FXR small molecule agonist and its preparation method and use

Abstract

The present invention discloses a potent small molecule FXR agonist, its preparation method, and use. The structure is shown in Formula I. The substituents in the formula are defined as described in the specification and claims. The compound of the present invention has the advantages of high FXR agonist activity, simple synthesis, and readily available raw materials, and can be used to prepare drugs for treating FXR-related diseases. #imgabs0#

Description

Technical Field

[0001] The present invention relates to the field of medicine, specifically to compounds that act as FXR agonists, their preparation, and use. Specifically, the invention relates to non-steroidal compounds that act as FXR agonists, their enantiomers, diastereomers, tautomers, solvates, prodrugs, or pharmaceutically acceptable salts thereof, their preparation methods, and their use in preparing medicaments for treating FXR-related diseases. Background Art

[0002] Nuclear receptors are widely present in organisms and are a class of nuclear transcriptional regulators activated by specific ligands. Metabolic nuclear receptors are a type of nuclear receptor that regulate metabolism, cell proliferation, apoptosis, and other processes in the body. The farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, was first discovered by Foman et al. in 1995 and named because its transcriptional activity is enhanced by farnesoids.

[0003] The FXR structure is a typical nuclear receptor, consisting of an amino-terminal ligand-independent transcriptional activation domain (AF1), a DNA-binding domain (DBD), a hinge region, a ligand-binding domain (LBD), and a carbon-terminal ligand-dependent transcriptional activation domain (AF2). FXR is activated in vivo by bile acids and participates in bile acid metabolism, lipid metabolism, and glucose metabolism. FXR regulates bile acid metabolism and transport primarily by modulating the transcription of cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis. Although FXR does not directly act on the CYP7A1 promoter, it can induce the expression of its small heterodimer partner (SHP) and bind to hepatocyte nuclear factor 4α (HNF-4α) and liver receptor homolog (LRH-1), thereby downregulating CYP7A1 transcription. During lipid metabolism, FXR in the liver regulates lipid metabolism and transport by directly or indirectly regulating PPARα, very low density lipoprotein receptor (VLDLR), proprotein convertase subtilisinkexin type 9 (PCSK9), scavenger receptor group B type 1 (SRB1), phosphor lipid transfer protein (PLTP), liver X receptor (LXR), sterol regulatory element-binding protein-1C (SREBP-1C), fatty acid synthetase (FAS), and activated lipoprotein lipase (LPL), thereby lowering plasma free fatty acids and triglycerides. During glucose metabolism, FXR activation promotes hepatic glycogen synthesis and increases insulin sensitivity and secretion, thereby controlling blood glucose levels. Since FXR plays an important role in bile acid metabolism, lipid metabolism and glucose metabolism, FXR ligand small molecule compounds are expected to become new drugs for the treatment of metabolic-related diseases such as hypertriglyceridemia, type 2 diabetes, metabolic syndrome and NAFLD. Summary of the Invention

[0004] The purpose of the present invention is to provide a small molecule FXR agonist and its preparation method and use.

[0005] The first aspect of the present invention provides a compound represented by general formula I, or a tautomer, solvate, prodrug or pharmaceutically acceptable salt thereof,

[0006]

[0007] Among them, R 11 、R 12 、R 13 、R 14 、R 15 are independently hydrogen, halogen, halogenated C 1-6 Alkyl, halogenated C1-C6 alkoxy, C1-C6 alkyl, C 1-6 Alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, cyano or nitro;

[0008] R 2 C6-C 12 Aryl, C1-C6 alkyl or C3-C6 cycloalkyl;

[0009] A is a substituted or unsubstituted group: phenyl, pyridyl, thienyl, furyl, indazolyl, indolyl, benzothienyl, benzofuranyl, wherein the substitution refers to one, two, or three substituents selected from the group consisting of halogen, C1-C6 alkyl, halogenated C 1-6 Alkyl, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy.

[0010] In another preferred embodiment, R 11 、R 12 、R 13 、R 14 、R 15 Each is independently hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, or trifluoromethoxy.

[0011] In another preferred embodiment, R 12 、R 13 、R 14 For hydrogen.

[0012] In another preferred embodiment, R 11 、R 15 Each is independently hydrogen, chlorine, bromine, trifluoromethyl, or trifluoromethoxy.

[0013] In another preferred embodiment, R 2 is phenyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl or cyclopentyl.

[0014] In another preferred embodiment, A is a substituted or unsubstituted group: phenyl, pyridyl, and the substitution refers to having one or two substituents selected from the following group: fluorine, chlorine, bromine, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C3-C6 cycloalkoxy.

[0015] In another preferred embodiment, A is substituted or unsubstituted by the following groups: phenyl, pyridyl, preferably, A is substituted or unsubstituted by the following groups: phenyl, pyridyl, indolyl, and the substitution refers to having one or two substituents selected from the following group: fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, methyl, ethyl, propyl.

[0016] In the present invention, when there are two or more substituents, each substituent may be the same or different.

