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WO2018133846A1 - 环硫脲类化合物及其用途 - Google Patents

环硫脲类化合物及其用途 Download PDF

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Publication number
WO2018133846A1
WO2018133846A1 PCT/CN2018/073460 CN2018073460W WO2018133846A1 WO 2018133846 A1 WO2018133846 A1 WO 2018133846A1 CN 2018073460 W CN2018073460 W CN 2018073460W WO 2018133846 A1 WO2018133846 A1 WO 2018133846A1
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group
substituted
unsubstituted
alkyl
compound
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PCT/CN2018/073460
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English (en)
French (fr)
Inventor
王喆
王晓光
范国钦
卢涔宾
杨赛
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上海长森药业有限公司
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Publication of WO2018133846A1 publication Critical patent/WO2018133846A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • 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
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention pertains to the field of medicine, and in particular, to the use of cyclic thiourea compounds 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.
  • hepatitis B virus 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.
  • direct treatment is currently limited to interferon as well as the following antiviral drugs; tenofovir, lamivudine, adefovir, entecavir and telbivudine.
  • heteroaryldihydropyrimidines have been identified as a class of HBV inhibitors in tissue culture and animal models (Weber et al., Antiviral Res. 54:69-78) . Also disclosed are WO sulfonyl-aryl amide compounds which are resistant to HBV activity, as disclosed in WO 2013/006394 and WO 2013/096744.
  • HBV antiviral drugs may encounter various problems such as toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability, and difficulty in synthesis.
  • a compound of formula A or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,
  • the R 11 and R 12 together with the adjacent C atoms constitute a substituted or unsubstituted 3-7 membered heterocycloalkyl group having 1 to 3 hetero atoms selected from the group consisting of N, S and O, wherein
  • Y is a substituted or unsubstituted C 1 -C 7 alkylene group or a C 2 -C 7 alkenylene group, and in the Y, the substitution means one or more selected from the group consisting of (for example, 2, 3) Substituted by four, four, etc. substituents: C 1 -C 4 alkyl, halogen, -OH, preferably C 1 -C 4 alkyl or -OH;
  • Z is selected from the group consisting of NH, O or a bond
  • Ring C is a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 heteroatoms selected from the group consisting of N, S and O, wherein said ring C is selected from the group consisting of Substituted by one or more (eg, 2, 3, 4, etc.) substituents: C 1 -C 3 alkyl (preferably methyl), C 3 -C 4 cycloalkyl, -CN or halogen ;
  • Ring B is a substituted or unsubstituted C 6 -C 10 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 hetero atoms selected from the group consisting of N, S and O;
  • the substitution refers to being substituted with one or more (e.g., 2, 3, 4, etc.) substituents selected from the group consisting of C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl , -CN or halogen;
  • R 1 and R 2 are each independently 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 3-10 membered heterocycloalkyl having 1 to 30 hetero atoms selected from the group consisting of N, S and O, substituted or unsubstituted C 6 -C 10 aryl, or substituted or unsubstituted a 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O, wherein in R 1 , R 2 the substitution is replaced by one or more selected from the group consisting of Substituted by: -OH, halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -O-;
  • R a , R b , R c and R d are substituents at any position on the benzene ring, as defined above.
  • R 12 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.
  • ring C is a substituted or unsubstituted 5 or 6 membered heteroaryl group, said substitution being selected from one or more selected from the group consisting of (eg, 2, 3, 4, etc.) Substituted by a substituent: methyl, -CN or halogen.
  • Ring B is phenyl or a substituted or unsubstituted 6-membered heteroaryl group, preferably a phenyl or pyridyl group.
  • the R a , R b , R c , 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, or -C 1 -C 4 alkyl.
  • the ring C is among them
  • R 4 is H, -C 1 -C 3 alkyl (preferably methyl), -C 3 -C 4 cycloalkyl;
  • R 5 is H or halogen (preferably F);
  • R 6 is selected from H, methyl, -CN or halogen.
  • the Z is O or a bond.
  • the R 7 is a substituted or unsubstituted 5-10 membered heteroaryl group having 1-2 heteroatoms selected from the group consisting of N, S and O.
  • the compound of formula A is selected from the group consisting of:
  • a process for the preparation of a compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof The compound of formula A is a compound of formula VII-1, and the method comprises the step (I):
  • the compound of formula A shown is a compound of formula VIII-1, said method comprising step (II):
  • R 2 , R a , R b , R c , R d , ring C, and ring B are as defined above, and m and n are each a positive integer of 1-5. ;
  • a pharmaceutical composition comprising the compound of the first aspect, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt or hydrate thereof, Or a solvate; (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.
  • the fifth aspect of the invention provides a 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 a third aspect of the invention.
  • the inventors have conducted extensive and intensive research and found a novel class of cyclic thiourea compounds which have an excellent therapeutic effect on hepatitis B.
  • the compounds of the present invention have novel cores in structure, especially those having a cyclic thiourea, and therefore have not only excellent anti-HBV activity but also lower cytotoxicity (especially for liver cells). 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 the group consisting of N, S and O" means having from 3 to 10 atoms and wherein 1-3 of the atoms are A saturated or partially saturated cyclic group selected from the group consisting of heteroatoms 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 the group consisting of N, S and O" refers to having 5-10 atoms and wherein 1-3 atoms are selected from A cyclic aromatic group of the following group of heteroatoms of N, 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 ), 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.
