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CN112592343A - Polycyclic compound and application thereof as antiviral drug - Google Patents

Polycyclic compound and application thereof as antiviral drug Download PDF

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CN112592343A
CN112592343A CN201910946024.9A CN201910946024A CN112592343A CN 112592343 A CN112592343 A CN 112592343A CN 201910946024 A CN201910946024 A CN 201910946024A CN 112592343 A CN112592343 A CN 112592343A
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hepatitis
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CN112592343B (en
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周雨恬
刘建波
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Abstract

The invention relates to a polycyclic compound and application thereof as an antiviral medicament, in particular to a compound shown as a formula (I) or pharmaceutically acceptable salt, solvate, geometric isomer, stereoisomer, tautomer 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 particularly relates to a novel polycyclic compound or a stereoisomer thereof, a pharmaceutical composition containing the novel polycyclic compound or the stereoisomer thereof and application of the pharmaceutical composition as an antiviral drug, in particular to application of the pharmaceutical composition as a hepatitis B Surface antigen inhibitors (HBV Surface antigen inhibitors) and hepatitis B DNA inhibitors (HBV DNA production inhibitors) for treating and/or preventing hepatitis B virus infection, and especially relates to application of the compound, a TLR7 inhibitor and a 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. There are currently about 3.5 million chronic HBV infected people worldwide, dying nearly 100 million people each year from chronic liver disease associated with HBV infection. China is a high incidence area of hepatitis B, and viral hepatitis, liver cirrhosis, liver cancer and the like caused by HBV persistent infection seriously harm the life health of people in China: nearly 10% of the population is HBV carriers, with over 3000 million present hepatitis B patients, and about 30 million people die of hepatitis B and its associated complications each year. Therefore, the search for effective treatment of hepatitis b has become a major issue to be solved urgently in the medical field.
Hepatitis B virus HBV belongs to hepadnavirus and is a circular DNA virus with envelope and partial double chain. The long strand of viral DNA is the minus strand and the short strand is the plus strand. The HBV genome is compact and exquisite and about 3.2kb in size. The viral particle consists of a lipid envelope embedded with a surface protein (HBsAg) that has a viral core surrounding the viral core. The core consists of a protein shell or capsid constructed with 120 core protein (Cp) dimers, which in turn contains relaxed circular dna (rcdna) viral genome and 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 for viral proteins. In the cytoplasm, Cp is assembled around a 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 classic markers of chronic hepatitis b is the high level of hepatitis b virus (HBsAg) in the patient's serum, which may reach 400 μ g/mL (0.4% of total serum protein). The antigenicity of the production of subviral particles is thought to play an important role in suppressing HBV-specific immune responses. Furthermore, recent reports have indicated that HBsAg acts directly on dendritic cells to limit cytokine production and adaptive immunity. The reduction in antigenicity induced by the experimental clevudine (clevudine) resulted in partial recovery of the immune response specific to the virus. Thus, inhibitors of HBsAg secretion would potentially enable therapeutic use of HBV vaccines or enable combination therapy with nucleoside (acid) drugs for the treatment of HBV infection.
There are currently 7 approved drugs for controlling HBV persistent infection, which are interferon- α, pegylated interferon- α, lamivudine, entecavir, telbivudine, adefovir dipivoxil and tenofovir disoproxil, but the efficacy of current antiviral therapies is not satisfactory: the sustained response rate of high-dose recombinant interferon is only about 30%, and nucleoside analogues such as lamivudine have strong antiviral activity, but the virus replication level rapidly rebounds after drug withdrawal and resistant virus strains appear, so that the implementation of clinical antiviral schemes faces great challenges. The new drug design aiming at curing hepatitis B requires the same mechanism requirement as interferon, the immune system of human body needs to be reactivated, and infected liver cells are identified and eliminated by the immune system, thus completely curing hepatitis B. Hepatitis B surface antigen and other viral antigens secreted by hepatocytes of chronic hepatitis B patients interfere with the immune system through a signal transduction system, block recognition of viruses by immune cells, and further limit their antiviral functions. In addition, persistent and excessive hepatitis B surface antigen can inactivate the immune system, cause T-cell depletion and cause functional impairment. Hepatitis B surface antigen can also directly suppress the virus-clearing function of immune cells. Based on the reasons, the development of the medicine for inhibiting the secretion of hepatitis B surface antigen can effectively recover the function of immune cells, relieve the pressure of the immune system, enable the immune system to identify and eliminate infected liver cells and achieve the aim of directly curing hepatitis B.
In addition, the reduction of hepatitis B surface antigen is also a biological index for the improvement of chronic hepatitis B, and the disappearance and seroconversion of hepatitis B surface antigen indicate that the hepatitis B has been cured functionally. At present, nucleoside medicaments cannot reduce hepatitis B surface antigens, a medicament with a new action mechanism is required to be designed and combined with potent nucleoside medicaments, and simultaneously, the nucleoside medicaments effectively remove the hepatitis B surface antigens and virus DNA in blood, activate and recover the immune function of the nucleoside medicaments, so that hepatitis B can be cured finally.
The search for new anti-HBV treatment schemes with high efficiency, specificity and low toxicity is always a continuously pursued 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. Although those agents have made a significant contribution in this area, there is a continuing need in this area for improved drugs.
