WO2021143885A1 - 稠合四环类化合物及其在药物中的应用 - Google Patents

稠合四环类化合物及其在药物中的应用 Download PDF

Info

Publication number
WO2021143885A1
WO2021143885A1 PCT/CN2021/072337 CN2021072337W WO2021143885A1 WO 2021143885 A1 WO2021143885 A1 WO 2021143885A1 CN 2021072337 W CN2021072337 W CN 2021072337W WO 2021143885 A1 WO2021143885 A1 WO 2021143885A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
butyl
ring atoms
alkylamino
alkyl
Prior art date
Application number
PCT/CN2021/072337
Other languages
English (en)
French (fr)
Inventor
张英俊
任青云
黄建洲
于方彩
王益锋
Original Assignee
东莞市东阳光新药研发有限公司
广东东阳光药业有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 东莞市东阳光新药研发有限公司, 广东东阳光药业有限公司 filed Critical 东莞市东阳光新药研发有限公司
Publication of WO2021143885A1 publication Critical patent/WO2021143885A1/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/18—Ring systems of four or more rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/14—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicine, and relates to a fused tetracyclic compound and its use as a medicine, especially as a medicine for treating and/or preventing hepatitis B.
  • the present invention also relates to a composition composed of these fused tetracyclic compounds and other antiviral agents, and their application in the treatment and/or prevention of hepatitis B virus (HBV) infection.
  • HBV hepatitis B virus
  • Hepatitis B virus belongs to the family of hepatitis. It can cause acute and/or progressive chronic diseases. Hepatitis B virus can also cause many other clinical manifestations in the pathological form—especially chronic inflammation of the liver, cirrhosis and canceration of liver cells. According to estimates by the World Health Organization, 2 billion people worldwide have been infected with HBV, about 350 million people are chronically infected, and about 1 million people die each year from liver failure, cirrhosis and primary hepatocellular carcinoma caused by HBV infection ( hepatocellular carcinoma, HCC).
  • HBV hepatocellular carcinoma
  • CLB chronic hepatitis B
  • Interferon alpha IFN- ⁇
  • pegylated IFN- ⁇ and 5 nucleoside (acid) analogs Lamivudine, adefovir dipivoxil, entecavir, telbivudine and tenofovir
  • FDA U.S. Food and Drug Administration
  • Interferon is the earliest anti-HBV drug approved by the FDA. It mainly achieves the effect of eliminating the virus through direct antiviral effects and inducing the body's immune response.
  • nucleoside (acid) drugs due to its low response rate, multiple side effects, expensive and limited treatment targets For other reasons, its application is subject to many restrictions.
  • the common point of anti-HBV nucleoside (acid) drugs is that they specifically act on viral DNA polymerase and have a powerful effect of inhibiting virus replication. Patients are better tolerated by drugs than interferon.
  • nucleoside (acid) drugs can induce DNA polymerase mutations to form drug resistance, leading to the continuous emergence of drug-resistant strains, making the treatment far from achieving the desired effect.
  • the invention relates to a new type of fused tetracyclic compound and its use in the preparation of medicines for the treatment and prevention of HBV infection.
  • the inventors found that the novel fused tetracyclic compound related to the present invention has good pharmacokinetic properties, good solubility, low toxicity, good liver microsome stability, and has good effects on the production or secretion of HBsAg and the replication of HBV DNA. Both have good inhibitory activity and other advantages, and they have good application prospects in anti-HBV.
  • the compounds of the present invention and their pharmaceutically acceptable compositions can also effectively inhibit HBV infection.
  • the present invention relates to a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically Acceptable salt or its prodrug,
  • each of R 1 , R 2 , R 3 , R 4 and R 7 is independently hydrogen, deuterium, F, Cl, Br, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy Group, C 2-6 alkynyl, C 2-6 alkenyl, C 3-7 cycloalkyl, phenyl, heteroaryl composed of 5-6 ring atoms or heterocyclic group composed of 3-10 ring atoms , wherein the C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 2-6 alkynyl, C 2-6 alkenyl, C 3-7 cycloalkyl, benzene Group, heteroaryl group composed of 5-6 ring atoms and heterocyclic group composed of 3-10 ring atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w ;
  • R 5 is hydrogen, deuterium, C 1-6 alkyl, C 3-7 cycloalkyl, heterocyclic group composed of 3-6 ring atoms, C 6-10 aryl group or heterocyclic group composed of 5-10 ring atoms Aryl, wherein the C 1-6 alkyl group, C 3-7 cycloalkyl group, heterocyclic group composed of 3-6 ring atoms, C 6-10 aryl group and heterocyclic group composed of 5-10 ring atoms
  • the aryl groups are each independently unsubstituted or substituted with 1, 2, 3, or 4 R j ;
  • R 6 is hydrogen, deuterium, F, Cl, Br, C 1-12 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 2-6 alkynyl, C 2-6 alkenyl, C 3-7 cycloalkyl group, C 6-10 aryl group, heteroaryl group composed of 5-10 ring atoms or heterocyclic group composed of 3-10 ring atoms, wherein the C 1-6 alkyl group, C 1-6 alkylamino, C 1-6 alkoxy, C 2-6 alkynyl, C 2-6 alkenyl, C 3-7 cycloalkyl, C 6-10 aryl, 5-10 ring atoms
  • the heteroaryl group and the heterocyclic group composed of 3-10 ring atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w ;
  • a heteroaryl group composed of atoms, wherein the amino group, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 alkylthio group, C 1-6 alkylamino group, C 2-6 alkenyl group, C 2-6 alkynyl, C 3-7 cycloalkyl, heterocyclic group composed of 3-10 ring atoms, C 6-10 aryl group and heteroaryl group composed of 5-10 ring atoms are each independently Replaced or replaced by 1, 2, 3 or 4 R w ;
  • n 0, 1, 2 or 3.
  • the present invention relates to a compound represented by formula (c-2) or formula (d-6) or a compound represented by formula (c-2) or formula (d-6). Constructs, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs,
  • each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 has the meaning described in the present invention.
  • R 5 in the present invention is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl Group, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, Tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, furanyl, pyrrolyl, Pyridyl, pyrazolyl, imidazo
  • each R j has the meaning described in the present invention.
  • R 6 in the present invention is hydrogen, deuterium, F, Cl, Br, C 1-6 alkyl, C 1-4 alkylamino, C 1-4 alkoxy, C 2-4 Alkynyl, C 2-4 alkenyl, C 3-6 cycloalkyl, phenyl, naphthyl, heteroaryl composed of 5-6 ring atoms or heterocyclic group composed of 3-6 ring atoms, among which The mentioned C 1-6 alkyl, C 1-4 alkylamino, C 1-4 alkoxy, C 2-4 alkynyl, C 2-4 alkenyl, C 3-6 cycloalkyl, phenyl, naphthalene Group, heteroaryl group composed of 5-6 ring atoms and heterocyclic group composed of 3-6 ring atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w ,
  • each R w has the meaning described in the present invention.
  • R 6 in the present invention is hydrogen, deuterium, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Tert-butyl, C 1-4 alkylamino, C 1-4 alkoxy, C 2-4 alkynyl, C 2-4 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl , Naphthyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazine Group, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl,
  • each R w has the meaning described in the present invention.
  • each R w has the meaning described in the present invention.
  • each R w has the meaning described in the present invention.
  • Each of R 1 , R 2 , R 3 , R 4 and R 7 is independently hydrogen, deuterium, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, S-butyl, tert-butyl, C 1-4 alkylamino, C 1-4 alkoxy, ethynyl, propargyl, propynyl, 1-ynbutyl, 2-ynbutyl, 3-ynbutyl Group, C 2-4 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl , Oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl,
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention.
  • the pharmaceutical composition further comprises pharmaceutically acceptable excipients or a combination of such excipients.
  • the pharmaceutical composition of the present invention further comprises other anti-HBV drugs.
  • the pharmaceutical composition of the present invention wherein the other anti-HBV drugs are HBV polymerase inhibitors, immunomodulators or interferons.
  • the pharmaceutical composition of the present invention wherein the other anti-HBV drugs are lamivudine, telbivudine, tenofovir dipivoxil, entecavir, adefovir dipivoxil, Alfaferone, Alloferon , Simo interleukin, clavudine, emtricitabine, faciclovir, interferon, baoganling CP, interferon, interferon alpha-1b, interferon alpha, interferon alpha-2a, interferon beta -1a, Interferon Alpha-2, Interleukin-2, Milvotate, Nitrazoxanide, Pegylated Interferon Alpha-2a, Ribavirin, Ruinterferon-A, Cizonan, Euforavac, Ampligen, Phosphazid, Heplisav, Interferon Alpha-2b, Levamisole, or Propagermanium.
  • the other anti-HBV drugs are lamivudine, tel
  • the present invention also provides the use of the compound or the pharmaceutical composition in the preparation of a medicament for the prevention, treatment or alleviation of viral diseases in patients.
  • the use according to the present invention wherein the viral disease refers to a hepatitis B virus infection or a disease caused by hepatitis B virus infection.
  • the use of the present invention, wherein the disease caused by hepatitis B virus infection refers to liver cirrhosis or hepatocellular carcinoma.
  • the present invention also provides the use of the compound or the pharmaceutical composition in the preparation of a medicament for inhibiting the production or secretion of HBsAg, and/or for inhibiting the production of HBV DNA.
  • the present invention relates to the use of the compound or pharmaceutical composition in the preparation of a medicament for preventing, treating or alleviating hepatitis B disease in patients.
  • Another aspect of the present invention relates to a method of preventing, treating, or alleviating a patient's HBV disorder, the method comprising administering to the patient a pharmaceutically acceptable effective dose of the compound of the present invention.
  • Another aspect of the present invention relates to a method for preventing, treating or alleviating a patient's HBV condition, the method comprising administering to the patient a pharmaceutical composition containing a compound of the present invention in a pharmaceutically acceptable effective dose.
  • Another aspect of the present invention relates to the use of a compound of the present invention in the preparation of a medicine for preventing, treating or treating a patient's HBV disease and reducing its severity.
  • Another aspect of the present invention relates to the use of a pharmaceutical composition containing the compound of the present invention in the preparation of a medicament for preventing or treating a patient's HBV disease and reducing its severity.
  • Another aspect of the present invention relates to a method of inhibiting HBV infection, which method comprises contacting a cell with a compound or composition of the present invention in a dose effective to inhibit HBV. In other embodiments, the method further comprises contacting the cells with other anti-HBV agents.
  • Another aspect of the present invention relates to a method of treating HBV disease in a patient, which method comprises administering to the patient an effective therapeutic amount of a compound of the present invention or a combination thereof. In other embodiments, the method further comprises the administration of other HBV treatments.
  • Another aspect of the present invention relates to a method for inhibiting HBV infection in a patient, which method comprises administering to the patient an effective therapeutic amount of a compound of the present invention or a composition thereof. In other embodiments, the method further comprises the administration of other anti-HBV therapies.
  • Another aspect of the present invention relates to methods for the preparation, separation and purification of compounds contained in formula (I), formula (c-2) or formula (d-6).
  • the present invention will list the documents corresponding to the determined specific content in detail, and the examples are accompanied by diagrams of structural formulas and chemical formulas.
  • the present invention prospectively covers all options, variants and equivalents, which may be included in the current invention field as defined by the claims.
  • Those skilled in the art will recognize many methods and substances similar or equivalent to those described herein, which can be applied in the practice of the present invention.
  • the present invention is by no means limited to the description of methods and materials. There are many documents and similar materials that differ or conflict with the application of the present invention, including but not limited to the definition of terms, the usage of terms, the described technology, or the scope controlled by the application of the present invention.
  • the compound of the present invention is substituted by one or more substituents, such as the compound of the general formula above, or special examples, subclasses, and a class of compounds included in the present invention.
  • substituents such as the compound of the general formula above, or special examples, subclasses, and a class of compounds included in the present invention.
  • substituted means that one or more hydrogen atoms in a given structure are replaced by specific substituents.
  • a substituted group may have a substituent at each substitutable position of the group.
  • substituents of the compounds disclosed in the present invention are disclosed according to the group type or scope.
  • C 1-6 alkyl refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • alkyl used in the present invention includes saturated linear or branched monovalent hydrocarbon groups of 1-20 carbon atoms, wherein the alkyl group may be independently optionally substituted with one or more substituents described in the present invention.
  • the alkyl group contains 1-12 carbon atoms, in other embodiments, the alkyl group contains 1-8 carbon atoms, and in other embodiments, the alkyl group contains 1-6 carbon atoms.
  • the alkyl group contains 1-4 carbon atoms, and in other embodiments, the alkyl group contains 1-3 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), 2-methylpropyl or isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu , -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-
  • haloalkyl means that an alkyl group is substituted with one or more halogen atoms, where the alkyl group has the meaning described in the present invention.
  • the haloalkyl group contains 1-12 carbon atoms; in other embodiments, the haloalkyl group contains 1-10 carbon atoms; in other embodiments, the haloalkyl group contains 1-8.
  • Carbon atoms; in other embodiments, the haloalkyl group contains 1-6 carbon atoms; in other embodiments, the haloalkyl group contains 1-4 carbon atoms, and in other embodiments, the haloalkyl group Contains 1-3 carbon atoms.
  • Such examples include, but are not limited to, trifluoromethyl, trifluoroethyl, and the like.
  • alkylamino and alkylamino are used interchangeably, and include “N-alkylamino” and “N,N-dialkylamino", in which the amino groups are each independently replaced by one or two C 1- 12 Alkyl groups are substituted.
  • the alkylamino group is a lower alkylamino group with one or two C 1-12 alkyl groups attached to the nitrogen atom.
  • the alkylamino group is a C 1-6 alkyl group.
  • the alkylamino group is a C 1-4 lower alkylamino group.
  • Suitable alkylamino groups can be monoalkylamino or dialkylamino.
  • alkylamino group may be independently unsubstituted or substituted with one or more substituents described in the present invention .
  • alkynyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least One position of CC is an sp triple bond, where the alkynyl group may be independently unsubstituted or substituted by one or more substituents described in the present invention.
  • alkynyl group may be independently unsubstituted or be substituted by one or more of the present invention The described substituents are substituted.
  • alkoxy means that the alkyl group is connected to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described in the present invention. Unless otherwise specified, the alkoxy group contains 1-20 carbon atoms. Some examples are that the alkoxy group contains 1-12 carbon atoms. Other examples are that the alkoxy group contains 1-12 carbon atoms. Containing 1-8 carbon atoms, in other embodiments, the alkoxy group contains 1-6 carbon atoms, in other embodiments, the alkoxy group contains 1-4 carbon atoms, and other embodiments Yes, the alkoxy group contains 1-3 carbon atoms.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butane Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ),
  • haloalkoxy means that an alkoxy group is substituted with one or more halogen atoms, wherein the alkoxy group has the meaning described in the present invention.
  • the halogenated alkoxy group contains 1-12 carbon atoms; in other embodiments, the halogenated alkoxy group contains 1-10 carbon atoms; in other embodiments, the halogenated alkoxy group contains 1-8 carbon atoms; in other embodiments, the halogenated alkoxy group contains 1-6 carbon atoms; in other embodiments, the halogenated alkoxy group contains 1-4 carbon atoms, and other embodiments are ,
  • the halogenated alkoxy group contains 1-3 carbon atoms. Such examples include, but are not limited to, trifluoromethoxy and the like.
  • cycloalkyl refers to a saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 ring carbon atoms with one or more points of attachment connected to the rest of the molecule.
  • cycloalkyl is a ring system containing 3-10 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing 3-8 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing 3-8 ring carbon atoms.
  • cycloalkyl is a ring system containing 3-7 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing 5-8 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing 3-6 ring carbons A ring system of atoms; in other embodiments, cycloalkyl is a ring system containing 5-6 ring carbon atoms; examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, and cyclopentyl Group, cyclohexyl, etc., and the cycloalkyl group may be independently unsubstituted or substituted with one or more substituents described in the present invention.
  • heterocyclic group and “heterocyclic ring” are used interchangeably herein, and both refer to a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic or tricyclic ring system containing 3-12 ring atoms, wherein At least one ring atom is selected from nitrogen, sulfur and oxygen atoms, and this ring system has one or more points of attachment to the rest of the molecule.
  • heterocyclyl includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems, and also includes wherein the heterocyclic ring may be combined with one or more non-aromatic carbocyclic or heterocyclic rings or one or more A fused polycyclic ring system of one aromatic ring or a combination thereof, wherein the atom group or point of the connection is on the heterocyclic ring.
  • the heterocyclic group is a ring system composed of 3-12 ring atoms; in other embodiments, the heterocyclic group is a ring system composed of 3-8 ring atoms; in other embodiments, The heterocyclic group is a ring system composed of 3-6 ring atoms; in some other embodiments, the heterocyclic group is a ring system composed of 5-7 ring atoms; in some other embodiments, the heterocyclic group is 5- A ring system composed of 8 ring atoms; in other embodiments, a heterocyclic group is a ring system composed of 6-8 ring atoms; in other embodiments, a heterocyclic group is composed of 5-6 ring atoms Ring system; in other embodiments, the heterocyclic group is a ring system composed of 3 ring atoms; in other embodiments,
  • heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, Morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxygen heterocycle Propyl, azepanyl, oxepanyl, thiepanyl, oxazepin, diazepin, thiazepin, 2-pyrrolinyl, 3-pyrrolinyl , Indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxopentyl, pyrazol
  • the heterocyclic group may be optionally substituted by one or more substituents described in the present invention.
  • MM composed of 1 ring atoms means that the cyclic group is composed of MM 1 ring atoms, and the ring atoms include carbon atoms and/or O, N, S, P and other heteroatoms.
  • heteroaryl group consisting of 6-10 ring atoms represents a heteroaryl group consisting of 6, 7, 8, 9 or 10 ring atoms.
  • heteroatom means one or more O, S, N, P and Si, including any oxidation state of N, S and P; primary, secondary, tertiary amine and quaternary ammonium salt forms; or nitrogen in heterocycle A form in which the hydrogen on the atom is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like N-substituted pyrrolidine) NR and R in the group represent the substituents described in the present invention).
  • halogen or "halogen atom” refers to F, Cl, Br or I.
  • unsaturated means that a part contains one or more degrees of unsaturation.
  • aryl can be used alone or as a large part of “aralkyl”, “aralkyloxy” or “aryloxyalkyl”, meaning it contains 6-14 carbon atoms, or 6-12 carbons Atoms, or monocyclic, bicyclic, and tricyclic carbocyclic ring systems of 6-10 carbon atoms, in which at least one ring system is aromatic, and each ring system contains a ring composed of 3-7 carbon atoms , And there are one or more attachment points connected to the rest of the molecule.
  • aryl can be used interchangeably with the term “aromatic ring” or "aromatic ring”.
  • aryl can include phenyl, naphthyl and anthracenyl.
  • the aryl group may be independently unsubstituted or substituted with one or more substituents described in the present invention.
  • heteroaryl can be used alone or as a large part of “heteroarylalkyl” or “heteroarylalkoxy”, which means a monocyclic, bicyclic or tricyclic ring system containing 5-16 ring atoms, At least one of the ring systems is aromatic, and at least one of the ring systems contains one or more heteroatoms, each of which contains a ring composed of 5-7 ring atoms, and has one or more attachment points with The rest of the molecule is connected.
  • heteroaryl can be used interchangeably with the terms “heteroaromatic ring” or “heteroaromatic compound”.
  • the heteroaryl group is a heteroaryl group consisting of 5-14 ring atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-12 ring atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-10 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-8 ring atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.
  • the heteroaryl group is a heteroaryl group consisting of 5-7 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl group is a heteroaryl group composed of 5-6 ring atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5 ring atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl group is a heteroaryl group composed of 6 ring atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.
  • heteroaryl groups include the following monocyclic groups, but are not limited to these monocyclic groups: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazole Group, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl , 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazine Group), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5H-tetrazolyl, 2H-tetrazolyl), triazolyl (such as 2-triazolyl,
  • the structural formula described in the present invention includes all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, those containing asymmetric centers R and S configurations, (Z) and (E) isomers of the double bond, and (Z) and (E) conformational isomers. Therefore, a single stereochemical isomer of the compound of the present invention or a mixture of its enantiomers, diastereomers, or geometric isomers (or conformational isomers) all belong to the scope of the present invention.
  • nitrogen oxide used in the present invention means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxide.
  • N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms.
  • the corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) to form N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • N-oxides can be prepared by the method of LWDeady (Syn.Comm.1977, 7,509-514), in which, for example, in an inert solvent (such as dichloromethane), an amine compound and m-chloroperoxybenzoic acid ( MCPBA) reaction.
  • an inert solvent such as dichloromethane
  • MCPBA m-chloroperoxybenzoic acid
  • prodrug used in the present invention represents the conversion of a compound into a compound represented by formula (I), formula (c-2) or formula (d-6) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the maternal structure in the blood or tissue.
  • the prodrug compounds of the present invention can be esters. In the existing invention, esters can be used as prodrugs including phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonates. , Carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug.
  • Other prodrug forms include phosphate esters.
  • these phosphate ester compounds are obtained by phosphorylation of the parent hydroxyl group.
  • Metal refers to the product obtained by the metabolism of a specific compound or its salt in the body.
  • the metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by oxidizing, reducing, hydrolyzing, amidating, deamidating, esterifying, degreasing, enzymatic cleavage and the like of the administered compound.
  • the present invention includes the metabolites of the compound, including the metabolites produced by fully contacting the compound of the present invention with a mammal for a period of time.
  • stereochemistry in the present invention usually refer to the following documents: SPParker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.
  • the compounds of the present invention may contain asymmetric centers or chiral centers, so there are different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to, diastereomers, enantiomers, atropisomers, and their mixtures, such as racemic mixtures, constitute the present invention Part.
  • optically active compounds that is, they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D, L or R, S are used to indicate the absolute configuration of the chiral center of the molecule.
  • the prefixes d, l or (+), (-) are used to name the symbols of the plane-polarized light rotation of the compound, (-) or l means that the compound is levorotatory, and the prefix (+) or d means that the compound is dextrorotatory.
  • the chemical structures of these stereoisomers are the same, but their three-dimensional structures are different.
  • a specific stereoisomer may be an enantiomer, and a mixture of isomers is usually called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which may result in no stereoselectivity or stereospecificity in the chemical reaction process.
  • the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomers, lacking optical activity.
  • tautomer or "tautomeric form” means that the structural isomers of different energies can be converted into each other through a low energy barrier.
  • proton tautomers ie, proton-transferred tautomers
  • Atomic (valence) tautomers include the interconversion of recombined bond electrons.
  • the "pharmaceutically acceptable salt” used in the present invention refers to the organic and inorganic salts of the compound of the present invention.
  • Pharmaceutically acceptable salts are well known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977.
  • Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or through other methods described in books and literature such as ion exchange These salts.
  • salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate , Borate, butyrate, camphorate, camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate Acid salt, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactic acid Salt, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate , Pectinate, pers
  • the desired salt can be prepared by a suitable method, for example, using inorganic or organic bases such as ammonia (primary amine, secondary amine, tertiary amine), alkali metal hydroxide, ammonium , N + (R 14 ) 4 salts and alkaline earth metal hydroxides, etc.
  • inorganic or organic bases such as ammonia (primary amine, secondary amine, tertiary amine), alkali metal hydroxide, ammonium , N + (R 14 ) 4 salts and alkaline earth metal hydroxides, etc.
  • Suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, such as primary, secondary and tertiary amines, and N + (R 14 ) 4 salts, such as R 14 is H, C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, etc., and cyclic ammonia, such as piperidine, morpholine and piperazine, etc., and from sodium, Calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium give inorganic salts.
  • amino acids such as glycine and arginine
  • ammonia such as primary, secondary and tertiary amines
  • N + (R 14 ) 4 salts such as R 14 is H, C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, etc.
  • cyclic ammonia such as piperidine,
  • ammonium, quaternary ammonium salts and amine cations formed by counter ions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 sulfonates and Aromatic sulfonate.
  • solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to the association formed by the solvent molecule being water.
  • protecting group refers to when a substituent reacts with another functional group, it is usually used to block or protect a particular functionality.
  • amino protecting group refers to a substituent connected to an amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, and tert-butoxycarbonyl. (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenemethyleneoxycarbonyl (Fmoc).
  • hydroxyl protecting group refers to a substituent of a hydroxyl group used to block or protect the functionality of the hydroxyl group.
  • Suitable protecting groups include acetyl and silyl groups.
  • Carboxyl protecting group refers to the substituent of the carboxyl group used to block or protect the functionality of the carboxyl group.
  • General carboxyl protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane Yl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl) Phosphonyl) ethyl, nitroethyl, etc.
  • protecting groups refer to the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
  • the compounds of the present invention and their pharmaceutically acceptable compositions can effectively inhibit HBV infection.
  • the present invention relates to a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically Acceptable salt or its prodrug,
  • each of R 1 , R 2 , R 3 , R 4 and R 7 is independently hydrogen, deuterium, F, Cl, Br, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy Group, C 2-6 alkynyl, C 2-6 alkenyl, C 3-7 cycloalkyl, phenyl, heteroaryl composed of 5-6 ring atoms or heterocyclic group composed of 3-10 ring atoms , wherein the C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 2-6 alkynyl, C 2-6 alkenyl, C 3-7 cycloalkyl, benzene Group, heteroaryl group composed of 5-6 ring atoms and heterocyclic group composed of 3-10 ring atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w ;
  • R 5 is hydrogen, deuterium, C 1-6 alkyl, C 3-7 cycloalkyl, heterocyclic group composed of 3-6 ring atoms, C 6-10 aryl group or heterocyclic group composed of 5-10 ring atoms Aryl, wherein the C 1-6 alkyl group, C 3-7 cycloalkyl group, heterocyclic group composed of 3-6 ring atoms, C 6-10 aryl group and heterocyclic group composed of 5-10 ring atoms
  • the aryl groups are each independently unsubstituted or substituted with 1, 2, 3, or 4 R j ;
  • R 6 is hydrogen, deuterium, F, Cl, Br, C 1-12 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 2-6 alkynyl, C 2-6 alkenyl, C 3-7 cycloalkyl group, C 6-10 aryl group, heteroaryl group composed of 5-10 ring atoms or heterocyclic group composed of 3-10 ring atoms, wherein the C 1-6 alkyl group, C 1-6 alkylamino, C 1-6 alkoxy, C 2-6 alkynyl, C 2-6 alkenyl, C 3-7 cycloalkyl, C 6-10 aryl, 5-10 ring atoms
  • the heteroaryl group and the heterocyclic group composed of 3-10 ring atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w ;
  • a heteroaryl group composed of atoms, wherein the amino group, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 alkylthio group, C 1-6 alkylamino group, C 2-6 alkenyl group, C 2-6 alkynyl, C 3-7 cycloalkyl, heterocyclic group composed of 3-10 ring atoms, C 6-10 aryl group and heteroaryl group composed of 5-10 ring atoms are each independently Replaced or replaced by 1, 2, 3 or 4 R w ;
  • n 0, 1, 2 or 3.
  • the present invention relates to a compound represented by formula (c-2) or formula (d-6) or a compound represented by formula (c-2) or formula (d-6). Constructs, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs,
  • each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 has the meaning described in the present invention.
  • R 5 in the present invention is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl Group, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, Tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, naphthyl, furanyl, pyrrolyl, Pyridyl, pyrazolyl, imidazo
  • each R j has the meaning described in the present invention.
  • R 6 in the present invention is hydrogen, deuterium, F, Cl, Br, C 1-6 alkyl, C 1-4 alkylamino, C 1-4 alkoxy, C 2-4 Alkynyl, C 2-4 alkenyl, C 3-6 cycloalkyl, phenyl, naphthyl, heteroaryl composed of 5-6 ring atoms or heterocyclic group composed of 3-6 ring atoms, among which The mentioned C 1-6 alkyl, C 1-4 alkylamino, C 1-4 alkoxy, C 2-4 alkynyl, C 2-4 alkenyl, C 3-6 cycloalkyl, phenyl, naphthalene Group, heteroaryl group composed of 5-6 ring atoms and heterocyclic group composed of 3-6 ring atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w ,
  • each R w has the meaning described in the present invention.
  • R 6 in the present invention is hydrogen, deuterium, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Tert-butyl, C 1-4 alkylamino, C 1-4 alkoxy, C 2-4 alkynyl, C 2-4 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl , Naphthyl, furanyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazine Group, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl,
