WO2025148623A1 - Compound, and pharmaceutical composition containing same and use thereof - Google Patents

Abstract

The present invention relates to a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof, and further relates to a pharmaceutical composition containing same, a preparation method therefor and the use thereof.

Description

A compound, a pharmaceutical composition containing the same and its use Technical Field

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

Background Art

Chronic hepatitis caused by hepatitis B virus (HBV) infection is a global public health problem, with nearly 300 million people infected worldwide. The incidence of liver cancer caused by HBV is about 8.5 per 100,000 people. Long-term chronic HBV infection will develop into cirrhosis and hepatocellular carcinoma, and the number of deaths caused by complications exceeds 800,000 each year. Clinical treatment drugs are mainly nucleoside analogs (NAs) and interferons (IFNs), which can improve the progression of HBV-related pathogenesis, reduce viral load and relieve hepatitis, but there are problems such as long treatment cycle and drug resistance, and it cannot be completely cured. The main reasons why HBV is difficult to treat are that HBV DNA can be integrated into host cell DNA after infection; second, covalently closed circular DNA (cccDNA) will generate pregenomic RNA (pgRNA), which can continuously replicate and release HBV as a template, causing new liver cells to be infected, thereby maintaining the chronic infection state and expanding the cccDNA pool. Therefore, a combined drug strategy of "preventing external troubles" and "eliminating internal evils" may be a good choice for the treatment of HBV infection. Developing HBV entry inhibitors to prevent new cells from being infected and combining them with antiviral reverse transcriptase drugs is a powerful means to reduce the cccDNA pool, which is of great significance for the treatment of HBV infection.

Hepatitis D is an infectious disease caused by hepatitis D virus (HDV) and hepatitis B virus and other hepatotropic DNA viruses. HDV is a defective single-stranded negative-strand RNA virus that must rely on hepatotropic DNA viruses such as HBV to provide it with a shell in order to replicate. HDV exists in the nuclei of liver cells and serum of HDV-infected people who are positive for hepatitis B virus surface antigen (HBsAg). It mainly replicates in liver cells. After a person is infected with HDV, the synthesis of HBV-DNA can be significantly inhibited. The appearance of hepatitis D virus antigen (HDAg) is consistent with the reduction of HBV-DNA in the serum. As HDAg turns negative and anti-HD appears, HBV-DNA returns to its original level. Over-infection of HDV and HBV can aggravate liver damage and easily develop into chronic active hepatitis, cirrhosis and severe hepatitis.

Sodium-taurocholate cotransporter (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.

At present, there are reports of a variety of compounds that target NTCP and inhibit HBV infection, including Myrcludex B, taurocholic acid (TCA), cyclosporin A (CsA) and its analogs, dimeric bile acid derivatives (such as DBA-41), irbesartan and ezetimibe, etc., but only two large molecules (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 new NTCP inhibitor, which has very important significance and role for clinical research and treatment of HBV.

Summary of the invention

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

or a pharmaceutically acceptable salt thereof, wherein X1, _X2 , _R1 , ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , ^R8 , ^R9 , ^R10 , ^R11 , ^R12 , ^R13 , m, n and ^o are as defined herein.

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

In a third aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating, ameliorating or preventing a condition responsive to inhibition of the sodium-taurocholate cotransporter.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1A shows the inhibitory effect of the compounds of the present application on hepatitis B E antigen (HBeAg); Figure 1B shows 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 taurocholic acid-d4 uptake.

FIG. 2 shows the test results of the toxicity test of the compounds JH-A27 and JH-A32 of the present application.

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

FIG4 shows a schematic diagram of the dosing regimen for the humanized liver mouse model.

FIG5 shows the test results of the in vivo efficacy validation test of the compound JH-A32 of the present application.

DETAILED DESCRIPTION

The present invention will be further described in detail below. Such description is for illustrative purposes only 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 contents 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.

General Terms and Definitions

Unless otherwise defined below, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art. If there is a conflict, the definition provided herein shall prevail. The technology used herein refers to the technology generally 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 commodity or its active ingredient. All patents, published patent applications and publications cited herein are incorporated herein by reference.

When a certain amount, concentration or other numerical value or parameter is described in the form of a range, a preferred range or a preferred upper limit or a preferred lower limit, it should be understood to be equivalent to specifically disclosing any range formed by combining any upper limit or preferred value with any lower limit or preferred value, regardless of whether the range is clearly stated. Unless otherwise stated, the numerical ranges listed herein are intended to include the endpoints of the range and all integers and fractions (decimals) within the range. For example, the expression "m is an integer of 0-6" means that m is any integer of 0-6, for example, m can be 0, 1, 2, 3, 4, 5 or 6. Other similar expressions such as n, o, p and q, etc. should also be understood in a similar manner.

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

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 a 95% confidence interval about the mean) or within ±10% or wider of the specified value.

The expressions "comprising," "including," "containing," and "having" are open ended and do not exclude additional unrecited elements, steps, or ingredients. The expression "consisting of excludes any element, step, or ingredient not specified. The expression "consisting essentially of means that the scope is limited to the specified elements, steps, or ingredients, as well as the optional presence of elements, steps, or ingredients that do not materially affect the basic and novel characteristics of the claimed subject matter. It should be understood that the expression "comprising" includes the expressions "consisting essentially of" and "consisting of.

The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond. The alkyl group can have 1-20 carbon atoms, referring to "C _1-20 alkyl", such as C _1-6 alkyl, C _1-4 alkyl, C _1-2 alkyl, C ₃ alkyl, C ₄ alkyl, C _3-6 alkyl. "C _1-6 alkyl" is used to represent a straight or branched saturated hydrocarbon group consisting 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 _2-4 alkyl, C ₆ alkyl and C ₅ alkyl, etc. Non-limiting examples of alkyl groups 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 isomers thereof.