[0017] In another preferred embodiment, A is phenyl,

[0018] In another preferred embodiment, the pharmaceutically acceptable salts of the present invention refer to salts formed with inorganic acids such as phosphoric acid, sulfuric acid, and hydrochloric acid, or organic acids such as acetic acid, tartaric acid, citric acid, and malic acid, or acidic amino acids such as aspartic acid and glutamic acid, or salts formed with inorganic bases, such as sodium, potassium, calcium, aluminum salts and ammonium salts.

[0019] In another preferred embodiment, the compound is:

[0020]

[0021] The second aspect of the present invention provides a method for preparing the compound of the first aspect, comprising the following steps:

[0022]

[0023] (a') reacting the compound represented by formula VII with hydroxylamine hydrochloride to form the compound represented by formula VIII;

[0024] (b') the compound represented by the general formula VIII reacts with phosgene, triphosgene, carbonyldiimidazole or thiocarbonyldiimidazole to generate the compound represented by the general formula I,

[0025] Among them, R 2 ,A,R 11 、R 12 、R 13 、R 14 、R 15 The definition of is as mentioned above.

[0026] In another preferred embodiment, the compound represented by general formula VII is prepared by the following steps:

[0027]

[0028] a) using a substituted benzaldehyde compound represented by the 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 obtain a compound represented by the general formula III;

[0029] b) reacting the compound of formula III with 3-oxopropionic acid ester to obtain the compound of formula IV;

[0030] c) reducing the ester in the compound of formula IV to generate an alcohol, and then brominating the alcohol to generate the compound shown in formula V,

[0031] d) reacting the compound represented by formula V with endo-8-azabicyclo[3.2.1]octan-3-ol to form the compound represented by formula VI;

[0032] e) the compound represented by the general formula VI is coupled with Br-A-CN under the catalysis of copper or palladium to obtain the compound represented by the general formula VII,

[0033] In various types, R 2 ,A,R 11 、R 12 、R 13 、R 14 、R 15 The definition of is as mentioned above.

[0034] In another preferred embodiment, the compound represented by general formula VII is prepared by the following steps:

[0035]

[0036] f) reacting endo-8-azabicyclo[3.2.1]octan-3-ol with FA-CN to form a compound of formula IX;

[0037] g) reacting the compound represented by the general formula V with the compound represented by the general formula IX to produce the compound represented by the general formula VII,

[0038] In various types, R 2 ,A,R 11 、R 12 、R 13 、R 14 、R 15 The definition of is as mentioned above.

[0039] The third aspect of the present invention provides a pharmaceutical composition comprising:

[0040] The compound represented by the general formula I of the first aspect, or its tautomer, solvate, prodrug or pharmaceutically acceptable salt; and

[0041] Pharmaceutically acceptable carrier.

[0042] The compounds provided by the present invention can be used alone or mixed with pharmaceutically acceptable excipients (such as excipients, diluents, etc.) to prepare oral tablets, capsules, granules or syrups, etc. The pharmaceutical composition can be prepared according to conventional pharmaceutical methods.

[0043] The fourth aspect of the present invention provides the use of the compound of formula I described in the first aspect, or its tautomer, solvate, prodrug or pharmaceutically acceptable salt, (a) as an FXR agonist; or

[0044] (b) for preparing a medicament for treating FXR-related diseases.

[0045] In another preferred embodiment, the FXR-related disease is a disease related to bile acid metabolism, sugar metabolism, lipid metabolism, inflammation, and / or liver fibrosis.

[0046] In another preferred embodiment, the FXR-related disease is non-alcoholic fatty liver disease (NASH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), gallstones, non-alcoholic cirrhosis, liver fibrosis, cholestatic liver disease, hyperlipidemia, hypercholesterolemia or diabetes.

[0047] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equal, or similar purpose. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0048] After extensive and in-depth research, the inventors of this application have developed a class of nonsteroidal compounds that act as FXR agonists, exhibiting FXR agonism at both the molecular and cellular levels. These compounds possess 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. This has led to the completion of the present invention.

[0049] the term

[0050] In the present invention, the halogen is F, Cl, Br or I.

[0051] In the present invention, unless otherwise specified, the terms used have the general meanings commonly known to those skilled in the art.

[0052] In the present invention, the term "C1-C6" refers to a group having 1, 2, 3, 4, 5 or 6 carbon atoms, "C1-C8" refers to a group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and so on. "3-10 membered" refers to a group having 3-10 ring atoms, and so on.

[0053] In the present invention, the term "alkyl" refers to a saturated linear or branched hydrocarbon moiety. For example, the term "C1-C6 alkyl" refers to a straight or branched 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, etc.; preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

[0054] In the present invention, the term "alkoxy" refers to an -O-(C1-C6 alkyl) group. For example, the term "C1-C6 alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy.

[0055] In the present invention, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon moiety, for example, the term "C3-C 10 "Cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl. The terms "C3-C8 cycloalkyl", "C3-C7 cycloalkyl", and "C3-C6 cycloalkyl" have similar meanings.

