Compound, pharmaceutical composition containing same and application thereof

Abstract

The invention relates to a compound with a structure as shown in a formula (I) or pharmaceutically acceptable salt thereof, and also relates to a pharmaceutical composition containing the compound, a preparation method and application thereof. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the fields of medicinal chemistry and biomedicine. Specifically, the present invention relates to a compound having a novel structure of formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the same, and its use in the preparation of a drug for preventing or treating hepatitis virus infection. Background Art

[0002] Chronic hepatitis caused by hepatitis B virus (HBV) infection is a global public health problem, with nearly 300 million people infected globally; the incidence of liver cancer caused by HBV is about 8.5 per 100,000. Long-term chronic HBV infection will develop into liver cirrhosis and hepatocellular carcinoma, and the number of deaths caused by complications exceeds 800,000 every year. The main clinical treatment drugs are nucleoside analogs (NAs) and interferons (IFNs). These drugs can improve the progression of HBV-related pathogenesis, reduce the viral load and relieve hepatitis, but there are problems such as long treatment cycles and drug resistance, and they cannot be completely cured. The main reasons for the difficulty in treating HBV are, firstly, that HBV DNA can be integrated into the host cell DNA after infection; secondly, covalently closed circular DNA (cccDNA) will generate pregenomic RNA (pgRNA), which can continuously replicate and release HBV as a template, resulting in new hepatocytes being infected, thus maintaining the chronic infection state and expanding the cccDNA pool. Therefore, the combined drug use strategy of "preventing external threats" and "eliminating internal evils" may be a good choice for treating HBV infection. Developing HBV entry inhibitors to prevent new cells from being infected, and at the same time combining with antiviral reverse transcriptase drugs is a powerful means to reduce the cccDNA pool, which is of great significance for treating HBV infection.

[0003] Hepatitis D is an infectious disease jointly caused by hepatitis D virus (HDV) and hepatotropic DNA viruses such as hepatitis B virus. HDV is a defective single-stranded negative-strand RNA virus and must rely on hepatotropic DNA viruses such as HBV to provide its outer shell for replication. HDV exists in the liver cell nuclei and sera of HDV-infected individuals positive for hepatitis B virus surface antigen (HBsAg). It mainly replicates in hepatocytes. After human infection with HDV, the synthesis of HBV-DNA can be significantly inhibited. The appearance of hepatitis D virus antigen (HDAg) is consistent with the decrease in HBV-DNA in the serum. As HDAg turns negative and anti-HD appears, HBV-DNA returns to the original level. After the overlapping infection of HDV and HBV, it can promote the aggravation of liver damage and is prone to develop into chronic active hepatitis, liver cirrhosis and severe hepatitis.

[0004] Sodium taurocholate cotransporting polypeptide (NTCP) is a functional receptor for hepatitis B virus (HBV) / hepatitis D virus (HDV) to enter hepatocytes. It is a transmembrane bile acid transporter expressed on the basolateral membrane of hepatocytes, providing a new target for the development of anti-HBV drugs.

[0005] Currently, there are reports of various compounds targeting NTCP to inhibit HBV infection, including Myrcludex B, taurocholic acid (TCA), cyclosporin A (CsA) and its analogs, dimeric bile acid derivatives (such as DBA-41), irbesartan, ezetimibe, etc. However, only two macromolecules (Myrcludex B and Hepalatide) have entered clinical trials, and no small molecules have entered clinical trials, and most small molecule inhibitors have low activity. The present invention provides a novel inhibitor of NTCP, which has very important significance and function for clinical research and the treatment of HBV. Summary of the Invention

[0006] In a first aspect, the present invention provides a compound having the structure of the following formula (I):

[0007]

[0008] or a pharmaceutically acceptable salt thereof, wherein X1, X2, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、m, n and o are as defined herein.

[0009] In a second aspect, the present invention provides a pharmaceutical composition comprising the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0010] In a third aspect, the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating, ameliorating or preventing a condition responsive to inhibition of sodium taurocholate cotransporting polypeptide. Brief Description of the Drawings

[0011] Figure 1A Shows the inhibitory effect of the compounds of the present application on hepatitis B e antigen (HBeAg); Figure 1BShows the inhibitory effect of the compounds of the present application on HBV 3.5-kb RNA; Figure 1C Shows the inhibitory effect of the compounds of the present application on the uptake of taurocholic acid-d4.

[0012] Figure 2 Shows the test results of the toxicity test of the compounds JH-A27 and JH-A32 of the present application.

[0013] Figure 3 Shows the test results of the inhibitory effects of the compounds JH-A27 and JH-A32 of the present application on the uptake of taurocholic acid-d4, HBV 3.5-kb RNA and hepatitis B e antigen (HBeAg).

[0014] Figure 4 Shows the schematic diagram of the dosing regimen for a humanized liver mouse model.

[0015] Figure 5 Shows the test results of the in vivo efficacy verification test of the compound JH-A32 of the present application. Detailed Description of the Invention

[0016] The present invention will be further described in detail below. Such a description is for illustrative purposes and is not intended to limit the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments. Those skilled in the art can make various modifications and changes without departing from the spirit of the present invention.

[0017] General terms and definitions

[0018] Unless otherwise defined below, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. In case of conflict, the definitions provided herein shall prevail. The techniques used herein refer to the techniques commonly understood in the art, including variants and equivalent substitutions that are obvious to those skilled in the art. Although it is believed that the following terms are easily understood by those skilled in the art, the following definitions are set forth to better illustrate the present invention. When a trade name appears herein, it refers to the corresponding product or its active ingredient. All patents, published patent applications and publications cited herein are incorporated herein by reference.

[0019] When a quantity, concentration, or other numerical value or parameter is set forth as a range, preferred range, or preferred upper or lower limit, it is to be understood as specifically disclosing any range formed by combining any upper or preferred value with any lower or preferred value, whether or not the ranges are explicitly recited. Unless otherwise stated, the numerical ranges recited herein are intended to include the endpoints of the range and all integers and fractions (decimals) within the range. For example, the statement "m is an integer from 0 to 6" means that m is any integer from 0 to 6, such as m can be 0, 1, 2, 3, 4, 5, or 6. Other similar statements such as for n, o, p, and q, etc. are to be understood in a similar manner.

[0020] Unless the context clearly dictates otherwise, singular forms such as "a", "an", and "the" include plural forms. The phrase "one or more" or "at least one" can mean 1, 2, 3, 4, 5, 6, 7, 8, 9, or more.

[0021] The terms "about" and "approximately" when used with a numerical variable generally mean that the value of the variable and all values of the variable are within the experimental error range (e.g., within the 95% confidence interval of the mean) or within the range of ±10% or wider of the specified value.

[0022] The terms "comprising", "including", "containing", and "having" are open-ended and do not exclude additional unrecited elements, steps, or components. The term "consisting of" does not include any unspecified elements, steps, or components. The term "consisting essentially of" means that the scope is limited to the specified elements, steps, or components, and optionally existing elements, steps, or components that do not materially affect the basic and novel features of the claimed subject matter. It should be understood that the term "comprising" includes the terms "consisting essentially of" and "consisting of".

[0023] The term "alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group composed of carbon and hydrogen atoms, which is connected to the rest of the molecule by a single bond. An alkyl can have 1 to 20 carbon atoms, referring to "C 1-20 alkyl", such as C 1-6 alkyl, C 1-4 alkyl, C 1-2 alkyl, C3 alkyl, C4 alkyl, C 3-6 alkyl. "C 1-6 alkyl" is used to represent a straight-chain or branched-chain saturated hydrocarbon group composed of 1 to 6 carbon atoms. The C 1-6 alkyl includes C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl, C 2-6 alkyl, C 2-4Alkyl, C6 alkyl, C5 alkyl, etc. Non-limiting examples of alkyl include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers.

[0024] A divalent group refers to a group obtained by removing a hydrogen atom from a carbon atom with a free valence electron in the corresponding monovalent group. A divalent group has two connection sites that connect to the rest of the molecule. For example, "alkylene" or "alkylidene" refers to a saturated straight-chain or branched divalent hydrocarbon group. Examples of "alkylene" include, but are not limited to, methylene (-CH2-), ethylene (-C2H4-), propylene (-C3H6-), butylene (-C4H8-), pentylene (-C5H 10 -), hexylene (-C6H 12 -), 1-methylethylene (-CH(CH3)CH2-), 2-methylethylene (-CH2CH(CH3)-), methylpropylene, or ethylpropylene, etc. For example, -(CH2) m -, -(CH2) n -, -(CH2) o -, -(CH2) p -, and -(CH2) q - all fall under the category of divalent groups.

