WO2018153326A1 - Sulfonyl hydrazine compound and use thereof - Google Patents

Sulfonyl hydrazine compound and use thereof Download PDF

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Publication number
WO2018153326A1
WO2018153326A1 PCT/CN2018/076728 CN2018076728W WO2018153326A1 WO 2018153326 A1 WO2018153326 A1 WO 2018153326A1 CN 2018076728 W CN2018076728 W CN 2018076728W WO 2018153326 A1 WO2018153326 A1 WO 2018153326A1
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compound
group
substituted
alkyl
unsubstituted
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PCT/CN2018/076728
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French (fr)
Chinese (zh)
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王喆
王晓光
卢涔宾
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上海长森药业有限公司
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    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • 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
    • 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
    • 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
    • C07D207/36—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
    • C07D231/18—One oxygen or sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
    • C07D231/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D515/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention pertains to the field of medicine, and in particular, to a sulfonyl hydrazide compound for the treatment of hepatitis B and uses thereof.
  • Hepatitis B virus is an enveloped, partially double-stranded DNA (dsDNA), hepatovirus DNA family (Hepadnaviridae) virus. Its genome contains four overlapping reading frames: the pronuclear/nuclear gene, the polymerase gene, the UM and S genes (which encode three envelope proteins), and the X gene.
  • the partially double-stranded DNA genome is transformed into a covalently closed circular DNA (cccDNA) in the host cell nucleus (open loop DNA, rcDNA) and the viral mRNA is transcribed.
  • the pre-genomic RNA which is also encoded by the core protein and Pol, is used as a template for reverse transcription, which regenerates this portion of the dsDNA genome (rcDNA) in the nucleocapsid.
  • HBV has caused epidemics in parts of Asia and Africa, and it is endemic in China. HBV has infected about 2 billion people worldwide, and about 350 million of them have developed chronic infectious diseases. The virus causes hepatitis B disease and chronic infectious diseases are associated with a high increased risk of development of cirrhosis and liver cancer.
  • the spread of hepatitis B virus is derived from exposure to infectious blood or body fluids, while viral DNA is detected in the saliva, tears, and urine of chronic carriers with high-priced DNA in serum.
  • heteroaryldihydropyrimidines have been identified as a class of HBV inhibitors in tissue culture and animal models (Weber et al., Antiviral Res. 54:69-78) .
  • a sulfamoyl-arylamide involving anti-HBV activity is also disclosed in WO 2013/006394 (published on Jan. 10, 2013) and WO 2013/096744 (published on June 27, 2013).
  • a compound of the formula A or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,
  • R 1 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted, having 1-3 selected from N, a 3-10 membered heterocycloalkyl group of a hetero atom of S and O, a substituted or unsubstituted C 6 -C 10 aryl group, and a substituted or unsubstituted hetero atom having 1-3 selected from N, S and O a 5-10 membered heteroaryl; wherein in R 1 the substitution is substituted with one or more (eg 1, 2, 3, 4 or 5) substituents selected from the group consisting of: -OH, Halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -O-;
  • Y is a substituted or unsubstituted C 1 -C 7 alkylene group or a C 2 -C 7 alkenylene group; in the Y, the substitution means one or more selected from the group consisting of (for example, 1, 2) , 3, 4 or 5) substituted by a substituent: C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, halogen, -OH (preferably C 1 -C 4 alkyl or -OH);
  • W is selected from the group consisting of -SO 2 -, -CO-;
  • Ring C is a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 heteroatoms selected from N, S and O; in said ring C, said substitution refers to a group selected from the group consisting of Or a plurality of (for example 1, 2, 3, 4 or 5, etc.) substituents substituted: C 1 -C 3 alkyl (preferably methyl), C 1 -C 3 haloalkyl, C 3 -C 4 -cycloalkyl, -CN or halogen;
  • Ring B is a substituted or unsubstituted C 6 -C 10 aryl group, or a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 hetero atoms selected from N, S and O; Wherein said substitution is substituted with one or more (e.g., 1, 2, 3, 4 or 5) substituents selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 3 -C 4 cycloalkyl, -CN or halogen;
  • n 0, 1 or 2;
  • p 0, 1 or 2;
  • Z is selected from the group consisting of NH, O or none;
  • Z is selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10, OR 9 or H.
  • the compound is a compound selected from the group consisting of:
  • R 1 , X, Y, Z, W, ring C, ring B, Ra, Rb, Rc, Rd, n, p are as defined above.
  • -(N) 2 (R 1 )- represents a structure: -NH-N(R 1 )-.
  • R 1 is H, unsubstituted C 1 -C 10 alkyl, -OH, -O- or halogen-substituted C 1 -C 10 alkyl.
  • R 3 is selected from the group consisting of H, substituted or unsubstituted C 1 -C 10 alkyl, preferably H, substituted or unsubstituted C 1 -C 6 alkyl, more preferably The ground is H or methyl.
  • the R 2 and R 3 together with an adjacent C atom constitute a substituted or unsubstituted 3-7 membered impurity having 1-3 hetero atoms selected from N, S and O.
  • Ring C is a substituted or unsubstituted 5- or 6-membered heteroaryl group, said substitution being one or more selected from the group consisting of (eg 1, 2, 3, 4 or 5) Etc.) Substituted by a substituent: methyl, -CN or halogen.
  • ring C is a substituted or unsubstituted 5-6 membered heteroaryl group having 1-3 N, and in said ring C, said substitution refers to one or two selected from the group consisting of Substituted by a substituent: C 1 -C 3 alkyl (preferably methyl), halogen, -CN.
  • Ring B is phenyl or a substituted or unsubstituted 6-membered heteroaryl group, preferably a phenyl or pyridyl group.
  • Ring B is phenyl or 6-membered heteroaryl.
  • the R a , R b , R c and R d are each independently selected from the group consisting of H, halogen, —CHF 2 , —CF 2 —methyl, —CH 2 F, —CF. 3 , -OCF 3 , -CN, -C 3 -C 4 cycloalkyl, -C 1 -C 4 alkyl.
  • the ring C is or among them
  • R 4 is H, -C 1 -C 3 alkyl (preferably methyl), -C 3 -C 4 cycloalkyl;
  • R 6 is selected from H, methyl, -CN or halogen.
  • Z is O or not.
  • the R 7 is a substituted or unsubstituted 5-10 membered heteroaryl group having 1-2 hetero atoms selected from N, S and O.
  • the compound of formula A is selected from the compounds listed in Table 1.
  • the compound of formula A is selected from the compounds prepared in Examples 1-49.
  • the method of the formula A compound is a compound of formula IX-1, the method comprising the steps of:
  • Z is selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10 , OR 9 or H;
  • n is an integer from 0-8.
  • a compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to the first aspect of the invention is provided
  • the method of formula A is a compound of formula VIII-2, the method comprising the steps of:
  • Z is selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10 , OR 9 or H;
  • n is an integer from 0-8.
  • the method of formula A is a compound of formula V-3, the method comprising the steps of:
  • Z is selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10 , OR 9 or H.
  • the method of formula A is a compound of formula VI-4, the method comprising the steps of:
  • Z is selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10 , OR 9 or H.
  • a pharmaceutical composition comprising (1) a compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable thereof a salt, hydrate or solvate; and (2) a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises other drugs for preventing and/or treating hepatitis B virus infection.
  • the other drug for preventing and/or treating hepatitis B virus infection may be selected from the group consisting of an immunomodulator (eg, interferon- ⁇ (IFN- ⁇ ), PEGylation interference) Au- ⁇ ) or a stimulant of the innate immune system (such as Toll-like receptor 7 and/or 8 agonists).
  • an immunomodulator eg, interferon- ⁇ (IFN- ⁇ ), PEGylation interference
  • Au- ⁇ e.g, PEGylation interference
  • a stimulant of the innate immune system such as Toll-like receptor 7 and/or 8 agonists
  • the other drug for preventing and/or treating hepatitis B virus infection may be selected from the group consisting of tenofovir, lamivudine, adefovir, entecavir, and telbiv. Set, or a combination thereof.
  • R1, ring C are as defined in relation to the first aspect of the invention.
  • Z is selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10 , OR 9 or H;
  • n is an integer from 0-8.
  • a hepatitis B virus inhibitor comprising the compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutical thereof An acceptable salt, hydrate or solvate.
  • a method for preventing and/or treating hepatitis B comprising the steps of: administering a compound according to the first aspect of the present invention, or a stereoisomer thereof or a mutual An isomer, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to the sixth aspect of the invention.
  • a method for inhibiting hepatitis B in vitro comprising the steps of: the compound of the first aspect of the invention, or a stereoisomer or tautomer thereof, or A pharmaceutically acceptable salt, hydrate or solvate is contacted with hepatitis B virus to inhibit hepatitis B.
  • the inventors have conducted extensive and intensive research and found a novel class of compounds having excellent therapeutic effects on hepatitis B.
  • the compound of the present invention has a novel mother nucleus in structure, especially a structural moiety having a sulfonyl hydrazide, and therefore, not only has excellent anti-HBV activity, but also has lower cytotoxicity (especially for liver cells), and is superior in medicine. It has the advantages of generational kinetics, improved solubility, and so on, so it has better drug-forming properties. On this basis, the inventors completed the present invention.
  • alkyl as used herein includes a straight or branched alkyl group.
  • C 1 -C 8 alkyl represents a straight or branched alkyl group having 1-8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl. Wait.
  • alkenyl as used herein, includes a straight or branched alkenyl group.
  • C 2 -C 6 alkenyl refers to a straight or branched alkenyl group having 2 to 6 carbon atoms, such as ethenyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2 a butenyl group, or a similar group.
  • alkynyl includes a straight or branched alkynyl group.
  • C 2 -C 6 alkynyl refers to a straight or branched alkynyl group having 2 to 6 carbon atoms, such as an ethynyl group, a propynyl group, a butynyl group, or the like.
  • C 3 -C 10 cycloalkyl means a cycloalkyl group having 3-10 carbon atoms. It may be a monocyclic ring such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or the like. It may also be in the form of a double loop, such as a bridged or spiro ring.
  • C 1 -C 8 alkylamino refers to an amine group substituted by a C 1 -C 8 alkyl group, which may be monosubstituted or disubstituted; for example, methylamino, ethylamino, Alanine, isopropylamino, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, two Tert-butylamine and the like.
  • C 1 -C 8 alkoxy refers to a straight or branched alkoxy group having from 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, iso Propyloxy, butoxy, isobutoxy, tert-butoxy and the like.
  • the term "3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from N, S and O” means having from 3 to 10 atoms and wherein 1-3 of the atoms are selected from A saturated or partially saturated cyclic group of a hetero atom of N, S and O. It may be a single ring or a double ring form, such as a bridge ring or a spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl and the like.
  • C 6 -C 10 aryl refers to an aryl group having 6 to 10 carbon atoms, for example, a phenyl or naphthyl group or the like.
  • the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O" refers to having 5-10 atoms and wherein 1-3 atoms are selected from N, A cyclic aromatic group of a hetero atom of S and O. It may be a single ring or a fused ring.
  • Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2, 4)-Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.
  • the groups of the present invention may be substituted with a substituent selected from the group consisting of halogen, nitrile group, nitro group, hydroxyl group, amino group, unless otherwise specified as "substituted or unsubstituted". , C 1 -C 6 alkyl-amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogenated C 1 - C 6 alkyl, halo C 2 -C 6 alkenyl, halo C 2 -C 6 alkynyl, halo C 1 -C 6 alkoxy, allyl, benzyl, C 6 -C 12 aryl , C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-carbonyl, phenoxycarbonyl, C 2 -C 6 alkynyl-carbonyl
  • halogen or halogen atom refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from the group consisting of F, Cl and Br. "Halo” means substituted with an atom selected from the group consisting of F, Cl, Br, and I.
  • the structural formulae described herein are intended to include all isomeric forms (such as enantiomeric, diastereomeric, and geometric isomers (or conformational isomers): for example, containing asymmetry The central R, S configuration, the (Z) and (E) isomers of the double bond.
  • a single stereochemical isomer of a compound of the invention, or a mixture of enantiomers, diastereomers or geometric isomers (or conformational isomers) thereof, is within the scope of the invention.
  • tautomer means that structural isomers having different energies can exceed the low energy barrier and thereby transform each other.
  • proton tautomers ie, proton shifts
  • proton transfer such as 1H-carbazole and 2H-carbazole.
  • Valence tautomers include interconversion through some bonding electron recombination.
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a particular ratio.
  • hydrate refers to a complex formed by the coordination of a compound of the invention with water.
  • a compound of the invention refers to a compound of formula (A), and also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (A).
  • pharmaceutically acceptable salt refers to a salt of the compound of the invention formed with an acid or base suitable for use as a medicament.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzoic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
  • Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid,
  • the pharmaceutical composition wherein the compound is the main active ingredient can be used for preventing and/or treating (stabilizing, alleviating or curing) hepatitis B virus infection or for preventing and/or treating (stabilizing, alleviating or curing) a hepatitis B virus-related disease ( For example, hepatitis B, progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, terminal liver disease, ethyl liver cancer).
  • hepatitis B progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, terminal liver disease, ethyl liver cancer.
  • compositions of the present invention comprise a safe and effective amount of a compound of the invention and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 10 to 200 mg of the compound of the invention per agent.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermixing with the compounds of the invention and between them without significantly reducing the potency of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as Tween ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • vegetable oil such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyol such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifier such as Tween
  • a wetting agent such as sodium lauryl sulfate
  • a coloring agent such as a flavoring agent, a stabilizer, an antioxidant, a preservative
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, parenteral (intravenous, intramuscular or subcutaneous).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., anti-HBV agents).
  • other pharmaceutically acceptable compounds e.g., anti-HBV agents.
  • the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (e.g., anti-HBV agents).
  • one or more (2, 3, 4, or more) of the other pharmaceutically acceptable compound e.g, an anti-HBV agent
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 20 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the compound of the present invention is novel in structure and has an excellent anti-HBV infection effect.
  • the compounds of the invention are very toxic to normal cells.
  • the compound of the present invention and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment of hepatitis B virus infection.
  • the compound of the present invention and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment of hepatitis B virus-related diseases (for example, hepatitis B, progressive liver fibrosis, inflammation leading to cirrhosis, and Necrosis, terminal liver disease, ethyl liver cancer).
  • hepatitis B virus-related diseases for example, hepatitis B, progressive liver fibrosis, inflammation leading to cirrhosis, and Necrosis, terminal liver disease, ethyl liver cancer.
  • the term “about” means that the value can vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the terms "containing” or “including” may be open, semi-closed, and closed. In other words, the terms also include “consisting essentially of,” or “consisting of.”
  • step 1
  • the preparation of the compound 6e was carried out in the same manner as in the step 1-4 of Example 1, except that in the step 1, 1-allyl-1-isopropylindole was used instead of 1-allyl-1-methylindole.
  • the compound 6e is used instead of the compound 6, and the 3-chloro-4-fluoro-1-aniline is substituted for the 3,4-difluoro-1-aniline.
  • n-heptane: ethyl acetate 2:1
  • the preparation of the compound 6f was carried out by referring to the step 1-4 of Example 1, except that in the step 1, 1-allyl-1-isopropylindole was used instead of 1-allyl-1-methylindole.
  • the compound 6f is used instead of the compound 6, and the 3-cyano-4-fluoro-1-aniline is substituted for the 3,4-difluoro-1-aniline.
  • the preparation of the compound 6f is carried out in the same manner as in the step 1-4 of the first embodiment except that 2-methyl-1-allyl-1-isopropylindole is used in place of 1-allyl-1-methyl. Hey.
  • the compound 6f is used instead of the compound 6, and the 3-cyano-4-fluoro-1-aniline is substituted for the 3,4-difluoro-1-aniline.
  • the preparation of the compound 26b was carried out by referring to the step 21-24 of Example 13, except that the 1-allyl-1-cyclopropyl hydrazine was replaced by 1-allyl-1-cyclopropyl hydrazine in the step 21.
  • the compound 26d was prepared by referring to Step 21-24 of Example 13, except that in Step 21, 1-(1-allylhydrazo)ethanol was used instead of 1-allyl-1-methyloxime.
  • the preparation of the compound 26e was carried out by referring to the step 21-24 of Example 13, except that the 1-allyl-1-isopropylindole was replaced with 1-allyl-1-isopropylindole in the step 21.
  • the preparation of the compound 26f was carried out by referring to the step 21-24 of Example 13, except that the 1-allyl-1-isopropylindole was replaced with 1-allyl-1-isopropylindole in the step 21.
  • step 25 of the embodiment 13 it is only necessary to replace the compound 26 with the compound 26f, and to replace the 3,4-difluoro-1-aniline with 3-cyano-4-fluoro-1-aniline, and the other conditions are unchanged.
  • the preparation of the compound 45b is carried out by referring to the steps 41-43 of Example 25, except that in the step 41, 1-tert-butoxycarbonyl-1-trifluoroisopropyl hydrazine is used in place of 1-tert-butoxycarbonyl-1-isopropyl group. Hey.
  • the compound 45c was prepared by following the procedure of Steps 41 to 43 of Example 25 except that 1-tert-butoxycarbonyl-1-tert-butylindole was used in place of 1-tert-butoxycarbonyl-1-isopropylindole.
  • the preparation of the compound 45d is carried out by referring to the steps 41-43 of Example 25, except that in the step 41, 1-tert-butoxycarbonyl-1-hydroxyisopropyl hydrazine is used instead of 1-tert-butoxycarbonyl-1-isopropyl hydrazine. .
  • step 41 The preparation of compound 45e is carried out by referring to steps 41-43 of Example 25, except that in step 41, 1-tert-butoxycarbonyl-1-trifluoroisopropyl hydrazine is used in place of 1-tert-butoxycarbonyl-1-isopropyl group.
  • the preparation of the compound 45f is carried out by referring to the steps 41-43 of Example 25, except that in the step 41, 1-tert-butoxycarbonyl-1-trifluoroisopropyl hydrazine is used in place of 1-tert-butoxycarbonyl-1-isopropyl group. Hey.
  • the compound 45f is used instead of the compound 45, and the 3-cyano-4-fluoro-1-aniline is substituted for the 3,4-difluoro-1-aniline.
  • the preparation of the compound 55b is carried out by referring to the steps 51-53 of Example 31 except that 1-tert-butoxycarbonyl-1-trifluoroisopropyl hydrazine is substituted for 1-tert-butoxycarbonyl-1-isopropyl group in the step 51. Hey.
  • the compound 55c was prepared by referring to the procedures 51-53 of Example 31 except that 1-tert-butoxycarbonyl-1-tert-butylindole was used in the step 51 instead of 1-tert-butoxycarbonyl-1-isopropylindole.
  • the preparation of the compound 55d is carried out by referring to the steps 51-53 of Example 31, except that in the step 41, 1-tert-butoxycarbonyl-1-hydroxyisopropyl hydrazine is used in place of 1-tert-butoxycarbonyl-1-isopropyl hydrazine. .
  • the compound 55d was used instead of the compound 55, and the other conditions were unchanged.
  • the preparation of the compound 55e is carried out by referring to the steps 51-53 of Example 31, except that in the step 51, 1-tert-butoxycarbonyl-1-trifluoroisopropyl hydrazine is used in place of 1-tert-butoxycarbonyl-1-isopropyl group. Hey.
  • the preparation of the compound 55f is carried out by referring to the steps 51-53 of Example 31 except that 1-tert-butoxycarbonyl-1-trifluoroisopropyl hydrazine is substituted for 1-tert-butoxycarbonyl-1-isopropyl group in the step 51.