  • each R w has the meaning described in the present invention.
  • R 6 in the present invention is Isopropyl, cyclopropyl or tert-butyl.
  • each R w has the meaning described in the present invention.
  • each R w has the meaning described in the present invention.
  • Each of R 1 , R 2 , R 3 , R 4 and R 7 is independently hydrogen, deuterium, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, S-butyl, tert-butyl, C 1-4 alkylamino, C 1-4 alkoxy, ethynyl, propargyl, propynyl, 1-ynbutyl, 2-ynbutyl, 3-ynbutyl Group, C 2-4 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl , Oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl,
  • the present invention relates to one of the following compounds or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or other Prodrugs, but by no means limited to these compounds:
  • stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically Acceptable salts or prodrugs thereof are all included in the scope of the present invention.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention.
  • the pharmaceutical composition further comprises pharmaceutically acceptable excipients or a combination of such excipients.
  • the pharmaceutical composition of the present invention further comprises other anti-HBV drugs.
  • the pharmaceutical composition of the present invention wherein the anti-HBV drug is an HBV polymerase inhibitor, an immunomodulator or an interferon.
  • the pharmaceutical composition of the present invention wherein the anti-HBV drug is lamivudine, telbivudine, tenofovir dipivoxil, entecavir, adefovir dipivoxil, Alfaferone, Alloferon , Simo interleukin, clavudine, emtricitabine, faciclovir, interferon, baoganling CP, interferon, interferon alpha-1b, interferon alpha, interferon alpha-2a, interferon beta -1a, Interferon Alpha-2, Interleukin-2, Milvotate, Nitrazoxanide, Pegylated Interferon Alpha-2a, Ribavirin, Ruinterferon-A, Cizonan, Euforavac, Ampligen, Phosphazid, Heplisav, Interferon Alpha-2b, Levamisole, or Propagermanium.
  • the anti-HBV drug is lamivudine, telbi
  • the present invention also provides the use of the compound or the pharmaceutical composition in the preparation of a medicament for the prevention, treatment or alleviation of viral diseases in patients.
  • the use of the present invention wherein the viral disease refers to hepatitis B virus infection or a disease caused by hepatitis B virus infection.
  • the use of the present invention, wherein the disease caused by hepatitis B virus infection refers to liver cirrhosis or hepatocellular carcinoma.
  • the present invention also provides the use of the compound or the pharmaceutical composition in the preparation of a medicament for inhibiting the production or secretion of HBsAg, and/or for inhibiting the production or replication of HBV DNA use.
  • the present invention relates to the use of the compound or pharmaceutical composition in the preparation of a medicament for preventing, treating or alleviating hepatitis B disease in patients.
  • Another aspect of the present invention relates to a method for preventing, treating or alleviating HBV disorders in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective dose of the compound of the present invention.
  • Another aspect of the present invention relates to a method for preventing, treating or alleviating HBV disorders in a patient, the method comprising administering to the patient a pharmaceutically acceptable effective dose of a pharmaceutical composition containing the compound of the present invention.
  • Another aspect of the present invention relates to the use of a compound of the present invention in the preparation of a medicament for preventing, treating or treating a patient's HBV disease and reducing its severity.
  • Another aspect of the present invention relates to the use of a pharmaceutical composition containing the compound of the present invention in the preparation of a medicament for preventing or treating a patient's HBV disease and reducing its severity.
  • Another aspect of the present invention relates to a method for inhibiting HBV infection, which method comprises contacting cells with a compound or composition of the present invention at a dose effective to inhibit HBV. In other embodiments, the method further comprises contacting the cells with other anti-HBV agents.
  • Another aspect of the present invention relates to a method of treating HBV disease in a patient, which method comprises administering to the patient an effective therapeutic amount of a compound of the present invention or a composition thereof. In other embodiments, the method further comprises the administration of other HBV treatments.
  • Another aspect of the present invention relates to a method for inhibiting HBV infection in a patient, which method comprises administering to the patient an effective therapeutic amount of a compound of the present invention or a composition thereof. In other embodiments, the method further comprises the administration of other HBV treatments.
  • Another aspect of the present invention relates to methods for the preparation, separation and purification of compounds contained in formula (I), formula (c-2) or formula (d-6).
  • the present invention also includes the use of the compounds of the present invention and their pharmaceutically acceptable salts for the production of pharmaceutical products to effectively inhibit HBV infection, including those described in the present invention:
  • the compounds of the present invention are effective in the production of drugs for effectively inhibiting HBV infection. application.
  • the compound of the present invention is also used in the production of a medicine to alleviate, prevent, control or treat the symptoms of hepatitis B in patients.
  • the present invention includes a pharmaceutical composition, which includes an effective therapeutic amount required for combining the compound represented by formula (I) and at least one pharmaceutically acceptable excipient.
  • the present invention also includes a method that effectively inhibits HBV infection or is sensitive to the disease.
  • the method includes using a therapeutically effective amount of a compound represented by formula (I), formula (c-2) or formula (d-6) to treat patients Get treatment.
  • the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable includes that the substance or composition must be chemically or toxicologically suitable, related to the other components of the formulation and the mammal used for treatment.
  • the salts of the compounds of the present invention also include intermediates or intermediates for the preparation or purification of compounds represented by formula (I), formula (c-2) or formula (d-6) or formula (I), formula (c-2) or The salt of formula (d-6) or its isomer, but not necessarily a pharmaceutically acceptable salt.
  • pharmaceutically acceptable refers to a substance that is acceptable for pharmaceutical applications from a toxicological point of view and does not adversely interact with the active ingredient.
  • the desired salt can be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or using Organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, malic acid, 2-hydroxypropionic acid, citric acid, oxalic acid, glycolic acid and salicylic acid; Flanose acids, such as glucuronic acid and galacturonic acid; ⁇ -hydroxy acids, such as citric acid and tartaric acid; amino acids, such as aspartic acid and glutamic acid; aromatic acids, such as benzoic acid and cinnamic acid; sulfonic acid , Such as p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid
  • the desired salt can be prepared by a suitable method, an inorganic base, such as the lithium salt of the compound represented by formula (I), formula (c-2) or formula (d-6), Sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, iron salt, ferrous salt, manganese salt, manganite salt, copper salt, zinc salt and ammonium salt, etc.; organic base, such as formula (I), formula ( c-2) or the compound represented by formula (d-6) and methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, tromethamine, diethylaminoethanol, isopropylamine, 2 -Ethylaminoethanol, pyridine, picoline, ethanolamine, diethanolamine, ammonium, dimethylethanolamine, tetramethylammonium, tetraethylammonium, triethanolamine, piperidine, piperazine, morpholine, imid
  • the pharmaceutical composition of the present invention includes the structure compound represented by formula (I), formula (c-2) or formula (d-6) or the compound of the structure shown in the examples, or its stereoisomers, tautomers Body, nitrogen oxides, solvates, metabolites and pharmaceutically acceptable salts or prodrugs, and pharmaceutically acceptable excipients.
  • Chronic viral diseases caused by HBV may lead to severe disease.
  • Chronic hepatitis B virus infection can cause liver cirrhosis and/or hepatocellular carcinoma in many cases.
  • the compound in the composition of the present invention can effectively inhibit hepatitis B virus, and is suitable for It is used in the treatment of diseases caused by viruses, especially acute and chronic persistent HBV virus infections.
  • the compound of the present invention is particularly suitable for the treatment of chronic hepatitis B virus infection and acute hepatitis B virus infection.
  • the present invention includes pharmaceutical preparations, in addition to non-toxic and inert pharmacologically suitable excipients, it also contains one or more of the compound (I), formula (c-2) or formula (d-6) or combination of the present invention Things.
  • compositions may also contain other active pharmaceutical ingredients other than compound (I), formula (c-2) or formula (d-6).
  • compositions of the present invention exist in free form, or are suitable as pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other that can be administered directly or indirectly according to the needs of patients.
  • the pharmaceutical composition of the present invention includes any one of the compounds represented by formula (I), formula (c-2) or formula (d-6) of the present invention, and further includes pharmaceutically acceptable excipients,
  • excipients such as those used in the present invention, include any solvents, solid excipients, diluents, binders, disintegrating agents, or other liquid excipients, dispersing agents, flavoring or suspending agents, and surface active agents.
  • Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum proteins; buffer substances such as phosphate; glycine; sorbic acid; Potassium acid; a mixture of partial glycerides of saturated plant fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt; colloidal silicon; magnesium trisilicate; polyethylene Pyrrolidone; polyacrylate; wax; polyethylene-polyoxypropylene-blocking polymer; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Sodium base cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as coco
  • the pharmaceutical composition of the compound of the present invention can be administered in any of the following ways: oral administration, spray inhalation, topical administration, rectal administration, nasal administration, vaginal administration, parenteral administration such as Subcutaneous, intravenous, intramuscular, intra-abdominal, intrapulmonary, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or medication with an explanted reservoir.
  • oral administration intramuscular injection, intraperitoneal administration or intravenous injection.
  • the compound of the present invention or a pharmaceutically acceptable composition containing it can be administered in a unit dosage form.
  • the dosage form for administration can be a liquid dosage form or a solid dosage form.
  • Liquid dosage forms can be true solutions, colloids, microparticles, and suspensions.
  • Other dosage forms such as tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, freeze-dried powder injections, inclusion compounds, implants, patches, rubs ⁇ etc.
  • Oral tablets and capsules may contain excipients such as binders, such as syrup, gum arabic, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, amino Acetic acid; lubricants, such as magnesium stearate, talc, polyethylene glycol, silica; disintegrants, such as potato starch; or acceptable moisturizers such as sodium lauryl sulfate.
  • binders such as syrup, gum arabic, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, amino Acetic acid
  • lubricants such as magnesium stearate, talc, polyethylene glycol, silica
  • disintegrants such as potato starch
  • acceptable moisturizers such as sodium lauryl sul
  • Oral liquids can be made into water and oil suspensions, solutions, emulsions, syrups or elixirs, or they can be made into dry products, supplemented with water or other suitable media before use.
  • This liquid preparation may contain conventional additives such as suspending agent, sorbitol, cellulose methyl ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated food Oils and fats; emulsifiers, such as lecithin, sorbitan monooleate, gum arabic; or non-aqueous excipients (may contain edible oils), such as almond oil; fats and oils such as glycerin, ethylene glycol or ethanol; preservatives, such as Methyl or propyl p-hydroxybenzoate, sorbic acid. Flavoring or coloring agents can be added if necessary.
  • Suppositories may contain conventional suppository bases such as cocoa butter or other glycerides.
  • the liquid dosage form is usually made of a compound and a sterile excipient.
  • Water is the first choice for excipients.
  • the compound can be dissolved in the excipients or made into a suspension solution.
  • the injection solution the compound is first dissolved in water, filtered and sterilized, and then filled into a sealed bottle or ampoule.
  • the compound of the present invention can be prepared in the form of an appropriate ointment, lotion, or cream, in which the active ingredient is suspended or dissolved in one or more excipients, and the excipients that can be used in ointment preparations include but Not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; auxiliary materials that can be used for lotions and creams include, but are not limited to: mineral oil, sorbitan mono Stearate, Tween 60, cetyl ester wax, hexadecenyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the total amount of the active compound of the present invention administered is about 0.01-500 mg/kg body weight, preferably 0.01-100 mg/kg body weight, every 24 hours, if appropriate If so, divide into multiple single doses to achieve the desired effect.
  • the amount of active compound contained in a single dose is preferably about 1-80 mg/kg body weight, more preferably 1-50 mg/kg body weight, but the above-mentioned dose may not be followed, that is, it depends on the type and weight of the subject to be treated, and the nature of the disease. And the severity, the type of preparation and the way the drug is administered, as well as the period or interval of administration.
  • anti-HBV drugs are HBV polymerase inhibitors, immunomodulators, interferons or other new anti-HBV agents such as HBV RNA replication inhibitors, HBsAg secretion inhibitors, HBV capsid inhibitors, antisense oligomers, siRNA, HBV Therapeutic vaccines, HBV preventive vaccines, HBV antibody therapy (monoclonal or polyclonal) and agonists for the treatment or prevention of HBV.
  • Anti-HBV drugs include lamivudine, telbivudine, tenofovir dipivoxil, entecavir, adefovir dipivoxil, Alfaferone, Alloferon, simo interleukin, clavudine, emtricitabine, faciclovir, Interferon, Baoganling CP, Interferon, Interferon ⁇ -1b, Interferon ⁇ , Interferon ⁇ -2a, Interferon ⁇ -1a, Interferon ⁇ -2, Interleukin-2, Milvotate , Nitrazoxanide, Pegylated Interferon Alpha-2a, Ribavirin, Ruinterferon-A, Cizonan, Euforavac, Ampligen, Phosphazid, Heplisav, Interferon Alpha-2b, Levamisole or Propane Pge and so on.
  • the compound or pharmaceutical composition of the present invention is used in the preparation of medicines for preventing, treating, treating or alleviating hepatitis B disease in patients.
  • Hepatitis B disease refers to liver disease caused by hepatitis B virus infection or hepatitis B virus infection, including acute hepatitis, chronic hepatitis, cirrhosis and liver cancer.
  • Acute hepatitis B virus infection can be asymptomatic or manifest as symptoms of acute hepatitis.
  • Patients with chronic viral infections have active diseases, which can develop into liver cirrhosis and liver cancer.
  • the use of the compound or pharmaceutical composition of the present invention includes inhibiting the production or secretion of HBsAg, and also includes administering a pharmaceutically acceptable effective dose of the compound or pharmaceutical composition of the present invention to a patient.
  • the use of the compound or pharmaceutical composition of the present invention includes inhibiting HBV DNA production, and also includes administering a pharmaceutically acceptable and effective dose of the compound or pharmaceutical composition of the present invention to a patient.
  • the use of the compound or pharmaceutical composition of the present invention for inhibiting HBV gene expression includes administering a pharmaceutically acceptable effective dose of the compound or pharmaceutical composition of the present invention to a patient.
  • anti-HBV drugs can be administered separately from the composition containing the compound of the invention as part of a multiple dosing regimen.
  • those drugs may be part of a single dosage form, mixed with the compounds of the invention to form a single composition. If the administration is part of a multiple dosing regimen, the two active agents can be delivered to each other continuously or over a period of time to obtain the activity of the target agent.
  • the amount of compound and composition (those comprising a composition as described in the present invention) that can be combined with adjuvant materials to produce a single dosage form varies depending on the main treatment and the particular mode of administration.
  • the compound of the present invention shows a strong antiviral effect.
  • Such compounds have unexpected antiviral activity against HBV, so they are suitable for the treatment of various diseases caused by viruses, especially those caused by acute and chronic persistent HBV infection.
  • Chronic viral diseases caused by HBV can cause various syndromes of varying severity. It is well known that chronic hepatitis B virus infection can cause liver cirrhosis and/or liver cancer.
  • indications that can be treated with the compounds of the present invention are: treatment of acute and chronic viral infections that can lead to infectious hepatitis, such as hepatitis B virus infection, particularly preferably treatment of chronic hepatitis B virus infection and acute hepatitis B virus Treatment of infection.
  • the present invention also relates to the use of the compounds and compositions of the present invention for the preparation of drugs for the treatment and prevention of viral diseases, especially hepatitis B.
  • the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, the definition of the substituents is as shown in formula (I), formula (c-2) or formula (d-6) .
  • the following synthesis schemes and examples are used to further illustrate the content of the present invention.
  • NMR spectrum data is measured by Bruker Avance 400 NMR spectrometer or Bruker Avance III HD 600 NMR spectrometer, with CDCl 3 , DMSO-d 6 , CD 3 OD or d 6 -acetone as solvent (reported in ppm as the unit ), using TMS (0ppm) or chloroform (7.26ppm) as the reference standard.
  • MS data is measured by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30°C).
  • the G1329A automatic sampler and G1315B DAD detector are used for analysis.
  • ESI source is used in LC-MS spectrometer.
  • MS data is measured by Agilent 6120 series LC-MS spectrometer equipped with G1311A quaternary pump and G1316A TCC (column temperature maintained at 30°C). G1329A automatic sampler and G1315D DAD detector are used for analysis. The ESI source is used in the LC-MS spectrometer.
  • the above two spectrometers are equipped with Agilent Zorbax SB-C18 column, the specification is 2.1 ⁇ 30mm, 5 ⁇ m.
  • the injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; the HPLC peak is recorded and read by UV-Vis wavelengths at 210 nm and 254 nm.
  • the mobile phases are 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure aqueous solution (phase B).
  • the gradient elution conditions are shown in Table 1:
  • the purification of the compound was evaluated by Agilent 1100 series high performance liquid chromatography (HPLC), with UV detection at 210nm and 254nm, Zorbax SB-C18 column, specification 2.1 ⁇ 30mm, 4 ⁇ m, 10 minutes, flow rate 0.6mL/min , 5-95% (0.1% formic acid acetonitrile solution) (0.1% formic acid aqueous solution), the column temperature is maintained at 40°C.
  • HPLC high performance liquid chromatography
  • each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 has the meaning as described in the present invention, and each of X 1 , X 2 and X 3 is independently Cl, Br or I.
  • R 1a is C 1-6 alkyl or C 3-6 cycloalkyl.
  • the compound represented by formula (a-10) can be prepared by the method described in Synthetic Scheme 1.
  • compound (a-1) reacts with halogenated compound R 5 X 2 under alkaline conditions (such as K 2 CO 3 ) to form compound (a-2);
  • compound (a-2) reacts under alkaline conditions to form Compound (a-3);
  • Compound (a-3) reacts with paraformaldehyde under high temperature and alkaline conditions to produce compound (a-4);
  • Compound (a-4) is protected by a benzyl group to obtain compound (a- 5);
  • Compound (a-5) is oxidized to compound (a-6) in the presence of sodium dihydrogen phosphate; compound (a-6) reacts with thionyl chloride to obtain compound (a-7);
  • compound ( a-7) reacts with compound (a-8) to produce compound (a-9);
  • compound (a-9) removes the benzyl protecting group to obtain compound (a-10).
  • Compound (b-6) can be prepared by the method described in Synthesis Scheme 2. First, compound (b-1) reacts with compound (b-2) under basic conditions (such as cesium carbonate, etc.) to produce compound (b-3); compound (b-3) is demethylated at low temperature Group to obtain compound (b-4); compound (b-4) and compound (b-5) are reacted to obtain compound (b-6).
  • Compound (c-2) can be prepared by the method described in Synthesis Scheme 3. First, compound (a-10) reacts with compound (b-2) under basic conditions (such as cesium carbonate, etc.) to produce compound (c-1); then, compound (c-1) under basic conditions ( For example, K 2 CO 3 ) undergoes a hydrolysis reaction to obtain compound (c-2).
  • compound (a-10) reacts with compound (b-2) under basic conditions (such as cesium carbonate, etc.) to produce compound (c-1); then, compound (c-1) under basic conditions ( For example, K 2 CO 3 ) undergoes a hydrolysis reaction to obtain compound (c-2).
  • Compound (d-6) can be prepared by the method described in Synthesis Scheme 4. First, compound (a-4) reacts with compound (d-1) under alkaline conditions (such as potassium carbonate, etc.) to produce compound (d-2); then, compound (d-2) undergoes an intramolecular ring-closure reaction To obtain compound (d-3); compound (d-3) reacts with compound (d-4) to produce compound (d-5); finally, compound (d-5) is hydrolyzed to obtain compound (d-6).
  • alkaline conditions such as potassium carbonate, etc.
  • Example 1 4-(2-Cyclopropylethoxy)-11-oxo-7-phenyl-1,2,7,11-tetrahydrobenzofuro[4,5-e]pyrido [1,2-c][1,3]oxazine-10-carboxylic acid
  • reaction mixture was filtered through Celite to remove solids, and the filter cake was washed with a pH 10 aqueous sodium hydroxide solution (100 mL) and methyl tert-butyl ether (100 mL). The filtrate was collected and separated, and the lower aqueous phase was collected and washed with methyl tert-butyl ether (50 mL ⁇ 2).
  • Step 11 6-(5-(Benzyloxy)-7-methoxy-2,3-dihydrobenzofuran-4-yl)-4-oxo-1,4-dihydropyridine-3- Ethyl formate
  • Step 12 Ethyl 6-(5-hydroxy-7-methoxy-2,3-dihydrobenzofuran-4-yl)-4-oxo-1,4-dihydropyridine-3-carboxylate
  • Step 13 4-Methoxy-11-oxo-7-phenyl-1,2,7,11-tetrahydrobenzofuro[4,5-e]pyrido[1,2-c][ 1,3]oxazine-10-ethyl formate
  • Step 14 4-Hydroxy-11-oxo-7-phenyl-1,2,7,11-tetrahydrobenzofuro[4,5-e]pyrido[1,2-c][1, 3]oxazine-10-formic acid
  • Ethyl oxazine-10-carboxylate (0.321 g, 0.765 mmol) was dissolved in anhydrous DCM (9.63 mL), and then cooled to -78°C. Take the DCM solution of BBr 3 (4.59 mL, 4.59 mmol) and slowly drop it into the reaction flask. After the addition, continue to react at -78°C for 1 h. Then transfer to room temperature and react for 12h.
  • Step 15 4-(2-Cyclopropylethoxy)-11-oxo-7-phenyl-1,2,7,11-tetrahydrobenzofuro[4,5-e]pyridyl[ 1,2-c][1,3]oxazine-10-carboxylic acid
  • Example 3 4-(2-Cyclopropylethoxy)-11-oxo-7-(thiazol-2-yl)-1,2,7,11-tetrahydrobenzofuro[4,5 -e]pyrido[1,2-c][1,3]oxazine-10-carboxylic acid
  • Step 2 4-(2-Cyclopropylethoxy)-11-oxo-7-(thiazol-2-yl)-1,2,7,11-tetrahydrobenzofuro[4,5- e]pyrido[1,2-c][1,3]oxazine-10-carboxylic acid
  • Step 2 6-(5-hydroxy-7-(3-methoxypropoxy)-2,3-dihydrobenzofuran-4-yl)-4-oxo-1,4-dihydropyridine Ethyl -3-formate
  • Step 3 7-(4-Chlorothiazol-5-yl)-4-(3-methoxypropoxy)-11-oxo-1,2,7,11-tetrahydrobenzofuro[4 ,5-e]pyrido[1,2-c][1,3]ox Oxazine-10-ethyl formate
  • Step 4 7-(4-Chlorothiazol-5-yl)-4-(3-methoxypropoxy)-11-oxo-1,2,7,11-tetrahydrobenzofuro[4 ,5-e]pyrido[1,2-c][1,3]ox Oxazine-10-formic acid
  • Example 5 4-(3-Methoxypropoxy)-11-oxo-7-(4-chlorothiazol-5-yl)-1,2,7,11-tetrahydrobenzofuro[ 4,5-e]pyrido[1,2-c][1,3]oxazine-10-carboxylic acid
  • Example 7 4-(2-Cyclopropylethoxy)-11-oxo-7-(thiazol-5-yl)-1,2,7,11-tetrahydrobenzofuro[4,5 -e]pyrido[1,2-c][1,3]oxazine-10-carboxylic acid
  • Step 1 (R)-(1-((4-Formyl-7-(3-methoxypropoxy)-2,3-dihydrobenzofuran-5-yl)oxy)-3- (Methylbut-2-yl) tert-butyl carbamate
  • Step 3 (8R)-8-isopropyl-4-(3-methoxypropoxy)-12-oxo-2,7,8,12,13,13a-hexahydro-1H-benzo Furo[4,5-f]pyrido [1,2-d][1,4]oxazepan-11-ethyl carboxylate
  • Step 4 (R)-8-isopropyl-4-(3-methoxypropoxy)-12-oxo-2,7,8,12-tetrahydro-1H-benzofuro[4 ,5-f]pyrido[1,2-d][1,4] oxygen nitrogen Heptane-11-ethyl formate
  • Step 5 (R)-8-isopropyl-4-(3-methoxypropoxy)-12-oxo-2,7,8,12-tetrahydro-1H-benzofuro[4 ,5-f]pyrido[1,2-d][1,4] oxygen nitrogen Heptane-11-carboxylic acid
  • Example 9 4-(3-Methoxypropoxy)-11-oxo-7-(thiazol-2-yl)-1,2,7,11-tetrahydrobenzofuro[4,5 -e]pyrido[1,2-c][1,3]oxazine-10-carboxylic acid
  • Step 1 4-Hydroxy-11-oxo-7-(thiazol-2-yl)-1,2,7,11-tetrahydrobenzofuro[4,5-e]pyrido[1,2- c][1,3]oxazine-10-carboxylic acid
  • Step 2 4-(Benzyloxy)-11-oxo-7-(thiazol-2-yl)-1,2,7,11-tetrahydrobenzofuro[4,5-e]pyrido[ 1,2-c][1,3]oxazine-10-carboxylic acid
  • Example 12 4-(Cyclopentylmethoxy)-11-oxo-7-(thiazol-2-yl)-1,2,7,11-tetrahydrobenzofuro[4,5-e ]Pyrido[1,2-c][1,3]oxazine-10-carboxylic acid
  • Example 13 11-oxo-4-((tetrahydro-2H-pyran-4-yl)methoxy)-7-(thiazol-2-yl)-1,2,7,11-tetrahydro Benzofuro[4,5-e]pyrido[1,2-c][1,3]oxazine-10-carboxylic acid
  • Example 15 4-(3-Methoxypropoxy)-2,2-dimethyl-11-oxo-7-phenyl-1,2,7,11-tetrahydrobenzofuro[ 4,5-e]pyrido[1,2-c][1,3]oxazine-10-carboxylic acid
  • the aqueous phase was extracted with ethyl acetate (300 mL ⁇ 2), the organic phases were combined, the organic phase was washed with saturated sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain
  • the title compound is a red-brown oily product (99.53 g, 97.04%).
  • TLC monitors that the raw material has basically reacted completely, the heating is turned off, the stirring is stopped, the potassium carbonate solid is removed by suction through diatomaceous earth, the filtrate is collected, and the filtrate is concentrated under reduced pressure to obtain a brown-red oily product (107.9 g, 103.5%).
  • Step 6 6-(5-hydroxy-7-(3-methoxypropoxy)-2,2-dimethyl-2,3-dihydrobenzofuran-4-yl)-4-oxo -1,4-Dihydropyridine-3-carboxylic acid ethyl ester
  • Step 7 4-(3-Methoxypropoxy)-2,2-dimethyl-11-oxo-7-phenyl-1,2,7,11-tetrahydrobenzofuro[4 ,5-e]pyrido[1,2-c][1,3]ox Oxazine-10-ethyl formate
  • Step 8 4-(3-Methoxypropoxy)-2,2-dimethyl-11-oxo-7-phenyl-1,2,7,11-tetrahydrobenzofuro[4 ,5-e]pyrido[1,2-c][1,3]ox Oxazine-10-formic acid
  • Example 16 7-(3-chlorophenyl)-4-(3-methoxypropoxy)-2,2-dimethyl-11-oxo-1,2,7,11-tetrahydro Benzofuro[4,5-e]pyrido[1,2-c][1,3]oxazine-10-carboxylic acid
  • Example 17 7-(4-chlorophenyl)-4-(3-methoxypropoxy)-2,2-dimethyl-11-oxo-1,2,7,11-tetrahydro Benzofuro[4,5-e]pyrido[1,2-c][1,3]oxazine-10-carboxylic acid
  • Example 18 7-(2-chlorophenyl)-4-(3-methoxypropoxy)-2,2-dimethyl-11-oxo-1,2,7,11-tetrahydro Benzofuro[4,5-e]pyrido[1,2-c][1,3]oxazine-10-carboxylic acid
  • Example 19 4-(3-Methoxypropoxy)-2,2-dimethyl-11-oxo-7-(2-(trifluoromethyl)phenyl)-1,2,7 ,11-Tetrahydrobenzofuro[4,5-e]pyrido[1,2-c][1,3]oxazine-10-carboxylic acid
  • Example 20 7-(2-fluorophenyl)-4-(3-methoxypropoxy)-2,2-dimethyl-11-oxo-1,2,7,11-tetrahydro Benzofuran[4,5-e]pyrido[1,2-c][1,3]oxazine-10-carboxylic acid
  • Example 21 7-(3-fluorophenyl)-4-(3-methoxypropoxy)-2,2-dimethyl-11-oxo-1,2,7,11-tetrahydro Benzofuro[4,5-e]pyrido[1,2-c][1,3]oxazine-10-carboxylic acid
  • Example 22 7-(4-fluorophenyl)-4-(3-methoxypropoxy)-2,2-dimethyl-11-oxo-1,2,7,11-tetrahydro Benzofuro[4,5-e]pyrido[1,2-c][1,3]oxazine-10-carboxylic acid
  • Example 24 7-(2-chloro-4-fluorophenyl)-4-(3-methoxypropoxy)-2,2-dimethyl-11-oxo-1,2,7, 11-Tetrahydrobenzofuro[4,5-e]pyrido[1,2-c][1,3]oxazine-10-carboxylic acid
  • Example 25 7-(2-bromo-4-fluorophenyl)-4-(3-methoxypropoxy)-2,2-dimethyl-11-oxo-1,2,7, 11-Tetrahydrobenzofuro[4,5-e]pyrido[1,2-c][1,3]oxazine-10-carboxylic acid
  • Example 27 4-(3-Methoxypropoxy)-2,2-dimethyl-11-oxo-7-(thiazol-2-yl)-1,2,7,11-tetrahydro Benzofuro[4,5-e]pyrido[1,2-c][1,3]oxazine-10-carboxylic acid
  • HepG2.2.15 cells The chromosomes of HepG2.2.15 cells (SELLS, PNAS, 1987 and SELLS, JV, 1988) integrate a complete HBV genome and stably express viral RNA and viral proteins.
  • HepG2.2.15 cells can secrete mature hepatitis B virus particles and HBsAg into the culture medium.
  • the viral particle DNA and HBsAg secreted by HepG2.2.15 cells can be quantified by qPCR and ELISA methods, and thus the influence of the compound on virus replication and HBsAg secretion can be detected.
  • Test 1 Inhibition experiment of the compound of the present invention on HBV virus replication
  • HepG 2.2.15 cells 8,000 cells per well were seeded into a 96-well cell culture plate in duplicate, and cultured for 3 days until the cells grow to full wells. The cells were treated with a 4-fold serial dilution of the compound for 10 days, and the solution was changed every other day for administration. The final concentration of DMSO in all wells was 0.5% and DMSO was used as a no-drug control. The supernatant was collected on the 11th day for HBV DNA quantitative detection.
  • HBV primers are as follows:
  • HBV-For-202 CAGGCGGGGTTTTTCTTGTTGA (SEQ ID NO:1);
  • HBV-Rev-315 GTGATTGGAGGTTGGGGACTGC (SEQ ID NO: 2).
  • Table 2 The replication inhibitory activity of some compounds of the present invention on HBV DNA
  • Test 2 Inhibition experiment of the compound of the present invention on HBsAg secretion
  • HepG 2.2.15 cells 8,000 cells per well were seeded into a 96-well cell culture plate in duplicate, and cultured for 3 days until the cells grow to full wells. The cells were treated with a 4-fold serial dilution of the compound for 10 days, and the solution was changed every other day for administration. The final concentration of DMSO in all wells was 0.5% and DMSO was used as a no-drug control. The supernatant was collected on the 11th day for HbsAg quantitative detection.
  • the ELISA method was used to detect the level of HBsAg secreted by the cells after the compound treatment.
  • the method used the hepatitis B surface antigen diagnostic kit (Shanghai Kehua Biological Engineering Co., Ltd. S10910113).
  • Add 25 ⁇ L of supernatant to be tested (diluted to 75 ⁇ L with PBS) in each well of the ELISA plate, and set the kit positive control and negative control.
  • After sealing the ELISA plate with mounting paper incubate at 37°C for 60 minutes. Take out the ELISA plate, tear off the cover, and add 50 ⁇ L of enzyme conjugate to each well. Shake on a shaker for 10 seconds, seal the ELISA plate with cover paper, and incubate at 37°C for 30 minutes.
  • Compounds of the invention HBsAg secretion inhibitory activity IC 50 of less than 0.1 ⁇ M, most of the compounds inhibit the secretion of HBsAg activity IC 50 of less than 0.05 ⁇ M.
  • the inhibitory activities of some compounds of the present invention on HBsAg secretion are shown in Table 3.
  • Example HBsAg IC 50 (nM) Example 1 5.79 Example 3 1.54 Example 6 4.10 Example 8 4.16 Example 9 3.67 Example 10 2.90 Example 11 2.54 Example 12 0.15 Example 13 0.32 Example 14 1.78 Example 15 1.74 Example 16 2.18 Example 18 0.87 Example 19 0.96 Example 21 1.59 Example 24 2.33 Example 25 1.79 Example 26 1.31 Example 27 3.02
  • Test 3 Pharmacokinetic experiment of the compound of the present invention in beagle dogs, mice and rats
  • Beagle dogs were given 2.5 mg/kg or 5 mg/kg or intravenously 0.5 mg/kg or 1 mg/kg of the test compound by gavage.
  • ICR mice were orally administered 10 mg/kg or 2 mg/kg or 10 mg/kg of the test compound via tail vein injection.
  • Blood was collected from the orbital vein at time points (0.083, 0.25, 0.5, 1, 2 , 4, 6, 8 and 24 hours) after administration, and collected in an anticoagulation tube with EDTA-K 2 added.
  • the plasma samples were quantitatively analyzed on a triple quadrupole tandem mass spectrometer using multiple reactive ion monitoring (MRM).
  • MRM multiple reactive ion monitoring
  • the non-compartmental model method was used to calculate the pharmacokinetic parameters using WinNonlin 6.3 software.
  • SD rats were orally administered 2.5 mg/kg or 5 mg/kg or intravenously 0.5 mg/kg or 1 mg/kg of the test compound.
  • blood was collected by vein at time points (0.083, 0.25, 0.5, 1, 2 , 5, 7 and 24 hours), and collected in an anticoagulant tube with EDTA-K 2.
  • the plasma samples were quantitatively analyzed on a triple quadrupole tandem mass spectrometer using multiple reactive ion monitoring (MRM). The non-compartmental model method was used to calculate the pharmacokinetic parameters using WinNonlin 6.3 software.
  • Test 4 Stability test of the compound of the present invention in liver microsomes of different species

