Patent Description:
Nuclear receptors are widely present in organisms and are a type of nuclear transcription regulators that rely on specific ligand activation. Metabolic nuclear receptors are a type of nuclear receptors that regulate substance metabolism, cell proliferation, and apoptosis in the body. Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily, which was first discovered by Foman et al. in <NUM> and named because its transcriptional activity can be enhanced by farnesoid.

The FXR structure contains ligand-independent transcription activation function domain (AF1) at amino-terminal, DNA binding domain (DBD), hinge region, ligand binding domain (LBD) and ligand-dependent transcription activation function domain (AF2) at carbon-terminal, which is a typical nuclear receptor structure. FXR is activated by bile acids in the body and participates in the processes of bile acid metabolism, lipid metabolism, and sugar metabolism in the living body. The mechanism by which FXR regulates bile acid metabolism and transport is mainly accomplished by regulating the transcription of cholesterol 7α-hydroxylase (CYP7A1) which is a rate-limiting enzyme of bile acid synthesis. Although FXR cannot directly act on the CYP7A1 promoter, it can induce the expression of small heterodimer partner (SHP) and combine HNF-4α (hepatocyte nuclear factor 4α) and LRH-<NUM> (liver receptor homolog) to down-regulate the transcription of CYP7A1. In the process of lipid metabolism, FXR in the liver regulates lipid metabolism and transport to reduce plasma free fatty acids and triglycerides by directly or indirectly regulating PPARα, VLDL receptor (very low density lipoprotein receptor, VLDLR), proprotein convertase subtilisin kexin type <NUM> (PCSK9), scavenger receptor group B type <NUM> (SRB1), phosphor lipid transfer protein (PLTP), liver X receptor (LXR), sterol regulatory element-binding protein-1C (SREBP-1C) and fatty acid synthetase (FAS), and activating lipoprotein lipase (LPL) and the like. In the process of glucose metabolism, the activation of FXR can promote liver glycogen synthesis and increase insulin sensitivity and insulin secretion to control blood glucose levels in the body. Since FXR plays an important role in the processes of bile acid metabolism, lipid metabolism and glucose metabolism, FXR ligand small molecule compounds are expected to be used as new medicament for the treatment of hypertriglyceridemia, type <NUM> diabetes, metabolic syndrome, NAFLD and other metabolic-related diseases.

<CIT>describes compounds that modulate the farnesoid X receptor (FXR), which can be used to treat related disorders and conditions such as liver disease, hyperlipidemia, hypercholesteremia, obesity, metabolic syndrome, cardiovascular disease, gastrointestinal disease, and atherosclerosis, and renal disease. It outlines the chemical structures and methods of synthesis of these compounds.

<CIT>relates to activators of FXR useful in the treatment of autoimmune disorders, liver disease, intestinal disease, kid ney disease, cancer, and other diseases in which FXR plays a role. It outlines the chemical structures, methods of synthesis of these compounds and their therapeutic applications.

The present invention and its preferred embodiments are apparent from the appendant set of claims.

In the first aspect of the present invention, it provides a compound represented by general formula I, or enantiomer, diastereomer, tautomer, racemate, solvate, or pharmaceutically acceptable salt thereof,
<CHM>.

In another preferred example, R<NUM> is phenyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl or cyclopentyl.

In the present invention, when there are two or more substituents, each substituent is the same or different.

In another preferred example, A is
<CHM>.

In another preferred example, the pharmaceutically acceptable salt in the present invention refers to a salt formed from inorganic acid such as phosphoric acid, sulfuric acid, hydrochloric acid, etc., or from organic acid such as acetic acid, tartaric acid, citric acid, malic acid, etc., or from acidic amino acid such as aspartic acid, glutamic acid, etc.; or a salt formed from inorganic base, such as sodium, potassium, calcium, aluminum and ammonium salts.

In another preferred example, the compound is:
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>.

The compound of the present invention has an asymmetric center, a chiral axis, and a chiral plane, and can exist in the form of racemate, R-isomer, or S-isomer. Those skilled in the art can use conventional technical means to obtain R-isomer and/or S-isomer from racemate resolution.

In the second aspect of the present invention, it provides a method for preparing the compound according to the first aspect, which includes the following steps:
<CHM>.

In another preferred example, the compound represented by general formula VII is prepared by the following steps:
<CHM>
<CHM>.

in each formula, the definitions of R<NUM>, Q, A, R<NUM>, R<NUM>, R<NUM>, R<NUM> and R<NUM> are described as above.

In another preferred example, the compound represented by general formula VII is prepared by the following steps:
<CHM>.

In the third aspect of the present invention, it provides a pharmaceutical composition, comprising:.

The compound provided by the present invention can be used alone or mixed with pharmaceutically acceptable auxiliary material (such as excipient, diluent, etc.) to prepare tablet, capsule, granule or syrup for oral administration. The pharmaceutical composition can be prepared according to conventional methods in pharmacy.

In the fourth aspect of the present invention, it provides the compound represented by the general formula I or pharmaceutically acceptable salt thereof as as outlined above for use.

In another preferred example, the FXR-related disease is a disease related to bile acid metabolism, carbohydrate metabolism, lipid metabolism, inflammation, and/or liver fibrosis.

In another preferred example, the FXR-related disease is non-alcoholic fatty liver (NASH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), gallstone, non-alcoholic liver cirrhosis, liver fibrosis, cholestatic liver disease, hyperlipidemia, hypercholesterolemia, or diabetes.

It should be understood that each of the above technical features of the present invention and each of the technical features specifically described below (e.g., examples) can be combined with each other, as long as the resulting combination is according to the invention as defined in the appended claims.