Disclosure of Invention
The present invention provides compounds of formula (I) or a pharmaceutically acceptable salt, solvate, geometric isomer, stereoisomer, tautomer and any mixture thereof:
Figure RE-GDA0002243597200000021
wherein:
(1)W1selected from oxygen, sulfur;
(2) z is selected from N and CR7；
(3)W2Selected from (a) COOR8；(b)-CONHR8；(c)-CONH0R8；(d)-NHNHR8；(e)-NHNHC(＝0)R8； (f)-NHS(＝0)2R8；
(g) A 4-8 membered heteroaromatic ring which is unsubstituted or substituted with one or more substituents selected from halogen, OH, mercapto, nitro, amino, cyano; (h) NHCOR9Wherein R is9Is amino; amino which is unsubstituted or substituted by one or more substituents selected from halogen, OH, mercapto, nitro, amino, carboxyl and cyano; (i) c (═ O) N (R)10)SO2R11Wherein R is10Selected from hydrogen, methyl or cyclopropane, R11The amino group is unsubstituted or substituted by one or more substituents selected from halogen, OH, sulfydryl, nitro, amino, carboxyl and cyano; boric acid; phosphoric acid and nitrogen-containing heterocycles;
(4) a is selected from a single bond or a double bond, wherein
(i) a bond is a single bond, Y is selected from O, S, S (═ O)2,NR3And CHR3
(ii) a bond is a double bond, then Y is CR3And R is2bIs absent;
(5)R1a，R1b，R2aand R2bEach independently selected from hydrogen, hydrocarbon and hydrocarbonoxy substituents, heteroaryl and substituted carbon number 3-8 cycloalkyl group; or R1a/R1b，R2a/R2bAnd R1a/R2aCombined to form alkanediyl having 1 to 6 carbon atoms, - (CH)2)m O(CH2)m-,-(CH2)mNR5(CH2)m-,-(CH2)mS(CH2)m-,-(CH2)mS(＝0)(CH2)m-, and- (CH)2)mS(＝0)2(CH2)m-, wherein m is independently selected from 1 or 2, and wherein each divalent group is optionally substituted by at least one C1-C6Alkyl or halogen substitution;
(6)X1selected from the group consisting of CR4IOr N;
X2selected from the group consisting of CR4IIOr N;
X3selected from the group consisting of CR4IIIOr N;
X4selected from the group consisting of CR4IVOr N;
X5is selected from C;
X4and X5Combine to form-N-with CR4IIAnd CR4IIICombined to form a substituted aromatic ring having 0-4 substituents R12；
X3And X4Or X1And X2Combine to form-S-, -O-;
R4I，R4II，R4IIIand R4IVIndependently selected from one or more structural units including H, halogen, cyano, substituted C1-C6 alkyl (e.g. C)1-C6Hydroxyalkyl, alkoxy-C1-C6Alkyl and C1-C6Haloalkyl), substituted cycloalkyl of 3 to 8 carbon atoms, substituted alkynyl of 2 to 6 carbon atoms, -OR, -SR, -N (R), substituted heterocyclyl and haloalkoxy of 1 to 6 carbon atoms (such as but not limited to OCF)2H,OCH2CF2H)；
Wherein R is independently selected from H, C1-C6Alkyl, R' substituted C1-C6Alkyl radical, C1-C6Hydroxyalkyl, substituted (C)1-C6Alkoxy group) - (C1-C6Alkyl), and substituted C3-C8A cycloalkyl group;
wherein R' is selected from-NH2，-NH(C1-C6Alkyl group), -N (C)1-C6Alkyl) (C1-C6Alkyl), -NHC (C ═ 0)0tBu， -N(C1-C6Alkyl) C (═ 0) OtBu or a 5 or 6 membered heterocyclyl, which is optionally N-linked;
or X2Is CR4II，X3Is CR4IIIAnd R is4IIAnd R4IIICombine to form a divalent group selected from-0 (CR)5R6) 0-，-0(CR5R6)(CR5R6)0-，-0(CR5R6)(CR5R6) -and-0 (CR)5R6)(CR5R6)(CR5R6) -; or X3Is CR4III，X4Is CR4IV，R4IIIAnd R4IVCombine to form a divalent group selected from-0 (CR)5R6)0-， -0(CR5R6)(CR5R6)0-，-0(CR5R6)(CR5R6) -and-0 (CR)5R6)(CR5R6)(CR5R6)-；
(7)R3May be independently selected from H, substituted C1-C6Alkyl and substituted C3-C8A cycloalkyl group;
(8)R5selected from H and C1-C6An alkyl group;
(9)R6selected from H, OH, C1-C6Alkyl radical, C1-C6Alkoxy, alkoxy-C1-C6Alkyl and alkoxy-C1-C6Alkoxy, wherein two R are6The group is bonded to the same carbon atom and is not OH at the same time; wherein R is6And is not OH if bonded to carbon further bonded to an oxygen atom.
Or two R6The radicals are combined with the carbon atom to which they are bonded to form a radical selected from the group consisting of C ═ 0, C ═ CH2And oxetane-3, 3-diyl moieties;
(10)R7selected from H, OH, halogen, substituted C1-C6Alkoxy, substituted C1-C6Alkyl and substituted C3-C8Cycloalkyl or heterocycloalkyl.
(11)R8Substituents selected from hydrogen, hydrocarbon and hydrocarbonoxy;
(12)R9selected from hydrogen, halogen, OH, mercapto, nitro, amino, carboxyl or cyano, or R9Substituents selected from the group consisting of hydrocarbon and hydrocarbonoxy;
(13)R10selected from hydrogen, methyl or cyclopropane;
(14)R11the amino group is unsubstituted or substituted by one or more substituents selected from halogen, OH, sulfydryl, nitro, amino, carboxyl and cyano;
(15)R12selected from H, halogen, OH, mercapto, nitro, amino, carboxyl or cyano; or R12Substituents selected from the group consisting of hydrocarbon and hydrocarbonoxy;
(16) the hydrocarbon and hydrocarbonoxy substituents include saturated or unsaturated hydrocarbon or hydrocarbonoxy groups having 1 to 20 carbon atoms, which are unsubstituted or substituted with one or more substituents selected from halogen, OH, mercapto, nitro, amino, carboxyl and cyano, and which are uninterrupted or interrupted by 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 independently substituted by one or more deuterium atoms.
In certain embodiments, such compounds are represented by the formula:
Figure RE-GDA0002243597200000041
Figure RE-GDA0002243597200000051
in the formula, W2,R1a,R1b,R2a,R2b,R4I,R4II,R4III,R4IV,R7And R12As defined above.
According to a particular aspect of the invention, R1aIs H, R1bSelected from methyl, ethyl, isopropyl, butyl, isobutyl, tert-butyl, methoxymethyl, methoxyethyl, methoxyisopropyl, methoxybutyl, methoxyisobutyl, ethoxymethyl, ethoxyethyl, ethoxyisopropyl, ethoxybutyl, ethoxyisobutyl, hydroxymethyl, hydroxyethyl, hydroxyisopropyl, hydroxybutyl, hydroxyisobutyl, hydroxy-tert-butyl, aryl or heteroaryl; r1aIs methyl, R1bIs isopropyl; r1aIs methyl, R1bIs a tert-butyl group; r1aIs methyl, R1bIs methyl; r1aIs methyl, R1bIs an ethyl group; r1aIs ethyl, R1bIs ethyl.
The compounds of the present invention may contain one or more asymmetric carbon atoms. Accordingly, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. Each asymmetric carbon atom may be in the R configuration or the S configuration, and both configurations are within the scope of the present invention.
Modified compounds, including any such compounds having modifications that improve (e.g., enhance, greater) pharmaceutical solubility, stability, bioavailability, and/or therapeutic index by the unmodified compound, are also contemplated. Exemplary modifications include, but are not limited to, prodrug derivatives, where applicable, and deuterium-enriched compounds.
It will be appreciated that the compounds of the invention may exist and optionally be administered in the form of a salt or solvate. The present invention encompasses any pharmaceutically acceptable salts and solvates of any of the above compounds and modifications thereof.
Compositions for treating diseases containing one or more of the compounds, modifications and/or salts and solvates thereof, therapeutic uses thereof, and uses of the compounds in the manufacture of a medicament for treating the diseases/disorders are also within the scope of the invention.
The compound of the invention can inhibit the secretion of HBsAg and inhibit HBV gene expression. Accordingly, the compounds of the present invention are useful for treating or preventing HBV infection.
The present invention relates to the use of a compound of formula (I) for inhibiting HBsAg production or secretion.
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 compounds of formula (I) for the treatment or prevention of HBV infection.
The use of compounds of formula (I) for the preparation of a medicament useful for the treatment or prevention of diseases associated with HBV infection is an object of the present invention.
The invention relates in particular to the use of compounds of formula (I) for the preparation of a medical article for the treatment or prevention of HBV infections.
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 above compounds, modifications, and/or salts thereof, and compositions thereof.
A pharmaceutical composition characterized by: the compound of the 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 are contained, and the dosage form of the pharmaceutical composition is preferably a tablet, a capsule or an injection.
The pharmaceutical composition is an antiviral pharmaceutical composition, and further comprises one or more therapeutic agents; the therapeutic agent is selected from the group consisting of: nucleoside drugs, interferon, ribavirin, HBV capsid inhibitor (capsid inhibitor), cccDNA formation inhibitor, cccDNA epigenetic modifier or hepatitis B RNAi drug, TLR7 agonist.
