WO2017101785A1

WO2017101785A1 - Compound, preparation method therefor, pharmaceutical composition thereof and use thereof

Info

Publication number: WO2017101785A1
Application number: PCT/CN2016/109913
Authority: WO
Inventors: 周星露; 董晓武; 刘兴国
Original assignee: 杭州和正医药有限公司
Priority date: 2015-12-15
Filing date: 2016-12-14
Publication date: 2017-06-22

Abstract

Disclosed in the present invention are a prodrug comprising a nucleoside analog structure as shown in formula I, a tautomer thereof, a stereisomer thereof, a stereisomer mixture thereof or a pharmaceutically acceptable solvate thereof. Also disclosed are a preparation method therefor, a pharmaceutical composition formed therefrom and a use thereof as an anti-hepatitis C drug. The present compound or the pharmaceutical composition thereof can be used for treating hepatitis C, and also has functions such as protecting liver tissue and liver cells, improving liver function and reducing aminotransferase.

Description

Compound, preparation method thereof, pharmaceutical composition and use thereof

Technical field

The invention belongs to the field of medicinal chemistry. In particular, the present invention relates to a compound or a tautomer thereof, a stereoisomer, a mixture of stereoisomers, a prodrug, a pharmaceutically acceptable salt or a solvate thereof, a process for the preparation thereof, a pharmaceutical combination And its use as an anti-hepatitis C drug.

Background technique

Hepatitis C is a liver disease caused by hepatitis C virus (HCV), which is a serious threat to human health. In 1978, hepatitis C virus was first discovered; in 1989, the completion of gene sequencing, HCV was confirmed as another major pathogen of non-A, non-B hepatitis. According to the HCV genome heterogeneity, it can be divided into 6 types and 30 subtypes. The type of infection has a strong regional nature, and China is mainly type 1. According to the 2011 study, among the HCV-infected people in China, type 1 accounted for 58.2%, of which gene type 1a was 1.4% and gene type 1b was 56.8%. At present, there are more than 200 million HCV-infected people worldwide, accounting for 3.3% of the world's total population. There are about 3.2 million infected people in the United States. The number of HCV patients in China exceeds 40 million, ranking first in the world. Many HCV-infected patients are also hepatitis B and even AIDS patients, which increases the complexity of treatment. There is currently no officially approved hepatitis C vaccine, so preventing hepatitis C transmission remains a challenge. The existing chronically infected patients are developing, and it is expected that the peak incidence will be ushered in the next 10-20 years. The standard clinical regimen for the treatment of hepatitis C is peginterferon alfa combined with ribavirin. The standard of cure is that the blood is not detected by HCV within 24 weeks after treatment. This treatment has many side effects, including depression, fatigue, flu-like symptoms, and anemia; the cost of treatment is high, and the standard treatment takes 48 weeks and costs about $40,000. In order to solve the above problems, in recent years, the development of anti-hepatitis C virus small molecule compound drugs against the hepatitis C virus RNA gene sequence has rapidly become a hot spot, and antiviral drugs will enter the era of small molecule drugs from the interferon era. At present, many HCV protease inhibitors have been extensively studied, among which Telaprevir (Terravir, VX-950, trade name Incivek) and Boceprevir (Bosipuvir, SCH-503034, trade name Victrelis) have been Approved for listing. The inhibitor of the non-structural protein NS5A is also a specific antiviral drug acting on the hepatitis C virus RNA chain, and various genotypes of HCV virus have significant inhibitory effects. In addition, drugs targeting NS5B polymerase are classified into two classes: nucleoside and non-nucleoside polymerase inhibitors. Among them, Sofosbuvir is by far the most potent anti-HCV drug, which is effective against HCV genotype 1, 2, 3, 4 and 6 infections.

Summary of the invention

The object of the present invention is to provide a novel anti-HCV virus and liver-protecting and liver-protecting bifunctional drugs, which can be used as a bifunctional drug, and has the characteristics of high oral bioavailability and good metabolic properties, and can be used for oral treatment. Viral hepatitis embolism.

It is an object of the present invention to provide a structural compound of the formula I or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable solvate thereof.

Another object of the invention is to provide a process for the preparation of the compounds provided herein.

Still another object of the present invention is to provide a structural compound of the formula I or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable solvate thereof as an NS5B inhibitor, which protects liver cells, liver tissue, and improves The use of liver function and its application in the preparation of the treatment of viral hepatitis.

A further object of the present invention is to provide a pharmaceutical composition comprising one or more of the structural compounds of the formula I or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable solvate thereof.

It is still another object of the present invention to provide a method for treating viral hepatitis while protecting liver cells, liver tissues, and improving liver function.

The invention adopts the technical solution as described below:

A compound having the structure of Formula I, or a tautomer, an optical isomer, a stereoisomer, a mixture of stereoisomers, a prodrug, a pharmaceutically acceptable salt of the structure of Formula I. Or solvate:

In formula I, X is hydroxy, F, Cl or Br;

R, R' are independent of H, or

And at least one of R and R' is

Where Linker may or may not be present, A is derived from a drug or derivative thereof for the treatment or adjuvant treatment of liver disease. The drug or derivative thereof for treating or assisting in the treatment of liver disease may be a drug already on the market. In the present invention, a group mentioned, such as the group I "from" the compound I, generally means that the group I is obtained by reacting the compound I.

According to one aspect of the invention, the invention protects a compound having the structure of formula I-1, or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt or solvate thereof Or a prodrug of the formula I-1:

Wherein X is a hydroxyl group or F, Cl, Br; R is

Linker A is

Or absent; G is derived from a drug or derivative thereof that has been marketed for the treatment or adjuvant treatment of liver disease; R ₁ is H or C ₁ -C ₅ alkyl; n is an integer from 1 to 19.

In the above formula I-1, a further preferred compound is a prodrug containing a nucleoside-like structure represented by the formula II-1A or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof. Or solvate:

Wherein X is a hydroxyl group or F, Cl, Br; Linker A is

or

Or absent; R ₁ is H or C ₁ -C ₅ alkyl; n is 1, 2, ₃ , 4 or 5; and R ₃ and R ₄ are each independently a hydrogen atom or a C ₁ -C ₅ alkyl group.

In the above formula II-1A, a further preferred compound is a structure represented by the formula II-1Aa or the formula II-1Ab or a tautomer, an optical isomer, a stereoisomer thereof, a stereoisomer Body mixture, prodrug, pharmaceutically acceptable salt or solvate:

Wherein X is a hydroxyl group or F, Cl, Br; Linker A is

or

In the above formula I-1, a further preferred compound is a structure represented by the formula II-1B or a tautomer, an optical isomer, a stereoisomer, a mixture of stereoisomers, and a former Drug, pharmaceutically acceptable salt or solvate:

Wherein X is a hydroxyl group or F, Cl, Br; Linker A is

In the above formula II-1B, a structure represented by the formula II-1Ba or the formula II-1Bb or an optical isomer, a pharmaceutically acceptable salt or a solvate thereof is further preferred:

Wherein X is a hydroxyl group or F, Cl, Br; Linker A is

In the above formula I-1, a prodrug containing a tiopronin structure represented by the formula II-1A-A(1) or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable substance thereof is further preferred. Accepted solvates:

Where X is hydroxyl or F, Cl, Br, and Linker A is

or

R ₁ is H or C ₁ -C ₅ alkyl, and n is an integer from 1 to 19.

Or, preferably, in the above formula I-1, a prodrug containing a tiopronin structure represented by the following formula II-1A-A(2) or a stereoisomer thereof, stereoisomerism a mixture or a pharmaceutically acceptable solvate thereof:

In the above formula: X, Linker A, R ₁ , and n are as defined in the above formula II-1A-A(1).

In the above formula II-1A-A(1), further preferred are the following prodrugs containing a tiopronin structure or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable solvate thereof:

Wherein X is a hydroxyl group or F, Cl, Br; R ₁ is H or a C ₁ -C ₅ alkyl group, and n is 1, 2, 3, 4 or 5.

Alternatively, preferably, in the above formula II-1A-A(1), the following prodrug containing a tiopronin structure or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable thereof is further preferred Solvate:

Where X, R ₁ and n are as defined above.

Where X, R ₁ and n are as defined above.

In the above formula II-1A-A, further preferred are the following prodrugs containing a tiopronin structure or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable solvate thereof:

Wherein R ₁ is H or C ₁ -C ₅ alkyl, and n is 1, 2, 3, 4 or 5.

Among the compounds represented by the formula I-1, further preferred specific compounds are one of the following compounds:

Another object of the present invention is to provide a process for the preparation of a compound of the formula II-1A, which comprises: 1) reacting a compound of the formula III with a compound of the formula IV-1A to give a formula V-1A a compound represented by the formula V-1A is subjected to a deprotection reaction to obtain a compound of the formula II-1A;

Wherein X is a hydroxyl group or a halogen (F, Cl, Br); Linker A is

Or absent; n is 1, 2, 3, 4 or 5; R ₁ is H or C ₁ -C ₅ alkyl; R ₃ and R ₄ are each independently a hydrogen atom or a C ₁ -C ₅ alkyl group; The leaving group is preferably a halogen; Z is a mercapto protecting group, preferably trityl, 4-methoxytrityl, 4,4'-bismethoxytrityl.

Another object of the present invention is to provide a process for the preparation of a compound of the formula II-1B, which comprises: 1) reacting a compound of the formula III with a compound of the formula IV-1B to give a formula V-1B a compound of the formula V-1B is subjected to a deprotection reaction to give a compound of the formula II-1B;

Among them, X hydroxyl or halogen (F, Cl, Br); Linker A is

Further, a method for preparing a compound represented by the formula II-1A-Aa can be obtained by subjecting a compound represented by the formula IIIm to a compound represented by the formula IV-1 to obtain a formula V-1A. The compound shown is then obtained by deprotection.

Wherein X is a hydroxyl group or F, Cl or Br; R ₁ is H or a C ₁ -C ₅ alkyl group; Y is a leaving group, preferably a halogen, such as fluorine, chlorine, bromine, iodine, etc., Z is The thiol protecting group is preferably trityl, 4-methoxytrityl, 4,4'-bismethoxytrityl.

A method for producing a compound represented by the formula II-1A-Ab, which can be obtained by subjecting a compound represented by the formula IIIm to a compound represented by the formula IV-1B to give a compound represented by the formula V-1B. Then through the deprotection reaction to get:

Wherein X is a hydroxyl group or a halogen (F, Cl, Br); R ₁ is H or a C ₁ -C ₅ alkyl group; n is an integer from 1 to 19; Y is a leaving group, preferably a halogen, such as may be Fluorine, chlorine, bromine, iodine, etc.; Z is a mercapto protecting group, preferably trityl, 4-methoxytrityl, 4,4'-bismethoxytrityl.

Another object of the present invention is to provide a process for the preparation of a compound of the formula II-1A-B which can be subjected to a protective reaction by a compound represented by III and then reacted with an aldehyde to give a compound of the formula VII-1, and then Esterification or acylation with a compound represented by VIII-1A represented by the formula to give a compound of the formula IX-1A-B, followed by removal of a protecting group to give a compound of the formula II-1A-B . The active site of the key intermediate of the preparation method is appropriately protected, which helps to reduce the occurrence of side reactions, has high reaction selectivity, and has high purity and easy purification of the obtained intermediate and final product. Moreover, the reaction involved in the method has the advantages of simple operation, convenient purification, and good controllability of the process, and is suitable for industrial production.

Wherein, X is hydroxy or halogen (F, Cl, Br); R 1 is H or C ₁ -C ₅ alkyl group; R _3, R ₄ are each independently a hydrogen atom or a C ₁ -C ₅ alkyl group; P ₁ Is a hydroxy protecting group, preferably a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, a triphenylsilyl group; P ₂ is an amide NH protecting group, preferably a tert-butoxycarbonyl group , benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl; P ₃ is a thiol protecting group, preferably trityl, 4-methoxytrityl, 4,4'-bismethoxytriphenyl methyl.