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • Engineering & Computer Science (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一种稠合四环类化合物及其在药物中的应用，尤其是作为用于治疗和/或预防乙型肝炎的药物的应用。具体地说，涉及通式(I)所示化合物或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，其中各变量如说明书所定义。还涉及通式(I)所示化合物或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药作为药物的用途，尤其是作为用于治疗和/或预防乙型肝炎的药物的用途。

Description

稠合四环类化合物及其在药物中的应用 技术领域
本发明属于药物领域，其涉及一种稠合四环类化合物及其作为药物的用途，尤其是作为用于治疗和/或预防乙型肝炎的药物的用途。本发明还涉及这些稠合四环类化合物同其他抗病毒剂组成的组合物，及其在用于治疗和/或预防乙型肝炎病毒(HBV)感染中的应用。
背景技术
乙型肝炎病毒属于肝病毒科。它可引起急性的和/或持续渐进的慢性病。乙型肝炎病毒还可引起病理形态中的许多其他的临床表征——尤其是肝脏的慢性炎症、肝硬化和肝细胞的癌变。据世界卫生组织估计，全球有20亿人感染过HBV，约有3.5亿的慢性感染者，每年大约有100万人死于HBV感染所致的肝衰竭、肝硬化和原发性肝细胞癌(hepatocellular carcinoma，HCC)。
目前对于慢性乙型肝炎(Chronic hepatitis B，CHB)的治疗主要为抗病毒治疗。干扰素α(IFN-α)和聚乙二醇化IFN-α及5种核苷(酸)类似物(拉米夫定、阿德福韦酯、恩替卡韦、替比夫定和替诺福韦)被美国食品药品监督管理局(FDA)批准用于临床治疗。干扰素是最早通过FDA批准的抗HBV药物，其主要通过直接抗病毒作用及诱导机体的免疫反应以达到清除病毒的效果，但因其应答率低，具有多种副作用，价格昂贵且治疗对象局限等原因，其应用受到很多限制。核苷(酸)类药物抗HBV共同点是特异性作用于病毒DNA聚合酶，具有强大的抑制病毒复制的效果，患者对药物的耐受性比干扰素好。但是核苷(酸)类药物的广泛长期使用，可诱导DNA聚合酶突变形成耐药性，导致耐药株的不断出现，使治疗远不能达到理想疗效。
因此，目前临床上仍然需要有新的能够有效地用作抗病毒药物的化合物，尤其是用作治疗和/或预防乙型肝炎的药物的化合物。
发明内容
本发明涉及一类新型的稠合四环类化合物和其在制备治疗与预防HBV感染的药物中的用途。发明人发现，本发明涉及的新型的稠合四环类化合物具有药代动力学性质较好、溶解性好、毒性小、肝微粒体稳定性好以及对HBsAg的生成或分泌和HBV DNA的复制都有很好的抑制活性等优点，其在抗HBV方面有很好的应用前景。特别地，本发明所涉及的化合物，及其药学上可接受的组合物，也都可以有效抑制HBV感染。
一方面，本发明涉及一种如式(I)所示的化合物或式(I)所示的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
Figure PCTCN2021072337-appb-000001
其中，各R 1、R 2、R 3、R 4和R 7独立地为氢、氘、F、Cl、Br、C 1-6烷基、C 1-6烷氨基、C 1-6烷氧基、C 2-6炔基、C 2-6烯基、C 3-7环烷基、苯基、5-6个环原子组成的杂芳基或3-10个环原子组成的杂环基，其中所述的C 1-6烷基、C 1-6烷氨基、C 1-6烷氧基、C 2-6炔基、C 2-6烯基、C 3-7环烷基、苯基、5-6个环原子组成的杂芳基和3-10个环原子组成的杂环基各自独立地未被取代或被1、2、3或4个R w所取代；
或R 1、R 2与其链接的碳原子，一起形成环丙基、环丁基、环戊基、环己基或-C(＝O)-，其中所述的环丙基、环丁基、环戊基和环己基各自独立地未被取代或被1、2、3或4个R w所取代；
或R 3、R 4与其链接的碳原子，一起形成环丙基、环丁基、环戊基、环己基或-C(＝O)-，其中所述的环丙基、环丁基、环戊基和环己基各自独立地未被取代或被1、2、3或4个R w所取代；
R 5为氢、氘、C 1-6烷基、C 3-7环烷基、3-6个环原子组成的杂环基、C 6-10芳基或5-10个环原子组成的杂芳基，其中所述的C 1-6烷基、C 3-7环烷基、3-6个环原子组成的杂环基、C 6-10芳基和5-10个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个R j所取代；
R 6为氢、氘、F、Cl、Br、C 1-12烷基、C 1-6烷氨基、C 1-6烷氧基、C 2-6炔基、C 2-6烯基、C 3-7环烷基、C 6-10芳基、5-10个环原子组成的杂芳基或3-10个环原子组成的杂环基，其中所述的C 1-6烷基、C 1-6烷氨基、C 1-6烷氧基、C 2-6炔基、C 2-6烯基、C 3-7环烷基、C 6-10芳基、5-10个环原子组成的杂芳基和3-10个环原子组成的杂环基各自独立地未被取代或被1、2、3或4个R w所取代；
各R j独立地为氘、F、Cl、Br、CN、＝O、HO-、氨基、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-10个环原子组成的杂环基、C 6-10芳基或5-10个环原子组成的杂芳基，其中所述的氨基、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-10个环原子组成的杂环基、C 6-10芳基和5-10个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个R w所取代；
各R w独立地为氘、F、Cl、Br、HO-、HOOC-、＝O、氨基、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 2-6烯基、C 2-6炔基、C 1-6烷基-OC(＝O)-、C 1-6烷基-S(＝O) 2-、C 3-6环烷基-S(＝O) 2-或C 3-7环烷基，其中所述的氨基、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 2-6烯基、C 2-6炔基、C 1-6烷基-OC(＝O)-、C 1-6烷基-S(＝O) 2-、C 3-6环烷基-S(＝O) 2-和C 3-7环烷基各自独立地未被取代或被1、2、3或4个选自F、Cl、Br、CN、HO-、＝O、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基或C 1-6烷氨基的取代基所取代；
n为0、1、2或3。
在一些实施例中，本发明涉及一种如式(c-2)或式(d-6)所示的化合物或式(c-2)或式(d-6)所示的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
Figure PCTCN2021072337-appb-000002
其中，各R 1、R 2、R 3、R 4、R 5、R 6和R 7具有本发明所述的含义。
在一些实施例中，本发明所述的R 5为氢、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、萘基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、萘基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3或4个R j所取代，
其中，各R j具有本发明所述的含义。
在一些实施例中，本发明所述的R 6为氢、氘、F、Cl、Br、C 1-6烷基、C 1-4烷氨基、C 1-4烷氧基、C 2-4 炔基、C 2-4烯基、C 3-6环烷基、苯基、萘基、5-6个环原子组成的杂芳基或3-6个环原子组成的杂环基，其中所述的C 1-6烷基、C 1-4烷氨基、C 1-4烷氧基、C 2-4炔基、C 2-4烯基、C 3-6环烷基、苯基、萘基、5-6个环原子组成的杂芳基和3-6个环原子组成的杂环基各自独立地未被取代或被1、2、3或4个R w所取代，
其中，各R w具有本发明所述的含义。
在一些实施例中，本发明所述的R 6为氢、氘、F、Cl、Br、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 1-4烷氨基、C 1-4烷氧基、C 2-4炔基、C 2-4烯基、环丙基、环丁基、环戊基、环己基、苯基、萘基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基或哌嗪基，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 1-4烷氨基、C 1-4烷氧基、C 2-4炔基、C 2-4烯基、环丙基、环丁基、环戊基、环己基、苯基、萘基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基和哌嗪基各自独立地未被取代或被1、2、3或4个R w所取代，
其中，各R w具有本发明所述的含义。
在一些实施例中，本发明所述的各R j独立地为氘、F、Cl、Br、CN、＝O、HO-、氨基、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷氨基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-6个环原子组成的杂环基、苯基、萘基、5个环原子组成的杂芳基或6个环原子组成的杂芳基，其中所述的氨基、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷氨基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-6个环原子组成的杂环基、苯基、萘基、5个环原子组成的杂芳基和6个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个R w所取代，
其中，各R w具有本发明所述的含义。
在一些实施例中，本发明所述的各R j独立地为氘、F、Cl、Br、CN、＝O、HO-、氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、C 1-3烷硫基、C 1-3烷氨基、C 2-4烯基、C 2-4炔基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、萘基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述的氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、C 1-3烷硫基、C 1-3烷氨基、C 2-4烯基、C 2-4炔基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、萘基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3或4个R w所取代，
其中，各R w具有本发明所述的含义。
在一些实施例中，本发明所述的各R w独立地为氘、F、Cl、Br、HO-、HOOC-、＝O、氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷氨基、C 2-4烯基、乙炔基、炔丙基、丙炔基、1-炔丁基、2-炔丁基、3-炔丁基、叔丁氧羰基、C 1-4烷基-S(＝O) 2-、环丙基-S(＝O) 2-、环戊基-S(＝O) 2-、环己基-S(＝O) 2-、环丙基、环丁基、环戊基或环己基，其中所述氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷氨基、C 2-4烯基、乙炔基、炔丙基、丙炔基、1-炔丁基、2-炔丁基、3-炔丁基、叔丁氧羰基、C 1-4烷基-S(＝O) 2-、环丙基-S(＝O) 2-、环戊基-S(＝O) 2-、环己基-S(＝O) 2-、环丙基、环丁基、环戊基和环己基各自独立地未被取代或被1、2、3或4个选自F、Cl、Br、CN、HO-、＝O、氨基、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷硫基、C 1-4卤代烷氧基或C 1-4烷氨基的取代基所取代；
各R 1、R 2、R 3、R 4和R 7独立地为氢、氘、F、Cl、Br、甲基、乙基、正丙基、异丙基、正丁基、异丁 基、仲丁基、叔丁基、C 1-4烷氨基、C 1-4烷氧基、乙炔基、炔丙基、丙炔基、1-炔丁基、2-炔丁基、3-炔丁基、C 2-4烯基、环丙基、环丁基、环戊基、环己基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基或哌嗪基，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 1-4烷氨基、C 1-4烷氧基、乙炔基、炔丙基、丙炔基、1-炔丁基、2-炔丁基、3-炔丁基、C 2-4烯基、环丙基、环丁基、环戊基、环己基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基和哌嗪基各自独立地未被取代或被1、2、3或4个R w所取代。
另一方面，本发明还提供了一种包含本发明所述的化合物的药物组合物，任选地，所述药物组合物进一步包含药学上可接受的辅料或所述辅料的组合。
在一些实施例中，本发明所述的药物组合物，其进一步地包含其它抗HBV药物。
在一些实施例中，本发明所述的药物组合物，其中所述其它抗HBV药物为HBV聚合酶抑制剂、免疫调节剂或干扰素。
在一些实施例中，本发明所述的药物组合物，其中所述其它抗HBV药物为拉米夫定、替比夫定、替诺福韦酯、恩替卡韦、阿德福韦酯、Alfaferone、Alloferon、西莫白介素、克拉夫定、恩曲他滨、法昔洛韦、干扰素、宝甘灵CP、因特芬、干扰素α-1b、干扰素α、干扰素α-2a、干扰素β-1a、干扰素α-2、白细胞介素-2、米伏替酯、硝唑尼特、聚乙二醇干扰素α-2a、病毒唑、罗扰素-A、西佐喃、Euforavac、安普利近、Phosphazid、Heplisav、干扰素α-2b、左旋咪唑或丙帕锗。
另一方面，本发明还提供了所述化合物或所述药物组合物在制备用于预防、治疗或减轻患者病毒性疾病的药物中的用途。
在一些实施例中，本发明所述的用途，其中所述病毒性疾病是指乙型肝炎病毒感染或乙型肝病毒炎感染引起的疾病。
在另外一些实施例中，本发明所述的用途，其中所述乙型肝炎病毒感染引起的疾病是指肝硬化或肝细胞癌变。
另一方面，本发明还提供了所述的化合物或所述的药物组合物在制备药物中的用途，所述药物用于抑制HBsAg的生成或分泌，和/或用于抑制HBV DNA的生成。
另一方面，本发明涉及所述的化合物或药物组合物在制备用于预防、治疗或减轻患者乙型肝炎疾病的药物中的用途。
本发明另一方面涉及预防、治疗或减轻患者HBV病症的方法，所述方法包含使用药学上可接受的有效剂量的本发明化合物对患者进行给药。
本发明另一方面涉及预防、治疗或减轻患者HBV病症的方法，所述方法包含使用药学上可接受的有效剂量的含有本发明化合物的药物组合物对患者进行给药。
本发明另一方面涉及使用一种本发明化合物在制备用于预防、处理或治疗患者HBV病症，并减轻其严重程度的药品的用途。
本发明另一方面涉及使用一种包含本发明化合物的药物组合物在制备用于预防或治疗患者HBV病症，并减轻其严重程度的药物的用途。
本发明另一方面涉及一种抑制HBV感染的方法，该方法包含细胞与有效抑制HBV的剂量的本发明化合物或组合物接触。另外一些实施例是，所述方法更进一步地包含细胞与其它抗HBV剂的接触。
本发明另一方面涉及治疗患者HBV疾病的方法，该方法包含给予患者有效治疗量的本发明化合物或 其组合物。另外一些实施例是，所述方法更进一步地包含其它HBV治疗的给药。
本发明另一方面涉及一种抑制患者HBV感染的方法，该方法包含给予患者有效治疗量的本发明化合物或其组合物。另外一些实施例是，所述方法更进一步地包含其它抗HBV治疗的给药。
本发明另一方面涉及式(I)、式(c-2)或式(d-6)所包含的化合物的制备、分离和纯化的方法。
前面所述内容只概述了本发明的某些方面，但并不限于这些方面。这些方面及其他的方面的内容将在下面作更加具体完整的描述。
本发明的详细说明书
定义和一般术语
本发明将会把确定的具体化的内容所对应的文献详细列出，实施例都伴随有结构式和化学式的图解。本发明有预期地涵盖所有的选择余地、变体和同等物，这些可能像权利要求所定义的那样包含在现有发明领域。所属领域的技术人员将识别许多类似或等同于在此所描述的方法和物质，这些可以应用于本发明的实践中去。本发明绝非限于方法和物质的描述。有很多文献和相似的物质与本发明申请相区别或抵触，其中包括但绝不限于术语的定义，术语的用法，描述的技术，或像本发明申请所控制的范围。
本发明将应用以下定义除非其他方面表明。根据本发明的目的，化学元素根据元素周期表，CAS版本和化学药品手册，75， thEd，1994来定义。另外，有机化学一般原理见"Organic Chemistry,"Thomas Sorrell,University Science Books,Sausalito:1999,and"March's Advanced Organic Chemistry,"by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007，因此所有的内容都融合了参考文献。
像本发明所描述的，本发明的化合物被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。一般而言，术语“取代”，表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个取代的基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不止一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1-6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基。
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。
本发明使用的术语“烷基”包括1-20个碳原子饱和直链或支链的单价烃基，其中烷基可以独立任选地被一个或多个本发明所描述的取代基所取代。其中一些实施例是，烷基基团含有1-12个碳原子，另外一些实施例是，烷基基团含有1-8个碳原子，另外一些实施例是，烷基基团含有1-6个碳原子，另外一些实施例是，烷基基团含有1-4个碳原子，另外一些实施例是，烷基基团含有1-3个碳原子。烷基基团更进一步的实例包括，但并不限于，甲基(Me，-CH 3)，乙基(Et，-CH 2CH 3)，正丙基(n-Pr，-CH 2CH 2CH 3)，异丙基(i-Pr，-CH(CH 3) 2)，正丁基(n-Bu，-CH 2CH 2CH 2CH 3)，2-甲基丙基或异丁基(i-Bu，-CH 2CH(CH 3) 2)，1-甲基丙基或仲丁基(s-Bu，-CH(CH 3)CH 2CH 3)，叔丁基(t-Bu，-C(CH 3) 3)，正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)，2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)，正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)，2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)，3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))，2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)，3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)，4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)，3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)，2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)， 2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)，3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3)、3,3-二甲基-丁基(-CH 2CH 2C(CH 3) 3)，正庚基，正辛基，等等。术语“卤代烷基”表示烷基基团被一个或多个卤素原子所取代，其中烷基具有本发明所述的含义。其中一些实施例是，卤代烷基基团含有1-12个碳原子；另外一些实施例是，卤代烷基基团含有1-10个碳原子；另外一些实施例是，卤代烷基基团含有1-8个碳原子；另外一些实施例是，卤代烷基基团含有1-6个碳原子；另外一些实施例是，卤代烷基基团含有1-4个碳原子，另外一些实施例是，卤代烷基基团含有1-3个碳原子。这样的实例包含，但并不限于，三氟甲基，三氟乙基等。
术语“羰基”，无论是单独使用还是和其他术语连用(如“氨基羰基”或“酰氧基”)，表示-(C＝O)-。
术语“烷基氨基”和“烷氨基”可以交换使用，包括“N-烷基氨基”和“N,N-二烷基氨基”，其中氨基基团分别独立地被一个或两个C 1-12烷基基团所取代。其中一些实施例中，烷基氨基是一个或两个C 1-12烷基连接到氮原子上的较低级的烷基氨基基团，一些实施例中，烷基氨基是C 1-6的较低级的烷基氨基基团，一些实施例中，烷基氨基是C 1-4的较低级的烷基氨基基团。合适的烷基氨基基团可以是单烷基氨基或二烷基氨基，这样的实例包括，但并不限于，N-甲氨基，N-乙氨基，N,N-二甲氨基，N,N-二乙氨基，N-丙氨基，N,N-二丙氨基，等等，其中所述烷基氨基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。
术语“烯基”表示含有2-12个碳原子，或2-8个碳原子，或2-6个碳原子，或2-4个碳原子的直链或支链的一价烃基，其中至少有一个位置的C-C为sp 2双键，其中烯基的基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代，包括有“顺”、“反”或"Z"、"E"异构体，其中具体的实例包括，但并不限于，乙烯基(-CH＝CH 2)，丙烯基(-CH＝CHCH 3)、烯丙基(-CH 2CH＝CH 2)等等，其中所述烯基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。
术语“炔基”表示含有2-12个碳原子，或2-8个碳原子，或2-6个碳原子，或2-4个碳原子的直链或支链的一价烃基，其中至少有一个位置的C-C为sp三键，其中炔基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代，具体的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH 2C≡CH)、丙炔基(-C≡C-CH 3)、1-炔丁基(-CH 2CH 2C≡CH)、2-炔丁基(-CH 2C≡CCH 3)、3-炔丁基(-C≡CCH 2CH 3)等等，其中所述炔基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的含义。除非另外详细说明，所述烷氧基基团含有1-20个碳原子，其中一些实施例是，烷氧基基团含有1-12个碳原子，另外一些实施例是，烷氧基基团含有1-8个碳原子，另外一些实施例是，烷氧基基团含有1-6个碳原子，另外一些实施例是，烷氧基基团含有1-4个碳原子，另外一些实施例是，烷氧基基团含有1-3个碳原子。
烷氧基基团的实例包含，但并不限于，甲氧基(MeO,-OCH 3)、乙氧基(EtO,-OCH 2CH 3)、1-丙氧基(n-PrO,n-丙氧基,-OCH 2CH 2CH 3)、2-丙氧基(i-PrO,i-丙氧基,-OCH(CH 3) 2)、1-丁氧基(n-BuO,n-丁氧基,-OCH 2CH 2CH 2CH 3)、2-甲基-l-丙氧基(i-BuO,i-丁氧基,-OCH 2CH(CH 3) 2)、2-丁氧基(s-BuO,s-丁氧基,-OCH(CH 3)CH 2CH 3)、2-甲基-2-丙氧基(t-BuO,t-丁氧基,-OC(CH 3) 3)、1-戊氧基(n-戊氧基,-OCH 2CH 2CH 2CH 2CH 3)、2-戊氧基(-OCH(CH 3)CH 2CH 2CH 3)、3-戊氧基(-OCH(CH 2CH 3) 2)、2-甲基-2-丁氧基(-OC(CH 3) 2CH 2CH 3)、3-甲基-2-丁氧基(-OCH(CH 3)CH(CH 3) 2)、3-甲基-l-丁氧基(-OCH 2CH 2CH(CH 3) 2)、2-甲基-l-丁氧基(-OCH 2CH(CH 3)CH 2CH 3)，等等，其中所述烷氧基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。
术语“卤代烷氧基”表示烷氧基基团被一个或多个卤素原子所取代，其中烷氧基具有本发明所述的含义。其中一些实施例是，卤代烷氧基基团含有1-12个碳原子；另外一些实施例是，卤代烷氧基基团含有1-10个碳原子；另外一些实施例是，卤代烷氧基基团含有1-8个碳原子；另外一些实施例是，卤代烷氧基基团含有1-6个碳原子；另外一些实施例是，卤代烷氧基基团含有1-4个碳原子，另外一些实施例是，卤代烷氧基基团含有1-3个碳原子。这样的实例包含，但并不限于，三氟甲氧基等。
术语“环烷基”是指有一个或多个连接点连接到分子的其余部分，饱和的，含有3-12个环碳原子的单环，双环或三环体系。其中一些实施例，环烷基是含3-10个环碳原子的环体系；另外一些实施例，环烷基是含3-8个环碳原子的环体系；另外一些实施例，环烷基是含3-7个环碳原子的环体系；另外一些实施例，环 烷基是含5-8个环碳原子的环体系；另外一些实施例，环烷基是含3-6个环碳原子的环体系；另外一些实施例，环烷基是含5-6个环碳原子的环体系；环烷基基团的实例包含，但并不限于，环丙基，环丁基，环戊基，环己基等等，且所述环烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。
术语“杂环基”和“杂环”在此处可交换使用，都是指包含3-12个环原子的饱和或部分不饱和的，非芳香性的单环、双环或三环体系，其中至少有一个环原子选自氮，硫和氧原子，且此环体系有一个或多个连接点与分子的其余部分相连。术语“杂环基”包括单环、双环或多环稠合、螺式或桥连杂环环系，还包括其中杂环可与一个或多个非芳香族碳环或杂环或一个或多个芳环或其组合稠合的多环环系，其中连接的原子团或点在杂环上。双环杂环基包括桥连双环杂环基、稠合双环杂环基和螺双环杂环基。除非另外说明，杂环基的-CH 2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。在一些实施方案中，杂环基为3-12个环原子组成的环体系；在其它一些实施方案中，杂环基为3-8个环原子组成的环体系；在其它一些实施方案中，杂环基为3-6个环原子组成的环体系；在其他一些实施方案中，杂环基为5-7个环原子组成的环体系；在其他一些实施方案中，杂环基为5-8个环原子组成的环体系；在其他一些实施方案中，杂环基为6-8个环原子组成的环体系；在其他一些实施方案中，杂环基为5-6个环原子组成的环体系；在其它一些实施方案中，杂环基为3个环原子组成的环体系；在其他一些实施方案中，杂环基为4个环原子组成的环体系；在其他一些实施方案中，杂环基为5个环原子组成的环体系；在其他一些实施方案中，杂环基为6个环原子组成的环体系；在其他一些实施方案中，杂环基为7个环原子组成的环体系；在其他一些实施方案中，杂环基为8个环原子组成的环体系。
杂环的实例包括，但并不限于，吡咯烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，四氢吡喃基，二氢吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，噻噁烷基，哌嗪基，高哌嗪基，氮杂环丁基，氧杂环丁基，硫杂环丁基，高哌啶基，氧杂环丙基，氮杂环庚基，氧杂环庚基，硫杂环庚基，氧氮杂卓基，二氮杂卓基，硫氮杂卓基，2-吡咯啉基，3-吡咯啉基，二氢吲哚基，2H-吡喃基，4H-吡喃基，二氧杂环己基，1,3-二氧戊基，吡唑啉基，二噻烷基，二噻茂烷基，二氢噻吩基，吡唑烷基，咪唑啉基，咪唑烷基，1,2,3,4-四氢异喹啉基，3-氮杂双环[3.1.0]己基，3-氮杂双环[4.1.0]庚基，氮杂双环[2.2.2]己基，3H-吲哚基喹嗪基和N-吡啶基尿素。杂环基团的实例还包括，1,1-二氧硫代吗啉基；其中，环上碳原子被氧代(＝O)基团所取代的实例包括，但不限于嘧啶二酮基、1,2,4-噻二唑-5(4H)-酮基，1,2,4-噁二唑-5(4H)-酮基，1H-1,2,4-三唑-5(4H)-酮基等；其中环上碳原子被＝S基团所取代的实例包括，但不限于1,2,4-噁二唑-5(4H)-硫酮基，1,3,4-噁二唑-2(3H)-硫酮基等。所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
术语“M-M 1个环原子组成的”表示所述环状基团由M-M 1个环原子所组成，所述的环原子包括碳原子和/或O、N、S、P等杂原子。例如，“6-10个环原子组成的杂芳基”代表其包括6、7、8、9或10个环原子组成的杂芳基。
术语“杂原子”表示一个或多个O，S，N，P和Si，包括N，S和P任何氧化态的形式；伯，仲，叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3,4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR，R表示本发明所描述的取代基)。
术语“卤素”或“卤原子”是指F，Cl，Br或I。
本发明所使用的术语“不饱和的”表示部分含有一个或多个不饱和度。
术语“芳基”可以单独使用或作为“芳烷基”，“芳烷氧基”或“芳氧基烷基”的一大部分，表示含有6-14个碳原子，或6-12个碳原子，或6-10个碳原子的单环，双环，和三环的碳环体系，其中，至少有一个环体系是芳香族的，其中每一个环体系包含3-7个碳原子组成的环，且有一个或多个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳环”或“芳香环”交换使用，如芳基可以包括苯基，萘基和蒽基。所述芳基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。
术语“杂芳基”可以单独使用或作为“杂芳基烷基”或“杂芳基烷氧基”的一大部分，表示含有5-16个环原子的单环，双环或三环体系，其中至少有一个环体系是芳香族的，且至少有一个环体系包含一个或多个杂原子，其中每一个环体系包含5-7个环原子组成的环，且有一个或多个附着点与分子其余部分相连。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。在一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-14个环原子组成的杂芳基。在另一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-12个环原子组成的杂芳基。在另一些实施方案中，杂芳基为包 含1，2，3或4个独立选自O，S和N的杂原子的5-10个环原子组成的杂芳基。在另一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-8个环原子组成的杂芳基。在另一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-7个环原子组成的杂芳基。在另一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-6个环原子组成的杂芳基。在另一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5个环原子组成的杂芳基。在另一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的6个环原子组成的杂芳基。
另外一些实施例是，杂芳基包括以下的单环基团，但并不限于这些单环基团：2-呋喃基，3-呋喃基，N-咪唑基，2-咪唑基，4-咪唑基，5-咪唑基，3-异噁唑基，4-异噁唑基，5-异噁唑基，2-噁唑基，4-噁唑基，5-噁唑基，N-吡咯基，2-吡咯基，3-吡咯基，2-吡啶基，3-吡啶基，4-吡啶基，2-嘧啶基，4-嘧啶基，5-嘧啶基，哒嗪基(如3-哒嗪基)，2-噻唑基，4-噻唑基，5-噻唑基，四唑基(如5H-四唑基，2H-四唑基)，三唑基(如2-三唑基，5-三唑基，4H-1,2,4-三唑基，1H-1,2,4-三唑基，1,2,3-三唑基)，2-噻吩基，3-噻吩基，吡唑基(如，2-吡唑基和3-吡唑基)，异噻唑基，1,2,3-噁二唑基，1,2,5-噁二唑基，1,2,4-噁二唑基，1,3,4-噁二唑基，1,2,3-硫代二唑基，1,3,4-硫代二唑基，1,2,5-硫代二唑基，吡嗪基，1,3,5-三嗪基；也包括以下的双或者三环基团，但绝不限于这些基团：苯并咪唑基，苯并呋喃基，苯并噻吩基，吲哚基(如2-吲哚基)，嘌呤基，喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)，异喹啉基(如1-异喹啉基，3-异喹啉基或4-异喹啉基)，吩噁噻基，二苯并咪唑基，二苯并呋喃基或二苯并噻吩基等。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。
除非其他方面表明，本发明所描述的结构式包括所有的同分异构形式(如对映异构，非对映异构，和几何异构(或构象异构))：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体，和(Z)、(E)的构象异构体。因此，本发明的化合物的单个立体化学异构体或其对映异构体，非对映异构体，或几何异构体(或构象异构体)的混合物都属于本发明的范围。