  • 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 6b was carried out in the same manner as in the step 1-5 of Example 1, except that in step 3, 1,3-dibromopropane was used instead of 1,4-dibromobutane.
  • the preparation of the compound 6g is carried out in the same manner as in the step 1-5 of the embodiment 1, except that the 1-isopropyl-1,4-dibromohexane is substituted for the 1,4-dibromobutane in the step 3, and the step 5 is used. 3,4-Difluoro-aniline instead of 4-fluoro-3-cyanoaniline.
  • the preparation of the compound 6h is carried out by referring to the steps 1-5 of the first embodiment, except that the 1-isopropyl-1,4-dibromohexane is substituted for the 1,4-dibromobutane in the step 3, and the step 5 is used.
  • 4-Fluoro-3-difluoromethylaniline instead of 4-fluoro-3-cyanoaniline.
  • the chlorosulfonic acid isocyanate (2 g) was dissolved in dichloromethane (40 mL), the temperature of the system was lowered to 0 °, then tert-butanol (1.3 g) was added to the reaction system, stirred for 30 min, triethylamine (3 g) and compound 12(2.0g) was added to the reaction system at 0 degree. After the addition was completed, the temperature was raised to room temperature and the reaction was stirred for 2 h.
  • the compound 14 (400 mg) was dissolved in dichloromethane (400 mL), then the catalyst CatB (42 mg) was added to the reaction system, and the reaction was carried out at 30 degrees for 12 hours.
  • the compound 17 (40 mg) was dissolved in dichloromethane (2 mL) and then 4N HCl (1 mL) was added to the reaction system, and the reaction was carried out at 30 °C for 2 h, the reaction solution was spun dry, and the saturated sodium hydrogen carbonate solution was adjusted to pH 7-8, acetic acid. Ethyl ester (3*10 mL) was extracted, dried over anhydrous sodium sulfate, and then evaporated to dryness.
  • the preparation of the compound 17d is carried out by referring to the step 11-16 of Example 9, except that in Step 13, 4-methylisoxazole benzyl-1-pentene was used instead of propylene bromide.
  • the preparation of the compound 17e is carried out by referring to the steps 11-16 of Example 9, except that in step 13, 1-isopropyl-1-propene is used instead of propylene bromide, and in step 16, 3,4-difluoro-aniline is used instead of 4- Fluoro-3-cyanoaniline.
  • the compound 26 (40 mg) was dissolved in dichloromethane (2 mL) and then 4N HCl (1 mL) was added to the reaction system, and the reaction was carried out at 30 °C for 2 h, the reaction solution was spun dry, and the saturated sodium hydrogen carbonate solution was adjusted to pH 7-8, acetic acid. Ethyl acetate (3*10 mL) was extracted, dried over anhydrous sodium sulfate, and then evaporated to dryness.
  • the chlorosulfonic acid isocyanate (2 g) was dissolved in dichloromethane (40 mL), the temperature of the system was lowered to 0 °, then tert-butanol (1.3 g) was added to the reaction system, stirred for 30 min, triethylamine (3 g) and compound 32 (2.0 g) was added to the reaction system at 0 °C. After the addition was completed, the mixture was warmed to room temperature and stirred for 2 h.
  • the compound 37 (40 mg) was dissolved in dichloromethane (2 mL) and then 4N HCl (1 mL) was added to the reaction system, and the reaction was carried out at 30 °C for 2 h, the reaction solution was spun dry, and the saturated sodium hydrogen carbonate solution was adjusted to pH 7-8. Ethyl ester (3*10 mL) was extracted, dried over anhydrous sodium sulfate, and then evaporated to dryness.
  • step 32 1-isopropyl-1-propene is used in place of propylene bromide, and in step 35, 3,4-difluoro-aniline is substituted for 4- Fluoro-3-cyanoaniline.
  • step 32 1-isopropyl-1-propene is used in place of propylene bromide, and in step 35, 3-difluoromethyl-4-fluoro- is used.
  • Aniline replaces 4-fluoro-3-cyanoaniline.
  • [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 - 1 M NaCl fluorescence value) / (0 M NaCl fluorescence value - 1 M 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
  • Bottom represents the bottom of the curve
  • 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 inoculated 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
  • Bottom represents the bottom of the curve
  • Top represents the top of the curve
  • 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.