Another object of the present invention is to provide a process for the preparation of a compound of the formula II-1B-B which may be esterified with a compound of the formula VII-1 and then with a compound of the formula VIII-1B or The acylation reaction gives the compound of the formula IX-1B-B, and then the protecting group is removed to give the compound of the formula II-1B-B. The active site of the key intermediate of the preparation method is appropriately protected, which helps to reduce the occurrence of side reactions, has high reaction selectivity, and has high purity and easy purification of the obtained intermediate and final product. Moreover, the reaction involved in the method has the advantages of simple operation, convenient purification, and good controllability of the process, and is suitable for industrial production.

Wherein X, R ₁ , R ₃ , R ₄ are as defined in the formula II-1B, and P ₁ is a hydroxy protecting group, preferably trimethylsilyl, triethylsilyl, tert-butyl a dimethylsilyl group, a triphenylsilyl group; P ₂ is an amide NH protecting group, preferably a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group; and P ₃ is a fluorenyl protecting group. Preferred is trityl, 4-methoxytrityl, and 4,4'-bismethoxytrityl.

Another object of the present invention is to provide an intermediate represented by the following VII-1 and its use for preparing an anti-hepatitis C virus drug:

Wherein X is a hydroxyl group or a halogen (F, Cl, Br); R ₁ is H or a C ₁ -C ₅ alkyl group; and P ₁ is a hydroxy protecting group, preferably a trimethylsilyl group, a triethylsilyl group, Tert-butyldimethylsilyl, triphenylsilyl.

Another object of the present invention is to provide an intermediate represented by the following VIII-1A or a stereoisomer thereof or a mixture of stereoisomers thereof:

Wherein P ₂ is an NH protecting group, preferably tert-butoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl; P ₃ is a fluorenyl protecting group, preferably trityl, 4-methoxy Tritylmethyl, 4,4'-bismethoxytrityl and the like.

Another object of the present invention is to provide a prodrug of the following IX-1A-B or a stereoisomer thereof, a mixture of stereoisomers:

Wherein X is a hydroxyl group or a halogen (F, Cl, Br); R ₁ is H or a C ₁ -C ₅ alkyl group; and P ₁ is a hydroxy protecting group, preferably a trimethylsilyl group, a triethylsilyl group, Tert-butyldimethylsilyl, triphenylsilyl; P ₂ is an NH protecting group, preferably tert-butoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, etc.; P ₃ is a fluorenyl protecting group The group is preferably a trityl group, a 4-methoxytrityl group, a 4,4'-bismethoxytrityl group or the like.

Another object of the present invention is to provide an intermediate represented by the following VIII-1B or a stereoisomer thereof or a mixture of stereoisomers thereof:

Wherein R ₃ and R ₄ are each independently a hydrogen atom or a C ₁ -C ₅ alkyl group; and P ₂ is an amide NH protecting group, preferably a tert-butoxycarbonyl group, a benzyloxycarbonyl group or a 4-methoxybenzyloxycarbonyl group. ; P ₃ is a thiol protecting group, preferably trityl, 4-methoxytrityl, 4,4'-bismethoxytrityl.

Another object of the present invention is to provide a prodrug of the following IX-1B-B or a stereoisomer thereof, a mixture of stereoisomers:

According to another aspect of the present invention, the present invention provides a prodrug of the formula I-2, or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt or solvate thereof. :

Wherein X is a hydroxyl group, F, Cl or Br; R' is

Where Linker B may or may not be present, B is derived from a drug or derivative thereof that has been marketed for the treatment or adjuvant treatment of liver disease, F is linked to Linker B via a covalent bond, and then Linker B is covalently bonded to the nucleoside 4 The hydroxyl group is bonded to a hydroxyl group. When Linker B is absent, F is directly bonded to the hydroxy atom of the nucleoside at the 4-position by a covalent bond.

Further preferred is a compound represented by the formula II-2(1) or II-2(2) or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt or solvate thereof:

Where X is F, Cl or Br, and R' is

Where Linker B is

Or absent, F is a drug or derivative thereof which has been marketed for the treatment or adjuvant treatment of liver diseases, R ₁ , R ₂ is H or C ₁ -C ₅ alkyl, further preferably methyl or ethyl or propyl .

Still more preferably a compound of the following formula III-2A, or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable solvate thereof:

Wherein X is F, Br or Cl;

Linker B is

Or absent, when Linker B is absent, tiopronin or its derivative is directly linked to the hydroxy atom of the nucleoside 4 through an ester bond; R ₁ , R ₂ are respectively H or C ₁ -C ₅ alkyl, further Preferred is a C ₁ -C ₅ alkyl group, still more preferably a methyl group or an ethyl group or a propyl group; R ₃ , R ₄ is a hydrogen atom or a C ₁ -C ₅ alkyl group, and still more preferably a methyl group or an ethyl group. Or propyl.

Still more preferably a compound of the formula III-2Aa or III-2 Ab, or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable solvate thereof:

Where is F, Br or Cl; Linker B is

Or absent, when Linker B is absent, tiopronin or its derivative is directly linked to the hydroxy atom of the nucleoside 4 via an ester bond, and R ₁ and R ₂ are respectively H or C ₁ -C ₅ alkyl, R ₃ , R ₄ is a hydrogen atom or a C ₁ - C ₅ alkyl group, and still more preferably a methyl group or an ethyl group or a propyl group.

Still more preferably a compound of the following formula III-2B, or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable solvate thereof:

Where X is F, Br or Cl; Linker B is

Or absent, when Linker B is absent, acetylcysteine or its derivative is directly linked to the hydroxy atom of the nucleoside 4 via an ester bond, and R ₁ and R ₂ are respectively H or C ₁ -C ₅ alkyl Further, it is preferably a C ₁ - C ₅ alkyl group, still more preferably a methyl group or an ethyl group or a propyl group, and R ₃ and R ₄ are a hydrogen atom or a C ₁ - C ₅ alkyl group, and still more preferably a methyl group. Or ethyl or propyl.

Still more preferably a compound of the formula III-2Ba or III-2Bb, or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable solvate thereof:

Where X is F, Br or Cl; Linker B is

Or absent, when Linker B is absent, acetylcysteine or its derivative is directly linked to the hydroxy atom of the nucleoside 4 via an ester bond, and R ₁ and R ₂ are respectively H or C ₁ -C ₅ alkyl Further, it is preferably a methyl group or an ethyl group or a propyl group, and R ₃ and R ₄ are a hydrogen atom or a C ₁ - C ₅ alkyl group, and still more preferably a methyl group or an ethyl group or a propyl group.

The compound of the formula II-2 may also be selected from the following compounds of the formula III-2C, or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable solvate thereof:

Where X is F or Cl; Linker B is

or

R ₃ and R ₄ are a C ₁ - C ₅ hydrocarbon group, more preferably a C ₁ - C ₅ alkyl group, still more preferably a methyl group or an ethyl group or a propyl group.

Still more preferably the following compounds, or stereoisomers thereof, mixtures of stereoisomers or pharmaceutically acceptable solvates thereof:

The compounds of formula I may contain one or more chiral centers, as stereoisomers, ie, enantiomers, diastereomers or mixtures thereof, may be present. Thus, the compounds of formula I- of the present invention may be individual isomers or mixtures of individual isomers.

The invention includes any prodrug form of the compound of Formula I.

The invention also includes pharmaceutically acceptable solvates of the compounds of formula I.

The invention also includes pharmaceutically acceptable oxides of the compounds of formula I, and pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof.

The invention also includes various crystalline forms of the compounds of formula I.

According to still another aspect of the present invention, the present invention provides a compound of the formula I or a tautomer, a stereoisomer thereof, a mixture of stereoisomers, a prodrug, a pharmaceutically acceptable salt or a solvent thereof Use of the compound as an NS5B inhibitor to simultaneously protect liver cells, liver tissue, improve liver function, and use in the preparation of a medicament for treating diseases such as viral hepatitis.

According to a further aspect of the present invention, the present invention provides a therapeutically effective amount of a compound of the formula I or a tautomer thereof, a stereoisomer, a mixture of stereoisomers, a prodrug, a pharmacy A pharmaceutical composition of one or more of the above acceptable salts or solvates thereof, which may act as an NS5B inhibitor, and which composition may optionally comprise a pharmaceutically acceptable carrier or excipient.

According to another aspect of the present invention, the present invention provides an NS5B inhibitor comprising a therapeutically effective amount of a compound of the formula I or a tautomer, a stereoisomer thereof, a mixture of stereoisomers One or more of a prodrug, a pharmaceutically acceptable salt or a solvate thereof, and the inhibitor may optionally comprise a pharmaceutically acceptable carrier or excipient.

The composition consists of a therapeutically effective amount of one or more compounds of formula I or a tautomer, stereoisomer, stereoisomeric mixture, prodrug, pharmaceutically acceptable salt thereof or The drug solvate is comprised of at least one pharmaceutically acceptable adjuvant. The choice of pharmaceutical excipients varies depending on the route of administration and the characteristics of the action, and is usually a filler, a diluent, a binder, a wetting agent, a disintegrant, a lubricant, an emulsifier, a suspending agent, and the like. The compound of the formula I, a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable solvate thereof, is present in the above composition in a proportion of from 0.1% to 99.9%, preferably from 1% to 99% by total weight. %.

The pharmaceutically acceptable carrier refers to a pharmaceutical carrier conventional in the pharmaceutical field, such as a diluent such as water; a filler such as starch, sucrose, etc.; a binder such as a cellulose derivative, an alginate, gelatin, Polyvinylpyrrolidone; wetting agent such as glycerin; disintegrants such as agar, calcium carbonate and sodium hydrogencarbonate; absorption enhancers such as quaternary ammonium compounds; surfactants such as cetyl alcohol; adsorption carriers such as kaolin and soap Clay; lubricants such as talc, calcium stearate and magnesium stearate, and polyethylene glycol. In addition, other adjuvants such as flavoring agents, sweeteners and the like may also be added to the pharmaceutical composition.

The present invention also provides a pharmaceutically acceptable compound of the formula I or a tautomer, a stereoisomer thereof, a mixture of stereoisomers, a prodrug, a pharmaceutically acceptable salt or a solvate thereof. A method of preparing a composition. A compound containing a tiopronin structure represented by Formula I or a tautomer thereof, a stereoisomer thereof, a mixture of stereoisomers, and a former The drug, the pharmaceutically acceptable salt or the solvate thereof is mixed with a pharmaceutically acceptable adjuvant, and is prepared in a form suitable for administration by a conventional preparation method (dosage form). Dosage forms include tablets, capsules, granules, pills, solutions, suspensions, emulsions, ointments, films, creams, aerosols, injections, suppositories, and the like. Preference is given to tablets and capsules.

The compound of the present invention is usually used in a dose of from 1 to 1000 mg per day, in single or multiple doses. However, if necessary, the above dosage can be appropriately deviated. Professionals can determine the optimal dose based on specific circumstances and expertise. These conditions include the severity of the disease, individual differences in the patient, characteristics of the formulation, and route of administration.

Furthermore, the present invention provides a compound of the formula I or a tautomer, a stereoisomer thereof, a mixture of stereoisomers, a prodrug, a pharmaceutically acceptable salt or a solvate thereof, or Use of a pharmaceutically acceptable composition as a human drug.

According to still another aspect of the present invention, the present invention provides a method of treating viral hepatitis, the method comprising administering a therapeutically effective amount of a compound of the formula I or a tautomer thereof, a stereoisomer thereof One or more of a mixture of stereoisomers, prodrugs, pharmaceutically acceptable salts or solvates thereof or the pharmaceutical composition of the present invention is administered to a patient.

The compounds or compositions provided herein can be administered orally, by injection (intravenous, intramuscular, subcutaneous and intracoronary), sublingual, buccal, rectal, transurethral, vaginal, nasal, inhalation or topical routes. The preferred route is oral. When used orally, it can be prepared into a conventional solid preparation such as a tablet, a powder, a granule, a capsule, etc., or as a liquid preparation, such as a water or oil suspension, or other liquid preparation, such as a syrup; For parenteral administration, it may be prepared as a solution for injection, water or an oily suspension, or the like.

