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WO2018153285A1 - 三并环类化合物及其应用 - Google Patents

三并环类化合物及其应用 Download PDF

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Publication number
WO2018153285A1
WO2018153285A1 PCT/CN2018/075995 CN2018075995W WO2018153285A1 WO 2018153285 A1 WO2018153285 A1 WO 2018153285A1 CN 2018075995 W CN2018075995 W CN 2018075995W WO 2018153285 A1 WO2018153285 A1 WO 2018153285A1
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WIPO (PCT)
Prior art keywords
compound
group
synthesis
nmr
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2018/075995
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English (en)
French (fr)
Inventor
贺海鹰
王静
江志赶
杨亚讯
邵鹏
张臣
黎健
陈曙辉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medshine Discovery Inc
Fujian Cosunter Pharmaceutical Co Ltd
Original Assignee
Medshine Discovery Inc
Fujian Cosunter Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Priority to PL18757445T priority Critical patent/PL3587420T3/pl
Priority to DK18757445.4T priority patent/DK3587420T3/da
Priority to SG11201907725SA priority patent/SG11201907725SA/en
Priority to CN201880001646.8A priority patent/CN109071544B/zh
Priority to EP18757445.4A priority patent/EP3587420B1/en
Priority to EA201991910A priority patent/EA038176B9/ru
Priority to CA3054324A priority patent/CA3054324C/en
Priority to SI201830287T priority patent/SI3587420T1/sl
Priority to KR1020197027723A priority patent/KR102085497B1/ko
Priority to BR112019017603-9A priority patent/BR112019017603B1/pt
Priority to ES18757445T priority patent/ES2874656T3/es
Priority to LTEP18757445.4T priority patent/LT3587420T/lt
Priority to MX2019010042A priority patent/MX379245B/es
Priority to HRP20210817TT priority patent/HRP20210817T1/hr
Application filed by Medshine Discovery Inc, Fujian Cosunter Pharmaceutical Co Ltd filed Critical Medshine Discovery Inc
Priority to AU2018223435A priority patent/AU2018223435B2/en
Priority to JP2019557752A priority patent/JP6764039B2/ja
Priority to RS20210671A priority patent/RS61913B1/sr
Priority to US16/488,244 priority patent/US11053260B2/en
Publication of WO2018153285A1 publication Critical patent/WO2018153285A1/zh
Priority to IL26882719A priority patent/IL268827A/en
Priority to PH12019501955A priority patent/PH12019501955A1/en
Anticipated expiration legal-status Critical
Priority to ZA2019/06135A priority patent/ZA201906135B/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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
    • 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
    • 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
    • A61K31/55—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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a compound of the formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof, and to its use in the preparation of a medicament for treating a disease associated with HBV.
  • Hepatitis B is an inflammatory reaction caused by hepatitis B virus invasion, which can lead to a series of problems such as liver pain, hepatosplenomegaly, liver fibrosis, and severe cirrhosis and even liver cancer. According to statistics, there are about 350-400 million hepatitis B virus carriers in the world, and one third of them are in China. In China, the number of deaths caused by hepatitis B is as high as 500,000 per year.
  • the first-line drugs for hepatitis B treatment in China are mainly nucleoside drugs, interferon and traditional Chinese medicine, but there are problems such as high cost and easy recurrence, so a new type of anti-hepatitis B is developed. Drugs are imperative.
  • WO2008154817A1 discloses the structure of GLS4 as follows:
  • the present invention provides a compound of the formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,
  • L 1 is selected from the group consisting of a single bond and -C 1-6 alkyl-;
  • R 1 is selected from H, Cl, F, Br, I, or a C 1-3 alkyl group optionally substituted by 1, 2 or 3 R;
  • R 2 is selected from C 1 -1-3 heteroalkyl, 4 to 8 membered heterocycloalkyl, 5 to 10 membered heteroaryl, 4 to 8 membered partially unsaturated, optionally substituted by 1, 2 or 3 R; a cyclic group, a phenyl group, a C 1-3 alkyl group, a C 3-8 cycloalkyl group, a 4-8 membered heterocycloalkyl-O- group, and a 5- to 10-membered heteroaryl-O-;
  • R 3 is selected from the group consisting of: H and C 1-3 alkyl
  • R' is independently selected from the group consisting of: Cl, F, Br, I, NH 2 , CH 3 , CN, and -N(CH 3 ) 2 ;
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2, 3 or 4.
  • the above R is selected from the group consisting of H, Cl, F, Br, I, NH 2 , OH, CN, or selected from: CH 3 optionally substituted by 1, 2 or 3 R, Other variables are as defined by the present invention.
  • the above R is selected from the group consisting of: H, Cl, F, Br, I, NH 2 , OH, CH 3 , CN, Other variables are as defined by the present invention.
  • R 1 is selected from the group consisting of H, Cl, F, Br, I, Me, Et, Other variables are as defined by the present invention.
  • R 2 is selected from optionally substituted with 1, 2, or 3 of R: CH 3, Other variables are as defined by the present invention.
  • R 2 is selected from Other variables are as defined by the present invention.
  • the above L 1 is selected from the group consisting of a single bond, Other variables are as defined by the present invention.
  • R 3 above is selected from the group consisting of H, CH 3 and -CH 2 CH 3 , and other variables are as defined herein.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of: among them,
  • n is selected from: 1, 2 or 3;
  • n is selected from: 1 or 2;
  • r is selected from: 0 or 1;
  • T 1 is selected from: N or CH;
  • R, L 1 , R 1 , R 3 are as defined in the present invention.
  • the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • R, L 1 , R 1 , R 3 and n are as defined in the present invention.
  • the present invention provides a compound of the formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,
  • L 1 is selected from the group consisting of: a single bond or -C 1-6 alkyl-;
  • R 1 is selected from H, Cl, F, Br, I, or from a C 1-3 alkyl group optionally substituted by 1, 2 or 3 R;
  • R 2 is selected from C 1 -1-3 heteroalkyl, 4 to 8 membered heterocycloalkyl, 5 to 10 membered heteroaryl, 4 to 8 membered partially unsaturated, optionally substituted by 1, 2 or 3 R; a cyclic group, a phenyl group, a C 1-3 alkyl group, a C 3-8 cycloalkyl group, a 4-8 membered heterocycloalkyl-O-, a 5- to 10-membered heteroaryl-O-;
  • R 3 is selected from the group consisting of: H or C 1-3 alkyl
  • R' is selected from the group consisting of: Cl, F, Br, I, NH 2 , CH 3 , CN, -N(CH 3 ) 2 ;
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2, 3 or 4.
  • R is selected from the group consisting of H, Cl, F, Br, I, NH 2 , OH, CN, or selected from: CH 3 optionally substituted by 1, 2 or 3 R',
  • the above R is selected from the group consisting of: H, Cl, F, Br, I, NH 2 , OH, CH 3 , CN,
  • R 1 is selected from the group consisting of H, Cl, F, Br, I, Me, Et,
  • R 2 is selected from optionally substituted with 1, 2, or 3 of R: CH 3,
  • R 2 is selected from the group consisting of
  • the above L 1 is selected from the group consisting of: a single bond, CH 2 ,
  • R 3 is selected from the group consisting of H, CH 3 , and -CH 2 CH 3 .
  • the structural unit From:
  • the above R is selected from the group consisting of H, Cl, F, Br, I, NH 2 , OH, CN, or selected from: CH 3 optionally substituted by 1, 2 or 3 R', Other variables are as defined above.
  • the above R is selected from the group consisting of: H, Cl, F, Br, I, NH 2 , OH, CH 3 , CN, Other variables are as defined above.
  • R 1 is selected from the group consisting of H, Cl, F, Br, I, Me, Et, Other variables are as defined above.
  • R 2 is selected from optionally substituted with 1, 2, or 3 of R: CH 3, Other variables are as defined above.
  • R 2 is selected from the group consisting of Other variables are as defined above.
  • the above L 1 is selected from the group consisting of: a single bond, CH 2 , Other variables are as defined above.
  • the above R 3 is selected from the group consisting of: H, CH 3 , -CH 2 CH 3 , and other variables are as defined above.
  • the structural unit From: Other variables are as defined above. Still other schemes can be arbitrarily combined by the variables of the present invention.
  • the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • n is selected from: 1, 2 or 3;
  • n is selected from: 1 or 2;
  • r is selected from: 0 or 1;
  • T 1 is selected from: N or CH;
  • R, L 1 , R 1 and R 3 are as defined above.
  • L 1 is selected from the group consisting of: a single bond or -C 1-6 alkyl-;
  • R 1 is selected from H, Cl, F, Br, or from a C 1-3 alkyl group optionally substituted by 1, 2 or 3 R;
  • R 2 is selected from C 1 -1-3 heteroalkyl, 4 to 8 membered heterocycloalkyl, 5 to 10 membered heteroaryl optionally substituted by 1, 2 or 3;
  • R 3 is selected from the group consisting of: H or C 1-3 alkyl
  • hetero of the 4- to 8-membered heterocycloalkyl group and the 5- to 10-membered heteroaryl group are each independently selected from: -S-, -O-, -NH-, N;
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.
  • R is selected from the group consisting of H, Cl, F, Br, NH 2 , OH, or selected from: CH 3 optionally substituted by 1, 2 or 3 R',
  • the above R is selected from the group consisting of: H, Cl, F, Br, NH 2 , OH, CH 3 ,
  • R 1 is selected from the group consisting of H, Cl, F, Br, Me, and Et.
  • R 2 is selected from the group consisting of: 1, 3 or 3, R: C 1-3 alkoxy, tetrahydrofuranyl, thiazolyl, 3-azabicyclo[3.1.0]hexane Base, pyridyl, benzimidazolyl, thienyl, pyrazolyl, benzothiazolyl, imidazo[1,2-a]pyridinyl.
  • R 2 is selected from the group consisting of, optionally substituted by 1, 2 or 3 R:
  • R 2 is selected from the group consisting of
  • the above L 1 is selected from the group consisting of: a single bond, CH 2 ,
  • R 3 is selected from the group consisting of H, CH 3 , and -CH 2 CH 3 .
  • the above R is selected from the group consisting of H, Cl, F, Br, NH 2 , OH, or selected from: CH 3 optionally substituted by 1, 2 or 3 R', Other variables are defined as above.
  • the above R is selected from the group consisting of: H, Cl, F, Br, NH 2 , OH, CH 3 , Other variables are defined as above.
  • R 1 is selected from the group consisting of H, Cl, F, Br, Me, and Et, and other variables are as defined above.
  • R 2 is selected from the group consisting of: 1, 3 or 3, R: C 1-3 alkoxy, tetrahydrofuranyl, thiazolyl, 3-azabicyclo[3.1.0]hexane Base, pyridyl, benzimidazolyl, thienyl, pyrazolyl, benzothiazolyl, imidazo[1,2-a]pyridinyl, other variables are as defined above.
  • R 2 is selected from the group consisting of, optionally substituted by 1, 2 or 3 R: Other variables are defined as above.
  • R 2 is selected from the group consisting of Other variables are defined as above.
  • the above L 1 is selected from the group consisting of: a single bond, CH 2 , Other variables are defined as above.
  • R 3 is selected from the group consisting of: H, CH 3 , -CH 2 CH 3 , and other variables are as defined above.
  • the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • R, L 1 , R 1 , and R 3 are as defined above; and n is selected from: 1 or 2.
  • the invention also provides a compound of the formula, an isomer thereof or a pharmaceutically acceptable salt thereof:
  • the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound, an isomer thereof or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a disease associated with HBV.
  • the present invention also provides the use of the above pharmaceutical composition for the preparation of a medicament for treating a disease associated with HBV.
  • the compound of the present invention has a significant inhibitory effect on HBV; it has a good single or partial index of canine pharmacokinetics, and good in vivo efficacy, and has a dose-dependent effect.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of one another.
  • cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate a single bond due to a double bond or a ring-forming carbon atom.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirrored relationship.
  • wedge-shaped dashed keys Represents the absolute configuration of a solid center with straight solid keys
  • straight dashed keys Indicates the relative configuration of the stereocenter, using wavy lines Indicates a wedge solid key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid key And straight dashed keys
  • tautomer or “tautomeric form” mean that the different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. If tautomers are possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions by proton transfer, such as keto-enol isomerization and imine-enes. Amine isomerization.
  • the valence tautomer includes the mutual transformation of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms "enriched in one isomer”, “isomer enriched”, “enriched in one enantiomer” or “enantiomeric enriched” refer to one of the isomers or pairs
  • the content of the oligo is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or greater than or equal to 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomeric excess (ee value) is 80%. .
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C).
  • hydrogen can be replaced by heavy hydrogen to form a deuterated drug.
  • the bond composed of barium and carbon is stronger than the bond composed of common hydrogen and carbon.
  • deuterated drugs have reduced side effects and increased drug stability. Enhance the efficacy and prolong the biological half-life of the drug. Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Oxygen substitution does not occur on the aromatic group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • a substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A.
  • the substituent can be attached to more than one atom on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit. It is indicated that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene.
  • substituents When the listed substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group.
  • the medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B. It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic.
  • the hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons) , C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .).
  • C 1-12 is selected from C 1
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • hydrocarbyl means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in conjunction with another term, is represented by a number of carbon atoms and at least A stable, linear, branched or cyclic hydrocarbon radical consisting of a hetero atom or a combination thereof.
  • heteroalkyl by itself or in conjunction with another term, refers to a stable straight or branched alkyl radical or composition thereof consisting of a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including the position at which the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy).
  • alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • heterocycloalkyl by itself or in conjunction with other terms, denotes a cyclized “heteroalkyl”, respectively, and further, in the case of the "heterocycloalkyl", a heteroatom may occupy a heterocycloalkyl group.
  • the heterocycloalkyl group is a 4-6 membered heterocycloalkyl group; in other embodiments, the heterocycloalkyl group is a 5-6 membered heterocycloalkane.
  • heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetra Hydropyranyl, piperidinyl, piperazinyl, morpholinyl, dioxoalkyl, dithiaalkyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2- Thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or oxetanyl.
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • alkenyl refers to an alkyl group having one or more carbon-carbon double bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkenyl group include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a butadienyl group, a pentadienyl group, a hexadienyl group and the like.
  • alkynyl refers to an alkyl group having one or more carbon-carbon triple bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and the like.
  • a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
  • a cycloalkenyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more unsaturated carbon-carbon double bonds at any position of the ring, and may be monosubstituted or polysubstituted, It can be one price, two price or multiple price.
  • Examples of such cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.
  • a cycloalkynyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more carbon-carbon triple bonds at any position of the ring, which may be monosubstituted or polysubstituted, and may be one Price, price or price.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents attached through an oxygen bridge
  • C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), they are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • aryl or heteroaryl groups include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isomerism Azyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, indolyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl, 1 -naphthyl, 2-naphthyl, 4-biphenylyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl
  • aryl groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • Figure 1 Hepatitis B virus DNA levels in plasma; fold line 1 indicates a blank control, 10% solutol aqueous solution is administered once a day (QD), oral gavage (PO); line 2 indicates a test compound at a dose of 15 mg/kg WX325 was administered twice a day (BID) at 8 h intervals, orally by intragastric administration (PO); line 3 indicates that the test compound WX325 at a dose of 50 mg/kg was taken twice a day (BID) at intervals of 8 h each time.
  • QD oral gavage
  • line 2 indicates a test compound at a dose of 15 mg/kg WX325 was administered twice a day (BID) at 8 h intervals, orally by intragastric administration (PO);
  • line 3 indicates that the test compound WX325 at a dose of 50 mg/kg was taken twice a day (BID) at intervals of 8 h each time.
  • Oral gavage (PO) administration line 5 indicates that the test compound WX325 at a dose of 150 mg/kg was administered twice a day (BID) at intervals of 8 h, administered by oral gavage (PO); 6 indicates that tenofovir (TDF), a positive compound at a dose of 15 mg/kg, was administered twice a day (BID) at 8 h intervals, orally by intragastric administration (PO); LLOQ indicates the lower limit of detection; day post- The first dose indicates the number of days of administration.
  • FIG. 1 Hepatitis B virus DNA levels in liver on day 28; Note: QD means once daily dosing; BID means twice daily dosing; MPK means mg/kg; Vehicle means blank control.
  • Step 1 Synthesis of compound BB-1-3.
  • BB-1-1 (40 g, 319.68 mmol) was added to a pre-dried 3-liter three-necked flask, and then tetrahydrofuran (500 mL) was added thereto.
  • Step 2 Synthesis of compound BB-1-4.
  • Iron powder (21.02 g, 376.45 mmol) was added to a solution of BB-1-3 (29.30 g, 75.29 mmol) in acetic acid (200.00 mL) at 18 ° C, then the reaction mixture was warmed to 70 ° C for 2 hours. The solid matter was removed by filtration, and the filter cake was washed with ethyl acetate. The filtrate was collected and the pH of the filtrate was adjusted to 7-8 with saturated sodium bicarbonate. The extract was separated, and the organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. Filtration and removal of the solvent under reduced pressure afforded crude br.
  • Step 3 Synthesis of Compound BB-1.
  • BB-1-4 (57 g, 158.69 mmol) was dissolved in toluene (50 mL), and a toluene solution of trimethylaluminum (2M, 79.34 mL) was added thereto, and the mixture was heated to 110 ° C and stirred for 2 hours.
  • the reaction liquid was cooled to room temperature, poured into 4 liters of water, and then extracted with a large amount of ethyl acetate. The combined organic layers were dried with anhydrous sodium sulfate, filtered and evaporated
  • the crude product was isolated by column chromatography to give BB-1 (48 g).
  • Step 1 Synthesis of Compound BB-2-1.
  • Step 2 Synthesis of compound BB-2.
  • raw material BB-2-1 (1.5 g, 4.90 mmol), lithium hydroxide monohydrate (205 mg, 4.90 mmol) and tetrahydrofuran (15 mL), water (3 mL) were placed, then the bottle was placed at 60 Stir in an oil bath at °C for 4 hours.
  • the THF was concentrated under reduced pressure, and then 20 ml of water was added, and the pH was adjusted to about 3 with 2M diluted hydrochloric acid, and a solid was precipitated, and the solid was collected by filtration to give BB-2.
  • Step 1 Synthesis of compound BB-3-2.
  • BB-3-1 (10.00 g, 47.07 mmol) and chloroform (50.00 mL) were added to a pre-dried 250 ml flask at 0 ° C, then sulfuryl chloride (12.71 g, 94.14 mmol, 9.41 mL) was added dropwise thereto. ). After the addition was completed, the reaction was stirred at 25 ° C for 3 hours. The reaction solution was poured into ice water (100 mL), and the aqueous phase was extracted with dichloromethane (100mL*3). The organic phase was combined, washed with water until neutral, dried over anhydrous sodium sulfate, filtered, and evaporated.
  • Step 2 Synthesis of compound BB-3-3.
  • BB-3-2 (10.00 g, 40.50 mmol) and methanol (100 mL) were added to a pre-dried 250 ml flask, and then sodium methoxide (2.63 g, 48.60 mmol) was added thereto. After the addition was completed, the reaction solution was nitrogen-protected and the reaction was stirred at 25 ° C for 1 hour. The organic layer was diluted with water (40 mL) and brine (30 mL). The crude product was purified by flash column chromatography to give BB-3-3.
  • Step 3 Synthesis of compound BB-3-4.
  • Step 4 Synthesis of compound BB-3-5.
  • Step 5 Synthesis of compound BB-3-6.
  • BB-3-5 (1.00 g, 2.54 mmol) and toluene (10 mL) were added to a pre-dried 50 ml flask, and then a toluene solution of trimethylaluminum (2.5 M, 1.52 mL) was added thereto. After the addition was completed, the reaction solution was stirred at 80 ° C for 1.5 hours under a nitrogen atmosphere. After the reaction system was cooled to room temperature, water (30 mL) was added to the reaction mixture to quench, and a pale yellow solid was precipitated. 2M hydrochloric acid was added dropwise until the solid was completely dissolved, and the aqueous phase was extracted with ethyl acetate (75 mL*2).
  • Step 6 Synthesis of compound BB-3-7.
  • BB-3-6 (170.00 mg, 470.13 ⁇ mol), triethylamine (71.36 mg, 705.20 ⁇ mol, 97.75 uL), Pd(dppf)Cl 2 .CH 2 Cl 2 (38.39 mg) was added to a pre-dried hydrogenation flask. , 47.01 ⁇ mol) and methanol (10 mL), DMF (1.00 mL). After the addition was completed, the reaction system was purged with carbon monoxide gas and stirred at 80 ° C, 50 psi for 12 hours. After the reaction system was cooled to room temperature, it was concentrated under reduced pressure to remove methanol and DMF to give crude product. The crude product was isolated by flash column chromatography to give BB-3-7.
  • Step 7 Synthesis of compound BB-3.
  • BB-3-7 (50.00 mg, 146.74 ⁇ mol), dilute hydrochloric acid (6 M, 300.00 ⁇ L) and dioxane (600.00 ⁇ L) were added to the pre-dried thumb bottle. After the completion of the addition, the reaction solution was purged with nitrogen and stirred at 50 ° C for 58 hours. The reaction solution was filtered to give the product BB-3. 1 H NMR (400 MHz, DMSO-d 6 ).
  • Step 1 Synthesis of compound BB-4-3.
  • Step 2 Synthesis of compound BB-4-4.
  • Step 3 Synthesis of compound BB-4-5.
  • Step 4 Synthesis of compound BB-4-6.
  • Sodium azide (148.22 mg, 2.28 mmol) was added to a solution of BB-4-5 (200.00 mg, 1.14 mmol) in DMF (2.00 mL). The reaction was warmed to 80 ° C and stirred for 16 hours. The reaction was quenched with saturated aqueous sodium carbonate (2. 0 mL) and then ethyl acetate The organic phases were combined and washed with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was separated by thin layer chromatography to obtain BB-4-6.
  • Step 5 Synthesis of compound BB-4.
  • Step 1 Synthesis of Compound BB-5-2.
  • Step 2 Synthesis of compound BB-5-3.
  • Step 3 Synthesis of compound BB-5-4.
  • Step 4 Synthesis of compound BB-5-5.
  • Step 5 Synthesis of compound BB-5-6.
  • Step 6 Synthesis of compound BB-5.
  • Step 1 Synthesis of Compound BB-6-2.
  • the temperature was lowered to 0 ° C, and a solution of BB-6-1 (10.95 g, 39.17 mmol) in THF (100 mL) was slowly added dropwise, and the temperature was controlled to not exceed 5 ° C, and the color of the solution became a dark red liquid.
  • the mixture was stirred at 25 ° C for 12 h, and the color of the solution turned yellow.
  • the reaction mixture was poured into 300 mL of water to quench the reaction.
  • the mixture was extracted with ethyl acetate (300 mL), and the combined organic phase was washed with 250 mL of brine.
  • Step 2 Synthesis of compound BB-6-3.
  • Step 3 Synthesis of compound BB-6-4.
  • Step 4 Synthesis of compound BB-6.
  • the raw material BB-6-4 (9 g, 28.10 mmol) and the solvent THF (90 mL) were added to a pre-dried 250 mL vial, followed by a solution of LiOH.H 2 O (2.36 g, 56.20 mmol) in water (25 mL).
  • BB-3 (15.00 mg, 45.91 ⁇ mol), EDCI (13.20 mg, 68.86 ⁇ mol), HOBt (9.31 mg, 68.86 ⁇ mol), DIPEA (10.68 mg, 82.64 ⁇ mol) and solvent DMF were added to the pre-dried thumb bottle. 1.00 mL), and finally WX143-1 (6.96 mg, 45.91 ⁇ mol, 1.00 eq) was added thereto at 0 °C. After the addition was completed, the reaction solution was shielded with nitrogen and the reaction was stirred at 25 ° C for 12 hours. The reaction solution was filtered to give a crude product. The crude product was isolated by HPLC to give WX 143.
  • WX145-3 (410.00 mg, 1.04 mmol) and toluene (1.00 mL) were added to a dry 100 ml single-mouth flask and stirred to dissolve. Subsequently, a toluene solution of trimethylaluminum (2.5 M, 624.94 ⁇ L) was added, and nitrogen gas was replaced three times. The reaction system was stirred at 110 ° C for 1.5 hours. After adding 1:1 water and ethyl acetate (10 mL), ethyl acetate (5 mL*3) The crude product was subjected to column chromatography to give WX145-4.
  • WX145-4 (50.00 mg, 138.27 ⁇ mol) and BB-4 (23.77 mg, 152.10 ⁇ mol) were dissolved in DMF (3.00 mL), followed by the addition of triethylamine (13.99 mg, 138.27 ⁇ mol, 19.16 ⁇ L) and Pd ( Dppf)Cl 2 (10.12 mg, 13.83 ⁇ mol). After argon gas was replaced three times, it was replaced with carbon monoxide three times and then pressurized to 50 PSI, and the reaction liquid was heated to 80 ° C and stirred for 16 hours. The reaction solution was cooled to room temperature and concentrated directly to give a crude material. The crude product was isolated by HPLC to give WX 145.
  • Step 1 Synthesis of compounds WX170 and WX171.
  • Chiral separation conditions chiral column: OJ (250 mm * 30 mm, 5 ⁇ m); mobile phase: 0.1% ammonia / ethanol; flow rate: 60 mL / min; column temperature: 40 ° C.
  • BB-2-1 (85.00 mg, 277.51 ⁇ mol) and compound WX175-1 (24.74 mg, 277.51 ⁇ mol, 28.44 ⁇ L) were added to a pre-dried 50 ml flask, followed by the addition of toluene (5.00 mL). Further, a toluene solution of trimethylaluminum (2M, 208.13 ⁇ L) was slowly added to the reaction solution at 25 ° C, and the reaction solution was stirred at 110 ° C for 1 hour. The reaction mixture was diluted with EtOAc EtOAc EtOAc. The crude product was isolated by pre-HPLC to give WX 175.
  • Step 1 Synthesis of Compound WX270.
  • WX185-1 (5 g, 24.51 mmol) was dissolved in dichloromethane (60 mL), triethylamine (5.46 g, 53.92 mmol, 7.50 mL), DMAP (299.40 mg, 2.45 mmol), followed by dropwise addition of benzoic acid
  • the acid chloride (4.76 g, 26.96 mmol, 3.45 mL) was stirred at 30 ° C for 5 hours.
  • Dichloromethane (100 mL) was added to the reaction mixture, and the mixture was evaporated.
  • the crude product was subjected to silica gel column chromatography to give WX185-2.
  • WX185-3 (9 g, 26.15 mmol) was dissolved in DMF (60 mL), EtOAc (EtOAc, EtOAc, EtOAc. The nitrogen was replaced three times, and the reaction was stirred at 100 ° C for 24 hours.
  • a cesium fluoride solution (8 g dissolved in 50 mL of water) was added, and the mixture was stirred for 6 hours, then ethyl acetate (100 mL) was added, washed with water (50 mL*2), and the ethyl acetate layer was filtered. The filtrate was dried over anhydrous sodium sulfate and evaporated.
  • the crude product was purified using silica gel column chromatography to afford WX185-3.
  • WX185-3 (5.7 g, 19.57 mmol) was dissolved in methanol (60 mL), sodium methoxide (1.37 g, 25.44 mmol) was added, and the mixture was stirred at 50 ° C for 12 hours. The reaction solution was concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography to give WX185-4.
  • WX185-5 (0.8 g, 1.93 mmol) was dissolved in acetic acid (10 mL), iron powder (430.39 mg, 7.71 mmol) was added, and the reaction was stirred at 65 ° C for 2 hours. The reaction solution was filtered, and the filtrate was evaporated. The crude product was subjected to silica gel column chromatography to give WX185-6.
  • WX185-6 (1.8 g, 4.67 mmol) was dissolved in DMSO (10 mL), potassium tert-butoxide (786.47 mg, 7.01 mmol) was added, and the mixture was stirred at 80 ° C for 2 hours. Ethyl acetate (50 mL) was added to the mixture, and the mixture was evaporated. The crude product was purified using silica gel column chromatography to afford WX185-7.
  • WX185-7 80 mg, 228.51 ⁇ mol
  • WX173-1 37.78 mg, 249.16 ⁇ mol
  • DMF 5 mL
  • triethylamine 45.84 mg, 453.01 ⁇ mol, 63.05 ⁇ L
  • Pd(dppf)Cl2 16.57 mg, 22.65 ⁇ mol
  • the solvent was removed under reduced pressure and purified by crude column chromatography to afford W?
  • WX185-8 (40 mg, 96.28 ⁇ mol) was dissolved in methanol (10 mL), Pd/C (40 mg, 377.36 ⁇ mol) was added, hydrogen was passed, and the mixture was kept at 30 ° C and stirred at 15 psi for 12 hours. The solvent was removed under reduced pressure. The crude product was purified using HPLC to give WX 185.
  • the synthesis of the compound WX186-3 was carried out by referring to the synthesis of the compound WX185-6 of the step 5 in Example 20.
  • the synthesis of the compound WX186-4 was carried out by referring to the synthesis of the compound WX185-7 of the step 6 in Example 20.
