Patent Description:
Farnesoid X receptor is a member of the nuclear receptor superfamily. It is a ligand-dependent nuclear transcription factor, which is mainly expressed in liver, intestine, kidney, bile duct and other systems. FXR is also known as bile acid receptor because it can be activated by endogenous ligand bile acid and participate in important links such as bile acid metabolism and cholesterol metabolism. FXR is directly involved in regulating the expression of more than <NUM> genes including physiological processes such as lipid metabolism, glucose metabolism, inflammation, fibrosis, liver regeneration, cell differentiation and proliferation. In the natural environment, ligands of FXR include primary bile acid: chenodeoxycholic acid, secondary bile acid: lithocholic acid, deoxycholic acid, etc. For example, FXR, activated by endogenous ligand bile acids, plays an important role in triglyceride (TG) metabolism. FXR can regulate key enzymes, lipoproteins and corresponding receptors involved in the metabolism of TG, so that the content of TG in the liver and circulating blood can reach stable equilibrium. Therefore, up to now, several FXR synthetic ligand molecules have been applied in the field of metabolic diseases such as the liver.

FXR agonist molecules have shown excellent clinical effects in the treatment of liver diseases such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), nonalcoholic steatohepatitis (NASH) and so on. So far, the FXR agonist molecule obeticholic acid (OCA), which will be the first to be approved for marketing, has been proven to significantly improve a variety of metabolic symptoms, such as reducing liver fat content, reducing inflammation and inhibiting liver fibrosis. However, many clinical shortcomings of OCA have also been increasingly highlighted, such as causing itching, lowering high-density lipoprotein (HDLc), increasing low-density lipoprotein (LDLc) and so on. Therefore, in terms of clinical needs, new FXR agonist molecules with good clinical effects and low toxicity and side effects are urgently needed.

In addition, studies have confirmed that FXR is closely related to the occurrence and development of tumors. In a variety of tumors, FXR acts as a tumor suppressor gene. For example, in hepatocellular carcinoma and rectal cancer, the expression of FXR is low; and after the activation of FXR, the progression of liver or rectal cancer is significantly inhibited by inhibiting the activity of β-catenin. Recent studies have shown that in cholangiocarcinoma, FXR agonist OCA can significantly inhibit the proliferation, migration and colony formation of intrahepatic cholangiocarcinoma.

Furthermore, FXR agonists can be used as a new antiviral drug candidate, and studies have confirmed that FXR ligands can be used as a new therapeutic strategy for inhibiting the replication of hepatitis B virus (HBV). FXR agonists can inhibit HBV surface antigen synthesis, inhibit HBV DNA and RNA replication, and most importantly, inhibit HBV cccDNA production. In the aspect of hepatitis C virus (HCV), the FXR agonist GW4064 can inhibit the invasion of HCV into liver tissue cells by indirect means. Therefore, agonist molecules of FXR also have great prospects as antiviral drugs. FXR agonists are disclosed, for example in <CIT>, <CIT>, <CIT> and elsewhere.

In summary, there is still a lack of novel FXR agonist molecules, which can be prepared by simple methods and have good inhibitory effects in the art.

The purpose of the present invention is to provide a novel FXR agonist molecule, which can be prepared by a simple method and have good inhibitory effects.

In the first aspect of the present invention, provided herein is a compound of formula I:
<CHM>
or an enantiomer, diastereomer, tautomer, racemate, hydrate, solvate, or pharmaceutically acceptable salt thereof;
wherein:.

In another embodiment, the R<NUM> is selected from the group consisting of a substituted or unsubstituted C<NUM>-C<NUM> alkyl, and substituted or unsubstituted C<NUM>-C<NUM> cycloalkyl;
wherein the "substituted" means that one or more hydrogen atoms on a group are each independently replaced by a substituent selected from the group consisting of a halogen, halogenated C<NUM>-C<NUM> alkyl, halogenated C<NUM>-C<NUM> alkoxy, C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> alkoxy, C<NUM>-C<NUM> cycloalkyl, C<NUM>-C<NUM> cycloalkoxy, cyano and nitro.

In another embodiment, the Ar is selected from the group consisting of a substituted or unsubstituted C<NUM>-C<NUM> aryl, substituted or unsubstituted <NUM>-<NUM> membered heteroaryl ring; and, the substituent is selected from the group consisting of H, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, and trifluoromethoxy.