The present invention also provides a compound of the formula I or a tautomer, a stereoisomer thereof, a mixture of stereoisomers, a prodrug, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. Use in the preparation of a human NS5B inhibitor drug.

The present invention also provides a compound represented by Formula I, or a tautomer, a stereoisomer thereof, a mixture of stereoisomers, a prodrug, a pharmaceutically acceptable salt or a solvate thereof, and other therapeutic liver diseases. The combination of drugs. At least one treatment selected from the group consisting of interferon, interferon beta, interferon gamma, and interferon ω; interleukins, including interleukin 10 and interleukin 12; ribavirin; interferon alpha or pegylated interferon alpha Combination of ribavirin or levovirin; levovirin; protease inhibitors, including NS3 inhibitors, NS3/4A inhibitors; NS5A inhibitors; helicase inhibitors; polymerase inhibitors, including HCV RNA polymerase And NS5B polymerase inhibitor; colloidal toxin; IRES inhibitor; antisense oligonucleotide; thiazolidine derivative; n-benzidine, ribozyme; another nucleoside, nucleoside prodrug or nucleoside Derivatives; 1-amino-alkylcyclohexane; antioxidants, including vitamin E; squalene; amantadine; bile acid; N-(phosphonoacetyl)-L-aspartic acid; benzene dicarboxamide Polyadenylation; benzimidazole; thymosin; prophylactic vaccine; immunomodulator, an IMPDH inhibitor; silymarin; silymarin-phosphatidylcholine endosome; and mycophenolate mofetil.

"Pharmaceutically acceptable" means a compound, material, composition, and/or dosage form that, within the scope of sound medical judgment, is suitable for contact with a patient's tissue without undue toxicity, irritation, allergies, or reasonable The benefits/risk ratios are commensurate with other problems and complications and are effectively used for the intended use.

The terms "halogen" and "halo" are used interchangeably herein and refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "alkyl" or "alkyl group" as used herein, denotes a saturated straight or branched monovalent hydrocarbon group containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally selected The ground is replaced by one or more substituents described herein. In one embodiment, the alkyl group contains from 1 to 6 carbon atoms; in another embodiment, the alkyl group contains from 1 to 4 carbon atoms; and in one embodiment, the alkyl group contains 1 - 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH ₂ CH) (CH ₃ ) ₂ ), sec-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu, -C(CH ₃ ) ₃ ), and the like.

The "pharmaceutically acceptable salt" as used in the present invention means an organic salt and an inorganic salt of the compound of the present invention. Pharmaceutically acceptable salts are well known in the art and are described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, mineral acid salts formed by reaction with amino groups, hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or by other methods described in the literature, such as ion exchange These salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid Salt, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained by appropriate bases include the alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates quaternary ammonium salts formed from any of the compounds comprising a group of N. Water soluble or oil soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C ₁ -C ₈ sulfonate and aromatic sulfonate.

"Solvate" as used herein refers to an association of one or more solvent molecules with a compound of the invention. Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine or mixtures thereof. The term "hydrate" means that the solvent molecule is an association formed by water.

When the solvent is water, the term "hydrate" can be used. In one embodiment, a molecule of the compound of the invention may be combined with a water molecule, such as a monohydrate; in another embodiment, a molecule of the invention may be combined with more than one water molecule, such as dihydrate. In yet another embodiment, a molecule of the compound of the invention may be combined with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the bioavailability of the compounds in a non-hydrated form.

All suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are included within the scope of the invention unless otherwise stated.

In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are contemplated within the invention, and as disclosed herein are included in the present invention. . When stereochemistry is indicated by a solid wedge or dashed line indicating a particular configuration, then the stereoisomers of the structure are defined and defined herein.

The compound of formula I can exist in the form of a salt. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal treated therewith. In another embodiment, the salt is not necessarily a pharmaceutically acceptable salt, and may be an enantiomer for the preparation and/or purification of a compound of formula I and/or for isolation of a compound of formula I. Intermediates.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety by conventional chemical methods. In general, such salts can be obtained by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base such as a hydroxide, carbonate, bicarbonate, or the like of Na, Ca, Mg or K. The free base form of these compounds is prepared by reaction with a stoichiometric amount of a suitable acid. This type of reaction is usually carried out in water or an organic solvent or a mixture of the two. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. For example, "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and A list of additional suitable salts can be found in Use), Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Any structural formula given by the present invention is also intended to indicate that these compounds are not isotopically enriched and isotopically enriched. Isotopically enriched compounds have the structure depicted by the general formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O ¹⁸ O, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I.

In another aspect, the invention relates to intermediates for the preparation of compounds of formula I.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention. In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or a combination thereof. In another embodiment, the pharmaceutical composition can be in the form of a liquid, solid, semi-solid, gel or spray.

The compound of the present invention or a pharmaceutical composition thereof can be used for the treatment of hepatitis C, and has the advantages of high oral bioavailability and good metabolic properties, and has the functions of protecting liver tissue, liver cells, and improving liver function.

detailed description

For the purpose of describing the invention, the examples are set forth below. However, it is to be understood that the invention is not limited to the embodiments, but merely provides a method of practicing the invention.

In general, the compounds of the present invention can be prepared by the methods described herein, unless otherwise stated, wherein the substituents are as defined in Formula I. The following reaction schemes and examples are provided to further illustrate the contents of the present invention.

Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare a number of other compounds of the invention, and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention. Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by modifications by those skilled in the art, such as appropriate protection of the interfering group, by the use of other known reagents in addition to those described herein, or The reaction conditions are subject to some conventional modifications. Additionally, the reactions or known reaction conditions disclosed herein are also recognized to be suitable for the preparation of other compounds of the invention.

The examples described below, unless otherwise indicated, all temperatures are set to degrees Celsius. The reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents from Shantou Xiqiao Chemical Plant, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant purchased it.

Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by refluxing with sodium metal. Anhydrous dichloromethane and chloroform were obtained by reflux drying of calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were previously dried over anhydrous sodium sulfate.

The following reaction is generally carried out under a positive pressure of nitrogen or argon or on a dry solvent (unless otherwise indicated), the reaction bottle is stoppered with a suitable rubber stopper, and the substrate is driven through a syringe. The glassware is dry.

The column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

¹ H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz NMR spectrometer. ^{The 1} H NMR spectrum was determined by using CDC1 ₃ , DMSO-d ₆ , CD ₃ OD or acetone-d ₆ as a solvent (in ppm) using TMS (0 ppm) or chloroform (7.26 ppm) as a reference standard. When multiple peaks appear, the following abbreviations are used: s (singlet, single peak), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), br (broadened, wide) Peak), dd (doublet of doublets), dt (doublet of triplets). Coupling constant, expressed in Hertz (Hz).

The conditions for the determination of low resolution mass spectrometry (MS) data were: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 micron, 6 min, flow rate 0.6 mL/min. Mobile phase: 5 ratio of 95% (0.1% formic acid in CH ₃ CN) in (H containing 0.1% formic acid ₂ O) in using electrospray ionization (ESI), at 210nm / 254nm, with UV detection.

Pure compound using Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50/80mm DAC), UV detection at 210nm/254nm.

The following abbreviations are used throughout the invention:

Example 1: Synthesis of Compound II-A-1

Method A:

Step 1: 529 mg (1.0 mmol) of III-1 was dissolved in 10 mL of anhydrous acetone, and 680 mg (1.5 mmol) of IV-A-1 and potassium carbonate 414 mg (3.0 mmol) were added at room temperature, and the mixture was stirred under reflux for 6 h. complete. After filtration, the filtrate was diluted with methylene chloride (30 mL). The residue was purified by silica gel column chromatography to give 710mg white solid VA-1, yield 75%, ESI-MS: m / z [M + H] + = 947.

Step 2: Dissolve 200 mg (0.21 mmol) of VA-1 in 10 mL of anhydrous dichloromethane, and add 2 mL at room temperature (volume ratio: dichloromethane / triisopropylsilane / trifluoroacetic acid = 5 / 1 / 1) The solution was reacted for about 1 h, and the reaction was completed by TLC. EtOAc (EtOAc m. The residue was purified by silica gel column chromatography toieliel ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (t, J = 5.7 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.39 (t, J = 7.7 Hz, 2H), 7.30 –7.14(m,3H), 6.14–5.96(m,2H), 5.90 (d, J=4.9Hz, 1H), 5.84 (d, J=9.6Hz, 1H), 5.81 (d, J=9.6Hz, 1H), 5.74 (d, J = 8.2 Hz, 1H), 4.87 (dt, J = 12.4, 6.2 Hz, 1H), 4.47 - 4.34 (m, 1H), 4.29 - 4.20 (m, 1H), 4.08 - 4.01 (m, 1H), 3.94 - 3.76 (m, 4H), 3.57 - 3.46 (m, 1H), 2.82 (d, J = 8.3 Hz, 1H), 1.35 (d, J = 6.9 Hz, 3H), 1.27 ( t, J = 15.0 Hz, 6H), 1.16 (d, J = 6.2 Hz, 6H). ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 173.7, 173.1, 173.0, 169.2, 161.1, 151.2, 151.1, 150.6, 130.1 , 125.1, 120.6, 120.5, 101.9, 101.6, 99.8, 80.2, 72.1, 71.9, 68.5, 65.1, 64.9, 50.3, 41.0, 36.3, 22.4, 22.3, 21.9, 21.8, 20.3, 20.2, 17.2, 16.9. ³¹ P NMR (162 MHz, DMSO) δ 3.83 (s) ESI-MS: m/z [M+H] ⁺ = 705.

Method B:

Step 1: 5.0 g (9.5 mmol) of compound III-1 was dissolved in 25 mL of anhydrous N,N-dimethylformamide (DMF), and 1.6 g (23.5 mmol) of imidazole, 0.12 g (stepwise) was added under Ar protection. 1.0 mmol) 4-dimethylaminopyridine (DMAP) and 1.6 mL (9.5 mmol) of triethylchlorosilane (TESCl). The reaction was stirred at room temperature for about 10 hours, and the reaction was completed by TLC. Then, 7 mL of a 37% HCHO solution was added to the reaction system, and the mixture was heated to 80 ° C and stirred for 1 hour. After cooling to room temperature, 80 mL of ethyl acetate was added, and the mixture was washed with EtOAc. step.

Step 2: The product VII-1 freshly obtained in the previous step was dissolved in 40 mL of anhydrous dichloromethane (DCM), cooled in an ice bath under argon atmosphere, and then added 62 mg (0.5 mmol) of 4-dimethylaminopyridine (DMAP). And 2.36 g (12.3 mmol) of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HCl), and 6.1 g (11.4 mmol) of compound VIII-A-1, The temperature was slowly raised to room temperature and the reaction was stirred for about 12 hours, and the reaction was completed by TLC. After adding 100 ml of dichloromethane, the mixture was washed with aq. The crude product was recrystallized from methylene chloride-n-heptane to afford 8.5 g of y. ^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.57 (d, J = 8.1Hz, 1H), 7.35 (dd, J = 17.2,7.6Hz, 6H), 7.31-7.12 (m, 12H), 6.77 (d, J = 8.5 Hz, 2H), 6.17 (d, J = 18.4 Hz, 1H), 6.04 - 5.87 (m, 2H), 5.68 (d, J = 8.2 Hz, 1H), 5.00 (dt, J = 12.3, 6.2 Hz, 1H), 4.60 (dd, J = 11.4, 6.4 Hz, 1H), 4.35 (q, J = 6.9 Hz, 1H), 4.29 - 4.20 (m, 2H), 4.15 - 4.08 (m, 1H), 4.02 – 3.85 (m, 3H), 3.78 (s, 3H), 3.71 (t, J = 10.0 Hz, 1H), 1.39 - 1.32 (m, 6H), 1.35 (s, 9H), 1.27 (d, J = 11.9) Hz, 3H), 1.23 (d, J = 6.2 Hz, 6H), 0.92 (s, 9H), 0.15 (s, 6H). ESI-MS: m/z [M+H] ⁺ =1191.

