WO2018121689A1 - 磺酰胺-芳基酰胺类化合物及其治疗乙型肝炎的药物用途 - Google Patents

磺酰胺-芳基酰胺类化合物及其治疗乙型肝炎的药物用途 Download PDF

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WO2018121689A1
WO2018121689A1 PCT/CN2017/119531 CN2017119531W WO2018121689A1 WO 2018121689 A1 WO2018121689 A1 WO 2018121689A1 CN 2017119531 W CN2017119531 W CN 2017119531W WO 2018121689 A1 WO2018121689 A1 WO 2018121689A1
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compound
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unsubstituted
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alkyl
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王喆
王晓光
卢涔宾
范国钦
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上海长森药业有限公司
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    • 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
    • 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
    • A61K31/41—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • 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
    • C07D231/16—Halogen atoms or nitro radicals
    • 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
    • C07D231/40—Acylated on said nitrogen atom
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention belongs to the field of chemical medicine, and in particular, to a sulfonamide-arylamide compound and a pharmaceutical use thereof for treating hepatitis B.
  • 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. Prior to 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.
  • dsDNA partially double-stranded DNA
  • Hepadnaviridae hepatovirus DNA family
  • X gene which encode three envelope proteins
  • 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 first aspect of the invention provides a compound of formula A, or a stereoisomer, cis-trans isomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof ,
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted, and 1-3 are selected from the group consisting of N, a 3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted heteroatom of S and O having from 1 to 3 heteroatoms selected from the group consisting of N, S and O a 5-10 membered heteroaryl; or R 1 , R 2 and the nitrogen atom to which they are attached form a substituted or unsubstituted heteroatom having 1 N and 0-3 selected from the group consisting of N, S and O. 3-10 membered heterocycloalkyl;
  • substitution means one or more (for example, 2, 3, 4, etc.) substituents selected from the group consisting of the following groups. Substituted: 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, carboxy, C6-C10 aryl, halogenated C6-C10 aryl, 5 having from 1 to 3 heteroatoms selected from the group consisting of N, S and O a 10-membered heteroaryl, halogenated 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O;
  • M is O, S, CR 7 R 7' or NR 8 ; wherein R 7 , R 7 ' and R 8 are each independently hydrogen, halogen, -CN, hydroxy, substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 alkoxy group, a substituted or unsubstituted C3-C8 cycloalkyl group; wherein said "substituted” means one or more selected from the group consisting of (for example, 2, 3 , 4, etc. substituted by a substituent: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, -CN, hydroxy, amino, carboxy;
  • Y is a carbonyl group (-(CO)-) or a sulfonyl group (-SO 2 -);
  • X Y cannot be a carbonyl group at the same time, and Y cannot be a sulfonyl group when X is a carbonyl group;
  • Z is N or CR 10 ; wherein R 10 is each independently hydrogen, halogen, -CN, hydroxy, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or not Substituted C3-C10 cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl having 1 to 3 heteroatoms selected from the group consisting of N, S and O, substituted or unsubstituted C6-C10 aryl And a substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O; wherein said "substituted” refers to a group selected from the group consisting of Or a plurality of (eg, 2, 3, 4, etc.) substituents substituted: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted, and 1-3 are selected from the group consisting of N, a 3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted heteroatom of S and O having from 1 to 3 heteroatoms selected from the group consisting of N, S and O a 5-10 membered heteroaryl; or R 1 , R 2 and the nitrogen atom to which they are attached form a substituted or unsubstituted heteroatom having 1 N and 0-3 selected from the group consisting of N, S and O. 3-10 membered heterocycloalkyl;
  • substitution means one or more (for example, 2, 3, 4, etc.) substituents selected from the group consisting of the following groups. Substituted: 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, carboxy, C6-C10 aryl, halogenated C6-C10 aryl, 5 having from 1 to 3 heteroatoms selected from the group consisting of N, S and O a 10-membered heteroaryl, halogenated 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O;
  • M is NR 8 ; wherein R 8 is a methyl group
  • X is NR 9 ; wherein R 9 is hydrogen;
  • Y is a sulfonyl group (-SO 2 -);
  • Z is N or CR 10 ; wherein R 10 is each independently hydrogen.
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted, and 1-3 are selected from the group consisting of N, a 3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted heteroatom of S and O having from 1 to 3 heteroatoms selected from the group consisting of N, S and O a 5-10 membered heteroaryl; or R 1 , R 2 and the nitrogen atom to which they are attached form a substituted or unsubstituted heteroatom having 1 N and 0-3 selected from the group consisting of N, S and O. 3-10 membered heterocycloalkyl;
  • substitution means one or more (for example, 2, 3, 4, etc.) substituents selected from the group consisting of the following groups. Substituted: 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, carboxy, C6-C10 aryl, halogenated C6-C10 aryl, 5 having from 1 to 3 heteroatoms selected from the group consisting of N, S and O a 10-membered heteroaryl, halogenated 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O;
  • M is NR 8 ; wherein R 8 is a methyl group
  • X is NR 9 ; wherein R 9 is hydrogen;
  • Y is a sulfonyl group (-SO 2 -);
  • Z is CR 10 ; wherein R 10 is hydrogen.
  • R 1 and R 2 are each independently hydrogen, a substituted or unsubstituted C 2 -C 8 alkyl group, a substituted or unsubstituted C 3 -C 4 cycloalkyl group; wherein the "substituted” means Substituted by one or more (e.g., 2, 3, 4, etc.) substituents selected from the group consisting of fluorine, chlorine, bromine, and iodine.
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 2 -C 4 alkyl, substituted or unsubstituted C 3 -C 4 cycloalkyl; wherein said "substituted” means Substituted by one or more (e.g., 2, 3, 4, etc.) substituents selected from the group consisting of fluorine, chlorine, bromine, and iodine.
  • R 3 is hydrogen, fluorine, chlorine, bromine, iodine, -CN, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C4 cycloalkyl group; "Substituted” means substituted by one or more (eg, 2, 3, 4, etc.) substituents selected from the group consisting of halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, - CN, hydroxyl.
  • R 3 is hydrogen, fluorine, chlorine, bromine or iodine.
  • R 4 , R 5 and R 6 are each independently hydrogen, fluorine, chlorine, bromine, iodine, -CN, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3- C4 cycloalkyl; wherein the "substituted” refers to being substituted with one or more (eg, 2, 3, 4, etc.) substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, C1 -C4 alkyl, halogenated C1-C4 alkyl.
  • R 4 , R 5 and R 6 are each independently hydrogen, fluorine, chlorine, bromine, iodine, -CN, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3- C4 cycloalkyl; wherein said "substituted” refers to being substituted with one or more (e.g., two, three, four, etc.) substituents selected from the group consisting of fluorine, chlorine, bromine, and iodine.
  • M is NR 8 ; wherein R 8 is hydrogen, halogen, -CN, hydroxy, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted Or unsubstituted C3-C4 cycloalkyl; wherein said "substituted” refers to being substituted with one or more (eg, 2, 3, 4, etc.) substituents selected from the group consisting of halogen, C1 -C4 alkyl, halogenated C1-C4 alkyl, -CN, hydroxy, amino, carboxy.
  • Z is N or CR 10 ; wherein R 10 is each independently hydrogen, fluoro, chloro, bromo, iodo, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3- C4 cycloalkyl; wherein the "substituted” refers to being substituted with one or more (eg, 2, 3, 4, etc.) substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, C1 -C4 alkyl, halogenated C1-C4 alkyl.
  • the compound is selected from the group consisting of:
  • a second aspect of the invention provides a compound according to the first aspect, or a stereoisomer, cis-trans isomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof Preparation method,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Z have the same meanings as defined above;
  • the compound of the formula A is a compound of the formula XIII-3, the method comprising the steps of:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Z and M have the same meanings as defined above;
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 have the same meanings as defined above;
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 have the same meanings as defined above.
  • the compound of formula VII-2 can be prepared from the compound of formula 1-2 as a starting material.
  • the preparation method may include the following steps:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Z have the same meanings as defined above.
  • the compound of formula V-3 can be prepared from the compound of formula 1-3 as a starting material.
  • the preparation method may include the following steps:
  • R 3 has the same definition as before.
  • the third aspect of the invention provides an intermediate represented by the formula: or a stereoisomer, cis-trans isomer or tautomer thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Z have the same meanings as defined above.
  • a fourth aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (1) the compound of the first aspect, or a stereoisomer, cis-trans isomer or tautomer thereof, or a pharmaceutically acceptable thereof a salt, hydrate or 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, tenofovir alafenamide (TAF), and Lamiv Ding, adefovir, entecavir and telbivudine.
  • the fifth aspect of the invention provides the compound of the first aspect, or a stereoisomer, cis-trans isomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof or Use of the pharmaceutical composition of the four aspects for the preparation of a medicament for the prevention and/or treatment of hepatitis B virus infection.
  • a sixth aspect of the present invention provides a method for treating hepatitis B, which comprises administering a compound of the first aspect, or a stereoisomer, cis-trans isomer or tautomer thereof, or A pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to the fourth aspect.