  • reaction solution A) is dropped into the reaction liquid B), and the reaction system is controlled to about 0 degree, and after the completion of the dropwise addition, the reaction is carried out at 0 degree for 0.5 hour.
  • Step 62
  • Compound 64c was prepared as described in steps 61-63 of Example 38, except that in step 62, t-butyloxazolidinone was used in place of isopropyloxazolidinone.
  • the compound 64d was used instead of the compound 64, and the other conditions were unchanged.
  • reaction solution A) was dropped into the reaction liquid B), and the reaction system was controlled to about 0 degree, and the reaction was carried out at 0 degree for 0.5 hour after the completion of the dropwise addition.
  • Step 74
  • the compound 74b was used instead of the compound 74, and the other conditions were unchanged.
  • Column chromatography (n-heptane: ethyl acetate 1:3) of the desired product 80b (5 mg).
  • the compound 74c was prepared by following the procedures 71-73 of Example 44, except that in step 72, t-butyloxazolidinone was used in place of the isopropyloxazolidinone.
  • the compound 74d was prepared by following the procedures 71-73 of Example 44, except that in step 72, hydroxyisopropyloxazolidinone was used in place of the isopropyloxazolidinone.
  • the compound 74d was used instead of the compound 74, and the other conditions were unchanged.
  • the compound 74f was prepared by following the procedures 71-73 of Example 44, except that in step 71, trifluoroisopropyloxazolidinone was used in place of the isopropyloxazolidinone.
  • the compound 74f is used instead of the compound 74, and the 3-cyano-4-fluoro-1-aniline is substituted for the 3,4-difluoro-1-aniline.
  • [C150Bo] (A280- x1300M -1 ) / 60,900M -1 ;
  • [C150Bo] represents the concentration of a fluorescently labeled protein
  • A504 represents an absorbance value of a wavelength of 504 nM
  • A280 represents an absorption value of a wavelength of 280 nM
  • M -1 represents the reciprocal of the molar concentration.
  • the mother liquor of the compound was diluted to 6 mM with DMSO, diluted to 600 ⁇ M with 50 mM HEPES, and then further diluted 8 times with 10% DMSO/50 mM HEPES.
  • C150Bo was diluted to 2 ⁇ M with 50 mM HEPES. 37.5 ⁇ L of C150Bo and 2.5 ⁇ L of each concentration of the compound were added to a 96-well reaction plate and mixed, and incubated at room temperature for 15 minutes. 10 ⁇ l of 750 mM NaCl/50 mM HEPES was added to the reaction well, and the final concentration of NaCl was 150 mM.
  • Control wells were assembled with 0% protein, 10 ⁇ L of 50 mM HEPES was added, and the final concentration of NaCl was 0 mM.
  • Control wells were assembled with 100% protein and 10 ⁇ L of 5 M NaCl/50 mM HEPES was added with a final concentration of 1 M NaCl.
  • the final concentration of DMSO was 0.5%, the maximum final concentration of the compound was 30 ⁇ M, and the final concentration of C150Bo was 1.5 ⁇ M. Incubate for 1 hour at room temperature. The fluorescence signal (excitation light 485 nm; emission light 535 nm) was measured.
  • % protein assembly [1- (sample fluorescence value - 1M NaCl fluorescence value) / (0M NaCl fluorescence value - 1M NaCl fluorescence value)] ⁇ 100.
  • the IC 50 value is calculated by the prism software and the equation is as follows:
  • X represents the logarithm of the concentration
  • Y represents the effect value
  • Y is fitted from the bottom to the top with an S-shape
  • Top indicates that Top represents the top of the curve
  • HillSlope represents the absolute value of the maximum slope of the curve.
  • HepG2.2.15 cells (4 x 10 4 cells/well) were plated into 96-well plates and incubated overnight at 37 ° C, 5% CO 2 . The next day, fresh culture medium containing different concentrations of compounds was added to the culture wells. On the fifth day, the old culture solution in the culture well was aspirated and fresh culture medium containing different concentrations of the compound was added.
  • the supernatant in the culture well was collected for extracting HBV DNA from the supernatant, and qPCR was used to detect the HBV DNA content in the supernatant of HepG2.2.15.
  • the culture medium and the Cell-titer Glo reagent were added to the culture well, and the chemiluminescence value of each well was detected by a microplate reader.
  • the activity calculation formula is as follows:
  • X represents the logarithm of the concentration
  • Y represents the effect value
  • Y is fitted from the bottom to the top with an S-shape
  • HillSlope represents the absolute value of the maximum slope of the curve.
  • test compounds The cytotoxicity of the test compounds was tested using HepG2 cells, and these cells were incubated for 4 days in the presence of the test compound. Cell rejuvenation was assessed using the resazurin assay.
  • the compound of the present invention has good anti-HBV nucleocapsid assembly activity and anti-HBV activity in vitro, and has low cytotoxicity.
  • +++ means IC 50 or EC 50 ⁇ 1 ⁇ M
  • ++ indicates an IC 50 or EC 50 of 1 to 100 ⁇ M
  • control compound is:
  • control group positive control compound
  • Test group Table 2 for each compound, comparing its pharmacokinetic differences.
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
  • Rats were briefly anesthetized after inhalation of ether, and 300 ⁇ L of blood samples were collected from the eyelids in test tubes. There was 30 ⁇ L of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at a later time point, the rats were anesthetized with ether and sacrificed.
  • Plasma samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube to indicate the name and time point of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.
  • the compound of the present invention has better pharmacokinetics in the animal than the control group, and the compound AUC of the present invention has an average increase of 15-100% and an average Cmax of 10-100% with respect to the control group. ), thus having better pharmacodynamics and therapeutic effects.
  • Test method 50 mg each of compound 10f, 60f and the positive control compound were taken at room temperature (20 ° C), and added to 2 ml of the corresponding solvent. After stirring, the supernatant was taken, and the solubility was measured by HPLC. The results are shown in the following table (unit: Mg/mL):
  • the compound of the present invention is excellent in anti-hepatitis B virus nucleocapsid assembly activity and anti-hepatitis B virus activity in vitro, and has lower cytotoxicity, and the compound of the present invention exhibits superior solubility and good pharmacokinetics of the reference compound. nature.

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Abstract

The present invention relates to a sulfonyl hydrazine compound and a use thereof as a medicament for use in treating hepatitis B. Specifically, the present invention discloses a compound which may act as an HBV inhibitor and which has the structure represented by chemical formula A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, a hydrate or a solvent thereof. For the definitions of each group, see the description for detail. The present invention also relates to a pharmaceutical composition containing said compound and a use thereof in the treatment of hepatitis B.

Description

磺酰肼类化合物及其用途Sulfonyl hydrazide compounds and uses thereof 技术领域Technical field
本发明属于医药领域，具体地，本发明涉及用于治疗乙型肝炎的磺酰肼类化合物及其用途。The present invention pertains to the field of medicine, and in particular, to a sulfonyl hydrazide compound for the treatment of hepatitis B and uses thereof.
背景技术Background technique
乙型肝炎病毒(HBV)是一种有包膜的、部分双链DNA(dsDNA)的、嗜肝病毒DNA家族(肝病毒科(Hepadnaviridae))的病毒。它的基因组包含4个重叠阅读框：前核/核基因，聚合酶基因，UM和S基因(它们编码三个包膜蛋白质)，以及X基因。在感染前时，该部分双链DNA基因组在宿主细胞核中(开环DNA，rcDNA)转变为共价闭合环状DNA(cccDNA)并且该病毒mRNA进行转录。一旦被壳体化，该前基因组RNA(pgRNA)(其还为核心蛋白和Pol编码)作为模板用于逆转录，这种逆转录在核衣壳中再生该部分dsDNA基因组(rcDNA)。Hepatitis B virus (HBV) is an enveloped, partially double-stranded DNA (dsDNA), hepatovirus DNA family (Hepadnaviridae) virus. Its genome contains four overlapping reading frames: the pronuclear/nuclear gene, the polymerase gene, the UM and S genes (which encode three envelope proteins), and the X gene. At the time of infection, the partially double-stranded DNA genome is transformed into a covalently closed circular DNA (cccDNA) in the host cell nucleus (open loop DNA, rcDNA) and the viral mRNA is transcribed. Once encapsidated, the pre-genomic RNA (pgRNA), which is also encoded by the core protein and Pol, is used as a template for reverse transcription, which regenerates this portion of the dsDNA genome (rcDNA) in the nucleocapsid.
HBV在亚洲和非洲的部分地区造成了流行病，并且它在中国是地方性的。HBV已经在全球感染了大约20亿人，其中大约3.5亿人发展成了慢性传染病。该病毒造成了乙型肝炎疾病并且慢性传染病与肝硬化和肝癌的发展的高增加风险相关联。HBV has caused epidemics in parts of Asia and Africa, and it is endemic in China. HBV has infected about 2 billion people worldwide, and about 350 million of them have developed chronic infectious diseases. The virus causes hepatitis B disease and chronic infectious diseases are associated with a high increased risk of development of cirrhosis and liver cancer.
乙型肝炎病毒的传播来源于暴露于传染性的血液或体液，同时在血清中具有高效价DNA的慢性携带者的唾液、泪液以及尿液中检测到了病毒DNA。The spread of hepatitis B virus is derived from exposure to infectious blood or body fluids, while viral DNA is detected in the saliva, tears, and urine of chronic carriers with high-priced DNA in serum.
虽然目前存在一种有效的并且具有良好耐受性的疫苗，但是直接治疗的选择目前还限于干扰素以及以下的抗病毒药；替诺福韦、拉米夫定、阿德福韦、恩替卡韦以及替比夫定。Although there is currently an effective and well tolerated vaccine, the choice of direct treatment is currently limited to interferon and the following antiviral drugs; tenofovir, lamivudine, adefovir, entecavir and Telbivudine.
此外，杂芳基二氢嘧啶(HAPs)在组织培养以及动物模型中被鉴别作为一类HBV抑制剂(韦伯(Weber)等人，《抗病毒研究》(Antiviral Res.)54:69-78)。In addition, heteroaryldihydropyrimidines (HAPs) have been identified as a class of HBV inhibitors in tissue culture and animal models (Weber et al., Antiviral Res. 54:69-78) .
WO 2013/006394(公开于2013年1月10日)和WO 2013/096744(公开于2013年6月27日)还公开了涉及抗HBV活性的氨磺酰基-芳基酰胺。A sulfamoyl-arylamide involving anti-HBV activity is also disclosed in WO 2013/006394 (published on Jan. 10, 2013) and WO 2013/096744 (published on June 27, 2013).
然而，在这些直接的HBV抗病毒药中会遇到的是毒性、致突变性、缺乏选择性、疗效差、生物利用度差以及合成困难等问题。However, problems encountered in these direct HBV antivirals are toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability, and difficulty in synthesis.
因此，本领域需要开发具有如效价高、毒性更低等优点的HBV抑制剂。Therefore, there is a need in the art to develop HBV inhibitors having advantages such as high potency and lower toxicity.
发明内容Summary of the invention
本发明的目的在于提供一类可用作HBV抑制剂的结构新颖的化合物。It is an object of the present invention to provide a novel class of compounds useful as HBV inhibitors.
本发明的第一方面，提供了一种化学式A所示的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物，According to a first aspect of the invention, there is provided a compound of the formula A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,
Figure PCTCN2018076728-appb-000001
Figure PCTCN2018076728-appb-000001
其中，among them,
R 1选自下组：氢、取代或未取代的C 1-C 10烷基、取代或未取代的C 3-C 10环烷基、取代或未取代的具有1-3个选自N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C 6-C 10芳基、和取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基；所述R 1中，所述取代指被选自下组的一个或多个(例如1、2、3、4或5个)取代基所取代：-OH、卤素、C 1-C 6烷基、卤代的C 1-C 6烷基、C 1-C 6烷氧基、-O-； R 1 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted, having 1-3 selected from N, a 3-10 membered heterocycloalkyl group of a hetero atom of S and O, a substituted or unsubstituted C 6 -C 10 aryl group, and a substituted or unsubstituted hetero atom having 1-3 selected from N, S and O a 5-10 membered heteroaryl; wherein in R 1 the substitution is substituted with one or more (eg 1, 2, 3, 4 or 5) substituents selected from the group consisting of: -OH, Halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -O-;
X为选自下组的二价基团：CR 2R 3或-CR 2＝CR 3-；其中，R 2和R 3各自独立地选自下组：H、卤素、取代或未取代的C 1-C 10烷基、取代或未取代的C 2-C 6烯基、取代或未取代的C 2-C 6炔基、取代或未取代的C 3-C 10环烷基、取代或未取代的具有1-3个选自N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、C 1-3烷基-R 7、-C(＝O)OC 1-4烷基；其中所述R 7选自下组：卤素、C 1-C 3烷基、取代的或未取代的具有1-2个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的3-7元杂环烷基、和-NR 9R 10，其中，所述R 9和R 10各自独立地选自：H、C 1-C 3烷基、和卤代的C 1-C 3烷基； X is a divalent group selected from the group consisting of CR 2 R 3 or -CR 2 =CR 3 -; wherein R 2 and R 3 are each independently selected from the group consisting of H, halogen, substituted or unsubstituted C 1- C 10 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or not Substituted 3-10 membered heterocycloalkyl having 1 to 3 heteroatoms selected from N, S and O, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted having 1-3 a 5-10 membered heteroaryl group selected from the group consisting of N, S and O, a C 1-3 alkyl-R 7 , -C(=O)OC 1-4 alkyl group; wherein said R 7 is selected from the group consisting of Group: halogen, C 1 -C 3 alkyl, substituted or unsubstituted 5-10 membered heteroaryl having 1-2 heteroatoms selected from N, S and O, having 1-3 selected from N a 3-7 membered heterocycloalkyl group of a hetero atom of S and O, and -NR 9 R 10 , wherein said R 9 and R 10 are each independently selected from the group consisting of: H, C 1 -C 3 alkyl, and Halogenated C 1 -C 3 alkyl;
或者，or,
所述R 2和R 3与相邻的C原子共同构成具有1-3个选自N、S和O的杂原子的取代或未取代的3-7元杂环烷基，其中，所述3-7元杂环烷基的取代指被选自下组的一个或多个(例如1、2、3、4或5个)取代基所取代：-OH、卤素、甲氧基、乙氧基、-O-、-C(＝O)OC 1-4烷基、苄基、C 1-4烷基、卤代的C 1-4烷基， The R 2 and R 3 together with the adjacent C atoms constitute a substituted or unsubstituted 3-7 membered heterocycloalkyl group having 1 to 3 hetero atoms selected from N, S and O, wherein the 3 Substitution of a -7 membered heterocycloalkyl refers to substitution with one or more (e.g., 1, 2, 3, 4 or 5) substituents selected from the group consisting of -OH, halogen, methoxy, ethoxy. , -O-, -C(=O)OC 1-4 alkyl, benzyl, C 1-4 alkyl, halogenated C 1-4 alkyl,
并且，所述R 2和R 3中，所述取代指被选自下组的一个或多个(例如1、2、3、4或5个)取代基所取代：-OH、卤素、C 1-C 6烷基、卤代的C 1-C 6烷基、-OH取代的C 1-C 6烷基、C 1-C 6烷氧基、-C(＝O)OC 1-4烷基； And, in R 2 and R 3 , the substitution refers to being substituted with one or more (for example, 1, 2, 3, 4 or 5) substituents selected from the group consisting of -OH, halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, -OH substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -C(=O)OC 1-4 alkyl ;
Y为取代或未取代的C 1-C 7亚烷基或C 2-C 7亚烯基；在所述Y中，所述取代指被选自下组的一个或多个(例如1、2、3、4或5个)取代基所取代：C 1-C 4烷基、C 1-C 4卤代烷基、卤素、-OH(较佳地为C 1-C 4烷基或-OH)； Y is a substituted or unsubstituted C 1 -C 7 alkylene group or a C 2 -C 7 alkenylene group; in the Y, the substitution means one or more selected from the group consisting of (for example, 1, 2) , 3, 4 or 5) substituted by a substituent: C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, halogen, -OH (preferably C 1 -C 4 alkyl or -OH);
W选自下组：-SO 2-、-CO-； W is selected from the group consisting of -SO 2 -, -CO-;
环C为取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基；在所述环C中，所述取代指被选自下组的一个或多个(例如1、2、3、4或5个等)取代基所取代：C 1-C 3烷基(较佳地为甲基)、C 1-C 3卤代烷基、C 3-C 4环烷基、-CN或卤素； Ring C is a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 heteroatoms selected from N, S and O; in said ring C, said substitution refers to a group selected from the group consisting of Or a plurality of (for example 1, 2, 3, 4 or 5, etc.) substituents substituted: C 1 -C 3 alkyl (preferably methyl), C 1 -C 3 haloalkyl, C 3 -C 4 -cycloalkyl, -CN or halogen;
环B为取代或未取代的C 6-C 10芳基、或取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基；所述环B中，所述取代指被选自下组的一个或多个(例如1、2、3、4或5个)取代基所取代：C 1-C 3烷基、C 1-C 3卤代烷基、C 3-C 4环烷基、-CN或卤素； Ring B is a substituted or unsubstituted C 6 -C 10 aryl group, or a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 hetero atoms selected from N, S and O; Wherein said substitution is substituted with one or more (e.g., 1, 2, 3, 4 or 5) substituents selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 3 -C 4 cycloalkyl, -CN or halogen;
R a、R b、R c和R d为环B上任意位置的取代基，其各自独立地选自下组：H、卤素、-CN、羟基、氨基、C1-C6羧基、-(C＝O)-取代或未取代的C 1-C 8烷基、取代或未取代的C 1-C 8烷基、取代或未取代的C2-C6烯基、取代或未取代的C 2-C 6炔基、取代或未取代的C 1-C 8烷胺基、取代或未取代的C1-C8烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、和取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基；在所述Ra、Rb、Rc、Rd中，所述“取代”是指被选自下组的一个或多个(例如1、2、3、4或5个等)取代基所取代：卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、氨基、C1-C3羧基、C6-C10芳基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、卤代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基； R a , R b , R c and R d are substituents at any position on Ring B, each independently selected from the group consisting of H, halogen, -CN, hydroxy, amino, C1-C6 carboxy, -(C= O)-substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 8 alkylamino, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having 1-3 3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl group selected from hetero atoms of N, S and O, and substituted or unsubstituted having 1-3 selected from N, S and O a 5-10 membered heteroaryl of a hetero atom; in the Ra, Rb, Rc, Rd, the "substituted" refers to one or more selected from the group consisting of (eg 1, 2, 3, 4) Or 5 or the like) substituted by a substituent: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl Halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxy, amino, C1-C3 carboxy, C6-C10 aryl, halogenated C6-C10 aryl, having 1-3 options a 5-10 membered heteroaryl group derived from a hetero atom of N, S and O, a halogenated 5-10 membered heteroaryl group having 1 to 3 hetero atoms selected from N, S and O;
n为0、1或2；n is 0, 1 or 2;
p为0、1或2；p is 0, 1 or 2;
---X---Y---中的“---”表示键或不存在；"---" in ---X---Y--- indicates a key or does not exist;
其中，当“---”表示键时，Z选自下组：NH、O或无；Wherein, when "---" indicates a bond, Z is selected from the group consisting of NH, O or none;
当“---”表示不存在时，X和Y均为无，Z选自下组：卤素、C1-C4烷基、C1-C4卤代烷基、-NR 9R 10、OR 9或H。 When "---" indicates the absence of, X and Y are both free, Z is selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10, OR 9 or H.