  • BB-2 (0.1 g, 342.15 ⁇ mol) and DMF (1 mL) were added to a dry single-mouth bottle, followed by HOBt (69.3 mg, 513.22 ⁇ mol), EDCI (98.4 mg, 513.22 ⁇ mol), DIPEA (88.4 mg, 684.30 ⁇ mol) ) and WX187-1 (43.5mg, 342.15 ⁇ mol),
  • BB-2 (0.1 g, 342.15 ⁇ mol) and DMF (1 mL) were added to a dry single-mouth bottle, followed by HOBt (69.3 mg, 513.22 ⁇ mol,), EDCI (98.4 mg, 513.22 ⁇ mol), DIPEA (88.4 mg, 684.30). ⁇ mol, 119.19 ⁇ L, 2 eq) and WX189-1 (42.8 mg, 342.15 ⁇ mol) were replaced with nitrogen three times, and the reaction was stirred at 20 ° C for 12 hours. The reaction solution was filtered through an organic phase needle filter to give a crude material. The crude product was isolated by HPLC to give WX189.
  • Step 1 Synthesis of Compound WX190-2.
  • BB-2 (0.2 g, 684.31 ⁇ mol) and DMF (1 mL) were added to a dry single-mouth bottle, followed by HOBt (138.7 mg, 1.03 mmol), EDCI (196.8 mg, 1.03 mmol), DIPEA (176.9 mg, 1.37 mmol) And WX190-1 (71.99 mg, 684.31 ⁇ mol), three times with nitrogen, and the reaction was stirred at 20 ° C for 12 hours. Concentration under reduced pressure gave a crude product which was purified by column chromatography.
  • WX 190-2 (0.2 g, 527.07 ⁇ mol), saturated sodium bicarbonate solution (4.32 g, 51.42 mmol, 2 mL) and EtOAc (3 mL) was then added to a dry-broiled vial, followed by the addition of m-chloroperoxybenzoic acid (374.52 mg). , 1.84 mmol, 85% purity), replaced with nitrogen three times, and the reaction was stirred at 20 ° C for 2 hours. The reaction solution was filtered through an organic phase needle filter to give a crude material. Purification by crude HPLC gave WX190.
  • Step 1 Synthesis of Compound WX200.
  • Step 1 Synthesis of Compound WX201-1.
  • WX201-1 200 mg, 577.43 ⁇ mol
  • DIPEA 149.26 mg, 1.15 mmol, 201.16 ⁇ L
  • dichloromethane 5 mL
  • the reaction solution was nitrogen-protected and lowered to 0 ° C.
  • WX201-2 54.57 mg, 577.43 ⁇ mol, 44.73 ⁇ L
  • the reaction mixture was quenched with EtOAc (EtOAc)EtOAc.
  • the crude product was purified by HPLC to give WX201.
  • Step 1 Synthesis of compounds WX289 and WX290.
  • Chiral separation conditions chiral column: AD (250 mm * 30 mm, 5 ⁇ m); mobile phase: [Neu-MeOH]; B%: 45% - 45%, 20 min).
  • WX211-2 (3.13 g, 13.99 mmol), KOH (660.76 mg, 11.78 mmol) and EtOH (10 mL) were added to a pre-dried 100 ml vial, and WX211-1 (1 g, 10.52 mmol, 1 eq) was added thereto.
  • the mixture was stirred under reflux at 80 ° C for 5 hours under a nitrogen atmosphere.
  • the reaction solution was directly dried under reduced pressure to give a crude product.
  • the crude column was chromatographed to give compound WX211-3.
  • Step 1 Synthesis of Compound WX220.
  • WX223-4 (1.3 g, 4.62 mmol) was added to a pre-dried three-necked flask and added to THF (5 mL), and the mixture was placed in an ice bath and cooled to 0 ° C. Then, NaH (369.59 mg, 9.24 mmol, 60%) was added under nitrogen atmosphere. The temperature of the system was controlled at 0-5 ° C. After the addition, the mixture was kept at 0 ° C for 30 minutes, and then slowly added dropwise methyl iodide to the system (721.32 mg, 5.08 mmol). , 316.37 ⁇ L), stirring was continued at 20 ° C for 3 hours after completion of the dropwise addition.
  • the reaction system was cooled to 0 ° C, and the reaction was quenched by the addition of 30 mL of water.
  • the aqueous phase was extracted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine. Concentration under reduced pressure gave a crude product.
  • the crude product column was chromatographed to obtain WX223-5.
  • the raw material WX223-5 (300 mg, 1.02 mmol) was added to a pre-dried hydrogenation bottle, followed by the solvent EtOH (5 mL), water (0.5 mL), Pd(OH) 2 (28.52 mg, 101.55 ⁇ mol, 50% purity). The H 2 was replaced and the mixture was reacted at 40 ° C for 12 hours at 40 ° C. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give crude product. The crude product was used directly in the next reaction.
  • Step 1 Synthesis of Compound WX227.
  • WX201-1 120 mg, 346.46 ⁇ mol
  • triethylamine 70.12 mg, 692.92 ⁇ mol, 96.45 ⁇ L
  • dichloromethane 3 mL
  • Sulfonyl chloride 39.69 mg, 346.46 ⁇ mol, 26.82 ⁇ L
  • the reaction solution was stirred at 25 ° C for 5 hours.
  • the reaction mixture was stirred with EtOAc EtOAc m.
  • the crude product was separated by HPLC to obtain WX232.
  • WX271-3 (0.25 g, 1.09 mmol) was dissolved in EtOAc /EtOAc (10 mL). The reaction solution was filtered, and the filter cake was collected to obtain WX271-4.
  • Step 1 Synthesis of Compound WX280-2.
  • WX280-4 400 mg, 1.71 mmol
  • solvent EtOH 5 mL
  • hydrazine hydrate 140.15 mg, 2.74 mmol, 136.07 ⁇ L
  • the reaction system was cooled to room temperature, and then transferred to a 100 mL single-necked flask, and stirred at room temperature for 30 hours by adding 30 ml of ethanol. After filtration, the filter cake was discarded, and the filtrate was spun to obtain WX280-5.
  • Step 1 Synthesis of Compound WX297-2.
  • WX297-2 (836.83 mg, 3.36 mmol) and dioxane (5 mL), water (1.5 mL) were added to a pre-dried 50 ml single-mouth bottle, and then K 2 CO 3 (1.16 g, 8.41 mmol) and WX297- were added to the reaction system. 3 (834.81 mg, 3.36 mmol), finally, tetratriphenylphosphine palladium (388.78 mg, 336.44 ⁇ mol) was added under a nitrogen atmosphere, and the system was stirred at 100 ° C for 12 hours. The reaction mixture was quenched with water (5 mL). The crude product was subjected to column chromatography to give WX297-4.
  • WX297-4 (900 mg, 2.69 mmol) and EtOAc (10 mL) was added EtOAc. The reaction solution was directly spun dry to obtain WX297-5.
  • BB-2 (80.17 mg, 342.15 ⁇ mol), EDCI (98.39 mg, 513.22 ⁇ mol), DIPEA (88.44 mg, 684.30 ⁇ mol, 119.19 ⁇ L), HOBt (69.35 mg, 513.22 ⁇ mol) and DMF were added to the pre-dried thumb bottle. (2 mL), finally, WX297-5 (100 mg, 342.15 ⁇ mol) was added thereto at 0 ° C, and the reaction solution was nitrogen-protected and the reaction was stirred at 25 ° C for 12 hours. The reaction mixture was filtered to give a crude material.
  • WX297-2 (850.83 mg, 3.42 mmol) and water (1.5 mL), DME (5 mL) were added to a pre-dried 50 ml vial, and then K 2 CO 3 (1.18 g, 8.55 mmol) and WX298- were added to the reaction system. 1 (502.63 mg, 3.42 mmol), finally Pd(dppf)Cl 2 (250.30 mg, 342.07 ⁇ mol) was added under a nitrogen atmosphere, and the system was stirred at 100 ° C for 12 hours. The reaction mixture was quenched with water (5 mL). The crude product was purified by column chromatography eluting with EtOAc.
  • Step 1 Synthesis of Compound WX300.
  • WX311-4 300 mg, 778.84 ⁇ mol, 1 eq was dissolved in dioxane (5.0 mL), and then 6M diluted hydrochloric acid (5.0 mL) was added, and the reaction was stirred at 50 ° C for 48 hours. The organic layer was dried over anhydrous sodium sulfate, filtered, and then evaporated. The crude column was chromatographed to give WX311-5.
  • 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ 11.47 (s, 1H), 8.33-8.07 (m, 2H), 8.06-7.98 (m, 2H), 7.85 (s, 1H), 7.22 (s, 1H) ).
  • Step 1 Synthesis of compounds WX221 and WX222.
  • Chiral separation conditions chiral column: AD (250 mm * 30 mm, 5 ⁇ m); mobile phase: [Neu-MeOH]; B%: 48% - 48%.
  • Compound 222 corresponds to a retention time of 6.62 minutes (peak 2).
  • Compound 221 corresponding retention time: 5.70 minutes (peak 1).
  • Step 1 Synthesis of Compound WX279-1.
  • WX279-1 (90mg, 211.81 ⁇ mol) and DMF (1mL) were added to the pre-dried thumb bottle, and Et 3 N (32.15mg, 317.72 ⁇ mol, 44.22 ⁇ L) was added and stirred for 30 minutes, then the reaction system was reduced.
  • Et 3 N 32.15mg, 317.72 ⁇ mol, 44.22 ⁇ L
  • WX285-1 25.96 mg, 211.81 ⁇ mol, 29.40 ⁇ L
  • the reaction mixture was filtered to give a crude material.
  • the WX321-7 (0.25g, 1.80mmol) was dissolved in MeOH (10mL), was added NH 3 .H 2 O (227.50mg, 1.82mmol, 0.25mL, 28% purity), Raney-Ni (0.25g) , the reaction The hydrogen was replaced three times, then the pressure was raised to 50 psi and reacted at 50 ° C for 3 hours. Filtration and concentration of the filtrate under reduced pressure. The crude product WX321-8 was used directly for the next reaction.
  • WX322-1 (0.2 g, 868.42 ⁇ mol) was dissolved in DCM (5 mL), TEA (131.81 mg, 1.30 mmol, 181.31 ⁇ L) was added, and acetyl chloride (74.99 mg, 955.26 ⁇ mol, 68.17) was slowly added dropwise at 0 °C. ⁇ L), the reaction was stirred at 0 ° C for 1.5 hours. DCM (30 mL) was added to the reaction mixture, washed with water (20 mL*2).
  • WX322-2 (0.2 g, 734.37 ⁇ mol) was dissolved in HCl / EtOAc (10 mL) and stirred at 25 ° C for 12 hours. It was concentrated under reduced pressure to give WX322-3.
  • Step 1 Synthesis of Compound WX323-1.
  • WX322-1 (0.2 g, 868.42 ⁇ mol) was dissolved in DCM (5 mL), TEA (131.81 mg, 1.30 mmol, 181.31 ⁇ L) was added, and methyl chloroformate (90.27 mg, 955.26 ⁇ mol, was slowly added dropwise at 0 ° C. 73.99 ⁇ L), the reaction was stirred at 0 ° C for 1.5 hours. DCM (30 mL) was added to the reaction mixture, washed with water (20 mL*2).
  • the synthesis of the compound WX323-2 was carried out by referring to the synthesis of the step 2WX22-2 in Example 81.
  • Step 1 Synthesis of compounds WX313 and WX315.
  • Chiral separation conditions chiral column: OJ (250 mm * 50 mm, 10 ⁇ m); mobile phase: 0.1% NH 3 .H 2 O MeOH; flow rate: 200 mL / min; column temperature: 40 ° C.
  • Compound 315 corresponds to a retention time of 4.825 minutes (peak 2).
  • Compound 313 corresponds to a retention time of 4.495 minutes (peak 1).
  • WX318-1 (1 g, 8.76 mmol)
  • WX318-2 (4.69 g, 13.47 mmol) was added to a pre-dried 20 ml microwave reaction tube followed by solvent chlorobenzene (10 mL). The mixture was subjected to microwave reaction at 180 ° C for 6 hours. Concentration under reduced pressure gave a crude product. The crude product was subjected to automatic column chromatography to obtain WX318-3.
  • WX318-3 (2.5 g, 13.57 mmol) was dissolved in EtOAc (10 mL). After replacing the hydrogen three times, it was pressurized to 40 psi and the reaction was stirred at 25 ° C for 16 hours. Filtration through celite and concentration of the filtrate under reduced pressure afforded crude material. The crude product was subjected to automatic column chromatography to obtain WX318-4.
  • Step 1 Synthesis of compounds WX319 and WX320.
  • Chiral separation conditions chiral column: OJ (250 mm * 50 mm, 10 ⁇ m); mobile phase: 0.1% NH 3 .H 2 O MeOH; flow rate: 200 mL / min; column temperature: 40 ° C.
  • Compound 319 corresponds to a retention time of 3.874 minutes (peak 2).
  • Compound 320 corresponds to a retention time of 3.475 minutes (peak 1).
  • Step 1 Synthesis of compounds WX325 and WX329.
  • Compound 325 corresponds to a retention time of 4.919 minutes (peak 2).
  • Compound 329 corresponds to a retention time of 4.563 minutes (peak 1).
  • Step 1 Synthesis of compounds WX339 and WX350.
  • Compound 339 corresponds to a retention time of 4.078 minutes (peak 2) and compound 350 corresponds to a retention time of 3.952 minutes (peak 1).
  • WX353-1 (20 g, 98.03 mmol) was dissolved in dichloromethane (200 mL), triethylamine (14.88 g, 147.04 mmol, 20.47 mL), DMAP (1.20 g, 9.80 mmol), followed by dropwise addition of benzenesulfonyl chloride (19.05 g, 107.83 mmol, 13.80 mL), the reaction was stirred at 30 ° C for 5 hours. DCM (100 mL) was added to the reaction mixture, and the mixture was evaporated.
  • WX353-2 (10 g, 29.05 mmol) was dissolved in DMF (80 mL), Pd(PPh 3 ) 4 (1.68 g, 1.45 mmol), WX353-3 (11.98 g, 37.77 mmol, 10.9 mL) The reaction was stirred at 100 ° C for 24 hours. EA (100 mL), 10 g of cesium fluoride in 50 mL of H 2 O solution was added to the reaction mixture, and the mixture was stirred for 6 hours, filtered, and the filtrate was washed with water (50 mL*3), and the EA layer was dried over anhydrous sodium sulfate. concentrate.
  • WX353-4 (7.6 g, 26.09 mmol) was dissolved in MeOH (EtOAc) (EtOAc)EtOAc. The reaction solution was concentrated under reduced pressure. The crude product was purified using silica gel column chromatography to give WX353-5.
  • WX353-7 (3 g, 7.61 mmol) was dissolved in EtOAc (60 mL) EtOAc (EtOAc)EtOAc. The reaction solution was filtered, and the filtrate was evaporated. The crude product was purified using silica gel column chromatography to afford WX353-8.
  • WX353-8 (0.35 g, 1.05 mmol) was dissolved in THF (9 mL), and a solution of LiOH.H2O (43.93 mg, 1.05 mmol) in H2O (3 mL) was obtained.
  • EA 100 mL was added to the reaction solution, water (50 mL*2) was washed, EA layer was discarded, EA (100 mL) was added to the aqueous layer, and 2 M HCl was slowly added to adjust the pH of the aqueous phase to 3-4 with stirring.
  • the EA phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give W?
  • Step 8 Synthesis of compounds WX353 and WX352.

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Abstract

本发明公开了式（Ⅰ）所示化合物、其互变异构体或其药学上可接受的盐，并公开了其在制备治疗HBV相关疾病药物中的应用。

Description

三并环类化合物及其应用
相关申请的交叉引用
本申请主张2018年01月04日提交的中国专利申请CN201810008592.X、2017年08月01日提交的中国专利申请CN201710648155.X和2017年02月23日提交的中国专利申请CN201710100309.1的优先权，其内容在此并入本申请。
技术领域
本发明涉及式(Ⅰ)所示化合物、其互变异构体或其药学上可接受的盐，并涉及其在制备治疗HBV相关疾病药物中的应用。
背景技术
乙型肝炎是由乙肝病毒入侵引起的炎症反应，其可导致肝区疼痛、肝脾肿大、肝纤维化等一系列问题，严重的还可能造成肝硬化甚至肝癌。据统计，全世界约有3.5-4亿乙肝病毒携带者，其中1/3的携带者在中国，在中国每年因为乙肝导致的死亡人数高达50万。
现阶段全世界范围内还没有治疗乙肝的特效药，在中国乙肝治疗的一线用药主要是核苷类药物，干扰素和中药，但存在费用昂贵、易复发等问题，所以开发新类型的抗乙肝药物势在必行。
WO2008154817A1公开了GLS4的结构如下：
Figure PCTCN2018075995-appb-000001
发明内容
本发明提供了式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2018075995-appb-000002
L 1选自单键和-C 1-6烷基-；
R 1选自H、Cl、F、Br、I，或选自任选被1、2或3个R取代的C 1-3烷基；
R 2选自任选被1、2或3个R取代的：C 1-3杂烷基、4～8元杂环烷基、5～10元杂芳基、4～8元部分不饱和杂环基、苯基、C 1-3烷基、C 3-8环烷基、4～8元杂环烷基-O-和5～10元杂芳基-O-；
R 3选自：H和C 1-3烷基；
R分别独立地选自H、Cl、F、Br、I、NH 2、OH、CN，或选自任选被1、2或3个R’取代的：C 1-6烷基、C 1-6杂烷基、苯基、苯基-O-C(＝O)-和5～6元杂芳基；
R'分别独立地选自：Cl、F、Br、I、NH 2、CH 3、CN和-N(CH 3) 2；
所述C 1-3杂烷基、4～8元杂环烷基、5～10元杂芳基、C 1-6杂烷基、5～6元杂芳基、4～8元部分不饱和杂环基之“杂”分别独立地选自：-S-、-O-、-NH-、N、-C(＝O)-、-O-C(＝O)-、-S(＝O) 2-、-S(＝O)-、-NH-C(＝O)-、-NH-C(＝O)-O-；
以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2、3或4。
本发明的一些方案中，上述R选自H、Cl、F、Br、I、NH 2、OH、CN，或选自任选被1、2或3个R'取代的：C 1-3烷基、C 1-6烷基-O-C(＝O)-、C 1-6烷基-C(＝O)-、C 1-3烷基-S(＝O) 2-、C 1-3烷基-S(＝O)-、C 1-3烷氨基、苯基、苯基-O-C(＝O)-和吡啶基，其他变量如本发明所定义。
本发明的一些方案中，上述R选自H、Cl、F、Br、I、NH 2、OH、CN，或选自任选被1、2或3个R取代的：CH 3、
Figure PCTCN2018075995-appb-000003
Figure PCTCN2018075995-appb-000004
其他变量如本发明所定义。
本发明的一些方案中，上述R选自：H、Cl、F、Br、I、NH 2、OH、CH 3、CN、
Figure PCTCN2018075995-appb-000005
Figure PCTCN2018075995-appb-000006
Figure PCTCN2018075995-appb-000007
其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自H、Cl、F、Br、I、Me、Et、
Figure PCTCN2018075995-appb-000008
其他变量如本发明所定义。
本发明的一些方案中，上述R 2选自任选被1、2或3个R取代的：C 1-3烷氧基、四氢呋喃基、噻唑基、3-氮杂双环[3.1.0]己烷基、吡啶基、苯并咪唑基、噻吩基、吡唑基、苯并噻唑基、咪唑并[1,2-a]吡啶基、甲基、C 1-3烷硫基、C 1-3烷基-S(＝O) 2-、环戊烷基、苯基、吖丁啶基、哌啶基、吡咯烷基、噁唑基、吡咯烷-2-酮基、吡啶-2(1H)-酮基、环己烷基、环丙烷基、异噻唑烷-1,1-二氧化物基、嘧啶基、1,3,4-噻 二唑基、恶唑烷-2-酮基、四氢吡喃基、环戊烷基-O-、吡啶基-O-、环氧己烷基、1,4-二氧六环基、1,4-二氧庚环基、吗啉基和2,3-二氢苯并[b][1,4]二氧杂环己烯基，其他变量如本发明所定义。
本发明的一些方案中，上述R 2选自任选被1、2或3个R取代的：CH 3、
Figure PCTCN2018075995-appb-000009
Figure PCTCN2018075995-appb-000010
Figure PCTCN2018075995-appb-000011
其他变量如本发明所定义。
本发明的一些方案中，上述R 2选自
Figure PCTCN2018075995-appb-000012
Figure PCTCN2018075995-appb-000013
Figure PCTCN2018075995-appb-000014
Figure PCTCN2018075995-appb-000015
其他变量如本发明所定义。
本发明的一些方案中，上述L 1选自单键、
Figure PCTCN2018075995-appb-000016
其他变量如本发明所定义。本发明的一些方案中，上述R 3选自H、CH 3和-CH 2CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018075995-appb-000017
选自
Figure PCTCN2018075995-appb-000018
Figure PCTCN2018075995-appb-000019
Figure PCTCN2018075995-appb-000020
Figure PCTCN2018075995-appb-000021
其他变量如本发明所定义。
本发明还有一些方案是由上述变量任意组合而来。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，选自：
Figure PCTCN2018075995-appb-000022
其中，
m选自：1、2或3；
n选自：1或2；
r选自：0或1；
T 1选自：N或CH；
R、L 1、R 1、R 3如本发明所定义。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，选自：
Figure PCTCN2018075995-appb-000023
其中，
R、L 1、R 1、R 3和n如本发明所定义。
本发明提供了式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2018075995-appb-000024
L 1选自：单键或-C 1-6烷基-；
R 1选自H、Cl、F、Br、I，或选自任选被1、2或3个R取代的：C 1-3烷基；
R 2选自任选被1、2或3个R取代的：C 1-3杂烷基、4～8元杂环烷基、5～10元杂芳基、4～8元部分不饱和杂环基、苯基、C 1-3烷基、C 3-8环烷基、4～8元杂环烷基-O-、5～10元杂芳基-O-；
R 3选自：H或者C 1-3烷基；
R选自H、Cl、F、Br、I、NH 2、OH、CN，或选自任选被1、2或3个R'取代的：C 1-6烷基、C 1-6杂烷基、苯基、苯基-O-C(＝O)-、5～6元杂芳基；
R'选自：Cl、F、Br、I、NH 2、CH 3、CN、-N(CH 3) 2；
