CN112592343B

CN112592343B - Polycyclic compound and application thereof as antiviral drug

Info

Publication number: CN112592343B
Application number: CN201910946024.9A
Authority: CN
Inventors: 周雨恬; 刘建波
Original assignee: Individual
Current assignee: Individual
Priority date: 2019-10-01
Filing date: 2019-10-01
Publication date: 2023-05-16
Anticipated expiration: 2039-10-01
Also published as: CN112592343A

Abstract

The invention relates to a polycyclic compound and application thereof as an antiviral drug, in particular to a compound shown in a formula (I) or pharmaceutically acceptable salts, solvates, geometric isomers, stereoisomers, tautomers and any mixture thereof.

Description

Polycyclic compound and application thereof as antiviral drug

Technical Field

The invention belongs to the field of medicinal chemistry, and in particular relates to a novel polycyclic compound or stereoisomer thereof, a pharmaceutical composition containing the novel polycyclic compound or stereoisomer thereof and application of the novel polycyclic compound or stereoisomer thereof as an antiviral drug, particularly application of the novel polycyclic compound or stereoisomer thereof as a drug of a hepatitis B surface antigen inhibitor (HBV Surface antigen inhibitors) and a hepatitis B DNA inhibitor (HBV DNA production inhibitors) for treating and/or preventing infection of hepatitis B virus, and particularly application of the novel polycyclic compound, the stereoisomer thereof and the nucleoside drug as a pharmaceutical composition for curing hepatitis B.

Background

Persistent infection with HBV is one of the current serious global health problems and is also the most common cause of chronic liver disease. Currently, about 3.5 hundred million people with chronic HBV infection worldwide, and nearly 100 ten thousand people die of chronic liver diseases related to HBV infection every year. China is a high-incidence area of hepatitis B, and viral hepatitis, cirrhosis, liver cancer and the like caused by HBV continuous infection seriously endanger the life health of people in China: approximately 10% of the population are HBV carriers, and more than 3000 tens of thousands of patients with hepatitis B are present, with about 30 tens of thousands dying of hepatitis B and its associated complications each year. Therefore, the search for an effective treatment of hepatitis b has become a major topic to be solved in the current medical community.

The hepatitis B virus HBV is a hepadnavirus, which is a cyclic DNA virus with envelope and partial double chain. The long strand of viral DNA is the negative strand and the short strand is the positive strand. The HBV genome is compact and exquisite, about 3.2kb in size. The viral particle consists of a lipid envelope around which the viral core has been embedded with surface proteins (HBsAg). The core consists of a protein shell or capsid constructed with 120 core protein (Cp) dimers, which in turn contain the relaxed circular DNA (rcDNA) viral genome, as well as viral and host proteins. Within the infected cell, the genome is found as covalently closed circular DNA (cccDNA) within the nucleus of the host cell. The cccDNA is a template for viral RNA and thus viral proteins. In the cytoplasm, cp assembles around the complex of full length viral RNA (so-called pregenomic RNA or pgRNA) and viral polymerase (P). After assembly, P reverse transcribes the pgRNA to rcDNA within the capsid to generate a DNA-filled viral core.

One of the classical markers of chronic hepatitis B is the high level of hepatitis B virus (HBsAg) in the serum of the patient, which may reach 400. Mu.g/mL (0.4% of total serum protein). The antigenemia caused by the production of subviral particles is thought to play an important role in suppressing HBV-specific immune responses. In addition, recent reports have indicated that HBsAg acts directly on dendritic cells to limit cytokine production and adaptive immunity. The reduction of antigenicity caused by the use of experimental Krafft-dine (clevudine) results in a partial recovery of the virus-specific immune response. Thus, inhibitors of HBsAg secretion would potentially enable therapeutic use of HBV vaccines, or combination therapy with nucleoside (nucleotide) drugs for the treatment of HBV infection.

There are 7 drugs approved at present for controlling HBV persistent infection, which are interferon- α, pegylated interferon- α, lamivudine, entecavir, telbivudine, adefovir dipivoxil and tenofovir dipivoxil, respectively, but the efficacy of antiviral treatment approaches to date is not satisfactory: the sustained response rate of high doses of recombinant interferon is only about 30%, and nucleoside analogues such as lamivudine have strong antiviral activity, but the rapid rebound of viral replication levels and the emergence of drug-resistant strains after drug withdrawal make the implementation of clinical antiviral regimens very challenging. The new medicine design aiming at curing hepatitis B has the mechanism requirement of the new design compound as same as that of interferon, and the immune system of the human body needs to be re-activated, and the infected liver cells are identified and cleared by the immune system of the human body, so that the hepatitis B is thoroughly cured. Hepatitis B surface antigen and other virus antigens secreted by liver cells of chronic hepatitis B patients interfere with the immune system through a signal transduction system, blocking the recognition of viruses by immune cells and further limiting the antiviral function of the immune cells. In addition, persistent and excessive hepatitis B surface antigen can inactivate the immune system, T-cell depletion and functional impairment. Hepatitis B surface antigen can also directly suppress the clearance function of immune cells to viruses. Based on the reasons, the development of the medicine for inhibiting the secretion of hepatitis B surface antigen can effectively restore the function of immune cells, lighten the pressure of an immune system, lead the immune system to identify and clear infected liver cells and achieve the aim of directly curing hepatitis B.

In addition, hepatitis B surface antigen reduction is also a biological index for improving chronic hepatitis B, and hepatitis B surface antigen elimination and serum conversion indicate that hepatitis B is cured functionally. At present, the nucleoside medicine can not reduce the hepatitis B surface antigen, and a new action mechanism medicine must be designed to be combined with the powerful nucleoside medicine, and simultaneously, the viral DNA in the hepatitis B surface antigen and blood is effectively removed, and the autoimmune function is activated and recovered, so that the hepatitis B can be cured finally.

Finding new high-efficiency, specific and low-toxicity anti-HBV treatment schemes is always a constantly pursuing goal. WO/2015/113990 and WO/2016/107832 report a class of HBsAg inhibitors useful in the treatment and prevention of hepatitis B virus infection. Paper J Med chem.2011,54 (16): 5660-5670 reports a novel triazole-pyrimidine derivative as a novel HBsAg secretion inhibitor. While those agents have contributed significantly in this area, there remains a continuing need in this area to search for improved medicaments.

Disclosure of Invention

The present invention provides compounds of formula (I) or pharmaceutically acceptable salts, solvates, geometric isomers, stereoisomers, tautomers, and any mixtures thereof:

Wherein:

(1)W ¹ selected from oxygen, sulfur;

(2) Z is selected from N and CR ⁷ ；

(3)W ² Selected from (a) COOR ⁸ ；(b)-CONHR ⁸ ；(c)-CONH0R ⁸ ；(d)-NHNHR ⁸ ；(e)-NHNHC(＝0)R ⁸ ； (f)-NHS(＝0) ₂ R ⁸ ；

(g) A 4-8 membered heteroaromatic ring which is unsubstituted or substituted by a member selected from halogen, OH, mercapto, nitroOne or more substituents selected from amino, cyano and the like; (h) NHCOR ⁹ Wherein R is ⁹ Is amino; an amine group which is unsubstituted or substituted with one or more substituents selected from halogen, OH, mercapto, nitro, amino, carboxyl, cyano; (i) C (=o) N (R) ¹⁰ )SO ₂ R ¹¹ Wherein R is ¹⁰ Selected from hydrogen, methyl or cyclopropane, R ¹¹ An amino group selected from a hydrocarbon group of 1 to 6 carbon atoms which is unsubstituted or substituted by halogen, an amino group which is unsubstituted or substituted by one or more substituents selected from halogen, OH, mercapto, nitro, amino, carboxyl and cyano; boric acid; phosphoric acid and nitrogen-containing heterocycles;

(4) a bond is selected from single bond or double bond, wherein

(i) a bond is a single bond, Y is selected from O, S, S (=O) ₂ ,NR ³ And CHR (CHR) ³

