CN106146335A - A kind of virtue oxygen benzoic acid analog derivative and the application as FXR antagonist thereof - Google Patents

Abstract

The present invention relates to an aryloxybenzoic acid derivative and its application as an FXR antagonist, specifically, it provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a preparation method thereof, Wherein: R1 is selected from hydroxyl, methoxyl, ethoxyl or amino, R2 is selected from _hydrogen , halogen, nitro, carboxyl, methoxyl or methyl, X is selected from N or O, n1 is 0 or ₁ , n2 is 0 or 1. In addition, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has the pharmacological effect of lowering blood lipid, and is a kind of FXR antagonist.

Description

A kind of aryloxybenzoic acid derivative and its application as FXR antagonist

technical field

The invention belongs to the field of new drug design and synthesis, and specifically relates to aryloxybenzoic acid derivatives, their preparation method and their application as FXR antagonists.

Background technique

Cardiovascular and cerebrovascular diseases are currently the most serious diseases that endanger human life and health. They are common and frequently-occurring diseases of middle-aged and elderly people. In many countries, they rank first in morbidity and mortality. Atherosclerosis is the basis of many cardiovascular and cerebrovascular diseases. A large number of experimental and clinical data prove that atherosclerosis is closely related to abnormal blood lipid metabolism. Therefore, blood lipid regulation has become an important field in the current research of this type of new drug.

Through prospective, random and controlled clinical studies, it has been proved that some statins can reduce the occurrence of atherosclerosis and coronary heart disease, reduce the mortality caused by coronary heart disease, and reduce the incidence of myocardial infarction. Further studies have also proved that the treatment of lipid-lowering drugs can reduce the lipid content in atherosclerotic plaques, strengthen fibrous lipids to stabilize plaques, and reduce serious events such as myocardial infarction and cerebral infarction caused by plaque rupture. In addition, lipid-regulating drugs can also restore the function of damaged vascular endothelial cells, enhance fibrinolysis and prevent thrombosis, and delay the progress of human atherosclerosis and subside the formed plaque. Therefore, active use of lipid-lowering drugs is an important measure to reduce atherosclerosis and reduce the incidence of coronary heart disease.

Currently, there are many clinical and commonly used drugs for regulating blood lipids, such as statins, phenoxyaromatic acids, ion exchange resins or bile acid chelating agents, nicotinic acid and other blood lipid regulating drugs. Among them, statins (ie, HMG-CoA reductase inhibitors) have attracted special attention.

Statins are inhibitors of cholesterol synthase. HMG-CoA is transformed into methoxylonic acid under the action of HMG-CoA reductase, and the open acid part of the chemical structure of statins is similar to HMG-CoA, which can competitively inhibit the formation of methoxylonic acid, thereby reducing the Synthesis of cholesterol, thus lowering blood cholesterol and low-density lipoprotein (LDL-C) levels. Clinical studies have proved that statins can prevent the occurrence and development of atherosclerotic plaques and reduce serious clinical events of coronary heart disease even if the levels of cholesterol and low-density lipoprotein in serum are not very high or normal in patients with coronary heart disease. However, long-term use of statins may cause digestive system symptoms such as epigastric discomfort, and a considerable number of patients may also have side effects such as liver function damage, elevated transaminases, muscle pain, and elevated creatine kinase.

FXR is a ligand-activated transcription factor that regulates the expression of target genes. Studies have found that bile acid is its natural ligand and participates in the metabolism of bile acid, so it is also called bile acid receptor; chenodeoxycholic acid (CDCA) is its The most suitable natural ligand. GW406 is the first synthetic FXR ligand. In addition to participating in the metabolism of bile acids in the body, FXR also plays an important role in regulating lipid metabolism and glucose metabolism. There are two main pathways for the metabolism of cholesterol into bile acids: 1. The classical pathway is catalyzed by CYP7A1 and is regulated by the negative feedback of bile acids; Complementary to the classic pathway. The classic metabolic pathway process is that the oxidation product of cholesterol binds to LXR and induces it to form a dimer with RXR, binds to the LXR reaction element of DNA, stimulates the expression of CYP7A1, and then CYP7A1 catalyzes cholesterol to generate bile acid, which binds to FXR And induce it to form a dimer with RXR, bind to the FXR response element of DNA, activate the expression of SHP, and the combination of SHP and LRH-1 inhibits the expression of CYP7A1, thereby maintaining the metabolic balance of cholesterol. The regulatory mechanism of FXR on triglyceride metabolism is reflected in the inhibition of TG synthesis: FXR down-regulates SREBP-1c through the SHP pathway, and SREBP-1c is the main transcription factor involved in fat synthesis genes, which can activate a variety of fatty acids and triglyceride synthesis The transcription of enzymes, including ACC, FAS, etc. Recent studies have found that FXR can induce the differentiation of adipocytes, thereby promoting the storage of TG in adipocytes. It has also been reported that FXR antagonists reduce TG by down-regulating SREBP-1c.

Currently, most of the reported FXR antagonists are steroidal compounds, including Z-guggulsterone (GS), CDRI/80-574, sulfated sterol, and scalarane sesterterpene. To date, non-steroidal FXR antagonists include AGN34, substituted isoxazole derivatives. Among them, the natural product GS is a high-efficiency antagonist of FXR, which can reduce the levels of low-density lipoprotein (LDL) and triglyceride (TG) in mice but cannot improve the blood lipid density of patients with high cholesterol. As a new target in the field of regulating blood lipids in recent years, FXR has attracted the attention of many researchers with its unique mechanism of regulating blood lipids. Therefore, it is of great significance to develop effective drugs for mixed hyperlipidemia for FXR.

