A cholesterol derivative, its preparation method and application

Abstract

This invention discloses a cholesterol derivative, its preparation method, and its applications. The structure is shown in Formula I, where the definitions of each substituent are as described in the specification and claims. The compound of this invention can effectively antagonize the FXR receptor.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, and specifically relates to a tricyclic FXR receptor antagonist, its preparation method, and the use of this type of FXR antagonist in FXR antagonistic activity. Background Technology

[0002] Besides their physiological functions such as promoting vitamin and lipid absorption, bile acids also participate in systemic metabolic regulation as signaling molecules. As signaling molecules, bile acids can bind to both membrane and nuclear receptors, with the farneside derivative receptor X (FXR) being a nuclear receptor specifically recognized by bile acids. FXR receptors play a crucial role in maintaining bile acid homeostasis. On one hand, activation of FXR receptors in the liver can induce the expression of small heterodimer chaperones (SHP), inhibiting the expression of rate-limiting enzymes CYP7A1 and CYP8B1 in the bile acid synthesis pathway, thereby reducing bile acid synthesis. On the other hand, activation of FXR receptors in intestinal epithelial cells can induce the expression of fibroblast growth factor 19 (FGF19, or FGF15 in mice). FGF19 / 15 binds to the FGFR4 receptor in the liver, inhibiting CYP7A1 expression and reducing bile acid synthesis. In addition, FXR receptors are closely related to glucose and lipid metabolism. Furthermore, studies have shown that FXR receptors are closely related to various diseases such as cholestasis and metabolic disorders.

[0003] Currently, multiple studies have shown that FXR antagonists can improve metabolism in mice. For example, researchers have found that metformin can alter the composition of the human gut microbiota, reduce the activity of bile salt hydrolases, thereby increasing the levels of FXR-antagonistic conjugated bile acids GUDCA and TUDCA, which inhibit intestinal FXR expression and improve metabolism, including hyperglycemia. Treatment of mice with the antioxidant Tempol also alters the gut microbiota, reduces bile salt hydrolases activity, and increases the level of conjugated bile acid T-β-MCA, thereby inhibiting FXR signaling. Inhibition of intestinal FXR signaling leads to improved mitochondrial function and inhibition of ceramide synthesis, resulting in decreased serum ceramide levels. Reduced circulating ceramides downregulate the expression of hepatic SREBP1C and CIDEA, thereby reducing hepatic steatosis. The natural FXR antagonist isoDCA can weaken immunostimulation by antagonizing FXR receptors in dendritic cells, increase the induction of Foxp3, and increase the number of intestinal CD4+ regulatory T cells, thus affecting gut health. Therefore, FXR antagonists offer new avenues for the treatment of some metabolic diseases.

[0004] Currently reported FXR antagonists can be divided into natural product-based and small molecule-based FXR antagonists. The most common natural product-based FXR antagonists are bound bile acids, including T-β-MCA, Gly-MAC, GUDCA, and TUDCA. Guggulaterone (GS) was the first reported FXR receptor antagonist; however, as an antagonist of bile acid-activated receptors, GS is not selective for FXR. In antagonism assays, GS reduced the FXR agonist activity of CDCA with an IC50 of 25 μM. IC50 values ​​for other nuclear receptors ranged from 0.32 to 62 μM. FLG249 is the first reported non-steroidal small molecule FXR receptor antagonist acting downstream of FXR in the mouse ileum. Oral administration of FLG249 downregulated the mRNA levels of FXR target genes Fgf15, Asbt, and Shp in the mouse ileum, and tissue distribution studies showed that FLG was mainly concentrated in the ileum.

[0005]

[0006] Currently available FXR antagonists have limited natural sources and are difficult to synthesize. There are few structural modifications to these compounds, and further research is needed. Summary of the Invention

[0007] The object of this invention is to provide a compound that can be used as a farnesoid derivative X receptor (FXR) antagonist.

[0008] In a first aspect, the present invention provides a compound of general formula (I), or a pharmaceutically acceptable salt thereof.

[0009]

[0010] In the formula,

[0011] R1 is selected from: hydrogen, hydroxyl, halogen, C1-C6 alkoxy, 3- to 10-membered cycloalkoxy, =O, =N-OH, Rd-C(=O)-O-; wherein Rd is a substituted or unsubstituted group of the following: C1-C8 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, 5-7-membered heteroaryl, RaNH- or RaO-; wherein each Ra is independently selected from: C1-C8 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, 5-7-membered heteroaryl;

[0012] R2 is hydrogen, hydroxyl, halogen, or C1-C6 alkyl; R3 is selected from: hydrogen, hydroxyl, halogen, C1-C6 alkoxy, 3- to 10-membered cycloalkoxy, Re-C(=O)-O- or Re-OC(=O)-; wherein each Re is independently hydrogen or substituted or unsubstituted of the following groups: C1-C8 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, 5-7-membered heteroaryl, RbNH- or RbO-; wherein each Rb is independently selected from: C1-C8 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, 5-7-membered heteroaryl;

[0013] Alternatively, R2 and R3 can form C=O or C=N-OH with the bonded carbon;

[0014] R4 is selected from: hydrogen, hydroxyl, hydroxymethyl, formyl, -(C2-C6 alkenyl)C(=O)-Rf-Rg, -(C1-C6 alkylene)C(=O)-Rf-Rg, wherein X is -NH-, -O-, -S- or -NHSO2-; Rc is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C6-C10 aryl; Rf is O, S or NH; Rg is hydrogen, substituted or unsubstituted C1-C6 alkyl;

[0015] Each * independently represents the R configuration, S configuration, or racemic configuration;

[0016] The substitution refers to the substitution of hydrogen on the group by one or more substituents selected from the group consisting of: hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, carboxyl (-COOH), and sulfonic acid (-SO2OH).