  • the inventors have conducted extensive and intensive research and found a novel class of compounds having excellent therapeutic effects on hepatitis B. On this basis, the inventors completed the present invention.
  • alkyl as used herein includes a straight or branched alkyl group.
  • C1-C8 alkyl means a straight or branched alkyl group having 1-8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like.
  • alkenyl as used herein, includes a straight or branched alkenyl group.
  • C2-C6 alkenyl refers to a straight or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butene Alkenyl, or the like.
  • alkynyl includes a straight or branched alkynyl group.
  • C2-C6 alkynyl refers to a straight or branched alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.
  • C3-C10 cycloalkyl refers to a cycloalkyl group having from 3 to 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.
  • C1-C8 alkylamino refers to an amine group substituted by a C1-C8 alkyl group, which may be monosubstituted or disubstituted; for example, methylamino, ethylamino, propylamino, iso Alanine, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di-tert-butylamine, and the like.
  • C1-C8 alkoxy refers to a straight or branched alkoxy group having from 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, isopropoxy Base, butoxy, isobutoxy, tert-butoxy and the like.
  • a 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 selected A saturated or partially saturated cyclic group of heteroatoms from the next group 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.
  • C6-C10 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”. , C1-C6 alkyl-amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo C1-C6 alkyl, halo C2-C6 alkenyl , halogenated C2-C6 alkynyl, halogenated C1-C6 alkoxy, allyl, benzyl, C6-C12 aryl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy a carbonyl group, a phenoxycarbonyl group, a C2-C6 alkynyl-carbonyl group, a C2-C6 alkeny
  • 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 compounds of the invention can be prepared according to methods generally used in the art. It can also be prepared according to the scheme route given below according to the present invention, using conventional synthesis conditions (e.g., reaction temperature or reaction time, etc.). Among them, the reaction temperature and the reaction time can be determined by those skilled in the art based on the conventional reaction conditions of the reaction.
  • the reaction temperature may be -78 ° C to reflux; preferably, it is -20 ° C to reflux or 0 to 100 ° C or the like.
  • the reaction time may be from 0.1 hour to 3 days or from 0.1 hour to 24 hours or from 0.1 hour to 5 hours, and the like.
  • the compound I-1 is subjected to a nitration reaction for a period of time to form a compound II-1;
  • the compound II-1 is subjected to a reduction reaction for a period of time to form a compound III-1;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Z have the same meanings as defined above.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Z have the same meanings as defined above.
  • the fluorinating reagent is a nucleophilic fluorinating reagent capable of converting a carbonyl group into a difluoromethylene group, such as DAST, BAST, and Ishikawa reagent 1-fluoropyridine tetrafluoroborate.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 have the same meanings as defined above.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Z and M have the same meanings as defined above.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 have the same meanings as defined above.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Z have the same meanings as defined above.
  • the compound of the formula V-1 can be prepared from the compound of the formula I-1 as a starting material. Specifically, the preparation method may include the following steps:
  • R 1 , R 2 , R 3 and Z have the same meanings as defined above.
  • the compound of the formula VI-1 can be prepared from the compound of the formula I-1 as a starting material. Specifically, the preparation method may include the following steps:
  • R 1 , R 2 , R 3 and Z have the same meanings as defined above.
  • the compound of the formula VII-3 can be prepared from the compound of the formula I-1 as a starting material. Specifically, the preparation method may include the following steps:
  • R 1 , R 2 and R 3 have the same meanings as defined above.
  • the compound of the formula VIII-3 can be prepared from the compound of the formula I-3 as a starting material. Specifically, the preparation method may include the following steps:
  • R 1 , R 2 and R 3 have the same meanings as defined above.
  • 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 compounds of the present invention are novel in structure and have excellent anti-HBV infection effects.
  • the compound of the present invention can effectively inhibit the assembly of the hepatitis B virus nucleocapsid, thereby effectively inhibiting the hepatitis B virus.
  • 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 and necrosis leading to cirrhosis, End stage liver disease, ethyl liver cancer).
  • hepatitis B virus-related diseases for example, hepatitis B, progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, End stage liver disease, ethyl liver cancer.
  • the compounds of the invention exhibit superior solubility properties and good pharmacokinetic properties to the reference compound.
  • the substrate 6 (50 mg) was dissolved in DMF (36 mL), then the compound 7 (20 mg), DIPEA (74 mg) was added to the reaction system, and HATU (78 mg) was added to the reaction system at 0 °C for about 5 hours.
  • the TLC detection of the raw material reaction is complete and new points are generated.
  • 20 mL of saturated brine was added to the reaction system, and ethyl acetate (3*20 mL) was extracted. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness.
  • Color solid compound 8 (5 mg).
  • the substrate 13 (90 mg) was dissolved in DCM (3 mL), the temperature of the system was reduced to 0 °, then the solution of compound 14 (112 mg) in dichloromethane was added to the reaction system, stirred at 0 ° for 30 min, then trichloro Aluminum (144 mg) was added to the reaction system in batches, and the reaction was carried out at 0 ° for 3 h.
  • the reaction of the starting material by TLC was complete and a new point was formed.
  • the substrate 15 (50 mg) was dissolved in tetrahydrofuran (1 mL) and ethanol (3 mL), and then aqueous sodium hydroxide (16 mg) was added to the system, and the mixture was reacted at 30 degrees for 0.5 h. The reaction of the starting material was confirmed by TLC, and a new point was formed. Water (20 mL) was added to the reaction mixture, and the mixture was adjusted to 3-4 EtOAc (EtOAc m. .
  • the substrate 16 (25 mg) was dissolved in DMF (2 mL), then tert-butylamine (6.8 mg), DIPEA (74 mg) was added to the reaction system, and HATU (37 mg) was added to the reaction system at 0 °C, and reacted at about 30 °C for 5 h. , TLC detects the reaction of the raw materials completely, and new points are generated. Saturated brine (20 mL) was added to the reaction mixture, and ethyl acetate (3*20 mL) was evaporated. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. ) A pale red solid compound 17 (5 mg) was isolated.
  • Substrate 17 (15 mg) was dissolved in ethanol (2 mL), then hydroxylamine hydrochloride (13 mg) was added to the reaction system, and the reaction temperature was raised to 60 °C for 10 h. The reaction mixture was dried, and the residue was dissolved in acetonitrile.
  • 1 H-NMR (CDCl 3 , 400 MHz) of 18-1 ⁇ : 1.42 (s, 9H), 3.96 (s, 3H), 6.54-6.57 (m, 1H), 7.16-7.20 (m, 1H), 7.69- 7.72 (m, 1H), 8.02 (s, 1H) 8.53 (d, J 8.0 Hz, 1H).
  • Compound 17a was prepared according to steps 11-15, except that isopropylamine was replaced with isopropylamine.
  • step 16 it is only necessary to replace the compound 17 with the compound 17a, and the other conditions are unchanged, and the target product 18a is obtained by high performance liquid chromatography.
  • Compound 17b was prepared according to steps 11-15, except that ethylamine was used instead of t-butylamine.
  • step 16 it is only necessary to replace the compound 17 with the compound 17b, and the other conditions are unchanged, and the target product 18b) is obtained by high performance liquid chromatography.
  • Compound 17c was prepared according to steps 11-15, except that with trifluoroacetic isopropylamine (CH 3 (CF 3) CHNH 2) instead of t-butylamine.
  • CH 3 (CF 3) CHNH 2 trifluoroacetic isopropylamine
  • step 16 it is only necessary to replace the compound 17 with the compound 17c, and the other conditions are unchanged, and the target product 18c is obtained by high performance liquid chromatography.
  • Compound 17d was prepared according to Steps 11-15, except that instead of t-butylamine, cyclopropylamine was used.
  • step 16 it is only necessary to replace the compound 17 with the compound 17d, and the other conditions are unchanged, and the target product 18d is obtained by high performance liquid chromatography.
  • Compound 19-6b was prepared according to Step 19-A-19-E, except that ethylamine was used instead of t-butylamine.
  • step 19-F it is only necessary to replace the compound 19-6 with the compound 19-6b, and the other conditions are unchanged, and the target product 19b is obtained by high performance liquid chromatography.
  • step 19-A-19-E Preparation of Compound 19-6c, except that isopropylamine was treated with trifluoroacetic (CH 3 (CF 3) CHNH 2) instead of t-butylamine.
  • step 19-F it is only necessary to replace the compound 19-6 with the compound 19-6c, and the other conditions are unchanged, and the target product 19c is obtained by high performance liquid chromatography.
  • Compound 19-6d was prepared according to Step 19-A-19-E, except that the bromoamine was used instead of t-butylamine.
  • step 19-F it is only necessary to replace the compound 19-6 with the compound 19-6d, and the other conditions are unchanged, and the target product 19d is obtained by high performance liquid chromatography.
  • the substrate 28 (80 mg), the compound 29 (50 mg) and DIPEA (70 mg) were dissolved in DMF (5 mL), then HATU (130 mg) was added to the reaction system, then reacted at 40 ° for 8 h, water (20 mL), acetic acid B The ester was extracted (3*20 mL), EtOAc (EtOAc m.