本发明所使用的“氮氧化物”是指当化合物含几个胺官能团时，可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例如，过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March,pages)。尤其是，N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514)，其中例如在惰性溶剂(例如二氯甲烷)中，使胺化合物与间-氯过氧苯甲酸(MCPBA)反应。
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)、式(c-2)或式(d-6)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51，2328-2345。
除非其他方面表明，本发明的化合物的所有互变异构形式都包含在本发明的范围之内。另外，除非其他方面表明，本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰胺化，脱酰胺作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明中立体化学的定义和惯例的使用通常参考以下文献：S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,NewYork；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994.本发明的化合物可以包含不对称中心或手性 中心，因此存在不同的立体异构体。本发明的化合物所有的立体异构形式，包括但绝不限于，非对映体，对映异构体，阻转异构体，和它们的混合物，如外消旋混合物，组成了本发明的一部分。很多有机化合物都以光学活性形式存在，即它们有能力旋转平面偏振光的平面。在描述光学活性化合物时，前缀D、L或R、S用来表示分子手性中心的绝对构型。前缀d、l或(+)、(-)用来命名化合物平面偏振光旋转的符号，(-)或l是指化合物是左旋的，前缀(+)或d是指化合物是右旋的。这些立体异构体的化学结构是相同的，但是它们的立体结构不一样。特定的立体异构体可以是对映体，异构体的混合物通常称为对映异构体混合物。50：50的对映体混合物被称为外消旋混合物或外消旋体，这可能导致化学反应过程中没有立体选择性或立体定向性。术语“外消旋混合物”和“外消旋体”是指等摩尔的两个对映异构体的混合物，缺乏光学活性。
术语“互变异构体”或“互变异构的形式”是指不同能量的结构的同分异构体可以通过低能垒互相转化。例如质子互变异构体(即质子转移的互变异构体)包括通过质子迁移的互变，如酮式-烯醇式和亚胺-烯胺的同分异构化作用。原子价(化合价)互变异构体包括重组成键电子的互变。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,66:1-19,1977.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，苹果酸盐，2-羟基丙酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。如果本发明的化合物是酸性的，则想得到的盐可以通过合适的方法制备得到，如，使用无机碱或有机碱，如氨(伯胺、仲胺、叔胺)，碱金属氢氧化物，铵，N +(R 14) 4的盐和碱土金属氢氧化物，等等。合适的盐包括，但并不限于，从氨基酸得到的有机盐，如甘氨酸和精氨酸，氨，如伯胺、仲胺和叔胺，N +(R 14) 4的盐，如R 14是H、C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基等，和环状氨，如哌啶、吗啉和哌嗪等，和从钠、钙、钾、镁、锰、铁、铜、锌、铝和锂得到无机盐。也包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物、氢氧化物、羧化物、硫酸化物、磷酸化物、硝酸化物、C 1-8磺酸化物和芳香磺酸化物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
术语“保护基团”或“Pg”是指一个取代基与别的官能团起反应的时候，通常用来阻断或保护特殊的功能性。例如，“氨基的保护基团”是指一个取代基与氨基基团相连来阻断或保护化合物中氨基的功能性，合适的氨基保护基团包括乙酰基，三氟乙酰基，叔丁氧羰基(BOC)，苄氧羰基(CBZ)和9-芴亚甲氧羰基(Fmoc)。相似地，“羟基保护基团”是指羟基的取代基用来阻断或保护羟基的功能性，合适的保护基团包括乙酰基和甲硅烷基。“羧基保护基团”是指羧基的取代基用来阻断或保护羧基的功能性，一般的羧基保护基包括-CH 2CH 2SO 2Ph，氰基乙基，2-(三甲基硅烷基)乙基，2-(三甲基硅烷基)乙氧基甲基，2-(对甲苯磺酰基)乙基，2-(对硝基苯磺酰基)乙基，2-(二苯基膦基)乙基，硝基乙基，等等。对于保护基团一般的描述可参考文献：T W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005。
本发明化合物的描述
本发明所涉及的化合物，及其药学上可接受的组合物，都可以有效抑制HBV感染。
一方面，本发明涉及一种如式(I)所示的化合物或式(I)所示的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
Figure PCTCN2021072337-appb-000003
其中，各R 1、R 2、R 3、R 4和R 7独立地为氢、氘、F、Cl、Br、C 1-6烷基、C 1-6烷氨基、C 1-6烷氧基、C 2-6炔基、C 2-6烯基、C 3-7环烷基、苯基、5-6个环原子组成的杂芳基或3-10个环原子组成的杂环基，其中所述的C 1-6烷基、C 1-6烷氨基、C 1-6烷氧基、C 2-6炔基、C 2-6烯基、C 3-7环烷基、苯基、5-6个环原子组成的杂芳基和3-10个环原子组成的杂环基各自独立地未被取代或被1、2、3或4个R w所取代；
或R 1、R 2与其链接的碳原子，一起形成环丙基、环丁基、环戊基、环己基或-C(＝O)-，其中所述的环丙基、环丁基、环戊基和环己基各自独立地未被取代或被1、2、3或4个R w所取代；
或R 3、R 4与其链接的碳原子，一起形成环丙基、环丁基、环戊基、环己基或-C(＝O)-，其中所述的环丙基、环丁基、环戊基和环己基各自独立地未被取代或被1、2、3或4个R w所取代；
R 5为氢、氘、C 1-6烷基、C 3-7环烷基、3-6个环原子组成的杂环基、C 6-10芳基或5-10个环原子组成的杂芳基，其中所述的C 1-6烷基、C 3-7环烷基、3-6个环原子组成的杂环基、C 6-10芳基和5-10个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个R j所取代；
R 6为氢、氘、F、Cl、Br、C 1-12烷基、C 1-6烷氨基、C 1-6烷氧基、C 2-6炔基、C 2-6烯基、C 3-7环烷基、C 6-10芳基、5-10个环原子组成的杂芳基或3-10个环原子组成的杂环基，其中所述的C 1-6烷基、C 1-6烷氨基、C 1-6烷氧基、C 2-6炔基、C 2-6烯基、C 3-7环烷基、C 6-10芳基、5-10个环原子组成的杂芳基和3-10个环原子组成的杂环基各自独立地未被取代或被1、2、3或4个R w所取代；
各R j独立地为氘、F、Cl、Br、CN、＝O、HO-、氨基、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-10个环原子组成的杂环基、C 6-10芳基或5-10个环原子组成的杂芳基，其中所述的氨基、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-10个环原子组成的杂环基、C 6-10芳基和5-10个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个R w所取代；
各R w独立地为氘、F、Cl、Br、HO-、HOOC-、＝O、氨基、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 2-6烯基、C 2-6炔基、C 1-6烷基-OC(＝O)-、C 1-6烷基-S(＝O) 2-、C 3-6环烷基-S(＝O) 2-或C 3-7环烷基，其中所述的氨基、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 2-6烯基、C 2-6炔基、C 1-6烷基-OC(＝O)-、C 1-6烷基-S(＝O) 2-、C 3-6环烷基-S(＝O) 2-和C 3-7环烷基各自独立地未被取代或被1、2、3或4个选自F、Cl、Br、CN、HO-、＝O、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基或C 1-6烷氨基的取代基所取代；
n为0、1、2或3。
在一些实施例中，本发明涉及一种如式(c-2)或式(d-6)所示的化合物或式(c-2)或式(d-6)所示的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
Figure PCTCN2021072337-appb-000004
其中，各R 1、R 2、R 3、R 4、R 5、R 6和R 7具有本发明所述的含义。
在一些实施例中，本发明所述的R 5为氢、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、萘基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、萘基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3或4个R j所取代，
其中，各R j具有本发明所述的含义。
在一些实施例中，本发明所述的R 6为氢、氘、F、Cl、Br、C 1-6烷基、C 1-4烷氨基、C 1-4烷氧基、C 2-4炔基、C 2-4烯基、C 3-6环烷基、苯基、萘基、5-6个环原子组成的杂芳基或3-6个环原子组成的杂环基，其中所述的C 1-6烷基、C 1-4烷氨基、C 1-4烷氧基、C 2-4炔基、C 2-4烯基、C 3-6环烷基、苯基、萘基、5-6个环原子组成的杂芳基和3-6个环原子组成的杂环基各自独立地未被取代或被1、2、3或4个R w所取代，
其中，各R w具有本发明所述的含义。
在一些实施例中，本发明所述的R 6为氢、氘、F、Cl、Br、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 1-4烷氨基、C 1-4烷氧基、C 2-4炔基、C 2-4烯基、环丙基、环丁基、环戊基、环己基、苯基、萘基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基或哌嗪基，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 1-4烷氨基、C 1-4烷氧基、C 2-4炔基、C 2-4烯基、环丙基、环丁基、环戊基、环己基、苯基、萘基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基和哌嗪基各自独立地未被取代或被1、2、3或4个R w所取代，
其中，各R w具有本发明所述的含义。
在一些实施例中，本发明所述的R 6为
Figure PCTCN2021072337-appb-000005
Figure PCTCN2021072337-appb-000006
Figure PCTCN2021072337-appb-000007
异丙基、环丙基或叔丁基。
在一些实施例中，本发明所述的各R j独立地为氘、F、Cl、Br、CN、＝O、HO-、氨基、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷氨基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-6个环原子组成的杂环基、苯基、萘基、5个环原子组成的杂芳基或6个环原子组成的杂芳基，其中所述的氨基、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷氨基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-6个环原子组成的杂环基、苯基、萘基、5个环原子组成的杂芳基和6个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个R w所取代，
其中，各R w具有本发明所述的含义。
在一些实施例中，本发明所述的各R j独立地为氘、F、Cl、Br、CN、＝O、HO-、氨基、甲基、乙基、 正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、C 1-3烷硫基、C 1-3烷氨基、C 2-4烯基、C 2-4炔基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、萘基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述的氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、C 1-3烷硫基、C 1-3烷氨基、C 2-4烯基、C 2-4炔基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、萘基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3或4个R w所取代，
其中，各R w具有本发明所述的含义。
在一些实施例中，本发明所述的各R w独立地为氘、F、Cl、Br、HO-、HOOC-、＝O、氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷氨基、C 2-4烯基、乙炔基、炔丙基、丙炔基、1-炔丁基、2-炔丁基、3-炔丁基、叔丁氧羰基、C 1-4烷基-S(＝O) 2-、环丙基-S(＝O) 2-、环戊基-S(＝O) 2-、环己基-S(＝O) 2-、环丙基、环丁基、环戊基或环己基，其中所述氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷氨基、C 2-4烯基、乙炔基、炔丙基、丙炔基、1-炔丁基、2-炔丁基、3-炔丁基、叔丁氧羰基、C 1-4烷基-S(＝O) 2-、环丙基-S(＝O) 2-、环戊基-S(＝O) 2-、环己基-S(＝O) 2-、环丙基、环丁基、环戊基和环己基各自独立地未被取代或被1、2、3或4个选自F、Cl、Br、CN、HO-、＝O、氨基、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷硫基、C 1-4卤代烷氧基或C 1-4烷氨基的取代基所取代；
各R 1、R 2、R 3、R 4和R 7独立地为氢、氘、F、Cl、Br、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 1-4烷氨基、C 1-4烷氧基、乙炔基、炔丙基、丙炔基、1-炔丁基、2-炔丁基、3-炔丁基、C 2-4烯基、环丙基、环丁基、环戊基、环己基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基或哌嗪基，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 1-4烷氨基、C 1-4烷氧基、乙炔基、炔丙基、丙炔基、1-炔丁基、2-炔丁基、3-炔丁基、C 2-4烯基、环丙基、环丁基、环戊基、环己基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基和哌嗪基各自独立地未被取代或被1、2、3或4个R w所取代。
还在一些实施例方案中，本发明涉及到以下其中之一的化合物或它们的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，但绝不限于这些化合物：
Figure PCTCN2021072337-appb-000008
Figure PCTCN2021072337-appb-000009
Figure PCTCN2021072337-appb-000010
Figure PCTCN2021072337-appb-000011
除非另作说明，式(I)、式(c-2)或式(d-6)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药都包含在本发明范围内。
另一方面，本发明还提供了一种包含本发明所述的化合物的药物组合物，任选地，所述药物组合物进一步包含在药学上可接受的辅料或所述辅料的组合。
在一些实施例中，本发明所述的药物组合物，其进一步地包含其它抗HBV药物。
在另一些实施例中，本发明所述的药物组合物，其中所述抗HBV药物为HBV聚合酶抑制剂、免疫调节剂或干扰素。
还在一些实施例中，本发明所述的药物组合物，其中所述抗HBV药物为拉米夫定、替比夫定、替诺福韦酯、恩替卡韦、阿德福韦酯、Alfaferone、Alloferon、西莫白介素、克拉夫定、恩曲他滨、法昔洛韦、干扰素、宝甘灵CP、因特芬、干扰素α-1b、干扰素α、干扰素α-2a、干扰素β-1a、干扰素α-2、白细胞介素-2、米伏替酯、硝唑尼特、聚乙二醇干扰素α-2a、病毒唑、罗扰素-A、西佐喃、Euforavac、安普利近、Phosphazid、Heplisav、干扰素α-2b、左旋咪唑或丙帕锗。
另一方面，本发明还提供了所述化合物或所述药物组合物在制备用于预防、治疗或减轻患者病毒性疾病的药物中的用途。
在一些实施例中，本发明所述的用途，其中所述病毒性疾病是指乙型肝炎病毒感染或乙型肝炎病毒感染引起的疾病。
在另外一些实施例中，本发明所述的用途，其中所述乙型肝炎病毒感染引起的疾病是指肝硬化或肝细胞癌变。
另一方面，本发明还提供了所述的化合物或所述的药物组合物在制备药物中的用途，所述药物用于抑制HBsAg生成或分泌，和/或用于抑制HBV DNA生成或复制的用途。
另一方面，本发明涉及所述的化合物或药物组合物在制备用于预防、治疗或减轻患者乙型肝炎疾病的药物中的用途。
本发明另一方面涉及预防、治疗或减轻患者HBV病症的方法，所述方法包含使用本发明的化合物药学上可接受的有效剂量对患者进行给药。
本发明另一方面涉及预防、治疗或减轻患者HBV病症的方法，所述方法包含使用含有本发明的化合物的药物组合物的药学上可接受的有效剂量对患者进行给药。
本发明另一方面涉及使用一种本发明的化合物在制备用于预防、处理或治疗患者HBV病症，并减轻其严重程度的药物的用途。
本发明另一方面涉及使用一种包含本发明的化合物的药物组合物在制备用于预防或治疗患者HBV病症，并减轻其严重程度的药物的用途。
本发明另一方面涉及一种抑制HBV感染的方法，该方法包含细胞与本发明的化合物或组合物能有效抑制HBV的剂量接触。另外一些实施例是，所述方法更进一步地包含细胞与其它抗HBV剂的接触。
本发明另一方面涉及治疗患者HBV疾病的方法，该方法包含给予患者有效治疗量的本发明的化合物或其组合物。另外一些实施例是，所述方法更进一步地包含其它HBV治疗的给药。
本发明另一方面涉及一种抑制患者HBV感染的方法，该方法包含给予患者有效治疗量的本发明的化合物或其组合物。另外一些实施例是，所述方法更进一步地包含其它HBV治疗的给药。
本发明另一方面涉及式(I)、式(c-2)或式(d-6)所包含的化合物的制备、分离和纯化的方法。
本发明还包含本发明的化合物及其药学上可接受的盐的应用，用于生产医药产品有效抑制HBV感染，包括那些本发明所描述的：本发明的化合物在生产有效抑制HBV感染药物中的应用。本发明的化合物同样用于生产一种医药品用来减轻，阻止，控制或治疗患者乙型肝炎的病症。本发明包含药物组合物，该药物组合物包括式(I)所代表的化合物与至少一个药学上可接受的辅料的结合所需的有效治疗用量。
本发明同样包含有效抑制HBV感染的疾病，或对此病症敏感的方法，该方法包含使用式(I)、式(c-2)或式(d-6)所代表化合物的治疗有效量对患者进行治疗。
除非其他方面表明，本发明的化合物所有的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药都属于本发明的范围。
具体地说，盐是药学上可接受的盐。术语“药学上可接受的”包括物质或组合物必须是适合化学或毒理学地，与组成制剂的其他组分和用于治疗的哺乳动物有关。
本发明的化合物的盐还包括用于制备或纯化式(I)、式(c-2)或式(d-6)所示化合物的中间体或式(I)、式(c-2)或式(d-6)或其异构体的盐，但不一定是药学上可接受的盐。
术语“药学上可接受的”是指从毒理学观点来看可接受用于制药应用且不会不利地与活性成分相互作用的物质。
如果本发明的化合物是碱性的，则想得到的盐可以通过文献上提供的任何合适的方法制备得到，例如，使用无机酸，如盐酸、氢溴酸、硫酸、硝酸和磷酸等等；或者使用有机酸，如乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、苹果酸、2-羟基丙酸、枸橼酸、草酸、羟乙酸和水杨酸；吡喃糖酸，如葡萄糖醛酸和半乳糖醛酸；α-羟酸，如柠檬酸和酒石酸；氨基酸，如天门冬氨酸和谷氨酸；芳香族酸，如苯甲酸和肉桂酸；磺酸，如对甲苯磺酸、苯磺酸、甲磺酸、乙磺酸、三氟甲磺酸等等或它们的组合。
如果本发明的化合物是酸性的，则想得到的盐可以通过合适的方法制备得到，无机碱，如式(I)、式(c-2)或式(d-6)所示化合物的锂盐、钠盐、钾盐、钙盐、镁盐、铝盐、铁盐、亚铁盐、锰盐、亚锰盐、铜盐、锌盐和铵盐等；有机碱，如式(I)、式(c-2)或式(d-6)所示化合物与甲胺、二甲胺、三甲胺、乙胺、二乙胺、三乙胺、氨基丁三醇、二乙氨基乙醇、异丙胺、2-乙氨基乙醇、吡啶、甲基吡啶、乙醇胺、二乙醇胺、铵、二甲基乙醇胺、四甲基铵、四乙基铵、三乙醇胺、哌啶、哌嗪、吗啉、咪唑盐、赖氨酸、精氨酸、L-精氨酸、组氨酸、N-甲基葡糖胺、二甲基葡糖胺、乙基葡糖胺、二环己基胺、1,6-己二胺、乙二胺、葡糖胺、肌氨酸、丝氨醇、氨基丙二醇、1-氨基-2,3,4-丁三醇、L-赖氨酸和鸟氨酸等形成的盐。
本发明的化合物的药物组合物，制剂，给药和化合物及药物组合物的用途
本发明的药物组合物包括式(I)、式(c-2)或式(d-6)所示结构化合物或实施例中所示结构的化合物，或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物以及药学上可接受的盐或前药，以及药学上可以接受的辅料。HBV引发的慢性病毒病可能导致病态变严重，慢性乙型肝炎病毒感染在许多情况下可导致肝硬化和/或肝细胞癌变，本发明的组合物中化合物能有效的抑制乙型肝炎病毒，适用于病毒引起的疾病尤其是急性和慢性持续的HBV病毒感染的治疗。
本发明的化合物尤其适合治疗慢性乙肝病毒感染和急性乙肝病毒感染。
本发明包括药物制剂，除了无毒，惰性的制药学上合适的辅料外，还含有一种或多种本发明的化合物(I)、式(c-2)或式(d-6)或组合物。
上述药物制剂也可以包含化合物(I)、式(c-2)或式(d-6)以外的其他活性药物成分。
本发明的化合物存在自由形态，或合适的、作为药学上可接受的衍生物。根据本发明，药学上可接受的衍生物包括，但并不限于，药学上可接受的前药，盐，酯，酯类的盐，或能直接或间接地根据患者的需要给药的其他任何加合物或衍生物，本发明其他方面所描述的化合物，其代谢产物或它的残留物。
像本发明所描述的，本发明药物组合物包含任何一种本发明的式(I)、式(c-2)或式(d-6)所示化合物，进一步包含药学上可接受的辅料，这些辅料，例如像本发明所应用的，包括任何溶剂，固体赋形剂，稀释剂，粘合剂，崩解剂，或其他液体赋形剂，分散剂，矫味剂或悬浮剂，表面活性剂，等渗剂，增稠剂，乳化剂，防腐剂，固体粘合剂或润滑剂，等等，适合于特有的目标剂型。如以下文献所描述的：In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York,综合此处文献的内容，表明不同的辅料可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的辅料与本发明的化合物不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本发明所考虑的范围。
可作为药学上可接受辅料的物质包括，但并不限于，离子交换剂；铝；硬脂酸铝；卵磷脂；血清蛋白，如人血清蛋白；缓冲物质如磷酸盐；甘氨酸；山梨酸；山梨酸钾；饱和植物脂肪酸的部分甘油酯混合物；水；盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐；胶体硅；三硅酸镁；聚乙烯吡咯烷酮；聚丙烯酸脂；蜡；聚乙烯-聚氧丙烯-阻断聚合体；羊毛脂；糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢 氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇；磷酸缓冲溶液；和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁；着色剂；释放剂；包衣衣料；甜味剂；调味剂；香料；防腐剂和抗氧化剂。
本发明化合物的的药物组合物，可以以下方面的任意方式施予：口服给药，喷雾吸入法，局部给药，经直肠给药，经鼻给药，阴道给药，非肠道给药如皮下，静脉，肌内，腹腔内，肺内，鞘内，心室内，胸骨内，或颅内注射或输液，或借助一种外植的储器用药。优选的方式为口服给药，肌注，向腹膜内给药或静脉注射。
本发明化合物或含有药学上可接受的组合物可以是以单位剂量形式给药。给药剂型可以是液体剂型、固体剂型。液体剂型可以是真溶液类、胶体类、微粒剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂、包合物、埋植剂、贴剂、擦剂等。
口服片剂和胶囊可以含有赋形剂如粘合剂，例如糖浆，阿拉伯胶，山梨醇，黄芪胶，或聚乙烯吡咯烷酮；填充剂，例如乳糖，蔗糖，玉米淀粉，磷酸钙，山梨醇，氨基乙酸；润滑剂，例如硬脂酸镁，滑石，聚乙二醇，硅土；崩解剂，例如马铃薯淀粉；或可接受的增润剂例如月桂醇钠硫酸盐。片剂可以用制药学上公知的方法包衣。
口服液可以制成水和油的悬浮液，溶液，乳浊液，糖浆或酏剂，也可以制成干品，用前补充水或其它合适的媒质。这种液体制剂可以包含常规的添加剂，如悬浮剂，山梨醇，纤维素甲醚，葡萄糖糖浆，凝胶，羟乙基纤维素，羧甲基纤维素，硬脂酸铝凝胶，氢化的食用油脂；乳化剂，如卵磷脂，山梨聚醣单油酸盐，阿拉伯胶；或非水辅料(可能包含可食用油)，如杏仁油；油脂如甘油，乙二醇或乙醇；防腐剂，如对羟基苯甲酸甲酯或丙酯，山梨酸。如需要可添加调味剂或着色剂。
栓剂可包含常规的栓剂基质，如可可黄油或其他甘油酯。
对胃外投药，液态剂型通常由化合物和一种消毒的辅料制成。辅料首选水。依照所选辅料和药物浓度的不同，化合物既可溶于辅料中也可制成悬浮溶液，在制成注射用溶液时先将化合物溶于水中，过滤消毒后装入封口瓶或安瓿中。
当皮肤局部施用时，本发明化合物可以制成适当的软膏，洗剂，或霜剂的形式，其中活性成分悬浮或溶解于一种或多种的辅料中，其中软膏制剂可以使用的辅料包括但不局限于：矿物油，液体凡士林，白凡士林，丙二醇，聚氧化乙烯，聚氧化丙烯，乳化蜡和水；洗剂和霜剂可使用的辅料包括但不限于：矿物油，脱水山梨糖醇单硬脂酸酯，吐温60，十六烷酯蜡，十六碳烯芳醇，2-辛基十二烷醇，苄醇和水。
一般而言，已经证明有利的是无论在人体医药还是在兽医药中，本发明活性化合物的给药总量每24小时为约0.01-500mg/kg体重，优选0.01-100mg/kg体重，如果合适的话，分多次单剂量给药，以达到所要求的效果。单剂量中含活性化合物的量优选为约1-80mg/kg体重，更优选为1-50mg/kg体重，但也可以不按照上述的剂量，即取决于治疗对象的种类和体重、疾病的性质和严重程度、制剂的类型和药物的给药方式，以及给药周期或时间间隔。
本发明提供的药物组合物中还包含抗HBV药物。其中抗HBV药物为HBV聚合酶抑制剂、免疫调节剂、干扰素或其它新型抗HBV剂如HBV RNA复制抑制剂、HBsAg分泌抑制剂、HBV衣壳抑制剂、反义寡聚体、siRNA、HBV治疗疫苗、HBV预防疫苗、HBV抗体疗法(单克隆或多克隆)以及用于治疗或预防HBV的激动剂。
抗HBV药物有拉米夫定，替比夫定，替诺福韦酯，恩替卡韦，阿德福韦酯，Alfaferone，Alloferon，西莫白介素，克拉夫定，恩曲他滨，法昔洛韦，干扰素，宝甘灵CP，因特芬，干扰素α-1b，干扰素α，干扰素α-2a，干扰素β-1a，干扰素α-2，白细胞介素-2，米伏替酯，硝唑尼特，聚乙二醇干扰素α-2a，病毒唑，罗扰素-A，西佐喃，Euforavac，安普利近，Phosphazid，Heplisav，干扰素α-2b，左旋咪唑或丙帕锗等。
一方面，本发明所述的化合物或药物组合物在制备用于预防、处理、治疗或减轻患者乙型肝炎疾病的药品的用途。乙型肝炎疾病是指乙型肝炎病毒感染或乙型肝炎病毒感染引起的肝脏疾病，包括急性肝炎，慢性肝炎，肝硬化和肝癌。急性乙型肝炎病毒感染可以是无症状或表现为急性肝炎症状。慢性病毒感染患者患有活动性疾病，可发展为肝硬化和肝癌。
本发明所述化合物或药物组合物的用途包括抑制HBsAg生成或分泌，还包括给予患者药学上可接受的有效剂量的本发明所述化合物或药物组合物。
本发明所述化合物或药物组合物的用途包括抑制HBV DNA生成，还包括给予患者药学上可接受的有效剂量的本发明所述化合物或药物组合物。
一方面，本发明所述化合物或药物组合物在抑制HBV基因表达上的用途，包括使用本发明所述化合物或药物组合物的药学上可接受的有效剂量对患者进行给药。
其它抗HBV药物可以与包含本发明的化合物的组合物分开给药，作为多给药方案的一部分。或者，那些药物可以是单剂型的一部分，与本发明的化合物混合在一起形成单个组合物。如果给药作为多给药方案的一部分，两个活性剂可以同时连续地或在一段时间内互相传递，从而得到目标试剂活性。
可以结合辅料物质产生单剂型的化合物和组合物的用量(那些包含一个组合物像本发明所描述的)的改变取决于主治和特殊给药模式。
本发明的化合物显示出较强的抗病毒作用。这类化合物对HBV具有出乎预料的抗病毒活性，因此适于用来治疗病毒引起的各种疾病，尤其是急性和慢性持久性HBV感染引起的疾病。由HBV引起的慢性病毒性疾病可以导致各种不同严重程度的综合症状，众所周知，慢性乙肝病毒感染可导致肝硬化和/或肝癌。
可用本发明化合物治疗的适应症的实例有：治疗可导致感染性肝炎的急性和慢性病毒感染，例如乙型肝炎病毒感染，特别优选的是慢性乙型肝炎病毒感染的治疗和急性乙型肝炎病毒感染的治疗。
本发明还涉及，本发明的化合物和组合物用于制备治疗和预防病毒性疾病特别是乙型肝炎的药物的用途。
一般合成方法
为描述本发明，以下列出了实施例。但需要理解，本发明不限于这些实施例，只是提供实践本发明的方法。
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I)、式(c-2)或式(d-6)所示。下面的合成方案和实施例用于进一步举例说明本发明的内容。
所属领域的技术人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度(℃)。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company，使用时都没有经过进一步纯化，除非其他方面表明。一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，青岛腾龙化学试剂有限公司，和青岛海洋化工厂购买得到。
核磁共振光谱数据通过Bruker Avance 400核磁共振谱仪或Bruker Avance III HD 600核磁共振谱仪来测定，以CDCl 3、DMSO-d 6、CD 3OD或d 6-丙酮为溶剂(报导以ppm为单位)，用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)，s,s(singlet，singlet，单峰，单峰)，d(doublet，双峰)，t(triplet，三重峰)，m(multiplet，多重峰)，br(broadened，宽峰)，dd(doublet of doublets，双二重峰)，ddd(doublet of doublet of doublets，双双二重峰)，dt(doublet of triplets，双三重峰)，ddt(doublet of doublet of triplets，双双三重峰)，td(triplet of doublets，三双重峰)，br.s(broadened singlet，宽单峰)。偶合常数J，单位用赫兹(Hz)表示。
低分辨率质谱(MS)数据通过配备G1312A二元泵和a G1316A TCC(柱温保持在30℃)的Agilent 6320系列LC-MS的光谱仪来测定，G1329A自动采样器和G1315B DAD检测器应用于分析，ESI源应用于LC-MS光谱仪。
低分辨率质谱(MS)数据通过配备G1311A四元泵和G1316A TCC(柱温保持在30℃)的Agilent 6120系列LC-MS的光谱仪来测定，G1329A自动采样器和G1315D DAD检测器应用于分析，ESI源应用于LC-MS光谱仪。
以上两种光谱仪都配备了Agilent Zorbax SB-C18柱，规格为2.1×30mm，5μm。注射体积是通过样品浓度来确定；流速为0.6mL/min；HPLC的峰值是通过在210nm和254nm处的UV-Vis波长来记录读取的。流动相为0.1％的甲酸乙腈溶液(相A)和0.1％的甲酸超纯水溶液(相B)。梯度洗脱条件如表1所示：
表1：梯度洗脱条件
时间(min) A(CH 3CN,0.1％HCOOH) B(H 2O,0.1％HCOOH)
0-3 5-100 95-0
3-6 100 0
6-6.1 100-5 0-95
6.1-8 5 95
化合物纯化是通过Agilent 1100系列高效液相色谱(HPLC)来评价的，其中UV检测在210nm和254nm处，Zorbax SB-C18柱，规格为2.1×30mm，4μm，10分钟，流速为0.6mL/min，5-95％的(0.1％甲酸乙腈溶液)的(0.1％甲酸水溶液)，柱温保持在40℃。
下面简写词的使用贯穿本发明：
Figure PCTCN2021072337-appb-000012
Figure PCTCN2021072337-appb-000013
合成方法
