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WO2021197486A1 - Nouveau composé spiro et son utilisation dans un médicament - Google Patents

Nouveau composé spiro et son utilisation dans un médicament Download PDF

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Publication number
WO2021197486A1
WO2021197486A1 PCT/CN2021/085352 CN2021085352W WO2021197486A1 WO 2021197486 A1 WO2021197486 A1 WO 2021197486A1 CN 2021085352 W CN2021085352 W CN 2021085352W WO 2021197486 A1 WO2021197486 A1 WO 2021197486A1
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Prior art keywords
butyl
group
formula
alkyl
atoms
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PCT/CN2021/085352
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English (en)
Chinese (zh)
Inventor
任青云
李中乐
冀石龙
张英俊
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
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Publication of WO2021197486A1 publication Critical patent/WO2021197486A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero 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
    • C07D471/02—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 two hetero rings
    • C07D471/10—Spiro-condensed systems
    • 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
    • C07D471/20—Spiro-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
    • C07D487/02—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 two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the invention belongs to the field of medicine. Specifically, it relates to a novel spirocyclic compound and its use as a medicine, especially as a medicine for the treatment and/or prevention of hepatitis B.
  • the present invention also relates to a composition containing these novel spirocyclic compounds and other antiviral agents, and its 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 novel spirocyclic compound and its use in the preparation of a medicine for the treatment and/or prevention of HBV infection.
  • the present invention relates to a new type of spirocyclic compound, and a pharmaceutically acceptable composition thereof.
  • the compound has the advantages of good solubility, good stability, no hepatic drug enzyme induction and low toxicity, etc., especially very Good pharmacokinetic properties.
  • the compound of the present invention can effectively inhibit HBV infection, and has a good application prospect in anti-HBV.
  • the present invention relates to a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutical
  • the acceptable salt or its prodrug
  • Ring A is a phenyl group, a heteroaryl group consisting of 5-6 atoms or a heterocyclic group consisting of 4-6 atoms, wherein the phenyl group, a heteroaryl group consisting of 5-6 atoms and 4-6 atoms
  • the heterocyclic groups composed of atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 R 2 ;
  • R 1a , R 1 and R 4 is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or C 1-4 haloalkyl ;
  • Each R 2 , R 5 and R 6 is independently hydrogen, deuterium, F, Cl, Br, I, CN, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl Group, isobutyl, sec-butyl, tert-butyl, -CH 2 F, -CH 2 Cl, -CHF 2 , -CHCl 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CHF 2 , -CH 2 CHCl 2 , -CHFCH 2 F, -CHClCH 2 Cl, -CH 2 CF 3 , -CH(CF 3 ) 2 , -CF 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , methoxy, ethoxy, N-methylamino or N-e
  • the cycloalkyl group and the heterocyclic group composed of 3-6 atoms are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R z ;
  • Ring B is a C 3-6 cycloalkyl group, a monocyclic heterocyclic group composed of 3-6 atoms, a spiro bicyclic alkyl group composed of 6-10 atoms, a condensed bicyclic alkyl group composed of 6-10 atoms, 6 A spiro bicyclic heterocyclic group consisting of -10 atoms or a condensed bicyclic heterocyclic group consisting of 6-10 atoms, wherein the C 3-6 cycloalkyl group and the monocyclic heterocyclic group consisting of 3-6 atoms , 6-10 atoms composed of spiro bicyclic alkyl groups, 6-10 atoms composed of fused bicyclic alkyl groups, 6-10 atoms composed of spiro bicyclic heterocyclic groups and 6-10 atoms composed of fused bicyclic heterocyclic groups
  • Each of the cyclic groups is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R x ;
  • the C 3-6 cycloalkyl group and the heterocyclic group composed of 3-6 atoms are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R y ;
  • R 7 is hydrogen, cyano, nitro, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 alkoxy, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1- 6 alkoxy groups are each independently unsubstituted or substituted with 1, 2, 3, or 4 selected from R z ;
  • R 8 is C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 1-6 alkylamino, C 3-6 ring Alkyl group, heterocyclic group composed of 3-8 atoms or heteroaryl group composed of 5-6 atoms, wherein the C 1-6 alkyl group, C 1-6 haloalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl, C 6-10 aryl, C 1-6 alkylamino, C 3-6 cycloalkyl, 3-8 heterocyclic group and 5-6 heteroaryl group Each is independently unsubstituted or substituted by 1, 2, 3 or 4 R z ;
  • Each R 9 is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl or C 3-6 cycloalkyl;
  • Each R 10a and R 10b is independently hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, Heterocyclic group composed of 3-6 atoms, C 6-10 aryl group, C 6-10 aryl group, C 1-4 alkyl group, heteroaryl group composed of 5-6 atoms, or heteroaryl group composed of 5-6 atoms
  • Aryl C 1-4 alkyl group wherein the C 1-6 alkyl group, C 1-6 alkoxy group, C 2-6 alkenyl group, C 2-6 alkynyl group, heterocyclic group composed of 3-6 atoms Cyclic group, C 3-6 cycloalkyl group, C 6-10 aryl group, C 6-10 aryl group, C 1-4 alkyl group, heteroaryl group composed of 5-6 atoms, and heteroaryl group composed of 5-6 atoms
  • the ring A described in the present invention is phenyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl , Tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, three Azolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein, The phenyl group, azetidiny
  • each R 2 has the meaning described in the present invention.