[0025] The term "alkenyl" is used to denote a straight-chain or branched hydrocarbon group containing one or more carbon-carbon double bonds, and the carbon-carbon double bonds can be located at any position in the group. Non-limiting examples of alkenyl include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, etc.

[0026] The term "alkynyl" is used to denote a straight-chain or branched hydrocarbon group containing one or more carbon-carbon triple bonds, and the carbon-carbon triple bonds can be located at any position in the group. Non-limiting examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, etc.

[0027] The term "cycloalkyl" refers to a cyclic saturated aliphatic group composed of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond, and it includes monocyclic, bicyclic, or tricyclic systems, where the bicyclic and tricyclic systems include spiro rings, fused rings, and bridged rings. Cycloalkyl can have 3 - 10 carbon atoms, i.e., "C3-10 "Cycloalkyl", such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl. "Cycloalkylene" refers to a divalent cycloalkyl.

[0028] The term "heterocyclic group" refers to one or more carbon atoms in the above cycloalkyl being replaced by heteroatoms selected from nitrogen, oxygen and sulfur, such as aziridinyl, oxiranyl, thioranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, tetrahydropyranyl or tetrahydrothiopyranyl. The heteroatom can occupy the connection position of the heterocyclic group to the rest of the molecule. "Heteroalkylene" refers to a divalent cycloalkyl.

[0029] The term "alkoxy" represents an alkyl group having a specific number of carbon atoms connected by an oxygen bridge. Non-limiting examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy. The term "C 1-6 alkoxy" means an alkyl group containing 1 to 6 carbon atoms connected to the rest of the molecule through an oxygen atom. The C 1-6 alkoxy includes C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 、C6, C5, C4 and C3 alkoxy, etc. Non-limiting examples of C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy, etc.

[0030] The terms "aromatic ring" and "aryl" can be used interchangeably. The term "aromatic ring" or "aryl" represents a polyunsaturated carbocyclic system, which can be a monocyclic, bicyclic or polycyclic system, where at least one ring is aromatic, and the rings in the bicyclic and polycyclic systems are fused together. Examples of aryl include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.).

[0031] The terms "heteroaromatic ring" and "heteroaryl" may be used interchangeably. The term "heteroaryl" refers to an aryl (or aromatic ring) containing 1, 2, 3, or 4 heteroatoms independently selected from B, N, O, and S, which may be a monocyclic, bicyclic, or tricyclic system. The heteroaryl may be attached to the rest of the molecule through a heteroatom. Non-limiting examples of the heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furyl (including 2-furyl, 3-furyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl, 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl, 5-quinoxalinyl, etc.), quinolinyl (including 3-quinolinyl, 6-quinolinyl, etc.), pyrazinyl, purinyl, phenylbenzooxazolyl.

[0032] As used herein, the term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable organic or inorganic salts. Exemplary salts include, but are not limited to: sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, bitartrates, ascorbates, succinates, maleates, fumarates, gluconates, glucuronates, galacturonates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and pamoates (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthoates)). The compounds used in the present invention can form pharmaceutically acceptable salts with various amino acids. Suitable basic salts include, but are not limited to, aluminum salts, calcium salts, lithium salts, magnesium salts, potassium salts, sodium salts, zinc salts, bismuth salts, and diethanolamine salts. A review of pharmaceutically acceptable salts can be found in Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, eds., Wiley-VCH, 2002).

[0033] "Optional" or "optionally" means that the subsequent described event or circumstance may, but does not necessarily, occur, and the description includes both the case where the described event or circumstance occurs and the case where the described event or circumstance does not occur.

[0034] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and variants of hydrogen, provided that the valence of the particular atom is normal and the resulting compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary based on what is chemically achievable.

[0035] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereoisomer-enriched mixtures, all of which mixtures are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are included within the scope of the present invention.

[0036] Unless otherwise specified, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0037] Unless otherwise specified, the terms "cis-trans isomer" or "geometric isomer" are caused by the inability of double bonds or single bonds of ring carbon atoms to rotate freely.

[0038] Unless otherwise specified, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and are not mirror images of each other.

[0039] Unless otherwise specified, "(D)" or "(+)" indicates dextrorotation, "(L)" or "(-)" indicates levorotation, and "(DL)" or "(±)" indicates racemization.

[0040] Unless otherwise specified, a solid wedge bond and a dashed wedge bond represent the absolute configuration of a stereocenter, and a solid straight bond and a dashed straight bond represent the relative configuration of a stereocenter. A wavy line represents a solid wedge bond or a dashed wedge bond or a wavy line represents a solid straight bond and a dashed straight bond

[0041] The term "pharmaceutically acceptable excipient" refers to those carrier substances that have no obvious stimulatory effect on the organism and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable excipients" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents or emulsifiers.

[0042] The term "pharmaceutical composition" or "composition of active pharmaceutical ingredients" refers to a substance composed of one or more active ingredients and optionally one or more pharmaceutically acceptable medicinal excipients.

[0043] The term "HBcAg" refers to hepatitis B core antigen. HBcAg plays an important role in HBV infection, can reflect the presence of Dane particles in serum and the replication of HBV in the liver, and can cooperate and complement with other HBV serological markers.

[0044] The term "Dane particle" refers to the large spherical particle of hepatitis B virus, which is an intact and infectious HBV particle.

[0045] The term "HBeAg" refers to hepatitis B e antigen, which is a soluble protein in the core particles of hepatitis B virus. Under normal circumstances, HBeAg is buried inside HBcAg. When HBcAg is cleaved, HBeAg dissolves into the serum from the virus particles. Its appearance is later than that of HBsAg, but it disappears earlier than HBsAg. Therefore, it is the second serological antigen marker that appears following HBsAg after human infection with HBV.

[0046] The term "HBsAg" refers to hepatitis B surface antigen, which is not the complete hepatitis B virus itself but the outer shell of the hepatitis B virus. It has no infectivity but has antigenicity and is only one of the markers of hepatitis B virus infection.

[0047] Compounds of the present invention

[0048] The present invention provides a compound having the structure of the following formula (I):

[0049]

[0050] or a pharmaceutically acceptable salt thereof,

[0051] wherein,

[0052] X1 is selected from

[0053] X2 is selected from O or NR 14 ;

[0054] R 1 is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 3-10 heterocyclic group, C 3-10 heterocyclic group-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, C 5-10 heteroaryl and C 5-10 heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is independently unsubstituted or substituted by at least one substituent selected from R X ;

[0055] R 2 is selected from hydrogen, halogen, amino, cyano, nitro, C 1-6 alkyl, C 1-6 alkyl-S-C 1-6Alkyl, C 1-6 Alkyl - O - C 1-6 Alkyl, C 1-6 Alkyl - C 6-10 Aryl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl - C 1-4 Alkyl, C 3-10 Heterocyclic group, C 3-10 Heterocyclic group - C 1-4 Alkyl, C 6-10 Aryl, C 6-10 Aryl - C 1-4 Alkyl, C 5-10 Heteroaryl, C 5-10 Heteroaryl - C 1-4 Alkyl, CN and NO2, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is unsubstituted or substituted by at least one substituent independently selected from R X ;

[0056] R 3 is selected from hydrogen and C 1-6 alkyl;

[0057] When R 4 is i) the formula (I) has the structure of the following formula (II - 1):

[0058]

[0059] When R 4 is ii) the formula (I) has the structure of the following formula (II - 2):

[0060] When R 4 is iii) the formula (I) has the structure of the following formula (II - 3):

[0061] When R 4 is iv) the formula (I) has the structure of the following formula (II - 4):

[0062] Or

[0063] When R 4 is v) the formula (I) has the structure of the following formula (II - 5):

[0064]

[0065] R 5 selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 3-10 heterocyclic group, C 3-10 heterocyclic group-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, C 5-10 heteroaryl and C 5-10 heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is independently unsubstituted or substituted with at least one substituent selected from R X ;