Step 3: 7.5 g (6.3 mmol) of compound IX-A-1 was dissolved in 50% water-acetone (20 mL) mixed solution, 30 mL of glacial acetic acid (HOAc) and 6 mL of trifluoroacetic acid (TFA) were added, and the reaction was stirred at room temperature. After about 6 hours, no remaining raw materials were detected by TLC. The acetone and water were removed by vacuum distillation under reduced pressure, and then 60 mL of dichloromethane, 9 ml of trifluoroacetic acid (TFA), and 6.5 mL of triisopropylsilane ( ^i- Pr ₃ SiH) were successively added, and the reaction was continued at room temperature for about 15 minutes, TLC The reaction was checked to completion and the reaction was quenched by carefully aqueous saturated sodium bicarbonate. After adding 100 ml of dichloromethane, the mixture was washed with water and aq. Recrystallization from ethyl acetate-petroleum ether gave 3.9 g of white solid II-A-1. ¹ H NMR (400 MHz, DMSO) δ 8.43 (t, J = 5.7 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.39 (t, J = 7.7 Hz, 2H), 7.30 - 7.14 ( m, 3H), 6.14 - 5.96 (m, 2H), 5.90 (d, J = 4.9 Hz, 1H), 5.84 (d, J = 9.6 Hz, 1H), 5.81 (d, J = 9.6 Hz, 1H), 5.74 (d, J = 8.2 Hz, 1H), 4.87 (dt, J = 12.4, 6.2 Hz, 1H), 4.47 - 4.34 (m, 1H), 4.29 - 4.20 (m, 1H), 4.08 - 4.01 (m, 1H), 3.94–3.76 (m, 4H), 3.57–3.46 (m, 1H), 2.82 (d, J=8.3 Hz, 1H), 1.35 (d, J=6.9 Hz, 3H), 1.27 (t, J) =15.0 Hz, 6H), 1.16 (d, J = 6.2 Hz, 6H). ESI-MS: m/z [M+H] ⁺ = 705.

The recrystallization mother liquor was concentrated and the residue was purified by silica gel column chromatography using a small amount of white solid to give ^{II-A-9, 1 H} NMR (400MHz, CDCl 3) δ7.51 (d, J = 7.9Hz, 1H), 7.35 (t , J = 7.8 Hz, 2H), 7.20 (dd, J = 14.5, 7.5 Hz, 3H), 6.19 (brs, 1H), 6.07 (d, J = 9.4 Hz, 1H), 5.99 (d, J = 9.4 Hz) , 1H), 5.72 (d, J = 8.2 Hz, 1H), 5.00 (dt, J = 12.5, 6.2 Hz, 1H), 4.59 - 4.39 (m, 2H), 4.37 - 4.22 (m, 2H), 4.14 ( d, J=8.6 Hz, 1H), 3.99–3.85 (m, 3H), 3.65–3.58 (m, 1H), 1.48 (d, J=7.0 Hz, 1H), 1.42–1.36 (m, 3H), 1.38 - 1.26 (m, 6H), 1.24 (d, J = 6.2 Hz, 6H). ESI-MS: m/z [M+H] ⁺ = 705.

Example 2: Synthesis of Compound II-A-1a

Compound VII-1 (3 mmol of compound III-1 was used as a starting material) was prepared by the method of Step B of Example 1, and dissolved in 12 mL of anhydrous dichloromethane (DCM), and cooled in an ice bath under argon atmosphere. 18 mg (0.15 mmol) of 4-dimethylaminopyridine (DMAP) and 0.75 g (3.9 mmol) of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HCl) were added in sequence. And 1.93 g (3.6 mmol) of compound VIII-A-1a (prepared by chiral tiopronin, R configuration chiral purity 95%, analytical method: AD-H column temperature: 25 C; detection wavelength: 210 nm; flow rate : 1.0 ml/min; mobile phase: n-Hex: EtOH: TFA = 90: 10: 0.1 isocratic elution), then slowly warmed to room temperature and stirred for about 12 hours, and the reaction was complete by TLC. The mixture was washed with aq. The crude product was recrystallized from methylene chloride-n-heptane to yield 8.7 g of y.

2.1 g (1.76 mmol) of compound IX-A-1a was dissolved in a 50% water-acetone (5 mL) mixed solution, 8 mL of glacial acetic acid (HOAc) and 2 mL of trifluoroacetic acid (TFA) were added, and the reaction was stirred at room temperature for about 6 hours. The remaining raw materials were not detected by TLC. The acetone and water were evaporated under reduced pressure, and then 15 mL of dichloromethane, 3 ml of trifluoroacetic acid (TFA), and 2.2 mL of triisopropylsilane (i-Pr ₃ SiH) were successively added, and the reaction was continued at room temperature for about 15 minutes, TLC The reaction was checked to completion and the reaction was quenched by carefully aqueous saturated sodium bicarbonate. After adding 30 ml of dichloromethane, the mixture was washed with water and aq. Recrystallization from ethyl acetate-petroleum ether gave 1.7 g of white solid II-A-1a, yield 86%. ESI-MS: m/z [M+H] ⁺ = 705.

Example 3: Synthesis of Compound II-A-1b

According to the first step and the second step in the method B of Example 1, VIII-A-1b (prepared by chiral tiopronin, the chiral purity of the S configuration is 97%, analysis method: AD-H column temperature: 25C; detection Wavelength: 210 nm; flow rate: 1.0 ml/min; mobile phase: n-Hex: EtOH: TFA = 90: 10: 0.1 isocratic elution instead of VIII-A-1, 5.3 g (10 mmol) of compound III-1 2.57 g of intermediate IX-A-1b was obtained in a yield of 72% (two steps).

According to the third step in the method B of Example 1, the compound IX-A-1b (2.9 mmol) was further deprotected, and 1.04 g of a white solid product II-A-1b was obtained in a yield of 84%. ESI-MS: m/z [M+H] ⁺ = 705.

Example 4: Synthesis of Compound II-A-2

Method A:

Step 1: 529 mg (1.0 mmol) of III-1 was dissolved in 10 mL of anhydrous acetone, and 680 mg (1.5 mmol) of IV-A-2 and potassium carbonate 414 mg (3.0 mmol) were added at room temperature, and the mixture was stirred under reflux for 6 h. complete. After filtration, the filtrate was diluted with methylene chloride (30 mL). The residue was purified by silica gel column chromatography to afford 306 ESI-MS: m / z [ M + H] + = 961.

Step 2: 200 mg (0.21 mmol) of VA-2 was dissolved in 10 mL of anhydrous dichloromethane, and 2 mL (volume ratio: dichloromethane/triisopropylsilane/trifluoroacetic acid=5/1/1) was added at room temperature. The solution was reacted for about 1 h, and the reaction was completed by TLC. EtOAc (EtOAc m. The residue was purified by silica gel column chromatography eluting elut eluting ^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.64 (s, 1H), 7.50 (dd, J = 8.1,2.3Hz, 1H), 7.36 (t, J = 7.8Hz, 2H), 7.30-7.22 (m, 3H), 7.19 (d, J = 7.6 Hz, 1H), 6.65 (q, J = 6.5 Hz, 1H), 6.19 (d, J = 17.9 Hz, 1H), 5.10 - 4.94 (m, 1H), 4.52 ( Dd, J=11.4, 5.7 Hz, 1H), 4.39–4.21 (m, 3H), 4.22–4.05 (m, 2H), 3.98 (tt, J=11.5, 5.8 Hz, 1H), 3.57–3.45 (m, 1H), 2.17 (dd, J = 8.5, 2.2 Hz, 1H), 1.86 (d, J = 6.5 Hz, 3H), 1.56 (dd, J = 7.1, 1.0 Hz, 3H), 1.37 (dd, J = 14.8) , 7.5 Hz, 6H), 1.27 (s, 1H), 1.25 (d, J = 6.3 Hz, 6H). ESI-MS: m/z [M+H] ⁺ = 719.

Method B:

According to the first step and the second step of the method B of Example 1, acetaldehyde was used instead of formaldehyde, and 4.6 g of the intermediate IX-A-2 was obtained in 5.3 g (10 mmol) of the compound III-1 in a yield of 38% (two steps). ESI-MS: m/z [M+H] ⁺ =1205.

According to the third step of the method B of Example 1, the compound IX-A-2 (2.9 mmol) was further deprotected, and 1.7 g of a white solid product II-A-2 was obtained in a yield of 82%. ESI-MS: m / z [ M + H] + = 719.

Example 5: Synthesis of Compound II-A-3

According to the first step and the second step of the method of Example 1, the formaldehyde is replaced by propionaldehyde, and 2 g of the intermediate IX-A-3 can be prepared with 2.65 g (5 mmol) of the compound III-1 in a yield of 33% (two steps). ESI-MS: m/z [M+H] ⁺ =121.

According to the third step of the method B of Example 1, the compound IX-A-3 (0.8 mmol) was further deprotected, and 445 mg of the white solid product II-A-3 was obtained in a yield of 76%. ESI-MS: m/z [M+H] ⁺ = 733.

Example 6: Synthesis of Compound II-A-4

Step 1: 529 mg (1.0 mmol) of III-1 was dissolved in 10 mL of anhydrous acetone, and 690 mg of IV-A-3 and potassium carbonate 414 mg (3.0 mmol) were added at room temperature, and the mixture was stirred under reflux for 6 hours, and the reaction was completely confirmed by TLC. After filtration, the filtrate was diluted with methylene chloride (30 mL). The residue was purified by silica gel column chromatography eluting with EtOAc

Step 2: Dissolve 200 mg (0.21 mmol) of VA-4 in 10 mL of anhydrous dichloromethane, and add 2 mL at room temperature (volume ratio: dichloromethane / triisopropylsilane / trifluoroacetic acid = 5 / 1 / 1) The solution was reacted for about 1 h, and the reaction was completed by TLC. EtOAc (EtOAc m. The residue was purified by silica gel column chromatography toield ^{1 H NMR (400MHz, CDCl3)} δ9.62 (s, 1H), 7.46 (dd, J = 8.1,2.2Hz, 1H), 7.34 (t, J = 7.8Hz, 2H), 7.29-7.22 (m, 3H ), 7.19 (d, J = 7.4 Hz, 1H), 6.16 (d, J = 18.1 Hz, 1H), 5.64 - 5.53 (m, 1H), 5.37 - 5.17 (m, 1H), 5.08 - 4.93 (m, 1H), 4.53 (dd, J = 11.4, 5.5 Hz, 1H), 4.38-4.20 (m, 3H), 4.40-4.08 (m, 6H), 3.97 (tt, J = 11.7, 5.9 Hz, 1H), 3.57 -3.43 (m, 1H), 2.17 (dd, J = 8.4, 2.2 Hz, 1H), 1.55 (dd, J = 7.1, 1.0 Hz, 3H), 1.38 (dd, J = 14.8, 7.7 Hz, 6H), 1.27 (s, 1H), 1.24 (d, J = 6.3 Hz, 6H). ESI-MS: 749 (M+1).

Example 7: Synthesis of Compound II-A-5

Step 1: 529 mg (1.0 mmol) of III-1 was dissolved in 10 mL of anhydrous acetone, and 800 mg of IV-A-4 and potassium carbonate 414 mg (3.0 mmol) were added at room temperature, and the mixture was stirred under reflux for 12 h. After filtration, the filtrate was diluted with methylene chloride (30 mL). The residue was purified by silica gel column chromatography to yield 400 mg of V-A-5.