以下合成方案列出了制备本发明中公开化合物的合成步骤。其中，各R 1、R 2、R 3、R 4、R 5、R 6和R 7具有如本发明所述的含义，各X 1、X 2和X 3独立地为Cl、Br或I。R 1a为C 1-6烷基或C 3-6环烷基。
合成方案1
Figure PCTCN2021072337-appb-000014
式(a-10)所示化合物可以通过合成方案1中所描述的方法制备得到。首先，化合物(a-1)与卤代物R 5X 2在碱性条件下(如K 2CO 3等)反应生成化合物(a-2)；化合物(a-2)在碱性条件下反应生成化合物(a-3)；化合物(a-3)与多聚甲醛在高温和碱性条件下反应，生成化合物(a-4)；化合物(a-4)经苄基保护，得到化合物(a-5)；化合物(a-5)在磷酸二氢钠存在的条件下，氧化成化合物(a-6)；化合物(a-6)与氯化亚砜反应得到化合物(a-7)；化合物(a-7)与化合物(a-8)反应生成化合物(a-9)；化合物(a-9)脱去苄基保护基得到化合物化合物(a-10)。
合成方案2
Figure PCTCN2021072337-appb-000015
化合物(b-6)可以通过合成方案2中所描述的方法制备得到。首先，化合物(b-1)与化合物(b-2)在碱性条件下(如碳酸铯等)反应，生成化合物(b-3)；化合物(b-3)在低温下脱去甲基保护基，得到化合物(b-4)；化合物(b-4)与化合物(b-5)反应得到化合物(b-6)。
合成方案3
Figure PCTCN2021072337-appb-000016
化合物(c-2)可以通过合成方案3中所描述的方法制备得到。首先，化合物(a-10)与化合物(b-2)在碱性条件下(如碳酸铯等)反应，生成化合物(c-1)；然后，化合物(c-1)在碱性条件下(如K 2CO 3)经水解反应，得到化合物(c-2)。
合成方案4
Figure PCTCN2021072337-appb-000017
化合物(d-6)可以通过合成方案4中所描述的方法制备得到。首先，化合物(a-4)与化合物(d-1)在 碱性条件下(如碳酸钾等)反应，生成化合物(d-2)；然后，化合物(d-2)发生分子内关环反应，得到化合物(d-3)；化合物(d-3)与化合物(d-4)反应生成化合物(d-5)；最后，化合物(d-5)经水解得到化合物(d-6)。
具体实施方式
以下实施例用于说明本发明，但不用来限制本发明的范围。
制备实施例
在以下制备实施例中，发明人以本发明的部分化合物为例，详细描述了本发明化合物的制备过程。
实施例1：4-(2-环丙基乙氧基)-11-氧代-7-苯基-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000018
步骤1：5-溴-2,3-二氢苯并呋喃
Figure PCTCN2021072337-appb-000019
将2,3-二氢苯并呋喃(15.26g,127.00mmol)溶解在DCM(300mL)中，冷却至0℃，加入三溴化吡啶(45.13g,127.00mmol)，搅拌10min后，升温到室温搅拌反应60min。向反应液中加入饱和亚硫酸氢钠溶液使溶液由棕红色变为淡黄色，分液，收集有机相，水相用二氯甲烷(100mL×3)萃取，合并有机相，合并的有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，得到标题化合物为淡黄色固体(22.8g,90％)。
1H NMR(400MHz,CDCl 3)δ(ppm):7.28(s,1H),7.20(d,J＝8.4Hz,1H),6.66(d,J＝8.4Hz,1H),4.57(t,J＝8.7Hz,2H),3.20(t,J＝8.7Hz,2H)。
步骤2：5-溴-7-碘-2,3-二氢苯并呋喃
Figure PCTCN2021072337-appb-000020
将5-溴-2,3-二氢苯并呋喃(20.9g,105mmol)溶解在甲醇(300mL)中，并加入硫酸银(16.5g,52.7mmol)和碘(29.3g,115mmol)，混合物于室温下搅拌反应3h，然后加入亚硫酸氢钠固体使溶液由棕红色变成淡黄色。通过硅藻土抽滤除去固体，用乙酸乙酯洗涤滤饼(100mL×2)。收集滤液，减压蒸馏除去溶剂，所得残留物用乙酸乙酯(200mL)和饱和亚硫酸氢钠水溶液(200mL)稀释，分液。收集上层有机相，有机相用饱和氯化钠溶液(200mL)洗涤，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，得到标题化合物为黄色固体(30.23g,93.03mmol,88.6％)。
1H NMR(400MHz,CDCl 3)δ(ppm):7.55(s,1H),7.23(s,1H),4.65(t,J＝8.8Hz,2H),3.33(t,J＝8.8Hz,2H)。
步骤3：5-溴-2,3-二氢苯并呋喃-7-醇
Figure PCTCN2021072337-appb-000021
干燥的反应瓶中加入5-溴-7-碘-2,3-二氢苯并呋喃(9.65g,29.7mmol)、N,N’-二(4-羟基-2,6-二甲基苯基)草酰胺(585mg,1.78mmol)、乙酰丙酮酸铜(467mg,1.78mmol)、二甲亚砜(24mL)和氢氧化钾(5g,89.11mmo)的水(6mL)溶液。反应混合物用氮气置换三次，升温到60℃，搅拌反应5h。反应完后，反应混合物通过硅藻土过滤除去固体，用pH为10的氢氧化钠水溶液(100mL)和甲基叔丁基醚(100mL)洗涤滤饼。收集滤液，分液，收集下层水相，用甲基叔丁基醚洗涤(50mL×2)。用1M盐酸将水相的pH调节到4左右，加入乙酸乙酯(100mL)，分液，收集上层有机相，水相用乙酸乙酯萃取(50mL×2)，合并有机相，用饱和氯化钠溶液(100mL×3)洗涤，无水硫酸钠干燥，过滤，减压蒸馏除去溶剂，得到标题化合物为棕黑色固体产物(6.12g,28.5mmol,95.8％)。
1H NMR(400MHz,CDCl 3)δ(ppm):6.97–6.62(m,2H),5.07(s,1H),4.62(t,J＝8.7Hz,2H),3.23(t,J＝8.7Hz,2H)。
步骤4：5-溴-7-甲氧基-2,3-二氢苯并呋喃
Figure PCTCN2021072337-appb-000022
向反应瓶中加入5-溴-2,3-二氢苯并呋喃-7-醇(33.53g,155.94mmol)、乙腈(350mL)、K 2CO 3(50.71g,311.9mmol)和碘甲烷(20.4mL,311mmol)，加热至60℃反应3h。反应完成后，过滤除去不溶物，减压蒸馏滤液，向残余物中加入水(200mL)和乙酸乙酯(200mL)，分液，有机相再用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，减压蒸馏得到标题化合物为棕色油状液体(35.2g,153.49mmol)。
步骤5：7-甲氧基-2,3-二氢苯并呋喃-5-甲醛
Figure PCTCN2021072337-appb-000023
反应瓶中加入5-溴-7-甲氧基-2,3-二氢苯并呋喃(5g,21.83mmol)和THF(50mL)，氮气保护下，冷却到-10℃，再依次滴加异丙基溴化镁的THF溶液(7.6mL,15mmol，2.0M)和正丁基锂的1,4-二氧六环溶液(8.7mL,22mmol,2.5M)，加毕，反应混合物继续搅拌1h，然后加入DMF(2.19mL,28.4mmol)，再转移至室温反应1h。反应完全后，在冰浴下，滴加1M稀盐酸调至酸性，乙酸乙酯(150mL)萃取，有机相用无水硫酸钠干燥，过滤后旋干，残留物经硅胶柱层析(PE/EA(V/V)＝5/1)纯化，得到标题化合物为白色固体(3.27g,18.4mmol,84.1％)。
MS(ESI,pos.ion)m/z:179.2[M+H] +。
步骤6：7-甲氧基-2,3-二氢苯并呋喃-5-醇
Figure PCTCN2021072337-appb-000024
反应瓶中加入7-甲氧基-2,3-二氢苯并呋喃-5-甲醛(2.27g,12.7mmol)，加入DCM(34mL)溶解，加入间氯过氧苯甲酸(3.62g,17.8mmol)，升温至50℃反应2h。反应完全后，冷却至室温，加入饱和亚硫酸 氢钠溶液(20mL)，搅拌10min。再用饱和碳酸钠溶液调节至碱性，分液后有机相再用饱和碳酸氢钠溶液洗涤(20mL×3)，无水硫酸钠干燥，过滤后减压蒸馏除去溶剂，所得残留物用甲醇(3mL)溶解。称取KOH(1.61g)，配成10％的水溶液，加入至上述甲醇溶液中，室温下搅拌反应20min。反应结束后，用1M稀盐酸调节pH至酸性，然后加入乙酸乙酯(30mL)萃取，无水硫酸钠干燥，过滤后旋干，残留物经硅胶柱层析(PE/EA(V/V)＝3/1)纯化，得到标题化合物为黄色固体(1.335g,8.034mmol,63.1％)。
MS(ESI,pos.ion)m/z:167.1[M+H] +。
步骤7：5-羟基-7-甲氧基-2,3-二氢苯并呋喃-4-甲醛
Figure PCTCN2021072337-appb-000025
向反应瓶中加入7-甲氧基-2,3-二氢苯并呋喃-5-醇(1.982g,11.93mmol)、TEA(3.621g,35.78mmol)、THF(20mL)、氯化镁(2.271g,23.85mmol)和多聚甲醛(2.25g,23.9mmol)，加热至80℃回流反应8h。反应完全后，加入1M稀盐酸调节pH至酸性，然后用乙酸乙酯(30mL)萃取，分液，有机相再用饱和食盐水(30mL)洗涤，无水硫酸钠干燥后过滤，旋干滤液，残留物经硅胶柱层析(PE/EA(V/V)＝3/1)纯化，得到标题化合物为亮黄色固体(1.7636g,9.1mmol,76.15％)。
MS(ESI,pos.ion)m/z:195.1[M+H] +。
步骤8：5-(苄氧基)-7-甲氧基-2,3-二氢苯并呋喃-4-甲醛
Figure PCTCN2021072337-appb-000026
向反应瓶中加入5-羟基-7-甲氧基-2,3-二氢苯并呋喃-4-甲醛(1.763g,9.079mmol)，加入MeCN(20mL)溶解，再加入K 2CO 3(2.506g,18.16mmol)和溴化苄(1.31mL,10.9mmol)，加热至80℃反应4h。反应完全后，过滤除去不溶物，旋干滤液，加入水(50mL)和乙酸乙酯(50mL)，分液，有机相再用无水硫酸钠干燥，过滤后旋干滤液，得到标题化合物为白色固体(1.767g,6.21mmol,68％)。
步骤9：5-(苄氧基)-7-甲氧基-2,3-二氢苯并呋喃-4-甲酸
Figure PCTCN2021072337-appb-000027
向反应瓶中加入5-(苄氧基)-7-甲氧基-2,3-二氢苯并呋喃-4-甲醛(0.20g,0.70mmol)，加入DMSO(4mL)溶解。向磷酸二氢钠(0.253g,2.11mmol)的H 2O(1.6mL)溶液中加入亚氯酸钠(0.318g,2.81mmol)，搅拌至溶解，在冰浴0℃将此溶液滴加至反应瓶中，所得混合物转移至室温下反应1h。反应完全后，向反应瓶中加入饱和亚硫酸氢钠溶液(20mL)，然后用乙酸乙酯(30mL)萃取，有机相用无水硫酸钠干燥后过滤，旋干滤液，残留物加入甲基叔丁基醚(30mL)稀释，搅拌3h后过滤得到标题化合物为白色固体(0.91g,3.0mmol,55％)。
MS(ESI,pos.ion)m/z：301.1[M+H] +。
步骤10：5-(苄氧基)-7-甲氧基-2,3-二氢苯并呋喃-4-甲酰氯
Figure PCTCN2021072337-appb-000028
向反应瓶中加入5-(苄氧基)-7-甲氧基-2,3-二氢苯并呋喃-4-甲酸(0.91g,3.0mmol)和DCM(10mL)，冷却到0℃，再滴加氯化亚砜(2.2mL,30mmol)。反应混合物升温至50℃反应回流反应3h。旋干溶剂，得到标题化合物为黄色油状液体(0.97g,3.0mmol,100％)，直接用于下一步反应。
步骤11：6-(5-(苄氧基)-7-甲氧基-2,3-二氢苯并呋喃-4-基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯
Figure PCTCN2021072337-appb-000029
向反应瓶中加入无水THF(10mL)和六甲基硅基氨基锂的甲苯溶液(6.1mL,6.1mmol，1M)，冷却至-78℃，再缓慢滴加2-((二甲氨基)亚甲基)-3-氧代丁酸乙酯(1.1g,5.9mmol)的THF(5mL)溶液和5-(苄氧基)-7-甲氧基-2,3-二氢苯并呋喃-4-甲酰氯(0.97g,3.0mmol)的THF(5mL)溶液，滴加完成后，继续反应10min，然后将反应瓶转移至室温，加入甲酸(5.2mL,91mmol)和醋酸铵(0.26g,3.4mmol)，加毕，再继续反应10min，然后减压出去THF，剩余物加热至60℃反应1h。反应结束后，加入水(30mL)和乙酸乙酯(30mL)稀释，分液。有机相用饱和食盐水洗涤(30mL×2)，无水硫酸钠干燥，过滤后旋干，残留物经硅胶柱层析(PE/EA(V/V)＝1/1)纯化，得到标题化合物为黄色固体(0.9g,2mmol,70％)。
MS(ESI,pos.ion)m/z：422.3[M+H] +。
步骤12：6-(5-羟基-7-甲氧基-2,3-二氢苯并呋喃-4-基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯
Figure PCTCN2021072337-appb-000030
将6-(5-(苄氧基)-7-甲氧基-2,3-二氢苯并呋喃-4-基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯(0.9g,2mmol)溶解在甲醇(10mL)和THF(10mL)中，然后加入和Pd/C(0.5g,2mmol)。反应混合物氢气置换三次，然后氢气氛围下，室温反应1h。反应结束后，用硅藻土过滤，旋干溶剂得到标题化合物为黄色固体(0.69g,2.1mmol,100％)。
MS(ESI,pos.ion)m/z：332.0[M+H] +。
步骤13：4-甲氧基-11-氧代-7-苯基-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸乙酯
Figure PCTCN2021072337-appb-000031
向反应瓶中加入6-(5-羟基-7-甲氧基-2,3-二氢苯并呋喃-4-基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯(0.500g,1.51mmol)、DMF(5mL)、碳酸铯(2.07g,6.04mmol)和二氯甲基苯(0.608g,3.78mmol)，加热至100℃ 反应12h。反应完全后，加入50mL水稀释，然后用1M稀盐酸调节pH至酸性，用EA萃取(30mL×2)，合并有机相。有机相用饱和食盐水洗涤(30mL×2)，再用无水硫酸钠干燥，过滤并旋干溶剂，残留物经硅胶柱层析(EA/MeOH(V/V)＝10/1)纯化，得到标题化合物为棕色固体(0.11g,0.25mmol,16.6％)。
MS(ESI,pos.ion)m/z：420.1[M+H] +。
步骤14：4-羟基-11-氧代-7-苯基-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000032
将4-甲氧基-11-氧代-7-苯基-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸乙酯(0.321g,0.765mmol)溶解在无水DCM(9.63mL)中，然后冷却至-78℃。取BBr 3(4.59mL,4.59mmol)的DCM溶液，缓慢滴加至反应瓶中，加毕，继续于-78℃反应1h。然后转移至室温反应12h。反应结束后，0℃下向反应瓶中滴加甲醇(5mL)淬灭反应，然后旋干溶剂，加入水(30mL)和乙酸乙酯(30mL)，分液，水相再用乙酸乙酯(20mL)萃取，合并有机相，用无水硫酸钠干燥，过滤并旋干溶剂，残留物用DMF(5mL)溶解，再加入K 2CO 3(0.211g,1.53mmol)，升温至75℃反应1h。反应结束后，不做后处理，直接投下一步反应。
MS(ESI,pos.ion)m/z：378.0[M+H] +。
步骤15：4-(2-环丙基乙氧基)-11-氧代-7-苯基-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶基[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000033
向反应瓶中加入4-羟基-11-氧代-7-苯基-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸(0.289g,0.766mmol)、DMF(5mL)、K 2CO 3(0.317g,2.29mmol)和2-环丙基乙基甲磺酸酯(0.264g,1.61mmol)，加热至70℃反应3h。反应结束后，再加入一水氢氧化锂(0.322g,7.67mmol)和甲醇(2mL)，室温搅拌反应2h。反应结束后，用1M稀盐酸调节pH至酸性，析出固体，过滤，滤液弃去。固体用二氯甲烷(20mL)溶解，再用无水硫酸钠干燥，过滤后旋干，残留物经硅胶柱层析(DCM/MeOH(V/V)＝10/1)分离纯化，得到标题化合物为淡黄色固体(50mg,0.11mmol,15％)。
MS(ESI,pos.ion)m/z：446.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm):15.60(s,1H),8.18(s,1H),7.56–7.45(m,3H),7.35(d,J＝6.7Hz,2H),6.93(s,1H),6.55(d,J＝12.6Hz,1H),6.52(s,1H),4.78–4.64(m,2H),4.11(t,J＝6.8Hz,2H),3.60–3.43(m,2H),1.72(q,J＝6.8Hz,2H),0.87–0.76(m,1H),0.54–0.43(m,2H),0.14–0.08(m,2H).
实施例2:7-(3-氟苯基)-4-甲氧基-11-氧代-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000034
以6-(5-羟基-7-甲氧基-2,3-二氢苯并呋喃-4-基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯和1-(二溴甲基)-3-氟-苯为原料，参考实施例1步骤13至步骤15的合成方法，制备得到标题化合物为黄色固体。
MS(ESI,pos.ion)m/z：410.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm):8.29(s,1H),7.44(dd,J＝13.6,7.9Hz,1H),7.18(t,J＝7.7Hz,1H),7.04(d,J＝6.0Hz,2H),6.93(s,1H),6.68(s,1H),6.55(s,1H),4.79–4.63(m,2H),3.90(s,3H),3.60–3.44(m,2H).
实施例3:4-(2-环丙基乙氧基)-11-氧代-7-(噻唑-2-基)-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
步骤1：2-(二溴甲基)噻唑
Figure PCTCN2021072337-appb-000035
反应瓶中加入2-醛基噻唑(2g,17.677mmol)、三苯基膦(9.37g,35.4mmol)、四丁基碘化铵(6.6g,18mmol)和1,2-二溴乙烷(40mL)，氮气保护后，加热至60℃反应12h。反应完成后，旋干溶剂，残留物经硅胶柱层析(PE/EA(V/V)＝10/1)，得到标题化合物为淡黄色油状产物(2.13g,8.29mmol,46.9％)。MS(ESI,pos.ion)m/z：257.8[M+H] +。
步骤2：4-(2-环丙基乙氧基)-11-氧代-7-(噻唑-2-基)-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000036
以6-(5-羟基-7-甲氧基-2,3-二氢苯并呋喃-4-基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯和2-(二溴甲基)噻唑为原料，参考实施例1步骤13至步骤15的合成方法，制备得到标题化合物为淡黄色固体。
MS(ESI,pos.ion)m/z：453.0[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm):15.50(s,1H),8.65(s,1H),7.76(d,J＝3.1Hz,1H),7.47(d,J＝3.1Hz,1H),7.06(s,1H),6.92(s,1H),6.66(s,1H),4.88–4.77(m,1H),4.61(q,J＝9.4Hz,1H),4.17(t,J＝6.8Hz,2H),3.60(dt,J＝15.6,10.0Hz,1H),3.41(ddd,J＝15.4,9.8,5.5Hz,1H),1.76(q,J＝6.9Hz,2H),0.86(dt,J＝7.7,5.2Hz,1H),0.53(dt,J＝7.9,5.1Hz,2H),0.15(q,J＝4.7Hz,2H).
实施例4:7-(4-氯噻唑-5-基)-4-(3-甲氧基丙氧基)-11-氧代-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000037
步骤1：5-溴-7-(3-甲氧基丙氧基)-2,3-二氢苯并呋喃
Figure PCTCN2021072337-appb-000038
以5-溴-2,3-二氢苯并呋喃-7-醇和1-溴-3-甲氧基丙烷为原料，参考实施例1步骤4合成方法，制备得到标题化合物为无色油状物。
步骤2：6-(5-羟基-7-(3-甲氧基丙氧基)-2,3-二氢苯并呋喃-4-基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯
Figure PCTCN2021072337-appb-000039
以5-溴-7-(3-甲氧基丙氧基)-2,3-二氢苯并呋喃为原料，参考实施1步骤5至步骤12的合成方法，制备得到标题化合物为黄色固体。
MS(ESI,pos.ion)m/z：390.1[M+H] +。
步骤3：7-(4-氯噻唑-5-基)-4-(3-甲氧基丙氧基)-11-氧代-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁 嗪-10-甲酸乙酯
Figure PCTCN2021072337-appb-000040
于反应瓶中加入4-氯-5-(二溴甲基)噻唑(1.05g,3.60mmol)、6-(5-羟基-7-(3-甲氧基丙氧基)-2,3-二氢苯并呋喃-4-基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯(350mg,0.90mmol)、K 2CO 3(580mg,4.2mmol)和DMF(10mL)，80℃搅拌反应20h，降至室温，加入水(20mL)，然后用DCM(40mL×2)萃取，合并有机相，有机相用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，浓缩溶剂，残留物经硅胶柱层析分离 (MeOH/DCM(V/V)＝1/20)，得标题化合物为褐色固体(145mg,0.90mmol,31％)。
MS(ESI,pos.ion)m/z：519.0[M+H] +。
步骤4：7-(4-氯噻唑-5-基)-4-(3-甲氧基丙氧基)-11-氧代-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁 嗪-10-甲酸
Figure PCTCN2021072337-appb-000041
于反应瓶中加入7-(4-氯噻唑-5-基)-4-(3-甲氧基丙氧基)-11-氧代-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸乙酯(145mg,0.90mmol)、MeOH(5mL)、LiOH·H 2O(62mg,1.478mmol)和H 2O(5mL)。反应混合物于室温搅拌4h，浓缩溶剂，加入DCM(20mL)，加2M盐酸调pH＝5左右，用DCM(20mL×2)萃取，合并有机相，有机相用饱和食盐水洗涤，减压浓缩，残留物经硅胶薄层制备分离(MeOH/DCM(V/V)＝1/10)得标题化合物为棕色固体(60mg,0.12mmol,41％)。
MS(ESI,pos.ion)m/z：491.0[M+H] +；
1H NMR(600MHz,CDCl 3)δ(ppm):15.32(s,1H),8.83(s,1H),8.37(s,1H),6.98(s,1H),6.60(s,1H),4.80(m,2H),4.17(m,2H),3.67(s,1H),3.56(m,2H),3.36(s,3H),2.11(m,4H)。
实施例5:4-(3-甲氧基丙氧基)-11-氧代-7-(4-氯噻唑-5-基)-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000042
以6-(5-羟基-7-甲氧基-2,3-二氢苯并呋喃-4-基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯和5-(二溴甲基)噻唑为原料，参考实施例4步骤3至步骤4的合成方法，制备得到标题化合物为米黄色固体。
MS(ESI,pos.ion)m/z：457.2[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm):15.42(s,1H),8.91(s,1H),8.50(s,1H),7.81(s,1H),7.06(s,1H),6.95(s,1H),6.58(s,1H),4.86–0.477(m,1H),4.75–4.65(m,1H),4.17(t,J＝6.4Hz,2H),3.69–3.43(m,4H),3.36(s,3H),2.17–2.08(m,2H)。
实施例6:4-(2-环丙基乙氧基)-11-氧代-7-(噻唑-4-基)-1,2,7,11-四氢呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000043
以6-(5-羟基-7-甲氧基-2,3-二氢苯并呋喃-4-基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯和4-(二溴甲基)噻唑为原料，参考实施例1步骤13至步骤15的合成方法，制备得到标题化合物为淡黄色固体。
MS(ESI,pos.ion)m/z：453.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm):15.58(s,1H),8.82(s,1H),8.48(s,1H),7.43(s,1H),6.89(s,2H),6.62(s,1H),4.77(dd,J＝16.0,9.3Hz,1H),4.65(q,J＝9.0Hz,1H),4.14(t,J＝6.7Hz,2H),3.62–3.38(m,2H),1.74(q,J＝6.8Hz,2H),0.83(s,1H),0.50(q,J＝5.0Hz,2H),0.12(d,J＝4.7Hz,2H)。
实施例7:4-(2-环丙基乙氧基)-11-氧代-7-(噻唑-5-基)-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000044
以6-(5-羟基-7-甲氧基-2,3-二氢苯并呋喃-4-基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯和5-(二溴甲基)噻唑为原料，参考实施例1步骤13至步骤15的合成方法，制备得到标题化合物为淡黄色固体。
MS(ESI,pos.ion)m/z：453.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm):15.52(s,1H),8.93–8.76(m,1H),8.61(s,1H),7.82(s,1H),7.18(s,1H),6.92(s,1H),6.54(s,1H),4.87–4.74(m,1H),4.68(q,J＝9.1Hz,1H),4.11(t,J＝6.7Hz,2H),3.66–3.52(m,1H),3.52–3.39(m,1H),1.77–1.68(m,2H),0.91–0.76(m,1H),0.49(d,J＝7.6Hz,2H),0.15–0.08(m,2H)。
实施例8：(R)-8-异丙基-4-(3-甲氧基丙氧基)-12-氧代-2,7,8,12-四氢-1H-苯并呋喃并[4,5-f]吡啶并[1,2-d][1,4]氧氮杂环庚烷-11-甲酸
Figure PCTCN2021072337-appb-000045
步骤1：(R)-(1-((4-甲酰基-7-(3-甲氧基丙氧基)-2,3-二氢苯并呋喃-5-基)氧基)-3-甲基丁-2-基)氨基甲酸叔丁酯
Figure PCTCN2021072337-appb-000046
将5-羟基-7-(3-甲氧基丙氧基)-2,3-二氢苯并呋喃-4-甲醛(4.0g,16mmol)、(R)-4-异丙基-1,2,3-氧硫唑烷-3-甲酸叔丁酯-2,2-二氧化物(4.6g,17mmol,参考Org.Lett.2018,20,17,5431–5434的合成方法得到)、碳酸钾(4.4g,32mmol)和DMF(10mL)依次加入单口瓶，70℃搅拌反应7h。降至25℃，加入乙酸乙酯(100mL)，1M稀盐酸调PH至中性，饱和食盐水(40mL)洗涤有机相，无水硫酸钠干燥，浓缩溶剂得标题化合物为棕色油状物(6.90g,99％)。
MS(ESI,pos.ion)m/z：338.2[M+H] +。
步骤2：(R)-3-异丙基-7-(3-甲氧丙氧基氧)-3,4,9,10-四氢苯并呋喃并[4,5-f][1,4]氧氮杂环庚烷
Figure PCTCN2021072337-appb-000047
将(R)-(1-((4-甲酰基-7-(3-甲氧基丙氧基)-2,3-二氢苯并呋喃-5-基)氧基)-3-甲基丁-2-基)氨基甲酸叔丁酯(6.9g,15mmol)和氯化氢的1,4-二氧六环溶液(20mL)依次加入单口瓶，25℃搅拌反应12h。反应完全后，浓缩溶剂，加入DCM(50mL)和饱和碳酸氢钠溶液(20mL)，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，浓缩溶剂，残留物经硅胶柱层析分离(MeOH/DCM(V/V)＝1/20)纯化，得标题化合物为黑色固体(3.10g,61％)。
MS(ESI,pos.ion)m/z：320.4[M+H] +。
步骤3：(8R)-8-异丙基-4-(3-甲氧基丙氧基)-12-氧代-2,7,8,12,13,13a-六氢-1H-苯并呋喃并[4,5-f]吡啶并 [1,2-d][1,4]氧氮杂环庚烷-11-甲酸乙酯
Figure PCTCN2021072337-appb-000048
将(R)-3-异丙基-7-(3-甲氧丙氧基氧)-3,4,9,10-四氢苯并呋喃并[4,5-f][1,4]氧氮杂环庚烷(1.5g,4.7mmol)、2-乙氧亚甲基乙酰乙酸乙酯(2.62g,14.1mmol)和乙醇(3mL)依次加入微波反应瓶，120℃微波反应13h。反应完全后，浓缩溶剂，停止反应，残留物经硅胶柱层析(MeOH/DCM(V/V)＝1/20)得标题化合物为褐色固体(0.56g,26％)。
MS(ESI,pos.ion)m/z：460.5[M+H] +。
步骤4：(R)-8-异丙基-4-(3-甲氧基丙氧基)-12-氧代-2,7,8,12-四氢-1H-苯并呋喃并[4,5-f]吡啶并[1,2-d][1,4]氧氮 杂环庚烷-11-甲酸乙酯
Figure PCTCN2021072337-appb-000049
(8R)-8-异丙基-4-(3-甲氧基丙氧基)-12-氧代-2,7,8,12,13,13a-六氢-1H-苯并呋喃并[4,5-f]吡啶并[1,2-d][1,4]氧氮杂环庚烷-11-甲酸乙酯(0.70g,1.5mmol)、乙二醇二甲醚(15mL)、甲苯(15mL)和四氯苯醌(1.1g,4.5mmol)的混合物在120℃下搅拌16h。浓缩溶剂，残留物经硅胶柱层析(甲醇/二氯甲烷(V/V)＝1/50)分离纯化，得标题化合物为褐色油状物(1.2g,60％)。
MS(ESI,pos.ion)m/z：458.1[M+H] +；
步骤5：(R)-8-异丙基-4-(3-甲氧基丙氧基)-12-氧代-2,7,8,12-四氢-1H-苯并呋喃并[4,5-f]吡啶并[1,2-d][1,4]氧氮 杂环庚烷-11-甲酸
Figure PCTCN2021072337-appb-000050
取(R)-8-异丙基-4-(3-甲氧基丙氧基)-12-氧代-2,7,8,12-四氢-1H-苯并呋喃并[4,5-f]吡啶并[1,2-d][1,4]氧氮杂环庚烷-11-甲酸乙酯(0.70g,1.53mmol)、甲醇(5.0mL)、水(5mL)和一水合氢氧化锂(0.31g,7.41mmol)依次加入单口瓶中，混合物于25℃搅拌2h。反应完全后，浓缩溶剂，加入水(5mL)和DCM(50mL)稀释，再加入2M的HCl溶液调pH至5左右，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，减压浓缩溶剂。残留物加入MeOH(5mL)溶解，然后升温至70℃搅拌0.5h，再降至室温搅拌24h，过滤，滤饼经干燥得棕色固体(380.0mg,57.82％)。
MS(ESI,pos.ion)m/z：430.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm):15.79(s,1H),8.62(s,1H),6.71(s,1H),6.64(s,1H),4.73(m,3H),4.34(m,2H),4.18(t,J＝6.3Hz,2H),3.87(s,1H),3.58(t,J＝5.9Hz,3H),3.38(s,3H),2.47(m,1H),2.13(p,J＝6.2Hz,2H),1.02(s,6H)。
实施例9：4-(3-甲氧基丙氧基)-11-氧代-7-(噻唑-2-基)-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000051
以6-(5-羟基-7-(3-甲氧基丙氧基)-2,3-二氢苯并呋喃-4-基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯和2-(二溴甲基)噻唑为原料，参考实施例4步骤3至步骤4合成方法，制备得到标题化合物为米黄色固体。
MS(ESI,pos.ion)m/z：457.1[M+H] +；