[0066] R 6 selected from hydrogen, amino, cyano, nitro, C 1-6 alkyl, C 1-6 alkyl-C 3-10 cycloalkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 alkyl-S-C 1-6 alkyl, C 1-6 alkyl-C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 3-10 heterocyclic group, C 3-10 heterocyclic group-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, C 5-10 heteroaryl and C 5-10 heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is independently unsubstituted or substituted with at least one substituent selected from R X ;

[0067] or R 5 and R 6 together with the atoms to which they are attached form a 5- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms, said 5- to 8-membered heterocyclic group being unsubstituted or substituted with at least one substituent selected from R Xsubstituted by a substituent of;

[0068] R 7 selected from hydrogen and C 1-6 alkyl;

[0069] R 8 selected from hydrogen, amino, cyano, nitro, C 1-6 alkyl, C 1-6 alkyl-C 3-10 cycloalkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 alkyl-S-C 1-6 alkyl, C 1-6 alkyl-C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 3-10 heterocyclic group, C 3-10 heterocyclic group-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, C 5-10 heteroaryl and C 5-10 heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is independently unsubstituted or substituted by at least one substituent independently selected from R X of;

[0070] R 9 selected from hydrogen and C 1-6 alkyl;

[0071] R 10 and R 11 are each independently selected from hydrogen, hydroxy, halogen, C 1-6 alkyl and C 1-6 alkoxy, wherein each alkyl and alkoxy is independently unsubstituted or substituted by at least one substituent independently selected from R X of;

[0072] R 12 and R 13 are each independently selected from hydrogen, hydroxy, halogen, C 1-6 alkyl and C 1-6 alkoxy, wherein each alkyl and alkoxy is independently unsubstituted or substituted by at least one substituent independently selected from R X of;

[0073] R 14 selected from hydrogen and C1-6 alkyl;

[0074] R X selected from hydroxy, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 3-10 heterocyclic group, C 3-10 heterocyclic group-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, C 5-10 heteroaryl and C 5-10 heteroaryl-C 1-4 alkyl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is independently unsubstituted or substituted with at least one substituent independently selected from R Y ;

[0075] R Y selected from hydroxy, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 3-10 heterocyclic group, C 3-10 heterocyclic group-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, C 5-10 heteroaryl and C 5-10 heteroaryl-C 1-4 alkyl;

[0076] m, n, o, p and q are each independently an integer selected from 0, 1, 2, 3, 4, 5 and 6;

[0077] *1 C, *2 C and *3 C each represent a chiral carbon atom connected to R 4 , R 6 and R 8 ;

[0078] In one embodiment, X1 is The formula (I) has the structure of the following formula (III):

[0079]

[0080] Among them, X2, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , m, n, o, and q are defined as in formula (I); * 1 C, *2 C, and *3 C respectively represent the chiral carbon atoms connected to R 4 , R 6 , and R 8 .

[0081] In one embodiment, X1 is Formula (I) has the structure of the following formula (III’):

[0082]

[0083] Among them, X2, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , m, n, o, and p are defined as in formula (I); * 1 C, *2 C, and *3 C respectively represent the chiral carbon atoms connected to R 4 , R 6 , and R 8 .

[0084] In one embodiment, X2 is O.

[0085] In one embodiment, R 1 is selected from hydrogen and C 1-6 alkyl. In one embodiment, R 1 is selected from hydrogen and methyl.

[0086] In one embodiment, R 2 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkyl-S-C 1-6 alkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 alkyl-C 6-10 aryl, wherein the alkyl and aryl are unsubstituted or substituted by at least one substituent independently selected from R X . In one embodiment, R 2 is selected from hydrogen, methyl, ethyl, isopropyl,

[0087] In one embodiment, R 3 is hydrogen.

[0088] In one embodiment, R 4 is Formula (I) has the structure of the following formula (II-1):

[0089]

[0090] wherein X1, X2, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , m, n and o are as defined herein.

[0091] In one embodiment, R 4 is Formula (I) has the structure of the following formula (II-2):

[0092]

[0093] wherein X1, X2, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13, m, n, and o are as defined herein.

[0094] In one embodiment, R 4 is Formula (I) has the structure of the following formula (II-3):

[0095]

[0096] wherein, X1, X2, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , m, n, and o are as defined herein.

[0097] In one embodiment, R 4 is Formula (I) has the structure of the following formula (II-4):

[0098]

[0099] wherein, X1, X2, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , m, n, and o are as defined herein.

[0100] In one embodiment, R 4 is Formula (I) has the structure of the following formula (II-5):

[0101]

[0102] wherein, X1, X2, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R11 , R 12 , R 13 , m, n, and o are as defined herein.

[0103] In one embodiment, R 5 is selected from hydrogen and C 1-6 alkyl. In one embodiment, R 5 is selected from hydrogen and methyl.

[0104] In one embodiment, R 6 is selected from C 1-6 alkyl, C 1-6 alkyl-C 3-10 cycloalkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 alkyl-S-C 1-6 alkyl, C 1-6 alkyl-C 6-10 aryl, wherein the alkyl, cycloalkyl, and aryl are unsubstituted or substituted with at least one substituent independently selected from R X . In one embodiment, R 6 is selected from

[0105] In one embodiment, R 5 and R 6 together with the atom to which they are attached form a 5-membered heterocyclic group containing 1 nitrogen heteroatom, and the 5-membered heterocyclic group is unsubstituted or substituted with at least one substituent independently selected from R X . In one embodiment, R 5 and R 6 together with the atom to which they are attached form

[0106] In one embodiment, R 7 is hydrogen.

[0107] In one embodiment, R 8 is selected from C 1-6 alkyl-C 3-10 cycloalkyl, C 1-6 alkyl-C 6-10 aryl, wherein the alkyl, cycloalkyl, and aryl are unsubstituted or substituted with at least one substituent independently selected from R X . In one embodiment, R 8 is selected from

[0108] In one embodiment, R 9 is selected from C 1-6 alkyl. In one embodiment, R9 is methyl.

[0109] In one embodiment, R 10 is selected from C 1-6 alkyl. In one embodiment, R 10 is methyl.

[0110] In one embodiment, R 11 is selected from C 1-6 alkyl. In one embodiment, R 11 is methyl.

[0111] In one embodiment, R 12 is selected from C 1-6 alkoxy. In one embodiment, R 12 is methoxy.

[0112] In one embodiment, R 13 is selected from C 1-6 alkoxy. In one embodiment, R 13 is methoxy.

[0113] In one embodiment, R X is selected from hydroxyl, halogen, C 1-6 alkyl, and C 1-6 alkoxy. In one embodiment, R X is selected from hydroxyl, fluorine, chlorine, methyl, tert-butyl, methoxy, and

[0114] In one embodiment, R Y is selected from halogen. In one embodiment, R Y is fluorine.

[0115] In one embodiment, m is 1. In one embodiment, n is 1. In one embodiment, o is 1. In one embodiment, p is 1. In one embodiment, q is 1.

[0116] In one embodiment, *1 the C chiral carbon atom is in the S or R configuration. In a preferred embodiment, *1 the C chiral carbon atom is in the S configuration. In one embodiment, *2 the C chiral carbon atom is in the S or R configuration. In a preferred embodiment, *2 the C chiral carbon atom is in the S configuration. In one embodiment, *3 the C chiral carbon atom is in the S or R configuration. In a preferred embodiment, * 3 the C chiral carbon atom is in the S configuration.

[0117] The compounds provided by the present invention are selected from the following structures:

[0118]

[0119]

[0120]

[0121]

[0122]

[0123] or a pharmaceutically acceptable salt thereof.

[0124] In a preferred embodiment, the compounds of the present invention are selected from

[0125] Pharmaceutically acceptable salts of the present invention

[0126] Those skilled in the art will understand that the compounds according to the present invention may exist in the form of pharmaceutically acceptable salts. As pharmaceutically acceptable salts, for example, the following instances may be provided: metal salts, ammonium salts, salts formed with organic bases, inorganic acids, organic acids, basic or acidic amino acids, etc. The pharmaceutically acceptable salts according to the present invention can be prepared from compounds containing acidic or basic groups by conventional chemical methods. Generally, it can be prepared by reacting a compound in the form of a free acid or base with a stoichiometrically appropriate base or acid in water, an organic solvent or a mixture thereof. Generally, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, etc. is preferred.

[0127] Routes of administration, pharmaceutical compositions and kits

[0128] The compounds according to the present invention will be administered in an effective amount, alone or in combination with additional therapeutic agents, by any common and acceptable means known in the art. The effective amount may vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors known to those skilled in the art.