The polycyclic compound is applied to the preparation of drugs for preventing and/or treating virus infection diseases and/or drugs for hepatitis B Surface antigen inhibitors (HBV Surface antigen inhibitors) and hepatitis B DNA inhibitors (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 drugs, interferon, ribavirin, HBV capsid inhibitors, cccDNA formation inhibitors, cccDNA epigenetic modifiers or hepatitis B RNAi drugs, and TLR7 agonists.
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. It is understood that all of the specific embodiments/features of the invention disclosed herein (compounds, pharmaceutical compositions, methods of preparation/use, etc.), including any specific features disclosed in the examples and the original claims, may be combined with each other, unless otherwise indicated or clearly contradicted.
Exemplary compounds disclosed herein include, but are not limited to, the following:
Figure RE-GDA0002243597200000061
Figure RE-GDA0002243597200000071
Figure RE-GDA0002243597200000081
Figure RE-GDA0002243597200000091
Figure RE-GDA0002243597200000101
Figure RE-GDA0002243597200000111
Figure RE-GDA0002243597200000121
Figure RE-GDA0002243597200000131
Figure RE-GDA0002243597200000141
Figure RE-GDA0002243597200000151
Figure RE-GDA0002243597200000161
Figure RE-GDA0002243597200000171
the invention also provides a pharmaceutical composition, which contains the polycyclic compound shown in the formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate or a 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 drugs, ribavirin, interferon, HBV capsid inhibitors (capsidiphilibitor), cccDNA formation inhibitors, cccDNA epigenetic modifiers or hepatitis B RNAi drugs, TLR7 agonists.
The invention also relates to application of the polycyclic compound shown in the formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate or a crystal thereof or a combination of the polycyclic compound and one or more therapeutic agents selected from nucleoside medicaments, ribavirin, interferon, HBV capsid inhibitors (capsid inhibitors), cccDNA formation inhibitors, cccDNA epigenetic modifiers or hepatitis B RNAi medicaments and TLR7 agonists in preparing medicaments for preventing and/or treating virus infection diseases, and/or hepatitis B Surface antigen inhibitors (HBV Surface antigen inhibitors) and hepatitis B DNA inhibitors (HBV DNA productoninhibitors), wherein the virus infection comprises the infection of HBV or HDV.
The invention also provides the application of the pharmaceutical composition in preparing the medicines for treating or preventing hepatitis B and hepatitis B virus infection and a method for preventing or slowing down the diseases of hepatitis B and hepatitis B virus infected patients 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.
The pharmaceutically acceptable carrier in the pharmaceutical composition can be pharmaceutically acceptable diluent, excipient, filler, binder, disintegrant, absorption enhancer, surfactant, lubricant, flavoring agent, sweetener, etc.
The medicine prepared by taking the compound of the invention as an active ingredient can be various forms such as tablets, powder, capsules, granules, oral liquid, injection preparations and the like. The dosage form of the pharmaceutical composition is preferably tablets, capsules or injections.
The medicaments in various dosage forms can be prepared by 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 prophylaxis or treatment of a viral infectious disease, preferably wherein the viral infectious disease is HBV viral infection.
The pharmaceutical composition of the invention can be prepared from the following components in proportion:
Figure RE-GDA0002243597200000181
due to the implementation of the technical scheme, compared with the prior art, the invention has the following advantages:
the present invention provides novel polycyclic compounds having very strong hepatitis B DNA inhibiting activity, EC50Can be less than 5 nanomolar, and has potent hepatitis B surface antigen inhibiting activity, EC50At around 5 nanomolar. In addition, the compounds have excellent pharmacokinetic properties.
Further, the compounds of the present invention will block the pathway of P450 oxidation, improve the bioavailability of the compounds, and reduce the toxicity of the compounds. The high-activity compounds can be combined with nucleoside compounds and TLR7 agonists to be used for clinically and possibly remarkably improving the treatment effect and the cure rate of hepatitis B.
The compounds of the present invention may contain one or more asymmetric carbon atoms. Accordingly, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. The synthesis of the compounds can employ racemates, diastereomers or enantiomers as starting materials or as intermediates. The diastereoisomeric compounds may be separated by chromatographic methods or crystallization methods. Likewise, enantiomeric mixtures can be separated using the same techniques or other techniques known in the art.
Each asymmetric carbon atom may be in the R configuration or 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 resulting from the different arrangement of atoms in a molecule. Including cis-trans isomers, enantiomers, and conformers. All stereoisomers are within the scope of the present 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 is 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 present invention that forms a solid or liquid complex by coordination with 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 the various solid forms formed by the compounds of the present invention, including crystalline forms, amorphous forms.
The term "hydrocarbyl" refers to a straight, 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. Alkyl includes in particular 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 1-20 carbon atoms. Alkyl groups include substituted and unsubstituted alkyl groups. When the alkyl group is substituted, the substituent may be substituted at any available point of attachment, and the substituent may be mono-or poly-substituted. The 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 usually preceded by alkyl when named, e.g. C1-3 alkoxy C3-8 cycloalkyl C1-6 alkyl refers to C1-6 alkyl substituted by C3-8 cycloalkyl which in turn is C1-3 alkoxy substituted, e.g.: the structural formula of the methoxycyclobutylmethyl group is as follows:
the terms "alkenyl" and "alkynyl" refer to straight, branched or cyclic unsaturated hydrocarbon groups containing double and triple bonds, preferably 2 to 20 carbon atoms, more preferably 2 to 12 carbon atoms, respectively. Alkenyl, alkynyl includes substituted and unsubstituted alkenyl, alkynyl groups. When substituted, the substituents may be substituted at any available point of attachment, and the substituents may be mono-or polysubstituted. The 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 usually preceded by alkenyl, alkynyl when named.
The term "cycloalkyl" refers to a saturated and/or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group. A single ring may comprise 3-10 carbon atoms. Non-limiting examples of monocyclocycloalkane 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 substituent is selected from one or more substituent groups, including but not limited to the following groups, independently selected from alkyl, cycloalkyl, alkoxy, halogen, carboxyl, ester group, amino, amido, hydroxyl, cyano, nitro, aryl, heteroaryl.
The term "aryl" refers to a 6-to 10-membered all-carbon monocyclic or polycyclic aromatic group, including phenyl, naphthyl, biphenyl, and the like. Aryl groups may be substituted and unsubstituted. The 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 a group of a heteroaromatic system comprising 1-10 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, etc. 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 alkyl, cycloalkyl (cyclopropane, cyclobutane, and 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" means fluorine, chlorine, bromine, iodine, preferably fluorine, chlorine, bromine.
The term "deuterium" is an isotope of hydrogen with an atomic mass 2 times that of the latter and is more strongly bound to carbon. Deuterated "and" deuterium "indicate that hydrogen is replaced with deuterium at the indicated position. One "deuterated substituent" is a substituent wherein at least one hydrogen is replaced with deuterium enriched in the specified percentage.
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. The heterocyclic group includes a mono-heterocyclic group and a poly-heterocyclic group.
The present invention further provides a method for preventing or treating HBV infection diseases. In one embodiment, the present 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 present invention. In one embodiment, the invention further provides the use of a compound of the invention in the manufacture of a medicament for delaying or reducing HBV infection.