  • each R z has the meaning described in the present invention.
  • the ring B described in the present invention is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxetanyl Propyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, Piperazinyl, or the following sub-structure: Wherein each Y 1 and Y 2 is independently -CH 2 -, -NH-, -O- or -S-, each Y 3 is CH or N, the cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, azet
  • the ring B described in the present invention has the following sub-structure:
  • formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), formula (II) -7), formula (II-8), formula (II-9), formula (II-10), formula (II-11), formula (II-12), formula (II-13), formula (II- 14), formula (II-15), formula (II-16), formula (II-17), formula (II-18), formula (II-19), formula (II-20), formula (II-21 ), formula (II-22), formula (II-23), formula (II-24) and (II-25) are each independently unsubstituted or substituted by 1, 2, 3, 4 or 5 R x ;
  • each R x has the meaning described in the present invention.
  • the ring B described in the present invention has the following sub-structure:
  • each R x has the meaning described in the present invention.
  • each of R 7 , R 8 , R 9 , R 10a , R 10b and R y has the meaning described in the present invention.
  • R 8 in the present invention is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 haloalkyl , C 2-4 alkenyl, C 2-4 alkynyl, phenyl, naphthyl, C 1-4 alkylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-7 atoms Heterocyclyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazole Group, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl,
  • each R z has the meaning described in the present invention.
  • each R z has the meaning described in the present invention.
  • R 7 in the present invention is hydrogen, cyano, nitro, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Tert-butyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, methoxy, ethoxy, n-propoxy, isopropoxy , N-butoxy, isobutoxy or tert-butoxy, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, methoxy, ethoxy, n-propoxy, isopropoxy,
  • Each R 9 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
  • Each R 10a and R 10b is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl Base, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, methoxy , Ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, C 2-4 alkenyl, C 2-4 alkynyl, cyclopropyl, cyclobutoxy Group, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolid
  • each R z has the meaning described in the present invention.
  • the present invention also provides a pharmaceutical composition comprising the compound of the present invention and pharmaceutically acceptable 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 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 relates to the use of the compound or pharmaceutical composition in the preparation of a medicament for the prevention, treatment or alleviation of hepatitis B disease in patients, including administering an effective therapeutic dose of the compound of the present invention or the present invention
  • the pharmaceutical composition is administered to the patient.
  • 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 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 to prepare a medicament for preventing 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 to prepare 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 a cell with a compound or pharmaceutical composition of the present invention in a dose effective to inhibit HBV. In other embodiments, the method further comprises contacting the cell with another anti-HBV therapeutic agent.
  • Another aspect of the present invention relates to a method of treating a patient with HBV disease, which method comprises administering an effective therapeutic dose of the compound of the present invention or a pharmaceutical composition thereof to the patient in need of treatment. In other embodiments, the method further comprises administering an effective therapeutic dose of other anti-HBV drugs to the patient in need of treatment.
  • Another aspect of the present invention relates to a method for inhibiting HBV infection in a patient, which method comprises administering an effective therapeutic dose of the compound of the present invention or a pharmaceutical composition thereof to the patient in need of treatment. In other embodiments, the method further comprises administering an effective therapeutic dose of other anti-HBV drugs to the patient in need of treatment.
  • Another aspect of the present invention relates to methods for the preparation, separation and purification of compounds contained in formula (I).
  • 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 compounds of the present invention can be optionally substituted by one or more substituents, such as the compounds of the general formula above, or the special examples, subclasses, and subclasses included in the examples.