(ii) a bond is a double bond, then Y is CR ³ And R is ^2b Absence of;

(5)R ^1a ，R ^1b ，R ^2a and R is ^2b Each independently selected from the group consisting of hydrogen, hydrocarbon and hydrocarbyloxy substituents, heteroaryl and substituted cycloalkyl of 3-8 carbon atoms; or R is ^1a /R ^1b ，R ^2a /R ^2b And R is ^1a /R ^2a Formed by combination of alkanediyl radicals having 1 to 6 carbon atoms, - (CH) ₂ ) _m O(CH ₂ ) _m -,-(CH ₂ ) _m NR ⁵ (CH ₂ ) _m -,-(CH ₂ ) _m S(CH ₂ ) _m -,-(CH ₂ ) _m S(＝0)(CH ₂ ) _m - (CH) ₂ ) _m S(＝0) ₂ (CH ₂ ) _m -, wherein m is independently selected from 1 or 2, and wherein each divalent group is optionally substituted with at least one C ₁ -C ₆ Alkyl or halogen substitution;

(6)X ¹ selected from CR ^4I Or N;

X ² selected from CR ^4II Or N;

X ³ selected from CR ^4III Or N;

X ⁴ selected from CR ^4IV Or N;

X ⁵ selected from C;

X ⁴ and X ⁵ Combining to form-N-, while CR ^4II And CR (CR) ^4III Are combined to form a substituted aromatic ring, wherein the aromatic ring has 0 to 4 substituent groups R ¹² ；

X ³ And X ⁴ Or X ¹ And X ² Combining to form-S-, -O-;

R ^4I ，R ^4II ，R ^4III and R is ^4IV Independently selected from the group consisting of one or more structural units including H, halogen, cyano, substituted C1-6 alkyl (e.g., C ₁ -C ₆ Hydroxyalkyl, alkoxy-C ₁ -C ₆ Alkyl and C ₁ -C ₆ Haloalkyl), substituted cycloalkyl of 3-8 carbons, substituted alkynyl of 2-6 carbons, -OR, -SR, -N (R) (R), substituted heterocyclyl and haloalkoxy of 1-6 carbons (e.g., without limitation OCF) ₂ H,OCH ₂ CF ₂ H)；

Wherein R is independently selected from H, C ₁ -C ₆ Alkyl, R' substituted C ₁ -C ₆ Alkyl, C ₁ -C ₆ Hydroxyalkyl, substituted (C) ₁ -C ₆ Alkoxy) - (C ₁ -C ₆ Alkyl), and substituted C ₃ -C ₈ Cycloalkyl;

wherein R' is selected from the group consisting of-NH ₂ ，-NH(C ₁ -C ₆ Alkyl group), -N (C ₁ -C ₆ Alkyl) (C) ₁ -C ₆ Alkyl), -NHC (c=0) 0 ^t Bu， -N(C ₁ -C ₆ Alkyl) C (=0) O ^t Bu or a 5 or 6 membered heterocyclyl, optionally N-linked;

or X ² Is CR (CR) ^4II ，X ³ Is CR (CR) ^4III And R is ^4II And R is ^4III Combine to form a divalent group selected from the group consisting of-0 (CR ⁵ R ⁶ ) 0-，-0(CR ⁵ R ⁶ )(CR ⁵ R ⁶ )0-，-0(CR ⁵ R ⁶ )(CR ⁵ R ⁶ ) -and-0 (CR) ⁵ R ⁶ )(CR ⁵ R ⁶ )(CR ⁵ R ⁶ ) -; or X ³ Is CR (CR) ^4III ，X ⁴ Is CR (CR) ^4IV ，R ^4III And R is ^4IV Combine to form a divalent group selected from the group consisting of-0 (CR ⁵ R ⁶ )0-， -0(CR ⁵ R ⁶ )(CR ⁵ R ⁶ )0-，-0(CR ⁵ R ⁶ )(CR ⁵ R ⁶ ) -and-0 (CR) ⁵ R ⁶ )(CR ⁵ R ⁶ )(CR ⁵ R ⁶ )-；

(7)R ³ May be independently selected from H, substituted C ₁ -C ₆ Alkyl and substituted C ₃ -C ₈ Cycloalkyl;

(8)R ⁵ selected from H and C ₁ -C ₆ An alkyl group;

(9)R ⁶ selected from H, OH, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy, alkoxy-C ₁ -C ₆ Alkyl and alkoxy-C ₁ -C ₆ Alkoxy, wherein two R' s ⁶ The groups bound to the same carbon atom are not simultaneously OH; wherein R is ⁶ If bonded to a carbon further bonded to an oxygen atom, it is not OH.

Or two R ⁶ The groups combine with the carbon atom to which they are bound to form a group selected from c=0, c=ch ₂ And oxetan-3, 3-diyl moieties;

(10)R ⁷ selected from H, OH, halogen, substituted C ₁ -C ₆ Alkoxy, substituted C ₁ -C ₆ Alkyl and substituted C ₃ -C ₈ Cycloalkyl or heterocycloalkyl.

(11)R ⁸ Selected from hydrogen, hydrocarbon and hydrocarbyloxy substituents;

(12)R ⁹ selected from hydrogen, halogen, OH, mercapto, nitro, amino, carboxyl or cyano, or R ⁹ Selected from hydrocarbon and hydrocarbon oxygen substituents;

(13)R ¹⁰ selected from hydrogen, methyl or cyclopropane;

(14)R ¹¹ selected from unsubstituted or halogen-substituted hydrocarbon radicals of 1-6 carbon atoms, amino radicals, unsubstituted or halogen-substituted hydrocarbon radicalsAn amine group substituted by one or more substituents selected from OH, mercapto, nitro, amino, carboxyl, and cyano;

(15)R ¹² selected from H, halogen, OH, mercapto, nitro, amino, carboxyl or cyano; or R is ¹² Selected from hydrocarbon and hydrocarbon oxygen substituents;

(16) The hydrocarbon and hydrocarbyloxy substituents include saturated or unsaturated hydrocarbon groups or hydrocarbyloxy groups of 1-20 carbon atoms, which are unsubstituted or substituted with one or more substituents selected from halogen, OH, mercapto, nitro, amino, carboxyl, cyano, and which are uninterrupted or interrupted with one or more substituents selected from O, S, NH, c=o, c=s, o=s=o.

In the general formula (I), all hydrogen atoms except the active hydrogen may be substituted with one or more deuterium atoms, respectively and independently.

In certain embodiments, such compounds are represented by the formula:

/>

in which W is ² ,R ^1a ,R ^1b ,R ^2a ,R ^2b ,R ^4I ,R ^4II ,R ^4III ,R ^4IV ,R ⁷ R is as follows ¹² Is defined as before.

According to a particular aspect of the invention, R ^1a Is H, R ^1b Selected from methyl, ethyl, isopropyl, butyl, isobutyl, tert-butyl, methoxymethyl, methoxyethyl, methoxyisopropyl, methoxybutyl, methoxyisobutyl, ethoxymethyl, ethoxyethyl, ethoxyisopropyl, ethoxybutyl, ethoxyisobutyl, hydroxymethyl, hydroxyethyl, hydroxyisopropyl, hydroxybutyl, hydroxyisobutyl, hydroxytert-butyl, aryl or heteroaryl; r is R ^1a Is methyl, R ^1b Is isopropyl; r is R ^1a Is methyl, R ^1b Is tert-butyl; r is R ^1a Is methyl, R ^1b Is methyl; r is R ^1a Is methyl, R ^1b Is ethyl; r is R ^1a Is ethyl, R ^1b Is ethyl.

The compounds of the invention may contain one or more asymmetric carbon atoms. Accordingly, the compound may exist as a diastereomer, enantiomer, or mixture thereof. Each asymmetric carbon atom may be in the R configuration or the S configuration, and both configurations are within the scope of the invention.