It is to be understood that the invention is not limited to the particular embodiments shown and disclosed herein, and that various changes and modifications may be made without departing from the spirit and scope of the invention as defined by the appended 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 chemical processes. The compounds and processes of the present invention may be better understood by reference to the following representative synthetic schemes and examples, which are intended as illustrative 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 changes and modifications including, but not limited to, chemical structures, substituents, derivatives, and/or methods of the invention 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
Figure RE-GDA0002243597200000201
Preparation of Compound a-3
Adding metal magnesium chips (245mg,10mmol) into 5mL of anhydrous tetrahydrofuran, adding 5mg of iodine, heating to 70 ℃, stirring for 30 minutes, slowly dropwise adding a-1(3.4g,10mmol) tetrahydrofuran (10mL), after dropwise adding, stirring the reaction solution for two hours at 70 ℃, and cooling to room temperature for later use.
Dissolving the compound a-2(1.7g,10mmol) in 10ml of tetrahydrofuran and cooling to zero degree, dropwise adding a prepared Grignard reagent under stirring, stirring the reaction solution at zero degree for 1 hour, and dropwise adding 10ml of saturated ammonium chloride solution to quench the reaction. Extracting twice with ethyl acetate (35 ml X2), combining the organic phases, drying over anhydrous sodium sulfate, filtering, rotary evaporating to remove the solvent, and removing the residueThe residue was purified by column chromatography on silica gel (hexane/ethyl acetate 15:1 to 2:1) to give compound a-3(260mg, 60%). LCMS (ESI) M/z ([ M +1 ]]+)432.2。
Preparation of Compound a-4
To compound a-3(4.32g,10mmol) and palladium on carbon (10%, 540 mg) was added methanol 35 ml, 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 removed by rotary evaporation, and the residue purified by column chromatography on silica gel (hexane/ethyl acetate 15:1 to 1:1) to give compound a-4 (2.04g, 72%). LCMS (ESI) M/z ([ M +1 ]]+)284.2。
Preparation of Compound a-6
To compound a-4(2.83g, 10mmol) was added 2N hydrochloric acid (20.0mL) and cooled to zero, 2N sodium nitrite solution (12 mL, 12mmol) was slowly added dropwise, after 1 hour, an aqueous solution (15 mL) of a-5(1.28 g,10mmol) was added and stirred at room temperature for 3 hours. Extracted twice with ethyl acetate (40ml 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 column chromatography on silica gel (hexane/ethyl acetate 15:1 to 4:1) to give compound a-6(2.45g, 66%). LCMS (ESI) M/z ([ M +1 ]]+) 373.2。
Preparation of Compound a-8
Compound a-6(3.73 g,10mmol) was dissolved in methanol (30ml), and 2N sodium hydroxide solution (15ml, 30 mmol) was added dropwise and stirred at room temperature for 15 hours. Extraction with ether twice (15mL X2), pH adjustment of the aqueous phase to 5 with 1N hydrochloric acid, extraction with ethyl acetate twice (40mL X2), combination of the organic phases, drying over anhydrous sodium sulfate, filtration, and rotary evaporation to remove the solvent gave compound a-7(3.44g, 96%). Polyphosphoric acid (15 g) was added and heated to 70 ℃ and stirred for 5 hours, after cooling diluted with 100ml 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(2.65g, 78%). LCMS (ESI) M/z ([ M +1 ]]+)341.2。
Preparation of Compound a-9
To a solution of a-8(680mg,2.0mmol) in dichloromethane (4mL) was added benzylamine (215mg,2.0mmol) and cooled to zero degrees. To the mixture was slowly added dropwise a 1M titanium tetrachloride solution (2.0mL, 2.0mmol), gradually warmed to room temperature, stirred for 16 hours, filtered, and the solvent was evaporated under reduced pressure. Add a-10(696mg,4.0mmol) and diphenyl ether (4mL), heat to 160 ℃, stir for 4 hours, cool to room temperature. Diluted with 30mL of ethyl acetate, washed three times with water (3X 10mL), the organic phase dried over anhydrous sodium sulfate, filtered, rotary evaporated to remove the solvent and the residue purified by column chromatography on silica gel (dichloromethane/methanol 50:1 to 20:1) to give compound a-11(238mg, 22%). LCMS (ESI) M/z ([ M +1 ]]+)540.2。
Preparation of Compound II-4a
Compound a-11(270 mg,0.5mmol) was dissolved in 4ml dichloromethane and cooled to-78 ℃. To the solution was added dropwise a 1.0M boron trichloride dichloromethane solution (1.0 ml, 1.0mmol), and the mixture was stirred at-78 ℃ for 2 hours. The reaction was quenched by the addition of sodium bicarbonate (170 mg,2.0mmol), 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, 4ml), 1M lithium chloride solution (1ml, 1mmol) was added dropwise, reacted at room temperature for 6 hours, PH adjusted to 5 with 1N hydrochloric acid, extracted three times with dichloromethane (20ml X3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, rotary evaporated to remove the solvent and the residue was purified by silica gel column chromatography (dichloromethane/methanol 50:1 to 10:1) to give compound II-4a (174mg, 80%). LCMS (ESI) M/z ([ M +1 ]]+)436.2。
The 20 mg mixture of enantiomers was separated by HPLC using a chiral column (ChiralPack AD) to give enantiomer 1(3.5mg) and enantiomer 2(5.4 mg). For both compounds, LCMS (ESI) M/z ([ M + 1)]+)436.2。
Example 2
Synthesis of Compound II-3a
Figure RE-GDA0002243597200000221
Preparation of Compound a-12
To compound a-11(135 mg, 0.25 mmol), Pd (PPh)3)2Cl2(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, 0.3mmol), ethyl acetate (1ml) was added, reacted at 70 ℃ for 24 hours, filtered, rotary evaporated to remove the solvent, and the residue was purified by silica gel column chromatography (dichloromethane/methanol 50:1 to 20:1) to give compound a-12(69mg, 46%). LCMS (ESI) M/z ([ M +1 ]]+)602.2。
Preparation of Compound II-3a
Using compound a-12 as a starting material, and referring to the preparation method of compound II-4a, compound II-3a was synthesized, and 20 mg of the enantiomeric mixture was separated by HPLC using a chiral column (ChiralPack AD) to obtain enantiomer 1(3.0mg) and enantiomer 2(5.1 mg). For both compounds, LCMS (ESI) M/z ([ M + 1)]+)426.2。
Example 3
Synthesis of Compound II-93
Figure RE-GDA0002243597200000231
Preparation of Compound a-15
Compound a-13(3.39g,10mmol), a-14(2.55g,10mmol), Pd (PPh)3)Cl2(0.7g,1.0mmol) and potassium acetate (1.96g,20mmol) were added 1, 4-dioxane (40ml), stirred at 100 ℃ for 15 hours, cooled and diluted with 60ml of water, extracted three times with ethyl acetate (40ml X3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the solvent evaporated off to give 3.48 g, 90% of crude product. LCMS (ESI) M/z ([ M +1 ]]+)388.2。
Preparation of Compound a-16
To compound a-15(3.88g,10mmol) was added tetrahydrofuran (30mL), hydrogen peroxide (30%, 2mL, 20.3mmol) and hydrogen hydroxide at zero degreesSodium (2M, 10ml, 20mmol) 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 (30ml X3). The combined organic phases were washed twice with brine (25 ml X2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the solvent and the crude product was purified by silica gel column chromatography (hexane/ethyl acetate 40:1 to 1:1) to give compound a-16(1.52g, 55%). LCMS (ESI) M/z ([ M +1 ]]+)278.1。
