WO2015180631A1 - 作为hbv抑制剂的二氢嘧啶并环衍生物 - Google Patents

作为hbv抑制剂的二氢嘧啶并环衍生物 Download PDF

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WO2015180631A1
WO2015180631A1 PCT/CN2015/079870 CN2015079870W WO2015180631A1 WO 2015180631 A1 WO2015180631 A1 WO 2015180631A1 CN 2015079870 W CN2015079870 W CN 2015079870W WO 2015180631 A1 WO2015180631 A1 WO 2015180631A1
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etoac
nmr
lcms
esi
group
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PCT/CN2015/079870
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English (en)
French (fr)
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贺海鹰
周凯
覃华
李小林
周跃东
王校飞
迟雪梅
黎健
陈曙辉
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南京明德新药研发股份有限公司
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Priority claimed from CN201410240665.XA external-priority patent/CN105153164B/zh
Priority to JP2016570343A priority Critical patent/JP6710642B2/ja
Priority to RU2016151893A priority patent/RU2693897C2/ru
Priority to ES15799888.1T priority patent/ES2687606T3/es
Priority to US15/314,599 priority patent/US9938301B2/en
Priority to EP15799888.1A priority patent/EP3150600B1/en
Priority to NZ727601A priority patent/NZ727601A/en
Priority to KR1020167037087A priority patent/KR102428878B1/ko
Application filed by 南京明德新药研发股份有限公司 filed Critical 南京明德新药研发股份有限公司
Priority to BR112016028000-8A priority patent/BR112016028000B1/pt
Priority to CA2950807A priority patent/CA2950807C/en
Priority to AU2015266481A priority patent/AU2015266481B2/en
Priority to CN201580026816.4A priority patent/CN106459061B/zh
Publication of WO2015180631A1 publication Critical patent/WO2015180631A1/zh
Priority to IL249261A priority patent/IL249261B/en
Priority to PH12016502398A priority patent/PH12016502398A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/527—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim spiro-condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to a dihydropyrimidocyclic derivative as an HBV inhibitor, and more particularly to a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • Hepatitis B virus belongs to the family of hepatic viruses. It can cause acute and/or persistent/progressive chronic diseases. Hepatitis B virus also causes many other clinical characterizations in pathological morphology - especially chronic inflammation of the liver, cirrhosis of the liver and carcinogenesis of hepatocytes. In addition, co-infection with hepatitis D can have an adverse effect in the development of the disease.
  • interferon Conventional agents that are approved for the treatment of chronic hepatitis are interferon and amifluudine.
  • interferon has only moderate activity and high toxic side effects; although lamivudine has good activity, its drug resistance increases rapidly during treatment and often after stopping treatment. A rebound effect occurs, and the IC50 value of lamivudine (3-TC)> is 300 nM (Science, 299 (2003), 893-896).
  • heteroaryl ring-substituted dihydropyrimidine (HAP) compounds represented by Bay41_4109 and Bay39_5493, which are capable of inhibiting HBV replication by preventing the formation of normal nucleocapsids.
  • Bay41-4109 showed better drug metabolism parameters in clinical studies (Science, 299 (2003), 893-896).
  • Studies on its mechanism of action have revealed that heteroaryl ring-substituted dihydropyrimidines change the angle between the dimers forming the nucleocapsid by acting on the 113-143 amino acid residues of the core protein, resulting in the formation of no Stable expanded nucleocapsid accelerates degradation of core proteins (Biochem. Pharmacol. 66 (2003), 2273-2279).
  • R 2 is selected from
  • R 3 are independently selected from R 01 is optionally substituted: C 1-10 alkyl or heteroalkyl, 3-6 membered cycloalkyl or heterocycloalkyl, 6 to 10-membered aromatic ring group or Heteroaromatic ring group;
  • R 3 ', R 21 , R d1-8 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, -COOH, or selected from those optionally substituted by R 01 : C 1- 4- alkyl, -C 0-4 alkylphenyl, -C 0-4 alkyl-3-6-membered heterocyclic, 3- to 6-membered heterocyclyl-, benzenesulfonylamino or heterophenylsulfonylamino , -D 01 -D 02 -D 03 -H,
  • D 01 is selected from a single bond, -C 1-4 alkyl-;
  • D 03 is selected from the group consisting of a single bond, -C 1-4 alkyl-, -C 2-4 alkenyl-, -C 3-6 cycloalkyl-, -3 to 6-membered heterocycloalkyl-, 5 to 6 Aryl, 5- to 6-membered heteroaryl; optionally, R 3 and R 3 ' are joined to the same carbon atom or hetero atom to form an optionally substituted 3 to 12 membered ring;
  • the numbers of R 01 and R 001 are each independently selected from 0, 1, 2 or 3, and the number of hetero atoms or heteroatoms is independently selected from 1, 2 or 3.
  • the above compound, or a pharmaceutically acceptable salt thereof has the structure of formula (II):
  • R 31-32 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, -COOH, or selected from the group consisting of 1, 2 or 3 R 01 : C 1 -4 alkyl, -C 0-4 alkylphenyl, -C 0-4 alkyl-3-6-membered heterocyclic, 3- to 6-membered heterocyclyl-, benzenesulfonylamino or heterobenzenesulfonyl Amino group, -D 01 -D 02 -D 03 -H,
  • D 01 is selected from a single bond, -C 1-4 alkyl-;
  • D 03 is selected from the group consisting of a single bond, -C 1-4 alkyl-, -C 2-4 alkenyl-, -C 3-6 cycloalkyl-, -3 to 6-membered heterocycloalkyl-, 5 to 6
  • An aryl group, a 5- to 6-membered heteroaryl group; m and n are each independently selected from 1 or 2;
  • the above -D 03 -H is selected from the group consisting of: H, Me, Et,
  • R 3 ', R 21 , R d1 - d8 , R 31-32 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, -COOH, or Selected from CH 3 optionally substituted by 1, 2 or 3 R 01 ,
  • R 3 ', R 21 , R d1 - d8 , and R 31-32 are each independently selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, -COOH, CH 3 ,
  • the structural unit From:
  • the structural unit From:
  • the above L, D 21 is selected from the group consisting of a single bond, -O-, -NH-; or R 21 is selected from the group consisting of C 1-4 alkyl, C 1-4 alkylamino, N, N-di ( C 1-4 alkyl)amino, C 1-4 alkylamino-C 1-4 alkyl-, N,N-di(C 1-4 alkyl)amino-C 1-4 alkyl-, C 1- 4 -alkoxy, C 1-4 alkoxy-C 1-4 alkyl-, halo C 1-4 alkyl-, dihalo C 1-4 alkyl-, aminooxy C 1-4 alkane Base-, hydroxy-C 1-4 alkyloxy-, hydroxy C 1-3 alkylamino-.
  • the above R 21 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, A Aminoethyl, ethylaminoethyl, propylaminoethyl, dimethylaminoethyl, diethylaminomethyl, dimethylaminomethyl, diethylaminoethyl, methoxymethyl, methoxy Base, methoxypropyl, ethoxymethyl, propoxymethyl, ethoxyethyl, propoxypropyl, fluoromethyl, fluoroethyl, fluoropropyl, difluoromethyl, difluoro Ethyl, difluoropropyl, aminooxymethyl, aminooxyethyl, aminooxypropyl, hydroxymethyloxy
  • R 3 or R 4 are each independently selected from the group consisting of 1, 2 or 3 R 001 substituted: phenyl, pyridyl, quinolyl, isoquinolinyl, thiazolyl, Thienyl, oxazolyl, isoxazolyl, pyrazolyl, isothiazole, furyl, pyrrolyl, pyrrolidinyl, 1,3-oxapentacyclyl, 2-pyrazolyl, pyrazolidinyl, Imidazolyl, 1,2,3-oxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, piperidinyl, 1,4 -dioxolyl, morpholinyl, piperazinyl, piperidinyl, pyrimidinyl, pyrazinyl, 1,3,5-trithiaalkyl, 1,3,5-triazinyl
  • R 001 is as defined above.
  • R 3 is selected from
  • R 4 is selected from
  • the structural unit From:
  • the compounds of the invention are selected from the group consisting of
  • 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 alkyl or heteroalkyl, C 3-12 cyclo or heterocycloalkyl, C 1-12 alkyl or heteroalkyl substituted by C 3-12 cycloalkyl or heterocycloalkyl includes, but is not limited to:
  • pharmaceutically acceptable as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • 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 salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
  • 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.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • 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. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention. Certain compounds of the invention may exist in polycrystalline or amorphous form.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers 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.
  • 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 salt of a diastereomer is formed with a suitable optically active acid or base, followed by stepping as is known in the art.
  • the diastereomeric resolution is carried out by crystallization or chromatography, and then 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). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are substituted.
  • Ketone substitution does not occur on the aryl 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.
  • substituents When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring.
  • substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof.
  • Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit It is indicated that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • R', R", R"', R"" and R""' are each independently preferred Hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl (eg substituted by 1 to 3 halogen aryl), substituted or unsubstituted alkyl, alkoxy, sulphur Alkoxy group or aralkyl group.
  • each R group is independently selected as if present Each of these groups of more than one R', R", R"', R"" and R""' groups.
  • R' and R" When R' and R" are attached to the same nitrogen atom, they may be bonded to the nitrogen The atoms combine to form a 5-, 6- or 7-membered ring.
  • -NR'R is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • alkyl is intended to include carbon.
  • a group bonded to a non-hydrogen group such as a haloalkyl group (e.g., -CF 3 , -CH 2 CF 3 ) and an acyl group (e.g., -C(O)CH 3 , -C(O)CF 3 ,- C(O)CH 2 OCH 3 , etc.).
  • a non-hydrogen group such as a haloalkyl group (e.g., -CF 3 , -CH 2 CF 3 ) and an acyl group (e.g., -C(O)CH 3 , -C(O)CF 3 ,- C(O)CH 2 OCH 3 , etc.).
  • Two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -TC(O)-(CRR')qU-, wherein T and U are independently selected From -NR-, -O-, CRR'- or a single bond, q is an integer from 0 to 3.
  • two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH2)r B-, wherein A and B are independently selected From -CRR'-, -O-, -NR-, -S-, -S(O)-, S(O) 2 -, -S(O) 2 NR'- or a single bond, r is 1 to 4 The integer.
  • a single bond on the new ring thus formed can be replaced with a double bond.
  • two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH2)r B-, wherein s and d are each independently An integer selected from 0 to 3, X is -O-, -NR', -S-, -S(O)-, -S(O) 2 - or -S(O) 2 NR'-.
  • the substituents R, R', R" and R"' are each independently preferably selected from hydrogen and substituted or unsubstituted (C 1 -C 6 )alkyl.
  • halo or halogen
  • 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.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • Alkoxy represents the above alkyl group having a specified number of carbon atoms attached through an oxygen bridge.
  • the C 1-6 alkoxy group includes a 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.
  • Cycloalkyl includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl.
  • the 3-7 cycloalkyl group includes C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl groups.
  • Alkenyl includes hydrocarbon chains in a straight or branched configuration wherein one or more carbon-carbon double bonds, such as vinyl and propylene groups, are present at any stable site on the chain.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • 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).
  • N nitrogen
  • S sulfur
  • Si silicon
  • Ge germanium
  • Al aluminum
  • 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).
  • 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). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed one.
  • 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, anthracycline, benzimidazolyl, benzofuranyl, benzinyl furanyl, Benzononylphenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzene And imidazolinyl, oxazolyl, 4aH-carbazolyl, porphyrinyl, chromanthyl, chromene, porphyrinyldecahydroquinolinyl, 2H,6H-1,5,2-di Thiazinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazo
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means straight-chain, branched or cyclic
  • the hydrocarbon radical or a combination thereof may be fully saturated, mono- or polyunsaturated, may be monosubstituted, disubstituted or polysubstituted, and may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (methine), may include a divalent or polyvalent radical having the specified number of carbon atoms (e.g., C 1 -C 10 represents 1 to 10 carbons).
  • 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.
  • alkyl refers to a straight or branched chain of atoms 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 alkyl 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 Structure.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having 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 heteroatom or heteroatom group can be located at any internal position of the heterohydrocarbyl group (including where the hydrocarbyl group is attached to the rest of the molecule).
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • alkoxy alkylamino and “alkylthio” (or thioalkoxy) are used conventionally to mean passing through an oxygen atom, respectively. Amino or a sulfur atom is attached to those alkyl groups of the remainder of the molecule.
  • 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.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, may be monovalent, divalent or polyvalent, it may be monocyclic or Polycyclic (such as 1 to 3 rings; at least one of which is aromatic), which 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, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, 5-
  • aryl groups when used in conjunction with other terms (eg, 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 replacement, 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 carbonyl Diimidazole; 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 ethyl acetate EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxycarbonyl and is an amine protecting group; BOC
  • A EC 50 ⁇ 100nM
  • B 100nM ⁇ EC 50 ⁇ 500nM
  • C 500nM ⁇ EC 50 ⁇ 1000nM
  • D 1000nM ⁇ EC 50 ⁇ 5000nM
  • Example 4 was prepared as described in Example 1.
  • Example 5 was prepared as described in Example 1 and isolated by SFC preparation.
  • Examples 8, 9 were prepared as described in Examples 6, 7 by high performance liquid phase separation.
  • Example 15 and 16 were dissolved in 1 mL of ethyl acetate, and then 4 mL of ethyl hydrogen chloride solution was added thereto, and the mixture was stirred at 20 ° C for 30 minutes, concentrated under reduced pressure, and lyophilized to give Example 15 and Example 16 respectively. .
  • Examples 17, 18 were prepared as described in Examples 15, 16 by high performance liquid phase separation.
  • Examples 19, 20 were prepared as described in Examples 15, 16 by SFC separation.
  • Examples 21, 22 were prepared as described in Examples 15, 16 by SFC separation.
  • Examples 26, 27 were obtained by high performance liquid phase separation from 23-5.
  • Examples 30, 31 were prepared as described in Examples 28, 29 by SFC separation.
  • Example 33 was prepared as described in Example 32.
  • the compound 34-2 (30 g, 158 mmol) was dissolved in anhydrous tetrahydrofuran (400 mL), and hexanes hexanes (16.5 mL, 165 mmol) was slowly added dropwise at room temperature, and the mixture was stirred at room temperature for 1 hour. The temperature was then lowered to 0 ° C, sodium borohydride (300 mg, 8 mmol) was added and the mixture was stirred vigorously for 30 min then warmed to room temperature and stirred overnight. Then, absolute ethanol (80 mL), p-TsOH (450 mg, 4 mmol) was added, and the mixture was stirred at room temperature for half an hour. The reaction mixture was concentrated under reduced pressure and purified to silicagel eluting eluting eluting eluting eluting
  • the compound 36-3 (10 g, 16.0 mmol) was dissolved in anhydrous tetrahydrofuran (1000 mL), and sodium borohydride (600 mg, 16.0 mmol) was added portionwise at room temperature, and methanol (1 mL) was added, and the mixture was stirred at room temperature for 10 min under nitrogen atmosphere. Thereafter, the temperature was raised to a reflux state, and stirred under reflux for 6 hours.
  • the reaction solution was cooled to room temperature, concentrated under reduced Celite, and then evaporated and evaporated. Extract with ethyl acetate (400 mL x 3), combine the organic phases, sequentially with water (200 mL x 2), saturated sodium chloride solution (100 The residue was washed with aq. EtOAc (EtOAc) (EtOAc) 75%.
  • Example 42 was isolated via SFC preparation to give the chiral pure Example 43 and Example 44.
  • This embodiment was prepared as described in Examples 42, 43 and 44.
  • This embodiment was prepared as described in Examples 42, 43 and 44.
  • This embodiment was prepared as described in Examples 42, 43, 44.
  • This embodiment was prepared as described in Examples 42, 43, 44.
  • This embodiment was prepared as described in Examples 42, 43, 44.
  • Example 36-6 (200 mg, 0.398 mmol) was dissolved in anhydrous pyridine (5 mL). After the completion of the addition, the mixture was stirred under nitrogen for 2 hours, and then cyclopropylsulfonyl chloride (56 mg, 0.477 mmol) was added, and stirring was continued for 2 hours under nitrogen atmosphere.
  • TLC (petroleum ether: ethyl acetate; 1:1) showed the disappearance of the starting material, the reaction mixture was poured into a saturated sodium hydrogen carbonate solution (15 mL), and extracted with dichloromethane (20 mL x 3).
  • Example 61 The diastereomer was isolated via SFC to give the chiral pure Example 61, and Example 62.
  • This embodiment was prepared as described in Examples 61, 62.
  • Example 69 was prepared as described in Example 1.
  • Example 70 was prepared as described in Example 1.
  • Example 71 was prepared as described in Example 1.
  • Example 72 was prepared as described in Example 1.
  • Example 73 was prepared as described in Example 1.
  • Example 74 was prepared as described in Example 1.
  • Example 76 was prepared as described in Example 1.
  • Example 77 was prepared as described in Example 1.
  • Example 78 was prepared as described in Example 1.
  • Example 79 was prepared as described in Example 1.
  • Example 81 was prepared as described in Example 80.
  • Example 83 was obtained as in Example 82-8.
  • Example 84 was obtained as in Example 82.
  • Example 85 was obtained as in Example 82.
  • Example 86 was obtained as in Example 82.
  • Example 87 was obtained as in Example 82.
  • Example 88 was obtained as in Example 82.
  • Example 89 was obtained as in Example 82.
  • Example 90 was obtained as in Example 82.
  • Example 91 was obtained as in Example 82.
  • Example 92 was obtained as in Example 82.
  • Example 93 was obtained as in Example 82.
  • Example 96 was obtained as in Example 95.
  • Example 97 was obtained as in Example 95.
  • Example 98 was obtained as in Example 95.
  • Example 99 was obtained as in Example 95.
  • Example 100 was obtained as in Example 94.
  • Example 101 was obtained as in Example 95.
  • Example 102 was obtained as in Example 94.
  • Example 103 was obtained as in Example 95.
  • Example 105 The second, third steps of Example 105 were prepared in the same manner as in Example 104.
  • This example was prepared in the same manner as in Example 104.
  • This example was prepared as described in Example 107.
  • the first step (synthesis of 113-3)
  • the compound 113-3 (1.76 g, 3.02 mmol, 1.0 eq) was dissolved in anhydrous THF (50 mL), and sodium borohydride (571 mg, 15.1 mmol, 5.0 eq) was added portionwise at 0 ° C. Stir at 60 ° C for 18 hours. The reaction solution was cooled to room temperature and quenched with water (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated. 39%.
  • the first step (synthesis of 115-3)
  • the first step (synthesis of 119-2)
  • Examples 121, 122 The synthesis of Examples 121, 122 is the same as in Examples 119, 120.
  • the first step (synthesis of 123)
  • Example 127 The synthesis of Example 127 was the same as that of Example 123.