所述C 1-3杂烷基、4～8元杂环烷基、5～10元杂芳基、C 1-6杂烷基、5～6元杂芳基、4～8元部分不饱和杂环基之“杂”分别独立地选自：-S-、-O-、-NH-、N、-C(＝O)-、-O-C(＝O)-、-S(＝O) 2-、-S(＝O)-、-NH-C(＝O)-、-NH-C(＝O)-O-；
以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2、3或4。
本发明的一些方案中，上述R选自H、Cl、F、Br、I、NH 2、OH、CN，或选自任选被1、2或3个R'取代的：C 1-3烷基、C 1-6烷基-O-C(＝O)-、C 1-6烷基-C(＝O)-、C 1-3烷基-S(＝O) 2-、C 1-3烷基-S(＝O)-、C 1-3烷氨基、苯基、苯基-O-C(＝O)-、吡啶基。
本发明的一些方案中，上述R选自H、Cl、F、Br、I、NH 2、OH、CN，或选自任选被1、2或3个R'取代的：CH 3、
Figure PCTCN2018075995-appb-000025
Figure PCTCN2018075995-appb-000026
本发明的一些方案中，上述R选自：H、Cl、F、Br、I、NH 2、OH、CH 3、CN、
Figure PCTCN2018075995-appb-000027
Figure PCTCN2018075995-appb-000028
本发明的一些方案中，上述R 1选自H、Cl、F、Br、I、Me、Et、
Figure PCTCN2018075995-appb-000029
本发明的一些方案中，上述R 2选自任选被1、2或3个R取代的：C 1-3烷氧基、四氢呋喃基、噻唑基、3-氮杂双环[3.1.0]己烷基、吡啶基、苯并咪唑基、噻吩基、吡唑基、苯并噻唑基、咪唑并[1,2-a]吡啶基、甲基、C 1-3烷硫基、C 1-3烷基-S(＝O) 2-、环戊烷基、苯基、吖丁啶基、哌啶基、吡咯烷基、噁唑基、吡咯烷-2-酮基、吡啶-2(1H)-酮基、环己烷基、环丙烷基、异噻唑烷-1,1-二氧化物基、嘧啶基、1,3,4-噻二唑基、恶唑烷-2-酮基、四氢吡喃基、环戊烷基-O-、吡啶基-O-、环氧己烷基、1,4-二氧六环基、1,4-二氧庚环基、吗啉基。
本发明的一些方案中，上述R 2选自任选被1、2或3个R取代的：CH 3、
Figure PCTCN2018075995-appb-000030
Figure PCTCN2018075995-appb-000031
本发明的一些方案中，上述R 2选自：
Figure PCTCN2018075995-appb-000032
Figure PCTCN2018075995-appb-000033
Figure PCTCN2018075995-appb-000034
本发明的一些方案中，上述L 1选自：单键、CH 2、
Figure PCTCN2018075995-appb-000035
本发明的一些方案中，上述R 3选自：H、CH 3、-CH 2CH 3。
本发明的一些方案中，上述结构单元
Figure PCTCN2018075995-appb-000036
选自：
Figure PCTCN2018075995-appb-000037
Figure PCTCN2018075995-appb-000038
Figure PCTCN2018075995-appb-000039
本发明的一些方案中，上述R选自H、Cl、F、Br、I、NH 2、OH、CN，或选自任选被1、2或3个R'取代的：C 1-3烷基、C 1-6烷基-O-C(＝O)-、C 1-6烷基-C(＝O)-、C 1-3烷基-S(＝O) 2-、C 1-3烷基-S(＝O)-、C 1-3烷氨基、苯基、苯基-O-C(＝O)-、吡啶基，其他变量如上述所定义。
本发明的一些方案中，上述R选自H、Cl、F、Br、I、NH 2、OH、CN，或选自任选被1、2或3个R'取代的：CH 3、
Figure PCTCN2018075995-appb-000040
Figure PCTCN2018075995-appb-000041
其他变量如上述所定义。
本发明的一些方案中，上述R选自：H、Cl、F、Br、I、NH 2、OH、CH 3、CN、
Figure PCTCN2018075995-appb-000042
Figure PCTCN2018075995-appb-000043
Figure PCTCN2018075995-appb-000044
其他变量如上述所定义。
本发明的一些方案中，上述R 1选自H、Cl、F、Br、I、Me、Et、
Figure PCTCN2018075995-appb-000045
其他变量如上述所定义。
本发明的一些方案中，上述R 2选自任选被1、2或3个R取代的：C 1-3烷氧基、四氢呋喃基、噻唑基、3-氮杂双环[3.1.0]己烷基、吡啶基、苯并咪唑基、噻吩基、吡唑基、苯并噻唑基、咪唑并[1,2-a]吡啶基、甲基、C 1-3烷硫基、C 1-3烷基-S(＝O) 2-、环戊烷基、苯基、吖丁啶基、哌啶基、吡咯烷基、噁唑基、吡咯烷-2-酮基、吡啶-2(1H)-酮基、环己烷基、环丙烷基、异噻唑烷-1,1-二氧化物基、嘧啶基、1,3,4-噻二唑基、恶唑烷-2-酮基、四氢吡喃基、环戊烷基-O-、吡啶基-O-、环氧己烷基、1,4-二氧六环基、1,4-二氧庚环基、吗啉基，其他变量如上述所定义。
本发明的一些方案中，上述R 2选自任选被1、2或3个R取代的：CH 3、
Figure PCTCN2018075995-appb-000046
Figure PCTCN2018075995-appb-000047
Figure PCTCN2018075995-appb-000048
其他变量如上述所定义。
本发明的一些方案中，上述R 2选自：
Figure PCTCN2018075995-appb-000049
Figure PCTCN2018075995-appb-000050
Figure PCTCN2018075995-appb-000051
Figure PCTCN2018075995-appb-000052
其他变量如上述所定义。
本发明的一些方案中，上述L 1选自：单键、CH 2、
Figure PCTCN2018075995-appb-000053
其他变量如上述所定义。本发明的一些方案中，上述R 3选自：H、CH 3、-CH 2CH 3，其他变量如上述所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018075995-appb-000054
选自：
Figure PCTCN2018075995-appb-000055
Figure PCTCN2018075995-appb-000056
Figure PCTCN2018075995-appb-000057
Figure PCTCN2018075995-appb-000058
其他变量如上述所定义。还有一些方案可以由本发明变量任意组合而来。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，选自：
Figure PCTCN2018075995-appb-000059
Figure PCTCN2018075995-appb-000060
其中，
m选自：1、2或3；
n选自：1或2；
r选自：0或1；
T 1选自：N或CH；
R、L 1、R 1、R 3如上述所定义。
本发明式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2018075995-appb-000061
L 1选自：单键或-C 1-6烷基-；
R 1选自H、Cl、F、Br，或选自任选被1、2或3个R取代的：C 1-3烷基；
R 2选自任选被1、2或3个R取代的：C 1-3杂烷基、4～8元杂环烷基、5～10元杂芳基；
R 3选自：H或者C 1-3烷基；
R选自H、Cl、F、Br、NH 2、OH，或选自任选被1、2或3个R'取代的：C 1-3烷基、C 1-6烷基-O-C(＝O)-；R'选自：Cl、F、Br、NH 2；
所述4～8元杂环烷基、5～10元杂芳基之“杂”分别独立地选自：-S-、-O-、-NH-、N；
以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
本发明一些方案中，上述R选自H、Cl、F、Br、NH 2、OH，或选自任选被1、2或3个R'取代的：CH 3、
Figure PCTCN2018075995-appb-000062
本发明一些方案中，上述R选自：H、Cl、F、Br、NH 2、OH、CH 3、
Figure PCTCN2018075995-appb-000063
本发明一些方案中，上述R 1选自H、Cl、F、Br、Me、Et。
本发明一些方案中，上述R 2选自任选被1、2或3个R取代的：C 1-3烷氧基、四氢呋喃基、噻唑基、3-氮杂双环[3.1.0]己烷基、吡啶基、苯并咪唑基、噻吩基、吡唑基、苯并噻唑基、咪唑并[1,2-a]吡啶基。
本发明一些方案中，上述R 2选自任选被1、2或3个R取代的：
Figure PCTCN2018075995-appb-000064
Figure PCTCN2018075995-appb-000065
本发明一些方案中，上述R 2选自：
Figure PCTCN2018075995-appb-000066
Figure PCTCN2018075995-appb-000067
本发明一些方案中，上述L 1选自：单键、CH 2、
Figure PCTCN2018075995-appb-000068
本发明一些方案中，上述R 3选自：H、CH 3、-CH 2CH 3。
本发明一些方案中，上述结构单元
Figure PCTCN2018075995-appb-000069
选自：
Figure PCTCN2018075995-appb-000070
Figure PCTCN2018075995-appb-000071
本发明一些方案中，上述R选自H、Cl、F、Br、NH 2、OH，或选自任选被1、2或3个R'取代的：CH 3、
Figure PCTCN2018075995-appb-000072
其他变量如上述定义。
本发明一些方案中，上述R选自：H、Cl、F、Br、NH 2、OH、CH 3、
Figure PCTCN2018075995-appb-000073
其他变量如上述定义。
本发明一些方案中，上述R 1选自H、Cl、F、Br、Me、Et，其他变量如上述定义。
本发明一些方案中，上述R 2选自任选被1、2或3个R取代的：C 1-3烷氧基、四氢呋喃基、噻唑基、3-氮杂双环[3.1.0]己烷基、吡啶基、苯并咪唑基、噻吩基、吡唑基、苯并噻唑基、咪唑并[1,2-a]吡啶基，其他变量如上述定义。
本发明一些方案中，上述R 2选自任选被1、2或3个R取代的：
Figure PCTCN2018075995-appb-000074
Figure PCTCN2018075995-appb-000075
其他变量如上述定义。
本发明一些方案中，上述R 2选自：
Figure PCTCN2018075995-appb-000076
Figure PCTCN2018075995-appb-000077
Figure PCTCN2018075995-appb-000078
其他变量如上述定义。
本发明一些方案中，上述L 1选自：单键、CH 2、
Figure PCTCN2018075995-appb-000079
其他变量如上述定义。
本发明一些方案中，上述R 3选自：H、CH 3、-CH 2CH 3，其他变量如上述定义。
本发明一些方案中，上述结构单元
Figure PCTCN2018075995-appb-000080
选自：
Figure PCTCN2018075995-appb-000081
Figure PCTCN2018075995-appb-000082
Figure PCTCN2018075995-appb-000083
其他变量如上述定义。
本发明一些方案中，上述化合物、其异构体或其药学上可接受的盐，选自：
Figure PCTCN2018075995-appb-000084
其中，R、L 1、R 1、R 3如上述所定义；n选自：1或2。
本发明还提供了下式化合物、其异构体或其药学上可接受的盐：
Figure PCTCN2018075995-appb-000085
Figure PCTCN2018075995-appb-000086
Figure PCTCN2018075995-appb-000087
Figure PCTCN2018075995-appb-000088
本发明一些方案中，上述的化合物、其异构体或其药学上可接受的盐，选自：
Figure PCTCN2018075995-appb-000089
本发明还提供了一种药物组合物，包括治疗有效量的上述化合物、其异构体或其药学上可接受的盐，以及药学上可接受的载体。
本发明还提供了上述化合物、其异构体或其药学上可接受的盐在制备治疗与HBV相关疾病的药物中的应用。
本发明还提供了上述药物组合物在制备治疗与HBV相关疾病的药物中的应用。
技术效果
作为新类型的抗乙肝药物，本发明化合物对HBV的抑制作用显著；具有良好的很好的犬药代动力学单项或部分指标，以及良好的体内药效，且呈剂量依赖效应。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包 括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2018075995-appb-000090
和楔形虚线键
Figure PCTCN2018075995-appb-000091
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2018075995-appb-000092
和直形虚线键
Figure PCTCN2018075995-appb-000093
表示立体中心的相对构型，用波浪线
Figure PCTCN2018075995-appb-000094
表示楔形实线键
Figure PCTCN2018075995-appb-000095
或楔形虚线键
Figure PCTCN2018075995-appb-000096
或用波浪线
Figure PCTCN2018075995-appb-000097
表示直形实线键
Figure PCTCN2018075995-appb-000098
和直形虚线键
Figure PCTCN2018075995-appb-000099
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选 地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当一个取代基可以连接到一个环上的一个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元
Figure PCTCN2018075995-appb-000100
表示取代基R可在环己基或者环己二烯上的任意一个位置发生取代。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2018075995-appb-000101
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2018075995-appb-000102
也可以按照与从左往右的读取顺序相反的方向连接环 A和环B构成
Figure PCTCN2018075995-appb-000103
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-或-S(＝O)N(H)-。
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的，本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是，当杂环中S及O原子的总数超过1时，这些杂原子彼此不相邻。另一个优选方案是，杂环中S及O原子的总数不超过1。如本文所用，术语“芳族杂环基团”或“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环，它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。值得注意的是，芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。
杂环化合物的实例包括但不限于：吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹 啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基、4H-1,2,4-三唑基和呫吨基。还包括稠环和螺环化合物。
除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、芳基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基)，可以是单取代或多取代的，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，可以包括二价或多价原子团，具有指定数量的碳原子(如C 1-C 12表示1至12个碳，C 1-12选自C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12；C 3-12选自C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12。)。“烃基”包括但不限于脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烃基”表示直链的或支链的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烃基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构体。
除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示由一定数目的碳原子和至少一个杂原子组成的，稳定的直链、支链或环状的烃原子团或其组合。在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示由一定数目的碳原子和至少一个杂原子组成的，稳定的直链或支链的烷基原子团或其组合物。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子或杂原子团可以 位于杂烃基的任何内部位置，包括该烃基与分子其余部分的连接位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。实例包括但不限于-CH 2-CH 2-O-CH 3、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(O)-CH 3、-CH 2-CH 2-S(O) 2-CH 3、-CH＝CH-O-CH 3、-CH 2-CH＝N-OCH 3和–CH＝CH-N(CH 3)-CH 3。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。
除非另有规定，术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外，就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言，杂原子可以占据该杂环附着于分子其余部分的位置。环烃基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。
除非另有规定，术语“杂环烷基”本身或者与其他术语联合分别表示环化的“杂烷基”，此外，就该“杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。在一些实施方案中，所述杂环烷基为4～6元杂环烷基；在另一些实施方案中，所述杂环烷基为5～6元杂环烷。杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基、四氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、二恶烷基、二噻烷基、异恶唑烷基、异噻唑烷基、1,2-恶嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或氧杂环庚烷基。
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH 2F)或多取代的(如-CF 3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等。
除非另有规定，“烯基”指在链的任何位点上具有一个或多个碳碳双键的烷基,可以是单取代或多取代的，可以是一价、二价或者多价。烯基的例子包括乙烯基，丙烯基，丁烯基，戊烯基，己烯基，丁间二烯基，戊间二烯基，己间二烯基等。
除非另有规定，“炔基”指在链的任何位点上具有一个或多个碳碳三键的烷基，可以是单取代或多取代的，可以是一价、二价或者多价。炔基的例子包括乙炔基，丙炔基，丁炔基，戊炔基等。
除非另有规定，环烷基包括任何稳定的环状或多环烃基，任何碳原子都是饱和的，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定，环烯基包括任何稳定的环状或多环烃基，该烃基在环的任何位点含有一个或多个不饱和的碳-碳双键，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烯基的实例包括， 但不限于，环戊烯基、环己烯基等。
除非另有规定，环炔基包括任何稳定的环状或多环烃基，该烃基在环的任何位点含有一个或多个碳-碳三键，可以是单取代或多取代的，可以是一价、二价或者多价。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C 1-C 4)烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。
“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基，除非另有规定，C 1-6烷氧基包括C 1、C 2、C 3、C 4、C 5和C 6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。
除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代或多取代的，可以是一价、二价或者多价，它可以是单环或多环(比如1至3个环；其中至少一个环是芳族的)，它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、萘基、联苯基、吡咯基、吡唑基、咪唑基、吡嗪基、恶唑基、苯基-恶唑基、异恶唑基、噻唑基、呋喃基、噻吩基、吡啶基、嘧啶基、苯并噻唑基、嘌呤基、苯并咪唑基、吲哚基、异喹啉基、喹喔啉基、喹啉基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
除非另有规定，芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此，术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如 链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁基羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂；EDCI代表碳化二亚胺；HOBt代表1-羟基苯并三唑；Pd(dppf)Cl 2代表[1,1'-双(二苯基膦)二茂铁]二氯化钯；MgSO4代表硫酸镁；DMAP代表4-二甲氨基吡啶；EEDQ代表2-乙氧基-1-乙氧碳酰基-1,2-二氢喹啉；LAWESSON'S代表2,4-双(对甲氧苯基)-1,3-二硫一二磷杂环丁烷-2,4硫化物(劳森试剂)；TEA代表三乙醇胺；TosCl代表对甲苯磺酰氯；Et 3N代表三乙胺；BF 3.Et 2O代表三氟化硼乙醚；Raney-Ni代表雷尼镍；PPh 3代表三苯基磷；IPA代表异丙醇；DPBS代表杜氏磷酸盐缓冲液；DIEA代表N,N-二异丙基乙胺；Pd(PPh 3) 4代表四(三苯基膦)钯；t-BuOK代表叔丁醇钾。
化合物经手工或者
Figure PCTCN2018075995-appb-000104
软件命名，市售化合物采用供应商目录名称。
附图说明
图1：血浆中乙肝病毒DNA水平；折线1表示空白对照，10％solutol水溶液采取一天一次(QD)，口服灌胃(PO)的方式给药；折线2表示剂量为15mg/kg的受试化合物WX325采取一天两次(BID)，每次间隔8h，口服灌胃(PO)的方式给药；折线3表示剂量为50mg/kg的受试化合物 WX325采取一天两次(BID)，每次间隔8h，口服灌胃(PO)的方式给药；折线5表示剂量为150mg/kg的受试化合物WX325采取一天两次(BID)，每次间隔8h，口服灌胃(PO)的方式给药；折线6表示剂量为15mg/kg的阳性化合物的替诺福韦(TDF)采取一天两次(BID)，每次间隔8h，口服灌胃(PO)的方式给药；LLOQ表示检测下限；day post-first dose表示给药天数。
图2：第28天肝脏中的乙肝病毒DNA水平；注：QD表示每天一次给药；BID表示每天两次给药；MPK表示mg/kg；Vehicle表示空白对照。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
参考例1：片段BB-1
Figure PCTCN2018075995-appb-000105
合成路线：
Figure PCTCN2018075995-appb-000106
步骤1：化合物BB-1-3的合成。
氮气保护下，在预先干燥过的3升三口烧瓶中加入BB-1-1(40g,319.68mmol)，随后向其中加入四氢呋喃(500mL)。0℃下向其中滴入叔丁醇钾的四氢呋喃溶液(1M,479.52mL)。滴加完毕，反应液在0℃下搅拌反应15分钟。15分钟后，将BB-1-2(115.28g,383.62mmol)的四氢呋喃溶液(500mL)在0℃下缓慢滴入上述反应液中。滴加完毕，将反应液恢复到25℃搅拌4.5小时。加水(600mL)淬灭反应，反应液用乙酸乙酯(1L*3)萃取。有机相无水硫酸钠干燥，过滤，减压除去溶剂得BB-1-3的粗品。粗品经打浆后得BB-1-3。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.29(d,J＝8.3Hz,1H),7.97-7.88(m,2H),7.65(dd,J＝2.0,3.3Hz,1H),7.13(dd,J＝1.9,3.6Hz,1H),6.36(t,J＝3.5Hz,1H),3.74(s,3H)。
步骤2：化合物BB-1-4的合成。
将铁粉(21.02g,376.45mmol)在18℃下加入BB-1-3(29.30g,75.29mmol)的醋酸(200.00mL)溶液中，然后将反应液升温至70℃反应2小时。过滤除去固体物质，滤饼大量乙酸乙酯洗。收集滤液，用饱和碳酸氢钠将滤液的PH值调至7-8。萃取分液，有机相饱和氯化钠溶液洗，无水硫酸钠干燥。过滤，减 压除去溶剂得BB-1-4的粗品。粗品经柱层析纯化得BB-1-4(15g)。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.61(dd,J＝2.0,3.3Hz,1H),7.42(d,J＝8.8Hz,1H),7.01(dd,J＝1.9,3.6Hz,1H),6.82(d,J＝1.8Hz,1H),6.78(dd,J＝1.8,8.8Hz,1H),6.23(t,J＝3.4Hz,1H),5.15(br s,2H),3.69(s,3H)。
步骤3：化合物BB-1的合成。
将BB-1-4(57g，158.69mmol)溶于甲苯(50mL)中，向其中加入三甲基铝(2M,79.34mL)的甲苯溶液后升温至110℃并搅拌2小时。将反应液冷却至室温后倒入4升水中，然后用大量乙酸乙酯萃取。合并有机相，有机相用无水硫酸钠干燥，过滤，减压除去溶剂得产物的粗品。粗品经柱层析分离得BB-1(48g)。 1H NMR(400MHz,DMSO-d 6)δ＝11.16(s,1H),7.91(d,J＝8.5Hz,1H),7.70-7.53(m,3H),7.15(dd,J＝1.6,3.6Hz,1H),6.53(t,J＝3.4Hz,1H)。
参考例2：片段BB-2
Figure PCTCN2018075995-appb-000107
合成路线：
Figure PCTCN2018075995-appb-000108
步骤1：化合物BB-2-1的合成。
在预先干燥过的氢化瓶中加入BB-1(6g,18.34mmol)，三乙胺(1.86g,18.34mmol,2.54mL)，Pd(dppf)Cl 2.CH 2Cl 2(1.50g,1.83mmol)和溶剂甲醇(360mL)，DMF(36.00mL)。加料完毕后，向反应液体系中通入CO，并在80℃，50psi下搅拌12小时。待反应体系冷却到室温后，减压浓缩除去甲醇和DMF后得到产物粗品。粗品用乙酸乙酯(800mL)溶解，有机相用水(300mL*2)洗涤，有机相无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂后得到产物BB-2-1。 1H NMR(400MHz,DMSO-d6)δ＝11.27(s,1H),8.15(d,J＝8.4Hz,1H),8.05(s,1H),7.91(d,J＝8.4Hz,1H),7.67-7.59(m,1H),7.17(dd,J＝1.7,3.4Hz,1H),6.56(t,J＝3.4Hz,1H),3.97-3.82(m,3H)。
步骤2：化合物BB-2的合成。
在干燥的单口瓶中加入原料BB-2-1(1.5g,4.90mmol)，一水合氢氧化锂(205mg,4.90mmol)和四氢呋喃(15mL)，水(3mL)，然后将拇指瓶置于60℃的油浴中搅拌4小时。减压浓缩除去THF，然后加入20毫升水，用2M的稀盐酸调其pH值至3左右，有固体析出，过滤收集固体得BB-2。 1H NMR(400MHz,DMSO-d6)δ＝11.26(s,1H),8.13(d,J＝8.2Hz,1H),8.02(d,J＝1.3Hz,1H),7.90(dd,J＝1.5,8.2Hz,1H),7.62 (dd,J＝1.8,3.1Hz,1H),7.16(dd,J＝1.7,3.6Hz,1H),6.55(t,J＝3.4Hz,1H)。
参考例3：片段BB-3
Figure PCTCN2018075995-appb-000109
合成路线：
Figure PCTCN2018075995-appb-000110
步骤1：化合物BB-3-2的合成。
0℃下，在预先干燥过的250毫升烧瓶中加入BB-3-1(10.00g,47.07mmol)和氯仿(50.00mL)，然后向其中逐滴加入硫酰氯(12.71g,94.14mmol,9.41mL)。加料完毕后，反应在25℃下搅拌3小时。将反应液加入到冰水(100mL)中，水相用二氯甲烷萃取(100mL*3)。合并有机相，用水洗至中性，无水硫酸钠干燥，过滤，减压浓缩得BB-3-2，直接用于下一步反应。
步骤2：化合物BB-3-3的合成。
在预先干燥过的250毫升烧瓶中加入BB-3-2(10.00g,40.50mmol)和甲醇(100mL)，然后向其中加入甲醇钠(2.63g,48.60mmol)。加料完毕后，反应液氮气保护并在25℃下搅拌反应1小时。减压浓缩除去甲醇后，加二氯甲烷(100mL)稀释，有机相依次用水(40mL)、饱和食盐水洗涤(30mL)，无水硫酸钠干燥，减压浓缩得到粗产品。粗产品通过快速柱层析分离纯化得BB-3-3。 1H NMR(400MHz,CHLOROFORM-d)δ＝9.17(br s,1H),6.93-6.90(m,1H),6.82(dd,J＝1.8,2.6Hz,1H),3.88(s,3H)
步骤3：化合物BB-3-4的合成。
在预先干燥过的氮气保护下的250毫升三口瓶中加入叔丁醇钾(1M,62.68mL)和四氢呋喃(30mL),然后于0℃下向其中缓慢滴入BB-3-3(4.00g,25.07mmol,1.00eq)的四氢呋喃(40mL)溶液。将反应体系升温到25℃搅拌15分钟后，再于0℃下缓慢滴加BB-1-2(15.07g,50.14mmol)的四氢呋喃(10.00mL)溶液。加料完毕后，反应液氮气保护并在25℃下搅拌反应4.5小时。加入水(150mL)淬灭反应，反应液减压浓缩除去四氢呋喃后水相用乙酸乙酯(100mL*3)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗产品通过快速柱层析分离纯化得BB-3-4。 1H NMR(400MHz,DMSO-d 6)δ＝8.53(d,J＝2.0 Hz,1H),8.17(dd,J＝1.9,8.6Hz,1H),7.96(d,J＝2.0Hz,1H),7.89(d,J＝8.7Hz,1H),7.36(d,J＝2.0Hz,1H),3.65(s,3H)。
步骤4：化合物BB-3-5的合成。
在预先干燥过的拇指瓶中加入BB-3-4(300.00mg,708.18μmol)和醋酸(3.00mL)，然后向其中加入铁粉(197.76mg,3.54mmol)。加料完毕后，反应液氮气保护并在70℃下搅拌反应40分钟。待反应体系冷却到室温后，将饱和碳酸氢钠水溶液滴加到反应体系中至pH＝6，乙酸乙酯(15mL*3)萃取，饱和食盐水(20mL*2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到产物BB-3-5。 1H NMR(400MHz,DMSO-d 6)δ＝8.23(d,J＝2.0Hz,1H),7.67(d,J＝8.8Hz,1H),7.16(d,J＝2.0Hz,1H),7.09(d,J＝1.9Hz,1H),6.87(dd,J＝1.9,8.8Hz,1H),6.50(s,2H),3.71(s,3H)。
步骤5：化合物BB-3-6的合成。
在预先干燥过的50毫升烧瓶中加入BB-3-5(1.00g,2.54mmol)和甲苯(10mL)，然后向其中加入三甲基铝的甲苯溶液(2.5M,1.52mL)。加料完毕，反应液氮气保护下于80℃搅拌1.5小时。待反应体系冷却到室温后，向反应液中加水(30mL)淬灭，有淡黄色固体析出，滴加2M的盐酸至固体完全溶解，水相用乙酸乙酯(75mL*2)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩得到产物BB-3-6。 1H NMR(400MHz,DMSO-d 6)δ＝11.33(s,1H),7.93(d,J＝8.3Hz,1H),7.85(d,J＝1.8Hz,1H),7.68-7.64(m,2H),7.21(d,J＝1.8Hz,1H)
步骤6：化合物BB-3-7的合成。
在预先干燥过的氢化瓶中加入BB-3-6(170.00mg,470.13μmol)，三乙胺(71.36mg,705.20μmol,97.75uL)，Pd(dppf)Cl 2.CH 2Cl 2(38.39mg,47.01μmol)和甲醇(10mL)，DMF(1.00mL)。加料完毕后，反应体系通入一氧化碳气体并在80℃，50psi下搅拌12小时。待反应体系冷却到室温后，减压浓缩除去甲醇和DMF后得到产物粗品。粗产品通过快速柱层析分离得BB-3-7。 1H NMR(400MHz,DMSO-d 6)δ＝13.78(s,1H),11.45(s,1H),11.53-11.36(m,1H),8.16(d,J＝8.4Hz,1H),8.04(d,J＝1.1Hz,1H),7.94(dd,J＝1.4,8.3Hz,1H),7.89(d,J＝2.0Hz,1H),7.26-7.18(m,1H),3.91(s,3H)。
步骤7：化合物BB-3的合成。
在预先干燥过的拇指瓶中加入BB-3-7(50.00mg,146.74μmol)，稀盐酸(6M,300.00μL)和二氧六环(600.00μL)。加料完毕后，反应液氮气保护并在50℃下搅拌反应58小时。反应液过滤得到产物BB-3。 1H NMR(400MHz,DMSO-d 6)。
δ＝13.79(s,1H),11.45(s,1H),8.13(d,J＝8.3Hz,1H),8.01(s,1H),7.94-7.87(m,2H),7.24-7.20(m,1H)。
参考例4：片段BB-4
Figure PCTCN2018075995-appb-000111
合成路线：
Figure PCTCN2018075995-appb-000112
步骤1：化合物BB-4-3的合成。
氮气保护下将化合物BB-4-1(2.90g,19.26mmol)，BB-4-2(1.45g,14.06mmol)和MgSO 4(4.82g,40.06mmol)溶于乙醇(30mL)中。将反应液升温至85℃搅拌12小时。加饱和碳酸钠溶液(30mL)淬灭反应，反应液乙酸乙酯萃取(20mL*3)。合并有机相，有机相饱和氯化钠溶液洗(10mL*2)。有机相无水硫酸钠干燥，过滤，减压除去溶剂。粗品柱层析得BB-4-3。 1H NMR(400MHz,DMSO-d 6)δ＝8.30(s,1H),4.29(q,J＝7.2Hz,2H),3.32-3.26(m,1H),1.34(d,J＝6.9Hz,6H),1.28(t,J＝7.1Hz,3H)。
步骤2：化合物BB-4-4的合成。