[0017] In another preferred embodiment, R1 is a hydroxyl group or Rd-C(=O)-O-; wherein Rd is a substituted or unsubstituted group of the following: C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 5-7 heteroaryl, RaNH- or RaO-; wherein each Ra is independently selected from C1-C6 alkyl.

[0018] The substitution refers to the substitution of hydrogen on the group by one or more substituents selected from the group consisting of halogens, C1-C6 alkanes, and C1-C6 alkoxy groups.

[0019] In another preferred embodiment, R1 is OH or -COO (C1-C4 alkyl).

[0020] In another preferred embodiment, the configuration of C connected to R1 is either S-type or R-type.

[0021] In another preferred embodiment, R2 is hydrogen; R3 is hydroxyl, halogen, C1-C4 alkoxy, 3- to 8-membered cycloalkoxy, Re-C(=O)-O- or Re-OC(=O)-; wherein each Re is independently hydrogen or a substituted or unsubstituted group of the following: C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 5-7-membered heteroaryl, RbNH- or RbO-; wherein each Rb is independently selected from: C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 5-7-membered heteroaryl; the substitution refers to the substitution of the hydrogen on the group by one or more substituents selected from the group consisting of: hydroxyl, halogen, C1-C4 alkyl, C1-C4 alkoxy, carboxyl;

[0022] Alternatively, R2 and R3 can form C=O with the bonded carbon.

[0023] In another preferred embodiment, R2 is hydrogen; R3 is a hydroxyl group. In another preferred embodiment, the carbon atom bonded to R2 and R3 has an S-type or R-type configuration. In another preferred embodiment, R2 and R3 form C=O with the bonded carbon atom.

[0024] In another preferred embodiment, R4 is selected from: hydrogen, hydroxyl, hydroxymethyl, formyl, ... -(C2-C4 alkenyl)C(=O)-Rf-Rg, -(C1-C4 alkylene)C(=O)-Rf-Rg, wherein X is -NH-, -O-, -S- or -NHSO2-; Rc is hydrogen, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted phenyl; Rf is O, S or NH; Rg is hydrogen, substituted or unsubstituted C1-C4 alkyl;

[0025] The substitution refers to the substitution of hydrogen on the group by one or more substituents selected from the group consisting of C1-C4 alkyl, carboxyl (-COOH), and sulfonic acid (-SO2OH).

[0026] In another preferred example, R4 is selected from: -COOR C -(C2-C4 alkenyl)COOH, -(C1-C4 alkylene)COOH, -CONHSO2R C -CONHR C Rc is hydrogen, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted phenyl; the substitution refers to the substitution of hydrogen on the substituent group by one, two or three substituents selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, carboxyl (-COOH), sulfonic acid (-SO2OH).

[0027] In another preferred embodiment, the compound is selected from the group consisting of:

[0028]

[0029]

[0030] A second aspect of the present invention provides a method for preparing the compound described in the first aspect or a pharmaceutically acceptable salt thereof, wherein the method uses cholesterol as a raw material, and the hydroxyl group at the C3 position can be modified in configuration; by shifting the double bond to C9 and C10 in a chemical reaction, and then by oxidative ring-opening, a compound containing an aldehyde side chain is obtained, and then the aldehyde group is oxidized to obtain a carboxyl group, on which a series of substitutions can be performed; or the aldehyde group can be extended to obtain a carboxyl group with an increased carbon chain; in addition, the carbonyl group at the C9 position can also be reduced to obtain the compound described in the first aspect with different hydroxyl-substituted configurations, and the definitions of each substituent are as described in the first aspect.

[0031] The compounds of this invention, with structures as shown in formulas H3, H4, H5, H6, or H7, are prepared via the following route:

[0032] Route 1:

[0033]

[0034] (i) Compound H1 is ozonated to obtain compound H2;

[0035] (ii) Compound H2 of formula H2 is obtained by oxidizing the aldehyde group to obtain compound H3 of formula H3;

[0036] Optionally, the compound of formula (iii) H3 is reacted with an amino acid or a sulfonamide to give the compound of formula H4;

[0037] Route 2: The reaction of compound H3 with sodium borohydride yields compound H5;

[0038]

[0039] Or Route 3:

[0040]

[0041] The reaction of compound (i') H2 with malonic acid, pyridine and piperidine yields compound H6;

[0042] Optionally, the reaction of compound (ii') H6 with sodium borohydride yields compound H7.

[0043] In each formula, R5 is OH or -COO (C1-C4 alkyl), and the C connected to R5 is in the configuration of R or S type, or an acetyl group in the configuration of R or S type;

[0044] A is -NH- or -NHSO2-;

[0045] R6 is selected from: hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C6-C10 aryl; the substitution means that the hydrogen on the group is replaced by one or more substituents selected from the group consisting of: hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, carboxyl (-COOH), sulfonic acid (-SO2OH).

[0046] R7 is hydrogen or hydroxyl;

[0047] R8 is either hydrogen or a hydroxyl group;

[0048] R9 is either hydrogen or hydroxyl;

[0049] R 10 It can be hydrogen or hydroxyl.

[0050] A third aspect of the present invention provides a pharmaceutical composition comprising:

[0051] The compounds of general formula (I) described in the first aspect, or pharmaceutically acceptable salts thereof; and

[0052] Pharmaceutically acceptable carrier.

[0053] "Pharmaceutically acceptable carrier" 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 means that the components of the composition can be mixed with and with the active ingredient of the present invention (the compound represented by general formula (I) or its pharmaceutically acceptable salt) without significantly reducing the efficacy of the active ingredient. 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, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0054] There are no particular limitations on the administration of the active ingredients or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.

[0055] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.

[0056] Liquid dosage forms for oral administration include pharmaceutically 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, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof. Besides these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances.

[0057] In addition to the active ingredient, the suspension may contain suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0058] 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.