A large number of compounds have been invented in the previous two patents of amide compounds, their preparation methods and applications (CN 102838505 A) and ester compounds, their preparation methods and applications (CN 102093II6 A) and their hypolipidemic effects in vivo have been confirmed. Based on the previous invention, he invented a class of aryloxybenzoic acid derivatives, represented by carboxylic acids, carboxylic acid esters and amides, and focused on the research on FXR antagonistic activity in vitro, which proved to have FXR antagonistic effect, while rats In vivo experiments confirmed that it has hypolipidemic effect.

Contents of the invention

In order to open up resources for clinical medicine, the present invention selects suitable aryloxybenzoic acid compounds (especially gemfibrozil) and amino or hydroxyl-containing benzoic acid or benzoate compounds, amino or hydroxyl-containing phenylacetic acid or benzene Acetate compounds and their derivatives are condensed through acylation reaction and connected in the form of amide bonds or ester bonds, thus providing a new class of FXR antagonists for the development of blood lipid-lowering drugs.

The first aspect of the present invention is to provide a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof,

in:

R ₁ is selected from hydroxyl, methoxy, ethoxy, amino.

R2 is selected from _hydrogen , halogen, nitro, carboxyl, methoxy, methyl.

X is selected from N, O.

n1 is 0 or 1.

n2 is 0 or 1.

As shown in formula (I), at R ₂ and The group can be any substitution position on the benzene ring.

In the present invention, the pharmaceutically acceptable salt of the compound represented by formula (I) is preferably a salt formed by the reaction of the compound of the present invention and a basic compound. The basic compound is preferably selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate or potassium bicarbonate and the like. The above pharmaceutically acceptable salts are easy to separate and can be purified by conventional separation methods, such as solvent extraction, dilution, recrystallization, column chromatography and preparative thin-layer chromatography.

In the first aspect of the present invention, the compound represented by formula (I) is preferably:

In the second aspect of the present invention, the present invention provides a method for preparing the compound represented by the above formula (I), comprising: reacting compound 23 and compound II in a suitable solvent under base catalysis, and the reaction formula is as follows:

Wherein, R is selected from hydroxyl, methoxy, ethoxy or amino _;

R is selected from _hydrogen , halogen, nitro, carboxyl, methoxy or methyl;

X is selected from N or O;

The base is triethylamine, N,N-diisopropylethylamine, pyridine, sodium hydroxide,

Appropriate solvents are dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, pyridine, dioxane/water, or their mixed solvents.

In a preferred embodiment, the base is selected from triethylamine, pyridine or sodium hydroxide; more preferably triethylamine or sodium hydroxide.

In a preferred embodiment, the appropriate solvent is selected from the group consisting of dichloromethane, dioxane/water.

References, Compound 23 was prepared by dissolving gemfibrozil in dichloromethane, adding quantitative catalyst-N,N dimethylformamide and stirring, adding oxalyl chloride dropwise at room temperature, and reacting for a period of time.

For the preparation method of the compound shown in the above formula (I), those skilled in the art can select specific operation steps based on experience, such as:

Dissolve compound 23 in the first solvent for later use, add compound II to the second solvent, add base and stir at room temperature for 30-60 minutes, then add the reserve solution of compound 23 dropwise under ice bath with stirring, and add dropwise After completion, stir overnight at room temperature, extract after acidification, and obtain the target compound through column chromatography; wherein: the first solvent is selected from dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, pyridine, and dioxane; the second solvent is selected from From the mixed solution of dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, pyridine, dioxane: water/1-10:1-10; the added base is triethylamine, N,N-diisopropyl ethylamine, pyridine, 2N sodium hydroxide solution.

In addition, the above-mentioned preferred compounds of the present invention can also be obtained by other synthetic methods, such as:

In one embodiment, compound 5 can also be synthesized by the following method:

Dissolve gemfibrozil in tetrahydrofuran, add alkali and stir for 30-60 minutes, slowly add the tetrahydrofuran solution of 4-(2-bromoacetyl)benzoic acid dropwise under ice bath conditions, stir overnight at room temperature, acidify and extract through the column layer Analyze and obtain compound 5.

It is characterized in that the added alkali is potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine.

In one embodiment, compound 8 can also be synthesized by the following method:

Dissolve compound 12 in ethanol, add base and reflux at 80°C for 1-3 hours, acidify and extract, and obtain compound 8 by column chromatography.

In another embodiment, compound 11 can also be synthesized by the following method:

Dissolve compound 8 in dichloromethane, add 1 drop of N,N-dimethylformamide dropwise, add oxalyl chloride dropwise at room temperature and stir for 2 hours, spin out the solvent and excess oxalyl chloride, and then dissolve in dichloromethane Methane was added dropwise to a methanol solution containing triethylamine in an ice bath, stirred overnight after the dropwise addition, extracted and subjected to column chromatography to obtain compound 11.

Another embodiment, compound 22 can also be synthesized by the following method:

Compound 27 was dissolved in dichloromethane, stirred slowly with ammonia gas under ice-bath conditions, reacted for 1 hour, extracted and obtained compound 22 by column chromatography.

In the third aspect of the present invention, the present invention provides a blood lipid-lowering pharmaceutical composition, which includes the compound described in formula (I) or a pharmaceutically acceptable salt thereof in the first aspect and a pharmaceutically acceptable carrier.

According to the purpose of treatment, the pharmaceutical composition can be made into various types of administration unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions), etc. .

In the fourth aspect of the present invention, the present invention provides the use of compound (I) represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as an FXR antagonist.

In addition, the present invention provides the application of compound (I) represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in regulating blood lipid.

The content of the compound shown in formula (I) of the present invention and its pharmaceutically acceptable salts in the pharmaceutical composition is not particularly limited, and can be selected within a wide range, usually 1-70% by mass , preferably 1-30% by mass.

In the present invention, the administration method of the pharmaceutical composition is not particularly limited. According to the patient's age, gender and other conditions and symptoms, various dosage forms of preparations can be selected for administration. For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are administered orally; injections can be administered alone, or mixed with injection delivery fluids (such as glucose solution and amino acid solution) for intravenous injection, if available If necessary, injections can be used simply for intramuscular, intradermal, subcutaneous or intraperitoneal injection; suppositories are administered to the rectum.