在另一优选例中，所述化合物为选自下组的化合物：In another preferred embodiment, the compound is a compound selected from the group consisting of:
Figure PCTCN2018076728-appb-000002
Figure PCTCN2018076728-appb-000002
其中，R 1、X、Y、Z、W、环C、环B、Ra、Rb、Rc、Rd、n、p如上文所定义。 Wherein R 1 , X, Y, Z, W, ring C, ring B, Ra, Rb, Rc, Rd, n, p are as defined above.
在另一优选例中，在式A-1所示的化合物中，当n为2时，-(N) 2(R 1)-表示如下结构：-NH-N(R 1)-。 In another preferred embodiment, in the compound of the formula A-1, when n is 2, -(N) 2 (R 1 )- represents a structure: -NH-N(R 1 )-.
在另一优选例中，R 1为H、未取代的C 1-C 10烷基、被-OH、-O-或卤素取代的C 1-C 10烷基。 In another preferred embodiment, R 1 is H, unsubstituted C 1 -C 10 alkyl, -OH, -O- or halogen-substituted C 1 -C 10 alkyl.
在另一优选例中，对于R 1，当取代基为-O-时，是指R 1中的碳原子上的两个氢同时被一个氧取代，即形成C＝O基团。 In another preferred embodiment, for R 1 , when the substituent is -O-, it means that two hydrogens on the carbon atom in R 1 are simultaneously substituted by one oxygen, that is, a C=O group is formed.
在另一优选例中，R 2选自下组：H、取代或未取代的C 1-C 10烷基、-C(＝O)OC 1-4烷基、 C 1-3烷基-R 7、取代或未取代的C 2-4炔基、具有1-3个选自N、S和O的杂原子的3-7元杂环烷基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基。 In another preferred embodiment, R 2 is selected from the group consisting of H, substituted or unsubstituted C 1 -C 10 alkyl, -C(=O)OC 1-4 alkyl, C 1-3 alkyl-R 7. A substituted or unsubstituted C 2-4 alkynyl group, a 3-7 membered heterocycloalkyl group having 1-3 hetero atoms selected from N, S and O, substituted or unsubstituted, having 1-3 options A 5-10 membered heteroaryl group derived from a hetero atom of N, S and O.
在另一优选例中，R 3选自下组：H、取代或未取代的C 1-C 10烷基，较佳地为H、取代或未取代的C 1-C 6烷基，更佳地为H或甲基。 In another preferred embodiment, R 3 is selected from the group consisting of H, substituted or unsubstituted C 1 -C 10 alkyl, preferably H, substituted or unsubstituted C 1 -C 6 alkyl, more preferably The ground is H or methyl.
在另一优选例中，对于“所述R 2和R 3与相邻的C原子共同构成具有1-3个选自N、S和O的杂原子的取代或未取代的3-7元杂环烷基”的情况，当取代基为-O-时，是指所述3-7元杂环烷基中的碳原子上的两个氢同时被一个氧取代，即形成C＝O基团。 In another preferred embodiment, for "the R 2 and R 3 together with an adjacent C atom constitute a substituted or unsubstituted 3-7 membered impurity having 1-3 hetero atoms selected from N, S and O. In the case of a cycloalkyl group, when the substituent is -O-, it means that two hydrogens on a carbon atom in the 3-7 membered heterocycloalkyl group are simultaneously substituted by one oxygen, that is, a C=O group is formed. .
在另一优选例中，环C为取代或未取代的5元或6元杂芳基，所述取代指被选自下组的一个或多个(例如1、2、3、4或5个等)取代基所取代：甲基、-CN或卤素。In another preferred embodiment, Ring C is a substituted or unsubstituted 5- or 6-membered heteroaryl group, said substitution being one or more selected from the group consisting of (eg 1, 2, 3, 4 or 5) Etc.) Substituted by a substituent: methyl, -CN or halogen.
在另一优选例中，环C为取代或未取代的含1-3个N的5-6元杂芳基，在所述环C中，所述取代指被选自下组的一个或两个取代基所取代：C 1-C 3烷基(较佳地为甲基)、卤素、-CN。 In another preferred embodiment, ring C is a substituted or unsubstituted 5-6 membered heteroaryl group having 1-3 N, and in said ring C, said substitution refers to one or two selected from the group consisting of Substituted by a substituent: C 1 -C 3 alkyl (preferably methyl), halogen, -CN.
在另一优选例中，环B为苯基或取代或未取代的6元杂芳基，较佳地为苯基或吡啶基。In another preferred embodiment, Ring B is phenyl or a substituted or unsubstituted 6-membered heteroaryl group, preferably a phenyl or pyridyl group.
在另一优选例中，环B为苯基或6元杂芳基。In another preferred embodiment, Ring B is phenyl or 6-membered heteroaryl.
在另一优选例中，所述R a、R b、R c和R d各自独立地选自下组：H、卤素、-CHF 2、-CF 2-甲基、-CH 2F、-CF 3、-OCF 3、-CN、-C 3-C 4环烷基、-C 1-C 4烷基。 In another preferred embodiment, the R a , R b , R c and R d are each independently selected from the group consisting of H, halogen, —CHF 2 , —CF 2 —methyl, —CH 2 F, —CF. 3 , -OCF 3 , -CN, -C 3 -C 4 cycloalkyl, -C 1 -C 4 alkyl.
在另一优选例中，所述环C为
Figure PCTCN2018076728-appb-000003
或
Figure PCTCN2018076728-appb-000004
其中， In another preferred embodiment, the ring C is
Figure PCTCN2018076728-appb-000003
or
Figure PCTCN2018076728-appb-000004
among them,
R 4为H、-C 1-C 3烷基(较佳地为甲基)、-C 3-C 4环烷基； R 4 is H, -C 1 -C 3 alkyl (preferably methyl), -C 3 -C 4 cycloalkyl;
R 6选自H、甲基、-CN或卤素。 R 6 is selected from H, methyl, -CN or halogen.
在另一优选例中，在式A-1中，所述Z为O或无。In another preferred embodiment, in Formula A-1, Z is O or not.
在另一优选例中，所述R 7为取代的或未取代的具有1-2个选自N、S和O的杂原子的5-10元杂芳基。 In another preferred embodiment, the R 7 is a substituted or unsubstituted 5-10 membered heteroaryl group having 1-2 hetero atoms selected from N, S and O.
在另一优选例中，所述式A化合物选自表1所列的化合物。In another preferred embodiment, the compound of formula A is selected from the compounds listed in Table 1.
在另一优选例中，所述式A化合物选自实施例1-49所制备的化合物。In another preferred embodiment, the compound of formula A is selected from the compounds prepared in Examples 1-49.
在本发明的第二方面，提供了一种制备如本发明第一方面所述化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物的方法，所示式A化合物为式IX-1所示的化合物，所述方法包括步骤：In a second aspect of the invention, there is provided a compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to the first aspect of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof The method of the formula A compound is a compound of formula IX-1, the method comprising the steps of:
Figure PCTCN2018076728-appb-000005
Figure PCTCN2018076728-appb-000005
各式中，环C、R 1、环B、R a、R b、R c和R d的定义同本发明第一方面所述； In each formula, the definitions of ring C, R 1 , ring B, R a , R b , R c and R d are as described in the first aspect of the invention;
Z选自下组：卤素、C1-C4烷基、C1-C4卤代烷基、-NR 9R 10、OR 9或H； Z is selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10 , OR 9 or H;
m为0-8的整数。m is an integer from 0-8.
在本发明的第三方面，提供了一种制备如本发明第一方面所述化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物的方法，所示式A化合物为式VIII-2所示的化合物，所述方法包括步骤：In a third aspect of the invention, a compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to the first aspect of the invention, is provided The method of formula A is a compound of formula VIII-2, the method comprising the steps of:
Figure PCTCN2018076728-appb-000006
Figure PCTCN2018076728-appb-000006
各式中，环C、R 1、环B、R a、R b、R c和R d的定义同本发明第一方面所述； In each formula, the definitions of ring C, R 1 , ring B, R a , R b , R c and R d are as described in the first aspect of the invention;
Z选自下组：卤素、C1-C4烷基、C1-C4卤代烷基、-NR 9R 10、OR 9或H； Z is selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10 , OR 9 or H;
m为0-8的整数。m is an integer from 0-8.
在本发明的第四方面，提供了一种制备如本发明第一方面所述化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物的方法，所示式A化合物为式V-3所示的化合物，所述方法包括步骤：In a fourth aspect of the invention, there is provided a compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to the first aspect of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof The method of formula A is a compound of formula V-3, the method comprising the steps of:
Figure PCTCN2018076728-appb-000007
Figure PCTCN2018076728-appb-000007
各式中，环C、R 1、环B、R a、R b、R c和R d的定义同本发明第一方面所述； In each formula, the definitions of ring C, R 1 , ring B, R a , R b , R c and R d are as described in the first aspect of the invention;
Z选自下组：卤素、C1-C4烷基、C1-C4卤代烷基、-NR 9R 10、OR 9或H。 Z is selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10 , OR 9 or H.
在本发明的第五方面，提供了一种制备如本发明第一方面所述化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物的方法，所示式A化合物为式VI-4所示的化合物，所述方法包括步骤：In a fifth aspect of the invention, there is provided a compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to the first aspect of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof The method of formula A is a compound of formula VI-4, the method comprising the steps of:
Figure PCTCN2018076728-appb-000008
Figure PCTCN2018076728-appb-000008
各式中，环C、R 1、环B、R a、R b、R c和R d的定义同本发明第一方面所述； In each formula, the definitions of ring C, R 1 , ring B, R a , R b , R c and R d are as described in the first aspect of the invention;
Z选自下组：卤素、C1-C4烷基、C1-C4卤代烷基、-NR 9R 10、OR 9或H。 Z is selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10 , OR 9 or H.
在本发明的第六方面，提供了一种药物组合物，其包含(1)本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物；和(2)药学上可接受的载体。In a sixth aspect of the invention, there is provided a pharmaceutical composition comprising (1) a compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable thereof a salt, hydrate or solvate; and (2) a pharmaceutically acceptable carrier.
在另一优选例中，所述药物组合物还包含其它用于预防和/或治疗乙型肝炎病毒感染的药物。In another preferred embodiment, the pharmaceutical composition further comprises other drugs for preventing and/or treating hepatitis B virus infection.
在另一优选例中，所述其它用于预防和/或治疗乙型肝炎病毒感染的药物可选自下组：免疫调节剂(例如干扰素-α(IFN-α)、聚乙二醇化干扰素-α)或先天免疫系统的刺激剂(如Toll样受体7和/或8激动剂)。In another preferred embodiment, the other drug for preventing and/or treating hepatitis B virus infection may be selected from the group consisting of an immunomodulator (eg, interferon-α (IFN-α), PEGylation interference) Au-α) or a stimulant of the innate immune system (such as Toll-like receptor 7 and/or 8 agonists).
在另一优选例中，所述其它用于预防和/或治疗乙型肝炎病毒感染的药物可选自下组：替诺福韦、拉米夫定、阿德福韦、恩替卡韦、替比夫定、或其组合。In another preferred embodiment, the other drug for preventing and/or treating hepatitis B virus infection may be selected from the group consisting of tenofovir, lamivudine, adefovir, entecavir, and telbiv. Set, or a combination thereof.
在本发明的第七方面，提供了如下式所示中间体化合物：In a seventh aspect of the invention, there is provided an intermediate compound of the formula:
Figure PCTCN2018076728-appb-000009
Figure PCTCN2018076728-appb-000009
式中，R1、环C定义同本发明第一方面所述；Wherein R1, ring C are as defined in relation to the first aspect of the invention;
Z选自下组：卤素、C1-C4烷基、C1-C4卤代烷基、-NR 9R 10、OR 9或H； Z is selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10 , OR 9 or H;
m为0-8的整数。m is an integer from 0-8.
在本发明的第八方面，提供了一种本发明第七方面所述的中间体化合物的用途，用于制备本发明第一方面所述的化合物。In an eighth aspect of the invention, there is provided the use of an intermediate compound according to the seventh aspect of the invention for the preparation of the compound of the first aspect of the invention.
在本发明的第九方面，提供了如本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物或如本发明第六方面所述的药物组合物的用途，用于制备预防和/或治疗乙型肝炎病毒感染的药物。In a ninth aspect of the invention, the compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or as Use of the pharmaceutical composition of the sixth aspect of the invention for the preparation of a medicament for preventing and/or treating hepatitis B virus infection.
在本发明的第十方面，提供了一种乙型肝炎病毒抑制剂，所述抑制剂包含本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物。In a tenth aspect of the invention, there is provided a hepatitis B virus inhibitor comprising the compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutical thereof An acceptable salt, hydrate or solvate.
在本发明的第十一方面，提供了一种预防和/或治疗乙型肝炎的方法，包括步骤：向所需患者施用本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物或本发明第六方面所述的药物组合物。In an eleventh aspect of the present invention, a method for preventing and/or treating hepatitis B, comprising the steps of: administering a compound according to the first aspect of the present invention, or a stereoisomer thereof or a mutual An isomer, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to the sixth aspect of the invention.
在本发明的第十二方面，提供了一种体外抑制乙型肝炎的方法，包括步骤：将本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物，与乙型肝炎病毒接触，从而抑制乙型肝炎。In a twelfth aspect of the invention, a method for inhibiting hepatitis B in vitro, comprising the steps of: the compound of the first aspect of the invention, or a stereoisomer or tautomer thereof, or A pharmaceutically acceptable salt, hydrate or solvate is contacted with hepatitis B virus to inhibit hepatitis B.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It is to be understood that within the scope of the present invention, the various technical features of the present invention and the various technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.
具体实施方式detailed description
本发明人经过广泛而深入的研究，发现了一类对乙型肝炎具有优异的治疗效果的新型化合物。本发明化合物在结构上具有新颖的母核，尤其是具有磺酰肼的结构部分，因此，不仅具有优异的抗HBV的活性，而且具有细胞毒性更低(尤其对于肝脏细胞)、更优异的药代动力学、改善的溶解性等优点，因此具有更好的成药性。在此基础上，发明人完成了本发明。The inventors have conducted extensive and intensive research and found a novel class of compounds having excellent therapeutic effects on hepatitis B. The compound of the present invention has a novel mother nucleus in structure, especially a structural moiety having a sulfonyl hydrazide, and therefore, not only has excellent anti-HBV activity, but also has lower cytotoxicity (especially for liver cells), and is superior in medicine. It has the advantages of generational kinetics, improved solubility, and so on, so it has better drug-forming properties. On this basis, the inventors completed the present invention.
定义definition
如本文所用，术语“烷基”包括直链或支链的烷基。例如C 1-C 8烷基表示具有1-8个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。 The term "alkyl" as used herein includes a straight or branched alkyl group. For example, C 1 -C 8 alkyl represents a straight or branched alkyl group having 1-8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl. Wait.
如本文所用，术语“烯基”包括直链或支链的烯基。例如C 2-C 6烯基指具有2-6个碳原子的直链或支链的烯基，例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、或类似基团。 The term "alkenyl" as used herein, includes a straight or branched alkenyl group. For example, C 2 -C 6 alkenyl refers to a straight or branched alkenyl group having 2 to 6 carbon atoms, such as ethenyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2 a butenyl group, or a similar group.
如本文所用，术语“炔基”包括直链或支链的炔基。例如C 2-C 6炔基是指具有2-6个碳原子的直链或支链的炔基，例如乙炔基、丙炔基、丁炔基、或类似基团。 The term "alkynyl", as used herein, includes a straight or branched alkynyl group. For example, C 2 -C 6 alkynyl refers to a straight or branched alkynyl group having 2 to 6 carbon atoms, such as an ethynyl group, a propynyl group, a butynyl group, or the like.
如本文所用，术语“C 3-C 10环烷基”指具有3-10个碳原子的环烷基。其可以是单环，例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式，例如桥环或螺环形式。 As used herein, the term "C 3 -C 10 cycloalkyl" means a cycloalkyl group having 3-10 carbon atoms. It may be a monocyclic ring such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or the like. It may also be in the form of a double loop, such as a bridged or spiro ring.
如本文所用，术语“C 1-C 8烷胺基”是指被C 1-C 8烷基所取代的胺基，可以是单取代或双取代的；例如，甲胺基、乙胺基、丙胺基、异丙胺基、丁胺基、异丁胺基、叔丁胺基、二甲胺 基、二乙胺基、二丙胺基、二异丙胺基、二丁胺基、二异丁胺基、二叔丁胺基等。 As used herein, the term "C 1 -C 8 alkylamino" refers to an amine group substituted by a C 1 -C 8 alkyl group, which may be monosubstituted or disubstituted; for example, methylamino, ethylamino, Alanine, isopropylamino, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, two Tert-butylamine and the like.
如本文所用，术语“C 1-C 8烷氧基”是指具有1-8个碳原子的直链或支链的烷氧基；例如，甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等。 As used herein, the term "C 1 -C 8 alkoxy" refers to a straight or branched alkoxy group having from 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, iso Propyloxy, butoxy, isobutoxy, tert-butoxy and the like.
如本文所用，术语“具有1-3个选自N、S和O的杂原子的3-10元杂环烷基”是指具有3-10个原子的且其中1-3个原子为选自N、S和O的杂原子的饱和或部分饱和的环状基团。其可以是单环，也可以是双环形式，例如桥环或螺环形式。具体的实例可以为氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、四氢呋喃基、吗啉基和吡咯烷基等。As used herein, the term "3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from N, S and O" means having from 3 to 10 atoms and wherein 1-3 of the atoms are selected from A saturated or partially saturated cyclic group of a hetero atom of N, S and O. It may be a single ring or a double ring form, such as a bridge ring or a spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl and the like.
如本文所用，术语“C 6-C 10芳基”是指具有6-10个碳原子的芳基，例如，苯基或萘基等类似基团。 As used herein, the term "C 6 -C 10 aryl" refers to an aryl group having 6 to 10 carbon atoms, for example, a phenyl or naphthyl group or the like.
如本文所用，术语“具有1-3个选自N、S和O的杂原子的5-10元杂芳基”指具有5-10个原子的且其中1-3个原子为选自N、S和O的杂原子的环状芳香基团。其可以是单环，也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。As used herein, the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O" refers to having 5-10 atoms and wherein 1-3 atoms are selected from N, A cyclic aromatic group of a hetero atom of S and O. It may be a single ring or a fused ring. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2, 4)-Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.
本发明所述的基团除非特别说明是“取代的或未取代的”，否则本发明的基团均可被选自下组的取代基所取代：卤素、腈基、硝基、羟基、氨基、C 1-C 6烷基-胺基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、卤代C 1-C 6烷基、卤代C 2-C 6烯基、卤代C 2-C 6炔基、卤代C 1-C 6烷氧基、烯丙基、苄基、C 6-C 12芳基、C 1-C 6烷氧基-C 1-C 6烷基、C 1-C 6烷氧基-羰基、苯氧羰基、C 2-C 6炔基-羰基、C 2-C 6烯基-羰基、C 3-C 6环烷基-羰基、C 1-C 6烷基-磺酰基等。 The groups of the present invention may be substituted with a substituent selected from the group consisting of halogen, nitrile group, nitro group, hydroxyl group, amino group, unless otherwise specified as "substituted or unsubstituted". , C 1 -C 6 alkyl-amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogenated C 1 - C 6 alkyl, halo C 2 -C 6 alkenyl, halo C 2 -C 6 alkynyl, halo C 1 -C 6 alkoxy, allyl, benzyl, C 6 -C 12 aryl , C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-carbonyl, phenoxycarbonyl, C 2 -C 6 alkynyl-carbonyl, C 2 -C 6 alkenyl a carbonyl group, a C 3 -C 6 cycloalkyl-carbonyl group, a C 1 -C 6 alkyl-sulfonyl group or the like.