  • the substrate 31 (0.8 g) was dissolved in tetrahydrofuran (12 mL), methanol (3 mL) and water (3 mL), then sodium hydroxide (0.44 g) was added to the system, and the reaction was carried out at 55 ° C for 1 h. , there are new points generated. 1N Hydrochloric acid was adjusted to pH 3-4, and water (20 mL) was added to the reaction mixture, and ethyl acetate (3*20 mL) was evaporated.
  • the substrate 32 (100 mg) was dissolved in DMF (3 mL), then 4-F-3-cyano-aniline (40 mg), DIPEA (84 mg) was added to the reaction system, and TBTU (78 mg) was added to the reaction at 0 degree. The system was reacted at room temperature (30 °C) for 5 h. The TLC detection of the raw materials was complete and a new point was formed. 20 mL of a saturated aqueous solution of sodium chloride was added to the reaction mixture, and ethyl acetate (3*20 mL) was evaporated.
  • the substrate 33 (0.3 g) was dissolved in acetic acid (5 mL), and iron powder (1.0 g) was added to the reaction system at room temperature, and reacted at room temperature for 3 hours.
  • the reaction of the starting material was completely detected by TLC, and the acetic acid was spin-dried to adjust the pH to 9-10.
  • Ethyl acetate (3*45 mL) was extracted, dried and dried, and then purified to give the product.
  • [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.
  • a1 indicates that the IC50 ( ⁇ M) is between 0.001 and 10;
  • A2 indicates that the IC50 ( ⁇ M) is between 10 and 100;
  • A3 indicates that the IC50 ( ⁇ M) is between 100 and 10000;
  • control compound is:
  • solubility and pharmacokinetic properties of the compounds of the present invention were superior to the control compounds as compared to the above control compounds by conventional solubility experiments and pharmacokinetic experiments.

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Abstract

本发明公开了一种磺酰胺-芳基酰胺类化合物及其治疗乙型肝炎的药物用途。具体地，本发明公开了一种可作为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、顺反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，各基团的定义详见说明书。本发明还公开了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

磺酰胺-芳基酰胺类化合物及其治疗乙型肝炎的药物用途 技术领域
本发明属于化学医药领域，具体地，本发明涉及一种磺酰胺-芳基酰胺类化合物及其治疗乙型肝炎的药物用途。
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)。
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。
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。
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、替诺福韦艾拉酚胺(TAF)、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(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。
然而，在这些直接的HBV抗病毒药中会遇到毒性、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。
因此，为了克服以上曲线，需要开发具有效价高、毒性更低等优点的HBV抑制剂。
发明内容
本发明的目的是提供一类可用作HBV抑制剂的结构新颖的化合物。
本发明第一方面提供了一种如式A所示的化合物，或其立体异构体、顺反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 PCTCN2017119531-appb-000001
其中，
R 1、R 2各自独立地为氢、取代或未取代的C1-C8烷基、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C6-C10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；或R 1、R 2与和它们相连的氮原子共同构成取代或未取代的具有1个N和0-3个选自下组N、S和O的杂原子的3-10元杂环烷基；
R 3为氢、卤素、-CN、羟基、氨基、羧基、-(C＝O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C1-C8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C6-C10芳基、和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；
R 4、R 5和R 6为苯环上任意位置的取代基，其各自独立地为氢、卤素、-CN、羟基、氨基、羧基、-(C＝O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C8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C6-C10芳基、和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；
R 1、R 2、R 3、R 4、R 5和R 6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、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、羧基、C6-C10芳基、卤代的C6-C10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；
M为O、S、CR 7R 7’或NR 8；其中，R 7、R 7’、R 8各自独立地为氢、卤素、-CN、羟基、取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷氧基、取代或未取代的C3-C8环烷基；其中，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、C1-C6烷基、卤代的C1-C6烷基、-CN、羟基、氨基、羧基；
X为NR 9、羰基(-(CO)-)、卤代亚C1-C4烷基(如CF 2)或羟肟(＝N-OH)；其中，R 9为氢、取代或未取代的C1-C8烷基、取代或未取代的C3-C8环烷基；其中，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、C1-C6烷基、卤代的C1-C6烷基、-CN、羟基、氨基、羧基；
Y为羰基(-(CO)-)或磺酰基(-SO 2-)；
且满足以下条件：X、Y不能同时为羰基，X为羰基时Y不能为磺酰基；
Z为N或CR 10；其中，R 10各自独立地为氢、卤素、-CN、羟基、取代或未取代的C1-C8烷基、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C6-C10芳基、和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；其中，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、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、羧基、C6-C10芳基、卤代的C6-C10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，所述化合物中，
R 1、R 2各自独立地为氢、取代或未取代的C1-C8烷基、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C6-C10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；或R 1、R 2与和它们相连的氮原子共同构成取代或未取代的具有1个N和0-3个选自下组N、S和O的杂原子的3-10元杂环烷基；
R 3为氢、卤素、-CN、羟基、氨基、羧基、-(C＝O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C1-C8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C6-C10芳基、和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；
R 4、R 5和R 6为苯环上任意位置的取代基，其各自独立地为氢、卤素、-CN、羟基、氨基、羧基、-(C＝O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C8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C6-C10芳基、和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；
R 1、R 2、R 3、R 4、R 5和R 6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、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、羧基、C6-C10芳基、卤代的C6-C10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；
M为NR 8；其中，R 8为甲基；
X为NR 9；其中，R 9为氢；
Y为磺酰基(-SO 2-)；
Z为N或CR 10；其中，R 10各自独立地为氢。
在另一优选例中，所述化合物中，
R 1、R 2各自独立地为氢、取代或未取代的C1-C8烷基、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C6-C10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；或R 1、R 2与和它们相连的氮原子共同构成取代或未取代的具有1个N和0-3个选自下组N、S和O的杂原子的3-10元杂环烷基；