Modified compounds including any of these compounds that have improved (e.g., enhanced, greater) pharmaceutical solubility, stability, bioavailability, and/or modification of the therapeutic index by the unmodified compound are also contemplated. Exemplary modifications include, but are not limited to, applicable prodrug derivatives, and deuterium-enriched compounds.

It will be appreciated that the compounds of the present invention may exist in the form of salts or solvates and are optionally administered in such form. The present invention encompasses any pharmaceutically acceptable salts and solvates of any of the above-mentioned compounds and modifications thereof.

Compositions containing one or more of the compounds, modifications and/or salts and solvates thereof for the treatment of diseases, therapeutic uses thereof, and the use of the compounds in the manufacture of a medicament for the treatment of such diseases/conditions are also within the scope of the invention.

The compounds of the present invention can inhibit secretion of HBsAg and inhibit HBV gene expression. Accordingly, the compounds of the present invention are useful for the treatment or prevention of HBV infection.

The present invention relates to the use of a compound of formula (I) for inhibiting the production or secretion of HBsAg.

The present invention relates to the use of compounds of formula (I) for inhibiting HBV DNA production.

The present invention relates to the use of compounds of formula (I) for inhibiting HBV gene expression.

The present invention relates to the use of a compound of formula (I) for the treatment or prophylaxis of HBV infection.

The use of compounds of formula (I) in the preparation of a medicament useful for the treatment or prophylaxis of diseases associated with HBV infection is an object of the present invention.

In particular, the invention relates to the use of a compound of formula (I) for the preparation of a medical article for the treatment or prophylaxis of HBV infection.

The present invention also relates to methods of treating or preventing HBV infection by administering to a subject in need thereof an effective amount of one or more of the compounds, modifications, and/or salts thereof, and combinations thereof.

A pharmaceutical composition characterized by: a dosage form comprising a compound of general formula (I), a stereoisomer, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof, as claimed in any one of claims 1 to 5, and a pharmaceutically acceptable carrier or excipient, the dosage form of the pharmaceutical composition preferably being a tablet, capsule or injection.

The pharmaceutical composition is an antiviral pharmaceutical composition, which further comprises one or more therapeutic agents; the therapeutic agent is selected from the group consisting of: nucleoside agents, interferon, ribavirin, HBV capsid inhibitors (capsid inhibitors), cccDNA formation inhibitors, cccDNA epigenetic modifiers or hepatitis b RNAi agents, TLR7 agonists.

The polycyclic compound is applied to preparing medicaments for preventing and/or treating viral infection diseases, and/or medicaments for inhibiting hepatitis B surface antigen (HBV Surface antigen inhibitors) and hepatitis B DNA (HBV DNA production inhibitors).

The viral infection includes infection with HBV or HDV.

The medicine also contains one or more therapeutic agents selected from nucleoside medicines, interferon, ribavirin, HBV capsid inhibitor, cccDNA formation inhibitor, cccDNA epigenetic modifier or hepatitis B RNAi medicine, and TLR7 agonist.

The details of one or more embodiments of the invention are set forth in the accompanying drawings. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. It is to be understood that all of the specific embodiments/features of the invention (compounds, pharmaceutical compositions, methods of making/using, etc.) disclosed herein, including any specific features disclosed in the embodiments and the original claims, may be combined with each other unless inapplicable or explicitly disclaimed.

Exemplary compounds disclosed herein include, but are not limited to, the following:

/>

/>

/>

/>

/>

/>

/>

/>

/>

/>

/>

the invention also provides a pharmaceutical composition which contains the polycyclic compound shown in the formula (I), the stereoisomer, the pharmaceutically acceptable salt, the solvate or the crystal thereof and a pharmaceutically acceptable carrier or excipient.

Preferably, the pharmaceutical composition is an antiviral pharmaceutical composition further comprising one or more therapeutic agents selected from the group consisting of: nucleoside agents, ribavirin, interferon, HBV capsid inhibitors (capsidinhibitor), cccDNA formation inhibitors, cccDNA epigenetic modifiers or hepatitis b RNAi agents, TLR7 agonists.

The invention also relates to the use of the polycyclic compound shown in the formula (I), the stereoisomer, the pharmaceutically acceptable salt, the solvate or the crystal or the combination of the polycyclic compound and one or more therapeutic agents selected from nucleoside drugs, ribavirin, interferon, HBV capsid inhibitor (cccDNA formation inhibitor), cccDNA epigenetic modifier or hepatitis B RNAi drug and TLR7 agonist in preparing a drug for preventing and/or treating viral infection diseases, and/or hepatitis B surface antigen inhibitor (HBV Surface antigen inhibitors) and hepatitis B DNA inhibitor (HBV DNA productioninhibitors), wherein the viral infection comprises HBV or HDV infection.

The invention also provides application of the pharmaceutical composition in preparing medicines for treating or preventing hepatitis B and hepatitis B virus infection, and a method for preventing or slowing down diseases of patients suffering from hepatitis B and hepatitis B virus infection by adopting the pharmaceutical composition.

The pharmaceutical composition according to the invention, wherein the compound according to the invention is preferably present in a therapeutically effective amount.

Pharmaceutically acceptable carriers in the above pharmaceutical compositions, such as pharmaceutically acceptable diluents, excipients, fillers, binders, disintegrants, absorption enhancers, surfactants, lubricants, fragrances, sweeteners, and the like.

The medicine prepared by taking the compound of the invention as an active ingredient can be in various forms such as tablets, powder, capsules, granules, oral liquid, injection and the like. The dosage form of the pharmaceutical composition is preferably a tablet, capsule or injection.

The medicaments of the various formulations can be prepared according to the conventional method in the pharmaceutical field.

The invention also provides the use of a compound of the invention in the preparation of a medicament for the prevention or treatment of a viral infection disease, preferably wherein the viral infection disease is HBV viral infection.

The medicine composition of the invention can be composed of the following components in proportion:

due to the implementation of the technical scheme, compared with the prior art, the invention has the following advantages:

The invention provides novel polycyclic compounds which have extremely strong activity of inhibiting hepatitis B DNA and EC ₅₀ Can be less than 5 nanomolar, and has potent inhibitory activity against hepatitis B surface antigen, EC ₅₀ About 5 nanomoles. In addition, the compounds have excellent pharmacokinetic properties.

Further, the compound of the invention can block the path of P450 oxidation, improve the bioavailability of the compound and reduce the toxicity of the compound. The high-activity compounds can be combined with nucleoside compounds and TLR7 agonists to clinically and obviously improve the treatment effect and cure rate of hepatitis B.

The compounds of the invention may contain one or more asymmetric carbon atoms. Accordingly, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. The compounds may be synthesized using racemates, diastereomers or enantiomers as starting materials or as intermediates. Diastereoisomeric compounds may be separated by chromatographic methods or crystallization methods. Likewise, the enantiomeric mixtures may be separated using the same techniques or other techniques known in the art.

Each asymmetric carbon atom may be in the R configuration or in the S configuration, both of which are within the scope of the present invention.

Definition of terms

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The term "stereoisomer" refers to an isomer produced by the spatial arrangement of atoms in a molecule. Including cis-trans isomers, enantiomers and conformational isomers. All stereoisomers are within the scope of the invention. The compounds of the invention may be individual stereoisomers or mixtures of other isomers, such as racemates, or mixtures of all other stereoisomers.

The term "salt" refers to a pharmaceutically acceptable salt of a compound of the invention with an acid, which may be an organic or inorganic acid, and may be specifically selected from: phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid or the like.

The term "solvate" refers to a form of a compound of the invention that forms a complex, either solid or liquid, by coordination to a solvent molecule. Hydrates are a special form of solvates in which coordination occurs with water. Within the scope of the present invention, the solvate is preferably a hydrate.

The term "crystalline" refers to various solid forms, including crystalline forms, amorphous forms, formed from the compounds described herein.