0℃下将BB-4-3(1.7g，8.53mmol)的四氢呋喃(5.00mL)溶液滴入四氢铝锂(809.39mg,21.33mmol)的四氢呋喃(5.00mL)溶液中。反应液保持5℃搅拌2小时然后升温至25℃搅拌12小时。向反应液中加入含结晶水的硫酸钠淬灭反应。过滤，滤饼大量乙酸乙酯洗，收集滤液。滤液无水硫酸钠干燥，过滤，减压除去溶剂得BB-4-4直接用于下一步反应。 1H NMR(400MHz,METHANOL-d4)δ＝7.47(s,1H),4.61(d,J＝5.6Hz,2H),3.29-3.16(m,1H),1.30(d,J＝6.9Hz,6H)。
步骤3：化合物BB-4-5的合成。
0℃下向BB-4-4(200.00mg,1.27mmol)的二氯甲烷(3.00mL)溶液中加入DMAP(15.52mg,127.00μmol)和三乙胺(385.53mg,3.81mmol,528.12μL)。然后向其中滴入甲基磺酰氯(218.22mg,1.91mmol,147.45μL)。将反应逐渐升温至25℃并保持该温度反应3小时。加水(5mL)淬灭反应，然后用二氯甲烷(10mL*3)萃取。合并有机相，并用无水硫酸钠干燥。过滤，减压除去溶剂得BB-4-5直接用于下一步反应。
步骤4：化合物BB-4-6的合成。
25℃下向BB-4-5(200.00mg,1.14mmol)的DMF(2.00mL)溶液中加入叠氮钠(148.22mg,2.28mmol)。将反应升温至80℃搅拌16小时。加饱和碳酸钠溶液(2.00mL)淬灭反应，然后用乙酸乙酯(5mL*3) 萃取。合并有机相并用饱和氯化钠洗。有机相用无水硫酸钠干燥，过滤，减压除去溶剂。粗品制备薄层层析分离得BB-4-6。 1H NMR(400MHz,DMSO-d 6)δ＝7.76-7.59(m,1H),4.69(s,2H),3.26(td,J＝6.8,13.7Hz,1H),1.32(d,J＝6.8Hz,6H)。
步骤5：化合物BB-4的合成。
向化合物BB-4-6((90.00mg,493.83μmol)的四氢呋喃(2.00mL)和水(400.00μL)的溶液中加入三苯基膦(259.05mg,987.66μmol)。反应在25℃下搅拌2小时。减压除去溶剂得产物粗品。粗品制备薄层层析分离得BB-4直接用于下一步反应。
参考例5：片段BB-5
Figure PCTCN2018075995-appb-000113
合成路线：
Figure PCTCN2018075995-appb-000114
步骤1：化合物BB-5-2的合成。
在干燥的500毫升三口瓶中加入化合物BB-5-1(9.70g,39.88mmol)和二氯甲烷(100.00mL)，将体系降温至-78℃，向反应体系中滴加DAST(25.71g,159.52mmol,21.07mL)。滴加完毕后，将该三口瓶置于25℃的油浴中搅拌4小时。将反应体系降温至0℃，向其中缓慢滴加饱和碳酸氢钠水溶液调节pH值至10左右，收集二氯甲烷层，水相再用二氯甲烷萃取(50mL*2)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩得BB-5-2。
步骤2：化合物BB-5-3的合成。
在干燥的500毫升单口瓶中加入化合物BB-5-2(9.05g,34.12mmol)和4M的氯化氢乙酸乙酯溶液(100.00mL)，然后将该单口瓶置于25℃的油浴中搅拌1小时。将反应液减压浓缩得到BB-5-3。该粗产物直接用于下一步反应。
步骤3：化合物BB-5-4的合成。
在干燥的单口瓶中加入化合物BB-5-3(6.88g,34.13mmol)、二氧化锰(11.87g,136.51mmol)和四氢呋喃(100mL)，氮气置换三次，然后将该单口瓶置于70℃的油浴中搅拌4小时。将该反应液过滤，滤液减压浓缩得到棕色固体粗产物。该粗产物通过硅胶柱层析得BB-5-4。
步骤4：化合物BB-5-5的合成。
在干燥的500毫升三口瓶中加入叔丁醇钾的四氢呋喃溶液(1M,64.63mL)，在0℃下，向体系中滴加化合物BB-5-4(3.7g,25.85mmol)的四氢呋喃(60mL)溶液，体系在25℃下搅拌15分钟。然后在0℃下，向体系中滴加化合物BB-1-2(15.54g,51.71mmol)的四呋喃(40mL)溶液。最后将该三口瓶置于25℃的油浴中搅拌5小时。将该反应混合物过滤，滤饼用乙酸乙酯(100mL)洗涤，滤液浓缩得到粗产物。该粗产物通过硅胶柱层析得BB-5-5。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.29(d,J＝8.6Hz,1H),7.98-7.91(m,2H),7.44(dd,J＝2.3,3.2Hz,1H),6.90(d,J＝2.2Hz,1H),3.75(s,3H)。
步骤5：化合物BB-5-6的合成。
在干燥的单口瓶中加入化合物BB-5-5(900mg,2.21mmol)、铁粉(493.76mg,8.84mmol)以及醋酸(5mL)，氮气置换三次，然后将该反应置于70℃的油浴中搅拌1小时。将该反应混合物通过垫有硅藻土的五孔漏斗进行热过滤，滤饼用二氯甲烷(10mL)洗涤，滤液减压浓缩得到BB-5-6。
步骤6：化合物BB-5的合成。
在干燥的单口中加入化合物BB-5-6(1.1g,2.92mmol)和甲苯(10mL)，氮气置换三次，加入三甲基铝的甲苯溶液(2.5M,1.75mL)，然后将该反应置于110℃的油浴中搅拌2小时。向反应体系中加入10毫升水，用乙酸乙酯萃取(30mL*3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩得到BB-5。
参考例6:片段BB-6
Figure PCTCN2018075995-appb-000115
合成路线：
Figure PCTCN2018075995-appb-000116
步骤1：化合物BB-6-2的合成。
在预先干燥过的500ml三口瓶中加入叔丁醇钾(1M,39.17mL)和THF(50mL)，随后抽真空用氮气置换3次，降温至0℃后逐滴加入WX186-1(5g,32.64mmol)的THF(50mL)溶液，控制温度在0-5℃，加完后升至25℃搅拌20min，溶液变成白色悬浊液。降温至0℃，缓慢滴加BB-6-1(10.95g,39.17mmol)的THF(100mL)溶液，控制温度不超过5℃，溶液颜色变成深红色液体。滴毕升至25℃搅拌12h，溶液颜色变成黄色。将反应液倾倒入300mL水中淬灭反应，加入300mL乙酸乙酯萃取，250mL饱和食盐水洗涤合并的有机相，无水硫酸钠干燥，过滤，收集滤液减压除去溶剂得BB-6-2。
步骤2：化合物BB-6-3的合成。
在预先干燥过的500mL三口瓶中加入原料BB-6-2(12.5g,31.54mmol)和醋酸(250mL)，使其充分溶解，随后加入铁粉(7.05g,126.14mmol)，在70℃下反应5h。将反应液趁热通过硅藻土过滤，滤液用500mL EtOAc冲洗，收集滤液，减压除去溶剂得粗品BB-6-3直接用于下一步反应。
步骤3：化合物BB-6-4的合成。
在预先干燥过的250mL的单口瓶中加入原料BB-6-3(14g,38.21mmol)和甲苯(150mL)，随后缓慢滴加三甲基铝(2M,28.66mL)，加完后在110℃下搅拌5h。加300mL饱和磷酸二氢钠水溶液淬灭反应，然后加入500mL EtOAc,充分搅拌，通过硅藻土过滤，滤液分液，水相用2*300mL EtOAc萃取，合并有机相，用250mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压除去溶剂得BB-6-4。
步骤4：化合物BB-6的合成。
在预先干燥过的250mL单口瓶中加入原料BB-6-4(9g,28.10mmol)和溶剂THF(90mL)，随后加入LiOH.H 2O(2.36g,56.20mmol)的水(25mL)溶液，溶液颜色变成深红色，反应在25℃下反应2h，加入1M HCl至溶液pH＝2-3,在冰浴下冷却析出固体，搅拌一段时间后过滤，滤饼用冰水50mL淋洗,得到的固体在油泵上拉干得BB-6。
实施例1：WX143
Figure PCTCN2018075995-appb-000117
合成路线：
Figure PCTCN2018075995-appb-000118
步骤1：化合物WX143的合成。
在预先干燥过的拇指瓶中加入BB-3(15.00mg,45.91μmol)，EDCI(13.20mg,68.86μmol)，HOBt(9.31mg,68.86μmol)，DIPEA(10.68mg,82.64μmol)和溶剂DMF(1.00mL)，最后于0℃下向其中加入WX143-1(6.96mg,45.91μmol,1.00eq)。加料完毕后，反应液氮气保护并在25℃下搅拌反应12小时。反应液过滤得到产物粗品。粗产品通过HPLC分离得WX143。
实施例2：WX145
Figure PCTCN2018075995-appb-000119
合成路线：
Figure PCTCN2018075995-appb-000120
步骤1：化合物WX145-2的合成。
在预先干燥过的100毫升烧瓶中加入叔丁醇钾(1M,15.67mL)，随后加入四氢呋喃(15mL)。在0℃下，将WX145-1(1.00g,6.27mmol)的四氢呋喃(15mL)溶液缓慢滴加到反应液中，然后反应液在20℃ 下搅拌反应15分钟。随后，BB-1-2(3.77g,12.54mmol,2.00eq)的四氢呋喃(20mL)溶液在0℃下缓慢滴入。体系恢复至20℃搅拌4.5小时。反应液用乙酸乙酯和水(1:1,100mL)稀释，水层用乙酸乙酯洗(100mL*2)，合并有机层，用无水硫酸钠干燥，过滤，浓缩。柱层析分离得WX145-2。 1H NMR(400MHz,DMSO-d 6)δ＝8.54(d,J＝2.0Hz,1H),8.18(dd,J＝2.0,8.6Hz,1H),7.85-7.79(m,2H),6.76(d,J＝3.7Hz,1H),3.66(s,3H)。
步骤2：化合物WX145-3的合成。
在干燥的拇指瓶中加入原料WX145-2(450.00mg,1.06mmol)和醋酸(2.00mL)搅拌溶解。随后加入铁粉(296.01mg,5.30mmol)，置换三次氮气。将反应体系置于70℃搅拌2小时。减压浓缩得到粗产品。粗产品通过柱层析得WX145-3。 1H NMR(400MHz,METHANOL-d4)δ＝7.55(d,J＝3.5Hz,1H),7.48(d,J＝8.8Hz,1H),6.96-6.84(m,2H),6.32(d,J＝3.5Hz,1H),5.20(br s,2H),3.85(s,3H)。
步骤3：化合物WX145-4的合成。
在干燥的100毫升单口瓶中加入WX145-3(410.00mg,1.04mmol)和甲苯(1.00mL)搅拌溶解。随后加入三甲基铝的甲苯溶液(2.5M,624.94μL)，置换三次氮气。将反应体系于110℃搅拌1.5小时。加入1:1水和乙酸乙酯(10mL)，用乙酸乙酯(5mL*3)萃取，合并有机相，用无水硫酸钠干燥，减压浓缩得到粗产品。粗产品通过柱层析得WX145-4。 1H NMR(400MHz,DMSO-d6)δ＝11.30(s,1H),7.91(d,J＝8.6Hz,1H),7.67-7.62(m,3H),6.68(d,J＝3.5Hz,1H)。
步骤4：化合物WX145的合成。
将WX145-4(50.00mg,138.27μmol)和BB-4(23.77mg,152.10μmol)溶入DMF(3.00mL)，然后向其中加入三乙胺(13.99mg,138.27μmol,19.16μL)和Pd(dppf)Cl 2(10.12mg,13.83μmol)。氩气置换三次后，用一氧化碳抽三次置换后加压至50PSI，反应液加热至80℃搅拌16小时。将反应液冷却至室温，直接浓缩得到粗产品。粗品HPLC分离得WX145。
1H NMR(400MHz,DMSO-d6)δ＝11.36(s,1H),9.49-9.43(m,1H),8.10(d,J＝8.2Hz,1H),7.88(s,1H),7.82(d,J＝8.4Hz,1H),7.64(d,J＝3.3Hz,1H),7.56(s,1H),6.68(d,J＝3.3Hz,1H),4.62(d,J＝5.7Hz,2H),3.21(td,J＝7.0,13.8Hz,1H),1.28(d,J＝6.8Hz,6H)。
实施例3：WX146
Figure PCTCN2018075995-appb-000121
合成路线：
Figure PCTCN2018075995-appb-000122
步骤1：化合物WX146的合成。
化合物WX146的合成参照实施例1WX143的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.22(s,1H),8.85(d,J＝4.2Hz,1H),8.10(d,J＝8.4Hz,1H),7.86(s,1H),7.77(d,J＝8.4Hz,1H),7.61(d,J＝1.1Hz,1H),7.18-7.11(m,1H),6.54(t,J＝3.3Hz,1H),3.53(d,J＝11.0Hz,2H),3.40-3.32(m,3H),1.79(br s,2H),1.39(s,9H)。
实施例4：WX170和WX171
Figure PCTCN2018075995-appb-000123
合成路线：
Figure PCTCN2018075995-appb-000124
步骤1：化合物WX170和WX171的合成。
化合物WX170和WX171的合成参照实施例2中步骤4WX145的合成。
化合物WX170： 1H NMR(400MHz,DMSO-d 6)δ＝11.22(s,1H),8.77(br t,J＝5.5Hz,1H),8.10(d,J＝8.5Hz,1H),7.86(d,J＝1.5Hz,1H),7.78(dd,J＝1.5,8.0Hz,1H),7.61(dd,J＝2.0,3.0Hz,1H),7.15(dd,J＝1.5,3.5Hz,1H),6.54(t,J＝3.3Hz,1H),3.82-3.69(m,2H),3.63-3.53(m,1H),3.33-3.25(m,2H),2.01-1.89(m,1H),1.88-1.74(m,2H),1.73-1.65(m,2H),1.49-1.28(m,1H)；
化合物WX171： 1H NMR(400MHz,DMSO-d 6)δ＝11.22(s,1H),8.77(br t,J＝5.4Hz,1H),8.10(d,J＝8.3Hz,1H),7.86(d,J＝1.3Hz,1H),7.78(dd,J＝1.3,8.3Hz,1H),7.61(dd,J＝1.8,3.0Hz,1H),7.15(dd,J＝1.8,3.5Hz,1H),6.54(t,J＝3.4Hz,1H),3.90-3.68(m,2H),3.65-3.53(m,1H),3.33-3.25(m,2H),1.99-1.91(m,1H),1.86-1.75(m,2H),1.69(q,J＝6.9Hz,2H),1.47-1.34(m,1H)。
手性拆分条件：手性柱：OJ(250mm*30mm,5μm)；流动相：0.1％氨水/乙醇；流速：60mL/min；柱温：40℃。
化合物WX171对应的保留时间：3.949分钟(峰2)；化合物WX170对应的保留时间：3.658分钟(峰1)。
实施例5：WX175
Figure PCTCN2018075995-appb-000125
合成路线：
Figure PCTCN2018075995-appb-000126
步骤1：化合物WX175的合成。
在预先干燥过的50毫升烧瓶中加入BB-2-1(85.00mg,277.51μmol)和化合物WX175-1(24.74mg,277.51μmol,28.44μL)，随后加入甲苯(5.00mL)。再将三甲基铝的甲苯溶液(2M,208.13μL)在25℃下缓慢加到反应液中，再将反应液在110℃下搅拌反应1小时。反应液用乙酸乙酯和水(1:1,20mL)稀释，水层用乙酸乙酯洗(20mL*2)，合并有机层，用无水硫酸钠干燥，过滤，浓缩。粗产品通过pre-HPLC分离得WX175。 1H NMR(400MHz,DMSO-d 6)δ＝8.79(br t,J＝5.4Hz,1H),8.11(d,J＝8.3Hz,1H),7.87(s,1H),7.79(dd,J＝1.5,8.3Hz,1H),7.62(dd,J＝1.6,2.9Hz,1H),7.16(dd,J＝1.8,3.5Hz,1H),6.55(t,J＝3.4Hz,1H),3.37-3.34(m,2H),3.32-3.27(m,2H),3.23(s,3H),1.75(q,J＝6.7Hz,2H)。
实施例6：WX176
Figure PCTCN2018075995-appb-000127
合成路线：
Figure PCTCN2018075995-appb-000128
步骤1：化合物WX176的合成。
化合物WX176的合成参照实施例2中步骤4WX145的合成。 1H NMR(400MHz,METHANOL-d 4)δ＝8.52(br d,J＝4.3Hz,1H),8.17(d,J＝8.8Hz,1H),7.90-7.80(m,3H),7.55(dd,J＝1.8,3.0Hz,1H),7.49-7.44(m,1H),7.35(dd,J＝5.3,7.0Hz,1H),7.19(dd,J＝1.6,3.6Hz,1H),6.52(t,J＝3.3Hz,1H),4.72(s,2H)。
实施例7：WX254
Figure PCTCN2018075995-appb-000129
合成路线：
Figure PCTCN2018075995-appb-000130
步骤1：化合物WX254的合成。
化合物WX254的合成参照实施例1WX143的合成。 1H NMR(400MHz,DMSO-d6)δ＝11.21(s,1H),9.44(t,J＝5.7Hz,1H),8.11(d,J＝8.4Hz,1H),7.90(s,1H),7.80(dd,J＝1.2,8.3Hz,1H),7.61(dd,J＝1.8,2.9Hz,1H),7.56(s,1H),7.15(dd,J＝1.5,3.5Hz,1H),6.54(t,J＝3.3Hz,1H),4.61(d,J＝5.7Hz,2H),3.20(t,J＝6.8Hz,1H),1.28(d,J＝6.8Hz,6H)。
实施例8：WX255
Figure PCTCN2018075995-appb-000131
合成路线：
Figure PCTCN2018075995-appb-000132
步骤1：化合物WX255的合成。
化合物WX255的合成参照实施例1WX143的合成。 1H NMR(400MHz,DMSO-d6)δ＝11.40(br s,1H),9.51(br s,1H),8.11(d,J＝8.3Hz,1H),7.91(s,1H),7.89-7.82(m,2H),7.56(s,1H),7.20(d,J＝1.9Hz,1H),4.61(br d,J＝5.6Hz,2H),3.20(quin,J＝6.8Hz,1H),1.28(d,J＝6.9Hz,6H)。
实施例9：WX257
Figure PCTCN2018075995-appb-000133
合成路线：
Figure PCTCN2018075995-appb-000134
步骤1：化合物WX257的合成。
化合物WX257的合成参照实施例1WX143的合成。 1H NMR(400MHz,DMSO-d6)δ＝11.21(s,1H),9.53(t,J＝5.6Hz,1H),8.12(d,J＝8.4Hz,1H),7.90(d,J＝1.5Hz,1H),7.80(dd,J＝1.5,8.4Hz,1H),7.63-7.58(m,2H),7.15(dd,J＝1.7,3.6Hz,1H),6.57-6.52(m,1H),4.60(d,J＝5.5Hz,2H)。
实施例10：WX258
Figure PCTCN2018075995-appb-000135
合成路线：
Figure PCTCN2018075995-appb-000136
步骤1：化合物WX258的合成。
化合物WX258的合成参照实施例1WX143的合成。 1H NMR(400MHz,DMSO-d6)δ＝11.42-11.12(m,1H),9.69-9.28(m,1H),8.19(s,1H),8.11(d,J＝8.4Hz,1H),7.97(d,J＝1.1Hz,1H),7.90(dd,J＝1.1,8.4Hz,1H),7.85(br d,J＝3.7Hz,2H),7.61(dd,J＝1.7,3.0Hz,1H),7.31(br s,1H),7.14(dd,J＝1.8,3.5Hz,1H),6.54(t,J＝3.3Hz,1H),5.07(d,J＝4.4Hz,2H),2.99(s,3H)。
实施例11：WX259
Figure PCTCN2018075995-appb-000137
合成路线：
Figure PCTCN2018075995-appb-000138
步骤1：化合物WX259的合成。
化合物WX259的合成参照实施例1WX143的合成。 1H NMR(400MHz,DMSO-d6)δ＝11.21(s,1H),9.32(t,J＝5.7Hz,1H),8.12(d,J＝8.4Hz,1H),7.90(d,J＝1.5Hz,1H),7.81(dd,J＝1.5,8.4Hz,1H),7.61(dd,J＝1.8,3.1Hz,1H),7.29(d,J＝5.1Hz,1H),7.15(dd,J＝1.8,3.5Hz,1H),6.84(d,J＝5.1Hz,1H),6.54(t,J＝3.3Hz,1H),4.55(d,J＝5.7Hz,2H),2.22(s,3H)。
实施例12：WX260
Figure PCTCN2018075995-appb-000139
合成路线：
Figure PCTCN2018075995-appb-000140
步骤1：化合物WX260的合成。
化合物WX260的合成参照实施例1中WX143的合成。 1H NMR(400MHz,DMSO-d6)δ＝11.23(s,1H),9.54(t,J＝5.6Hz,1H),8.11(d,J＝8.2Hz,1H),7.89(d,J＝1.3Hz,1H),7.80(dd,J＝1.4,8.3Hz,1H),7.60(dd,J＝1.8,3.1Hz,1H),7.14(dd,J＝1.8,3.5Hz,1H),6.53(t,J＝3.4Hz,1H),4.53(d,J＝5.7Hz,2H),2.67-2.62(m,3H),2.38(s,3H)。
实施例13：WX261
Figure PCTCN2018075995-appb-000141
合成路线：
Figure PCTCN2018075995-appb-000142
步骤1：化合物WX261的合成。
化合物WX261的合成参照实施例1的WX143的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.25(s,1H),9.69(t,J＝5.2Hz,1H),8.92(s,1H),8.18(s,1H),8.20-8.16(m,1H),8.20-8.16(m,1H),8.20-8.16(m,1H), 8.11(d,J＝8.2Hz,1H),7.95-7.82(m,4H),7.60(dd,J＝1.8,3.1Hz,1H),7.14(dd,J＝1.7,3.6Hz,1H),6.53(t,J＝3.3Hz,1H),4.88(d,J＝5.3Hz,2H),2.44(s,3H)。
实施例14：WX262
Figure PCTCN2018075995-appb-000143
合成路线：
Figure PCTCN2018075995-appb-000144
步骤1：化合物WX262的合成。
化合物WX262的合成参照实施例1WX143的合成。 1H NMR(400MHz,DMSO-d6)δ＝11.21(s,1H),9.37(t,J＝5.8Hz,1H),8.11(d,J＝8.2Hz,1H),7.90(d,J＝1.3Hz,1H),7.80(dd,J＝1.4,8.3Hz,1H),7.61(dd,J＝1.5,3.1Hz,1H),7.15(dd,J＝1.7,3.6Hz,1H),6.79(d,J＝3.3Hz,1H),6.62(dd,J＝1.1,3.3Hz,1H),6.54(t,J＝3.3Hz,1H),4.53(d,J＝5.7Hz,2H),2.38(s,3H)。
实施例15：WX263
Figure PCTCN2018075995-appb-000145
合成路线：
Figure PCTCN2018075995-appb-000146
步骤1：化合物WX263的合成。
化合物WX263的合成参照实施例1中WX143的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.22(s,1H),9.31(br t,J＝5.5Hz,1H),8.11(d,J＝8.2Hz,1H),7.91(s,1H),7.83(dd,J＝1.4,8.3Hz,1H),7.61(dd,J＝1.6,3.0Hz,1H),7.32(d,J＝1.6Hz,1H),7.15(dd,J＝1.6,3.5Hz,1H),6.54(t,J＝3.4Hz,1H),6.18(d,J＝1.6Hz,1H),4.52(d,J＝5.5Hz,2H),3.81(s,3H)。
实施例16：WX265
Figure PCTCN2018075995-appb-000147
合成路线
Figure PCTCN2018075995-appb-000148
步骤1：化合物WX265的合成。
化合物WX265的合成参照实施例1中WX143的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.24(s,1H),9.48-9.40(m,1H),8.86-8.75(m,2H),8.14(d,J＝8.3Hz,1H),7.93(s,1H),7.86(br d,J＝8.3Hz,1H),7.76(d,J＝5.0Hz,1H),7.62(br d,J＝1.3Hz,1H),7.21-7.10(m,1H),6.54(t,J＝3.3Hz,1H),4.69(br d,J＝4.6Hz,2H)。
实施例17：WX266
Figure PCTCN2018075995-appb-000149
合成路线：
Figure PCTCN2018075995-appb-000150
步骤1：化合物WX266的合成。
化合物WX266的合成参照实施例1WX143的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.22(s,1H),8.17-7.97(m,3H),7.65-7.59(m,1H),7.58-7.44(m,4H),7.22-7.10(m,1H),6.55(br s,1H),5.18-4.83(m,2H),3.10-3.00(m,3H)。
实施例18：WX267
Figure PCTCN2018075995-appb-000151
合成路线：
Figure PCTCN2018075995-appb-000152
步骤1：化合物WX267的合成。
化合物WX267的合成参照实施例1WX143的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.25(s,1H),9.60(br s,1H),8.98(br d,J＝6.8Hz,1H),8.24(s,1H),8.12(d,J＝8.3Hz,1H),8.03-7.96(m,2H),7.92(s,1H),7.85(br d,J＝8.2Hz,1H),7.64-7.54(m,2H),7.14(br d,J＝1.8Hz,1H),6.58-6.49(m,1H),4.93(br d,J＝4.9Hz,2H)。
实施例19：WX270
Figure PCTCN2018075995-appb-000153
合成路线：
Figure PCTCN2018075995-appb-000154
步骤1：化合物WX270的合成。
化合物WX270的合成参照实施例2中步骤4WX145的合成。 1H NMR(400MHz,DMSO-d6)δ＝11.39(s,1H),8.82(br t,J＝5.2Hz,1H),8.09(d,J＝8.2Hz,1H),7.89(s,1H),7.82(d,J＝9.0Hz,1H),7.74-7.68(m,1H),7.14(d,J＝1.8Hz,1H),3.83-3.70(m,2H),3.63-3.54(m,1H),3.31-3.25(m,2H),2.02-1.90(m,1H),1.86-1.74(m,2H),1.69(m,2H),1.48-1.33(m,1H).
实施例20：WX185
Figure PCTCN2018075995-appb-000155
合成路线：
Figure PCTCN2018075995-appb-000156
步骤1：化合物WX185-2的合成。
将WX185-1(5g,24.51mmol)溶解于二氯甲烷(60mL)中，加入三乙胺(5.46g,53.92mmol,7.50mL)，DMAP(299.40mg,2.45mmol)，随后滴入苯甲磺酰氯(4.76g,26.96mmol,3.45mL)，反应在30℃搅拌5小时。向反应液中加入二氯甲烷(100mL)，2M稀盐酸(30mL*2)洗，二氯甲烷层使用无水硫酸钠干燥，减压除去溶剂。粗产品使用硅胶柱层析得WX185-2。 1H NMR(400MHz,DMSO-d 6)δ＝8.06(td,J＝2.2,4.4Hz,2H),7.79(d,J＝7.5Hz,1H),7.72-7.65(m,2H),7.19(d,J＝2.0Hz,1H),3.69(s,3H)。
步骤2：化合物WX185-3的合成。
将WX185-3(9g,26.15mmol)溶解于DMF(60mL)中，加入四三苯基膦钯(1.51g,1.31mmol)，三叔丁基乙烯基锡(10.78g,33.99mmol,9.89mL)，氮气置换三次，反应在100℃搅拌24小时。向反应液中加入氟化铯溶液(8g溶于50mL水中)，搅拌6小时，随后加入乙酸乙酯(100mL)，水洗(50mL*2)，乙酸乙酯层过滤(EA层存在固体有机物)，滤液使用无水硫酸钠干燥后，减压浓缩。粗产品使用硅胶柱层析进行纯化得WX185-3。 1H NMR(400MHz,DMSO-d 6)δ＝8.03-7.98(m,2H),7.94(d,J＝1.9Hz,1H),7.76(d,J＝7.5Hz,1H),7.68(d,J＝8.2Hz,2H),7.37(d,J＝1.9Hz,1H),6.66-6.56(m,1H),5.72(dd,J＝1.0,17.7Hz,1H),5.21(dd,J＝1.1,11.0Hz,1H),3.68(s,3H)。
步骤3：化合物WX185-4的合成。
将WX185-3(5.7g,19.57mmol)溶于甲醇(60mL)中，加入甲醇钠(1.37g,25.44mmol)，反应在50℃搅拌12小时。反应液减压浓缩。粗产品使用硅胶柱层析得WX185-4。 1H NMR(400MHz,DMSO-d 6)δ＝11.88(br s,1H),7.11(dd,J＝1.6,2.9Hz,1H),6.94(s,1H),6.53(dd,J＝10.9,17.7Hz,1H),5.46(dd,J＝1.5,17.7Hz,1H),4.94(dd,J＝1.6,10.9Hz,1H),3.75(s,3H)。
步骤4：化合物WX185-5的合成。
0℃下，向叔丁醇钾的四氢呋喃溶液(1M,29.60mL,2.5eq)中滴入WX185-4(1.79g,11.84mmol)的四氢呋喃(30mL)溶液，体系在30℃下搅拌30分钟，随后体系温度降至0℃，加入BB-1-2(7.12g,23.68mmol,2eq)的四氢呋喃(30mL)溶液，随后反应升至30℃搅拌3小时。减压除去溶剂。粗产品使用硅胶柱层析进行纯化得WX185-5。 1H NMR(400MHz,DMSO-d 6)δ＝8.51(d,J＝2.0Hz,1H),8.16(dd,J＝1.9,8.7Hz,1H),7.90-7.80(m,2H),7.55(d,J＝1.6Hz,1H),6.65(dd,J＝11.0,17.7Hz,1H),5.79(br d,J＝17.6Hz,1H),5.26(d,J＝10.9Hz,1H),3.65(s,3H)。
步骤5：化合物WX185-6的合成。
将WX185-5(0.8g,1.93mmol)溶于醋酸(10mL)中，加入铁粉(430.39mg,7.71mmol)，反应在65℃搅拌2小时。反应液过滤，滤液减压浓缩。粗产品使用硅胶柱层析得WX185-6。 1H NMR(400MHz,DMSO-d 6)δ＝8.09(d,J＝1.9Hz,1H),7.62(d,J＝8.8Hz,1H),7.36(d,J＝1.8Hz,1H),7.08(d,J＝1.9Hz,1H),6.89-6.82(m,1H),6.60-6.48(m,1H),6.42(s,2H),5.70(dd,J＝1.0,17.7Hz,1H),5.23-5.11(m,1H),3.70(s,3H),1.99(s,1H)。
步骤6：化合物WX185-7的合成。
将WX185-6(1.8g,4.67mmol)溶解于DMSO(10mL)中，加入叔丁醇钾(786.47mg,7.01mmol)，反应升至80℃搅拌2小时。向反应液中加入乙酸乙酯(50mL)，1M稀盐酸(30mL*2)洗，水(30mL)洗，有机相用无水硫酸钠干燥后，减压浓缩。粗产品使用硅胶柱层析进行纯化得WX185-7。 1H NMR(400MHz,DMSO-d 6)δ＝11.20(s,1H),7.92(d,J＝8.4Hz,1H),7.69(dd,J＝1.7,9.6Hz,2H),7.64(dd,J＝1.5,8.6Hz,1H),7.42(d,J＝1.8Hz,1H),6.58(dd,J＝11.0,17.6Hz,1H),5.79-5.72(m,1H),5.21(d,J＝11.2Hz,1H)。
步骤7：化合物WX185-8的合成。
将WX185-7(80mg,226.51μmol)，WX173-1(37.78mg,249.16μmol)溶解于DMF(5mL)中，加入三乙胺(45.84mg,453.01μmol,63.05μL)，Pd(dppf)Cl2(16.57mg,22.65μmol)，反应通入一氧化碳气体，反应保持80℃，50psi反应16小时。减压除去溶剂，粗品柱层析进行纯化得WX185-8。
步骤8：化合物WX185的合成。
将WX185-8(40mg,96.28μmol)溶解于甲醇(10mL)中，加入Pd/C(40mg,377.36μmol)，通入氢气，保持30℃，15psi搅拌12小时。减压除去溶剂。粗产品使用HPLC进行纯化得WX185。 1H NMR(400MHz,DMSO-d 6)δ＝11.17(br s,1H),8.83(br s,1H),8.06(d,J＝8.2Hz,1H),7.88(s,1H),7.80(br d,J＝8.4Hz,1H),7.38(s,1H),7.06(s,1H),3.83-3.69(m,2H),3.58(br d,J＝6.4Hz,1H),2.46-2.40(m,4H),1.96(br d,J＝7.3Hz,1H),1.80(br dd,J＝7.1,14.1Hz,2H),1.73-1.64(m,2H),1.47-1.36(m,1H),1.12(t,J＝7.5Hz,3H)。
实施例21：WX186
Figure PCTCN2018075995-appb-000157
合成路线：
Figure PCTCN2018075995-appb-000158
步骤1：化合物WX186-2的合成。
化合物WX186-2的合成参照实施例20中步骤4化合物WX185-5的合成。 1H NMR(400MHz,DMSO-d 6)δ＝8.53(d,J＝2.0Hz,1H),8.18(dd,J＝1.9,8.7Hz,1H),7.88-7.80(m,1H),7.53(d,J＝1.6Hz,1H),6.62(dd,J＝11.0,17.7Hz,1H),3.89(s,3H)，2.04(s,3H)。
步骤2：化合物WX186-3的合成。
化合物WX186-3的合成参照实施例20中步骤5化合物WX185-6的合成。
步骤3：化合物WX186-4的合成。
化合物WX186-4的合成参照实施例20中步骤6化合物WX185-7的合成。
步骤4：化合物WX186的合成。
化合物WX186的合成参照实施例2中步骤4WX145的合成。 1H NMR(400MHz,DMSO-d6)δ＝11.36(s,1H),8.80(br t,J＝5.2Hz,1H),8.07(d,J＝8.2Hz,1H),7.87(s,1H),7.80(d,J＝9.0Hz,1H),7.72-7.69(m,1H),7.13(d,J＝1.8Hz,1H),3.81-3.70(m,2H),3.61-3.53(m,1H),3.30-3.23(m,2H),2.04(s,3H)，2.00-1.90(m,1H),1.86-1.74(m,2H),1.69(m,2H),1.48-1.33(m,1H)。
实施例22:WX184
Figure PCTCN2018075995-appb-000159
合成路线：
Figure PCTCN2018075995-appb-000160
步骤1：化合物WX184的合成。
在预先干燥的拇指瓶中加入BB-2(38.7mg,342.15μmol)，EDCI(98.4mg,513.23μmol)，DIPEA(88.4mg,684.31μmol)和DMF(1mL)，最后于0℃下向其中加入WX184-1(100mg,342.15μmol)，反应液氮气保护并在25℃下搅拌反应12小时。反应液过滤得到产物粗品。粗品经HPLC分离纯化得WX184。 1H NMR(400MHz,CHLOROFORM-d)δ8.94(br s,1H),8.09(d,J＝8.16Hz,1H),7.79(br s,1H),7.63(br d,J＝7.72Hz,1H),7.45(br s,1H),6.43(t,J＝3.20Hz,1H),6.20(br s,1H),3.54-3.49(m,2H),1.87-1.74(m,3H),1.49-1.67(m,5H),1.25(s,1H),1.14(br s,2H).