R 3为氢、卤素、-CN、羟基、氨基、羧基、-(C＝O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C1-C8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C6-C10芳基、和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；
R 4、R 5和R 6为苯环上任意位置的取代基，其各自独立地为氢、卤素、-CN、羟基、氨基、羧基、-(C＝O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C8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C6-C10芳基、和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；
R 1、R 2、R 3、R 4、R 5和R 6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、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、羧基、C6-C10芳基、卤代的C6-C10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；
M为NR 8；其中，R 8为甲基；
X为NR 9；其中，R 9为氢；
Y为磺酰基(-SO 2-)；
Z为CR 10；其中，R 10为氢。
在另一优选例中，R 1、R 2各自独立地为氢、取代或未取代的C2-C8烷基、取代或未取代的C3-C4环烷基；其中，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：氟、氯、溴、碘。
在另一优选例中，R 1、R 2各自独立地为氢、取代或未取代的C2-C4烷基、取代或未取代的C3-C4环烷基；其中，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：氟、氯、溴、碘。
在另一优选例中，R 3为氢、氟、氯、溴、碘、-CN、取代或未取代的C1-C4烷基、取代或未取代的C3-C4环烷基；其中，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、C1-C4烷基、卤代的C1-C4烷基、-CN、羟基。
在另一优选例中，R 3为氢、氟、氯、溴、碘。
在另一优选例中，R 4、R 5和R 6各自独立地为氢、氟、氯、溴、碘、-CN、取代或未取代的C1-C4烷基、取代或未取代的C3-C4环烷基；其中，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：氟、氯、溴、碘、C1-C4烷基、卤代的C1-C4烷基。
在另一优选例中，R 4、R 5和R 6各自独立地为氢、氟、氯、溴、碘、-CN、取代或未取代的C1-C4烷基、取代或未取代的C3-C4环烷基；其中，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：氟、氯、溴、碘。
在另一优选例中，X为NH、CF 2或羟肟(＝N-OH)。
在另一优选例中，M为NR 8；其中，R 8为氢、卤素、-CN、羟基、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C3-C4环烷基；其中，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、C1-C4烷基、卤代的C1-C4烷基、-CN、羟基、氨基、羧基。
在另一优选例中，Z为N或CR 10；其中，R 10各自独立地为氢、氟、氯、溴、碘、取代或未取代的C1-C4烷基、取代或未取代的C3-C4环烷基；其中，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：氟、氯、溴、碘、C1-C4烷基、卤代的C1-C4烷基。
在另一优选例中，所述化合物选自下组：
Figure PCTCN2017119531-appb-000002
Figure PCTCN2017119531-appb-000003
Figure PCTCN2017119531-appb-000004
本发明第二方面提供了一种第一方面所述的化合物，或其立体异构体、顺反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制备方法，
方法(a)：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：
Figure PCTCN2017119531-appb-000005
(a1)在惰性溶剂中，将化合物III-1与化合物IV-1进行反应，从而形成化合物V-1；
(a2)在惰性溶剂中，将化合物V-1进行水解反应，从而形成化合物VI-1；
(a3)在惰性溶剂中，将化合物VI-1与化合物VII-1进行反应，从而形成化合物VIII-1；
各式中，R 1、R 2、R 3、R 4、R 5、R 6和Z的定义同前；
或方法(a’)：所述式A化合物为式XIII-3所示的化合物，所述方法包括步骤：
Figure PCTCN2017119531-appb-000006
(a’1)在惰性溶剂中，将化合物IX-3进行水解反应，从而形成化合物X-3；
(a’2)在惰性溶剂中，将化合物X-3与化合物VII-1进行反应，从而形成化合物XI-3；
(a’3)在惰性溶剂中，将化合物XI-3进行还原反应，从而形成化合物XII-3；
(a’4)在惰性溶剂中，将化合物X-3与化合物IV-1进行反应，从而形成化合物XIII-3；
各式中，R 1、R 2、R 3、R 4、R 5、R 6、Z和M的定义同前；
或方法(b)：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：
Figure PCTCN2017119531-appb-000007
(b1)在惰性溶剂中，将化合物VII-2和羟胺进行反应，从而形成化合物VIII-2；各式中，R 1、R 2、R 3、R 4、R 5、R 6和Z的定义同前；
或方法(c)：所示式A化合物为式IX-2所示的化合物，所述方法包括步骤：
Figure PCTCN2017119531-appb-000008
(c1)在惰性溶剂中，将化合物VII-2与氟化试剂进行反应，从而形成化合物 IX-2；各式中，R 1、R 2、R 3、R 4、R 5、R 6和Z的定义同前；
或方法(d)：所示式A化合物为式IX-3所示的化合物，所述方法包括步骤：
Figure PCTCN2017119531-appb-000009
(d1)在惰性溶剂中，将化合物V-3与磺酰氯进行反应，从而形成化合物VI-3；
(d2)在惰性溶剂中，将化合物VI-3与HNR 1R 2进行反应，从而形成化合物VII-3；
(d3)在惰性溶剂中，将化合物VII-3进行水解反应，从而形成化合物VIII-3；
(d4)在惰性溶剂中，将化合物VIII-3与化合物VII-1进行反应，从而形成化合物IX-3；
各式中，R 1、R 2、R 3、R 4、R 5和R 6的定义同前；
或方法(e)：所示式A化合物为式VI-5所示的化合物，所述方法包括步骤：
Figure PCTCN2017119531-appb-000010
(e1)在惰性溶剂中，将化合物I-5与氟化试剂进行反应，从而形成化合物II-5；
(e2)在惰性溶剂中，将化合物II-5进行水解反应，从而形成化合物III-5；
(e3)在惰性溶剂中，将化合物III-5与R 1R 2NH进行反应，从而形成化合物IV-5；
(e4)在惰性溶剂中，将化合物IV-5进行水解反应，从而形成化合物V-5；
(e5)在惰性溶剂中，将化合物V-5与化合物VII-1进行反应，从而形成化合物VI-5；
各式中，R 1、R 2、R 3、R 4、R 5和R 6的定义同前。
在另一优选例中，所述式VII-2化合物可由式I-2化合物为起始原料制备得到。具体地制备方法可包括如下步骤：
Figure PCTCN2017119531-appb-000011
各式中，R 1、R 2、R 3、R 4、R 5、R 6和Z的定义同前。
在另一优选例中，所述式V-3化合物可由式I-3化合物为起始原料制备得到。
具体地制备方法可包括如下步骤：
Figure PCTCN2017119531-appb-000012
各式中，R 3的定义同前。
发明第三方面提供了如下式所示的中间体，或其立体异构体、顺反异构体或互变异构体，
Figure PCTCN2017119531-appb-000013
各式中，R 1、R 2、R 3、R 4、R 5、R 6和Z的定义同前。
在另一优选例中，所述式V-1所示的中间体为
Figure PCTCN2017119531-appb-000014
在另一优选例中，所述式VI-1所示的中间体为
Figure PCTCN2017119531-appb-000015
本发明第四方面提供了一种药物组合物，包含(1)第一方面所述的化合物，或其立体异构体、顺反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***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、替诺福韦艾拉酚胺(TAF)、拉米夫定、阿德福韦、恩替卡韦以及替比夫定。
本发明第五方面提供了第一方面所述的化合物，或其立体异构体、顺反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第四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。
本发明第六方面提供了一种治疗乙型肝炎的方法，对有需要的个体施用第一方面所述的化合物，或其立体异构体、顺反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第四方面所述的药物组合物。
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化合物。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C1-C8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C2-C6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C2-C6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“C3-C10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“C1-C8烷胺基”是指被C1-C8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“C1-C8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，“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“C6-C10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)-***基以及(1,2,4)-***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、C1-C6烷基-胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、卤代C1-C6烷基、卤代C2-C6烯基、卤代C2-C6炔基、卤代C1-C6烷氧基、烯丙基、苄基、C6-C12芳基、C1-C6烷氧基-C1-C6烷基、C1-C6烷氧基-羰基、苯氧羰基、C2-C6炔基-羰基、C2-C6烯基-羰基、C3-C6环烷基-羰基、C1-C6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。
制备方法
本发明化合物可根据本领域常用方法制备得到。也可按照本发明如下给出的方案路线，采用常规的合成条件(例如反应温度或反应时间等)制备得到。其中，反应温度和反应时间可由本领域技术人员根据该反应的常规反应条件确定。反应温度可以为-78℃～回流；较佳地，为-20℃～回流或0～100℃等。反应时间可以为0.1小时～3天或0.1小时～24小时或0.1小时～5小时等更短的时间。
方案一：
Figure PCTCN2017119531-appb-000016
(1)在惰性溶剂中，在一定温度下，将化合物I-1进行硝化反应一段时间，从而形成化合物II-1；
(2)在惰性溶剂中，在一定温度下，将化合物II-1进行还原反应一段时间，从而形成化合物III-1；
(3)在惰性溶剂中，在一定温度下，将化合物III-1与化合物IV-1进行反应一段时间，从而形成化合物V-1；
(4)在惰性溶剂中，在一定温度下，将化合物V-1进行水解反应一段时间，从而形成化合物VI-1；和
(5)在惰性溶剂中，在一定温度下，将化合物VI-1与化合物VII-1进行反应一段时间，从而形成化合物VIII-1；
