FXR small molecule agonists and their preparation methods and uses

Abstract

The present invention provides a potent FXR small molecule agonist, its preparation method, and use, whose structure is as shown in Formula I. In the formula, the definitions of each substituent are as described in the specification and claims. The compounds of the present invention have advantages such as high FXR agonist activity, simple synthesis, and readily available raw materials, and can be used to prepare drugs for treating FXR-related diseases. [Formula 1] TIFF2023545677000045.tif39170

Description

Detailed Description of the Invention

[0001] [Technical field] The present invention relates to the field of medicine, and to compounds as FXR agonists, and their preparation and use.Specifically, the present invention relates to non-steroidal compounds and their enantiomers, diastereomers, tautomers, solvates, prodrugs, or pharma-ceutically acceptable salts that can be used as FXR agonists, their preparation methods, and applications in the preparation of drugs for treating FXR-related diseases.

[0002] [Background technology] Nuclear receptors are nuclear transcriptional regulators that exist widely in the body of living organisms and depend on specific ligand activation, and metabolic nuclear receptors are a type of nuclear receptor that regulates metabolism, cell proliferation, apoptosis, etc. in the body. The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and was first discovered by Foman et al. in 1995. It was named after the fact that its transcriptional activity can be enhanced by farnesyl esters.

[0003] The FXR structure is a typical nuclear receptor structure, containing an amino-terminal ligand-independent transcription activation domain (AF1), a DNA-binding domain (DBD), a hinge region, a ligand-binding domain (LBD) and a carbon-terminal ligand-dependent transcription activation domain (AF2). FXR is activated by bile acids in the body and is involved in processes such as bile acid metabolism, lipid metabolism and glucose metabolism in the body. FXR completes the regulation of bile acid metabolism and transport mechanism mainly by regulating the transcription of cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme of bile acid synthesis. Although FXR cannot act directly on the CYP7A1 promoter, it can induce the expression of small heterodimer partner (SHP) and bind to HNF-4α (hepatocyte nuclear factor 4α) and LRH-1 (liver receptor homolog) to downregulate the transcription of CYP7A1.In the lipid metabolism process, hepatic FXR can directly or indirectly regulate PPARα, VLDL receptor (very low density lipoprotein receptor, VLDLR), proprotein convertase subtilisin kexin type 9 (PCSK9), hepatic scavenger receptor group B type 1 (SRB1), phosphor lipid transfer protein (PLTP), liver X receptor (LXR), sterol regulatory element-binding protein-1C (SREBP-1C), and fatty acid synthetase (FAS), and activate lipoprotein lipase (LPL), etc., thereby regulating lipid metabolism and transport and lowering plasma free fatty acids and triglycerides. In the glucose metabolism process, activation of FXR can promote hepatic glycogen synthesis and increase insulin sensitivity and insulin secretion to control blood glucose levels in the body. Because FXR plays an important role in processes such as bile acid metabolism, lipid metabolism, and glucose metabolism, FXR ligand small molecule compounds are expected to be new therapeutic agents for treating metabolic-related diseases such as hypertriglyceridemia, type 2 diabetes, metabolic syndrome, and NAFLD.

[0004] [Summary of the invention] The object of the present invention is to provide FXR small molecule agonists and their preparation methods and uses.

[0005] A first aspect of the present invention provides a compound represented by general formula I, or a tautomer, solvate, prodrug or a pharma- ceutically acceptable salt thereof:

[0006] [ka]

[0007] Here, R 11 , R 12 , R 13 , R 14 , R 15 are each independently hydrogen, halogen, or halogenated C 1-6 Alkyl groups, halogenated C 1 -C 6 Alkoxy group, C 1 -C 6 Alkyl group, C 1-6 Alkoxy group, C 3 -C 6 Cycloalkyl groups, C 3 -C 6 a cycloalkoxy group, a cyano group, or a nitro group; R 2 is C 6 -C 12 Aryl group, C 1 -C 6 Alkyl group or C 3 -C 6 is a cycloalkyl group, A is a substituted or unsubstituted group of a phenyl group, a pyridyl group, a thienyl group, a furyl group, an indazolyl group, an indolyl group, a benzothienyl group, or a benzofuryl group, the substitution being halogen, C 1 -C 6 Alkyl groups, halogenated C 1-6 Alkyl groups, halogenated C 1 -C 6 Alkoxy group, C 3 -C 6 Cycloalkyl groups, C 1 -C 6 Alkoxy group, C 3 -C 6 cycloalkoxy groups.

[0008] In another preferred embodiment, R 11 , R 12 , R 13 , R 14 , R 15are each independently hydrogen, fluorine, chlorine, bromine, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a trifluoromethyl group, or a trifluoromethoxy group.

[0009] In another preferred embodiment, R 12 , R 13 , R 14 is hydrogen. In another preferred embodiment, R 11 , R 15 are each independently a hydrogen atom, a chlorine atom, a bromine atom, a trifluoromethyl group, or a trifluoromethoxy group.

[0010] In another preferred embodiment, R 2 is a phenyl group, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group.

[0011] In another preferred embodiment, A is a substituted or unsubstituted phenyl or pyridyl group, the substitution being fluorine, chlorine, bromine, C 1 -C 4 Alkyl group, C 3 -C 6 Cycloalkyl groups, C 1 -C 4 Alkoxy group, C 3 -C 6 It refers to having one or two substituents selected from the group consisting of cycloalkoxy groups.

[0012] In another preferred example, A is a substituted or unsubstituted phenyl group or pyridyl group, and preferably A is a substituted or unsubstituted phenyl group, pyridyl group or indolyl group, and the substitution refers to having one or two substituents selected from the group consisting of fluorine, chlorine, bromine, trifluoromethyl group, trifluoromethoxy group, methyl group, ethyl group and propyl group.

[0013] In the present invention, when a compound has two or more substituents, the respective substituents may be the same or different.

[0014] In another preferred embodiment, A is a phenyl group.

[0015] [ka] It is.

[0016] In another preferred example, the pharma- ceutically acceptable salt of the present invention refers to a salt formed with an inorganic acid such as phosphoric acid, sulfuric acid, or hydrochloric acid, or an organic acid such as acetic acid, tartaric acid, citric acid, or malic acid, or an acidic amino acid such as aspartic acid or glutamic acid, or a salt formed with an inorganic base such as sodium, potassium, calcium, aluminum salts, and ammonium salts.

[0017] In another preferred embodiment, the compound is

[0018] [ka] It is.

[0019] A second aspect of the present invention provides a method for preparing a compound according to the first aspect, comprising the steps of:

[0020] [ka]

[0021] (a') reacting a compound represented by formula VII with hydroxylamine hydrochloride to produce a compound represented by formula VIII; (b') reacting a compound represented by general formula VIII under the action of phosgene, triphosgene, carbonyldiimidazole or thiocarbonyldiimidazole to produce a compound represented by general formula I; Here, R 2 , A, R11 , R 12 , R 13 , R 14 , R 15 The definition of is as described above.