Preparation of Compound a-18
To compounds a-16(2.77g,10mmol), a-17(1.29g,10mmol) and triphenylphosphine (2.63g, 10mmol) was added tetrahydrofuran (25 ml) at zero degrees, diisopropyl azodicarboxylate (2.5g,12.5mmol) was added dropwise, and the reaction mixture was stirred at 40 degrees overnight. Diluted with 50ml of water and extracted 3 times with ethyl acetate (30ml X3). The combined organic phases were washed twice with brine (25 ml X2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the solvent and the crude product was purified by silica gel column chromatography (hexane/ethyl acetate 40:1 to 1:1) to give compound a-18 (2.75g, 58%). LCMS (ESI) M/z ([ M +1 ]]+)476.1。
Preparation of Compounds a-19
To compound a-18(4.75g,10mmol) 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, rinsed twice with methanol (25 ml X2), the solvent removed by rotary evaporation, and the residue purified by column chromatography on silica gel (hexane/ethyl acetate 15:1 to 1:1) to give compound a-19(2.04g, 72%). LCMS (ESI) M/z ([ M +1 ]]+)342.2。
Preparation of Compound a-20
To compound a-19(3.41g, 10mmol) was added 2N hydrochloric acid (20.0mL) and cooled to zero, 2N sodium nitrite solution (12 mL, 12mmol) was slowly added dropwise, after 1 hour, an aqueous solution (15 mL) of a-5(1.28 g,10mmol) was added and stirred at room temperature for 3 hours. Extracting twice with ethyl acetate (40ml X2), combining the organic phases, drying over anhydrous sodium sulfate, filtering, rotary evaporating to remove the solvent, and purifying the residue by column chromatography on silica gel (hexane/ethyl acetate 15:1 to 4:1) to give compound a-20(2.45 g),66％)。LCMS(ESI)m/z([M+1]+) 431.2。
Preparation of Compound a-22
Trifluoroacetic acid/dichloromethane (1:1, 20ml) was added to compound a-20(2.15 g, 5mmol), stirred at room temperature for 2 hours,
the solvent was removed by rotary evaporation. Polyphosphoric acid (15 g) was added to the resulting compound a-19, and heated to 70 degrees and stirred for 6 hours, after cooling, diluted with 100ml of 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-22(1.28g, 72%). LCMS (ESI) M/z ([ M +1 ]]+) 357.2。
Preparation of Compound a-24
To a solution of a-22(712mg,2.0mmol) in dichloromethane (4mL) was added benzylamine (215mg,2.0mmol) and cooled to zero degrees. To the mixture was slowly added dropwise a 1M titanium tetrachloride solution (2.0mL, 2.0mmol), gradually warmed to room temperature, stirred for 16 hours, filtered, and the solvent was evaporated under reduced pressure. Add a-10(696mg,4.0mmol) and diphenyl ether (4mL), heat to 160 ℃, stir for 4 hours, cool to room temperature. Diluted with 30mL of ethyl acetate, washed three times with water (3 × 10mL), the organic phase dried over anhydrous sodium sulfate, filtered, rotary evaporated to remove the solvent and the residue purified by column chromatography on silica gel (dichloromethane/methanol 50:1 to 20:1) to give compound a-24(345mg, 31%). LCMS (ESI) M/z ([ M +1 ]]+)558.2。
Preparation of Compound II-93
Compound II-93 was synthesized in accordance with the procedure for Compound II-4a, starting from compound a-24(278 mg,0.5 mmol). The 20 mg mixture of enantiomers was separated by HPLC using a chiral column (ChiralPack AD) to give enantiomer 1(3.5mg) and enantiomer 2(4.5 mg). For both compounds, LCMS (ESI) M/z ([ M + 1)]+) 454.2。
The following compounds were synthesized in a similar manner
Figure RE-GDA0002243597200000241
Figure RE-GDA0002243597200000251
Example 4
Preparation of Compound I-1
Figure RE-GDA0002243597200000252
Preparation of Compound b-2
2-bromo-4-hydroxy-5-methoxybenzaldehyde b-1(10.3g,44.6mmol) and hydroxylamine hydrochloride (9.3g) were dissolved in hot formic acid (155 ml). The solution was heated to boiling point and then anhydrous sodium acetate (22.0g) was added. The mixture was refluxed for 2 hours. Acetic anhydride (18.2g) 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 (20ml) and dried to give compound b-2 in a yield of 9.4g (92%).1H 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 (24.9g,162.7mmol) was added dropwise to a suspension of b-2(12.3g, 54.2mmol) and anhydrous potassium carbonate (22.5g, 162.8mmol) in DMF (20mL), stirred overnight at room temperature, poured into water, extracted three times with ethyl acetate, the combined organic phases 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(7.5g,25.0mmol), Pd2(dba) (460mg,0.5mmol), xantphos (580mg, 1.0mmol) and sodium tert-butoxide (4.3g, 45.0mmol) was added anhydrous THF (100mL), the mixture was evacuated and charged with nitrogen three times, 3-methylbutan-2-one (3.3g, 38.3mmol) was added, the reaction was heated at 50 ℃ for 4-6 hours under nitrogen, cooled, filtered over celite,the filtrate was concentrated under reduced pressure to give the crude product b-4(5.2g, 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(5.2g, 17.0mmol) and ammonium acetate (22g, 285.4mmol) in methanol (60mL) was cooled in an ice bath, sodium cyanoborohydride (2.4g,38.2mmol) was added portionwise, the reaction was allowed to warm 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 compound b-5, 4.8g, 91.7%. The reaction was carried out without further purification. LC-MS: [ M + H]+：307.4。
Preparation of Compound b-6
The crude compound b-5 (4.8g,15.6mmol) was dissolved in DMSO (50mL) 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 (3.8g, 79.2%). LC-MS: [ M + H]+：307.3。
Preparation of Compound b-7
B-6(614mg,2.0mmol), a-10(696mg,4.0mmol) and diphenyl ether (4mL) were added to the reaction flask, and the reaction mixture was heated to 160 deg.C, stirred for 4 hours, and cooled to room temperature. Diluted with 30mL of ethyl acetate, washed three times with water (3 × 10mL), the organic phase dried over anhydrous sodium sulfate, filtered, rotary evaporated to remove the solvent and the residue purified by column chromatography on silica gel (dichloromethane/methanol 50:1 to 20:1) to give compound b-7(216mg, 26%). LCMS (ESI) M/z ([ M +1 ]]+)417.2。
Preparation of Compound I-1
Dissolving compound b-7(208 mg,0.5mmol) in tetrahydrofuran/water (1:1, 4ml), adding 1M lithium chloride solution (1ml, 1mmol) dropwise, reacting at room temperature for 6 hours, adjusting pH to 5 with 1N hydrochloric acid, extracting with dichloromethane three times (20ml X3), combining organic phases, drying with anhydrous sodium sulfate, filtering, rotary evaporating to remove solventThe reagent and the residue were purified by column chromatography on silica gel (dichloromethane/methanol 50:1 to 10:1) to obtain Compound I-1(157mg, 78%). LCMS (ESI) M/z ([ M +1 ]]+)403.3。
The 20 mg mixture of enantiomers was separated by HPLC using a chiral column (ChiralPack AD) to give enantiomer 1(3.8mg) and enantiomer 2(5.6 mg). For both compounds, LCMS (ESI) M/z ([ M + 1)]+)403.3。
Example 5
Preparation of Compound III-13
Figure RE-GDA0002243597200000271
Preparation of Compound c-2