In the present invention, the dosage can be appropriately selected according to the administration method, patient's age, sex and other conditions and symptoms. The usual dosage can be: about 0.1-300 mg active ingredient/kg body weight/day. Generally, each dosage unit may contain 1-200 mg of active pharmaceutical ingredients.

The following will further illustrate the present invention through specific examples, but it is not intended to limit the protection scope of the present invention. Without departing from the concept of the present invention, those skilled in the art can make improvements to the preparation method and equipment used within the scope of the claims, and these improvements should also be regarded as the protection scope of the present invention. Therefore, the protection scope of the patent for the present invention should be based on the appended claims.

detailed description

Example 1: Preparation of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride

Dissolve 25.3 g of gemfibrozil in 150 mL of dichloromethane, add 1 mL of N,N-dimethylformamide and stir, add 19.0 g of oxalyl chloride dropwise at 0°C, react at room temperature for 3 hours, and spin out the dichloromethane , to obtain 26.2 g of the target compound with a yield of 97.5%. Example 2: Preparation of 4-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyloxy)benzoic acid (compound 1)

Dissolve 2.68g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride in 15mL of 1,4-dioxane for later use, add 1.38g of p-hydroxybenzoic acid to 1,4-dioxane:water/1:1 15mL mixed solvent, add 10mL 2N sodium hydroxide at 0°C, stir for 30 minutes, then add the reserved solution dropwise at 0°C, continue stirring After 10 hours, it was acidified, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and subjected to column chromatography to obtain 2.9 g of the target compound with a yield of 78.4%. ESI-MSm/z: 369[MH] ⁺ . ¹ H-NMR (400MHz, DMSO) δ: 7.99-7.97(d, 2H, J＝8.0Hz), 7.18-7.16(d, 2H, J＝8.0Hz) ,6.98-6.96(d,1H,J=8.0Hz),6.73(s,1H),6.64-6.62(d,1H,J=8.0Hz),4.00-3.98(t,2H,J=5.6Hz), 2.II(s,3H),2.08(s,3H),1.98-1.79(m,4H),1.32(s,6H).

Example 3: Preparation of 3-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyloxy)benzoic acid (compound 2)

Dissolve 2.68g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride in 15mL of 1,4-dioxane for later use, add 1.38g of m-hydroxybenzoic acid to 1,4-dioxane:water/1:1 15mL mixed solvent, add 10mL 2N sodium hydroxide aqueous solution at 0°C, stir for 30 minutes, then add the reserved solution dropwise at 0°C, continue Stir for 10 hours, acidify, extract with ethyl acetate, dry over anhydrous magnesium sulfate, and perform column chromatography to obtain 3.4 g of the target compound with a yield of 91.9%. ESI-MS m/z:369[MH] ⁺ .

Example 4: Preparation of 2-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyloxy)benzoic acid (compound 3)

Dissolve 2.68g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride in 15mL of 1,4-dioxane for later use, add 1.38g of o-hydroxybenzoic acid to 1,4-dioxane:water/1:1 15mL mixed solvent, add 10mL 2N sodium hydroxide aqueous solution at 0°C, stir for 30 minutes, then add the reserved solution dropwise at 0°C, continue Stir for 10 hours, acidify, extract with ethyl acetate, dry over anhydrous magnesium sulfate, and perform column chromatography to obtain 3.2 g of the target compound with a yield of 86.5%. ESI-MS m/z: 369[MH] ⁺ .761[2M+Na-H] ⁺ . ¹ H NMR (400MHz, DMSO) δ13.08(s, 1H), 7.91(d, J＝7.8Hz, 1H ),7.61(t,J=7.8Hz,1H),7.37(t,J=7.8Hz,1H),7.06(d,J=7.8Hz,1H),6.98(d,J=7.4Hz,1H), 6.73(s,1H),6.63(d,J=7.4Hz,1H),3.98(t,J=4.7Hz,2H),2.25(s,3H),2.09(s,3H),1.87–1.73(m ,4H),1.31(s,6H).

Example 5: Preparation of 2-(4-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyloxy)phenyl)acetic acid (compound 4)

Dissolve 2.68g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride in 15mL of 1,4-dioxane for later use, add 1.52g of p-hydroxyphenylacetic acid to 1,4-dioxane:water/1:1 15mL mixed solvent, add 10mL 2N sodium hydroxide aqueous solution at 0°C, stir for 30 minutes, then add the reserved solution dropwise at 0°C, continue Stir for 10 hours, acidify, extract with ethyl acetate, dry over anhydrous magnesium sulfate, and perform column chromatography to obtain 3.2 g of the target compound with a yield of 83.3%. ESI-MS m/z:383[MH] ⁺ . ¹ H NMR(400MHz,DMSO)δ12.35(s,1H),7.29(d,J＝8.6Hz,2H),6.99(d,J＝8.6Hz ,2H),6.98(d,J=7.3Hz,1H),6.74(s,1H),6.64(d,J=7.3Hz,1H),3.99(t,J=5.7Hz,2H),3.59(s ,2H),2.25(s,3H),2.09(s,3H),1.85–1.72(m,4H),1.30(s,6H).