[0129] As a general example, a daily dose of about 0.001 to about 100 mg / kg body weight may be used, or particularly a daily dose of about 0.03 to 2.5 mg / kg body weight. In larger mammals, such as humans, the daily dose may be in the range of about 0.5 mg to about 2000 mg.

[0130] The compounds of the present invention are generally administered in the form of pharmaceutical compositions, which comprise a pharmaceutically active ingredient and various other pharmaceutically acceptable components, see, e.g., Remington's Pharmaceutical Science (15th ed., Mack Publishing Company, Easton, Pa., 1980). The preferred or desired form depends on the intended mode of administration and therapeutic application. Depending on the required formulation, the composition may also include a pharmaceutically acceptable non-toxic carrier or diluent, which is defined as a carrier commonly used in formulating pharmaceutical compositions for animal or human administration. The choice of diluent does not affect the biological activity of the combination. Examples of diluents include, but are not limited to, distilled water, physiological phosphate buffered saline, Ringer's solution, glucose solution, and Hank's solution. In addition, the pharmaceutical composition or formulation may also include other carriers, adjuvants, or non-toxic, non-therapeutic, non-immunogenic stabilizers, etc.

[0131] The compounds of the present invention can be administered in the form of pharmaceutical compositions by any conventional route; for example, enterally, e.g., orally, e.g., in the form of tablets or capsules; parenterally, e.g., in the form of injectable solutions or suspensions; or topically, e.g., via the eye, nasal cavity, e.g., in the form of emulsions, gels, ointments, creams, or suppositories.

[0132] Accordingly, the present invention also provides a pharmaceutical composition comprising a compound according to the present invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. The compounds of the present invention can exist in free form or in pharmaceutically acceptable salt form in combination with at least one pharmaceutically acceptable carrier, and can be prepared in a conventional manner, e.g., by mixing, granulating, coating, dissolving, or lyophilization processes.

[0133] In one embodiment, the pharmaceutical composition is a solution of the active ingredient, including suspensions or dispersions, such as isotonic aqueous solutions. For compositions that contain only the active ingredient in lyophilized form or lyophilized compositions that also contain the active ingredient together with a carrier (such as mannitol), dispersions or suspensions can be prepared prior to use.

[0134] Non-limiting examples of carriers include fillers such as sugars, such as lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate, and binders such as starches, such as corn, wheat, rice or potato starch, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and / or, if necessary, disintegrants such as the above starches, carboxymethyl starch, cross-linked polyvinylpyrrolidones, alginic acid or its salts, such as sodium alginate. Other carriers include, but are not limited to, rheology modifiers and lubricants such as silicic acid, talc, stearic acid or its salts, such as magnesium or calcium stearate, and / or polyethylene glycol or its derivatives.

[0135] The present invention also provides a pharmaceutical combination, such as a kit, which comprises a) a first agent, which is a compound according to the invention or a pharmaceutically acceptable salt thereof, and b) at least one additional agent. The kit may further comprise instructions for its administration.

[0136] Therapeutic methods and uses of the compounds of the present invention

[0137] The present invention provides a method for treating a condition responsive to inhibition of the sodium taurocholate co-transporting polypeptide, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) according to the invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the invention.

[0138] The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition for treating, ameliorating or preventing a condition responsive to inhibition of the sodium taurocholate co-transporting polypeptide.

[0139] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition in the preparation of a medicament for treating, ameliorating or preventing a condition responsive to inhibition of the sodium taurocholate co-transporting polypeptide.

[0140] In one embodiment, conditions responsive to inhibition of the sodium taurocholate co-transporting polypeptide include, but are not limited to, hepatitis virus infections. In one embodiment, hepatitis virus infections include hepatitis B virus and / or hepatitis D virus infections.

[0141] Beneficial effects

[0142] The present invention provides a novel small molecule inhibitor of NTCP, which has a good inhibitory effect on NTCP. Compared with macromolecular drugs, the small molecule inhibitor of the present invention has a simple synthesis method and can have better drug-forming properties and pharmacokinetic properties, providing more choices for clinical research on small molecule drugs for the treatment of HBV and HDV.

[0143] Examples

[0144] The solutions of the present invention will be further described in detail below with reference to specific embodiments.

[0145] It should be noted that the following embodiments are merely examples for clearly illustrating the technical solutions of the present invention and are not intended to limit the present invention. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the description of the present invention. It is not necessary and impossible to enumerate all the implementation manners here, and the obvious changes or modifications derived therefrom are still within the protection scope of the present invention. Unless otherwise specified, the instruments, equipment, reagents and materials used herein are all commercially available.

[0146] The sources of the raw materials used in the present invention are as follows:

[0147] Table 1 Sources of Conventional Reagents

[0148]

[0149]

[0150] Table 2 Amino Acid Information Table

[0151]

[0152]

[0153] Example 1 Synthesis of Compound JH-A27

[0154] 1.1 Synthesis of the FKBD Fragment of the Compound

[0155]

[0156] i) KOH, H2O / EtOH, rt; ii) Pd / C (10%), H2, MeOH, rt; iii) tert-Butyl 2-bromoacetate, K2CO3, DMF, rt; iv) (+)-DIPCl, THF, -20 °C - rt; v) S8, benzoyl chloride, DMAP, Et3N, DCM / THF, rt; vi) TFA (10%), DCM, rt.

[0157] i) Dissolve 3,4-dimethoxybenzaldehyde (8.31 g, 50 mmol) and 3-hydroxyacetophenone (6.81 g, 50 mmol) in ethanol (EtOH) (50 mL), and add NaOH (0.5 g dissolved in 4 mL of water); stir the reaction mixture at room temperature until the reaction is complete as detected by TLC (the reaction mixture becomes a yellowish-brown precipitate slurry after completion); then dilute the reaction mixture with ethyl acetate (EtOAc) and wash and extract it 3 times with water. The crude product obtained after concentrating the organic phase is directly used for the next step.

[0158] ii) Dissolve the crude product obtained in i) in methanol (MeOH) (40 mL). After displacing the oxygen in the reaction system with an inert gas, add Pd / C (2.3 g, 10%). Then, introduce H2 for gas displacement to fill the reaction system with H2. Monitor the reaction progress by TLC. After the reaction is complete, displace the H2 in the system with an inert gas, filter off the Pd / C, concentrate the filtrate, and purify it by silica gel column chromatography (the eluent is petroleum ether:ethyl acetate (PE:EtOAc) = 3:1) to obtain 10.3 g of a light yellow oily liquid compound S1. The total yield of the two-step reaction is 72%.

[0159] iii) Dissolve compound S1 (10.3 g, 36 mmol) in 30 mL of N,N-dimethylformamide (DMF). Subsequently, add tert-butyl 2-bromoacetate (6.4 mL, 7.72 g, 39.6 mmol) and K2CO3 (5.97 g, 43.2 mmol). Stir the reaction mixture at room temperature and monitor the reaction progress by TLC spotting until compound S1 is completely consumed. After the reaction is complete, dissolve the reactants in EtOAc, add 1 N HCl for washing, wash the organic phase with saturated brine, dry it with anhydrous Na2SO4, then concentrate and purify it by silica gel column chromatography (the eluent is PE:EtOAc = 4:1) to obtain 11.68 g of compound S2 with a yield of 81%.

[0160] iv) Dissolve compound S2 (11.68 g, 29.16 mmol) in dry THF (40 mL) and cool it to -20 °C. Then, slowly add (+)-diisopinocampheylborane ((+)-DIPCl) (1.6 M in hexane, 27.3 mL, 43.74 mmol). Subsequently, slowly warm it to room temperature. After the reaction is complete, add 2,2'-(ethylenedioxy)diethylamine (equivalent to (+)-DIPCl) to quench and form an insoluble complex. Stir the suspension at room temperature for 30 minutes, then filter it through a Celite pad and concentrate it. Purify it by silica gel column chromatography (the eluent is PE:EtOAc = 2:1) to obtain 10.56 g of a colorless liquid compound S3 with a yield of 90%.

[0161] 11H NMR (600 MHz, CDCl3) δ 7.26 (t, J = 7.2 Hz, 1H), 6.96 (d, J = 7.2 Hz, 1H), 6.93 (s, 1H), 6.82 - 6.77 (m, 2H), 6.74 - 6.70 (m, 2H), 4.68 - 4.64 (m, 1H), 4.52 (s, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 2.73 - 2.66 (m, 1H), 2.65 - 2.58 (m, 1H), 2.12 - 2.05 (m, 1H), 2.00 - 1.95 (m, 1H), 1.48 (s, 9H) ppm.

