. 2 Only cell pores with specific diameters can be used for the penetration test, TEER value (ohm·cm). 2 = Measured resistance (ohms) × Film area (cm²) 2 ).

[0180] (3) Drug penetration test 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.

[0181] 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.

[0182] 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, mixing it 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 starting dosing end sample TA0 (A→B). Add 1300 μL of the receiving end solution to each well of the lower chamber (base).

[0183] 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).

[0184] e) The Transwell plates were incubated at 37°C for 120 minutes.

[0185] 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.

[0186] 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.

[0187] 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.

[0188] (4) Data Analysis a) Apparent permeability coefficient (P) app cm / s 10 -6 It is calculated using the following formula: ; In the formula: C R This represents the concentration at the receiving end after incubation. C D0 This is the initial concentration at the dosing end; V RThe volume of the solution at the receiving end is 1.3 mL for A→B and 0.2 mL for B→A. A is the area of ​​a single cell membrane (0.33 cm²). 2 ); T represents the incubation time (7200 seconds).

[0189] b) The efflux ratio is calculated using the following formula: ; In the formula: P app (B→A) The apparent permeability coefficient is measured from the base to the tip. P app (A→B) The apparent permeability coefficient is measured from the top to the base.

[0190] c) Recovery rate is calculated using the following formula: ; In the formula: C R This represents the concentration at the receiving end after incubation. 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. C D This is the concentration at the dosing end after incubation; 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. C D0 This represents the initial concentration at the dosing point.

[0191] d) Parameter standards are shown in Table 5 Table 5. Caco-2 Results Parameter Standards

[0192] (5) The data results are shown in Table 6. Table 6. Permeability results of compound Caco-2

[0193] According to the parameter standards, the results showed that the tested compounds were all similar to cabotegravir, with moderate permeability, and none of them were efflux transporter substrates, making them suitable for the development of long-acting drugs.

[0194] Example 11. Rat PK (1) Intravenous administration Compounds I-11-1, I-11-2, and the control compound Cabotegravir were administered intravenously to SD rats, with three male SD rats in each group. The intravenous dose for each group was 1 mg / kg. Blood samples of 0.15–0.2 mL were collected via the jugular vein or other suitable vein at 0.03 h, 1 h, 4 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h, and 240 h post-administration. The samples were placed in EDTA-K2 anticoagulant tubes, gently mixed, centrifuged at 4000 rpm for 10 min at 4°C, and the plasma was separated and frozen at -80°C for analysis. The plasma concentrations of the corresponding compounds in each group were determined by LC-MS / MS, and pharmacokinetic parameters were calculated. The results are shown in Table 7.

[0195] Table 7. Pharmacokinetic parameters of compounds administered via a single intravenous injection in SD rats.

[0196] Table 7 shows that in rats, compounds I-11-1 and I-11-2 both exhibited long half-lives and low clearance rates; in particular, compound I-11-1, compared with the control compound Cabotegravir, significantly prolonged the half-life and increased the in vivo exposure, highlighting typical long-acting characteristics and showing high development potential.

[0197] (2) Oral administration via gavage Compounds I-11-1, I-11-2, and the positive control compound Cabotegravir were administered orally to SD rats via gavage. Three male SD rats were used in each group. Rats were fasted overnight but had free access to water before the experiment. The gavage dose for each group was 5 mg / kg, with 0.5% methylcellulose solution as the solvent. Blood samples of 0.15–0.2 mL were collected via the jugular vein or other suitable vein at 1 h, 4 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h, and 240 h after administration. The samples were placed in EDTA-K2 anticoagulant tubes, gently mixed, centrifuged at 4000 rpm for 10 min at 4°C, and the plasma was separated and frozen at -80°C for analysis. The plasma concentrations of the corresponding compounds in each group were determined by LC-MS / MS, and pharmacokinetic parameters were calculated. The results are shown in Table 8.

[0198] Table 8: Pharmacokinetic parameters of the compound administered via single oral gavage to SD rats

[0199] The data in Table 8 show that, consistent with the results of intravenous injection in rats, compounds I-11-1 and I-11-2 both exhibited longer half-lives and lower clearance rates. It is worth emphasizing again that, in particular, compound I-11-1 showed better absorption and in vivo exposure than the control compound after oral administration, demonstrating excellent potential for developing long-acting drugs.