Compound c-1(880mg, 7.78mmol) was suspended in water (13mL) and cooled on an ice bath. Sodium hydroxide (560mg, 14.0mmol) was added to make a solution, and then a 5% aqueous sodium hypochlorite solution (11.6mL, 7.78mmol) was added dropwise 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 a 5% aqueous sodium hypochlorite solution (2.32mL, 1.56mmol) was added dropwise. After stirring for 10 minutes, the temperature was raised to room temperature. After stirring for 72 hours, the pH was adjusted to 2 by addition of 6N hydrochloric acid, 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
The obtained compound c-2 was suspended in water (7mL), and potassium carbonate (2.01g, 14.6mmol) was added to prepare a solution. Iodine (1.06g, 4.16mmol) was added and stirred for 18 hours, then saturated aqueous sodium thiosulfate solution was added. The pH was adjusted to 2 by 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(1.94g, 91%). LC-MS: [ M + H]+：274.2
Preparation of Compound c-4
1-bromo-3-methoxypropane (24.9g,162.7mmol) was added dropwise to c-3(14.8g, 54.2mmol)mmol) and anhydrous potassium carbonate (22.5g, 162.8mmol) in DMF (20mL) were stirred at room temperature overnight, poured into water, extracted three times with ethyl acetate, the combined organic phases washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and the residue purified by silica gel column (0-40% ethyl acetate/hexanes) to give compound c-4(14.7g, 78.6%). LC-MS: [ M + H]+：346.1。
Preparation of Compound c-5
Zinc cyanide (1.3g, 11mmol), zinc powder (72mg, 1.1mmol) and [1, 1-bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (0.86g, 1.2mmol) was added to a solution of c-4(8.15g, 23.6mmol) in N, N-dimethylformamide (30 mL). The reaction mixture was stirred at 140 ℃ for 13 h, then diluted with tert-butyl methyl ether (100mL) and water (75mL) and filtered through a pad of celite. The aqueous layer of the filtrate was extracted with additional tert-butyl methyl ether (3X 50mL) and the combined organic layers were washed with saturated aqueous sodium chloride (8X 30mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give product c-5(3.65g, 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(2.02g, 8.26mmol, 1.0 equiv). It was then dissolved in anhydrous THF (5.00mL) and the reaction mixture was cooled to 0 ℃. Compound c-6(866mg, 8.40mmol, 1.02 equiv.) was then added to the reaction mixture. After the reaction mixture was stirred for 15 minutes, a solution of potassium tert-butoxide (9.10mL, 1.0M in THF, 9.10mmol, 1.1 eq.) was slowly added dropwise to maintain the internal temperature below 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. The filtrate was added dropwise to concentrated hydrochloric acid (0.70mL, 8.34mmol, 1.01 equiv.) and the precipitated solid was filtered and washed with 2-MeTHF (2X 5mL) to give compound c-7(2.16g, 72%). LC-MS: [ M + H]+：328.2。
Preparation of Compound c-8
Adding the compound c-7(364.3mg, 1.00mmol) followed by magnesium ethoxide (0.257g, 2.20 mmol). The vial was sealed with a teflon cap and then evacuated and refilled with nitrogen 3 times. Then anhydrous methanol (1mL) was added to the vial. After stirring the vial for 20 minutes, 2-MeTHF (3mL) 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 half-saturated aqueous ammonium chloride (5mL), 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(240.3mg, 73.3%). LC-MS: [ M + H]+：328.1。
Preparation of Compound c-9
C-8(655mg,2.0mmol), a-10(696mg,4.0mmol) and diphenyl ether (4mL) were added to the reaction flask, and the reaction mixture was heated to 160 deg.C, stirred for 4 hours, and cooled to room temperature. Diluted with 30mL of ethyl acetate, washed three times with water (3X 15mL), the organic phase dried over anhydrous sodium sulfate, filtered, and the solvent removed by rotary evaporation, and the residue purified by column chromatography on silica gel (dichloromethane/methanol 50:1 to 20:1) to give compound c-9(201mg, 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, 4ml), 1M lithium chloride solution (1ml, 1mmol) was added dropwise, reacted at room temperature for 6 hours, the PH was adjusted to 5 with 1N hydrochloric acid, extracted three times with dichloromethane (30ml 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 III-13(137mg, 81%). LCMS (ESI) M/z ([ M +1 ]]+)424.3。
The 20 mg mixture of enantiomers was separated by HPLC using a chiral column (ChiralPack AD) to give enantiomer 1(3.6mg) and enantiomer 2(5.5 mg). For both compounds, LCMS (ESI) M/z ([ M + 1)]+)424.3。
Example 6
Preparation of Compound III-15
Figure RE-GDA0002243597200000291
Preparation of Compound c-10
Compound c-10 was synthesized in a yield of 43% by reference to the method for producing compound a-12 using compound c-9 as a starting material. 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 of compound II-4a, a mixture of 20 mg enantiomers of compound III-15 was synthesized and separated by HPLC using a chiral column (ChiralPack AD) to give enantiomer 1(3.4mg) and enantiomer 2(5.3 mg). For both compounds, LCMS (ESI) M/z ([ M + 1)]+)414.2。
The following compounds were synthesized in a similar manner
Figure RE-GDA0002243597200000292
Figure RE-GDA0002243597200000301
Example 7
Preparation of Compound IV-1
Figure RE-GDA0002243597200000302
Preparation of Compound d-2
4-hydroxy-3, 3-dimethylbutan-2-one (43g, 370mmol), benzyl bromide (48.4ml, 407mmol) and DIPEA (71.1ml, 407mmol) were charged to a 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.1HNMR(400MHz,CDCl3)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 were added d-2(5g, 24.24mmol) and methanol (300mL), cooled to below 0 ℃ with an ice-methanol bath, and a solution of bromine (1.44mL, 27.9mmol) in methanol (50mL) 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 organic is dried and concentrated to obtain the desired product d-3 with quantitative yield, which is directly used without purification.1H 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 THF (50mL) was added to 4- (difluoromethoxy) -1H-indole-2-carboxylic acid (1.95g, 8.58mmol), which was dissolved by heating and then cooled to room temperature. A2M solution of lithium aluminum hydride in THF (6.44mL, 12.88mmol) was then added. Stir at room temperature for 3 hours until the reaction is complete (LC-MS detection). The reaction was cooled in an ice bath and then carefully quenched by dropwise addition of excess water (2ml) and magnesium sulfate was added as the salt 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
The solution containing d-5(3.90g, 18.3mmol) and dry dichloromethane (50ml) was cooled in an ice water bath and manganese (IV) oxide (7.93g, 91.2mmol) was added with stirring. The reaction mixture was allowed to warm 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 silica gel column separation of the crude product using ethyl acetate/petroleum ether as eluent gave compound d-6(3.09g, 80%). LC-MS (m/z): 212.2[ M + H]+。
Preparation of Compound d-7