  • A1 indicates IC50 ( ⁇ M) at ⁇ 1;
  • A2 indicates that the IC50 ( ⁇ M) is between 1 and 100;
  • A3 indicates that the IC50 ( ⁇ M) is >100
  • control compound is:

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Abstract

本发明涉及一种环硫脲类化合物及其用途。具体地，本发明公开了一种可作HBV复制抑制剂的具有化学式(A)所示结构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。本发明还涉及包含上述化合物的药物组合物及其在治疗乙型肝炎中的用途。

Description

环硫脲类化合物及其用途 技术领域
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环硫脲类化合物及其用途。
背景技术
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)。
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。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。
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)。WO 2013/006394和WO 2013/096744还公开了涉及抗HBV活性的氨磺酰基-芳基酰胺化合物。
然而，上述这些直接的HBV抗病毒药中会遇到种种问题，例如毒性、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。
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。
发明内容
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环硫脲类化合物。
本发明第一方面，提供一种如式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，
Figure PCTCN2018073460-appb-000001
其中，
R 1、R 2各自独立地选自下组：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个选自下组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、卤素或取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基，所述R 1、R 2中，所述取代指被选自下组的一个或多个(例如2个、 3个、4个等)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、-O-；
X为CR 11R 12或-CR 11＝CR 12-；其中，R 11和R 12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个选自下组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个选自下组N、S和O的杂原子的5-10元杂芳基、取代或未取代的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个选自下组N、S和O的杂原子的5-10元杂芳基、具有1-3个选自下组N、S和O的杂原子的3-7元杂环烷基、-NR 9R 10，其中，所述R 9、R 10各自独立地选自：H、C 1-C 3烷基、卤代的C 1-C 3烷基；
或者，
所述R 11和R 12与相邻的C原子共同构成具有1-3个选自下组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2个、3个、4个等)取代基所取代：-OH、卤素、甲氧基、-O-、-C(＝O)OC 1-4烷基、苄基、C 1-4烷基、卤代的C 1-4烷基，
并且，所述R 11、R 12中，所述取代指被选自下组的一个或多个(例如2个、3个、4个等)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；
Y为取代或未取代的C 1-C 7亚烷基或C 2-C 7亚烯基，所述Y中，所述取代指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：C 1-C 4烷基、卤素、-OH，较佳地为C 1-C 4烷基或-OH；
Z选自下组：NH、O或一个键；
环C为取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基，所述环C中，所述取代指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：C 1-C 3烷基(较佳地为甲基)、C 3-C 4环烷基、-CN或卤素；
环B为取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自下组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2个、3个、4个等)取代基所取代：C 1-C 3烷基、C 3-C 4环烷基、-CN或卤素；
R a、R b、R c、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、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 1-C 8烷胺基、取代或未取代的C 1-C 8烷氧基、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个选自下组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、或取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基；所述R a、R b、R c、R d中，所述“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C 1-C 6烷基、卤代的C 1-C 6烷基、C 1-C 6烷氧基、卤代的C 1-C 6烷 氧基、C 3-C 8环烷基、卤代的C 3-C 8环烷基、氧代、-CN、羟基、氨基、羧基、C 6-C 10芳基、卤代的C 6-C 10芳基、具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基、卤代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基。
在另一优选例中，R 1、R 2各自独立地选自下组：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个选自下组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、或取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基，所述R 1、R 2中，所述取代指被选自下组的一个或多个取代基所取代：-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-；
X为CR 11R 12或-CR 11＝CR 12-；其中，R 11和R 12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个选自下组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个选自下组N、S和O的杂原子的5-10元杂芳基、C 1-3烷基-R 7、或-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个选自下组N、S和O的杂原子的5-10元杂芳基、具有1-3个选自下组N、S和O的杂原子的3-7元杂环烷基、-NR 9R 10，其中，所述R 9、R 10各自独立地选自：H、C 1-C 3烷基、卤代的C 1-C 3烷基；
或者，