各式中，R 1、R 2、R 3、R 4、R 5、R 6和Z的定义同前。
方案二和方案三：
Figure PCTCN2017119531-appb-000017
(i)在惰性溶剂中，在一定温度下，将化合物I-2进行水解反应一段时间，从而形成化合物II-2；
(ii)在惰性溶剂中，在一定温度下，将化合物II-2与苯胺化合物进行反应一段时间，从而形成化合物III-2；
(iii)在惰性溶剂中，在一定温度下，将化合物III-2与化合物IV-2进行反应一段时间从而形成化合物V-2；
(iv)在惰性溶剂中，在一定温度下，将化合物V-2进行水解反应一段时间，从而形成化合物VI-2；
(v)在惰性溶剂中，在一定温度下，将化合物VI-2与HNR 1R 2进行反应一段时间，从而形成化合物VII-2；和
(vi-1)在惰性溶剂中，在一定温度下，将化合物VII-2和羟胺进行反应一段时间，从而形成化合物VIII-2；或
(vi-2)在惰性溶剂中，在一定温度下，将化合物VII-2与氟化试剂进行反应一段时间，从而形成化合物IX-2；
各式中，R 1、R 2、R 3、R 4、R 5、R 6和Z的定义同前。
在另一优选例中，所述氟化试剂为可以将羰基转化为二氟亚甲基的亲核氟化试剂，例如DAST、BAST、石川试剂1-氟吡啶四氟硼酸盐等常规试剂。
方案四：
Figure PCTCN2017119531-appb-000018
(a)在惰性溶剂中，在一定温度下，将化合物I-3与甲基肼进行反应一段时间，从而形成化合物II-3；
(b)在惰性溶剂中，在一定温度下，将化合物II-3与进行溴化反应一段时间，从而形成化合物III-3；
(c)在惰性溶剂中，在一定温度下，将化合物III-3进行反应一段时间，从而形成化合物IV-3；
(d)在惰性溶剂中，在一定温度下，将化合物IV-3进行胺化反应一段时间，从而形成化合物V-3；
(e)在惰性溶剂中，在一定温度下，将化合物V-3与磺酰氯进行反应一段时间，从而形成化合物VI-3；
(f)在惰性溶剂中，在一定温度下，将化合物VI-3与HNR 1R 2进行反应一段时间，从而形成化合物VII-3；
(g)在惰性溶剂中，在一定温度下，将化合物VII-3进行水解反应一段时间，从而形成化合物VIII-3；
(h)在惰性溶剂中，在一定温度下，将化合物VIII-3与苯胺进行反应一段时间，从而形成化合物IX-3；
各式中，R 1、R 2、R 3、R 4、R 5和R 6的定义同前。
方案五：
Figure PCTCN2017119531-appb-000019
(a’1)在惰性溶剂中，将化合物IX-3进行水解反应，从而形成化合物X-3；
(a’2)在惰性溶剂中，将化合物X-3与化合物VII-1进行反应，从而形成化合物XI-3；
(a’3)在惰性溶剂中，将化合物XI-3进行还原反应，从而形成化合物XII-3；
(a’4)在惰性溶剂中，将化合物X-3与化合物IV-1进行反应，从而形成化合物XIII-3；
各式中，R 1、R 2、R 3、R 4、R 5、R 6、Z和M的定义同前。
方案六：
Figure PCTCN2017119531-appb-000020
(e1)在惰性溶剂中，将化合物I-5与氟化试剂进行反应，从而形成化合物II-5；
(e2)在惰性溶剂中，将化合物II-5进行水解反应，从而形成化合物III-5；
(e3)在惰性溶剂中，将化合物III-5与R 1R 2NH进行反应，从而形成化合物IV-5；
(e4)在惰性溶剂中，将化合物IV-5进行水解反应，从而形成化合物V-5；
(e5)在惰性溶剂中，将化合物V-5与化合物VII-1进行反应，从而形成化合物VI-5；
各式中，R 1、R 2、R 3、R 4、R 5和R 6的定义同前。
中间体
适用于制备本发明化合物的中间体包括如下化合物：
Figure PCTCN2017119531-appb-000021
各式中，R 1、R 2、R 3、R 4、R 5、R 6和Z的定义同前。
在另一优选例中，所述式V-1所示的中间体为
Figure PCTCN2017119531-appb-000022
在另一优选例中，所述式VI-1所示的中间体为
Figure PCTCN2017119531-appb-000023
所述式V-1化合物可由式I-1化合物为起始原料制备得到。具体地制备方法可包括如下步骤：
Figure PCTCN2017119531-appb-000024
各式中，R 1、R 2、R 3和Z的定义同前。
所述式VI-1化合物可由式I-1化合物为起始原料制备得到。具体地制备方法可包括如下步骤：
Figure PCTCN2017119531-appb-000025
各式中，R 1、R 2、R 3和Z的定义同前。
所述式VII-3化合物可由式I-1化合物为起始原料制备得到。具体地制备方法可包括如下步骤：
Figure PCTCN2017119531-appb-000026
各式中，R 1、R 2和R 3的定义同前。
所述式VIII-3化合物可由式I-3化合物为起始原料制备得到。具体地制备方法可包括如下步骤：
Figure PCTCN2017119531-appb-000027
各式中，R 1、R 2和R 3的定义同前。
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(如吐温
Figure PCTCN2017119531-appb-000028
)、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***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。
本发明的主要优点包括：
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。
本发明的化合物可有效抑制乙肝病毒核衣壳的组装，从而有效抑制乙肝病毒。
本发明的化合物对正常细胞的毒性非常低。
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。
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)。
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。
下面结合具体实施，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，否则百分比和份数按重量计算。本发明实施例中所用原料或仪器，若非特别说明，均市售可得。
实施例1：化合物8的合成
Figure PCTCN2017119531-appb-000029
步骤1：化合物2的合成
Figure PCTCN2017119531-appb-000030
将底物1(1.0g)溶于乙酸酐(2mL)，将体系温度降至0度，然后将发烟硝酸(0.5mL)加入反应体系，0度反应3h，然后将碘甲烷(668mg)加入反应体系，室温下反应3h。TLC检测原料反应完全，将水(20mL)加入反应体系，乙酸乙酯(3*30mL)萃取，有机相干燥、旋干，粗品柱层析(正庚烷：乙酸乙酯＝1：5)，得产物2(400mg)。MS(M+1＝219)。
步骤2：化合物3的合成
Figure PCTCN2017119531-appb-000031
将底物2(0.4g)溶于乙酸(5mL)，室温下将铁粉(1.8g)加入反应体系，室温反应3h，TLC检测原料反应完全，将乙酸旋干后，调节残留物的pH值至9-10，乙酸乙酯(3*25mL)萃取，有机相干燥、旋干，粗品柱层析(正庚烷：乙酸乙酯＝1：5)，得产物3(200mg)。MS(M+1＝189)。
步骤3：化合物5的合成
Figure PCTCN2017119531-appb-000032
将底物3(0.2g)溶于乙腈(8mL)，室温下将三乙胺(0.6g)加入反应体系，然后将化合物4(0.35g)加入反应体系，加热回流8h，TLC检测原料反应完全，有新点生成，向反应体系中加水(20mL),乙酸乙酯(3*25mL)萃取，有机相干燥、旋干，粗品柱层析(正庚烷：乙酸乙酯＝1：5)，得产物5(80mg)。 1H-NMR(CDCl 3,400MHz)δ:1.33(d,J＝6.8Hz,3H)，3.85(s,3H),3.86(s,3H),3.95-4.02(m,1H),4.80(d,J＝9.2Hz,1H)，6.19(s,1H),6.90(s,1H).
步骤4：化合物6的合成
Figure PCTCN2017119531-appb-000033
将底物5(80mg)溶于四氢呋喃(2mL)，甲醇(0.5mL)和水(0.5mL)中，然后将氢氧化锂(0.21g)加入反应体系，室温下反应8h，TLC检测原料有少量剩余，有新点生成。将水(20mL)加入反应体系，用1N盐酸调pH值至3-4，二氯甲烷(3*25mL)萃取，有机相无水硫酸钠干燥，旋干，粗品经柱层析(正庚烷：乙酸乙酯＝1：5)分离得黄色固体化合物6(50mg)。MS(M+1＝350)。
步骤5：化合物8的合成
Figure PCTCN2017119531-appb-000034
将底物6(50mg)溶于DMF(36mL)中，然后将化合物7(20mg)，DIPEA(74mg)，加入反应体系，0度下将HATU(78mg)加入反应体系约30度下反应5h，TLC检测原料反应完全，有新点生成。将饱和食盐水20mL加入反应体系，乙酸乙酯(3*20mL)萃取，有机相无水硫酸钠干燥，旋干，粗品高效液相(正庚烷：乙酸乙酯＝1：5)分离得粉红色固体化合物8(5mg)。 1H-NMR(CDCl 3,400MHz)δ:1.16(d,J＝6.8Hz,3H)，3.76(s,3H),3.92-3.99(m,1H)，7.52-7.57(m,1H),7.67(s,1H),7.94-7.98(m,1H),8.16-8.18(m,1H),8.49(br,1H)10.68(s,1H).MS(M+1＝468)。
实施例2化合物8a的合成
Figure PCTCN2017119531-appb-000035
根据步骤5，只需将化合物7用化合物7a代替即可，其他条件不变，经高效液相 色谱分离得目标产物8a。MS(M+1＝461)。
实施例3化合物8b的合成
Figure PCTCN2017119531-appb-000036
根据步骤5，只需将化合物7用化合物7b代替即可，其他条件不变，经高效液相色谱分离得目标产物8b。MS(M+1＝457)。
实施例4化合物8c的合成
Figure PCTCN2017119531-appb-000037
根据步骤5，只需将化合物7用化合物7c代替即可，其他条件不变，经高效液相色谱分离得目标产物8c。MS(M+1＝477)。
实施例5化合物8d的合成
Figure PCTCN2017119531-appb-000038
根据步骤5，只需将化合物7用化合物7d代替即可，其他条件不变，经高效液相色谱分离得目标产物8d。MS(M+1＝495)。
实施例6化合物18的合成
Figure PCTCN2017119531-appb-000039
步骤11：化合物12的合成
Figure PCTCN2017119531-appb-000040
将底物11(0.2g)溶于四氢呋喃(2mL)，甲醇(0.5mL)和水(0.5mL)中，然后将氢氧化锂(0.24g)加入反应体系，室温下反应8h，TLC检测原料有少量剩余，有新点生成。将水(20mL)加入反应体系，用1N盐酸调pH值至3-4，二氯甲烷(3*25mL)萃取，有机相无水硫酸钠干燥，旋干，粗品经柱层析(正庚烷：乙酸乙酯＝1：5)分离得白色固体化合物12(0.16g)。MS(M+1＝160)。
步骤12：化合物13的合成
Figure PCTCN2017119531-appb-000041
将底物12(120mg)溶于DMF(3mL)中，然后将化合物12a(112mg)，DIPEA(292mg)，加入反应体系，0度下将HATU(372mg)加入反应体系，约30度下反应5h，TLC检测原料反应完全，有新点生成。将饱和食盐水(20mL)加入反应体系，乙酸乙酯(3*20mL)萃取，有机相无水硫酸钠干燥，旋干，粗品经柱层析(正庚烷：乙酸乙酯＝1：5)分离得黄色固体化合物13(90mg)。MS(M+1＝278)。
步骤13：化合物15的合成
Figure PCTCN2017119531-appb-000042
将底物13(90mg)溶于DCM(3mL)中，将体系温度降至0度，然后将化合物14(112mg)的二氯甲烷溶液加入反应体系，在0度下搅拌30min，然后将三氯化铝 (144mg)分批加入反应体系，0度反应3h，TLC检测原料反应完全，有新点生成。将反应液倒入冰水(10mL)中，二氯甲烷(3*25mL)萃取，有机相用饱和食盐水20mL洗涤，无水硫酸钠干燥，旋干，粗品经柱层析(正庚烷：乙酸乙酯＝1：8)分离得黄色固体化合物15(55mg)。MS(M+1＝378)。 1H-NMR(CDCl 3,400MHz)δ:1.38-1.42(m,3H)，4.02(s,3H),4.35-4.41(m,1H)，7.19-7.21(m,1H),7.67-7.72(m,1H),7.92(s,1H),8.06-8.08(m,1H),8.66(br,1H).