实施例23:WX187
Figure PCTCN2018075995-appb-000161
合成路线：
Figure PCTCN2018075995-appb-000162
步骤1：化合物WX187的合成。
在干燥的单口瓶中加入BB-2(0.1g,342.15μmol)和DMF(1mL)，随后加入HOBt(69.3mg,513.22μmol)、EDCI(98.4mg,513.22μmol)、DIPEA(88.4mg,684.30μmol)和WX187-1(43.5mg,342.15μmol)，
氮气置换3次，将反应置于20℃搅拌12小时。反应液通过有机相针头式滤器过滤，得到粗品。粗产品HPLC分离得WX187。 1H NMR(400MHz,DMSO-d6)δ＝11.21(s,1H),8.82(t,J＝5.6Hz,1H),8.11(d,J＝8.2Hz,1H),7.88(s,1H),7.80(d,J＝8.2Hz,1H),7.61(dd,J＝1.7,3.0Hz,1H),7.15(dd,J＝1.7,3.6Hz,1H),6.54(t,J＝3.3Hz,1H),3.35-3.30(m,2H),2.37-2.24(m,2H),1.78-1.70(m,2H).
实施例24:WX189
Figure PCTCN2018075995-appb-000163
合成路线：
Figure PCTCN2018075995-appb-000164
步骤1：化合物WX189的合成。
在干燥的单口瓶中加入BB-2(0.1g,342.15μmol)和DMF(1mL)，随后加入HOBt(69.3mg,513.22μmol,)、EDCI(98.4mg,513.22μmol)、DIPEA(88.4mg,684.30μmol,119.19μL,2eq)和WX189-1(42.8mg,342.15μmol)，氮气置换3次，将反应置于20℃搅拌12小时。反应液通过有机相针头式滤器过滤，得到粗品。粗产品通过HPLC分离得WX189。 1H NMR(400MHz,DMSO-d6)δ＝11.21(s,1H),9.33(br t,J＝6.0Hz,1H),8.12(d,J＝8.2Hz,1H),7.92(s,1H),7.84(d,J＝8.2Hz,1H),7.61(dd,J＝1.8,3.1Hz,1H),7.35(dd,J＝5.6,8.5Hz,2H),7.21-7.10(m,3H),6.54(t,J＝3.3Hz,1H),4.46(d,J＝5.7Hz,2H).
实施例25:WX190
Figure PCTCN2018075995-appb-000165
合成路线：
Figure PCTCN2018075995-appb-000166
步骤1：化合物WX190-2的合成。
在干燥的单口瓶中加入BB-2(0.2g,684.31μmol)和DMF(1mL)，随后加入HOBt(138.7mg,1.03mmol)、EDCI(196.8mg,1.03mmol)、DIPEA(176.9mg,1.37mmol)和WX190-1(71.99mg,684.31μmol)，氮气置换3次，将反应置于20℃搅拌12小时。减压浓缩得到粗产品，粗产品通过柱层析纯化得WX190-2。 1H NMR(400MHz,DMSO-d6)δ＝11.19(br s,1H),8.77(t,J＝5.3Hz,1H),8.10(d,J＝8.2Hz,1H),7.88(s,1H),7.79(d,J＝8.4Hz,1H),7.61(d,J＝1.5Hz,1H),7.18-7.13(m,1H),6.54(q,J＝3.4Hz,1H),3.38-3.32(m,2H),2.52(br s,2H),2.04(s,3H),1.78(q,J＝7.0Hz,2H).
步骤2：化合物WX190的合成。
在干燥的单口瓶中加入WX 190-2(0.2g,527.07μmol)、饱和碳酸氢钠溶液(4.32g,51.42mmol,2mL)和EtOAc(3mL),随后加入间氯过氧苯甲酸(374.52mg,1.84mmol,85％纯度)，氮气置换3次，将反应置于20℃搅拌2小时。反应液通过有机相针头式滤器过滤，得到粗品。粗品HPLC纯化得WX190。 1H NMR(400MHz,DMSO-d6)δ＝11.22(s,1H),8.85(t,J＝5.5Hz,1H),8.12(d,J＝8.4Hz,1H),7.89(s,1H), 7.81(d,J＝8.2Hz,1H),7.61(br s,1H),7.15(dd,J＝1.5,3.5Hz,1H),6.54(t,J＝3.3Hz,1H),3.39(q,J＝6.6Hz,2H),3.22-3.10(m,2H),2.97(s,3H),1.94(q,J＝7.3Hz,2H).
实施例26:WX195
Figure PCTCN2018075995-appb-000167
合成路线：
Figure PCTCN2018075995-appb-000168
步骤1：化合物WX195的合成。
化合物WX195的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.22(br s,1H),9.30(br d,J＝6.9Hz,1H),8.14(d,J＝8.3Hz,1H),7.93-7.80(m,2H),7.61(d,J＝1.6Hz,1H),7.15(d,J＝1.9Hz,1H),6.59-6.49(m,1H),4.64(d,J＝6.4Hz,1H),4.12(br s,2H),3.84(br s,2H),1.44-1.34(m,9H).
实施例27:WX196
Figure PCTCN2018075995-appb-000169
合成路线：
Figure PCTCN2018075995-appb-000170
步骤1：化合物WX196的合成。
化合物WX196的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d6)δ＝11.34-11.10(m,1H),8.89(t,J＝5.5Hz,1H),8.12(d,J＝8.3Hz,1H),7.88(d,J＝1.4Hz,1H),7.78(dd,J＝1.5,8.3Hz,1H),7.61(dd,J＝1.7,3.1Hz,1H),7.15(dd,J＝1.7,3.6Hz,1H),6.54(t,J＝3.3Hz,1H),3.87(br s,3H),3.58(br s,2H),3.45(br t,J＝6.3Hz,2H),1.34(s,9H).
实施例28:WX197
Figure PCTCN2018075995-appb-000171
合成路线：
Figure PCTCN2018075995-appb-000172
步骤1：化合物WX197的合成。
化合物WX197的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.22(s,1H),8.76(br s,1H),8.10(d,J＝8.3Hz,1H),7.87(s,1H),7.80(s,1H),7.61(br s,1H),7.15(d,J＝1.9Hz,1H),6.54(t,J＝3.2Hz,1H),4.00-3.80(m,2H),3.30(br d,J＝5.6Hz,2H),2.65(m,2H),1.71-1.60(m,2H),1.48-1.43(m,3H),1.38(s,9H),1.05-0.90(m,2H).
实施例29:WX198
Figure PCTCN2018075995-appb-000173
合成路线：
Figure PCTCN2018075995-appb-000174
步骤1：化合物WX198的合成。
化合物WX198的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ11.07-11.36(m,1H),8.81(br t,J＝5.77Hz,1H),8.12(br d,J＝5.40Hz,1H),7.89(s,1H),7.80(br s,1H),7.62(dd,J＝1.76,3.01Hz,1H),7.16(dd,J＝1.69,3.58Hz,1H),6.55(t,J＝3.39Hz,1H),3.93(m,2H),3.25(br s,3H),1.82(br s,4H),1.40(s,9H).
实施例30:WX200
Figure PCTCN2018075995-appb-000175
合成路线：
Figure PCTCN2018075995-appb-000176
步骤1：化合物WX200的合成。
化合物WX200的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ11.16(s,1H),8.75(br t,J＝5.62Hz,1H),8.07(d,J＝8.16Hz,1H),7.85(s,1H),7.77(d,J＝8.16Hz,1H),7.58(dd,J＝1.65,2.98Hz,1H),7.12(dd,J＝1.54,3.53Hz,1H),6.51(t,J＝3.31Hz,1H),3.89(br d,J＝12.35Hz,2H),3.13(br t,J＝5.95Hz,2H),2.64(br s,2H),1.56-1.75(m,3H),1.35(s,9H),0.99(dq,J＝3.86,12.09Hz,2H).
实施例31:WX201
Figure PCTCN2018075995-appb-000177
合成路线：
Figure PCTCN2018075995-appb-000178
步骤1：化合物WX201-1的合成。
在预先干燥过的50毫升单口瓶中加入WX195(400mg,895.90μmol)和氯化氢的乙酸乙酯溶液(15mL)，于25℃搅拌反应2小时。反应液减压浓缩除去溶剂后得WX201-1，直接用于下一步的反应。
步骤2：化合物WX201的合成。
向预先干燥的50毫升三口瓶中加入WX201-1(200mg,577.43μmol)，DIPEA(149.26mg,1.15mmol,201.16μL)和二氯甲烷(5mL)，反应液氮气保护并降至0℃后再缓慢滴入WX201-2(54.57mg,577.43μmol,44.73μL)，并于25℃下搅拌反应3小时。反应液加水(10mL)淬灭，二氯甲烷(10mL*3)萃取，有机相无水硫酸钠干燥，过滤，滤液减压浓缩得到产物。产物粗品经过HPLC分离纯化得WX201。 1H NMR(400MHz,DMSO-d 6)δ＝11.24(s,1H),9.35(br d,J＝7.2Hz,1H),8.14(br d,J＝8.3Hz,1H),7.92-7.88(m,1H),7.88-7.80(m,1H),7.65-7.59(m,1H),7.18-7.12(m,1H),6.54(t,J＝3.3Hz,1H),4.81-4.63(m,1H),4.20(br s,2H),3.92(d,J＝5.3Hz,1H),3.57(s,3H),1.98-1.74(m,1H).
实施例32:WX206
Figure PCTCN2018075995-appb-000179
合成路线：
Figure PCTCN2018075995-appb-000180
步骤1：化合物WX206的合成。
化合物WX206的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.24(s,1H),8.99(br t,J＝5.5Hz,1H),8.24(s,1H),8.10(d,J＝8.4Hz,1H),7.87(s,1H),7.78(d,J＝8.2Hz,1H),7.63-7.56(m,1H),7.14(dd,J＝1.5,3.5Hz,1H),6.95(s,1H),6.53(t,J＝3.3Hz,1H),3.52(q,J＝6.5Hz,2H),2.98-2.90(m,2H).
实施例33:WX208
Figure PCTCN2018075995-appb-000181
合成路线：
Figure PCTCN2018075995-appb-000182
步骤1：化合物WX208的合成。
化合物WX208的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.25(s,1H),8.83(s,1H),8.11(d,J＝8.3Hz,1H),7.84(d,J＝1.4Hz,1H),7.73(dd,J＝1.4,8.3Hz,1H),7.61(dd,J＝1.7,3.1Hz,1H),7.15(dd,J＝1.7,3.6Hz,1H),6.54(t,J＝3.3Hz,1H),3.41(br s,1H),3.38-3.31(m,3H),2.56(m,2H),2.16(t,J＝8.1Hz,2H),1.95-1.82(m,2H).
实施例34:WX289和290
Figure PCTCN2018075995-appb-000183
合成路线：
Figure PCTCN2018075995-appb-000184
步骤1：化合物WX289和WX290的合成。
化合物WX289和WX290的合成参照实施例24中步骤1WX189的合成。
化合物WX289： 1H NMR(400MHz,DMSO-d 6)δ＝11.19(br s,1H),8.70(br t,J＝5.51Hz,1H),8.09(d,J＝8.16Hz,1H),7.85(s,1H),7.77(d,J＝8.38Hz,1H),7.60(d,J＝1.76Hz,1H),7.14(dd,J＝1.43,3.42Hz,1H),6.53(t,J＝3.31Hz,1H),3.85(br d,J＝10.14Hz,1H),3.22-3.29(m,4H),1.74(br s,1H),1.61(q,J＝6.98Hz,3H),1.43(br s,3H),1.13-1.23(m,1H)；
化合物WX289： 1H NMR(400MHz,DMSO-d 6)δ11.17(s,1H),8.68(br t,J＝5.18Hz,1H),8.07(d,J＝8.38Hz,1H),7.83(s,1H),7.75(d,J＝8.38Hz,1H),7.58(dd,J＝1.76,2.87Hz,1H),7.12(dd,J＝1.54,3.53Hz,1H),6.51(t,J＝3.31Hz,1H),3.83(br d,J＝10.36Hz,1H),3.30-3.37(m,1H),3.19-3.28(m,3H),1.71(br s,1H),1.49-1.62(m,3H),1.40(br s,3H),1.13-1.22(m,1H).
手性拆分条件：手性柱:AD(250mm*30mm,5μm)；流动相：[Neu-MeOH]；B％:45％-45％,20min)。
化合物WX290对应的保留时间：11.13分钟(峰2)。化合物WX289对应的保留时间：8.88分钟(峰1)。
实施例35:WX211
Figure PCTCN2018075995-appb-000185
合成路线：
Figure PCTCN2018075995-appb-000186
步骤1：化合物WX211-3的合成。
在预先干燥的100ml单口瓶中加入WX211-2(3.13g,13.99mmol)，KOH(660.76mg,11.78mmol)和EtOH(10mL)，再向其中加入WX211-1(1g,10.52mmol,1eq),氮气气氛下80℃搅拌回流5小时。将反应液直接减压旋干，得到粗产品。粗品柱层析得化合物WX211-3。
步骤2：化合物WX211-4的合成。
在预先干燥的单口瓶中加入WX211-3(200mg,839.34μmol)和EtOAc(2mL)，在氮气气氛下加入氯化氢的乙酸乙酯溶液(4M,3mL)，将该反应液在25℃下搅拌0.5小时。将反应液直接旋干，粗品直接用于下一步反应。
步骤3：化合物WX211的合成。
化合物WX211的合成见实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.23(s,1H),8.88(br t,J＝5.63Hz,1H),8.09(d,J＝8.25Hz,1H),7.82(s,1H),7.71(dd,J＝1.50,8.34Hz,1H),7.59(dd,J＝1.67,3.03Hz,1H),7.49(dd,J＝2.03,6.73Hz,1H),7.36(ddd,J＝2.02,6.74,8.98Hz,1H),7.13(dd,J＝1.70,3.57Hz,1H),6.52(t,J＝3.31Hz,1H),6.35(d,J＝9.04Hz,1H),6.12(t,J＝6.17Hz,1H),4.03(br t,J＝5.73Hz,2H),3.56(q,J＝5.73Hz,2H).
实施例36:WX215
Figure PCTCN2018075995-appb-000187
合成路线：
Figure PCTCN2018075995-appb-000188
步骤1：化合物WX215的合成。
化合物WX215的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.21(s,1H),8.70(t,J＝5.5Hz,1H),8.10(d,J＝8.3Hz,1H),7.86(s,1H),7.78(dd,J＝1.4,8.3Hz,1H),7.61(dd,J＝1.7,3.1Hz,1H),7.15(dd,J＝1.7,3.6Hz,1H),6.54(t,J＝3.3Hz,1H),3.31-3.24(m,2H),1.75-1.56(m,6H),1.41(q,J＝7.0Hz,2H),1.23-1.12(m,3H),0.94-0.85(m,2H).
实施例37:WX216
Figure PCTCN2018075995-appb-000189
合成路线：
Figure PCTCN2018075995-appb-000190
步骤1：化合物WX216的合成。
化合物WX216的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.23(s,1H),8.84(br t,J＝5.4Hz,1H),8.10(d,J＝8.3Hz,1H),7.89-7.82(m,1H),7.75(dd,J＝1.4,8.3Hz,1H),7.61(dd,J＝1.8,3.0Hz,1H),7.26(dd,J＝5.7,8.3Hz,2H),7.18-7.06(m,3H),6.54(t,J＝3.4Hz,1H),3.52-3.44(m,2H),2.83(br t,J＝7.2Hz,2H).
实施例38:WX217
Figure PCTCN2018075995-appb-000191
合成路线：
Figure PCTCN2018075995-appb-000192
步骤1：化合物WX217的合成。
化合物WX217的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.23(s,1H),8.83(t,J＝5.5Hz,1H),8.11(d,J＝8.3Hz,1H),7.86(d,J＝1.4Hz,1H),7.76(dd,J＝1.5,8.3Hz,1H),7.61(dd,J＝1.8,3.0Hz,1H),7.17-7.11(m,3H),6.85(d,J＝8.7Hz,2H),6.54(t,J＝3.4Hz,1H),3.71(s,3H),3.48-3.40(m,2H),2.76(br t,J＝7.3Hz,2H).
实施例39:WX218
Figure PCTCN2018075995-appb-000193
合成路线：
Figure PCTCN2018075995-appb-000194
步骤1：化合物WX218的合成。
化合物WX218的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.24(s,1H),8.87(br t,J＝5.4Hz,1H),8.11(d,J＝8.3Hz,1H),7.86(d,J＝1.4Hz,1H),7.76(dd,J＝1.5,8.3Hz,1H),7.61(dd,J＝1.8,3.1Hz,1H),7.33-7.19(m,5H),7.15(dd,J＝1.8,3.6Hz,1H),6.54(t,J＝3.4Hz,1H),3.55-3.45(m,2H),2.84(t,J＝7.3Hz,2H).
实施例40:WX219
Figure PCTCN2018075995-appb-000195
合成路线：
Figure PCTCN2018075995-appb-000196
步骤1：化合物WX219的合成。
化合物WX219的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)
δ＝11.23(s,1H),8.90(br t,J＝5.5Hz,1H),8.12(d,J＝8.3Hz,1H),7.88(d,J＝1.3Hz,1H),7.79(dd,J＝1.5,8.3Hz,1H),7.61(dd,J＝1.7,3.1Hz,1H),7.15(dd,J＝1.7,3.6Hz,1H),6.54(t,J＝3.3Hz,1H),3.46(q,J＝6.4Hz,2H),2.65(t,J＝7.0Hz,2H),2.09(s,3H).
实施例41:WX220
Figure PCTCN2018075995-appb-000197
合成路线：
Figure PCTCN2018075995-appb-000198
步骤1：化合物WX220的合成。
化合物WX220的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.26(s,1H),9.65(br t,J＝5.8Hz,1H),8.88(s,1H),8.80(d,J＝5.1Hz,1H),8.46(br d,J＝8.0Hz,1H),8.14(d,J＝8.3Hz,1H),8.00-7.89(m,3H),7.62(dd,J＝1.8,3.0Hz,1H),7.15(dd,J＝1.7,3.6Hz,1H),6.54(t,J＝3.3Hz,1H),4.66(d,J＝5.6Hz,2H).
实施例42:WX223
Figure PCTCN2018075995-appb-000199
合成路线：
Figure PCTCN2018075995-appb-000200
步骤1：化合物WX223-2的合成。
在干燥的100mL三口瓶中加入EtOH(50mL)氮气置换3次，体系冰甲醇浴冷却至-10℃，随后加入SOCl 2(50mL)在-10℃搅拌30min，将WX223-1(10g,112.24mmol)的EtOH(50mL)溶液滴入上述反应体系中。滴加完毕，将反应置于80℃回流2小时。将反应体系降至室温，加100ml甲基叔丁基醚搅拌20min减压抽滤，收集滤饼减压干燥，得化合物WX223-2。 1H NMR(400MHz,DMSO-d6)δ＝7.95(br s,2H),4.10(q,J＝7.3Hz,2H),3.07-2.93(m,2H),2.74-2.61(m,2H),1.20(t,J＝7.2Hz,3H).
步骤2：化合物WX223-3的合成。
在干燥的单口瓶中加入WX223-2(16g,104.16mmol)溶于MeCN(200mL)，随后加入K 2CO 3(35.99g,260.40mmol)和BnBr(35.63g,208.32mmol,24.74mL)，氮气置换3次，将反应置于40℃搅拌16小时。向反应加入200mL水淬灭，用乙酸乙酯(400mL*3)萃取，合并有机相，用饱和食盐水(200mL*3)洗涤，有机相用无水硫酸钠干燥，减压浓缩得到粗产品。粗产品柱层析纯化得WX223-3。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.27(s,7H),7.25-7.18(m,2H),4.07(q,J＝7.2Hz,2H),3.57(s,4H),3.62 -3.53(m,1H),3.62-3.53(m,1H),2.80(t,J＝7.2Hz,2H),2.48(t,J＝7.2Hz,2H),1.19(t,J＝7.2Hz,3H).
步骤3：化合物WX223-4的合成。
在干燥的三口瓶中加入WX223-3(5.5g,18.49mmol)和Et 2O(50mL)，随后加入四异丙基氧钛(525.63mg,1.85mmol,545.83μL)，冷却体系至0℃，最后向体系滴加溴乙基格氏试剂(3M,18.49mL)，保持体系温度在0-4℃，滴加完毕后将反应置于20℃搅拌12小时。加入50mL饱和氯化铵溶液，搅拌15min，加入饱和碳酸氢钠溶液调至pH＝9，用乙酸乙酯(100mL*3)萃取，合并有机相用饱和食盐水(50mL*2)洗涤，用无水硫酸钠干燥，减压浓缩得到粗产品。粗产品柱层析分离得WX223-4。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.31-7.27(m,5H),7.26-7.19(m,5H),3.56(s,4H),2.74-2.70(m,2H),2.07-1.93(m,1H),1.72-1.67(m,2H),0.49-0.45(m,2H),0.16-0.12(m,2H).
步骤4：化合物WX223-5的合成。
在预先干燥过的三口烧瓶中加入WX223-4(1.3g,4.62mmol)加入THF(5mL)中，氮气抽换气三次之后将该反应器置于冰浴中冷却至0℃。随后在氮气保护下加入NaH(369.59mg,9.24mmol,60％)，体系温度控制在0-5℃，加料完毕保持0℃搅拌30分钟，随后向体系缓慢滴加碘甲烷(721.32mg,5.08mmol,316.37μL)，滴加完毕后在20℃继续搅拌3小时。将反应体系冷却到0℃，缓慢加入30mL水淬灭该反应，水相用乙酸乙酯萃取50mL*3,合并有机相用饱和食盐水洗涤50mL*2，有机相用无水硫酸钠干燥，过滤减压浓缩得到粗产品。粗产品柱层析得WX223-5。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.42-7.36(m,4H),7.32(t,J＝7.4Hz,4H),7.26-7.21(m,2H),3.61(s,4H),3.13(s,3H),2.71-2.62(m,2H),1.81-1.72(m,2H),0.71-0.65(m,2H),0.36-0.30(m,2H).
步骤5：化合物WX223-6的合成。
在预先干燥过的氢化瓶中加入原料WX223-5(300mg,1.02mmol)，随后加入溶剂EtOH(5mL)、水(0.5mL)、Pd(OH) 2(28.52mg,101.55μmol,50％纯度)，置换H 2，该混合物在20℃，40psi反应12小时。硅藻土过滤，滤液减压浓缩，得到粗产品。粗产品直接用于下一步反应。
步骤6：化合物WX223的合成。
化合物WX223的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d6)δ＝11.24(s,1H),8.78(t,J＝5.3Hz,1H),8.11(d,J＝8.3Hz,1H),7.86(d,J＝1.3Hz,1H),7.78(dd,J＝1.4,8.3Hz,1H),7.61(dd,J＝1.7,3.1Hz,1H),7.15(dd,J＝1.7,3.6Hz,1H),6.54(t,J＝3.3Hz,1H),3.41-3.36(m,2H),3.18(s,3H),1.81-1.76(m,2H),0.69-0.64(m,2H),0.44-0.39(m,2H).
实施例43:WX225
Figure PCTCN2018075995-appb-000201
合成路线：
Figure PCTCN2018075995-appb-000202
步骤1：化合物WX225的合成。
化合物WX225的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.23(br s,1H),8.75(br s,1H),8.10(d,J＝8.3Hz,1H),7.86(s,1H),7.78(br d,J＝8.3Hz,1H),7.61(dd,J＝1.7,2.9Hz,1H),7.15(dd,J＝1.6,3.5Hz,1H),6.54(t,J＝3.4Hz,1H),3.29(br d,J＝6.3Hz,2H),1.98(br d,J＝7.3Hz,2H),1.82-1.65(m,4H),1.47(br d,J＝6.1Hz,3H),1.15(br d,J＝10.5Hz,2H).
实施例44:WX226
Figure PCTCN2018075995-appb-000203
合成路线：
Figure PCTCN2018075995-appb-000204
步骤1：化合物WX226的合成。
化合物WX226的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d6)δ＝11.25(s,1H),8.84(br t,J＝5.4Hz,1H),8.12(d,J＝8.3Hz,1H),7.87(d,J＝1.4Hz,1H),7.79(dd,J＝1.5,8.3Hz,1H),7.62(dd,J＝1.8,3.1Hz,1H),7.15(dd,J＝1.7,3.6Hz,1H),6.54(t,J＝3.3Hz,1H),3.44(q,J＝6.3Hz,2H),3.27(t,J＝6.7Hz,2H),3.15(t,J＝7.6Hz,2H),3.09(t,J＝6.3Hz,2H),2.26-2.15(m,2H).
实施例45:WX227
Figure PCTCN2018075995-appb-000205
合成路线：
Figure PCTCN2018075995-appb-000206
步骤1：化合物WX227的合成。
化合物WX227的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d6)δ＝11.24(s,1H),9.41(br s,1H),8.13(br d,J＝8.3Hz,1H),7.92(s,1H),7.85(br d,J＝8.2Hz,1H),7.62(br s,1H),7.52-7.43(m,1H),7.40-7.21(m,3H),7.15(br s,1H),6.54(br s,1H),4.53(br d,J＝6.0Hz,2H).
实施例46:WX228
Figure PCTCN2018075995-appb-000207
合成路线：
Figure PCTCN2018075995-appb-000208
步骤1：化合物WX228的合成。
化合物WX228的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.29(s,1H),9.77(br t,J＝5.7Hz,1H),8.84(d,J＝6.7Hz,2H),8.17(d,J＝8.2Hz,1H),7.98-7.91(m,4H),7.63(dd,J＝1.7,3.1Hz,1H),7.16(dd,J＝1.7,3.6Hz,1H),6.55(t,J＝3.4Hz,1H),4.75(br d,J＝5.5Hz,2H).
实施例47:WX229
Figure PCTCN2018075995-appb-000209
合成路线：
Figure PCTCN2018075995-appb-000210
步骤1：化合物WX229的合成。
化合物WX229的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.25(s,1H),9.03(br t,J＝5.5Hz,1H),8.79(br d,J＝4.8Hz,1H),8.42(br t,J＝7.8Hz,1H),8.09(d,J＝8.3Hz,1H),7.91-7.84(m,2H),7.81(d,J＝1.4Hz,1H),7.75(dd,J＝1.4,8.3Hz,1H),7.61(dd,J＝1.7,3.1Hz,1H),7.15(dd,J＝1.7,3.6Hz,1H),6.54(t,J＝3.4Hz,1H),3.72(q,J＝6.1Hz,2H),3.28(br t,J＝6.3Hz,2H).
实施例48:WX230
Figure PCTCN2018075995-appb-000211
合成路线：
Figure PCTCN2018075995-appb-000212
步骤1：化合物WX230的合成。
化合物WX230的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.26(br s,1H),9.01(br t,J＝5.5Hz,1H),8.14(d,J＝8.3Hz,1H),7.88(d,J＝1.3Hz,1H),7.78(dd,J＝1.4,8.3Hz,1H),7.62(dd,J＝1.7,3.1Hz,1H),7.15(dd,J＝1.7,3.6Hz,1H),6.54(t,J＝3.3Hz,1H),3.56-3.45(m,2H),2.60-2.53(m,2H).
实施例49:WX231
Figure PCTCN2018075995-appb-000213
合成路线：
Figure PCTCN2018075995-appb-000214
步骤1：化合物WX231的合成。
化合物WX231的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.22(s,1H),9.46(br t,J＝5.5Hz,1H),9.10(s,1H),8.79(s,2H),8.12(d,J＝8.2Hz,1H),7.92(s,1H),7.85(d,J＝8.4Hz,1H),7.61(dd,J＝1.8,2.9Hz,1H),7.15(dd,J＝1.5,3.5Hz,1H),6.54(t,J＝3.3Hz,1H),4.52(d,J＝5.5Hz,2H).
实施例50:WX232
Figure PCTCN2018075995-appb-000215
合成路线：
Figure PCTCN2018075995-appb-000216
步骤1：化合物WX232的合成。
向预先干燥过的拇指瓶中加入WX201-1(120mg,346.46μmol)，三乙胺(70.12mg,692.92μmol,96.45μL)和二氯甲烷(3mL)，反应液氮气保护，最后向其中加入甲基磺酰氯(39.69mg,346.46μmol,26.82μL)，反应液于25℃下搅拌反应5小时。反应液加水(5mL)淬灭，二氯甲烷(10mL*3)萃取，有机相无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产物。粗品经过HPLC分离得WX232。 1H NMR(400MHz,DMSO-d 6)δ＝11.26(s,1H),9.36(br d,J＝6.8Hz,1H),8.15(d,J＝8.3Hz,1H),7.91-7.81(m,2H),7.63(dd,J＝1.6,3.0Hz,1H),7.16(dd,J＝1.6,3.5Hz,1H),6.55(t,J＝3.4Hz,1H),4.69(sxt,J＝7.0Hz,1H),4.13(t,J＝8.2Hz,2H),4.01-3.84(m,2H),3.04(s,3H).
实施例51:WX233
Figure PCTCN2018075995-appb-000217
合成路线：
Figure PCTCN2018075995-appb-000218
步骤1：化合物WX233的合成。
化合物WX233的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.28(s,1H),9.67(br t,J＝5.4Hz,1H),8.13(d,J＝8.3Hz,1H),7.93(s,1H),7.85(dd,J＝1.4,8.3Hz,1H),7.62(dd,J＝1.7,3.1Hz,1H),7.42(s,1H),7.16(dd,J＝1.7,3.6Hz,1H),6.54(t,J＝3.3Hz,1H),4.46(br d,J＝5.4Hz,2H),3.17(s,6H).