A divalent group refers to a group obtained by removing a hydrogen atom from a carbon atom with free valence electrons of a corresponding monovalent group. A divalent group has two attachment sites connected to the rest of the molecule. For example, "alkylene" or "alkylene" refers to a saturated straight or branched divalent hydrocarbon group. Examples of "alkylene" include, but are _not limited to, methylene ( _-CH2- ), _ethylidene ( _-C2H4- ), propylene ( _-C3H6- ) _{, butylene (-C4H8- )} , pentylene ( _-C5H10- ), hexylene ( _-C6H12- ), 1-methylethylidene ( _-CH ( _{CH3 ) CH2-} ), 2-methylethylidene ( _-CH2CH ( _CH3 )-), methylpropylene or ethylpropylene, etc. For example, as used herein, -(CH ₂ ) _m -, -(CH ₂ ) _n -, -(CH ₂ ) _o -, -(CH ₂ ) _p -, and -(CH ₂ ) _q - all belong to the case of a divalent group.

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

The term "alkynyl" is used to refer to a straight or branched hydrocarbon group containing one or more carbon-carbon triple bonds, which may be located at any position of the group. Non-limiting examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, etc.

The term "cycloalkyl" refers to a cyclic saturated aliphatic group consisting of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond, including monocyclic, bicyclic or tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spirocyclic, cyclic and bridged rings. Cycloalkyl can have 3-10 carbon atoms, i.e., "C _3-10 cycloalkyl", such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl. "Cycloalkylene" refers to a divalent cycloalkyl.

The term "heterocyclyl" refers to a cycloalkyl in which one or more carbon atoms are replaced by heteroatoms selected from nitrogen, oxygen and sulfur, such as azepine, oxa- or thiirane, azepine, oxa- or thiether, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, tetrahydropyranyl or tetrahydrothiopyranyl. Heteroatoms may occupy the position of attachment of the heterocyclyl to the rest of the molecule. "Heterocyclylene" refers to a divalent cycloalkyl.

The term "alkoxy" represents an alkyl group with 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-pentoxy. The term "C _1-6 alkoxy" represents an alkyl group containing 1 to 6 carbon atoms connected to the rest of the molecule by an oxygen atom. The C _1-6 alkoxy includes C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ , C ₅ , C ₄ and C ₃ 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), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy, etc.

The terms "aromatic ring" and "aryl" can be used interchangeably. The term "aromatic ring" or "aryl" refers to a polyunsaturated carbon ring system, which can be a monocyclic, bicyclic or polycyclic system, wherein at least one ring is aromatic, and each ring in the bicyclic and polycyclic system is fused together. Examples of aryl include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.).

The terms "heteroaromatic ring" and "heteroaryl" are used interchangeably, and the term "heteroaryl" refers to an aromatic group (or aromatic ring) containing 1, 2, 3 or 4 heteroatoms independently selected from B, N, O and S, which can be a monocyclic, bicyclic or tricyclic ring system. The heteroaryl group can 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 and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5 -thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.), quinolyl (including 3-quinolyl and 6-quinolyl, etc.), pyrazinyl, purinyl, phenyloxazolyl.

As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt. 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, sugarates, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and pamoates (i.e., 1-1-methylene-bis(2-hydroxy-3-naphthoate)). The compounds used in the present invention can form pharmaceutically acceptable salts with various amino acids. Suitable alkali salts include, but are not limited to, aluminum salts, calcium salts, lithium salts, magnesium salts, potassium salts, sodium salts, zinc salts, bismuth, and diethanolamine salts. For a review of pharmaceutically acceptable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

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 hydrogen variants, as long as the valence state of the particular atom is normal and the substituted 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 be substituted or not substituted, and unless otherwise specified, the type and number of the substituent can be arbitrary on the basis of chemical achievable.

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, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability of a ring carbon atom to rotate freely about double bonds or single bonds forming a ring.

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

Unless otherwise indicated, "(D)" or "(+)" indicates dextrorotatory, "(L)" or "(-)" indicates levorotatory, and "(DL)" or "(±)" indicates racemic.

Unless otherwise specified, the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Denotes a solid wedge bond or dotted wedge key Or use a wavy line Represents a straight solid bond and straight dashed key

The term "pharmaceutically acceptable excipients" refers to those carrier materials that have no significant irritation to organisms and do not impair the biological activity and performance 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.

The term "pharmaceutical composition" or "pharmaceutically active ingredient composition" refers to a substance consisting of one or more active ingredients and optionally one or more pharmaceutically acceptable excipients.

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

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

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

The term "HBsAg" refers to the surface antigen of hepatitis B virus, which is not a complete hepatitis B virus itself, but the outer shell of hepatitis B virus. It is not contagious but has antigenicity and is only one of the signs of hepatitis B virus infection.

Compounds of the present invention

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

or a pharmaceutically acceptable salt thereof,

in,

X ₁ selected from

X ₂ is selected from O or NR ¹⁴ ;

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 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, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from ^RX ;

R ² is selected from hydrogen, halogen, amino, cyano, nitro, C _1-6 alkyl, C _1-6 alkyl-SC _1-6 alkyl, C _1-6 alkyl-OC _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 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, C _5-10 heteroaryl-C _1-4 alkyl, CN and NO ₂ , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from ^RX ;

^R3 is selected from hydrogen and _C1-6 alkyl;

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

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

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

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

or

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

R ⁵ 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 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, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from ^RX ;

^R is selected from hydrogen, amino, cyano, nitro, C _1-6 alkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _1-6 alkyl-OC _1-6 alkyl, C _1-6 alkyl-SC _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 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, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from ^RX ;

or R ⁵ and R ⁶ together with the atoms to which they are attached form a 5-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms, wherein the 5-8 membered heterocyclic group is unsubstituted or substituted with at least one substituent independently selected from ^RX ;

R ⁷ is selected from hydrogen and C _1-6 alkyl;

^R is selected from hydrogen, amino, cyano, nitro, C _1-6 alkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _1-6 alkyl-OC _1-6 alkyl, C _1-6 alkyl-SC _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 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, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from ^RX ;

R ⁹ is selected from hydrogen and C _1-6 alkyl;

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 unsubstituted or substituted with at least one substituent independently selected from ^RX ;

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 unsubstituted or substituted with at least one substituent independently selected from ^RX ;

R ¹⁴ is selected from hydrogen and C _1-6 alkyl;

^RX is selected from hydroxy, halogen, _C1-6 alkyl, _C1-6 alkoxy, _C2-6 alkenyl, C2-6 alkynyl, _C3-10 cycloalkyl, _C3-10 cycloalkyl- _C1-4 alkyl, _C3-10 heterocyclyl, _C3-10 heterocyclyl- _C1-4 alkyl, _C6-10 aryl, _C6-10 aryl- _C1-4 alkyl, _C5-10 heteroaryl and _{C5-10 heteroaryl} - _C1-4 alkyl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from ^RY ;

R ^Y is 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;

m, n, o, p and q are each independently selected from integers of 0, 1, 2, 3, 4, 5 and 6;

^*1 C, ^*2 C and ^*3 C represent chiral carbon atoms connected to R ⁴ , R ⁶ and R ⁸ , respectively.