所述R 11和R 12与相邻的C原子共同构成具有1-3个选自下组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取代基所取代：-OH、卤素、甲氧基、-O-、-C(＝O)OC 1-4烷基、苄基、C 1-4烷基、卤代的C 1-4烷基，
并且，所述R 11、R 12中，所述取代指被选自下组的一个或多个取代基所取代：-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；
R a、R b、R c、R d为苯环上任意位置的取代基，定义如前所述。
在另一优选例中，R 1为H、未取代的C 1-C 10烷基、C 3-C 10环烷基、被-OH、＝O、-O-或卤素取代的C 1-C 10烷基。
在另一优选例中，R 11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个选自下组N、S和O的杂原子的3-7元杂环烷基、或取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基。
在另一优选例中，R 12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。
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2个、3个、4个等)取代基所取代：甲基、-CN或卤素。
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。
在另一优选例中，所述R a、R b、R c、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、或-C 1-C 4烷基。
在另一优选例中，所述环C为
Figure PCTCN2018073460-appb-000002
其中，
R 4为H、-C 1-C 3烷基(较佳地为甲基)、-C 3-C 4环烷基；
R 5为H或卤素(较佳地为F)；
R 6选自H、甲基、-CN或卤素。
在另一优选例中，所述Z为O或一个键。
在另一优选例中，所述R 7为取代的或未取代的具有1-2个选自下组N、S和O的杂原子的5-10元杂芳基。
在另一优选例中，所述式A化合物选自下组：
Figure PCTCN2018073460-appb-000003
Figure PCTCN2018073460-appb-000004
本发明第二方面，提供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VII-1所示的化合物，所述方法包括步骤(I)：
Figure PCTCN2018073460-appb-000005
或者，
所示式A化合物为式VIII-1所示的化合物，所述方法包括步骤(II)：
Figure PCTCN2018073460-appb-000006
所述步骤(I)或(II)中，R 2、R a、R b、R c、R d、环C、环B的定义同前所述，m、n分别为1-5的正整数；
其中，R 3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个选自下组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、或取代或未取代的具有1-3个选自下组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个选自下组N、S和O的杂原子的5-10元杂芳基、具有1-3个选自下组N、S和O的杂原子的3-7元杂环烷基、-NR 9R 10，其中，所述R 9、R 10各自独立地选自：H、C 1-C 3烷基、卤代的C 1-C 3烷基。
本发明第三方面，提供一种药物组合物，其包含(1)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；(2)药学上可接受的载体。
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。
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)。
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。
本发明第四方面，提供如下式所示化合物：
Figure PCTCN2018073460-appb-000007
Figure PCTCN2018073460-appb-000008
本发明第五方面，提供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本发明第三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。
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。
具体实施方式
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环硫脲类化合物。本发明化合物在结构上具有新颖的母核，尤其是具有环硫脲的结构部分，因此，不仅具有优异的抗HBV的活性，而且细胞毒性更低(尤其对于肝脏细胞)。在此基础上，发明人完成了本发明。
定义
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。
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。
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。
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。
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。
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。
如本文所用，术语“具有1-3个选自下组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个原子为选自下组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。
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。
如本文所用，术语“具有1-3个选自下组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个原子为选自下组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。
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。
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。
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。
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。
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。
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。
活性成分
如本文所用，“本发明化合物”指式(A)所示的化合物，并且还包括及式(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。
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。
药物组合物和施用方法
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)。
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。
“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
Figure PCTCN2018073460-appb-000009
Figure PCTCN2018073460-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。