  • the first step (synthesis of 134-3)

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Abstract

本发明公开了作为HBV抑制剂的二氢嘧啶并环衍生物，具体涉及式(I)所示化合物或其药学上可接受的盐。

Description

作为HBV抑制剂的二氢嘧啶并环衍生物 技术领域
本发明涉及作为HBV抑制剂的二氢嘧啶并环衍生物，具体涉及式(I)所示化合物或其药学上可接受的盐。
背景技术
乙型肝炎病毒属于肝病毒科。它可引起急性的和或持续/渐进的慢性病。乙型肝炎病毒还引起病理形态中的许多其他的临床表征一尤其是肝脏的慢性炎症、肝硬化和肝细胞的癌变。另外，与丁型肝炎的共同感染在疾病的发展过程中会产生不利影响。
被许可用于治疗慢性肝炎治疗的常规药剂是干扰素和拉米夫定(Iamivudine)。然而，干扰素只具有中等的活性，并具有较高的毒副反应；虽然拉米夫定(Iamivudine)具有良好的活性，但其耐药性在治疗过程中增幅迅速，并在停止治疗之后常常出现反弹效应，拉米夫定(3-TC)>的IC5tl值为300nM(Science，299(2003)，893-896)。
Deres等报道了以Bay41_4109、Bay39_5493为代表的杂芳环取代的二氢嘧啶类(HAP)化合物，该类化合物能够通过阻止正常核衣壳的形成起到抑制HBV复制的作用。Bay41-4109在临床研究中表现了较好的药物代谢参数(Science，299(2003)，893-896)。对其作用机制的研究发现，杂芳环取代的二氢嘧啶类化合物通过与核心蛋白的113-143氨基酸残基作用，改变了形成核衣壳的二聚体之间的夹角，导致形成不稳定的膨胀核衣壳，加速核心蛋白的降解(Biochem.Pharmacol.66(2003)，2273-2279)。
Figure PCTCN2015079870-appb-000001
目前仍然需要有新的能够有效地用作抗病毒药物的化合物，尤其是用作治疗和/或预防乙型肝炎的药物。
发明内容
本发明的目的在于提供式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2015079870-appb-000002
其中，
D11-14中的0～2个分别独立地选自单键、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-S(＝O)N(Rd7)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-或-S(＝O)2-，其余选自-C(Rd1)(Rd2)-；
L选自单键、-O-、-S-、-NH-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(＝O)N(Rd3)-、-N(Rd4)-、-[C(Rd1)(Rd2)]0～ 6；
R2选自
Figure PCTCN2015079870-appb-000003
D21选自单键、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-S(＝O)N(Rd7)-、-O-、-S-、-[C(Rd1)(Rd2)]0～6；
R3、R4分别独立地选自任选被R01取代的：C1-10烷基或杂烷基、3～6元环烷基或杂环烷基、6～10元芳环基或杂芳环基；
R3’、R21、Rd1-8分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、-COOH，或选自任选被R01取代的：C1-4烷基、-C0-4烷基苯基、-C0-4烷基-3～6元杂环基、3～6元杂环基酰基-、苯磺酰氨基或杂苯磺酰氨基、-D01-D02-D03-H、
Figure PCTCN2015079870-appb-000004
D01选自单键、-C1-4烷基-；
D02选自O、S、NH、-C(＝O)-、-S(＝O)2-、-C(＝O)O-、-C(＝O)NH-、-C(＝S)NH-、-S(＝O)2NH-、-S(＝O)NH-、-NHC(＝O)O-、-NHC(＝O)NH-、-NHS(＝O)2NH-、-C(＝O)NHS(＝O)2-、-NHS(＝O)NH-、-C(＝O)NHS(＝O)-、-NHS(＝O)2O-、-NHS(＝O)O-、-C(＝N)-、-NH-C(＝N)-；
D03选自单键、-C1-4烷基-、-C2-4烯基-、-C3-6环烷基-、-3～6元杂环烷基-、5～6元芳基、5～6元杂芳基；任选地，R3与R3’共同连接到同一个碳原子或杂原子上形成一个任选被取代的3～12元环；
“杂”表示杂原子或杂原子团，选自-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-S(＝O)N(Rd7)-、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O)2-或/和-P(＝O)(ORd8)2；
R01选自F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH、＝NH、＝O、＝S、或任选被R001取代的：C1-10烷基、C1-10烷氨基、N,N-二(C1-10烷基)氨基、C1-10烷氧基、C1-10烷酰基、C1-10烷氧羰基、-C1-5烷基-C(＝O)O-C1-5烷基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、3～10元环烷基、3～10元环烷氨基、3～10元杂环烷氨基、3～10元环烷氧基、3～10元环烷基酰基、3～10元环烷氧羰基、3～10元环烷基磺酰基、3～10元环烷基亚磺酰基；
R001选自F、Cl、Br、I、CN、OH、N(CH3)2、NH(CH3)、NH2、CHO、COOH、＝NH、＝O、＝S、三卤代甲基、二卤代甲基、一卤代甲基、氨甲基、羟甲基、甲基、甲氧基、甲酰基、甲氧羰基、甲磺酰基、甲基亚磺酰基；
在上述任意一种情况下，R01、R001的数目分别独立地选自0、1、2或3，杂原子或杂原子团的数目分别独立地选自1、2或3。
本发明的一些方案中，上述的化合物或其药学上可接受的盐，其具有式(Ⅱ)所示结构：
Figure PCTCN2015079870-appb-000005
其中，R31-32分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、-COOH，或选自任选被1、2或3个R01取代的：C1-4烷基、-C0-4烷基苯基、-C0-4烷基-3～6元杂环基、3～6元杂环基酰基-、苯磺酰氨基或杂苯磺酰氨基、-D01-D02-D03-H、
Figure PCTCN2015079870-appb-000006
D01选自单键、-C1-4烷基-；
D02选自O、S、NH、-C(＝O)-、-S(＝O)2-、-C(＝O)O-、-C(＝O)NH-、-C(＝S)NH-、-S(＝O)2NH-、-S(＝O)NH-、-NHC(＝O)O-、-NHC(＝O)NH-、-NHS(＝O)2NH-、-C(＝O)NHS(＝O)2-、-NHS(＝O)NH-、-C(＝O)NHS(＝O)-、-NHS(＝O)2O-、-NHS(＝O)O-、-C(＝N)-、-NH-C(＝N)-；
D03选自单键、-C1-4烷基-、-C2-4烯基-、-C3-6环烷基-、-3～6元杂环烷基-、5～6元芳基、5～6元杂芳基；m、n分别独立地选自1或2；
Figure PCTCN2015079870-appb-000007
表示单键或双键。
本发明的一些方案中，上述-D03-H选自：H、Me、Et、
Figure PCTCN2015079870-appb-000008
Figure PCTCN2015079870-appb-000009
本发明的一些方案中，R01选自卤素、CN、＝NH、＝O、＝S、COOH，或任选被1、2或3个R001取代的羟基、氨基、C1-4烷基、C1-4烷氧基、C0-4烷基-C(＝O)O-C1-4烷基；
具体地，R01选自F、Cl、Br、I、OH、CN、NH2、＝NH、＝O、＝S、-SMe、Me、Et、
Figure PCTCN2015079870-appb-000010
Figure PCTCN2015079870-appb-000011
本发明的一些方案中，上述R3’、R21、Rd1-d8、R31-32分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、-COOH，或选自任选被1、2或3个R01取代的CH3、
Figure PCTCN2015079870-appb-000012
Figure PCTCN2015079870-appb-000013
本发明的一些方案中，上述R3’、R21、Rd1-d8、R31-32分别独立地选自：H、F、Cl、Br、I、OH、NH2、 CN、-COOH、CH3、
Figure PCTCN2015079870-appb-000014
Figure PCTCN2015079870-appb-000015
Figure PCTCN2015079870-appb-000016
本发明的一些方案中，结构单元
Figure PCTCN2015079870-appb-000017
选自：
Figure PCTCN2015079870-appb-000018
Figure PCTCN2015079870-appb-000019
Figure PCTCN2015079870-appb-000020
Figure PCTCN2015079870-appb-000021
Figure PCTCN2015079870-appb-000022
Figure PCTCN2015079870-appb-000023
Figure PCTCN2015079870-appb-000024
本发明的一些方案中，上述结构单元
Figure PCTCN2015079870-appb-000025
选自：
Figure PCTCN2015079870-appb-000026
Figure PCTCN2015079870-appb-000027
Figure PCTCN2015079870-appb-000028
Figure PCTCN2015079870-appb-000030
Figure PCTCN2015079870-appb-000031
Figure PCTCN2015079870-appb-000032
Figure PCTCN2015079870-appb-000033
Figure PCTCN2015079870-appb-000034
Figure PCTCN2015079870-appb-000035
本发明的一些方案中，上述L、D21选自单键、-O-、-NH-；或R21选自C1-4烷基、C1-4烷氨基、N,N-二(C1-4烷基)氨基、C1-4烷氨基-C1-4烷基-、N,N-二(C1-4烷基)氨基-C1-4烷基-、C1-4烷氧基、C1-4烷氧基-C1-4烷基-、卤代C1-4烷基-、二卤代C1-4烷基-、氨氧基C1-4烷基-、羟代C1-4烷基氧基-、羟代C1-3烷基氨基-。
本发明的一些方案中，上述R21选自甲基、乙基、正丙基、异丙基、甲氨基、乙氨基、丙氨基、二甲氨基、二乙基氨基、二丙基氨基、甲氨基乙基、乙氨基乙基、丙氨基乙基、二甲基氨基乙基、二乙基氨基甲基、二甲基氨基甲基、二乙基氨基乙基、甲氧甲基、甲氧乙基、甲氧丙基、乙氧基甲基、丙氧基甲基、乙氧基乙基、丙氧基丙基、氟甲基、氟乙基、氟丙基、二氟甲基、二氟乙基、二氟丙基、氨氧基甲基、氨氧基乙基、氨氧基丙基、羟甲基氧基、羟乙基氧基、羟丙基氧基。
本发明的一些方案中，上述结构单元
Figure PCTCN2015079870-appb-000036
选自
Figure PCTCN2015079870-appb-000037
Figure PCTCN2015079870-appb-000038
本发明的一些方案中，上述结构单元
Figure PCTCN2015079870-appb-000039
选自
Figure PCTCN2015079870-appb-000040
本发明的一些方案中，上述R3或R4分别独立地选自任选被1、2或3个R001取代的：苯基、吡啶基、喹啉基、异喹啉基、噻唑基、噻吩基、恶唑基、异恶唑基、吡唑基、异噻唑、呋喃基、吡咯基、吡咯烷基、1，3-氧五环基、2-吡唑啉基、吡唑烷基、咪唑基、1,2,3-唑基、1,2,3-三唑基、1,2,4-三唑基、1,3,4-噻二唑基、哌啶基、1,4-二氧六环基、吗啉基、哌嗪基、哌啶基、嘧啶基、吡嗪基、1,3,5-三噻烷基、1,3,5-三嗪基、茚基、萘基、苯并呋喃基、苯并噻吩基、吲哚基、苯并咪唑基、苯并噻唑基、苯并戊烷基、环丙基；
或者结构单元
Figure PCTCN2015079870-appb-000041
选自任选被1、2或3个R001取代的苯并戊烷基、茚基；
R001如上所定义。
本发明的一些方案中，R3选自
Figure PCTCN2015079870-appb-000042
Figure PCTCN2015079870-appb-000043
本发明的一些方案中，R4选自
Figure PCTCN2015079870-appb-000044
Figure PCTCN2015079870-appb-000045
本发明的一些方案中，上述结构单元
Figure PCTCN2015079870-appb-000046
选自：
Figure PCTCN2015079870-appb-000047
Figure PCTCN2015079870-appb-000048
具体地，本发明化合物选自：
Figure PCTCN2015079870-appb-000049
Figure PCTCN2015079870-appb-000050
Figure PCTCN2015079870-appb-000051
Figure PCTCN2015079870-appb-000052
Figure PCTCN2015079870-appb-000053
Figure PCTCN2015079870-appb-000054
Figure PCTCN2015079870-appb-000055
Figure PCTCN2015079870-appb-000056
Figure PCTCN2015079870-appb-000057
Figure PCTCN2015079870-appb-000058
Figure PCTCN2015079870-appb-000059
Figure PCTCN2015079870-appb-000060
Figure PCTCN2015079870-appb-000061
Figure PCTCN2015079870-appb-000062
Figure PCTCN2015079870-appb-000063
Figure PCTCN2015079870-appb-000064
有关定义：
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。
C1-12选自C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11和C12；C3-12选自C3、C4、C5、C6、C7、C8、C9、C10、C11和C12。
C1-12烷基或杂烷基、C3-12环基或杂环烃基、被C3-12环烃基或杂环烃基取代的C1-12烷基或杂烷基包括但不限于：
C1-12烷基、C1-12烷氨基、N,N-二(C1-12烷基)氨基、C1-12烷氧基、C1-12烷酰基、C1-12烷氧羰基、C1-12烷基磺酰基、C1-12烷基亚磺酰基、C3-12环烷基、C3-12环烷氨基、C3-12杂环烷氨基、C3-12环烷氧基、C3-12环烷基酰基、C3-12环烷基氧羰基、C3-12环烷基磺酰基、C3-12环烷基亚磺酰基、5～12元芳基或杂芳基、5～12元芳烷基或杂芳烷基；
甲基、乙基、正丙基、异丙基、-CH2C(CH3)(CH3)(OH)、环丙基、环丁基、丙基亚甲基、环丙酰基、苄氧基、三氟甲基、氨甲基、羟甲基、甲氧基、甲酰基、甲氧羰基、甲磺酰基、甲基亚磺酰基、乙氧基、乙酰基、乙磺酰基、乙氧羰基、二甲基氨基、二乙基氨基、二甲基氨基羰基、二乙基氨基羰基；
N(CH3)2,NH(CH3),-CH2CF3,-CH2CH2CF3,-CH2CH2F,-CH2CH2S(＝O)2CH3,-CH2CH2CN,-CH2CH(OH)(CH3)2,-CH2CH(F)(CH3)2,-CH2CH2F,-CH2CF3,-CH2CH2CF3,-CH2CH2NH2,-CH2CH2OH,-CH2CH2OCH3,-CH2CH2CH2OCH3,-CH2CH2N(CH3)2,-S(＝O)2CH3,-CH2CH2S(＝O)2CH3,；和
苯基、噻唑基、联苯基、萘基、环戊基、呋喃基、3-吡咯啉基、吡咯烷基、1,3-氧五环基、吡唑基、2-吡唑啉基、吡唑烷基、咪唑基、恶唑基、噻唑基、1,2,3-唑基、1,2,3-三唑基、1,2,4-三唑基、1,3,4-噻二唑基、4H-吡喃基、吡啶基、哌啶基、1,4-二氧六环基、吗啉基、哒嗪基、嘧啶基、吡嗪基、哌嗪基、1,3,5-三噻烷基、1,3,5-三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、苯并咪唑基、苯并噻唑基、嘌呤基、喹啉基、异喹啉基、噌啉基或喹喔啉基；
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(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。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。
优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐，例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸。
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。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
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。本发明的某些化合物可以以多晶或无定形形式存在。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
本文中消旋体、ambiscalemic and scalemic或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。1985年，62：114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括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。
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分步结晶法或色谱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)。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。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
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，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。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮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。
当一个取代基的键可以交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。当所列举的取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时，这种取代基可以通过其任何原子相键合。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。例如，结构单元
Figure PCTCN2015079870-appb-000065
表示其可在环己基或者环己二烯上的任意一个位置发生取代。
烷基和杂烷基原子团的取代基一般被称为“烷基取代基”，它们可以选自但不限于下列基团中的一个或多个：-R’、-OR’、＝O、＝NR’、＝N-OR’、-NR’R”、-SR’、卤素、-SiR’R”R”’、OC(O)R’、-C(O)R’、-CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、NR’C(O)NR”R”’、-NR”C(O)2R’、-NR””’-C(NR’R”R”’)＝NR””、NR””C(NR’R”)＝NR”’、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、NR”SO2R’、-CN、–NO2、-N3、-CH(Ph)2和氟代(C1-C4)烷基,取代基的数目为0～(2m’+1),其中m’是这类原子团中碳原子的总数。R'、R”、R”'、R””和R””’各自独立地优选氢、被取代或未被取代的杂烷基、被取代或未被取代的芳基(例如被1～3个卤素取代芳基)、被取代或未被取代的烷基、烷氧基、硫代烷氧基基团或芳烷基。当本发明的化合物包括一个以上的R基团时，例如，每一个R基团是独立地加以选择的，如同当存在一个以上的R'、R”、R”'、R””和R””’基团时的每个这些基团。当R'和R”附着于同一个氮原子时，它们可与该氮原子结合形成5-，6-或7-元环。例如，-NR'R“意在包括但不仅限于1-吡咯烷基和4-吗啉基。根据上述关于取代基的讨论中，本领域技术人员可以理解，术语“烷基”意在包括碳原子键合于非氢基团所构成的基团，如卤代烷基(例如-CF3、-CH2CF3)和酰基(例如-C(O)CH3、-C(O)CF3、-C(O)CH2OCH3等)。
与烷基原子团所述取代基相似，芳基和杂芳基取代基一般统称为“芳基取代基”，选自例如-R’、-OR’、-NR’R”、-SR’、-卤素,-SiR’R”R”’、OC(O)R’、-C(O)R’、-CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、NR’C(O)NR”R”’、-NR”C(O)2R’、-NR””’-C(NR’R”R”’)＝NR””、NR””C(NR’R”)＝NR”’、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、NR”SO2R’、-CN、–NO2、-N3、-CH(Ph)2、氟(C1-C4)烷氧基和氟(C1-C4)烷基等，取代基的数量为0到芳香环上开放化合价的总数之间；其中R’、R”、R”’、R””和R””’独立地优选自氢、被取代或未被取代的烷基、被取代或未被取代的杂烷基、被取代或未被取代的芳基和被取代或未被取代的杂芳基。当本发明的化合物包括一个以上的R基团时，例如，每个R基团是独立地加以选择的，如同当存在一个以上R’、R”、R”’、R””和R””’基团时的每个这些基团。
芳基或杂芳基环的相邻原子上的两个取代基可以任选地被通式为–T-C(O)-(CRR’)q-U-的取代基所取代，其中T和U独立地选自-NR-、-O-、CRR'-或单键，q是0到3的整数。作为替代选择，芳基或杂芳基环的相邻原子上的两个取代基可以任选地被通式为–A(CH2)r B-的取代基所取代，其中A和B独立的选自–CRR’-、-O-、-NR-、-S-、-S(O)-、S(O)2-、-S(O)2NR’-或单键，r是1～4的整数。任选地，由此形成的新环上的一个单键可以替换为双键。作为替代选择，芳基或杂芳基环的相邻原子上的两个取代基可以任选地被通式为–A(CH2)r B-的取代基所取代，其中s和d分别独立的选自0～3的整数，X是–O-、-NR’、-S-、-S(O)-、-S(O)2-或–S(O)2NR’-。取代基R、R’、R”和R”’分别独立地优选自氢和被取代或未被取代的(C1-C6)烷基。
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(C1-C4)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。
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。C1-6烷氧基包括C1、C2、C3、C4、C5和C6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。“环烷基”包括饱和环基，如环丙基、环丁基或环戊基。3-7环烷基包括C3、C4、C5、C6和C7环烷基。“链烯基”包括直链或支链构型的烃链，其中该链上任何的稳定位点上存在一个或多个碳-碳双键，例如乙烯基和丙烯基。
术语“卤”或“卤素”是指氟、氯、溴和碘。
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)。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)。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、isatino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、噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基。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、苯基等等)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、单元或多元不饱和的，可以是单取代、二取代或多取代的，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C1-C10表示1至10个碳)。“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“烷基”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。不饱和烷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稳定的直链的、支链的或环状的烃原子团或其组合，有一定数目的碳原子和至少一个杂原子组成。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稳定的直链的、支链的烃原子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。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(包括该烃基附着于分子其余部分的位置)。实例包括但不限于-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH＝CH-O-CH3、-CH2-CH＝N-OCH3和–CH＝CH-N(CH3)-CH3。至多两个杂原子可以是连续的，例如-CH2-NH-OCH3。
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。
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。环烷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“芳基”表示多不饱和的芳族烃取代基，可以是单取代、二取代或多取代的，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、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。
为简便起见，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；NaCNBH3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；Boc2O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；SOCl2代表氯化亚砜；CS2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-Bu4NF代表氟化四丁基铵；iPrOH代表2-丙醇；NBS代表1-溴吡咯烷-2,5-二酮；AIBN代表偶氮二异丁腈；BTC代表三光气；mp代表熔点。
化合物经手工或者
Figure PCTCN2015079870-appb-000066
软件命名，市售化合物采用供应商目录名称。
具体实施例目标化合物及其对HBV DNA的抑制作用结论：
生物活性定义：A：EC50≤100nM；B:100nM＜EC50≤500nM；C:500nM＜EC50≤1000nM；D:1000nM＜EC50≤5000nM；
结论：本发明化合物对HBV DNA的抑制作用显著。
实施例目标化合物其对HBV DNA的抑制作用列表(生物活性同表2)
Figure PCTCN2015079870-appb-000067
Figure PCTCN2015079870-appb-000068
Figure PCTCN2015079870-appb-000069
Figure PCTCN2015079870-appb-000070
Figure PCTCN2015079870-appb-000071
Figure PCTCN2015079870-appb-000072
Figure PCTCN2015079870-appb-000073
Figure PCTCN2015079870-appb-000074
Figure PCTCN2015079870-appb-000075
Figure PCTCN2015079870-appb-000076
Figure PCTCN2015079870-appb-000077
Figure PCTCN2015079870-appb-000078
Figure PCTCN2015079870-appb-000079
Figure PCTCN2015079870-appb-000080
Figure PCTCN2015079870-appb-000081
Figure PCTCN2015079870-appb-000082
Figure PCTCN2015079870-appb-000083
Figure PCTCN2015079870-appb-000084
Figure PCTCN2015079870-appb-000085
Figure PCTCN2015079870-appb-000086
Figure PCTCN2015079870-appb-000087
Figure PCTCN2015079870-appb-000088
Figure PCTCN2015079870-appb-000089
Figure PCTCN2015079870-appb-000090
Figure PCTCN2015079870-appb-000091
Figure PCTCN2015079870-appb-000092
Figure PCTCN2015079870-appb-000093
Figure PCTCN2015079870-appb-000094
Figure PCTCN2015079870-appb-000095
Figure PCTCN2015079870-appb-000096
Figure PCTCN2015079870-appb-000097
Figure PCTCN2015079870-appb-000098
Figure PCTCN2015079870-appb-000099
Figure PCTCN2015079870-appb-000100
Figure PCTCN2015079870-appb-000101
Figure PCTCN2015079870-appb-000102
Figure PCTCN2015079870-appb-000103
Figure PCTCN2015079870-appb-000104
Figure PCTCN2015079870-appb-000106
Figure PCTCN2015079870-appb-000107
Figure PCTCN2015079870-appb-000108
Figure PCTCN2015079870-appb-000109
Figure PCTCN2015079870-appb-000110
Figure PCTCN2015079870-appb-000111
Figure PCTCN2015079870-appb-000112
Figure PCTCN2015079870-appb-000113
Figure PCTCN2015079870-appb-000114
Figure PCTCN2015079870-appb-000115
具体实施方式
为了更详细地说明本发明，给出下列实例，但本发明的范围并非限定于此。
实施例1，2
Figure PCTCN2015079870-appb-000116
Figure PCTCN2015079870-appb-000117
第一步(化合物1-2的合成)
将化合物1-1(12.5g,100mmol)溶于甲醇(30mL)中，在室温下加入THP(12.6g,150mmol)，p-TsOH(250mg,1.3mmol)，在室温下搅拌过夜。将反应液减压浓缩后用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝30:1)纯化，得到产物1-2，产率：80％。
1H NMR(400MHz,CDCl3)δ:4.68(t,J＝3.6Hz,1H),4.03(td,J＝6.4,11.2Hz,1H),3.90(ddd,J＝3.0,8.4,11.2Hz,1H),3.73-3.82(m,1H),3.45-3.58(m,3H),1.80-1.91(m,1H),1.70-1.79(m,1H),1.51-1.63(m,4H).
第二步(化合物1-4的合成)
将氢化钠(4.0g,100mmol)溶于无水四氢呋喃(30mL)中，在-40℃加入1-3(9.4g,72mmol)，在-20℃下搅拌30分钟。保持温度不变，慢慢滴加正丁基锂(40mL，2.5N)溶液，滴加结束后在0℃下搅拌30分钟。将化合物1-2(10g,48mmol)，溶于四氢呋喃(100mL)中，并将该溶液慢慢滴加到反应液中。反应液在0℃下搅拌2小时，并将温度升至室温搅拌过夜。将反应液用的饱和氯化铵水溶液(1000mL)淬灭，用乙酸乙酯(1000mL x 3)萃取，有机层用饱和食盐水溶液(1000mL x 2)洗涤，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝20:1)纯化得到7.0g的产物1-4，产率：56％。
1H NMR(400MHz,CDCl3)δ:4.50-4.61(m,1H),4.20(q,J＝7.2Hz,2H),3.69-3.89(m,2H),3.32-3.57(m,4H),2.58-2.75(m,2H),1.91(q,J＝6.4Hz,2H),1.75-1.84(m,1H),1.63-1.75(m,2H),1.51-1.57(m,3H),1.23-1.33(m,3H).
第三步(化合物1-7的合成)
将化合物1-4(4.3g,27mmol)溶于乙醇(20mL)，加入化合物1-5(7.0g,27mmol)，化合物1-6(8.8g,54mmol)，醋酸钠(6.6g,81mmol)。反应液温度慢慢升至回流，回流下将反应搅拌过夜。将反应液减压浓缩后用乙酸乙酯(500mLx3)萃取，有机层用饱和食盐水溶液(1000mL x 2)洗涤，合 并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，所得到5.0g的产物1-7(黄色固体)，产率：61％。
LCMS(ESI)m/z:508.0[M+H+].
第四步(化合物1-8的合成)
将化合物1-7(5.0g,10mmol)溶于乙醇(250mL)中，在室温下，加入p-TsOH(5.5g,30mmol)，并在室温下搅拌30min。将反应液用饱和的碳酸氢钠水溶液(200mL)调制中性，用乙酸乙酯萃取(500mL x 3)，有机相用水(300mL x 3)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗产物5.5g化合物1-8，产率：85％。
LCMS(ESI)m/z:423.9[M+H+].
第五步(实施例1的合成)
将化合物1-8(5.5g,13mmol)溶于无水二氯甲烷(5mL)中，在0℃下，加入三乙胺(6.5g,65mmol)，甲磺酰氯(7.4g,39mmol)，加料结束，升至室温搅拌3小时。反应液倒入300mL水中，用二氯甲烷(500mL x 3)萃取，合并有机相，依次用水(50mL x 2)、饱和氯化钠溶液(100mL x 2)洗涤，无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到2.0g实施例1，产率：47％。
实施例1的核磁数据：1H NMR(400MHz,CDCl3)δ:7.81(d,J＝3.2Hz,1H),7.37(d,J＝3.2Hz,1H),7.28-7.32(m,1H),7.12(dd,J＝2.4,8.4Hz,1H),6.92(dt,J＝2.4,8.4Hz,1H),6.19(s,1H),4.20-4.45(m,2H),4.01-4.11(m,2H),3.40(ddd,J＝3.6,8.4,18.0Hz,1H),3.06(td,J＝9.2,18.0Hz,1H),1.93-2.29(m,2H),1.14(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:405.9[M+H+].
第六步(化合物2-1的合成)
将化合物1(800mg,1.96mmol)溶于的四氯化碳(20mL)中，室温下加入NBS(528mg,3.0mmol)和AIBN(3.2mg,0.02mmol)，加完后，室温搅拌3小时。将反应液加压浓缩，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化所得到400mg产物2-1，产率：42％。
1H NMR(400MHz,CDCl3)δ:7.77-7.88(m,1H),7.34-7.48(m,2H),7.08-7.18(m,1H),6.87-7.00(m,1H),6.17-6.25(m,1H),6.00-6.08(m,1H),4.99-5.12(m,1H),4.19-4.32(m,1H),4.02-4.17(m,2H),2.37-2.47(m,2H),1.08-1.18(m,3H).
第七步(实施例2的合成)
将化合物2-1(150mg,0.3mmol)溶于乙醇(5mL)中，在室温下，加入化合物2-2(69mg,0.9mmol)，碳酸钾(123mg,0.9mmol)，加料结束，升至60℃搅拌3小时。将反应液过滤，滤液减压浓缩用二氯甲烷(50mL x 3)萃取，合并有机相，依次用水(50mL x 2)、饱和氯化钠溶液(100mL x 2)洗涤，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到47mg实施例2，产率：33％。
实施例2的核磁数据：1H NMR(400MHz,DMSO-d6)δ:7.81(d,J＝3.2Hz,1H),7.38(d,J＝3.2Hz,1H),7.26-7.31(m,1H),7.13(dd,J＝2.4,8.4Hz,1H),6.93(dt,J＝2.4,8.4Hz,1H),6.29(s,1H),4.92(br.s.,1H),4.38(d,J＝9.2Hz,2H),4.04(q,J＝7.2Hz,2H),3.54-3.79(m,2H),3.28-3.35(m,1H),2.52-2.58(m,2H),2.74(br.s.,1H),2.31(s.,3H),2.01(s,1H),1.02-1.12(m,3H).
LCMS(ESI)m/z:479.0[M+H+].
实施例3
Figure PCTCN2015079870-appb-000118
第一步(化合物3-1的合成)
将化合物2-1(150mg,0.31mmol)溶于N,N-二甲基甲酰胺(3mL)中，加入氰化钠(54mg,2.2mmol)，室温搅拌3小时。将反应液用乙酸乙酯(10mL x 3)萃取，合并有机相，依次用水(10mL x 2)、饱和氯化钠溶液(10mL x 3)洗涤，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到产物50mg化合物3-1，产率：37％。
LCMS(ESI)m/z:430.9[M+H+].
第二步(实施例3的合成)
将化合物3-1(50mg,0.11mmol)溶于无水乙醇(0.8mL)中，加入DMSO(0.2mL)，氢氧化钠溶液(0.1mL，5N)，双氧水(0.1mL)，在室温下搅拌3小时。将反应液减压浓缩后用二氯甲烷(30mL x 3)萃取，合并有机相，依次用水(20mL x 2)、饱和氯化钠溶液(20mL x 2)洗涤，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到10mg实施例3，产率：19％。
实施例3的核磁数据：1H NMR(400MHz,CDCl3)δ:7.83(d,J＝3.2Hz,1H),7.45(br.s.,1H),7.38(d,J＝3.2Hz,1H),7.30(d,J＝6.4Hz,1H),7.16(dd,J＝2.4,8.4Hz,1H),6.95(dt,J＝2.4,8.4Hz,1H),6.21(s,1H),5.34(br.s.,1H),4.61(d,J＝7.6Hz,1H),4.51-4.59(m,1H),4.34-4.44(m,1H),4.00-4.17(m,2H),2.72(dd,J＝6.0,12.4Hz,1H),2.09-2.23(m,1H),1.12(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:449.1[M+H+].
实施例4
Figure PCTCN2015079870-appb-000119
实施例4如实施例1中描述的方法制备。
实施例4的核磁数据：1H NMR(400MHz,CDCl3)δ:7.79(d,J＝3.2Hz,1H),7.35(d,J＝3.2Hz,1H),7.30(dd,J＝2.8,8.4Hz,1H),7.26(d,J＝6.4Hz,1H),6.95(dt,J＝2.8,8.4Hz,1H),6.15(s,1H),4.19-4.43(m,2H),3.97-4.10(m,2H),3.40(ddd,J＝3.6,8.4,18.0Hz,1H),3.06(td,J＝9.2,18.0Hz,1H),1.97-2.21(m,2H),1.13(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:449.9[M+H+].