In one embodiment, X ₁ is Formula (I) has the structure of the following formula (III):

wherein _X2 , R1, ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , ^R8 , ^R9 , ^R10 , ^R11 , ^R12 , ^R13 , m, n, o and q are as defined in formula (I) ^{; *} 1C, ^*2C and ^*3C represent chiral carbon atoms connected to ^R4 , ^R6 and ^R8 , respectively.

In one embodiment, X ₁ is Formula (I) has the structure of the following formula (III'):

wherein _X2 , ^R1 , R2, ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , ^R8 , ^R9 , ^R10 , ^R11 , ^R12 , ^R13 , m, n, o and p are as defined in formula (I) ^{; *} 1C, ^*2C and ^*3C represent chiral carbon atoms connected to ^R4 , ^R6 and ^R8, respectively.

In one embodiment, _X2 is O.

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.

In one embodiment, R ² is selected from hydrogen, C _1-6 alkyl, C _1-6 alkyl-SC _1-6 alkyl, C _1-6 alkyl-OC _1-6 alkyl, C _1-6 alkyl-C _6-10 aryl, wherein the alkyl and aryl groups are unsubstituted or substituted with at least one substituent independently selected from ^RX . In one embodiment, R ² is selected from hydrogen, methyl, ethyl, isopropyl,

In one embodiment, R ³ is hydrogen.

In one embodiment, ^R4 is Formula (I) has the following structure:

wherein X ₁ , X ₂ , 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.

In one embodiment, ^R4 is Formula (I) has the following structure:

wherein X ₁ , X ₂ , 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.

In one embodiment, ^R4 is Formula (I) has the following structure:

wherein X ₁ , X ₂ , 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.

In one embodiment, ^R4 is Formula (I) has the following structure:

wherein X ₁ , X ₂ , 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.

In one embodiment, ^R4 is Formula (I) has the following structure:

wherein X ₁ , X ₂ , 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.

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.

In one embodiment, R ⁶ is selected from C _1-6 alkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _1-6 alkyl-OC _1-6 alkyl, C _1-6 alkyl-SC _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 ^RX . In one embodiment, R ⁶ is selected from

In one embodiment, R ⁵ and R ⁶ together with the atoms to which they are attached form a 5-membered heterocyclic group containing 1 nitrogen heteroatom, said 5-membered heterocyclic group being unsubstituted or substituted with at least one substituent independently selected from ^RX . In one embodiment, R ⁵ and R ⁶ together with the atoms to which they are attached form

In one embodiment, ^R7 is hydrogen.

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 ^RX . In one embodiment, R ⁸ is selected from

In one embodiment, R ⁹ is selected from C _1-6 alkyl. In one embodiment, R ⁹ is methyl.

In one embodiment, R ¹⁰ is selected from C _1-6 alkyl. In one embodiment, R ¹⁰ is methyl.

In one embodiment, R ¹¹ is selected from C _1-6 alkyl. In one embodiment, R ¹¹ is methyl.

In one embodiment, R ¹² is selected from C _1-6 alkoxy. In one embodiment, R ¹² is methoxy.

In one embodiment, R ¹³ is selected from C _1-6 alkoxy. In one embodiment, R ¹³ is methoxy.

In one embodiment, R ^X is selected from hydroxy, halogen, C _1-6 alkyl and C _1-6 alkoxy. In one embodiment, R ^X is selected from hydroxy, fluorine, chlorine, methyl, tert-butyl, methoxy and

In one embodiment, R ^Y is selected from halogen. In one embodiment, R ^Y is fluorine.

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.

In one embodiment, the ^*1 C chiral carbon atom is in S or R configuration. In a preferred embodiment, ^{the *1} C chiral carbon atom is in S configuration. In one embodiment, the ^*2 C chiral carbon atom is in S or R configuration. In a preferred embodiment, the ^*2 C chiral carbon atom is in S configuration. In one embodiment, the ^*3 C chiral carbon atom is in S or R configuration. In a preferred embodiment, the ^*3 C chiral carbon atom is in S configuration.

The compound provided by the present invention is selected from the following structures:

or a pharmaceutically acceptable salt thereof.

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

Pharmaceutically acceptable salts of the present invention

Those skilled in the art will appreciate that compounds according to the present invention can exist in the form of pharmaceutically acceptable salts. As pharmaceutically acceptable salts, for example, the following examples can be provided: metal salts, ammonium salts, salts formed with organic bases, inorganic acids, organic acids, alkaline or acidic amino acids, etc. Pharmaceutically acceptable salts according to the present invention can be prepared by conventional chemical methods from compounds containing acidic or basic groups. Usually, compounds in the form of free acids or bases can be prepared by the reaction of stoichiometrically suitable bases or acids in water, organic solvents, or mixtures thereof. Usually, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, etc., are preferred.

Administration, pharmaceutical composition and kit

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 efficacy of the compound used, and other factors known to those skilled in the art.

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

The compounds of the present invention are generally administered in the form of a pharmaceutical composition comprising a pharmaceutically active ingredient and various other pharmaceutically acceptable components, for example, see 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 desired formulation, the composition may also include a pharmaceutically acceptable non-toxic carrier or diluent, which is defined as a carrier commonly used to formulate a pharmaceutical composition for administration to animals or humans. 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.

The compounds of the invention can be administered in the form of a pharmaceutical composition by any conventional route; for example, enterally, such as orally, for example in the form of tablets or capsules; parenterally, for example in the form of injectable solutions or suspensions; or topically, for example via the eye or nasal cavity, for example in the form of emulsions, gels, ointments, creams or suppositories.

Therefore, 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 compound of the present invention may be present in a free form or a pharmaceutically acceptable salt form combined with at least one pharmaceutically acceptable carrier, and may be prepared in a conventional manner, for example by mixing, granulating, coating, dissolving or lyophilizing processes.