Example 6: Preparation of 4-(2-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyloxy)acetyl)benzoic acid (compound 5)

Add 2.68g of gemfibrozil and 2.76g of anhydrous K ₂ CO ₃ to 15mL of tetrahydrofuran and stir for 1 hour, slowly drop 10mL of 4-(2-bromoacetyl)benzoic acid in tetrahydrofuran with a constant pressure dropping funnel Add it to the above mixture, continue to stir at 20°C for 10 hours, acidify, extract with ethyl acetate, dry over anhydrous magnesium sulfate, and perform column chromatography to obtain 2.3 g of the target compound with a yield of 55.8%. ESI-MS m/z: 411[MH] ⁺ . ¹ H NMR (400MHz, DMSO) δ8.08(d, J=8.4Hz, 2H), 8.04(d, J=8.4Hz, 2H), 6.98(d ,J=7.4Hz,1H),6.73(s,1H),6.63(d,J=7.4Hz,1H),5.50(s,2H),3.93(d,J=4.2Hz,2H),2.25(s ,3H), 2.10(s,3H), 1.75(s,4H), 1.II(s,6H).

Example 7: Preparation of 4-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanyl)benzoic acid (compound 6)

Dissolve 2.68g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride in 15mL of 1,4-dioxane for later use, add 1.37g of p-aminobenzoic acid to 1,4-dioxane:water/1:1 15mL mixed solvent, add 10mL 2N sodium hydroxide at 0°C, stir for 30 minutes, then add the reserved solution dropwise at 0°C, continue stirring After 10 hours, it was acidified, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and subjected to column chromatography to obtain 3.3 g of the target compound with a yield of 89.4%. ESI-MSm/z: 370[M+H] ⁺ . ¹ H-NMR (400MHz, DMSO) δ: 12.68(s, 1H), 9.48(s, 1H), 7.86-7.88(d, 2H, J＝8.0 Hz), 7.77-7.79(d, 2H, J=8.0Hz), 6.95-6.97(d, 1H, J=8.0Hz), 6.66(s, 1H), 6.59-6.61(d, 1H, J=8.0Hz ),3.89-3.91(t,2H),2.20(s,3H),2.06(s,3H),1.66-1.78(m,4H),1.25(s,6H).

Example 8: Preparation of 3-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanyl)benzoic acid (compound 7)

Dissolve 2.68g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride in 15mL of 1,4-dioxane for later use, add 1.37g of m-aminobenzoic acid to 1,4-dioxane:water/1:1 15mL mixed solvent, add 10mL 2N sodium hydroxide at 0°C, stir for 30 minutes, then add the reserved solution dropwise at 0°C, continue stirring After 10 hours, it was acidified, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and subjected to column chromatography to obtain 3.5 g of the target compound with a yield of 94.9%. ESI-MSm/z:384[M+H] ⁺ . ¹ H NMR(400MHz,DMSO)δ12.75(s,1H),9.43(s,1H),8.27(s,1H),7.93(d,J =8.2Hz, 1H), 7.63(d, J=7.8Hz, 1H), 7.41(t, J=7.9Hz, 1H), 6.96(d, J=7.5Hz, 1H), 6.67(s, 1H), 6.60(d, J=7.6Hz, 1H), 3.90(t, J=5.8Hz, 2H), 2.21(s, 3H), 2.07(s, 3H), 1.85–1.73(m, 2H), 1.65(dd ,J＝11.6,6.1Hz,2H),1.25(s,6H).

Example 9: Preparation of 2-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamido)benzoic acid (compound 8)

Dissolve 2.68g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride in 15mL of dichloromethane for later use, add 1.65g of ethyl anthranilate to dichloromethane Add 4.2 mL of triethylamine to 15 mL at 0°C, stir for 30 minutes, then add the reserved solution dropwise at 0°C, continue stirring for 10 hours, acidify with dilute hydrochloric acid, extract with ethyl acetate, and dry over anhydrous magnesium sulfate , spin dry the extract, add ethanol 30mL and sodium hydroxide 0.8g, reflux at 80°C for 2 hours, spin out the solvent, acidify with dilute hydrochloric acid to PH2, extract with ethyl acetate, dry with anhydrous magnesium sulfate, spin dry and perform column chromatography. 2.9 g of the target compound was obtained with a yield of 78.6%. ESI-MS m/z:370[M+H] ⁺ .392[M+Na] ⁺ .H NMR(400MHz,DMSO)δ11.56(s,1H),8.63(d,J＝8.0Hz,1H) ,8.01(d,J=8.0Hz,1H),7.66–7.51(t,J=7.6Hz,1H),7.14(t,J=7.6Hz,1H),6.94(d,J=7.5Hz,1H) ,6.64(s,1H),6.59(d,J=7.4Hz,1H),3.89(t,J=5.9Hz,2H),2.20(s,3H),2.04(s,3H),1.81–1.57( m,4H), 1.27(s,6H).

Example 10: Preparation of 2-(4-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamido)phenyl)acetic acid (compound 9)

Dissolve 2.68g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride in 15mL of 1,4-dioxane for later use, add 1.52g of p-aminophenylacetic acid to 1,4-dioxane:water/1:1 15mL mixed solvent, add 10mL 2N sodium hydroxide aqueous solution at 0°C, stir for 30 minutes, then add the reserved solution dropwise at 0°C, continue Stir for 10 hours, acidify, extract with ethyl acetate, dry over anhydrous magnesium sulfate, and perform column chromatography to obtain 3.4 g of the target compound with a yield of 88.7%. ESI-MS m/z: 384[M+H] ⁺ .406[M+Na] ⁺ . ¹ H NMR (400MHz, DMSO) δ9.17(s, 1H), 7.55(d, J＝8.4Hz, 2H ), 7.16(d, J=8.4Hz, 2H), 6.97(d, J=7.5Hz, 1H), 6.68(s, 1H), 6.61(d, J=7.4Hz, 1H), 3.91(t,J =6.1Hz,2H),3.49(s,2H),2.22(s,3H),2.08(s,3H),1.85–1.58(m,4H),1.23(s,6H).