[0162] v) Dissolve compound S3 (10.56 g, 26.24 mmol), compound S8 (9.8 g, 31.4 mmol) and 4-dimethylaminopyridine (DMAP) (3.2 g, 26.24 mmol) in anhydrous tetrahydrofuran (THF) and dichloromethane (DCM) (60 mL, THF / DCM = 1:1). Under argon protection, add triethylamine (Et3N) (6.2 mL, 4.51 g, 44.6 mmol) and benzoyl chloride (6.0 mL, 7.28 g, 39.36 mmol) slowly in turn. Stir the reaction mixture at room temperature for 2 hours. Monitor the reaction by TLC. After complete conversion, dilute the reaction mixture with 300 mL of EtOAc and wash it with 5% HCl and saturated NaHCO3. Wash the organic phase with saturated brine and dry it with anhydrous Na2SO4. After concentration, purify it by silica gel column chromatography (the eluent is PE:EtOAc = 10:1 - 3:1) to obtain 12.78 g of light yellow solid compound S4 with a yield of 70%.

[0163] vi) Dissolve compound S4 (12.78 g, 18.37 mmol) in DCM (60 mL). Under argon protection, add trifluoroacetic acid (TFA) (17.83 mL, 27.37 g, 0.24 mol) in batches and stir at room temperature until the reaction is completely converted. After the reaction is completed, remove the solvent and TFA, and purify it by silica gel column chromatography (the eluent is PE:EtOAc = 3:1 - 1:1) to obtain 10.8 g of light yellow foamy solid FKBD fragment (compound B) with a yield of 92%.

[0164] 11H NMR (600 MHz, CDCl3) δ 7.28 (d, J = 7.8 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 6.90 (dd, J1 = 8.4, J2 = 2.4 Hz, 1H), 6.86 (s, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.70 - 6.66 (m, 2H), 6.37 (d, J = 17.4 Hz, 1H), 6.04 (dd, J1 = 17.4, J2 = 10.2 Hz, 1H), 5.81 (d, J = 10.8 Hz, 1H), 5.73 (dd, J1 = 8.4, J2 = 5.4 Hz, 1H), 5.28 (d, J = 5.4 Hz, 1H), 4.71 (d, J = 16.2, 1H), 4.66 (d, J = 16.2, 1H), 4.33 (d, J = 10.8 Hz, 1H), 4.26 (d, d, J = 10.8, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.49 - 3.44 (m, 1H), 3.25 - 3.20 (m, 1H), 2.67 - 2.61 (m, 1H), 2.59 - 2.54 (m, 1H), 2.40 (d, J = 14.4 Hz, 1H), 2.29 - 2.20 (m, 1H), 2.10 - 2.04 (m, 1H), 1.83 - 1.73 (m, 2H), 1.63 (d, J = 12.6 Hz, 1H), 1.54 - 1.46 (m, 1H), 1.43 - 1.35 (m, 1H), 1.32 (s, 3H), 1.31 (s, 3H) ppm.

[0165] 1.2 Synthesis of Intermediate Compound S8

[0166]

[0167] i) Allyl bromide, Cs2CO3, DMF, rt; ii) DMAP, TFA, DCM, rt; iii) Toluene, reflux; iv) Acryloyl chloride, DIPEA, DCM, 0 °C; v) N - methylaniline, Pd(PPh3)4, THF, rt.

[0168] i) Dissolve N-Boc-L-proline (11.47 g, 50 mmol) in DMF (70 mL), add Cs2CO3 (32.58 g, 100 mmol), stir the resulting suspension at room temperature for 5 minutes, and then add allyl bromide (6.35 g, 52.5 mmol). Stir the reaction mixture at room temperature until the reaction is complete as detected by TLC. Filter the suspension through a Celite pad, wash with EtOAc (60 mL), and wash with HCl (1 M, 50 mL × 3). Dry the organic phase over anhydrous Na2SO4 and co-evaporate with toluene (30 mL × 2). Obtain 14.66 g of a crude product as a yellow oil, which is used directly in the next step without further purification.

[0169] ii) Dissolve the crude product obtained in i) in DCM (30 mL), add TFA (7.5 mL), stir at room temperature until the starting materials are completely reacted, and concentrate to obtain 5.6 g of a crude product S5 as a yellow oil, which is used directly in the next step.

[0170] iii) Dissolve the crude product S5 (5.6 g, 33.09 mmol) obtained in ii), dihydro-4,4-dimethyl-2,3-furandione (4.24 g, 33.09 mmol), and DMAP (808.5 mg, 6.62 mmol) in anhydrous toluene (PhMe) (35 mL), heat in an oil bath to reflux for 16 hours; then remove the solvent and purify by silica gel column chromatography (eluent: PE:EtOAc = 3:1) to obtain 9.05 g of a yellow oil compound S6. The total yield of the three-step reaction is 61%.

[0171] 1 1H NMR (600 MHz, CDCl3) δ 5.96 - 5.88 (m, 1H), 5.36 (d, J = 17.4 Hz, 1H), 5.30 - 5.27 (m, 2H), 4.70 - 4.65 (m, 2H), 3.71 - 3.60 (m, 2H), 3.50 (d, J = 15.6 Hz, 1H), 3.32 (s, 1H), 3.20 (td, J1 = 13.2, J2 = 3.0 Hz, 1H), 2.36 (d, J = 13.8 Hz, 1H), 1.81 - 1.62 (m, 3H), 1.56 - 1.36 (m, 2H), 1.24 (s, 6H) ppm.

[0172] (iv) Dissolve compound S6 (9.05 g, 30.4 mmol) and DIPEA (6.53 mL, 5.11 g, 39.52 mmol, 1.3 equiv) in anhydrous DCM (30 mL), and then slowly add acryloyl chloride (2.7 mL, 3.026 g, 33.44 mmol) dropwise thereto; the reaction mixture was stirred at room temperature until the reaction was complete, and then quenched with saturated NaHCO3 solution. The organic phase was washed and extracted with water, dried over anhydrous Na2SO4, concentrated and purified by silica gel column chromatography (eluent: PE:EtOAc = 5:1) to obtain 8.12 g of colorless oily compound S7 with a yield of 76%.

[0173] 1 H NMR (600 MHz, CDCl3) δ 6.39 (d, J = 17.4 Hz, 1H), 6.07 (dd, J1 = 17.4, J2 = 10.2 Hz, 1H), 5.93 - 5.87 (m, 1H), 5.83 (d, J = 10.8 Hz, 1H), 5.34 (d, J = 16.8 Hz, 1H), 5.28 - 5.25 (m, 2H), 4.67 - 4.64 (m, 2H), 4.37 (d, J = 10.8 Hz, 1H), 4.26 (d, J = 10.8 Hz, 1H), 3.51 (d, J = 12.0 Hz, 1H), 3.22 (td, J1 = 13.2, J2 = 3.0 Hz, 1H), 2.34 (d, J = 13.8 Hz, 1H), 1.81 - 1.76 (m, 1H), 1.73 - 1.68 (m, 1H), 1.64 (d, J = 13.2 Hz, 1H), 1.56 - 1.48 (m, 1H), 1.44 - 1.38 (m, 1H), 1.35 (s, 3H), 1.34 (s, 3H) ppm.

[0174] (v) Dissolve compound S7 (8.12 g, 23.1 mmol), Pd(PPh3)4 (800.8 mg, 0.693 mmol, 3%), and N-methylaniline (7.5 mL, 7.425 g, 69.3 mmol) in dry THF (35 mL) and stir at room temperature for 6 hours; then dilute the reaction mixture with EtOAc (50 mL) and wash and extract with HCl (1 M, 40 mL × 3); the organic phase was dried over Na2SO4, filtered and concentrated; the crude product was purified by silica gel column chromatography (eluent: DCM:MeOH = 30:1) to obtain 5.47 g of white solid compound S8 with a yield of 86%.