After extensive and intensive researches, the inventors of the present application developed a class of non-steroidal compounds that can be used as FXR agonist, which have the ability to agonize FXR at the molecular and cellular levels. Studies have shown that the compounds of the present application can reduce ALP, ALT, AST, and TBA levels in serum, reduce the amount of hydroxyproline in the liver tissue, down-regulate the expression of α-SMA and Col1α1 mRNA in the liver tissue, and reduce the content of collagen in the liver. The compound of the present invention has the advantages of high FXR agonistic activity, simple synthesis, easy availability of raw materials, etc., and can be used for the manufacture of a medicament for treating FXR-related diseases. On this basis, the present invention has been completed.

In the present invention, the halogen is F, Cl, Br or I.

In the present invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

In the present invention, the term "C<NUM>-C<NUM>" refers to <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM> carbon atoms, and "C<NUM>-C<NUM>" refers to <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM> carbon atoms, and so on. "<NUM>-<NUM> membered" refers to <NUM>-<NUM> ring atoms, and so on.

In the present invention, the term "alkyl" refers to a saturated linear or branched hydrocarbon moiety. For example, the term "C<NUM>-C<NUM> alkyl" refers to a straight or branched chain alkyl having <NUM> to <NUM> carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, etc.; preferably ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

In the present invention, the term "alkoxy" means -O-(C<NUM>-C<NUM> alkyl) group. For example, the term "C<NUM>-C<NUM> alkoxy" refers to a straight or branched chain alkoxy having <NUM> to <NUM> carbon atoms, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, butoxy and so on.

In the present invention, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon moiety, for example, the term "C<NUM>-C<NUM> cycloalkyl" refers to a cyclic alkyl group having <NUM> to <NUM> carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and the like. The terms "C<NUM>-C<NUM> cycloalkyl", "C<NUM>-C<NUM> cycloalkyl" and "C<NUM>-C<NUM> cycloalkyl" have similar meanings.

In the present invention, the term "cycloalkoxy" means cycloalkyl-O-, and cycloalkyl is described as above.

In the present invention, the term "<NUM>-<NUM> membered nitrogen-containing heterocyclyl" refers to a cycloalkyl ring having <NUM>-<NUM> ring atoms and containing <NUM>, <NUM> or <NUM> N atoms, and includes, but not limited to, azacyclopentane ring, azacyclohexane ring, azacycloheptane ring and the like.

In the present invention, the term "aryl" means a hydrocarbyl moiety containing one or more aromatic rings. For example, the term "C<NUM>-C<NUM> aryl" refers to an aromatic ring group with <NUM> to <NUM> carbon atoms that does not contain heteroatoms in the ring, such as phenyl, naphthyl and the like. The term "C<NUM>-C<NUM> aryl" has a similar meaning. Examples of aryl include, but are not limited to, phenyl (Ph), naphthyl, pyrenyl, anthracenyl, and phenanthryl.

In the present invention, the term "heteroaryl" means a moiety containing one or more aromatic rings with at least one heteroatom (such as N, O or S), for example, the term "<NUM>-<NUM> membered heterocyclyl" means a saturated or unsaturated <NUM>-<NUM> membered ring group containing <NUM> to <NUM> heteroatoms selected from oxygen, sulfur and nitrogen on the ring, such as dioxolyl and the like. The term "<NUM>-<NUM> membered heterocyclyl" has a similar meaning. Examples of heteroaryl groups include furyl, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolinyl, isoquinolinyl, and indolyl.

In the present invention, the term "heterocyclyl" means a cyclic group containing at least one ring heteroatom (such as N, O or S), such as furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, pyrimidinyl, tetrahydropyridyl, pyrrolinyl, dihydropyridyl, dihydrofuranyl, dihydrothienyl, pyranyl.

Unless otherwise specified, the alkyl, alkoxy, cycloalkyl, heterocyclyl, and aryl described herein are substituted and unsubstituted groups. Possible substituents on alkyl, alkoxy, cycloalkyl, heterocyclyl and aryl include, but are not limited to: hydroxyl, amino, nitro, cyano, halogen, C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> alkenyl, C<NUM>-C<NUM> alkynyl, C<NUM>-C<NUM> cycloalkyl, C<NUM>-C<NUM> cycloalkenyl, C<NUM>-C<NUM> heterocycloalkyl, C<NUM>-C<NUM> heterocycloalkenyl, C<NUM>-C<NUM> alkoxy, aryl, heteroaryl, heteroaryloxy, C<NUM>-C<NUM> alkylamino, C<NUM>-C<NUM> dialkylamino, arylamino, diarylamino, C<NUM>-C<NUM> alkylsulfamoyl, arylsulfamoyl, C<NUM>-C<NUM> alkylimino, C<NUM>-C<NUM> alkylsulfoimino, arylsulfoimino, mercapto, C<NUM>-C<NUM> alkylthio, C<NUM>-C<NUM> alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, guanidinyl, ureido, cyano, acyl, thioacyl, acyloxy, carboxyl and carboxylate group. On the other hand, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl may also be fused to each other.

In the present invention, the substitution is mono-substitution or poly-substitution, and the poly-substitution is di-substitution, tri-substitution, tetra-substitution, or penta-substitution. The di-substitution means that there are two substituents, and so on.

The pharmaceutically acceptable salt of the present invention may be a salt formed by an anion and a positively charged group on the compound of formula I. Suitable anion is chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methane sulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate or maleate ion. Similarly, a salt can be formed from a cation and a negatively charged group on the compound of formula I. Suitable cation includes sodium ion, potassium ion, magnesium ion, calcium ion and ammonium ion, such as tetramethylammonium ion.