[0200] Example 12. Intravenous injection of PK in beagle dogs Drug concentrations were determined in beagle dogs after a single intravenous administration of I-11-1, I-11-2, and the control compound Cabotegravir. Three male beagle dogs were used in each group. All animals were fasted for at least 12 hours before administration and resumed feeding 4 hours after administration. All animals had free access to water during the experiment. Each group was administered 1 mg / kg via cephalic intravenous injection. Following administration, at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 10 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, and 168 h, approximately 0.5 mL of blood was collected via jugular vein. The collected whole blood was placed in EDTA-K2 anticoagulant tubes, inverted several times to mix thoroughly, stored on moist ice, and centrifuged (1500–1600 g) for 10 min within 30 min to separate the plasma. The resulting plasma samples were stored at -90 to -60 °C for biological sample analysis. An LC-MS / MS method was established for determining the concentration of beagle plasma in beagle blood, used for the determination of the concentration of biological samples obtained in this experiment. The corresponding pharmacokinetic parameters were calculated using a non-compartmental model in Phoenix WinNonlin 8.3, and the results are shown in Table 9.

[0201] Table 9. Pharmacokinetic parameters of the compound after a single intravenous injection in beagle dogs.

[0202] The data in Table 9 show that compounds I-11-1 and I-11-2 exhibited more stable metabolic properties than cabotegravir when metabolized in beagle dogs. Comparing their half-lives, compounds I-11-1 and I-11-2 were approximately 7-fold and 20-fold longer than cabotegravir, respectively. This level of improved metabolic stability, combined with in vivo PK data from rats, fully demonstrates the great potential of the compounds of this invention for the development of long-acting drugs.

[0203] 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) Each R1 is independently selected from halogen, cyano, hydroxyl, C 1-6 Alkyl or halogenated C 1-6 Alkyl group; n is 1, 2, 3 or 4; (2) R2 and R3 are independently selected from H, D or C 1-6 alkyl; (3) Q is selected from amides, unsubstituted or substituted 4-6 membered heteroaryl rings; wherein the substituent used for substitution is selected from one, two or more of the following groups: halogen, cyano, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy or deuterated C 1-6 Alkoxy; (4) X is CH or N; (5) A is selected from 6-20 saturated heterocyclic groups or 6-20 unsaturated heterocyclic groups; the 6-20 saturated heterocyclic groups and 6-20 unsaturated heterocyclic groups are single rings, double rings or multiple rings, the double ring is a fused ring, a bridged ring or a spiral ring composed of two rings, the multiple ring includes 3 or more rings, and the rings in the multiple ring are connected by one, two or more of the connection methods of fused rings, bridged rings and spiral rings; (6) Each R4 is independently selected from H, D, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, halogenated, deuterated C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkyl, C 3-8 cycloalkyl, C 3-6 cycloalkyl C 1-6 Alkyl, C 1-6 Alkyl mercapto, halogenated C 1-6 Alkyl mercapto, halogen, cyano, oxo, unsubstituted or substituted 5-10 membered alicyclic or heterocyclic, where m is 1, 2, 3, 4 or 5; Alternatively, when m equals or is greater than 2, any two independent R4 groups are connected to the same or different carbon atoms and form an unsubstituted or substituted spirocyclic or fused ring with A, wherein the spirocyclic or fused ring independently comprises a carbocyclic or heterocyclic ring; wherein the substituents used for substitution are selected from one, two or more of the following groups: halogen, cyano, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy or deuterated C 1-6 Alkoxy; (7) P is selected from H or a group that shields the hydroxyl group; (8) Y is selected from CH, CD, N, CF or CCl; (9) The heteroatoms in the 4-6 membered heteroaromatic ring group, 5-10 membered aliphatic heteroaromatic ring group, and 5-10 membered heteroaromatic ring group are independently selected from one, two or more of O, S, Se, N, -SO2- and oxo; The heteroatoms in the 6-20 saturated heterocyclic groups and 6-20 unsaturated heterocyclic groups are all nitrogen, or independently contain nitrogen and one, two or more of O, S, -SO2- 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, A is selected from , , , , , , , , or .

3. The pyridone derivative or its stereoisomer, the prodrug of the pyridone derivative, or the pharmaceutically acceptable salt according to claim 2, characterized in that, Selected from , , , , , , , , , , or .

4. The pyridone derivative or its stereoisomer, prodrug, or pharmaceutically acceptable salt according to any one of claims 1-3, characterized in that, Each R4 is independently H, D, methyl, ethyl, propyl, deuterated methyl, deuterated ethyl, deuterated propyl, trifluoromethyl, difluoromethyl, monofluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, hydroxyl, methyl mercapto, ethyl mercapto, propyl mercapto, fluoromethyl mercapto, fluoroethyl mercapto, fluoropropyl mercapto, fluorine, chlorine, or bromine.