[0175] 1.3 Synthesis of Linker

[0176]

[0177] i) m-CPBA, K2HPO4, DCM, rt, 12 h; ii) H2SO4, THF:H2O = 1:1, reflux; iii) NaIO4, MeOH, 20 h; iv) NaBH4, MeOH, 0 °C; v) TsCl, Ag2O, KI, DCM, rt; vi) 2-chlorotrityl chloride resin, DIPEA, THF, 50 °C, 24 h; vii) MeNH2, THF, 40 °C, 12 h.

[0178] i) Dissolve 1,4-cyclohexadiene (6.41 g, 80.0 mmol) in DCM (80 mL), then add K2HPO4 (14.63 g, 84.0 mmol, 1.05), and add m-chloroperbenzoic acid (m-CPBA) (17.05 g, 84.0 mmol, 85%) in 10 portions at 0 °C, and stir the reaction overnight; after the reaction is completed, filter through a sintered funnel lined with diatomaceous earth, and wash the filter cake with DCM; wash the organic phase successively with Na2S2O3 (150 mL) and saturated NaHCO3 (150 mL); dry the organic phase with Na2SO4, filter and concentrate to obtain a colorless transparent oily crude product compound S9, which is directly used in the next step of the reaction.

[0179] ii) Dissolve the crude product compound S9 in a mixed solvent (THF:H2O = 1:1, 40 mL), slowly drop concentrated H2SO4 (3 mL) under stirring and reflux for 3 - 4 hours, and monitor the reaction by TLC. After the reaction is complete, add an appropriate amount of K2CO3 (about 4 g) to terminate the reaction. Extract with EtOAc 3 times and with n-butanol 3 times, combine the organic phases and dry with anhydrous NaSO4, and concentrate to obtain a light yellow transparent oily crude product compound S10.

[0180] iii) Dissolve the crude product compound S10 in MeOH (40 mL), add NaHCO3 (2.52 g, 29.95 mmol), and then add NaIO4 (17.1 g, 80.0 mmol) in portions, and react at room temperature for 3 - 4 hours, and monitor the reaction by TLC. After the reaction is complete, filter through a sintered funnel lined with diatomaceous earth, wash the filter cake with DCM, and concentrate to obtain a brown transparent oily crude product compound S11, which is directly used in the next step of the reaction.

[0181] iv) The crude product compound S11 was dissolved in a mixed solvent (DCM:MeOH = 1:2, 45 mL). NaBH4 (3.02 g, 80.0 mmol) was added portionwise under an ice-water bath. After the addition, the mixture was stirred and reacted for about 0.5 h, and the reaction was monitored by TLC. After the reaction was complete, a small amount of saturated NH4Cl solution was added to quench the reaction. It was extracted with EtOAc (30 mL × 2) and then with n-butanol (20 mL × 3). Finally, it was concentrated and purified by silica gel column chromatography (the eluent was PE:EtOAc = 2:1) to obtain 3.88 g of a pale yellow oily liquid compound S12, and the total yield of the four-step reaction was 42%.

[0182] 1 H NMR (600 MHz, CDCl3) δ 5.59 (t, J = 6.0 Hz, 2H), 3.69 (t, J = 6.0 Hz, 4H), 2.38 (q, J = 6.0 Hz, 4H) ppm.

[0183] v) Compound S12 (3.88 g, 33.4 mmol) was dissolved in anhydrous DCM solution. p-Toluenesulfonyl chloride (TsCl) (5.09 g, 26.72 mmol), KI (831.7 mg, 5.01 mmol) and Ag2O (8.5 g, 36.74 mmol) were added successively. After reacting at room temperature for 2 days, it was filtered. The filter cake was washed with DCM, concentrated and then purified by silica gel column chromatography (the eluent was PE:EtOAc = 2:1) to obtain 4.4 g of a colorless oily liquid compound S13. At the same time, the raw material compound S12 (1.68 g, recovery rate 43%) was recovered, and the yield was 49% (conversion rate 86%).

[0184] 1 H NMR (600 MHz, CDCl3) δ 7.79 (d, J = 7.8 Hz, 2H), 7.34 (d, J = 7.8 Hz, 2H), 5.56 - 5.50 (m, 1H), 5.46 - 5.40 (m, 1H), 4.04 (t, J = 6.6 Hz, 2H), 3.63 (t, J = 6.6 Hz, 2H), 2.45 (s, 3H), 2.44 (q, J = 6.6 Hz, 2H), 2.28 (q, J = 6.6 Hz, 2H) ppm.

[0185] (vi) Take 2-chlorotrityl chloride resin (8.47 g, 10.08 mmol, 1.19 mmol / g) in a 100 mL round-bottom flask, add THF (25 mL) and swell for 15 - 20 minutes. Sequentially add compound S13 (3.0 g, 11.09 mmol) and DIPEA (13.3 mL, 10.4 g, 80.64 mmol), and stir the mixture slowly at 50 °C for 24 hours; after the reaction is completed, filter with a fritted funnel, and wash the resin alternately with DCM and MeOH until clean. Collect the resin and dry it under vacuum to obtain compound S14, which is directly used for the next reaction.

[0186] (vii) Take compound S14 in a 100 mL round-bottom flask and add THF (15 mL) to swell for 15 - 20 minutes. Add MeNH2·MeOH solution (15 mL), and stir slowly at 40 °C for 12 hours. After the reaction is completed, filter with a fritted funnel, and wash the resin alternately with DCM and MeOH until clean. Collect the resin and dry it under vacuum to obtain compound 15 (Linker).

[0187] (viii) Determination of the loading of compound S15

[0188] Take compound S15 (100 mg) in a screw-thread standard sample bottle, add DMF (1 - 2 mL) to swell for 5 minutes, then add the condensing agent HATU (68.4 mg, 0.18 mmol), N-Fmoc-Tyr(O-tBu) (82.7 mg, 0.18 mmol) and DIPEA (60 μL, 46.5 mg, 0.36 mmol) and dissolve. Place the vial on a decolorizing shaker and react for 2 - 3 hours.

[0189] After the reaction is complete, filter with a fritted funnel, wash the resin alternately with DCM and MeOH until clean, then transfer the resin to a new reaction flask, add 2 mL of a mixed solvent (TFA:MeOH:DCM = 1:1:8), place it on a shaker and react for 1 hour to cleave the Linker-N-Fmoc-Tyr(O-tBu) conjugated with one amino acid.

[0190] After the reaction is complete, filter with a fritted funnel, wash the resin alternately with DCM and MeOH until clean, collect the filtrate, concentrate it and weigh it to obtain 44.8 mg of a light yellow oily substance. Calculate the resin loading based on this mass, and the value of the loading is 0.78 mmol / g.

[0191] 1.4 Solid-phase synthesis and ring-closing metathesis

[0192]

[0193] 1) Compound S15 (100 mg, 0.078 mmol) was placed in a solid phase synthesis tube, and DMF (3 mL) was added to swell for 5 minutes. Then, Fmoc-protected p-fluorophenylalanine (3.0 equivalents), HATU (3.0 equivalents) and DIPEA (3.5 equivalents) were added to the reactor in sequence and completely dissolved; the reaction tube was placed on a shaker for reaction, and the completion of the reaction was monitored by Kaiser reagent (generally 1-3 hours). After the reaction was completed, the solution in the synthesis tube was drained, and it was rinsed with DMF, MeOH and DCM successively, and the residual reactants were rinsed clean and then vacuum dried (about 15-30 minutes).

[0194] 2) Add 3 mL of 20% piperidine-DMF solution (piperidine:DMF=1:4, volume ratio) to the reaction tube and place on a shaker for 5-10 min; repeat this operation twice to completely remove the Fmoc group on the amino acid. Drain the solvent, rinse with DMF and DCM in turn, rinse the piperidine clean, and then vacuum dry to obtain a resin coupled with one amino acid.

[0195] 3) DMF (3 mL) was added to the system in the previous step to swell for 3-5 min, and then Fmoc-protected N-Me-phenylalanine (3.0 equivalents), HATU (3.0 equivalents) and DIPEA (3.5 equivalents) were added in sequence. After the reactants were completely dissolved, the operations of 1) and 2) were repeated to obtain a resin coupled with two amino acids.

[0196] 4) Repeat the above operation, and successively couple thiophene alanine and methylglycine to obtain a system of coupling 4 amino acids, then add compounds FKBD (1.5 equivalents), HATU (1.6 equivalents) and DIPEA (2.0 equivalents) to the reaction system and completely dissolve them in DMF, and shake on a shaker for 3-4 hours to allow the reaction to proceed fully. After the reaction is completed, drain the solvent, rinse with DMF, MeOH and DCM in turn, rinse the remaining reactants clean and vacuum dry.