实施例5
Figure PCTCN2015079870-appb-000120
实施例5如实施例1中描述的方法制备，通过SFC制备分离得到。
实施例5的核磁数据：1H NMR(400MHz,DMSO-d6)δ:7.79(d,J＝3.2Hz,1H),7.35(d,J＝3.2Hz,1H),7.30(dd,J＝2.8,8.4Hz,1H),7.26(d,J＝6.0Hz,1H),6.95(dt,J＝2.8,8.4Hz,1H),6.15(s,1H),4.19-4.43(m,2H),3.97-4.10(m,2H),3.40(ddd,J＝3.6,8.4,18.0Hz,1H),3.06(td,J＝9.2,18.4Hz,1H),1.97-2.21(m,2H),1.13(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:449.9[M+H+].
实施例6，7
Figure PCTCN2015079870-appb-000121
Figure PCTCN2015079870-appb-000122
第一步(化合物1-6的合成)
将化合物6-1(6.0g,54.5mmol)溶于甲醇(20mL)中，在室温下，分批加入甲醇钠(2.9g,54.5mmol)，在室温下，搅拌3小时。将氯化铵(11.7g,218mmol)分批加入到反应液中，加料完毕，温度慢慢升至回流，回流下将反应搅拌过夜。将反应液冷却至室温，减压浓缩得到产品1-6为白色固体，产物不经纯化直接进行下一步反应，产率：80％。
LCMS(ESI)m/z:128.2[M+H+].
第二步(化合物6-4的合成)
将化合物1-6(2.0g,12.2mmol)溶于乙醇(50mL)中，加入化合物6-2(0.98mL,9.8mmol)，化合物6-3(2.0g,9.8mmol)，醋酸钠(1.0g,12.2mmol)。反应液温度慢慢升至回流，回流下搅拌过夜。将反应液减压浓缩后加入乙酸乙酯(100mL)，有机层用饱和食盐水溶液(100mL x 2)洗涤，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，并通过SFC分离，得到化合物6-4为黄色固体，产率：40％。
1H NMR(400MHz,CDCl3)δ:9.88(s,1H),7.95(d,J＝3.2Hz,1H),7.86(d,J＝3.2Hz,1H),7.53(dd,J＝2.4,8.4Hz,1H),7.34(dd,J＝6.4,8.8Hz,1H),7.22(dt,J＝2.4,8.4Hz,1H),5.95(s,1H),3.92(q,J＝7.2Hz,2H),2.45(s,3H),1.06-0.97(m,3H).
LCMS(ESI)m/z:425.8[M+H+].
第三步(化合物6-5的合成)
将化合物6-4(2.08g,4.9mmol)溶于四氯化碳(30mL)中，在室温下，加入NBS(920mg,5.2mmol)和AIBN(81mg,0.49mmol)，加料完毕，升到50℃，搅拌直至6-4完全反应完毕。将反应液冷却至室 温，加压浓缩，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到产物6-5为黄固体，产率：64％。
1H NMR(400MHz,CDCl3)δ:7.83(d,J＝3.2Hz,1H),7.52(d,J＝3.2Hz,2H),7.39(dd,J＝6.0,8.4Hz,1H),7.31(dd,J＝2.4,8.0Hz,1H),7.01(dt,J＝2.4,8.0Hz,1H),6.06(d,J＝2.4Hz,1H),4.92(d,J＝8.4Hz,1H),4.58(d,J＝8.4Hz,1H),4.10(q,J＝7.2Hz,2H),1.14(t,J＝7.2Hz,3H).
第四步(化合物6-7的合成)
将化合物6-6(1.27g,7.94mmol)溶于无水N’,N-二甲基甲酰胺(100mL)中，在室温下，分批加入氢化钠(238mg,5.96mmol)，并在室温下搅拌15分钟。加入化合物6-5(2.00g,3.97mmol)并在室温下搅拌3小时。将反应液用饱和的氯化铵水溶液(50mL)淬灭，用乙酸乙酯(100mL x 3)萃取，有机相用水(50mL x 3)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到1.76g化合物6-7，产率：76％。
LCMS(ESI)m/z:583.7[M+H+].
第五步(化合物6-8的合成)
将化合物6-7(1.76g,3.02mmol)溶于无水四氢呋喃(50mL)，在0℃慢慢加入硼氢化钠(571mg,15.1mmol),加完后温度升至60℃，在60℃反应18小时。反应液冷却至室温，用二氯甲烷(100mL x3)萃取，有机相用水(60mL x 3)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(二氯甲烷：甲醇＝20:1)纯化得到产物780mg化合物6-8，产率：39％。
LC/MS(ESI)m/z:521.7[M+Na+].
第六步(化合物6-9的合成)
将化合物6-8(780mg,1.57mmol)溶于无水二氯甲烷(40mL)中，在0℃下，加入三乙胺(318mg,3.14mmol)，甲磺酰氯(270mg,2.36mmol)，保持温度不变，搅拌2小时后，升至室温搅拌6小时。反应液倒入水(30mL)中，用二氯甲烷(30mL x 3)萃取，合并有机相，依次用水(10mL x 2)、饱和氯化钠溶液(10mL x 2)洗涤，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到产物340mg化合物6-9，产率：39％。
LCMS(ESI)m/z:481.8[M+H+].
第七步(化合物6,7的合成)
将化合物外6-9(340mg)经由SFC制备分离得到手性纯47mg实施例6，34mg实施例7。
实施例6的核磁数据：1H NMR(400MHz,CDCl3)δ:7.81(d,J＝3.2Hz,1H),7.38(d,J＝3.2Hz,1H),7.32(dd,J＝2.8,8.4Hz,1H),7.29(s,1H),6.96(dt,J＝2.8,8.4Hz,1H),6.16(s,1H),4.45(dd,J＝7.2,11.6Hz,1H),4.31(dd,J＝3.2,11.6Hz,1H),4.01-4.11(m,2H),3.73-3.80(m,1H),3.64-3.72(m,1H),3.23-3.29(m,2H),2.68(d,J＝3.2Hz,1H),1.67(t,J＝5.2Hz,1H),1.15(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:481.8[M+H+].
实施例7的核磁数据：1H NMR(400MHz,CDCl3)δ:7.81(d,J＝3.2Hz,1H),7.38(d,J＝3.2Hz,1H),7.33(dd,J＝2.8,8.4Hz,1H),7.25(s,1H),6.97(dt,J＝2.4,8.4Hz,1H),6.16(s,1H),4.43(dd,J＝7.6,11.2Hz,1H),4.23(dd,J＝7.6,11.2Hz,1H),4.00-4.10(m,2H),3.78-3.86(m,1H),3.72(br.s.,1H),3.47(dd,J＝8.0,18.0Hz,1H),2.95(dd,J＝8.4,18.0Hz,1H),2.63-2.74(m,1H),1.83(br.s.,1H),1.15(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:481.8[M+H+].
实施例8，9
Figure PCTCN2015079870-appb-000123
实施例8,9如实施例6，7中的描述方法制备由高效液相分离得到。
实施例8的核磁数据：1H NMR(400MHz,CDCl3)δ:7.81(d,J＝3.0Hz,1H),7.37(d,J＝3.0Hz,1H),7.29-7.34(m,1H),7.26(br.s.,1H),6.96(dt,J＝2.5,8.2Hz,1H),6.16(s,1H),4.45(dd,J＝7.2,11.5Hz,1H),4.31(dd,J＝2.,11.5Hz,1H),4.06(q,J＝6.6Hz,2H),3.62-3.81(m,2H),3.22-3.28(m,2H),2.61-2.73(m,1H),1.66(t,J＝5Hz,1H),1.15(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:479.8[M+H+].
实施例9的核磁数据：1H NMR(400MHz,CDCl3)δ:7.81(d,J＝3.0Hz,1H),7.38(d,J＝3.2Hz,1H),7.33(dd,J＝2.5,8.2Hz,1H),7.29(br.s.,1H),7.25(s,1H),6.94-7.01(m,1H),6.16(s,1H),4.42(dd,J＝7.5,11.0Hz,1H),4.23(dd,J＝7.8,11.29Hz,1H),4.01-4.10(m,2H),3.79-3.86(m,1H),3.68-3.77(m,1H),3.47(dd,J＝8.0,18.08Hz,1H),2.95(dd,J＝8.5,18.0Hz,1H),2.64-2.76(m,1H),1.11-1.18(m,3H).
LCMS(ESI)m/z:479.8[M+H+].
实施例10
Figure PCTCN2015079870-appb-000124
第一步(化合物10-2的合成)
将化合物10-1(合成方法与化合物6-8相同)(200mg,0.40mmol)溶于(5mL)无水二氯甲烷中，在室温下加入三乙胺(406mg,4.01mmol)，甲基磺酰氯(460mg,4.01mmol)，将反应液室温搅拌过夜。用(50mLx3)二氯甲烷萃取，合并有机相，依次用水(30mLx2)、饱和氯化钠溶液洗涤(30mLx2)，用无水硫酸钠干燥，过滤，减压浓缩得到150mg化合物10-2。
LCMS(ESI)m/z:557.6[M+H+].
第二步(实施例10的合成)
将化合物10-2(100mg,0.18mmol)溶于(3mL)无水甲醇中，在室温下加入甲醇钠(48mg,0.90mmol)，将反应液回流搅拌过夜。减压浓缩后用(50mLx3)二氯甲烷萃取，合并有机相，依次用水(30mLx2)、饱和氯化钠溶液洗涤(30mLx2)，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝3:1)纯化，得到6mg实施例10，产率：7％。
1H NMR(400MHz,CDCl3)δ:7.81(d,J＝3.0Hz,1H),7.37(d,J＝3.0Hz,1H),7.28-7.35(m,2H),6.96(dt,J＝2.5,8.2Hz,1H),6.14(s,1H),4.44-4.56(m,1H),4.22(dd,J＝2.5,11.5Hz,1H),3.62(s,3H),3.41-3.56(m,2H),3.40(s,3H),3.17-3.30(m,2H),2.72(br.s.,1H).
LCMS(ESI)m/z:479.8[M+H+].
实施例11,12
Figure PCTCN2015079870-appb-000125
将化合物10-2(30mg,0.05mmol)溶于(0.5mL)无水DMF中，加入氰化钠(4.0mg,0.08mmol)，将温度升高至80℃并在该温度下搅拌过夜。将反应液用(10mLx3)乙酸乙酯萃取，合并有机相，依次用水(10mLx2)、饱和氯化钠溶液洗涤(10mLx3)，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到12mg实施例11，8mg实施例12，产率：70％。
实施例11的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.0Hz,1H),7.39(d,J＝3.0Hz,1H),7.33(dd,J＝2.2,8.2Hz,1H),7.22-7.26(m,1H),6.97(dt,J＝2.5,8.2Hz,1H),6.16(s,1H),4.66(dd,J＝7.2,11.2Hz,1H),4.15(dd,J＝8.5,11.0Hz,1H),4.07(dq,J＝3.6,7.0Hz,2H),3.68(dd,J＝7.8,17.8Hz,1H),2.94(dd,J＝9.0,17.6Hz,1H),2.75-2.86(m,1H),2.64(d,J＝6.4Hz,2H),1.15(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:488.9[M+H+].
实施例12的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.6Hz,1H),7.39(d,J＝3.0Hz,1H),7.33(dd,J＝2.5,8.0Hz,1H),7.29(br.s.,1H),7.00(dt,J＝2.4,8.2Hz,1H),6.17(s,1H),4.63(dd,J＝7.0,11.6Hz,1H),4.30(dd,J＝3.7,11.8Hz,1H),4.06(q,J＝7.0Hz,2H),3.40-3.48(m,1H),3.25(dd,J＝4.2,18.3Hz,1H),2.86(d,J＝3.6Hz,1H),2.55-2.61(m,2H),1.14(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:488.9[M+H+].
实施例13,14
Figure PCTCN2015079870-appb-000126
将化合物13-1(合成方法与11,12相同)(137mg,0.28mmol)溶于(3mL)无水乙醇中，加入5N的硫酸水溶液(2mL)，将温度升高至110℃并在该温度下搅拌3小时。将反应液冷却至室温用碳酸钠水溶液中和到pH＝5后用(10mLx3)乙酸乙酯萃取，合并有机相，依次用水(10mL x 2)、饱和氯化钠溶液洗涤(10mL x 3)，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，再经SFC分离得到1mg实施例13，2mg实施例14，产率：2％。
实施例13的核磁数据：1H NMR(400MHz,DMSO-d6)δ:7.94(d,J＝3.0Hz,1H),7.85(d,J＝3.0Hz,1H),7.53-7.57(m,1H),7.31-7.38(m,1H),7.26(d,J＝9.2Hz,1H),5.98(s,1H),4.41-4.48(m,1H),3.98-4.03(m,1H),3.94(d,J＝4.0Hz,2H),3.26(d,J＝7.8Hz,2H),2.92-3.02(m,2H),1.94-2.04(m,1H),1.04(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:508.0[M+H+].
实施例14的核磁数据：1H NMR(400MHz,DMSO-d6)δ:7.93(br.s.,1H),7.85(d,J＝3.0Hz,1H),7.55(dd,J＝2.4,8.4Hz,1H),7.40(br.s.,1H),7.22(d,J＝7.5Hz,1H),5.96(s,1H),4.53(br.s.,1H),3.95(d,J＝6.8Hz,2H),3.78(t,J＝9.6Hz,1H),3.50(d,J＝9.8Hz,2H),2.68(d,J＝15.0Hz,2H),1.93-2.03(m,1H),1.05(br.s.,3H).
LCMS(ESI)m/z:508.0[M+H+].
实施例15,16
Figure PCTCN2015079870-appb-000127
将化合物15-1(合成方法与化合物10-2相同)(80mg,0.14mmol)溶于(3mL)乙腈中，加入碳酸钾(39mg,0.29mmol)，吗啡啉(125mg,1.53mmol)，将温度升高至80℃并在该温度下搅拌过夜。将反应液用(30mL x 3)乙酸乙酯萃取，合并有机相，依次用水(20mL x 2)、饱和氯化钠溶液洗涤(20mL x 3)，用无水硫酸钠干燥，过滤，减压浓缩后通过SFC分离得到6mg实施例15，15mg实施例16，产率：35％。
将实施例15，16分别溶于1mL乙酸乙酯中，然后分别加入4mL氯化氢乙酸乙酯溶液，20℃下搅拌30分钟，减压浓缩，冻干法分别给出实施例15，和实施例16。
实施例15的核磁数据：1H NMR(400MHz,DMSO-d6)δ:10.94(br.s.,1H),7.91-8.02(m,2H),7.57(dd,J＝2.4,8.4Hz,1H),7.47(dd,J＝6.2,8.4Hz,1H),7.20-7.31(m,1H),6.00(s,1H),4.57(dd,J＝7.4,11.2Hz,1H),4.18(dd,J＝5.2,11.2Hz,2H),3.91-4.03(m,5H),3.78-3.91(m,3H),3.31(br.s.,2H),2.93-3.19(m,4H),1.06(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:549.1[M+H+].
实施例16的核磁数据：1H NMR(400MHz,DMSO-d6)δ:11.19(br.s.,1H),7.89-7.98(m,2H),7.57(dd,J＝2.5,8.4Hz,1H),7.45(dd,J＝6.5,8.4Hz,1H),7.22(dt,J＝2.5,8.5Hz,1H),5.97(s,1H),4.64(dd,J＝7.8,10.4Hz,1H),4.14-4.32(m,1H),3.93-4.03(m,4H),3.82-3.92(m,3H),3.66(dd,J＝7.5,17.4Hz,2H),3.33-3.37(m,2H),2.96-3.15(m,3H),2.84(dd,J＝10.2,17.4Hz,1H),1.08(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:549.1[M+H+].
实施例17，18
Figure PCTCN2015079870-appb-000128
实施例17,18如实施例15,16中的描述方法制备由高效液相分离得到。
实施例17的核磁数据：1H NMR(400MHz,DMSO-d6)δ:7.96(d,J＝3.6Hz,1H),7.85(d,J＝3.0Hz,1H),7.54(d,J＝6.0Hz,1H),7.38-7.45(m,1H),7.20(t,J＝8.2Hz,1H),5.96(s,1H),4.37-4.45(m,1H),3.96(q,J＝7.0Hz,2H),3.83-3.89(m,1H),3.58(br.s.,4H),2.65-2.75(m,3H),2.30-2.44(m,6H),1.06(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:549.1[M+H+].
实施例18的核磁数据：1H NMR(400MHz,DMSO-d6)δ:7.95(d,J＝3.0Hz,1H),7.85(d,J＝3.0Hz,1H),7.55(d,J＝6.4Hz,1H),7.21-7.33(m,2H),5.97(s,1H),4.32(dd,J＝7.2,10.8Hz,1H),4.09(d,J＝8.0Hz,1H),3.95(q,J＝7.0Hz,2H),3.58(br.s.,4H),3.18(dd,J＝8.0,18.0Hz,1H),2.98-3.08(m,1H),2.67(br.s.,1H),2.26-2.44(m,6H),1.06(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:549.1[M+H+].
实施例19，20
Figure PCTCN2015079870-appb-000129
实施例19,20如实施例15,16中的描述方法制备由SFC分离得到。
实施例19的核磁数据：1H NMR(400MHz,CDCl3)δ：7.82(d,J＝3.2Hz,1H),7.36(d,J＝3.2Hz,1H),7.32(dd,J＝2.4,8.4Hz,1H),7.23(dd,J＝6.4,8.8Hz,1H),6.97(dt,J＝2.4,8.4Hz,1H),6.15(s,1H),4.46(dd,J＝6.4,11.6Hz,1H),4.20(dd,J＝2.8,11.6Hz,1H),4.14(q,J＝7.2Hz,2H),4.06(dq,J＝1.6,7.2Hz,2H),3.26-3.40(m,2H),3.17-3.24(m,2H),2.54-2.75(m,3H),2.45(s,3H),1.24(t,J＝7.2Hz,3H),1.15(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:580.9[M+H+].
实施例20的核磁数据：1H NMR(400MHz,CDCl3)δ：7.82(d,J＝3.2Hz,1H),7.36(d,J＝3.2Hz,1H),7.29-7.34(m,1H),7.24-7.29(m,1H),6.97(dt,J＝2.4,8.4Hz,1H),6.15(s,1H),4.50(dd,J＝6.8,11.6Hz,1H),4.18(q,J＝7.2Hz,2H),3.94-4.11(m,3H),3.52(dd,J＝7.2,17.6Hz,1H),3.27-3.40(m,2H),2.58-2.87(m,4H),2.46(s,3H),1.25(t,J＝7.2Hz,3H),1.14(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:580.9[M+H+].
实施例21，22
Figure PCTCN2015079870-appb-000130
实施例21,22如实施例15,16中的描述方法制备由SFC分离得到。
实施例21的核磁数据：1H NMR(400MHz,CDCl3)δ：7.83(d,J＝3.2Hz,1H),7.36(d,J＝3.2Hz,1H),7.27-7.34(m,2H),6.97(dt,J＝2.4,8.4Hz,1H),6.15(s,1H),4.52(dd,J＝7.2,11.2Hz,1H),3.93-4.15(m,3H),3.64-3.80(m,3H),3.54(dd,J＝7.2,17.6Hz,1H),3.26(dd,J＝8.4,14.0Hz,2H),2.70-2.94(m,2H),2.53-2.69(m,2H),2.47(q,J＝7.6Hz,1H),2.04-2.22(m,1H),1.80-2.03(m,3H),1.14(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:592.9[M+H+].
实施例22的核磁数据：1H NMR(400MHz,CDCl3)δ：7.80(d,J＝3.2Hz,1H),7.36(d,J＝3.2Hz,1H),7.33(dd,J＝2.4,8.4Hz,1H),7.19-7.26(m,1H),7.00(dt,J＝2.4,8.4Hz,1H),6.15(s,1H),4.41(dd,J＝6.8,11.6Hz,1H),3.99-4.18(m,3H),3.66(s,3H),3.38-3.51(m,1H),3.29(dd,J＝5.2,8.4Hz,1H),3.09-3.22(m,2H),2.71-2.83(m,1H),2.40-2.64(m,3H),2.12(d,J＝4.4Hz,1H),1.92-2.04(m,2H),1.85(d,J＝7.6Hz,1H),1.15(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:592.9[M+H+].
实施例23
Figure PCTCN2015079870-appb-000131
Figure PCTCN2015079870-appb-000132
第一步(化合物23-3的合成)
将化合物23-2(680mg,6mmol)溶于无水N,N-二甲基甲酰胺(50mL)中，在0℃慢慢加入氢化钠(200mg,5mmol)，保持温度不变搅拌30分钟。然后加入化合物23-1(合成方法与化合物6-5制备方法相同)(2g,4mmol)，室温下搅拌2小时。减压浓缩后用二氯甲烷(50mL x 3)萃取，合并有机相，依次用水(30mL x 2)、饱和氯化钠溶液洗涤(30mL x 2)，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到产物1.6g化合物23-3，产率：75％。
LCMS(ESI)m/z:536.6[M+H+].
第二步(化合物23-4的合成)
将化合物23-3(1.2g,2.24mmol)溶于无水甲醇(30mL)中，在0℃慢慢加入硼氢化钠(426mg,11.2mmol)，保持温度不变搅拌30分钟。减压浓缩后用二氯甲烷(50mL x 3)萃取，合并有机相，依次用水(30mL x 2)、饱和氯化钠溶液(30mL x 2)洗涤，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到产物800mg化合物23-4，产率：74％。
LCMS(ESI)m/z:494.7[M+H+].
第三步(化合物23-5的合成)
将化合物23-4(800mg,1.6mmol)溶于无水二氯甲烷(40mL)中，在0℃慢慢加入三乙胺(240mg,2.4mmol)，甲基磺酰氯(276mg,2.4mmol)，将温度升至室温搅拌过夜。反应液用二氯甲烷(50mL x3)萃取，合并有机相，依次用水(30mL x 2)、饱和氯化钠溶液(30mL x 2)洗涤，用无水硫酸钠干燥，过滤，减压浓缩得到560mg化合物23-5，产率：74％。
LCMS(ESI)m/z:476.7[M+H+].
第四步(化合物23-6的合成)
将化合物23-5(180mg,0.38mmol)溶于无水甲醇(5mL)中，在室温下慢慢加入甲醇钠(426mg,11.2mmol)，在室温氮气保护下搅拌过夜。减压浓缩后用二氯甲烷(50mL x 3)萃取，合并有机相，依次用水(30mL x 2)、饱和氯化钠溶液(30mL x 2)洗涤，用无水硫酸钠干燥，过滤，用硅胶柱色谱法 以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到200mg化合物23-6，产率：90％。
LCMS(ESI)m/z:509.0[M+H+].
第五步(实施例23的合成)
将化合物23-6(200mg,0.39mmol)溶于乙二醇二甲醚(3mL)中，加入水(3mL)，硫酸(0.3mL)，在室温下搅拌1小时后，将温度升高至80℃并在该温度下反应6小时。将反应液冷却至室温，减压浓缩后用二氯甲烷(50mL x 3)萃取，合并有机相，依次用水(30mL x 2)、饱和氯化钠溶液(30mL x 2)洗涤，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到6.6mg实施例23，产率：4％。
实施例23的核磁数据：1H NMR(400MHz,MeOD-d4)δ:8.39-8.29(m,2H),7.77(dd,J＝6.0,8.4Hz,1H),7.56(dd,J＝2.0,8.0Hz,1H),7.28(t,J＝6.8Hz,1H),6.35(s,1H),4.72-4.61(m,1H),4.61-4.50(m,1H),4.24-4.09(m,2H),3.85-3.72(m,1H),3.72-3.45(m,2H),1.19(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:494.0[M+H+].
实施例24,25
Figure PCTCN2015079870-appb-000133
实施例24,25的合成如实施例23-5的方法制备，并通过SFC分离得到。
实施例24的核磁数据：1H NMR(400MHz,CDCl3)δ:7.86-7.80(m,1H),7.40(d,J＝3.2Hz,1H),7.23(dd,J＝6.0,8.8Hz,1H),7.13(dd,J＝2.4,8.8Hz,1H),6.91(dt,J＝2.8,8.4Hz,1H),6.18(s,1H),4.83(dd,J＝7.6,11.6Hz,1H),4.56(dd,J＝8.4,11.6Hz,1H),4.06(q,J＝7.2Hz,2H),3.80(dd,J＝7.6,17.6Hz,1H),3.50-3.27(m,2H),1.21-1.08(m,3H).
LCMS(ESI)m/z:431.0[M+H+].
实施例25的核磁数据：1H NMR(400MHz,CDCl3)δ:7.84(d,J＝3.2Hz,1H),7.53(d,J＝3.2Hz,1H),7.48-7.44(m,1H),7.41(dd,J＝6.0,8.8Hz,1H),7.16-7.12(m,1H),6.98(dt,J＝2.4,8.4Hz,1H),6.16-6.06(m,1H),6.01(s,1H),5.98(s,1H),4.12-4.06(m,2H),4.06-4.00(m,1H),3.96-3.87(m,1H),1.13(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:431.0[M+H+].