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)。
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。
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。
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。
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。
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。
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。
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。
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。
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。
本发明化合物：
Figure PCTCN2018073460-appb-000011
Figure PCTCN2018073460-appb-000012
Figure PCTCN2018073460-appb-000013
Figure PCTCN2018073460-appb-000014
本发明的主要优点包括：
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。
2.本发明的化合物对正常细胞的毒性非常低。
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。
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)。
术语说明
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。
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)。
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”。
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。
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。
下面为10类化合物的合成：
实施例1：化合物10a的合成
Figure PCTCN2018073460-appb-000015
步骤1:
Figure PCTCN2018073460-appb-000016
将化合物1(1.5g)溶于醋酸(20mL),然后将铁粉(1.9g)加入反应体系，将温度升至50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2(1g)。ESI-MS,(M+H＝189.04)
步骤2：
Figure PCTCN2018073460-appb-000017
将氯磺酸异氰酸酯(200mg)溶于二氯甲烷(5mL),将体系温度降至0度，然后将叔丁醇(105mg)加入反应体系，搅拌30min，将三乙胺(214mg)和化合物2(266mg)在0度下加入反应体系，，加完后升温至室温搅拌反应2h，将反应体系加水(20mL),二氯甲烷(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(150mg),ESI-MS,(M+H＝368.06)
步骤3:
Figure PCTCN2018073460-appb-000018
将化合物3(100mg)和1，4-二溴丁烷(58.8mg)溶于丙酮(10mL),将碳酸铯(266mg)加入反应体系，60度反应24h，将水(15mL)加入反应体系,乙酸乙酯(3*20mL)萃取，无水硫酸钠干燥，将有机相旋干，粗品经柱层析分离得黄色固体80mg，ESI-MS,(M+H＝422.11)
步骤4：
Figure PCTCN2018073460-appb-000019
将化合物4(80mg)溶于四氢呋喃(2mL),水(0.5mL),甲醇(0.5mL),然后室温下将一水合氢氧化锂(80mg)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(50mg)ESI-MS,(M+H＝408.09)
步骤5：
Figure PCTCN2018073460-appb-000020
将化合物5(50mg)，三乙胺(70mg)，4-氟-3-乙腈-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，粗品柱层析得化合物6(40mg)ESI-MS,(M+H＝526.13)
步骤6：
Figure PCTCN2018073460-appb-000021
将化合物6(40mg)溶于二氯甲烷(2mL)然后将4NHCl(1mL)加入反应体系，30度下反应2h，将反应液旋干，饱和碳酸氢钠溶液调pH值至7-8，乙酸乙酯(3*10mL)萃取，无水硫酸钠干燥，旋干有机相，粗品经柱层析分离得化合物10a(8mg)
实施例2：化合物10b的合成
Figure PCTCN2018073460-appb-000022
化合物6b的制法参照实施例1的步骤1-5，不同点在于步骤3中用1，3-二溴丙烷代替1，4-二溴丁烷。
根据实施例1的步骤6，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)。
实施例3：化合物10c的合成
Figure PCTCN2018073460-appb-000023
化合物6c的制法参照实施例1的步骤1-5，不同点在于步骤3中用1，5-二溴戊烷代替1，4-二溴丁烷。
根据实施例1的步骤6，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)。
实施例4：化合物10d的合成
Figure PCTCN2018073460-appb-000024
化合物6d的制法参照实施例1的步骤1-5，不同点在于步骤3中用2，5-二溴戊烷代替1，4-二溴丁烷。
根据实施例1的步骤6，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(7mg)。
实施例5：化合物10e的合成
Figure PCTCN2018073460-appb-000025
化合物6e的制法参照实施例1的步骤1-5，不同点在于步骤3中用2-二氟甲基-5-溴丙烷代替1，4-二溴丁烷。
根据实施例1的步骤6，只需用化合物6e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10e(11mg)。
实施例6：化合物10f的合成
Figure PCTCN2018073460-appb-000026
化合物6f的制法参照实施例1的步骤1-5，不同点在于步骤3中用2-甲基异恶唑苄基-2，5-二溴己烷代替1，4-二溴丁烷。
根据实施例1的步骤6，只需用化合物6f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10f(8mg)。
实施例7：化合物10g的合成
Figure PCTCN2018073460-appb-000027
化合物6g的制法参照实施例1的步骤1-5，不同点在于步骤3中用1-异丙基-1，4-二溴己烷代替1，4-二溴丁烷，步骤5中用3,4-二氟-苯胺代替4-氟-3-氰基苯胺。
根据实施例1的步骤6，只需用化合物6g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10g(4mg)。
实施例8：化合物10h的合成
Figure PCTCN2018073460-appb-000028
化合物6h的制法参照实施例1的步骤1-5，不同点在于步骤3中用1-异丙基-1，4-二溴 己烷代替1，4-二溴丁烷，步骤5中用4-氟-3-二氟甲基苯胺代替4-氟-3-氰基苯胺。
根据实施例1的步骤6，只需用化合物6h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10h(9mg)。