Example 11: Preparation of 4-(2-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamido)acetyl)benzoic acid (compound 10)

Add 2.43g of 4-(2-bromoacetyl)benzoic acid and 1.40g of hexamethylenetetramine to 20mL of tetrahydrofuran, stir at 20°C for 6 hours, and add the filter cake to 20mL of absolute ethanol after suction filtration. Add 4mL of concentrated hydrochloric acid to the mixture, stir at 45°C for 2 hours, cool and suction filter, wash with 5mL of absolute ethanol, add to 15mL of dichloromethane after drying, then add triethyl ether to the mixture at 0°C Amine 4.2mL, slowly drop into 10mL of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride 2.68g prepared in advance, stir for 12 hours, acidify, extract, anhydrous sulfuric acid Dried over magnesium, spin-dried and then column chromatographed to obtain 1.2 g of the target compound, 29.2%. ESI-MS m/z: 410[MH] ⁺ . ¹ H NMR (400MHz, DMSO) δ8.02(q, J=8.5Hz, 4H), 7.92(t, J=5.5Hz, 1H), 6.98(d ,J=7.5Hz,1H),6.71(s,1H),6.62(d,J=7.4Hz,1H),4.54(d,J=5.5Hz,2H),3.88(t,J=5.5Hz,2H ),2.25(s,3H),2.10(s,3H),1.82–1.50(m,4H),1.14(s,6H).

Example 12: Preparation of methyl 2-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamido)benzoate (compound 11)

Dissolve 3.69 g of 2-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanyl)benzoic acid (compound 8) in 30 mL of dichloromethane, add N,N - Stir 0.5mL of dimethylformamide, add oxalyl chloride dropwise at 0°C, react at room temperature for 5 hours, spin out excess dichloromethane oxalyl chloride, add it to 25mL of methylene chloride, add dropwise at 0°C 10mL of methanol and 2.1mL of triethylamine mixture was stirred for 12 hours. Acidify with dilute hydrochloric acid, dry over anhydrous magnesium sulfate, and perform column chromatography to obtain 3.1 g of the target compound with a yield of 80.9%. ESI-MS m/z: 384[M+H] ⁺ . ¹ H NMR (400MHz, DMSO) δ11.08(s, 1H), 8.56(dd, J=8.5, 0.9Hz, 1H), 7.98(dd, J=8.0,1.6Hz,1H),7.72–7.54(m,1H),7.26–7.08(m,1H),6.94(d,J=7.5Hz,1H),6.64(s,1H),6.58(d ,J=7.5Hz,1H),3.90(d,J=6.1Hz,2H),3.88(s,3H),2.20(s,3H),2.04(s,3H),1.79–1.73(m,2H) ,1.71–1.64(m,2H),1.28(s,6H).

Example 13: Preparation of ethyl 2-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamido)benzoate (compound 12)

Dissolve 2.68g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride in 15mL of dichloromethane for later use, add 1.65g of ethyl anthranilate to dichloromethane Add 4.2 mL of triethylamine to 15 mL at 0°C, stir for 30 minutes, then add the reserved solution dropwise at 0°C, continue stirring for 10 hours, acidify with dilute hydrochloric acid, extract with ethyl acetate, and dry over anhydrous magnesium sulfate , column chromatography, the target compound was obtained 3.3g, yield 89.4%. ESI-MS m/z: 398[M+H] ⁺ .420[M+Na] ⁺ . ¹ H NMR (400MHz, DMSO) δ11.13(s, 1H), 8.57(d, J＝8.4Hz, 1H ),8.00(d,J=6.8Hz,1H),7.62(t,J=6.8Hz,1H),7.17(t,J=8.4Hz,1H),6.95(d,J=7.4Hz,1H), 6.65(s,1H),6.59(d,J=7.4Hz,1H),4.35(q,J=7.1Hz,2H),3.90(t,J=5.0Hz,2H),2.20(s,3H), 2.04(s,3H),1.79–1.73(m,2H),1.71–1.64(m,2H),1.34(t,J＝7.1Hz,3H),1.28(s,6H).

Example 14: Preparation of 2-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamido)-6-methylbenzoic acid (compound 13)

Dissolve 2.68 g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride in 15 mL of 1,4-dioxane for later use, and 2-amino-6-methyl Add 1.51g of benzoic acid to 15mL of 1,4-dioxane:water/1:1 mixed solvent, add 10mL of 2N sodium hydroxide at 0°C, stir for 30 minutes, then add dropwise at 0°C The spare solution was stirred for 10 hours, acidified, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and subjected to column chromatography to obtain 3.5 g of the target compound with a yield of 91.4%. ESI-MS m/z: 382[MH] ⁺ . ¹ H NMR (400MHz, DMSO) δ9.82(s, 1H), 7.79(d, J＝8.4Hz, 1H), 7.34(t, J＝7.7Hz ,1H),7.05(d,J=7.7Hz,1H),6.97(d,J=7.4Hz,1H),6.68(s,1H),6.61(d,J=7.4Hz,1H),3.91(t ,J＝5.2Hz,2H),2.41(s,3H),2.23(s,3H),2.07(s,3H),1.77–1.61(m,4H),1.22(s,6H).

Example 15: Preparation of 2-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamido)-6-fluorobenzoic acid (compound 14)

Dissolve 2.68 g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride in 15 mL of 1,4-dioxane for later use, and 2-amino-6-fluorobenzene Add 1.55g of formic acid to 1,4-dioxane:water/1:1 15mL mixed solvent, add 10mL of 2N sodium hydroxide at 0°C, stir for 30 minutes, then add dropwise at 0°C for later use The solution was stirred for 10 hours, acidified, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and subjected to column chromatography to obtain 3.1 g of the target compound with a yield of 80.1%. ESI-MS m/z: 386[MH] ⁺ . ¹ H NMR (400MHz, DMSO) δ10.65(s, 1H), 8.07(d, J=8.4Hz, 1H), 7.54(dd, J=14.6, 8.4Hz, 1H), 7.15(dd, J=14.4, 8.2Hz, 1H), 6.95(d, J=7.6Hz, 1H), 6.66(s, 1H), 6.56(d, J=8.4Hz, 1H) , 3.90(t, J=5.7Hz, 2H), 2.21(s, 3H), 2.06(s, 3H), 1.78–1.62(m, 4H), 1.II(s, 6H).