In another embodiment, the A is selected from the group consisting of a substituted or unsubstituted C<NUM>-C<NUM> aryl, substituted or unsubstituted <NUM>-<NUM> membered heteroaryl ring; wherein, the substituent on the aryl or heteroaryl is selected from the group consisting of H, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, and trifluoromethoxy.

In another embodiment, the Ar is selected from the group consisting of a substituted or unsubstituted phenyl, substituted or unsubstituted <NUM>-<NUM> membered heteroaryl ring (including a single ring or fused ring containing <NUM>-<NUM> heteroatoms selected from O, S or N).

In another embodiment, the A is selected from the group consisting of a substituted or unsubstituted phenyl, substituted or unsubstituted <NUM>-<NUM> membered heteroaryl ring (including a single ring or fused ring containing <NUM>-<NUM> heteroatoms selected from O, S or N).

In another embodiment, the A is a benzothiazole.

In another embodiment, the Ar or A are each independently selected from the group consisting of a substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thiazolyl, and substituted or unsubstituted imidazolyl.

In another embodiment, the R<NUM> is selected from the group consisting of a substituted or unsubstituted C<NUM>-C<NUM> alkyl, and substituted or unsubstituted cyclopropyl.

In another embodiment, the Ar is a substituted or unsubstituted phenyl.

In another embodiment, the Ar is selected from the group consisting of a <NUM>,<NUM>-dichlorophenyl, <NUM>-methylphenyl, <NUM>-trifluoromethylphenyl, <NUM>-trifluoromethoxyphenyl.

In another embodiment, the R<NUM> is selected from the group consisting of a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl and cyclopentyl.

In another embodiment, the compound of formula I has the structure as shown in the formula below:
<CHM>.

In another embodiment, the compound is selected from the group consisting of
<CHM>
<CHM>
<CHM>.

In the second aspect of the present invention, provided herein is a preparation method of the compound of the first aspect, and said method comprises preparing a compound of formula I by a method selected from the following route <NUM> or <NUM>:
<CHM>
<CHM>.

In another embodiment, the compound of formula VII is prepared through the step below:
<CHM>
k) a compound of formula XII and a compound of formula XIII generate the compound shown in the general formula VII under the presence of a base;.

In each formula, the definition of A is as described in the first aspect of the present invention.

In another preferred embodiment, when the product has an optical isomer, a raw material with the corresponding optical configuration is used for preparation.

In the third aspect of the present invention, provided herein is a pharmaceutical composition comprising the compound of formula I, or an enantiomer, diastereomer, tautomer, racemate, hydrate, solvate, or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

In the fourth aspect of the present invention, provided herein is the use of the compound of formula I, or an enantiomer, diastereomer, tautomer, racemate, hydrate, solvate, or pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for treating diseases or conditions related to FXR activity or expression.

In another embodiment, the diseases related to FXR is selected from the group consisting of diseases related to bile acid metabolism, glucose metabolism, lipid metabolism, inflammation, and/or liver fibrosis process.

In another embodiment, the diseases related to FXR is nonalcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), gallstones, nonalcoholic cirrhosis, hepatitis B (HBV), hepatitis C (HCV), liver fibrosis, cholestatic liver disease, hyperlipidemia, hypercholesterolemia, or diabete.

In another embodiment, the pharmaceutical composition is used as an FXR agonist.

In another embodiment, the pharmaceutical composition is used to reduce the levels of ALP, ALT, AST and TBA in serum.

In another embodiment, the pharmaceutical composition is used to reduce the content of hydroxyproline in liver tissue.

In another embodiment, the pharmaceutical composition is used to downregulate the expression of α-SMA and Col1α1 mRNA in liver tissue.

In another embodiment, the pharmaceutical composition is used to inhibit the synthesis of HBV surface antigen, inhibit the replication of HBV DNA and RNA, and inhibit the production of HBV cccDNA.

In another embodiment, the pharmaceutical composition is used to reduce the collagen content in liver.

In another embodiment, the pharmaceutical composition is prepared by the following method: mixing the compound of formula I with pharmaceutically acceptable excipients (such as excipients, diluents, etc.), and formulating it into tablets, capsules, granules or syrup, etc..