In another preferred example, "pharmaceutically acceptable salt" refers to a salt formed by a compound of formula I and an acid selected from the group consisting of hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, aminosulfonic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, <NUM>-acetoxybenzoic acid and isethionic acid, etc.; or sodium salt, potassium salt, calcium salt, aluminum salt or ammonium salt formed by a compound of formula I and inorganic base; or methylamine salt, ethylamine salt or ethanolamine salt formed by a compound of general formula I and organic base.

The preparation method of the compound represented by the general formula I of the present invention, the synthetic route is as follows:
<CHM>
<CHM>
<CHM>.

The preparation method includes the following steps:.

The cyano compound represented by the general formula VII can also be prepared by the above route, including the following steps:.

The alkali in steps a), b), d), a'), f) and g) is selected from triethylamine, diisopropylethylamine, pyridine, <NUM>-dimethylaminopyridine, <NUM>,<NUM>-diazabicycloundec-<NUM>-ene, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, sodium tert-butoxide, butyl lithium, lithium diisopropylamide.

The alkali in step b) is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, DBU, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, and potassium ethoxide.

The reducing agent in step c) is selected from the group consisting of sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium aluminum hydride, diisopropyl aluminum hydride, and borane.

The copper catalyst in step e) is cuprous iodide, cuprous oxide, and cuprous sulfate; the palladium catalyst is palladium acetate, tetrakis(triphenylphosphine) palladium, bis(acetonitrile) palladium (II) chloride, dichloride palladium, tris(dibenzylideneacetone)dipalladium, bistriphenylphosphorus palladium dichloride, tris(dibenzylideneacetone)dipalladium-chloroform adduct, <NUM>,<NUM>'-bis(diphenylphosphino) ferrocene palladium(II) dichloride.

The present invention also provides a pharmaceutical composition, which contains active ingredient in a safe and effective amount, and a pharmaceutically acceptable carrier.

The "active ingredient" in the present invention refers to the compound of formula I in the present invention.

The present invention also relates to the "active ingredient" and pharmaceutical composition of the present invention for use:.

"Safe and effective amount" means that the amount of the active ingredient is sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains <NUM>-<NUM> of active ingredient/dose, more preferably, <NUM>-<NUM> of active ingredient/dose. Preferably, the "one dose" is a tablet.

"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility" herein means that each component in the composition can be blended with each other and can be blended with the active ingredient of the present invention without significantly reducing the efficacy of the active ingredient.

Examples of pharmaceutically acceptable carriers include cellulose and derivatives thereof (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as Tween®), Wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water and the like.

The administration method of the active ingredient or the pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral administration, intratumoral administration, rectal administration, parenteral (intravenous, intramuscular, or subcutaneous) administration and the like.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, <NUM>,<NUM>-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances. In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying agents and suspending agents, sweetening agents, flavoring agents and perfumes.

In addition to the active ingredient, the suspension may contain suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitan ester, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.

The composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyol and suitable mixtures thereof.

The compound of the present invention can be administered alone or in combination with other therapeutic drugs (such as hypolipidemic drugs).

When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is administered to the mammal (such as a human) in need of treatment, wherein the dosage at which the drug is administered is the pharmaceutically effective administration dosage. For a person of <NUM> body weight, the daily dose is usually <NUM>-<NUM>, and <NUM>-<NUM> is preferred. Centainly, the specific dosage should be determined by considering factors such as the route of administration, the patient's health status, etc., which are within the skill range of a skilled physician.

The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention. The experimental methods without specific conditions in the following examples generally follow the conventional conditions (eg. the conditions described in<NPL>)) or the conditions recommended by the manufacturer. Unless stated otherwise, percentages and parts are percentages by weight and parts by weight.

Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to the skilled in the art. In addition, any methods and materials similar to or equivalent to those described can be applied to the method of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

The instruments and main experimental materials used are as follows.

The reagents and anhydrous solvents used were purchased from Chinese commercial companies. Unless otherwise specified, they were used directly. <NUM>H and <NUM>C NMR were measured by BrukerAM-<NUM> and Varian Mercury plus-<NUM> nuclear magnetic resonance instruments, and mass spectrometry was measured by Agilent <NUM> mass spectrometer and <NUM>- <NUM> mesh of column chromatography silica gel (Qingdao Ocean Chemical Factory), HSGF254 TLC plate (Yantai Chemical Industry Research Institute). <CHM>
<CHM>
<CHM>.

At <NUM>, aqueous potassium carbonate solution (<NUM> N, <NUM> mmol) was added dropwise to a stirring solution of hydroxylamine hydrochloride (<NUM> mmol) in ethanol (<NUM>), <NUM>,<NUM>-dichlorobenzaldehyde (<NUM>, <NUM> mmol) was dissolved in <NUM> of ethanol, and then added to the hydroxylamine solution. The temperature was raised to <NUM> and the mixture was reacted for two hours. The mixture was cooled to room temperature and then concentrated to a solid. A water/ethanol (<NUM>/<NUM>) solution was added and the solid was stirred to break up, filtered, and dried under vacuum at <NUM> overnight to obtain a compound intermediate (<NUM>). This intermediate was dissolved in N,N-dimethylformamide (<NUM>), and added dropwise to N-chlorosuccinimide (<NUM> mmol) solution in N,N-dimethylformamide (<NUM>) at <NUM> and stirred overnight. The reaction solution was poured into ice water at <NUM>, and then extracted with methyl tert-butyl ether (<NUM> each time, <NUM> times in total), the organic phase was washed with saturated brine, and concentrated to obtain a crude product. N-hexane (<NUM>) was added to the flask containing the crude product, stirred with a magnetic stir bar, filter, and the solid was dried under vacuum (<NUM>. ) to obtain Intermediate III-<NUM> (<NUM>, yield <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Triethylamine (<NUM>) was added to methyl <NUM>-cyclopropyl-<NUM>-oxopropionate (<NUM> mmol) and stirred for <NUM> minutes. Then the mixture was cooled to <NUM>, and a solution of III-<NUM> (<NUM>, <NUM> mmol) in absolute ethanol (<NUM>) was added dropwise (internal temperature did not exceed <NUM>), and the reaction was kept overnight at room temperature. The reaction solution was diluted by adding ethyl acetate (<NUM>), washed with water, and the aqueous phase was extracted with ethyl acetate (<NUM> each time, <NUM> times in total). The organic phases were mixed, washed with saturated brine, and concentrated. <NUM> of ether was added to the concentrate and stirred, and the solvent was removed under vacuum to obtain solid product IV-<NUM> (<NUM>, yield <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