  • substituents such as the compounds of the general formula above, or the special examples, subclasses, and subclasses included in the examples.
  • a class of compounds such as the compounds of the general formula above, or the special examples, subclasses, and subclasses included in the examples.
  • 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 1-10 carbon atoms, and in other embodiments, the alkyl group contains 1-8 carbon atoms. Carbon atoms.
  • the alkyl group contains 1-6 carbon atoms.
  • the alkyl group contains 1-4 carbon atoms.
  • the alkyl group contains 1-4 carbon atoms. It contains 1-3 carbon atoms.
  • the alkyl group contains 1-2 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-
  • alkylamino and alkylamino are used interchangeably, and include “N-alkylamino” and “N,N-dialkylamino", in which the amino group is 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. Specific examples include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), propynyl (-C ⁇ C- CH 3 ), 1-alkynyl butyl (-CH 2 CH 2 C ⁇ CH), 2-alkynyl butyl (-CH 2 C ⁇ CCH 3 ), 3-alkynyl butyl (-C ⁇ CCH 2 CH 3 ), etc. Etc., wherein the alkynyl group may be independently unsubstituted or substituted with one or more substituents described in the present invention.
  • haloalkyl means an alkyl group, an alkenyl or alkoxy group is substituted with one or more halogen atoms, among which, alkyl, alkenyl and alkoxy
  • the radical has the meaning described in the present invention.
  • arylalkyl means that an alkyl group is substituted with one or two aryl group substituents, wherein the alkyl group and the aryl group have the meanings described in the present invention. Such examples include, but are not limited to, -CH 2 phenyl, -CH 2 CH 2 phenyl, -C(CH 3 ) 2 phenyl, and the like.
  • carboxyalkyl means that an alkyl group is substituted with one or two carboxyl substituents, wherein the "carboxyl group” is -COOH, and the alkyl group has the meaning described in the present invention.
  • Such examples include, but are not limited to, -CH 2 COOH, -CH 2 CH 2 COOH, -CH 2 CH 2 CH 2 COOH, -CH 2 CH 2 CH 2 COOH, and the like.
  • 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 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-8 carbon atoms; in other embodiments, the alkoxy group contains 1-6 carbon atoms; in other embodiments, the alkoxy group Groups contain 1-4 carbon atoms; in still other embodiments, alkoxy groups contain 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described in this invention.
  • 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-but 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 ), 2-(
  • 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.
  • Carbocyclic group or "carbocyclic ring” means a monovalent or multivalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3-12 ring carbon atoms.
  • Carbobicyclic groups include spirocarbon bicyclic groups, fused carbon bicyclic groups and bridged carbon bicyclic groups. Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl groups.
  • carbocyclic groups further include, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl- 3-alkenyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl Group, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.
  • 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 includes monocyclic, bicyclic or polycyclic fused, spiro or bridged ring systems.
  • the cycloalkyl group is a spiro bicyclic alkyl group consisting of 6-10 atoms; in other embodiments, the cycloalkyl group is a condensed bicyclic alkyl group consisting of 6-10 atoms; in other embodiments, a cycloalkane
  • the group is a ring system containing 3-10 ring carbon atoms; in other embodiments, the cycloalkyl group is a ring system containing 3-8 ring carbon atoms; in other embodiments, the cycloalkyl group contains 3-7 rings.
  • a cycloalkyl group is a ring system containing 5-8 ring carbon atoms; in other embodiments, a cycloalkyl group is a ring system containing 3-6 ring carbon atoms; other examples In an embodiment, cycloalkyl is a ring system containing 5-6 ring carbon atoms; examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., And the cycloalkyl group may be independently unsubstituted or substituted by 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.
  • fused bicyclic ring refers to monovalent or multivalent, saturated or partially unsaturated but non-aromatic A ring system in which two rings share one bond. Such systems may contain independent or conjugated unsaturated systems, but their core structure does not contain aromatic rings or aromatic heterocycles (but aromatic groups can be used as substituents on them).
  • spirocyclyl refers to a monovalent or multivalent, saturated or partially unsaturated ring system in which one ring originates A specific ring carbon atom on another ring, and the two rings share only one atom.
  • a saturated ring system (rings C and C') is called a "fused bicyclic ring", and ring D'and ring C share one carbon atom and are called "spiro Ring” or "spiro double ring”.