In one embodiment, the pharmaceutical composition is a solution of the active ingredient, including a suspension or dispersion, such as an isotonic aqueous solution. For a lyophilisate containing only the active ingredient or a lyophilized composition containing the active ingredient and a carrier (such as mannitol), a dispersion or suspension can be prepared before use.

The 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 polyvinyl pyrrolidone, and/or if necessary, disintegrants, such as the above-mentioned starches, carboxymethyl starch, cross-linked polyvinyl pyrrolidones, 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.

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

Therapeutic methods and uses of the compounds of the present invention

The present invention provides a method for treating a condition responsive to inhibition of sodium ion taurocholate cotransporter, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention.

The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition for treating, improving or preventing a condition responsive to inhibition of the sodium ion taurocholate cotransporter.

The present invention also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition in the preparation of a drug for treating, ameliorating or preventing a condition responsive to inhibition of the sodium ion taurocholate cotransporter.

In one embodiment, conditions responsive to inhibition of the sodium ion taurocholate cotransporter include, but are not limited to, hepatitis virus infection. In one embodiment, the hepatitis virus infection comprises hepatitis B virus and/or hepatitis D virus infection.

Beneficial Effects

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, can have better drug performance and pharmacokinetic properties, and provides more options for clinical research on small molecule drugs for the treatment of HBV and HDV.

Example

The solution of the present invention is further described in detail below in conjunction with specific embodiments.

It should be noted that the following examples are only 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 exhaustively list all the embodiments here, and the obvious changes or modifications derived therefrom are still within the scope of protection of the present invention. Unless otherwise specified, the instruments, equipment and reagents used herein are all commercially available.

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

Table 1 Sources of conventional reagents

Table 2 Amino Acid Information

Example 1 Synthesis of Compound JH-A27

1.1 Synthesis of compound FKBD fragment

i) KOH, H ₂ O/EtOH, rt; ii) Pd/C (10%), H ₂ , MeOH, rt; iii) tert-butyl 2-bromoacetate, K ₂ CO ₃ , DMF, rt; iv) (+)-DIPCl, THF, -20°C-rt; v) S8, benzoyl chloride, DMAP, Et ₃ N, DCM/THF, rt; vi) TFA (10%), DCM, rt.

i) 3,4-dimethoxybenzaldehyde (8.31 g, 50 mmol) and 3-hydroxyacetophenone (6.81 g, 50 mmol) were dissolved in ethanol (EtOH) (50 mL), and NaOH (0.5 g dissolved in 4 mL water) was added; the reaction mixture was stirred at room temperature until the reaction was complete as detected by TLC (a yellow-brown precipitate slurry appeared after the reaction was completed); the reaction mixture was then diluted with ethyl acetate (EtOAc) and washed and extracted with water for 3 times, and the crude product obtained after the organic phase was concentrated was directly used in the next step.

ii) The crude product obtained in i) was dissolved in methanol (MeOH) (40 mL), and Pd/C (2.3 g, 10%) was added after replacing the oxygen in the reaction system with an inert gas, and then H ₂ was introduced for gas replacement to fill the reaction system with H ₂ ; the reaction progress was monitored by TLC, and after the reaction was complete, the H ₂ in the system was replaced with an inert gas, and the Pd/C was filtered out. The filtrate was concentrated and purified by silica gel column chromatography (eluent was petroleum ether:ethyl acetate (PE:EtOAc) = 3:1) to obtain 10.3 g of light yellow oily liquid compound S1, and the total yield of the two-step reaction was 72%.

iii) Compound S1 (10.3 g, 36 mmol) was dissolved in 30 mL N,N-dimethylformamide (DMF), followed by the addition of tert-butyl 2-bromoacetate (6.4 mL, 7.72 g, 39.6 mmol) and K ₂ CO ₃ (5.97 g, 43.2 mmol). The reaction mixture was stirred at room temperature, and the progress of the reaction was monitored by TLC spot plate until the compound S1 was completely consumed; after the reaction was completed, the reactant was dissolved in EtOAc, and 1N HCl was added for washing, the organic phase was washed with saturated brine and dried over anhydrous Na ₂ SO ₄ , then concentrated and separated and purified by silica gel column chromatography (eluent: PE: EtOAc = 4: 1), to obtain 11.68 g of compound S2, with a yield of 81%.

iv) Compound S2 (11.68 g, 29.16 mmol) was dissolved in dry THF (40 mL) and cooled to -20°C, followed by slow dropwise addition of (+)-diisopinocampheylborane ((+)-DIPCl) (1.6 M in hexane, 27.3 mL, 43.74 mmol), and then slowly warmed to room temperature. After the reaction was completed, 2,2'-(ethylenedioxy)diethylamine (equal to (+)-DIPCl) was added to quench the reaction to form an insoluble complex; after stirring at room temperature for 30 minutes, the suspension was filtered through a diatomaceous earth pad and concentrated; separated and purified by silica gel column chromatography (eluent: PE:EtOAc = 2:1) to obtain 10.56 g of colorless liquid compound S3 with a yield of 90%.

¹ H NMR (600MHz, CDCl ₃ )δ7.26(t,J＝7.2Hz,1H),6.96(d,J＝7.2Hz,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.

v) 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) were dissolved in anhydrous tetrahydrofuran (THF) and dichloromethane (DCM) (60 mL, THF/DCM=1:1), and triethylamine ( _Et3N ) (6.2 mL, 4.51 g, 44.6 mmol) and benzoyl chloride (6.0 mL, 7.28 g, 39.36 mmol) were slowly added in sequence under argon protection, and the reaction mixture was stirred at room temperature for 2 hours; the reaction was monitored by TLC, and when the conversion was complete, the reaction mixture was diluted with 300 mL EtOAc, washed with 5% HCl and saturated _NaHCO3 ; the organic phase was washed with saturated brine and washed with anhydrous _{Na2SO 4} was dried; after concentration, the product was purified by silica gel column chromatography (eluent: PE:EtOAc = 10:1-3:1) to obtain 12.78 g of light yellow solid compound S4 with a yield of 70%.

vi) Compound S4 (12.78 g, 18.37 mmol) was dissolved in DCM (60 mL), and trifluoroacetic acid (TFA) (17.83 mL, 27.37 g, 0.24 mol) was added in batches under argon protection, and stirred at room temperature until the reaction was completely converted; after the reaction was completed, the solvent and TFA were removed, and the mixture was separated and purified by silica gel column chromatography (eluent: 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%.