IV-<NUM> (<NUM>, <NUM> mmol) was dissolved in tetrahydrofuran (<NUM>) and cooled to <NUM>. A solution of diisobutylaluminum hydride (<NUM>, <NUM>) in toluene was slowly added and the reaction solution is stirred at room temperature for <NUM>. The reaction solution was slowly poured into ice water, and <NUM> aqueous hydrochloric acid solution was added to adjust the pH to about <NUM>. The mixture was extracted with ethyl acetate (<NUM> each time, three times in total), concentrated, and subjected to column chromatography to obtain the intermediate alcohol. This intermediate and triphenyl phosphine (<NUM> mmol) were dissolved in dichloromethane (<NUM>) and cooled to <NUM>, and a solution of carbon tetrabromide (<NUM> mmol) in dichloromethane (<NUM>) was added dropwise under the protection of nitrogen and reacted at room temperature for <NUM>. The solvent was removed from the reaction solution to obtain an oily substance, which was subjected to column chromatography to obtain intermediate V-<NUM> (<NUM>, yield <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

At <NUM>, potassium tert-butoxide (<NUM> mmol) was added to a solution of tert-butyl <NUM>-hydroxypiperidine-<NUM>-carboxylate (<NUM>, <NUM> mmol) in anhydrous tetrahydrofuran (<NUM>) and stirred for <NUM> minutes, and then a solution of V-<NUM> (<NUM> mmol) in anhydrous tetrahydrofuran (<NUM>) was added dropwise, and the reaction was carried out for <NUM>. Water (<NUM>) was added to the reaction solution, extracted with ethyl acetate (<NUM> each time, <NUM> times in total), the organic phase was washed with saturated brine, concentrated, and subjected to column chromatography to obtain intermediate tert-butyl <NUM>-((<NUM>-cyclopropyl)-<NUM>-(<NUM>,<NUM>-dichlorophenyl)isoxazol-<NUM>-yl)methoxy)piperidine-<NUM>-carboxylate (<NUM>). Intermediate tert-butyl <NUM>-((<NUM>-cyclopropyl)-<NUM>-(<NUM>,<NUM>-dichlorophenyl)isoxazol-<NUM>-yl)methoxy)piperidine-<NUM>-carboxylate (<NUM> , <NUM> mmol) was dissolved in dichloromethane (<NUM>)and cooled to <NUM>, and trifluoroacetic acid (<NUM>) was added dropwise and stirred at room temperature for <NUM>. The solvent was removed under vacuum, and the residue was dissolved in ethyl acetate (<NUM>), washed with <NUM> N sodium hydroxide solution, saturated brine, and the solvent was removed to obtain intermediate VI-<NUM> (<NUM>, yield <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Intermediate VI-<NUM> (<NUM>, <NUM> mmol), <NUM>-bromobenzonitrile (<NUM> mmol), sodium tert-butoxide (<NUM> mmol), palladium acetate (<NUM> mmol), and <NUM>,<NUM>'-binaphthalene-<NUM>,<NUM>'-bisdiphenylphosphine (<NUM> mmol) were added to a round bottom flask, and toluene (<NUM>) was added under the protection of nitrogen, heated to reflux, and reacted overnight. The reaction solution was cooled to room temperature, and added with water, extracted, concentrated, and subjected to column chromatography to obtain intermediate VII-<NUM> (<NUM>, yield <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>- <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (qt, J = <NUM>, <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>).

VII-<NUM> (<NUM>, <NUM> mmol), hydroxylamine hydrochloride (<NUM> mmol), and absolute ethanol (<NUM>) were added into a round bottom flask and stirred. Triethylamine (<NUM> mmol) was slowly added dropwise, and heated to <NUM> to react for <NUM>. After the mixture was cooled to room temperature, the solvent was removed, and the residue was dissolved in ethyl acetate (<NUM>), and washed with water and saturated brine. The organic phase was concentrated, and subjected to silica gel column chromatography to obtain intermediate <NUM>-(<NUM>-((<NUM>-cyclopropyl-<NUM>-(<NUM>,<NUM>-dichlorophenyl)isoxazol-<NUM>-yl)methoxy)piperidin-<NUM>-yl)-N'-hydro xybenzamidine VIII-<NUM> (<NUM>, yield <NUM>% ).

<NUM>-(<NUM>-((<NUM>-cyclopropyl-<NUM>-(<NUM>,<NUM>-dichlorophenyl)isoxazol-<NUM>-yl)methoxy)piperidin-<NUM>-yl)-N'-h ydroxybenzamidine VIII-<NUM> (<NUM>, <NUM> mmol), N,N'-carbonyldiimidazole (<NUM> mmol), and <NUM>,<NUM>-dioxane (<NUM>) were added to a round bottom flask, and then <NUM>,<NUM>-diazabicyclo[<NUM>. <NUM>]undec-<NUM>-ene (<NUM> mmol) was added, heated to <NUM> and reacted for <NUM> hours. The reaction solution was cooled to room temperature, diluted with water (<NUM>), adjusted to pH approximately equal to <NUM> with a <NUM> aqueous hydrochloric acid solution, and then extracted with ethyl acetate (<NUM> each time, <NUM> times in total). The organic phases were combined, washed with saturated brine, and concentrated and the crude product obtained was subjected to silica gel column chromatography to obtain the final product <NUM> (<NUM>, yield <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>). MS(ESI, m/z): <NUM>[M+H]+.