[0022] In another preferred embodiment, the compound of formula VII is prepared by the steps of:

[0023] [ka]

[0024] a) using a substituted benzaldehyde compound of general formula II as a starting material, reacting it with hydroxylamine hydrochloride to obtain an intermediate, which is then chlorinated with N-chlorosuccinimide (NCS) to produce a compound of general formula III; b) then reacting the compound of general formula III with a 3-oxopropionate to obtain a compound of general formula IV; c) reducing the ester in the compound of formula IV to produce an alcohol, which is then brominated to produce a compound of formula V; d) reacting a compound of formula V with endo-8-azabicyclo[3.2.1]octan-3-ol to produce a compound of formula VI; e) coupling a compound of general formula VI with Br-A-CN under copper or palladium catalysis to obtain a compound of general formula VII; In each formula, R 2 , A, R 11 , R 12 , R 13 , R 14 , R 15 The definition of is as described above.

[0025] In another preferred embodiment, the compound of formula VII is prepared by the steps of:

[0026] [ka]

[0027] f) reacting endo-8-azabicyclo[3.2.1]octan-3-ol with FA-CN to produce a compound of general formula IX; g) reacting a compound of general formula V with a compound of general formula IX to produce a compound of general formula VII; In each formula, R 2 , A, R 11 , R 12 , R 13 , R 14 , R 15 The definition of is as described above.

[0028] A third aspect of the invention provides a pharmaceutical composition comprising: A compound of general formula I according to the first aspect, or a tautomer, solvate, prodrug or a pharma- ceutically acceptable salt thereof; and and a pharma- ceutically acceptable carrier.

[0029] The compounds provided by the present invention can be used alone or mixed with pharma- ceutically acceptable auxiliaries (e.g., excipients, diluents, etc.) to be formulated into tablets, capsules, granules, syrups, etc. for oral administration. The pharmaceutical compositions can be prepared according to conventional methods in pharmacy.

[0030] A fourth aspect of the present invention provides the use of a compound of general formula I as defined in the first aspect, or a tautomer, solvate, prodrug or a pharma- ceutically acceptable salt thereof, (a) as an FXR agonist, or (b) for use in the preparation of a medicament for treating an FXR-related disease.

[0031] In another preferred embodiment, the FXR-related disease is a disease associated with bile acid metabolism, glucose metabolism, lipid metabolism, inflammation, and / or liver fibrosis. In another preferred embodiment, the FXR-related disease is nonalcoholic fatty liver disease (NASH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), gallstones, nonalcoholic cirrhosis, hepatic fibrosis, cholestatic liver disease, hyperlipidemia, hypercholesterolemia or diabetes.

[0032] It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form a new or preferred technical solution. Each feature disclosed in the specification can be replaced by any alternative feature providing the same, equivalent or similar purpose. Due to space limitations, they will not be repeated here. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] After extensive and detailed research, the inventors of the present invention have developed a non-steroidal compound that can be used as an FXR agonist, and has the ability to act on FXR at the molecular and cellular levels. The compound of the present invention has the advantages of high FXR agonist activity, simple synthesis, and easy availability of raw materials, and can be used to prepare drugs for treating FXR-related diseases. Based on this, the present invention has been completed.

[0034] [term] In the present invention, the halogen is F, Cl, Br or I. In the present invention, unless otherwise specified, the terms used have the common meanings known to those skilled in the art.

[0035] In the present invention, "C 1 -C 6 " refers to having 1, 2, 3, 4, 5 or 6 carbon atoms, and "C 1 -C 8" refers to having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and the like, and "3-10 membered" refers to having 3-10 ring atoms, and the like, and the like, and "3-10 membered" refers to having 3-10 ring atoms, and the like, and the like, and the like, and the like,

[0036] In the present invention, the term "alkyl group" refers to a saturated linear or branched chain hydrocarbon moiety, e.g., "C 1 -C 6 The term "alkyl group" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl groups, and preferably includes ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl groups.

[0037] In the present invention, the term "alkoxy group" means -O-(C 1 -C 6 For example, "C 1 -C 6 The term "alkoxy group" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including, but not limited to, methoxy group, ethoxy group, propoxy group, isopropoxy group, and butoxy group.

[0038] In the present invention, the term "cycloalkyl group" refers to a saturated cyclic hydrocarbon group moiety, e.g., "C 3 -C 10The term "cycloalkyl group" refers to a cyclic alkyl group having 3 to 10 carbon atoms on the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl groups. 3 -C 8 Cycloalkyl group, C 3 -C 7 Cycloalkyl groups" and "C 3 -C 6 The term "cycloalkyl group" has an analogous meaning.

[0039] In the present invention, the term "cycloalkoxy group" denotes a cycloalkyl group -O-, wherein the cycloalkyl group is as defined above. In the present invention, the term "4-7 membered nitrogen-containing heterocyclic group" refers to a cycloalkyl ring having 3-7 ring atoms and containing 1, 2 or 3 N atoms, including, but not limited to, a cycloazapentane ring, a cycloazahexane ring, a cycloazaheptane ring, and the like.

[0040] In the present invention, the term "aryl group" refers to a hydrocarbon moiety that contains one or more aromatic rings. For example, 6 -C 12 The term "aryl group" refers to an aromatic ring group having 6 to 12 carbon atoms, without heteroatoms in the ring, such as phenyl group, naphthyl group, etc. The term "C6-C10 aryl group" has an analogous meaning. Examples of aryl groups include, but are not limited to, phenyl group (Ph), naphthyl group, pyrenyl group, anthryl group, and phenanthryl group.

[0041] In the present invention, the term "heteroaryl group" refers to a moiety containing one or more aromatic rings having at least one heteroatom (e.g., N, O or S), for example, the term "3-12 membered heterocyclic group" refers to a saturated or unsaturated 3-12 membered ring group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen in the ring, such as dioxane pentyl groups. The term "3-7 membered heterocyclic group" has an analogous meaning. Examples of heteroaryl groups include a furyl group, a fluorenyl group, a pyrrolyl group, a thienyl group, an oxazolyl group, an imidazolyl group, a thiazolyl group, a pyridyl group, a pyrimidinyl group, a quinazolinyl group, a quinolinyl group, an isoquinolinyl group, and an indolyl group.

[0042] In the present invention, the term "heterocyclic group" refers to a cyclic group containing at least one ring heteroatom (e.g., N, O or S), such as a furyl group, a pyrrolyl group, a thienyl group, an oxazolyl group, an imidazolyl group, a thiazolyl group, a pyridyl group, a quinolyl group, an isoquinolyl group, an indolyl group, a pyrimidinyl group, a tetrahydropyridyl group, a pyrrolinyl group, a dihydropyridyl group, a dihydrofuranyl group, a dihydrothienyl group, a pyranyl group, and the like.

[0043] Unless otherwise stated, the alkyl, alkoxy, cycloalkyl, heterocyclic and aryl groups described herein are substituted and unsubstituted groups. Possible substituents on the alkyl, alkoxy, cycloalkyl, heterocyclic and aryl groups include hydroxyl groups, amino groups, nitro groups, nitrile groups, halogens, C 1 -C 6 Alkyl group, C 2 -C 10 Alkenyl group, C 2 -C 10 Alkynyl group, C 3 -C 20 Cycloalkyl groups, C 3 -C 20 Cycloalkenyl group, C 1 -C 20 Heterocycloalkyl group, C 1 -C 20 Heteroaryloxy group, C 1 -C 6 Alkoxy group, aryl group, heteroaryl group, heteroaryloxy group, C 1 -C 10 Alkylamino group, C 1 -C 20 Dialkylamino group, arylamino group, diarylamino group, C 1 -C 10 Alkylsulfamoyl group, arylsulfamoyl group, C 1 -C 10 Alkylimino group, C 1 -C 10Alkylsulfoimino group, arylsulfoimino group, mercapto group, C 1 -C 10 Alkylthiol group, C 1 -C 10 These include, but are not limited to, alkylsulfonyl groups, arylsulfonyl groups, acylamino groups, aminoacyl groups, aminothioacyl groups, guanidino groups, ureido groups, cyano groups, acyl groups, thioacyl groups, acyloxy groups, carboxyl groups, and carboxylate groups, etc. In another embodiment, cycloalkyl groups, heterocycloalkyl groups, heterocycloalkenyl groups, aryl groups, and heteroaryl groups can also be fused with each other.