¹ H NMR (600MHz, CDCl ₃ ) δ7.28 (d, J = 7.8Hz, 1H), 6.92 (d, J = 7.8Hz, 1H), 6.90 (dd, J ₁ = 8.4, J ₂ ＝2.4Hz,1H),6.86(s,1H),6.79(d,J＝8.4Hz,1H),6.70-6.66(m,2H),6.37(d,J＝17.4Hz,1H),6.04(dd,J ₁ ＝17.4,J ₂ ＝10.2Hz,1H),5.81(d,J＝10.8Hz,1H),5.73(dd,J ₁ ＝8.4,J ₂ =5.4Hz,1H),5.28(d,J＝5.4Hz,1H),4.71(d,J＝16.2,1H),4.66(d,J＝16.2,1H),4.33(d,J＝10.8Hz,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),2.67-2.6 1(m,1H),2.59-2.54(m,1H),2.40(d,J＝14.4Hz,1H),2.29-2.20(m,1H),2.10-2.04(m,1H),1.83-1.7 3(m,2H),1.63(d,J=12.6Hz,1H),1.54-1.46(m,1H),1.43-1.35(m,1H),1.32(s,3H),1.31(s,3H)ppm.

1.2 Synthesis of intermediate compound S8

i) Allyl bromide, Cs ₂ CO ₃ , DMF, rt; ii) DMAP, TFA, DCM, rt; iii) Toluene, reflux; iv) Acryloyl chloride, DIPEA, DCM, 0° C.; v) N-methylaniline, Pd(PPh ₃ ) ₄ , THF, rt.

i) N-Boc homoproline (11.47 g, 50 mmol) was dissolved in DMF (70 mL) and Cs ₂ CO ₃ (32.58 g, 100 mmol) was added. The resulting suspension was stirred at room temperature for 5 minutes, and then allyl bromide (6.35 g, 52.5 mmol) was added. The reaction mixture was stirred at room temperature until the reaction was complete as determined by TLC. The suspension was filtered through a celite pad, rinsed with EtOAc (60 mL), and washed with HCl (1 M, 50 mL×3). The organic phase was dried over anhydrous Na ₂ SO ₄ and co-evaporated with toluene (30 mL×2). 14.66 g of a crude yellow oil was obtained, which was used directly in the next step without further purification.

ii) The crude product obtained in i) was dissolved in DCM (30 mL) and TFA (7.5 mL) was added. The mixture was stirred at room temperature until the reaction of the raw material was complete. The mixture was concentrated to obtain 5.6 g of yellow oily liquid crude product S5, which was directly used in the next step.

iii) 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) were dissolved in anhydrous toluene (PhMe) (35 mL) and heated to reflux in an oil bath for 16 hours; then the solvent was removed and the mixture was separated and purified by silica gel chromatography (eluent: PE:EtOAc=3:1) to obtain 9.05 g of yellow oily compound S6. The total yield of the three-step reaction was 61%.

¹ H NMR (600MHz, CDCl ₃ )δ5.96-5.88(m,1H),5.36(d,J＝17.4Hz,1H),5.30-5.27(m,2H),4.70-4.65 (m,2H),3.71-3.60(m,2H),3.50(d,J＝15.6Hz,1H),3.32(s,1H),3.20(td,J ₁ = 13.2, J ₂ = 3.0Hz, 1H), 2.36 (d, J = 13.8Hz, 1H), 1.81-1.62 (m, 3H), 1.56-1.36 (m, 2H), 1.24 (s, 6H) ppm.

iv) Compound S6 (9.05 g, 30.4 mmol) and DIPEA (6.53 mL, 5.11 g, 39.52 mmol, 1.3 equivalents) were dissolved in anhydrous DCM (30 mL), and then acryloyl chloride (2.7 mL, 3.026 g, 33.44 mmol) was slowly added dropwise thereto; the reaction mixture was stirred at room temperature until the reaction was complete, and then quenched with a saturated NaHCO ₃ solution. The organic phase was washed with water, extracted, dried over anhydrous Na ₂ SO ₄ , concentrated, and separated and purified by silica gel chromatography (eluent: PE: EtOAc = 5: 1) to obtain 8.12 g of colorless oily compound S7, with a yield of 76%.

¹ H NMR (600MHz, CDCl ₃ ) δ6.39 (d, J = 17.4Hz, 1H), 6.07 (dd, J ₁ = 17.4, J ₂ ＝10.2Hz,1H),5.93-5.87(m,1H),5.83(d,J＝10.8Hz,1H),5.34(d,J＝16.8Hz,1H),5.28-5.25(m,2H), 4.67-4.64(m,2H),4.37(d,J＝10.8Hz,1H),4.26(d,J＝10.8Hz,1H),3.51(d,J＝12.0Hz,1H),3.22(td,J ₁ =13.2,J ₂ ＝3.0Hz,1H),2.34(d,J＝13.8Hz,1H),1.81-1.76(m,1H),1.73-1.68(m,1H),1.64(d, J＝13.2Hz,1H),1.56-1.48(m,1H),1.44-1.38(m,1H),1.35(s,3H),1.34(s,3H)ppm.

v) Compound S7 (8.12 g, 23.1 mmol), Pd(PPh ₃ ) ₄ (800.8 mg, 0.693 mmol, 3%) and N-methylaniline (7.5 mL, 7.425 g, 69.3 mmol) were dissolved in dry THF (35 mL) and stirred at room temperature for 6 hours; the reaction mixture was then diluted with EtOAc (50 mL) and extracted with HCl (1 M, 40 mL×3); the organic phase was dried over Na ₂ SO ₄ , filtered and concentrated; the crude product was separated and purified by silica gel chromatography (eluent: DCM:MeOH=30:1) to obtain 5.47 g of white solid compound S8 with a yield of 86%.