Example 16: Preparation of 2-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamido)-5-methylbenzoic acid (compound 15)

Dissolve 2.68 g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride in 15 mL of 1,4-dioxane for later use, and 2-amino-5-methyl Add 1.51g of benzoic acid to 15mL of 1,4-dioxane:water/1:1 mixed solvent, add 10mL of 2N sodium hydroxide at 0°C, stir for 30 minutes, then add dropwise at 0°C The spare solution was stirred for 10 hours, acidified, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and subjected to column chromatography to obtain 3.7 g of the target compound with a yield of 96.7%. ESI-MS m/z:382[MH] ^{+ .1H} NMR(400MHz,DMSO)δ11.43(s,1H),8.52(d,J＝8.5Hz,1H),7.82(s,1H),7.40 (dd,J=8.7,2.0Hz,1H),6.95(d,J=7.5Hz,1H),6.64(s,1H),6.59(d,J=7.5Hz,1H),3.89(t,J= 5.9Hz, 2H), 2.29(s, 3H), 2.20(s, 3H), 2.04(s, 3H), 1.78–1.71(m, 2H), 1.70–1.62(m, 2H), 1.26(s, 6H ).

Example 17: Preparation of 2-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanylamino)-5-fluorobenzoic acid (compound 16)

Dissolve 2.68 g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride in 15 mL of 1,4-dioxane for later use, and 2-amino-5-fluorobenzoic acid Add 1.51g to 15mL of 1,4-dioxane:water/1:1 mixed solvent, add 10mL of 2N sodium hydroxide at 0°C, stir for 30 minutes, then add dropwise at 0°C The solution was stirred for 10 hours, acidified, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and subjected to column chromatography to obtain 3.4 g of the target compound with a yield of 87.9%. ESI-MS m/z: 386[MH] ⁺ . ¹ H NMR (400MHz, DMSO) δ11.37(s, 1H), 8.63(dd, J=9.4, 5.2Hz, 1H), 7.71(dd, J= 9.4,3.2Hz,1H),7.56–7.40(m,1H),6.94(d,J＝7.6Hz,1H),6.63(s,1H),6.58(d,J＝7.6Hz,1H),3.89( t,J=5.9Hz,2H),2.20(s,3H),2.04(s,3H),1.78–1.60(m,4H),1.26(s,6H).

Example 18: Preparation of 2-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamido)terephthalic acid (compound 17)

Dissolve 2.68 g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride in 15 mL of 1,4-dioxane for later use, and 1.81 g of 2-aminoterephthalic acid Add g to 1,4-dioxane:water/1:1 15mL mixed solvent, add 2N sodium hydroxide 20mL at 0°C, stir for 30 minutes, then add the reserved solution dropwise at 0°C , continued to stir for 10 hours, acidified, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and column chromatographed to obtain 3.9 g of the target compound with a yield of 94.4%. ESI-MS m/z: 412[MH] ⁺ . ¹ H NMR (400MHz, DMSO) δ11.51(s, 1H), 9.20(d, J＝1.6Hz, 1H), 8.08(d, J＝8.2Hz ,1H),7.66(dd,J=8.2,1.7Hz,1H),6.92(d,J=7.4Hz,1H),6.63(s,1H),6.56(d,J=7.4Hz,1H),3.90 (t,J=5.7Hz,2H),2.19(s,3H),2.03(s,3H),1.77–1.64(m,4H),1.28(s,6H).

Example 19: Preparation of 2-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamido)-4-methoxybenzoic acid (compound 18)

Dissolve 2.68g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride in 15mL of 1,4-dioxane for later use. Add 1.67g of benzoic acid to 15mL of 1,4-dioxane:water/1:1 mixed solvent, add 10mL of 2N sodium hydroxide at 0°C, stir for 30 minutes, then add dropwise at 0°C The spare solution was stirred for 10 hours, acidified, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and subjected to column chromatography to obtain 3.6 g of the target compound with a yield of 90.2%. ESI-MS m/z:398[MH] ⁺ .

Example 20: Preparation of 2-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamido)-4-chlorobenzoic acid (compound 19)

Dissolve 2.68 g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride in 15 mL of 1,4-dioxane for later use, and 2-amino-4-chlorobenzoic acid Add 1.71g to 1,4-dioxane:water/1:1 15mL mixed solvent, add 10mL 2N sodium hydroxide at 0°C, stir for 30 minutes, then add dropwise at 0°C The solution was stirred for 10 hours, acidified, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and subjected to column chromatography to obtain 3.4 g of the target compound with a yield of 84.4%. ESI-MS m/z: 402[MH] ⁺ . ¹ H NMR (400MHz, DMSO) δ11.67(s,1H),8.72(s,1H),8.00(d,J＝8.6Hz,1H),7.20 (dd,J=8.6,2.2Hz,1H),6.98(d,J=7.5Hz,1H),6.93(d,J=7.6Hz,1H),6.70(s,1H),6.63(s,1H) ,6.58(t,J=6.0Hz,1H),3.90(d,J=4.1Hz,2H),2.20(s,3H),2.03(s,3H),1.78–1.71(m,2H),1.68– 1.64(m,2H),1.27(s,6H).