[0044] In the present invention, the substitution is single substitution or polysubstitution, and the polysubstitution is disubstitution, trisubstitution, tetrasubstitution, or pentasubstitution. The disubstitution refers to having two substituents, and thus infers others.

[0045] The pharma- ceutically acceptable salts of the present invention can be salts formed by anions and positively charged groups on the compound of formula I. Suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate or maleate. Similarly, salts can be formed by cations and negatively charged groups on the compound of formula I. Suitable cations include sodium, potassium, magnesium, calcium and ammonium ions, such as tetramethylammonium.

[0046] In another preferred embodiment, the term "a pharma- ceutically acceptable salt" refers to a salt of a compound of formula I with 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, acid, naphthalene disulfonic 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-aminobenzene sulfonic acid, 2-acetoxybenzoic acid, and isethionic acid.or the sodium, potassium, calcium, aluminum or ammonium salt formed by a compound of formula I and an inorganic base; or the methylamine, ethylamine or ethanolamine salt formed by a compound of general formula I and an organic base.

[0047] [Preparation method] The preparation method and synthesis route of the compound represented by general formula I of the present invention are as follows:

[0048] [ka]

[0049] The preparation method comprises the steps of: a) using a substituted benzaldehyde as a starting material, reacting it with hydroxylamine hydrochloride under the action of a base to obtain an intermediate, which is then chlorinated with N-chlorosuccinimide (NCS) to form a compound represented by general formula III; b) then reacting the compound of general formula III with the corresponding 3-oxopropionate under basic conditions to form a compound of general formula IV; c) reducing the ester in the compound of formula IV with a reducing agent to produce the corresponding alcohol, and brominating the alcohol to produce the compound of formula V; d) reacting the compound of formula V with endo-8-azabicyclo[3.2.1]octan-3-ol under the action of a base to form a compound of formula VI; e) coupling the compound of formula VI with Br-A-CN under copper or palladium catalysis to obtain the cyano compound of formula VII; a') reacting a compound of general formula VII with hydroxylamine hydrochloride under the action of a base to produce a compound of general formula VIII; b') reacting a compound represented by the general formula VIII with phosgene, triphosgene, carbonyldiimidazole or dimethyl carbonate to produce a compound represented by the general formula I.

[0050] [ka]

[0051] The cyano compound represented by the general formula VII is also f) substitution of the amino group of endo-8-azabicyclo[3.2.1]octan-3-ol for the fluorine of FA-CN under the action of a base to give compound IX; g) reacting the compound of general formula V directly with the prepared IX under the action of a base to form the compound of general formula VI, Here, R 2 , R 11 , R 12 , R 13 , R 14 , R 15 and the A ring is as defined above.

[0052] the base in steps a), b), d), a′), f) and g) is selected from triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, sodium tert-butoxide, butyllithium, lithium diisopropylamide; the base in step b) is selected from triethylamine, diisopropylethylamine, pyridine, DBU, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium ethoxide; the reducing agent of step c) is selected from sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium aluminium hydride, diisopropylaluminium hydride, borane; The copper catalysts in step e) are cuprous iodide, cuprous oxide, cuprous sulfate, and the palladium catalysts are palladium acetate, tetrakis(triphenylphosphine)palladium, bis(acetonitrile)palladium(II) chloride, palladium dichloride, tris(dibenzylideneacetone)dipalladium, bistriphenylphosphorus palladium dichloride, tris(dibenzylideneacetone)dipalladium-chloroform adduct, 1,1'-bis(diphenylphosphino)ferrocenedichloridepalladium(II).

[0053] [Pharmaceutical composition] The present invention further provides pharmaceutical compositions comprising an active ingredient within a safe and effective amount, and a pharma- ceutically acceptable vector.

[0054] "Active ingredient" according to the present invention refers to the compound of formula I according to the present invention. The "active ingredient" and pharmaceutical composition according to the present invention are used to prepare a drug for treating FXR-related diseases. The "active ingredient" and pharmaceutical composition according to the present invention can be used as an FXR agonist. In another preferred embodiment, the "active ingredient" and pharmaceutical composition according to the present invention are used to prepare a drug for preventing and / or treating diseases regulated by FXR agonists.

[0055] "Safe and effective amount" refers to an amount of active ingredient sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1-2000 mg of active ingredient / dose, more preferably 10-200 mg of active ingredient / dose. Preferably, the "single dose" is one tablet.

[0056] "Pharmaceutically acceptable vector" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here refers to the ability of each component in the composition to be blended with the active ingredient of the present invention and between them without significantly reducing the efficacy of the active ingredient. Some examples of pharma- ceutically acceptable vectors include cellulose and its derivatives (e.g., sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0057] The method of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to) oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.

[0058] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide and oils, 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 compositions may also contain auxiliary agents, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings and perfumes.

[0059] In addition to the active ingredient, suspensions may contain suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0060] Compositions for parenteral injection may include 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 vectors, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0061] The compounds of the invention can be administered alone or in combination with other therapeutic agents (eg, lipid-lowering agents). When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., human) in need of treatment, where the dosage at the time of administration is a pharmacologic effective dosage, and for a human weighing 60 kg, the daily dosage is generally 0.1-200 mg, preferably 0.5-5 mg. Of course, the specific dosage must take into account factors within the skill range of a skilled physician, such as the route of administration and the health condition of the patient.

[0062] 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 and do not limit the scope of the present invention. In the following examples, the experimental methods that do not show specific conditions are usually in accordance with conventional conditions (such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989)) or conditions suggested by manufacturers. Unless otherwise specified, percentages and parts are calculated by weight percentages and parts by weight.

[0063] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the method of the present invention. The preferred implementation methods and materials used herein are used for demonstration purposes only.

[0064] The equipment and main experimental materials used are as follows: The reagents and anhydrous solvents used were purchased from commercial companies in China and were all used directly unless otherwise stated. 1H and 13C NMR were performed using Bruker AM-400 and Varian Mercury plus-400 nuclear magnetic resonance instruments, and mass spectrometry was performed using an Agilent 6230 mass spectrometer, 200-300 mesh column chromatography silica gel (Qingdao Marine Science and Technology Industrial Brand), and HSGF254 TLC plates (Yantai Institute of Science and Technology).