It should be understood that within the scope of the present invention, the technical features mentioned above of the present invention and the technical features specifically described below, e.g., in the examples, can be combined with each other to form new or preferred technical solutions. Due to the limited pages, they are not described here. The scope of the present invention is defined in the appended claims.

After extensive and deep research, the inventors of the present application have developed a class of non-steroidal compounds that can be used as FXR agonists and have agonistic ability to FXR at both molecular and cellular levels. Studies have shown that the compounds of the present application can reduce the levels of ALP, ALT, AST and TBA in serum, reduce the content of hydroxyproline in liver tissue, down-regulate the expression of α-SMA and Col1á1 mRNA in liver tissue, reduce the content of collagen in liver, inhibit the synthesis of HBV surface antigen, inhibit the replication of HBV DNA and RNA, and inhibit the production of HBV cccDNA. The compound of the present invention has advantages, such as high FXR agonistic activity, convenience in synthesis, easy availability of raw materials. The compound of the present invention can be used for preparing medicines for treating FXR-related diseases. On this basis, the present invention has been completed.

In the present invention, unless otherwise indicated, the terms used herein have the ordinary meanings known to those skilled in the art.

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

In the present invention, the term "C<NUM>-C<NUM>" means that a group has <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM> carbon atoms, and "C<NUM>-C<NUM>" means that a group has <NUM>, <NUM>, <NUM> or <NUM> carbon atoms, and so on.

In the present invention, the term "alkyl" refers to a saturated linear or branched hydrocarbon moiety. For example, the term "C1-C6 alkyl" refers to a straight or branched chain alkyl group having <NUM> to <NUM> carbon atoms including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.; preferably ethyl, propyl, isopropyl , butyl, isobutyl, sec-butyl and tert-butyl.

In the present invention, the term "alkoxy" denotes a -O-(C1-C6 alkyl) group. For example, the term "C1-C6 alkoxy" refers to a straight or branched chain alkoxy group having <NUM> to <NUM> carbon atoms, including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc..

In the present invention, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon moiety. For example, the term "C3-C6 cycloalkyl" refers to a cyclic alkyl group having <NUM> to <NUM> carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc..

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

In the present invention, the term "aryl" refers to a hydrocarbyl moiety comprising one or more aromatic rings. Examples of aryl groups include, but not limited to, phenyl (Ph), naphthyl, pyrenyl, fluorenyl, anthracenyl, and phenanthryl.

In the present invention, the term "heteroaryl" refers to a moiety comprising one or more aromatic rings having at least one heteroatom, e.g. N, O or S. Examples of heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolinyl, isoquinolinyl, indolyl, and the like.

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

In the present invention, the substitution is monosubstitution or polysubstitution, and the polysubstitution is disubstitution, trisubstitution, tetrasubstitution, or pentasubstitution. The disubstitution refers to a group having two substituents, and so on.

The pharmaceutically acceptable salts of the present invention may be salts fromed from anions with positively charged groups on the compounds of formula I. Suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methane sulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate or maleate. Similarly, salts can be formed from cations with negatively charged groups on compounds of formula I. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium, such as tetramethylammonium.

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

In another preferred embodiment, in the compound, any one of ring A, Ar, X and R<NUM> is the corresponding group in the specific compound described in the embodiments.

The compounds of the present invention possess asymmetric centers, chiral axes and chiral planes, and may exist as racemates, R-isomers or S-isomers. Those skilled in the art can obtain the R-isomer and/or S-isomer from the racemate by conventional technical means.

The preparation method of the compound of formula I of the present invention is shown in the synthetic route below:
<CHM>.

In another embodiment, the compound of formula VII is prepared through the step below:
<CHM>
k) a compound of formula XII and a compound of formula XIII generate a compound shown in the general formula VII under the presence of a base;.

The compounds provided herein can be used alone or mixed with pharmaceutically acceptable excipients, such as excipients, diluents, etc., to prepare tablets, capsules, granules or syrups for oral administration. The pharmaceutical composition can be prepared according to conventional methods in pharmacy. The pharmaceutical composition of the present invention contains the active ingredient in a safe and effective amount, and a pharmaceutically acceptable carrier.