步骤14：化合物16的合成
Figure PCTCN2017119531-appb-000043
将底物15(50mg)溶于四氢呋喃(1mL)和乙醇(3mL)中，然后将体系内加入氢氧化钠(16mg)水溶液，30度反应0.5h，TLC检测原料反应完全，有新点生成。将水(20mL)加入反应体系，用1N盐酸调pH值至3-4，二氯甲烷(3*25mL)萃取，有机相无水硫酸钠干燥，旋干，得黄色固体化合物16(0.16g)。
步骤15：化合物17的合成
Figure PCTCN2017119531-appb-000044
将底物16(25mg)溶于DMF(2mL)中，然后将叔丁胺(6.8mg)，DIPEA(74mg)，加入反应体系，0度下将HATU(37mg)加入反应体系，约30度下反应5h，TLC检测原料反应完全，有新点生成。将饱和食盐水(20mL)加入反应体系，乙酸乙酯(3*20mL)萃取，有机相无水硫酸钠干燥，旋干，粗品经高效液相柱(正庚烷：乙酸乙酯＝1：5)分离得淡红色固体化合物17(5mg)。 1H-NMR(CDCl 3,400MHz)δ:1.41(s,9H)，4.00(s,3H),7.19-7.23(m,1H),7.69-7.77(m,1H),8.04-8.06(m,1H),8.54(br,1H)8.68(s,1H).Ms(ESI)m/z＝403(M-1)。
步骤16：化合物18的合成
Figure PCTCN2017119531-appb-000045
将底物17(15mg)溶于乙醇(2mL)中，然后将盐酸羟胺(13mg)的加入反应体系， 将反应温度升至60度反应10h。旋干反应液，用乙腈将残留固体溶解后，高效液相反相分离得到化合物18-1(1.8mg)，18-2(2.0mg)。18-1的 1H-NMR(CDCl 3,400MHz)δ:1.42(s,9H)，3.96(s,3H),6.54-6.57(m,1H),7.16-7.20(m,1H),7.69-7.72(m,1H),8.02(s,1H)8.53(d,J＝8.0Hz,1H).18-2的 1H-NMR(CDCl 3,400MHz)δ:1.42(s,9H)，3.96(s,3H),6.54-6.57(m,1H),7.16-7.20(m,1H),7.69-7.72(m,1H),8.02(s,1H)8.53(d,J＝8.0Hz,1H).
实施例7化合物18a的合成
Figure PCTCN2017119531-appb-000046
根据步骤11-15制备化合物17a，不同点在于用异丙胺代替叔丁胺。
根据步骤16，只需将化合物17用化合物17a代替即可，其他条件不变，经高效液相色谱分离得目标产物18a。
实施例8化合物18b的合成
Figure PCTCN2017119531-appb-000047
根据步骤11-15制备化合物17b，不同点在于用乙胺代替叔丁胺。
根据步骤16，只需将化合物17用化合物17b代替即可，其他条件不变，经高效液相色谱分离得目标产物18b)。
实施例9化合物18c的合成
Figure PCTCN2017119531-appb-000048
根据步骤11-15制备化合物17c，不同点在于用三氟异丙胺(CH 3(CF 3)CHNH 2)代替叔丁胺。
根据步骤16，只需将化合物17用化合物17c代替即可，其他条件不变，经高效液相色谱分离得目标产物18c。
实施例10化合物18d的合成
Figure PCTCN2017119531-appb-000049
根据步骤11-15制备化合物17d，不同点在于用环丙胺代替叔丁胺。
根据步骤16，只需将化合物17用化合物17d代替即可，其他条件不变，经高效液相色谱分离得目标产物18d。
实施例11化合物19的合成
Figure PCTCN2017119531-appb-000050
步骤19-A
Figure PCTCN2017119531-appb-000051
化合物19-1(1g，5.8mmol，1equiv)溶解在DCM(30mL)中，草酰氯单乙酯(2g，14.5mmol，2.5euqiv)于Ar保护和0度下滴加入上述溶液中。AlCl 3(3.9g，29mmol，5euqiv)加入反应液中升至室温搅拌过夜。在冰浴下向反应液中滴加水(2.25mL)和EtOAc(7.5mL)。反应液倒入冰水，并以稀盐酸稀释，以EtOAc提取。有机相干燥浓缩后MPLC(庚烷:EtOAc＝50:50)得棕色油状物LW107-44-56(125mg)。 1H NMR(400MHz,氯仿-d)δ7.80(s,1H),4.37(q,J＝7.1Hz,2H),3.95(s,3H),3.91(s,3H),1.40(t,J＝7.2Hz,3H).
步骤19-B
Figure PCTCN2017119531-appb-000052
19-2(100mg，0.38mmol，1equiv)和DAST(1.2g，7.3mmol，20equiv)溶 解在DCM(5mL)中，氩气保护在40度下搅拌过夜。反应液倒入NaHCO 3饱和水溶液并以DCM提取，有机相经饱和食盐水洗后干燥，由制备TLC(庚烷：EtOAc＝3：1)得到棕色油状-固体LW107-44-73(35mg)。 1H NMR(400MHz,氯仿-d)δ7.04(s,1H),4.35(q,J＝7.1Hz,2H),3.90(d,J＝7.9Hz,6H),1.34(t,J＝7.1Hz,3H).
步骤19-C
Figure PCTCN2017119531-appb-000053
19-3(60mg，0.2mmol，1equiv)，LiOH H 2O(9mg,0.2mmol,1equiv)在5度下在Dioxane：H 2O(5mL：1mL)中搅拌2.5h。反应液加水和EtOAc分液，水相在冰浴下以浓盐酸酸化至pH 2-3并以EtOAc提取后以Na 2SO 4干燥，浓缩得到白色固体LW107-44-83(40mg)。 1H NMR(400MHz,DMSO-d 6)δ7.53(s,1H),3.85(s,3H),3.80(s,3H).MS(ESI +):m/z calcd.for[M+H] +:268,found:268.
步骤19-D
Figure PCTCN2017119531-appb-000054
19-4(1235mg，4.63mmol，1equiv)，叔丁胺(1350mg，18.5mmol，4equiv)，DIPEA(3g，23.2mmol，5euqiv)溶解在DMF(60mL)中。HATU(3581mg，9.26mmol，2equiv)在0度下加入上述反应液，并恢复至室温过夜。反应液加入食盐水和EtOAc分液，有机相以食盐水清洗浓缩。由MPLC(庚烷：EtOAc＝88：21-82：18)得到白色固体LW107-44-87(960mg)。 1H NMR(400MHz,氯仿-d)δ7.45(s,1H),4.08(d,J＝1.7Hz,6H),1.61(s,9H).MS(ESI +):m/z calcd.for[M+H] +:323,found:323.
步骤19-E
Figure PCTCN2017119531-appb-000055
19-5(300mg，0.93mmol，1equiv)和LiOH H 2O(313mg，7.45mmol，8equiv) 在MeOH：THF：水(3：12：3mL)中室温搅拌过夜。反应液加水和EtOAc分液，水相在冰浴下以浓盐酸酸化至pH 2-3并以EtOAc提取后以Na 2SO 4干燥，浓缩得到白色固体LW107-68-5(258mg)。 1H NMR(400MHz,DMSO-d 6)δ13.05(s,1H),8.00(s,1H),7.36(s,1H),3.84(s,3H),1.32(s,9H).MS(ESI +):m/z calcd.for[M+H] +:309,found:309.
步骤19-F
Figure PCTCN2017119531-appb-000056
19-6(80mg，0.26mmol，1equiv)，3-氟-4-氰基-苯胺(71mg，0.52mmol，2equiv)和TEA(131mg，1.3mmol，5equiv)溶解在DCM(5mL)。TBTU(167mg，0.52mmol，2equiv)在0度下加入并恢复至室温搅拌过夜。反应液加8％盐酸酸化并以DCM分液，有机相以NaHCO 3溶液清洗，浓缩MPLC(Heptane：EtOAc＝70：30)得粗品(81mg)。制备LC(水:ACN＝45:55,C-18,Det＝260nm,峰＝50min,v＝17ml/min)冻干得白色固体19(25mg)。 1H NMR(400MHz,氯仿-d)δ8.11(d,J＝8.5Hz,1H),7.64–7.40(m,3H),7.36(s,1H),6.47(s,1H),3.95(s,3H),1.46(s,9H).