[0065] [Line 1]

[0066] [ka]

[0067] [Line 2]

[0068] [ka]

[0069] Example 1:

[0070] [ka]

[0071] Synthesis of intermediate V-1:

[0072] [ka]

[0073] Add potassium carbonate solution (3N, 182mmol) dropwise to a stirred solution of hydroxylamine hydrochloride (182mmol) in ethanol (100mL) at 0℃, dissolve 2,6-dichlorobenzaldehyde (20g, 114mmol) in 100ml ethanol, then add to the hydroxylamine solution, raise the temperature to 90℃, and react for 2 hours. Allow the mixture to cool to room temperature and concentrate until it becomes solid. Add water / ethanol (1000mL / 100mL) solution, stir to crush the solid, filter, and vacuum dry overnight at 50℃ to obtain compound intermediate (18.4g). Dissolve this intermediate in N,N-dimethylformamide (50mL) and add dropwise to a solution of N-chlorosuccinimide (97mmol) in N,N-dimethylformamide (100mL) at 0℃ and stir overnight. The reaction mixture is poured into ice water at 0°C, then extracted with methyl tert-butyl ether (200 mL each time, 3 times in total), the organic phase is washed with saturated brine, and concentrated to obtain the crude product. The flask containing the crude product is added with n-hexane (600 mL), stirred with a magnet, filtered, and the solid is dried under vacuum (30°C) to obtain intermediate III-1 (18.3 g, 73% yield). 1 H NMR (400 MHz, CDCl 3 )δ7.43-7.39(m, 2H), 7.39-7.33(m, 1H).

[0074] Add triethylamine (8.2 g) to methyl 3-cyclopropyl-3-oxopropionate (82 mmol) and stir for 30 min. Then, cool to 10 °C, add a solution of III-1 (18.3 g, 82 mmol) in absolute ethanol (80 mL) dropwise (internal temperature does not exceed 30 °C), and leave the reaction at room temperature overnight. Add ethyl acetate (100 mL) to dilute the reaction, wash with water, and extract the aqueous phase with ethyl acetate (100 mL each time, total 3 times). Mix the organic phase, wash with saturated saline, and concentrate. Add 100 mL of ether to the concentrate and stir, and remove the solvent under vacuum to obtain solid product IV-1 (21.6 g, 84% yield). 1 H NMR (400 MHz, CDCl 3)δ7.43-7.39(m, 2H), 7.39-7.33(m, 1H), 3.72(s, 3H), 2.21-2.09(m, 1H), 1.35-1.28(m, 2H), 1.25-1.18(m, 2H).

[0075] IV-1 (21.6 g, 69 mmol) is dissolved in tetrahydrofuran (140 mL), cooled to 0° C., and a solution of diisobutylaluminum hydride in toluene (1.5 M, 102 mL) is slowly added dropwise to the solution, and the reaction solution is stirred at room temperature for 6 hours. The reaction solution is slowly poured into ice water, and 1 M aqueous hydrochloric acid is added to adjust the pH to about 2, and the solution is extracted with ethyl acetate (100 mL each time, a total of three times), concentrated, and subjected to column chromatography to obtain an intermediate alcohol. This intermediate and triphenylphosphine (59 mmol) are dissolved in dichloromethane (60 mL), cooled to 0° C., and under nitrogen gas protection, a solution of carbon tetrabromide (62 mmol) in dichloromethane (60 mL) is added dropwise, and the mixture is reacted at room temperature for 4 hours. The solvent is removed from the reaction solution to obtain an oily substance, and intermediate V-1 (15.3 g, 96% yield) is obtained by column chromatography. 1 H NMR (400 MHz, CDCl 3 )δ7.49-7.44(m, 2H), 7.43-7.37(m, 1H), 4.25(d, J=1.3Hz, 2H), 2.21-2.09(m, 1H), 1.35-1.28(m, 2H), 1.25-1.18(m, 2H).

[0076] Synthesis of Example 1:

[0077] [ka]

[0078] At 0°C, potassium t-butoxide (6.5mmol) is added to a solution of 3-hydroxy-8-azabicyclo[3.2.1]octane-8 tert-butyl carboxylate (1.5g, 6.5mmol) in anhydrous tetrahydrofuran (20mL), stirred for 30 minutes, then a solution of V-1 (4.3mmol) in anhydrous tetrahydrofuran (5mL) is added dropwise and reacted for 8 hours. Water (20mL) is added to the reaction solution, and it is extracted with ethyl acetate (15mL each time, a total of 3 times), and the organic phase is washed with saturated saline, concentrated, and the crude intermediate product is obtained by column chromatography. The intermediate is dissolved in dichloromethane (8mL), cooled to 0°C, trifluoroacetic acid (8mL) is added dropwise, and stirred at room temperature for 3 hours. The solvent is removed under vacuum, and ethyl acetate (20mL) is added to dissolve it, washed with 2N sodium hydroxide solution and saturated saline, and the solvent is removed to obtain intermediate VI-1 (1.1g, 72% yield). 1 H NMR (400 MHz, CDCl 3 )δ7.42-7.39(m, 2H), 7.36-7.31(m, 1H), 4.27-4.18(m, 2H), 4.10-3.96(m, 2H), 3.53(t, J=4.7Hz, 1H), 2.16-1.60(m, 9H), 1.26-1.05(m, 4H).

[0079] Add intermediate VI-1 (1.0 g, 2.7 mmol), 3-bromobenzonitrile (4.1 mmol), sodium t-butoxide (5.4 mmol), palladium acetate (0.14 mmol), and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.27 mmol) to a round-bottom flask, add toluene (80 mL) under nitrogen gas protection, heat to reflux, and react overnight. Cool the reaction solution to room temperature, add water to extract, concentrate, and obtain intermediate VII-1 (0.56 g, 43% yield) by column chromatography. 1 H NMR (400 MHz, CDCl 3 )δ7.47-7.34(m, 5H), 6.65(d, J=8.9Hz, 2H), 4.26(s, 2H), 4.13-4.10(m, 2H), 3.46-3.41(m, 1H), 2.17-1.81(m, 7H), 1.66-1.11(m, 6H).

[0080] Add VII-1 (0.4 g, 0.9 mmol), hydroxylamine hydrochloride (2.3 mmol), and absolute ethanol (5 mL) to a round-bottom flask and stir, slowly add triethylamine (2.3 mmol), and heat to 80 °C for 4 hours. Cool to room temperature, remove the solvent, dissolve in ethyl acetate (15 mL), wash with water and saturated saline, concentrate the organic phase, and obtain intermediate VIII-1 (0.42 g, 95% yield) by silica gel column chromatography.

[0081] VIII-1 (0.41 g, 0.83 mmol), N,N'-carbonyldiimidazole (1.0 mmol), 1,4-dioxane (4 mL) were added to a round-bottom flask, followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.91 mmol), and the mixture was heated to 100 °C for 3 h. The reaction mixture was cooled to room temperature, diluted with water (5 mL), and adjusted to pH 2 with 1 M aqueous hydrochloric acid, then extracted with ethyl acetate (4 mL each time, 3 times in total). The organic phases were combined, washed with saturated saline, and the resulting crude product was concentrated and then purified by silica gel column chromatography to obtain the final product 1 (0.29 g, 64% yield).

[0082] 1 H NMR (400 MHz, CDCl 3 )δ7.60(d, J=8.8Hz, 2H), 7.44-7.32(m, 3H), 6.70(d, J=9.0Hz, 2H), 4.25(s, 2H), 4.12-4 .08(m, 2H), 3.42(s, 1H), 2.18-1.82(m, 7H), 1.61(d, J=14.4Hz, 2H), 1.26-1.10(m, 4H). MS(ESI, m / z):553[M+H] + .