Example <NUM> was carried out by referring to the operation of example <NUM>. The compound was prepared from intermediate VI-<NUM> via route <NUM>. The synthetic route was as follows.

Compound <NUM> was synthesized from raw material VI-<NUM> according to the synthetic method of compound <NUM>, wherein
VIII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS (EI,m/z): <NUM>[M-H]+.

Compound <NUM>, white solid, yield <NUM>%, <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (tt, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (m, <NUM>); MS(ESI,m/z): <NUM>[M+H]+.

Example <NUM> was carried out by referring to the operation of example <NUM>. The compound was prepared from intermediate V-<NUM> via route <NUM>. The synthetic route was as follows.

At <NUM>, potassium tert-butoxide (<NUM> mmol) was added to a solution of tert-butyl <NUM>-hydroxyhexahydroazepine-<NUM>-carboxylate (<NUM> mmol) in anhydrous tetrahydrofuran (<NUM>) and stirred for <NUM> minutes, and then a solution of V-<NUM> (<NUM> mmol) in anhydrous tetrahydrofuran (<NUM>) was added dropwise, and the reaction was carried out for <NUM>. Water (<NUM>) was added to the reaction solution, which was then extracted with ethyl acetate (<NUM> each time, <NUM> times in total). The organic phase was washed with saturated brine, concentrated, and subjected to column chromatography to obtain an intermediate. The intermediate was dissolved in dichloromethane (<NUM>) and cooled to <NUM>, and trifluoroacetic acid (<NUM>) was added dropwise, and stirred at room temperature for <NUM>. The solvent was removed under vacuum, ethyl acetate (<NUM>) was added to dissolve, washed with 2N sodium hydroxide solution, saturated brine, and the solvent was removed to obtain intermediate VI-<NUM> (<NUM>, yield <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Intermediate VI-<NUM> (<NUM>), <NUM>-bromobenzonitrile (<NUM> mmol), sodium tert-butoxide (<NUM> mmol), palladium acetate (<NUM> mmol), and <NUM>,<NUM>'-binaphthyl-<NUM>,<NUM>'-bisdiphenylphosphine (<NUM> mmol) were added to a round bottom flask, and toluene (<NUM>) was added under the protection of nitrogen, heated to reflux, and reacted overnight. The reaction solution was cooled to room temperature and water was added. The mixture was extracted, concentrated, and subjected to column chromatography to obtain intermediate VII-<NUM> (<NUM>, yield <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, yield <NUM>%, <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM>[M+H]+.

Example <NUM> was carried out by referring to the operation of example <NUM>. The compound was prepared from intermediate VI-<NUM> via route <NUM>. The synthetic route was as follows.

Compound <NUM> was synthesized from VI-<NUM> as the raw material according to the synthesis method of compound <NUM>, wherein,
VII-<NUM>, white solid, yield <NUM>%, <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM>, white solid, yield <NUM>%, <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM>[M+H]+.

Compound <NUM> was synthesized from V-<NUM> as the raw material according to the synthesis method of compound <NUM>, wherein.

Compound <NUM> was synthesized from VI-<NUM> as the raw material according to the synthesis method of compound <NUM>, wherein,
VII-<NUM>, white solid, yield <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

<NUM>, white solid, yield <NUM>%. <NUM>H NMR (<NUM>, DMSO-d6) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM>[M+H]+.

Compound <NUM> was synthesized from V-<NUM> as the raw material according to the synthesis method of compound <NUM>, wherein,.

<NUM>, white solid, yield <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM>[M+H]+.

Example <NUM>, i.e., the preparation of LXF-<NUM> was carried out by referring to the operation of example <NUM>. The compound was prepared from intermediate II-<NUM> via route <NUM>. The synthetic route was as follows.

Compound <NUM> was synthesized from II-<NUM> as the raw material according to the synthesis method of compound <NUM>, wherein,.

<NUM>, white solid, yield <NUM>%. <NUM>H NMR (<NUM>, DMSO-d6) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM>[M+H]+.

Example <NUM> was carried out by referring to the operation of example <NUM>. The compound was prepared from intermediate II-<NUM> via route <NUM>. The synthetic route was as follows.

<NUM>, white solid, yield <NUM>%. <NUM>H NMR (<NUM>, DMSO) δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(EsI,m/z): <NUM>[M+H]+.

The synthetic route of example <NUM> was as follows.

At <NUM>, sodium methoxide/methanol solution (<NUM>, <NUM>) was slowly added dropwise into a solution of methyl acetoacetate (<NUM> mmol) in anhydrous tetrahydrofuran (<NUM>), and then a solution of III-<NUM> (<NUM>, <NUM> mmol) ) in anhydrous tetrahydrofuran (<NUM>) was added and stirred at room temperature for <NUM>. Ethyl acetate (<NUM>) was added to the reaction solution, the organic phase was washed with water and saturated brine, and the solvent was removed to obtain an oily substance, which was then subjected to column chromatography to obtain intermediate IV-<NUM> (<NUM>, yield <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

<NUM>-fluorobenzonitrile (<NUM>, <NUM> mmol), <NUM>-hydroxypiperidine (<NUM> mmol), anhydrous potassium carbonate (<NUM> mmol) and DMSO (<NUM>) were added to a round bottom flask, heated to <NUM>, and reacted for <NUM>. The mixture was cooled to room temperature, added with <NUM> of water, and filtered. The solid was washed with water to obtain intermediate IX-<NUM> (<NUM>, yield <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