[0056] In the present invention, the term "cycloalkoxy" means cycloalkyl-O-, and the cycloalkyl group is as defined above.

[0057] 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 cycloazapentane ring, cycloazahexane ring, cycloazaheptane ring and the like.

[0058] In the present invention, the term "aryl" refers to a hydrocarbon moiety containing one or more aromatic rings. For example, the term "C6-C 12 "Aryl" refers to an aromatic ring group with 6 to 12 carbon atoms and no heteroatoms in the ring, such as phenyl, naphthyl, etc. The term "C6-C 10 Examples of aryl groups include, but are not limited to, phenyl (Ph), naphthyl, pyrenyl, anthracenyl, and phenanthrenyl.

[0059] In the present invention, the term "heteroaryl" 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 heterocyclyl" refers to a saturated or unsaturated 3-12 membered ring group containing 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen, such as dioxolanyl. The term "3-7 membered heterocyclyl" has a similar meaning. Examples of heteroaryl groups include furanyl, fluorenyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolinyl, isoquinolinyl, and indolyl.

[0060] In the present invention, the term "heterocyclyl" refers to a cyclic group containing at least one ring heteroatom (such as N, O or S), such as furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, quinolyl, isoquinolyl, indolyl, pyrimidinyl, tetrahydropyridyl, pyrrolinyl, dihydropyridyl, dihydrofuranyl, dihydrothienyl, pyranyl.

[0061] Unless otherwise specified, the alkyl, alkoxy, cycloalkyl, heterocyclyl and aryl groups described herein are substituted and unsubstituted groups. Possible substituents on alkyl, alkoxy, cycloalkyl, heterocyclyl and aryl groups include, but are not limited to, hydroxy, amino, nitro, nitrile, halogen, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl, C1-C20 heterocycloalkyl, C1-C20 heterocycloalkenyl, C1-C6 alkoxy, aryl, heteroaryl, heteroaryloxy, C1-C10 alkylamino ... C20 dialkylamino, arylamino, diarylamino, C1-C10 alkylsulfamoyl, arylsulfamoyl, C1-C10 alkylimino, C1-C10 alkylsulfoimino, arylsulfoimino, mercapto, C1-C10 alkylthio, C1-C10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, guanidino, urea, cyano, acyl, thioacyl, acyloxy, carboxyl, and carboxylate groups. On the other hand, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl groups may be fused to each other.

[0062] In the present invention, the substitution is mono- or poly-substituted, and the poly-substituted is di-, tri-, tetra-, or penta-substituted. The di-substituted refers to having two substituents, and so on.

[0063] Pharmaceutically acceptable salts of the present invention can be salts formed by positively charged groups on anions and compounds of formula I. Suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, toluenesulfonate, tartrate, fumarate, glutamate, glucuronide, lactate, glutarate or maleate. Similarly, salts can be formed by negatively charged groups on cations and compounds of formula I. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion and ammonium ion, such as tetramethylammonium ion.

[0064] In another preferred embodiment, "pharmaceutically acceptable salts" refer to salts formed by the compound of formula I with 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, 2-acetoxybenzoic acid and isethionic acid; or sodium salts, potassium salts, calcium salts, aluminum salts or ammonium salts formed by the compound of formula I with an inorganic base; or methylamine salts, ethylamine salts or ethanolamine salts formed by the compound of general formula I with an organic base.

[0065] Preparation method

[0066] The preparation method of the compound represented by general formula I of the present invention has the following synthetic route:

[0067]

[0068] The preparation method comprises the following steps:

[0069] a) using substituted benzaldehyde as a starting material, reacting it with hydroxylamine hydrochloride in the presence of a base to obtain an intermediate, which is then chlorinated with N-chlorosuccinimide (NCS) to form a compound represented by formula III;

[0070] b) reacting the compound of formula III with the corresponding 3-oxopropionic acid ester under alkaline conditions to form a compound of formula IV;

[0071] c) The ester in the compound shown in general formula IV is reduced with a reducing agent to generate the corresponding alcohol, which is then brominated to generate the compound shown in V,

[0072] d) reacting the compound represented by the general formula V with endo-8-azabicyclo[3.2.1]octan-3-ol in the presence of a base to form the compound represented by the general formula VI;

[0073] e) coupling the compound represented by the general formula VI with Br-A-CN under the catalysis of copper or palladium to obtain the cyano compound represented by the general formula VII;

[0074] a') reacting the compound represented by the general formula VII with hydroxylamine hydrochloride in the presence of a base to generate a compound represented by the general formula VIII;

[0075] b') The compound represented by the general formula VIII reacts with phosgene, triphosgene, carbonyldiimidazole or dimethyl carbonate to generate the compound represented by the general formula I.

[0076]

[0077] The cyano compound represented by the general formula VII can also be prepared by the above route, comprising the following steps:

[0078] f) replacing the fluorine in FA-CN with the amino group in endo-8-azabicyclo[3.2.1]octan-3-ol under the action of a base to generate compound IX;

[0079] g) directly reacting the compound represented by the general formula V with the prepared IX in the presence of a base to form a compound represented by the general formula VI;

[0080] Among them, R 2 、R 11 、R 12 、R 13 、R 14 、R 15 , and A ring are defined as above.