[0083] Example 2:

[0084] [ka]

[0085] The preparation of Example 2 refers to the procedure of Example 1, and is prepared from intermediate VI-1 through Route 1, and the synthetic route is as follows:

[0086] [ka]

[0087] Starting from raw material V-1, compound 2 is synthesized according to the synthesis method for synthesizing compound 1, The yield of oily intermediate VI-1 is 56%. 1 H NMR (500MHz, Chloroform-d) δ7.45-7.41(m, 2H), 7.39-7.34(m, 1H), 4.32-4.24(m, 2H), 4.0 1-3.91(m, 2H), 3.59-3.49(m, 1H), 2.19-2.08(m, 3H), 1.93-1.65(m, 6H), 1.28-1.11(m, 4H).

[0088] The yield of white solid VII-2 is 88%. 1 H NMR (500MHz, Chloroform-d) δ7.50-7.45(m, 2H), 7.38-7.34(m, 2H), 7.31-7.26(m, 1H), 6.71-6.65(m, 2H), 4.3 1-4.20(m, 4H), 3.81-3.71(m, 1H), 2.13-2.02(m, 3H), 1.78-1.66(m, 4H), 1.47-1.39(m, 2H), 1.30-1.08(m, 4H).

[0089] The yield of the white solid 2 is 52%. 1 H NMR (500MHz, DMSO-d6) δ7.63(d, J=8.8Hz, 2H), 7.52-7.48(m, 2H), 7.48-7.43(m, 1H), 6.86(d, J=8.8Hz, 2H), 4.35-4.27(m, 2H), 4.21(s, 2H), 3.76-3.66(m, 1H), 2.34-2.23(m, 1H), 1.94-1.58(m, 6H), 1.20-1.03(m, 6H). MS(ESI, m / z):553[M+H] + .

[0090] Example 3:

[0091] [ka]

[0092] Synthesis of intermediate V-3:

[0093] [ka]

[0094] 6-Fluoronicotinonitrile (2 g, 16.5 mmol), endo-8-azabicyclo[3.2.1]octan-3-ol (18.2 mmol), anhydrous potassium carbonate (41.3 mmol) and DMSO (16 mL) were added to a round bottom flask, heated to 130 °C and reacted for 12 h. Cooled to room temperature, added 30 mL of water, filtered and washed the solid with water to obtain intermediate IX-3 (3.2 g, 93% yield). White solid, yield is 94%. 1 H NMR (400 MHz, CDCl 3 )δ8.41(d, J=1.8Hz, 1H), 7.58(dd, J=9.0, 2.3Hz, 1H), 6.49(d, J=8.9Hz, 1H), 4.9 1-4.26(m, 2H), 4.12(t, J=4.7Hz, 1H), 2.39(d, J=7.3Hz, 2H), 2.18-1.81(m, 6H).

[0095] Starting from raw material II-3, compound V-3 is synthesized according to the synthesis method for synthesizing compound V-1, wherein The yield of white solid IV-3 is 64%. 1 H NMR (400 MHz, CDCl 3 )δ7.43-7.34(m, 1H), 7.00-6.91(m, 2H), 3.69(s, 3H), 2.92-2.83(m, 1H), 1.36-1.31(m, 2H), 1.25-1.20(m, 2H).

[0096] The yield of colorless liquid V-3 is 82%.1 H NMR (400 MHz, CDCl 3 )δ7.54-7.44(m, 1H), 7.11-7.04(m, 2H), 4.33(s, 2H), 2.20-2.08(m, 1H), 1.34-1.17(m, 4H).

[0097] Starting from raw materials V-3 and IX-3, according to the synthesis method of compound VII-1, intermediate compound VII-3 was synthesized as a white solid, the yield was 51%. 1 H NMR (400 MHz, CDCl 3 )δ8.35(d, J=2.1Hz, 1H), 7.52(dd, J=9.0, 2.1Hz, 1H), 7.47-6.94(m, 3H), 6.42(d, J=9.0 Hz, 1H), 4.75-4.18(m, 4H), 3.48(t, J=4.5Hz, 1H), 2.16-1.81(m, 7H), 1.69-1.08(m, 6H).

[0098] Starting from the raw material VII-3, compound 3 was synthesized according to the synthesis method of compound 1, as a white solid, the yield was 71%. 1 H NMR (400MHz, DMSO) δ8.48(d, J=2.4Hz, 1H), 7.81-7.61(m, 3H), 7.30(t, J=8.0Hz, 2H), 6.79(d, J=9.0Hz, 1H), 4.43(s, 2H), 4.33(s, 2H), 3.45(s, 1H), 2.41-2.26(m, 1H), 1.87-1.04(m, 12H). MS(ESI, m / z):522[M+H] + .

[0099] Example 4:

[0100] [ka]

[0101] The synthetic route of Example 4 is as follows.

[0102] [ka]

[0103] Starting from raw materials V-1 and IX-3, compound intermediate VII-4 is synthesized according to the synthesis method of compound VII-3. White solid, 72% yield. 1 H NMR (400 MHz, CDCl 3 )δ8.34(d, J=2.1Hz, 1H), 7.51(dd, J=9.0, 2.1Hz, 1H), 7.42-7.30(m, 3H), 6.41(d, J=9.0Hz, 1H), 4 .63-4.16(m, 4H), 3.46(t, J=4.3Hz, 1H), 2.15-2.07(m, 1H), 1.97-1.70(m, 8H), 1.25-1.07(m, 4H).

[0104] Starting from the raw material VII-4, compound 4 is synthesized according to the synthesis method of compound 1. White solid, yield is 47%. 1 H NMR (400MHz, DMSO) δ8.43(d, J=2.4Hz, 1H), 7.77(dd, J=9.0, 2.4Hz, 1H), 7.67-7.52(m, 3H), 6.75 (d, J=9.0Hz, 1H), 4.40(s, 2H), 4.24(s, 2H), 3.41(s, 1H), 2.36-2.26(m, 1H), 1.84-1.03(m, 12H). MS(ESI, m / z):554[M+H] + .

[0105] Example 5:

[0106] [ka]

[0107] Starting from raw material II-5, compound 5 is synthesized according to the synthesis method for synthesizing compound 3, wherein: The yield of white solid IV-5 is 58%. 1 H NMR (400 MHz, CDCl 3)δ7.82(d, J=7.5Hz, 1H), 7.74-7.59(m, 2H), 7.56(d, J=7.5Hz, 1H), 3.3.73(s, 3H), 2.19-2.09(m, 1H), 1.33-1.27(m, 2H), 1.24-1.15(m, 2H).

[0108] The yield of colorless liquid V-5 is 88%. 1 H NMR (400 MHz, CDCl 3 )δ7.84(d, J=7.4Hz, 1H), 7.73-7.61(m, 2H), 7.57(d, J=7.4Hz, 1H), 4.23(s, 2H), 2.17-2.09(m, 1H), 1.32-1.27(m, 2H), 1.23-1.17(m, 2H).

[0109] Starting from raw materials V-5 and IX-3, compound intermediate VII-5 is synthesized according to the synthesis method of compound VII-3. White solid, yield is 63%. 1 H NMR (400 MHz, CDCl 3 )δ8.32(d, J=2.0Hz, 1H), 7.76(d, J=7.2Hz, 1H), 7.63-7.53(m, 2H), 7.49-7.40(m, 2H), 6.39(d, J=9.0Hz, 1H), 4.57-4.12(m, 4H), 3.42(t, J=4.4Hz, 1H), 2.13-1.69(m, 9H), 1.20-1.05(m, 4H).