The compound intermediate V-<NUM> was synthesized by IV-<NUM> as the raw material according to the synthesis method of the compound V-<NUM>. At <NUM>, potassium tert-butoxide (<NUM> mmol) was added to a solution of IX-<NUM> (<NUM>, <NUM> mmol) in anhydrous tetrahydrofuran (<NUM>) and stirred for <NUM> minutes, and then a solution of V-<NUM> (<NUM> mmol) in anhydrous tetrahydrofuran (<NUM>) was added dropwise and reacted for <NUM>. Water (<NUM>) was added to the reaction solution, which was then extracted with ethyl acetate (<NUM> × <NUM>). The organic phase was washed with saturated brine, concentrated, and subjected to column chromatography to obtain intermediate VII-<NUM> (<NUM>, yield <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM>[M+H]+.

Compound intermediate IV-<NUM>( yield <NUM>%) was synthesized from III-<NUM> as the raw material according to the synthesis method of compound IV-<NUM>, wherein, methyl acetoacetate was replaced by methyl isobutyryl acetate. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Compound intermediate VII-<NUM> was synthesized from IV-<NUM> as the raw material according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>). MS(ESI,m/z): <NUM>[M+H]+.

Compound intermediate IV-<NUM> ( yield <NUM>%) was synthesized from III-<NUM> as the raw material according to the synthesis method of compound IV-<NUM>, wherein, methyl acetoacetate was replaced by methyl benzoylacetate. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>).

Compound intermediate VII-<NUM> was synthesized from IV-<NUM> as the raw material according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ7. <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI, m/z): <NUM>[M+H]+.

Compound intermediate IX-<NUM> was synthesized from <NUM>-hydroxypiperidine as the raw material according to the synthesis method of compound IX-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound intermediate VII-<NUM> was synthesized from V-<NUM> as the raw material according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM>[M+H]+.

Compound intermediate IX-<NUM> was synthesized from <NUM>-hydroxypiperidine as the raw material according to the synthesis method of compound IX-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound intermediate VII-<NUM> was synthesized from V-<NUM> as the raw material according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM>[M+H]+.

Compound intermediate IX-<NUM> was synthesized from <NUM>-hydroxypiperidine as the raw material according to the synthesis method of compound IX-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound intermediate VII-<NUM> was synthesized from V-<NUM> as the raw material according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>),<NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM>[M+H]+.

Compound intermediate IX-<NUM> was synthesized from <NUM>-hydroxypiperidine as the raw material according to the synthesis method of compound IX-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound intermediate VII-<NUM> was synthesized from V-<NUM> as the raw material according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM>[M+H]+.

Compound intermediate IX-<NUM> was synthesized from <NUM>-hydroxypiperidine as the raw material according to the synthesis method of compound IX-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM>[M+H]+.

Compound intermediate IX-<NUM> was synthesized from <NUM>-hydroxypiperidine as the raw material according to the synthesis method of compound IX-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, DMSO) δ <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound intermediate VII-<NUM> was synthesized from V-<NUM> as the raw material according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m,<NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM> [M+H]+.

Compound intermediate VII-<NUM> was synthesized from VI-<NUM> as the raw material according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, DMSO-d6) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM> [M+H]+.

VIII-<NUM> (<NUM>, <NUM> mmol), N,N'-thiocarbonyldiimidazole (<NUM> mmol) and <NUM>,<NUM>-dioxane (<NUM>) were added into a round bottom flask, and then <NUM>,<NUM>-diazabicyclic[<NUM>. <NUM>]undecarbon-<NUM>-ene (<NUM> mmol) was heated to <NUM> and reacted for <NUM> hours. The reaction solution was cooled to room temperature, diluted with water (<NUM>), adjusted to pH approximately equal to <NUM> with a <NUM> aqueous hydrochloric acid solution, and then extracted with ethyl acetate (<NUM> each time, <NUM> times in total). The organic phases were combined, washed with saturated brine, concentrated and the crude product obtained was subjected to silica gel column chromatography to obtain the final product <NUM> (<NUM>, yield <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM> [M+H]+.

Compound intermediate VII-<NUM> was synthesized from V-<NUM> and IX-<NUM> as the raw materials according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, DMSO) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m,<NUM>), <NUM> - <NUM> (m,<NUM>). MS(ESI,m/z): <NUM> [M+H]+.

Compound intermediate VII-<NUM> was synthesized from V-<NUM> and IX-<NUM> as the raw materials according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, DMSO) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM> [M+H]+.

Compound intermediate VII-<NUM> was synthesized from V-<NUM> and IX-<NUM> as the raw materials according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, DMSO) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM> [M+H]+.

Compound intermediate VII-<NUM> was synthesized from V-<NUM> and IX-<NUM> as the raw materials according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, DMSO) δ <NUM> (d, J = <NUM>, <NUM>), <NUM>- <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (mS, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM> [M+H]+.

Compound intermediate VII-<NUM> was synthesized from V-<NUM> and IX-<NUM> as the raw materials according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, DMSO) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM> [M+H]+.

Compound intermediate VII-<NUM> was synthesized from V-<NUM> and IX-<NUM> as the raw materials according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, DMSO) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM> [M+H]+.

Compound intermediate VII-<NUM> was synthesized from V-<NUM> and IX-<NUM> as the raw materials according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, DMSO) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM> [M+H]+.

Compound intermediate VII-<NUM> was synthesized from V-<NUM> and IX-<NUM> as the raw materials according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, DMSO) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM> [M+H]+.