Compound d-6(2.36g,11.2mmol) and hydroxylamine hydrochloride (2.33g) were dissolvedIn hot formic acid (40 ml). The solution was heated to boiling point and then anhydrous sodium acetate (5.5g) 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 (10ml) and dried to give compound d-7 in 1.51g (65%). LC-MS (m/z): 209.0[ M + H]+。
Preparation of Compound d-8
To a solution of compound h-7(1.74g, 8.37mmol) in DMF (40mL) at room temperature was added sodium hydride (60%, 668mg, 16.7mmol) in portions and stirring was continued for 15 min. Then compound d-3(4.29g, 15mmol) was added and stirred overnight at room temperature. Adding 250ml ethyl acetate, washing with saturated bicarbonate, water, saturated salt solution, drying over anhydrous sodium sulfate, filtering and concentrating, and purifying the residue with silica gel column (0-20% ethyl acetate/hexane); compound d-8(2.35g, 68%) was obtained. LC-MS (m/z): 413.3[ M + H]+。
Preparation of Compound d-9
A mixture of compound d-8(2.1g, 5.1mmol) and ammonium acetate (6.6g, 85.6mmol) in methanol (20mL) was cooled in an ice bath, sodium cyanoborohydride (0.72g,11.5mmol) was added portionwise, the reaction was allowed to warm 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 compound d-9, 1.51g, 71.5%. The reaction was carried out without further purification. LC-MS: [ M + H]+：414.3。
Preparation of Compound d-10
To a dry reaction flask was added compound d-9(413.5mg, 1.00mmol) followed by magnesium ethoxide (0.257g, 2.20 mmol). The vial was sealed with a teflon cap and then evacuated and refilled with nitrogen 3 times. Then anhydrous methanol (1mL) was added to the vial. After stirring the vial for 20 minutes, 2-MeTHF (3mL) 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 half-saturated aqueous ammonium chloride (5mL), and the mixture was extracted with ethyl acetate. MergingThe organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give a crude product, which was purified by column chromatography (0-15% methanol/dichloromethane) to give compound d-10(262mg, 61.3%). LC-MS: [ M + H]+：428.2。
Preparation of Compound d-11
D-10(428mg,1.0mmol), a-10(348mg,2.0mmol) and diphenyl ether (2mL) were added to the reaction flask, and the reaction mixture was heated to 160 deg.C, stirred for 4 hours, and cooled to room temperature. Diluted with 30mL of ethyl acetate, washed three times with water (3X 15mL), the organic phase dried over anhydrous sodium sulfate, filtered, and the solvent removed by rotary evaporation, and the residue purified by column chromatography on silica gel (dichloromethane/methanol 50:1 to 20:1) to give compound d-11(136.1mg, 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 boron trichloride dichloromethane solution (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 (68mg, 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, 2ml), 1M lithium chloride solution (0.4 ml, 0.4 mmol) was added dropwise, reacted at room temperature for 6 hours, PH adjusted to 5 with 1N hydrochloric acid, extracted three times with dichloromethane (20ml X3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, rotary evaporated to remove the solvent and the residue was purified by silica gel column chromatography (dichloromethane/methanol 50:1 to 10:1) to give compound IV-1(68mg, 81%). LCMS (ESI) M/z ([ M +1 ]]+)420.2。
The 20 mg mixture of enantiomers was separated by HPLC using a chiral column (ChiralPack AD) to give enantiomer 1(3.3mg) and enantiomer 2(5.1 mg). For both compounds, LCMS (ESI) M/z ([ M + 1)]+)420.2。
The following compounds were synthesized in a similar manner
Figure RE-GDA0002243597200000331
Biological assay
Test for inhibiting activity of hepatitis B surface antigen by compound
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% non-essential amino acids, Invitrogen-11140050; 2mM L-glutamine, Invitrogen-25030081; 300. mu.g/ml geneticin, Invitrogen-10131027)
2. The specific steps refer to the product specification (hepatitis B virus surface antigen magnetic particle chemiluminescence quantitative detection kit CM0310, Zhengzhou Antu bioengineering, Inc. of China)
The steps are briefly described as follows:
HepG2.2.15 cell (4X 10)4Cells/well) to 96-well plates at 37 ℃, 5% CO2The culture was carried out overnight. The next day, compounds were diluted for a total of 8 concentrations, 3-fold gradient dilutions. Different concentrations of compounds were added to the culture wells, and the wells were double plated. The final concentration of DMSO in the culture broth was 0.5%. 0.5% DMSO served as 0% inhibition control. On the fifth day, fresh medium containing compound was replaced. Collecting culture solution from the culture hole on the eighth day, and taking part of samples to measure the content of the hepatitis B virus surface antigen by ELISA.
3. The percent inhibition for each compound was calculated using the following formula: inhibition (%) - (1-value in sample/DMSO control) x 100%. Percent inhibition of HBV by each compound was fitted to a dose-response curve using GraphPadprism software and the 50% inhibitory concentration (EC) of the compound against hepatitis B surface antigen was calculated50) The value is obtained.
Test result of compound for inhibiting activity of hepatitis B surface antigen
Figure RE-GDA0002243597200000332
Figure RE-GDA0002243597200000341
Figure RE-GDA0002243597200000351
Figure RE-GDA0002243597200000361
0.1nM≤+++++≤1nM；1nM≤++++≤10nm；10nm≤+++≤50nM；50nm≤++≤ 150nM
From the above results, it is understood that most of the compounds showed a high inhibitory effect against hepatitis b surface antigen, and therefore, the compounds of the examples can be used for the preparation of a therapeutic drug for the symptoms/diseases induced by hepatitis b virus infection.

Claims (10)

1. A polycyclic compound characterized by: a compound of formula (I) or a salt, solvate, geometric isomer, stereoisomer, tautomer, and any mixture thereof:
Figure FDA0002224135270000011
wherein:
(1)W1selected from oxygen, sulfur;
(2) z is selected from N and CR7；
(3)W2Selected from (a) COOR8；(b)-CONHR8；(c)-CONH0R8；(d)-NHNHR8；(e)-NHNHC(＝0)R8；(f)-NHS(＝0)2R8；
(g) A 4-8 membered heteroaromatic ring which is unsubstituted or substituted with one or more substituents selected from halogen, OH, mercapto, nitro, amino, cyano; (h) NHCOR9Wherein R is9Is amino, unsubstituted or selected from halogen, OH, mercapto, nitroAmino substituted by one or more substituents of amino, carboxyl and cyano; (i) c (═ O) N (R)10)SO2R11Wherein R is10Selected from hydrogen, methyl or cyclopropane, R11The amino group is unsubstituted or substituted by one or more substituents selected from halogen, OH, sulfydryl, nitro, amino, carboxyl and cyano; boric acid; phosphoric acid and nitrogen-containing heterocycles;
(4) a is selected from a single bond or a double bond, wherein
(i) a bond is a single bond, Y is selected from O, S, S (═ O)2,NR3And CHR3；
(ii) a bond is a double bond, then Y is CR3And R is2bIs absent;
(5)R1a，R1b，R2aand R2bEach independently selected from hydrogen, hydrocarbon and hydrocarbonoxy substituents, aryl, heteroaryl and substituted cycloalkyl of carbon number 3-8, heterocycloalkyl; or R1a/R1b，R2a/R2bAnd R1a/R2aCombined to form an alkane disubstituent selected from C1-C6 groups, - (CH)2)mO(CH2)m-,-(CH2)mNR5(CH2)m-,-(CH2)mS(CH2)m-,-(CH2)mS(＝0)(CH2)m-,-(CH2)mS(＝0)2(CH2)m-, wherein m is independently selected from 1 or 2, and wherein each divalent group is optionally substituted by at least one C1-C6Alkyl or halogen substitution;