[0110] Starting from the raw material VII-5, compound 5 is synthesized according to the synthesis method of compound 1. White solid, yield is 52%. 1 H NMR (400MHz, DMSO) δ8.45(d, J=2.4Hz, 1H), 7.92(d, J=7.2Hz, 1H), 7.84-7.60(m, 4H), 6.79(d, J=9.1Hz , 1H), 4.19(s, 2H), 4.23(s, 2H), 3.43(s, 1H), 2.37-2.28(m, 1H), 1.82-1.62(m, 8H), 1.17-1.03(m, 4H). MS(ESI, m / z):554[M+H] + .

[0111] Example 6:

[0112] [ka]

[0113] Starting from raw material II-6, compound V-6 is synthesized according to the synthesis method for compound 3, The yield of white solid IV-6 is 59%. 1 H NMR (400 MHz, CDCl 3 )δ7.66-7.50(m, 2H), 7.49-7.41(m, 2H), 3.70(s, 2H), 2.18-2.10(m, 1H), 1.31-1.26(m, 2H), 1.23-1.17(m, 2H).

[0114] The yield of colorless liquid V-6 is 82%. 1 H NMR (400 MHz, CDCl 3 )δ7.65-7.52(m, 2H), 7.49-7.40(m, 2H), 4.36(s, 2H), 2.18-2.10(m, 1H), 1.31-1.26(m, 2H), 1.23-1.17(m, 2H).

[0115] Starting from raw materials V-6 and IX-3, compound intermediate VII-6 is synthesized according to the synthesis method of compound VII-3. White solid, yield is 79%. 1 H NMR (400 MHz, CDCl 3 )δ8.35(d, J=2.0Hz, 1H), 7.58-7.35(m, 5H), 6.44-6.38(m, 1H), 4.57-4.22(m, 4H), 3.48(t, J=4.4Hz, 1H), 2.16-1.70(m, 9H), 1.22-1.07(m, 4H).

[0116] Starting from the raw material VII-6, compound 6 is synthesized according to the synthesis method of compound 1. White solid, yield is 51%. 1H NMR (400MHz, DMSO) δ8.47(d, J=2.4Hz, 1H), 7.79(dd, J=9.0, 2.4Hz, 1H), 7.69-7.49(m, 4H), 6.75 (d, J=9.0Hz, 1H), 4.41(s, 2H), 4.32(s, 2H), 3.47(s, 1H), 2.35-2.26(m, 1H), 1.86-1.02(m, 12H). MS(ESI, m / z):570[M+H] + .

[0117] Example 7:

[0118] [ka]

[0119] Starting from raw materials endo-8-azabicyclo[3.2.1]octan-3-ol and 2,4-difluorobenzonitrile, compound intermediate IX-7 is synthesized according to the synthesis method of compound IX-3. White solid, yield is 64%. 1 H NMR (400 MHz, CDCl 3 )δ7.36-7.28(m, 1H), 6.65-6.47(m, 2H), 4.00-3.90(m, 1H), 3.76-3.55(m, 2H), 3.26-3.04(m, 2H), 2.00-1.53(m, 4H).

[0120] Starting from raw materials V-3 and IX-7, compound intermediate VII-7 is synthesized according to the synthesis method of compound VII-3. White solid, yield is 84%. 1 H NMR (400 MHz, CDCl 3 )δ7.49-7.30(m, 2H), 7.07-7.00(m, 2H), 6.44-6.31(m, 2H), 4.31(s, 2H), 4.06(s, 2 H), 3.46(t, J=4.5Hz, 1H), 2.16-2.08(m, 1H), 1.99-1.63(m, 8H), 1.25-1.09(m, 4H).

[0121] Starting from the raw material VII-7, compound 7 is synthesized according to the synthesis method of compound 1. White solid, yield is 60%. 1 H NMR (400MHz, DMSO) δ7.70-7.59(m, 1H), 7.50(t, J=8.6Hz, 1H), 7.29(t, J=8.0Hz, 2H), 6.76-6.64(m, 2 H), 4.31(s, 2H), 4.17(s, 2H), 3.43(s, 1H), 2.37-2.26(m, 1H), 1.83-1.52(m, 8H), 1.16-1.04(m, 4H). MS(ESI, m / z):539[M+H] + .

[0122] Example 8:

[0123] [ka]

[0124] The synthetic route of Example 8 is as follows.

[0125] [ka]

[0126] Starting from raw materials V-1 and IX-7, compound intermediate VII-8 is synthesized according to the synthesis method of compound VII-3. White solid, yield is 75%. 1 H NMR (400 MHz, CDCl 3 )δ7.46-7.31(m, 4H), 6.42(dd, J=8.8, 2.1Hz, 1H), 6.35(d, J=12.8Hz, 1H), 4.26(s, 2H), 4.07 (s, 2H), 3.46(t, J=4.4Hz, 1H), 2.17-1.82(m, 7H), 1.66(d, J=14.7Hz, 2H), 1.29-1.10(m, 4H).

[0127] Starting from the raw material VII-7, compound 7 is synthesized according to the synthesis method of compound 1. White solid, yield is 60%. 1H NMR (400MHz, DMSO) δ7.65-7.47(m, 4H), 6.69(m, 2H), 4.25(s, 2H), 4.17(s, 2H), 3.41(s, 1H), 2.38-2.27(m, 1H), 1.83-1.54(m, 8H), 1.16-1.04(m, 4H). MS(ESI, m / z):571[M+H] + .

[0128] Example 9:

[0129] [ka]

[0130] The synthetic route of Example 9 is as follows.

[0131] [ka]

[0132] Starting from raw materials V-5 and IX-7, compound intermediate VII-9 is synthesized according to the synthesis method of compound VII-3. White solid, yield is 78%. 1 H NMR (400 MHz, CDCl 3 )δ7.84-7.79(m, 1H), 7.67-7.58(m, 2H), 7.48-7.32(m, 2H), 6.45-6.31(m, 2H), 4.20(s, 2H) ), 4.08(s, 2H), 3.43(s, 1H), 2.14-1.83(m, 7H), 1.66(d, J=14.7Hz, 2H), 1.29-1.09(m, 4H).

[0133] Starting from the raw material VII-9, compound 9 is synthesized according to the synthesis method of compound 1. White solid, yield is 55%. 1H NMR (400MHz, DMSO) δ7.91(d, J=7.6Hz, 1H), 7.83-7.70(m, 2H), 7.64-7.47(m, 2H), 6.75-6.64(m , 2H), 4.26-4.13(m, 4H), 3.40(s, 1H), 2.38-2.24(m, 1H), 1.83-1.55(m, 8H), 1.18-1.02(m, 4H). MS(ESI, m / z):571[M+H] + .

[0134] Example 10:

[0135] [ka]

[0136] The synthetic route of Example 10 is as follows.