如本文所用，“卤素”或“卤原子”指F、Cl、Br、和I。更佳地，卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from the group consisting of F, Cl and Br. "Halo" means substituted with an atom selected from the group consisting of F, Cl, Br, and I.
除非特别说明，本发明所描述的结构式意在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体(或构象异构体))：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体等。因此，本发明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。Unless otherwise stated, the structural formulae described herein are intended to include all isomeric forms (such as enantiomeric, diastereomeric, and geometric isomers (or conformational isomers): for example, containing asymmetry The central R, S configuration, the (Z) and (E) isomers of the double bond. Thus, a single stereochemical isomer of a compound of the invention, or a mixture of enantiomers, diastereomers or geometric isomers (or conformational isomers) thereof, is within the scope of the invention.
如本文所用，术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒，从而互相转化。比如，质子互变异构体(即质子移变)包括通过质子迁移进行互变，如1H-吲唑与2H-吲唑。化合价互变异构体包括通过一些成键电子重组而进行互变。As used herein, the term "tautomer" means that structural isomers having different energies can exceed the low energy barrier and thereby transform each other. For example, proton tautomers (ie, proton shifts) include interconversions by proton transfer, such as 1H-carbazole and 2H-carbazole. Valence tautomers include interconversion through some bonding electron recombination.
如本文所用，术语“溶剂合物”是指本发明化合物与溶剂分子配位形成特定比例的配合物。As used herein, the term "solvate" refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a particular ratio.
如本文所用，术语“水合物”是指本发明化合物与水进行配位形成的配合物。As used herein, the term "hydrate" refers to a complex formed by the coordination of a compound of the invention with water.
活性成分Active ingredient
如本文所用，“本发明化合物”指式(A)所示的化合物，并且还包括式(A)化合物的各种晶 型形式、药学上可接受的盐、水合物或溶剂合物。As used herein, "a compound of the invention" refers to a compound of formula (A), and also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (A).
如本文所用，“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。As used herein, "pharmaceutically acceptable salt" refers to a salt of the compound of the invention formed with an acid or base suitable for use as a medicament. Pharmaceutically acceptable salts include inorganic and organic salts. A preferred class of salts are the salts of the compounds of the invention with acids. Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzoic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
药物组合物和施用方法Pharmaceutical composition and method of administration
由于本发明化合物具有优异的乙型肝炎病毒(HBV)的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗(稳定、减轻或治愈)乙型肝炎病毒感染或用于预防和/或治疗(稳定、减轻或治愈)乙型肝炎病毒相关疾病(例如，乙型肝炎、进展性肝纤维化、导致肝硬化的炎症和坏死、末期肝病、乙基肝癌)。Since the compound of the present invention has excellent inhibitory activity against hepatitis B virus (HBV), the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and the present invention The pharmaceutical composition wherein the compound is the main active ingredient can be used for preventing and/or treating (stabilizing, alleviating or curing) hepatitis B virus infection or for preventing and/or treating (stabilizing, alleviating or curing) a hepatitis B virus-related disease ( For example, hepatitis B, progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, terminal liver disease, ethyl liver cancer).
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the invention and a pharmaceutically acceptable excipient or carrier. By "safe and effective amount" it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. In general, the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 10 to 200 mg of the compound of the invention per agent. Preferably, the "one dose" is a capsule or tablet.
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2018076728-appb-000010
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。 "Pharmaceutically acceptable carrier" means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By "compatibility" it is meant herein that the components of the composition are capable of intermixing with the compounds of the invention and between them without significantly reducing the potency of the compound. Examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid). , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as Tween
Figure PCTCN2018076728-appb-000010
), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)。The mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, parenteral (intravenous, intramuscular or subcutaneous).
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂 中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, hard Calcium citrate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof. In capsules, tablets and pills, the dosage form may also contain a buffer.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。In addition to these inert diluents, the compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。In addition to the active compound, the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
本发明化合物可以单独给药，或者与其他药学上可接受的化合物(例如抗-HBV剂)联合给药。The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., anti-HBV agents).
联合给药时，所述药物组合物还包括与一种或多种(2种，3种，4种，或更多种)其他药学上可接受的化合物(例如抗-HBV剂)。该其他药学上可接受的化合物(例如抗-HBV剂)中的一种或多种(2种，3种，4种，或更多种)可与本发明的化合物同时、分开或顺序地用于预防和/或治疗HBV感染或HBV相关疾病。When administered in combination, the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (e.g., anti-HBV agents). One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compound (eg, an anti-HBV agent) may be used simultaneously, separately or sequentially with the compound of the present invention. For the prevention and / or treatment of HBV infection or HBV related diseases.
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。When a pharmaceutical composition is used, a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight, The dose to be administered is usually from 1 to 2000 mg, preferably from 20 to 500 mg. Of course, specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
根据本发明化合物10a、20a、30a、40a、50a、60a、70a和80a的合成方法，合成了表1中的本发明的化合物。According to the synthesis method of the compounds 10a, 20a, 30a, 40a, 50a, 60a, 70a and 80a of the present invention, the compounds of the present invention in Table 1 were synthesized.
表1Table 1
Figure PCTCN2018076728-appb-000011
Figure PCTCN2018076728-appb-000011
Figure PCTCN2018076728-appb-000012
Figure PCTCN2018076728-appb-000012
Figure PCTCN2018076728-appb-000013
Figure PCTCN2018076728-appb-000013
Figure PCTCN2018076728-appb-000014
Figure PCTCN2018076728-appb-000014
Figure PCTCN2018076728-appb-000015
Figure PCTCN2018076728-appb-000015
Figure PCTCN2018076728-appb-000016
Figure PCTCN2018076728-appb-000016
本发明的主要优点包括：The main advantages of the invention include:
1.本发明的化合物结构新颖且具有优异的抗乙肝病毒感染的作用。1. The compound of the present invention is novel in structure and has an excellent anti-HBV infection effect.
2.本发明的化合物对正常细胞的毒性非常低。2. The compounds of the invention are very toxic to normal cells.
3.本发明化合物以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗乙型肝炎病毒感染。3. The compound of the present invention and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment of hepatitis B virus infection.
4.本发明化合物以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗乙型肝炎病毒相关疾病(例如，乙型肝炎、进展性肝纤维化、导致肝硬化的炎症和坏死、末期肝病、乙基肝癌)。4. The compound of the present invention and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment of hepatitis B virus-related diseases (for example, hepatitis B, progressive liver fibrosis, inflammation leading to cirrhosis, and Necrosis, terminal liver disease, ethyl liver cancer).
术语说明Terminology
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, unless otherwise defined.
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。As used herein, when used in reference to a particular recited value, the term "about" means that the value can vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。As used herein, the terms "containing" or "including" may be open, semi-closed, and closed. In other words, the terms also include "consisting essentially of," or "consisting of."
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight and parts by weight.
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。The experimental materials and reagents used in the following examples are available from commercially available sources unless otherwise specified.
下面为10类化合物的合成：The following is the synthesis of 10 compounds:
实施例1：化合物10a的合成Example 1: Synthesis of Compound 10a
Figure PCTCN2018076728-appb-000017
Figure PCTCN2018076728-appb-000017
步骤1:step 1:
Figure PCTCN2018076728-appb-000018
Figure PCTCN2018076728-appb-000018
将化合物1(1.5g)和化合物2(0.5g)溶于乙腈(20mL),然后将吡啶(1.5g)加入反应体系，将温度升至85度反应2h，反应体系加入乙酸乙酯(30mL),加水30(mL)，乙酸乙酯(3*20mL)萃取，无水硫酸钠干燥，将有机相旋干，粗品柱层析得化合物3(1.0g)。ESI-MS,(M+H＝366)Compound 1 (1.5 g) and Compound 2 (0.5 g) were dissolved in acetonitrile (20 mL), then pyridine (1.5 g) was added to the reaction system, the temperature was raised to 85 °C for 2 h, and the reaction system was added ethyl acetate (30 mL). The mixture was extracted with EtOAc (3 mL) (EtOAc) ESI-MS, (M+H=366)
步骤2：Step 2:
Figure PCTCN2018076728-appb-000019
Figure PCTCN2018076728-appb-000019
将化合物3(0.8g)，乙烯基硼酐吡啶盐(0.75g)和碳酸钾(1.8g)溶于二氧六环(5mL)和水(0.5mL)，然后将四三苯基膦钯(100mg)加入反应体系，将体系温度升至100度，氮气保护下反应8h，将反应体系加水(20mL),乙酸乙酯(3*30mL)萃取，无水硫酸钠干燥，将有机相旋干，粗品柱层析得化合物4(400mg),ESI-MS,(M+H＝314)Compound 3 (0.8 g), vinyl boronic anhydride pyridinium salt (0.75 g) and potassium carbonate (1.8 g) were dissolved in dioxane (5 mL) and water (0.5 mL), then tetratriphenylphosphine palladium ( 100 mg) was added to the reaction system, the temperature of the system was raised to 100 °C, and the reaction was carried out for 8 h under nitrogen. The reaction mixture was added with water (20 mL), ethyl acetate (3*30 mL), and dried over anhydrous sodium sulfate. Crude column chromatography gave compound 4 (400 mg), ESI-MS, (M+H= 314)
步骤3:Step 3:
Figure PCTCN2018076728-appb-000020
Figure PCTCN2018076728-appb-000020
将化合物4(400mg)溶于二氯甲烷(800mL),将詹氏催化剂CAT-C(90mg)加入反应体系，30度反应36h，将水(600mL)加入反应体系,二氯甲烷(3*400mL)萃取，无水硫酸钠干燥，将有机相旋干，粗品经柱层析分离得黄色固体5(120mg)，ESI-MS,(M+H＝286)Compound 4 (400 mg) was dissolved in dichloromethane (800 mL), Jane's catalyst CAT-C (90 mg) was added to the reaction system, reacted at 30 degrees for 36 h, and water (600 mL) was added to the reaction system, dichloromethane (3*400 mL) The extract is dried over anhydrous sodium sulfate, and the organic phase is evaporated to dryness. The crude product is purified by column chromatography to give a yellow solid 5 (120 mg), ESI-MS, (M+H=286)
步骤4：Step 4:
Figure PCTCN2018076728-appb-000021
Figure PCTCN2018076728-appb-000021
将化合物5(120mg)溶于四氢呋喃(2.4mL),水(0.6mL),甲醇(0.6mL),然后室温下将一水合氢氧化锂(83mg)加入反应体系，40度下反应5h，然后将体系pH值用1N盐酸调至3-4，乙酸乙酯(3*15mL)萃取，无水硫酸钠干燥，有机相旋干得黄色固体6(50mg)ESI-MS,(M+H＝272)Compound 5 (120 mg) was dissolved in tetrahydrofuran (2.4 mL), water (0.6 mL), methanol (0.6 mL), then lithium hydroxide monohydrate (83 mg) was added to the reaction system at room temperature, reacted at 40 ° for 5 h, then The pH of the system was adjusted to 3-4 with 1N hydrochloric acid, ethyl acetate (3*15 mL), and dried over anhydrous sodium sulfate.
步骤5：Step 5:
Figure PCTCN2018076728-appb-000022
Figure PCTCN2018076728-appb-000022
将化合物6(50mg)，三乙胺(70mg)，3，4-二氟-1-苯胺(22mg)溶于二氯甲烷(3mL)中，然后将温度降至5度左右，然后将TBTU(70mg)加入反应体系，室温下反应12h,加水(15mL),二氯甲烷(3*20mL)萃取，无水硫酸钠干燥，将有机相旋干，粗品经柱层析(正庚烷：乙酸乙酯＝1：1)得化合物10a(10mg)Compound 6 (50 mg), triethylamine (70 mg), 3,4-difluoro-1-aniline (22 mg) was dissolved in dichloromethane (3 mL), then the temperature was reduced to about 5 deg. 70 mg) was added to the reaction system, and the reaction was carried out for 12 h at room temperature. Water (15 mL), dichloromethane (3*20 mL) was evaporated. Ester = 1:1) to give compound 10a (10 mg)
实施例2：化合物10b的合成Example 2: Synthesis of Compound 10b
Figure PCTCN2018076728-appb-000023
Figure PCTCN2018076728-appb-000023
化合物6b的制法参照实施例1的步骤1-4，不同点在于步骤1中用1-烯丙基-1-环丙基肼代替1-烯丙基-1-甲基肼。The preparation of Compound 6b was carried out in the same manner as in Step 1-4 of Example 1, except that in Step 1, 1-allyl-1-cyclopropyl hydrazine was used instead of 1-allyl-1-methyloxime.
根据实施例1的步骤5，只需用化合物6b代替化合物6，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：1)目标产物10b(11mg)。According to the step 5 of Example 1, the compound 6b was used instead of the compound 6 and the other conditions were unchanged, and the objective product 10b (11 mg) was subjected to column chromatography (n-heptane: ethyl acetate = 1:1).
实施例3：化合物10c的合成Example 3: Synthesis of Compound 10c
Figure PCTCN2018076728-appb-000024
Figure PCTCN2018076728-appb-000024
化合物6c的制法参照实施例1的步骤1-4，不同点在于步骤1中用1-烯丙基-1-异丙基肼代替1-烯丙基-1-甲基肼。The preparation of Compound 6c was carried out in the same manner as in Step 1-4 of Example 1, except that in Step 1, 1-allyl-1-isopropylindole was used instead of 1-allyl-1-methylindole.
根据实施例1的步骤5，只需用化合物6c代替化合物6，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝2：1)目标产物10c(6mg)。According to the step 5 of Example 1, only the compound 6c was used instead of the compound 6, and the other conditions were unchanged, and the objective product 10c (6 mg) was subjected to column chromatography (n-heptane: ethyl acetate = 2:1).
实施例4：化合物10d的合成Example 4: Synthesis of Compound 10d
Figure PCTCN2018076728-appb-000025
Figure PCTCN2018076728-appb-000025
化合物6d的制法参照实施例1的步骤1-4，不同点在于步骤1中用1-(1-烯丙基肼基)乙醇代替1-烯丙基-1-甲基肼。The preparation of Compound 6d was carried out in the same manner as in Step 1-4 of Example 1, except that in Step 1, 1-(1-allylhydrazino)ethanol was used instead of 1-allyl-1-methyloxime.
根据实施例1的步骤5，只需用化合物6d代替化合物6，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝2：1)目标产物10d(6mg)。According to the step 5 of Example 1, only the compound 6d was used instead of the compound 6, and the other conditions were unchanged, and the objective product was obtained by column chromatography (n-heptane: ethyl acetate = 2:1) 10d (6 mg).
实施例5：化合物10e的合成Example 5: Synthesis of Compound 10e
Figure PCTCN2018076728-appb-000026
Figure PCTCN2018076728-appb-000026
化合物6e的制法参照实施例1的步骤1-4，不同点在于步骤1中用1-烯丙基-1-异丙基肼代替1-烯丙基-1-甲基肼。The preparation of the compound 6e was carried out in the same manner as in the step 1-4 of Example 1, except that in the step 1, 1-allyl-1-isopropylindole was used instead of 1-allyl-1-methylindole.
根据实施例1的步骤5，只需用化合物6e代替化合物6，用3-氯-4-氟-1-苯胺取代3,4-二氟-1-苯胺，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝2：1)目标产物10e(11mg)。According to the step 5 of the first embodiment, the compound 6e is used instead of the compound 6, and the 3-chloro-4-fluoro-1-aniline is substituted for the 3,4-difluoro-1-aniline. (n-heptane: ethyl acetate = 2:1) title product 10e (11 mg).
实施例6：化合物10f的合成Example 6: Synthesis of Compound 10f
Figure PCTCN2018076728-appb-000027
Figure PCTCN2018076728-appb-000027
化合物6f的制法参照实施例1的步骤1-4，不同点在于步骤1中用1-烯丙基-1-异丙基肼 代替1-烯丙基-1-甲基肼。The preparation of the compound 6f was carried out by referring to the step 1-4 of Example 1, except that in the step 1, 1-allyl-1-isopropylindole was used instead of 1-allyl-1-methylindole.
根据实施例1的步骤5，只需用化合物6f代替化合物6，用3-氰基-4-氟-1-苯胺取代3,4-二氟-1-苯胺，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝2：1)目标产物10f(8mg)。According to the step 5 of the first embodiment, the compound 6f is used instead of the compound 6, and the 3-cyano-4-fluoro-1-aniline is substituted for the 3,4-difluoro-1-aniline. The title product 10f (8 mg) was obtained (n-heptane: ethyl acetate = 2:1).
实施例7：化合物10g的合成Example 7: Synthesis of Compound 10g
Figure PCTCN2018076728-appb-000028
Figure PCTCN2018076728-appb-000028
化合物6f的制法参照实施例1的步骤1-4，不同点在于步骤1中用2-甲基-1-烯丙基-1-异丙基肼代替1-烯丙基-1-甲基肼。The preparation of the compound 6f is carried out in the same manner as in the step 1-4 of the first embodiment except that 2-methyl-1-allyl-1-isopropylindole is used in place of 1-allyl-1-methyl. Hey.
根据实施例1的步骤5，只需用化合物6f代替化合物6，用3-氰基-4-氟-1-苯胺取代3,4-二氟-1-苯胺，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝2：1)目标产物10g(8mg)。According to the step 5 of the first embodiment, the compound 6f is used instead of the compound 6, and the 3-cyano-4-fluoro-1-aniline is substituted for the 3,4-difluoro-1-aniline. The title product (10 mg) was obtained (n-heptane: ethyl acetate = 2:1).
下面为20类化合物的合成：The following are the synthesis of 20 compounds:
实施例8：化合物20a的合成Example 8: Synthesis of Compound 20a
Figure PCTCN2018076728-appb-000029
Figure PCTCN2018076728-appb-000029
步骤11：Step 11:
将化合物10a(20mg)溶于乙酸乙酯(2mL),然后将湿钯碳(5mg)加入反应体系，25度,在氢气环境下反应3h，反应液抽滤，旋干柱层析(正庚烷：乙酸乙酯＝1：1)目标产物20a(7mg)Compound 10a (20 mg) was dissolved in ethyl acetate (2 mL), then wet palladium carbon (5 mg) was added to the reaction system at 25 ° C, and reacted under a hydrogen atmosphere for 3 h. Alkane: ethyl acetate = 1:1) target product 20a (7mg)
实施例9：化合物20b的合成Example 9: Synthesis of Compound 20b
Figure PCTCN2018076728-appb-000030
Figure PCTCN2018076728-appb-000030
根据实施例7的步骤11，只需用化合物10b代替化合物10a，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：1)目标产物20b(6mg)。According to the step 11 of Example 7, the compound 10b (6 mg) was obtained by column chromatography (n-heptane: ethyl acetate = 1:1).
实施例10：化合物20c的合成Example 10: Synthesis of Compound 20c
Figure PCTCN2018076728-appb-000031
Figure PCTCN2018076728-appb-000031
根据实施例7的步骤11，只需用化合物10c代替化合物10a，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：1)目标产物20c(7mg)。According to the step 11 of Example 7, the compound 10c (7 mg) was obtained by column chromatography (n-heptane: ethyl acetate = 1:1).