[0081] 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, butyl lithium, lithium diisopropylamide;

[0082] 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;

[0083] The reducing agent in step c) is selected from sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium aluminum hydride, diisopropylaluminum hydride, and borane;

[0084] The copper catalyst in step e) is cuprous iodide, cuprous oxide, or cuprous sulfate; the palladium catalyst is palladium acetate, tetrakis(triphenylphosphine)palladium, bis(acetonitrile)palladium(II) chloride, palladium dichloride, tris(dibenzylideneacetone)dipalladium, bistriphenylphosphine palladium dichloride, tris(dibenzylideneacetone)dipalladium-chloroform adduct, or 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride.

[0085] Pharmaceutical composition

[0086] The present invention also provides a pharmaceutical composition comprising an active ingredient within a safe and effective amount and a pharmaceutically acceptable carrier.

[0087] The "active ingredient" of the present invention refers to the compound of formula I of the present invention.

[0088] The "active ingredients" and pharmaceutical compositions described herein are used to prepare medicaments for treating FXR-related diseases. The "active ingredients" and pharmaceutical compositions described herein can be used as FXR agonists. In another preferred embodiment, they are used to prepare medicaments for preventing and / or treating diseases modulated by FXR agonists.

[0089] A "safe and effective amount" refers to an amount of the active ingredient sufficient to significantly improve the condition without causing serious side effects. Typically, a pharmaceutical composition contains 1-2000 mg of active ingredient per dose, more preferably 10-200 mg per dose. Preferably, "one dose" is one tablet.

[0090] "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" here means that the components in the composition can be mixed with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0091] There is no particular limitation on the administration of the active ingredient or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.

[0092] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0093] 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 commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0094] In addition to the active ingredients, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0095] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0096] The compounds of the present invention can be administered alone or in combination with other therapeutic drugs (such as lipid-lowering drugs).

[0097] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 0.1 to 200 mg, preferably 0.5 to 5 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0098] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally performed under conventional conditions (such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989)) or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0099] Unless otherwise defined, all technical and scientific terms used herein have the same meanings 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 methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0100] The instruments and main experimental materials used are as follows:

[0101] All reagents and anhydrous solvents were purchased from Chinese commercial companies and used directly unless otherwise specified. 1H and 13C NMR were performed using Bruker AM-400 and Varian Mercury plus-400 NMR instruments, respectively. Mass spectrometry was performed using an Agilent 6230 mass spectrometer with 200-300 mesh silica gel column chromatography (Qingdao Ocean Chemical Plant) and HSGF254 TLC plates (Yantai Chemical Research Institute).

[0102] Line 1

[0103]

[0104] Route 2

[0105]

[0106] Example 1:

[0107]

[0108] Synthesis of intermediate V-1:

[0109]

[0110] Aqueous potassium carbonate (3N, 182 mmol) was added dropwise to a stirred solution of hydroxylamine hydrochloride (182 mmol) in ethanol (100 mL) at 0°C. 2,6-Dichlorobenzaldehyde (20 g, 114 mmol) was dissolved in 100 mL of ethanol and added to the hydroxylamine solution. The temperature was raised to 90°C and the reaction was allowed to proceed for two hours. The mixture was allowed to cool to room temperature and then concentrated to a solid. A water / ethanol solution (1000 mL / 100 mL) was added and stirred to break up the solid. The solid was filtered and dried under vacuum at 50°C overnight to yield the intermediate compound (18.4 g). This intermediate was dissolved in N,N-dimethylformamide (50 mL) and a solution of N-chlorosuccinimide (97 mmol) in N,N-dimethylformamide (100 mL) was added dropwise at 0°C and stirred overnight. The reaction mixture was poured into ice-cold water at 0°C, then extracted with methyl tert-butyl ether (200 mL each, three times). The organic phase was washed with saturated brine and concentrated to yield the crude product. n-Hexane (600 mL) was added to the flask containing the crude product, stirred with a magnetic stirrer, filtered, and the solid dried under vacuum (30°C) to yield Intermediate III-1 (18.3 g, 73% yield). 1 H NMR (400MHz, CDCl3) δ7.43–7.39(m,2H),7.39–7.33(m,1H).

[0111] Triethylamine (8.2 g) was added to methyl 3-cyclopropyl-3-oxopropionate (82 mmol) and stirred for 30 minutes. The mixture was then cooled to 10°C and a solution of III-1 (18.3 g, 82 mmol) in anhydrous ethanol (80 mL) was added dropwise (with the internal temperature not exceeding 30°C). The reaction was allowed to proceed overnight at room temperature. Ethyl acetate (100 mL) was added to dilute the reaction solution, washed with water, and the aqueous phase was extracted with ethyl acetate (100 mL each, 3 times). The organic phases were mixed, washed with saturated brine, and concentrated. 100 mL of ether was added to the concentrate and stirred. The solvent was removed under vacuum to obtain a solid product IV-1 (21.6 g, 84% yield). 1 H NMR (400MHz, CDCl3) 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).