[0137] [ka]

[0138] Starting from raw materials V-6 and IX-7, compound intermediate VII-10 is synthesized according to the synthesis method of compound VII-3. White solid, yield is 70%. 1 H NMR (400 MHz, CDCl 3 )δ7.59-7.52(m, 2H), 7.44-7.35(m, 3H), 6.43(dd, J=8.8, 2.0Hz, 1H), 6.36(dd, J=12.8, 2.0Hz, 1H), 4.36( s, 2H), 4.08(s, 2H), 3.48(t, J=4.4Hz, 1H), 2.17-1.86(m, 7H), 1.66(d, J=14.4Hz, 2H), 1.27-1.10(m, 4H).

[0139] Starting from the raw material VII-10, compound 10 is synthesized according to the synthesis method of compound 1. White solid, yield is 70%. 1H NMR (400MHz, DMSO) δ7.71-7.46(m, 5H), 6.77-6.64(m, 2H), 4.32(s, 2H), 4.18( s, 2H), 3.45(s, 1H), 2.37-2.27(m, 1H), 1.86-1.56(m, 8H), 1.17-1.03(m, 4H). MS(ESI, m / z):587[M+H] + .

[0140] Example 11:

[0141] [ka]

[0142] Starting from raw material II-11, compound V-11 is synthesized according to the synthesis method for synthesizing compound V-1, wherein The yield of white solid IV-11 is 54%. 1 H NMR (400 MHz, CDCl 3 )δ7.52-7.44(m, 2H), 7.32-7.26(m, 1H), 7.21(d, J=8.5Hz, 1H), 6.46(t, J=73.7 Hz, 1H), 3.72(s, 3H), 2.88-2.80(m, 1H), 1.37-1.32(m, 2H), 1.26-1.22(m, 2H).

[0143] The yield of colorless liquid V-11 is 72%. 1 H NMR (400 MHz, CDCl 3 )δ7.60-7.51(m, 2H), 7.41-7.32(m, 2H), 6.51(t, J=73.7Hz, 1H), 4.38(s, 2H), 2.18-2.10(m, 1H), 1.32-1.17(m, 4H).

[0144] Starting from raw materials V-11 and IX-3, according to the synthesis method of compound VII-3, intermediate compound VII-11 was synthesized as a white solid, the yield is 66%. 1 H NMR (400 MHz, CDCl 3)δ8.37(d, J=2.0Hz, 1H), 7.56-7.23(m, 5H), 6.45(t, J=74.0Hz, 1H), 6.42(d, J=8.8Hz, 1H), 4.50- 4.18(m, 4H), 3.49(t, J=4.4Hz, 1H), 2.16-1.80(m, 7H), 1.72(d, J=14.4Hz, 2H), 1.23-1.06(m, 4H).

[0145] Starting from the raw material VII-11, compound 11 was synthesized according to the synthesis method of compound 1, as a white solid, the yield was 63%. 1 H NMR (400MHz, DMSO) δ8.46(d, J=2.4Hz, 1H), 7.79(dd, J=9.0, 2.4Hz, 1H), 7.64-7.33(m, 4H), 7.23(d, J=74.0Hz, 1H) , 6.78(d, J=9.0Hz, 1H), 4.54-4.22(m, 4H), 3.46(s, 1H), 2.36-2.26(m, 1H), 1.86-1.62(m, 8H), 1.15-1.07(m, 4H). MS(ESI, m / z):552[M+H] + .

[0146] Example 12:

[0147] [ka]

[0148] The synthetic route of Example 12 is as follows.

[0149] [ka]

[0150] Starting from raw material II-12, compound V-12 is synthesized according to the synthesis method for synthesizing compound V-1, wherein The yield of white solid IV-12 is 54%. 1 H NMR (400 MHz, CDCl 3)δ7.42-7.31(m, 2H), 7.30-7.24(m, 2H), 3.69(s, 3H), 2.95-2.87(m, 1H), 2.23(s, 3H), 1.42-1.36(m, 2H), 1.30-1.23(m, 2H).

[0151] The yield of colorless liquid V-12 is 72%. 1 H NMR (400 MHz, CDCl 3 )δ7.42-7.29(m, 4H), 4.27(s, 2H), 2.33(s, 3H), 2.19-2.10(m, 1H), 1.32-1.27(m, 2H), 1.23-1.16(m, 2H).

[0152] Starting from raw materials V-12 and IX-3, according to the synthesis method of compound VII-3, intermediate compound VII-12 was synthesized as a white solid, the yield is 64%. 1 H NMR (400 MHz, CDCl 3 )δ8.38(d, J=1.8Hz, 1H), 7.55(dd, J=8.8, 2.4Hz, 1H), 7.38-7.23(m, 4H), 6.44(d, J=8.8Hz, 1H), 4.77 -4.31(m, 2H), 4.21(s, 2H), 3.50(t, J=4.4Hz, 1H), 2.31(s, 3H), 2.17-1.78(m, 9H), 1.26-1.07(m, 4H).

[0153] Starting from the raw material VII-12, compound 12 was synthesized according to the synthesis method of compound 1, as a white solid, the yield was 69%. 1 H NMR (400MHz, DMSO) δ8.45(d, J=2.4Hz, 1H), 7.78(dd, J=9.0, 2.4Hz, 1H), 7.37-7.22(m, 4H), 6.73(d, J=9.0 Hz, 1H), 4.42(s, 2H), 4.20(s, 2H), 3.44(s, 1H), 2.33-2.21(m, 4H), 1.91-1.64(m, 8H), 1.14-1.07(m, 4H). MS(ESI, m / z):500[M+H] + .

[0154] Example 13:

[0155] [ka]

[0156] The synthetic route of Example 13 is as follows.

[0157] [ka]

[0158] Starting from raw materials V-11 and IX-3, according to the synthesis method of compound VII-3, intermediate compound VII-13 was synthesized as a white solid, the yield is 69%. 1 H NMR (400 MHz, CDCl 3 )δ7.56-7.28(m, 5H), 6.47(t, J=74.0Hz, 1H), 6.44-6.31(m, 2H), 4.33(s, 2H), 4.08-4.02 (m, 2H), 3.52-3.44 (m, 1H), 2.14-1.84 (m, 7H), 1.64 (d, J=15.0Hz, 2H), 1.24-1.07 (m, 4H).

[0159] Starting from the raw material VII-13, compound 13 was synthesized according to the synthesis method of compound 1, as a white solid, the yield was 61%. 1 H NMR (400MHz, DMSO) δ7.60(td, J=8.4, 1.6Hz, 1H), 7.54-7.34(m, 4H), 7.23(t, J=74.0Hz, 1H), 6.78-6.62( m, 2H), 4.31(s, 2H), 4.19(s, 2H), 3.42(s, 1H), 2.36-2.26(m, 1H), 1.86-1.55(m, 8H), 1.16-1.00(m, 4H). MS(ESI, m / z):569[M+H] + .

[0160] Example 14:

[0161] [ka]

[0162] The synthetic route of Example 14 is as follows.

[0163] [ka]

[0164] Starting from raw materials V-12 and IX-3, according to the synthesis method of compound VII-10, intermediate compound VII-42 was synthesized as a white solid, the yield is 49%. 1 H NMR (400 MHz, CDCl 3 )δ7.39-7.24(m, 5H), 6.46-6.41(m, 1H), 6.39-6.34(m, 1H), 4.21(s, 2H), 4.13-4.06(m, 2H) , 3.50-3.43(m, 1H), 2.31(s, 3H), 2.15-1.87(m, 7H), 1.75-1.67(m, 2H), 1.29-1.09(m, 4H).