The term "hydrocarbyl" refers to a linear, branched, or cyclic saturated or unsaturated substituent consisting essentially of carbon and hydrogen. Preferably 1 to 20 carbon atoms, more preferably 1 to 12 carbon atoms. The term "alkyl" refers to a straight, branched or cyclic saturated hydrocarbon group. The alkyl group specifically includes methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, n-hexyl, isohexyl, 2, -methylbutyl and 2, 3-dimethylbutyl, 16-alkyl, 18-alkyl. The term "C1-20 alkyl" refers to a straight, branched or cyclic saturated hydrocarbon group containing 1 to 20 carbon atoms. Alkyl groups include substituted and unsubstituted alkyl groups. When alkyl is substituted, the substituent may be substituted at any available point of attachment, and the substituent may be mono-or poly-substituted. Substituents are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, deuterium, halogen, thiol, hydroxy, nitro, carboxyl, ester, cyano, cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, oxo, the substituents usually being placed before the alkyl group when named, e.g., C1-3 alkoxy C3-8 cycloalkyl C1-6 alkyl refers to C1-6 alkyl which is substituted with C3-8 cycloalkyl, which C3-8 cycloalkyl is in turn substituted with C1-3 alkoxy, e.g.: the structural formula of the methoxycyclobutylmethyl is as follows:

The terms "alkenyl" and "alkynyl" refer to straight, branched or cyclic unsaturated hydrocarbon groups containing double and triple bonds, respectively, preferably from 2 to 20 carbon atoms, more preferably from 2 to 12 carbon atoms. Alkenyl, alkynyl include substituted and unsubstituted alkenyl, alkynyl. When substituted, the substituents may be substituted at any available point of attachment, and the substituents may be mono-or poly-substituted. Substituents are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, deuterium, halogen, thiol, hydroxy, nitro, carboxy, ester, cyano, cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, oxo, the substituents typically precede alkenyl, alkynyl when named.

The term "cycloalkyl" refers to saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon groups. The monocyclic ring may comprise 3 to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, and the like. Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl includes unsubstituted and substituted. The substituents are selected from one or more substituents including, but not limited to, groups independently selected from alkyl, cycloalkyl, alkoxy, halogen, carboxyl, ester, amino, amide, hydroxy, cyano, nitro, aryl, heteroaryl.

The term "aryl" refers to 6-10 membered all-carbon monocyclic or polycyclic aromatic groups including phenyl, naphthyl, biphenyl and the like. Aryl groups may be substituted and unsubstituted. Substituents are independently selected from alkyl, cycloalkyl (cyclopropane, cyclobutane, cyclopentane, etc.), alkenyl, alkynyl, azide, amino, deuterium, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, alkylsilyl, etc.

The term "heteroaryl" refers to groups of a heteroaromatic system containing 1 to 10 heteroatoms. Heteroatoms include oxygen, sulfur, nitrogen, phosphorus, and the like. Wherein the mono-heterocyclic group includes, but is not limited to, furan, thiophene, pyrrole, thiazole, imidazole, 1,2, 3-triazole, 1,2, 4-triazole, 1,2, 3-thiadiazole, oxazole, 1,2, 4-oxadiazole, 1,3, 4-oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, tetrahydrofuran, tetrahydropyrrole, piperidine, piperazine, morpholine, isoxazoline, and the like. Fused heterocyclic groups include, but are not limited to, quinoline, isoquinoline, indole, benzofuran, benzothiophene, purine, acridine, carbazole, fluorene, chromene, fluorenone, quinoxaline, 3, 4-dihydronaphthalenone, dibenzofuran, hydrogenated dibenzofuran, benzoxazolyl, and the like. Heteroaryl groups may be substituted and unsubstituted. The substituents are independently selected from substituents independently selected from alkyl, cycloalkyl (cyclopropane, cyclobutane, cyclopentane, etc.), alkenyl, alkynyl, azide, amino, deuterium, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, alkylsilyl, etc.

The term "halogen" refers to fluorine, chlorine, bromine, iodine, preferably fluorine, chlorine, bromine.

The term "deuterium" is an isotope of hydrogen, having an atomic mass 2 times that of the latter, and more strongly bound to carbon. Deuterated "and" deuterium "mean that hydrogen is replaced with deuterium at the indicated position. One "deuterated substituent" is a substituent in which at least one hydrogen is replaced with deuterium enriched at the indicated percentages.

The term "haloalkyl" refers to an alkyl group substituted with at least one halogen atom.

The term "heterocyclyl" refers to a cyclic group containing at least one heteroatom, wherein the heteroatom is nitrogen, oxygen, sulfur, and the like. Heterocyclyl groups include mono-and multi-heterocyclyl groups.

The invention further provides methods of preventing or treating HBV infection. In a specific embodiment, the invention relates to a method of treating HBV infection in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the invention. In a specific embodiment, the invention further provides the use of a compound of the invention in the manufacture of a medicament for retarding or alleviating HBV infection.

It is to be understood that the invention is not limited to the specific embodiments shown and described herein, and that various changes and modifications may be made without departing from the spirit and scope of the invention as defined by the following claims.

The compounds according to the invention can be synthesized according to a variety of reaction schemes. The necessary starting materials can be obtained by standard organic chemistry procedures. The compounds and processes of the present invention may be better understood in connection with the following representative synthetic equations and examples, which are provided by way of illustration only and are not intended to limit the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and may be made without departing from the spirit of the invention and the scope of the appended claims.

Detailed Description

Example 1

Synthesis of Compound II-4a

Preparation of Compound a-3

Magnesium turnings (245 mg,10 mmol) were added to 5 mL of anhydrous tetrahydrofuran, 5mg of iodine was added, heated to 70 ℃ and stirred for 30 minutes, a solution of a-1 (3.4 g,10 mmol) in tetrahydrofuran (10 mL) was slowly added dropwise, after the dropwise addition was completed, the reaction solution was stirred at 70 ℃ for two hours and cooled to room temperature for use.

Compound a-2 (1.7 g,10 mmol) was dissolved in 10ml of tetrahydrofuran and cooled to zero, the previously prepared formative reagent was added dropwise with stirring, the reaction solution was stirred at zero for 1 hour, and 10ml of saturated ammonium chloride solution was added dropwise to quench the reaction. Extraction twice with ethyl acetate (35 ml X2), drying the combined organic phases over anhydrous sodium sulfate, filtration, rotary evaporation to remove solvent, and purification of the residue by silica gel column chromatography (hexane/ethyl acetate 15:1 to 2:1) afforded compound a-3 (260 mg, 60%). LCMS (ESI) M/z ([ M+1) ] ⁺ )432.2。

Preparation of Compound a-4

To compound a-3 (4.32 g,10 mmol) and palladium on carbon (10%, 540 mg) was added 35 ml of methanol and hydrogenated at 50psi for 24 hours. The reaction mixture was filtered through celite and rinsed twice with methanol (25 ml X2), the solvent was removed by rotary evaporation and the residue was purified by column chromatography on silica gel (hexane/ethyl acetate 15:1 to 1:1) to give compound a-4 (2.04 g, 72%). LCMS (ESI) M/z ([ M+1)] ⁺ )284.2。

Preparation of Compound a-6

To compound a-4 (2.83 g,10 mmol) was added 2N hydrochloric acid (20.0 mL) and cooled to zero, 2N sodium nitrite solution (12 mL, 12 mmol) was slowly added dropwise, after 1 hour, an aqueous solution of a-5 (1.28 g,10 mmol) was added (15 mL) and stirred at room temperature for 3 hours. Extraction twice with ethyl acetate (40 ml X2), drying the combined organic phases over anhydrous sodium sulfate, filtration, rotary evaporation to remove the solvent, and purification of the residue by column chromatography on silica gel (hexane/ethyl acetate 15:1 to 4:1) gives compound a-6 (2.45 g, 66%). LCMS (ESI) M/z ([ M+1)] ⁺ ) 373.2。