(6)X1selected from the group consisting of CR4IOr N;
X2selected from the group consisting of CR4IIOr N;
X3selected from the group consisting of CR4IIIOr N;
X4selected from the group consisting of CR4IVOr N;
X5is selected from C;
X4and X5Combine to form-N-at the same timeCR4IIAnd CR4IIICombined to form a substituted aromatic ring having 0-4 substituents R12；
X3And X4Or X1And X2Combine to form-S-, -O-; or
Wherein the substituent X1，X2，X3And X4N selected from 0-2, each optionally substituted with alkyl of carbon number 1-6 if adjacent carbon atoms in the ring are substituted with-OH;
R4I，R4II，R4IIIand R4IVIndependently selected from the group consisting of one OR more structural units comprising H, halogen, cyano, substituted alkyl of carbon number 1 to 6, substituted cycloalkyl of carbon number 3 to 8, substituted alkynyl of carbon number 2 to 6, -OR, -SR, -N (R), substituted heterocyclyl and haloalkoxy of carbon number 1 to 6;
wherein R is independently selected from H, C1-C6Alkyl, R' substituted C1-C6Alkyl radical, C1-C6Hydroxyalkyl, substituted (C)1-C6Alkoxy group) - (C1-C6Alkyl), substituted C3-C8A cycloalkyl group;
wherein R' is selected from-NH2，-NH(C1-C6Alkyl group), -N (C)1-C6Alkyl) (C1-C6Alkyl), -NHC (C ═ 0)0tBu，-N(C1-C6Alkyl) C (═ 0) OtBu or a 5 or 6 membered heterocyclyl, which is optionally N-linked;
or X2Is CR4II，X3Is CR4IIIAnd R is4IIAnd R4IIICombine to form a divalent group selected from-0 (CR)5R6)0-，-0(CR5R6)(CR5R6)0-，-0(CR5R6)(CR5R6) -and-0 (CR)5R6)(CR5R6)(CR5R6)-；
Or X3Is CR4III，X4Is CR4IV，R4IIIAnd R4IVCombine to form a divalent group selected from-0 (CR)5R6)0-，-0(CR5R6)(CR5R6)0-，-0(CR5R6)(CR5R6) -and-0 (CR)5R6)(CR5R6)(CR5R6)-；
(7)R3May be independently selected from H, substituted C1-C6Alkyl, substituted C3-C8A cycloalkyl group;
(8)R5selected from H and C1-C6An alkyl group;
(9)R6selected from H, OH, C1-C6Alkyl radical, C1-C6Alkoxy, alkoxy-C1-C6Alkyl and alkoxy-C1-C6An alkoxy group; wherein two R are6The radicals bound to the same carbon atom not being OH at the same time, wherein R6Is not OH if bonded to a carbon further bonded to an oxygen atom;
or two R6The radicals are combined with the carbon atom to which they are bonded to form a radical selected from the group consisting of C ═ 0, C ═ CH2And oxetane-3, 3-diyl moieties;
(10)R7selected from H, OH, halogen, substituted C1-C6Alkoxy, substituted C1-C6Alkyl and substituted C3-C8Cycloalkyl or heterocycloalkyl;
(11)R8substituents selected from hydrogen, hydrocarbons oxides;
(12)R9selected from hydrogen, halogen, OH, mercapto, nitro, amino, carboxyl, cyano, or R9Substituents selected from the group consisting of hydrocarbon and hydrocarbonoxy;
(13)R10selected from hydrogen, methyl, cyclopropane;
(14)R11the amino group is unsubstituted or substituted by one or more substituents selected from halogen, OH, sulfydryl, nitro, amino, carboxyl and cyano;
(15)R12is selected fromH. Halogen, OH, mercapto, nitro, amino, carboxyl or cyano; or R12Substituents selected from the group consisting of hydrocarbon and hydrocarbonoxy;
(16) the hydrocarbon and hydrocarbonoxy substituent comprises saturated or unsaturated hydrocarbon or hydrocarbonoxy with carbon number of 1-20, which is unsubstituted or substituted by one or more substituents selected from halogen, OH, mercapto, nitro, amino, carboxyl and cyano, and which is uninterrupted or interrupted by 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 independently substituted by one or more deuterium atoms.
2. A polycyclic compound according to claim 1, characterized in that: it is selected from:
Figure FDA0002224135270000031
Figure FDA0002224135270000041
3. polycyclic compound according to claim 1 or 2, characterized in that: any one of the compounds, at least one suitable:
(a)X1，X2，X3and X40-2N in the total;
(b)R1aor R1bAt least one of which is independently selected from substituted C1-C6Alkyl and substituted C3-C8A cycloalkyl group.
4. Polycyclic compound according to claim 1 or 2, characterized in that: wherein at least one compound is suitable: r1aIs H, R1bSelected from methyl, ethyl, isopropyl, butyl, isobutyl, tert-butyl, methoxymethylEthyl, methoxyisopropyl, methoxybutyl, methoxyisobutyl, ethoxymethyl, ethoxyethyl, ethoxyisopropyl, ethoxybutyl, ethoxyisobutyl, hydroxymethyl, hydroxyethyl, hydroxyisopropyl, hydroxybutyl, hydroxyisobutyl; r1aIs methyl, R1bIs isopropyl; r1aIs methyl, R1bIs a tert-butyl group; r1aIs methyl, R1bIs methyl; r1aIs methyl, R1bIs an ethyl group; r1aIs ethyl, R1bIs ethyl.
5. Polycyclic compound according to claim 1 or 2, characterized in that: the compound is one of the compounds represented by the following structural formula:
Figure FDA0002224135270000042
Figure FDA0002224135270000051
Figure FDA0002224135270000061
Figure FDA0002224135270000071
Figure FDA0002224135270000081
Figure FDA0002224135270000091
Figure FDA0002224135270000101
Figure FDA0002224135270000111
Figure FDA0002224135270000121
Figure FDA0002224135270000131
Figure FDA0002224135270000141
Figure FDA0002224135270000151
Figure FDA0002224135270000161
6. a pharmaceutical composition characterized by: the compound of the 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 are contained, and the dosage form of the pharmaceutical composition is preferably a tablet, a capsule or an injection.
7. The pharmaceutical composition of claim 6, wherein: the pharmaceutical composition is an antiviral pharmaceutical composition, and further comprises one or more therapeutic agents; the therapeutic agent is selected from the group consisting of: nucleoside drugs, interferon, ribavirin, HBV capsid inhibitor (capsid inhibitor), cccDNA formation inhibitor, cccDNA epigenetic modifier or hepatitis B RNAi drug, TLR7 agonist.
8. Use of the polycyclic compound according to claim 1 for the preparation of a medicament for the prophylaxis and/or treatment of viral infectious diseases, and/or hepatitis b Surface antigen inhibitors (HBV Surface antigen inhibitors) and hepatitis b DNA inhibitors (HBV DNA production inhibitors).
9. The use of the polycyclic compound according to claim 8 for the preparation of a medicament for the prevention and/or treatment of viral infectious diseases, and/or a medicament for the inhibition of hepatitis b surface antigen and hepatitis b DNA, characterized in that: the viral infection includes infection with HBV or HDV.
10. The use of the polycyclic compound according to claim 8 or 9 for the preparation of a medicament for preventing and/or treating viral infectious diseases, and/or a medicament for inhibiting hepatitis b surface antigen and a medicament for inhibiting hepatitis b DNA, characterized in that: the medicine also contains one or more therapeutic agents selected from nucleoside drugs, interferon, ribavirin, HBV capsid inhibitors, cccDNA formation inhibitors, cccDNA epigenetic modifiers or hepatitis B RNAi drugs, and TLR7 agonists.
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