[0059] The compounds of this invention can be administered alone or in combination with other therapeutic agents.

[0060] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 20–500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0061] A fourth aspect of the invention provides the use of a compound of formula (I) as described in the first aspect, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in the third aspect, (i) for the preparation of a farnesoid derivative X receptor (FXR) antagonist; (ii) for the preparation of a medicament for the treatment of diseases associated with farnesoid derivative X receptors; or (iii) for the preparation of a medicament for the treatment of metabolic diseases.

[0062] In another preferred embodiment, the disease associated with the farnesoid derivative X receptor is selected from: hyperlipidemia, bile acid stasis, diabetes (such as type 2 diabetes), obesity, non-alcoholic fatty liver disease, biliary cirrhosis, and hypercholesterolemia.

[0063] In another preferred embodiment, the metabolic disease is selected from: hyperlipidemia, bile acid stasis, diabetes, obesity, non-alcoholic fatty liver disease, biliary cirrhosis, and hypercholesterolemia.

[0064] The compounds of this invention can effectively antagonize FXR receptors at micromolar concentrations, and have richer natural sources and simpler synthetic methods compared to some existing naturally derived FXR antagonists.

[0065] In vitro activity assays demonstrated that these compounds possess good FXR antagonistic activity and can regulate the expression of downstream genes of the FXR receptor in vivo. Therefore, these compounds could serve as candidate drugs for the treatment of metabolic diseases.

[0066] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described 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, equivalent, or similar purpose. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0067] The inventors of this application, through extensive and in-depth research, have developed a class of compounds obtained by ring-opening cholesterol. The main characteristic of these compounds is the introduction of a carboxyl group into the C-ring of cholesterol, followed by the introduction of glycine, taurine, or sulfonamide groups, reducing the carbonyl group at position 9 to a hydroxyl group. This series of compounds exhibits significant FXR receptor antagonistic activity. The inventors are the first to study the influence of this structure on activity, obtaining a series of compounds with excellent performance, showing significantly superior activity compared to some existing naturally derived FXR antagonists. Furthermore, cholesterol is not only more abundant and inexpensive, but the synthetic route is also simple and the yield is ideal, making them promising novel drugs for treating metabolic diseases targeting this receptor. Based on this, this invention was completed.

[0068] the term

[0069] In this document, expressions in the form "C1-C8" are intended to include corresponding groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. For example, "C1-C8 alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and "C2-C10 alkenyl" refers to an alkenyl group having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0070] In this document, the alkyl group is preferably an aliphatic alkyl group, which may be a straight-chain alkyl group or a branched alkyl group, and includes, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.

[0071] "Alkylene" refers to a straight-chain or branched saturated aliphatic group, i.e., a divalent hydrocarbon group, having a specified number of carbon atoms and being attached to at least two other groups. The two groups attached to the alkylene can be the same or different atoms on the alkylene. For example, a straight-chain alkylene can be a divalent group of -(CH2)n-, where n is 1, 2, 3, 4, 5, or 6. Representative alkylenes include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene.

[0072] In this document, the alkenyl group is preferably vinyl, propenyl, butenyl, styrene, styrene, or similar.

[0073] "Alkenyl" refers to a straight-chain or branched alkenyl group having a specified number of carbon atoms and being attached to at least two other groups. Representative alkenyl groups include, but are not limited to, vinylene, n-propenylene, isopropenylene, n-butenylene, isobutenylene, and sec-butenylene.

[0074] In this document, alkoxy refers to -O-(alkyl), where alkyl is defined as described above. "C1-6 alkoxy" refers to alkyloxy groups containing 1-6 carbons, and non-limiting examples include methoxy, ethoxy, propoxy, butoxy, etc.

[0075] In this document, the cycloalkyl group can be a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0076] In this article, cycloalkoxy refers to -O- (cycloalkyl), where cycloalkyl is defined as described above.

[0077] The aryl group refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group, and the group has a conjugated π-electron system, such as phenyl and naphthyl. The aryl ring may be fused with a heterocyclic, heteroaryl, or cycloalkyl ring, and non-limiting examples include benzimidazole, benzothiazole, benzoxazole, benzoisoxazole, benzopyrazole, quinoline, benzoindole, and benzodihydrofuran.

[0078] The heteroaryl group refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl group can be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.

[0079] Unless otherwise indicated in this invention, Indicates the connection site.

[0080] Unless otherwise specified, the structural formulas described in this invention are intended to include all tautomers, optical isomers, and stereoisomers (e.g., enantiomers, diastereomers, geometric isomers, or conformational isomers): for example, R, S configurations containing an asymmetric center, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, any single stereochemical isomer, tautomer, or enantiomer, diastereomer, geometric isomer, conformational isomer, or mixture of tautomers of the compounds of this invention is within the scope of this invention.

[0081] The term "tautomer" refers to structural isomers with different energies that can cross a low energy barrier and thus interconvert. For example, proton tautomers (i.e., proton shifts) include interconversions via proton migration, such as 1H-indazole and 2H-indazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole. Valence tautomers include interconversions via some bonding electron recombination.

[0082] In this document, there are no particular limitations on the pharmaceutically acceptable salts, but they preferably include: inorganic acid salts, organic acid salts, alkyl sulfonates, and aryl sulfonates; the inorganic acid salts include hydrochlorides, hydrobroms, nitrates, sulfates, phosphates, etc.; the organic acid salts include formates, acetates, propionates, benzoates, maleates, fumarates, succinates, tartrates, citrates, etc.; the alkyl sulfonates include methyl sulfonates, ethyl sulfonates, etc.; and the aryl sulfonates include benzene sulfonates, p-toluene sulfonates, etc.

[0083] Preparation method

[0084] The compounds of the present invention can be prepared using the following route.