[0165] Starting from the raw material VII-40, compound 40 was synthesized according to the synthesis method of compound 1, as a white solid, the yield was 61%. 1 H NMR (400 MHz, CDCl 3 )δ7.66(t, J=8.8Hz, 1H), 7.37-7.22(m, 4H), 6.52(dd, J=9.0, 2.0Hz, 1H), 6.39(dd, J=14.9, 2.0Hz, 1H), 4.20(s, 2H), 4.09(s, 2H), 3.49-3.43(m, 1H), 2.31(s, 3H), 2.17-1.89(m, 7H), 1.69(d, J=14.5Hz, 2H), 1.28-1.08(m, 4H). MS(ESI, m / z):517[M+H] + .

[0166] [Examples of pharmacological experiments] [FXR molecular level activity test method] The recombinant GST-FXR fusion protein is used to measure FXR activity with AlphaScreen detection reagent from Perkin Elmer. The reaction of this method is carried out in a 384-well plate, and the total reaction volume is 15 μL. The mixture of protein, agonist, coregulator, AlphaScreen® receptor microbeads and AlphaScreen® donor microbeads is reacted in a buffer containing 50 mM Tris-HCl (pH 7.4), 50 mM NaCl, 0.1% BSA, and 1 mM DTT, and the fluorescence signal intensity reflecting FXR activity at a wavelength of 570 nm is detected by a fluorescence detector Envision. EC 50 The values ​​of A and C are calculated by the software Graphpad Prism 5 (A = EC 50 <10nM, B=10nM <EC 50 <100nM, C=100nM <EC 50 <1000nM, D>1000nM).

[0167] [FXR cellular activity assay] FXR expression plasmid and FXRE luciferase reporter plasmid were co-transfected into 293T cells at a ratio of 1:9, and then 5 × 10 5 The cells transfected at 1000 / well are seeded into a 96-well flat-bottom microwell plate (ViewPlate-96, White 96-well Microplate with Clear Bottom, PerkinElmer). The cells are cultured for 24 hours to ensure the expression of the plasmid, and the test FXR receptor agonist is added. After the test compound is allowed to act for 18 hours, the fluorescence intensity is detected using a luciferase kit (steady-Glo Luciferase Assay system) to reflect the activation efficiency of the compound on the FXR receptor.

[0168] [ka]

[0169] In the first screening, the test compound and the two positive compounds OCA and GW4064 were applied to cells at 10 μM, and the relative activity of the test compound to the two positive compounds was measured (relative activity=(signal intensity of test compound-blank) / (signal intensity of positive compound-blank)×100%). Compounds with relative activity exceeding 50% of the positive compounds were rescreened to select an appropriate concentration interval and to determine their dose-dependent relationship, i.e., EC 50 Calculate the value (A=EC 50 <0.1nM, B=0.1nM <EC 50 <1nM, C=1nM <EC 50 <10nM, D=10nM <EC 50 <100nM, E>100nM).

[0170] [Table 1]

[0171] Conclusion: The test results show that the compounds described in the present invention have good agonist ability for FXR at both molecular and cellular levels, and the activity of the compounds of the present invention in internal configuration is much better than that of the corresponding compounds in external configuration, where the activity of FXR at molecular level is at least 10 times different. Take compounds 1 and 2 as an example, the activity of compound 1 in internal configuration example 1 is much better than that of compound 2 in external configuration example 2 (the activity difference at FXR molecular level is more than 100 times), where the activity of the compound in internal configuration is significantly better than that of the two positive controls.

[0172] All documents mentioned in the present invention are incorporated by reference in this application as if each document was incorporated by reference individually. Furthermore, after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalents are also included in the scope defined by the appended claims of this application.

Claims

1. A compound represented by general formula I, or a tautomer, solvate or a pharma- ceutically acceptable salt thereof, 【Chemistry 1】 Here, R １１ , R １２ , R １３ , R １４ , R １５ are each independently hydrogen, halogen, or halogenated C １－６ Alkyl groups, halogenated C １ -C ６ Alkoxy group, C １ -C ６ Alkyl group, C １－６ Alkoxy group, C ３ -C ６ Cycloalkyl group, C ３ -C ６ a cycloalkoxy group, a cyano group, or a nitro group; R ２ is C ６ Aryl group, C １ -C ６ Alkyl group or C ３ -C ６ is a cycloalkyl group, A is, 【Chemistry 2】 The compound,

2. R １１ , R １２ , R １３ , R １４ , R １５ are each independently hydrogen, fluorine, chlorine, bromine, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a trifluoromethyl group, or a trifluoromethoxy group. The compound of claim 1.

3. R １１ and R １５ are each independently a hydrogen atom, a chlorine atom, a bromine atom, a trifluoromethyl group, or a trifluoromethoxy group; R １２ , R １３ and R １４ is hydrogen The compound of claim 1.

4. R ２ is a phenyl group, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group. The compound of claim 1.

5. The compound is 【Chemistry 3】 characterized in that The compound of claim 1.

6. A process for preparing the compound of claim 1, comprising the steps of: The preparation method includes the following steps: 【Chemistry 4】 (a') reacting a compound represented by formula VII with hydroxylamine hydrochloride to produce a compound represented by formula VIII; (b') reacting a compound represented by general formula VIII under the action of phosgene, triphosgene, carbonyldiimidazole or dimethyl carbonate to produce a compound represented by general formula I; Here, R ２ , A, R １１ , R １２ , R １３ , R １４ , R １５ 2. A process for the preparation of a compound according to claim 1, characterized in that the definition of is as set out in claim 1.

7. The compound of formula VII can be prepared by the following steps: 【Chemistry 5】 a) using a substituted benzaldehyde compound of general formula II as a starting material, reacting it with hydroxylamine hydrochloride to obtain an intermediate, which is then chlorinated with N-chlorosuccinimide (NCS) to produce a compound of general formula III; b) then reacting the compound of general formula III with a 3-oxopropionate to give a compound of general formula IV; c) reducing the ester in the compound of general formula IV to give an alcohol, which is brominated to give a compound of formula V; d) reacting a compound of formula V with endo-8-azabicyclo[3.2.1]octan-3-ol to produce a compound of formula VI; e) coupling of the compound of general formula VI with Br-A-CN under copper or palladium catalysis to obtain the compound of general formula VII; In each formula, R ２ , A, R １１ , R １２ , R １３ , R １４ , R １５ is defined as in claim 1, Alternatively, the compound of formula VII may be prepared by the following steps: 【Chemistry 6】 f) reacting endo-8-azabicyclo[3.2.1]octan-3-ol with F-A-CN to produce a compound of general formula IX; g) reacting a compound of general formula V with a compound of general formula IX to produce a compound of general formula VII; In each formula, R ２ , A, R １１ , R １２ , R １３ , R １４ , R １５ The definition of A process for preparing the compound of claim 6.

8. 1. A pharmaceutical composition comprising: A compound of general formula I according to claim 1, or a tautomer, solvate or a pharma- ceutically acceptable salt thereof; and a pharma- ceutical composition comprising the compound of formula (I) and a pharma- ceutical acceptable carrier.

9. (a) as an FXR agonist, or (b) as a drug for treating FXR-related diseases, 2. A compound of general formula I as defined in claim 1, or a tautomer, solvate or a pharma- ceutically acceptable salt thereof, for use.

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