实施例52:WX235
Figure PCTCN2018075995-appb-000219
合成路线：
Figure PCTCN2018075995-appb-000220
步骤1：化合物WX235的合成。
化合物WX235的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.25(s,1H),9.52-9.37(m,1H),8.14(br d,J＝8.2Hz,1H),7.93(s,1H),7.87(br d,J＝8.4Hz,1H),7.70(br d,J＝7.9Hz,2H),7.62(br s,1H),7.53(br d,J＝7.9Hz,2H),7.15(br s,1H),6.54(br s,1H),4.56(br d,J＝5.4Hz,2H).
实施例53:WX237
Figure PCTCN2018075995-appb-000221
合成路线：
Figure PCTCN2018075995-appb-000222
步骤1：化合物WX237的合成。
化合物WX237的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.23(s,1H),8.90-8.79(m,1H),8.10(d,J＝8.2Hz,1H),7.85(s,1H),7.79-7.71(m,1H),7.62-7.57(m,1H),7.37-7.26(m,1H),7.18-7.11(m,1H),7.11-7.05(m,2H),7.01(br t,J＝8.6Hz,1H),6.58-6.51(m,1H),3.57-3.46(m,2H),2.87(s,2H).
实施例54:WX239
Figure PCTCN2018075995-appb-000223
合成路线：
Figure PCTCN2018075995-appb-000224
步骤1：化合物WX239的合成。
化合物WX239的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.24(s,1H),9.39(br t,J＝5.6Hz,1H),8.13(d,J＝8.3Hz,1H),7.93(d,J＝1.1Hz,1H),7.86(dd,J＝1.3,8.3Hz,1H),7.62(dd,J＝1.7,2.9Hz,1H),7.45-7.30(m,1H),7.22-6.99(m,4H),6.54(t,J＝3.3Hz,1H),4.49(br d,J＝5.8Hz,2H).
实施例55:WX271
Figure PCTCN2018075995-appb-000225
合成路线：
Figure PCTCN2018075995-appb-000226
步骤1：化合物WX271-2的合成。
将WX271-1(1g,5.71mmol)溶于DCM(20mL)中，加入EEDQ(1.41g,5.71mmol)，搅拌30分钟，然后加入乙酰肼(520.15mg,7.02mmol)，反应在30℃搅拌12小时。将反应液过滤得化合物WX271-2。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.82(br s,1H),8.27-8.18(m,1H),5.23(br s,1H),3.91(br d,J＝6.0Hz,2H),2.07(s,3H),1.47(s,9H).
步骤2：化合物WX271-3的合成。
将WX271-2(300mg,1.30mmol)溶解于THF(25mL)中，加入LAWESSON'S试剂(629.66mg,1.56mmol)，反应在70℃反应3小时，随后降至30℃反应12小时。减压浓缩，粗产品硅胶柱层析进行纯化得WX271-3。 1H NMR(400MHz,CHLOROFORM-d)δ＝4.73-4.59(m,2H),3.90-3.83(m,1H),2.74 (br s,3H),1.45(s,9H).
步骤3：化合物WX271-4的合成。
将WX271-3(0.25g,1.09mmol)溶于HCl/EtOAc(10mL)中，反应在15℃搅拌12小时。反应液过滤，收集滤饼得WX271-4。 1H NMR(400MHz,DMSO-d 6)δ＝8.89(br s,3H),4.49(br d,J＝5.5Hz,2H),2.74(s,3H).
步骤4：化合物WX271的合成。
化合物WX271的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.27(s,1H),9.77(s,1H),8.14(d,J＝8.3Hz,1H),7.93(d,J＝1.3Hz,1H),7.87-7.79(m,1H),7.62(dd,J＝1.8,3.0Hz,1H),7.16(dd,J＝1.7,3.6Hz,1H),6.54(t,J＝3.4Hz,1H),4.81(d,J＝5.8Hz,2H),2.67(s,3H).
实施例56:WX272
Figure PCTCN2018075995-appb-000227
合成路线：
Figure PCTCN2018075995-appb-000228
步骤1：化合物WX272的合成。
化合物WX272的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.22(s,1H),9.14(br s,1H),8.09(d,J＝8.3Hz,1H),7.89(d,J＝1.4Hz,1H),7.80(dd,J＝1.3,8.3Hz,1H),7.64-7.58(m,2H),7.36(s,1H),7.15(dd,J＝1.7,3.6Hz,1H),6.54(t,J＝3.3Hz,1H),4.29(d,J＝5.5Hz,2H),3.78(s,3H).
实施例57:WX275
Figure PCTCN2018075995-appb-000229
合成路线：
Figure PCTCN2018075995-appb-000230
步骤1：化合物WX275-2的合成。
在干燥的单口瓶中加入WX275-1(7.9g,54.44mmol)和DMF(80mL)，随后加入Cs 2CO 3(35.48g,108.88mmol)、CH 3I(9.27g,65.33mmol,4.07mL)，氮气置换3次，将反应置于21℃搅拌3小时。向反应体系中加入100mL乙酸乙酯，体系析出大量固体，通过硅藻土过滤，滤饼用100mL乙酸乙酯淋洗，收集滤液减压浓缩得WX275-2。 1H NMR(400MHz,CHLOROFORM-d)δ＝4.88(dd,J＝5.5,9.7Hz,1H),3.84-3.76(m,4H),3.61(dd,J＝5.5,9.0Hz,1H),2.86(s,3H).
步骤2：化合物WX275-3的合成。
在预先干燥三口烧瓶中加入WX275-2(9g,56.55mmol)和MeOH(60mL)、DCM(30mL)，氮气抽换气三次之后将该反应冷却至0℃。随后在氮气保护下分批加入NaBH 4(2.78g,73.52mmol,1.3eq)，体系温度控制在0-5℃。30分钟后加料完毕，混合物在0℃继续搅拌0.5小时。加入50mL饱和氯化铵淬灭反应，反应液减压浓缩得到粗产品。加入100mL二氯甲烷搅拌10min，过滤滤掉不容物，滤液减压浓缩得WX275-3。 1H NMR(400MHz,DMSO-d6)δ＝4.43(br s,1H),3.49(br dd,J＝7.5,17.4Hz,2H),3.39-3.22(m,2H),2.95(br s,1H),2.72(br s,3H).
步骤3：化合物WX275-4的合成。
在干燥的三口瓶中加入WX275-3(0.5g,3.81mmol)和DCM(5mL)，抽换三次氮气，体系冷却至0℃，随后加入TEA(463.01mg,4.58mmol,636.87μL)和TosCl(872.33mg,4.58mmol)，保持反应温度在0-5℃，滴加完毕后反应在0℃搅拌1小时。加入10mL水淬灭反应，用乙酸乙酯萃取(10mL*3)。合并有机相，用饱和食盐水洗涤10mL*2)，无水硫酸钠干燥，减压浓缩得到残余物。粗产品柱层析得WX275-4。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.79(d,J＝8.2Hz,2H),7.38(d,J＝8.2Hz,2H),4.66(qd,J＝4.8,9.6Hz,1H),4.23-4.07(m,2H),3.64(t,J＝8.9Hz,1H),3.42(dd,J＝6.2,8.8Hz,1H),2.86(s,3H),2.47(s,3H).步骤4：化合物WX275-5的合成。
在干燥的单口瓶中加入WX275-4(0.4g,1.40mmol)和DMF(5mL)，随后加入NaN 3(546.85mg,8.41mmol)，氮气置换3次，将反应置于65℃搅拌16小时。反应液加入10mL水淬灭反应，用乙酸乙酯(10mL*5)萃取，合并有机相用无水硫酸钠干燥。减压浓缩至5mL，加入10mL乙醇，重复3次，剩余5mL乙醇溶液。将反应液直接用于下一步反应，未纯化处理。
步骤5：化合物WX275-6的合成。
将化合物WX275-5(218mg,1.40mmol)溶于EtOH(5mL)，加入Pd/C(0.1g,5％纯度)。H 2抽三次置换后加压至15psi，反应液加热至40℃搅拌24小时。硅藻土过滤，滤液减压浓缩得WX275-6。
1H NMR(400MHz,CHLOROFORM-d)δ＝4.53(br s,1H),3.57(br t,J＝8.7Hz,1H),3.31(br t,J＝7.6Hz,1H),2.97-2.93(m,3H),2.38(br s,2H).
步骤6：化合物WX275的合成。
化合物WX275的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d6)δ＝11.23(s,1H),9.06(br t,J＝5.6Hz,1H),8.13(d,J＝8.2Hz,1H),7.89(s,1H),7.81(d,J＝8.4Hz,1H),7.61(dd,J＝1.7,3.0Hz,1H),7.15(dd,J＝1.8,3.5Hz,1H),6.54(t,J＝3.3Hz,1H),4.69-4.57(m,1H),3.62(t,J＝8.7Hz,1H),3.53(t,J＝5.6Hz,2H),3.30-3.26(m,1H),2.73(s,3H)..
实施例58:WX278
Figure PCTCN2018075995-appb-000231
合成路线：
Figure PCTCN2018075995-appb-000232
步骤1：化合物WX278的合成。
化合物WX278的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d6)δ＝11.25(s,1H),8.98(br t,J＝5.6Hz,1H),8.87(s,1H),8.77(br d,J＝5.4Hz,1H),8.45(br d,J＝7.9Hz,1H),8.09(d,J＝8.3Hz,1H),7.96(dd,J＝5.9,7.8Hz,1H),7.82(s,1H),7.75(br d,J＝8.3Hz,1H),7.62(br d,J＝1.6Hz,1H),7.18-7.12(m,1H),6.54(t,J＝3.3Hz,1H),3.62(br d,J＝5.9Hz,2H),3.07(br t,J＝6.3Hz,2H).
实施例59:WX280
Figure PCTCN2018075995-appb-000233
合成路线：
Figure PCTCN2018075995-appb-000234
步骤1：化合物WX280-2的合成。
在预先干燥的三口瓶中加入WX280-1(2g,19.58mmol,1.89mL)和DCM(10mL)，氮气抽换气三次后将该反应器置于冰浴中，并于0℃下向其中加入对甲苯磺酰氯(5.60g,29.37mmol)和吡啶(10mL)，加料完毕后反应液继续于25℃下搅拌反应2小时。反应液加水(20mL)稀释，水相用二氯甲烷萃取(3*50mL)，有机相无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂后得WX280-2。
步骤2：化合物WX280-4的合成。
在干燥的50mL三口瓶中加入原料WX280-2(1g,3.90mmol)和DMF(10mL)，将WX280-3(1.16g,6.24mmol)加入反应液，该反应体系在100℃下搅拌12小时。反应液加水(10mL)淬灭，水相用二氯甲烷萃取(3*20mL)，有机相无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂后得到产物粗品。粗品柱层析纯化得WX280-4。
步骤3：化合物WX280-5的合成。
在预先干燥的拇指瓶中加入WX280-4(400mg,1.71mmol)以及溶剂EtOH(5mL)，搅拌均匀后加入水合肼(140.15mg,2.74mmol,136.07μL)，在70℃下搅拌0.5小时，反应液先由白色转变为黑色，后凝成白色膏状物。将反应体系冷却至室温，然后将其转移至100mL单口烧瓶后，加入30ml乙醇常温搅拌0.5小时，过滤后，滤饼丢弃，滤液旋干得WX280-5。
步骤4：化合物WX280的合成。
化合物WX280的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ11.20(s,1H),8.85(br t,J＝5.40Hz,1H),8.10(d,J＝8.16Hz,1H),7.87(s,1H),7.79(d,J＝8.16Hz,1H),7.60(dd,J＝1.76,2.87Hz,1H),7.14(dd,J＝1.54,3.53Hz,1H),6.53(t,J＝3.31Hz,1H),3.56-3.77(m,3H),3.45(dd,J＝5.29,8.60Hz,1H),3.20-3.28(m,2H),2.40-2.47(m,1H),1.87-1.98(m,1H),1.53-1.63(m,1H).
实施例60:WX288
Figure PCTCN2018075995-appb-000235
合成路线：
Figure PCTCN2018075995-appb-000236
步骤1：化合物WX288的合成。
化合物WX288的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ11.19(s,1H),8.80(br t,J＝5.84Hz,1H),8.10(d,J＝8.38Hz,1H),7.87(s,1H),7.79(d,J＝8.16Hz,1H),7.60(br s,1H),7.14(dd,J＝1.43,3.42Hz,1H),6.53(t,J＝3.31Hz,1H),3.17(t,J＝6.17Hz,2H),2.00(br d,J＝6.84Hz,2H),1.61-1.86(m,5H),1.12-1.28(m,2H).
实施例61:WX292
Figure PCTCN2018075995-appb-000237
合成路线：
Figure PCTCN2018075995-appb-000238
步骤1：化合物WX292的合成。
化合物WX292的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),8.82-8.75(m,1H),8.11(d,J＝8.2Hz,1H),7.87(s,1H),7.79(d,J＝8.2Hz,1H),7.61(dd,J＝1.8,3.1Hz,1H),7.15(dd,J＝1.5,3.5Hz,1H),6.54(t,J＝3.4Hz,1H),3.93-3.85(m,1H),3.45(d,J＝5.3Hz,2H),3.38(br d,J＝5.7Hz,2H),1.69-1.51(m,6H),1.49-1.41(m,2H).
实施例62:WX293
Figure PCTCN2018075995-appb-000239
合成路线：
Figure PCTCN2018075995-appb-000240
步骤1：化合物WX293的合成。
化合物WX293的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),8.82(s,1H),8.10(d,J＝8.4Hz,1H),7.84(s,1H),7.74(d,J＝8.4Hz,1H),7.61(dd,J＝1.7,2.8Hz,1H),7.36-7.27(m,2H),7.15(dd,J＝1.7,3.4Hz,1H),7.09-7.03(m,1H),6.56-6.52(m,1H),3.50(br d,J＝6.0Hz,2H),2.84(br t,J＝6.8Hz,2H).
实施例63:WX295
Figure PCTCN2018075995-appb-000241
合成路线：
Figure PCTCN2018075995-appb-000242
步骤1：化合物WX295的合成。
化合物WX295的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d6)δ11.24(s,1H),9.14(br t,J＝5.4Hz,1H),8.66(d,J＝2.6Hz,1H),8.47(d,J＝5.1Hz,1H),8.14-8.05(m,2H),7.94-7.80(m,3H),7.59(dd,J＝1.5,2.9Hz,1H),7.13(dd,J＝1.5,3.5Hz,1H),6.52(t,J＝3.3Hz,1H),4.37(br t,J＝5.4Hz,2H),3.68(q,J＝5.3Hz,2H).
实施例64:WX297
Figure PCTCN2018075995-appb-000243
合成路线：
Figure PCTCN2018075995-appb-000244
步骤1：化合物WX297-2的合成。
将WX297-1(2g,13.46mmol)溶解于DCM(20mL)中，然后向其中加入三乙胺(4.09g,40.37mmol,5.62mL)，(Boc) 2O(3.52g,16.15mmol,3.71mL)，反应在30℃搅拌12小时。反应液加水(10mL)淬灭后，水相用二氯甲烷萃取(3*20mL)，有机相无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂后得到产物粗品。粗品柱层析分离得WX297-2。
步骤2：化合物WX297-4的合成。
在预先干燥的50ml单口瓶中加入WX297-2(836.83mg,3.36mmol)和dioxane(5mL)，水(1.5mL)，然后向反应体系加入K 2CO 3(1.16g,8.41mmol)和WX297-3(834.81mg,3.36mmol)，最后在氮气气氛下加入四三苯基膦钯(388.78mg,336.44μmol)，该体系在100℃下搅拌反应12小时。反应液加水(5mL)淬灭后，水相用乙酸乙酯萃取(3*10mL)，有机相无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂后得到产物粗品。粗品经柱层析得WX297-4。
步骤3：化合物WX297-5的合成。
在预先干燥的拇指瓶中加入WX297-4(900mg,2.69mmol)和EtOAc(10mL)，在氮气气氛下加入HCl/EtOAc(4M,20mL)，将该反应液在25℃下搅拌0.5小时。将反应液直接旋干得WX297-5。
步骤4：化合物WX297的合成。
在预先干燥的拇指瓶中加入BB-2(80.17mg,342.15μmol)，EDCI(98.39mg,513.22μmol)，DIPEA(88.44mg,684.30μmol,119.19μL)，HOBt(69.35mg,513.22μmol)和DMF(2mL)，最后于0℃下向其中加入WX297-5(100mg,342.15μmol),反应液氮气保护并在25℃下搅拌反应12小时。反应液过滤得到产物粗品,粗品经HPLC分离得WX297。 1H NMR(400MHz,DMSO-d 6)δ11.22(s,1H),9.60(br t,J＝5.73Hz,1H),8.41(d,J＝1.98Hz,1H),8.22(br d,J＝8.82Hz,1H),8.11(d,J＝8.38Hz,1H),7.92(s,1H),7.78-7.86(m,2H),7.56-7.62(m,1H),7.13(dd,J＝1.54,3.53Hz,2H),6.52(t,J＝3.31Hz,1H),4.68(br d,J＝5.51Hz,2H),3.22(s,6H).
实施例65:WX298
Figure PCTCN2018075995-appb-000245
合成路线：
Figure PCTCN2018075995-appb-000246
步骤1：化合物WX298-2的合成。
在预先干燥的50ml单口瓶中加入WX297-2(850.83mg,3.42mmol)和水(1.5mL)、DME(5mL)，然后向反应体系加入K 2CO 3(1.18g,8.55mmol)和WX298-1(502.63mg,3.42mmol)，最后在氮气气氛下加入Pd(dppf)Cl 2(250.30mg,342.07μmol)，该体系在100℃下搅拌反应12小时。反应液加水(5mL)淬灭后，水相用乙酸乙酯萃取(3*10mL)，有机相无水硫酸钠干燥，过滤，滤液减压浓缩除去溶剂后得到产物粗品。粗品经柱层析得WX298-2(0.8g,2.54mmol)。
步骤2：化合物WX298-3的合成。
化合物WX298-3的合成参照实施例64中步骤3WX297-5的合成。
步骤3：化合物WX298的合成。
化合物WX298的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ11.21(s,1H),9.55(br t,J＝5.62Hz,1H),8.11(d,J＝8.38Hz,1H),8.06(d,J＝8.38Hz,2H),7.90-7.94(m,4H),7.81(d,J＝8.38Hz,1H),7.59(dd,J＝1.65,2.98Hz,1H),7.13(dd,J＝1.54,3.53Hz,1H),6.52(t,J＝3.31Hz,1H),4.72(d,J＝5.73Hz,2H).
实施例66:WX299
Figure PCTCN2018075995-appb-000247
合成路线：
Figure PCTCN2018075995-appb-000248
步骤1：化合物WX299的合成。
化合物WX299的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),8.78(br t,J＝5.3Hz,1H),8.10(d,J＝8.3Hz,1H),7.88(d,J＝1.1Hz,1H),7.79(dd,J＝1.4,8.4Hz,1H),7.61(dd,J＝1.7,3.1Hz,1H),7.25(dd,J＝5.7,8.5Hz,2H),7.15(dd,J＝1.7,3.6Hz,1H),7.13-7.06(m,2H),6.54(t,J＝3.4Hz,1H),3.29-3.23(m,2H),2.61(br t,J＝7.7Hz,2H),1.80(q,J＝7.3Hz,2H).
实施例67:WX300
Figure PCTCN2018075995-appb-000249
合成路线：
Figure PCTCN2018075995-appb-000250
步骤1：化合物WX300的合成。
化合物WX300的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),8.85(br t,J＝5.4Hz,1H),8.10(d,J＝8.2Hz,1H),7.85(s,1H),7.75(d,J＝8.4Hz,1H),7.61(dd,J＝1.7,2.8Hz,1H),7.34-7.28(m,2H),7.27-7.23(m,1H),7.19(d,J＝7.3Hz,1H),7.15(dd,J＝1.5,3.5Hz,1H),6.54(t,J＝3.3Hz,1H),3.55-3.46(m,2H),2.85(t,J＝7.2Hz,2H).
实施例68:WX301
Figure PCTCN2018075995-appb-000251
合成路线：
Figure PCTCN2018075995-appb-000252
步骤1：化合物WX301的合成。
化合物WX301的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),8.83(br t,J＝5.3Hz,1H),8.10(d,J＝8.2Hz,1H),7.84(s,1H),7.74(d,J＝8.4Hz,1H),7.61(br d,J＝1.1Hz,1H),7.36-7.30(m,2H),7.29-7.23(m,2H),7.17-7.12(m,1H),6.54(t,J＝3.3Hz,1H),3.49(q,J＝6.6Hz,2H),2.83(br t,J＝7.1Hz,2H).
实施例69:WX305
Figure PCTCN2018075995-appb-000253
合成路线：
Figure PCTCN2018075995-appb-000254
步骤1：化合物WX305的合成。
化合物WX305的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),8.79(t,J＝5.4Hz,1H),8.04(d,J＝8.4Hz,1H),7.80(s,1H),7.71(d,J＝8.4Hz,1H),7.36(s,1H),7.23(dd,J＝5.7,8.6Hz,2H),7.07(t,J＝8.9Hz,2H),6.97(d,J＝1.3Hz,1H),3.45(q,J＝6.8Hz,2H),2.80(t,J＝7.2Hz,2H),2.02(s,3H).
实施例70:WX306
Figure PCTCN2018075995-appb-000255
合成路线：
Figure PCTCN2018075995-appb-000256
步骤1：化合物WX306的合成。
化合物WX306的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),9.38(t,J＝5.8Hz,1H),8.56(d,J＝1.8Hz,1H),8.47(dd,J＝1.5,4.8Hz,1H),8.10(d,J＝8.3Hz,1H),7.91(d,J＝1.4Hz,1H),7.83(dd,J＝1.6,8.3Hz,1H),7.72(d,J＝7.3Hz,1H),7.43-7.34(m,2H),7.01(d,J＝1.8Hz, 1H),4.51(d,J＝5.8Hz,2H),2.5(s,3H).
实施例71:WX308
Figure PCTCN2018075995-appb-000257
合成路线：
Figure PCTCN2018075995-appb-000258
步骤1：化合物WX308的合成。
化合物WX308的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),9.56(s,1H),8.14-8.03(m,3H),7.97-7.90(m,4H),7.81(d,J＝7.3Hz,1H),7.39(s,1H),7.01(s,1H),4.73(d,J＝5.5Hz,2H),2.05(s,3H).
实施例72:WX309
Figure PCTCN2018075995-appb-000259
合成路线：
Figure PCTCN2018075995-appb-000260
步骤1：化合物WX309的合成。
化合物WX309的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.14(s,1H),8.72(s,1H),8.07(d,J＝8.3Hz,1H),7.85(s,1H),7.77(d,J＝8.0Hz,1H),7.39(s,1H),7.00(s,1H),3.86(d,J＝10.3Hz,1H),3.32-3.22(m,4H),2.05(s,3H),1.74(s,1H),1.66-1.53(m,3H),1.43(s,3H),1.24-1.13(m,1H).
实施例73:WX311
Figure PCTCN2018075995-appb-000261
合成路线：
Figure PCTCN2018075995-appb-000262
步骤1：化合物WX311-2的合成。
化合物WX311-2的合成参照参考片段6中步骤1BB-6-2的合成。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.49(s,1H),8.44(s,2H),7.70(d,J＝1.8Hz,1H),7.11(d,J＝1.8Hz,1H),4.03(s,3H),3.75(s,3H).
步骤2：化合物WX311-3的合成。
化合物WX311-3的合成参照参考片段6中步骤1BB-6-3的合成。 1H NMR(400MHz,DMSO-d 6)δ＝8.28(d,J＝2.0Hz,1H),7.85(d,J＝8.5Hz,1H),7.50(d,J＝1.3Hz,1H),7.19-7.18(m,1H),7.16(dd,J＝1.5,8.5Hz,1H),6.55(br s,2H),3.83(s,3H),3.67(s,3H).
步骤3：化合物WX311-4的合成。
化合物WX311-4的合成参照参考片段6中步骤1BB-6-4的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.44(s,1H),8.16(d,J＝8.3Hz,1H),8.04(d,J＝1.3Hz,1H),7.94(dd,J＝1.5,8.3Hz,1H),7.88(d,J＝2.0Hz,1H),7.25(d,J＝1.8Hz,1H),3.91(s,3H)
步骤4：化合物WX311-5的合成。
将WX311-4(300mg,778.84μmol,1eq)溶于二氧六环(5.0mL)中，再加入6M的稀盐酸(5.0mL)，反应在50℃下搅拌48小时。减压浓缩，萃取，收集有机相无水硫酸钠干燥，过滤，滤液减压浓缩。粗品柱层析得WX311-5。 1H NMR(400MHz,DMSO-d 6)δ＝11.47(s,1H),8.33-8.07(m,2H),8.06-7.98(m,2H),7.85(s,1H),7.22(s,1H).
步骤5：化合物WX311的合成。
化合物WX311的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d6)δ＝11.34(s,1H),8.76(t,J＝5.5Hz,1H),8.07(d,J＝8.2Hz,1H),7.83(dd,J＝1.7,6.5Hz,2H),7.77(dd,J＝1.5,8.4Hz,1H),7.19(d,J＝1.8Hz,1H),3.78-3.68(m,2H),3.55(dt,J＝6.4,7.9Hz,1H),3.29-3.23(m,2H),1.97-1.88(m,1H),1.82-1.73(m,2H),1.66(q,J＝7.1Hz,2H),1.45-1.30(m,1H).
实施例74:WX312
Figure PCTCN2018075995-appb-000263
合成路线：
Figure PCTCN2018075995-appb-000264
步骤1：化合物WX312的合成。
化合物WX312的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d6)δ＝11.38(s,1H),8.75(br t,J＝5.5Hz,1H),8.11(d,J＝8.3Hz,1H),7.87(dd,J＝1.6,4.0Hz,2H),7.81(dd,J＝1.4,8.3Hz,1H),7.23(d,J＝1.9Hz,1H),3.90-3.83(m,1H),3.33-3.23(m,4H),1.75(br d,J＝3.6Hz,1H),1.66-1.56(m,3H),1.47-1.46(m,1H),1.44(br s,2H),1.24-1.13(m,1H).
实施例75:WX221和WX222
Figure PCTCN2018075995-appb-000265
合成路线：
Figure PCTCN2018075995-appb-000266
步骤1：化合物WX221和WX222的合成。
在干燥的氢化瓶中加入化合物BB-5(100mg,289.73μmol)、化合物WX143-1(65.90mg,434.60μmol)、Pd(dppf)Cl 2(21.20mg,28.97μmol)、Et 3N(73.29mg,724.33μmol,100.82μL)和DMF(5mL)，CO置换三次并加压至50psi，在80℃的油浴中搅拌16小时。加入400mg除钯硅胶25℃搅拌12小时，过滤，滤液减压浓缩。将上述浓缩后的滤液通过Prep-HPLC纯化得到消旋体。消旋体SFC分离得到WX221和WX222。化合物WX221： 1H NMR(400MHz,DMSO-d 6)δ＝8.83-8.76(m,1H),8.10(d,J＝8.3Hz,1H),7.88(s,1H),7.81(d,J＝8.3Hz,1H),7.73(br s,1H),7.15(d,J＝1.9Hz,1H),3.83-3.70(m,2H),3.66-3.54(m,1H),3.32-3.25(m,2H),2.03-1.91(m,1H),1.80(dd,J＝6.9,14.2Hz,2H),1.69(m,2H),1.47-1.35(m,1H)；
化合物WX222： 1H NMR(400MHz,DMSO-d 6)δ＝8.79(t,J＝5.4Hz,1H),8.10(d,J＝8.3Hz,1H),7.88(d, J＝1.4Hz,1H),7.81(dd,J＝1.5,8.3Hz,1H),7.73(dd,J＝2.1,3.4Hz,1H),7.15(d,J＝2.0Hz,1H),3.82-3.71(m,2H),3.63-3.55(m,1H),3.32-3.26(m,2H),2.01-1.91(m,1H),1.86-1.76(m,2H),1.69(m,2H),1.47-1.36(m,1H).
手性拆分条件：手性柱:AD(250mm*30mm,5μm)；流动相：[Neu-MeOH]；B％:48％-48％。
化合物222对应的保留时间：6.62分钟(峰2)。化合物221对应的保留时间：5.70分钟(峰1)。
实施例76:WX279
Figure PCTCN2018075995-appb-000267
合成路线：
Figure PCTCN2018075995-appb-000268
步骤1：化合物WX279-1的合成。
将WX200(1g,2.05mmol)加入至HCl/EtOAc(50mL)中，反应在20℃搅拌2小时。反应液过滤，收集滤饼得WX279-1。 1H NMR(400MHz,DMSO-d 6)δ＝11.21(s,1H),8.90(br s,2H),8.66-8.53(m,1H),8.10(d,J＝8.2Hz,1H),7.89(s,1H),7.82(br d,J＝8.2Hz,1H),7.60(dd,J＝1.8,2.9Hz,1H),7.14(dd,J＝1.8,3.5Hz,1H),6.53(t,J＝3.3Hz,1H),3.17(br t,J＝6.0Hz,2H),2.84-2.78(m,2H),1.79(br d,J＝12.1Hz,5H),1.36(br d,J＝12.1Hz,3H).