[0085] Route 1:

[0086]

[0087] Route 2:

[0088]

[0089]

[0090] Route 3:

[0091]

[0092] Route 4:

[0093]

[0094] Route 5:

[0095]

[0096] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions (such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harboraboratory Press, 198) or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0097] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0098] In the following preparation examples, NMR was measured using a Varian Mercury-Vx 400M instrument, with NMR calibration: δH 7.26 ppm (CDCl3), 2.50 ppm (DMSO-d6); mass spectrometry was performed using an Agilent 1200 Quadrupole LC / MS system or a SHIMADZU GCMS-QP5050A; reagents were mainly provided by Shanghai Chemical Reagent Company; TLC silica gel plates were manufactured by Shandong Yantai Huiyou Silica Gel Development Co., Ltd., model HSGF 254; normal phase column silica gel used for compound purification was manufactured by the Qingdao Marine Chemical Plant Branch of Shandong, model ZCX-11, 200-300 mesh.

[0099] The Chinese translations of the abbreviations in this article are as follows:

[0100] DMAP: 4-Dimethylaminopyridine; DCM: Dichloromethane; DMF: N,N-Dimethylformamide; TFA: Trifluoroacetic acid.

[0101] Example 1

[0102]

[0103] (1) Dihydrocholesterol S-1 (2 g, 5.15 mmol) was dissolved in 20 mL of dry tetrahydrofuran, followed by the addition of m-iodobenzoic acid (1.56 g, 7.72 mmol) and triphenylphosphine (1.91 g, 7.72 mmol). The reaction was then stirred in an ice bath. Under ice bath conditions, diisopropyl azodicarbonate (2.02 g, 7.72 mmol) was slowly added dropwise to the reaction flask. After the addition was complete, the mixture was stirred at room temperature for 12 hours, and the reaction was monitored by TLC to ensure complete reaction. The tetrahydrofuran was directly evaporated to dryness under vacuum, and then purified by rapid column chromatography to obtain intermediate S-2 2.56 g (4.14 mmol), with a molar yield of 80.41%. 1 H NMR(400MHz,Chloroform-d)δ8.37(q,J=2.0Hz,1H),8.04–7.99(m,1H),7.88(dt,J=8.0 ,1.6Hz,1H),7.20(t,J=8.0Hz,1H),5.26(t,J=2.8Hz,1H),1.99(dt,J=12.4,3.2Hz,1H), 1.91–1.64 (m, 4H), 1.64–0.93 (m, other aliphatic protons), 0.91 (d, J = 6.4 Hz, 3H), 0.87 (d, J = 1.6 Hz, 3H), 0.86 (d, J = 1.6 Hz, 3H), 0.84 (s, 3H), 0.78 (ddd, J = 12.4, 10.4, 4.4 Hz, 1H), 0.66 (s, 3H).

[0104] (2) Compound S-2 (500 mg, 0.808 mmol) was dissolved in 80 mL of carbon tetrachloride, and then peroxyphenylacetyl (40 mg, 0.161 mmol) and sulfonyl chloride (1 mL) were added. The mixture was refluxed overnight. After the reaction was complete as monitored by TLC, the carbon tetrachloride was evaporated to dryness. The resulting viscous crude product was dissolved in 20 mL of 1,4-dioxane, and then 20 mL of 10% KOH in methanol solution was added. The mixture was refluxed for 2 hours. After the reaction was complete as monitored by TLC, the reaction was quenched with 1N hydrochloric acid aqueous solution, and then extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated to dryness. The intermediate S-3 was purified by rapid column chromatography to obtain 230 mg (0.595 mmol) of intermediate S-3, with a molar yield of 44.60%. 1H NMR(400MHz,Chloroform-d)δ5.28(d,J=5.6Hz,1H),4.08–4.00(m,1H),2.20–2.11(m ,1H),2.03–1.92(m,2H),1.92–1.80(m,2H),1.80–1.58(m,5H),1.53-1.058(m,other aliphatic ring protons),1.05–0.93(m,3H),0.91–0.90(m,6H),0.87(d,J=1.6Hz,3H),0.86(d,J=1.6Hz,3H),0.59(s,3H).

[0105] (3) Compound S-3 (100 mg, 0.259 mmol) and DMAP (3.2 mg, 0.026 mmol) were dissolved in 5 mL of pyridine, and then acetic anhydride (53 mg, 0.518 mmol) was added. The reaction was carried out at room temperature for 12 hours. The reaction was monitored by TLC until complete. The pyridine was neutralized by adding 1 N HCl aqueous solution, and then extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then the solution was evaporated to dryness. The intermediate S-499 mg was purified by rapid column chromatography with a molar yield of 89%.

[0106] (4) Compound S-4 was dissolved in 20 mL of dichloromethane, and ozone was introduced at -78 °C. After about 30 min, the reaction was monitored by TLC to ensure it was complete. The ozone introduction was stopped, and the remaining ozone in the reaction flask was purged with argon. 2 mL of dimethyl sulfide solution was added to quench the reaction, and the mixture was stirred overnight at 0 °C. The reaction mixture was then evaporated to dryness, and the intermediate S-5 was obtained by rapid column chromatography.

[0107] (5) Intermediate S-5 (1 g, 2.17 mmol) was dissolved in 20 mL of a 1:1 mixture of tert-butanol and water. Sodium dihydrogen phosphate dihydrate (1.69 g, 10.85 mmol) and 2-methyl-2-butene (1.07 g, 15.19 mmol) were then added, and the mixture was stirred in an ice bath for 10 minutes. Sodium chlorite (589 mg, 6.51 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC until complete. The mixture was diluted with water, extracted with ethyl acetate (3 × 30 mL), and the organic phases were combined. The solutions were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated to dryness. Rapid column chromatography was used to purify intermediate F-2 700 mg (1.47 mmol), with a molar yield of 67.75%. 1H NMR (400MHz, DMSO-d6) δ11.75(s,1H),4.88(s,1H),3.09–2.97(m,1H),2.45(t,J=10Hz,1H),2.33–2.17(m,2H),1.99(s,3H),1.96–1.25(m,otheraliphatic ring protons),1.13(s,3H),0.96(d,J=6.8Hz,3H),087(d,J=1.6Hz,3H),0.85(d,J=1.6Hz,3H),0.74(s,3H).