实施例26，27
Figure PCTCN2015079870-appb-000134
Figure PCTCN2015079870-appb-000135
实施例26,27由23-5通过高效液相分离得到。
实施例26的核磁数据：1H NMR(400MHz,DMSO-d6)δ:7.98(d,J＝3.2Hz,1H),7.89(d,J＝3.2Hz,1H),7.57(dd,J＝8.4,2.4Hz,1H),7.46(dd,J＝8.4,6.4Hz,1H),7.12-7.30(m,1H),6.00(s,1H),4.63-4.74(m,1H),4.42-4.52(m,1H),3.99(q,J＝7.2Hz,2H),3.64-3.82(m,2H),3.29-3.33(m,1H),1.08(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:476.8[M+H+].
实施例27的核磁数据：1H NMR(400MHz,DMSO-d6)δ:7.97(d,J＝3.2Hz,1H)，7.90(d,J＝3.2Hz,1H),7.53-7.67(m,1H),7.37-7.45(m,1H),7.23(t,J＝8.4Hz,1H),6.01(s,1H),4.48-4.64(m,2H),3.95-4.06(m,2H),3.72-3.84(m,1H),3.41-3.60(m,1H),3.32-3.34(m,1H),1.09(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:476.8[M+H+].
实施例28,29
Figure PCTCN2015079870-appb-000136
将化合物23-5(80mg,0.16mmol)溶于无水乙醇(1mL)中，加入DMSO(0.1mL)，的氢氧化钠溶液(0.05mL，5N)，双氧水(0.06mL)，在室温下搅拌3小时。将反应液减压浓缩后用二氯甲烷(30mL x 3)萃取，合并有机相，依次用水(20mL x 2)、饱和氯化钠溶液(20mL x 2)洗涤，用无水硫酸钠干燥，过滤，用HPLC制备分离得到15mg实施例28，11mg实施例29，产率：35％。
实施例28的核磁数据：1H NMR(400MHz,CDCl3)δ:7.81(d,J＝3.2Hz,1H),7.38(d,J＝3.2Hz,1H),7.33(dd,J＝2.4,8.4Hz,1H),7.23-7.26(m,1H),6.97(dt,J＝2.4,8.4Hz,1H),6.17(s,1H),5.83(br.s.,1H),5.62(br.s.,1H),4.67(dd,J＝8.4,11.2Hz,1H),4.47(dd,J＝8.4,11.2Hz,1H),3.99-4.14(m,2H),3.69(dd,J＝8.4,18.0Hz,1H),3.34-3.47(m,1H),3.21(q,J＝8.4Hz,1H),1.15(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:493.0[M+H+].
实施例29的核磁数据：1H NMR(400MHz,CDCl3)δ:7.80(d,J＝3.2Hz,1H),7.48(dd,J＝6.0,8.4Hz,1H),7.38(d,J＝3.6Hz,1H),7.31(dd,J＝2.4,8.4Hz,1H),7.01(dt,J＝2.4,8.4Hz,1H),6.17(s,1H),5.60(br.s.,1H),5.46(br.s.,1H),4.71(dd,J＝7.6,11.6Hz,1H),4.51(dd,J＝3.6,11.6Hz,1H),3.99-4.13(m,2H),3.67(dd,J＝3.6,18.0Hz,1H),3.33-3.43(m,1H),3.18(tt,J＝3.6,8.0Hz,1H),1.15(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:493.0[M+H+].
实施例30，31
Figure PCTCN2015079870-appb-000137
实施例30,31如实施例28，29中的描述方法制备由SFC分离得到。
实施例31的核磁数据：1H NMR(400MHz,CDCl3)δ:7.83(d,J＝3.2Hz,1H),7.41(d,J＝3.2Hz,1H),7.29(dd,J＝6.0,8.8Hz,1H),7.12(dd,J＝2.4,8.4Hz,1H),6.92(m,1H),6.19(s,1H),5.97-5.59(m,2H),4.65(dd,J＝8.4,11.6Hz,1H),4.47(dd,J＝8.4,11.6Hz,1H),4.13-3.98(m,2H),3.67(dd,J＝8.4,18.0Hz,1H),3.45-3.33(m,1H),3.21(quin,J＝8.4Hz,1H),1.15(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:449.0[M+H+].
实施例32
Figure PCTCN2015079870-appb-000138
将化合物24(50mg,0.11mmol)，TBAF(15mg,0.06mmol),TMSN3(134mg,1.16mmol)加入到微波管中，在110℃微波反应1小时。将反应液冷却至室温，加入用乙酸乙酯(10mL)，5％的碳酸钠水溶液(10mL)，用(10mL x 3)乙酸乙酯萃取，合并有机相，依次用水(10mL x 2)、饱和氯化钠溶液 洗涤(10mL x 2)，用无水硫酸钠干燥，过滤，滤液减压浓缩后用高效液相分离得到产物16mg实施例32，产率：29％。
1H NMR(400MHz,MeOD-d4)δ:8.08(br.s.,1H),7.93(br.s.,1H),7.65(br.s.,1H),7.15(d,J＝8.0Hz,1H),7.08(br.s.,1H),6.25(s,1H),4.80(br.s.,1H),4.68(br.s.,1H),4.33(br.s.,1H),4.07(q,J＝7.2Hz,2H),4.01-3.84(m,1H),3.31(br.s.,1H),1.13(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:474.1[M+H+].
实施例33
Figure PCTCN2015079870-appb-000139
实施例33如实施例32中描述的方法制备。
实施例33的核磁数据：1H NMR(400MHz,MeOD-d4)δ:8.39-8.29(m,2H),7.84(dd,J＝6.0,8.4Hz,1H),7.58(dd,J＝2.4,8.4Hz,1H),7.31(dt,J＝2.4,8.4Hz,1H),6.39(s,1H),4.88-4.72(m,2H),4.43-4.29(m,1H),4.16(dq,J＝4.4,7.2Hz,2H),4.07(dd,J＝8.0,18.0Hz,1H),3.60(dd,J＝8.0,18.0Hz,1H),1.19(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:520.0[M+H+].
实施例34，35
Figure PCTCN2015079870-appb-000140
第一步(化合物34-2的合成)
将化合物34-1(80g,600mmol)溶于无水乙醇(500mL)中，在0℃加入氯化亚砜(100mL,1.5mmol)，在0℃下搅拌20分钟。然后将温度升至室温搅拌过夜。将反应液减压浓缩，用乙酸乙酯(1000mL x 3)萃取，合并有机相，依次用水(500mL x 2)、饱和氯化钠溶液(500mL x 2)洗涤，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝20:1)纯化，得到产物113g化合物34-2，产率：99％。
1H NMR(400MHz,CDCl3)δ:4.47(q,J＝4.8Hz,1H),4.26(dq,J＝2.4,7.2Hz,2H),4.16(q,J＝7.2Hz,2H),3.28(d,J＝4.8Hz,1H),2.72-2.89(m,2H),1.20-1.34(m,6H).
第二步(化合物34-3的合成)
将化合物34-2(30g,158mmol)溶于无水四氢呋喃(400mL)中，在室温下慢慢滴加硼烷的二甲硫醚溶液(16.5mL,165mmol)，在室温下搅拌1小时。然后将温度降至0℃，加入硼氢化钠(300mg,8mmol)，剧烈搅拌30分钟后将温度升至室温并搅拌过夜。然后加入无水乙醇(80mL)，p-TsOH(450mg,4mmol)，该反应液再在室温下搅拌半小时。将反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝1:1)纯化，得到产物13.6g化合物34-3，产率：60％。
第三步(化合物34-4的合成)
将化合物34-3(15g,100mmol)溶于丙酮(200mL)中，在室温下慢慢滴加2,2-二甲氧基丙烷(21g,200mmol)和p-TsOH(350mg,2mmol)，在室温下搅拌过夜。将反应液减压浓缩，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化所得到产物12g的化合物34-4，产率：64％。
1H NMR(400MHz,CDCl3)δ:4.48(q,J＝6.4Hz,1H),4.09-4.24(m,3H),3.66(dd,J＝6.4,8.4Hz,1H),2.72 (dd,J＝6.4,15.6Hz,1H),2.52(dd,J＝7.2,15.6Hz,1H),1.42(s,3H),1.37(s,3H),1.27(t,J＝7.2Hz,3H).
第四步(化合物34-5的合成)
冰水浴条件下将化合物34-4(6.2g,32.9mmol)溶于2N的氢氧化钠(33mL)溶液中，然后将温度升至室温搅拌3小时。将反应液用二氯甲烷(50mL x 3)萃取，保留水层，水层加入乙酸乙酯(50mL)，2N的硫酸氢钠水溶液(50mL)，剧烈搅拌15分钟。乙酸乙酯(100mL x 3)萃取，合并有机相，依次用水(50mL x 2)、饱和氯化钠溶液洗涤(50mL x 2)，用无水硫酸钠干燥，过滤，减压浓缩，得到粗产品4.2g化合物34-5，产率：79％。
1H NMR(400MHz,CDCl3)δ:4.49(q,J＝6.4Hz,1H),4.18(dd,J＝6.0,8.4Hz,1H),3.68(dd,J＝6.4,8.4Hz,1H),2.70-2.80(m,1H),2.54-2.64(m,1H),1.44(s,3H),1.37(s,3H).
第五，六步(化合物34-7的合成)
冰水浴条件下将化合物34-5(1.0g,6.24mmol)溶于无水四氢呋喃(17mL)溶液中，加入二羰基咪唑(1.21g,7.49mmol)，在室温氮气保护下搅拌4小时。然后在氮气保护下加入氯化镁(594mg,6.24mmol),2-甲酸乙酯乙酸钾(2.12g,12.48mmol)，三乙胺(1.26g,12.49mmol)，加料完毕在室温下搅拌过夜。反应液用1N的盐酸溶液酸化至PH＝5，用乙酸乙酯(100mL x 3)萃取，合并有机相，依次用水(50mL x 2)、饱和氯化钠溶液(50mL x 2)洗涤，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝5:1)纯化，得到产物336mg化合物34-7，产率：23％。
1H NMR(400MHz,CDCl3)δ:4.48(q,J＝6.4Hz,1H),4.16-4.25(m,3H),3.57(dd,J＝6.8,8.4Hz,1H),3.49(s,2H),3.00(dd,J＝6.0,17.2Hz,1H),2.75(dd,J＝7.2,17.2Hz,1H),1.39-1.44(m,3H),1.33-1.38(m,3H),1.27-1.32(m,3H).
第七步(化合物34-8的合成)
将化合物34-7(438mg,2.76mmol)溶于无水乙醇(25mL)溶液中，加入化合物1-5(636mg,2.76mmol)，化合物1-6(542mg,3.31mmol)，乙酸钠(566mg,6.91mmol)在氮气保护下回流搅拌过夜。将反应液减压浓缩，用乙酸乙酯(50mLx3)萃取，合并有机相，依次用水(30mL x 2)、饱和氯化钠溶液(30mL x 2)洗涤，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝3:1)纯化，得到产物720mg化合物34-8，产率：54％。
1H NMR(400MHz,CDCl3)δ:8.77(br.s.,1H),7.82(br.s.,1H),7.37-7.48(m,2H),7.13(d,J＝8.4Hz,1H),6.94(d,J＝7.2Hz,1H),6.22(s,1H),4.42-4.56(m,1H),4.19(t,J＝7.2Hz,1H),3.98-4.08(m,2H),3.78(t,J＝7.2Hz,1H),3.61(d,J＝15.6Hz,1H),3.04(dd,J＝7.6,14.4Hz,1H),1.47-1.57(m,3H),1.38-1.44(m,3H),1.13(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:480.0[M+H+].
第八步(化合物34-9的合成)
将化合物34-8(340mg,0.71mmol)溶于无水甲醇(7mL)溶液中，加入p-TsOH(81mg,0.43mmol)，水(2mL)，反应液回流搅拌过夜。将反应液减压浓缩，用乙酸乙酯(50mL x 3)萃取，,合并有机相，依次用水(30mL x 2)、饱和氯化钠溶液洗涤(30mL x 2)，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(二氯甲烷：甲醇＝20:1)纯化，得到214mg化合物34-9，产率：69％。
1H NMR(400MHz,CDCl3)δ:7.80-7.90(m,1H),7.56(br.s.,1H),7.42(dd,J＝6.4,8.4Hz,1H),7.16(d,J＝7.6Hz,1H),6.90-7.05(m,1H),6.08-6.25(m,1H),4.66(br.s.,1H),4.17-4.29(m,1H),4.07(d,J＝7.2Hz, 2H),3.71(br.s.,2H),3.30-3.53(m,1H),2.88-3.26(m,2H),1.15(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:440.0[M+H+].
第九步(实施例34,35的合成)
将化合物34-8(199mg,0.45mmol)溶于无水二氯甲烷(5mL)溶液中，在0℃加入三乙胺(69mg,0.68mmol)，甲基磺酰氯(52mg,0.45mmol)，保持温度不变搅拌1.5小时，将温度升至室温搅拌过夜。用二氯甲烷(50mL x 3)萃取，,合并有机相，依次用水(30mL x 2)、饱和氯化钠溶液(30mL x 2)洗涤，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝1:1)纯化，得到3mg实施例34，10mg实施例35，产率：6.8％。
实施例34的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.2Hz,1H),7.38(d,J＝3.2Hz,1H),7.28-7.32(m,1H),7.12(dd,J＝2.4,8.4Hz,1H),6.92(dt,J＝2.4,8.4Hz,1H),6.21(s,1H),4.59-4.72(m,2H),4.29(dd,J＝4.4,12.4Hz,1H),4.04(dt,J＝5.2,6.8Hz,2H),3.38-3.50(m,1H),3.25-3.37(m,1H),1.12(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:422.0[M+H+].
实施例35的核磁数据：1H NMR(400MHz,CDCl3)δ:7.81(d,J＝3.2Hz,1H),7.34-7.43(m,2H),7.13(dd,J＝2.8,8.8Hz,1H),6.92(dt,J＝2.4,8.4Hz,1H),6.21(s,1H),4.70(br.s.,1H),4.34-4.49(m,2H),4.00-4.14(m,2H),3.56(d,J＝18.0Hz,1H),3.14(dd,J＝5.3,18.4Hz,1H),1.17(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:422.0[M+H+].
实施例36,37
Figure PCTCN2015079870-appb-000142
Figure PCTCN2015079870-appb-000143
第一步(化合物36-2的合成)
将化合物36-1(15.9g,119.2mmol)溶于无水N’,N-二甲基乙酰胺(300mL)中，在室温下分批加入氢化钠(2.14g,89.4mmol)，氮气保护下室温搅拌2小时。然后将化合物6-5(30.0g,59.6mmol)加入到反应液中，加料结束，氮气保护下室温搅拌过夜。将反应液用乙酸乙酯(400mL x 3)萃取，合并有机相，依次用水(100mL x 2)、饱和氯化钠溶液(100mL x 2)洗涤，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝20:1)纯化,得到26g化合物36-2，产率：79％。
LCMS(ESI)m/z:556.9[M+H+].
第二步(化合物36-3的合成)
将兰尼镍(3.0g)溶于四氢呋喃(1000mL)中，在室温下加入化合物36-2(26g,46.8mmol)，(Boc)2O(30.6g,140mmol)，氢气氛围下将温度升高至50℃并在该温度下搅拌4小时。将反应液过滤，滤液减压浓缩并用乙酸乙酯(500mL x 3)萃取，合并有机相，依次用水(200mL x 2)、饱和氯化钠溶液洗涤(100mL x 2)，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝5:1)纯化,得到产物20g化合物36-3，产率：70％
LCMS(ESI)m/z:627.0[M+H+].
第三步(化合物36-4的合成)
将化合物36-3(10g,16.0mmol)溶于无水四氢呋喃(1000mL)中，在室温下分批加入硼氢化钠(600mg,16.0mmol)，加入甲醇(1mL)，氮气保护下室温搅拌10分钟后升高温度到回流状态，并在回流状态下搅拌6小时。将反应液冷却到室温，减压浓缩并将残留物倾倒入冰水(1500mL)中，搅拌20分钟。用乙酸乙酯(400mL x 3)萃取，合并有机相，依次用水(200mL x 2)、饱和氯化钠溶液(100 mL x 2)洗涤，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝5:1)纯化,得到7.0g化合物36-4，产率：75％。
LCMS(ESI)m/z:584.9[M+H+].
第四步(化合物36-5的合成)
将化合物36-4(6.0g,10.3mmol)溶于无水二氯甲烷(500mL)中，在室温下滴加三乙胺(1.56g,15.4mmol)，甲基磺酰氯(2.94g,15.4mmol)，滴加完毕将温度升高至45℃，氮气保护下搅拌6小时。将反应液冷却至室温，减压浓缩并用乙酸乙酯(200mL x 3)萃取，合并有机相，依次用水(100mL x 2)、饱和氯化钠溶液(40mL x 2)洗涤，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝5:1)纯化,得到3.0g化合物36-5，产率：52％。
LCMS(ESI)m/z:567.1[M+H+].
第五步(化合物36-6的合成)
将化合物36-5(3.0g,5.3mmol)溶于乙酸乙酯(10mL)中，在室温下滴加盐酸乙酸乙酯(50mL)，滴加完毕，氮气保护下室温搅拌过夜。将反应液减压浓缩得到2.4g的化合物36-6，产物不经纯化直接进行下一步反应，产率：84％。
LCMS(ESI)m/z:466.8[M+H+].
第六步(化合物36-7的合成)
将化合物36-6(80mg,0.17mmol)溶于无水二氯甲烷(5mL)中，在室温下加入三乙胺(17mg,0.17mmol)，多聚甲醛(26mg,0.86mmol)，醋酸硼氢化钠(109mg,0.52mmol)，加料完毕后将温度升高至45℃，氮气保护下搅拌过夜。将反应液冷却至室温，减压浓缩后将残留物倾倒入冰水(15mL)中，并用乙酸乙酯(20mL x 3)萃取，合并有机相，依次用水(10mL x 2)、饱和氯化钠溶液(10mL x 2)洗涤，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝3:1)纯化，得到20mg化合物36-7，产率：24％。
LCMS(ESI)m/z:492.9[M+H+].
第七步(化合物36,37的合成)
将化合物36-7经由SFC制备分离得到手性纯的实施例36和实施例37。
实施例36的核磁数据：1H NMR(400MHz,CDCl3)δ:7.81(d,J＝3.2Hz,1H),7.37(d,J＝3.6Hz,1H),7.30(dd,J＝2.4,8.4Hz,1H),7.24(s,1H),6.95(dt,J＝2.4,8.4Hz,1H),6.15(s,1H),4.69(dd,J＝6.8,11.6Hz,1H),4.11-4.05(m,1H),4.05-3.99(m,2H),3.48-3.37(m,1H),3.22-3.09(m,2H),2.33(s,6H),1.15(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:493.2[M+H+].
实施例37的核磁数据：1H NMR(400MHz,CDCl3)δ:7.81(d,J＝3.2Hz,1H),7.36(d,J＝3.2Hz,1H),7.31(dd,J＝2.4,8.4Hz,1H),7.26-7.23(m,1H),6.96(dt,J＝2.4,8.4Hz,1H),6.14(s,1H),4.55(dd,J＝6.4,11.2Hz,1H),4.14-4.06(m,1H),4.05-3.97(m,2H),3.63(dd,J＝6.4,16.4Hz,1H),3.05-2.89(m,2H),2.34(s,6H),1.14(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:465.1[M+H+].
实施例38,39
Figure PCTCN2015079870-appb-000144
将化合物26-5(30mg)经由SFC制备分离得到手性纯实施例38，实施例39。
实施例38的核磁数据：1H NMR(400MHz,CDCl3)δ:7.80(d,J＝3.2Hz,1H),7.37(d,J＝3.2Hz,1H),7.31(dd,J＝2.8,8.4Hz,1H),7.24-7.20(m,1H),6.97(dt,J＝2.4,8.4Hz,1H),6.15(s,1H),4.74(br.s.,1H),4.46(d,J＝10.0Hz,1H),4.35-4.29(m,1H),4.04(q,J＝7.2Hz,2H),3.58(dd,J＝7.2,18.4Hz,1H),3.08(dd,J＝5.6,17.6Hz,1H),1.46(s,9H),1.13(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:567.1[M+H+].
实施例39的核磁数据：1H NMR(400MHz,CDCl3)δ:7.80(d,J＝3.6Hz,1H),7.37(d,J＝3.2Hz,1H),7.35-7.27(m,2H),6.99(dt,J＝2.4,8.4Hz,1H),6.16(s,1H),4.77(br.s.,1H),4.42(s,2H),4.06(q,J＝7.2Hz,2H),3.42-3.27(m,2H),1.51-1.41(m,9H),1.15(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:567.1[M+H+].
实施例40，41
Figure PCTCN2015079870-appb-000145
将化合物36-6(500mg)经由制备色谱分离得到手性纯化合物115mg实施例40，130mg的实施例41。
实施例40的核磁数据：1H NMR(400MHz,DMSO-d6)δ:7.96(d,J＝3.2Hz,1H),7.87(d,J＝3.2Hz,1H),7.55(dd,J＝2.4,8.8Hz,1H),7.42(dd,J＝6.4,8.4Hz,1H),7.22(dt,J＝2.4,8.4Hz,1H),6.00(s,1H),4.33(dd,J＝6.3,11.2Hz,1H),4.18(dd,J＝4.4,11.2Hz,1H),4.01-3.91(m,2H),3.3(m,1H),3.03(dd,J＝5.2,18.0Hz,2H),1.06(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:465.1[M+H+].
实施例41的核磁数据:1H NMR(400MHz,DMSO-d6)δ:7.97(d,J＝3.2Hz,1H),7.89(d,J＝3.2Hz,1H),7.66(dd,J＝6.4,8.4Hz,1H),7.57(dd,J＝2.4,8.4Hz,1H),7.23(dt,J＝2.4,8.4Hz,1H),6.06-5.99(m,1H),4.56(d,J＝12.4Hz,1H),4.33(dd,J＝6.4,12.4Hz,1H),4.05(br.s.,1H),4.00-3.89(m,2H),3.3(m,2H),1.06(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:465.1[M+H+].
实施例42，43,44
Figure PCTCN2015079870-appb-000146
第一步(42的合成)
将实施例36-6(200mg,0.398mmol)溶于无水二氯甲烷(5mL)中，在室温下加入三乙胺(120.99mg,1.20mmol)，甲氧基氯甲酰氯(113mg,1.2mmol)。加料完毕后，氮气保护下充分搅拌3小时。当TLC(石油醚：乙酸乙酯＝1:1)显示原料消失，将反应液倾倒入饱和碳酸氢钠溶液(15mL)中，并用二氯甲烷(20mL x 3)萃取，合并有机相，依次用水(10mL x 2)、饱和氯化钠溶液(10mL x 2)洗涤，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝100:1～3:1)纯化得到130mg的实施例42,产率：62.23％。
实施例42的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.2Hz,1H),7.40(d,J＝3.2Hz,1H),7.35(m,1H),7.27-7.24(m,1H),7.05-6.97(m,1H),6.18(d,J＝3.6Hz,1H),4.95(br.s.,1H),4.55-4.40(m,2H),4.15-4.01(m,1H),3.73(br.s.,3H),3.66-3.58(m,1H),3.47-3.28(m,1H),3.13(dd,J＝5.6,18.0Hz,1H),1.16(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:523.0[M+H+].
将实施例42经由SFC制备分离得到手性纯的实施例43和实施例44。
实施例43的核磁数据：1H NMR(400MHz,CDCl3)δ:7.80(d,J＝3.2Hz,1H),7.37(d,J＝3.2Hz,1H),7.33(dd,J＝2.4,8.4Hz,1H),7.29(br.s.,1H),7.25(br.s.,1H),6.16(s,1H),4.97(br.s.,1H),4.45(s,2H),4.42(br.s.,1H),4.06(q,J＝7.2Hz,2H),3.71(br.s.,3H),3.49-3.38(m,1H),3.35-3.22(m,1H),1.15(t,J＝7.2Hz,3H).LCMS(ESI)m/z:523.0[M+H+].
实施例44的核磁数据：1H NMR(400MHz,CDCl3)δ:7.80(d,J＝3.2Hz,1H),7.37(d,J＝3.2Hz,1H),7.32(dd,J＝2.4,8.4Hz,1H),7.26-7.21(m,1H),6.98(dt,J＝2.4,8.4Hz,1H),6.15(s,1H),5.03(br.s.,1H),4.55-4.42(m,2H),4.33(d,J＝5.6Hz,1H),4.04(q,J＝7.2Hz,2H),3.70(br.s.,3H),3.61(m,1H),3.11(m,1H),1.13(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:523.0[M+H+].
实施例45，46，47
Figure PCTCN2015079870-appb-000147
这个实施例如实施例42,43,44中描述的方法制备。
实施例45的核磁数据：1H NMR(400MHz,CDCl3)δ:7.81(d,J＝3.2Hz,1H),7.38(d,J＝3.2Hz,1H),7.34(dd,J＝2.4,8.4Hz,1H),7.30(br.s.,1H),7.04-6.94(m,1H),6.17(s,1H),4.95(br.s.,1H),4.84(br.s.,1H),4.45(s,3H),4.06(q,J＝7.2Hz,2H),3.48-3.25(m,2H),1.26(br.s.,6H),1.16(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:551.1[M+H+].
实施例46的核磁数据：1H NMR(400MHz,CDCl3)δ:7.81(d,J＝3.2Hz,1H),7.38(d,J＝3.2Hz,1H),7.34(dd,J＝2.4,8.4Hz,1H),7.30(br.s.,1H),7.04-6.94(m,1H),6.17(s,1H),4.95(br.s.,1H),4.84(br.s.,1H),4.45(s,3H),4.06(q,J＝7.2Hz,2H),3.48-3.25(m,2H),1.26(br.s.,6H),1.16(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:551.1[M+H+].