[0112] IV-1 (21.6 g, 69 mmol) was dissolved in tetrahydrofuran (140 mL) and cooled to 0°C. A 1.5 M solution of diisobutylaluminum hydride in toluene (102 mL) was slowly added dropwise to the solution, and the reaction mixture was stirred at room temperature for 6 h. The reaction mixture was slowly poured into ice water, and the pH was adjusted to approximately 2 by adding 1 M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (100 mL each, three times), concentrated, and subjected to column chromatography to obtain the intermediate alcohol. This intermediate and triphenylphosphine (59 mmol) were dissolved in dichloromethane (60 mL), cooled to 0°C, and a solution of carbon tetrabromide (62 mmol) in dichloromethane (60 mL) was added dropwise under nitrogen. The reaction mixture was allowed to react at room temperature for 4 h. The solvent was removed from the reaction mixture to obtain an oil, which was purified by column chromatography to obtain intermediate V-1 (15.3 g, 96% yield). 1 H NMR (400MHz, CDCl3) 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).

[0113] Example 1 Synthesis:

[0114]

[0115] To a solution of tert-butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (1.5 g, 6.5 mmol) in anhydrous tetrahydrofuran (20 mL) at 0°C was added potassium tert-butoxide (6.5 mmol) and stirred for 30 minutes. Then, a solution of V-1 (4.3 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise and allowed to react for 8 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL each, 3 times). The organic phase was washed with saturated brine, concentrated, and column chromatography to obtain the crude intermediate. The intermediate was dissolved in dichloromethane (8 mL), cooled to 0°C, and trifluoroacetic acid (8 mL) was added dropwise. The mixture was stirred at room temperature for 3 hours. The solvent was removed under vacuum, and ethyl acetate (20 mL) was added to dissolve the mixture. The mixture was washed with 2N sodium hydroxide solution and saturated brine, and the solvent was removed to obtain intermediate VI-1 (1.1 g, 72% yield). 1 H NMR(400MHz, CDCl3)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).

[0116] Intermediate VI-1 (1.0 g, 2.7 mmol), 3-bromobenzonitrile (4.1 mmol), sodium tert-butoxide (5.4 mmol), palladium acetate (0.14 mmol), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (0.27 mmol) were added to a round-bottom flask. Toluene (80 mL) was added under nitrogen, and the mixture was heated to reflux and allowed to react overnight. The reaction solution was cooled to room temperature, added with water, extracted, and concentrated. Intermediate VII-1 (0.56 g, 43% yield) was obtained by column chromatography. 1 H NMR (400MHz, CDCl3) 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).

[0117] VII-1 (0.4 g, 0.9 mmol), hydroxylamine hydrochloride (2.3 mmol), and anhydrous ethanol (5 mL) were added to a round-bottom flask with stirring. Triethylamine (2.3 mmol) was slowly added dropwise and heated to 80°C for 4 h. The mixture was cooled to room temperature, the solvent was removed, and the mixture was dissolved in ethyl acetate (15 mL). The mixture was washed with water and saturated brine. The organic phase was concentrated and purified by silica gel column chromatography to obtain intermediate VIII-1 (0.42 g, 95% yield).

[0118] VIII-1 (0.41 g, 0.83 mmol), N,N'-carbonyldiimidazole (1.0 mmol), and 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). The mixture was heated to 100°C and reacted for 3 hours. The reaction solution was cooled to room temperature, diluted with water (5 mL), and the pH was adjusted to approximately 2 with 1M hydrochloric acid. The solution was then extracted with ethyl acetate (4 mL each, three times). The organic phases were combined, washed with saturated brine, and concentrated to obtain the crude product, which was then purified by silica gel column chromatography to afford the final product 1 (0.29 g, 64% yield).

[0119] 1 H NMR(400MHz, CDCl3)δ7.60(d,J=8.8Hz,2H),7.44–7.32(m,3H),6.70(d,J=9.0Hz,2H),4.25(s,2H),4.12–4.0 8(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] + .

[0120] Example 2:

[0121]

[0122] Example 2 was prepared according to the procedure of Reference Example 1, starting from Intermediate VI-1 and prepared by Route 1. The synthetic route is as follows:

[0123]

[0124] Compound 2 was synthesized from raw material V-1 according to the synthesis method of compound 1, wherein

[0125] 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).

[0126] 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).

[0127] White solid 2 yield 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] + .

[0128] Example 3:

[0129]

[0130] Synthesis of intermediate V-3:

[0131]

[0132]

[0133] 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 and heated to 130°C for 12 h. The mixture was cooled to room temperature, 30 mL of water was added, filtered, and the solid was washed with water to afford Intermediate IX-3 (3.2 g, 93% yield). A white solid was obtained with a yield of 94%. 1 H NMR (400MHz, CDCl3) δ8.41(d,J=1.8Hz,1H),7.58(dd,J=9.0,2.3Hz,1H),6.49(d,J=8.9Hz ,1H),4.91–4.26(m,2H),4.12(t,J=4.7Hz,1H),2.39(d,J=7.3Hz,2H),2.18–1.81(m,6H);

[0134] Compound V-3 was synthesized from raw material II-3 according to the synthesis method of compound V-1, wherein

[0135] The yield of white solid IV-3 was 64%. 1 H NMR (400MHz, CDCl3) 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).