[0197] 5) The resin coupled with four amino acids and compound FKBD in the previous step was weighed into a microwave reaction bottle, DCE (2.0 mL) was used as solvent, Hoveyda-Grubbs II (0.3 equivalents) was used as catalyst, and the reaction was placed in a microwave reactor after sealing at 140°C for 0.5 hours. After the microwave reaction was completed, it was cooled to room temperature and opened, filtered with a sand core funnel, and the resin was washed with DCM and MeOH. The filtrate was concentrated and separated and purified by HPLC to obtain a light yellow solid product compound JH-A27. MS [M+H] + :1229.5247.

[0198] Referring to the synthesis method of reference compound JH-A27, the amino acids used were replaced with the appropriate compounds in Table 2 to prepare the following compounds:

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210] Example 2 Anti-HBV Screening Test

[0211] HepG2-NTCP cell culture: The HepG2-NTCP cell line was cultured in modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum, 100 IU / mL penicillin, and 100 μg / mL streptomycin, and further cultured in a humidified incubator at 37 °C and 5% CO2 for later use.

[0212] The HepG2-NTCP cells were plated in a 12-well plate at a density of 2×10 5 cells / well. After complete incubation in an environment of 37 °C and 5% CO2 for 48 hours, the cells were incubated with a test compound at a concentration of 3 μM for 1 hour, and DMSO was set as the control group. After the pre-incubation of the compound was completed, an HBV infection system (500 vge / cell HBV virus particles + 4% w / v PEG 8000) was added, and the incubation was continued for 16 hours for HBV infection. After the incubation was completed, the cells were washed three times with PBS solution to remove the uninfected virus and residual drugs, and fresh medium was added for continued culture. The cell supernatant was collected every day and the medium was changed. After 5 days, the cells were collected for detection.

[0213] Enzyme-linked immunosorbent assay (ELISA): The culture supernatant was centrifuged at 2000 g for 5 minutes, and the HBeAg in the supernatant was detected using an enzyme-linked immunosorbent assay kit (Shanghai Kehua) according to the manufacturer's instructions.

[0214] Cellular RNA was extracted using TRNzol Total RNA extraction reagent (Tiangen, Beijing, DP405), and the HBV 3.5-kb RNA level in the cells was detected by quantitative PCR (qPCR) (QuantStudio6 FLEX Q6, Thermofisher).

[0215] Tauroursodeoxycholic acid-d4 (TCA-d4) uptake assay: HepG2-NTCP cells were plated in a 12-well plate at a density of 2×10 5 cells / well and incubated for 48 hours in a complete culture environment at 37 °C and 5% CO2. The medium was removed, and the cells were washed twice with 0.5 mL of buffer (100 mM NaCl, 2 mM KCl, 1 mM MgCl2, 1 mM CaCl2, 10 mM HEPES, pH 7.4) per well, and then pre-incubated in 0.5 mL of buffer for 15 minutes at 37 °C and 5% CO2. The buffer was removed, and the cells were washed again with buffer. Then, after adding 0.5 mL of buffer, compounds (JH-A01 to JH-A51) were added to make the final concentration of the compounds 2 μM, and a group with an equal volume of DMSO added was set as the control group, with 3 replicates in each group. The cells were incubated for 15 minutes at 37 °C and 5% CO2. Then, TCA-d4 was added to the cells to make the final concentration 5 μM, and the cells were co-incubated for 15 minutes at 37 °C and 5% CO2. The cells were washed three times with 0.5 mL of buffer per well, and the cells were lysed with 200 μl of absolute ethanol. The cell lysate was transferred to an EP tube, and the supernatant was collected by centrifugation at 12000 rpm for 10 minutes at 4 °C, and the uptake of TCA was quantified by LC-MS / MS.

[0216] The test results are shown in Figure 1.

[0217] According to the test results, compared with the control group, the compounds JH-A01 to JH-A51 of the present application have inhibitory effects on tauroursodeoxycholic acid-d4 uptake, HBV 3.5-kb RNA, and hepatitis B e antigen (HBeAg).

[0218] Example 3 Toxicity test of the compounds of the present invention

[0219] A CCK8 assay was performed using a microplate reader (Synergy H1, Biotek) to detect drug toxicity. A HepG2-NTCP cell suspension (2×103 Cells / well). After pre-incubating for 24 hours in an incubator (Mod3111, Thermofisher) (37 °C, 5% CO2), different concentrations of compounds JH-A27 and JH-A32 were added to the culture plates and incubation was continued for 48 hours. 10 μL of CCK8 assay solution (HY-K0301, MCE) was added to each well, and after 1 hour, the absorbance at 450 nm was measured using a microplate reader and the cytotoxic activity was analyzed.

[0220] The test results are as Figure 2 shown.

[0221] According to the test results, the half-toxic concentration (CC 50 ) of both compounds JH-A27 and JH-A32 exceeded 10 μM, neither of them had cytotoxicity, and they had good safety.

[0222] Example 4 Test for the inhibitory effect of the compounds of the present invention

[0223] Compound JH-A27 and JH-A32 were respectively formulated into test solutions with different concentration gradients for pre-incubation and the IC 50 value was tested.

[0224] HepG2-NTCP cells were plated in a 12-well plate at a density of 2×10 5 cells / well and completely cultured for 48 hours in an environment of 37 °C and 5% CO2. The culture medium was removed, and the cells were washed twice with 0.5 mL of buffer (100 mM NaCl, 2 mM KCl, 1 mM MgCl2, 1 mM CaCl2, 10 mM HEPES, pH 7.4) per well, and then pre-incubated in 0.5 mL of buffer for 15 minutes in an environment of 37 °C and 5% CO2. The buffer was removed, and the cells were washed again with the buffer. Then, after adding 0.5 mL of buffer, different concentration gradients of compound JH-A27 (final concentrations were 2000, 400, 80, 16, 3.2, 0.64, 0.128 nM respectively) and JH-A32 (final concentrations were 2000, 667, 222, 74, 25, 8.2, 2.7 nM respectively) were added, and a group with an equal volume of DMSO added was set as the control group, with 3 replicates in each group. Incubation was carried out for 15 minutes in an environment of 37 °C and 5% CO2. Then, TCA-d4 was added to the cells to make its final concentration 5 μM, and co-incubation was carried out for 15 minutes in an environment of 37 °C and 5% CO2. Each well was washed three times with 0.5 mL of buffer, and the cells were lysed with 200 μl of absolute ethanol. The cell lysate was transferred to an EP tube, and the supernatant was collected by centrifuging at 12000 rpm for 10 minutes at 4 °C.

[0225] The levels of HBeAg were detected using the enzyme-linked immunosorbent assay in Example 2, the levels of HBV 3.5-kb RNA were detected by quantitative PCR, and the uptake of TCA was detected by LC-MS / MS, respectively.

[0226] The test results are as follows Figure 3 shown.

[0227] According to the test results, it can be seen that compounds JH-A27 and JH-A32 both have inhibitory effects on the uptake of taurocholic acid-d4, HBV 3.5-kb RNA, and hepatitis B e antigen (HBeAg). Among them, the IC 50 values of compounds JH-A27 and JH-A32 for inhibiting the uptake of taurocholic acid-d4 were 163 nM and 20 nM, respectively. The IC 50 values of compound JH-A27 for inhibiting the levels of HBV 3.5-kb RNA and HBeAg were 279 nM and 243 nM, respectively. The IC 50 values of compound JH-A32 for inhibiting the levels of HBV 3.5-kb RNA and HBeAg were 237 nM and 200 nM, respectively, and their inhibitory activities on the levels of HBV 3.5-kb RNA and HBeAg were relatively close.

[0228] Example 5 In Vivo Pharmacodynamic Verification Test of the Compounds of the Present Invention

[0229] By constructing a humanized liver mouse model, compound JH-A32 was selected for in vivo pharmacodynamic verification.