1.3 Linker Synthesis

i) m-CPBA, K ₂ HPO ₄ , DCM, rt, 12 h; ii) H ₂ SO ₄ , THF:H ₂ O=1:1, reflux; iii) NaIO ₄ , MeOH, 20 h; iv) NaBH ₄ , MeOH, 0° C.; v) TsCl, Ag ₂ O, KI, DCM, rt; vi) 2-chlorotriphenylmethyl chloride resin, DIPEA, THF, 50° C., 24 h; vii) MeNH ₂ , THF, 40° C., 12 h.

i) 1,4-cyclohexadiene (6.41 g, 80.0 mmol) was dissolved in DCM (80 mL), and then K ₂ HPO ₄ (14.63 g, 84.0 mmol, 1.05) was added. m-Chloroperbenzoic acid (m-CPBA) (17.05 g, 84.0 mmol, 85%) was added in 10 portions at 0°C, and the reaction was stirred overnight. After the reaction was completed, the mixture was filtered using a sand core funnel covered with diatomaceous earth, and the filter cake was washed with DCM. The organic phase was washed with Na ₂ S ₂ O ₃ (150 mL) and saturated NaHCO ₃ (150 mL) in turn. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated to obtain a colorless transparent oily crude product, compound S9, which was directly used in the next reaction.

ii) The crude product compound S9 was dissolved in a mixed solvent (THF:H ₂ O＝1:1, 40mL), and concentrated H ₂ SO ₄ (3mL) was slowly added dropwise under stirring and refluxed for 3-4 hours, and the reaction was monitored by TLC. After the reaction was complete, an appropriate amount of K ₂ CO ₃ (about 4g) was added to terminate the reaction. The product was extracted with EtOAc 3 times and with n-butanol 3 times, and the organic phases were combined and dried with anhydrous NaSO _4. After concentration, a light yellow transparent oily crude product compound S10 was obtained.

iii) The crude product compound S10 was dissolved in MeOH (40 mL), NaHCO ₃ (2.52 g, 29.95 mmol) was added, and then NaIO ₄ (17.1 g, 80.0 mmol) was added in batches, and the mixture was reacted at room temperature for 3-4 hours, and the reaction was monitored by TLC. After the reaction was complete, the mixture was filtered using a sand core funnel covered with diatomaceous earth, the filter cake was washed with DCM, and concentrated to obtain a brown transparent oily crude product compound S11, which was directly used in the next step reaction.

iv) The crude product compound S11 was dissolved in a solvent mixture (DCM:MeOH=1:2, 45 mL), and NaBH ₄ (3.02 g, 80.0 mmol) was added in batches under an ice-water bath. After the addition, the mixture was stirred for about 0.5 hours, and the reaction was monitored by TLC. After the reaction was complete, a small amount of saturated NH ₄ Cl solution was added to quench the reaction. The mixture was extracted with EtOAc (30 mL×2) and n-butanol (20 mL×3), and finally concentrated and purified by silica gel chromatography (eluent: PE:EtOAc=2:1) to obtain 3.88 g of light yellow oily liquid compound S12. The total yield of the four-step reaction was 42%.

¹ H NMR (600MHz, CDCl ₃ ) δ5.59 (t, J = 6.0 Hz, 2H), 3.69 (t, J = 6.0 Hz, 4H), 2.38 (q, J = 6.0 Hz, 4H) ppm.

v) Compound S12 (3.88 g, 33.4 mmol) was dissolved in anhydrous DCM solution, and 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 in sequence. The mixture was reacted at room temperature for 2 days and then filtered. The filter cake was washed with DCM, concentrated and separated and purified using a silica gel column (eluent: 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 with a yield of 49% (conversion rate 86%).

¹ H NMR (600MHz, CDCl ₃ )δ7.79(d,J＝7.8Hz,2H),7.34(d,J＝7.8Hz,2H),5.56-5.50(m,1H),5.46-5.40(m,1H),4.04(t,J＝ 6.6Hz,2H),3.63(t,J＝6.6Hz,2H),2.45(s,3H),2.44(q,J＝6.6Hz,2H),2.28(q,J＝6.6Hz,2H)ppm.

vi) Take 2-chlorotriphenylmethyl 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. Add compound S13 (3.0 g, 11.09 mmol) and DIPEA (13.3 mL, 10.4 g, 80.64 mmol) in sequence, and slowly stir the mixture at 50 ° C for 24 hours; after the reaction is completed, filter with a sand core funnel, and wash the resin alternately with DCM and MeOH until it is clean. Collect the resin and use vacuum to dry to obtain compound S14, which is directly used in the next step reaction.

vii) Compound S14 was placed in a 100 mL round-bottom flask and THF (15 mL) was added to swell for 15-20 minutes. MeNH ₂ ·MeOH solution (15 mL) was added and slowly stirred at 40° C. for 12 hours. After the reaction was completed, it was filtered using a sand core funnel, and the resin was washed alternately with DCM and MeOH until it was clean. The resin was collected and dried using a vacuum pump to obtain compound 15 (Linker).

viii) Determination of the loading of compound S15

Compound S15 (100 mg) was placed in a threaded standard sample bottle and DMF (1-2 mL) was added to swell for 5 minutes. Subsequently, condensation 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) were added and dissolved. The vial was placed on a decolorizing shaker to react for 2-3 hours.

After the reaction is complete, filter with a sand core funnel, wash the resin with DCM and MeOH alternately until it is clean, then transfer the resin to a new reaction bottle, add 2 mL of mixed solvent (TFA:MeOH:DCM=1:1:8), place on a shaker to react for 1 hour, and cut off Linker-N-Fmoc-Tyr(O-tBu) coupled with an amino acid.

After the reaction was complete, the resin was filtered with a sand core funnel, and DCM and MeOH were used alternately to wash the resin until it was clean. The filtrate was collected, concentrated and weighed to obtain 44.8 mg of a light yellow oily substance. The resin loading was calculated based on the mass, and the loading value was 0.78 mmol/g.

1.4 Solid-phase synthesis and ring-close metathesis

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).

2) Add 3 mL of 20% piperidine-DMF solution (piperidine:DMF=1:4, volume ratio) to the reaction tube and place it 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.

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.

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.

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 sealed and placed in a microwave reactor 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.

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

Example 2 Anti-HBV Screening Test

HepG2-NTCP cell culture: HepG2-NTCP cell line was cultured in modified Eagle 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 until use.