Preparation of Compound a-8

Compound a-6 (3.73 g,10 mmol) was dissolved in methanol (30 ml) and added dropwise2N sodium hydroxide solution (15 ml, 30 mmol) was stirred at room temperature for 15 hours. The mixture was extracted twice with diethyl ether (15 mL X2), the pH of the aqueous phase was adjusted to 5 with 1N hydrochloric acid, extracted twice with ethyl acetate (40 mL X2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to give compound a-7 (3.44 g, 96%). Polyphosphoric acid (15 g) was added and heated to 70 degrees and stirred for 5 hours, after cooling, diluted with 100 ml ice water, extracted twice with ethyl acetate (35 ml X2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 15:1 to 4:1) to give compound a-8 (2.65 g, 78%). LCMS (ESI) M/z ([ M+1) ] ⁺ )341.2。

Preparation of Compound a-9

To a solution of a-8 (680 mg,2.0 mmol) in dichloromethane (4 mL) was added benzylamine (215 mg,2.0 mmol) and cooled to zero degrees. To the mixture was slowly added dropwise a 1M titanium tetrachloride solution (2.0 mL,2.0 mmol), gradually warmed to room temperature, stirred for 16 hours, filtered, and the solvent was distilled off under reduced pressure. A-10 (696 mg,4.0 mmol) and diphenyl ether (4 mL) were added, heated to 160 degrees, stirred for 4 hours, and cooled to room temperature. 30 ml of ethyl acetate was added to dilute, and the organic phase was washed three times with water (3X 10 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (dichloromethane/methanol 50:1 to 20:1) to give compound a-11 (238 mg, 22%). LCMS (ESI) M/z ([ M+1)] ⁺ )540.2。

Preparation of Compound II-4a

Compound a-11 (270 mg, 0.5 mmol) was dissolved in 4ml dichloromethane and cooled to-78 ℃. To the solution was added dropwise a 1.0M solution of boron trichloride in dichloromethane (1.0 ml, 1.0 mmol), and the mixture was stirred at-78 ℃ for 2 hours. The reaction was quenched by the addition of sodium bicarbonate (170 mg,2.0 mmol), gradually warmed to room temperature, diluted with dichloromethane, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The crude product obtained was dissolved in tetrahydrofuran/water (1:1, 4 ml), 1M lithium chloride solution (1 ml, 1 mmol) was added dropwise, reacted at room temperature for 6 hours, adjusted to PH 5 with 1N hydrochloric acid, and quenched with dichloro Methane was extracted three times (20 ml X3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, the solvent was removed by rotary evaporation, and the residue was purified by column chromatography on silica gel (dichloromethane/methanol 50:1 to 10:1) to give compound II-4a (174 mg, 80%). LCMS (ESI) M/z ([ M+1)] ⁺ )436.2。

The 20 mg enantiomer mixture was separated by HPLC with chiral column (ChiralPack AD) to give enantiomer 1 (3.5 mg) and enantiomer 2 (5.4 mg). The two compounds were both LCMS (ESI) M/z ([ M+1)] ⁺ )436.2。

Example 2

Synthesis of Compound II-3a

Preparation of Compounds a-12

To compound a-11 (135 mg, 0.25 mmol), pd (PPh ₃ ) ₂ Cl ₂ To (17.5 mg, 0.025 mmol), cuprous iodide (4.75 mg, 0.025 mmol), triethylamine (34. Mu.l, 0.25 mmol) and trimethylsilylacetylene (30 mg, 0.3 mmol) were added ethyl acetate (1 ml), reacted at 70℃for 24 hours, filtered, and the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (dichloromethane/methanol 50:1 to 20:1) to give compound a-12 (69 mg, 46%). LCMS (ESI) M/z ([ M+1)] ⁺ )602.2。

Preparation of Compound II-3a

Using the compound a-12 as a starting material, with reference to the preparation method of the compound II-4a, a 20 mg enantiomer mixture of the compound II-3a was separated by HPLC with a chiral column (ChiralPack AD) to give enantiomer 1 (3.0 mg) and enantiomer 2 (5.1 mg). The two compounds were both LCMS (ESI) M/z ([ M+1) ] ⁺ )426.2。

Example 3

Synthesis of Compound II-93

Preparation of Compounds a-15

Compound a-13 (3.39 g,10 mmol), a-14 (2.55 g,10 mmol), pd (PPh) ₃ )Cl ₂ 1, 4-dioxane (40 ml) was added to (0.7 g,1.0 mmol) and potassium acetate (1.96 g,20 mmol), stirred at 100℃for 15 hours, cooled, diluted with 60 ml of water, extracted three times with ethyl acetate (40 ml X3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the solvent was distilled off to give a crude product of 3.48 g, 90%. LCMS (ESI) M/z ([ M+1)] ⁺ )388.2。

Preparation of Compounds a-16

Tetrahydrofuran (30 ml), hydrogen peroxide (30%, 2 ml, 20.3 mmol) and sodium hydroxide (2 m,10 ml, 20 mmol) were added to compound a-15 (3.88 g,10 mmol) at zero degree, and the reaction mixture was warmed to room temperature and reacted for 5 hours. The pH was adjusted to 4 with 1N hydrochloric acid and extracted 3 times with ethyl acetate (30 ml X3). The combined organic phases were washed twice with brine (25 ml X2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the solvent was distilled off to give the crude product which was purified by column chromatography over silica gel (hexane/ethyl acetate 40:1 to 1:1) to give compound a-16 (1.52 g, 55%). LCMS (ESI) M/z ([ M+1)] ⁺ )278.1。

Preparation of Compounds a-18

Tetrahydrofuran (25 mL) was added to compound a-16 (2.77 g,10 mmol) and a-17 (1.29 g,10 mmol) and triphenylphosphine (2.63 g,10 mmol) at zero, diisopropyl azodicarboxylate (2.5 g,12.5 mmol) was added dropwise and the reaction mixture was stirred at 40℃overnight. 50 ml of water was added for dilution, and extraction was performed 3 times with ethyl acetate (30 ml X3). The combined organic phases were washed twice with brine (25 ml X2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the solvent was evaporated to give the crude product which was purified by silica gel column chromatography (hexane/ethyl acetate 40:1 to 1:1) to give compound a-18 (2.75 g, 58%). LCMS (ESI) M/z ([ M+1) ] ⁺ )476.1。

Preparation of Compounds a-19

To compound a-18 (4.75 g,10 mmol) and palladium on carbon (10%, 540 mg) was added 35 ml of methanol and the mixture was hydrogenated at 50psi for 24 hours. The reaction mixture was filtered through celite and rinsed twice with methanol (25 ml X2), the solvent was removed by rotary evaporation and the residue was taken up in silicaPurification by column chromatography (hexane/ethyl acetate 15:1 to 1:1) afforded compound a-19 (2.04 g, 72%). LCMS (ESI) M/z ([ M+1)] ⁺ )342.2。

Preparation of Compounds a-20

To compound a-19 (3.41 g,10 mmol) was added 2N hydrochloric acid (20.0 mL) and cooled to zero, 2N sodium nitrite solution (12 mL, 12 mmol) was slowly added dropwise, after 1 hour, an aqueous solution of a-5 (1.28 g,10 mmol) was added (15 mL) and stirred at room temperature for 3 hours. Extraction twice with ethyl acetate (40 ml X2), drying the combined organic phases over anhydrous sodium sulfate, filtration, rotary evaporation to remove the solvent, and purification of the residue by column chromatography on silica gel (hexane/ethyl acetate 15:1 to 4:1) gives compound a-20 (2.45 g, 66%). LCMS (ESI) M/z ([ M+1)] ⁺ ) 431.2。