Step 2: Dissolve 200 mg (0.21 mmol) of VA-5 in 10 mL of anhydrous dichloromethane, and add 2 mL at room temperature (volume ratio: dichloromethane / triisopropylsilane / trifluoroacetic acid = 5 / 1 / 1) The solution was reacted for about 1 h, and the reaction was completed by TLC. EtOAc (EtOAc m. The residue was purified by silica gel column chromatography toield ^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.66 (s, 1H), 7.44 (dd, J = 7.9,2.1Hz, 1H), 7.32 (t, J = 7.8Hz, 2H), 7.28-7.20 (m, 3H), 7.16 (d, J = 7.5 Hz, 1H), 6.13 (d, J = 17.6 Hz, 1H), 5.15 - 5.03 (m, 1H), 4.60 (t, J = 7.5 Hz, 2H), 4.55 ( Dd, J = 11.5, 5.7 Hz, 1H), 4.48 - 4.25 (m, 3H), 4.23 - 4.09 (m, 2H), 3.95 (tt, J = 11.8, 5.8 Hz, 1H), 3.59 - 3.42 (m, 1H), 3.25 (t, J = 7.5 Hz, 2H), 2.16 (dd, J = 8.4, 2.2 Hz, 1H), 1.54 (dd, J = 7.1, 1.0 Hz, 3H), 1.39 (dd, J = 14.7) , 7.6 Hz, 6H), 1.28 (s, 1H), 1.25 (d, J = 6.5 Hz, 6H). ESI-MS: m/z [M+H] ⁺ = 719.

Example 8: Synthesis of Compound II-A-7

According to the first step and the second step of the method of the first embodiment, only the III-2 is substituted for the III-1, and the colorless oil IX-A-7 can be prepared with 1.1 g (2 mmol) of the compound III-2, the yield is 71%. (two steps). ESI-MS: m/z [M+H] ⁺ =1207.

According to the third step of the method B of Example 1, 0.79 g of the compound IX-A-7 (0.65 mmol) was further deprotected, and the white solid product II-A-7 was obtained in a yield of 83%. ESI-MS: m/z [M+H] ⁺ = 721.

Example 9: Synthesis of Compound II-A-8

According to the first step, the second step of the method B, VIII-A-2 is substituted for VIII-A-1, and 1.29 g of the intermediate IX-A-8 can be prepared by using 1.6 g (3 mmol) of the compound III-1. The rate is 65% (two steps). ESI-MS: m/z [M+H] ⁺ =1219.

According to the third step of the method B of Example 1, the compound IX-A-8 (0.8 mmol) was further deprotected, and 0.5 g of a white solid product II-A-8 was obtained in a yield of 83%. ESI-MS: m/z [M+H] ⁺ = 733.

Example 10: Synthesis of Compound II-B-1

According to the method B of Example 1, in the second step, VIII-B-1 (obtained from (DL)-N-acetylcysteine) is substituted for VIII-1, and 2.1 g (4 mmol) of compound III-1 can be prepared. 3.38 g of intermediate IX-B-1, yield 71% (two steps). ESI-MS: m/z [M+H] ⁺ =1191.

According to the third step of the method B of Example 1, the compound IX-B-1 (2 mmol) was further deprotected, and 1.17 g of the white solid product II-B-1 was obtained in a yield of 83%. ESI-MS: m/z [M+H] ⁺ = 705.

Example 11: Synthesis of Compound II-B-1a

According to the method B of Example 1, in the second step, VIII-B-1a (prepared by L-acetylcysteine, chiral purity >99%) is substituted for VIII-1, and 2.65 g (5 mmol) of compound III-1 is used. Intermediate IX-B-1a can be prepared in a yield of 67% (two steps). ESI-MS: m/z [M+H] ⁺ =1191.

According to the third step of the method B of Example 1, the compound IX-B-1a (2.1 mmol) was further deprotected, and 1.2 g of the white solid product II-B-1a was obtained in a yield of 85%. ESI-MS: m/z [M+H] ⁺ = 705.

Example 12: Synthesis of Compound II-B-1b

According to the method B of the first embodiment, in the second step, VIII-B-1b (prepared by D-cysteine, the chiral purity is 95%) is substituted for VIII-1, and 2.65 g (5 mmol) of compound III-1 can be prepared. 4.2 g of intermediate IX-B-1b was obtained in a yield of 70% (two steps). ESI-MS: m/z [M+H] ⁺ =1191.

According to the third step of the method B of Example 1, the compound IX-B-1b (2.1 mmol) was further deprotected, and 1.2 g of the white solid product II-B-1b was obtained in a yield of 81%. ESI-MS: m/z [M+H] ⁺ = 705.

Example 13: Synthesis of Compound II-B-2

According to the first step of the method B of Example 1, acetaldehyde is substituted for formaldehyde, and according to the second step of the method B of the first embodiment, the VIII-B-1a (prepared by L-acetylcysteine, chiral purity >99%) is replaced. VIII-1, whereby 1.3 g of intermediate IX-B-2 can be prepared in 1.6 g (3 mmol) of compound III-1 in a yield of 36% (two steps). ESI-MS: m/z [M+H] ⁺ =1205.

According to the third step of the method B of Example 1, the compound IX-B-2 (1 mmol) was further deprotected, and 0.57 g of a white solid product II-B-2 was obtained in a yield of 79%. ESI-MS: m/z [M+H] ⁺ = 719.

Example 14: Synthesis of Compound II-B-3

According to the first step, the second step of the method of the first embodiment, the VIII-B-2 (prepared by L-acetylcysteine, chiral purity >99%) is substituted for VIII-1, thereby giving 1.6 g (3 mmol) of the compound. Intermediate IX-B-3 can be prepared in III-1 in a yield of 76% (two steps). ESI-MS: m/z [M+H] ⁺ =1205.

According to the third step of the method B of Example 1, the compound IX-B-3 (1 mmol) was further deprotected, and 0.57 g of a white solid product II-B-3 was obtained in a yield of 82%. ESI-MS: m/z [M+H] ⁺ = 719.

Example 15: Synthesis of Compound II-B-4

According to the first step, the second step in the method B of the first embodiment, the III-1 is replaced by III-2, and the VIII-B-1a (prepared by L-acetylcysteine, the chiral purity is >99%) is substituted for VIII. -1, 2.64 g of Intermediate IX-B-4 can be obtained in 1.6 g (3 mmol) of compound III-2 in a yield of 72% (two steps). ESI-MS: m/z [M+H] ⁺ =1207.

According to the third step of Example 6, compound IX-B-4 (1.5 mmol) was further deprotected, and 0.93 g of white solid product II-B-4 was obtained in a yield of 84%. ESI-MS: m/z [M+H] ⁺ = 721.

Example 16: Synthesis of Compound III-2A-1

Method A:

Step 1: 529 mg (1.0 mmol) of III-1 was dissolved in 10 mL of anhydrous dichloromethane, and 405 mg (1.0 mmol) of XA-1 was added at room temperature (preparation method refers to Polymer Chemistry, 2011, 2, 906-913) cyclohexyl carbon two The imine 412 mg (2.0 mmol) and DMAP 12.2 mg (0.1 mmol) were stirred for 6 h, and the reaction was confirmed by TLC. The solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography to give white solid XI-A-1, a yield of 43%, LC-ESI-MS : [M + H] + 916, was used directly in the next reaction.

Step 2: Dissolve 183 mg (0.2 mmol) of XI-A-1 in 10 mL of anhydrous dichloromethane, and add 2 mL at room temperature (volume ratio: dichloromethane/triisopropylsilane/trifluoroacetic acid=5/1/ 1) The solution was reacted for about 1 h, and the reaction was completed by TLC. EtOAc (EtOAc m. The residue was purified by silica gel column chromatography to afford white crystals, ^{1 H NMR (400MHz, DMSO)} δ11.57 (s, 1H), 8.55 (d, J = 7.8Hz, 1H), 7.71 (d, J = 7.7Hz, 1H), 7.38 (t, J = 7.6Hz, 2H), 7.20 (dd, J = 18.6, 7.6 Hz, 3H), 6.18 - 5.88 (m, 2H), 5.63 (d, J = 7.8 Hz, 1H), 5.34 (s, 1H), 4.86 (dt, J =12.2, 6.0 Hz, 1H), 4.35–4.16 (m, 3H), 4.08–3.88 (m, 2H), 3.87–3.72 (m, 1H), 3.54 (dd, J = 12.9, 6.8 Hz, 1H), 2.86 (d, J = 6.9 Hz, 1H), 1.43 - 1.26 (m, 6H), 1.23 (d, J = 6.9 Hz, 3H), 1.16 (d, J = 6.1 Hz, 6H). LC-ESI-MS :[M+H] ⁺ 675.

Method B:

Step 1: 5.4 g (10 mmol) of compound III-1 was dissolved in 50 mL of anhydrous dichloromethane (DCM), cooled in an ice bath under Ar protection, and 61 mg (0.5 mmol) of 4-dimethylaminopyridine (DMAP) and 2.3 g (12 mmol) of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HCl), after stirring for 5 minutes, 4.5 g (8.5 mmol) of compound VIII-A-1 was added. The reaction was stirred for about 6 hours and the reaction was complete by TLC. After adding 50 ml of dichloromethane, the mixture was washed with EtOAc EtOAc. The residue was purified by silica gel column chromatography to afford 177 g of pale yellow oily of ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.66 (s, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.37 (s, 4H), 7.34 - 7.09 (m, 14H), 6.77 (d, J=8.4 Hz, 2H), 6.16 (d, J = 17.9 Hz, 1H), 5.51–5.38 (m, 1H), 5.21–5.05 (m, 1H), 5.05–4.90 (m, 1H), 4.52 (s) , 1H), 4.37–4.26 (m, 1H), 4.25–4.08 (m, 4H), 4.05–3.92 (m, 2H), 3.78 (s, 3H), 1.42 (t, J = 6.3 Hz, 3H), 1.35 (s, 9H), 1.37 - 1.23 (m, 6H), 1.20 (d, J = 5.9 Hz, 6H). ³¹ P NMR (162 MHz, CDCl ₃ ) δ 2.74 (d, J = 7.0 Hz).

Step 2: 4.7 g (4.5 mmol) of compound XII-A-1 was dissolved in 50 mL of dichloromethane, and 3.5 mL of trifluoroacetic acid (TFA) and 3.5 mL of triisopropylsilane ( ^i- Pr ₃ SiH) were added at room temperature. After the reaction for 15 minutes, 3.5 mL of trifluoroacetic acid (TFA) was further added, and the reaction was continued for about 10 to 20 minutes. The reaction was completely confirmed by TLC, and the reaction was cautiously added with a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was separated and dried over anhydrous sodium The residue was purified by silica gel column chromatography to give 2.5g white solid, yield 82%, LC-ESI-MS : [M + H] + 675.

Example 17: Synthesis of Compound III-2A-1a

According to the method of Example 16 Step B, Step 2, VIII-A-1a (prepared by chiral tiopronin, R configuration chiral purity 95%, analytical method: AD-H column temperature: 25C; detection wavelength : 210 nm; flow rate: 1.0 ml/min; mobile phase: n-Hex: EtOH: TFA = 90: 10: 0.1 isocratic elution instead of VIII-A-1, using 5.3 g (10 mmol) of compound III-1 as raw material The white solid product III-2A-1a was obtained in a yield of 78% (two steps). ESI-MS: m / z [ M + H] + = 675.

Example 18: Synthesis of Compound III-2A-1b

According to the first step and the second step of the method B of Example 16, VIII-A-1b (prepared by chiral tiopronin, the chiral purity of the S configuration is 97%, analytical method: AD-H column temperature: 25C; detection Wavelength: 210 nm; flow rate: 1.0 ml/min; mobile phase: n-Hex: EtOH: TFA = 90: 10: 0.1 isocratic elution instead of VIII-A-1, with 5.3 g (10 mmol) of compound III-1 Starting material, 5.0 g of a white solid product III-2A-1b was obtained in a yield of 75% (two steps). ESI-MS: m/z [M+H] ⁺ = 675.