实施例13化合物19b的合成
Figure PCTCN2017119531-appb-000057
根据步骤19-A-19-E制备化合物19-6b，不同点在于用乙胺代替叔丁胺。
根据步骤19-F的合成，只需将化合物19-6用化合物19-6b代替即可，其他条件不变，经高效液相色谱分离得目标产物19b。
实施例14化合物19c的合成
Figure PCTCN2017119531-appb-000058
根据步骤19-A-19-E制备化合物19-6c，不同点在于用三氟异丙胺 (CH 3(CF 3)CHNH 2)代替叔丁胺。
根据步骤19-F的合成，只需将化合物19-6用化合物19-6c代替即可，其他条件不变，经高效液相色谱分离得目标产物19c。
实施例15化合物19d的合成
Figure PCTCN2017119531-appb-000059
根据步骤19-A-19-E制备化合物19-6d，不同点在于用环丙胺代替叔丁胺。
根据步骤19-F的合成，只需将化合物19-6用化合物19-6d代替即可，其他条件不变，经高效液相色谱分离得目标产物19d。
实施例16化合物20的合成
Figure PCTCN2017119531-appb-000060
步骤18：化合物22的合成
Figure PCTCN2017119531-appb-000061
将化合物甲基肼(10g)溶于甲醇(20mL)和水(10mL)中，降温至0度，搅拌15min后然后将化合物21(12g)滴加入反应体系，加热至70度反应10h，然后将体系温度回复至室温，反应12h，抽滤，滤饼用水(5mL)洗涤，得22淡黄色固体5g，MS(M+1＝157)。
步骤19：化合物23的合成
Figure PCTCN2017119531-appb-000062
将底物22(5g)溶于DMF(10mL)，室温下将三氯氧磷(10mL)加入反应体系，升温至100度，反应5h，将反应体系倒入冰水中，乙酸乙酯(3*30mL)萃取，有机相干燥、旋干，粗品柱层析(正庚烷：乙酸乙酯＝1：5)，得产物23(2g)。MS(M+1＝219)。
步骤20：化合物24的合成
Figure PCTCN2017119531-appb-000063
将底物23(2g)溶于乙腈(10mL)，室温下将NBS(4g)加入反应体系，然后将体系温度升至60度，向反应体系中加水(20mL),乙酸乙酯(3*25mL)萃取，有机相干燥、旋干，粗品柱层析(正庚烷：乙酸乙酯＝1：5)，得产物5(1g)。MS(M+1＝299)。
步骤21：化合物25的合成
Figure PCTCN2017119531-appb-000064
将底物24(1g)溶于二氯甲烷(10mL)，然后将氨水(5mL)加入反应体系，室温下反应2h，将水(20mL)加入反应体系，用1N盐酸调pH值至3-4，二氯甲烷(3*25mL)萃取，有机相无水硫酸钠干燥，旋干，粗品经柱层析(正庚烷：乙酸乙酯＝1：5)分离得黄色固体化合物25(300mg)。MS(M+1＝234)。
步骤22：化合物26的合成
Figure PCTCN2017119531-appb-000065
将底物25(300mg)溶于二氯甲烷(3mL)中，然后将磺酰氯(1mL)，加入反应体系，40度下反应5h，将饱和食盐水20mL加入反应体系，乙酸乙酯(3*20mL)萃取，有机相无水硫酸钠干燥，旋干，柱层析(正庚烷：乙酸乙酯＝1：3)分离得黄色固体化合物26(150mg)。MS(M+1＝332)。
步骤23：化合物27的合成
Figure PCTCN2017119531-appb-000066
将底物26(150mg)溶于乙腈(5mL)中，然后将三乙胺(0.1mL)加入反应体系，然 后将三氟甲基乙胺盐酸盐(0.5g)加入反应体系，80度下反应5h，将饱和食盐水20mL加入反应体系，乙酸乙酯(3*20mL)萃取，有机相无水硫酸钠干燥，旋干，柱层析(正庚烷：乙酸乙酯＝1：3)分离得黄色固体化合物27(120mg)。MS(M+1＝409)。
步骤24：化合物28的合成
Figure PCTCN2017119531-appb-000067
将底物27(120mg)溶于四氢呋喃(2mL)，水(0.5mL)和甲醇(0.5mL)中，然后将一水合氢氧化锂(100mg)加入反应体系，然后40度下反应8h，用1N盐酸调pH至3-4，乙酸乙酯(3*20mL)萃取，有机相无水硫酸钠干燥，旋干，柱层析(正庚烷：乙酸乙酯＝1：3)分离得黄色固体化合物27(80mg)。MS(M+1＝395)。
步骤25：化合物20的合成
Figure PCTCN2017119531-appb-000068
将底物28(80mg),化合物29(50mg)和DIPEA(70mg)溶于DMF(5mL)中，然后将HATU(130mg)加入反应体系，然后40度下反应8h，加水(20mL),乙酸乙酯(3*20mL)萃取，有机相无水硫酸钠干燥，旋干，柱层析(正庚烷：乙酸乙酯＝1：3)分离得黄色固体化合物20(10mg)。
实施例17化合物20b的合成
Figure PCTCN2017119531-appb-000069
根据步骤25，将化合物29用29b取代，其他不变，柱层析(正庚烷：乙酸乙酯＝1：3)分离得黄色固体化合物20b(8mg)。
实施例18化合物20c的合成
Figure PCTCN2017119531-appb-000070
根据步骤25，将化合物29用29c取代，其他不变，柱层析(正庚烷：乙酸乙酯＝1：3)分离得黄色固体化合物20c(11mg)。
实施例19化合物30a的合成
Figure PCTCN2017119531-appb-000071
步骤26:化合物32的合成
Figure PCTCN2017119531-appb-000072
将底物31(0.8g)溶于四氢呋喃(12mL)，甲醇(3mL)和水(3mL)中，然后将体系内加入氢氧化钠(0.44g)，55度反应1h，TLC检测原料有反应完全，有新点生成。1N盐酸调pH值至3-4，水20mL加入反应体系，乙酸乙酯(3*20mL)萃取，无水硫酸钠干燥，旋干，粗品经柱层析分离得黄色固体32(0.5g)。
步骤27:化合物33的合成
Figure PCTCN2017119531-appb-000073
将底物32(100mg)溶于DMF(3mL)中，然后将4-F-3-氰基-苯胺(40mg)，DIPEA(84mg)，加入反应体系，0度下将TBTU(78mg)加入反应体系，室温(30度)反应5h，TLC检测原料有反应完全，有新点生成。饱和食盐水20mL加入反应体系，乙酸乙酯(3*20mL)萃取，无水硫酸钠干燥，旋干，粗品柱层析得黄色固体33(100mg)。
步骤28:化合物34的合成
Figure PCTCN2017119531-appb-000074
将底物33(0.3g)溶于乙酸(5mL)，室温下将铁粉(1.0g)加入反应体系，室温反应3h，TLC检测原料反应完全，将乙酸旋干调pH值至9-10，乙酸乙酯(3*45mL)萃取，干燥旋干，柱层析得产物0.15g。
步骤29:化合物30a的合成
Figure PCTCN2017119531-appb-000075
将化合物34(80mg)和化合物34a(63mg)溶于乙腈(3mL),然后将三乙胺(83mg)，将反应体系升至85度反应8h，将水(10mL)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，高效液相制备得白色固体(8mg)。Ms/ESI＝411.6(M-1)。 1H-NMR(CDCl 3,400MHz)δ:1.11(d,J＝6.4Hz，6H)，3.41-3.49(m,1H),3.74(s,3H)，6.93(d,J＝7.2Hz，1H),7.06(s,1H),7.52-7.56(m,1H),7.96-8.00(m,1H),8.19-8.21(m,1H),8.76(s,1H)，10.31(s,1H)Ms/ESI＝411.6(M-H).
实施例20化合物30b的合成
Figure PCTCN2017119531-appb-000076
根据步骤29，将化合物34a用34b取代，其他不变，柱层析(正庚烷：乙酸乙酯＝1：3)分离得黄色固体化合物30b(11mg)。 1H-NMR(CDCl 3,400MHz)δ:10.33(s,1H),8.94(s,1H),8.20(dd,J＝5.8,2.6Hz,1H),7.99(ddd,J＝9.1,4.8,2.7Hz,1H),7.60(s,1H),7.54(t,J＝9.1Hz,1H),7.12(s,1H),4.72(d,J＝6.0Hz,2H),4.19(d,J＝6.1Hz,2H),3.75(s,3H),1.65(s,3H).
实施例21化合物30c的合成
Figure PCTCN2017119531-appb-000077
根据步骤29，将化合物34a用34c取代，其他不变，柱层析(正庚烷：乙酸乙酯＝1：3)分离得黄色固体化合物30c(11mg)。 1H-NMR(CDCl 3,400MHz)δ:10.33(s,1H),8.94(s,1H),8.20(dd,J＝5.8,2.6Hz,1H),7.99(ddd,J＝9.1,4.8,2.7Hz,1H),7.60(s,1H),7.54(t,J＝9.1Hz,1H),7.12(s,1H),4.72(d,J＝6.0Hz,2H),4.19(d,J＝6.1Hz,2H),3.75(s,3H),1.65(s,3H).