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

The "active ingredients" and pharmaceutical compositions of the present invention are used to prepare medicines for treating FXR-related diseases.

The "active ingredients" and pharmaceutical compositions of the present invention are useful as FXR agonists. In another preferred embodiment, the active ingredient can be used to prepare a medicament for preventing and/or treating diseases regulated by FXR agonists.

The "safe and effective amount" refers to an amount of the active ingredient sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains <NUM>-<NUM> of active ingredient/agent, more preferably <NUM>-<NUM> of active ingredient/agent. Preferably, the "one dose" is one tablet.

"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "Compatibility" as used herein refers to that the components of the composition can be blended with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients. Examples of pharmaceutically acceptable carrier moieties include cellulose and derivatives thereof (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), moisturizing agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc..

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

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

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

In addition to the active ingredient, suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures thereof, and the like.

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.

The compounds of the present invention may be administered alone or in combination with other therapeutic agents, e.g., hypolipidemic agents.

When a pharmaceutical composition is used, a safe and effective amount of a compound of the present invention is administered in a mammal (e.g., a human) in need thereof, wherein the administered dose is a pharmaceutically effective dose. For a person weighing <NUM>, the daily dose is usually <NUM> to <NUM>, preferably <NUM> to <NUM>. Of course, the route of administration, the patient's health and other factors should also be taken into account for a specific dosage, all of which are within the skill of the skilled physician.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention.

In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions, such as the conditions described in <NPL>, or in accordance with the conditions suggested by the manufacturer. Unless otherwise indicated, percentages and parts are weight percentages and parts.

Unless otherwise indicated, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the methods of the present invention. Preferred methods and materials described herein are provided for illustrative purposes only.

The instruments and main experimental materials used are as follows:
The used reagents and anhydrous solvents were purchased from Chinese commercial companies, and were directly used unless otherwise indicated. <NUM>H and <NUM>C NMR were performed on Bruker AM-<NUM> and Varian Mercury plus-<NUM> nuclear magnetic resonance apparatus. Mass spectrometry was performed on Agilent <NUM> mass spectrometer. <NUM>-<NUM> mesh column chromatography silica gel from Qingdao Ocean Chemical Plant and HSGF254 TLC plate from Yantai Chemical Research Institute were used.

The compound of the present invention was prepared according to any method selected from the following route <NUM> or <NUM>, using suitable starting materials:
<CHM>
<CHM>
<CHM>.

Endo-<NUM>-azabicyclo[<NUM>. <NUM>]octan-<NUM>-ol XII (<NUM>, <NUM>. 7mmol) and p-fluorobenzonitrile. XIII-<NUM> (<NUM>. 7mmol) were dissolved in N,N-dimethylformamide (<NUM>). Potassium carbonate (197mmol) was added in batches at room temperature. The reaction was carried out at <NUM> overnight. The reaction solution was diluted by adding ethyl acetate (<NUM>), and washed with water. The aqueous phase was extracted with ethyl acetate (<NUM> x <NUM> times). The organic phases were combined, washed with saturated brine, and concentrated. Intermediate VII-<NUM> (<NUM>, yield <NUM>%) was obtained by column chromatography. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>). MS(ESI, m/z): <NUM>[M+H]+.