[0108] (6) Compound F-2 (50 mg, 0.105 mmol) was dissolved in 5 mL of methanol, and then 2 mL of 10% KOH aqueous solution was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete as monitored by TLC, 1N hydrochloric acid aqueous solution was added to adjust the pH to 2-3, and then extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then the solution was evaporated to dryness. The intermediate F-1 was purified by rapid column chromatography to obtain 41 mg (0.095 mmol), with a molar yield of 90%. 1 H NMR(600MHz,Chloroform-d)δ4.04(p,J=2.4Hz,1H),2.94-2.90(m,1H),2.44(d,J=13.2Hz,1H),2. 43–2.37(m,1H),2.23(d,J=13.2Hz,1H),2.11–2.04(m,1H),2.04–1.90(m,2H),1.84-1.61(m,other aliphatic ring protons),1.15(s,3H),1.14–1.03(m,3H),0.98(d,J=6.6Hz,3H),0.96-0.92(m,1H),0.84(d,J=1.2Hz,3H),0.83(d,J=1.2Hz,3H),0.71(s,3H).

[0109] (7) Compound F-1 (100 mg, 0.230 mmol) was dissolved in 15 mL of tert-butanol, and sodium borohydride (18 mg, 0.460 mmol) was added. The reaction was carried out at 70 °C for 30 min. The reaction was monitored by TLC until complete. The sodium borohydride was neutralized by adding 1 N hydrochloric acid aqueous solution, and then extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then the solution was evaporated to dryness. The intermediate F-5 was purified by rapid column chromatography to obtain 25.2 mg (0.050 mmol) in molar yield of 25%. 1¹H NMR (400MHz, Chloroform-d) δ 4.04 (s, 1H), 3.57 (s, 1H), 2.73–2.45 (m, 2H), 2.11 (td, J = 12.8, 5.2 Hz, 1H), 2.01–1.88 (m, 2H), 1.87–1.05 (m, other aliphatic ring protons), 1.00 (d, J = 6.8 Hz, 3H), 0.93 (d, J = 10 Hz, 2H), 0.87 (s, 6H), 0.85 (s, 3H), 0.82 (s, 3H). F-6 45.4 mg (0.104 mmol), molar yield 45%. 1 H NMR(400MHz,Chloroform-d)δ4.06(s,1H),3.00(dd,J=10.4,2.8Hz,1H),2.63–2.28(m,2H),2.15(t,J=10Hz,1H),1.83–1.73(m,2H),1.71–1.11(m,other aliphatic ring protons),1.03(d,J=6.4Hz,3H),1.00–0.90(m,2H),0.88(s,3H),0.86(s,6H),0.77(s,3H).

[0110] Using the method in Example 1, the following compounds with different configurations at the 3-position can be synthesized:

[0111]

[0112]

[0113] Example 2

[0114]

[0115] (1) S-3 (2 g, 5.17 mmol) was dissolved in 20 mL of dichloromethane, and ozone was introduced at -78 °C. After about 30 min, the reaction was monitored by TLC to ensure it was complete. The ozone introduction was stopped, and the remaining ozone in the reaction flask was purged with argon. 2 mL of dimethyl sulfide solution was added to quench the reaction, and the mixture was stirred overnight at 0 °C. The reaction mixture was then evaporated to dryness, and rapid column chromatography was used to separate and purify the intermediate S-10 to obtain 990 mg (2.17 mmol), with a molar yield of 42%. 1H NMR(400MHz,Chloroform-d)δ9.88(s,1H),4.03(p,J=2.8Hz,1H),2.86-2.80(m,1H),2.77–2.68(m,1H),2.40–2.15(m,2H),2.07–1.22(m,otheraliphatic protons),1.12(s,3H),1.01–0.95(m,2H),0.92(d,J=6.4Hz,3H),0.85(d,J=1.6Hz,3H),0.84(d,J=1.6Hz,3H),0.74(s,3H).

[0116] (2) Compound S-10 (400 mg, 0.955 mmol) was dissolved in 20 mL of pyridine, and then malonic acid (250 mg, 2.39 mmol) and piperidine (41 mg, 0.478 mmol) were added. The reaction was carried out at 90 °C for about 4 hours. The reaction was monitored by TLC until complete. The pyridine was neutralized by adding 1 N hydrochloric acid aqueous solution, and then extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then the solution was evaporated to dryness. The solution was purified by rapid column chromatography to obtain compound F-10 160 mg (0.344 mmol), with a molar yield of 36%. 1 H NMR(400MHz,Chloroform-d)δ5.41(d,J=15.6Hz,1H),5.23(dt,J=15.6,6.4Hz,1H),4.0 3(s,1H),3.08-2.98(m,2H),2.73-2.60(m,1H),2.48-2.36(m,1H),1.99-1.04(m,other aliphatic protons),1.00(s,3H),0.98-0.91(m,1H),0.86(s,3H),0.84(s,3H),0.77(s,3H),0.75(d,J=8.0Hz,3H).