  • Each ring of the fused bicyclic group and the spiro bicyclic group may be a carbocyclic group or a heterocyclic group, and each ring is optionally substituted with one or more substituents described in the present invention.
  • 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 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 5-8 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, R containing an asymmetric center , S configuration, double bond (Z), (E) isomers, and (Z), (E) conformational isomers. Therefore, a single stereochemical isomer of the compound of the present invention or its enantiomer Mixtures of isomers, diastereomers, or geometric isomers (or conformational isomers) are all within the scope of the present invention.
  • prodrug used in the present invention represents the conversion of a compound into a compound represented by formula (I) 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 tissues.
  • the prodrug compounds of the present invention can be esters.
  • 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, that is, it can be acylated to obtain a compound in the form of a prodrug.
  • prodrug forms include phosphate esters.
  • these phosphate ester compounds are obtained by phosphorylation of the parent hydroxyl group.
  • prodrugs please refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.
  • 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 administering compounds through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic cleavage, and the like.
  • 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 of the invention.
  • 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 enantiomers 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 during the chemical reaction.
  • the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomers, lacking optical activity.
  • 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 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, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate Acid salt, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactic acid Salt, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate , Pectinate, pers
  • Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also intends to contemplate any quaternary ammonium salts formed by compounds containing N groups. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that resist counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, and C 1 -8 Sulfonates and aromatic sulfonates.
  • 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.
  • Carboxy protecting group refers to the carboxyl substituent 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 Base) 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, pharmaceutical
  • the acceptable salt or its prodrug
  • Ring A is a phenyl group, a heteroaryl group consisting of 5-6 atoms or a heterocyclic group consisting of 4-6 atoms, wherein the phenyl group, a heteroaryl group consisting of 5-6 atoms and 4-6 atoms
  • the heterocyclic groups composed of atoms are each independently unsubstituted or substituted with 1, 2, 3 or 4 R 2 ;
  • R 1a , R 1 and R 4 is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or C 1-4 haloalkyl ;
  • Each R 2 , R 5 and R 6 is independently hydrogen, deuterium, F, Cl, Br, I, CN, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl Group, isobutyl, sec-butyl, tert-butyl, -CH 2 F, -CH 2 Cl, -CHF 2 , -CHCl 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CHF 2 , -CH 2 CHCl 2 , -CHFCH 2 F, -CHClCH 2 Cl, -CH 2 CF 3 , -CH(CF 3 ) 2 , -CF 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , methoxy, ethoxy, N-methylamino or N-e
  • the cycloalkyl group and the heterocyclic group composed of 3-6 atoms are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R z ;
  • Ring B is a C 3-6 cycloalkyl group, a monocyclic heterocyclic group composed of 3-6 atoms, a spiro bicyclic alkyl group composed of 6-10 atoms, a condensed bicyclic alkyl group composed of 6-10 atoms, 6 A spiro bicyclic heterocyclic group consisting of -10 atoms or a condensed bicyclic heterocyclic group consisting of 6-10 atoms, wherein the C 3-6 cycloalkyl group and the monocyclic heterocyclic group consisting of 3-6 atoms , 6-10 atoms composed of spiro bicyclic alkyl groups, 6-10 atoms composed of fused bicyclic alkyl groups, 6-10 atoms composed of spiro bicyclic heterocyclic groups and 6-10 atoms composed of fused bicyclic heterocyclic groups
  • Each of the cyclic groups is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R x ;
  • the C 3-6 cycloalkyl group and the heterocyclic group composed of 3-6 atoms are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5 R y ;
  • R 7 is hydrogen, cyano, nitro, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 alkoxy, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1- 6 alkoxy groups are each independently unsubstituted or substituted with 1, 2, 3, or 4 selected from R z ;
  • R 8 is C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 1-6 alkylamino, C 3-6 ring Alkyl group, heterocyclic group composed of 3-8 atoms or heteroaryl group composed of 5-6 atoms, wherein the C 1-6 alkyl group, C 1-6 haloalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl, C 6-10 aryl, C 1-6 alkylamino, C 3-6 cycloalkyl, 3-8 heterocyclic group and 5-6 heteroaryl group Each is independently unsubstituted or substituted by 1, 2, 3 or 4 R z ;
  • Each R 9 is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl or C 3-6 cycloalkyl;
  • Each R 10a and R 10b is independently hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, Heterocyclic group composed of 3-6 atoms, C 6-10 aryl group, C 6-10 aryl group, C 1-4 alkyl group, heteroaryl group composed of 5-6 atoms, or heteroaryl group composed of 5-6 atoms
  • Aryl C 1-4 alkyl group wherein the C 1-6 alkyl group, C 1-6 alkoxy group, C 2-6 alkenyl group, C 2-6 alkynyl group, heterocyclic group composed of 3-6 atoms Cyclic group, C 3-6 cycloalkyl group, C 6-10 aryl group, C 6-10 aryl group, C 1-4 alkyl group, heteroaryl group composed of 5-6 atoms, and heteroaryl group composed of 5-6 atoms
  • the ring A described in the present invention is phenyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl , Tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, three Azolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl, wherein, The phenyl group, azetidiny
  • each R 2 has the meaning described in the present invention.