Aqueous potassium carbonate (3N, <NUM> mmol) was added dropwise to a solution of hydroxylamine hydrochloride (<NUM> mmol) in ethanol (<NUM>) with stirring at <NUM>. <NUM>,<NUM>-Dichlorobenzaldehyde II-<NUM> (<NUM>, <NUM> mmol) was dissolved in <NUM> of ethanol, and then added to the above reaction solution. The temperature was raised to <NUM> and the reaction was carried out for two hours. After the reaction was cooled to room temperature, it was concentrated to a solid. A solution of water/ethanol (<NUM>/<NUM>) was added and stirred to break up the solid. The mixture was filtered and dried under vacuum at <NUM> overnight to obtain the intermediate (<NUM>). The intermediate was dissolved in N,N-dimethylformamide (<NUM>). A solution of N-chlorosuccinimide (<NUM> mmol) in N,N-dimethylformamide (<NUM>) was added dropwise at <NUM> and stirred overnight. The reaction solution was poured into ice water at <NUM>, then extracted with methyl tert-butyl ether (<NUM> x <NUM> times). The organic phase was washed with saturated brine, and concentrated to obtain a crude product. n-Hexane (<NUM>) was added to the flask containing the crude product, stirred with a magnetic bar, and filtered. The solid was dried under vacuum (<NUM>) to obtain intermediate III-<NUM> (<NUM>, yield <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Triethylamine (<NUM>) was added to methyl <NUM>-cyclopropyl-<NUM>-oxopropanoate (<NUM> mmol) and stirred for <NUM> minutes. The mixture was then cooled to <NUM>, and a solution of III-<NUM> (<NUM>, <NUM> mmol) in anhydrous ethanol (<NUM>) was added dropwise (internal temperature should not exceed <NUM>), and the reaction was carried out at room temperature overnight. The reaction solution was diluted with Ethyl acetate (<NUM>), and washed with water, and the aqueous phase was extracted with ethyl acetate (<NUM> x <NUM> times). The organic phases were combined, washed with saturated brine, and concentrated. <NUM> of diethyl ether was added to the concentrate and stirred, and the solvent was removed under vacuum to obtain a solid product IV-<NUM> (<NUM>, yield <NUM>%). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>); MS(ESI, m/z): <NUM>[M+H]+.

Deuterated Lithium aluminum hydride (<NUM>) was added to tetrahydrofuran (<NUM>) and cooled to <NUM>. Then IV-<NUM> (<NUM>, <NUM> mmol) in tetrahydrofuran (<NUM>) was added dropwise (internal temperature should not exceed <NUM>), and the reaction solution was stirred at room temperature for <NUM>. The reaction was quenched by adding ice water (<NUM>) at <NUM>, then <NUM>% aqueous sodium hydroxide solution (<NUM>) and ice water (<NUM>) were added dropwise and respectively. Afterwards, anhydrous magnesium sulfate (<NUM>) was added, and the above mixture was stirred at room temperature for <NUM>, filtered and concentrated. The intermediate V-<NUM> (<NUM>, yield <NUM>%) was obtained by column chromatography. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI, m/z): <NUM>[M+H]+.

V-<NUM> (<NUM>, <NUM> mmol) was dissolved in dichloromethane (<NUM>), and cooled to <NUM>. Phosphorus tribromide (<NUM> mmol) was slowly added dropwise to the solution, and the reaction solution was stirred at room temperature for <NUM>. The solvent was removed to obtain an oily substance, which was then diluted with ethyl acetate (<NUM>), and the pH value of the reaction solution was adjusted to neutral with saturated aqueous sodium bicarbonate solution. The mixture was washed with water and the aqueous phase was extracted with ethyl acetate (<NUM> x <NUM> times). The organic phases were combined, washed with saturated brine, and concentrated. Intermediate VI-<NUM> (<NUM>, yield <NUM>%) was obtained by column chromatography. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI, m/z): <NUM>[M+H]+.

Potassium tert-butoxide (<NUM> mmol) was added to a solution of VII-<NUM> (<NUM>, <NUM> mmol) in anhydrous tetrahydrofuran (<NUM>) at <NUM>, and stirred for <NUM> minutes. Then a solution of VI-<NUM> (<NUM> mmol) in anhydrous tetrahydrofuran (<NUM>) was added dropwise, and the reaction solution was stirred at room temperature for <NUM>. Water (<NUM>) was added to the reaction solution, and the mixture was extracted with ethyl acetate (<NUM> x <NUM> times). The organic phase was washed with saturated brine, and concentrated. Intermediate VIII-<NUM> (<NUM>, <NUM>% yield) was obtained by column chromatography. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM>-<NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI, m/z): <NUM>[M+H]+.

VIII-<NUM> (<NUM>, <NUM> mmol), hydroxylamine hydrochloride (<NUM> mmol), absolute ethanol (<NUM>) were added to a round bottom flask and stirred. Triethylamine (<NUM> mmol) was slowly added dropwise. The mixture was heated to <NUM> and reacted overnight. The mixture was cooled to room temperature. The solvent was removed and the residue was dissolved with dichloromethane (<NUM>). The solution was washed with water and saturated brine, and the organic phase was concentrated. Intermediate IX-<NUM> (<NUM>, yield <NUM>%) was obtained by silica gel column chromatography. <NUM>HNMR (<NUM>, DMSO-d<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI, m/z): <NUM>[M+H]+.