实施例47的核磁数据：1H NMR(400MHz,CDCl3)δ:7.80(d,J＝3.2Hz,1H),7.37(d,J＝3.02Hz,1H),7.32(dd,J＝2.4,8.4Hz,1H),7.26-7.22(m,1H),6.98(dt,J＝2.4,8.4Hz,1H),6.16(s,1H),4.94(br.s.,1H),4.82(br.s.,1H),4.57-4.45(m,2H),4.39-4.26(m,1H),4.05(q,J＝7.2Hz,2H),3.61(dd,J＝7.2,18.0Hz,1H),3.10(dd,J＝6.0,18.0Hz,1H),1.26(d,J＝4.4Hz,6H),1.13(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:551.1[M+H+].
实施例48，49，50
Figure PCTCN2015079870-appb-000148
这个实施例如实施例42,43,44中描述的方法制备。
实施例48的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝2.8Hz,1H),7.42-7.38(m,1H),7.38-7.31(m,1H),7.30(d,J＝2.4Hz,1H),7.27-7.22(m,1H),7.04-6.96(m,1H),6.19(s,1H),5.83-5.70(m,1H),4.77-4.62(m,1H),4.52-4.38(m,1H),4.07(m,1H),3.64-3.57(m,1H),3.45-3.31(m,1H),3.16(dd,J＝5.6,18.0Hz,1H),2.05(d,J＝4.4Hz,3H),1.16(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:507.1[M+H+].
实施例49的核磁数据：1H NMR(400MHz,CDCl3)δ:7.79(d,J＝3.2Hz,1H),7.37(d,J＝3.2Hz,1H),7.32(dd,J＝2.4,8.0Hz,1H),7.26-7.20(m,1H),6.98(dt,J＝2.4,8.4Hz,1H),6.16(s,1H),5.95(d,J＝7.0Hz,1H),4.76-4.63(m,1H),4.48-4.40(m,2H),4.04(q,J＝7.2Hz,2H),3.56(dd,J＝7.2,18.0Hz,1H),3.16(dd,J＝5.6,18.4Hz,1H),2.00(s,3H),1.13(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:507.1[M+H+].
实施例50的核磁数据：1H NMR(400MHz,CDCl3)δ:7.80(d,J＝3.2Hz,1H),7.38(d,J＝3.2Hz,1H),7.36-7.27(m,2H),6.97(dt,J＝2.4,8.4Hz,1H),6.17(s,1H),5.78(d,J＝5.6Hz,1H),4.69-4.59(m,1H),4.49-4.36(m,2H),4.06(q,J＝7.2Hz,2H),3.45-3.27(m,2H),2.10-1.99(m,3H),1.15(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:507.1[M+H+].
实施例51，52，53
Figure PCTCN2015079870-appb-000149
该实施例如实施例42,43,44中描述的方法制备。
实施例51的核磁数据：1H NMR(400MHz,CDCl3)δ:7.80(d,J＝3.6Hz,1H),7.37(d,J＝3.6Hz,1H),7.31(m,2H),6.94(dt,J＝2.4,8.4Hz,1H),6.16(s,1H),4.62(d,J＝5.6Hz,1H),4.51(br.s.,1H),4.47-4.38(m,3H),4.05(q,J＝7.2Hz,2H),3.42-3.34(m,1H),3.34-3.25(m,1H),2.79(d,J＝5.2Hz,3H),1.15(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:522.0[M+H+].
实施例52的核磁数据：1H NMR(400MHz,CDCl3)δ:7.80(d,J＝3.6Hz,1H),7.37(d,J＝3.2Hz,1H),7.31(m,2H),6.94(dt,J＝2.4,8.4Hz,1H),6.16(s,1H),4.62(d,J＝5.6Hz,1H),4.51(br.s.,1H),4.47-4.38(m,3H),4.05(q,J＝7.2Hz,2H),3.42-3.34(m,1H),3.34-3.25(m,1H),2.79(d,J＝5.6Hz,3H),1.15(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:522.0[M+H+].
实施例53的核磁数据：1H NMR(400MHz,CDCl3)δ:7.79(d,J＝3.2Hz,1H),7.36(d,J＝3.2Hz,1H),7.32(dd,J＝2.4,8.4Hz,1H),7.26-7.22(m,1H),6.99(dt,J＝2.4,8.4Hz,1H),6.14(s,1H),4.76(d,J＝7.2Hz,1H),4.65-4.53(m,1H),4.49-4.41(m,1H),4.41-4.31(m,2H),4.04(q,J＝7.2Hz,2H),3.55(dd,J＝7.2,18.0Hz,1H),3.12(dd,J＝5.6,17.6Hz,1H),2.77(d,J＝4.4Hz,3H),1.13(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:522.0[M+H+].
实施例54，55，56
Figure PCTCN2015079870-appb-000150
该实施例如实施例42,43,44中描述的方法制备。
实施例54的核磁数据：1H NMR(400MHz,CDCl3)δ:7.81(t,J＝3.2Hz,1H),7.39(t,J＝3.2Hz,1H),7.33(td,J＝2.8,8.4Hz,1H),7.30-7.27(m,1H),6.98(dq,J＝2.4,8.0Hz,1H),6.17(s,1H),4.67-4.60(m,1H),4.51(d,J＝6.0Hz,1H),4.48-4.32(m,2H),4.25-4.17(m,1H),4.11-4.01(m,2H),3.63-3.52(m,1H),3.35-3.21(m,1H),2.74(dd,J＝5.6,8.8Hz,3H),1.15(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:558.1[M+H+].
实施例55的核磁数据：1H NMR(400MHz,CDCl3)δ:7.80(d,J＝3.2Hz,1H),7.38(d,J＝3.6Hz,1H),7.35-7.28(m,2H),6.99(dt,J＝2.4,8.4Hz,1H),6.17(s,1H),4.70-4.59(m,2H),4.44-4.35(m,2H),4.21(br.s.,1H),4.05(m,2H),3.55(d,J＝18.0Hz,1H),3.31(dd,J＝6.8,18.0Hz,1H),2.74(d,J＝3.2Hz,3H),1.14(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:558.1[M+H+].
实施例56的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.2Hz,1H),7.39(d,J＝3.2Hz,1H),7.33(dd,J＝2.4,8.4Hz,1H),7.23(dd,J＝6.4,8.8Hz,1H),6.98(dt,J＝2.4,8.34Hz,1H),6.16(s,1H),4.66-4.57(m,2H),4.50(d,J＝5.6Hz,1H),4.43(dd,J＝6.0,12.0Hz,1H),4.25-4.17(m,1H),4.05(q,J＝7.2Hz,2H),3.59(dd,J＝7.2,18.0Hz,1H),3.25(dd,J＝5.6,18.0Hz,1H),2.73(d,J＝5.6Hz,3H),1.13(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:558.1[M+H+].
实施例57，58,59
Figure PCTCN2015079870-appb-000151
该实施例如实施例42,43,44中描述的方法制备。
实施例57的核磁数据：1H NMR(400MHz,CDCl3)δ:7.81(d,J＝3.2Hz,1H),7.38(d,J＝3.2Hz,1H),7.33 (td,J＝3.2,8.4Hz,1H),7.30-7.22(m,1H),6.99(dq,J＝2.4,8.4Hz,1H),6.16(d,J＝4.8Hz,1H),4.72-4.65(m,1H),4.61-4.53(m,1H),4.52-4.44(m,1H),4.35-4.27(m,1H),4.09-4.01(m,2H),3.71-3.648(m,1H),3.40-3.17(m,1H),3.06(d,J＝2.4Hz,3H),1.13(q,J＝6.8Hz,3H).
LCMS(ESI)m/z:543.1[M+H+].
实施例58的核磁数据：1H NMR(400MHz,CDCl3)δ:7.80(d,J＝3.6Hz,1H),7.38(d,J＝3.2Hz,1H),7.35-7.27(m,2H),7.00(dt,J＝2.4,8.4Hz,1H),6.17(s,1H),4.84(d,J＝5.6Hz,1H),4.63-4.54(m,1H),4.52-4.44(m,1H),4.32(d,J＝2.4Hz,1H),4.13-3.99(m,2H),3.56-3.46(m,1H),3.42-3.31(m,1H),3.05(s,3H),1.14(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:543.1[M+H+].
实施例59的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.2Hz,1H),7.39(d,J＝3.2Hz,1H),7.33(dd,J＝2.4,8.4Hz,1H),7.23(dd,J＝6.4,8.8Hz,1H),6.98(dt,J＝2.4,8.4Hz,1H),6.16(s,1H),4.66-4.57(m,1H),4.50(d,J＝5.6Hz,1H),4.43(dd,J＝6.0,12.0Hz,1H),4.25-4.17(m,1H),4.05(q,J＝7.2Hz,2H),3.59(dd,J＝7.2,18.0Hz,1H),3.25(dd,J＝5.6,18.0Hz,1H),2.73(d,J＝5.6Hz,3H),1.13(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:543.1[M+H+].
实施例60，61，62
Figure PCTCN2015079870-appb-000152
将实施例36-6(200mg,0.398mmol)溶于无水吡啶(5mL)中，在室温下加入环丙基磺酰氯(56mg,0.477mmol)。加料完毕后，氮气保护下充分搅拌2小时，补加环丙基磺酰氯(56mg,0.477mmol)，氮气保护下继续搅拌2小时。当TLC(石油醚：乙酸乙酯；1:1)显示原料消失，将反应液倾倒入饱和碳酸氢钠溶液(15mL)中，并用二氯甲烷(20mL x 3)萃取，合并有机相，依次用水(10mL x 2)、饱和氯化钠溶液(10mL x 2)洗涤，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝100:1～3:1)纯化得到140mg的非对映异构体，产率：62％。
实施例60的核磁数据：1H NMR(400MHz,CDCl3)δ:7.81(d,J＝3.6Hz,1H),7.39(d,J＝3.2Hz,1H),7.36-7.31(m,1H),7.31-7.27(m,1H),7.01(dt,J＝2.4,8.0Hz,1H),6.17(s,1H),4.63(d,J＝6.4Hz,1H),4.62-4.56(m,1H),4.54-4.45(m,1H),4.39-4.29(m,1H),4.12-4.00(m,2H),3.59-3.49(m,1H),3.43-3.32(m,1H),2.57-2.42(m,1H),1.29-1.20(m,2H),1.15(t,J＝7.2Hz,3H),1.07(d,J＝7.2Hz,2H).
LCMS(ESI)m/z:569.1[M+H+].
将该非对映异构体经由SFC制备分离得到手性纯的实施例61，和实施例62。
实施例61的核磁数据：1H NMR(400MHz,CDCl3)δ:7.81(d,J＝3.6Hz,1H),7.39(d,J＝3.2Hz,1H),7.36-7.31(m,1H),7.31-7.27(m,1H),7.01(dt,J＝2.4,8.0Hz,1H),6.17(s,1H),4.63(d,J＝6.0Hz,1H),4.62-4.56(m,1H),4.54-4.45(m,1H),4.39-4.29(m,1H),4.12-4.00(m,2H),3.59-3.49(m,1H),3.43-3.32(m,1H),2.57-2.42(m,1H),1.29-1.20(m,2H),1.15(t,J＝7.2Hz,3H),1.06-1.08(m,2H).
LCMS(ESI)m/z:569.1[M+H+].
实施例62的核磁数据：1H NMR(400MHz,CDCl3)δ:7.81(d,J＝3.2Hz,1H),7.39(d,J＝3.2Hz,1H),7.33(dd,J＝2.4,8.4Hz,1H),7.25-7.20(m,1H),6.99(dt,J＝2.4,8.4Hz,1H),6.16(s,1H),4.65-4.60(m,1H),4.59-4.54(m,1H),4.49-4.42(m,1H),4.37-4.26(m,1H),4.05(q,J＝7.2Hz,2H),3.69(dd,J＝7.6,18.1Hz,1H),3.19(dd,J＝6.8,17.6Hz,1H),2.57-2.45(m,1H),1.27-1.22(m,2H),1.13(t,J＝7.2Hz,3H),1.08(d,J＝3.2Hz,1H),1.07-1.06(m,1H).
LCMS(ESI)m/z:569.1[M+H+].
实施例63，64
Figure PCTCN2015079870-appb-000153
这个实施例如实施例61,62中描述的方法制备。
实施例63的核磁数据：1H NMR(400MHz,DMSO-d6)δ:7.96(d,J＝3.2Hz,1H),7.86(d,J＝3.6Hz,1H),7.55(dd,J＝2.4,8.4Hz,1H),7.44(dd,J＝6.0,8.4Hz,1H),7.22(dt,J＝2.4,8.4Hz,1H),5.98(s,1H),4.42-4.39(m,1H),4.00–3.95(m,2H),3.48-3.38(m,3H),2.94(dd,J＝7.6,18.0Hz,1H),1.06(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:599.0[M+H+].
实施例64的核磁数据：1H NMR(400MHz,DMSO-d6)δ:7.96(d,J＝3.0Hz,1H),7.86(d,J＝3.6Hz,1H),7.57(dd,J＝2.4,8.4Hz,2H),7.22(dd,J＝6.0,8.4Hz,1H),5.99(s,1H),4.32-4.25(m,2H),4.03-3.95(m,2H),3.48-3.38(m,2H),3.26(s,1H),1.08(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:598.9[M+H+].
实施例65，66
Figure PCTCN2015079870-appb-000154
Figure PCTCN2015079870-appb-000155
第一步(化合物65-2的合成)
将化合物36-5(350mg,0.7mmol)溶于无水二氯甲烷(15mL)中，室温下加入三乙胺(211mg,2.09mmol)，65-1(149mg,1.05mmol)。加料结束后室温搅拌过夜。将反应液减压浓缩后用(30mL x 3)乙酸乙酯萃取，合并有机相，依次用水(20mL x 2)、饱和氯化钠溶液洗涤(20mL x 2)，用无水硫酸钠干燥，过滤，滤液减压浓缩后用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝2:1)纯化，得到220mg化合物65-2,产率：55％。
LCMS(ESI)m/z:571.1[M+H+].
第二步(实施例65，66的合成)
将化合物65-2(200mg,0.35mmol)溶于乙腈(15mL)中，加入碳酸钾(241mg,1.75mmol)，氮气保护下50℃搅拌6小时。将反应液冷却后减压浓缩，用(30mLx3)乙酸乙酯萃取，合并有机相，依次用水(20mL x 2)、饱和氯化钠溶液洗涤(20mL x 2)，用无水硫酸钠干燥，过滤，滤液减压浓缩后用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝1:1)纯化，经SFC分离得到49mg化合物65，55mg化合物66。产率：65％。
实施例65的核磁数据：1H NMR(400MHz,CDCl3)δ:7.81(d,J＝3.2Hz,1H),7.39(d,J＝3.6Hz,1H),7.32(dd,J＝2.4,8.4Hz,1H),7.22(dd,J＝6.0,8.4Hz,1H),6.99(dt,J＝2.4,8.4Hz,1H),6.16(s,1H),4.80-4.68(m,2H),4.42-4.36(m,2H),4.36-4.32(m,1H),4.05(q,J＝7.0Hz,2H),3.68-3.58(m,2H),3.54(dd,J＝7.6,18.0Hz,1H),3.39-3.29(m,1H),1.13(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:537.1[M+H+].
实施例66的核磁数据：1H NMR(400MHz,CDCl3)δ:7.80(d,J＝3.2Hz,1H),7.39(d,J＝3.0Hz,1H),7.33(dd,J＝2.0,8.4Hz,1H),7.23(dd,J＝6.34,8.4Hz,1H),7.00-6.91(m,1H),6.18(s,1H),4.77-4.70(m,1H),4.62(d,J＝12.4Hz,1H),4.46(dd,J＝6.8,12.4Hz,1H),4.43-4.35(m,2H),4.06(q,J＝7.0Hz,2H),3.66(t,J＝7.8Hz,2H),3.54-3.39(m,2H),1.14(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:537.1[M+H+].
实施例67
Figure PCTCN2015079870-appb-000156
Figure PCTCN2015079870-appb-000157
第一步(化合物67-1的合成)
将化合物23-1(1.3g,2.6mmol)溶于四氢呋喃(40mL)和水(10mL)中，加入碳酸钾(717mg,5.2mmol)。反应液在80℃下搅拌16小时。将反应液减压浓缩后得到粗产品，加入30mL乙酸乙酯和20mL水。乙酸乙酯(20mL x 2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到400mg化合物67-1。产率：35％。
LCMS(ESI)m/z:439.8[M+H+].
第二步(实施例67的合成)
将化合物67-1(210mg,0.48mmol)溶于无水二氯甲烷(10mL)中，加入三乙胺(242mg,2.4mmol)，然后加入三光气(210mg,0.72mmol)，在15℃搅拌30分钟。该反应液用20mL水淬灭，二氯甲烷(20mL x 3)萃取，有机层用饱和食盐水溶液(30mL x 2)洗涤，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用快速过柱仪纯化得到80mg实施例67。产率：24％。
实施例67的核磁数据：1H NMR(400MHz,DMSO-d6)δ:7.92(d,J＝4.5Hz,2H),7.73-7.83(m,1H),7.63(d,J＝6.5Hz,1H),7.32(t,J＝7.2Hz,1H),6.12(s,1H),5.45(s,2H),3.92-4.12(m,2H),1.08(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:466.0[M+H+].
实施例68
Figure PCTCN2015079870-appb-000158
Figure PCTCN2015079870-appb-000159
第一步(化合物68-2的合成)
将化合物23-1(500mg,1mmol)溶于无水N,N-二甲基甲酰胺(10mL)中，加入68-1(216mg,1mmol)，氢化钠(29mg,1.2mmol)。加料结束后，室温搅拌过夜。将反应液减压浓缩后用(200mL x 3)乙酸乙酯萃取，有机层用饱和食盐水溶液(200mL x 2)洗涤，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到120mg产物68-2。产率：19％。
LCMS(ESI)m/z:638.1[M+H+].
第二步(化合物68-3的合成)
将化合物68-2(120mg,0.19mmol)溶于甲苯(5mL)中，加入三氟乙酸酐(21.9mg,0.23mmol)。加料结束后，室温搅拌过夜。将反应液减压浓缩后用(100mLx3)二氯甲烷萃取，有机层用饱和食盐水溶液(50mL x 2)洗涤，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝5:1)纯化，得到100mg粗产物68-3。产率：100％。
LCMS(ESI)m/z:526.0[M+H+].
第三步(化合物68-4的合成)
将化合物68-3(100mg,0.19mmol)溶于甲苯(5mL)中回流搅拌过夜。将反应液减压浓缩后用(100mL x 3)二氯甲烷萃取，有机层用饱和食盐水溶液(50mL x 2)洗涤，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到60mg粗产物68-4。产率：66％。
LCMS(ESI)m/z:482.0[M+H+].
第四步(化合物68的合成)
将化合物68-4(60mg,0.13mmol)溶于无水二氯甲烷(10mL)中，加入HATU(56mg,0.16mmol)，三乙胺(53mg,0.52mmol)。加料结束，室温搅拌3小时。将反应液用(100mL x 3)二氯甲烷萃取，有机层用饱和食盐水溶液(50mLx2)洗涤，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝5:1)纯化，得到50mg产物68。产率：88％。
实施例68的核磁数据：1H NMR(400MHz,ACETONITRILE-d3)δ:7.82(d,J＝3.0Hz,1H),7.61(d,J＝3.3 Hz,1H),7.43-7.52(m,2H),7.16(dt,J＝2.6,8.4Hz,1H),6.20(s,1H),4.00-4.11(m,2H),3.34-3.45(m,1H),3.19-3.31(m,1H),2.68(t,J＝7.8Hz,2H),1.13(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:464.0[M+H+].
实施例69
Figure PCTCN2015079870-appb-000160
实施例69如实施例1中描述的方法制备。
实施例69的核磁数据：1H NMR(400MHz,CDCl3)δ:8.15(s,1H),7.92(br.s.,1H),7.45(br.s.,1H),7.30-7.38(m,1H),7.21(d,J＝8.0Hz,1H),6.17(s,1H),4.71(br.s.,1H),4.07-4.35(m,3H),3.69(d,J＝11.80Hz,1H),3.17(br.s.,1H),2.41(br.s.,1H),2.21(br.s.,1H),1.21(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:390.1[M+H+].
实施例70
Figure PCTCN2015079870-appb-000161
实施例70如实施例1中描述的方法制备。
实施例70的核磁数据：1H NMR(400MHz,CDCl3)δ:7.94(d,J＝3.3Hz,1H),7.85(d,J＝3.3Hz,1H),7.39-7.21(m,3H),6.06(s,1H),4.34(ddd,J＝3.8,7.7,10.8Hz,1H),4.21-4.11(m,1H),4.01-3.91(m,2H),3.31-3.22(m,1H),3.00(td,J＝9.2,17.9Hz,1H),2.14-1.98(m,2H),1.06(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:406.0[M+H+].
实施例71
Figure PCTCN2015079870-appb-000162
实施例71如实施例1中描述的方法制备。
LCMS(ESI)m/z:386.1[M+H+].
实施例72
Figure PCTCN2015079870-appb-000163
实施例72如实施例1中描述的方法制备。
实施例72的核磁数据：1H NMR(400MHz,CDCl3)δ:7.84(d,J＝3.2Hz,1H),7.39(d,J＝3.2Hz,1H),7.28-7.33(m,1H),6.73-6.84(m,2H),6.02(s,1H),4.39-4.43(m,1H),4.22-4.32(m,1H),4.05-4.11(m,2H),3.31-3.37(m,1H),3.00-3.04(m,1H),2.09-2.21(m,1H),1.97-2.09(m,1H),1.18(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:390.0[M+H+].
实施例73
Figure PCTCN2015079870-appb-000164
实施例73如实施例1中描述的方法制备。
实施例73的核磁数据：1H NMR(400MHz,CDCl3)δ:7.86(br.s.,1H),7.39(d,J＝15.0Hz,3H),6.99(br.s.,2H),5.83(br.s.,1H),4.05-4.50(m,4H),3.34(br.s.,1H),2.99(br.s.,1H),1.89-2.27(m,2H),1.25(br.s.,3H).
LCMS(ESI)m/z:372.0[M+H+].
实施例74
Figure PCTCN2015079870-appb-000165
实施例74如实施例1中描述的方法制备。
实施例74的核磁数据：1H NMR(400MHz,CDCl3)δ:7.85(d,J＝3.2Hz,1H),7.41(d,J＝3.0Hz,1H),6.68(s,1H),5.89(s,1H),4.45(ddd,J＝3.0,8.2,11.2Hz,1H),4.20-4.30(m,1H),4.07-4.18(m,2H),3.34(ddd,J＝3.2,8.4,18.0Hz,1H),2.98(td,J＝9.4,18.3Hz,1H),1.95-2.22(m,2H),1.24(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:427.9[M+H+].
实施例75
Figure PCTCN2015079870-appb-000166
第一步(化合物75-2的合成)
将化合物75-1(30g,250mmol)溶于(500mL)二甲苯中，在室温下，加入三氯化铟(5.5g,25mmol)，加料结束，升至140℃搅拌过夜。将反应液减压浓缩用DCM(500mL x 3)萃取，合并有机相，依次用水(200mL x 2)、饱和氯化钠溶液洗涤(200mL x 2)，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到5.1克包含顺式和反式的混合物75-2,构型之比为3:2，产率：8％。
一个构型的核磁数据：1H NMR(400MHz,CDCl3)δ:7.22-7.19(m,2.4H),7.09-7.05(m,2.4H),3.80(s,3H),2.41(s,3H),1.90(s,3H).
另外一个构型的核磁数据：1H NMR(400MHz,CDCl3)δ:7.22-7.19(m,1.6H),7.09-7.05(m,1.6H),3.53(s,2H),2.36(s,2H),2.30(s,2H).
第二步(化合物75-4的合成)
将化合物75-3(3.3g,20.4mmol)溶于(50mL)N-甲基吡咯烷酮中，在室温下，加入碳酸氢钠(4.97g,59.2mmol)，加料结束，升至120℃搅拌过夜。反应液冷却后慢慢加入75-2(5.1g,20.4mmol)，加料结束，将反应液在微波120℃下反应30分钟。将反应液将用乙酸乙酯(50mL x 3)萃取，合并有机相，依次用水(20mL x 2)、饱和氯化钠溶液洗涤(20mL x 3)，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝3:1)纯化，得到3.1g化合物75-4，产率：42％。
1H NMR(400MHz,CDCl3)δ:7.95(d,J＝3.0Hz,1H),7.72(br.s.,1H),7.56(d,J＝3.0Hz,1H),7.46(br.s., 2H),7.01(d,J＝7.5Hz,2H),3.94(qdd,J＝3.5,7.0,10.4Hz,2H),2.32(br.s.,3H),1.93(br.s.,3H),1.02(t,J＝6.9Hz,3H).