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

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

Cellular RNA was extracted using TRNzol Total RNA extraction reagent (Beijing Tiangen, DP405), and quantitative PCR (qPCR) was used to detect the level of HBV 3.5-kb RNA in cells (QuantStudio6FLEX Q6, Thermofisher).

Taurocholic acid-d4 (TCA-d4) uptake assay: HepG2-NTCP cells were plated at a density of 2×10 ⁵ cells/well in a 12-well plate and incubated for 48 hours at 37°C in a 5% CO ₂ environment. 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 MgCl ₂ , 1 mM CaCl ₂ , 10 mM HEPEs, pH 7.4) per well, and then pre-incubated in 0.5 mL of buffer at 37°C in a 5% CO ₂ environment for 15 minutes. The buffer was removed, and the cells were washed again with buffer, and then the compounds (JH-A01 to JH-A51) were added after adding 0.5 mL of buffer, so that the final concentration of the compounds was 2 μM, and the group with an equal volume of DMSO was set as the control group, and 3 replicates were set for each group, and incubated at 37°C in a 5% CO ₂ environment for 15 minutes. TCA-d4 was then added to the cells to a final concentration of 5 μM and incubated for 15 minutes at 37°C in a 5% CO ₂ environment. 0.5 mL of buffer was added to each well to wash the cells three times, and the cells were lysed with 200 μl of anhydrous ethanol. The cell lysate was transferred to an EP tube, the supernatant was collected by centrifugation at 12,000 rpm for 10 minutes at 4°C, and the uptake of TCA was quantified by LC-MS/MS.

[Corrected 10.01.2025 in accordance with Article 91]
The test results are shown in FIG. 1A , FIG. 1B , and FIG. 1C .

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 taurocholic acid-d4 uptake, HBV 3.5-kb RNA and hepatitis B E antigen (HBeAg).

Example 3 Toxicity test of the compounds of the present invention

CCK8 assay was performed using a microplate reader (Synergy H1, Biotek) to detect drug toxicity. HepG2-NTCP cell suspension (2×10 ³ cells/well) was prepared in a 96-well plate. After pre-culture in an incubator (Mod3111, Thermofisher) for 24 hours (37°C, 5% CO ₂ ), different concentrations of compounds JH-A27 and JH-A32 were added to the culture plate and incubated for 48 hours. 10 μL of CCK8 detection solution (HY-K0301, MCE) was added to each well, and the absorbance at 450 nm was measured using a microplate reader after 1 hour to analyze the cytotoxic activity.

The test results are shown in Figure 2.

According to the test results, the half toxic concentration (CC ₅₀ ) of compounds JH-A27 and JH-A32 are both over 10 μM, both of them are non-cytotoxic and have good safety.

Example 4 Inhibitory effect test of the compounds of the present invention

Compounds JH-A27 and JH-A32 were prepared into test solutions with different concentration gradients for pre-incubation and testing of IC ₅₀ values.

HepG2-NTCP cells were plated at a density of 2×10 ⁵ cells/well in a 12-well plate and incubated for 48 hours at 37°C in a 5% CO ₂ environment. 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 MgCl ₂ , 1 mM CaCl ₂ , 10 mM HEPEs, pH 7.4) per well, and then pre-incubated in 0.5 mL of buffer at 37°C in a 5% CO ₂ environment for 15 minutes. Remove the buffer and wash the cells again with the buffer, then add different concentration gradients of compounds JH-A27 (final concentrations of 2000, 400, 80, 16, 3.2, 0.64, 0.128 nM) and JH-A32 (final concentrations of 2000, 667, 222, 74, 25, 8.2, 2.7 nM) after adding 0.5 mL of buffer, and set the group to which an equal volume of DMSO was added as the control group, with 3 replicates per group, and incubate for 15 minutes at 37 ° C, 5% CO ₂ environment. Then add TCA-d4 to the cells to a final concentration of 5 μM, and incubate for 15 minutes at 37 ° C, 5% CO ₂ environment. Wash the cells three times by adding 0.5 mL of buffer to each well, and lyse the cells with 200 μl of anhydrous ethanol. Transfer the cell lysate to an EP tube, and collect the supernatant by centrifugation at 12000 rpm for 10 minutes at 4 ° C.

The enzyme-linked immunosorbent assay in Example 2 was used to detect the HBeAg level, the quantitative PCR was used to detect the HBV 3.5-kb RNA level, and the LC-MS/MS was used to detect the TCA uptake.

The test results are shown in Figure 3.

According to the test results, compounds JH-A27 and JH-A32 have inhibitory effects on taurocholic acid-d4 uptake, HBV 3.5-kb RNA and hepatitis B E antigen (HBeAg). Among them, the IC ₅₀ of compound JH-A27 and compound JH-A32 on taurocholic acid-d4 uptake inhibition are 163nM and 20nM, respectively. The IC ₅₀ of compound JH-A27 on HBV 3.5-kb RNA level and HBeAg level inhibitory activity are 279nM and 243nM, respectively, and the IC ₅₀ of compound JH-A32 on HBV 3.5-kb RNA level and HBeAg level inhibitory activity are 237nM and 200nM, respectively. The inhibitory activity of the two on HBV 3.5-kb RNA level and HBeAg level is relatively close.

Example 5 In vivo efficacy test of the compounds of the present invention

By constructing a humanized liver mouse model, compound JH-A32 was selected for in vivo efficacy verification.

Human liver chimeric mice (10 mice) were randomly divided into a treatment group and a control group, with 5 mice in each group, and the compound JH-A32 and DMSO were administered at a dose of 4 mg/kg. The dosing scheme is shown in Figure 4. The two groups of mice were administered once 3 days and 1 hour before HBV infection for pretreatment. The time of HBV infection was recorded as day 0, and the drug was administered once on days 1, 2, 3, and 5, respectively, and then once a week (i.e., days 15, 22, 29, 36, 43, and 50) for a total of 8 weeks. Blood was collected for biochemical analysis every week (i.e., days 7, 14, 21, 28, 35, 42, 49, and 56), and the mice were killed after 8 weeks and the livers were collected for various index tests. The test results are shown in Figure 5.