Example 19: Synthesis of Compound III-2A-2

Step 1: Dissolve 529 mg (1.0 mmol) of III-1 in 5 mL of dimethyl sulfoxide, add 4 mL of acetic anhydride and 1.5 mL of acetic acid, stir at room temperature for 48 hours, carefully add saturated brine and ethyl acetate, and separate the organic phase. The extract was washed with aq. The solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography to give a pale yellow gum XIII-1, a yield of 25%, LC-ESI-MS : [M + H] + 590.

Step 2: 118 mg (0.2 mmol) of XIII-1 was dissolved in anhydrous dichloromethane, and 0.3 mL of dichloromethane (1 M) of thionyl chloride was added thereto under ice-cooling. The reaction mixture was slowly warmed to room temperature and stirred for 2 h. The solvent was concentrated under reduced pressure to give a yellow gum. The above-mentioned gum XIII-1 was dissolved in 1 mL of anhydrous tetrahydrofuran, and 93 mg (0.2 mmol) of IX-A-1 and potassium carbonate 55 mg (0.4 mmol) were added at room temperature, and stirred for 6 hours, and the reaction was completely confirmed by TLC. The solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography to obtain white solid IX-A-1, a yield of 45%, LC-ESI-MS : [M + H] + 946. Step 3: 36.6 mg (0.04 mmol) of IX-A-1 was dissolved in 1 mL of anhydrous dichloromethane, and 0.5 mL was added at room temperature (volume ratio: dichloromethane / triisopropylsilane / trifluoroacetic acid = 5 / 1/1) The solution was reacted for about 1 h, and the reaction was completed by TLC. EtOAc (EtOAc m. The residue was purified by silica gel column chromatography to afford white crystal ^{1 H NMR (400MHz, DMSO-} d6) δ11.56 (s, 1H), 8.53 (d, J = 7.8Hz, 1H), 7.70 (d, J = 7.5Hz, 1H), 7.28 (t, J = 7.5 Hz, 2H), 7.21 (dd, J = 18.0, 7.6 Hz, 3H), 6.15 - 5.71 (m, 2H), 5.61 (d, J = 7.8 Hz, 1H), 5.55 (d, J = 6.2 Hz, 1H) ), 5.49 (d, J = 6.2 Hz, 1H), 5.34 (s, 1H), 4.84 (dt, J = 12.0, 6.0 Hz, 1H), 4.31 - 4.14 (m, 3H), 4.11 - 3.85 (m, 2H), 3.85–3.73 (m, 1H), 3.54 (dd, J=12.0, 6.5 Hz, 1H), 2.84 (d, J=7.0 Hz, 1H), 1.45–1.23 (m, 6H), 1.21 (d) , J = 6.9 Hz, 3H), 1.19 (d, J = 6.1 Hz, 6H). LC-ESI-MS: [M+H] ⁺ 704.

Example 20: Synthesis of Compound III-2A-5

According to the method of Example 16 Step B, Step 2, VIII-A-2 is substituted for VIII-A-1, and 5.3 g (10 mmol) of compound III-1 is used as a raw material to prepare 4.9 g of white solid product III-2A- 5, yield 71% (two steps). ESI-MS: m/z [M+H] ⁺ = 702.

Example 21: Synthesis of Compound III-2A-6

According to the method of Example 16 Step B, Step 2, replacing III-1 with III-2, and preparing 5.4 g (10 mmol) of compound III-2 as raw material, 4.5 g of white solid product III-2A-6 can be prepared. 65% (two steps). ESI-MS: m/z [M+H] ⁺ = 691.

Example 22: Synthesis of Compound III-2B-1

Method A:

Step 1: 529 mg (1.0 mmol) of III-1 was dissolved in 10 mL of anhydrous dichloromethane, and 405 mg of XB-1 (1.0 mmol), cyclohexylcarbodiimide 412 mg (2.0 mmol) and DMAP 12.2 mg ( 0.1 mmol), stirred for 12 h, and the reaction was complete by TLC. The solvent was removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography to give white solid XI-B-1, LC- ESI-MS: [M + H] + 916, was used directly in the next reaction.

Step 2: Dissolve 183 mg (0.2 mmol) of XI-B-1 in 10 mL of anhydrous dichloromethane, and add 2 mL at room temperature (volume ratio: dichloromethane/triisopropylsilane/trifluoroacetic acid=5/1/ 1) The solution was reacted for about 1 h, and the reaction was completed by TLC. EtOAc (EtOAc m. The residue was purified by silica gel column chromatography to afford white crystals. ^{1 H NMR (400MHz, DMSO-} d6) δ11.60 (s, 1H), 8.61 (d, J = 7.5Hz, 1H), 7.69 (d, J = 8.0Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.22 (m, 3H), 6.19 - 5.90 (m, 2H), 5.69 (d, J = 7.8 Hz, 1H), 5.36 (s, 1H), 5.12 to 5.06 (m, 1H), 4.89 (dt, J = 12.2, 6.0 Hz, 1H), 4.37 - 4.15 (m, 3H), 4.18 - 3.98 (m, 2H), 3.57 (dd, J = 12.9, 6.8 Hz, 1H), 2.88 (d, J) = 6.9 Hz, 1H), 2.24 (s, 3H), 1.48 - 1.23 (m, 6H), 1.18 (d, J = 6.1 Hz, 6H). LC-ESI-MS: [M+H] ⁺ 675.

Method B:

According to the method of Step B and Step 2 of Example 16, VIII-A-1 was replaced by VIII-B-1, and 5.3 g (10 mmol) of compound III-1 was used as a raw material to prepare 5.7 g of white solid product III-2B- 1, the yield of 85% (two steps). ESI-MS: m / z [ M + H] + = 675.

Synthesis of Compound 23-2B-1a of Example 23

According to the method of Example 16 Step B, Step 2, VIII-B-1a (prepared by L-acetylcysteine, L configuration chiral purity 99%, analytical method: AD-H column temperature: 25C; Detection wavelength: 210 nm; flow rate: 1.0 ml/min; mobile phase: n-Hex: EtOH: TFA = 90: 10: 0.1 isocratic elution instead of VIII-A-1, 5.3 g (10 mmol) of compound III-1 As a raw material, 4.6 g of a white solid product III-2B-1a was obtained in a yield of 68% (two steps). ESI-MS: m/z [M+H] ⁺ = 675.

Synthesis of Example 14 Compound III-2B-1b

According to the method of Example 22, Step B, Step 2, VIII-B-1b (prepared by D-acetylcysteine, D configuration chiral purity 99%, analytical method: AD-H column temperature: 25C; Detection wavelength: 210 nm; flow rate: 1.0 ml/min; mobile phase: n-Hex: EtOH: TFA = 90: 10: 0.1 isocratic elution instead of VIII-A-1, 5.3 g (10 mmol) of compound III-1 As a raw material, 5.2 g of a white solid product II-A-1b was obtained in a yield of 77% (two steps). ESI-MS: m/z [M+H] ⁺ = 675.

Example 25: Synthesis of Compound III-2B-2

According to the first, second and third steps of Example 19, VIII-B-1a (prepared from L-acetylcysteine, L-form chiral purity 99%) was substituted for VIII-A-1 at 5.3 g (10 mmol). Compound III-1 was used as a starting material to obtain 3.6 g of a white solid product II-A-1b in a yield of 51%. ^{1 H NMR (400MHz, DMSO-} d6) δ11.59 (s, 1H), 8.60 (d, J = 7.6Hz, 1H), 7.68 (d, J = 7.6Hz, 1H), 7.37 (t, J = 7.5 Hz, 2H), 7.21 (m, 3H), 6.17 - 5.95 (m, 2H), 5.69 (d, J = 7.5 Hz, 1H), 5.65 (d, J = 6.2 Hz, 1H), 5.50 (d, J) = 6.2 Hz, 1H), 5.37 (s, 1H), 5.22 to 5.16 (m, 1H), 4.84 (dt, J = 12.2, 6.0 Hz, 1H), 4.35 - 4.17 (m, 3H), 4.18 - 3.90 ( m, 2H), 3.53 (m, 1H), 2.85 (d, J = 6.9 Hz, 1H), 2.21 (s, 3H), 1.44 - 1.22 (m, 6H), 1.16 (d, J = 6.1 Hz, 6H) LC-ESI-MS: [M+H] ⁺ 704.

Example 26: Synthesis of Compound II-2B-5

Substituting VIII-A-1 (prepared from L-acetylcysteine, L-form chiral purity 99%) in place of VIII-A-1, in the presence of III-2, according to steps 19, 2 and 3 of Example 19. Instead of III-1, 5.4 g (10 mmol) of compound III-2 was used as a starting material to obtain 4.2 g of a white solid product III-2B-5 in a yield of 58% (two steps). LC-ESI-MS: [M+H] ⁺ 721.

Example 27: Synthesis of Compound III-2C-1

Step 1: 529 mg (1.0 mmol) of III-1 was dissolved in 10 mL of anhydrous dichloromethane, and 452 mg (1.0 mmol) of XV-1 was added under ice bath (preparation method refers to Chemistry-A European Journal, 2014, 20, 6526- 6531) and DMAP 122 mg (1.0 mmol), stirred for 1 h, filtered, EtOAc EtOAc (EtOAc)EtOAc. The solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography toield ^{_{1 H NMR (400MHz, CDCl 3}} ) δ9.62 (s, 1H), 7.46 (dd, J = 8.1,2.2Hz, 1H), 7.30-7.35 (m, 3H), 7.29-7.22 (m, 3H), 7.19 (d, J = 7.4 Hz, 1H), 6.79 (s, 1H), 6.16 (d, J = 18.1 Hz, 1H), 6.06 (d, J = 8.3 Hz, 2H), 6.00 (s, 2H), 5.64–5.53 (m, 1H), 4.50-4.60 (m, 3H), 4.38–4.20 (m, 3H), 4.20–4.04 (m, 1H), 3.90-4.00 (m, 7H), 3.77 (s, 3H) ), 2.17 (dd, J = 8.4, 2.2 Hz, 1H), 1.46-1.55 (m, 3H), 1.38 (d, J = 7.7 Hz, 3H), 1.27 (s, 1H), 1.24 (d, J = 6.3 Hz, 6H), LC-ESI-MS: [M+H] ⁺ 946.

Example 28: Anti-hepatitis C virus activity (HCV, EC ₅₀ ) and cytotoxicity (CC ₅₀ )

Due to the lack of ideal HCV in vitro infected cells and animal models, in general, HCV viral activity evaluation uses an enzyme that plays a key role in HCV RNA replication to establish an extracellular molecular replication model.

Experimental method: Huh7 cells containing HCV-replicon (1b genotype) were cultured in DMEM medium containing 10% fetal calf serum, 1X non-essential amino acid, Pen-Strep-Glu, G418. Antiviral screening tests were performed in different media without G418. The cells were seeded in 96-well plates, and the test compounds were added immediately after inoculation of the cells, and incubated at 37 ° C in an incubator. The medium is then removed and the cells are used for whole nucleic acid extraction (including replicon RNA and host RNA). The replicon RNA can be amplified in the Q-RT-PCR protocol and quantified accordingly. The difference in the level of the observed replicon HCV RNA from the untreated control group was used as the manner of antiviral efficacy of the test compound, and the results are shown in Table 1.