步骤2：化合物WX279的合成。
在干燥的单口瓶中加入WX279-1(100mg,235.35μmol)、新戊酰氯(31.22mg,258.89μmol,31.85μL)和DCM(2mL)，随后加入TEA(47.63mg,470.70μmol,65.52μL)，氮气置换3次，将反应置于20℃搅拌12小时。反应液过滤，得到粗品，粗品HPLC分离得WX279。 1H NMR(400MHz,DMSO-d6)δ＝11.21(s,1H),8.81(br t,J＝5.5Hz,1H),8.10(d,J＝8.3Hz,1H),7.87(s,1H),7.79(d,J＝8.3Hz,1H),7.62(dd,J＝1.8,3.0Hz,1H),7.15(dd,J＝1.6,3.5Hz,1H),6.54(t,J＝3.4Hz,1H),4.25(br d,J＝12.8Hz,2H),3.16(br t,J＝6.2Hz,2H),2.74(br t,J＝12.4Hz,2H),1.81(br s,1H),1.69(br d,J＝12.9Hz,2H),1.17(s,9H),1.10-0.94(m,2H).
实施例77:WX285
Figure PCTCN2018075995-appb-000269
合成路线：
Figure PCTCN2018075995-appb-000270
步骤1：化合物WX285的合成。
向预先干燥过的拇指瓶中加入WX279-1(90mg,211.81μmol)和DMF(1mL)，再加入Et 3N(32.15mg,317.72μmol,44.22μL)并搅拌30分钟后，将反应体系降至0℃，加入WX285-1(25.96mg,211.81μmol,29.40μL)，反应液氮气保护并升温至25℃继续搅拌反应10小时。反应液过滤得到产物粗品，产物粗品经HPLC分离得WX285。 1H NMR(400MHz,DMSO-d 6)δ＝11.21(s,1H),8.80(br t,J＝5.5Hz,1H),8.10(d,J＝8.3Hz,1H),7.87(s,1H),7.83-7.75(m,1H),7.62(dd,J＝1.7,2.9Hz,1H),7.15(dd,J＝1.6,3.5Hz,1H),6.54(t,J＝3.3Hz,1H),4.74(dt,J＝6.3,12.5Hz,1H),3.95(d,J＝11.4Hz,2H),3.15(t,J＝6.1Hz,2H),2.69(d,J＝17.7Hz,2H),1.78-1.62(m,3H),1.16(d,J＝6.3Hz,6H),1.10-1.09(m,1H),1.10-0.98(m,1H).
实施例78:WX286
Figure PCTCN2018075995-appb-000271
合成路线：
Figure PCTCN2018075995-appb-000272
步骤1：化合物WX286的合成。
化合物WX286的合成参照实施例77中步骤1WX285的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.21(s,1H),8.82(s,1H),8.11(d,J＝8.4Hz,1H),7.89(s,1H),7.82(d,J＝8.2Hz,1H),7.62(br s,1H),7.41-7.34 (m,2H),7.20(s,1H),7.15(dd,J＝1.7,3.4Hz,1H),7.10(d,J＝7.7Hz,2H),6.54(t,J＝3.3Hz,1H),4.20-3.97(m,2H),3.21(br t,J＝6.0Hz,2H),3.06-2.78(m,2H),1.87-1.70(m,3H),1.21(br d,J＝16.3Hz,2H).
实施例79:WX287
Figure PCTCN2018075995-appb-000273
合成路线：
Figure PCTCN2018075995-appb-000274
步骤1：化合物WX287的合成。
化合物WX287的合成参照实施例76中步骤2WX279的合成。 1H NMR(400MHz,DMSO-d6)δ＝11.21(s,1H),8.80(br t,J＝5.6Hz,1H),8.10(d,J＝8.2Hz,1H),7.87(d,J＝1.1Hz,1H),7.79(dd,J＝1.4,8.3Hz,1H),7.61(dd,J＝1.8,3.0Hz,1H),7.15(dd,J＝1.7,3.6Hz,1H),6.54(t,J＝3.4Hz,1H),4.38(br d,J＝12.3Hz,1H),3.91-3.82(m,1H),3.22-3.08(m,2H),2.94(br t,J＝11.7Hz,1H),2.20-2.11(m,2H),1.95(dt,J＝6.7,13.4Hz,1H),1.83-1.62(m,3H),1.10-0.91(m,2H),0.91-0.83(m,7H).
实施例80:WX321
Figure PCTCN2018075995-appb-000275
合成路线：
Figure PCTCN2018075995-appb-000276
步骤1：化合物WX321-3的合成。
将乙二醇(10g,161.11mmol,9.01mL)，WX321-1(36.77g,322.23mmol)溶解于DCM(350mL)中，0℃条件下，缓慢滴入BF 3.Et 2O(345.29mg,2.43mmol,300.25μL)，反应在0℃搅拌2小时，随后缓慢 升至25℃搅拌36小时。减压浓缩得粗产品WX321-3。 1H NMR(400MHz,CHLOROFORM-d)δ＝4.24-4.18(m,4H),4.16(s,4H),3.78(s,4H),1.28(t,J＝7.2Hz,6H)
步骤2：化合物WX321-4的合成。
将t-BuOLi(23.92g,298.83mmol,26.94mL)，WX321-3(35g,149.42mmol)溶解于DMF(350mL)中，反应在90℃搅拌12小时。减压浓缩，向粗产品中加入EA(200mL)，2M HCl(100mL*2)洗，水洗(50mL)，EA层使用无水硫酸钠干燥后，过滤，减压浓缩得粗品WX321-4。 1H NMR(400MHz,CHLOROFORM-d)δ＝4.39-4.08(m,7H),3.92-3.85(m,1H),3.79-3.75(m,1H),1.34-1.28(m,3H).
步骤3：化合物WX321-5的合成。
将WX321-4(19g,100.97mmol)加入至HCl(120mL)中，反应在100℃搅拌4小时。向反应液中加入EA(50mL*2)萃取，EA层合并，无水硫酸钠干燥，过滤，减压浓缩得粗产品WX321-5。 1H NMR(400MHz,CHLOROFORM-d)δ＝4.23(s,4H),3.96(s,4H).
步骤4：化合物WX321-7的合成。
将WX321-5(0.2g,1.72mmol)，WX321-6(570.90mg,1.89mmol)溶解于DCM(5mL)中，反应在25℃搅拌12小时。减压浓缩，粗产品使用硅胶柱层析纯化得WX321-7。 1H NMR(400MHz,CHLOROFORM-d)δ＝5.29(tt,J＝1.2,2.0Hz,1H),4.68-4.65(m,2H),4.36(d,J＝0.7Hz,2H),3.86-3.79(m,4H).
步骤5：化合物WX321-8的合成。
将WX321-7(0.25g,1.80mmol)溶解于MeOH(10mL)中，加入NH 3.H 2O(227.50mg,1.82mmol,0.25mL,28％纯度)，Raney-Ni(0.25g)，反应氢气置换三次，随后压力升至50psi，50℃反应3小时。过滤，滤液减压浓缩。粗产品WX321-8直接用于下一步反应。 1H NMR(400MHz,CHLOROFORM-d)δ＝3.87(ddd,J＝2.6,5.2,12.2Hz,2H),3.80-3.75(m,1H),3.82-3.66(m,4H),3.55(ddd,J＝1.2,7.1,12.3Hz,2H),2.74-2.69(m,1H),2.63-2.57(m,1H),2.20-2.07(m,1H),1.69(br s,2H),1.48-1.35(m,2H).
步骤6：化合物WX321的合成。
化合物WX321的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.19(s,1H),8.73(t,J＝5.5Hz,1H),8.07(d,J＝8.2Hz,1H),7.83(d,J＝1.3Hz,1H),7.75(dd,J＝1.5,8.2Hz,1H),7.58(dd,J＝1.8,3.1Hz,1H),7.12(dd,J＝1.8,3.5Hz,1H),6.51(t,J＝3.3Hz,1H),3.75(dd,J＝5.0,12.2Hz,2H),3.65-3.53(m,4H),3.43(dd,J＝6.8,12.3Hz,2H),3.26-3.20(m,2H),2.02-1.92(m,1H),1.43(q,J＝7.1Hz,2H).
实施例81:WX322
Figure PCTCN2018075995-appb-000277
合成路线：
Figure PCTCN2018075995-appb-000278
步骤1：化合物WX322-2的合成。
将WX322-1(0.2g,868.42μmol)溶解于DCM(5mL)中，加入TEA(131.81mg,1.30mmol,181.31μL)，0℃条件下，缓慢滴加乙酰氯(74.99mg,955.26μmol,68.17μL)，反应在0℃搅拌1.5小时。向反应体系中加入DCM(30mL)，水洗(20mL*2)，DCM层使用无水硫酸钠干燥后，过滤，减压浓缩得WX322-2。 1H NMR(400MHz,CHLOROFORM-d)δ＝4.84(br s,1H),4.41(br dd,J＝2.1,13.1Hz,1H),3.96-3.89(m,1H),3.69-3.38(m,3H),3.35-3.17(m,3H),3.04-2.90(m,1H),2.76(br s,1H),2.47(dd,J＝10.6,13.2Hz,1H),2.10(s,3H),1.74-1.57(m,2H),1.45(s,9H),1.32(s,1H).
步骤2：化合物WX322-3的合成。
将WX322-2(0.2g,734.37μmol)溶解于HCl/EtOAc(10mL)中，反应25℃搅拌12小时。减压浓缩得WX322-3。 1H NMR(400MHz,DMSO-d 6)δ＝8.08(br d,J＝19.2Hz,3H),4.20-4.09(m,1H),3.81(dd,J＝2.6,11.5Hz,1H),3.75-3.61(m,1H),3.44(br dd,J＝2.3,11.8Hz,2H),3.18-2.99(m,1H),2.92-2.79(m,3H),2.00(d,J＝4.2Hz,3H),1.70(br dd,J＝8.3,14.7Hz,2H).
步骤3：化合物WX322的合成。
化合物WX322的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.21(d,J＝3.5Hz,1H),8.78(br d,J＝18.5Hz,1H),8.10(dd,J＝3.6,8.3Hz,1H),7.87(s,1H),7.79(d,J＝8.4Hz,1H),7.61(dd,J＝1.8,3.1Hz,1H),7.15(dd,J＝1.8,3.5Hz,1H),6.54(t,J＝3.4Hz,1H),4.23-4.09(m,1H),3.83(dd,J＝2.5,11.4Hz,1H),3.79-3.60(m,1H),3.38-3.27(m,3H),3.13(br s,1H),2.89-2.82(m,1H),2.68-2.61(m,1H),2.43-2.43(m,1H),2.44-2.31(m,1H),1.99(d,J＝4.2Hz,3H),1.74-1.58(m,2H).
实施例82:WX323
Figure PCTCN2018075995-appb-000279
合成路线：
Figure PCTCN2018075995-appb-000280
步骤1：化合物WX323-1的合成。
将WX322-1(0.2g,868.42μmol)溶解于DCM(5mL)中，加入TEA(131.81mg,1.30mmol,181.31μL)，0℃下，缓慢滴加氯甲酸甲酯(90.27mg,955.26μmol,73.99μL)，反应在0℃搅拌1.5小时。向反应体系中加入DCM(30mL)，水洗(20mL*2)，DCM层使用无水硫酸钠干燥后，过滤，减压浓缩得WX323-1。 1H NMR(400MHz,CHLOROFORM-d)δ＝4.86(br s,1H),3.88(br d,J＝9.7Hz,3H),3.71(s,3H),3.51(br s,2H),3.30(br d,J＝6.6Hz,1H),3.26-3.17(m,1H),2.97(br s,1H),2.67(br s,1H),1.66-1.55(m,2H),1.44(s,9H).
步骤2：化合物WX323-2的合成。
化合物WX323-2的合成参照实施例81中步骤2WX22-2的合成。
步骤3：化合物WX323的合成。
化合物WX323的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.21(s,1H),8.75(t,J＝5.4Hz,1H),8.10(d,J＝8.2Hz,1H),7.86(d,J＝1.5Hz,1H),7.78(dd,J＝1.5,8.4Hz,1H),7.61(dd,J＝1.8,3.1Hz,1H),7.15(dd,J＝1.8,3.5Hz,1H),6.54(t,J＝3.4Hz,1H),3.85-3.68(m,3H),3.59(s,3H),3.37(br dd,J＝2.9,11.9Hz,5H),2.90(br s,1H),1.72-1.58(m,2H).
实施例83:WX313和315
Figure PCTCN2018075995-appb-000281
合成路线：
Figure PCTCN2018075995-appb-000282
步骤1：化合物WX313和WX315的合成。
化合物WX313和WX315的合成参照实施例24中步骤1WX189的合成。
化合物WX313： 1H NMR(400MHz,DMSO-d 6)δ＝8.77(br d,J＝5.1Hz,1H),8.06(d,J＝8.4Hz,1H),7.85(s,1H),7.77(d,J＝8.2Hz,1H),7.39(s,1H),7.00(d,J＝1.3Hz,1H),3.80-3.71(m,2H),3.65-3.50(m,2H),3.28-3.24(m,1H),2.05(s,3H),1.99-1.92(m,1H),1.85-1.76(m,2H),1.69(q,J＝7.1Hz,2H),1.40(s,1H).化合物WX315： 1H NMR(400MHz,DMSO-d 6)δ＝11.17(br s,1H),8.78(br t,J＝5.5Hz,1H),8.06(d,J＝8.4Hz,1H),7.85(s,1H),7.78(d,J＝8.4Hz,1H),7.39(s,1H),7.00(d,J＝1.8Hz,1H),3.81-3.71(m,2H),3.61-3.54(m,1H),3.31-3.25(m,2H),2.05(s,3H),1.99-1.91(m,1H),1.85-1.76(m,2H),1.69(q,J＝7.1Hz,2H),1.46-1.37(m,1H).
手性拆分条件：手性柱:OJ(250mm*50mm,10μm)；流动相：0.1％NH 3.H 2O MeOH；流速：200mL/min；柱温：40℃。
化合物315对应的保留时间：4.825分钟(峰2)。化合物313对应的保留时间：4.495分钟(峰1)。
实施例84:WX318
Figure PCTCN2018075995-appb-000283
合成路线：
Figure PCTCN2018075995-appb-000284
步骤1：化合物WX318-3的合成。
在预先干燥过的20毫升微波反应管中加入WX318-1(1g,8.76mmol)，WX318-2(4.69g,13.47mmol)随后加入溶剂氯苯(10mL)。该混合物在180℃微波反应6小时。减压浓缩得到粗产品。粗产品通过自 动柱层析得WX318-3。 1H NMR(400MHz,CHLOROFORM-d)δ＝4.87(s,1H),4.30-4.25(m,2H),4.11(q,J＝7.1Hz,2H),2.46-2.36(m,2H),1.91-1.77(m,6H),1.25(t,J＝7.2Hz,3H).
步骤2：化合物WX318-4的合成。
将WX318-3(2.5g,13.57mmol)溶入EtOAc(10mL)，加入Pd/C(0.3g,5％纯度)。氢气置换三次后，加压至40psi，反应在至25℃搅拌16小时。通过硅藻土过滤，滤液减压浓缩，得到粗品。粗产品通过自动柱层析得WX318-4。 1H NMR(400MHz,CHLOROFORM-d)δ＝4.15(q,J＝7.2Hz,2H),4.02-3.92(m,1H),3.88-3.77(m,1H),3.58(d,J＝4.3,7.4,12.1Hz,1H),2.57-2.29(m,2H),1.87-1.50(m,8H),1.26(t,J＝7.2Hz,3H).
步骤3：化合物WX318-5的合成。
在干燥的单口瓶中加入化合物WX318-4(700mg,3.76mmol,1eq)和THF(8mL)，氮气置换三次，降温至0℃，加入LiAlH 4(213.97mg,5.64mmol)，然后在0℃下搅拌2小时。向反应液中依次缓慢加入水(0.21mL)、10％氢氧化钠水溶液(0.63mL)、水(0.21mL)淬灭反应，然后再加入10mL乙酸乙酯，搅拌10min，经垫有硅藻土的五孔漏斗过滤，滤液减压浓缩得WX318-5。 1H NMR(400MHz,CHLOROFORM-d)δ＝3.95-3.84(m,1H),3.82-3.67(m,3H),3.62-3.49(m,1H),2.92(br s,1H),1.84-1.48(m,10H).
步骤4：化合物WX318-6的合成。
在干燥的拇指瓶中加入化合物WX318-5(480mg,3.33mmol)和DCM(8mL)，将体系温度降至0℃，再加入MsCl(457.53mg,3.99mmol,309.14μL)和Et 3N(673.61mg,6.66mmol,926.57μL)，在20℃搅拌1小时。向反应体系中加入10mL饱和碳酸氢钠水溶液和10mL二氯甲烷，分液，有机相用水洗涤(5mL)，然后用无水硫酸钠干燥，过滤，滤液减压浓缩得WX318-6。 1H NMR(400MHz,CHLOROFORM-d)δ＝4.44-4.35(m,1H),4.34-4.26(m,1H),3.90-3.80(m,1H),3.67-3.50(m,2H),3.01(s,3H),1.86-1.49(m,10H).
步骤5：化合物WX318-7的合成。
在干燥的拇指瓶中依次加入化合物WX318-6(866mg,3.90mmol)、DMF(8mL)，降温至0℃，然后加入NaN 3(379.88mg,5.84mmol)，升温至20℃，搅拌16小时。向反应体系中加入10毫升水，用乙酸乙酯萃取(15mL*2)，合并有机相，用饱和食盐水洗涤(10mL*3)，然后用无水硫酸钠干燥，过滤，滤液减压浓缩得WX318-7。 1H NMR(400MHz,CHLOROFORM-d)δ＝3.93-3.82(m,1H),3.60-3.52(m,2H),3.44-3.35(m,2H),1.76-1.49(m,10H).
步骤6：化合物WX318-8的合成。
在拇指瓶中加入化合物WX318-7(150mg,886.40μmol)和THF(2mL)、H 2O(0.4mL)，将体系降温至0℃，加入PPh 3(348.74mg,1.33mmol)，升温至25℃，搅拌16小时。将反应液直接减压浓缩得到 白色固体粗产物WX318-8，直接用于下一步反应。
步骤7：化合物WX318的合成。
化合物WX318的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d6)δ＝11.22(s,1H),8.71(br t,J＝5.5Hz,1H),8.10(d,J＝8.3Hz,1H),7.86(d,J＝1.4Hz,1H),7.78(dd,J＝1.5,8.3Hz,1H),7.64-7.59(m,1H),7.15(dd,J＝1.7,3.6Hz,1H),6.54(t,J＝3.3Hz,1H),3.80-3.68(m,1H),3.53-3.40(m,2H),3.32-3.27(m,2H),1.78-1.68(m,1H),1.67-1.54(m,6H),1.52-1.34(m,3H).
实施例85:WX326
Figure PCTCN2018075995-appb-000285
合成路线：
Figure PCTCN2018075995-appb-000286
步骤1：化合物WX326的合成。
化合物WX326的合成参照实施例24中步骤1WX189的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.24(s,1H),8.88(t,J＝5.4Hz,1H),8.12(d,J＝8.3Hz,1H),7.88(s,1H),7.81(d,J＝8.3Hz,1H),7.62(dd,J＝1.6,3.0Hz,1H),7.15(dd,J＝1.7,3.6Hz,1H),6.54(t,J＝3.4Hz,1H),4.02(dd,J＝3.0,12.8Hz,1H),3.80-3.64(m,2H),3.33(s,1H),2.98(d,J＝12.8Hz,1H),2.90-2.71(m,4H),1.79-1.55(m,2H).
实施例86:WX319和320
Figure PCTCN2018075995-appb-000287
合成路线：
Figure PCTCN2018075995-appb-000288
步骤1：化合物WX319和WX320的合成。
化合物WX319和WX320的合成参照实施例24中步骤1WX189的合成。
化合物WX320： 1H NMR(400MHz,DMSO-d 6)δ＝11.21(br s,1H),8.81-8.70(m,1H),8.09(d,J＝8.2Hz, 1H),7.85(d,J＝1.3Hz,1H),7.77(s,1H),7.60(dd,J＝1.6,3.0Hz,1H),7.12(dd,J＝1.6,3.5Hz,1H),6.53(t,J＝3.3Hz,1H),3.74-3.36(m,7H),3.29(br s,1H),3.16(s,1H),1.55(br d,J＝7.0Hz,2H)；
化合物WX319： 1H NMR(400MHz,ACETONITRILE-d 3)δ＝9.00(br s,1H),8.08(d,J＝8.4Hz,1H),7.77(d,J＝1.5Hz,1H),7.67(dd,J＝1.5,8.4Hz,1H),7.46(dd,J＝1.8,3.1Hz,1H),7.29(br s,1H),7.14(dd,J＝1.8,3.7Hz,1H),6.47(t,J＝3.3Hz,1H),3.73(d,J＝2.9Hz,1H),3.70-3.60(m,4H),3.54-3.47(m,1H),3.44(d,J＝6.0Hz,2H),3.24(dd,J＝9.9,11.2Hz,1H),1.65-1.57(m,1H),1.61(s,1H).
手性拆分条件：手性柱:OJ(250mm*50mm,10μm)；流动相：0.1％NH 3.H 2O MeOH；流速：200mL/min；柱温：40℃。
化合物319对应的保留时间：3.874分钟(峰2)。化合物320对应的保留时间：3.475分钟(峰1)。
实施例87:WX328
Figure PCTCN2018075995-appb-000289
合成路线：
Figure PCTCN2018075995-appb-000290
步骤1：化合物WX328的合成。
化合物WX328的合成参照实施例24中步骤1WX189的合成。δ＝11.23(br s,1H),8.83-8.76(m,1H),8.09(d,J＝8.2Hz,1H),7.85(d,J＝1.3Hz,1H),7.77(s,1H),7.60(dd,J＝1.6,3.0Hz,1H),7.12(dd,J＝1.6,3.5Hz,1H),3.74-3.36(m,7H),3.29(br s,1H),3.16(s,1H),2.97(s,2H),1.55(br d,J＝7.0Hz,2H).
实施例88:WX325和329
Figure PCTCN2018075995-appb-000291
合成路线
Figure PCTCN2018075995-appb-000292
步骤1：化合物WX325和WX329的合成。
将BB-6(500mg,1.63mmol)，WX319-1(278.37mg,2.12mmol)，HBTU(928.62mg,2.45mmol)，TEA(495.55mg,4.90mmol,681.64μL)，溶于DMF(5mL)中，反应在30℃下搅拌12小时。减压浓缩，通过柱层析分离，减压浓缩，经SFC分离得WX325和WX329。化合物329： 1H NMR(400MHz,DMSO-d 6)δ＝11.11(br s,1H),8.73(br t,J＝5.5Hz,1H),8.05(d,J＝8.2Hz,1H),7.83(d,J＝1.3Hz,1H),7.74(dd,J＝1.5,8.4Hz,1H),7.36(s,1H),6.98(d,J＝2.0Hz,1H),3.71-3.48(m,5H),3.45-3.31(m,1H),3.45-3.30(m,1H),3.27-3.21(m,1H),3.14(dd,J＝9.9,11.2Hz,1H),2.03(s,3H),1.53(q,J＝7.0Hz,2H)；
化合物325： 1H NMR(400MHz,DMSO-d 6)δ＝11.13(br s,1H),8.73(br t,J＝5.5Hz,1H),8.05(d,J＝8.2Hz,1H),7.83(d,J＝1.3Hz,1H),7.74(dd,J＝1.5,8.4Hz,1H),7.36(s,1H),6.98(d,J＝2.0Hz,1H),3.71-3.48(m,5H),3.45-3.31(m,1H),3.45-3.30(m,1H),3.27-3.21(m,1H),3.14(dd,J＝9.9,11.2Hz,1H),2.03(s,3H),1.53(q,J＝7.0Hz,2H)。
手性拆分条件：手性柱:OJ-3 150×4.6mm；流动相：A：二氧化碳,B:甲醇(0.1％氨水)；梯度:B％＝33％；流速：60mL/min；柱温：40℃。
化合物325对应的保留时间：4.919分钟(峰2)。化合物329对应的保留时间：4.563分钟(峰1)。
实施例89:WX339和350
Figure PCTCN2018075995-appb-000293
合成路线：
Figure PCTCN2018075995-appb-000294
步骤1：化合物WX339和WX350的合成。
将BB-6(0.16g,522.37μmol,1eq)，WX339-1(102.98mg,574.61μmol)溶解于DMF(1mL)中，加入HATU(297.93mg,783.56μmol)，DIEA(202.54mg,1.57mmol,272.96μL)，反应在30℃搅拌12小时。将反应液倒入水(20mL)中，过滤，滤饼溶解于乙酸乙酯(20mL)中，乙酸乙酯层用无水硫酸钠干燥，过滤，减压浓缩。粗产品使用硅胶柱层析进行纯化得混旋的产物，经SFC分离得到WX339和WX350。化合物350： 1H NMR(400MHz,DMSO-d 6)δ＝11.15(s,1H),8.88(t,J＝5.5Hz,1H),8.08(d,J＝8.4Hz,1H),7.87(d,J＝1.3Hz,1H),7.79(dd,J＝1.3,8.4Hz,1H),7.39(s,1H),7.00(d,J＝1.8Hz,1H),6.90-6.75(m,4H),4.32(dd,J＝2.1,11.4Hz,1H),4.28-4.20(m,1H),3.91(dd,J＝7.5,11.2Hz,1H),3.56-3.40(m,2H),2.05(s,3H),1.89-1.81(m,2H)；
化合物339： 1H NMR(400MHz,DMSO-d 6)δ＝11.13(s,1H),8.86(t,J＝5.5Hz,1H),8.08(d,J＝8.4Hz,1H), 7.87(d,J＝1.3Hz,1H),7.79(dd,J＝1.3,8.4Hz,1H),7.39(s,1H),7.00(d,J＝1.8Hz,1H),6.90-6.75(m,4H),4.32(dd,J＝2.1,11.4Hz,1H),4.28-4.20(m,1H),3.91(dd,J＝7.5,11.2Hz,1H),3.56-3.40(m,2H),2.05(s,3H),1.89-1.81(m,2H).
手性拆分条件：手性柱:AS(250mm*30mm,5μm)；流动相：A:二氧化碳,B:甲醇；梯度:B％＝45％；流速：80mL/min；柱温：40℃。
化合物339对应的保留时间：4.078分钟(峰2)，化合物350对应的保留时间：3.952分钟(峰1)。
实施例90:WX352和353
Figure PCTCN2018075995-appb-000295
合成路线：
Figure PCTCN2018075995-appb-000296
步骤1：化合物WX353-3的合成。
将WX353-1(20g,98.03mmol)溶解于二氯甲烷(200mL)中，加入三乙胺(14.88g,147.04mmol,20.47mL)，DMAP(1.20g,9.80mmol)，随后滴入苯磺酰氯(19.05g,107.83mmol,13.80mL)，反应在30℃搅拌5小时。向反应液中加入DCM(100mL)，2M HCl(30mL*2)洗，有机相层使用无水硫酸钠干燥，减压除去溶剂得WX353-2。 1H NMR(400MHz,DMSO-d 6)δ＝8.08-8.02(m,3H),7.83-7.76(m,1H), 7.72-7.66(m,2H),7.19(d,J＝2.0Hz,1H),3.68(s,3H)。
步骤2：化合物WX353-4的合成。
将WX353-2(10g,29.05mmol)溶解于DMF(80mL)中，加入Pd(PPh 3) 4(1.68g,1.45mmol)，WX353-3(11.98g,37.77mmol,10.99mL)，氮气置换三次，反应在100℃搅拌24小时。向反应液中加入加入EA(100mL)，10g氟化铯的50mL H 2O溶液，搅拌6小时，过滤，滤液水洗(50mL*3)，EA层用无水硫酸钠干燥后，过滤，减压浓缩。粗产品使用硅胶柱层析进行纯化得WX353-4。 1H NMR(400MHz,DMSO-d 6)δ＝8.04-7.94(m,3H),7.80-7.75(m,1H),7.71-7.63(m,2H),7.37(d,J＝1.5Hz,1H),6.60(dd,J＝11.0,17.6Hz,1H),5.72(d,J＝17.6Hz,1H),5.21(d,J＝11.2Hz,1H),3.67(s,3H).
步骤3：化合物WX353-5的合成。
将WX353-4(7.6g,26.09mmol)溶解于MeOH(80mL)中，加入CH3ONa(2.82g,52.18mmol)，反应在50℃搅拌12小时。反应液减压浓缩。粗产品使用硅胶柱层析进行纯化得WX353-5。 1H NMR(400MHz,CHLOROFORM-d)δ＝9.02(br s,1H),7.05-6.94(m,2H),6.57(dd,J＝10.9,17.5Hz,1H),5.48(dd,J＝1.1,17.6Hz,1H),5.06(dd,J＝1.2,10.9Hz,1H),3.87(s,3H).
步骤4：化合物WX353-7的合成。
0℃条件下，向WX353-5(3.6g,23.82mmol)的THF(36mL)溶液中滴加t-BuOK(1M,28.58mL)，体系温度升至30℃搅拌30分钟，随后体系温度降至0℃，加入WX353-6(7.99g,28.58mmol)的THF(36mL)溶液，随后反应缓慢升至30℃搅拌12小时。减压除去溶剂，向粗产品中加入EA(100mL)，加入饱和NH4Cl(50mL)洗，水洗(50mL*2)，EA层使用无水硫酸钠干燥后，过滤，减压浓缩。粗产品使用硅胶柱层析进行纯化得WX353-7。 1H NMR(400MHz,CHLOROFORM-d)δ＝8.45(s,1H),8.41-8.38(m,2H),7.62(d,J＝2.0Hz,1H),7.27(d,J＝2.2Hz,1H),6.56(dd,J＝10.9,17.5Hz,1H),5.59(d,J＝17.6Hz,1H),5.27(d,J＝11.5Hz,1H),4.01(s,3H),3.73(s,3H).