[0117] Using the method in Example 2, the following compounds with different configurations at the 3-position can be synthesized:

[0118]

[0119] Example 3

[0120]

[0121] (1) Compound F-1 (100 mg, 0.230 mmol) was dissolved in 10 mL of DMF, and benzylglycine hydrochloride (93 mg, 0.460 mmol), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (114 mg, 0.460 mmol), and triethylamine (115 mg, 0.460 mmol) were added. The reaction was carried out at 90 °C for 12 hours, and the reaction was monitored by TLC until complete. After the reaction was complete, water was added for dilution, and then the mixture was extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then the solution was evaporated to dryness. The benzyl-protected precursor of F16 was purified by rapid column chromatography. The obtained compound was dissolved in 10 mL of a mixed solvent of ethyl acetate and tert-butanol, and 10% Pd / C was added. The reaction was carried out under a hydrogen atmosphere for 2 hours. After the reaction was monitored by TLC until it was complete, Pd / C was removed by diatomaceous earth filtration. The reaction solution was concentrated and purified by rapid column chromatography to obtain compound F16 35 mg (0.071 mmol), with a molar yield of 31%. 1 H NMR(500MHz,Chloroform-d)δ8.27(t,J=5Hz,1H),4.68(sbr,2H),4.17(dd,J=15,5Hz,1H),4.06(p,J=5Hz,1H),3.99(dd,J=15,5Hz,1H),2.88-2. 83(m,1H),2.42(q,J=6.8Hz,1H),2.28(dd,J=49.5,13.5,2H),2.13-2.08(m,1H),2.03(td,J=15,5Hz,1H),1.96-1.92(m,1H),1.82-1.18(m,other aliphatic protons),1.16(s,3H),1.15-1.04(m,3H),0.97(d,J=6.5Hz,3H),0.86(s,3H),0.84(s,3H),0.68(s,3H).

[0122] Using the method in Example 3, the following compounds with different configurations at the 3-position or different substituents of the carboxyl group can be synthesized.

[0123]

[0124] Example 4:

[0125]

[0126] (1) Compound F-10 (53 mg, 0.115 mmol) was dissolved in 10 mL of DMF, and potassium carbonate (48 mg, 0.345 mmol) and iodomethane (33 mg, 0.230 mmol) were added. The reaction was carried out at room temperature for 3 hours. The reaction was monitored by TLC until complete. The solution was diluted with water, extracted with ethyl acetate (3 × 20 mL), and the organic phases were combined. The solutions were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain crude S-11. The crude S-11 was dissolved in 3 mL of dry tetrahydrofuran, and borane dimethyl sulfide complex (18 mg, 0.232 mmol) was added dropwise under ice bath. After the addition was complete, the reaction was carried out under ice bath for 5 hours. The reaction was monitored by TLC until complete. Methanol solution was added dropwise to quench the reaction until no more bubbles were generated. The reaction solution was evaporated to dryness, and rapid column chromatography was used to separate and purify S-12 24 mg (0.049 mmol), with a molar yield of 43%. 1 ¹H NMR (400MHz, Chloroform-d) δ 5.67 (d, J = 16.0 Hz, 1H), 5.34 (dt, J = 16.0, 7.2 Hz, 1H), 3.99 (s, 1H), 3.67 (s, 3H), 3.34 (s, 1H), 3.01 (d, J = 6.8 Hz, 2H), 2.12–1.92 (m, 2H), 1.88–0.92 (m, other aliphatic protons), 0.88 (s, 3H), 0.86 (d, J = 2.0 Hz, 3H), 0.84 (d, J = 2.0 Hz, 3H), 0.78 (s, 3H), 0.76 (d, J = 6.4 Hz, 3H). Compound S-13 was obtained in 8 mg (0.016 mmol) molar yield of 14%. 1 H NMR(400MHz,Chloroform-d)δ5.49(d,J=16.0Hz,1H),5.31(dt,J=16.0,6.8Hz,1H),4.04(s,1H),3.67(s, 3H),3.06–3.00(m,2H),2.77(d,J=10.4Hz,1H),2.20–2.11(m,1H),1.95-1.82(m,1H),1.77-1.04(m,other aliphatic protons),1.03–0.91(m,2H),0.86(d,J=2.0Hz,3H),0.84(d,J=2.0Hz,3H),0.80-0.73(m,9H).

[0127] (2) Compound S-12 (24 mg, 0.049 mmol) was dissolved in 5 mL of methanol. 2 mL of 10% potassium hydroxide aqueous solution was added to the system, and the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was monitored by thin-layer chromatography, hydrochloric acid aqueous solution (1N) was added to quench the reaction, and the pH was adjusted to 3–4. The mixture was then extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and then separated by rapid column chromatography (dichloromethane:methanol = 90:10) to obtain compound F-17 (20 mg), with a molar yield of 86%. 1 H NMR (400MHz, DMSO-d6) δ12.07(s,1H),5.49(d,J=16.0Hz,1H),5.27(dt,J=16.0,6.8Hz,1H),4.03(d,J=2.4H z,1H),3.77(s,1H),3.29(s,1H),3.02(s,1H),2.92(d,J=7.2Hz,2H),2.06–1.86(m,2H),1.81-0.87(m,other aliphatic protons),0.85(d,J=2.0Hz,3H),0.83(d,J=2.0Hz,3H),0.77(s,3H),0.76(d,J=6.4Hz,3H),0.66(s,3H)ppm. 13 C NMR(101MHz,DMSO-d6)δ173.19,146.03,117.95,99.49,76.10,64.53,55.24,50.76,48.64,38.97,38.11,37.76,35 .78,35.34,34.49,29.14,28.65,28.59,28.36,27.35,25.24,25.10,23.32,22.64,22.38,19.05,14.72,11.18ppm.