[0136] The yield of colorless liquid V-3 was 82%. 1 H NMR (400MHz, CDCl3) 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).

[0137] Starting from raw materials V-3 and IX-3, compound intermediate VII-3 was synthesized according to the synthesis method of compound VII-1. The product was a white solid with a yield of 51%. 1H NMR(400MHz, CDCl3)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=9.0Hz,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).

[0138] Compound 3 was synthesized from raw material VII-3 according to the synthesis method of compound 1 as a white solid with a yield of 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] + .

[0139] Example 4:

[0140]

[0141] Example 4 Synthesis route is as follows:

[0142]

[0143] Starting from raw materials V-1 and IX-3, compound intermediate VII-4 was synthesized according to the synthesis method of compound VII-3. It is a white solid with a yield of 72%. 1 H NMR(400MHz, CDCl3)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=9.0 Hz,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).

[0144] Compound 4 was synthesized from raw material VII-4 according to the synthesis method of compound 1. White solid, yield 47%; 1H 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] + .

[0145] Example 5:

[0146]

[0147]

[0148] Compound 5 was synthesized from raw material II-5 according to the synthesis method of compound 3, wherein

[0149] The yield of white solid IV-5 was 58%. 1 H NMR(400MHz, CDCl3)δ7.82(d,J=7.5Hz,1H),7.74–7.59(m,2H),7.56(d,J=7.5H z,1H),3.3.73(s,3H),2.19–2.09(m,1H),1.33–1.27(m,2H),1.24–1.15(m,2H).

[0150] The yield of colorless liquid V-5 was 88%. 1 H NMR(400MHz, CDCl3)δ7.84(d,J=7.4Hz,1H),7.73–7.61(m,2H),7.57(d,J=7.4 Hz,1H),4.23(s,2H),2.17–2.09(m,1H),1.32–1.27(m,2H),1.23–1.17(m,2H).

[0151] Starting from raw materials V-5 and IX-3, compound intermediate VII-5 was synthesized according to the synthesis method of compound VII-3. It is a white solid with a yield of 63%. 1H NMR(400MHz, CDCl3)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).

[0152] Compound 5 was synthesized from raw material VII-5 according to the synthesis method of compound 1. White solid, yield 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] + .

[0153] Example 6:

[0154]

[0155]

[0156] Compound V-6 was synthesized from raw material II-6 according to the synthesis method of compound 3, wherein

[0157] The yield of white solid IV-6 was 59%. 1 H NMR (400MHz, CDCl3) 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).

[0158] The yield of colorless liquid V-6 was 82%. 1 H NMR (400MHz, CDCl3) 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).

[0159] Starting from raw materials V-6 and IX-3, compound intermediate VII-6 was synthesized according to the synthesis method of compound VII-3. It is a white solid with a yield of 79%. 1 H NMR(400MHz, CDCl3)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).

[0160] Compound 6 was synthesized from raw material VII-6 according to the synthesis method of compound 1. White solid, yield 51%; 1 H 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] + .

[0161] Example 7:

[0162]

[0163]

[0164] Intermediate IX-7 was synthesized from endo-8-azabicyclo[3.2.1]octan-3-ol and 2,4-difluorobenzonitrile according to the synthesis method of compound IX-3. It was a white solid in 64% yield. 1 H NMR (400MHz, CDCl3) 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).

[0165] Starting from raw materials V-3 and IX-7, compound intermediate VII-7 was synthesized according to the synthesis method of compound VII-3. It is a white solid with a yield of 84%. 1H NMR(400MHz, CDCl3)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,2H),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).

[0166] Compound 7 was synthesized from raw material VII-7 according to the synthesis method of compound 1. White solid, yield 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,2H),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] + .

[0167] Example 8:

[0168]

[0169] Example 8 Synthesis route is as follows:

[0170]

[0171] Starting from raw materials V-1 and IX-7, compound intermediate VII-8 was synthesized according to the synthesis method of compound VII-3. It is a white solid with a yield of 75%. 1 H NMR (400MHz, CDCl3) 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).

[0172] Compound 7 was synthesized from raw material VII-7 according to the synthesis method of compound 1. White solid, yield 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] + .

[0173] Example 9:

[0174]

[0175] Example 9 Synthesis route is as follows:

[0176]

[0177] Starting from raw materials V-5 and IX-7, compound intermediate VII-9 was synthesized according to the synthesis method of compound VII-3. It is a white solid with a yield of 78%. 1 H NMR (400MHz, CDCl3) 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).