Example 21: Preparation of 2-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamido)-4-bromobenzoic acid (compound 20)

Dissolve 2.68 g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride in 15 mL of 1,4-dioxane for later use, and 2-amino-4 bromobenzoic acid Add 2.16g to 1,4-dioxane:water/1:1 15mL mixed solvent, add 10mL 2N sodium hydroxide at 0°C, stir for 30 minutes, then add dropwise at 0°C The solution was stirred for 10 hours, acidified, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and subjected to column chromatography to obtain 3.9 g of the target compound with a yield of 87.1%. ESI-MS m/z:446[MH] ⁺ . ¹ H NMR (400MHz,DMSO)δ11.72(s,1H),8.87(s,1H),7.92(d,J＝8.5Hz,1H),7.33 (dd,J=8.5,2.1Hz,1H),6.93(d,J=7.5Hz,1H),6.63(s,1H),6.57(d,J=7.5Hz,1H),3.90(t,J= 5.9Hz,2H),2.20(s,3H),2.03(s,3H),1.80–1.71(m,2H),1.71–1.62(m,2H),1.26(s,6H).

Example 22: Preparation of 2-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanylamino)-4-nitrobenzoic acid (compound 21)

Dissolve 2.68 g of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride in 15 mL of 1,4-dioxane for later use, and 2-amino-4 nitrobenzene Add 1.82g of formic acid to 1,4-dioxane:water/1:1 15mL mixed solvent, add 10mL of 2N sodium hydroxide at 0°C, stir for 30 minutes, then add dropwise at 0°C for later use The solution was stirred for 10 hours, acidified, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and subjected to column chromatography to obtain 3.6 g of the target compound with a yield of 87.0%. Example 23: Preparation of 2-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamido)benzamide (compound 22)

Dissolve 3.69 g of 2-(5-(2,5-dimethylphenoxy)-2,2-dimethylpentanyl)benzoic acid (compound 8) in 30 mL of dichloromethane, add N,N - Stir 0.5mL of dimethylformamide, add oxalyl chloride dropwise at 0°C, react at room temperature for 5 hours, spin out excess oxalyl chloride in dichloromethane, then add it to 30mL of dichloromethane, and pass it in at 0°C Ammonia gas for 1 hour, washed with dilute hydrochloric acid, washed with saturated aqueous sodium bicarbonate solution, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and subjected to column chromatography to obtain 3.3 g of the target compound with a yield of 89.7%. ESI-MS m/z: 370[M+H] ⁺ . ¹ H NMR (400MHz, DMSO) δ11.55(s, 1H), 8.63(d, J=7.6Hz, 1H), 8.01(d, J= 6.4Hz, 1H), 7.68–7.51(m, 1H), 7.14(t, J=8.2Hz, 1H), 6.95(d, J=11.5Hz, 1H), 6.65(s, 1H), 6.59(d, J＝7.1Hz, 1H), 3.90(t, J＝5.9Hz, 2H), 2.20(s, 3H), 2.04(s, 3H), 1.85–1.53(m, 4H), 1.27(s, 6H).

Example 24: FXR antagonistic activity test

The suppliers of reagent materials used are as follows:

1. Preparation of basic buffer

a. Prepare 20ml 1x basic buffer, mix and set aside. The detailed list of buffers is as follows:

Material Final concentration (mM) Tris-Hcl 20 EDTA 1 glycerol 10% Triton X-100 0.0025% KF 400 BSA 0.01% Sodium Molybdate 10 DTT 5 H2O Make up to 20ml

2. Preparation of compound solution

a. For the reference compound GS, first dilute with 100% DMSO to 30 mM stock solution, and then dilute to the desired final concentration by 3 times.

b. For the compound to be detected, first dilute with 100% DMSO to 20 mM stock solution, and then dilute to the required final concentration by 3 times.

c. For the activating compound GW4064, dilute it with 100% DMSO to 520uM stock solution, then add 5nl to each well of a 384-well plate (excluding the low-value well) for use, and its final concentration reaches 130nM.

3. Preparation of 1x protein mixture

a. Based on the calculation of 10ul solution required per well, first prepare 2xFXR-LBD/Eu Anti-GST protein solution with 1x basic buffer to make the final concentration of GST-FXR-LBD protein solution reach 3nM. The detailed table is as follows:

Material Final concentration (mM) GST-FXR-LBD 3 Eu Anti-GST(nl) 50nl/well

b. Based on the calculation of 10ul solution required for each well, first prepare 2xFXR Biotin-SRC1/SA-APC polypeptide solution with 1x basic buffer to make the final concentration of SRC1 polypeptide solution reach 500nM. The detailed table is as follows:

Material Final concentration (mM) Biotin-Peptide 500 SA-APC 50nl/well

c. Mix the above two 2x GST-ER/Eu Anti-GST solutions and 2x peptide/SA-APC solutions in a volume ratio of 1:1 and set aside.

d. Add 1x protein mixture solution to each well of the 384-well plate, and add 20ul to each well.

e. Place the 384-well plate in a centrifuge at room temperature at 1000 rpm for 10 seconds, then take it out.

f. Place the 384-well plate at room temperature for 3 hours and then read.

4. TR-FRET assay readout

Put the 384 plate into the EnVision multi-function microplate reader and read.

5. Result processing

a. Read the 665 and 615 (nm) values, and use the 615 value as the correction value, and the final value is expressed as 665 value/615 value.

b. Calculation of inhibition rate (%)

Calculate the inhibition rate (%) according to the following formula

$<span\; class="notranslate">\; \%</span>\mathrm{<span\; class="notranslate">\; Inhibition</span>}<span\; class="notranslate">\; =</span><span\; class="notranslate">\; (</span>\frac{\mathrm{<span\; class="notranslate">\; Max</span>}<span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; x</span>}}{\mathrm{<span\; class="notranslate">\; Max</span>}<span\; class="notranslate">\; -</span>\mathrm{<span\; class="notranslate">\; Min</span>}}<span\; class="notranslate">\; )</span><span\; class="notranslate">\; \&times;</span>\mathrm{<span\; class="notranslate">\; 100</span>}<span\; class="notranslate">\; \%</span>$

X is the "665 value vs. 615 value" for each concentration. Min is the average value of "665 value to 615 value" of the blank control wells only added with DMSO. Max is the mean of "665 vs. 615" for hyperintensity control wells with activating compound and DMSO alone.