1H NMR(600MHz,CDCl 3)δ(ppm):15.51(s,1H),8.65(s,1H),7.76(d,J＝2.9Hz,1H),7.47(d,J＝2.9Hz,1H),7.06(s,1H),6.92(s,1H),6.67(s,1H),4.82(td,J＝9.7,5.6Hz,1H),4.62(q,J＝9.3Hz,1H),4.19(t,J＝6.4Hz,2H),3.69–3.52(m,3H),3.46–3.39(m,1H),3.38(s,3H),2.13(dt,J＝12.2,6.1Hz,2H)。
实施例10：4-(苄氧基)-11-氧代-7-(噻唑-2-基)-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000052
步骤1：4-羟基-11-氧代-7-(噻唑-2-基)-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000053
以6-(5-羟基-7-甲氧基-2,3-二氢苯并呋喃-4-基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯和2-(二溴甲基)噻唑为原料，参考实施例1步骤13至步骤14的合成方法，制备得到标题化合物为褐色固体。
MS(ESI,pos.ion)m/z：385.2[M+H] +。
步骤2：4-(苄氧基)-11-氧代-7-(噻唑-2-基)-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000054
以4-羟基-11-氧代-7-(噻唑-2-基)-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸和溴化苄为原料，参考实施例1步骤15的合成方法，制备得到标题化合物为白色固体。
MS(ESI,pos.ion)m/z：475.1[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm):15.96(s,1H),9.03(s,1H),7.93(s,1H),7.88(d,J＝3.0Hz,1H),7.76(d,J＝3.1Hz,1H),7.47–7.33(m,5H),7.02(s,1H),6.91(s,1H),5.22(s,2H),4.75–4.63(m,1H),4.49–4.38(m,1H),3.80–3.66(m,1H),3.31–3.24(m,1H)。
实施例11：4-异丁氧基-11-氧代-7-(噻唑-2-基)-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10–甲酸
Figure PCTCN2021072337-appb-000055
以4-羟基-11-氧代-7-(噻唑-2-基)-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸和1-溴-2-甲基丙烷为原料，参考实施例1步骤15的合成方法，制备得到标题化合物为白色固体。
MS(ESI,pos.ion)m/z：441.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm):15.52(s,1H),8.64(s,1H),7.77(s,1H),7.48(s,1H),6.98(d,J＝47.7Hz,2H),6.63(s,1H),4.83(d,J＝4.6Hz,1H),4.62(d,J＝8.7Hz,1H),3.85(d,J＝4.9Hz,2H),3.59(s,1H),3.41(s,1H),2.37–2.12(m,1H),1.07(d,J＝5.4Hz,6H)。
实施例12：4-(环戊基甲氧基)-11-氧代-7-(噻唑-2-基)-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000056
以4-羟基-11-氧代-7-(噻唑-2-基)-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸和(溴甲基)环丙烷为原料，参考实施例1步骤15的合成方法，制备得到标题化合物为白色固体。
MS(ESI,pos.ion)m/z：467.0[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm):15.49(s,1H),8.62(s,1H),7.74(d,J＝2.6Hz,1H),7.45(d,J＝2.5Hz,1H),7.03(s,1H),6.89(s,1H),6.61(s,1H),4.80(td,J＝9.8,5.6Hz,1H),4.59(q,J＝9.4Hz,1H),3.93(d,J＝7.1Hz,2H),3.57(dt,J＝15.5,9.9Hz,1H),3.49(s,1H),3.38(ddd,J＝15.4,9.8,5.6Hz,1H),2.41(dq,J＝15.0,7.5Hz,1H),1.87(d,J＝5.9Hz,2H),1.63(d,J＝7.8Hz,3H),1.35(dd,J＝12.3,6.8Hz,2H)。
实施例13：11-氧代-4-((四氢-2H-吡喃-4-基)甲氧基)-7-(噻唑-2-基)-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000057
以4-羟基-11-氧代-7-(噻唑-2-基)-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]恶嗪-10-甲酸和4-(溴甲基)四氢-2H-吡喃为原料，参考实施例1步骤15的合成方法，制备得到标题化合物为白色固体。
MS(ESI,pos.ion)m/z：483.1[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ(ppm):15.97(s,1H),9.06–8.98(m,1H),7.97–7.84(m,2H),7.76(d,J＝2.9Hz,1H),6.92(d,J＝10.0Hz,2H),4.75–4.62(m,1H),4.48–4.36(m,1H),3.99–3.90(m,2H),3.86(d,J＝7.8Hz,2H),3.77–3.66(m,1H),2.04–1.91(m,2H),1.68–1.58(m,2H),1.37–1.25(m,4H).
实施例14：(R)-8-(叔丁基)-4-(3-甲氧基丙氧基)-12-氧代-2,7,8,12-四氢-1H-苯并呋喃并[4,5-f]吡啶并[1,2-d][1,4] 噁嗪-11-甲酸
Figure PCTCN2021072337-appb-000058
以5-羟基-7-(3-甲氧基丙氧基)-2,3-二氢苯并呋喃-4-甲醛、(R)-4-叔丁基-1,2,3-氧硫唑烷-3-甲酸叔丁酯-2,2-二氧化物(参考Org.Lett.2018,20,17,5431–5434的合成方法得到)为原料，参考实施例8步骤1至步骤4的合成方法，制备得到标题化合物为白色固体产物。
MS(ESI,pos.ion)m/z：444.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm):15.71(s,1H),8.96(s,1H),6.70(s,1H),6.64(s,1H),4.88–4.75(m,1H),4.68(dd,J＝18.1,9.0Hz,1H),4.61–4.47(m,1H),4.43–4.30(m,1H),4.26–4.12(m,3H),3.70–3.50(m,2H),3.38(s,3H),3.21–2.97(m,1H),2.19–2.01(m,3H),1.25(s,9H).
实施例15：4-(3-甲氧基丙氧基)-2,2-二甲基-11-氧代-7-苯基-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000059
步骤1：2,2-二甲基-2,3-二氢苯并呋喃-7-乙酸酯
Figure PCTCN2021072337-appb-000060
将呋喃酚(50.70g,308.8mmol)溶解在二氯甲烷(500mL)中，然后加入三乙胺(47.10g,463.2mmol)和4-二甲氨基吡啶(3.81g,30.88mmol)，将反应瓶转移到冰水浴中，滴加醋酸酐(31.8mL,336.0mmol)，滴毕，转移至室温搅拌5h。TLC监测原料反应基本完全后，停止搅拌，依次用饱和碳酸氢钠溶液(300mL)、水(300mL)、1M盐酸(300mL)和饱和氯化钠溶液(300mL)洗涤，无水硫酸钠干燥，过滤，收集滤液，滤液减压旋蒸除去溶剂，得到标题化合物为棕红色油状产物，直接用于下一步反应。
步骤2：5-碘-2,2-二甲基-2,3-二氢苯并呋喃-7-乙酸酯
Figure PCTCN2021072337-appb-000061
向反应瓶中加入2,2-二甲基-2,3-二氢苯并呋喃-7-乙酸酯(63.69g,308.8mmol)，加入乙腈(315mL)搅拌溶解，转移到0℃加入N-碘代丁二酰亚胺(104.2g,463.2mmol)，加毕，搅拌10min后，升温到60℃ 搅拌反应27h。关闭加热，冷却到室温，加入10％的亚硫酸氢钠溶液(500mL)淬灭反应。减压除去大部分乙腈，水相用乙酸乙酯(300mL×2)萃取，合并有机相，有机相用饱和氯化钠溶液(300mL)洗涤，无水硫酸钠干燥，过滤，旋干滤液，得到标题化合物为棕红色油状产物(99.53g,97.04％)。
步骤3：5-碘-2,2-二甲基-2,3-二氢苯并呋喃-7-醇
Figure PCTCN2021072337-appb-000062
将5-碘-2,2-二甲基-2,3-二氢苯并呋喃-7-乙酸酯(99.53g,299.7mmol)溶解在甲醇(500mL)中，然后加入氢氧化钾(33.8g,599.0mmol)，室温搅拌17h。TLC监测基本反应完全，停止搅拌，旋干溶剂，残留物加入水(200mL)和乙酸乙酯(200mL)稀释，用浓盐酸将溶液调节至pH＝5，分液，收集上层有机相，水相用乙酸乙酯(200mL)萃取，合并有机相，合并的有机相用无水硫酸钠干燥，过滤，滤液旋干，得到标题化合物为棕红色油状产物(83.46g,96.00％)。
步骤4：5-碘-7-(3-甲氧基丙氧基)-2,2-二甲基-2,3-二氢苯并呋喃
Figure PCTCN2021072337-appb-000063
将5-碘-2,2-二甲基-2,3-二氢苯并呋喃-7-醇(83.46g,287.7mmol)溶解在乙腈(500mL)中，加入碳酸钾(114.1g,1.151mol)、碘化钾(4.78g,28.8mmol)和1-溴-3-甲氧基丙烷(66.03g,431.5mmol)，升温到回流，搅拌反应6h。TLC监测原料基本反应完全，关闭加热，停止搅拌，硅藻土抽滤除去碳酸钾固体，收集滤液，滤液减压浓缩，得到棕红色油状产物(107.9g,103.5％)。
步骤5：7-(3-甲氧基丙氧基)-2,2-二甲基-2,3-二氢苯并呋喃-5-醇
Figure PCTCN2021072337-appb-000064
在反应瓶中加入5-碘-7-(3-甲氧基丙氧基)-2,2-二甲基-2,3-二氢苯并呋喃(107.9g,297.9mmol)、N 1,N 2-双(4-羟基-2,6-二甲基苯基)草酰胺(4.89g,14.9mmol)、乙酰丙酮酸铜(3.09g,14.9mmol)和二甲亚砜(430mL)，然后加入溶有氢氧化钠(36.11g,893.8mmol)的水溶液(108mL)，氮气置换三次，在氮气保护下，升温到80℃搅拌反应19h。反应完全后，关闭加热，转移到0℃，加入乙酸乙酯(400mL)和水(400mL)，用浓盐酸将溶液的pH调节到5左右。硅藻土抽滤，除去滤渣，滤液分液，收集上层有机相，水相用乙酸乙酯(400mL)萃取，合并有机相。有机相用饱和氯化钠溶液洗涤，有絮状物析出，再用硅藻土抽滤一次，滤液分液，收集上层有机相，有机相减压蒸除溶剂，残留物经硅胶柱层析(PE/EA(V/V)＝10/1-4/1)纯化，得到标题化合物为淡黄色固体产物(49.60g,65.99％)。
MS(ESI,pos,ion)m/z:253.2[M+H] +。
步骤6：6-(5-羟基-7-(3-甲氧基丙氧基)-2,2-二甲基-2,3-二氢苯并呋喃-4-基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯
Figure PCTCN2021072337-appb-000065
以7-(3-甲氧基丙氧基)-2,2-二甲基-2,3-二氢苯并呋喃-5-醇和多聚甲醛为原料，参考实施例1步骤7至步骤12的合成方法，制备得到标题化合物为白色固体。
MS(ESI,pos.ion)m/z：418.2[M+H] +。
步骤7：4-(3-甲氧基丙氧基)-2,2-二甲基-11-氧代-7-苯基-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁 嗪-10-甲酸乙酯
Figure PCTCN2021072337-appb-000066
干燥的反应瓶中加入6-(5-羟基-7-(3-甲氧基丙氧基)-2,2-二甲基-2,3-二氢苯并呋喃-4-基)-4-氧代-1,4-二氢吡啶-3-甲酸乙酯(160mg,0.383mmol)、碳酸铯(500mg,1.53mmol)、二甲基亚砜(5mL)和二氯甲苯(246mg,1.53mmol)，氮气置换三次，氮气保护下升温到100℃搅拌反应14h，然后关闭加热，冷却到室温后，加入水(15mL)溶解固体。溶液用二氯甲烷萃取(15mL×2)，合并有机相，有机相依次用水(20mL×2)和饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤，旋干滤液，残留物经硅胶柱层析(DCM/MeOH(V/V)＝30/1)纯化，得到标题化合物为棕黄色油状产物(101mg,52.11％)。
MS(ESI,pos,ion)m/z:506.2[M+H] +。
步骤8：4-(3-甲氧基丙氧基)-2,2-二甲基-11-氧代-7-苯基-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁 嗪-10-甲酸
Figure PCTCN2021072337-appb-000067
以4-(3-甲氧基丙氧基)-2,2-二甲基-11-氧代-7-苯基-1,2,7,11-四氢苯并呋喃[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸乙酯为原料，参考实施例4步骤3至步骤4的合成方法，制备得到标题化合物为白色固体。
MS(ESI,pos.ion)m/z:478.2[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm):15.65(s,1H),8.13(s,1H),7.59–7.48(m,3H),7.38(d,J＝6.6Hz,2H),6.88(s,1H),6.58(s,1H),6.47(s,1H),4.16(t,J＝6.5Hz,2H),3.52(t,J＝5.9Hz,2H),3.43–3.22(m,5H),2.15–2.04(m,2H),1.57(s,3H),1.51(s,3H)。
以下实施例16至实施例26为参考实施例15的制备方法制备得到的。
实施例16：7-(3-氯苯基)-4-(3-甲氧基丙氧基)-2,2-二甲基-11-氧代-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000068
MS(ESI,pos.ion)m/z:512.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm):15.59(s,1H),8.21(s,1H),7.51(d,J＝7.6Hz,1H),7.44(t,J＝7.7Hz,1H),7.38(s,1H),7.21(d,J＝7.0Hz,1H),6.91(s,1H),6.60(s,1H),6.53(s,1H),4.18(t,J＝6.5Hz,2H),3.53(dd,J＝13.5,7.6Hz,2H),3.38–3.30(m,5H),2.16–2.06(m,2H),1.55(d,J＝4.8Hz,6H)。
实施例17：7-(4-氯苯基)-4-(3-甲氧基丙氧基)-2,2-二甲基-11-氧代-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000069
MS:(ESI,pos.ion)m/z:512.2[M+H] +；
1H NMR(400MHz,CDCl 3)δ15.59(s,1H),8.15(s,1H),7.47(d,J＝8.4Hz,2H),7.29(d,J＝8.4Hz,2H),6.88(s,1H),6.56(s,1H),6.50(s,1H),4.16(t,J＝6.5Hz,2H),3.52(t,J＝5.9Hz,2H),3.39–3.13(m,5H),2.19–1.95(m,2H),1.55(s,3H),1.52(s,3H)。
实施例18：7-(2-氯苯基)-4-(3-甲氧基丙氧基)-2,2-二甲基-11-氧代-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000070
MS:(ESI,pos.ion)m/z:512.2[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm):15.58(s,1H),7.93(s,1H),7.61–7.53(m,3H),7.52–7.44(m,1H),6.90(s,1H),6.71(s,1H),6.60(s,1H),4.17(t,J＝6.5Hz,2H),3.52(t,J＝5.9Hz,2H),3.33(s,3H),3.29(d,J＝15.8Hz,2H),2.16–2.03(m,2H),1.65(s,3H),1.51(s,3H)。
实施例19：4-(3-甲氧基丙氧基)-2,2-二甲基-11-氧代-7-(2-(三氟甲基)苯基)-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000071
MS(ESI,pos.ion)m/z:546.2[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm):15.51(s,1H),7.90(d,J＝7.2Hz,1H),7.81(s,1H),7.80–7.68(m,3H),6.89(s,1H),6.68(s,1H),6.59(s,1H),4.16(td,J＝6.5,2.0Hz,2H),3.52(t,J＝5.9Hz,2H),3.46(d,J＝15.9Hz,1H),3.37–3.17(m,4H),2.21–1.91(m,2H),1.65(s,3H),1.51(s,3H)。
实施例20：7-(2-氟苯基)-4-(3-甲氧基丙氧基)-2,2-二甲基-11-氧代-1,2,7,11-四氢苯并呋喃[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000072
MS(ESI,pos.ion)m/z:496.2[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm):15.60(s,1H),8.07(s,1H),7.60(dd,J＝13.4,6.2Hz,1H),7.44(t,J＝6.7Hz,1H),7.34(d,J＝7.6Hz,1H),7.30–7.21(m,1H),6.89(s,1H),6.67(s,1H),6.59(s,1H),4.16(t,J＝6.5Hz,2H),3.52(t,J＝5.9Hz,2H),3.43(d,J＝15.8Hz,1H),3.32(s,3H),3.28(d,J＝15.7Hz,1H),2.28–1.85(m,2H),1.62(s,3H),1.50(s,3H)。
实施例21：7-(3-氟苯基)-4-(3-甲氧基丙氧基)-2,2-二甲基-11-氧代-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000073
MS(ESI,pos.ion)m/z:496.3[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm):15.61(s,1H),8.21(s,1H),7.54–7.44(m,1H),7.24(t,J＝8.2Hz,1H),7.11(d,J＝7.6Hz,2H),6.91(s,1H),6.60(s,1H),6.55(s,1H),4.19(t,J＝6.5Hz,2H),3.55(t,J＝5.9Hz,2H),3.33(dd,J＝14.3,12.5Hz,5H),2.16–2.07(m,2H),1.56(d,J＝3.7Hz,6H)。
实施例22：7-(4-氟苯基)-4-(3-甲氧基丙氧基)-2,2-二甲基-11-氧代-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000074
MS(ESI,pos.ion)m/z:496.2[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm):15.61(s,1H),8.10(s,1H),7.39(dd,J＝8.6,5.0Hz,2H),7.20(t,J＝8.4Hz,2H),6.87(s,1H),6.57(s,1H),6.48(s,1H),4.16(t,J＝6.5Hz,2H),3.52(t,J＝5.9Hz,2H),3.41–3.16(m,5H),2.17–2.02(m,2H),1.57(s,3H),1.51(s,3H)。
实施例23：7-(2-异丙基苯基)-4-(3-甲氧基丙氧基)-2,2-二甲基-11-氧代-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000075
MS(ESI,pos.ion)m/z:520.2[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm):15.59(s,1H),8.03(s,1H),7.60–7.51(m,2H),7.41–7.32(m,2H),6.89(s,1H),6.58(s,1H),6.54(s,1H),4.16(t,J＝6.5Hz,2H),3.52(t,J＝5.9Hz,2H),3.47(d,J＝15.8Hz,1H),3.32(s,3H),3.27(d,J＝15.7Hz,1H),3.10–2.97(m,1H),2.17–2.01(m,2H),1.65(s,3H),1.50(s,3H),1.29(d,J＝6.8Hz,3H),1.25(d,J＝6.8Hz,3H)。
实施例24：7-(2-氯-4-氟苯基)-4-(3-甲氧基丙氧基)-2,2-二甲基-11-氧代-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000076
MS(ESI,pos.ion)m/z:530.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm):15.53(s,1H),7.92(s,1H),7.58(dd,J＝8.7,5.7Hz,1H),7.34(dd,J＝8.0,2.4Hz,1H),7.20(td,J＝8.8,2.4Hz,1H),6.89(s,1H),6.66(s,1H),6.59(s,1H),4.17(t,J＝6.5Hz,2H),3.52(t,J＝5.9Hz,2H),3.49–3.41(m,1H),3.33(s,3H),3.28(d,J＝15.7Hz,1H),2.10(p,J＝6.2Hz,2H),1.64(s,3H),1.50(s,3H)。
实施例25：7-(2-溴-4-氟苯基)-4-(3-甲氧基丙氧基)-2,2-二甲基-11-氧代-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000077
MS(ESI,pos.ion)m/z:574.1[M+H] +；576.1[M+2+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm):15.53(s,1H),7.91(s,1H),7.58(dd,J＝8.7,5.7Hz,1H),7.52(dd,J＝7.8,2.4Hz,1H),7.29–7.16(m,1H),6.89(s,1H),6.63(s,1H),6.59(s,1H),4.17(t,J＝6.5Hz,2H),3.52(t,J＝5.9Hz,2H),3.46(d,J＝16.1Hz,1H),3.33(s,3H),3.28(d,J＝15.7Hz,1H),2.18–2.03(m,2H),1.64(s,3H),1.50(s,3H)。
实施例26：7-(2-氯-3-氟苯基)-4-(3-甲氧基丙氧基)-2,2-二甲基-11-氧代-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000078
MS(ESI,pos.ion)m/z:530.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ(ppm):15.51(s,1H),7.96(s,1H),7.52–7.34(m,2H),7.29(d,J＝7.4Hz,1H),6.90(s,1H),6.73(s,1H),6.58(s,1H),4.16(t,J＝6.5Hz,2H),3.52(t,J＝5.9Hz,2H),3.43(d,J＝15.8Hz,1H),3.36–3.25(m,4H),2.20–2.00(m,2H),1.62(s,3H),1.51(s,3H)。
实施例27：4-(3-甲氧基丙氧基)-2,2-二甲基-11-氧代-7-(噻唑-2-基)-1,2,7,11-四氢苯并呋喃并[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸
Figure PCTCN2021072337-appb-000079
以4-(3-甲氧基丙氧基)-2,2-二甲基-11-氧代-7-苯基-1,2,7,11-四氢苯并呋喃[4,5-e]吡啶并[1,2-c][1,3]噁嗪-10-甲酸乙酯和2-(二溴甲基)噻唑为原料，参考实施例4步骤3至步骤4的合成方法，制备得标题化合物为米黄色固体。MS(ESI,pos.ion)m/z：485.1[M+H] +； 1H NMR(600MHz,CDCl 3)δ(ppm):15.51(s,1H),8.65(s,1H),7.76(d,J＝2.9Hz,1H),7.47(d,J＝2.9Hz,1H),7.06(s,1H),6.92(s,1H),6.67(s,1H),4.16(t,J＝6.5Hz,2H),3.52(t,J＝5.9Hz,2H),3.43–3.22(m,5H),2.15–2.04(m,2H),1.57(s,3H),1.51(s,3H)。
生物活性测试
HBV细胞系
HepG2.2.15细胞(SELLS,PNAS,1987和SELLS,JV,1988)的染色体整合有完整的HBV基因组，并稳 定表达病毒RNA和病毒蛋白质。HepG2.2.15细胞能够向培养基中分泌成熟的乙肝病毒颗粒和HBsAg。HepG2.2.15细胞分泌的病毒粒子DNA和HBsAg可以通过qPCR和ELISA的方法来定量，并由此检测化合物对病毒复制和HBsAg分泌的影响。
测试1：本发明化合物对HBV病毒复制的抑制实验
实验方法：
HepG 2.2.15细胞8,000个每孔接种到96孔细胞培养板，一式两份，培养3天至细胞长至满孔。用4倍系列稀释的化合物处理细胞10天，隔天换液给药一次，所有孔中DMSO的终浓度为0.5％并将DMSO用作无药物对照。第11天收取上清液用作HBV DNA定量检测。
qPCR方法检测病毒基因组DNA，HBV引物如下：
HBV-For-202，CAGGCGGGGTTTTTCTTGTTGA(SEQ ID NO:1)；
HBV-Rev-315，GTGATTGGAGGTTGGGGACTGC(SEQ ID NO:2)。
使用SYBR Premix Ex Taq II–Takara DRR081S试剂盒，以1μL细胞培养上清液作为模板，用包含HBV基因组的质粒做标准曲线，并以标准曲线来计算病毒拷贝数。用Graphpad Prism 5软件处理浓度-病毒拷贝数，通过四参数非线性回归模型计算化合物对病毒复制抑制的IC 50。本发明化合物对HBV DNA的复制抑制活性的IC 50小于0.1μM，大部分化合物对HBV DNA的复制抑制活性的IC 50小于0.05μM。具体地，本发明部分化合物对HBV DNA的复制抑制活性如表2所示。
表2：本发明部分化合物对HBV DNA的复制抑制活性
实施例 DNA IC 50(nM)
实施例1 3.65
实施例3 1.33
实施例6 2.11
实施例8 4.99
实施例9 1.98
实施例10 2.40
实施例11 3.42
实施例12 0.08
实施例13 0.38
实施例14 2.46
实施例15 0.50
实施例16 1.86
实施例18 1.37
实施例19 1.36
实施例21 2.72
实施例24 1.31
实施例25 1.60
实施例26 0.92
实施例27 1.20
结论：本发明化合物对HBV病毒复制的抑制实验表明，本发明化合物对HBV DNA的复制具有很好的抑制活性。
测试2：本发明化合物对HBsAg分泌的抑制实验
实验方法：
HepG 2.2.15细胞8,000个每孔接种到96孔细胞培养板，一式两份，培养3天至细胞长至满孔。用4 倍系列稀释的化合物处理细胞10天，隔天换液给药一次，所有孔中DMSO的终浓度为0.5％并将DMSO用作无药物对照。第11天收取上清用作HbsAg定量检测。
使用ELISA方法检测化合物处理后细胞分泌的HBsAg水平，该方法使用乙型肝炎表面抗原诊断试剂盒(上海科华生物工程股份有限公司S10910113)。在ELISA板中每孔加入25μL待检上清液(PBS稀释至75μL)，并设置试剂盒阳性对照和阴性对照。用封片纸封闭ELISA板后，37℃孵育60分钟。取出ELISA板，撕去封片，每孔中加入50μL酶结合物。振荡器上震荡10秒钟，用封片纸封闭ELISA板，37℃孵育30分钟。取出ELISA板，撕去封片纸，重复洗涤5次：每次弃去孔内液体，加洗涤液注满各孔，静置60秒，甩干，在吸水纸上拍干液体残留。洗涤结束后立即在所有孔内加入新鲜配制的显色剂A和显色剂B的混合液：100μL每孔。振荡器上震荡10秒钟，用封片纸封闭ELISA板后，37℃孵育30分钟。在所有孔内加入50μL终止液。在Envision读板仪上以波长450nm读数。用Graphpad Prism 5软件处理浓度-HbsAg OD450值数据，通过四参数非线性回归模型计算化合物对HbsAg分泌抑制的IC 50。本发明化合物对HBsAg分泌的抑制活性的IC 50小于0.1μM，大部分化合物对HBsAg分泌的抑制活性的IC 50小于0.05μM。具体地，本发明部分化合物对HBsAg分泌的抑制活性如表3所示。
表3：本发明部分化合物对HBsAg分泌的抑制活性
实施例 HBsAg IC 50(nM)
实施例1 5.79
实施例3 1.54
实施例6 4.10
实施例8 4.16
实施例9 3.67
实施例10 2.90
实施例11 2.54
实施例12 0.15
实施例13 0.32
实施例14 1.78
实施例15 1.74
实施例16 2.18
实施例18 0.87
实施例19 0.96
实施例21 1.59
实施例24 2.33
实施例25 1.79
实施例26 1.31
实施例27 3.02
结论：本发明化合物对HBsAg分泌的抑制实验表明，本发明化合物对HBsAg分泌具有很好的抑制活性。
测试3：本发明化合物在比格犬、小鼠、大鼠中的药代动力学实验
(1)比格犬PK测试实验
本发明化合物在比格犬(体重10-12kg，雄性，年龄10-12个月，口服每组3只，静脉注射每组3只)体内的PK测定实验
实验方法：
比格犬经口灌胃给予2.5mg/kg或5mg/kg或经静脉注射0.5mg/kg或1mg/kg的测试化合物。
给药后按时间点(0.083、0.25、0.5、1、2、4、6、8和24小时)静脉采血，收集于加EDTA-K 2的抗 凝管内。血浆样品经液液萃取后，在三重四极杆串联质谱仪上，以多重反应离子监测(MRM)方式进行定量分析。采用WinNonlin 6.3软件用非房室模型法计算药代动学参数。
结论：药代实验数据表明，在静脉注射给药或口服给药时，本发明所述化合物在比格犬体内表现出很好的药代动力学性质，包括较好的吸收(AUC (0-t)和AUC (INF))和好的口服生物利用度(F)。
(2)ICR小鼠PK测试实验
本发明化合物在ICR小鼠(体重20-25g，雄性，年龄45-60天，口服每组3只，静脉注射每组3只)体内的PK测定实验
实验方法：
ICR小鼠经口灌胃给予10mg/kg或经尾静脉注射2mg/kg或10mg/kg的测试化合物。给药后按时间点(0.083，0.25，0.5，1，2，4，6，8和24小时)眼眶静脉采血，收集于加EDTA-K 2的抗凝管内。血浆样品经液液萃取后，在三重四极杆串联质谱仪上，以多重反应离子监测(MRM)方式进行定量分析。采用WinNonlin 6.3软件用非房室模型法计算药代动学参数。
结论：药代实验数据表明，本发明化合物在ICR小鼠体内具有较好的药代动力学性质，在抗HBV病毒方面有很好的应用前景。
(3)SD大鼠PK测试实验
本发明化合物在SD大鼠(体重200-250g，雄性，年龄2-3个月，口服每组3只，静脉注射每组3只)体内的PK测定实验
实验方法：
SD大鼠经口灌胃给予2.5mg/kg或5mg/kg或经静脉注射0.5mg/kg或1mg/kg的测试化合物。给药后按时间点(0.083、0.25、0.5、1、2、5、7和24小时)静脉采血，收集于加EDTA-K 2的抗凝管内。血浆样品经液液萃取后，在三重四极杆串联质谱仪上，以多重反应离子监测(MRM)方式进行定量分析。采用WinNonlin 6.3软件用非房室模型法计算药代动学参数。
Figure PCTCN2021072337-appb-000080
结论：药代实验数据表明，在静脉注射给药或口服给药时，本发明所述化合物在SD大鼠体内表现出很好的药代动力学性质，包括较好的吸收(AUC (0-t)和AUC (INF))和好的口服生物利用度(F)。
测试4：本发明化合物在不同种属的肝微粒体中的稳定性测试
实验方法：
向96孔板中加入空白溶液与肝微粒体的混合溶液30μL，在各孔中加入15μL含待测化合物的缓冲液，平行做两份样品。37℃预孵育10min后按0min、15min、20min和60min时间点加入15μL NADPH溶液(8mM)，待测化合物的终浓度为1μM，肝微粒体的浓度为0.1mg/mL，NADPH的终浓度为2mM。分别孵育0、15、30、60min，孵育结束后将150μL乙腈(含内标)加入混合体系中。乙腈稀释后的样品在4000rpm下离心5min，取150μL上清液至LC-MS/MS进行分析。
结论：肝微粒体稳定性实验数据表明，本发明化合物在不同种属的肝微粒体中稳定性较好。