  • each R z has the meaning described in the present invention.
  • the ring B described in the present invention is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxetanyl Propyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, Piperazinyl, or the following sub-structure: Wherein each Y 1 and Y 2 is independently -CH 2 -, -NH-, -O- or -S-, each Y 3 is CH or N, the cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, azet
  • the ring B described in the present invention has the following sub-structure:
  • formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (II-6), formula (II) -7), formula (II-8), formula (II-9), formula (II-10), formula (II-11), formula (II-12), formula (II-13), formula (II- 14), formula (II-15), formula (II-16), formula (II-17), formula (II-18), formula (II-19), formula (II-20), formula (II-21 ), formula (II-22), formula (II-23), formula (II-24) and (II-25) are each independently unsubstituted or substituted by 1, 2, 3, 4 or 5 R x ;
  • each R x has the meaning described in the present invention.
  • the ring B described in the present invention has the following sub-structure:
  • each R x has the meaning described in the present invention.
  • each of R 7 , R 8 , R 9 , R 10a , R 10b and R y has the meaning described in the present invention.
  • R 8 in the present invention is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 1-4 haloalkyl , C 2-4 alkenyl, C 2-4 alkynyl, phenyl, naphthyl, C 1-4 alkylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-7 atoms Heterocyclyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazole Group, thienyl, pyrazinyl, pyridazinyl or pyrimidinyl,
  • each R z has the meaning described in the present invention.
  • each R z has the meaning described in the present invention.
  • R 7 in the present invention is hydrogen, cyano, nitro, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Tert-butyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, methoxy, ethoxy, n-propoxy, isopropoxy , N-butoxy, isobutoxy or tert-butoxy, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, methoxy, ethoxy, n-propoxy, isopropoxy,
  • Each R 9 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
  • Each R 10a and R 10b is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl Base, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, methoxy , Ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, C 2-4 alkenyl, C 2-4 alkynyl, cyclopropyl, cyclobutoxy Group, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thietanyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, imidazolid
  • each R z has the meaning described in the present invention.
  • the present invention relates to one of the following compounds or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs, But it is by no means limited to these compounds:
  • the present invention also provides a pharmaceutical composition comprising the compound of the present invention and pharmaceutically acceptable 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,
  • 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 compound or the pharmaceutical composition of the present invention is used to prepare drugs for preventing, treating or alleviating viral diseases in patients.
  • the use of the compound or the pharmaceutical composition of 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 compound or the pharmaceutical composition of the present invention, wherein the disease caused by the hepatitis B virus infection refers to liver cirrhosis or hepatocellular carcinoma.
  • 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.
  • the method of the present invention wherein the viral disease refers to a hepatitis B virus infection or a disease caused by hepatitis B virus infection.
  • the method of the present invention wherein the disease caused by hepatitis B virus infection refers to liver cirrhosis or hepatocellular carcinoma.
  • the present invention relates to the use of the compound or pharmaceutical composition in the preparation of medicines 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 the use of a compound of the present invention to prepare a medicament for preventing 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 to prepare a medicament for preventing or treating a patient's HBV disease and reducing its severity.
  • the patient is a mammal, and in other embodiments, the patient is a human.
  • the use further comprises contacting the cell with an anti-HBV therapeutic agent.
  • Another aspect of the present invention relates to a method for inhibiting HBV infection, which method comprises contacting a cell with a compound or pharmaceutical composition of the present invention in a dose effective to inhibit HBV. In other embodiments, the method further comprises contacting the cell with another anti-HBV therapeutic agent.
  • Another aspect of the present invention relates to a method of treating a patient with HBV disease, which method comprises administering an effective therapeutic dose of the compound of the present invention or a pharmaceutical composition thereof to the patient in need of treatment.