Anti-hepatitis C virus activity (HCV, EC ₅₀ ) and cytotoxicity (CC ₅₀ ) results for the compounds of Table 1

化合物编号Compound number	EC₅₀(μM)EC ₅₀ (μM)	CC₅₀(μM)CC ₅₀ (μM)
SofosbuvirSofosbuvir	0.180.18	>50>50
硫普罗宁Thiopronin	>100>100	>50>50
II-A-1II-A-1	0.110.11	>50>50
II-A-1aII-A-1a	0.120.12	>50>50
II-A-1bII-A-1b	0.140.14	>50>50
II-A-2II-A-2	0.090.09	>50>50
II-A-4II-A-4	0.170.17	>50>50
II-A-5II-A-5	0.140.14	>50>50
II-A-8II-A-8	0.250.25	>50>50
II-B-1II-B-1	0.200.20	>50>50
II-B-1aII-B-1a	0.150.15	>50>50
II-B-2II-B-2	0.310.31	>50>50
II-B-4II-B-4	0.170.17	>50>50
III-2A-1III-2A-1	0.090.09	>50>50
III-2A-1aIII-2A-1a	0.130.13	>50>50
III-2A-1bIII-2A-1b	0.100.10	>50>50
III-2A-2III-2A-2	0.120.12	>50>50
III-2B-1III-2B-1	0.180.18	>50>50
III-2B-1aIII-2B-1a	0.150.15	>50>50
III-2B-2III-2B-2	0.160.16	>50>50
III-2C-1III-2C-1	0.130.13	>50>50

The results of the inhibitory activity of the compound of intracellular replicon 1b of HCV (EC ₅₀₎ was evaluated as an anti-hepatitis C virus activity, while cytotoxic activity (CC ₅₀₎ for excluding a synchronization test false positive results due to the cytotoxicity caused. The higher the therapeutic index, the more promising the representative compound is. The results indicate that the compounds provided by the present invention exhibit similar or superior activity and therapeutic index to Sofosbuvir, as II-A-1, II-A-1a, II-A-1b, II-A-2, III-2A. -1, III-2A-2, for example, inhibitory activity on intracellular HCV replicon (EC ₅₀₎ was stronger than that in the positive control Sofosbuvir, indicating that the compound may be rapidly Sofosbuvir as intracellular degradation in the liver cells The form that becomes an active metabolite exerts an anti-HCV effect. In addition, another sub-thiopronin obtained by degradation in the molecule has a certain gain effect on antiviral activity, and this synergistic effect enables the compound provided by the present invention to be resistant to HCV. The disease aspect has more application prospects.

Example 29: Study on the protective effect of mouse CCl ₄ liver damage model

Experimental Method: Male mice were taken before the experiment body weight of 24 ~ 28g, water, fasted 6 hours, were randomly divided into 3 groups, 5 mice per group, divided into blank control group, CCl ₄ group, compound group (thio general Ning 50mg/kg, test compound 200mg/kg). The drug was administered once every 12 hours, and the perfusion volume was 10 mL/kg, which was administered 4 times. The blank control group and the model control group were simultaneously administered with an equal volume of physiological saline. One hour after the third administration, the other two groups of mice were intraperitoneally injected with 50% CCl ₄ corn oil solution at 2 mg/kg bw of CCl ₄ except for the blank control group. After 12 hours, each group was administered once more. After 24 hours, the rats were bled and serum ALT and AST (Table 2) were measured. The liver was cut into small pieces, fixed in formaldehyde, paraffin-embedded, stained with hematoxylin and eosin, and the liver cells were observed under a microscope.

Table 2 Results of the protective effect of the CCl4 liver damage model of the compound of the present invention

组别Group	ALT(U/L)ALT (U/L)	AST(U/L)AST (U/L)
空白blank	58.258.2	125.4125.4
CCl₄对照组CCl ₄ control group	1423.21423.2	1214.31214.3
SofosbuvirSofosbuvir	1325.71325.7	1185.21185.2
硫普罗宁Thiopronin	689.3689.3	733.8733.8

II-A-1II-A-1	617.5617.5	690.2690.2
II-A-1aII-A-1a	596.3596.3	672672
II-A-1bII-A-1b	620.5620.5	701.5701.5
II-A-2II-A-2	560.7560.7	656.3656.3
II-A-4II-A-4	701.5701.5	677.8677.8
II-A-5II-A-5	596.2596.2	702.3702.3
II-B-1II-B-1	725.6725.6	833.1833.1
II-B-1aII-B-1a	699.1699.1	795.3795.3
III-2A-1aIII-2A-1a	663.5663.5	701.5701.5
III-2A-1bIII-2A-1b	682.3682.3	679.2679.2
III-2B-1aIII-2B-1a	710.3710.3	695.8695.8
III-2C-1III-2C-1	505.2505.2	609.3609.3

The results showed that ALT and AST were abnormally elevated in the CCl ₄ model group, and tiopronin significantly reversed the effect of this enzyme. In comparison, Sofosbuvir did not have this activity. However, the compounds provided by the present invention have a significant enzyme-lowering effect, and the activity is comparable to or superior to that of tiopronin. The reason may be that the thiopronin's carboxyl group is made into a prodrug, which improves its stability and its ability to be absorbed orally, thereby enhancing its activity. Taking II-A-1, II-Aa, II-A-2, II-A-5, and III-2A-1a as examples, the CCl4-induced liver injury leads to an increase in ALT and AST, and has significant inhibitory activity. And superior to the positive control tiopronin. In addition, liver histopathology observation result, CCl ₄ model group, the central hepatic venous congestion, around lobular central or peripheral necrosis, liver cell swelling, ballooning deformation, II-A-1, II -Aa, II -A-2, II-A-5, III-2A-1a and other administration groups showed a small amount of punctate and fragmented necrosis, most of which showed balloon-like deformation, indicating that the toxicity caused by CCl ₄ has been greatly reduced, indicating the present invention The compounds involved do have a protective effect on liver damage caused by CCl ₄ .

Due to the lack of an ideal animal model of HCV infection, it is not feasible to directly evaluate the protective effect of the compounds provided by the present invention on HCV-induced liver injury, but in theory and clinical application, the compound provided by the present invention has the function of protecting liver and protecting liver It also has a protective effect on the inflammatory response caused by HCV.

Example 30: Study on pharmacokinetic properties

1 experimental material

1.1 compound

The compounds of the present invention prepared using the above examples II-A-1, II-A-1a, II-A-1b, II-A-2, II-B-1, III-2A-1, III-2A- 1a (30mg/kg, the molar mass of the nucleoside moiety is consistent with the Sophie group), the positive control drug is Sophibuvir (25mg/kg), and each compound is added to 5% DMSO + 60% PEG400 + 35% physiological Saline was prepared by vortexing to a 10 mg/ml suspension for intragastric administration.

GS331007 was purchased from Shunyuan Technology (Shanghai) Co., Ltd.

1.2 Experimental animals and sampling

SD rats were used as experimental animals (body weight 180-220 g), and 6 SD rats per test compound were randomly divided into 2 groups (gavage group and intravenous injection group), 3 in each group. The time of blood collection from the tail vein of the intragastric administration was 0.17, 0.33, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 hours; the time of blood collection by intravenous administration was 0.05, 0.1, 0.17, 0.5. 1,2,4,6,8,12,24 hours. 0.3 ml of whole blood was taken, and 0.1 ml of plasma was taken after centrifugation and analyzed by LC-MS.

1.3 instruments

Agilent 1200 LC System, API4000QTRAP Triple Quadrupole Mass Spectrometer

1.4 sample processing

30 μl of liver homogenate sample or standard curve sample was added to 100 μl of acetonitrile containing internal standard (100 ng/ml), vortexed for 2 min, centrifuged for 10 min (6000 rpm), and the supernatant was transferred to a sample vial;

5 μL of the supernatant was taken, injected, and the concentration of GS331007 in the sample was measured by LC-MS/MS. Based on the obtained liver homogenate drug concentration-time data, the pharmacokinetic parameters of the metabolite GS331007 of each test compound were calculated using the pharmacokinetic calculation software WinNonlin 6.2.1 non-compartmental model. The results are shown in Table 3.

Table 3 Summary of main pharmacokinetic parameters of SD rats after oral administration

According to the literature, its metabolic pathway in vivo is shown in the figure below, in which GS331007 is the final metabolite and is a marker for studying the metabolic behavior of Sofosbuvir in vivo. The blood concentration and metabolic behavior of GS331007 in rats II-A-1, II-A-1a, II-A-1b, II-A-2, II-B-1 and III-2A-1a were investigated. In order to investigate the pharmacokinetic properties of the test compound, the results showed that the blood concentration of GS331007 and the area under the curve of the test compound were significantly improved compared with the blood concentration of GS331007 in the sofosbuvir group. Oral bioavailability improved significantly. Taking the compounds II-A-1, II-A-2, and II-B-1 as examples, the oral bioavailability was 3.38, 2.75, and 2.25 times of Soofibvir, respectively. In addition, the half-lives of II-A-1 and II-A-2 reached 6.14 and 6.23 hours, respectively, which were 2.95 and 2.51 times that of Sophibuvir, respectively, and the drug-time curve was more moderate. Therefore, the compounds of the present invention are superior in pharmacokinetic properties and can be administered by oral absorption for the treatment of hepatitis C diseases.

Example 31: In vitro PK properties study

Test compound III-2A-1 (1 mg/mL) was tested for stability in human simulated gastric juice, simulated intestinal fluid, human plasma, and human liver microsomes. The results showed that III-2A-1 has high stability in simulated gastric fluid (1 hour metabolic rate <5%), III-2A-1 in simulated intestinal fluid (5 minutes metabolic rate is greater than 90%), plasma (5 minutes metabolism) Both rates are greater than 99%) and liver microsomes (more than 99% in 5 minutes) can rapidly degrade and release sofosbuvir and tiopronin. This result demonstrates that the test compound can be rapidly metabolized by the intestine, plasma, and liver by oral administration, and the prototype drug is released. Compared to the similar compound II-A-1 (CN201510932904.2) derivatized with the sofosbuvir pyrimidine nitrogen atom, it is more stable in simulated gastric fluid, but mimics metabolism in intestinal fluid, plasma and liver microsomes. The conversion rate is faster. Considering that the absorption of the drug mainly occurs in the small intestine, it is derived from the nucleoside hydroxyl group of Sophibruvir compared to the pyrimidine nitrogen atom derivative of Sophibruvir (CN201510932904.2), and the resulting compound III-2A- The PK properties of 1 and its analogues in vitro are more favorable for its in vivo transformation and absorption, and it is expected to be more effective as a bifunctional prodrug molecule for anti-hepatitis C "speculation and treatment".

Example 32: Chemical stability study of test compounds

The test compound III-2A-1 test (100 mg) was taken and placed in a stable container of 40 ± 2 ° C and 75 ± 5% to carry out an accelerated stability test. A one-month experiment showed that the degradation rate of III-2 was <1% (new impurity content), and similar compound II-A-1 was derivatized with the pyrimidine nitrogen atom of Sofibvir previously found (CN201510932904.2). Compared with its chemical stability, it has obvious advantages (the degradation rate of II-A-1 is 4.5% under the same conditions). Therefore, compared with a similar compound derivatized with the pyrimidine nitrogen atom of Sophibruvir, the chemical stability of the obtained compound is higher by derivatization from the nucleoside hydroxyl group of Sophibuvir, which facilitates its further development into a dual function. Anti-HC candidate drugs.

The above are only the preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalents, and improvements made within the spirit and scope of the present invention are included in the scope of the present invention. Inside.