实施例11：化合物20d的合成Example 11: Synthesis of Compound 20d
Figure PCTCN2018076728-appb-000032
Figure PCTCN2018076728-appb-000032
根据实施例7的步骤11，只需用化合物10d代替化合物10a，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：1)目标产物20d(8mg)。According to the step 11 of Example 7, only the compound 10d was used instead of the compound 10a, and the other conditions were unchanged, and the objective product was 20d (8 mg) by column chromatography (n-heptane: ethyl acetate = 1:1).
实施例12：化合物20e的合成Example 12: Synthesis of Compound 20e
Figure PCTCN2018076728-appb-000033
Figure PCTCN2018076728-appb-000033
根据实施例7的步骤11，只需用化合物10e代替化合物10a，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：1)目标产物20e(5mg)。According to the step 11 of Example 7, the compound 10e was used instead of the compound 10a, and the other conditions were unchanged, and the objective product 20e (5 mg) was subjected to column chromatography (n-heptane: ethyl acetate = 1:1).
实施例13：化合物20f的合成Example 13: Synthesis of Compound 20f
Figure PCTCN2018076728-appb-000034
Figure PCTCN2018076728-appb-000034
根据实施例7的步骤11，只需用化合物10f代替化合物10a，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：1)目标产物20f(10mg)。According to the step 11 of Example 7, the compound 10a was used instead of the compound 10a, and the other conditions were unchanged, and the objective product 20f (10 mg) was subjected to column chromatography (n-heptane: ethyl acetate = 1:1).
下面为30类化合物的合成：The following is the synthesis of 30 compounds:
实施例14：化合物30a的合成Example 14: Synthesis of Compound 30a
Figure PCTCN2018076728-appb-000035
Figure PCTCN2018076728-appb-000035
步骤21:Step 21:
Figure PCTCN2018076728-appb-000036
Figure PCTCN2018076728-appb-000036
将化合物21(1.5g)和化合物22(0.6g)溶于乙腈(20mL),然后将吡啶(1.5g)加入反应体系，将温度升至85度反应2h，反应体系加入乙酸乙酯(30mL),加水30(mL)，乙酸乙酯(3*20mL)萃取，无水硫酸钠干燥，将有机相旋干，粗品柱层析得化合物23(0.9g)。ESI-MS,(M+H＝367)Compound 21 (1.5 g) and compound 22 (0.6 g) were dissolved in acetonitrile (20 mL), then pyridine (1.5 g) was added to the reaction system, the temperature was raised to 85 °C for 2 h, and the reaction system was added ethyl acetate (30 mL). The mixture was extracted with EtOAc (3 mL). ESI-MS, (M+H=367)
步骤22：Step 22:
Figure PCTCN2018076728-appb-000037
Figure PCTCN2018076728-appb-000037
将化合物23(0.8g)，乙烯基硼酐吡啶盐(0.75g)和碳酸钾(1.8g)溶于二氧六环(5mL)和水(0.5mL)，然后将四三苯基膦钯(100mg)加入反应体系，将体系温度升至100度，氮气保护下反应8h，将反应体系加水(20mL),乙酸乙酯(3*30mL)萃取，无水硫酸钠干燥，将有机相旋干，粗品柱层析得化合物24(350mg),ESI-MS,(M+H＝315)Compound 23 (0.8 g), vinyl boron anhydride pyridinium salt (0.75 g) and potassium carbonate (1.8 g) were dissolved in dioxane (5 mL) and water (0.5 mL), then tetratriphenylphosphine palladium ( 100 mg) was added to the reaction system, the temperature of the system was raised to 100 °C, and the reaction was carried out for 8 h under nitrogen. The reaction mixture was added with water (20 mL), ethyl acetate (3*30 mL), and dried over anhydrous sodium sulfate. Crude column chromatography gave compound 24 (350 mg), ESI-MS, (M+H= 315)
步骤23:Step 23:
Figure PCTCN2018076728-appb-000038
Figure PCTCN2018076728-appb-000038
将化合物24(350mg)溶于二氯甲烷(800mL),将詹氏催化剂CAT-C(90mg)加入反应体系，30度反应36h，将水(600mL)加入反应体系,二氯甲烷(3*400mL)萃取，无水硫酸钠干燥，将有机相旋干，粗品经柱层析分离得黄色固体25(110mg)，ESI-MS,(M+H＝287)Compound 24 (350 mg) was dissolved in dichloromethane (800 mL), and Jane's catalyst CAT-C (90 mg) was added to the reaction system, reacted at 30 degrees for 36 h, and water (600 mL) was added to the reaction system, dichloromethane (3*400 mL). The extract is dried over anhydrous sodium sulfate, and the organic phase is evaporated to dryness.
步骤24：Step 24:
Figure PCTCN2018076728-appb-000039
Figure PCTCN2018076728-appb-000039
将化合物25(110mg)溶于四氢呋喃(2.4mL),水(0.6mL),甲醇(0.6mL),然后室温下将一水合氢氧化锂(83mg)加入反应体系，40度下反应5h，然后将体系pH值用1N盐酸调至3-4，乙酸乙酯(3*15mL)萃取，无水硫酸钠干燥，有机相旋干得黄色固体26(50mg)ESI-MS,(M+H＝273)。Compound 25 (110 mg) was dissolved in tetrahydrofuran (2.4 mL), water (0.6 mL), methanol (0.6 mL), then lithium hydroxide monohydrate (83 mg) was added to the reaction system at room temperature, and reacted at 40 ° for 5 h, then The pH of the system was adjusted to 3-4 with 1N hydrochloric acid, ethyl acetate (3*15 mL), and dried over anhydrous sodium sulfate. .
步骤25：Step 25:
Figure PCTCN2018076728-appb-000040
Figure PCTCN2018076728-appb-000040
将化合物26(50mg)，三乙胺(70mg)，3，4-二氟-1-苯胺(22mg)溶于二氯甲烷(3mL)中，然后将温度降至5度左右，然后将TBTU(70mg)加入反应体系，室温下反应12h,加水(15mL),二氯甲烷(3*20mL)萃取，无水硫酸钠干燥，将有机相旋干，粗品经柱层析(正庚烷：乙酸乙酯＝1：1)得化合物30a(12mg)。Compound 26 (50 mg), triethylamine (70 mg), 3,4-difluoro-1-aniline (22 mg) was dissolved in dichloromethane (3 mL), then the temperature was reduced to about 5 deg. 70 mg) was added to the reaction system, and the reaction was carried out for 12 h at room temperature. Water (15 mL), dichloromethane (3*20 mL) was evaporated. Ester = 1:1) gave compound 30a (12 mg).
实施例15：化合物30b的合成Example 15: Synthesis of Compound 30b
Figure PCTCN2018076728-appb-000041
Figure PCTCN2018076728-appb-000041
化合物26b的制法参照实施例13的步骤21-24，不同点在于步骤21中用1-烯丙基-1-环丙基肼代替1-烯丙基-1-甲基肼。The preparation of the compound 26b was carried out by referring to the step 21-24 of Example 13, except that the 1-allyl-1-cyclopropyl hydrazine was replaced by 1-allyl-1-cyclopropyl hydrazine in the step 21.
根据实施例13的步骤25，只需用化合物26b代替化合物26，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：1)目标产物30b(9mg)。According to the step 25 of Example 13, the compound 26b was used instead of the compound 26, and the other conditions were unchanged, and the objective product 30b (9 mg) was subjected to column chromatography (n-heptane: ethyl acetate = 1:1).
实施例16：化合物30c的合成Example 16: Synthesis of Compound 30c
Figure PCTCN2018076728-appb-000042
Figure PCTCN2018076728-appb-000042
化合物26c的制法参照实施例13的步骤21-24，不同点在于步骤21中用1-烯丙基-1-异丙基肼代替1-烯丙基-1-甲基肼。The procedure for the preparation of the compound 26c is as shown in Step 21-24 of Example 13, except that in Step 21, 1-allyl-1-isopropylindole was used instead of 1-allyl-1-methylindole.
根据实施例13的步骤25，只需用化合物26c代替化合物26，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：1)目标产物30c(6mg)。According to the step 25 of Example 13, the compound 26c was used instead of the compound 26, and the other conditions were unchanged, and the objective product 30c (6 mg) was subjected to column chromatography (n-heptane: ethyl acetate = 1:1).
实施例17：化合物30d的合成Example 17: Synthesis of Compound 30d
Figure PCTCN2018076728-appb-000043
Figure PCTCN2018076728-appb-000043
化合物26d的制法参照实施例13的步骤21-24，不同点在于步骤21中用1-(1-烯丙基肼基)乙醇代替1-烯丙基-1-甲基肼。The compound 26d was prepared by referring to Step 21-24 of Example 13, except that in Step 21, 1-(1-allylhydrazo)ethanol was used instead of 1-allyl-1-methyloxime.
根据实施例13的步骤25，只需用化合物26d代替化合物26，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：1)目标产物30d(6mg)。According to the step 25 of Example 13, only the compound 26d was used instead of the compound 26, and the other conditions were unchanged, and the objective product was 30d (6 mg) by column chromatography (n-heptane: ethyl acetate = 1:1).
实施例18：化合物30e的合成Example 18: Synthesis of Compound 30e
Figure PCTCN2018076728-appb-000044
Figure PCTCN2018076728-appb-000044
化合物26e的制法参照实施例13的步骤21-24，不同点在于步骤21中用1-烯丙基-1-异丙基肼代替1-烯丙基-1-甲基肼。The preparation of the compound 26e was carried out by referring to the step 21-24 of Example 13, except that the 1-allyl-1-isopropylindole was replaced with 1-allyl-1-isopropylindole in the step 21.
根据实施例13的步骤25，只需用化合物26e代替化合物26，用3-氯-4-氟-1-苯胺取代3,4-二氟-1-苯胺，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：1)目标产物30e(11mg)。According to the step 25 of the embodiment 13, it is only necessary to replace the compound 26 with the compound 26e, and to replace the 3,4-difluoro-1-aniline with 3-chloro-4-fluoro-1-aniline. (n-heptane: ethyl acetate = 1:1) title product 30e (11 mg).
实施例19：化合物30f的合成Example 19: Synthesis of Compound 30f
Figure PCTCN2018076728-appb-000045
Figure PCTCN2018076728-appb-000045
化合物26f的制法参照实施例13的步骤21-24，不同点在于步骤21中用1-烯丙基-1-异丙基肼代替1-烯丙基-1-甲基肼。The preparation of the compound 26f was carried out by referring to the step 21-24 of Example 13, except that the 1-allyl-1-isopropylindole was replaced with 1-allyl-1-isopropylindole in the step 21.
根据实施例13的步骤25，只需用化合物26f代替化合物26，用3-氰基-4-氟-1-苯胺取代3,4-二氟-1-苯胺，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝2：1)目标产物30f(8mg)。According to the step 25 of the embodiment 13, it is only necessary to replace the compound 26 with the compound 26f, and to replace the 3,4-difluoro-1-aniline with 3-cyano-4-fluoro-1-aniline, and the other conditions are unchanged. The title product 30f (8 mg) was obtained (n-heptane: ethyl acetate = 2:1).
下面为40类化合物的合成：The following is the synthesis of 40 compounds:
实施例20：化合物40a的合成Example 20: Synthesis of Compound 40a
Figure PCTCN2018076728-appb-000046
Figure PCTCN2018076728-appb-000046
步骤31：Step 31:
将化合物30a(20mg)溶于乙酸乙酯(2mL),然后将湿钯碳(5mg)加入反应体系，25度,在氢气环境下反应3h，反应液抽滤，旋干柱层析(正庚烷：乙酸乙酯＝1：1)目标产物30a(7mg)。The compound 30a (20 mg) was dissolved in ethyl acetate (2 mL), then wet palladium carbon (5 mg) was added to the reaction system at 25 ° C, and reacted under a hydrogen atmosphere for 3 h. Alkane: ethyl acetate = 1:1) target product 30a (7 mg).
实施例21：化合物40b的合成Example 21: Synthesis of Compound 40b
Figure PCTCN2018076728-appb-000047
Figure PCTCN2018076728-appb-000047
根据实施例19的步骤31，只需用化合物30b代替化合物30a，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：1)目标产物40b(6mg)。According to the step 31 of Example 19, the compound 30b (6 mg) was obtained by column chromatography (n-heptane: ethyl acetate = 1:1).
实施例22：化合物40c的合成Example 22: Synthesis of Compound 40c
Figure PCTCN2018076728-appb-000048
Figure PCTCN2018076728-appb-000048
根据实施例19的步骤31，只需用化合物30c代替化合物30a，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：1)目标产物40c(7mg)。According to the step 31 of Example 19, the compound 30c (7 mg) was obtained by column chromatography (n-heptane: ethyl acetate = 1:1).
实施例23：化合物40d的合成Example 23: Synthesis of Compound 40d
Figure PCTCN2018076728-appb-000049
Figure PCTCN2018076728-appb-000049
根据实施例19的步骤31，只需用化合物30d代替化合物30a，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：1)目标产物40d(8mg)。According to the step 31 of Example 19, the compound 30d was used instead of the compound 30a, and the other conditions were unchanged, and the objective product was 40d (8 mg) by column chromatography (n-heptane: ethyl acetate = 1:1).
实施例24：化合物40e的合成Example 24: Synthesis of Compound 40e
Figure PCTCN2018076728-appb-000050
Figure PCTCN2018076728-appb-000050
根据实施例19的步骤31，只需用化合物30e代替化合物30a，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：1)目标产物40e(5mg)。According to the step 31 of Example 19, the compound 30e was replaced with the compound 30e, and the other conditions were unchanged, and the objective product 40e (5 mg) was subjected to column chromatography (n-heptane: ethyl acetate = 1:1).
实施例25：化合物40f的合成Example 25: Synthesis of Compound 40f
Figure PCTCN2018076728-appb-000051
Figure PCTCN2018076728-appb-000051
根据实施例19的步骤31，只需用化合物30f代替化合物30a，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：1)目标产物40f(10mg)。According to the step 31 of Example 19, the compound 30f was used instead of the compound 30a, and the other conditions were unchanged, and the objective product 40f (10 mg) was subjected to column chromatography (n-heptane: ethyl acetate = 1:1).
下面为50类化合物的合成：The following is the synthesis of 50 compounds:
实施例26：化合物50a的合成Example 26: Synthesis of Compound 50a
Figure PCTCN2018076728-appb-000052
Figure PCTCN2018076728-appb-000052
步骤41:Step 41:
Figure PCTCN2018076728-appb-000053
Figure PCTCN2018076728-appb-000053
将化合物41(0.5g)和化合物42(0.2g)溶于乙腈(20mL),然后将吡啶(0.5g)加入反应体系，将温度升至85度反应2h，反应体系加入乙酸乙酯(30mL),加水30(mL)，乙酸乙酯 (3*20mL)萃取，无水硫酸钠干燥，将有机相旋干，粗品柱层析得化合物43(0.2g)。ESI-MS,(M+H＝410)Compound 41 (0.5g) and compound 42 (0.2g) were dissolved in acetonitrile (20mL), then pyridine (0.5g) was added to the reaction system, the temperature was raised to 85 degrees for 2h, and the reaction system was added with ethyl acetate (30mL) The mixture was extracted with EtOAc (3 mL). ESI-MS, (M+H=410)
步骤42：Step 42:
Figure PCTCN2018076728-appb-000054
Figure PCTCN2018076728-appb-000054
将化合物43(0.2g)溶于四氢呋喃(2.5mL),水(0.8mL),甲醇(0.8mL),然后室温下将一水合氢氧化锂(100mg)加入反应体系，40度下反应5h，然后将体系pH值用1N盐酸调至3-4，乙酸乙酯(3*15mL)萃取，无水硫酸钠干燥，有机相旋干得黄色固体44(80mg)ESI-MS,(M+H＝396)Compound 43 (0.2 g) was dissolved in tetrahydrofuran (2.5 mL), water (0.8 mL), methanol (0.8 mL), then lithium hydroxide monohydrate (100 mg) was added to the reaction system at room temperature, and reacted at 40 ° for 5 h, then The pH of the system was adjusted to 3-4 with 1N EtOAc (EtOAc) (EtOAc (EtOAc) )
步骤43：Step 43:
Figure PCTCN2018076728-appb-000055
Figure PCTCN2018076728-appb-000055
将化合物44(80mg)，三乙胺(80mg)，3，4-二氟-1-苯胺(32mg)溶于二氯甲烷(3mL)中，然后将温度降至5度左右，然后将TBTU(90mg)加入反应体系，室温下反应12h,加水(15mL),二氯甲烷(3*20mL)萃取，无水硫酸钠干燥，将有机相旋干，粗品经柱层析得化合物45(30mg)，ESI-MS,(M+H＝514)Compound 44 (80 mg), triethylamine (80 mg), 3,4-difluoro-1-aniline (32 mg) was dissolved in dichloromethane (3 mL), then the temperature was reduced to about 5 deg. 90 mg) was added to the reaction system, and the reaction was carried out for 12 h at room temperature, and then added with water (15 mL), dichloromethane (3*20 mL), and dried over anhydrous sodium sulfate. ESI-MS, (M+H=514)
步骤44：Step 44:
Figure PCTCN2018076728-appb-000056
Figure PCTCN2018076728-appb-000056
将化合物45(30mg)溶于二氯甲烷(1mL)中，然后将4N盐酸(1mL)，室温下反应2h,将二氯甲烷旋干，粗品经柱层析(石油醚：乙酸乙酯＝1:2)得化合物50a(10mg)The compound 45 (30 mg) was dissolved in dichloromethane (1 mL), then 4N hydrochloric acid (1 mL). : 2) Compound 50a (10mg)
实施例27：化合物50b的合成Example 27: Synthesis of Compound 50b
Figure PCTCN2018076728-appb-000057
Figure PCTCN2018076728-appb-000057
化合物45b的制法参照实施例25的步骤41-43，不同点在于步骤41中用1-叔丁氧羰基-1-三氟异丙基肼代替1-叔丁氧羰基-1-异丙基肼。The preparation of the compound 45b is carried out by referring to the steps 41-43 of Example 25, except that in the step 41, 1-tert-butoxycarbonyl-1-trifluoroisopropyl hydrazine is used in place of 1-tert-butoxycarbonyl-1-isopropyl group. Hey.
根据实施例25的步骤44，只需用化合物45b代替化合物45，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：2)目标产物50b(9mg)。According to the step 44 of Example 25, the compound 45b was used instead of the compound 45, and the other conditions were unchanged, and the objective product 50b (9 mg) was subjected to column chromatography (n-heptane: ethyl acetate = 1:2).
实施例28：化合物50c的合成Example 28: Synthesis of Compound 50c
Figure PCTCN2018076728-appb-000058
Figure PCTCN2018076728-appb-000058
化合物45c的制法参照实施例25的步骤41-43，不同点在于步骤41中用1-叔丁氧羰基-1-叔丁基肼代替1-叔丁氧羰基-1-异丙基肼。The compound 45c was prepared by following the procedure of Steps 41 to 43 of Example 25 except that 1-tert-butoxycarbonyl-1-tert-butylindole was used in place of 1-tert-butoxycarbonyl-1-isopropylindole.