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, When there are 2, 3, 4, or 5 R4s, two of them form rings with the same or different carbon atoms attached to them, and the rings are selected from... , , , , , , or .

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, When X is N for , Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; Alternatively, when X is N, and R2 and R3 are both selected from D, for , Selected from , , or .

7. The pyridone derivative or its stereoisomer, the prodrug of the pyridone derivative, or a pharmaceutically acceptable salt according to claim 1, characterized in that, When X is CH, and R2 and R3 are H, for , Selected from , , , or .

8. The pyridone derivative or its stereoisomer, the prodrug of the pyridone derivative, or a pharmaceutically acceptable salt according to claim 1, characterized in that, When X is CH, and R2 and R3 are D, for , Selected from , , , , , or .

9. The pyridone derivative or its stereoisomer, the prodrug of the pyridone derivative, or a pharmaceutically acceptable salt according to claim 1, characterized in that, Q is selected from amides, or from unsubstituted or substituted five-membered heterocycles.

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, 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... , , , , , or .

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 described herein have the structures shown in formula (IA), formula (IB), or formula (IC): 、 、 ； In formula (IA), formula (IB) or formula (IC): R1, n, R2, R3, P, X, Y are defined as in claim 1; R 11 R 12 R 13 R 14 R 15 R 16 Independently selected from H, D, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkyl, C 3-8 cycloalkyl, C 3-6 cycloalkyl C 1-6 Alkyl, C 1-6 Alkyl mercapto, halogenated C 1-6 Alkyl mercapto, halogen, or cyano; Or R 11 R 12 The carbon atoms connected to each other and together form a 3-6 membered carbon ring, or an unsubstituted or substituted 3-12 membered heterocycle. The substituents used for substitution are one, two or more selected from the following groups: halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl C 1-6 Alkyl or halogenated C 1-6 Alkyl mercapto; Or R 13 R 14 The carbon atoms connected to each other and together form a 3-6 membered carbon ring, or an unsubstituted or substituted 3-12 membered heterocycle. The substituents used for substitution are one, two or more selected from the following groups: halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl C 1-6 Alkyl or halogenated C 1-6 Alkyl mercapto; Or R 15 R 16 The carbon atoms connected to each other together form an unsubstituted or substituted 4-6 membered heterocycle, wherein the substituents used for substitution are one, two or more selected from the following groups: halogen, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl C 1-6 Alkyl or halogenated C 1-6 Alkyl mercapto; The heteroatoms in the 3-12 membered heterocycles and 4-6 membered heterocycles are independently selected from one, two or more of O, S, N, -SO2- and oxo.

12. The pyridinone derivative or its stereoisomer, the prodrug of the pyridinone derivative, or a pharmaceutically acceptable salt according to claim 11, characterized in that, The pyridone derivatives described herein have the structures shown in formula (I-A1), formula (I-B1), or formula (I-C1): 、 、 ； In formula (I-A1), formula (I-B1), or formula (I-C1): R1, n, R2, R3, P, X, Y, R 11 R 12 R 13 R 14 R 15 R 16 The definition is the same as in claim 11.

13. The pyridinone derivative or its stereoisomer, prodrug, or pharmaceutically acceptable salt according to claim 11 or 12, characterized in that, R 11 R 12 Independently selected from H, D, methyl, ethyl, propyl, deuterated methyl, deuterated ethyl, deuterated propyl, trifluoromethyl, difluoromethyl, monofluoromethyl, fluoroethyl, fluoropropyl, cyclopropyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, methoxy, ethoxy, propoxy, or hydroxyl, and R 11 R 12 Not both H; Or, R 11 R 12 The carbon atoms connected to each other and together form unsubstituted or substituted groups as follows: , or The substituents used in the substitution are selected from one, two or more of the following groups: fluorine, chlorine, bromine, methyl, ethyl, propyl, trifluoromethyl, difluoromethyl, monofluoromethyl, fluoroethyl, fluoropropyl, methoxy, ethoxy, propoxy, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, fluoromethyl mercapto, fluoroethyl mercapto, or fluoropropyl mercapto.