Experimental results:

Example 25: Preparation of Tablets

prescription: Dosage Compound 1 50mg microcrystalline cellulose 250mg Cross-linked polyvinylpyrrolidone 50mg pregelatinized starch 100mg Magnesium stearate 5mg

Preparation method: According to the above formula, the pulverized and sieved compound 1, microcrystalline cellulose, pregelatinized starch and cross-linked polyvinylpyrrolidone were uniformly mixed, then mixed with 5% ethanol solution, granulated, dried, and then mixed with Lubricants are mixed and compressed into tablets. Wherein, the compound 1 is crushed and sieved to pass through a 60 mesh sieve; the microcrystalline cellulose, pregelatinized starch and cross-linked polyvinylpyrrolidone are crushed and sieved to pass through a 80 mesh sieve; the granulated granules The particle size is 20 mesh; the drying temperature is preferably 90°C to control the water mass percentage within 3%.

Example 28: Preparation of Capsules

Preparation method: according to the formula in the above table, mix the medicine and auxiliary materials, and fill them into the capsule shell.

Embodiment 26: preparation of injection

Preparation method: according to the above formula, use a mortar to grind and mix the compound or its salt and wetting agent evenly, then mix evenly with suspending agent, preservative and water for injection, and then grind. Wherein, the particle size of the grinding is 0.5 μm. Example 27: Study on the pharmacodynamics of compounds for lowering blood lipids

Reagent and batch number:

lard commercially available

Cholesterol Shanghai Blue Season Technology Development Co., Ltd. Batch number: 090720

Propylthiouracil Shanghai Lanji Technology Development Co., Ltd. Batch number: 090505

Deoxycholic acid Shanghai Lanji Technology Development Co., Ltd. Batch number: 090615

Tween 80 CP Sinopharm Chemical Reagent Co., Ltd. Lot number: F20090507

1,2-Propanediol Sinopharm Chemical Reagent Co., Ltd. AR batch number: T20070125

Preparation method of fat emulsion: Take 25g of lard, put it in a 200ml beaker, and heat it on a gas stove. When the temperature rises to 100°C, add 10g of cholesterol, dissolve it, then add 1g of propylthiouracil, and stir well. Then add 25ml Tween 80 to make the oil phase. At the same time, add 30ml of distilled water and 20ml of 1,2-propanediol to another beaker, heat it to 60°C in a water bath, then add 2g of sodium deoxycholate, stir until it is completely dissolved, and make a water phase. Then add the water phase to the oil phase and mix thoroughly to make a fat emulsion.

Animals were adaptively fed for 3 days, and 6 animals were selected according to body weight as a blank control group (Control), and the rest of the animals were fed with fat emulsion at 9:00-11:00 every morning, 1ml/100g body weight, for 2 consecutive weeks. Animals administered with fat emulsion were divided into model group (Model) positive drug group and administration group according to body weight, and the number of animals in each group was determined according to the total amount of compound.

The fat emulsion was continued to be administered intragastrically. Simultaneously, Sim (10mg/kg) and SIPI-762380mg/kg were given to the positive drug group. Oral administration starts on the day of grouping, and is administered at 3:00-4:00 p.m. every day. Weigh the body weight every Monday and observe the condition of the animals. The administration was continued for 14 days, the animals were fasted for 12 hours, and 1 ml of orbital blood was collected. Perform a lipid profile.

Serum cholesterol (CHO), triglyceride (TG), low-density lipoprotein (LDL-c) and high-density lipoprotein (HDL-c) were measured by Hitachi automatic biochemical analyzer 7080.

Rat blood lipid level after administration (X±SD, mmol/L)

Claims (12)

1. compound or its pharmaceutically acceptable salt as shown in formula (I),

Wherein:

R₁Selected from hydroxyl, methoxyl group, ethyoxyl or amino,

R₂Selected from hydrogen, halogen, nitro, carboxyl, methoxyl group or methyl,

X is selected from N or O,

N1 is 0 or 1,

N2 is 0 or 1.

2. compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein, n1 is 0.

3. compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein, n1 is 1.

4. compound shown in the Formulas I as described in claim 1-3 any one or its pharmaceutically acceptable salt, it is characterised in that R₂ AndGroup is any the position of substitution on phenyl ring.

5. compound shown in the Formulas I as described in claim 1-4 any one or its pharmaceutically acceptable salt, under which is but being not limited to Row compound:

6. the synthetic method of compound as shown in formula (I) for the claim 1-5 any one, including by compound 23 and compound II, under base catalysis, reacts in appropriate solvent and obtains, and reaction equation is shown in following:

Wherein, R₁Selected from hydroxyl, methoxyl group, ethyoxyl or amino；

R₂Selected from hydrogen, halogen, nitro, carboxyl, methoxyl group or methyl；

X is selected from N or O；

Described alkali is triethylamine, DIPEA, pyridine, NaOH,

Appropriate solvent dichloromethane, chloroform, oxolane, dimethylformamide, pyridine, dioxane/water or its mixed solvent.

7. synthetic method according to claim 6, wherein, described alkali is triethylamine, pyridine or NaOH.

8. synthetic method according to claim 7, wherein, described alkali is triethylamine or NaOH.

9. comprise compound or its pharmaceutically acceptable salt shown in the formula described in claim 1-5 any one (I) and pharmaceutically may be used Accept the pharmaceutical composition of carrier.

10. pharmaceutical composition as claimed in claim 9, it is characterised in which is tablet, pill, pulvis, liquid, suspension, Emulsion, granule, capsule, suppository or injection form.

11. compounds (I) as described in claim 1-5 any one or its pharmaceutically acceptable salt or its pharmaceutical composition are made Application for FXR antagonist.

12. compounds (I) as described in claim 1-5 any one or its pharmaceutically acceptable salt or its pharmaceutical composition exist Application in regulation blood fat.