Compound intermediate VII-<NUM> was synthesized from V-<NUM> and IX-<NUM> as the raw materials according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, DMSO) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM> [M+H]+.

Compound intermediate VII-<NUM> was synthesized from V-<NUM> and IX-<NUM> as the raw materials according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, DMSO) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM> [M+H]+.

Compound intermediate IX-<NUM> was synthesized from nortropine as the raw material according to the synthesis method of compound IX-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>);.

Compound V-<NUM> was synthesized from II-<NUM> as the raw material according to the synthesis method of compound <NUM>, wherein,.

Compound intermediate VII-<NUM> was synthesized from V-<NUM> and IX-<NUM> as the raw materials according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%. <NUM>H NMR (<NUM>, DMSO) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM>[M+H]+.

Compound intermediate VII-<NUM> was synthesized from V-<NUM> and IX-<NUM> as the raw materials according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, DMSO) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM> [M+H]+.

Compound intermediate VII-<NUM> was synthesized from V-<NUM> and IX-<NUM> as the raw materials according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, DMSO) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM> [M+H]+.

Compound intermediate VII-<NUM> was synthesized from V-<NUM> and IX-<NUM> as the raw materials according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, DMSO) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM> [M+H]+.

Compound intermediate IX-<NUM> was synthesized from nortropine as the raw material according to the synthesis method of compound IX-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>);.

Compound intermediate VII-<NUM> was synthesized from V-<NUM> and IX-<NUM> as the raw materials according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>. White solid, yield <NUM>%; <NUM>H NMR (<NUM>, DMSO) δ <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM> [M+H]+.

Compound intermediate VII-<NUM> was synthesized from V-<NUM> and IX-<NUM> as the raw materials according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, DMSO) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM>. - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM> [M+H]+.

Compound intermediate VII-<NUM> was synthesized from V-<NUM> and IX-<NUM> as the raw materials according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, DMSO) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM> [M+H]+.

Compound intermediate VII-<NUM> was synthesized from V-<NUM> and IX-<NUM> as the raw materials according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%; <NUM>H NMR (<NUM>, DMSO) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM> [M+H]+.

Compound intermediate VII-<NUM> was synthesized from V-<NUM> and IX-<NUM> as the raw materials according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%. <NUM>H NMR (<NUM>, DMSO) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM>[M+H]+.

Compound intermediate VII-<NUM> was synthesized from V-<NUM> and IX-<NUM> as the raw materials according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%. <NUM>H NMR (<NUM>, DMSO) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM>[M+H]+.

Compound intermediate VII-<NUM> was synthesized from V-<NUM> and IX-<NUM> as the raw materials according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%. <NUM>H NMR (<NUM>, DMSO) δ <NUM> (td, J = <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM>[M+H]+.

Compound intermediate VII-<NUM> was synthesized from V-<NUM> and IX-<NUM> as the raw materials according to the synthesis method of compound VII-<NUM>, white solid, yield <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Compound <NUM> was synthesized from VII-<NUM> as the raw material according to the synthesis method of compound <NUM>, white solid, yield <NUM>%. <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI,m/z): <NUM>[M+H]+.

FXR activity was determined using recombinant GST-FXR fusion protein by Perkin Elmer's AlphaScreen detection reagent. The reaction in this method was carried out in a <NUM>-well plate, and the total reaction volume was <NUM>µL. The mixture of protein, agonist, co-regulatory factor, AlphaScreen® acceptor beads and AlphaScreen® donor beads was reacted in a buffer containing Tris-HCl <NUM> (pH7. <NUM>), <NUM> NaCl, BSA <NUM>%, and <NUM> DTT. The FXR activity was reflected by the fluorescence signal intensity at <NUM> wavelength detected by the Envision fluorescence detector. The value of EC50 was calculated by the software Graphpad Prism <NUM>.

The FXR expression plasmid and FXRE luciferase reporter plasmid at a ratio of <NUM>:<NUM> was co-transfected into 293T cells, and then the transfected cells were seeded on a <NUM>-well flat-bottom microplate (ViewPlate-<NUM>, White <NUM>- well Microplate with Clear Bottom, PerkinElmer) at <NUM>×<NUM><NUM>/well. The cells were cultured for <NUM> hours to ensure plasmid expression. Then the FXR receptor agonist to be tested was added and acted for <NUM> hours. The fluorescence intensity was detected using luciferase kit (steady-Glo Luciferase Assay system) to reflect the compound's activation efficiency on the FXR receptor.

In the preliminary screening, the test compound and the two positive compounds OCA, GW4064 acted on the cells at <NUM>, and the relative activities of the test compound to the two positive compounds were determined respectively (relative activity = (signal intensity of test compound -blank)/(signal intensity of positive compound -blank)×<NUM>%). The compound whose relative activity is higher than <NUM>% of the positive compound enters the re-screening. The appropriate concentration interval was selected, and the dose-dependent relationship, that is, the EC50 value, was calculated.

Conclusion: The test results show that the compounds of the present invention have good agonistic ability to FXR at the molecular level and the cell level, and the activities of several compounds are significantly better than those of the two positive controls.

In vivo pharmacological activity test of liver fibrosis.

In this experiment, TAA induced hepatic fibrosis model rats were used to investigate the effect of long-term oral administration of compound <NUM> on hepatic fibrosis in the model rats.