14. The pyridinone derivative or its stereoisomer, prodrug, or pharmaceutically acceptable salt according to claim 11 or 12, characterized in that, R 13 R 14 Independently selected from H, D, methyl, ethyl, propyl, deuterated methyl, deuterated ethyl, deuterated propyl, trifluoromethyl, difluoromethyl, monofluoromethyl, fluoroethyl, fluoropropyl, methoxy, ethoxy, propoxy, or hydroxy, and R 13 R 14 Not both H; or, R 13 R 14 The carbon atoms connected to and jointly connected to each other constitute unsubstituted or substituted groups such as cyclopropyl, cyclobutyl, oxacyclobutyl, cyclopentyl, and cyclohexyl. The substituents used for substitution are selected from one, two, or more of the following groups: fluorine, chlorine, bromine, methyl, ethyl, propyl, trifluoromethyl, or difluoromethyl. And / or, R 15 R 16 The carbon atoms connected to each other and to which they are connected together form unsubstituted or substituted groups as follows: The substituents used for substitution are selected from one, two or more of the following groups: fluorine, chlorine, bromine, methyl, ethyl, propyl, trifluoromethyl or difluoromethyl.

15. The pyridinone derivative or its stereoisomer, the prodrug of the pyridinone derivative, or a pharmaceutically acceptable salt according to claim 11, characterized in that, The pyridone derivatives described herein have the structure shown in formula (ID): ， In formula (ID), R1, n, R2, R3, P, X, Y, R 11 R 12 The definition is the same as that in claim 11; Z is a single bond, CH2, O, or S, and E is CH2, CH2CH2, O, or S, and Z and E are not simultaneously O or S.

16. The pyridinone derivative or its stereoisomer, prodrug, or pharmaceutically acceptable salt according to claim 1 or 11, characterized in that, The pyridone derivatives described herein have the structures shown in formula (IE) or formula (IF): 、 ， In equations (IE) and (IF), R1, n, P, and X are defined as in claim 1, and R 11 R 12 R 13 R 14 Independently selected from H, D, C 1-6 Alkyl, deuterated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl, C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 1-6 Alkoxy C 1-3 Alkyl, C 3-8 cycloalkyl, C 3-6 cycloalkyl C 1-6 Alkyl, C 1-6 Alkyl mercapto, halogenated C 1-6 Alkyl mercapto, halogen, cyano, or R 11 and R 12 Or R 13 and R 14 The carbon atoms that are connected to each other and together form unsubstituted or substituted spiroheterocyclic groups or spirocycloalkyl groups.

17. The pyridinone derivative or its stereoisomer, prodrug, or pharmaceutically acceptable salt according to claim 1 or 11, characterized in that, Each R1 is independently selected from F, Cl, Br, hydroxy, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl or fluoroethyl, and n is 1, 2 or 3; and / or, R2 and R3 are independently selected from H or D; And / or, the shielding hydroxyl group includes C 6-20 OC(=O)-、C 6-20 C(=O)-、C 6-20 OCH2O-、 , , , , , or ; And / or, the prodrug refers to a compound that is metabolized into the original drug by chemical methods or by enzymes in the body through the metabolism of a group containing a shielded hydroxyl group; And / or, the pyridone derivative is the racemic form, R configuration, or S configuration of the corresponding compound.

18. The pyridone derivative or its stereoisomer, prodrug, or pharmaceutically acceptable salt according to claim 1 or 11, characterized in that, Selected from: , , , , , , , , , , , , , , , , , , , , , , , , or .

19. 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 or their stereoisomers are selected from the following compounds: ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， 。 20. A pharmaceutical composition comprising a pyridone derivative or its stereoisomer as described in any one of claims 1-19, 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, said one or more therapeutic agents being anti-HIV 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.

21. 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 20 in the preparation of a medicament for the prevention and / or treatment of viral infectious diseases; further, the medicament for the prevention and / or treatment of viral infectious diseases has a long-acting effect, and the medicament for the prevention and / or treatment of viral infectious diseases includes an oral formulation, an injectable formulation, or a topical formulation.

22. 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 20 in the preparation of a medicament for the prevention and / or treatment of HIV infection; further, the medicament for the prevention and / or treatment of HIV infection has a long-acting effect, and the medicament for the prevention and / or treatment of HIV infection includes an oral formulation, an injectable formulation, or a topical formulation.

23. 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 1-19, characterized in that, The intermediate has the structure shown in formula (Ⅳ), formula (Ⅴ), formula (Ⅵ) or formula (Ⅶ): 、 、 、 ； The definitions of R1, n, R2, R3, R4, X, and Q are the same as in claim 1; R 11 R 12 R 13 R 14 The definition is the same as in claim 11; R 17 It is an H or hydroxyl protecting group.

24. The intermediate according to claim 23, characterized in that, The intermediate has the structure shown in formula (Ⅳ-1), formula (Ⅳ-2), formula (Ⅴ-1), formula (Ⅴ-2), formula (Ⅴ-3), formula (Ⅵ-1), or formula (Ⅶ-1): 、 、 、 、 、 、 。 25. 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 1-19, characterized in that, The intermediate is selected from the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。

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