  • the method further comprises administering an effective therapeutic dose of another anti-HBV therapeutic agent to the patient in need of treatment.
  • Another aspect of the present invention relates to a method for inhibiting HBV infection in a patient, which method comprises administering an effective therapeutic dose of the compound of the present invention or a pharmaceutical composition thereof to the patient in need of treatment. In other embodiments, the method further comprises administering an effective therapeutic dose of another anti-HBV therapeutic agent to the patient in need of treatment.
  • Another aspect of the present invention relates to methods for the preparation, separation and purification of compounds contained in formula (I).
  • the present invention also relates to the application of the compound of the present invention and the pharmaceutically acceptable salt thereof in the production of medicinal products to effectively inhibit HBV infection, and the application of the compound of the present invention in the production of drugs for effectively inhibiting HBV infection.
  • the compound of the present invention is also used in the production of a medicine for alleviating, preventing, controlling or treating the symptoms of hepatitis B in patients.
  • 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 used in the preparation or purification of the compound represented by formula (I) or the salts of the separated enantiomers of the compound represented by formula (I), but not necessarily pharmaceutically acceptable Salt.
  • 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, and the like.
  • 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 ; Pyranonic 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 acids, such as p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, etc. or a combination thereof.
  • organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, malic acid,
  • the desired salt can be prepared by a suitable method, for example, using an inorganic or organic base, such as ammonia (primary, secondary, tertiary), alkali metal hydroxide, ammonium , N + (R 14 ) 4 salts and alkaline earth metal hydroxides, etc.
  • an inorganic or organic base such as ammonia (primary, secondary, tertiary), 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 ammonia, 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 ammonia
  • 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, morph
  • ammonium, quaternary ammonium salts and amine cations that are resistant to counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 sulfonates and Aromatic sulfonate.
  • the pharmaceutical composition of the present invention includes the compound represented by formula (I), the compounds listed in the present invention, or the compounds of the examples, and pharmaceutically acceptable excipients.
  • the compound in the pharmaceutical composition of the present invention can effectively inhibit hepatitis B virus, and is suitable for the treatment of virus-induced diseases, especially acute and chronic persistent HBV infection. Chronic viral diseases caused by HBV may lead to severe and chronic diseases. Hepatitis B virus infection can cause liver cirrhosis and/or hepatocellular carcinoma in many cases.
  • the area of disease treatment that may be mentioned is, for example, the treatment of acute and chronic viral infections that may lead to infectious hepatitis, for example, hepatitis B virus infection.
  • the compounds of the present invention are particularly suitable for the treatment of chronic hepatitis B infection and acute and chronic hepatitis B virus infections.
  • the present invention includes pharmaceutical preparations, which, in addition to non-toxic and inert pharmaceutical suitable excipients, also contain one or more of the compounds represented by formula (I) of the present invention or their pharmaceutical compositions.
  • compositions may also contain other pharmaceutical active ingredients other than the compound represented by formula (I).
  • 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 contains any one of the compounds represented by formula (I) of the present invention, and further includes pharmaceutically acceptable excipients, such as those used in the present invention, including any Solvents, solid excipients, diluents, binders, disintegrants, or other liquid excipients, dispersants, flavoring or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, Preservatives, solid binders or lubricants, etc., are suitable for specific target dosage forms. As described in the following documents: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed.
  • 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 sorbate; 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 salts; colloidal silicon; magnesium trisilicate; poly Vinylpyrrolidone; 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 carboxylate Sodium methyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients
  • the pharmaceutical composition of the compound of the present invention can be administered in any of the following ways: oral administration, topical administration, rectal administration, nasal administration, topical administration, vaginal administration, parenteral administration such as subcutaneous, Intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or medication with the aid of an explanted reservoir.
  • oral administration is oral administration, intramuscular injection, intraperitoneal administration or intravenous injection.
  • the compound of the present invention or its pharmaceutical composition 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; disintegrating agents, such as potato starch; or acceptable moisturizers such as sodium lauryl sulfate.
  • the tablets can be coated by methods known in pharmaceutics.
  • Oral liquids can be made into hydrated oil suspensions, solutions, emulsions, syrups or elixirs, and can also 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, emulsifiers, such as lecithin, sorbitan monooleate, gum arabic; or non-aqueous excipients (may contain edible oils), such as almond oil, fats 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 administration amount of the active compound of the present invention is about 0.5-500 mg/kg body weight per 24 hours, preferably 1-100 mg/kg body weight, 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 or interferons.