第三步(化合物75-5的合成)
将化合物75-4(3.1g,8.6mmol)溶于(50mL)四氯化碳中，在室温下，加入NBS(1.84g,10.32mmol)，AIBN(141mg,0.86mmol)，加料结束，升至90℃搅拌1小时。反应液冷却后慢慢加入化合物75-2(5.1g,20.4mmol)，加料结束，将反应液在微波120℃下反应30分钟。将反应液将用乙酸乙酯(50mL x 3)萃取，合并有机相，依次用水(20mL x 2)、饱和氯化钠溶液洗涤(20mL x 3)，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝5:1)纯化，得到900mg化合物75-5，产率：24％。
1H NMR(400MHz,CDCl3)δ:7.97(d,J＝3.0Hz,1H),7.86(br.s.,1H),7.69(d,J＝3.0Hz,1H),7.50-7.58(m,2H),7.00-7.13(m,2H),4.84(s,2H),3.98(q,J＝7.0Hz,2H),2.11(s,3H),1.03(t,J＝7.2Hz,3H).
第四步(化合物75-6的合成)
将丙二酸二叔丁酯(285mg,1.32mmol)溶于10mL无水N,N-二甲基甲酰胺中，慢慢加入氢化钠(53mg,1.32mmol)，室温搅拌30分钟。将化合物75-5(480mg,1.1mmol)加入到反应液中，室温搅拌过夜。反应液用乙酸乙酯(50mL x 3)萃取，合并有机相，依次用水(20mL x 2)、饱和氯化钠溶液洗涤(20mL x 3)，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝5:1)纯化，得到200mg化合物75-6，产率：32％。
1H NMR(400MHz,CDCl3)δ:7.84(s.,1H),7.53-7.63(m,1H),7.34-7.53(m,2H),7.01(d,J＝8.0Hz,2H),3.94(q,J＝7.0Hz,2H),3.74(br.s.,1H),3.01-3.31(m,3H),1.86-2.04(m,3H),1.41-1.54(m,18H),1.02(t,J＝5.8Hz,3H).
LCMS(ESI)m/z:574.1[M+H+].
第五步(化合物75-7的合成)
将化合物75-6(200mg,0.35mmol)溶于(5mL)甲苯中，慢慢加入三氟乙酸(798mg,7mmol)，将温度升高至120℃并在该温度下搅拌1小时。将反应液冷却至室温减压浓缩，用二氯甲烷(50mL x 3)萃取，合并有机相，依次用水(20mL x 2)、饱和氯化钠溶液洗涤(20mL x 3)，用无水硫酸钠干燥，过滤，减压浓缩得到粗产品130mg实施例75-7，产率：86％。
LCMS(ESI)m/z:418.1[M+H+].
第六步(化合物75-8的合成)
将化合物75-6(130mg,0.31mmol)溶于10mL干燥四氢呋喃中，在室温下，加入羰基二咪唑(147mg,0.91mmol)，室温搅拌15分钟。将反应液加入到硼氢化钠(118mg,3.1mmol)的10mL甲醇溶液中，加料结束，室温反应10分钟。将反应液减压浓缩后将用二氯甲烷(30mL x 3)萃取，合并有机相，依次用水(20mL x 2)、饱和氯化钠溶液洗涤(20mL x 3)，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝3:1)纯化，得到70mg化合物75-8，产率：56％。
LCMS(ESI)m/z:403.9[M+H+].
第七步(实施例75的合成)
将化合物75-8(70mg,0.17mmol)溶于10mL干燥二氯甲烷中，在室温下，加入三乙胺(35mg,0.34mmol)，甲基磺酰氯(29mg,0.25mmol)室温搅拌30分钟。将反应液用二氯甲烷(30mL x 3) 萃取，合并有机相，依次用水(20mL x 2)、饱和氯化钠溶液洗涤(20mL x 3)，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝3:1)纯化，得到50mg实施例75，产率：76％。
实施例75的核磁数据：1H NMR(400MHz,CDCl3)δ:7.84(d,J＝3.2Hz,1H),7.46(dd,J＝5.5,8.5Hz,2H),7.38(d,J＝3.2Hz,1H),6.99(t,J＝8.6Hz,2H),4.21-4.39(m,2H),3.98(q,J＝7.2Hz,2H),3.12(t,J＝7.8Hz,2H),2.06(q,J＝7.4Hz,2H),1.94(s,3H),1.06(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:386.5[M+H+].
实施例76
Figure PCTCN2015079870-appb-000167
实施例76如实施例1中描述的方法制备。
实施例76的核磁数据：1H NMR(400MHz,DMSO-d6)δ:8.54(d,J＝2.0Hz,1H),8.09(dt,J＝2.0,9.2Hz,1H),7.45(dd,J＝6.0,8.4Hz,1H),7.38(dd,J＝2.4,8.4Hz,1H),7.21(dt,J＝2.4,8.4Hz,1H),6.02(s,1H),3.90-4.03(m,2H),3.52-3.54(m,1H),3.34-3.38(m,1H),3.23-3.27(m,1H),3.05-3.10(m,1H),1.91-2.03(m,2H),1.08(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:436.0[M+H+].
实施例77
Figure PCTCN2015079870-appb-000168
实施例77如实施例1中描述的方法制备。
实施例77的核磁数据：1H NMR(400MHz,CDCl3)δ:8.56(d,J＝5.0Hz,1H),7.67(br.s.,1H),7.34(dd,J＝6.2,8.2Hz,1H),7.08-7.14(m,1H),6.93(dt,J＝2.5,8.2Hz,1H),6.21(s,1H),4.18-4.29(m,1H),3.97-4.13(m,3H),3.39(ddd,J＝4.0,8.4,18.2Hz,1H),3.02-3.16(m,1H),1.96-2.19(m,2H),1.15(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:406.1[M+H+].
实施例78
Figure PCTCN2015079870-appb-000169
实施例78如实施例1中描述的方法制备。
实施例78的核磁数据：1H NMR(400MHz,CDCl3)δ:7.33-7.26(m,1H),7.12(d,J＝7.0Hz,1H),6.98(br.s.,1H),6.92(t,J＝7.4Hz,1H),6.84(s,1H),6.20(s,1H),4.21(d,J＝8.5Hz,1H),4.04(q,J＝6.9Hz,2H),3.96(br.s.,1H),3.63(br.s.,3H),3.44-3.31(m,1H),3.10(td,J＝8.9,17.8Hz,1H),2.15-1.91(m,2H),1.13(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:403.1[M+H+].
实施例79
Figure PCTCN2015079870-appb-000170
实施例79如实施例1中描述的方法制备。
实施例79的核磁数据：1H NMR(400MHz,CDCl3)δ:7.29-7.33(m,1H),7.13(dd,J＝2.5,8.8Hz,1H),6.87-6.98(m,2H),6.19(s,1H),4.40(ddd,J＝3.5,8.0,11.2Hz,1H),4.19-4.31(m,1H),4.07(dq,J＝1.6,7.0Hz,2H),3.34-3.47(m,1H),3.08(td,J＝9.2,18.2Hz,1H),2.46(s,3H),2.01-2.25(m,2H),1.16(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:420.1[M+H+].
实施例80
Figure PCTCN2015079870-appb-000171
第一步(化合物80-1的合成)
将化合物4(500mg,1.11mmol)溶于无水四氢呋喃(10mL)中，慢慢加入1mL三溴化硼，室温下搅拌1小时。将反应液减压浓缩，用(50mL x 3)乙酸乙酯萃取，合并有机相，依次用水(30mL x 2)、饱和氯化钠溶液洗涤(30mL x 2)，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝5:1)纯化，得到产物400mg化合物80-1，产率：85％。
第二步(实施例80的合成)
将化合物80-1(50mg,0.12mmol)溶于无水四氢呋喃(3mL)中，慢慢加入三乙胺(48mg,0.48mmol)，化合物80-2(19mg,0.24mmol)，室温下搅拌2小时。将反应液减压浓缩，用乙酸乙酯(30mL x 3)萃取，合并有机相，依次用水(20mL x2)、饱和氯化钠溶液洗涤(20mL x 2)，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到产物400mg实施例80，产率：61％。
实施例80的核磁数据：1H NMR(400MHz,CDCl3)δ:7.76(d,J＝3.2Hz,1H),7.32(d,J＝3.2Hz,1H),7.29-7.26(m,1H),7.23(dd,J＝2.8,8.8Hz,1H),6.93(dt,J＝2.4,8.2Hz,1H),6.15(s,1H),5.19(d,J＝6.0Hz,1H),5.04(d,J＝6.0Hz,1H),4.43-4.32(m,1H),4.28-4.18(m,1H),3.41(ddd,J＝3.6,8.4,18.0Hz,1H),3.19(s,3H),3.06(td,J＝9.3,18.4Hz,1H),2.20-2.08(m,1H),2.06-1.93(m,1H).
LCMS(ESI)m/z:466.0[M+H+].
实施例81
Figure PCTCN2015079870-appb-000172
实施例81如实施例80中描述的方法制备。
实施例81的核磁数据：1H NMR(400MHz,CDCl3)δ:7.81(d,J＝3.2Hz,1H),7.37(d,J＝3.2Hz,1H),7.32(dd,J＝2.6,8.4Hz,1H),7.28-7.24(m,1H),6.97(dt,J＝2.6,8.2Hz,1H),6.19-6.14(m,1H),5.99-5.66(m,1H),4.47-4.38(m,1H),4.34-4.25(m,1H),4.20(dt,J＝4.0,13.6Hz,2H),3.39(ddd,J＝3.8,8.5,18.3Hz,1H),3.08(td,J＝9.2,18.3Hz,1H),2.25-2.13(m,1H),2.13-2.02(m,1H).
LCMS(ESI)m/z:486.0[M+H+].
实施例82
Figure PCTCN2015079870-appb-000173
Figure PCTCN2015079870-appb-000174
第一步(化合物82-3的合成)
将化合物82-1(2.25g,36.9mmol)溶于甲醇(30mL)中，在室温下加入化合物82-2(5.01g,36.9mmol)，将温度升高到70℃并搅拌过夜。将反应液冷却至室温，慢慢的加入硼氢化钠(1.4g,36.9mmol)，加料结束，将温度升高到70℃搅拌2小时。将反应液冷却至室温，用乙酸乙酯(30mL x 3)萃取，合并有机相，依次用水(50mL x 2)、饱和氯化钠溶液洗涤(100mL x 3)，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10：1)纯化，得到6.0g化合物82-3，产率：90％。1H NMR(400MHz,CDCl3)δ:7.24(d,J＝8.8Hz,2H),6.88(d,J＝8.8Hz,2H),3.81(s,3H),3.75(s,2H),3.65(t,J＝5.2Hz,2H),2.79(t,J＝5.2Hz,2H),2.34(br,2H).
第二步(化合物82-4的合成)
将化合物82-3(1.0g,5.5mmol)溶于乙腈(30mL)中，在室温下加入化合物6-5(2.8g,5.5mmol)，碳酸钾(1.5g,11mmol)，加料完毕，在室温搅拌过夜。将反应液加压浓缩，用乙酸乙酯(30mL x 3)萃取，合并有机相，依次用水(50mL x 2)、饱和氯化钠溶液洗涤(100mL x 2)，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到2.7g的化合物82-4，产率：82％。
LCMS(ESI)m/z:602.9[M+H+].
第三步(化合物82-5的合成)
将化合物82-4(2.5g,4.2mmol)溶于无水二氯甲烷(20mL)中，加入三乙胺(839mg,8.3mmol)，甲磺酰氯(710mg,6.23mmol)，加料结束，室温搅拌3小时。将反应用(200mL x 3)二氯甲烷萃取，有机层用饱和食盐水溶液(200mL x 2)洗涤，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到2.8g产物82-5，产率：99％。
LCMS(ESI)m/z:681.0[M+H+].
第四步(化合物82-6的合成)
将化合物82-5(2.8g,4.1mmol)溶于乙腈(30mL)中，在室温下，加入碳酸钾(1.1g,8.2mmol,加料完毕，将反应液升至80℃并搅拌过夜。将反应液加压浓缩，用乙酸乙酯(30mL x 3)萃取，合并有 机相，依次用水(50mL x 2)、饱和氯化钠溶液洗涤(100mL x 2)，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到2.0g化合物82-6，产率：83％。
1H NMR(400MHz,CDCl3)δ:7.93(d,J＝3.2Hz,1H),7.84(d,J＝3.2Hz,1H),7.58(dd,J＝2.4,8.6Hz,1H),7.30-7.38(m,1H),7.27-7.30(m,1H),7.25(s,2H),6.91(d,J＝8.6Hz,2H),5.94(s,1H),4.53-4.62(m,1H),4.10(d,J＝16.4Hz,1H),3.91(dqd,J＝3.6,7.01,13.2Hz,2H),3.70-3.75(m,4H),3.60(s,2H),3.45-3.53(m,1H),2.68-2.79(m,2H),0.98(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:585.0[M+H+].
第五步(化合物82-8的合成)
将化合物82-6(420mg,0.7mmol)溶于无水二氯甲烷(10mL)中，在0℃下，加入三乙胺(145mg,1.43mmol)，化合物82-7(205mg,1.43mmol)，0℃搅拌1.5小时，将反应液减压浓缩，加入5mL甲醇，将温度升至80℃并搅拌1小时。将反应液加压浓缩，用乙酸乙酯(30mL x 3)萃取，合并有机相，依次用水(50mL x 2)、饱和氯化钠溶液洗涤(50mL x 2)，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到300mg化合物82-8,产率：90％。
1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.0Hz,1H),7.42-7.33(m,2H),7.28(d,J＝6.4Hz,1H),6.99(dt,J＝2.4,8.4Hz,1H),6.14(s,1H),4.75-4.64(m,1H),4.58-4.29(m,2H),4.15-3.97(m,2H),3.52-3.30(m,2H),3.17-3.04(m,1H),1.14(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:465.0[M+H+].
第六步(实施例82的合成)
将化合物82-8(100mg,0.2mmol)溶于的无水二氯甲烷(10mL)中，室温下加入三乙胺(22mg,0.2mmol)，化合物82-9(23mg,0.2mmol)，加料结束，室温搅拌1小时。加水淬灭，将反应液用(30mL x 3)二氯甲烷萃取，有机层用饱和食盐水溶液(20mL x 2)洗涤，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到56mg实施例82，产率：49％。
实施例82的核磁数据：1H NMR(400MHz,CDCl3)δ:7.6(d,J＝3.0Hz,1H),7.41(d,J＝3.0Hz,1H),7.35(d,J＝6.0Hz,1H),7.13-7.19(m,1H),6.96(t,J＝7.2Hz,1H),6.14(s,1H),5.23(br.s.,1H),4.95-5.12(m,1H),4.69(br.s.,1H),4.20(q,J＝6.4Hz,2H),4.03-4.15(m,2H),3.92(d,J＝14.4Hz,2H),3.55(br.s.,1H),1.30(t,J＝6.8Hz,3H),1.17(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:537.2[M+H+].
实施例83
Figure PCTCN2015079870-appb-000175
实施例83如实施例82-8制备方法得到。
实施例83的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.0Hz,1H),7.42-7.33(m,2H),7.28(d, J＝6.4Hz,1H),6.99(dt,J＝2.4,8.4Hz,1H),6.14(s,1H),4.75-4.64(m,1H),4.58-4.29(m,2H),4.15-3.97(m,2H),3.52-3.30(m,2H),3.17-3.04(m,1H),1.14(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:465.0[M+H+].
实施例84
Figure PCTCN2015079870-appb-000176
实施例84如实施例82制备方法得到。
实施例84的核磁数据：1H NMR(400MHz,CDCl3)δ:7.84(d,J＝3.0Hz,1H),7.42(d,J＝3.0Hz,1H),7.30-7.39(m,2H),7.01(dt,J＝2.8,8.0Hz,1H),6.17(s,1H),5.24(d,J＝16.6Hz,1H),4.77-4.87(m,1H),4.64(d,J＝16.6Hz,1H),4.42(d,J＝5.0Hz,1H),4.00-4.20(m,2H),3.75-3.88(m,2H),3.66-3.74(m,1H),2.78(d,J＝5.6Hz,3H),1.17(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:558.1[M+H+].
实施例85
Figure PCTCN2015079870-appb-000177
实施例85如实施例82制备方法得到。
实施例85的核磁数据：1H NMR(400MHz,CDCl3)δ:7.85(d,J＝3.2Hz,1H),7.43(d,J＝3.2Hz,1H),7.39(dd,J＝2.4,8.4Hz,1H),7.21(dd,J＝6.0,8.4Hz,1H),6.96-7.04(m,1H),6.19(s,1H),5.24-5.41(m,1H),5.05(d,J＝19.2Hz,1H),4.77(br.s.,1H),4.08-4.23(m,2H),3.99(br.s.,2H),3.82(s,3H),3.56-3.67(m,1H),1.21(t,J＝6.4Hz,3H).
LCMS(ESI)m/z:522.8[M+H+].
实施例86
Figure PCTCN2015079870-appb-000178
实施例86如实施例82制备方法得到。
实施例86的核磁数据：1H NMR(400MHz,CDCl3)δ:7.84(d,J＝3.2Hz,1H),7.44(d,J＝3.2Hz,1H),7.38(dd,J＝2.4,8.0Hz,1H),7.20(dd,J＝6.0,8.8Hz,1H),6.99(dt,J＝2.4,8.4Hz,1H),6.17(s,1H),5.15-4.90(m,2H),4.89-4.82(m,1H),4.19-4.04(m,2H),3.96-3.86(m,1H),3.77-3.67(m,2H),2.89(s,3H),1.18(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:507.0[M+H+].
实施例87
Figure PCTCN2015079870-appb-000179
实施例87如实施例82制备方法得到。
实施例87的核磁数据：1H NMR(400MHz,CDCl3)δ:7.84(d,J＝3.2Hz,1H),7.44(d,J＝3.2Hz,1H),7.38(dd,J＝2.8,8.4Hz,1H),7.20(dd,J＝6.0,8.8Hz,1H),6.99(dt,J＝2.8,8.4Hz,1H),6.17(s,1H),5.14-4.90(m,2H),4.90-4.82(m,1H),4.20-4.04(m,2H),3.96-3.85(m,1H),3.76-3.66(m,2H),2.89(s,3H),1.18(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:543.0[M+H+].
实施例88
Figure PCTCN2015079870-appb-000180
实施例88如实施例82制备方法得到。
实施例88的核磁数据：1H NMR(400MHz,CDCl3)δ:7.84(d,J＝3.2Hz,1H),7.42(d,J＝3.2Hz,1H),7.38(dd,J＝2.5,8.2Hz,1H),7.20(dd,J＝6.0,8.5Hz,1H),7.00(dt,J＝2.5,8.2Hz,1H),6.18(s,1H),4.99-5.20(m,2H),4.88(d,J＝3.8Hz,1H),4.70-4.82(m,1H),3.93-4.23(m,4H),3.54-3.66(m,1H),2.89(d,J＝4.5Hz,3H),1.19(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:544.0[M+Na+].
实施例89
Figure PCTCN2015079870-appb-000181
实施例89如实施例82制备方法得到。
实施例89的核磁数据：1H NMR(400MHz,CDCl3)δ:7.85(d,J＝3.2Hz,1H),7.43(d,J＝3.2Hz,1H),7.39(dd,J＝2.4,8.4Hz,1H),7.22-7.14(m,1H),7.05-6.95(m,1H),6.22-6.17(m,1H),5.39-5.07(m,2H),5.04-4.77(m,2H),4.22-3.95(m,4H),3.80-3.50(m,4H),1.20(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:522.0[M+H+].
实施例90
Figure PCTCN2015079870-appb-000182
实施例90如实施例82制备方法得到。
实施例90的核磁数据：1H NMR(400MHz,CDCl3)δ:7.83(d,J＝3.2Hz,1H),7.41(d,J＝3.2Hz,1H),7.36(dd,J＝2.4,8.0Hz,1H),7.14(dd,J＝6.0,8.8Hz,1H),6.98(dt,J＝2.4,8.4Hz,1H),6.18(s,1H),5.02(dd,J＝2.8,5.6Hz,2H),4.97-4.77(m,3H),4.48(t,J＝6.8Hz,2H),4.16-3.96(m,4H),3.76-3.67(m,1H),1.72(s,3H),1.20-1.08(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:563.1[M+H+].
实施例91
Figure PCTCN2015079870-appb-000183
实施例91如实施例82制备方法得到。
实施例91的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.2Hz,1H),7.40(d,J＝3.2Hz,1H),7.37(dd,J＝2.4,8.4Hz,1H),7.19(dd,J＝6.0,8.4Hz,1H),6.99(t,J＝7.2Hz,1H),6.22-6.14(m,1H),5.78-5.23(m,2H),4.95-4.70(m,1H),4.27-3.99(m,4H),3.73-3.40(m,1H),2.04-1.83(m,1H),1.23-1.11(m,3H),1.11-0.99(m,2H),0.86(s,2H).
LCMS(ESI)m/z:533.1[M+H+].
实施例92
Figure PCTCN2015079870-appb-000184
实施例92如实施例82制备方法得到。
实施例92的核磁数据：1H NMR(400MHz,CDCl3)δ:7.83(d,J＝3.2Hz,1H),7.40(d,J＝3.2Hz,1H),7.39-7.34(m,J＝2.4,8.4Hz,1H),7.16(dd,J＝6.0,8.4Hz,1H),6.97(dt,J＝2.4,8.4Hz,1H),6.19(s,1H),5.55-5.11(m,2H),4.84-4.71(m,1H),4.20-4.00(m,4H),3.68-3.53(m,1H),2.98(td,J＝6.8,13.6Hz,1H),1.23-1.12(m,9H).
LCMS(ESI)m/z:535.1[M+H+].
实施例93
Figure PCTCN2015079870-appb-000185
实施例93如实施例82制备方法得到。
实施例93的核磁数据：1H NMR(400MHz,CDCl3)δ:7.84(d,J＝3.2Hz,1H),7.43(d,J＝3.2Hz,1H),7.38(dd,J＝2.4,8.4Hz,1H),7.21(dd,J＝6.0,8.8Hz,1H),6.99(dt,J＝2.4,8.4Hz,1H),6.18(s,1H),5.15-4.91(m,2H),4.87(td,J＝4.4,13.6Hz,1H),4.20-4.06(m,2H),4.01(m,1H),3.75(td,J＝4.0,12.0Hz,1H),3.66(m,1H),2.44-2.35(m,1H),1.24-1.15(m,5H),1.01-0.86(m,2H).
LCMS(ESI)m/z:569.0[M+H+].
实施例94
Figure PCTCN2015079870-appb-000186
将化合物82-8(93mg,0.2mmol)溶于二氯乙烷(10mL)中，加入相应的醛(44mg,0.4mmol)，醋酸硼氢化钠(127mg,0.6mmol)和醋酸(60mg,1mmol)。反应物在室温搅拌20分钟。减压浓缩后得到粗品，经过HPLC制备分离得到10mg实施例94,产率10％。
实施例94的核磁数据：1H NMR(400MHz,CDCl3)δ:7.96(d,J＝3.2Hz,1H),7.87(d,J＝3.2Hz,1H),7.60(dd,J＝8.4,2.4Hz,1H),7.24-7.39(m,2H),5.96(s,1H),4.56-4.65(m,1H),4.43(d,J＝5.6Hz,1H),4.19(d,J＝16.4Hz,1H),3.96(m,2H),3.84(d,J＝16.4Hz,1H),3.74(s,2H),3.48-3.57(m,1H),2.77-2.89(m,2H),2.40(s,3H),1.04(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:560.1[M+H+].
实施例95
Figure PCTCN2015079870-appb-000187
将化合物83(50mg,0.11mmol)溶于乙腈(10mL)中，加入化合物95-1(45mg,0.33mmol)，碳酸钾(76mg,0.55mmol)。加料结束后，将温度升高至50℃搅拌过夜。将反应液冷却后抽滤，滤液减压浓缩后得到粗品，经过HPLC制备分离得到23mg实施例95,产率41％。
实施例95的核磁数据：1H NMR(400MHz,CDCl3)δ:7.95(d,J＝3.2Hz,1H),7.86(d,J＝3.2Hz,1H),7.60(dd,J＝2.4,8.4Hz,1H),7.45-7.38(m,2H),7.26(dt,J＝2.4,8.4Hz,1H),7.18(br.s.,1H),5.97(s,1H),4.64-4.54(m,1H),4.23(d,J＝16.6Hz,1H),4.05-3.91(m,2H),3.87(d,J＝16.8Hz,1H),3.61-3.53(m,1H),3.10(s,2H),2.92-2.81(m,2H),1.05(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:522.0[M+H+].
实施例96
Figure PCTCN2015079870-appb-000188
实施例96如实施例95制备方法得到。
实施例96的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(br.s.,1H),7.43-7.28(m,3H),6.99(br.s.,1H),6.13(br.s.,1H),4.87(d,J＝11.2Hz,1H),4.56(d,J＝15.6Hz,1H),4.20-3.92(m,2H),3.49(d,J＝15.6Hz,2H),2.91-2.68(m,2H),2.49(br.s.,3H),1.14(t,J＝6.4Hz,3H).
LCMS(ESI)m/z:479.1[M+H+].
实施例97
Figure PCTCN2015079870-appb-000189
实施例97如实施例95制备方法得到。
实施例97的核磁数据：1H NMR(400MHz,CDCl3)δ:7.93(d,J＝3.2Hz,1H),7.84(d,J＝3.2Hz,1H),7.58(dd,J＝2.4,8.4Hz,1H),7.30-7.38(m,1H),7.27-7.30(m,1H),7.25(s,2H),6.91(d,J＝8.4Hz,2H),5.94(s,1H),4.53-4.62(m,1H),4.10(d,J＝16.4Hz,1H),3.91(m,2H),3.70-3.75(m,4H),3.60(s,2H),3.45-3.53(m,1H),2.68-2.79(m,2H),0.98(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:585.0[M+H+].