Preparation of Compounds a-22

Compound a-20 (2.15 g, 5 mmol) was added trifluoroacetic acid/dichloromethane (1:1, 20 ml), stirred at room temperature for 2 hours,

the solvent was removed by rotary evaporation. To the resulting compound a-19 was added polyphosphoric acid (15 g), and heated to 70 degrees and stirred for 6 hours, cooled, diluted with 100 ml of ice water, extracted twice with ethyl acetate (35 ml of X2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate 15:1 to 4:1), to give compound a-22 (1.28 g, 72%). LCMS (ESI) M/z ([ M+1) ] ⁺ ) 357.2。

Preparation of Compounds a-24

To a solution of a-22 (710 mg,2.0 mmol) in dichloromethane (4 mL) was added benzylamine (215 mg,2.0 mmol) and cooled to zero degrees. To the mixture was slowly added dropwise a 1M titanium tetrachloride solution (2.0 mL,2.0 mmol), gradually warmed to room temperature, stirred for 16 hours, filtered, and the solvent was distilled off under reduced pressure. A-10 (696 mg,4.0 mmol) and diphenyl ether (4 mL) were added, heated to 160 degrees, stirred for 4 hours, and cooled to room temperature. 30 ml of ethyl acetate was added to dilute, the organic phase was washed three times with water (3X 10 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (dichloromethane/methanol 50:1 to 20:1) to give compound a-24 (345 mg, 31%)。 LCMS(ESI)m/z([M+1] ⁺ )558.2。

Preparation of Compound II-93

Compound II-93 was synthesized by the method described above with reference to compound II-4a starting from compound a-24 (278 mg, 0.5 mmol). The 20 mg enantiomer mixture was separated by HPLC with chiral column (ChiralPack AD) to give enantiomer 1 (3.5 mg) and enantiomer 2 (4.5 mg). The two compounds were both LCMS (ESI) M/z ([ M+1)] ⁺ ) 454.2。

The following compounds were synthesized in a similar manner

/>

Example 4

Preparation of Compound I-1

Preparation of Compound b-2

2-bromo-4-hydroxy-5-methoxybenzaldehyde b-1 (10.3 g,44.6 mmol) and hydroxylamine hydrochloride (9.3 g) were dissolved in hot formic acid (155 ml). The solution was heated to the boiling point, and then anhydrous sodium acetate (22.0 g) was added. The mixture was refluxed for 2 hours. Acetic anhydride (18.2 g) was added dropwise to the hot reaction mixture and refluxed for 4 hours. The mixture was allowed to cool to room temperature overnight and then stirred in an ice bath. The solid was filtered, washed with ice-cold water (20 ml) and dried to give compound b-2 in 9.4g (92%). ¹ H NMR(400MHz，DMSO-d6)ppm 10.10(br s,1 H),7.45(s,1H),7.31(S,1h),3.91(s,3H)。LC-MS:[M+H] ⁺ ：228.2。

Preparation of Compound b-3

1-bromo-3-methoxypropane (24.9 g,162.7 mmol) was added dropwise to a suspension of b-2 (12.3 g,54.2 mmol) and anhydrous potassium carbonate (22.5 g,162.8 mmol) in DMF (20 mL), stirred overnight at room temperature, poured into water, and ethyl acetateThe ethyl acetate was extracted three times, the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a yellow oily liquid, 13.6g,83.6%. LC-MS: [ M+H ]] ⁺ ：300.1。

Preparation of Compound b-4

To a reaction flask containing compound b-3 (7.5 g,25.0 mmol), pd2 (dba) (460 mg,0.5 mmol), xantphos (580 mg, 1.0 mmol) and sodium t-butoxide (4.3 g,45.0 mmol) was added anhydrous THF (100 mL), the mixture was evacuated and purged with nitrogen three times, 3-methylbutan-2-one (3.3 g,38.3 mmol) was added, the reaction solution was heated at 50℃for 4-6 hours under nitrogen, cooled, celite filtered, and the filtrate was concentrated under reduced pressure to give crude product b-4 (5.2 g, 68.1%) which was directly subjected to the next reaction. LC-MS: [ M+H ]] ⁺ ：306.3。

Preparation of Compound b-5

A mixture of Compound b-4 (5.2 g,17.0 mmol) and ammonium acetate (22 g,285.4 mmol) in methanol (60 mL) was cooled in an ice bath, sodium cyanoborohydride (2.4 g,38.2 mmol) was added in portions, the reaction solution was warmed to room temperature, stirred at room temperature for 2 days, then poured into saturated sodium bicarbonate water, extracted three times with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give crude 4.8g,91.7% of Compound b-5. The next reaction was directly carried out without purification. LC-MS: [ M+H ] ] ⁺ ：307.4。

Preparation of Compound b-6

The crude product of compound b-5 (4.8 g,15.6 mmol) was dissolved in DMSO (50 mL) and 50% NaOH (30 mL). The reaction mixture was stirred at room temperature for 3 hours and then poured into ice water, extracted three times with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography (0-10% methanol/dichloromethane) to give compound b-6 (3.8 g, 79.2%). LC-MS: [ M+H ]] ⁺ ：307.3。

Preparation of Compound b-7

To the reaction flask were added b-6 (614 mg,2.0 mmol), a-10 (696 mg,4.0 mmol) and diphenyl ether (4 mL), and the reaction mixture was heated to 160℃and stirred for 4 hours and cooled to room temperature. 30ml of ethyl acetate was added for dilution, washed three times with water (3X 10 mL) and the organic phase was driedDrying over sodium sulfate, filtration, rotary evaporation to remove solvent, and purification of the residue by silica gel column chromatography (dichloromethane/methanol 50:1 to 20:1) afforded compound b-7 (216 mg, 26%). LCMS (ESI) M/z ([ M+1)] ⁺ )417.2。

Preparation of Compound I-1

Compound b-7 (208 mg, 0.5 mmol) was dissolved in tetrahydrofuran/water (1:1, 4 ml), 1M lithium chloride solution (1 ml, 1 mmol) was added dropwise, the reaction was carried out at room temperature for 6 hours, pH was adjusted to 5 with 1N hydrochloric acid, three times with dichloromethane (20 ml X3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (dichloromethane/methanol 50:1 to 10:1) to give compound I-1 (157 mg, 78%). LCMS (ESI) M/z ([ M+1) ] ⁺ )403.3。

The 20 mg enantiomer mixture was separated by HPLC with chiral column (ChiralPack AD) to give enantiomer 1 (3.8 mg) and enantiomer 2 (5.6 mg). The two compounds were both LCMS (ESI) M/z ([ M+1)] ⁺ )403.3。

Example 5

Preparation of Compound III-13

Preparation of Compound c-2

Compound c-1 (660 mg,7.78 mmol) was suspended in water (13 mL) and cooled in an ice bath. Sodium hydroxide (560 mg, 14.0 mmol) was added to make a solution, followed by dropwise addition of 5% aqueous sodium hypochlorite (11.6 mL,7.78 mmol) over 5 minutes. After stirring for 10 minutes, the temperature was raised to room temperature. After stirring for 20 hours, the mixture was ice cooled and 5% aqueous sodium hypochlorite (2.32 mL,1.56 mmol) was added dropwise. After stirring for 10 minutes, the temperature was raised to room temperature. After stirring for 72 hours, 6N hydrochloric acid was added to adjust the pH to 2, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give compound c-2.LC-MS: [ M+H ]] ⁺ ：148.4。

Preparation of Compound c-3

Suspending the resulting compound c-2 inTo water (7 mL) was added potassium carbonate (2.01 g,14.6 mmol) to prepare a solution. Iodine (1.06 g,4.16 mmol) was added and stirred for 18 hours, then saturated aqueous sodium thiosulfate solution was added. The pH was adjusted to 2 by the addition of 6N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated, and the residue was purified by silica gel column (0-60% ethyl acetate/hexane) to give compound c-3 (1.94 g, 91%). LC-MS: [ M+H ] ] ⁺ ：274.2