  • the anti-HBV drugs include lamivudine, telbivudine, tenofovir dipivoxil, entecavir, adefovir dipivoxil, Alfaferone, Alloferon, simo interleukin, clavudine, emtricitabine, and fapro Wei, Interferon, Baoganling CP, Interferon, Interferon ⁇ -1b, Interferon ⁇ , Interferon ⁇ -2a, Interferon ⁇ -1a, Interferon ⁇ -2, Interleukin-2, Mivot Ester, Nitrazoxanide, Pegylated Interferon Alpha-2a, Ribavirin, Rointerferon-A, Cizonan, Euforavac, Ampligen, Phosphazid, Heplisav, Interferon Alpha-2b, Levamisole Or propa germanium and so on.
  • Hepatitis B disease refers to liver disease caused by hepatitis B virus infection or hepatitis B infection, including acute hepatitis, chronic hepatitis, cirrhosis and hepatocellular carcinoma.
  • 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 anti-HBV drug 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 pharmaceutical composition (those containing a pharmaceutical composition as described in the present invention) that can be combined with excipients to produce a single dosage form varies depending on the main treatment and the particular mode of administration. Normally, the amount of the pharmaceutical composition of the present invention will not exceed the amount normally administered where the composition contains as the sole active agent. On the other hand, the range of the amount of the currently disclosed pharmaceutical composition is approximately 50%-100% of the normal amount of the existing pharmaceutical composition, and the contained agent is used as the only active therapeutic agent. Among those included compositions, the composition will act synergistically with the compound of the present invention.
  • 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 hepatocellular carcinoma.
  • indications that can be treated with the compounds of the present invention are: acute and chronic viral infections that can lead to infectious hepatitis, such as hepatitis B virus infection. Particularly preferred are chronic hepatitis B infection and acute hepatitis B virus infection.
  • the present invention also relates to the use of the compound and the pharmaceutical composition of the present invention in 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, wherein the definition of the substituents is as shown in formula (I).
  • the following synthesis schemes and examples are used to further illustrate the content of the present invention.
  • MS mass spectrometry
  • MS data is also 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 , ESI source is used in 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 purity 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 of 2.1 ⁇ 30mm, 4 ⁇ m, 10 minutes, flow rate of 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
  • the compound represented by formula (a-7) can be prepared by the method described in Synthetic Scheme 1.
  • Compound (a-1) and compound (a-2) react under alkaline conditions (eg, lithium bistrimethylsilylamide, etc.) to produce compound (a-3); then, compound (a-3) and compound (a-4), compound (a-5) is produced under suitable conditions; finally, compound (a-5) and compound (a-6) undergo a condensation reaction to obtain compound (a-7).
  • alkaline conditions eg, lithium bistrimethylsilylamide, etc.
  • the resulting mixture was extracted with ethyl acetate (400 mL), the organic phase was adjusted to pH 6 with 1M dilute hydrochloric acid, and then washed with saturated brine, dried over anhydrous sodium sulfate, concentrated part of the solvent, a large amount of solid precipitated, stirred at room temperature for 2h, After filtration, the filter cake was rinsed with ethyl acetate (10 mL) to obtain a white solid, the filtrate was concentrated, and the concentrated residue was slurried with ethyl acetate (20 mL) and petroleum ether (300 mL), and then rinsed with petroleum ether (50 mL) to obtain Light yellow solid. The above solids were combined and dried to obtain the title compound as a gray solid (18.4 g, 90%).
  • Step 3 Synthesis of 2-(5-((3,4-difluorophenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxoacetic acid
  • Step 4 Synthesis of Compound 3 (ie Example 3)
  • Step 3 Synthesis of Compound 7 (ie Example 7)
  • Examples 8-9 can be obtained by referring to the synthesis method of Example 7, and the characterization data of Examples 8-9 are shown in Table 2 below.
  • Step 4 Synthesis of compound 10 (ie Example 10)
  • Examples 11-27 can be obtained by referring to the synthesis method of Example 10, and the characterization data of Examples 11-27 are shown in Table 3 below.
  • Examples 29-30 can be obtained by referring to the synthesis method of Example 28, and the characterization data of Examples 29-30 are shown in Table 4 below.