[0128] (3) Compound S-13 (8 mg, 0.017 mmol 1 equiv) was dissolved in 5 mL of methanol. 2 mL of 10% potassium hydroxide aqueous solution was added to the system, and the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was monitored by thin-layer chromatography, hydrochloric acid aqueous solution (1N) was added to quench the reaction, and the pH was adjusted to 3–4. The mixture was then extracted three times with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and then separated by rapid column chromatography (dichloromethane:methanol = 90:10) to obtain compound F-18 (6 mg), with a molar yield of 77%. 1H NMR(400MHz,Chloroform-d)δ5.50(d,J=16.0Hz,1H),5.29(dt,J=16.0,6.8Hz,1H),4.04(s,1H),3.0 4(d,J=9.6Hz,2H),2.80(d,J=10.8Hz,1H),2.23–2.07(m,1H),1.93-1.83(m,1H),1.74–0.89(m,other aliphatic protons),0.86(d,J=2.0Hz,3H),0.85(d,J=2.0Hz,3H),0.80-0.71(m,9H)ppm. 13 C NMR (101MHz, CDCl3) δ176.06,149.50,117.10,82.61,66.61,56.19,49.64,47.74,39.87,39.64,37.07,36.77,36.02 ,35.86,35.33,35.12,31.62,29.65,28.72,28.15,27.92,27.79,23.99,22.95,22.70,22.36,18.95,12.02,9.77ppm.

[0129] Example 5 FXR Antagonism Test

[0130] 1. Experimental Objective

[0131] The antagonistic activity of the compound against FXR was detected using a reporter gene assay.

[0132] 2. Experimental Principle

[0133] Luciferase reporter gene assay is a reporter system that uses luciferin as a substrate to detect the activity of firefly luciferase. Luciferase catalyzes the oxidation of luciferin to oxyluciferin, during which bioluminescence is emitted. This bioluminescence can be measured using a fluorescence spectrometer. In this experiment, the agonist ligand binds to the ligand-binding domain (LBD) and promotes the binding of the DNA-binding domain (DBD) to DNA, initiating luciferase transcription. The addition of the substrate produces fluorescence, and the intensity of the fluorescence reflects the degree of receptor activation.

[0134] 3. Experimental Samples

[0135] Before the experiment, the compound was dissolved in DMSO to prepare a stock solution, which was then diluted with culture medium to the required concentration before use.

[0136] 4. Experimental Methods

[0137] Hek293T cells were grown to approximately 80% confluence, then digested and diluted to 2 x 10⁻⁶ cells. 5 A suspension of 100 μL / mL was seeded into each well of a white, opaque 96-well plate. Following the Lipofectamine 3000 kit instructions, serum-depleted opti-MEM medium was transferred 1:1 by volume into two separate centrifuge tubes. 20 μg / mL of plasmid and 2 μg / mL of liposomes were added to each tube, with the pCMV-Script-hFXR and pGL4.11-hSHP-Luciferase reporter plasmids premixed at a 1:1 ratio to a concentration of 20 μg / mL. The opti-MEM medium containing liposomes and the opti-MEM medium containing plasmids were then gently mixed and packaged at room temperature for 20 min. After packaging, 10 μL of the opti-MEM medium containing the plasmid-liposome mixture was added to each well of a 96-well plate and incubated at 37°C in a 5% CO2 incubator. After 24 hours, gently discard all the culture medium in the wells using a pipette, and replace it with medium containing 1% FBS for starvation treatment. After 6 hours, add the test compound in antagonistic mode, and then add GW4064 (final concentration 5 μM) after 1 hour. Continue incubation in an incubator for another 24 hours. Following the Firefly-Glo kit instructions, add the same volume of the test reagent as the culture medium to a 96-well plate, and allow it to fully lyse in the dark for 15 minutes. Then, read the fluorescence values ​​using a multi-label microplate reader.

[0138] Inhibition efficiency calculation: The ratio of the difference between 1 and the fluorescence intensity of the test compound minus the fluorescence intensity of the blank well to the difference between the fluorescence intensity of the activator model group minus the fluorescence intensity of the blank well is defined as the inhibition efficiency (Inhibition%) of the compound, as shown in the following formula:

[0139]

[0140] According to the above formula, the compound was tested at a concentration of 10 μM, with 3 replicates for each concentration (blank group: cells without drug treatment after plasmid co-transfection).

[0141]

[0142] The experimental results are shown in Table 1.

[0143] Table 1 Results of FXR antagonistic activity tests of compounds

[0144]

[0145] Note: Inhibition% is the rate of inhibition of the sample drug on the antagonistic activity of FXR, and SD is the standard deviation.

[0146] These compounds were able to compete with the FXR agonist GW4064 in HEK293T cells expressing the FXR ligand-binding domain and antagonize the FXR activation effect of GW4064.

[0147] As shown in Table 1, the compounds of this invention achieve an inhibition rate of 100% at 10 μM, which is higher than that of existing FXR receptor antagonists. Moreover, these compounds have a novel structure containing a tricyclic structure and are easy to synthesize, further enriching the variety of FXR receptor antagonists.

[0148] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of general formula (I), or a pharmaceutically acceptable salt thereof, In the formula, R1 is selected from: hydrogen, hydroxyl, halogen, C1-C6 alkoxy, 3- to 10-membered cycloalkoxy, =O, =N-OH, Rd-C(=O)-O-; wherein Rd is a substituted or unsubstituted group of the following: C1-C8 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, 5-7-membered heteroaryl, RaNH- or RaO-; wherein, Each Ra is independently selected from: C1-C8 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, 5-7 heteroaryl; R2 is hydrogen, hydroxyl, halogen, or C1-C6 alkyl; R3 is selected from: hydrogen, hydroxyl, halogen, C1-C6 alkoxy, 3- to 10-membered cycloalkoxy, Re-C(=O)-O- or Re-OC(=O)-; wherein each Re is independently hydrogen or substituted or unsubstituted of the following groups: C1-C8 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, 5-7-membered heteroaryl, RbNH- or RbO-; wherein each Rb is independently selected from: C1-C8 alkyl, C3-C10 cycloalkyl, C6-C10 aryl, 5-7-membered heteroaryl; Alternatively, R2 and R3 can form C=O or C=N-OH with the bonded carbon; R4 is selected from: hydrogen, hydroxyl, formyl, -(C2-C6 alkenyl)C(=O)-Rf-Rg, -(C1-C6 alkylene)C(=O)-Rf-Rg, wherein X is -NH-, -O-, -S- or -NHSO2-; Rc is hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C6-C10 aryl; Rf is O, S or NH; Rg is hydrogen, substituted or unsubstituted C1-C6 alkyl; Each * independently represents the R configuration, S configuration, or racemic configuration; The substitution refers to the substitution of hydrogen on the substituted group by one or more substituents selected from the group consisting of: hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, carboxyl (-COOH), and sulfonic acid (-SO2OH).