实施例9：化合物20a的合成
Figure PCTCN2018073460-appb-000029
步骤11：
Figure PCTCN2018073460-appb-000030
将烯丙基溴(1.4g)滴加到化合物2(2g)和碳酸钾(2.3g)的乙腈(30mL)溶液中，将体系温度升至85度，反应1h，将水加入反应体系，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12(2.1g)ESI-MS,(M+H＝229.07)
步骤12：
Figure PCTCN2018073460-appb-000031
将氯磺酸异氰酸酯(2g)溶于二氯甲烷(40mL),将体系温度降至0度，然后将叔丁醇(1.3g)加入反应体系，搅拌30min，将三乙胺(3g)和化合物12(2.0g)在0度下加入反应体系，，加完后升温至室温搅拌反应2h，将反应体系加水(50mL),二氯甲烷(3*50mL)萃取，无水硫酸钠干燥，将有机相旋干，粗品柱层析得化合物13(1.4g),ESI-MS,(M+H＝408.10)
步骤13：
Figure PCTCN2018073460-appb-000032
将化合物13(1.2g)和烯丙基溴(1.1g)溶于乙腈中，然后将碳酸铯加入反应体系，升温至80度，反应2h，将水(20mL)加入反应体系，乙酸乙酯(3*20mL)萃取，无水硫酸钠干燥，将有机相旋干得化合物14(1g)ESI-MS,(M+H＝448.12)
步骤14：
Figure PCTCN2018073460-appb-000033
将化合物14(400mg)溶于二氯甲烷(400mL)中，然后将赞式催化剂CatB(42mg)加入反应体系，30度反应12h，将反应体系加入硅胶旋干至白色粉末，柱层析得化合物15(130mg)ESI-MS,(M+H＝420.09)
步骤15：
Figure PCTCN2018073460-appb-000034
将化合物15(80mg)溶于四氢呋喃(2mL),水(0.5mL),甲醇(0.5mL),然后室温下将一水合氢氧化锂(80mg)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16(40mg)ESI-MS,(M+H＝406.07)
步骤16：
Figure PCTCN2018073460-appb-000035
将化合物16(40mg)，三乙胺(60mg)，4-氟-3-乙腈-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，粗品柱层析得化合物17(40mg)ESI-MS,(M+H＝524.11)
步骤17：
Figure PCTCN2018073460-appb-000036
将化合物17(40mg)溶于二氯甲烷(2mL)然后将4NHCl(1mL)加入反应体系，30度下反应2h，将反应液旋干，饱和碳酸氢钠溶液调pH值至7-8，乙酸乙酯(3*10mL)萃取，无水硫酸钠干燥，旋干有机相，粗品经柱层析分离得化合物20a(12mg)
实施例10：化合物20b的合成
Figure PCTCN2018073460-appb-000037
化合物17b的制法参照实施例9的步骤11-16，不同点在于步骤13中用4-溴-1-丁烯代替丙烯溴。
根据实施例9的步骤17，只需用化合物17b代替化合物17，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝2：1)目标产物20b(6mg)。
实施例11：化合物20c的合成
Figure PCTCN2018073460-appb-000038
化合物17c的制法参照实施例9的步骤11-16，不同点在于步骤13中用3-溴-1-丁烯代替丙烯溴。
根据实施例9的步骤17，只需用化合物17c代替化合物17，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝2：1)目标产物20c(13mg)。
实施例12：化合物20d的合成
Figure PCTCN2018073460-appb-000039
化合物17d的制法参照实施例9的步骤11-16，不同点在于步骤13中用4-甲基异恶唑苄 基-1-戊烯代替丙烯溴。
根据实施例9的步骤17，只需用化合物17d代替化合物17，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝2：1)目标产物20d(22mg)。
实施例13：化合物20e的合成
Figure PCTCN2018073460-appb-000040
化合物17e的制法参照实施例9的步骤11-16，不同点在于步骤13中用1-异丙基-1-丙烯代替丙烯溴，步骤16中用3,4-二氟-苯胺代替4-氟-3-氰基苯胺。
根据实施例9的步骤17，只需用化合物17e代替化合物17，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：1)目标产物20e(14mg)。
实施例14：化合物20f的合成
Figure PCTCN2018073460-appb-000041
化合物17f的制法参照实施例9的步骤11-16，不同点在于步骤13中用1-异丙基-1-丙烯代替丙烯溴，步骤16中用4-氟-3-二氟甲基基苯胺代替4-氟-3-氰基苯胺。
根据实施例9的步骤17，只需用化合物17f代替化合物17，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝1：1)目标产物20f(8mg)。
实施例15：化合物30a的合成
Figure PCTCN2018073460-appb-000042
步骤21:
Figure PCTCN2018073460-appb-000043
将化合物21(1.5g)溶于醋酸(20mL),然后将铁粉(1.9g)加入反应体系，将温度升至50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22(1g)。ESI-MS,(M+H＝190.03)
步骤22：
Figure PCTCN2018073460-appb-000044
将氯磺酸异氰酸酯(200mg)溶于二氯甲烷(5mL),将体系温度降至0度，然后将叔丁醇(105mg)加入反应体系，搅拌30min，将三乙胺(214mg)和化合物22(266mg)在0度下加入反应体系，，加完后升温至室温搅拌反应2h，将反应体系加水(20mL),二氯甲烷(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(150mg),ESI-MS,(M+H＝369.06)
步骤23:
Figure PCTCN2018073460-appb-000045
将化合物23(100mg)和1，4-二溴丁烷(58.8mg)溶于丙酮(10mL),将碳酸铯(266mg)加入反应体系，60度反应24h，将水(15mL)加入反应体系,乙酸乙酯(3*20mL)萃取，无水硫酸钠干燥，将有机相旋干，粗品经柱层析分离得黄色固体化合物24(80mg)，ESI-MS,(M+H＝422.11)
步骤24：
Figure PCTCN2018073460-appb-000046
将化合物24(80mg)溶于四氢呋喃(2mL),水(0.5mL),甲醇(0.5mL),然后室温下将一水合氢氧化锂(80mg)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25(50mg)ESI-MS,(M+H＝408.09)
步骤25：
Figure PCTCN2018073460-appb-000047
将化合物25(50mg)，三乙胺(70mg)，4-氟-3-乙腈-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，粗品柱层析得化合物26(40mg)ESI-MS,(M+H＝526.13)
步骤26：
Figure PCTCN2018073460-appb-000048
将化合物26(40mg)溶于二氯甲烷(2mL)然后将4NHCl(1mL)加入反应体系，30度下反应2h，将反应液旋干，饱和碳酸氢钠溶液调pH值至7-8，乙酸乙酯(3*10mL)萃取，无水硫酸钠干燥，旋干有机相，粗品经柱层析分离得化合物30a(8mg)
实施例16：化合物30b的合成
Figure PCTCN2018073460-appb-000049
化合物26b的制法参照实施例15的步骤21-25，不同点在于步骤23中用2，4-二溴戊烷代替1，4-二溴丁烷。