IX-<NUM> (<NUM>, <NUM> mmol), N,N'-carbonyldiimidazole (<NUM> mmol), <NUM>,<NUM>-dioxane (<NUM>) was added to a round bottom flask. Then <NUM>,<NUM>-diazabicyclo[<NUM>. <NUM>]undec-<NUM>-ene (<NUM> mmol) was added. The mixture was heated to <NUM> and reacted for <NUM> hours. The reaction solution was cooled to room temperature, and diluted with water (<NUM>), and the pH value adjusted to about <NUM> with <NUM> aqueous hydrochloric acid. Then the mixture was extracted with ethyl acetate (<NUM> x <NUM> times). The organic phase were combined, washed with saturated brine, and concentrated to obtain a crude product. The final product <NUM> (<NUM>, yield <NUM>%) was obtained by silica gel column chromatography. <NUM>HNMR (<NUM>, DMSO-d<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI, m/z): <NUM>[M+H]+.

The synthesis of example <NUM> was performed from intermediate VII-<NUM> through route <NUM>. The synthetic route is as follows:
<CHM>.

Starting from raw material XIII-<NUM>, compound VII-<NUM> was synthesized according to the synthetic method of intermediate VII-<NUM>, and then <NUM> was prepared through route <NUM>, wherein:.

The synthesis of Example <NUM> was performed from intermediate VII-<NUM> through route <NUM>, and the synthetic route is as follows:
<CHM>.

Synthesis of Example <NUM> was performed with reference to the operation of Example <NUM>, and <NUM> was prepared from intermediate IV-<NUM> through route <NUM>. The synthetic route is as follows:
<CHM>.

Lithium aluminum hydride (<NUM>, <NUM> mmol) was added to tetrahydrofuran (<NUM>) and cooled to <NUM>. Then IV-<NUM> (<NUM> mmol) in tetrahydrofuran (<NUM>) was added dropwise (internal temperature shall not exceed <NUM>), and the reaction solution was stirred at room temperature for <NUM>. The reaction was quenched by adding ice water (<NUM>) at <NUM>, then <NUM>% aqueous sodium hydroxide solution (<NUM>) and ice water (<NUM>) were added dropwise. Then anhydrous magnesium sulfate (<NUM>) was added. The mixture was stirred at room temperature for <NUM>, filtered and concentrated. Intermediate X-<NUM> (<NUM>, yield <NUM>%) was obtained by column chromatography. MS(ESI, m/z): <NUM>[M+H]+.

X-<NUM> (<NUM>, <NUM> mmol) was added to dichloromethane (<NUM>), and pyridinium chlorochromate (<NUM> mmol) was added at room temperature. The reaction solution was stirred at room temperature for <NUM>, then filtered and concentrated. Intermediate XI-<NUM> (<NUM>, yield <NUM>%) was obtained by column chromatography. MS(ESI, m/z): <NUM>[M+H]+.

Lithium aluminum hydride (<NUM>, <NUM> mmol) was added to tetrahydrofuran (<NUM>) and cooled to <NUM>. Then XI-<NUM> (<NUM> mmol) in tetrahydrofuran (<NUM>) was added dropwise (internal temperature shall not exceed <NUM>), and the reaction solution was stirred at room temperature for <NUM>. The reaction was quenched by adding ice water (<NUM>) at <NUM>, then <NUM>% aqueous sodium hydroxide solution (<NUM>) and ice water (<NUM>) were added dropwise, respectively. Then anhydrous magnesium sulfate (<NUM>) was added, and the above mixture was stirred at room temperature for <NUM>, filtered and concentrated. Intermediate V-<NUM> (<NUM>, yield <NUM>%) was obtained by column chromatography. <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI, m/z): <NUM>[M+H]+.