步骤5：化合物WX353-8的合成。
将WX353-7(3g,7.61mmol)溶解于EtOAc(60mL)和MeOH(60mL)中，加入Raney-Ni(1.5g)，氢气置换三次，压力升至30psi，30℃搅拌6小时。反应液过滤，滤液减压浓缩。粗产品使用硅胶柱层析进行纯化得WX353-8。 1H NMR(400MHz,CHLOROFORM-d)δ＝7.63(d,J＝8.4Hz,1H),7.49(s,1H),7.40(d,J＝0.9Hz,1H),7.33(d,J＝8.6Hz,1H),6.98(d,J＝2.0Hz,1H),5.28(br s,2H),3.91(s,3H),3.73(s,3H),2.49(q,J＝7.6Hz,2H),1.25-1.19(m,1H),1.22(t,J＝7.5Hz,2H).
步骤6：化合物WX353-9的合成。
将WX353-8(1g,2.73mmol)加入至DMSO(10mL)中，加入t-BuOK(459.39mg,4.09mmol)，反应在30℃搅拌0.5小时。向反应液中加入EA(100mL)，饱和NH4Cl(30mL*2)洗，水洗(30mL)，EA层使用无水硫酸钠干燥后，过滤，减压浓缩得WX353-9。 1H NMR(400MHz,CHLOROFORM-d)δ＝9.36(s, 1H),8.12(d,J＝8.4Hz,1H),8.04(d,J＝1.1Hz,1H),8.00-7.95(m,1H),7.27-7.25(m,1H),7.19(d,J＝1.8Hz,1H),3.99(s,3H),2.52(q,J＝7.5Hz,2H),1.22(t,J＝7.5Hz,3H).
步骤7：化合物WX353-10的合成。
将WX353-8(0.35g,1.05mmol)溶解于THF(9mL)中，加入LiOH.H2O(43.93mg,1.05mmol)的H2O(3mL)溶液，反应在30度搅拌12小时。向反应液中加入EA(100mL)，水(50mL*2)洗，EA层丢弃，水层中加入EA(100mL)，搅拌情况下，缓慢加入2M HCl调节水相pH至3-4，分液，EA相使用无水硫酸钠干燥后，过滤，减压浓缩得WX353-9。 1H NMR(400MHz,DMSO-d 6)δ＝13.70(br s,1H),11.22(s,1H),8.10(d,J＝8.4Hz,1H),8.01(d,J＝1.3Hz,1H),7.89(dd,J＝1.4,8.3Hz,1H),7.40(d,J＝0.9Hz,1H),7.08(d,J＝1.8Hz,1H),2.45(d,J＝7.7Hz,2H),1.13(t,J＝7.5Hz,3H)。
步骤8：化合物WX353和WX352的合成。
化合物WX352和WX353的合成见实施例89中步骤1化合物WX339和WX350的合成。
化合物WX352： 1H NMR(400MHz,DMSO-d 6)δ＝11.18(s,1H),8.79(t,J＝5.6Hz,1H),8.08(d,J＝8.4Hz,1H),7.85(d,J＝1.5Hz,1H),7.77(dd,J＝1.5,8.2Hz,1H),7.43-7.36(m,1H),7.07(d,J＝2.0Hz,1H),3.73-3.66(m,2H),3.62(dd,J＝2.1,11.1Hz,1H),3.58-3.49(m,2H),3.45(dd,J＝2.6,11.0Hz,1H),3.33-3.23(m,2H),3.16(dd,J＝10.0,11.4Hz,1H),2.44(d,J＝7.5Hz,2H),1.60-1.50(m,2H),1.12(t,J＝7.5Hz,3H)；
化合物WX353： 1H NMR(400MHz,DMSO-d 6)δ＝11.18(s,1H),8.79(t,J＝5.4Hz,1H),8.08(d,J＝8.4Hz,1H),7.85(d,J＝1.1Hz,1H),7.77(dd,J＝1.3,8.4Hz,1H),7.39(d,J＝0.7Hz,1H),7.07(d,J＝1.8Hz,1H),3.74-3.66(m,2H),3.60(s,1H),3.59-3.48(m,2H),3.44(dd,J＝2.4,11.0Hz,1H),3.33-3.24(m,2H),3.20-3.12(m,1H),2.44(d,J＝7.7Hz,2H),1.59-1.51(m,2H),1.12(t,J＝7.5Hz,3H)。
手性拆分条件：手性柱:OJ-H 250*30mm i.d.5μm；流动相：A:二氧化碳，B:甲醇；梯度:B％＝30％；流速：70mL/min；柱温：40℃。
化合物WX352对应的保留时间：0.86分钟(峰1)。化合物WX353对应的保留时间：0.98分钟(峰2)。
实施例91:WX355和356
Figure PCTCN2018075995-appb-000297
合成路线：
Figure PCTCN2018075995-appb-000298
步骤1：化合物WX356-2的合成。
在预先干燥过的100mL三口瓶中加入NaH(1.66g,41.62mmol,60％纯度)和DMF(50mL)，随后抽真空用氮气置换3次，降温至0℃后逐滴加入WX356-1(5g,37.83mmol)的DMF(5mL)溶液，控制温度在0-5度，搅拌30min，溶液变成白色悬浊液。降温至0℃，缓慢滴加溴丙烯(4.12g,34.05mmol)的DMF(5mL)溶液，控制温度不超过5℃，溶液颜色变成黄色液体。滴毕升至25℃搅拌12h，溶液颜色变成黄色。将反应液倾倒入50mL H 2O中淬灭反应，加入50mL EtOAc，分液，用2*50mL EtOAc萃取水相，合并有机相，20mL饱和食盐水洗涤合并的有机相，无水硫酸钠干燥，过滤，浓缩有机相得WX356-2。
步骤2：化合物WX356-3的合成。
在预先干燥过的250mL的单口瓶中加入原料WX356-2(4.5g,26.13mmol)和溶剂THF(60mL)，随后缓慢滴加LiBH4(1.14g,52.26mmol)，加完后在25℃下搅拌16h。将反应液倾倒入50mL H2O中淬灭反应，加入50mL EtOAc，分液，用2*50mL EtOAc萃取水相，合并有机相，20mL饱和食盐水洗涤合并的有机相，无水硫酸钠干燥，过滤，水泵上浓缩有机相得WX356-3。
步骤3：化合物WX356-4的合成。
在预先干燥过的250毫升烧瓶中加入WX356-3(3g,23.04mmol)和溶剂MeCN(200mL)，随后加入NaHCO3(5.81g,69.13mmol,2.69mL)和I2(17.55g,69.13mmol,13.93mL)。该反应在25℃搅拌16小时。反应液倾倒入100mL水中淬灭反应，加入200mL EtOAc，分液，用2*200mL EtOAc萃取水相，合并有机相，100mL饱和食盐水洗涤合并的有机相，无水硫酸钠干燥，过滤，水泵上浓缩有机相得到WX356-4。
步骤4：化合物WX356-5的合成。
在干燥的单口瓶中加入WX356-4(500mg,1.95mmol)和DMSO(5mL)，随后加入KCN(508.56mg,7.81mmol,334.58μL)和NaI(585.34mg,3.91mmol)，氮气置换3次，将反应置于100℃搅拌2小时。加入20mL(水：乙酸乙酯＝1:1)，用4M NaOH溶液将体系pH调至大于12，用乙酸乙酯(5mL*3)萃取， 有机相用饱和食盐水(5mL*2)洗涤，用无水硫酸钠干燥，过滤，减压浓缩得WX356-5。 1H NMR(400MHz,CHLOROFORM-d)δ＝3.79-3.72(m,1H),3.71-3.52(m,4H),2.52(dt,J＝0.9,5.1Hz,2H),1.34(s,3H),1.14(s,3H).
步骤5：化合物WX356-6的合成。
在干燥的单口瓶中加入WX356-5(300mg,1.93mmol)和THF(1mL)，随后加入BH 3.THF(1M,3.87mL)，氮气置换3次，将反应置于70℃搅拌5小时。加入10mL水，用2M盐酸将体系调试pH＝2，用乙酸乙酯(5mL*2)洗涤水相，分液，水相用油泵减压浓缩得WX356-6。 1H NMR(400MHz,METHANOL-d 4)δ＝3.61-3.55(m,5H),3.12-3.06(m,2H),1.78-1.68(m,2H),1.31(s,3H),1.09(s,3H).
步骤6：化合物WX356和WX355的合成。
在干燥的单口瓶中加入BB-6(521.74mg,1.70mmol)和DMF(2mL)，随后加入HATU(971.53mg,2.56mmol)和DIPEA(550.37mg,4.26mmol,741.74μL)，最后加入WX356-6(400mg,2.04mmol,HCl)，氮气置换3次，将反应置于28℃搅拌12h。反应液通过有机相针头式滤器过滤，得到粗品。粗产柱层析分离(梯得消旋体产物。再通过SFC分离得到WX355和WX356。化合物355： 1H NMR(400MHz,DMSO-d6)δ＝11.17(s,1H),8.79(t,J＝5.5Hz,1H),8.08(d,J＝8.4Hz,1H),7.85(d,J＝1.3Hz,1H),7.77(dd,J＝1.5,8.4Hz,1H),7.81-7.72(m,1H),7.40(dd,J＝1.1,1.8Hz,1H),7.01(d,J＝1.8Hz,1H),3.52-3.37(m,5H),3.31-3.21(m,2H),2.05(s,3H),1.65-1.52(m,2H),1.21(s,3H)；化合物356： 1H NMR(400MHz,DMSO-d6)(Peak 2)δ＝11.17(br s,1H),8.79(br t,J＝5.3Hz,1H),8.08(d,J＝8.2Hz,1H),7.85(s,1H),7.77(d,J＝8.2Hz,1H),7.40(s,1H),7.01(d,J＝1.3Hz,1H),3.53-3.38(m,5H),3.30-3.20(m,2H),2.05(s,3H),1.58(br d,J＝5.3Hz,2H),1.21(s,3H),1.01(s,3H).
手性拆分条件：手性柱:AD(250mm*30mm,5μm)；流动相：A：水(10mM碳酸氢铵),B:异丙醇；梯度:B from.4％to.4％in 20min；流速：75mL/min；柱温：35℃。
化合物355对应的保留时间：2.5分钟(峰1)。化合物356对应的保留时间：2.7分钟(峰2)。
实施例92:WX338
Figure PCTCN2018075995-appb-000299
合成路线：
Figure PCTCN2018075995-appb-000300
步骤1：化合物WX338的合成。
化合物WX338的合成见实施例89中步骤1化合物WX339和WX350的合成。 1H NMR(400MHz,DMSO-d 6)δ＝11.17(s,1H),8.76(t,J＝5.4Hz,1H),8.08(d,J＝8.4Hz,1H),7.86(d,J＝1.3Hz,1H),7.77(dd,J＝1.5,8.2Hz,1H),7.37-7.34(m,1H),7.12(d,J＝2.0Hz,1H),3.74-3.35(m,7H),3.16(dd,J＝10.1,11.2Hz,1H),2.80(td,J＝6.9,13.7Hz,1H),1.60-1.50(m,2H),1.15(d,J＝6.8Hz,6H).
HBV体外测试定量qPCR试验
1实验目的：
通过实时定量qPCR试验(real time-qPCR)检测HepG2.2.15细胞内的HBV DNA含量，以化合物的EC 50值为指标，来评价化合物对HBV的抑制作用。
2实验材料:
2.1细胞系：HepG2.2.15细胞
HepG2.2.15细胞培养基(DMEM/F12，Invitrogen-11330057；10％血清，Invitrogen-10099141；100units/ml青霉素和10μg/ml链霉素，Invitrogen-15140122；1％非必需氨基酸，Invitrogen-11140076；2mM左旋谷氨酰胺，Invitrogen-25030081；300μg/ml遗传霉素，Invitrogen-10131027
2.2试剂：
胰酶(Invitrogen-25300062)
DPBS(Hyclone-SH30028.01B)
DMSO(Sigma-D2650-100ML)
高通量DNA纯化试剂盒(QIAamp 96DNA Blood Kit，Qiagen-51162)
定量快速启动通用探针试剂(FastStart Universal Probe Master，Roche-04914058001)
2.3耗材与仪器：
96孔细胞培养板(Corning-3599)
CO 2培养箱(HERA-CELL-240)
光学封板膜(ABI-4311971)
定量PCR 96孔板(Applied Biosystems-4306737)
荧光定量PCR仪(Applied Biosystems-7500real time PCR system)
3.实验步骤和方法：
3.1种HepG2.2.15细胞(4x10 4细胞/孔)到96孔板，在37℃，5％CO 2培养过夜。
3.2第二天，稀释化合物，共8个浓度，3倍梯度稀释。加不同浓度化合物到培养孔中，双复孔。培养液中DMSO的终浓度为1％。1μM GLS4作为100％抑制对照；1％的DMSO作为0％抑制对照。
3.3第五天，更换含有化合物的新鲜培养液。
3.4第八天收取培养孔中的培养液，使用高通量DNA纯化试剂盒(Qiagen-51162)提取DNA，具体步骤参照该产品说明书。
3.5PCR反应液的配制如表1所示：
表1 PCR反应液的配制
Figure PCTCN2018075995-appb-000301
上游引物序列：GTGTCTGCGGCGTTTTATCA
下游引物序列：GACAAACGGGCAACATACCTT
探针序列：5'+FAM+CCTCTKCATCCTGCTGCTATGCCTCATC+TAMRA-3'
3.6在96孔PCR板中每孔加入15μl的反应混合液，然后每孔加入10μl的样品DNA或HBV DNA的标准品。
3.7PCR的反应条件为：95℃加热10分钟；然后95℃变性15秒，60℃延伸1分钟，共40个循环。3.8数据分析：
3.8.1计算抑制百分比：％Inh.＝【1-(样品中DNA拷贝数–1μM GLS4中DNA拷贝数)/(DMSO对照中DNA拷贝数–1μM GLS4中DNA拷贝数)】x100。
3.8.2计算EC 50：使用GraphPad Prism软件计算化合物对HBV的50％抑制浓度(EC 50)值。
4 实验结果如表2所示：
表2 qPCR实验检测EC 50测试结果
Figure PCTCN2018075995-appb-000302
Figure PCTCN2018075995-appb-000303
Figure PCTCN2018075995-appb-000304
注：A：EC 50≤100nM；B:100nM＜EC 50≤500nM；C:500nM＜EC 50≤1000nM；
D:1000nM＜EC 50≤10000nM；
结论：本发明化合物对HBV的抑制作用显著。
细胞色素P450同工酶抑制性研究
实验目的：测定受试化合物对对人肝微粒体细胞色素P450同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)活性的抑制作用。
实验操作：首先将受试化合物(10mM)进行梯度，制备工作液(100×最终浓度)，工作液浓度分别为：5,1.5,0.5,0.15,0.05,0.015,0.005mM，同时准备P450同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)各阳性抑制剂及其特异性底物混合物(5in 1)的工作液；将冷冻于–80℃冰箱的人肝微粒体置于冰上解冻，待人肝微粒体全部溶解，用PB进行稀释，制备一定浓度工作液(0.253mg/ml)；并将20ul底物混合液加至反应板中(Blank孔中加入20μl PB)同时将158μl人肝微粒体工作液加入反应板中，将反应板置于冰上，待用；此时将2μl各个浓度的受试化合物(N＝1)及特异性抑制剂(N＝2)加入对应孔中，无抑制剂(受试化合物或阳性抑制剂)组加入对应的有机溶剂，作为对照组样品(受试化合物对照样品为1:1DMSO:MeOH,阳性对照样品为1:9DMSO:MeOH,)；在37℃水浴预孵育10min后，将20μl辅酶因子(NADPH)溶液加入反应板中，置于37℃水浴孵育10min；加入400μL冷的乙腈溶液(内标为200ng/mL Tolbutamide和Labetalol)终止反应；将反应板置于摇床，振荡10min；4,000rpm离心20min；取200μL上清加至100μL水中，进行样品稀释；最后封板，振荡，摇匀，进行LC/MS/MS检测。实验结果如表3所示：
表3.受试化合物对对人肝微粒体细胞色素P450同工酶活性的抑制作用结果
Figure PCTCN2018075995-appb-000305
实验结论：受试化合物对CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4均无明显抑制作用。
血浆蛋白结合率研究
实验目的：测定受试化合物在人及CD-1小鼠血浆中的蛋白结合率
实验操作：取人以及CD-1小鼠的空白血浆796μL，加入4μL受试化合物工作溶液(400μM)或华法林工作溶液(400μM)，使血浆样品中受试化合物与华法林终浓度均为2μM。将样品充分混合。有机相DMSO的终浓度为0.5％；移取50μL受试化合物和华法林血浆样品到样品接收板中(三个平行)，立即加入相应体积的对应空白血浆或缓冲液，使得每个样品孔的终体积为100μL，血浆：透析缓冲液的体积比为1:1，然后向这些样品中加入400μL终止液，此样品将作为T0样品用于回收率及稳定性测定。将T0样品存储于2-8℃，等待与其它透析完的样品一起进行后续处理；将150μL受试化合物和华法林血浆样品加入到每个透析孔的给药端，在透析孔对应的接收端中加入150μL空白透析缓冲液。然后将透析板封上透气膜后置于湿润的、5％CO2的培养箱中，在37℃下、约100rpm振荡孵育4-hr。透析结束后，移取50μL透析后的缓冲液样品和透析后的血浆样品到新的样品接收板。在样品中加入相应体积的对应空白血浆或缓冲液，使得每个样品孔的终体积为100μL，血浆：透析缓冲液的体积比为1:1。所有样品经过蛋白沉淀后进行LC/MS/MS分析，并通过公式：％Unbound(未结合率)＝100*FC/TC,％Bound(结合率)＝100-％Unbound,％Recovery(回收率)＝100*(FC+TC)/T0计算蛋白结合率以及回收率。实验结果如表4所示：
表4.受试化合物在人及CD-1小鼠血浆中的蛋白结合率
Figure PCTCN2018075995-appb-000306
实验结论：受试化合物在人及CD-1小鼠血浆中均表现出较低的蛋白结合率。
体内药代动力学研究
Balb/c小鼠口服及静脉注射WX325的药代动力学研究
WX325与5％DMSO/55％聚乙二醇400/40％水溶液混合，涡旋并超声，制备得到1mg/mL近似澄清溶液，微孔滤膜过滤后备用。选取7至10周龄的Balb/c雌性小鼠，静脉注射给予候选化合物溶液，剂量为1mg/kg。WX325与10％solutol(聚乙二醇-15羟基硬脂酸酯)水溶液混合，涡旋并超声，制备得到1mg/mL近似澄清溶液，微孔滤膜过滤后备用。选取7至10周龄的Balb/c雌性小鼠，口服给予候选化合物溶液，剂量为10mg/kg。
收集一定时间的全血，制备得到血浆，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNonlin软件(美国Pharsight公司)计算药代参数。
SD大鼠口服及静脉注射WX325的药代动力学研究
WX325与5％DMSO/55％聚乙二醇400/40％水溶液混合，涡旋并超声，制备得到1mg/mL近似澄清溶液，微孔滤膜过滤后备用。选取7至10周龄的SD雄性大鼠，静脉注射给予候选化合物溶液，剂量为1mg/kg。
WX325与10％solutol水溶液混合，涡旋并超声，制备得到1mg/mL近似澄清溶液，微孔滤膜过滤后备用。选取7至10周龄的SD雄性大鼠，口服给予候选化合物溶液，剂量为10mg/kg。
收集一定时间的全血，制备得到血浆，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNonlin软件(美国Pharsight公司)计算药代参数。
比格犬口服及静脉注射WX325的药代动力学研究
WX325与5％DMSO/55％聚乙二醇400/40％水溶液混合，涡旋并超声，制备得到1mg/mL近似澄清溶液，微孔滤膜过滤后备用。选取10kg左右的雄性比格犬，静脉注射给予候选化合物溶液，剂量为1mg/kg。WX325与10％solutol水溶液混合，涡旋并超声，制备得到2mg/mL均一的混悬液，微孔滤膜过滤后备用。选取10kg左右的雄性比格犬，口服给予候选化合物溶液，剂量为10mg/kg。
收集一定时间的全血，制备得到血浆，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNonlin软件(美国Pharsight公司)计算药代参数。
实验结果如表5所示：
表5.受试化合物的药代动力学结果
Figure PCTCN2018075995-appb-000307
注：T 1/2表示半衰期；Vd ss表示表观分布容积；Cl表示清除率；AUC 0-last表示药时曲线下面积；T max表示达峰时间；C max表示达峰浓度；F％表示口服生物利用度；iv表示静脉注射；PO表示口服给药；mpk表示mg/kg。
实验结论：本发明化合物具有很好的犬药代动力学单项或部分指标。
体内药效研究
AAV/HBV模型
实验目的：通过AAV/HBV小鼠模型来检测化合物在小鼠体内抗乙肝病毒效果。
实验操作：将首次给药当天定为第0天，给药前1天为第-1天，给药后1天为第1天，依此类推。在给药前第28天所有动物经尾静脉注射1*10 11v.g.rAAV8-1.3HBV病毒，每只动物注射200μL。在给药前14天及前7天，所有注射rAAV8-1.3HBV病毒的小鼠经颌下静脉采血收集血清。收集的血样放置于37℃约30分钟，4℃，13,200g离心3分钟，取上清。血清用于检测HBV DNA、HBeAg和HBsAg含量。HBV DNA，HBsAg，HBeAg水平较低及体重较轻的小鼠将可能从该实验中移除。将挑选出的25只小鼠平均分配到各组中，并确保各化合物处理组小鼠在病毒注射后第21天的HBV DNA，HBsAg，HBeAg水平及体重和溶剂组相比没有统计学差异(P>0.05)。受试化合物WX325与10％solutol水溶液混合，涡旋并超声，制备得到均一的混悬液，微孔滤膜过滤后备用。作为阳性化合物的替诺福韦，溶于生理盐水中，超声并搅拌至溶解，配制成0.1mg/ml的母液，用生理盐水稀释到0.01mg/ml，保存于4℃直至使用。受试化合物WX325采取一天两次(BID)，每次间隔8h，口服灌胃(PO)的方式给药。参比化合物替诺福韦采取每天两次口服灌胃的方式给药。两种药物都给药28天，其中取给药后第3,7,10,28天的血样，qPCR法检测血浆中HBV DNA的水平。在第28天，将小鼠经CO 2吸入安乐死，收集肝脏，qPCR法检测小鼠肝脏中HBV DNA的水平。实验结果如图1、图2所示。
实验结论：本发明化合物显示出良好的体内药效，且呈剂量依赖效应。

Claims (18)

  1. 式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2018075995-appb-100001
    L 1选自单键和-C 1-6烷基-；
    R 1选自H、Cl、F、Br、I，或选自任选被1、2或3个R取代的C 1-3烷基；
    R 2选自任选被1、2或3个R取代的：C 1-3杂烷基、4～8元杂环烷基、5～10元杂芳基、4～8元部分不饱和杂环基、苯基、C 1-3烷基、C 3-8环烷基、4～8元杂环烷基-O-和5～10元杂芳基-O-；
    R 3选自：H和C 1-3烷基；
    R分别独立地选自H、Cl、F、Br、I、NH 2、OH、CN，或选自任选被1、2或3个R'取代的：C 1-6烷基、C 1-6杂烷基、苯基、苯基-O-C(＝O)-和5～6元杂芳基；
    R'分别独立地选自：Cl、F、Br、I、NH 2、CH 3、CN和-N(CH 3) 2；
    所述C 1-3杂烷基、4～8元杂环烷基、5～10元杂芳基、C 1-6杂烷基、5～6元杂芳基、4～8元部分不饱和杂环基之“杂”分别独立地选自：-S-、-O-、-NH-、N、-C(＝O)-、-O-C(＝O)-、-S(＝O) 2-、-S(＝O)-、-NH-C(＝O)-、-NH-C(＝O)-O-；
    以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2、3或4。
  2. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，R选自H、Cl、F、Br、I、NH 2、OH、CN，或选自任选被1、2或3个R'取代的：C 1-3烷基、C 1-6烷基-O-C(＝O)-、C 1-6烷基-C(＝O)-、C 1-3烷基-S(＝O) 2-、C 1-3烷基-S(＝O)-、C 1-3烷氨基、苯基、苯基-O-C(＝O)-和吡啶基。
  3. 根据权利要求2所述的化合物、其异构体或其药学上可接受的盐，其中，R选自H、Cl、F、Br、I、NH 2、OH、CN，或选自任选被1、2或3个R'取代的：CH 3、
    Figure PCTCN2018075995-appb-100002
    Figure PCTCN2018075995-appb-100003
  4. 根据权利要求3所述的化合物、其异构体或其药学上可接受的盐，其中，R选自：H、Cl、F、Br、I、NH 2、OH、CH 3、CN、
    Figure PCTCN2018075995-appb-100004
    Figure PCTCN2018075995-appb-100005
  5. 根据权利要求1～4任意一项所述的化合物、其异构体或其药学上可接受的盐，其中，R 1选自H、Cl、F、Br、I、Me、Et、
    Figure PCTCN2018075995-appb-100006
  6. 根据权利要求1～4任意一项所述的化合物、其异构体或其药学上可接受的盐，其中，R 2选自任选被1、2或3个R取代的：C 1-3烷氧基、四氢呋喃基、噻唑基、3-氮杂双环[3.1.0]己烷基、吡啶基、苯并咪唑基、噻吩基、吡唑基、苯并噻唑基、咪唑并[1,2-a]吡啶基、甲基、C 1-3烷硫基、C 1-3烷基-S(＝O) 2-、环戊烷基、苯基、吖丁啶基、哌啶基、吡咯烷基、噁唑基、吡咯烷-2-酮基、吡啶-2(1H)-酮基、环己烷基、环丙烷基、异噻唑烷-1,1-二氧化物基、嘧啶基、1,3,4-噻二唑基、恶唑烷-2-酮基、四氢吡喃基、环戊烷基-O-、吡啶基-O-、环氧己烷基、1,4-二氧六环基、1,4-二氧庚环基、吗啉基和2,3-二氢苯并[b][1,4]二氧杂环己烯基。
  7. 根据权利要求6所述的化合物、其异构体或其药学上可接受的盐，其中，R 2选自任选被1、2或3个R取代的：CH 3、
    Figure PCTCN2018075995-appb-100007
    Figure PCTCN2018075995-appb-100008
  8. 根据权利要求7所述的化合物、其异构体或其药学上可接受的盐，其中，R 2选自
    Figure PCTCN2018075995-appb-100009
    Figure PCTCN2018075995-appb-100010
    Figure PCTCN2018075995-appb-100011
    CF 3、
    Figure PCTCN2018075995-appb-100012
    Figure PCTCN2018075995-appb-100013
  9. 根据权利要求1～4任意一项所述的化合物、其异构体或其药学上可接受的盐，其中，L 1选自单键、CH 2、
    Figure PCTCN2018075995-appb-100014
  10. 根据权利要求1～4任意一项所述的化合物、其异构体或其药学上可接受的盐，其中，R 3选自H、CH 3和-CH 2CH 3。
  11. 根据权利要求1～4任意一项所述的化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018075995-appb-100015
    选自：
    Figure PCTCN2018075995-appb-100016
    Figure PCTCN2018075995-appb-100017
    Figure PCTCN2018075995-appb-100018
  12. 根据权利要求1～5或9～10任意一项所述化合物、其异构体或其药学上可接受的盐，选自：
    Figure PCTCN2018075995-appb-100019
    Figure PCTCN2018075995-appb-100020
    其中，
    m选自：1、2或3；
    n选自：1或2；
    r选自：0或1；
    T 1选自：N或CH；
    R如权利要求1～4任意一项所定义；
    L 1如权利要求1或9所定义；
    R 1如权利要求1或5所定义；
    R 3如权利要求1或10所定义。
  13. 根据权利要求12所述化合物、其异构体或其药学上可接受的盐，选自：
    Figure PCTCN2018075995-appb-100021
    其中，
    R如权利要求1～4任意一项所定义；
    L 1如权利要求1或9所定义；
    R 1如权利要求1或5所定义；
    R 3如权利要求1或10所定义；
    n如权利要求12所定义。
  14. 下式化合物、其异构体或其药学上可接受的盐：
    Figure PCTCN2018075995-appb-100022
    Figure PCTCN2018075995-appb-100023
    Figure PCTCN2018075995-appb-100024
    Figure PCTCN2018075995-appb-100025
  15. 根据权利要求14所述的化合物、其异构体或其药学上可接受的盐，选自：
    Figure PCTCN2018075995-appb-100026
  16. 一种药物组合物，包括治疗有效量的根据权利要求1～15任意一项所述的化合物、其异构体或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
  17. 根据权利要求1～15任意一项所述的化合物、其异构体或其药学上可接受的盐在制备治疗与HBV相关疾病的药物中的应用。
  18. 根据权利要求16所述的药物组合物在制备治疗与HBV相关疾病的药物中的应用。
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