实施例98
Figure PCTCN2015079870-appb-000190
实施例98如实施例95制备方法得到。
实施例98的核磁数据：1H NMR(400MHz,CDCl3)δ:7.95(d,J＝3.2Hz,1H),7.86(d,J＝3.2Hz,1H),7.64-7.55(m,1H),7.42-7.33(m,1H),7.32-7.24(m,1H),5.97(s,1H),4.67-4.54(m,1H),4.30(d,J＝16.6Hz,1H),4.05-3.89(m,3H),3.65(s,3H),3.58-3.48(m,3H),3.03-2.86(m,2H),1.05(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:537.1[M+H+].
实施例99
Figure PCTCN2015079870-appb-000191
实施例99如实施例95制备方法得到。
实施例99的核磁数据：1H NMR(400MHz,CDCl3)δ:7.92(br.s.,1H),7.86(br.s.,1H),7.59(d,J＝7.2Hz, 1H),7.37(br.s.,1H),7.26(br.s.,1H),5.97(s,1H),4.57(br.s.,1H),4.33-4.02(m,2H),3.92(br.s.,2H),3.23-2.79(m,5H),1.02(br.s.,3H).
LCMS(ESI)m/z:523.0[M+H+].
实施例100
Figure PCTCN2015079870-appb-000192
实施例100如实施例94制备方法得到。
实施例100的核磁数据：1H NMR(400MHz,DMSO-d6)δ:8.38(s,1H),8.09(s,1H),7.95(d,J＝3.2Hz,1H),7.87(d,J＝3.2Hz,1H),7.60(dd,J＝8.4,2.4Hz,1H),7.23-7.40(m,2H),5.96(s,1H),4.55-4.67(m,1H),4.24(d,J＝16.4Hz,1H),3.89-4.04(m,2H),3.78(d,J＝16.4Hz,1H),3.64(s,2H),3.47-3.54(m,1H),2.84(t,J＝5.6Hz,2H),1.05(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:546.1[M+H+].
实施例101
Figure PCTCN2015079870-appb-000193
实施例101如实施例95制备方法得到。
实施例101的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.2Hz,1H),7.42(d,J＝3.2Hz,1H),7.38(dd,J＝2.4,8.4Hz,1H),7.21(dd,J＝6.0,8.8Hz,1H),7.02(dt,J＝2.4,8.4Hz,1H),6.17(s,1H),5.06-4.79(m,3H),4.19-4.00(m,2H),3.90-3.77(m,2H),3.68-3.60(m,1H),1.16(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:489.8[M+H+].
实施例102
Figure PCTCN2015079870-appb-000194
实施例102如实施例94制备方法得到。
实施例102的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.2Hz,1H),7.41-7.33(m,2H),7.29(dd,J＝6.0,8.8Hz,1H),7.02(dt,J＝2.4,8.4Hz,1H),6.15(s,1H),4.87(td,J＝4.4,12.0Hz,1H),4.77(q,J＝6.4Hz,2H),4.69(q,J＝6.4Hz,2H),4.39(d,J＝15.8Hz,1H),4.15-4.04(m,1H),3.99(qd,J＝7.2,10.8Hz,1H),3.72(quin,J＝6.2Hz,1H),3.56(d,J＝16.0Hz,1H),3.53-3.45(m,1H),2.74(t,J＝5.6Hz,2H),1.13(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:521.0[M+H+].
实施例103
Figure PCTCN2015079870-appb-000195
实施例103如实施例95制备方法得到。
实施例103的核磁数据：1H NMR(400MHz,CDCl3)δ:7.85(d,J＝3.2Hz,1H),7.44(d,J＝3.2Hz,1H),7.39(dd,J＝2.4,8.4Hz,1H),7.19(dd,J＝6.0,8.4Hz,1H),7.01(dt,J＝2.4,8.4Hz,1H),6.19(s,1H),6.17(br.s.,1H),5.34-5.47(m,2H),4.88(m,1H),4.47(ddd,J＝4.4,7.2,12.0Hz,1H),4.14-4.23(m,2H),4.05-4.13(m,1H),3.93(ddd,J＝4.4,7.6,12.0Hz,1H),3.76(quin,J＝6.4Hz,2H),1.27-1.32(m,3H),1.20(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:551.8[M+H+].
实施例104
Figure PCTCN2015079870-appb-000196
Figure PCTCN2015079870-appb-000197
第一步(实施例104-1的合成)
将化合物23-1(1.0g,1.99mmol)溶于的无水N,N-二甲基甲酰胺(100mL)中，室温下加入叠氮化钠(240mg,9.69mmol)，加料结束，氮气保护下室温搅拌1小时。将反应液用(300mL x 3)二氯甲烷萃取，有机层用饱和食盐水溶液(200mL x 2)洗涤，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩得到1.1g实施例104-1，产率：100％。
LCMS(ESI)m/z:466.6[M+H+].
第二步(实施例104-2的合成)
将Pd/C(100mg)溶于100mL的无水四氢呋喃中，室温下加入104-1(1.1g,2.37mmol)，Boc2O(618mg,2.84mmol)，加料结束，氢气氛围下(45psi)室温搅拌过夜。将反应液过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到760mg实施例104-2，产率：60％。
LCMS(ESI)m/z:560.9[M+Na+].
第三步(实施例104-3的合成)
将104-2(760mg,1.41mmol)溶于乙酸乙酯(5mL)中，室温下加入盐酸的乙酸乙酯溶液(10mL)，室温搅拌1小时。将反应液减压浓缩，用乙酸乙酯洗涤，过滤得到700mg实施例104-3，产率：97％。
LCMS(ESI)m/z:462.7[M+Na+].
第四步(实施例104-4的合成)
将104-3(700mg,1.4mmol)溶于无水二氯甲烷(10mL)中，0℃加入三乙胺(470mg,4.6mmol)，氯乙酰氯(0.1mL,1.4mmol)，加料结束，将温度升高到室温搅拌1小时。将反应液用(100mL x 3)二氯甲烷萃取，有机层依次用水(100mL x 2)，饱和食盐水溶液(100mL x 2)洗涤，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到700mg实施例104-4，产率：97％。
LCMS(ESI)m/z:538.7[M+H+].
第五步(实施例104的合成)
将104-4(110mg,0.21mmol)溶于乙腈(2mL)中，室温加入碳酸钾(59mg,0.42mmol)，加料 结束，将温度升高到回流状态搅拌过夜。将反应液冷却到室温，过滤，滤液减压浓缩后用(30mL x 3)二氯甲烷萃取，有机层依次用水(30mL x 2)，饱和食盐水溶液(30mL x 2)洗涤，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝5:1)纯化，得到5mg实施例104，产率：5％。
实施例104的核磁数据：1H NMR(400MHz,CDCl3)δ:7.92(d,J＝3.2Hz,1H),7.46(d,J＝3.2Hz,2H),7.36(dd,J＝2.4,8.4Hz,1H),7.05-6.97(m,1H),6.97-6.90(m,1H),6.00(d,J＝16.8Hz,1H),5.72(s,1H),5.52(d,J＝4.4Hz,1H),4.42(d,J＝16.8Hz,1H),4.23(dq,J＝3.2,7.1Hz,2H),3.47(d,J＝1.6Hz,1H),1.28(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:478.8[M+H+].
实施例105
Figure PCTCN2015079870-appb-000198
第一步(实施例105-1的合成)
将化合物23-1(300mg,0.6mmol)溶于无水N,N-二甲酰乙酰胺(10mL)中，室温下加入甲胺盐酸盐(405mg,0.6mmol)，叔丁醇钾(334mg,2.98mmol)加料结束，氮气保护下室温搅拌1小时。将反应液倒入冰水中，用乙酸乙酯(100mL x 3)萃取，有机层用饱和食盐水溶液(50mL x 2)洗涤，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝5:1)纯化，得到160mg实施例105-1，产率：59％。
LCMS(ESI)m/z:452.9[M+H+].
第二，三步(实施例105的合成)
实施例105的第二，三步如实施例104相同方法制备。
实施例105的核磁数据：1H NMR(400MHz,CDCl3)δ:7.93(d,J＝3.2Hz,1H),7.71(d,J＝3.2Hz,1H),7.49-7.38(m,2H),7.12(dt,J＝2.4,8.4Hz,1H),6.17(s,1H),5.26(d,J＝16.0Hz,1H),5.06(d,J＝4.0Hz,2H),4.37(d,J＝16.0Hz,1H),4.09(dq,J＝3.2,7.2Hz,2H),3.11(s,3H),1.15(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:492.8[M+H+].
实施例106
Figure PCTCN2015079870-appb-000199
该实施例如实施例104相同方法制备。
实施例106的核磁数据：1H NMR(400MHz,MeOD-d4)δ:7.95(d,J＝3.2Hz,1H),7.73(d,J＝3.2Hz,1H),7.60(dd,J＝6.0,8.8Hz,1H),7.46(dd,J＝2.8,8.4Hz,1H),7.13(dt,J＝2.4,8.4Hz,1H),6.19(s,1H),5.38-5.19(m,2H),5.03(d,J＝16.8Hz,1H),4.62-4.53(m,2H),4.21(d,J＝17.6Hz,1H),4.16-4.03(m,2H),3.80(s,3H),1.16(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:550.8[M+H+].
实施例107
Figure PCTCN2015079870-appb-000200
Figure PCTCN2015079870-appb-000201
第一步(化合物107-2的合成)
将化合物107-1(8.0g,39.6mmol)溶于无水乙醇(200mL)，加入2-溴-4-氟苯甲醛(8.0g,39.6mmol)，噻唑二甲脒盐酸盐(6.5g,39.6mmol)，醋酸钠(6.5g,79.2mmol)。反应液温度慢慢升至回流，回流下将反应搅拌过夜。将反应液减压浓缩后用(500mL x 3)乙酸乙酯萃取，有机层用饱和食盐水溶液(300mL x 2)洗涤，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，所得到5.0g的产物107-2，产率：25.5％。
LCMS(ESI)m/z:496.0[M+H+].
第二步(化合物107-3的合成)
将化合物107-2(5.0g,10.0mmol)溶于80mL四氢呋喃和80mL水中，加入氢氧化锂(1.3g,30.2mmol)。反应液在15℃下搅拌2小时。将反应液减压浓缩后得到粗产品，加入100mL甲基叔丁醚和水(50mL)，缓慢的加入1N的盐酸调节PH＝3萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到3.0g的化合物107-3,产率：37.9％。
1H NMR(400MHz,DMSO-d6)δ:10.13(s,1H),7.85-7.96(m,2H),7.60(dd,J＝6.4,8.8Hz,1H),7.52(dd,J＝2.4,8.4Hz,1H),7.18(dt,J＝2.4,8.4Hz,1H),5.96(s,1H),3.88(d,J＝6.8Hz,2H),0.99(t,J＝7.2Hz,3H).
第三步(化合物107-4的合成)
将化合物107-3(3.0g,6.4mmol)溶于无水二氯甲烷(60mL)中，加入羰基二咪唑(2.1g,12.8mmol)，在15℃搅拌30分钟。该反应液倾倒入硼氢化钠(4.9g,64mmol)的甲醇(30mL)中，搅拌15分钟。该反应液用水(50mL)和二氯甲烷(100mL)稀释，二氯甲烷(50mL x 3)萃取，有机层用饱和食盐水溶液(30mL x 2)洗涤，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝1:1)纯化，所得到1.0g的化合物107-4,产率：34.4％。
1H NMR(400MHz,CDCl3)δ:8.59(br.s.,1H),7.84(d,J＝2.4Hz,1H),7.48-7.64(m,1H),7.41(dd,J＝6.4,8.8Hz,1H),7.32(dd,J＝2.4,8.0Hz,1H),7.02(d,J＝5.6Hz,1H),6.02-6.25(m,1H),4.04(d,J＝7.2Hz,4H),3.27-3.38(m,1H),3.19(br.s.,1H),1.11(t,J＝7.2Hz,3H).
第四步(实施例107的合成)
将化合物107-4(200mg,0.44mmol)溶于无水四氢呋喃(10mL)中，加入三光气(196mg,0.66 mmol)，在15℃搅拌10分钟。向该反应液中加入叔丁醇钾(1.32mL,1.32mmol,1M in THF)，搅拌60分钟。该反应液用水(20mL)和二氯甲烷(10mL)稀释，二氯甲烷(20mL x 3)萃取，有机层用饱和食盐水溶液(30mL x 2)洗涤，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶制备板纯化得到粗品，再用制备色谱得到11mg实施例107，产率：5.2％。
实施例107的核磁数据：1H NMR(400MHz,CDCl3)δ:7.80-7.88(m,1H),7.53(d,J＝3.2Hz,1H),7.35-7.42(m,1H),7.33(dd,J＝2.4,8.0Hz,1H),6.88-7.13(m,1H),5.99-6.27(s,1H),4.66-4.75(m,1H),4.07(q,J＝7.0Hz,2H),3.30-3.68(m,1H),3.01-3.09(m,2H),1.13(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:479.9[M+H+].
实施例108
Figure PCTCN2015079870-appb-000202
第一步(化合物108-3的合成)
将化合物108-1(1.0g,4.3mmol)溶于无水乙醇(30mL)，加入2-溴-4-氟苯甲醛(883mg,4.3mmol)，噻唑二甲脒盐酸盐(709mg,4.3mmol)，醋酸钠(1.06g,12.9mmol)。反应液温度慢慢升至回流，回流下将反应搅拌过夜。将反应液减压浓缩后用(40mL x 3)乙酸乙酯萃取，有机层用饱和食盐水溶液(30mLx2)洗涤，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，所得到600mg的产物108-3，产率：27％。
LCMS(ESI)m/z:524.0[M+H+].
第二步(化合物108-4的合成)
将化合物108-4(600mg,1.1mmol)溶于甲醇(8mL)和水(8mL)中，加入氢氧化锂(264mg,11mmol)。反应液在15℃下搅拌16小时。TLC(PE:EA；5:1)显示反应完成，将反应液减压浓缩后得到粗产品，加入乙酸乙酯(30mL)和水(20mL)，缓慢的加入1N的盐酸调节PH＝1.乙酸乙酯萃取(30mL x 3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到400mg的化合物108-4，产率：71％。
LCMS(ESI)m/z:496[M+H+].
第三步(实施例108的合成)
将化合物108-4(270mg,0.54mmol)溶于无水四氢呋喃(10mL)中，加入HATU(310mg,0.82mmol)，DIPEA(209mg,1.62mmol)。反应液在20℃下搅拌16小时。当LC-MS显示反应完全，将反应液减压浓缩后用乙酸乙酯(40mL x 3)萃取，有机层用饱和食盐水溶液(30mL x 2)洗涤，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到66mg实施例108，产率：26％。
实施例108的核磁数据：1H NMR(400MHz,CDCl3)δ:7.78(m,1H),7.37(d,J＝3.2Hz,2H),7.04(m,1H),6.95(dd,J＝2.4,8.0Hz,1H),6.30(s,1H),4.20-4.08(m,2H),3.40-3.34(m,2H),2.87(t,J＝6.4Hz,1H),2.56(d,J＝7.2Hz,1H),2.22-2.08(m,2H),1.18(m,3H).
LCMS(ESI)m/z:478.0[M+H+].
实施例109
Figure PCTCN2015079870-appb-000203
Figure PCTCN2015079870-appb-000204
第一步(化合物109-2的合成)
将化合物109-1(1.34g,5.8mmol)溶于无水乙醇(30mL)，加入2-氯-4-氟苯甲醛(1.08g,5.8mmol)，噻唑二甲脒盐酸盐(0.95g,5.8mmol)，醋酸钠(1.1g,17.4mmol)。反应液温度慢慢升至回流，回流下将反应搅拌过夜。将反应液减压浓缩后用乙酸乙酯(40mL x3)萃取，有机层用饱和食盐水溶液(30mLx2)洗涤，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝5:1)纯化，所得到1.5g的化合物109-2，产率：62％。
LCMS(ESI)m/z:480.0[M+H+].
第二步(化合物109-3的合成)
将化合物109-2(1.5g,3.1mmol)溶于四氢呋喃(20mL)和水(20mL)中，加入氢氧化锂(394mg,9.3mmol)。反应液在15℃下搅拌16小时。TLC(PE:EA；5:1)显示反应完成，将反应液减压浓缩后得到粗产品，加入乙酸乙酯(30mL)和水(20mL)，缓慢的加入1N的盐酸调节PH＝1。乙酸乙酯萃取(3x 30mL)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到1.3g化合物109-3，产率：93％。
LCMS(ESI)m/z:452.0[M+H+].
第三步(化合物109-4的合成)
将化合物109-3(500mg,1.11mmol)溶于无水二氯甲烷(20mL)中，加入羰基二咪唑(360mg,2.22mmol)，在15℃搅拌30分钟。该反应液倾倒入硼氢化钠(360mg,2.22mmol)的甲醇(20mL)中，搅拌15分钟。该反应液用水(50mL)和二氯甲烷(100mL)稀释，二氯甲烷(50mL x 3)萃取，有机层用饱和食盐水溶液(30mL x 2)洗涤，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝3:1)纯化，得到300mg化合物109-4，产率：61.7％。
LCMS(ESI)m/z:437.9[M+H+].
第四步(化合物109-5的合成)
将化合物109-4(300mg,0.68mmol)溶于无水二氯甲烷(10mL)中，在室温下加入三乙胺(206mg,2.04mmol)，甲磺酰氯(118mg,1.03mmol)。加料完毕后，氮气保护下充分搅拌15小时。当TLC(石油 醚：乙酸乙酯；1:1)显示原料消失，将反应液倾倒入饱和碳酸氢钠溶液(15mL)中，并用二氯甲烷(20mL x 3)萃取，合并有机相，依次用水(10mL x 2)、饱和氯化钠溶液(10mL x 2)洗涤，用无水硫酸钠干燥，过滤，用快速过柱仪以洗脱剂体系(石油醚：乙酸乙酯＝100:1～5:1)纯化，得到130mg的化合物109-5，产率：36.8％。
LCMS m/z:516.1[M+H+].
第五步(实施例109的合成)
将化合物109-5(130mg,0.25mmol)溶于无水乙腈(10mL)中，在室温下加入碳酸钾(69mg,0.5mmol)。加料完毕后，氮气保护下在45℃下充分搅拌1小时。当LC-MS显示反应完成，在真空下浓缩，加水(10mL),并用二氯甲烷(20mLx3)萃取，合并有机相，依次用水(10mL x 2)、饱和氯化钠溶液(10mL x 2)洗涤，用无水硫酸钠干燥，过滤，制备色谱法纯化，得到35mg的实施例109，产率，33.2％。
实施例109的核磁数据：1H NMR(400MHz,MeOD-d4)δ:7.95(d,J＝3.2Hz,1H),7.73(d,J＝3.2Hz,1H),7.38(dd,J＝6.4,8.8Hz,1H),7.28(dd,J＝2.4,8.4Hz,1H),7.09(dt,J＝2.4,8.4Hz,1H),6.12(s,1H),4.20-4.30(m,1H),4.03-4.17(m,2H),3.61(td,J＝6.0,16.4Hz,1H),3.44(ddd,J＝4.2,8.0,12.8Hz,1H),3.00-3.13(m,1H),2.04-2.17(m,1H),1.93(quin,J＝6.8Hz,2H),1.75-1.86(m,1H),1.18(t,J＝7.2Hz,3H).
LCMS m/z:420.0[M+H+].
实施例110
Figure PCTCN2015079870-appb-000205
第一步(化合物110-2的合成)
将化合物110-1(1.07g,3.57mmol)溶于无水四氢呋喃(10mL)中，在室温下加入叔丁醇钾(400mg,3.57mmol)。加料完毕后，氮气保护下在20℃充分搅拌0.5小时。然后加入实施例23-1(600mg,1.19 mmol)，并在氮气保护下在20℃充分搅拌16小时。当LC-MS显示反应完成，在真空下浓缩，加10mL水,并用二氯甲烷(20mL x 3)萃取，合并有机相，依次用水(10mL x 2)、饱和氯化钠溶液(10mL x 2)洗涤，用无水硫酸钠干燥，过滤，旋干，840mg产品，没有纯化直接用于下一步。产率，98％。
LCMS(ESI)m/z:723.9[M+H+].
第二步(化合物110-3的合成)
将化合物110-2(840mg,1.16mmol)溶于无水四氢呋喃(10mL)中，在室温下加入TBAF(10mmol,10mL,1M in THF)。加料完毕后，氮气保护下在20℃充分搅拌16小时。当LC-MS显示反应完成，在真空下浓缩，加水(10mL),并用二氯甲烷(20mL x 3)萃取，合并有机相，依次用水(10mL x 2)、饱和氯化钠溶液(10mL x 2)洗涤，用无水硫酸钠干燥，过滤，旋干，制备色谱法(PE:EA＝1:1)纯化，得到300mg的化合物110-3，产率，53％。
1H NMR(400MHz,CDCl3)δ:9.08(br.s.,1H),7.82(d,J＝3.2Hz,1H),7.43(d,J＝3.2Hz,1H),7.36-7.29(m,2H),6.97(dt,J＝2.4,8.4Hz,1H),6.18(s,1H),4.96(d,J＝2.0Hz,2H),4.11-3.97(m,2H),3.90(br.s.,2H),3.84-3.69(m,2H),1.13(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:486.0[M+H+].
第三步(化合物110-4的合成)
将化合物110-3(280mg,0.58mmol)溶于无水DCM(10mL)中，在室温下加入三乙胺(176mg,1.74mmol)，甲磺酰氯(132mg,1.16mmol)。加料完毕后，氮气保护下充分搅拌15小时。当TLC(石油醚：乙酸乙酯；1:1)显示原料消失，将反应液倾倒入饱和碳酸氢钠(15mL)溶液中，并用二氯甲烷(20mLx3)萃取，合并有机相，依次用水(10mL x 2)、饱和氯化钠溶液(10mL x 2)洗涤，用无水硫酸钠干燥，过滤，用快速过柱仪以洗脱剂体系(石油醚：乙酸乙酯＝3:1)纯化得到150mg的化合物110-4,产率，46％。
1H NMR(400MHz,CDCl3)δ:8.95(br.s.,1H),7.83(d,J＝3.2Hz,1H),7.47(d,J＝3.2Hz,1H),7.40-7.31(m,1H),7.00(dt,J＝2.4,8.4Hz,1H),6.20(s,1H),5.09-4.92(m,2H),4.58-4.44(m,2H),4.13-4.00(m,2H),4.00-3.90(m,2H),3.17(s,3H),1.15(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:564.0[M+H+].
第四步(实施例110的合成)
将化合物110-4(140mg,0.24mmol)溶于无水乙腈(5mL)中，在室温下加入碳酸钾(68mg,0.50mmol)。加料完毕后，氮气保护下在90℃下充分搅拌16小时。当LC-MS显示反应完成，在真空下浓缩，加10mL水,并用二氯甲烷(20mL x 3)萃取，合并有机相，依次用水(10mL x 2)、饱和氯化钠溶液(10mLx2)洗涤，用无水硫酸钠干燥，过滤，制备色谱法纯化得到64mg的实施例110.产率，52％。
实施例110的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.6Hz,1H),7.42-7.34(m,2H),7.31-7.27(m,1H),7.01(dt,J＝2.4,8.4Hz,1H),6.14(s,1H),5.29(d,J＝16.8Hz,1H),5.00(d,J＝16.8Hz,1H),4.80(ddd,J＝4.0,6.8,12.4Hz,1H),4.15-4.05(m,2H),4.04-3.97(m,1H),3.96-3.86(m,1H),3.64(ddd,J＝3.6,6.8,12.4Hz,1H),1.14(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:467.9[M+1].
实施例111
Figure PCTCN2015079870-appb-000206
该实施例如实施例107中描述的方法制备。
实施例111的核磁数据：1H NMR(400MHz,CDCl3)δ:7.85(d,J＝3.2Hz,1H),7.44(d,J＝3.2Hz,1H),7.16-7.25(m,2H),6.98(dt,J＝2.2,8.0Hz,1H),6.39(s,1H),4.55-4.72(m,2H),4.11-4.22(m,2H),3.83(d,J＝19.58Hz,1H),3.32-3.43(m,1H),1.22(t,J＝7.15Hz,3H).
LCMS(ESI)m/z:436.0[M+H+].
实施例112
Figure PCTCN2015079870-appb-000207
第一步(化合物112-1的合成)
将化合物107-4(150mg,0.33mmol)溶于无水二氯甲烷(10mL)中，在室温下加入三乙胺(101mg,1.0mmol)，甲基磺酰氯(56mg,0.5mmol)，室温搅拌过夜。将反应液减压浓缩后用二氯甲烷(20mLx3)萃取，合并有机相，依次用水(20mL x 2)、饱和氯化钠溶液(20mL x 2)洗涤，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝10:1)纯化，得到120mg化合物112-1,产率：68％。
1H NMR(400MHz,CDCl3)δ:7.80-7.88(m,1H),7.53(d,J＝3.01Hz,1H),7.35-7.42(m,1H),7.33(dd,J＝2.52,8.03Hz,1H),6.88-7.13(m,1H),6.0(s,1H),4.66-4.75(m,1H),4.07(q,J＝7.04Hz,2H),3.30-3.68(m,1H),3.01-3.09(m,3H),1.99-2.06(m,2H),1.13(t,J＝7.04Hz,3H).