Experimental method: Male SD rats were intraperitoneally injected with thioacetamide (TAA, dissolved in normal saline) at a dose of <NUM>/kg three times a week to induce a liver fibrosis model. Four weeks after the model was made, the blood was taken from the retro-ocular venous plexus of the rats to detect serum ALP indicators. According to indicators such as ALP and body weight, the rats were randomly divided into <NUM> groups, each with <NUM> rats, which were respectively the model control group (Vehicle), Compound <NUM> group (<NUM>/kg), positive compound OCA group (<NUM>/kg), etc., orally administered by gavage, once a day. During the administration period, the animal's food intake and body weight were monitored. After <NUM> weeks of administration, the blood was taken from the retro-ocular venous plexus of the rats to detect serum ALP indicators. After <NUM> weeks of administration, the blood was taken from the retro-ocular venous plexus and the rats were dislocated and sacrificed. The livers were taken out and weighed. Part of the liver was fixed with <NUM>% paraformaldehyde, and part of the liver was frozen at -<NUM>. During the whole experiment, another <NUM> rats in the same cage were injected intraperitoneally with the same volume of normal saline as the system normal control group (WT). This experiment detected indicators such as the level of liver function index ALP in serum, the expression of α-SMA and Col1α1 (fibrosis-related genes) gene level in the liver, the content of hydroxyproline (a characteristic amino acid of collagen) in the liver, and the pathological changes of the liver (Sirius scarlet stain), etc., thereby reflecting whether the compound has the effect of relieving liver fibrosis.

The research results showed that the compound <NUM> significantly reduced the level of ALP in serum, reduced the content of hydroxyproline in liver tissue, and significantly down-regulated the expression of α-SMA and Col1α1 mRNA in liver tissue after <NUM> weeks of administration (<FIG>). In the quantitative analysis of liver pathological sections stained with Sirius Scarlet, compound <NUM> reduced the collagen content in the liver, because there were large differences within the model group, and there was no statistical difference (<FIG>).

In summary, long-term administration of compound <NUM> (LXF-<NUM>) could significantly improve the liver function of TAA-induced hepatic fibrosis rats, down-regulate the expression of α-SMA and Col1α1 mRNA, reduce the deposition of collagen in the liver, and have a certain alleviating effect on liver fibrosis.

<NUM>) Pharmacodynamic evaluation of compound <NUM> (LXF-<NUM>) on CCL4-induced hepatic fibrosis model mice.

In this experiment, CCL4 induced hepatic fibrosis model mice were used to investigate the effect of long-term oral administration of compound <NUM> on hepatic fibrosis in the model mice.

Experimental method: Male C57BL/6j mice were injected intraperitoneally with <NUM>/kg, <NUM>% CC14 (dissolved in olive oil) three times a week to induce liver fibrosis model. Two weeks after the model was made, the blood was taken from the retro-ocular venous plexus of the mice to detect serum ALT, AST, TBA and LDH indicators. According to ALT, AST, TBA, LDH, body weight and other indicators, the mice were randomly divided into <NUM> groups. There are <NUM> animals in each group, namely the model control group (Vehicle), low-dose compound <NUM> group (<NUM>/kg), high-dose compound <NUM> group (<NUM>/kg), low-dose positive compound OCA group (<NUM>/kg), high-dose OCA group (<NUM>/kg), etc., orally administered by gavage, once a day. During the administration period, the animals' food intake and body weight were monitored. After <NUM> weeks of administration, the blood was taken from the retro-ocular venous plexus of the mice to detect serum ALT, AST, TBA and LDH indicators. After <NUM> weeks of administration, the blood was taken from the retro-ocular venous plexus and the mice were dislocated and sacrificed. The livers were taken out and weighed. Part of the liver was fixed with <NUM>% paraformaldehyde, and part of the liver was frozen at -<NUM>. During the whole experiment, another <NUM> mice in the same cage were intraperitoneally injected with the same volume of olive oil as the system normal control group (WT).

This experiment detected indicators such as the levels of liver function indicators ALT, AST, TBA, LDH in serum, the expression of α-SMA and Col1α1 gene levels in the liver, and the pathological changes of the liver (Sirius scarlet stain), etc., thereby reflecting whether the compound has the effect of relieving liver fibrosis.

The research results showed that the high-dose compound <NUM> group and low-dose compound <NUM> group of the present invention significantly reduced the levels of ALT, AST and TBA in serum after <NUM> weeks of administration, and had little effect on LDH; the high dose positive compound OCA group significantly reduced the levels of ALT, AST and TBA in serum and the low-dose group only had a lowering effect on TBA; the low-dose compound <NUM> group had a slightly better effect than the low-dose OCA group (<FIG>). The high-dose compound <NUM> group significantly down-regulated the expression of α-SMA in the liver, and down-regulated the expression of collα1 in the liver (<FIG>); in the quantitative analysis of liver pathological sections stained with Sirius scarlet, both the high-dose compound <NUM> group and low-dose compound <NUM> group significantly reduced the collagen content in the liver, and the effect of low-dose compound <NUM> group was slightly better than that of the low-dose OCA group (<FIG>).

Claim 1:
A compound represented by general formula I, or enantiomer, diastereomer, tautomer, racemate, solvate or pharmaceutically acceptable salt thereof,
<CHM>
wherein, R<NUM>, R<NUM>, R<NUM>, R<NUM> and R<NUM> are each independently hydrogen, halogen, halogenated C<NUM>-<NUM> alkyl, halogenated C<NUM>-C<NUM> alkoxy, C<NUM>-C<NUM> alkyl, or C<NUM>-<NUM> alkoxy;
R<NUM> is C<NUM>-C<NUM> aryl, C<NUM>-C<NUM> alkyl or C<NUM>-C<NUM> cycloalkyl;
Q is
<CHM>
, wherein N is attached to A;
A is substituted or unsubstituted phenyl, or substituted or unsubstituted pyridyl, and the "substituted" means that there is one, two or three substituents selected from the group consisting of halogen, C<NUM>-C<NUM> alkyl, halogenated C<NUM>-<NUM> alkyl;
X is O or S.