根据实施例25的步骤44，只需用化合物45c代替化合物45，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：2)目标产物50c(4mg)。According to the step 44 of Example 25, the compound 45c was used instead of the compound 45, and the other conditions were unchanged, and the objective product 50c (4 mg) was obtained by column chromatography (n-heptane: ethyl acetate = 1:2).
实施例29：化合物50d的合成Example 29: Synthesis of Compound 50d
Figure PCTCN2018076728-appb-000059
Figure PCTCN2018076728-appb-000059
化合物45d的制法参照实施例25的步骤41-43，不同点在于步骤41中用1-叔丁氧羰基-1-羟基异丙基肼代替1-叔丁氧羰基-1-异丙基肼。The preparation of the compound 45d is carried out by referring to the steps 41-43 of Example 25, except that in the step 41, 1-tert-butoxycarbonyl-1-hydroxyisopropyl hydrazine is used instead of 1-tert-butoxycarbonyl-1-isopropyl hydrazine. .
根据实施例25的步骤44，只需用化合物45d代替化合物45，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：1)目标产物50d(10mg)。According to the step 44 of Example 25, the compound 45d was used instead of the compound 45, and the other conditions were unchanged, and the aimed product (n-heptane: ethyl acetate = 1:1) was afforded 50d (10 mg).
实施例30：化合物50e的合成Example 30: Synthesis of Compound 50e
Figure PCTCN2018076728-appb-000060
Figure PCTCN2018076728-appb-000060
化合物45e的制法参照实施例25的步骤41-43，不同点在于步骤41中用1-叔丁氧羰基-1-三氟异丙基肼代替1-叔丁氧羰基-1-异丙基肼。The preparation of compound 45e is carried out by referring to steps 41-43 of Example 25, except that in step 41, 1-tert-butoxycarbonyl-1-trifluoroisopropyl hydrazine is used in place of 1-tert-butoxycarbonyl-1-isopropyl group. Hey.
根据实施例25的步骤44，只需用化合物45e代替化合物45，用3-氯-4-氟-1-苯胺取代3,4-二氟-1-苯胺，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：1)目标产物50e(11mg)。According to the step 44 of Example 25, the compound 45e is used instead of the compound 45, and the 3-chloro-4-fluoro-1-aniline is substituted for the 3,4-difluoro-1-aniline. (n-heptane: ethyl acetate = 1:1) title product 50e (11 mg).
实施例31：化合物50f的合成Example 31: Synthesis of Compound 50f
Figure PCTCN2018076728-appb-000061
Figure PCTCN2018076728-appb-000061
化合物45f的制法参照实施例25的步骤41-43，不同点在于步骤41中用1-叔丁氧羰基-1-三氟异丙基肼代替1-叔丁氧羰基-1-异丙基肼。The preparation of the compound 45f is carried out by referring to the steps 41-43 of Example 25, except that in the step 41, 1-tert-butoxycarbonyl-1-trifluoroisopropyl hydrazine is used in place of 1-tert-butoxycarbonyl-1-isopropyl group. Hey.
根据实施例25的步骤44，只需用化合物45f代替化合物45，用3-氰基-4-氟-1-苯胺取代3,4-二氟-1-苯胺，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：1)目标产物50f(13mg)。According to the step 44 of Example 25, the compound 45f is used instead of the compound 45, and the 3-cyano-4-fluoro-1-aniline is substituted for the 3,4-difluoro-1-aniline. The title product 50f (13 mg) was obtained (n-heptane: ethyl acetate = 1:1).
下面为60类化合物的合成：The following is the synthesis of 60 compounds:
实施例32：化合物60a的合成Example 32: Synthesis of Compound 60a
Figure PCTCN2018076728-appb-000062
Figure PCTCN2018076728-appb-000062
步骤51:Step 51:
Figure PCTCN2018076728-appb-000063
Figure PCTCN2018076728-appb-000063
将化合物51(0.5g)和化合物52(0.2g)溶于乙腈(20mL),然后将吡啶(0.5g)加入反应体系，将温度升至85度反应2h，反应体系加入乙酸乙酯(30mL),加水30(mL)，乙酸乙酯(3*20mL)萃取，无水硫酸钠干燥，将有机相旋干，粗品柱层析得化合物53(0.2g)。ESI-MS,(M+H＝411)Compound 51 (0.5g) and compound 52 (0.2g) were dissolved in acetonitrile (20mL), then pyridine (0.5g) was added to the reaction system, the temperature was raised to 85 degrees for 2h, and the reaction system was added with ethyl acetate (30mL) The mixture was extracted with EtOAc (3 mL). ESI-MS, (M+H=411)
步骤52：Step 52:
Figure PCTCN2018076728-appb-000064
Figure PCTCN2018076728-appb-000064
将化合物53(0.2g)溶于四氢呋喃(2.5mL),水(0.8mL),甲醇(0.8mL),然后室温下将一水合氢氧化锂(100mg)加入反应体系，40度下反应5h，然后将体系pH值用1N盐酸调至3-4，乙酸乙酯(3*15mL)萃取，无水硫酸钠干燥，有机相旋干得黄色固体54(80mg)ESI-MS,(M+H＝397)Compound 53 (0.2 g) was dissolved in tetrahydrofuran (2.5 mL), water (0.8 mL), methanol (0.8 mL), then lithium hydroxide monohydrate (100 mg) was added to the reaction system at room temperature, and reacted at 40 ° for 5 h, then The pH of the system was adjusted to 3-4 with EtOAc (EtOAc) (EtOAc) (EtOAc) )
步骤53：Step 53:
Figure PCTCN2018076728-appb-000065
Figure PCTCN2018076728-appb-000065
将化合物54(80mg)，三乙胺(80mg)，3，4-二氟-1-苯胺(32mg)溶于二氯甲烷(3mL)中，然后将温度降至5度左右，然后将TBTU(90mg)加入反应体系，室温下反应12h,加水(15mL),二氯甲烷(3*20mL)萃取，无水硫酸钠干燥，将有机相旋干，粗品经柱层析得化合物55(30mg)ESI-MS,(M+H＝515)Compound 54 (80 mg), triethylamine (80 mg), 3,4-difluoro-1-aniline (32 mg) was dissolved in dichloromethane (3 mL), then the temperature was reduced to about 5 deg. 90 mg) was added to the reaction system, and the reaction was carried out at room temperature for 12 h, then water (15 mL), dichloromethane (3*20 mL) -MS, (M+H=515)
步骤54：Step 54:
Figure PCTCN2018076728-appb-000066
Figure PCTCN2018076728-appb-000066
将化合物55(30mg)溶于二氯甲烷(1mL)中，然后将4N盐酸(1mL)，室温下反应2h,将二氯甲烷旋干，粗品经柱层析(石油醚：乙酸乙酯＝1:2)得化合物60a(10mg)The compound 55 (30 mg) was dissolved in dichloromethane (1 mL), then 4N hydrochloric acid (1 mL). : 2) Compound 60a (10mg)
实施例33：化合物60b的合成Example 33: Synthesis of Compound 60b
Figure PCTCN2018076728-appb-000067
Figure PCTCN2018076728-appb-000067
化合物55b的制法参照实施例31的步骤51-53，不同点在于步骤51中用1-叔丁氧羰基-1-三氟异丙基肼代替1-叔丁氧羰基-1-异丙基肼。The preparation of the compound 55b is carried out by referring to the steps 51-53 of Example 31 except that 1-tert-butoxycarbonyl-1-trifluoroisopropyl hydrazine is substituted for 1-tert-butoxycarbonyl-1-isopropyl group in the step 51. Hey.
根据实施例31的步骤54，只需用化合物55b代替化合物55，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：2)目标产物60b(9mg)。According to the step 54 of Example 31, the compound 55b (yield: n-heptane: ethyl acetate = 1:2) was obtained by column chromatography (n-heptane: ethyl acetate = 1:2).
实施例34：化合物60c的合成Example 34: Synthesis of Compound 60c
Figure PCTCN2018076728-appb-000068
Figure PCTCN2018076728-appb-000068
化合物55c的制法参照实施例31的步骤51-53，不同点在于步骤51中用1-叔丁氧羰基-1-叔丁基肼代替1-叔丁氧羰基-1-异丙基肼。The compound 55c was prepared by referring to the procedures 51-53 of Example 31 except that 1-tert-butoxycarbonyl-1-tert-butylindole was used in the step 51 instead of 1-tert-butoxycarbonyl-1-isopropylindole.
根据实施例31的步骤54，只需用化合物55c代替化合物55，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：2)目标产物60c(7mg)。According to the step 54 of Example 31, the compound 55c (7 mg) was obtained by column chromatography (n-heptane: ethyl acetate = 1:2).
实施例35：化合物60d的合成Example 35: Synthesis of Compound 60d
Figure PCTCN2018076728-appb-000069
Figure PCTCN2018076728-appb-000069
化合物55d的制法参照实施例31的步骤51-53，不同点在于步骤41中用1-叔丁氧羰基-1-羟基异丙基肼代替1-叔丁氧羰基-1-异丙基肼。The preparation of the compound 55d is carried out by referring to the steps 51-53 of Example 31, except that in the step 41, 1-tert-butoxycarbonyl-1-hydroxyisopropyl hydrazine is used in place of 1-tert-butoxycarbonyl-1-isopropyl hydrazine. .
根据实施例31的步骤54，只需用化合物55d代替化合物55，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：1)目标产物60d(11mg)。According to the step 54 of Example 31, the compound 55d was used instead of the compound 55, and the other conditions were unchanged. Column chromatography (n-heptane: ethyl acetate = 1:1).
实施例36：化合物60e的合成Example 36: Synthesis of Compound 60e
Figure PCTCN2018076728-appb-000070
Figure PCTCN2018076728-appb-000070
化合物55e的制法参照实施例31的步骤51-53，不同点在于步骤51中用1-叔丁氧羰基-1-三氟异丙基肼代替1-叔丁氧羰基-1-异丙基肼。The preparation of the compound 55e is carried out by referring to the steps 51-53 of Example 31, except that in the step 51, 1-tert-butoxycarbonyl-1-trifluoroisopropyl hydrazine is used in place of 1-tert-butoxycarbonyl-1-isopropyl group. Hey.
根据实施例31的步骤54，只需用化合物55e代替化合物55，用3-氯-4-氟-1-苯胺取代3,4-二氟-1-苯胺，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：1)目标产物60e(10mg)。According to the step 54 of Example 31, the compound 55e is used instead of the compound 55, and the 3-chloro-4-fluoro-1-aniline is substituted for the 3,4-difluoro-1-aniline. (n-heptane: ethyl acetate = 1:1) title product 60e (10 mg).
实施例37：化合物60f的合成Example 37: Synthesis of Compound 60f
Figure PCTCN2018076728-appb-000071
Figure PCTCN2018076728-appb-000071
化合物55f的制法参照实施例31的步骤51-53，不同点在于步骤51中用1-叔丁氧羰基-1-三氟异丙基肼代替1-叔丁氧羰基-1-异丙基肼。The preparation of the compound 55f is carried out by referring to the steps 51-53 of Example 31 except that 1-tert-butoxycarbonyl-1-trifluoroisopropyl hydrazine is substituted for 1-tert-butoxycarbonyl-1-isopropyl group in the step 51. Hey.
根据实施例31的步骤54，只需用化合物55f代替化合物55，用3-氰基-4-氟-1-苯胺取代3,4-二氟-1-苯胺，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：1)目标产物60f(9mg)。According to the step 54 of Example 31, it is only necessary to replace the compound 55 with the compound 55f, and to replace the 3,4-difluoro-1-aniline with 3-cyano-4-fluoro-1-aniline, and the other conditions are unchanged. The title product 60f (9 mg) was obtained (n-heptane: ethyl acetate = 1:1).
下面为70类化合物的合成：The following is the synthesis of 70 compounds:
实施例38：化合物70a的合成Example 38: Synthesis of Compound 70a
Figure PCTCN2018076728-appb-000072
Figure PCTCN2018076728-appb-000072
步骤61:Step 61:
Figure PCTCN2018076728-appb-000073
Figure PCTCN2018076728-appb-000073
A)将化合物61(300mg)溶于浓盐酸(1.35mL),降温至-5度，搅拌均匀，然后将亚硝酸钠(100mg)的水溶液滴加入反应体系，搅拌0.5h。A) Compound 61 (300 mg) was dissolved in concentrated hydrochloric acid (1.35 mL), cooled to -5, and stirred well. Then, aqueous solution of sodium nitrite (100 mg) was added dropwise to the reaction system and stirred for 0.5 h.
B)将二氯化锡(729mg)溶于浓盐酸，搅拌溶解降至0度。B) Dissolving tin dichloride (729 mg) in concentrated hydrochloric acid and stirring to reduce it to 0 degree.
C)将反应液A)滴入反应液B)中，将反应体系控制0度左右，滴完后0度反应0.5h。C) The reaction solution A) is dropped into the reaction liquid B), and the reaction system is controlled to about 0 degree, and after the completion of the dropwise addition, the reaction is carried out at 0 degree for 0.5 hour.
将水(15mL)加入反应体系，乙酸乙酯(3*20mL)萃取，干燥旋干得黄色固体62(250mg)直接进行下下一步反应。ESI-MS,(M+H＝204)Water (15 mL) was added to the reaction mixture, and ethyl acetate (3*20 mL) was evaporated. ESI-MS, (M+H=204)
步骤62：Step 62:
Figure PCTCN2018076728-appb-000074
Figure PCTCN2018076728-appb-000074
将粗品62(250mg)和异丙基恶唑烷酮(200mg)溶于乙腈(5mL)中，然后将三乙胺(400mg)加入反应体系，将体系温度升至85度，反应8h,将反应体系加入水(10mL)，乙酸乙酯(3*20mL)萃取，无水硫酸钠干燥，将有机相旋干，粗品经柱层析得白色固体(200mg)ESI-MS,(M+H＝325)The crude product 62 (250 mg) and isopropyl oxazolidinone (200 mg) were dissolved in acetonitrile (5 mL), then triethylamine (400 mg) was added to the reaction system, the temperature of the system was raised to 85 degrees, and the reaction was carried out for 8 hours. The system was added with water (10 mL), EtOAc (EtOAc) (EtOAc m. )
步骤63：Step 63:
Figure PCTCN2018076728-appb-000075
Figure PCTCN2018076728-appb-000075
将化合物63(0.2g)溶于四氢呋喃(4mL),水(1mL),甲醇(1mL),然后室温下将一水合氢氧化锂(150mg)加入反应体系，40度下反应5h，然后将体系pH值用1N盐酸调至3-4，乙酸乙酯(3*15mL)萃取，无水硫酸钠干燥，有机相旋干得黄色固体64(80mg)ESI-MS,(M+H＝311)Compound 63 (0.2 g) was dissolved in tetrahydrofuran (4 mL), water (1 mL), methanol (1 mL), then lithium hydroxide monohydrate (150 mg) was added to the reaction system at room temperature, reacted at 40 ° for 5 h, then the pH of the system was The value was adjusted to 3-4 with EtOAc (EtOAc) (EtOAc) (EtOAc)
步骤64：Step 64:
Figure PCTCN2018076728-appb-000076
Figure PCTCN2018076728-appb-000076
将化合物64(90mg)，三乙胺(80mg)，3，4-二氟-1-苯胺(32mg)溶于二氯甲烷(3mL)中，然后将温度降至5度左右，然后将TBTU(90mg)加入反应体系，室温下反应12h,加水(15mL),二氯甲烷(3*20mL)萃取，无水硫酸钠干燥，将有机相旋干，粗品经柱层析(石油醚：乙酸乙酯＝1:3)得化合物70a(10mg)Compound 64 (90 mg), triethylamine (80 mg), 3,4-difluoro-1-aniline (32 mg) was dissolved in dichloromethane (3 mL), then the temperature was reduced to about 5 deg. 90 mg) was added to the reaction system, and the reaction was carried out for 12 h at room temperature, then water (15 mL), dichloromethane (3*20 mL) =1:3) Compound 70a (10 mg)
实施例39：化合物70b的合成Example 39: Synthesis of Compound 70b
Figure PCTCN2018076728-appb-000077
Figure PCTCN2018076728-appb-000077
化合物64b的制法参照实施例38的步骤61-63，不同点在于步骤62中用三氟异丙基恶唑烷酮代替异丙基恶唑烷酮。The procedure for the preparation of compound 64b is as described in steps 61-63 of Example 38, except that in step 62, trifluoroisopropyloxazolidinone is used in place of isopropyloxazolidinone.
根据实施例38的步骤64，只需用化合物64b代替化合物64，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：3)目标产物70b(5mg)。According to the step 64 of Example 38, the compound 64b was used instead of the compound 64, and the other conditions were unchanged, and the objective product 70b (5 mg) was subjected to column chromatography (n-heptane: ethyl acetate = 1:3).
实施例40：化合物70c的合成Example 40: Synthesis of Compound 70c
Figure PCTCN2018076728-appb-000078
Figure PCTCN2018076728-appb-000078
化合物64c的制法参照实施例38的步骤61-63，不同点在于步骤62中用叔丁基恶唑烷酮代替异丙基恶唑烷酮。Compound 64c was prepared as described in steps 61-63 of Example 38, except that in step 62, t-butyloxazolidinone was used in place of isopropyloxazolidinone.
根据实施例38的步骤64，只需用化合物64c代替化合物64，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：3)目标产物70c(6mg)。According to the step 64 of Example 38, the compound 64c was used instead of the compound 64, and the other conditions were unchanged, and the objective product 70c (6 mg) was subjected to column chromatography (n-heptane: ethyl acetate = 1:3).
实施例41：化合物70d的合成Example 41: Synthesis of Compound 70d
Figure PCTCN2018076728-appb-000079
Figure PCTCN2018076728-appb-000079
化合物64d的制法参照实施例38的步骤61-63，不同点在于步骤62中用羟基异丙基恶唑烷酮代替异丙基恶唑烷酮。The procedure for the preparation of compound 64d is as described in Steps 61-63 of Example 38, except that in step 62, hydroxyisopropyloxazolidinone is used in place of isopropyloxazolidinone.
根据实施例38的步骤64，只需用化合物64d代替化合物64，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：3)目标产物70d(5mg)。According to the step 64 of Example 38, the compound 64d was used instead of the compound 64, and the other conditions were unchanged. Column chromatography (n-heptane: ethyl acetate = 1:3) of the desired product 70d (5 mg).
实施例42：化合物70e的合成Example 42: Synthesis of Compound 70e
Figure PCTCN2018076728-appb-000080
Figure PCTCN2018076728-appb-000080
化合物64e的制法参照实施例38的步骤61-63，不同点在于步骤62中用三氟异丙基恶唑烷酮代替异丙基恶唑烷酮。The procedure for the preparation of compound 64e is as described in steps 61-63 of Example 38, except that in step 62, trifluoroisopropyloxazolidinone is used in place of isopropyloxazolidinone.
根据实施例38的步骤64，只需用化合物64e代替化合物64，用3-氯-4-氟-1-苯胺取代3,4-二氟-1-苯胺，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：3)目标产物70e(8mg)。According to the step 64 of Example 38, it is only necessary to replace the compound 64 with the compound 64e, and to replace the 3,4-difluoro-1-aniline with 3-chloro-4-fluoro-1-aniline. (n-heptane: ethyl acetate = 1:3) title product 70e (8 mg).
实施例43：化合物70f的合成Example 43: Synthesis of Compound 70f
Figure PCTCN2018076728-appb-000081
Figure PCTCN2018076728-appb-000081
化合物64f的制法参照实施例38的步骤61-63，不同点在于步骤61中用三氟异丙基恶唑烷酮代替异丙基恶唑烷酮。The procedure for the preparation of compound 64f is as described in Steps 61-63 of Example 38, except that in step 61, trifluoroisopropyloxazolidinone is used in place of isopropyloxazolidinone.