Preparation of Compound c-4

1-bromo-3-methoxypropane (24.9 g,162.7 mmol) was added dropwise to a suspension of c-3 (14.8 g,54.2 mmol) and anhydrous potassium carbonate (22.5 g,162.8 mmol) in DMF (20 mL), stirred overnight at room temperature, poured into water, extracted three times with ethyl acetate, the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by a silica gel column (0-40% ethyl acetate/hexane) to give compound c-4 (14.7 g, 78.6%). LC-MS: [ M+H ]] ⁺ ：346.1。

Preparation of Compound c-5

Zinc cyanide (1.3 g,11 mmol), zinc powder (72 mg,1.1 mmol) and [1, 1-bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (0.86 g,1.2 mmol) was added to a solution containing c-4 (8.15 g,23.6 mmol) in N, N-dimethylformamide (30 mL). The reaction mixture was stirred at 140 ℃ for 13 hours, then diluted with tert-butyl methyl ether (100 mL) and water (75 mL) and filtered through a celite pad. The aqueous layer of the filtrate was extracted with additional tert-butyl methyl ether (3X 50 mL), the combined organic layers were washed with saturated aqueous sodium chloride (8X 30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford product c-5 (3.65 g, 63.3%) as a brown solid. LC-MS: [ M+H ]] ⁺ ：245.1。

Preparation of Compound c-7

To a dry round bottom flask was added compound c-5 (2.02 g,8.26mmol,1.0 eq). Then it was dissolved in anhydrous THF (5.00 mL) and the reaction mixture was cooled to 0 ℃. Compound c-6 (866 mg,8.40mmol,1.02 eq.) was then added to the reaction mixture. After stirring the reaction mixture for 15 minutes, potassium tert-butoxide (9.10 mL, 1.0M in THF, 9.10) was slowly added dropwisemmol,1.1 eq) solution to maintain the internal temperature less than 5 ℃. The reaction mixture was then warmed to room temperature, stirred for 16 hours, and then quenched with water (1 mL). The reaction mixture was then extracted with 2-MeTHF (3X 5 mL). The combined organics were dried over anhydrous magnesium sulfate and filtered. Concentrated hydrochloric acid (0.70 mL,8.34mmol,1.01 eq.) was added dropwise to the filtrate, the precipitated solid was filtered off, and washed with 2-MeTHF (2X 5 ml) to give compound c-7 (2.16 g, 72%). LC-MS: [ M+H ]] ⁺ ：328.2。

Preparation of Compound c-8

To the dried reaction flask was added compound c-7 (364.3 mg,1.00 mmol) followed by magnesium ethoxide (0.257 g, 2.20 mmol). The vials were sealed with teflon caps and then evacuated and refilled with nitrogen 3 times. Anhydrous methanol (1 mL) was then added to the vial. After stirring the vial for 20 minutes, 2-MeTHF (3 mL) was added. The reaction mixture was heated to 80 ℃ and stirred for 20 hours, and the reaction mixture was cooled to room temperature. To this was added a half-saturated aqueous ammonium chloride solution (5 mL), and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the crude product which was purified by column chromatography (0-15% methanol/dichloromethane) to give compound c-8 (240.3 mg, 73.3%). LC-MS: [ M+H ] ] ⁺ ：328.1。

Preparation of Compound c-9

To the reaction flask were added c-8 (650 mg,2.0 mmol), a-10 (696 mg,4.0 mmol) and diphenyl ether (4 mL) and the reaction mixture was heated to 160℃and stirred for 4 hours and cooled to room temperature. 30 ml of ethyl acetate was added to dilute, and the organic phase was washed three times with water (3X 15 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (dichloromethane/methanol 50:1 to 20:1) to give compound c-9 (201 mg, 23%). LCMS (ESI) M/z ([ M+1)] ⁺ )438.2。

Preparation of Compound III-13

Compound c-9 (175 mg, 0.4 mmol) was dissolved in tetrahydrofuran/water (1:1, 4 ml), 1M lithium chloride solution (1 ml, 1 mmol) was added dropwise, reacted at room temperature for 6 hours, PH was adjusted to 5 with 1N hydrochloric acid, extracted three times with dichloromethane (30 ml X3), and the mixture was combinedThe organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (dichloromethane/methanol 50:1 to 10:1) to give compound III-13 (137 mg, 81%). LCMS (ESI) M/z ([ M+1)] ⁺ )424.3。

The 20 mg enantiomer mixture was separated by HPLC with chiral column (ChiralPack AD) to give enantiomer 1 (3.6 mg) and enantiomer 2 (5.5 mg). The two compounds were both LCMS (ESI) M/z ([ M+1) ] ⁺ )424.3。

Example 6

Preparation of Compound III-15

Preparation of Compound c-10

Compound c-10 was synthesized in 43% yield by using compound c-9 as a starting material and referring to the method for producing compound a-12. LCMS (ESI) M/z ([ M+1)] ⁺ )500.1。

Preparation of Compound III-15

Using compound c-10 as a starting material, and referring to the preparation method of compound II-4a, a mixture of enantiomers of compound III-15 was synthesized, and 20 mg was separated by HPLC with chiral column (ChiralPack AD) to give enantiomer 1 (3.4 mg) and enantiomer 2 (5.3 mg). The two compounds were both LCMS (ESI) M/z ([ M+1)] ⁺ )414.2。

The following compounds were synthesized in a similar manner

Example 7

Preparation of Compound IV-1

Preparation of Compound d-2

4-hydroxy-3, 3-dimethylbutan-2-one (43 g,370 mmol) and benzyl bromide (48.4 ml,407 mmol) and DIPEA (71.1 ml,407 mmol) were added to the reaction flask and the mixture was heated at 150℃for 1 hour. After cooling to room temperature, the mixture was added to ethyl acetate and water. The aqueous layer was adjusted to pH 1-2 with 2M hydrochloric acid. The organic layer was then separated, dried over anhydrous sodium sulfate and concentrated to give 76g of the desired product d-2 in 100% yield. ¹ HNMR(400MHz,CDCl ₃ )δppm 7.26-7.38(m,5H),4.47 -4.53(m,2H),3.45-3.54(t 2.16(s,3H),1.1 1-1.17(m,6H)；LC-MS(m/z)：207.3[M+ H] ⁺ 。

Preparation of Compound d-3

To the reaction flask was added d-2 (5 g,24.24 mmol) and methanol (300 ml) and cooled to below 0deg.C with an ice-methanol bath, and a solution of bromine (1.44 mL,27.9 mmol) in methanol (50 ml) was added dropwise. The reaction was stirred at this temperature for 1 hour and then at room temperature overnight. The crude product was concentrated, redissolved in dichloromethane and washed with saturated sodium bicarbonate solution. The organics were dried and concentrated to give the desired product d-3 in quantitative yield, which was used directly without purification. ¹ H NMR(400 MHz,CDCI3)δppm 7.24-7.38(m,5H),4.48-4.51(m,2H),4.21-4.25(m,2H),3.40-3.48(m,2H),1.22-1.25(m,6H)；LC-MS(m/z):285.1[M+H] ⁺ 。

Preparation of Compound d-5 to 4- (difluoromethoxy) -1H-indole-2-carboxylic acid (1.95 g,8.58 mmol) was added THF (50 mL), heated to dissolve, and then cooled to room temperature. Then a 2M solution of lithium aluminum hydride in THF (6.44 mL,12.88 mmol) was added. Stir at room temperature for 3 hours until reaction is complete (LC-MS detection). The reaction was cooled in an ice bath and then carefully quenched by dropwise addition of excess water (2 ml) and magnesium sulfate was added as salt was formed. The reaction was removed from the ice bath and stirred for 1 hour, filtered through celite, and concentrated to give 1.80g of the desired product d-5 in 98% yield. LC-MS (m/z): 214.1[ M+H ]] ⁺ 。