Claims

A compound having the structure of Formula I, or a tautomer, an optical isomer, a stereoisomer, a mixture of stereoisomers, a prodrug, a pharmaceutically acceptable salt of the structure of Formula I. Or solvate:

In formula I, X is hydroxy, F, Cl or Br;

R, R' are independent of H, or
And at least one of R and R' is
Where Linker may or may not be present, and D is derived from a drug or derivative thereof for use in the treatment or adjuvant treatment of liver disease.
The compound according to claim 1, which has a structure represented by Formula I-1, or a tautomer, an optical isomer, a stereoisomer, a mixture of stereoisomers of the structure represented by Formula I-1, Prodrug, pharmaceutically acceptable salt or solvate:

Wherein X is a hydroxyl group or F, Cl, Br;

R is

Linker A is
Or absent, G is derived from a drug or a derivative thereof for treating or assisting in the treatment of liver disease;

R 1 is H or C 1 -C 5 alkyl; n is an integer from 1 to 19.
The compound according to claim 2, which has the structure of the formula II-1A or a tautomer, an optical isomer, a stereoisomer, a mixture of stereoisomers, a prodrug, and a pharmaceutically acceptable compound. Salt or solvate:

Wherein X is a hydroxyl group or F, Cl, Br;

Linker A is
Or does not exist;

R 1 is H or C 1 -C 5 alkyl; n is 1, 2, 3 , 4 or 5; and R 3 and R 4 are each independently a hydrogen atom or a C 1 -C 5 alkyl group.
The compound according to claim 3, which has the structure represented by Formula II-1Aa or Formula II-1Ab or a tautomer, optical isomer, stereoisomer, stereoisomer mixture, prodrug thereof a pharmaceutically acceptable salt or solvate:

Wherein X is a hydroxyl group or F, Cl, Br;

Linker A is
Or does not exist;

R 1 is H or C 1 -C 5 alkyl; n is 1, 2, 3 , 4 or 5; and R 3 and R 4 are each independently a hydrogen atom or a C 1 -C 5 alkyl group.
The compound according to claim 2, which has the structure of the formula II-1B or a tautomer, an optical isomer, a stereoisomer, a mixture of stereoisomers, a prodrug, and a pharmaceutically acceptable compound. Salt or solvate:

Wherein X is a hydroxyl group or F, Cl, Br;

Linker A is
Or does not exist;

R 1 is H or C 1 -C 5 alkyl; n is 1, 2, 3 , 4 or 5; and R 3 and R 4 are each independently a hydrogen atom or a C 1 -C 5 alkyl group.
The compound according to claim 5, which has the structure represented by Formula II-1Ba or Formula II-1Bb or an optical isomer, pharmaceutically acceptable salt or solvate thereof:

Wherein X is a hydroxyl group or F, Cl, Br;

Linker A is
Or does not exist;

R 1 is H or C 1 -C 5 alkyl; n is 1, 2, 3 , 4 or 5; and R 3 and R 4 are each independently a hydrogen atom or a C 1 -C 5 alkyl group.
The compound according to claim 2, which is a prodrug of a tiopronin structure represented by the formula II-1A-A or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt or solvate thereof Object:

Wherein X is a hydroxyl group or F, Cl, Br;

Linker A is

R 1 is H or C 1 -C 5 alkyl; n is an integer from 1 to 19.
a compound according to claim 7 which is a prostaglandin containing prodrug of formula II-1A-Aa, formula II-1A-Ab, formula II-1A-Ac, formula II-1A-Ad or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt or solvate thereof:

Wherein X is a hydroxyl group or F, Cl, Br; R 1 is H or a C 1 -C 5 alkyl group; and n is 1, 2, 3, 4 or 5.
The compound according to claim 8, which is a profenofin-containing prodrug represented by the formula II-1A-Aa1, the formula II-1A-Ab1, the formula II-1A-Ac1, and the formula II-1A-Ad1, respectively. Or a tautomer, a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt or solvate thereof:

Wherein, R 1 is H or C 1 -C 5 alkyl group; n is 3, 4 or 5.
The compound according to claim 3, which has the structure shown below or a tautomer, a stereoisomer, a mixture of stereoisomers, a pharmaceutically acceptable salt or a solvate of the structural compound shown below. :
A method for preparing a compound of the formula II-1A, the steps are:

1) a compound of formula III is reacted with a compound of formula IV-1A to give a compound of formula V-1A;

2) a compound of the formula V-1A is subjected to a deprotection reaction to give a compound of the formula II-1A;

Wherein X is a hydroxyl group or F, Cl, Br;

Linker A is
Or does not exist;

n is 1, 2, 3, 4 or 5; R 1 is H or C 1 -C 5 alkyl; R 3 and R 4 are each independently a hydrogen atom or a C 1 -C 5 alkyl group; LG is a leaving group. Group; Z is a thiol protecting group.
A method for preparing a compound of the formula II-1B, the steps are:

1) a compound of formula III is reacted with a compound of formula IV-1B to give a compound of formula V-1B;

2) a compound represented by the formula V-1B is subjected to a deprotection reaction to obtain a compound represented by the formula II-1B;

Wherein X is a hydroxyl group or F, Cl, Br;

Linker A is
Or does not exist;

n is 1, 2, 3, 4 or 5; R 1 is H or C 1 -C 5 alkyl; R 3 and R 4 are each independently a hydrogen atom or a C 1 -C 5 alkyl group; LG is a leaving group. Group; Z is a thiol protecting group.
A process for the preparation of a compound of the formula II-1A-Aa, wherein a compound of the formula IIIm and a compound of the formula IV-1 are subjected to an alkylation reaction to obtain a compound of the formula V-1A, which is then subjected to deprotection. The reaction is obtained:

Wherein X is a hydroxyl group or F, Cl or Br; R 1 is H or a C 1 -C 5 alkyl group; Y is a leaving group; and Z is a thiol protecting group.
A process for the preparation of a compound of the formula II-1A-Ab, wherein a compound of the formula IIIm and a compound of the formula IV-1B are subjected to an alkylation reaction to obtain a compound of the formula V-1B, which is then subjected to deprotection. The reaction is obtained:

Wherein X is hydroxy or F, Cl, Br; R 1 is H or C 1 -C 5 alkyl; n is 1, 2, 3, 4 or 5; Y is a leaving group; Z is a thiol protecting group .
A method for preparing a compound of the formula II-1A-B, the steps are:

1) a compound of formula III is subjected to a protective reaction and then reacted with an aldehyde to give a compound of formula VII-1;

2) a compound of the formula VII-1 is reacted with a compound of VIII-1A to give a compound of the formula IX-1A-B;

3) a compound of formula IX-1A-B is deprotected to give a compound of formula II-1A-B;

Wherein X is a hydroxyl group or F, Cl, Br; R 1 is H or a C 1 -C 5 alkyl group; R 3 and R 4 are each independently a hydrogen atom or a C 1 -C 5 alkyl group; and P 1 is a hydroxy group. a group; P 2 is an amide NH protecting group; and P 3 is a thiol protecting group.
A method for preparing a compound of the formula II-1B-B, the steps are:

1) a compound of the formula VII-1 is reacted with a compound represented by VIII-1B to give a compound of the formula IX-1B-B;

2) a compound of formula IX-1B-B is deprotected to give a compound of formula II-1B-B;

Wherein X is a hydroxyl group or F, Cl, Br; R 1 is H or a C 1 -C 5 alkyl group; R 3 and R 4 are each independently a hydrogen atom or a C 1 -C 5 alkyl group; and P 1 is a hydroxy group. a group; P 2 is an amide NH protecting group; and P 3 is a thiol protecting group.
A compound having the structure of formula VII-1 or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof:

Wherein X is a hydroxyl group or F, Cl, Br; R 1 is H or a C 1 -C 5 alkyl group; and P 1 is a hydroxy protecting group.
A compound having the structure of Formula VIII-1A or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof:

Wherein P 2 is an NH protecting group; and P 3 is a fluorenyl protecting group.
A compound having the structure of the formula IX-1A-B or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof:

Wherein X is a hydroxyl group or F, Cl, Br; R 1 is H or a C 1 -C 5 alkyl group; P 1 is a hydroxy protecting group; P 2 is an NH protecting group; and P 3 is a thiol protecting group.
A compound having the structure of Formula VIII-1B or a stereoisomer thereof, a mixture of stereoisomers thereof or a pharmaceutically acceptable salt thereof:

Wherein: R 3 and R 4 are each independently a hydrogen atom or a C 1 -C 5 alkyl group; P 2 is an amide NH protecting group; and P 3 is a fluorenyl protecting group.
A compound having the structure of the formula IX-1B-B or a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable salt thereof:

Wherein X is a hydroxyl group or F, Cl, Br; R 1 is H or a C 1 -C 5 alkyl group; R 3 and R 4 are each independently a hydrogen atom or a C 1 -C 5 alkyl group; and P 1 is a hydroxy group. a group; P 2 is an amide NH protecting group; and P 3 is a thiol protecting group.
A compound having a structure of the formula I-2, or a prodrug of a structural compound represented by the formula I-2, or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt or solvate thereof:

Wherein X is a hydroxyl group, F, Cl or Br;

R' is
Where Linker B may or may not be present, and G is a drug or a derivative thereof for treating or assisting in the treatment of liver diseases.
The compound according to claim 21, which has a structure represented by formula II-2, or a tautomer, an optical isomer, a stereoisomer, a mixture of stereoisomers, or a structure of the formula Prodrug, pharmaceutically acceptable salt or solvate:

Wherein X is a hydroxyl group, F, Cl or Br;

R' is
Where Linker B is

Or absent, G is derived from a drug or a derivative thereof for use in the treatment or adjuvant treatment of liver disease; R 1 , R 2 is H or a C 1 -C 5 alkyl group.
A compound according to claim 23 having the structure of formula III-2A, or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt or solvate thereof:

Wherein X is a hydroxyl group, F, Br or Cl;

Linker B is
Or absent; R 1 , R 2 are each H or a C 1 -C 5 alkyl group; and R 3 , R 4 are a hydrogen atom or a C 1 -C 5 hydrocarbon group.
The compound according to claim 24, having the structure of the formula III-2Aa or the formula III-2Ab, or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt or solvate thereof:

Wherein X is a hydroxyl group, F, Br or Cl;

Linker B is
Or absent; R 1 , R 2 are each H or a C 1 -C 5 alkyl group; and R 3 , R 4 are a hydrogen atom or a C 1 -C 5 hydrocarbon group.
A compound according to claim 23 having the structure of formula III-2B, or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt or solvate thereof:

Wherein X is a hydroxyl group, F, Br or Cl;

Linker B is
Or absent; R 1 , R 2 are each H or a C 1 -C 5 alkyl group; and R 3 , R 4 are a hydrogen atom or a C 1 -C 5 hydrocarbon group.
The compound according to claim 26, having the structure of the formula III-2Ba or the formula III-2Bb, or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt or solvate thereof:

Wherein X is a hydroxyl group, F, Br or Cl;

Linker B is
Or absent; R 1 , R 2 are each H or a C1-C5 alkyl group; and R 3 , R 4 are a hydrogen atom or a C1-C5 hydrocarbon group.
A compound according to claim 23 having the structure of the formula III-2C, or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt or solvate thereof:

Wherein X is F or Cl;

Linker B is
R 3 and R 4 are a C1-C5 hydrocarbon group.
The compound according to claim 22, which has the structure shown below, or a stereoisomer thereof, a mixture of stereoisomers or a pharmaceutically acceptable salt or solvate thereof:
A pharmaceutical composition comprising one or more of the compounds of any one of claims 1-10, 22-29.
The pharmaceutical composition according to claim 30, wherein the structure represented by the formula (I) or a tautomer, an optical isomer, a stereoisomer, a mixture of stereoisomers, a prodrug, and a pharmaceutically acceptable compound are shown. The acceptable salt or solvate is used in an amount of from 1 to 1000 mg/day.
Use of a compound according to any one of claims 1 to 10, 22-29 or a composition according to claim 30 for the preparation of a medicament for the treatment of hepatitis C.
The use according to claim 32, wherein the compound or composition is further used in combination with other drugs for treating liver diseases.
The use according to claim 31, wherein the drug in combination is: interferon, interferon beta, interferon gamma, and interferon ω; interleukin, including interleukin 10 and interleukin 12; ribavirin; Interferon alpha or pegylated interferon alpha in combination with ribavirin or levovirin; levovirin; protease inhibitors, including NS3 inhibitors, NS3/4A inhibitors; NS5A inhibitors; helicase inhibition Polymerase inhibitors, including HCV RNA polymerase and NS5B polymerase inhibitor; colloidal toxin; IRES inhibitor; antisense oligonucleotide; thiazolidine derivative; n-benzidine, ribozyme; a nucleoside, a nucleoside prodrug or a nucleoside derivative; 1-amino-alkylcyclohexane; an antioxidant, including vitamin E; squalene; amantadine; bile acid; N-(phosphonoacetyl) -L-aspartic acid; phenyl dicarboxamide; polyadenylation; benzimidazole; thymosin; prophylactic vaccine; immunomodulator, an IMPDH inhibitor; silymarin; silymarin-phosphatidylcholine endosome; Mycophenolate mofetil.