根据实施例38的步骤64，只需用化合物64f代替化合物64，用3-氰基-4-氟-1-苯胺取代3,4-二氟-1-苯胺，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：3)目标产物70f(11mg)。According to the step 64 of Example 38, it is only necessary to replace the compound 64 with the compound 64f, and to replace the 3,4-difluoro-1-aniline with 3-cyano-4-fluoro-1-aniline, and the other conditions are unchanged. The title product 70f (11 mg) was obtained (n-heptane: ethyl acetate = 1:3).
下面为80类化合物的合成：The following is the synthesis of 80 compounds:
实施例44：化合物80a的合成Example 44: Synthesis of Compound 80a
Figure PCTCN2018076728-appb-000082
Figure PCTCN2018076728-appb-000082
步骤71:Step 71:
Figure PCTCN2018076728-appb-000083
Figure PCTCN2018076728-appb-000083
D)将化合物71(300mg)溶于浓盐酸(1.35mL),降温至-5度，搅拌均匀，然后将亚硝酸钠(100mg)的水溶液滴加入反应体系，搅拌0.5h。D) Compound 71 (300 mg) was dissolved in concentrated hydrochloric acid (1.35 mL), cooled to -5, and stirred, and then aqueous solution of sodium nitrite (100 mg) was added dropwise to the reaction system and stirred for 0.5 h.
E)将二氯化锡(729mg)溶于浓盐酸，搅拌溶解降至0度。E) Dissolving tin dichloride (729 mg) in concentrated hydrochloric acid and stirring to reduce it to 0 degree.
F)将反应液A)滴入反应液B)中，将反应体系控制0度左右，滴完后0度反应0.5h。F) The reaction solution A) was dropped into the reaction liquid B), and the reaction system was controlled to about 0 degree, and the reaction was carried out at 0 degree for 0.5 hour after the completion of the dropwise addition.
将水(15mL)加入反应体系，乙酸乙酯(3*20mL)萃取，干燥旋干得黄色固体72(250mg)直接进行下下一步反应。ESI-MS,(M+H＝205)Water (15 mL) was added to the reaction mixture, and ethyl acetate (3*20 mL) was evaporated. ESI-MS, (M+H=205)
步骤72：Step 72:
Figure PCTCN2018076728-appb-000084
Figure PCTCN2018076728-appb-000084
将粗品72(250mg)和异丙基恶唑烷酮(200mg)溶于乙腈(5mL)中，然后将三乙胺(400mg)加入反应体系，将体系温度升至85度，反应8h,将反应体系加入水(10mL)，乙酸乙酯(3*20mL)萃取，无水硫酸钠干燥，将有机相旋干，粗品经柱层析得白色固体(200mg)ESI-MS,(M+H＝326)The crude product 72 (250 mg) and isopropyloxazolidinone (200 mg) were dissolved in acetonitrile (5 mL), then triethylamine (400 mg) was added to the reaction system, the temperature of the system was raised to 85 degrees, and the reaction was carried out for 8 hours. The system was added with water (10 mL), EtOAc (EtOAc) (EtOAc) )
步骤73：Step 73:
Figure PCTCN2018076728-appb-000085
Figure PCTCN2018076728-appb-000085
将化合物73(0.2g)溶于四氢呋喃(4mL),水(1mL),甲醇(1mL),然后室温下将一水合氢氧化锂(150mg)加入反应体系，40度下反应5h，然后将体系pH值用1N盐酸调至3-4，乙酸乙酯(3*15mL)萃取，无水硫酸钠干燥，有机相旋干得黄色固体74(80mg)ESI-MS,(M+H＝312)Compound 73 (0.2 g) was dissolved in tetrahydrofuran (4 mL), water (1 mL), methanol (1 mL), then lithium hydroxide monohydrate (150 mg) was added to the reaction system at room temperature, reacted at 40 °C for 5 h, then the pH of the system was The value was adjusted to 3-4 with EtOAc (EtOAc) (EtOAc (EtOAc)
步骤74：Step 74:
Figure PCTCN2018076728-appb-000086
Figure PCTCN2018076728-appb-000086
将化合物74(90mg)，三乙胺(80mg)，3，4-二氟-1-苯胺(32mg)溶于二氯甲烷(3mL)中，然后将温度降至5度左右，然后将TBTU(90mg)加入反应体系，室温下反应12h,加水(15mL),二氯甲烷(3*20mL)萃取，无水硫酸钠干燥，将有机相旋干，粗品经柱层析(石油醚：乙酸乙酯＝1:3)得化合物80a(10mg)Compound 74 (90 mg), triethylamine (80 mg), 3,4-difluoro-1-aniline (32 mg) was dissolved in dichloromethane (3 mL), then the temperature was reduced to about 5 deg. 90 mg) was added to the reaction system, and the reaction was carried out for 12 h at room temperature, then water (15 mL), dichloromethane (3*20 mL) =1:3) Compound 80a (10 mg)
实施例45：化合物80b的合成Example 45: Synthesis of Compound 80b
Figure PCTCN2018076728-appb-000087
Figure PCTCN2018076728-appb-000087
化合物74b的制法参照实施例44的步骤71-73，不同点在于步骤72中用三氟异丙基恶唑烷酮代替异丙基恶唑烷酮。The preparation of compound 74b is carried out by reference to steps 71-73 of Example 44, except that in step 72, trifluoroisopropyloxazolidinone is used in place of isopropyloxazolidinone.
根据实施例44的步骤74，只需用化合物74b代替化合物74，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：3)目标产物80b(5mg)。According to the step 74 of Example 44, the compound 74b was used instead of the compound 74, and the other conditions were unchanged. Column chromatography (n-heptane: ethyl acetate = 1:3) of the desired product 80b (5 mg).
实施例46：化合物80c的合成Example 46: Synthesis of Compound 80c
Figure PCTCN2018076728-appb-000088
Figure PCTCN2018076728-appb-000088
化合物74c的制法参照实施例44的步骤71-73，不同点在于步骤72中用叔丁基恶唑烷酮代替异丙基恶唑烷酮。The compound 74c was prepared by following the procedures 71-73 of Example 44, except that in step 72, t-butyloxazolidinone was used in place of the isopropyloxazolidinone.
根据实施例44的步骤74，只需用化合物74c代替化合物74，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：3)目标产物80c(6mg)。According to the step 74 of Example 44, the compound 74c was used instead of the compound 74, and the other conditions were unchanged, and the objective product 80c (6 mg) was subjected to column chromatography (n-heptane: ethyl acetate = 1:3).
实施例47：化合物80d的合成Example 47: Synthesis of Compound 80d
Figure PCTCN2018076728-appb-000089
Figure PCTCN2018076728-appb-000089
化合物74d的制法参照实施例44的步骤71-73，不同点在于步骤72中用羟基异丙基恶唑烷酮代替异丙基恶唑烷酮。The compound 74d was prepared by following the procedures 71-73 of Example 44, except that in step 72, hydroxyisopropyloxazolidinone was used in place of the isopropyloxazolidinone.
根据实施例44的步骤74，只需用化合物74d代替化合物74，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：3)目标产物80d(5mg)。According to the step 74 of Example 44, the compound 74d was used instead of the compound 74, and the other conditions were unchanged. Column chromatography (n-heptane: ethyl acetate = 1:3).
实施例48：化合物80e的合成Example 48: Synthesis of Compound 80e
Figure PCTCN2018076728-appb-000090
Figure PCTCN2018076728-appb-000090
化合物74e的制法参照实施例44的步骤71-73，不同点在于步骤72中用三氟异丙基恶唑烷酮代替异丙基恶唑烷酮。The preparation of compound 74e is carried out by reference to steps 71-73 of Example 44, except that in step 72, trifluoroisopropyloxazolidinone is used in place of isopropyloxazolidinone.
根据实施例44的步骤74，只需用化合物74e代替化合物74，用3-氯-4-氟-1-苯胺取代3,4-二氟-1-苯胺，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：3)目标产物80e(8mg)。According to the step 74 of Example 44, the compound 74e is used instead of the compound 74, and the 3-chloro-4-fluoro-1-aniline is substituted for the 3,4-difluoro-1-aniline. (n-heptane: ethyl acetate = 1:3) title product 80e (8 mg).
实施例49：化合物80f的合成Example 49: Synthesis of Compound 80f
Figure PCTCN2018076728-appb-000091
Figure PCTCN2018076728-appb-000091
化合物74f的制法参照实施例44的步骤71-73，不同点在于步骤71中用三氟异丙基恶唑烷酮代替异丙基恶唑烷酮。The compound 74f was prepared by following the procedures 71-73 of Example 44, except that in step 71, trifluoroisopropyloxazolidinone was used in place of the isopropyloxazolidinone.
根据实施例44的步骤74，只需用化合物74f代替化合物74，用3-氰基-4-氟-1-苯胺取代3,4-二氟-1-苯胺，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：3)目标产物80f(11mg)。According to the step 74 of Example 44, the compound 74f is used instead of the compound 74, and the 3-cyano-4-fluoro-1-aniline is substituted for the 3,4-difluoro-1-aniline. The title product 80f (11 mg) was obtained (n-heptane: ethyl acetate = 1:3).
生物学实施例--抗-HBV活性实验Biological Example--Anti-HBV Activity Experiment
实验一：体外抗乙肝病毒核衣壳组装活性试验方法Experiment 1: In vitro anti-HBV nucleocapsid assembly activity test method
主要试剂和原料：Main reagents and raw materials:
C150蛋白为药明康德公司表达和纯化；C150 protein is expressed and purified by WuXi PharmaTech;
Figure PCTCN2018076728-appb-000092
购自赛默飞世尔科技公司。
Figure PCTCN2018076728-appb-000092
Purchased from Thermo Fisher Scientific.
蛋白荧光标记：Protein fluorescent label:
向96孔板每孔加入150μL 2％w/v脱脂牛奶，室温孵育2小时。吸掉脱脂牛奶，用去离子水清洗后烘干，室温保存。将C150蛋白(每管3毫克)用5ml Hitrap脱盐柱脱盐。向每管脱盐后的C150蛋白加入50mM
Figure PCTCN2018076728-appb-000093
荧光染料20μl混合均匀，4℃ 避光孵育过夜。用Sephadex G-25凝胶过滤去除未与C150结合的荧光染料。计算C150的荧光标记效率，公式如下： 150 μL of 2% w/v skim milk was added to each well of a 96-well plate and incubated for 2 hours at room temperature. Aspirate skim milk, wash it with deionized water, dry it, and store at room temperature. C150 protein (3 mg per tube) was desalted using a 5 ml Hitrap desalting column. Add 50 mM to the C150 protein after desalting each tube
Figure PCTCN2018076728-appb-000093
20 μl of the fluorescent dye was mixed well and incubated overnight at 4 ° C in the dark. The fluorescent dye not bound to C150 was removed by filtration with Sephadex G-25 gel. Calculate the fluorescence labeling efficiency of C150, the formula is as follows:
Figure PCTCN2018076728-appb-000094
＝A504/78,000M -1；
Figure PCTCN2018076728-appb-000094
=A504/78,000M -1 ;
[C150Bo]＝(A280-
Figure PCTCN2018076728-appb-000095
x1300M -1)/60,900M -1； [C150Bo]=(A280-
Figure PCTCN2018076728-appb-000095
x1300M -1 ) / 60,900M -1 ;
荧光标记效率＝
Figure PCTCN2018076728-appb-000096
Fluorescent labeling efficiency =
Figure PCTCN2018076728-appb-000096
其中，among them,
Figure PCTCN2018076728-appb-000097
表示荧光标记的浓度；
Figure PCTCN2018076728-appb-000097
Indicates the concentration of the fluorescent label;
[C150Bo]表示荧光标记蛋白的浓度；[C150Bo] represents the concentration of a fluorescently labeled protein;
A504表示波长504nM的吸光值；A504 represents an absorbance value of a wavelength of 504 nM;
A280表示波长280nM的吸光值；A280 represents an absorption value of a wavelength of 280 nM;
M -1表示摩尔浓度的倒数。 M -1 represents the reciprocal of the molar concentration.
化合物稀释：Compound dilution:
将化合物母液用DMSO稀释到6mM，再用50mM HEPES稀释到600μM，然后用10％DMSO/50mM HEPES进一步3倍系列稀释8个浓度。The mother liquor of the compound was diluted to 6 mM with DMSO, diluted to 600 μM with 50 mM HEPES, and then further diluted 8 times with 10% DMSO/50 mM HEPES.
将C150Bo用50mM HEPES稀释到2μM。取37.5μL C150Bo和2.5μL各个浓度的化合物加入到96孔反应板中混匀，室温孵育15分钟。取10μl的750mM NaCl/50mM HEPES加入到反应孔中，NaCl的终浓度为150mM。C150Bo was diluted to 2 μM with 50 mM HEPES. 37.5 μL of C150Bo and 2.5 μL of each concentration of the compound were added to a 96-well reaction plate and mixed, and incubated at room temperature for 15 minutes. 10 μl of 750 mM NaCl/50 mM HEPES was added to the reaction well, and the final concentration of NaCl was 150 mM.
0％蛋白组装对照孔，加入10μL的50mM HEPES，NaCl的终浓度为0mM。Control wells were assembled with 0% protein, 10 μL of 50 mM HEPES was added, and the final concentration of NaCl was 0 mM.
100％蛋白组装对照孔，加入10μL的5M NaCl/50mM HEPES，NaCl的终浓度为1M。Control wells were assembled with 100% protein and 10 μL of 5 M NaCl/50 mM HEPES was added with a final concentration of 1 M NaCl.
DMSO终浓度为0.5％，化合物最高终浓度为30μM，C150Bo终浓度为1.5μM。室温孵育1小时。测量荧光信号(激发光485nm；发射光535nm)。The final concentration of DMSO was 0.5%, the maximum final concentration of the compound was 30 μM, and the final concentration of C150Bo was 1.5 μM. Incubate for 1 hour at room temperature. The fluorescence signal (excitation light 485 nm; emission light 535 nm) was measured.
数据分析data analysis
％蛋白组装＝【1-(样品荧光值–1M NaCl荧光值)/(0M NaCl荧光值-1M NaCl荧光值)】×100.% protein assembly = [1- (sample fluorescence value - 1M NaCl fluorescence value) / (0M NaCl fluorescence value - 1M NaCl fluorescence value)] × 100.
IC 50值通过prism软件计算，方程如下： The IC 50 value is calculated by the prism software and the equation is as follows:
Y＝Bottom+(Top-Bottom)/(1+10 ((LogIC50-X)*HillSlope))； Y=Bottom+(Top-Bottom)/(1+10 ((LogIC50-X)*HillSlope) );
其中，among them,
X表示浓度的对数值，Y表示效应值，Y从底部起始以S型拟合至顶部；X represents the logarithm of the concentration, Y represents the effect value, and Y is fitted from the bottom to the top with an S-shape;
Bottom表示表示曲线的底部；Bottom indicates the bottom of the curve;
Top表示Top表示曲线的顶部；Top indicates that Top represents the top of the curve;
HillSlope表示：曲线的最大斜率的绝对值。HillSlope represents the absolute value of the maximum slope of the curve.
实验二：在HepG2.2.15细胞的抗乙肝病毒活性测定Experiment 2: Determination of anti-HBV activity in HepG2.2.15 cells
主要试剂：Main reagents:
QIAamp 96DNA血液试剂盒(12)(Qiagen，货号51162)；QIAamp 96 DNA Blood Kit (12) (Qiagen, Cat. No. 51162);
FastStart Universal Probe Master(Roche，货号04914058001)；FastStart Universal Probe Master (Roche, article number 04914058001);
Cell–titer Glo检测试剂(Promega，货号G7573)。Cell–titer Glo detection reagent (Promega, Cat. No. G7573).
化合物稀释：体外抗HBV活性实验和细胞毒性实验所有化合物均3倍系列稀释，8个浓度。受试化合物最终起始浓度为30μM，参照化合物GLS4最终起始浓度为1μM，DMSO终浓度为0.5％。Compound dilution: in vitro anti-HBV activity assay and cytotoxicity assay All compounds were serially diluted 3 times, 8 concentrations. The final starting concentration of the test compound was 30 μM, the final starting concentration of the reference compound GLS4 was 1 μM, and the final concentration of DMSO was 0.5%.
种HepG2.2.15细胞(4×10 4细胞/孔)到96孔板，在37℃，5％CO 2培养过夜。第二天，加入含不同浓度化合物的新鲜培养液到培养孔中。第五天，吸除培养孔中旧的培养液，加入含不同浓度化合物的新鲜培养液。 HepG2.2.15 cells (4 x 10 4 cells/well) were plated into 96-well plates and incubated overnight at 37 ° C, 5% CO 2 . The next day, fresh culture medium containing different concentrations of compounds was added to the culture wells. On the fifth day, the old culture solution in the culture well was aspirated and fresh culture medium containing different concentrations of the compound was added.
第八天，收集培养孔中的上清，用于提取上清中的HBV DNA，qPCR检测HepG2.2.15上清中的HBV DNA含量。收集上清后，再向培养孔中补加培养基和Cell-titer Glo试剂，酶标仪检测各孔的化学发光值。On the eighth day, the supernatant in the culture well was collected for extracting HBV DNA from the supernatant, and qPCR was used to detect the HBV DNA content in the supernatant of HepG2.2.15. After collecting the supernatant, the culture medium and the Cell-titer Glo reagent were added to the culture well, and the chemiluminescence value of each well was detected by a microplate reader.
活性计算公式如下:The activity calculation formula is as follows:
Y＝Bottom+(Top-Bottom)/(1+10 ((LogIC50-X)*HillSlope))； Y=Bottom+(Top-Bottom)/(1+10 ((LogIC50-X)*HillSlope) );
其中，among them,
X表示浓度的对数值，Y表示效应值，Y从底部起始以S型拟合至顶部；X represents the logarithm of the concentration, Y represents the effect value, and Y is fitted from the bottom to the top with an S-shape;
Bottom表示曲线的底部；Bottom represents the bottom of the curve;
Top表示曲线的顶部；Top indicates the top of the curve;
HillSlope表示：曲线的最大斜率的绝对值。HillSlope represents the absolute value of the maximum slope of the curve.
实验三：细胞毒性测定Experiment 3: Determination of cytotoxicity
待测化合物的细胞毒性是使用HepG2细胞进行测试的，将这些细胞在待测化合物存在下孵育4天。使用刃天青测定来评估细胞活力。The cytotoxicity of the test compounds was tested using HepG2 cells, and these cells were incubated for 4 days in the presence of the test compound. Cell rejuvenation was assessed using the resazurin assay.
结果表明：本发明的化合物的体外抗乙肝病毒核衣壳组装活性和抗乙肝病毒活性良好，且细胞毒性低。The results showed that the compound of the present invention has good anti-HBV nucleocapsid assembly activity and anti-HBV activity in vitro, and has low cytotoxicity.