Claims (16)

  1. 一种化合物，其为如式(I)所示的化合物或式(I)所示的化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药，
    Figure PCTCN2021072337-appb-100001
    其中，各R 1、R 2、R 3、R 4和R 7独立地为氢、氘、F、Cl、Br、C 1-6烷基、C 1-6烷氨基、C 1-6烷氧基、C 2-6炔基、C 2-6烯基、C 3-7环烷基、苯基、5-6个环原子组成的杂芳基或3-10个环原子组成的杂环基，其中所述的C 1-6烷基、C 1-6烷氨基、C 1-6烷氧基、C 2-6炔基、C 2-6烯基、C 3-7环烷基、苯基、5-6个环原子组成的杂芳基和3-10个环原子组成的杂环基各自独立地未被取代或被1、2、3或4个R w所取代；
    或R 1、R 2与其链接的碳原子，一起形成环丙基、环丁基、环戊基、环己基或-C(＝O)-，其中所述的环丙基、环丁基、环戊基和环己基各自独立地未被取代或被1、2、3或4个R w所取代；
    或R 3、R 4与其链接的碳原子，一起形成环丙基、环丁基、环戊基、环己基或-C(＝O)-，其中所述的环丙基、环丁基、环戊基和环己基各自独立地未被取代或被1、2、3或4个R w所取代；
    R 5为氢、氘、C 1-6烷基、C 3-7环烷基、3-6个环原子组成的杂环基、C 6-10芳基或5-10个环原子组成的杂芳基，其中所述的C 1-6烷基、C 3-7环烷基、3-6个环原子组成的杂环基、C 6-10芳基和5-10个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个R j所取代；
    R 6为氢、氘、F、Cl、Br、C 1-12烷基、C 1-6烷氨基、C 1-6烷氧基、C 2-6炔基、C 2-6烯基、C 3-7环烷基、C 6-10芳基、5-10个环原子组成的杂芳基或3-10个环原子组成的杂环基，其中所述的C 1-6烷基、C 1-6烷氨基、C 1-6烷氧基、C 2-6炔基、C 2-6烯基、C 3-7环烷基、C 6-10芳基、5-10个环原子组成的杂芳基和3-10个环原子组成的杂环基各自独立地未被取代或被1、2、3或4个R w所取代；
    各R j独立地为氘、F、Cl、Br、CN、＝O、HO-、氨基、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-10个环原子组成的杂环基、C 6-10芳基或5-10个环原子组成的杂芳基，其中所述的氨基、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、3-10个环原子组成的杂环基、C 6-10芳基和5-10个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个R w所取代；
    各R w独立地为氘、F、Cl、Br、HO-、HOOC-、＝O、氨基、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 2-6烯基、C 2-6炔基、C 1-6烷基-OC(＝O)-、C 1-6烷基-S(＝O) 2-、C 3-6环烷基-S(＝O) 2-或C 3-7环烷基，其中所述的氨基、C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 2-6烯基、C 2-6炔基、C 1-6烷基-OC(＝O)-、C 1-6烷基-S(＝O) 2-、C 3-6环烷基-S(＝O) 2-和C 3-7环烷基各自独立地未被取代或被1、2、3或4个选自F、Cl、Br、CN、HO-、＝O、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、C 1-6卤代烷氧基或C 1-6烷氨基的取代基所取代；
    n为0、1、2或3。
  2. 根据权利要求1所述的化合物，其中，R 5为氢、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、萘基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃 基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、萘基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3或4个R j所取代。
  3. 根据权利要求1或2所述的化合物，其中，R 6为氢、氘、F、Cl、Br、C 1-6烷基、C 1-4烷氨基、C 1-4烷氧基、C 2-4炔基、C 2-4烯基、C 3-6环烷基、苯基、萘基、5-6个环原子组成的杂芳基或3-6个环原子组成的杂环基，其中所述的C 1-6烷基、C 1-4烷氨基、C 1-4烷氧基、C 2-4炔基、C 2-4烯基、C 3-6环烷基、苯基、萘基、5-6个环原子组成的杂芳基和3-6个环原子组成的杂环基各自独立地未被取代或被1、2、3或4个R w所取代。
  4. 根据权利要求1-3任意一项所述的化合物，其中，R 6为氢、氘、F、Cl、Br、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 1-4烷氨基、C 1-4烷氧基、C 2-4炔基、C 2-4烯基、环丙基、环丁基、环戊基、环己基、苯基、萘基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基或哌嗪基，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 1-4烷氨基、C 1-4烷氧基、C 2-4炔基、C 2-4烯基、环丙基、环丁基、环戊基、环己基、苯基、萘基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基和哌嗪基各自独立地未被取代或被1、2、3或4个R w所取代。
  5. 根据权利要求1-4任意一项所述的化合物，其中，各R j独立地为氘、F、Cl、Br、CN、＝O、HO-、氨基、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷氨基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-6个环原子组成的杂环基、苯基、萘基、5个环原子组成的杂芳基或6个环原子组成的杂芳基，其中所述的氨基、C 1-4烷基、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷氨基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-6个环原子组成的杂环基、苯基、萘基、5个环原子组成的杂芳基和6个环原子组成的杂芳基各自独立地未被取代或被1、2、3或4个R w所取代。
  6. 根据权利要求1-5任意一项所述的化合物，其中，各R j独立地为氘、F、Cl、Br、CN、＝O、HO-、氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、C 1-3烷硫基、C 1-3烷氨基、C 2-4烯基、C 2-4炔基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、萘基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基或嘧啶基，其中所述的氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、C 1-3烷硫基、C 1-3烷氨基、C 2-4烯基、C 2-4炔基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、苯基、萘基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基和嘧啶基各自独立地未被取代或被1、2、3或4个R w所取代。
  7. 根据权利要求1-6任意一项所述的化合物，其中，各R w独立地为氘、F、Cl、Br、HO-、HOOC-、＝O、氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷氨基、C 2-4烯基、乙炔基、炔丙基、丙炔基、1-炔丁基、2-炔丁基、3-炔丁基、叔丁氧羰基、C 1-4烷基-S(＝O) 2-、环丙基-S(＝O) 2-、环戊基-S(＝O) 2-、环己基-S(＝O) 2-、环丙基、环丁基、环戊基或环己基，其中所述氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 1-4烷氧基、C 1-4烷硫基、C 1-4烷氨基、C 2-4烯基、乙炔基、炔丙基、丙炔基、1-炔丁基、2-炔丁基、3-炔丁基、叔丁氧羰基、C 1-4烷基-S(＝O) 2-、环丙基-S(＝O) 2-、环戊基-S(＝O) 2-、环己基-S(＝O) 2-、环丙基、环丁基、环戊基和环己基各自独立地未被取代或被1、2、3或4个选自F、Cl、Br、CN、HO-、＝O、氨基、C 1-4烷基、C 1-4卤代烷基、C 1-4 烷氧基、C 1-4烷硫基、C 1-4卤代烷氧基或C 1-4烷氨基的取代基所取代；
    各R 1、R 2、R 3、R 4和R 7独立地为氢、氘、F、Cl、Br、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 1-4烷氨基、C 1-4烷氧基、乙炔基、炔丙基、丙炔基、1-炔丁基、2-炔丁基、3-炔丁基、C 2-4烯基、环丙基、环丁基、环戊基、环己基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基或哌嗪基，其中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、C 1-4烷氨基、C 1-4烷氧基、乙炔基、炔丙基、丙炔基、1-炔丁基、2-炔丁基、3-炔丁基、C 2-4烯基、环丙基、环丁基、环戊基、环己基、苯基、呋喃基、吡咯基、吡啶基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、1,3,5-三嗪基、噻唑基、噻吩基、吡嗪基、哒嗪基、嘧啶基、氮杂环丁基、氧杂环丁基、硫杂环丁基、氧杂环丙基、吡咯烷基、吡唑烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基和哌嗪基各自独立地未被取代或被1、2、3或4个R w所取代。
  8. 根据权利要求1-7任意一项所述的化合物，其包含以下其中之一的化合物：
    Figure PCTCN2021072337-appb-100002
    Figure PCTCN2021072337-appb-100003
    Figure PCTCN2021072337-appb-100004
    Figure PCTCN2021072337-appb-100005
    Figure PCTCN2021072337-appb-100006
    或它们的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它的前药。
  9. 一种药物组合物，包含权利要求1-8任意一项所述的化合物；任选地，所述药物组合物进一步包含药学上可接受的辅料或所述辅料的组合。
  10. 根据权利要求9所述的药物组合物，其更进一步地包含其它抗HBV药物。
  11. 根据权利要求10所述的药物组合物，其中所述其它抗HBV药物为HBV聚合酶抑制剂、免疫调节剂或干扰素。
  12. 根据权利要求10所述的药物组合物，其中所述其它抗HBV药物为拉米夫定、替比夫定、替诺福韦酯、恩替卡韦、阿德福韦酯、Alfaferone、Alloferon、西莫白介素、克拉夫定、恩曲他滨、法昔洛韦、干扰素、宝甘灵CP、因特芬、干扰素α-1b、干扰素α、干扰素α-2a、干扰素β-1a、干扰素α-2、白细胞介素-2、米伏替酯、硝唑尼特、聚乙二醇干扰素α-2a、病毒唑、罗扰素-A、西佐喃、Euforavac、安普利近、Phosphazid、Heplisav、干扰素α-2b、左旋咪唑或丙帕锗。
  13. 权利要求1-8任意一项所述的化合物或权利要求9-12任意一项所述的药物组合物在制备预防、治疗或减轻患者病毒性疾病的药物中的用途。
  14. 根据权利要求13所述的用途，其中所述病毒性疾病是指乙型肝炎病毒感染或乙型肝炎病毒感染引起的疾病。
  15. 根据权利要求14所述的用途，其中所述乙型肝炎病毒感染引起的疾病是指肝硬化或肝细胞癌变。
  16. 权利要求1-8任意一项所述的化合物或权利要求9-12任意一项所述的药物组合物在制备药物中的用途，所述药物用于抑制HBsAg的生成或分泌，和/或用于抑制HBV DNA的生成。
PCT/CN2021/072337 2020-01-19 2021-01-16 稠合四环类化合物及其在药物中的应用 WO2021143885A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010057191 2020-01-19
CN202010057191.0 2020-01-19