Preparation of Compound d-6

A solution containing d-5 (3.90 g,18.3 mmol) and anhydrous dichloromethane (50 ml) was cooled with an ice-water bath, manganese (IV) oxide (7.93 g,91.2 mmol). The reaction mixture was warmed to room temperature and stirred for 12 hours, then the reaction mixture was diluted with dichloromethane, filtered through celite, and the solid was washed twice with dichloromethane. Concentration and column chromatography of the crude product using ethyl acetate/petroleum ether as eluent gave compound d-6 (3.09 g, 80%). LC-MS (m/z): 212.2[ M+H ]] ⁺ 。

Preparation of Compound d-7

Compound d-6 (2.36 g,11.2 mmol) and hydroxylamine hydrochloride (2.33 g) were dissolved in hot formic acid (40 ml). The solution was heated to the boiling point, and then anhydrous sodium acetate (5.5 g) was added. The mixture was refluxed for 2 hours. Acetic anhydride (4.6) was added dropwise to the hot reaction mixture and refluxed for 4 hours. The mixture was allowed to cool to room temperature overnight and then stirred in an ice bath. The solid was filtered, washed with ice water (10 ml) and dried to give compound d-7 in a yield of 1.51g (65%). LC-MS (m/z): 209.0[ M+H ] ] ⁺ 。

Preparation of Compound d-8

Sodium hydride (60%, 668mg,16.7 mmol) was added in portions to a solution of compound h-7 (1.74 g,8.37 mmol) in DMF (40 mL) at room temperature and stirring was continued for 15 min. Compound d-3 (4.29 g,15 mmol) was then added and stirred overnight at room temperature. 250ml of ethyl acetate was added, each washed with saturated bicarbonate, water, saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column on silica gel (0-20% ethyl acetate/hexane); compound d-8 (2.35 g, 68%) was obtained. LC-MS (m/z): 413.3[ M+H ]] ⁺ 。

Preparation of Compound d-9

A mixture of compound d-8 (2.1 g,5.1 mmol) and ammonium acetate (6.6 g,85.6 mmol) in methanol (20 mL) was cooled with an ice bath, sodium cyanoborohydride (0.72 g,11.5 mmol) was added in portions, the reaction solution was warmed to room temperature, stirred at room temperature for 2 days, then poured into saturated sodium bicarbonate water, extracted three times with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 1.51g,71.5% of compound d-9. The next reaction was directly carried out without purification. LC-MS: [ M+H ]] ⁺ ：414.3。

Preparation of Compound d-10

To the dried reaction flask was added compound d-9 (413.5 mg,1.00 mmol) followed by magnesium ethoxide (0.257 g,2.20 mmol). The vials were sealed with teflon caps and then evacuated and refilled with nitrogen 3 times. Anhydrous methanol (1 mL) was then added to the vial. After stirring the vial for 20 minutes, 2-MeTHF (3 mL) was added. The reaction mixture was heated to 80 ℃ and stirred for 20 hours, and the reaction mixture was cooled to room temperature. To this was added a half-saturated aqueous ammonium chloride solution (5 mL), and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the crude product which was purified by column chromatography (0-15% methanol/dichloromethane) to give compound d-10 (262 mg, 61.3%). LC-MS: [ M+H ] ] ⁺ ：428.2。

Preparation of Compound d-11

To the reaction flask were added d-10 (428 mg,1.0 mmol), a-10 (348 mg,2.0 mmol) and diphenyl ether (2 mL) and the reaction mixture was heated to 160℃and stirred for 4 hours and cooled to room temperature. 30 ml of ethyl acetate was added to dilute, and the organic phase was washed three times with water (3X 15 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (dichloromethane/methanol 50:1 to 20:1) to give compound d-11 (136.1 mg, 26%). LCMS (ESI) M/z ([ M+1)] ⁺ )524.2。

Preparation of Compound IV-1

Compound d-11 (104.7 mg, 0.2 mmol) was dissolved in 2ml dichloromethane and cooled to-78 ℃. To the solution was added dropwise a 1.0M solution of boron trichloride in dichloromethane (0.4 ml, 0.4 mmol), and the mixture was stirred at-78 ℃ for 2 hours. The reaction was quenched by the addition of sodium bicarbonate (68 mg, 0.8 mmol), gradually warmed to room temperature, diluted with dichloromethane, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The crude product obtained was dissolved in tetrahydrofuran/water (1:1, 2 ml), 1M lithium chloride solution (0.4 ml, 0.4 mmol) was added dropwise, reacted at room temperature for 6 hours, adjusted to PH 5 with 1N hydrochloric acid, extracted three times with dichloromethane (20 ml X3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, the solvent was removed by rotary evaporation, and the residue was purified by silica gel column chromatography (dichloromethane Methanol 50:1 to 10:1) to give compound IV-1 (68 mg, 81%). LCMS (ESI) M/z ([ M+1)] ⁺ )420.2。

The 20 mg enantiomer mixture was separated by HPLC with chiral column (ChiralPack AD) to give enantiomer 1 (3.3 mg) and enantiomer 2 (5.1 mg). The two compounds were both LCMS (ESI) M/z ([ M+1)] ⁺ )420.2。

The following compounds were synthesized in a similar manner

Biological testing

Compound inhibition hepatitis B surface antigen activity test

1. Cell lines

HepG2.2.15 cell culture Medium (DMEM/F12, invitrogen-11330032;10% serum, invitrogen-10099141;100units/ml penicillin and 100. Mu.g/ml streptomycin, fetal bovine serum-SV 30010; 1% nonessential amino acids, invitrogen-11140050;2mM L-glutamine, invitrogen-25030081; 300. Mu.g/ml geneticin, invitrogen-10131027)

2. Specific steps refer to the product instruction book (hepatitis B virus surface antigen magnetic particle chemiluminescence method quantitative detection kit CM0310, zhengzhou Anji bioengineering Co., ltd.)

The steps are briefly described as follows:

HepG2.2.15 cells of the species (4X 10 ⁴ Cell/well) to 96-well plates at 37 ℃,5% co ₂ Culturing overnight. The next day, the compound was diluted at 8 total concentrations, 3-fold gradient dilution. Adding different concentrations of compounds into the culture wells, and doubling the wells. The final concentration of DMSO in the culture was 0.5%.0.5% DMSO served as a 0% inhibition control. On the fifth day, the fresh culture broth containing the compound was changed. And collecting culture solution in the culture holes on the eighth day, and taking partial samples for ELISA to determine the content of the hepatitis B virus surface antigen.

3. The percent inhibition of each compound was calculated using the following formula: inhibition (%) = (value in 1-sample/DMSO control value) x100%. Percentage of HBV inhibition by each compound was soft with GraphPadPrismFitting a dose-response curve and calculating the 50% inhibition concentration (EC ₅₀ ) Values.

Test results of inhibiting hepatitis B surface antigen Activity by Compounds

/>

/>

/>

0.1nM≤+++++≤1nM；1nM≤++++≤10nm；10nm≤+++≤50nM；50nm≤++≤ 150nM

From the above results, it is understood that most of the compounds exhibit a high effect of inhibiting hepatitis B surface antigen, and thus, the compounds of the examples can be used for the preparation of therapeutic drugs for symptoms/diseases induced by hepatitis B virus infection.

Claims

1. A polycyclic compound characterized by: is a compound represented by the following chemical formula or a salt thereof:

2. a pharmaceutical composition characterized by: comprising a compound according to claim 1, a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or excipient.

3. Use of the polycyclic compound according to claim 1 for the preparation of a medicament for preventing and/or treating viral infection diseases, and/or a hepatitis b surface antigen inhibitor and a hepatitis b DNA inhibitor.

4. Use of the polycyclic compound according to claim 3 for the preparation of a medicament for preventing and/or treating viral infection diseases, and/or a hepatitis b surface antigen inhibitor and a hepatitis b DNA inhibitor, characterized in that: the viral infection includes infection with HBV or HDV.