根据实施例15的步骤26，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(11mg)。
实施例17：化合物30c的合成
Figure PCTCN2018073460-appb-000050
化合物26c的制法参照实施例15的步骤21-25，不同点在于步骤23中用2-甲基异恶唑苄基-2，5-二溴己烷代替1，4-二溴丁烷。
根据实施例15的步骤26，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＝2：1)目标产物30c(8mg)。
实施例18：30d的合成
Figure PCTCN2018073460-appb-000051
化合物26d的制法参照实施例15的步骤21-25，不同点在于步骤23中用1-异丙基-1，4-二溴己烷代替1，4-二溴丁烷。步骤25中用3,4-二氟-苯胺代替4-氟-3-氰基苯胺。根据实施例15的步骤26，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＝2：1)目标产物30d(9mg)。
实施例19：化合物30e的合成
Figure PCTCN2018073460-appb-000052
化合物26e的制法参照实施例15的步骤21-25，不同点在于步骤23中用用1-异丙基-1，4-二溴己烷代替1，4-二溴丁烷。步骤25中用3-二氟甲基-4-氟-苯胺代替4-氟-3-氰基苯胺。根据实施例15的步骤26，只需用化合物26e代替化合物26，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝2：1)目标产物30e(11mg)。
实施例20：化合物40a的合成
Figure PCTCN2018073460-appb-000053
步骤31：
Figure PCTCN2018073460-appb-000054
将烯丙基溴(1.4g)滴加到化合物31(2g)和碳酸钾(2.3g)的乙腈(30mL)溶液中，将体系温度升至85度，反应1h，将水加入反应体系，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32(2.1g)ESI-MS,(M+H＝230.07)
步骤32：
Figure PCTCN2018073460-appb-000055
将氯磺酸异氰酸酯(2g)溶于二氯甲烷(40mL),将体系温度降至0度，然后将叔丁醇(1.3g)加入反应体系，搅拌30min，将三乙胺(3g)和化合物32(2.0g)在0度下加入反应体系，，加完后升温至室温搅拌反应2h，将反应体系加水(50mL),二氯甲烷(3*50mL)萃取，无水硫酸钠干燥，将有机相旋干，粗品柱层析得化合物33(1.4g),ESI-MS,(M+H＝409.11)
步骤33：
Figure PCTCN2018073460-appb-000056
将化合物33(1.2g)和烯丙基溴(1.1g)溶于乙腈中，然后将碳酸铯加入反应体系，升温至80度，反应2h，将水(20mL)加入反应体系，乙酸乙酯(3*20mL)萃取，无水硫酸钠干燥，将有机相旋干得化合物34(1g)ESI-MS,(M+H＝449.13)
步骤34：
Figure PCTCN2018073460-appb-000057
将化合物34(400mg)溶于二氯甲烷(400mL)中，然后将赞式催化剂CatB(42mg)加入反应体系，30度反应12h，将反应体系加入硅胶旋干至白色粉末，柱层析得化合物35(130mg)ESI-MS,(M+H＝421.10)
步骤35：
Figure PCTCN2018073460-appb-000058
将化合物35(80mg)溶于四氢呋喃(2mL),水(0.5mL),甲醇(0.5mL),然后室温下将一水合氢氧化锂(80mg)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36(40mg)ESI-MS,(M+H＝407.08)
步骤36：
Figure PCTCN2018073460-appb-000059
将化合物36(40mg)，三乙胺(60mg)，4-氟-3-乙腈-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，粗品柱层析得化合物37(40mg)ESI-MS,(M+H＝525.11)
步骤37：
Figure PCTCN2018073460-appb-000060
将化合物37(40mg)溶于二氯甲烷(2mL)然后将4NHCl(1mL)加入反应体系，30度下反应2h，将反应液旋干，饱和碳酸氢钠溶液调pH值至7-8，乙酸乙酯(3*10mL)萃取，无水硫酸钠干燥，旋干有机相，粗品经柱层析分离得化合物40a(12mg)
实施例21：化合物40b的合成
Figure PCTCN2018073460-appb-000061
化合物37b的制法参照实施例20的步骤31-36，不同点在于步骤32中用3-溴-1-丁烯代替丙烯溴。
根据实施例20的步骤37，只需用化合物37b代替化合物37，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝2：1)目标产物40b(6mg)。
实施例22：化合物40c的合成
Figure PCTCN2018073460-appb-000062
化合物37c的制法参照实施例20的步骤31-36，不同点在于步骤32中用4-甲基异恶唑苄基-1-戊烯代替丙烯溴根据实施例20的步骤37，只需用化合物37c代替化合物37，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝2：1)目标产物40c(13mg)。
实施例23：化合物40d的合成
Figure PCTCN2018073460-appb-000063
化合物37d的制法参照实施例20的步骤31-36，不同点在于步骤32中用1-异丙基-1-丙烯代替丙烯溴，步骤35中用3,4-二氟-苯胺代替4-氟-3-氰基苯胺。
根据实施例20的步骤37，只需用化合物37d代替化合物37，其他条件不变，经柱层析(正 庚烷：乙酸乙酯＝2：1)目标产物40d(12mg)。
实施例24：化合物40e的合成
Figure PCTCN2018073460-appb-000064
化合物37e的制法参照实施例20的步骤31-36，不同点在于步骤32中用1-异丙基-1-丙烯代替丙烯溴，步骤35中用3-二氟甲基-4-氟-苯胺代替4-氟-3-氰基苯胺。
根据实施例20的步骤37，只需用化合物37e代替化合物37，其他条件不变，经柱层析(正庚烷：乙酸乙酯＝2：1)目标产物40e(13mg)。
生物学实施例--抗-HBV活性实验
实验一：体外抗乙肝病毒核衣壳组装活性试验方法
主要试剂和原料：
C150蛋白为药明康德公司表达和纯化；
Figure PCTCN2018073460-appb-000065
购自赛默飞世尔科技公司。
蛋白荧光标记：
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 PCTCN2018073460-appb-000066
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：
Figure PCTCN2018073460-appb-000067
Figure PCTCN2018073460-appb-000068
Figure PCTCN2018073460-appb-000069
其中，
Figure PCTCN2018073460-appb-000070
表示荧光标记的浓度；
[C150Bo]表示荧光标记蛋白的浓度；
A504表示波长504nM的吸光值；
A280表示波长280nM的吸光值；
M -1表示摩尔浓度的倒数。
化合物稀释：
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。
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。
0％蛋白组装对照孔，加入10μL的50mM HEPES，NaCl的终浓度为0mM。
100％蛋白组装对照孔，加入10μL的5M NaCl/50mM HEPES，NaCl的终浓度为1M。
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)。
数据分析
％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.