  • Example 2 (278 mg, 0.539 mmol) was dissolved in a mixed solution of methanol (10 mL) and water (3 mL), and then sodium hydroxide (108 mg, 2.700 mmol) was added. After the mixture was stirred and reacted at room temperature for 14 hours, the solvent was evaporated to dryness under reduced pressure. The residue was diluted with water (20 mL) and ethyl acetate (20 mL), then the pH of the solution was adjusted to between 4-5 with 1M HCl, the aqueous phase was extracted with ethyl acetate (20 mL), and the organic phases were combined.
  • Examples 33-34 can be obtained by referring to the synthesis method of Example 32, and the characterization data of Examples 33-34 are shown in Table 5 below.
  • Step 1 2-(2-(5-(((3,4-Difluorophenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxy Acetyl)-2,8-diaza spiro[4.5] Synthesis of tert-butyl decane-8-carboxylate
  • the 2-(2-(5-(((3,4-difluorophenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxoacetyl Yl)-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (100mg, 0.171mmol) was dissolved in DCM (5mL), then trifluoroacetic acid (3mL) was added, and the reaction was stirred at room temperature After 1h, spin off the solvent and proceed directly to the next reaction.
  • Examples 36-39 can be obtained by referring to the synthesis method of Example 35, and the characterization data of Examples 36-39 are shown in Table 6 below.
  • Step 1 Synthesis of methyl 2-methylpiperidine-4-carboxylate (40-1)
  • the aqueous phase was extracted with ethyl acetate (70mL ⁇ 3).
  • the organic phases were combined, washed with 100mL saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • the aqueous phase was extracted with ethyl acetate (200 mL ⁇ 2), the organic phases were combined, the organic phase was washed with saturated brine (100 mL ⁇ 1), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 40 (240mg, 0.401mmol) was dissolved in DCM (5mL), then trifluoroacetic acid (3mL) was added, and the reaction was stirred at room temperature for 0.5h, then the solvent was spin-dried to obtain the title compound as a pale yellow oil, proceed directly Next reaction. .
  • Examples 42-44 can be obtained by referring to the synthesis method of Example 41, and the characterization data of Examples 42-44 are shown in Table 7 below.
  • Test 1 Anti-HBV EC 50 test method
  • 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, HBsAg and HBeAg into the culture medium.
  • HepG2.2.15 was cultured in DMEM medium containing 10% fetal bovine serum, 100U/mL penicillin, 100U/mL streptomycin, 1% non-essential amino acids, 1mM sodium pyruvate 300 ⁇ g/mL G418.
  • the virus particle DNA secreted by HepG2.2.15 cells can be quantified by qPCR method, and thus the influence of the compound on virus replication can be detected.
  • HepG 2.2.15 cells were seeded into a 96-well cell culture plate per well, and cultured at 37°C and 5% CO 2 for 3 days until the cells grew to full wells. On day 0 of the test, discard the old medium and add 200 ⁇ L of fresh test medium (5% FBS (fetal bovine serum)).
  • FBS fetal bovine serum
  • compound preparation and cell treatment dissolve the compound with DMSO to 30 mM, further dilute the compound with DMSO to 800 ⁇ M, and then perform a 4-fold dilution of 8 dilutions, with the highest concentration of 800 ⁇ M.
  • TDF tenofovir disoproxil fumarate, Selleck, Cat S1400
  • Table A EC 50 values of the compounds of the present invention in inhibiting HBV replication
  • Graphpad Prism 5 software was used to process the concentration-cytotoxicity (%) data, and the CC 50 was calculated by a four-parameter nonlinear regression model. A CC 50 greater than 50 indicates that the cytotoxicity is relatively low.
  • Table B The experimental results of the compound of the present invention are shown in Table B.
  • Table B CC 50 value of cytotoxicity of the compounds of the present invention

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Abstract

L'invention concerne un nouveau composé spiro et son utilisation dans un médicament, en particulier son utilisation en tant que médicament pour le traitement et/ou la prévention de l'hépatite B. Plus particulièrement, la présente invention concerne un composé représenté par la formule (I) ou un stéréoisomère, un tautomère, un oxynitrure, un solvate, un métabolite, ou un sel pharmaceutiquement acceptable de celui-ci, ou un promédicament de celui-ci, et l'utilisation des composés en tant que médicament, en particulier, l'utilisation en tant que médicament pour le traitement et la prévention de l'hépatite B, les variables étant définies dans la description.
PCT/CN2021/085352 2020-04-03 2021-04-02 Nouveau composé spiro et son utilisation dans un médicament WO2021197486A1 (fr)

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