[0178] Compound 9 was synthesized from raw material VII-9 according to the synthesis method of compound 1. White solid, yield 55%; 1 H 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(m8H),1.18–1.02(m,4H).MS(ESI,m / z): 571[M+H] + .

[0179] Example 10:

[0180]

[0181] Example 10 The synthetic route is as follows:

[0182]

[0183] Starting from raw materials V-6 and IX-7, compound intermediate VII-10 was synthesized according to the synthesis method of compound VII-3. It is a white solid with a yield of 70%. 1 H NMR (400MHz, CDCl3) 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,1 H), 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).

[0184] Compound 10 was synthesized from raw material VII-10 according to the synthesis method of compound 1. White solid, yield 70%; 1 H 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] + .

[0185] Example 11:

[0186]

[0187]

[0188] Compound V-11 was synthesized from raw material II-11 according to the synthesis method of compound V-1, wherein

[0189] The yield of white solid IV-11 was 54%. 1 H NMR (400MHz, CDCl3) δ7.52–7.44(m,2H),7.32–7.26(m,1H),7.21(d,J=8.5Hz,1H),6.46( t,J=73.7Hz,1H),3.72(s,3H),2.88–2.80(m,1H),1.37–1.32(m,2H),1.26–1.22(m,2H).

[0190] The yield of colorless liquid V-11 was 72%. 1H NMR (400MHz, CDCl3) 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).

[0191] Starting from raw materials V-11 and IX-3, compound intermediate VII-11 was synthesized according to the synthesis method of compound VII-3. The product was a white solid with a yield of 66%. 1 H NMR (400MHz, CDCl3) 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,1 H),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).

[0192] Compound 11 was synthesized from raw material VII-11 according to the synthesis method of compound 1 as a white solid with a yield of 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] + .

[0193] Example 12:

[0194]

[0195] Example 12 Synthesis route is as follows:

[0196]

[0197] Compound V-12 was synthesized from raw material II-12 according to the synthesis method of compound V-1, wherein

[0198] The yield of white solid IV-12 was 54%. 1H NMR (400MHz, CDCl3) 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).

[0199] The yield of colorless liquid V-12 was 72%. 1 H NMR (400MHz, CDCl3) 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).

[0200] Starting from raw materials V-12 and IX-3, compound intermediate VII-12 was synthesized according to the synthesis method of compound VII-3. The product was a white solid with a yield of 64%. 1 H NMR(400MHz, CDCl3)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).

[0201] Compound 12 was synthesized from raw material VII-12 according to the synthesis method of compound 1 as a white solid with a yield of 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=9.0Hz,1H),4.4 2(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] + .

[0202] Example 13:

[0203]

[0204] Example 13 Synthesis route is as follows:

[0205]

[0206] Starting from raw materials V-11 and IX-3, compound intermediate VII-13 was synthesized according to the synthesis method of compound VII-3. The product was a white solid with a yield of 69%. 1 H NMR(400MHz, CDCl3)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).

[0207] Compound 13 was synthesized from raw material VII-13 according to the synthesis method of compound 1 as a white solid with a yield of 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] + .

[0208] Example 14:

[0209]

[0210] Example 14 Synthesis route is as follows:

[0211]

[0212] Starting from raw materials V-12 and IX-3, compound intermediate VII-42 was synthesized according to the synthesis method of compound VII-10. The product was a white solid with a yield of 49%. 1 H NMR (400MHz, CDCl3) 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).

[0213] Compound 40 was synthesized from raw material VII-40 according to the synthesis method of compound 1 as a white solid with a yield of 61%. 1 H NMR (400MHz, CDCl3) 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] + .

[0214] Pharmacological Experiment Example

[0215] FXR molecular activity test method

[0216] FXR activity was measured using recombinant GST-FXR fusion protein using Perkin Elmer's AlphaScreen assay. The reaction was performed in a 384-well plate with a total reaction volume of 15 μL. Acceptor beads and The mixed solution of donor microbeads was reacted in a buffer containing: Tris-HCl 50mM (pH 7.4), 50mM NaCl, BSA 0.1%, 1mM DTT, and the fluorescence signal intensity at a wavelength of 570nm was detected by Envision fluorescence detector to reflect FXR activity. 50 The values were calculated using Graphpad Prism 5 software (A = EC50 < 10 nM; B = 10 nM <EC50<100nΜ;C=100nΜ<EC50<1000nΜ;D> 1000nM).

[0217] FXR cell-level activity assay

[0218] FXR expression plasmid and FXRE luciferase reporter plasmid were co-transfected into 293T cells at a ratio of 1:9 and 5*10 5Transfected cells were seeded into 96-well flat-bottom microplates (ViewPlate-96, White 96-well Microplate with Clear Bottom, PerkinElmer) at 1:1 ratio per well. The cells were cultured for 24 hours to ensure plasmid expression, and the FXR receptor agonist to be tested was added. After 18 hours of exposure to the test compound, fluorescence intensity was measured using a luciferase kit (steady-Glo Luciferase Assay system) to reflect the compound's FXR receptor activation efficiency.