V-<NUM> (<NUM>, <NUM> mmol) was dissolved in dichloromethane (<NUM>) and cooled to <NUM>. Phosphorus tribromide (<NUM> mmol) was slowly added dropwise to the solution, and the reaction solution was stirred at room temperature for <NUM>. The solvent was removed from the reaction solution to obtain an oily substance, which was diluted with ethyl acetate (<NUM>). The pH of the reaction solution was adjusted to neutral with saturated aqueous sodium bicarbonate solution. The mixture was washed with water, and the aqueous phase was extracted with ethyl acetate (<NUM> x <NUM> times). The organic phases were combined, washed with saturated brine, and concentrated. Intermediate VI-<NUM> (<NUM>, <NUM>% yield) was obtained by column chromatography. MS(ESI, m/z): <NUM>[M+H]+.

Potassium tert-butoxide (<NUM> mmol) was added to a solution of VII-<NUM> (<NUM>, <NUM> mmol) in anhydrous tetrahydrofuran (<NUM>) at <NUM>, and the solution was stirred for <NUM> minutes. Then a solution of VI-<NUM> (<NUM> mmol) in anhydrous tetrahydrofuran (<NUM>) was added dropwise, and the reaction solution was stirred at room temperature for <NUM>. Water (<NUM>) was added to the reaction solution. The solution was extracted with ethyl acetate (<NUM> x <NUM> times). The organic phase was washed with saturated brine and concentrated. Intermediate VIII-<NUM> was obtained by column chromatography (<NUM>, yield <NUM>%). MS(ESI, m/z): <NUM>[M+H]+.

VIII-<NUM> (<NUM>, <NUM> mmol), hydroxylamine hydrochloride (<NUM> mmol), absolute ethanol (<NUM>) were added to a round bottom flask and stirred. Triethylamine (<NUM> mmol) was slowly added dropwise. The mixture was heated to <NUM> and reacted overnight, then cooled to room temperature. The solvent was removed, and the residue was dissolved with dichloromethane (<NUM>). The solution was washed with water and saturated brine, and then the organic phase was concentrated. Intermediate IX-<NUM> (<NUM>, yield <NUM>%) was obtained by silica gel column chromatography. MS(ESI, m/z): <NUM>[M+H]+.

IX-<NUM> (<NUM>, <NUM> mmol), N,N'-carbonyldiimidazole (<NUM> mmol), <NUM>,<NUM>-dioxane (<NUM>) was added to a round bottom flask, then <NUM>,<NUM>-diazabicyclo[<NUM>. <NUM>]undec-<NUM>-ene (<NUM> mmol) was added. The solution was heated to <NUM> and reacted for <NUM> hours, then cooled to room temperature. The mixture was diluted with water (<NUM>), and the pH value was adjusted to about <NUM> with <NUM> aqueous hydrochloric acid. The mixture was then extracted with ethyl acetate (<NUM> x <NUM> times). The organic phases were combined, washed with saturated brine, and concentrated. The final product <NUM> (<NUM>, <NUM>% yield) was obtained by silica gel column chromatography. <NUM>HNMR (<NUM>, DMSO-d<NUM>) δ7. <NUM>-<NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>). MS(ESI, m/z): <NUM>[M+H]+.

Starting from raw material XIII-<NUM>, compound VII-<NUM> was synthesized through the synthetic method of synthesizing intermediate VII-<NUM>, and then <NUM> was prepared through route <NUM>, wherein:.

The synthesis of Example <NUM> was performed from intermediate II-<NUM> through route <NUM>, and the synthetic route is as follows:
<CHM>.

The pGAL4-FXR-LBD and pG5-Luc plasmids used in the reporter gene detection system were constructed according to conventional molecular cloning methods, including main steps:.

HEK293T cells were seeded in <NUM>-well plates at a density of <NUM>×<NUM><NUM>/well one day before plasmid transfection. Cell transfection was performed according to the instructions of the transfection reagent FuGENE® HD (Promega, #E2311), including main steps:.

<NUM> after cells were co-transfected, the compounds were diluted to <NUM> concentrations with a <NUM>-fold gradient, with <NUM> as the highest concentration. Then the diluted compounds were added to the cell culture medium for treatment for <NUM>. <NUM> duplicate wells were set up in total. Compound LJN452 was used as positive control.

After cells were treated with compounds for <NUM>, detections were performed according to the instructions of the Dual-Glo® Luciferase Assay System (Promega, #E2940), including main steps:.