IC 50值通过prism软件计算，方程如下：
Y＝Bottom+(Top-Bottom)/(1+10 ((LogIC50-X)*HillSlope))；
其中，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；
Bottom表示曲线的底部；Top表示曲线的顶部；
HillSlope表示：曲线的最大斜率的绝对值。
实验二：在HepG2.2.15细胞的抗乙肝病毒活性测定
主要试剂：
QIAamp 96DNA血液试剂盒(12)(Qiagen，货号51162)；
FastStart Universal Probe Master(Roche，货号04914058001)；
Cell–titer Glo检测试剂(Promega，货号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％。
接种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。
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。
活性计算公式如下:
Y＝Bottom+(Top-Bottom)/(1+10 ((LogIC50-X)*HillSlope))；
其中，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；
Bottom表示曲线的底部；Top表示曲线的顶部；
HillSlope表示：曲线的最大斜率的绝对值。
实验三：细胞毒性测定
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。
Figure PCTCN2018073460-appb-000071
表中：
a1表示IC50(μM)在<1；
a2表示IC50(μM)在1～100之间；
a3表示IC50(μM)在>100；
b1表示EC50(μM)在<1之间；
b2表示EC50(μM)在1～100之间；
b3表示EC50(μM)在>100；
其中，对照化合物为：
Figure PCTCN2018073460-appb-000072
(参见WO2014184350A1)
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，且细胞毒性更低。
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。

Claims (10)

  1. 一种如式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，
    Figure PCTCN2018073460-appb-100001
    其中，
    R 1、R 2各自独立地选自下组：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个选自下组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、卤素或取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基，所述R 1、R 2中，所述取代指被选自下组的一个或多个取代基所取代：-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、-O-；
    X为CR 11R 12或-CR 11＝CR 12-；其中，R 11和R 12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个选自下组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个选自下组N、S和O的杂原子的5-10元杂芳基、取代或未取代的C 1-3烷基-R 7、或-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个选自下组N、S和O的杂原子的5-10元杂芳基、具有1-3个选自下组N、S和O的杂原子的3-7元杂环烷基、-NR 9R 10，其中，所述R 9、R 10各自独立地选自：H、C 1-C 3烷基、卤代的C 1-C 3烷基；
    或者，
    所述R 11和R 12与相邻的C原子共同构成具有1-3个选自下组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取代基所取代：-OH、卤素、甲氧基、-O-、-C(＝O)OC 1-4烷基、苄基、C 1-4烷基、卤代的C 1-4烷基，
    并且，所述R 11、R 12中，所述取代指被选自下组的一个或多个取代基所取代：-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；
    Y为取代或未取代的C 1-C 7亚烷基或C 2-C 7亚烯基，所述Y中，所述取代指被选自下组的一个或多个取代基所取代：C 1-C 4烷基、卤素、-OH，较佳地为C 1-C 4烷基或-OH；
    Z选自下组：NH、O或一个键；
    环C为取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基，所 述环C中，所述取代指被选自下组的一个或多个取代基所取代：C 1-C 3烷基、C 3-C 4环烷基、-CN或卤素；
    环B为取代或未取代的C 6-C 10芳基、取代或未取代的具有1-3个选自下组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取代基所取代：C 1-C 3烷基、C 3-C 4环烷基、-CN或卤素；
    R a、R b、R c、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、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 1-C 8烷胺基、取代或未取代的C 1-C 8烷氧基、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个选自下组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、或取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基；所述R a、R b、R c、R d中，所述“取代”是指被选自下组的一个或多个取代基所取代：卤素、C 1-C 6烷基、卤代的C 1-C 6烷基、C 1-C 6烷氧基、卤代的C 1-C 6烷氧基、C 3-C 8环烷基、卤代的C 3-C 8环烷基、氧代、-CN、羟基、氨基、羧基、C 6-C 10芳基、卤代的C 6-C 10芳基、具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基、卤代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基。
  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，R 1、R 2各自独立地选自下组：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个选自下组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、或取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基，所述R 1、R 2中，所述取代指被选自下组的一个或多个取代基所取代：-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-；
    X为CR 11R 12或-CR 11＝CR 12-；其中，R 11和R 12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个选自下组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个选自下组N、S和O的杂原子的5-10元杂芳基、C 1-3烷基-R 7、或-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个选自下组N、S和O的杂原子的5-10元杂芳基、具有1-3个选自下组N、S和O的杂原子的3-7元杂环烷基、-NR 9R 10，其中，所述R 9、R 10各自独立地选自：H、C 1-C 3烷基、卤代的C 1-C 3烷基；
    或者，
    所述R 11和R 12与相邻的C原子共同构成具有1-3个选自下组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 个取代基所取代：-OH、卤素、甲氧基、-O-、-C(＝O)OC 1-4烷基、苄基、C 1-4烷基、卤代的C 1-4烷基，
    并且，所述R 11、R 12中，所述取代指被选自下组的一个或多个取代基所取代：-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；
    R a、R b、R c、R d为苯环上任意位置的取代基，定义如权利要求1所述。
  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，R 1为H、未取代的C 1-C 10烷基、C 3-C 10环烷基、或被-OH、＝O、-O-或卤素取代的C 1-C 10烷基。
  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取代基所取代：甲基、-CN或卤素。
  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R a、R b、R c、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、或-C 1-C 4烷基。
  6. 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，所述式A化合物选自下组：
    Figure PCTCN2018073460-appb-100002
    Figure PCTCN2018073460-appb-100003
  7. 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，所示式A化合物为式VII-1所示的化合物，所述方法包括步骤(I)：
    Figure PCTCN2018073460-appb-100004
    或者，
    所示式A化合物为式VIII-1所示的化合物，所述方法包括步骤(II)：
    Figure PCTCN2018073460-appb-100005
    所述步骤(I)或(II)中，R 2、R a、R b、R c、R d、环C、环B的定义同权利要求1所述，m、n分别为1-5的正整数；
    其中，R 3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个选自下组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、或取代或未取代的具有1-3个选自下组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个选自下组N、S和O的杂原子的5-10元杂芳基、具有1-3个选自下组N、S和O的杂原子的3-7元杂环烷基、-NR 9R 10，其中，所述R 9、R 10各自独立地选自：H、C 1-C 3烷基、卤代的C 1-C 3烷基。
  8. 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；(2)药学上可接受的载体。
  9. 如下所示化合物：
    Figure PCTCN2018073460-appb-100006
  10. 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、或权利要求8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。
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