实验一至实验三的活性数据见表2：The activity data of Experiment 1 to Experiment 3 are shown in Table 2:
表2Table 2
Figure PCTCN2018076728-appb-000098
Figure PCTCN2018076728-appb-000098
Figure PCTCN2018076728-appb-000099
Figure PCTCN2018076728-appb-000099
表中：In the table:
+++表示IC 50或EC 50<1μM； +++ means IC 50 or EC 50 <1 μM;
++表示IC 50或EC 50为1～100μM； ++ indicates an IC 50 or EC 50 of 1 to 100 μM;
+表示IC 50或EC 50为>100μM； + indicates an IC 50 or EC 50 of >100 μM;
其中，对照化合物为：Among them, the control compound is:
Figure PCTCN2018076728-appb-000100
Figure PCTCN2018076728-appb-000100
实验四：大鼠中的药代动力学评价Experiment 4: Pharmacokinetic evaluation in rats
8只雄性Sprague-Dawley大鼠，7-8周龄，体重约210g，分成2组，每组4只，单次口服给予3mg/kg剂量的(a)对照组：阳性对照化合物，或(b)试验组：表2各个化合物，比较其药代动力学差异。Eight male Sprague-Dawley rats, 7-8 weeks old, weighing about 210 g, divided into 2 groups, 4 in each group, a single oral dose of 3 mg/kg (a) control group: positive control compound, or (b) ) Test group: Table 2 for each compound, comparing its pharmacokinetic differences.
大鼠采用标准饲料饲养，给予水。试验前16小时开始禁食。药物用PEG400和二甲亚砜溶解。眼眶采血，采血的时间点为给药后0.083小时，0.25小时、0.5小时、1小时、2小时、4小时、6小时、8小时、12小时和24小时。Rats were fed a standard diet and given water. Fasting began 16 hours before the test. The drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
大鼠吸入乙醚后短暂麻醉，眼眶采集300μL血样于试管。试管内有30μL 1％肝素盐溶液。使用前，试管于60℃烘干过夜。在随后一个时间点血样采集完成之后，大鼠乙醚麻醉后处死。Rats were briefly anesthetized after inhalation of ether, and 300 μL of blood samples were collected from the eyelids in test tubes. There was 30 μL of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at a later time point, the rats were anesthetized with ether and sacrificed.
血样采集后，立即温和地颠倒试管至少5次，保证混合充分后放置于冰上。血样在4℃5000rpm离心5分钟，将血浆与红细胞分离。用移液器吸出100μL血浆到干净的塑料离心管中，表明化合物的名称和时间点。血浆在进行分析前保存在-80℃。用LC-MS/MS测定血浆中本发明化合物的浓度。药代动力学参数基于每只动物在不同时间点的血药浓度进行计算。Immediately after the blood sample is collected, gently invert the tube at least 5 times to ensure adequate mixing and place on ice. Blood samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 μL of plasma into a clean plastic centrifuge tube to indicate the name and time point of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.
从试验结果可知，相对于对照组，本发明化合物在动物体内具有更好的药物动力学，相对于对照组，本发明的化合物AUC平均提高了15-100％，Cmax平均提高了10-100％)，因而具有更好的药效学和治疗效果。From the test results, the compound of the present invention has better pharmacokinetics in the animal than the control group, and the compound AUC of the present invention has an average increase of 15-100% and an average Cmax of 10-100% with respect to the control group. ), thus having better pharmacodynamics and therapeutic effects.
实验五 溶解度测试Experiment 5 Solubility test
通过溶解实验，测试化合物10f，60f和阳性对照化合物的溶能性变化。The solubility changes of the compounds 10f, 60f and the positive control compound were tested by a dissolution test.
Figure PCTCN2018076728-appb-000101
Figure PCTCN2018076728-appb-000101
Figure PCTCN2018076728-appb-000102
Figure PCTCN2018076728-appb-000102
试验方法：在室温下(20℃)，分别取化合物10f、60f和阳性对照化合物各50mg，加到2ml相应溶剂中，搅拌后取上清液，用HPLC测溶解度，结果见下表(单位：mg/mL)：Test method: 50 mg each of compound 10f, 60f and the positive control compound were taken at room temperature (20 ° C), and added to 2 ml of the corresponding solvent. After stirring, the supernatant was taken, and the solubility was measured by HPLC. The results are shown in the following table (unit: Mg/mL):
溶剂Solvent 10f10f 60f60f 阳性对照化合物Positive control compound
去离子水Deionized water 0.0150.015 0.0120.012 0.0020.002
甲醇Methanol 3.13.1 3.03.0 2.22.2
乙醇Ethanol 2.52.5 2.22.2 1.81.8
丙酮acetone 2.92.9 2.52.5 2.02.0
三氯甲烷Trichloromethane 1.21.2 1.01.0 0.80.8
石油醚(沸程：60～90℃)Petroleum ether (boiling range: 60 ~ 90 ° C) <0.001<0.001 <0.001<0.001 <0.001<0.001
上表结果可见，本发明的化合物10f和60f的水溶性明显增加，而脂溶性减少。这种溶解性的变化对药物在体内吸收和药物剂型的选择等问题都会带来有利影响。As a result of the above table, it is seen that the water solubility of the compounds 10f and 60f of the present invention is remarkably increased, and the fat solubility is decreased. This change in solubility has a beneficial effect on the absorption of the drug in the body and the choice of pharmaceutical dosage form.
结果表明：本发明的化合物的体外抗乙肝病毒核衣壳组装活性和抗乙肝病毒活性优良，而且细胞毒性更低，本发明化合物显示出优于参比化合物的溶解性质及良好的药代动力学性质。The results show that the compound of the present invention is excellent in anti-hepatitis B virus nucleocapsid assembly activity and anti-hepatitis B virus activity in vitro, and has lower cytotoxicity, and the compound of the present invention exhibits superior solubility and good pharmacokinetics of the reference compound. nature.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims (10)

  1. 一种化学式A所示的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物，a compound of the formula A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,
    Figure PCTCN2018076728-appb-100001
    Figure PCTCN2018076728-appb-100001
    其中，among them,
    R 1选自下组：氢、取代或未取代的C 1-C 10烷基、取代或未取代的C 3-C 10环烷基、取代或未取代的具有1-3个选自N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C 6-C 10芳基、和取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基；所述R 1中，所述取代指被选自下组的一个或多个(例如1、2、3、4或5个)取代基所取代：-OH、卤素、C 1-C 6烷基、卤代的C 1-C 6烷基、C 1-C 6烷氧基、-O-； R 1 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted, having 1-3 selected from N, a 3-10 membered heterocycloalkyl group of a hetero atom of S and O, a substituted or unsubstituted C 6 -C 10 aryl group, and a substituted or unsubstituted hetero atom having 1-3 selected from N, S and O a 5-10 membered heteroaryl; wherein in R 1 the substitution is substituted with one or more (eg 1, 2, 3, 4 or 5) substituents selected from the group consisting of: -OH, Halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -O-;
    X为选自下组的二价基团：CR 2R 3或-CR 2＝CR 3-；其中，R 2和R 3各自独立地选自下组：H、卤素、取代或未取代的C 1-C 10烷基、取代或未取代的C 2-C 6烯基、取代或未取代的C 2-C 6炔基、取代或未取代的C 3-C 10环烷基、取代或未取代的具有1-3个选自N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、C 1-3烷基-R 7、-C(＝O)OC 1-4烷基；其中所述R 7选自下组：卤素、C 1-C 3烷基、取代的或未取代的具有1-2个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的3-7元杂环烷基、和-NR 9R 10，其中，所述R 9和R 10各自独立地选自：H、C 1-C 3烷基、和卤代的C 1-C 3烷基； X is a divalent group selected from the group consisting of CR 2 R 3 or -CR 2 =CR 3 -; wherein R 2 and R 3 are each independently selected from the group consisting of H, halogen, substituted or unsubstituted C 1- C 10 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or not Substituted 3-10 membered heterocycloalkyl having 1 to 3 heteroatoms selected from N, S and O, substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted having 1-3 a 5-10 membered heteroaryl group selected from the group consisting of N, S and O, a C 1-3 alkyl-R 7 , -C(=O)OC 1-4 alkyl group; wherein said R 7 is selected from the group consisting of Group: halogen, C 1 -C 3 alkyl, substituted or unsubstituted 5-10 membered heteroaryl having 1-2 heteroatoms selected from N, S and O, having 1-3 selected from N a 3-7 membered heterocycloalkyl group of a hetero atom of S and O, and -NR 9 R 10 , wherein said R 9 and R 10 are each independently selected from the group consisting of: H, C 1 -C 3 alkyl, and Halogenated C 1 -C 3 alkyl;
    或者，or,
    所述R 2和R 3与相邻的C原子共同构成具有1-3个选自N、S和O的杂原子的取代或未取代的3-7元杂环烷基，其中，所述3-7元杂环烷基的取代指被选自下组的一个或多个(例如1、2、3、4或5个)取代基所取代：-OH、卤素、甲氧基、乙氧基、-O-、-C(＝O)OC 1-4烷基、苄基、C 1-4烷基、卤代的C 1-4烷基， The R 2 and R 3 together with the adjacent C atoms constitute a substituted or unsubstituted 3-7 membered heterocycloalkyl group having 1 to 3 hetero atoms selected from N, S and O, wherein the 3 Substitution of a -7 membered heterocycloalkyl refers to substitution with one or more (e.g., 1, 2, 3, 4 or 5) substituents selected from the group consisting of -OH, halogen, methoxy, ethoxy. , -O-, -C(=O)OC 1-4 alkyl, benzyl, C 1-4 alkyl, halogenated C 1-4 alkyl,
    并且，所述R 2和R 3中，所述取代指被选自下组的一个或多个(例如1、2、3、4或5个)取代基所取代：-OH、卤素、C 1-C 6烷基、卤代的C 1-C 6烷基、-OH取代的C 1-C 6烷基、C 1-C 6烷氧基、-C(＝O)OC 1-4烷基； And, in R 2 and R 3 , the substitution refers to being substituted with one or more (for example, 1, 2, 3, 4 or 5) substituents selected from the group consisting of -OH, halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, -OH substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -C(=O)OC 1-4 alkyl ;
    Y为取代或未取代的C 1-C 7亚烷基或C 2-C 7亚烯基；在所述Y中，所述取代指被选自下组的一个或多个(例如1、2、3、4或5个)取代基所取代：C 1-C 4烷基、C 1-C 4卤代烷基、卤素、-OH(较佳地为C 1-C 4烷基或-OH)； Y is a substituted or unsubstituted C 1 -C 7 alkylene group or a C 2 -C 7 alkenylene group; in the Y, the substitution means one or more selected from the group consisting of (for example, 1, 2) , 3, 4 or 5) substituted by a substituent: C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, halogen, -OH (preferably C 1 -C 4 alkyl or -OH);
    W选自下组：-SO 2-、-CO-； W is selected from the group consisting of -SO 2 -, -CO-;
    环C为取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基；在所述环C中，所述取代指被选自下组的一个或多个(例如1、2、3、4或5个等)取代基所取代：C 1-C 3烷基(较佳地为甲基)、C 1-C 3卤代烷基、C 3-C 4环烷基、-CN或卤素； Ring C is a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 heteroatoms selected from N, S and O; in said ring C, said substitution refers to a group selected from the group consisting of Or a plurality of (for example 1, 2, 3, 4 or 5, etc.) substituents substituted: C 1 -C 3 alkyl (preferably methyl), C 1 -C 3 haloalkyl, C 3 -C 4 -cycloalkyl, -CN or halogen;
    环B为取代或未取代的C 6-C 10芳基、或取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基；所述环B中，所述取代指被选自下组的一个或多个(例如1、2、3、4或5个)取代基所取代：C 1-C 3烷基、C 1-C 3卤代烷基、C 3-C 4环烷基、-CN或卤素； Ring B is a substituted or unsubstituted C 6 -C 10 aryl group, or a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 hetero atoms selected from N, S and O; Wherein said substitution is substituted with one or more (e.g., 1, 2, 3, 4 or 5) substituents selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 3 -C 4 cycloalkyl, -CN or halogen;
    R a、R b、R c和R d为环B上任意位置的取代基，其各自独立地选自下组：H、卤素、-CN、羟基、氨基、C1-C6羧基、-(C＝O)-取代或未取代的C 1-C 8烷基、取代或未取代的C 1-C 8烷基、取代或未取代的C2-C6烯基、取代或未取代的C 2-C 6炔基、取代或未取代的C 1-C 8烷胺基、取代或未取代的C1-C8烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、和取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基； R a , R b , R c and R d are substituents at any position on Ring B, each independently selected from the group consisting of H, halogen, -CN, hydroxy, amino, C1-C6 carboxy, -(C= O)-substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 Alkynyl, substituted or unsubstituted C 1 -C 8 alkylamino, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having 1-3 3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl group selected from hetero atoms of N, S and O, and substituted or unsubstituted having 1-3 selected from N, S and O 5-10 membered heteroaryl of a hetero atom;
    在所述Ra、Rb、Rc、Rd中，所述“取代”是指被选自下组的一个或多个(例如1、2、3、4或5个等)取代基所取代：卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、氨基、C1-C3羧基、C6-C10芳基、卤代的C6-C10芳基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、卤代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基；In the above, R, Rb, Rc, and Rd, the "substitution" means substitution with one or more (for example, 1, 2, 3, 4 or 5, etc.) substituents selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxygen Generation, -CN, hydroxy, amino, C1-C3 carboxy, C6-C10 aryl, halogenated C6-C10 aryl, 5-10 membered with 1-3 heteroatoms selected from N, S and O Aryl, halogenated 5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O;
    n为0、1或2；n is 0, 1 or 2;
    p为0、1或2；p is 0, 1 or 2;
    “---”表示键或不存在；"---" means the key or does not exist;
    其中，当“---”表示键时，Z选自下组：NH、O或无；Wherein, when "---" indicates a bond, Z is selected from the group consisting of NH, O or none;
    当“---”表示无时，X和Y均为无，且Z选自下组：卤素、C1-C4烷基、C1-C4卤代烷基、-NR 9R 10、OR 9或H。 When "---" represents no, X and Y are both absent, and Z is selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10, OR 9 or H.
    在另一优选例中，所述的“---”表示单键、双键或不存在。In another preferred embodiment, the "---" means a single bond, a double bond or absent.
  2. 如权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物，其特征在于，所述的式A化合物具有如下式A-1或A-2所示的结构：The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound of formula A has the formula Structure shown in A-1 or A-2:
    Figure PCTCN2018076728-appb-100002
    Figure PCTCN2018076728-appb-100002
  3. 如权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接 受的盐、水合物或溶剂化物，其特征在于，环C为取代或未取代的含1-3个N的5-6元杂芳基。The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein ring C is substituted or unsubstituted 1-3 N 5-6 membered heteroaryl groups.
    在另一优选例中，在所述环C中，所述取代指被选自下组的一个或两个取代基所取代：C 1-C 3烷基(较佳地为甲基)、卤素、-CN。 In another preferred embodiment, in the ring C, the substitution refers to being substituted with one or two substituents selected from the group consisting of C 1 -C 3 alkyl (preferably methyl), halogen , -CN.
  4. 如权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物，其特征在于，环B选自下组：苯基、取代或未取代的6元杂芳基，较佳地为苯基或吡啶基。The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein Ring B is selected from the group consisting of phenyl The substituted or unsubstituted 6-membered heteroaryl group is preferably a phenyl group or a pyridyl group.
  5. 如权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物，其特征在于，所述的化合物选自下组：The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound is selected from the group consisting of:
    Figure PCTCN2018076728-appb-100003
    Figure PCTCN2018076728-appb-100003
    Figure PCTCN2018076728-appb-100004
    Figure PCTCN2018076728-appb-100004
    Figure PCTCN2018076728-appb-100005
    Figure PCTCN2018076728-appb-100005
  6. 一种制备如权利要求1所述化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物的方法，其特征在于：A method of preparing a compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
    当所示式A化合物为式IX-1所示的化合物时，所述方法包括步骤：When the compound of formula A is shown as a compound of formula IX-1, the method comprises the steps of:
    Figure PCTCN2018076728-appb-100006
    Figure PCTCN2018076728-appb-100006
    各式中，环C、R 1、环B、R a、R b、R c和R d的定义同权利要求1所述； In the formula, the definitions of ring C, R 1 , ring B, R a , R b , R c and R d are as defined in claim 1;
    Z选自下组：卤素、C1-C4烷基、C1-C4卤代烷基、-NR 9R 10、OR 9或H； Z is selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10 , OR 9 or H;
    m为0-8的整数；m is an integer from 0-8;
    当所示式A化合物为式VIII-2所示的化合物时，所述方法包括步骤：When the compound of formula A is shown as a compound of formula VIII-2, the method comprises the steps of:
    Figure PCTCN2018076728-appb-100007
    Figure PCTCN2018076728-appb-100007
    各式中，环C、R 1、环B、R a、R b、R c和R d的定义同权利要求1所述； In the formula, the definitions of ring C, R 1 , ring B, R a , R b , R c and R d are as defined in claim 1;
    Z选自下组：卤素、C1-C4烷基、C1-C4卤代烷基、-NR 9R 10、OR 9或H； Z is selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10 , OR 9 or H;
    m为0-8的整数；m is an integer from 0-8;
    当所示式A化合物为式V-3所示的化合物时，所述方法包括步骤：When the compound of formula A is shown as a compound of formula V-3, the method comprises the steps of:
    Figure PCTCN2018076728-appb-100008
    Figure PCTCN2018076728-appb-100008
    各式中，环C、R 1、环B、R a、R b、R c和R d的定义同权利要求1所述； In the formula, the definitions of ring C, R 1 , ring B, R a , R b , R c and R d are as defined in claim 1;
    Z选自下组：卤素、C1-C4烷基、C1-C4卤代烷基、-NR 9R 10、OR 9或H； Z is selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10 , OR 9 or H;
    当所示式A化合物为式VI-4所示的化合物时，所述方法包括步骤：When the compound of formula A is shown as a compound of formula VI-4, the method comprises the steps of:
    Figure PCTCN2018076728-appb-100009
    Figure PCTCN2018076728-appb-100009
    各式中，环C、R 1、环B、R a、R b、R c和R d的定义同权利要求1所述； In the formula, the definitions of ring C, R 1 , ring B, R a , R b , R c and R d are as defined in claim 1;
    Z选自下组：卤素、C1-C4烷基、C1-C4卤代烷基、-NR 9R 10、OR 9或H。 Z is selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10 , OR 9 or H.
  7. 一种药物组合物，其包含(1)权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物；和(2)药学上可接受的载体。A pharmaceutical composition comprising (1) the compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (2) a pharmaceutically acceptable carrier.
  8. 如下式所示中间体化合物：An intermediate compound as shown in the following formula:
    Figure PCTCN2018076728-appb-100010
    Figure PCTCN2018076728-appb-100010
    Figure PCTCN2018076728-appb-100011
    Figure PCTCN2018076728-appb-100011
    式中，R1、环C定义同权利要求1所述；Wherein R1 and ring C are as defined in claim 1;
    Z选自下组：卤素、C1-C4烷基、C1-C4卤代烷基、-NR 9R 10、OR 9或H； Z is selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10 , OR 9 or H;
    m为0-8的整数。m is an integer from 0-8.
  9. 如权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物或如权利要求6所述的药物组合物的用途，其特征在于，用于制备预防和/或治疗乙型肝炎病毒感染的药物。The use of a compound according to claim 1 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 6 It is characterized by being used for the preparation of a medicament for preventing and/or treating hepatitis B virus infection.
  10. 一种乙型肝炎病毒抑制剂，其特征在于，所述抑制剂包含权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物。A hepatitis B virus inhibitor, which comprises the compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt or hydrate thereof Or solvate.
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