2. The compound according to claim 1, characterized in that, R1 is a hydroxyl group or Rd-C(=O)-O-; wherein Rd is a substituted or unsubstituted group of the following: C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 5-7 heteroaryl, RaNH- or RaO-; wherein each Ra is independently selected from C1-C6 alkyl. The substitution refers to the replacement of the hydrogen on the substituted group by one or more substituents selected from the group consisting of halogens, C1-C6 alkanes, and C1-C6 alkoxy groups.

3. The compound according to claim 1, characterized in that, R1 is OH or -COO (C1-C4 alkyl).

4. The compound according to claim 1, characterized in that, The configuration of C connected to R1 is either S-type or R-type.

5. The compound according to claim 1, characterized in that, R2 is hydrogen; R3 is hydroxyl, halogen, C1-C4 alkoxy, 3- to 8-membered cycloalkoxy, Re-C(=O)-O- or Re-OC(=O)-; wherein each Re is independently hydrogen or a substituted or unsubstituted group of the following: C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 5-7-membered heteroaryl, RbNH- or RbO-; wherein each Rb is independently selected from: C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 5-7-membered heteroaryl; the substitution refers to the hydrogen on the substituted group being replaced by one or more substituents selected from the group consisting of: hydroxyl, halogen, C1-C4 alkyl, C1-C4 alkoxy, carboxyl; Alternatively, R2 and R3 can form C=O with the bonded carbon.

6. The compound according to claim 1, characterized in that, R2 is hydrogen; R3 is hydroxyl.

7. The compound according to claim 1, characterized in that, The configuration of C connected to R2 and R3 is either S-type or R-type.

8. The compound according to claim 1, characterized in that, R2 and R3 form C=O with the bonded carbon.

9. The compound according to claim 1, characterized in that, R4 is selected from: hydrogen, hydroxyl, formyl, -(C2-C4 alkenyl)C(=O)-Rf-Rg, -(C1-C4 alkylene)C(=O)-Rf-Rg, wherein X is -NH-, -O-, -S- or -NHSO2-; Rc is hydrogen, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted phenyl; Rf is O, S or NH; Rg is hydrogen, substituted or unsubstituted C1-C4 alkyl; The substitution refers to the replacement of the hydrogen on the substituted group by one or more substituents selected from the group consisting of C1-C4 alkyl, carboxyl (-COOH), and sulfonic acid (-SO2OH).

10. The compound according to claim 1, characterized in that, R4 is selected from: -COOR C -(C2-C4 alkenyl)COOH, -(C1-C4 alkylene)COOH, -CONHSO2R C -CONHR C Rc is hydrogen, unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted phenyl; the substitution means that the hydrogen on the substituted group is replaced by one, two or three substituents selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, carboxyl (-COOH), sulfonic acid (-SO2OH).

11. The compound according to claim 1, characterized in that, The compounds are selected from the group consisting of:

12. The method for preparing the compound according to claim 1, characterized in that, The compounds, with structures as shown in formulas H3, H4, H5, H6, or H7, are prepared via the following route: Route 1: (i) Compound H1 is ozonated to obtain compound H2; (ii) Compound H2 of formula H2 is obtained by oxidizing the aldehyde group to obtain compound H3 of formula H3; Optionally, the compound of formula (iii) H3 is reacted with an amino acid or a sulfonamide to give the compound of formula H4; Route 2: The reaction of compound H3 with sodium borohydride yields compound H5; Route 3: The reaction of compound (i') H2 with malonic acid, pyridine and piperidine yields compound H6; Optionally, the reaction of compound (ii') H6 with sodium borohydride yields compound H7. In each formula, R5 is OH or -COO (C1-C4 alkyl), the C connected to R5 is in the configuration of R or S, or R5 is an acetyl group in the configuration of R or S; A is -NH- or -NHSO2-; R6 is selected from: hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C6-C10 aryl; the substitution means that the hydrogen on the substituted group is replaced by one or more substituents selected from the group consisting of: hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, carboxyl (-COOH), sulfonic acid (-SO2OH); R7 is hydrogen or hydroxyl; R8 is either hydrogen or a hydroxyl group; R9 is either hydrogen or hydroxyl; R 10 It can be hydrogen or hydroxyl.

13. A pharmaceutical composition, characterized in that, Include: The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof; and Pharmaceutically acceptable carrier.

14. Use of the compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 8, characterized in that, (i) for the preparation of farnesoid derivative X receptor (FXR) antagonists; (ii) for the preparation of medicaments for the treatment of diseases associated with farnesoid derivative X receptors; or (iii) for the preparation of medicaments for the treatment of metabolic diseases.

15. The use as described in claim 14, characterized in that, The diseases associated with farnesoid derivative X receptors are selected from: hyperlipidemia, bile acid stasis, diabetes, obesity, non-alcoholic fatty liver disease, biliary cirrhosis, and hypercholesterolemia.

16. The use as described in claim 14, characterized in that, The metabolic diseases mentioned are selected from: hyperlipidemia, bile acid stasis, diabetes, obesity, non-alcoholic fatty liver disease, biliary cirrhosis, and hypercholesterolemia.

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