[0219]

[0220] In the initial screening, the test compound and two positive compounds, OCA and GW4064, were treated with 10 μM to act on the cells. The relative activity of the test compound against the two positive compounds was measured (relative activity = (test compound signal intensity - blank) / (positive compound signal intensity - blank) * 100%). Compounds with relative activity higher than 50% of the positive compounds were selected for secondary screening. The appropriate concentration range was selected and the dose-dependent relationship, i.e., EC 50 Value (A=EC50<0.1nM; B=0.1nM <EC50<1nΜ;C=1nΜ<EC50<10nΜ;D=10nΜ<EC50<100nΜ;E> 100nM).

[0221] Table 1 Activity test results

[0222]

[0223]

[0224] Conclusion: Test results demonstrate that the compounds described herein exhibit potent FXR agonism at both the molecular and cellular levels. Compounds with inward-facing configurations exhibit significantly greater activity than their exo-facing counterparts, with the difference in FXR molecular activity at least 10-fold. For example, Compounds 1 and 2, with inward-facing configurations, exhibit significantly greater activity than Compound 2 with exo-facing configurations (a difference of over 100-fold in FXR molecular activity), with the inward-facing compound significantly outperforming both positive controls.

[0225] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that 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 that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound represented by general formula I or a pharmaceutically acceptable salt thereof, in, R 11 、R 12 、R 13 、R 14 、R 15 are independently hydrogen, halogen, halogenated C 1-6 Alkyl, halogenated C1-C6 alkoxy, C1-C6 alkyl, C 1-6 alkoxy; R 2 is a C3 cycloalkyl group; A is a substituted or unsubstituted group: phenyl, pyridyl, wherein the substitution refers to having one, two, or three substituents selected from the group consisting of halogen, C1-C6 alkyl, halogenated C 1-6 Alkyl, halogenated C1-C6 alkoxy, C1-C6 alkoxy.

2. The compound according to claim 1, wherein R 11 、R 12 、R 13 、R 14 、R 15 Each is independently hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, or trifluoromethoxy.

3. The compound according to claim 1, wherein R 12 、R 13 、R 14 For hydrogen.

4. The compound according to claim 1, wherein R 11 、R 15 Each is independently hydrogen, chlorine, bromine, trifluoromethyl, or trifluoromethoxy.

5. The compound according to claim 1, wherein R 2 It is cyclopropyl.

6. The compound according to claim 1, wherein A is a substituted or unsubstituted group: phenyl, pyridyl, wherein the substitution refers to having one or two substituents selected from the following group: fluorine, chlorine, bromine, C1-C4 alkyl, C1-C4 alkoxy.

7. The compound according to claim 1, wherein A is a substituted or unsubstituted group: phenyl, pyridyl, wherein the substitution refers to having one or two substituents selected from the following group: fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, methyl, ethyl, propyl.

8. The compound according to claim 1, wherein A is phenyl, 9. The compound according to claim 1, wherein The compound is:

10. The method for preparing the compound according to claim 1, wherein The preparation method comprises the following steps: (a') reacting the compound represented by formula VII with hydroxylamine hydrochloride to form the compound represented by formula VIII; (b') the compound represented by the general formula VIII reacts with phosgene, triphosgene, carbonyldiimidazole or dimethyl carbonate to generate the compound represented by the general formula I, Among them, R 2 ,A,R 11 、R 12 、R 13 、R 14 、R 15 The definition as in claim 1.

11. The method for preparing the compound according to claim 10, wherein The compound represented by general formula VII is prepared by the following steps: a) using a substituted benzaldehyde compound represented by the 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 obtain a compound represented by the general formula III; b) reacting the compound of formula III with 3-oxopropionic acid ester to obtain the compound of formula IV; c) reducing the ester in the compound of formula IV to generate an alcohol, and then brominating the alcohol to generate the compound shown in formula V, d) reacting the compound represented by formula V with endo-8-azabicyclo[3.2.1]octan-3-ol to form the compound represented by formula VI; e) coupling the compound represented by the general formula VI with Br-A-CN under the catalysis of copper or palladium to obtain the compound represented by the general formula VII; In various types, R 2 ,A,R 11 、R 12 、R 13 、R 14 、R 15 As defined in claim 1, Alternatively, the compound represented by the general formula VII is prepared by the following steps: f) reacting endo-8-azabicyclo[3.2.1]octan-3-ol with FA-CN to form a compound of formula IX; g) reacting the compound represented by the general formula V with the compound represented by the general formula IX to produce the compound represented by the general formula VII, In various types, R 2 ,A,R 11 、R 12 、R 13 、R 14 、R 15 The definition as in claim 1.

12. A pharmaceutical composition comprising: The compound of general formula I according to claim 1 or a pharmaceutically acceptable salt thereof; and Pharmaceutically acceptable carrier.

13. The use of the compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: Used for preparing drugs for treating FXR-related diseases, wherein the FXR-related diseases are bile acid metabolism, sugar metabolism, lipid metabolism, inflammation, and / or liver fibrosis diseases.

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