根据本发明化合物8、18、19、20和30a的合成方法，合成了表1中的其它化合物。
表1
Figure PCTCN2017119531-appb-000078
Figure PCTCN2017119531-appb-000079
Figure PCTCN2017119531-appb-000080
Figure PCTCN2017119531-appb-000081
Figure PCTCN2017119531-appb-000082
Figure PCTCN2017119531-appb-000083
Figure PCTCN2017119531-appb-000084
Figure PCTCN2017119531-appb-000085
Figure PCTCN2017119531-appb-000086
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 PCTCN2017119531-appb-000087
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 PCTCN2017119531-appb-000088
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 PCTCN2017119531-appb-000089
Figure PCTCN2017119531-appb-000090
Figure PCTCN2017119531-appb-000091
其中，
Figure PCTCN2017119531-appb-000092
[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表示表示曲线的底部；
Top表示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％。
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。
上述实验的结果在表2中展示。
表2化合物活性数据
Figure PCTCN2017119531-appb-000093
Figure PCTCN2017119531-appb-000094
表中：a1表示IC50(μM)在0.001～10之间；
a2表示IC50(μM)在10～100之间；
a3表示IC50(μM)在100～10000之间；
b1表示EC50(μM)在0.001～1之间；
b2表示EC50(μM)在1～100之间；
其中，对照化合物为：
Figure PCTCN2017119531-appb-000095
(参见WO2014184350A1)。
另外，经过常规的溶解度实验和药代动力学实验证明，与上述对照化合物相比，本发明的化合物的溶解性和药代动力学性能均优于对照化合物。
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 (11)

  1. 一种如式A所示的化合物，或其立体异构体、顺反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 PCTCN2017119531-appb-100001
    其中，
    R 1、R 2各自独立地为氢、取代或未取代的C1-C8烷基、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C6-C10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；或R 1、R 2与和它们相连的氮原子共同构成取代或未取代的具有1个N和0-3个选自下组N、S和O的杂原子的3-10元杂环烷基；
    R 3为氢、卤素、-CN、羟基、氨基、羧基、-(C＝O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C1-C8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C6-C10芳基、和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；
    R 4、R 5和R 6为苯环上任意位置的取代基，其各自独立地为氢、卤素、-CN、羟基、氨基、羧基、-(C＝O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C8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C6-C10芳基、和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；
    R 1、R 2、R 3、R 4、R 5和R 6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、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、羧基、C6-C10芳基、卤代的C6-C10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；
    M为O、S、CR 7R 7’或NR 8；其中，R 7、R 7’、R 8各自独立地为氢、卤素、-CN、羟基、取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷氧基、取代或未取 代的C3-C8环烷基；其中，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、C1-C6烷基、卤代的C1-C6烷基、-CN、羟基、氨基、羧基；
    X为NR 9、羰基(-(CO)-)、卤代亚C1-C4烷基(如CF 2)或羟肟(＝N-OH)；其中，R 9为氢、取代或未取代的C1-C8烷基、取代或未取代的C3-C8环烷基；其中，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、C1-C6烷基、卤代的C1-C6烷基、-CN、羟基、氨基、羧基；
    Y为羰基(-(CO)-)或磺酰基(-SO 2-)；
    且满足以下条件：X、Y不能同时为羰基，X为羰基时Y不能为磺酰基；
    Z为N或CR 10；其中，R 10各自独立地为氢、卤素、-CN、羟基、取代或未取代的C1-C8烷基、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C6-C10芳基、和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；其中，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、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、羧基、C6-C10芳基、卤代的C6-C10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、顺反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各自独立地为氢、取代或未取代的C2-C8烷基、取代或未取代的C3-C4环烷基；其中，所述“取代”是指被选自下组的一个或多个取代基所取代：氟、氯、溴、碘。
  3. 如权利要求1所述的化合物，或其立体异构体、顺反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 3为氢、氟、氯、溴、碘、-CN、取代或未取代的C1-C4烷基、取代或未取代的C3-C4环烷基；其中，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、C1-C4烷基、卤代的C1-C4烷基、-CN、羟基。
  4. 如权利要求1所述的化合物，或其立体异构体、顺反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 4、R 5和R 6各自独立地为氢、氟、氯、溴、碘、-CN、取代或未取代的C1-C4烷基、取代或未取代的C3-C4环烷基；其中，所述“取代”是指被选自下组的一个或多个取代基所取代：氟、氯、溴、碘、C1-C4烷基、卤代的C1-C4烷基。
  5. 如权利要求1所述的化合物，或其立体异构体、顺反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，X为NH、CF 2或羟肟(＝N-OH)。
  6. 如权利要求1所述的化合物，或其立体异构体、顺反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，所述化合物中，
    M为NR 8；其中，R 8为甲基；
    X为NR 9；其中，R 9为氢；
    Y为磺酰基(-SO 2-)；
    Z为N或CR 10；其中，R 10为氢。
  7. 如权利要求1所述的化合物，或其立体异构体、顺反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，所述化合物选自下组：
    Figure PCTCN2017119531-appb-100002
    Figure PCTCN2017119531-appb-100003
    Figure PCTCN2017119531-appb-100004
  8. 如权利要求1所述的化合物，或其立体异构体、顺反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制备方法，其特征在于，
    方法(a)：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：
    Figure PCTCN2017119531-appb-100005
    (a1)在惰性溶剂中，将化合物III-1与化合物IV-1进行反应，从而形成化合物V-1；
    (a2)在惰性溶剂中，将化合物V-1进行水解反应，从而形成化合物VI-1；
    (a3)在惰性溶剂中，将化合物VI-1与化合物VII-1进行反应，从而形成化合物VIII-1；
    各式中，R 1、R 2、R 3、R 4、R 5、R 6和Z的定义同前；
    或方法(a’)：所述式A化合物为式XIII-3所示的化合物，所述方法包括步骤：
    Figure PCTCN2017119531-appb-100006
    (a’1)在惰性溶剂中，将化合物IX-3进行水解反应，从而形成化合物X-3；
    (a’2)在惰性溶剂中，将化合物X-3与化合物VII-1进行反应，从而形成化合物XI-3；
    (a’3)在惰性溶剂中，将化合物XI-3进行还原反应，从而形成化合物XII-3；
    (a’4)在惰性溶剂中，将化合物X-3与化合物IV-1进行反应，从而形成化合物XIII-3；
    各式中，R 1、R 2、R 3、R 4、R 5、R 6、Z和M的定义同前；
    或方法(b)：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：
    Figure PCTCN2017119531-appb-100007
    (b1)在惰性溶剂中，将化合物VII-2和羟胺进行反应，从而形成化合物VIII-2；各式中，R 1、R 2、R 3、R 4、R 5、R 6和Z的定义同前；
    或方法(c)：所示式A化合物为式IX-2所示的化合物，所述方法包括步骤：
    Figure PCTCN2017119531-appb-100008
    (c1)在惰性溶剂中，将化合物VII-2与氟化试剂进行反应，从而形成化合物IX-2；各式中，R 1、R 2、R 3、R 4、R 5、R 6和Z的定义同前；
    或方法(d)：所示式A化合物为式IX-3所示的化合物，所述方法包括步骤：
    Figure PCTCN2017119531-appb-100009
    (d1)在惰性溶剂中，将化合物V-3与磺酰氯进行反应，从而形成化合物VI-3；
    (d2)在惰性溶剂中，将化合物VI-3与HNR 1R 2进行反应，从而形成化合物VII-3；
    (d3)在惰性溶剂中，将化合物VII-3进行水解反应，从而形成化合物VIII-3；
    (d4)在惰性溶剂中，将化合物VIII-3与化合物VII-1进行反应，从而形成化合物IX-3；
    各式中，R 1、R 2、R 3、R 4、R 5和R 6的定义同前；
    或方法(e)：所示式A化合物为式VI-5所示的化合物，所述方法包括步骤：
    Figure PCTCN2017119531-appb-100010
    (e1)在惰性溶剂中，将化合物I-5与氟化试剂进行反应，从而形成化合物II-5；
    (e2)在惰性溶剂中，将化合物II-5进行水解反应，从而形成化合物III-5；
    (e3)在惰性溶剂中，将化合物III-5与R 1R 2NH进行反应，从而形成化合物IV-5；
    (e4)在惰性溶剂中，将化合物IV-5进行水解反应，从而形成化合物V-5；
    (e5)在惰性溶剂中，将化合物V-5与化合物VII-1进行反应，从而形成化合物VI-5；
    各式中，R 1、R 2、R 3、R 4、R 5和R 6的定义同前。
  9. 如下式所示的中间体，或其立体异构体、顺反异构体或互变异构体，
    Figure PCTCN2017119531-appb-100011
    各式中，R 1、R 2、R 3、R 4、R 5、R 6和Z的定义同前。
  10. 一种药物组合物，其特征在于，包含(1)如权利要求1所述的化合物，或其立体异构体、顺反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。
  11. 如权利要求1所述的化合物，或其立体异构体、顺反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10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。
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