Publications (1)

Publication Number Publication Date
WO2021143885A1 true WO2021143885A1 (zh) 2021-07-22

Family

ID=76810904

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/072337 WO2021143885A1 (zh) 2020-01-19 2021-01-16 稠合四环类化合物及其在药物中的应用

Country Status (2)

Country Link
CN (1) CN113135937A (zh)
WO (1) WO2021143885A1 (zh)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015113990A1 (en) * 2014-01-30 2015-08-06 F. Hoffmann-La Roche Ag Novel dihydroquinolizinones for the treatment and prophylaxis of hepatitis b virus infection
WO2017216685A1 (en) * 2016-06-16 2017-12-21 Novartis Ag Pentacyclic pyridone compounds as antivirals
WO2018019297A1 (zh) * 2016-07-29 2018-02-01 银杏树药业(苏州)有限公司 异喹啉酮类化合物及其制备抗病毒药物的应用
WO2018154466A1 (en) * 2017-02-21 2018-08-30 Glaxosmithkline Intellectual Property Development Limited Dihydroquinolizinones as antivirals
CN108727378A (zh) * 2017-04-19 2018-11-02 银杏树药业(苏州)有限公司 新型异喹啉类化合物及其医药用途
WO2020063870A1 (en) * 2018-09-30 2020-04-02 Sunshine Lake Pharma Co., Ltd. Fused tetracyclic compounds and uses thereof in medicine

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015113990A1 (en) * 2014-01-30 2015-08-06 F. Hoffmann-La Roche Ag Novel dihydroquinolizinones for the treatment and prophylaxis of hepatitis b virus infection
WO2017216685A1 (en) * 2016-06-16 2017-12-21 Novartis Ag Pentacyclic pyridone compounds as antivirals
WO2018019297A1 (zh) * 2016-07-29 2018-02-01 银杏树药业(苏州)有限公司 异喹啉酮类化合物及其制备抗病毒药物的应用
WO2018154466A1 (en) * 2017-02-21 2018-08-30 Glaxosmithkline Intellectual Property Development Limited Dihydroquinolizinones as antivirals
CN108727378A (zh) * 2017-04-19 2018-11-02 银杏树药业(苏州)有限公司 新型异喹啉类化合物及其医药用途
WO2020063870A1 (en) * 2018-09-30 2020-04-02 Sunshine Lake Pharma Co., Ltd. Fused tetracyclic compounds and uses thereof in medicine

Also Published As

Publication number Publication date
CN113135937A (zh) 2021-07-20

Similar Documents

Publication Publication Date Title
CN110066278B (zh) 稠合三环类化合物及其在药物中的应用
TWI785116B (zh) 流感病毒複製抑制劑及其用途
CN108976223B (zh) 稠合三环类化合物及其在药物中的应用
AU2017376541B2 (en) Inhibitors of influenza virus replication and uses thereof
CN110862390B (zh) 稠合三环类化合物及其在药物中的应用
CN110950860B (zh) 稠合三环类化合物及其在药物中的应用
CN109988106B (zh) 抑制ssao/vap-1的胺类化合物及其在医药上的应用
WO2020135439A1 (zh) 氘代二氢嘧啶类化合物及其在药物中的应用
CN111116577A (zh) 稠合四环类化合物及其在药物中的应用
WO2018127096A1 (en) Inhibitors of influenza virus replication and uses thereof
CN111825676B (zh) 二氢嘧啶类化合物及其在药物中的应用
WO2020221280A1 (zh) 二氢嘧啶类化合物及其在药物中的应用
CN110964023B (zh) 稠合四环类化合物及其在药物中的应用
CN107793409B (zh) 二氢嘧啶类化合物及其在药物中的应用
WO2018157830A1 (en) Inhibitors of influenza virus replication and uses thereof
WO2022143610A1 (zh) 新型酰胺吡咯类化合物及其在药物中的应用
WO2022156758A1 (zh) 新型酰胺吡咯类化合物及其在药物中的用途
CN113493441B (zh) 新型螺环类化合物及其在药物中的应用
CN111217811B (zh) 稠合三环类化合物及其在药物中的应用
CN111116588B (zh) 稠合四环类化合物及其在药物中的应用
WO2021143885A1 (zh) 稠合四环类化合物及其在药物中的应用
CN110903284B (zh) 稠合三环类化合物及其在药物中的应用
WO2021078221A1 (zh) 二氢嘧啶类化合物及其在药物中的应用
CN108069957B (zh) 脯氨酰羟化酶抑制剂及其用途
CN117143109A (zh) 稠合四环类化合物及其在药物中的应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21741062

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21741062

Country of ref document: EP

Kind code of ref document: A1