[0230] Ten human liver chimeric mice were randomly divided into a drug administration group and a control group, with 5 mice in each group. Compound JH-A32 and DMSO were administered respectively, and the administration dose was 4 mg / kg. The administration protocol is as follows Figure 4 shown. Three days and 1 hour before HBV infection, the two groups of mice were pretreated with 1 dose of drug each. The time of HBV infection was recorded as day 0, and the drug was administered once on days 1, 2, 3, and 5, and then once a week (i.e., on days 15, 22, 29, 36, 43, and 50), for a total of 8 weeks of drug administration. Blood was collected once a week (i.e., on days 7, 14, 21, 28, 35, 42, 49, and 56) for biochemical analysis. After 8 weeks, the mice were sacrificed and the livers were collected for various index tests. The test results are as follows Figure 5 shown.

[0231] According to the test results, during the administration process, human serum albumin HSA remained stable, and HBV DNA in the serum was significantly inhibited. After administration, the relative HBV 3.5-kb RNA level, HBV DNA, and the copy number of HBV cccDNA in the livers of mice decreased significantly compared with the control group, indicating that JH-A32 has a significant effect on inhibiting HBV-infected hepatocytes. JH-A32 showed good anti-HBV activity at the animal level.

[0232] The above are only specific embodiments of the present invention, and do not limit the patent scope of the present invention. Any equivalent transformation made using the present invention, directly or indirectly applied in other related technical fields, shall be similarly included in the protection scope of the present invention.

Claims

1. A compound having the structure of the following formula (I): or a pharmaceutically acceptable salt thereof, wherein, X1 is selected from X2 is selected from O or NR 14 ; R 1 selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 3-10 heterocyclic group, C 3-10 heterocyclic group-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, C 5-10 heteroaryl and C 5-10 heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from R X ; R 2 selected from hydrogen, halogen, amino, cyano, nitro, C 1-6 alkyl, C 1-6 alkyl-S-C 1-6 alkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 alkyl-C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 3-10 heterocyclic group, C 3-10 heterocyclic group-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, C 5-10 heteroaryl, C 5-10 heteroaryl-C 1-4 alkyl, CN and NO2, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is unsubstituted or substituted by at least one substituent independently selected from R X ; R 3 selected from hydrogen and C 1-6 alkyl; When R 4 is i) the formula (I) has the structure of the following formula (II-1): When R 4 is ii) the formula (I) has the following structure of formula (II-2): When R 4 is iii) the formula (I) has the following structure of formula (II-3): When R 4 is iv) the formula (I) has the structure of the following formula (II-4): Or When R 4 is v) the formula (I) has the structure of the following formula (II-5): R 5 selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 3-10 heterocyclic group, C 3-10 heterocyclic group-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, C 5-10 heteroaryl and C 5-10 heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is unsubstituted or substituted by at least one substituent independently selected from R X ; R 6 Selected from hydrogen, amino, cyano, nitro, C 1-6 alkyl, C 1-6 alkyl-C 3-10 cycloalkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 alkyl-S-C 1-6 alkyl, C 1-6 alkyl-C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 3-10 heterocyclic group, C 3-10 heterocyclic group-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, C 5-10 heteroaryl and C 5-10 heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is unsubstituted or substituted by at least one substituent independently selected from R X ; or R 5 and R 6 Together with the atom to which it is attached, form a 5- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms, said 5- to 8-membered heterocyclic group being unsubstituted or substituted by at least one substituent independently selected from R X ; R 7 selected from hydrogen and C 1-6 alkyl; R 8 selected from hydrogen, amino, cyano, nitro, C 1-6 alkyl, C 1-6 alkyl-C 3-10 cycloalkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 alkyl-S-C 1-6 alkyl, C 1-6 alkyl-C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 3-10 heterocyclic group, C 3-10 heterocyclic group-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, C 5-10 heteroaryl and C 5-10 heteroaryl-C 1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl is unsubstituted or substituted by at least one substituent independently selected from R X ; R 9 selected from hydrogen and C 1-6 alkyl group; R 10 and R 11 each independently selected from hydrogen, hydroxyl, halogen, C 1-6 alkyl and C 1-6 alkoxy, wherein each alkyl and alkoxy is unsubstituted or substituted by at least one substituent independently selected from R X ; R 12 and R 13 each independently selected from hydrogen, hydroxy, halogen, C 1-6 alkyl and C 1-6 alkoxy, wherein each alkyl and alkoxy is unsubstituted or substituted with at least one substituent independently selected from R X ; R 14 selected from hydrogen and C 1-6 alkyl; R X Selected from hydroxy, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 3-10 heterocyclyl, C 3-10 heterocyclyl-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, C 5-10 heteroaryl and C 5-10 heteroaryl-C 1-4 alkyl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted by at least one substituent independently selected from R Y ; R Y Selected from hydroxy, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl, C 3-10 heterocyclic group, C 3-10 heterocyclic group-C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, C 5-10 heteroaryl and C 5-10 heteroaryl-C 1-4 alkyl; m, n, o, p, and q are each independently selected from the integers 0, 1, 2, 3, 4, 5, and 6; *1 C, *2 C and *3 C respectively represent chiral carbon atoms connected to R 4 , R 6 and R 8 respectively.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, i) When X1 is , formula (I) has the structure of the following formula (III): wherein, X2, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、m, n, o and q are as defined in claim 1; *1 C, *2 C and *3 C respectively represent chiral carbon atoms connected to R 4 , R 6 and R 8 ; or ii) When X1 is , formula (I) has the following structure of formula (III’): Among them, X2, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、m, n, o, and p are as defined in claim 1; *1 C, *2 C and *3 C respectively represent chiral carbon atoms connected to R 4 , R 6 and R 8 respectively.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, X2 is O; and / or R 1 selected from hydrogen and C 1-6 alkyl groups, preferably hydrogen and methyl; and / or R 2 selected from hydrogen, C 1-6 alkyl, C 1-6 alkyl-S-C 1-6 alkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 alkyl-C 6-10 aryl, wherein the alkyl and aryl are unsubstituted or substituted by at least one substituent independently selected from R X , preferably hydrogen, methyl, ethyl, isopropyl, and / or R 3 is hydrogen; and / or R 5 selected from hydrogen and C 1-6 alkyl, preferably hydrogen and methyl; and / or R 6 selected from C 1-6 alkyl, C 1-6 alkyl-C 3-10 cycloalkyl, C 1-6 alkyl-O-C 1-6 alkyl, C 1-6 alkyl-S-C 1-6 alkyl, C 1-6 alkyl-C 6-10 aryl, wherein the alkyl, cycloalkyl and aryl are unsubstituted or substituted by at least one substituent independently selected from R X and preferably and / or R 5 and R 6 together with the atom(s) to which it is attached form a 5-membered heteroaryl group containing 1 nitrogen heteroatom, said 5-membered heteroaryl group being unsubstituted or substituted by at least one substituent independently selected from R X preferably and / or R 7 is hydrogen; and / or R 8 selected from C 1-6 alkyl-C 3-10 cycloalkyl, C 1-6 alkyl-C 6-10 aryl, wherein the alkyl, cycloalkyl and aryl are unsubstituted or substituted by at least one substituent independently selected from R X and preferably and / or R 9 selected from C 1-6 alkyl, preferably methyl; and / or R 10 selected from C 1-6 alkyl, preferably methyl; and / or R 11 selected from C 1-6 alkyl, preferably methyl; and / or R 12 selected from C 1-6 alkoxy, preferably methoxy; and / or R 13 selected from C 1-6 alkoxy, preferably methoxy.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R X Selected from hydroxyl, halogen, C 1-6 alkyl and C 1-6 alkoxy, preferably hydroxyl, fluorine, chlorine, methyl, tert-butyl, methoxy and 5. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R Y Selected from halogens, preferably fluorine.

6. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein, m is 1; and / or n is 1; and / or o is 1; and / or p is 1; and / or q is 1.

7. The compound according to any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein, *1 The C chiral carbon atom is in the S or R configuration, preferably the S configuration; and / or *2 The C chiral carbon atom has an S or R configuration, preferably an S configuration; and / or *3 The C chiral carbon atom has an S or R configuration, preferably an S configuration.

8. The compound according to claim 1, selected from the following structures: or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-8 and at least one pharmaceutically acceptable carrier.

10. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-8 or the pharmaceutical composition according to claim 9 in the manufacture of a medicament for treating, ameliorating or preventing a condition responsive to inhibition of the sodium taurocholate cotransporter.

11. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-8 or the pharmaceutical composition according to claim 9 in the manufacture of a medicament for preventing or treating hepatitis virus infection, preferably, the hepatitis virus infection is hepatitis B virus and / or hepatitis D virus infection.

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