The experimental data show that the compounds all have certain FXR agonistic activity. Wherein the EC<NUM> values of Examples <NUM>, <NUM>, <NUM>, and <NUM> are all less than <NUM>, which have very strong FXR agonistic activity. The FXR agonistic activity data of other examples are shown in Table <NUM>.

The results show that the compounds of the present invention exhibited better cellular level activity than the existing FXR agonist compound LJN452 and the non-deuterated Control <NUM>. Especially, the compound of Example <NUM> of the present application is the deuterated compound of Control <NUM>, which shows significantly improved activity, suggesting that this position is a key deuterated site for this type of compound.

Mice were used to compare the bioavailability and pharmacokinetic behaviors of deuterated embodiment <NUM> and non-deuterated embodiment <NUM>. In each group of embodiment, <NUM> male ICR mice with a similar body weight were selected, of which <NUM> mice were dosed orally in a single dose of <NUM>/kg, and <NUM> mice were dosed intravenously in a single dose of <NUM>/kg. Blood samples were collected at time points of <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after administration. The concentrations of plasma samples were analyzed by LC-MS/MS. A free tool of PKSolver and the non-compartment model (NCA) ware applied to analyze the pharmacokinetic parameters of compounds, as shown in Table <NUM> below.

<NUM> healthy male ICR mice, commercially available from Charles River with an animal production license NO. : <NUM>1Abzz0619000376, were divided into <NUM> groups, <NUM> in each group.

Formulation preparation: a certain amount of compounds were weighed and added into a <NUM>% DMSO+<NUM>% Solutol+<NUM>% saline, to prepare a clear solution.

Dosage: ICR mice were fasted overnight and given each compound at an oral dose of <NUM>/kg or an intravenous dose of <NUM>/kg. The administrated volume for oral and intravenous administration are <NUM>/kg and <NUM>/kg, respectively. Food was withheld until <NUM> post-dose.

Sample collection: About <NUM>µL of blood was collected via great saphenous vein at <NUM>, <NUM>, <NUM>, <NUM>, <NUM> and <NUM> after dosage. The blood was placed into a commercial tube containing K<NUM>-EDTA. Plasma samples were then obtained by centrifuging the blood samples at approximately <NUM>, <NUM> rpm for <NUM> minutes. All plasma samples were then quickly frozen on dry ice and kept at -<NUM> until LC-MS/MS analysis.

Sample preparation: <NUM>µL of plasma samples were precipitated by methanol containing <NUM> nmol/L of α-naphthoflavone as internal standard. The mixture was votex-mixed well and centrifuged at <NUM> rpm for <NUM> at <NUM>. <NUM>µL of the supernatant was taken and mixed with <NUM>µL of methanol, and introduced for LC-MS/MS analysis.

Results of the pharmacokinetic parameters are shown in Table <NUM>.

Claim 1:
A compound of formula I:
<CHM>
or an enantiomer, diastereomer, tautomer, racemate, hydrate, solvate, or pharmaceutically acceptable salt thereof;
wherein:
Ar is selected from the group consisting of a substituted or unsubstituted C<NUM>-C<NUM> aryl, and substituted or unsubstituted <NUM>-<NUM> membered heteroaryl ring (including a single ring or fused ring, and containing <NUM>-<NUM> heteroatoms selected from O, S or N);
A is selected from the group consisting of a substituted or unsubstituted C<NUM>-C<NUM> aryl, substituted or unsubstituted <NUM>-<NUM> membered heteroaryl ring (including a single ring or fused ring, and containing <NUM>-<NUM> heteroatoms selected from O, S or N);
R<NUM> is selected from the group consisting of a substituted or unsubstituted C<NUM>-C<NUM> alkyl, substituted or unsubstituted C<NUM>-C<NUM> cycloalkyl, substituted or unsubstituted <NUM>-<NUM> membered heterocyclic group (containing <NUM>-<NUM> heteroatoms selected from O, S or N);
X is selected from the group consisting of H and D;
wherein, the "substituted" means that one or more hydrogen atoms on a group are each independently replaced by a substituent selected from the group consisting of a halogen, halogenated C<NUM>-C<NUM> alkyl, halogenated C<NUM>-C<NUM> alkoxy, C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> alkoxy, C<NUM>-C<NUM> cycloalkyl, C<NUM>-C<NUM> cycloalkoxy, cyano and nitro.