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

The above description is only a specific embodiment of the present invention, and does not limit the patent scope of the present invention. Any equivalent transformation made by using the present invention, or directly or indirectly applied in other related technical fields, is also included in the protection scope of the present invention.

Claims (11)

A compound having the structure of the following formula (I):
or a pharmaceutically acceptable salt thereof, in, X ₁ selected from X ₂ is selected from O or NR ¹⁴ ; 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 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, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from ^RX ; R ² is selected from hydrogen, halogen, amino, cyano, nitro, C _1-6 alkyl, C _1-6 alkyl-SC _1-6 alkyl, C _1-6 alkyl-OC _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 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, C _5-10 heteroaryl-C _1-4 alkyl, CN and NO ₂ , wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from ^RX ; ^R3 is selected from hydrogen and _C1-6 alkyl; When R ⁴ is i) When the formula (I) has the following structure (II-1):
When R ⁴ is ii) When the formula (I) has the following structure (II-2):
When R ⁴ is iii) When the formula (I) has the following structure (II-3):
When R ⁴ is iv) When the formula (I) has the following structure (II-4):
or When R ⁴ is v) When the formula (I) has the following structure (II-5):
R ⁵ 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 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, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from ^RX ; ^R is selected from hydrogen, amino, cyano, nitro, C _1-6 alkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _1-6 alkyl-OC _1-6 alkyl, C _1-6 alkyl-SC _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 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, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from ^RX ; or R ⁵ and R ⁶ together with the atoms to which they are attached form a 5-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms, wherein the 5-8 membered heterocyclic group is unsubstituted or substituted with at least one substituent independently selected from ^RX ; R ⁷ is selected from hydrogen and C _1-6 alkyl; ^R is selected from hydrogen, amino, cyano, nitro, C _1-6 alkyl, C _1-6 alkyl-C _3-10 cycloalkyl, C _1-6 alkyl-OC _1-6 alkyl, C _1-6 alkyl-SC _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 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, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from ^RX ; R ⁹ is selected from hydrogen and C _1-6 alkyl; 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 unsubstituted or substituted with at least one substituent independently selected from ^RX ; 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 unsubstituted or substituted with at least one substituent independently selected from ^RX ; R ¹⁴ is selected from hydrogen and C _1-6 alkyl; ^RX is selected from hydroxy, halogen, _C1-6 alkyl, _C1-6 alkoxy, _C2-6 alkenyl, C2-6 alkynyl, _C3-10 cycloalkyl, _C3-10 cycloalkyl- _C1-4 alkyl, _C3-10 heterocyclyl, _C3-10 heterocyclyl- _C1-4 alkyl, _C6-10 aryl, _C6-10 aryl- _C1-4 alkyl, _C5-10 heteroaryl and _{C5-10 heteroaryl} - _C1-4 alkyl, wherein each alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is unsubstituted or substituted with at least one substituent independently selected from ^RY ; R ^Y is 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; m, n, o, p and q are each independently selected from integers of 0, 1, 2, 3, 4, 5 and 6; ^*1 C, ^*2 C and ^*3 C represent chiral carbon atoms connected to R ⁴ , R ⁶ and R ⁸ , respectively. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein i) When _X1 is When the formula (I) has the structure of the following formula (III):
wherein X ₂ , 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 represent chiral carbon atoms connected to R ⁴ , R ⁶ and R ⁸ respectively; or ii) When _X1 is When the formula (I) has the following structure (III'):
wherein X ₂ , 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 represent chiral carbon atoms connected to R ⁴ , R ⁶ and R ⁸ , respectively. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein _X2 is O; and/or R ¹ is selected from hydrogen and C _1-6 alkyl, preferably hydrogen and methyl; and/or ^R2 is selected from hydrogen, _C1-6 alkyl, _C1-6 alkyl- _SC1-6 alkyl, _C1-6 alkyl- _OC1-6 alkyl, _C1-6 alkyl- _C6-10 aryl, wherein the alkyl and aryl are unsubstituted or substituted by at least one substituent independently selected from ^RX , preferably hydrogen, methyl, ethyl, isopropyl, and/or ^R3 is hydrogen; and/or R ⁵ is selected from hydrogen and C _1-6 alkyl, preferably hydrogen and methyl; and/or ^R6 is selected from _C1-6 alkyl, _C1-6 alkyl- _C3-10 cycloalkyl, _C1-6 alkyl- _OC1-6 alkyl, _C1-6 alkyl- _SC1-6 alkyl, _C1-6 alkyl- _C6-10 aryl, wherein the alkyl, cycloalkyl and aryl are unsubstituted or substituted with at least one substituent independently selected from ^RX , preferably and/or ^R5 and ^R6 together with the atoms to which they are attached form a 5-membered heterocyclic group containing 1 nitrogen heteroatom, wherein the 5-membered heterocyclic group is unsubstituted or substituted by at least one substituent independently selected from ^RX , preferably and/or ^R7 is hydrogen; and/or ^R8 is selected from _C1-6 alkyl- _C3-10 cycloalkyl, _C1-6 alkyl- _C6-10 aryl, wherein the alkyl, cycloalkyl and aryl are unsubstituted or substituted by at least one substituent independently selected from ^RX , preferably and/or R ⁹ is selected from C _1-6 alkyl, preferably methyl; and/or R ¹⁰ is selected from C _1-6 alkyl, preferably methyl; and/or R ¹¹ is selected from C _1-6 alkyl, preferably methyl; and/or R ¹² is selected from C _1-6 alkoxy, preferably methoxy; and/or R ¹³ is selected from C _1-6 alkoxy, preferably methoxy. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R ^X is selected from hydroxy, halogen, C _1-6 alkyl and C _1-6 alkoxy, preferably hydroxy, fluorine, chlorine, methyl, tert-butyl, methoxy and The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein ^RY is selected from halogen, preferably fluorine. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 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. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein ^*1 The chiral carbon atom is in S or R configuration, preferably S configuration; and/or ^*2 The C chiral carbon atom is in S or R configuration, preferably S configuration; and/or ^*3 The C chiral carbon atom is in S or R configuration, preferably S configuration. The compound of claim 1, which is selected from the following structures:



or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating, ameliorating or preventing a condition responsive to inhibition of the sodium ion taurocholate cotransporter. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 9 in the preparation 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.