第二步(实施例112的合成)
将化合物112-1(100mg,0.19mmol)溶于乙腈(3mL)中，在室温下加入碳酸钾(52mg,0.38mmol)， 将温度升高至45℃并在该温度下搅拌1小时。将反应液减压浓缩后用二氯甲烷(20mLx3)萃取，合并有机相，依次用水(20mLx2)、饱和氯化钠溶液(20mLx2)洗涤，用无水硫酸钠干燥，过滤，用硅胶柱色谱法以洗脱剂体系(石油醚：乙酸乙酯＝2:1)纯化，得到28mg实施例112。产率：34％。
实施例112的核磁数据：1H NMR(400MHz,CDCl3)δ:7.84(d,J＝3.2Hz,1H),7.36-7.44(m,2H),7.31(dd,J＝2.4,8.4Hz,1H),6.97(dt,J＝2.4,8.4Hz,1H),6.17(s,1H),4.61-4.77(m,2H),4.11(ttd,J＝3.60,7.2,10.4Hz,2H),3.37-3.58(m,2H),1.22(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:435.8[M+H+].
实施例113,114
Figure PCTCN2015079870-appb-000208
第一步(113-3的合成)
将化合物113-2(1.27g,7.94mmol)溶于无水DMF(100mL),在0℃下分批加入NaH(238.2mg,5.96mmol,1.5eq),在此温度下搅拌15分钟.随后,向反应液中加入113-1(2.0g,3.97mmol,1.0eq),反应液升温至16℃,继续搅拌3小时.反应液用饱和氯化铵溶液淬灭,用乙酸乙酯(300mL)萃取三次,并用水(150mL)洗涤三次.有机相用无水硫酸钠干燥,过滤,减压浓缩.剩余物用硅胶柱纯化,洗脱液为石油醚:乙酸乙酯＝3:1,得产品1.76g,收率76％.
LCMS(ESI)m/z:583.7[M+H+].
第二步(113-4的合成)
将化合物113-3(1.76g,3.02mmol,1.0eq)溶于无水THF(50mL),在0℃下分批加入硼氢化钠(571mg,15.1mmol,5.0eq).加入完毕,反应液升温至60℃,搅拌18小时.反应液降至室温,用水(50mL)淬灭, 二氯甲烷(100mL)萃取三次.有机相用无水硫酸钠干燥,过滤,减压浓缩.剩余物用硅胶柱纯化,洗脱液二氯甲烷:甲醇＝20:1,得产品780mg,收率39％.
LCMS(ESI)m/z:521.7[M+Na+].
第三步(113-5的合成)
将化合物113-4(2.70g,5.42mmol,1.0eq)溶于无水二氯甲烷(100mL),在15℃下依次加入三乙胺(1.65g,16.26mmol,3.0eq),甲烷磺酰氯(7.67g,66.96mmol,12.35eq).加入完毕,搅拌18小时.反应液用水(100mL)淬灭,二氯甲烷(200mL)萃取三次.有机相用无水硫酸钠干燥,过滤,减压浓缩.剩余物用硅胶柱纯化,洗脱液二氯甲烷:甲醇＝20:1,得产品1.4g,收率46％.
LCMS(ESI)m/z:582.0[M+Na+].
第四步(113-6的合成)
将化合物113-5(200mg,358.14umol,1.0eq)溶于无水DMA(8mL),在20℃下加入甲硫醇钠(30mg,429.77umol,1.2eq).加入完毕,搅拌3小时.反应液用水(10mL)淬灭,乙酸乙酯(50mL)萃取三次.有机相用无水硫酸钠干燥,过滤,减压浓缩.剩余物用硅胶柱纯化,洗脱液石油醚:乙酸乙酯＝3:1,得产品160mg,收率88％.
LCMS(ESI)m/z:512.0[M+H+].
第五步(113，114的合成)
将化合物113-6(160mg,313umol,1.0eq)溶于无水DCM(10mL),在20℃下加入间氯过氧苯甲酸(81mg,470umol,1.5eq)。加料完毕,搅拌3小时。补加间氯过氧苯甲酸(27mg,156umol,0.5eq),继续搅拌3小时。反应液用1M碳酸钾(10mL)淬灭,二氯甲烷(20mL)萃取三次。有机相用无水硫酸钠干燥,过滤,减压浓缩.剩余物用手性柱分离分别得实施例11350mg,收率29％,实施例11423mg,收率13％.
实施例113的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.0Hz,1H),7.38(d,J＝3.0Hz,1H),7.33(dd,J＝2.4,8.4Hz,1H),7.22(dd,J＝6.0,8.4Hz,1H),6.99(dt,J＝2.4,8.0Hz,1H),6.17(s,1H),4.76(dd,J＝7.0,12.0Hz,1H),4.31(dd,J＝5.2,11.80Hz,1H),4.05(q,J＝7.0Hz,2H),3.57(dd,J＝8.0,18.0Hz,1H),3.17-3.25(m,3H),3.05-3.15(m,1H),3.02(s,3H),1.13(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:544.1[M+H+].
实施例114的核磁数据:1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.01Hz,1H),7.38(d,J＝3.0Hz,1H),7.34(dd,J＝2.4,8.0Hz,1H),7.22-7.26(m,1H),6.99(dt,J＝2.4,8.2Hz,1H),6.16(s,1H),4.78(dd,J＝7.6,11.6Hz,1H),4.13(d,J＝10.0Hz,1H),4.02-4.10(m,2H),3.83(dd,J＝7.6,17.6Hz,1H),3.23-3.35(m,2H),3.05-3.13(m,1H),3.04(s,3H),2.88(dd,J＝10.2,17.2Hz,1H),1.16(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:544.0[M+H+].
实施例115
Figure PCTCN2015079870-appb-000209
Figure PCTCN2015079870-appb-000210
第一步(115-3的合成)
将化合物115-1(1.51g,3.0mmol,1.0eq),115-2(4.12g,30mmol,10.0eq)溶于乙腈(10mL),氮气条件下，在20℃下加入碳酸钾(4.15g,30mmol,10eq).加料完毕,搅拌6小时.反应液浓缩，剩余物加入冰水混合物中(w/w,10mL),搅拌20分钟。水相用乙酸乙酯(20mL)萃取三次.有机相用无水硫酸钠干燥,过滤,减压浓缩.剩余物用硅胶柱纯化,得产品1.2g,收率71％.
LCMS(ESI)m/z:561.1[M+H+].
第二步(115的合成)
将化合物115-3(168mg,300.2umol 1.0eq),115-4(74mg,300.3umol 1.0eq)溶于乙腈(5mL),氮气条件下，在28℃下加入碳酸钾(83mg,600.58umol,2eq)。加料完毕,搅拌48小时.反应液浓缩，剩余物加入冰水混合物中(w/w,10mL),搅拌20分钟。水相用乙酸乙酯(20mL)萃取三次。有机相用无水硫酸钠干燥,过滤,减压浓缩.剩余物用硅胶柱纯化,得产品50mg。
实施例115的核磁数据:1H NMR(400MHz,CDCl3)δ7.91(dd,J＝6.2,8.6Hz,1H),7.74(d,J＝3.0Hz,1H),7.33-7.39(m,2H),7.26(d,J＝8.6Hz,2H),7.12(dt,J＝2.6,8.4Hz,1H),6.90(d,J＝8.4Hz,2H),6.34(t,J＝3.8Hz,1H),6.19(s,1H),4.80(d,J＝16.6Hz,1H),3.91-4.14(m,2H),3.77-3.87(m,4H),3.44-3.59(m,5H),3.25(dd,J＝2.4,11.8Hz,1H),2.77(dd,J＝4.2,11.8Hz,1H),1.11(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:644.5[M+H+].
实施例116，117
Figure PCTCN2015079870-appb-000211
第一步(116-3的合成)
将化合物116-1(150mg,322.34umol,1.0eq)溶于无水DCM(10mL),在20℃下依次加入DBU(147mg,967.02umol,3.0eq),116-2(92mg,644.68umol,2.0eq)。加入完毕,搅拌6小时，TLC显示反应完成。反应液用水(10mL)淬灭,DCM(20mL)萃取三次.有机相用无水硫酸钠干燥,过滤,减压浓缩.剩余物用硅胶柱纯化,洗脱液石油醚:乙酸乙酯＝100:1～1:1,得产品87mg,收率27％。
第二步(116,117的合成)
将化合物116-3(87mg,0.15mmol)进行手性分离得化合物116(8mg),117(12mg).
实施例116的核磁数据:1H NMR(400MHz,CDCl3)δ:7.80(d,J＝3.0Hz,1H),7.37(d,J＝3.0Hz,1H),7.35-7.27(m,2H),6.99(dt,J＝2.3,8.2Hz,1H),6.16(s,1H),4.54(d,J＝8.5Hz,2H),4.50-4.44(m,1H),4.31(d,J＝2.5Hz,1H),4.10-4.01(m,2H),3.52-3.43(m,1H),3.41-3.31(m,1H),3.20(td,J＝6.8,13.6Hz,1H),1.39(d,J＝6.8Hz,6H),1.14(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:572.4[M+H+].
实施例117的核磁数据:1H NMR(400MHz,CDCl3)δ：7.81(br.s.,1H),7.38(br.s.,1H),7.32(d,J＝7.3Hz,1H),7.22(br.s.,1H),6.98(br.s.,1H),6.14(br.s.,1H),4.56(d,J＝6.8Hz,2H),4.37(d,J＝11.0Hz,1H),4.28(d,J＝6.3Hz,1H),4.04(d,J＝6.8Hz,2H),3.68(dd,J＝6.5,17.6Hz,1H),3.31-3.11(m,2H),1.41(d,J＝5.5Hz,6H),1.12(br.s.,3H).
LCMS(ESI)m/z:572.4[M+H+].
实施例118
Figure PCTCN2015079870-appb-000212
第一步(118的合成)
将化合物118-1(80mg,171.9umol,1.0eq),118-2(35mg,343.8umol,2.0eq)溶于无水DMF(2mL),在20℃下依次加入HATU(130mg,343.8umol,2.0eq),TEA(87mg,859.6umol,5.0eq)。加料完毕,搅拌2小时，TLC显示反应完成。反应液用水(10mL)淬灭,DCM(20mL)萃取三次.有机相用无水硫酸钠干燥,过滤,减压浓缩.剩余物用机分(氨水体系)纯化,得黄色固体实施例11822mg,收率23％。
实施例118的核磁数据：1H NMR(400MHz,CDCl3)δ:7.83(d,J＝3.3Hz,1H),7.44-7.40(m,1H),7.37(dd, J＝2.5,8.3Hz,1H),7.12(dd,J＝6.0,8.8Hz,1H),6.98(dt,J＝2.5,8.3Hz,1H),6.19-6.16(m,1H),5.12(d,J＝16.1Hz,1H),5.01-4.79(m,6H),4.25-4.01(m,5H),3.74-3.62(m,1H),1.23-1.12(m,3H).
LCMS(ESI)m/z:551.1[M+H+].
实施例119,120
Figure PCTCN2015079870-appb-000213
第一步(119-2的合成)
将化合物119-1(100mg,179.1umol,1.0eq)溶于乙腈(4mL),依次加入NH3.H2O(1mL)，碘化钠(5mg,35.8umol,0.2Eq)。加料完毕,在110℃条件下封管反应5小时。检测反应完成，将至室温，减压浓缩得粗产品60mg,该粗产品直接用于下一步反应。
第二步(119,120的合成)
将化合物119-1(60mg,125.2umol,1.0eq)溶于无水DCM(3mL),在20℃下依次加入TEA(126mg,1.25mmol,10eq),Ac2O(127mg,1.25mmol,10eq)。加料完毕,搅拌3小时，TLC显示反应完成。反应液用水(10mL)淬灭,DCM(20mL)萃取三次.有机相用无水硫酸钠干燥,过滤,减压浓缩。剩余物用机分纯化,得实施例119(10mg),实施例120(44mg).
实施例119的核磁数据：1H NMR(400MHz,DMSO-d6)δ：7.81(d,J＝3.2Hz,1H),7.38(d,J＝3.2Hz,1H),7.33(dd,J＝2.4,8.0Hz,1H),7.29(s,1H),7.25(s,1H),7.00(dt,J＝2.4,8.0Hz,1H),6.16(s,1H),5.77(br.s.,1H),4.43(dd,J＝7.2,11.6Hz,1H),4.15(dd,J＝3.2,11.6Hz,1H),3.98-4.11(m,2H),3.34(t,J＝6.8Hz,2H),3.09-3.29(m,1H),2.72(dt,J＝3.6,7.2Hz,1H),2.03(s,3H),1.14(t,J＝6.8Hz,3H).
LCMS(ESI)m/z:522.0[M+H+].
实施例120的核磁数据：1H NMR(400MHz,DMSO-d6)δ：7.82(d,J＝3.2Hz,1H),7.39(d,J＝3.2Hz,1H),7.33(dd,J＝2.4,8.0Hz,1H),7.24(dd,J＝6.4,8.8Hz,1H),6.97(dt,J＝2.4,8.0Hz,1H),6.15(s,1H),5.82(br.s.,1H),4.41(dd,J＝7.2,11.2Hz,1H),3.96-4.20(m,3H),3.52(dd,J＝7.6,18.0Hz,1H),3.42(t,J＝6.8Hz,2H),2.80-2.92(m,1H),2.69-2.79(m,1H),2.03(s,3H),1.15(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:522.0[M+H+].
实施例121,122
Figure PCTCN2015079870-appb-000214
实施例121,122的合成同实施例119,120。
实施例121的质荷比：LCMS(ESI)m/z:583.1[M+H+].
实施例122的核磁数据：1H NMR(400MHz,DMSO-d6)δ：7.82(d,J＝3.2Hz,1H),7.39(d,J＝3.2Hz,1H),7.33(dd,J＝2.4,8.4Hz,1H),7.24(dd,J＝6.0,8.4Hz,1H),6.98(dt,J＝2.4,8.4Hz,1H),6.16(s,1H),4.73(t,J＝6.4Hz,1H),4.42(dd,J＝7.2,11.2Hz,1H),4.24(dd,J＝7.6,11.6Hz,1H),4.06(dq,J＝4.0,7.2Hz,2H),3.52(dd,J＝7.6,18.0Hz,1H),3.33-3.43(m,1H),3.21-3.32(m,1H),2.92(dd,J＝8.0,18.0Hz,1H),2.74(quin,J＝7.2Hz,1H),2.38-2.52(m,1H),1.20(d,J＝3.6Hz,2H),1.15(t,J＝7.2Hz,3H),0.96-1.09(m,2H).
LCMS(ESI)m/z:582.9[M+H+].
实施例123
Figure PCTCN2015079870-appb-000215
第一步(123的合成)
将化合物123-1(20mg,42.98umol,1.0eq)溶于无水吡啶(0.5mL),在20℃下依次加入DMAP(10.5mg,85.96umol,2.0eq),123-2(9.7mg,64.5umol,1.5eq)。加入完毕,搅拌0.5小时，TLC显示反应完成。反应液用水(5mL)淬灭,乙酸乙酯(10mL)萃取三次.有机相用无水硫酸钠干燥,过滤,减压浓缩.剩余物用制备板纯化,得产品2.8mg,收率11％。
实施例123的核磁数据：1H NMR(400MHz,CDCl3)δ:7.83(d,J＝3.51Hz,1H),7.40(d,J＝3.01Hz,1H),7.34(dd,J＝2.51,8.03Hz,1H),7.29(br.s.,1H),6.99(dt,J＝2.51,8.03Hz,1H),6.18(s,1H),6.11-6.40(m,1H),5.31(br.s.,1H),4.59-4.71(m,1H),4.43-4.53(m,2H),4.03-4.12(m,2H),3.59(d,J＝19.07Hz,1H),3.40(dd,J＝6.53,18.57Hz,1H),1.16(t,J＝7.03Hz,3H).
LCMS(ESI)m/z:581.0[M+H+].
实施例124,125,126,128,129,130,132,137,138,140,141,144,145,148,149,150,151,153,154,155,156,158,159,160,162,163,164,165,167,168,170,172,173,174,175的合成同实施例123的合成。
实施例124
Figure PCTCN2015079870-appb-000216
实施例124的核磁数据：1H NMR(400MHz,CDCl3)δ:7.83(d,J＝3.6Hz,1H),7.41(d,J＝3.6Hz,1H),7.33(dd,J＝2.6,8.4Hz,1H),7.23(dd,J＝6.0,8.4Hz,1H),6.99(dt,J＝2.6,8.4Hz,1H),6.15(s,1H),6.11-6.42(m,1H),5.70(br.s.,1H),4.53-4.62(m,1H),4.39-4.53(m,2H),4.00-4.10(m,2H),3.69(dd,J＝7.2,18.2Hz,1H),3.27(dd,J＝6.0,18.2Hz,1H),1.13(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:581.0[M+H+].
实施例125
Figure PCTCN2015079870-appb-000217
实施例125的核磁数据：1H NMR(400MHz,CDCl3)δ:7.84(d,J＝3.2Hz,1H),7.41(d,J＝3.0Hz,1H),7.24-7.28(m,1H),7.15(dd,J＝2.6,8.4Hz,1H),6.96(dt,J＝2.6,8.4Hz,1H),6.19(s,1H),4.76(d,J＝7.6Hz,1H),4.47-4.60(m,2H),4.32(sxt,J＝6.8Hz,1H),4.07(q,J＝7.0Hz,2H),3.68(dd,J＝7.2,18.0Hz,1H),3.19(dd,J＝6.4,18.0Hz,1H),3.09(s,3H),1.15(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:499.2[M+H+].
实施例126
Figure PCTCN2015079870-appb-000218
实施例126的核磁数据：1H NMR(400MHz,CDCl3)δ:7.84(d,J＝3.0Hz,1H),7.41(d,J＝3.2Hz,1H),7.33(dd,J＝6.2,8.6Hz,1H),7.16(dd,J＝2.6,8.6Hz,1H),6.98(dt,J＝2.6,8.2Hz,1H),6.20(s,1H),4.72(d,J＝6.2Hz,1H),4.57-4.65(m,1H),4.45-4.54(m,1H),4.29-4.40(m,1H),4.08(q,J＝7.2Hz,2H),3.47-3.56(m,1H),3.32-3.43(m,1H),3.08(s,3H),1.17(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:521.2[M+Na+].
实施例127
Figure PCTCN2015079870-appb-000219
实施例127的合成同实施例123的合成。
实施例127的核磁数据：1H NMR(400MHz,CDCl3-d6)δ:7.97(d,J＝2.5Hz,1H),7.65(br.s.,1H),7.43-7.37(m,1H),7.34(dd,J＝2.4,8.2Hz,1H),7.05-6.95(m,1H),6.29(s,1H),4.82(br.s.,2H),4.41(d,J＝8.8Hz,1H),4.08(q,J＝7.2Hz,2H),3.59-3.43(m,2H),2.93(d,J＝4.5Hz,6H),1.15(t,J＝7.2Hz,3H)
LCMS(ESI)m/z:559.0[M+H+].
实施例128
Figure PCTCN2015079870-appb-000220
实施例128的核磁数据：1H NMR(400MHz,DMSO-d6)δ：7.85(d,J＝3.2Hz,1H),7.42(d,J＝3.2Hz,1H),7.23-7.28(m,1H),7.15(dd,J＝2.6,8.6Hz,1H),6.96(dt,J＝2.6,8.2Hz,1H),6.18(s,1H),6.12-6.43(m,1H),4.39-4.64(m,3H),4.01-4.12(m,2H),3.70(dd,J＝7.2,18.2Hz,1H),3.28(dd,J＝6.2,18.2Hz,1H),1.15(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:535.1[M+H+].
实施例129
Figure PCTCN2015079870-appb-000221
实施例129的核磁数据:1H NMR(400MHz,CDCl3)δ：7.82(d,J＝3.2Hz,1H),7.45(dd,J＝8.8,12.8Hz,1H),7.41(d,J＝3.0Hz,1H),7.25(dd,J＝6.0,8.6Hz,1H),7.16(dd,J＝2.6,8.6Hz,1H),6.96(dt,J＝2.6,8.2Hz,1H),6.15(s,2H),5.19(br.s.,1H),4.82(d,J＝11.6Hz,1H),4.29-4.42(m,1H),3.93-4.16(m,3H),3.37-3.56(m,2H),1.15(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:529.1[M+H+].
实施例130
Figure PCTCN2015079870-appb-000222
实施例130的核磁数据：1H NMR(400MHz,CDCl3)δ：7.83(br.s.,1H),7.40(br.s.,1H),7.33(dd,J＝2.6,8.6Hz,1H),7.25(d,J＝6.0Hz,1H),6.98(dt,J＝2.6,8.2Hz,1H),6.15(s,1H),4.57(dd,J＝7.0,11.0Hz,1H),3.97-4.18(m,3H),3.77(t,J＝4.6Hz,4H),3.66(dd,J＝7.2,17.2Hz,1H),3.15(quin,J＝7.9Hz,1H),2.96(dd,J＝9.2,17.2Hz,1H),2.42-2.68(m,4H),1.14(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:491.0[M+H+].
实施例131
Figure PCTCN2015079870-appb-000223
Figure PCTCN2015079870-appb-000224
第一步(131-2的合成)
在干燥的三口瓶中，将化合物131-1(18.00g,99.43mmol,1.0eq)溶于氯化亚砜(59.15g,497.15mmol,5.0eq)，混合物升温至80℃,搅拌1小时后，降温至50℃。Br2(31.78g,198.8mmol,2.0eq)加入反应液中，在50℃下搅拌40小时。反应液降温至30℃，小心加入无水甲醇(40mL),升温50℃，继续搅拌1小时。反应液降温至25℃，减压浓缩，剩余物用乙酸乙酯溶解，用饱和亚硫酸钠洗涤。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩得粗产品黄色油状物20g。该粗产品直接用于下一步反应。
1H NMR(400MHz,CDCl3)δ：4.28(q,J＝6.0Hz,2H),3.80(s,3H),3.43(t,J＝6.0Hz,2H),1.95-2.26(m,3H)
第二步(131的合成)
将化合物131-3(80mg,190.1umol,1.0eq)溶于乙腈(2mL),在0℃下缓慢依次加入131-2(52.1mg,190.1umol,1.0eq)，碳酸钾(138mg,998.4umol,5.25eq)。加料完毕,反应液用氮气置换三次，升温至85℃,搅拌24小时。TLC显示反应完成，反应液降至室温，过滤，减压浓缩。剩余物用机分(盐酸体系)可得目标产物。
实施例131的核磁数据：1H NMR(400MHz,DMSO-d6)δ：8.30(s,2H),7.82(dd,J＝5.90,8.66Hz,1H),7.36(dd,J＝1.25,8.53Hz,1H),7.23(dt,J＝2.26,8.28Hz,1H),6.39(d,J＝10.79Hz,1H),4.91-5.02(m,1H),4.64-4.82(m,3H),4.12-4.20(m,2H),3.87-4.00(m,3H),3.84(s,2H),3.69-3.81(m,1H),3.53(dd,J＝8.66,17.94Hz,1H),2.63(dd,J＝8.28,13.05Hz,1H),2.21-2.41(m,2H),2.06-2.17(m,1H),1.16(dt,J＝4.77,7.03Hz,3H).
LCMS(ESI)m/z:533.1[M+H+].
实施例132
Figure PCTCN2015079870-appb-000225
实施例132的核磁数据：1H NMR(400MHz,DMSO-d6)δ：8.30(s,1H),8.00(br.s.,1H),7.94(d,J＝3.2Hz,1H),7.86(d,J＝3.0Hz,1H),7.36-7.50(m,2H)7.79(s,1H),7.15(td,J＝8.4,2.6Hz,1H),6.00(s,1H),4.36(dd,J＝11.2,6.8Hz,1H),4.09-4.21(m,1H),3.86-4.04(m,7H),3.02(dd,J＝17.8,6.2Hz,1H),1.04(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:565.1[M+H+].
实施例133
Figure PCTCN2015079870-appb-000226
将化合物133-2(13.69mg,142.56umol,1.2eq)溶于DCM(2mL),在28℃下缓慢加入CDI(38.53mg,237.60umol,2.0eq),搅拌10分钟。向反应液中加入已溶于DCM(1mL)的133-1(50mg,118.80umol,1.0eq)溶液。反应液继续搅拌20分钟。TLC显示反应完成，反应液减压浓缩。剩余物用机分(甲酸体系)可得目标产物实施例133(12mg,收率20％)。
实施例133的核磁数据：1H NMR(400MHz,CDCl3)δ：7.84(d,J＝3.26Hz,1H),7.42(d,J＝3.01Hz,1H),7.30(d,J＝12.00Hz,1H),7.15(dd,J＝2.51,8.53Hz,1H),6.96(dt,J＝2.64,8.22Hz,1H),6.77(d,J＝6.53Hz,1H),6.21(s,1H),5.95(t,J＝52.0Hz 1H),4.71-4.82(m,1H),4.54(d,J＝5.77Hz,2H),4.07(q,J＝7.19Hz,2H),3.66(dd,J＝7.53,18.32Hz,1H),3.26(dd,J＝5.77,18.32Hz,1H),1.15(t,J＝7.15Hz,3H)
LCMS(ESI)m/z:499.2[M+H+].
实施例139，142的合成同实施例133的合成。
实施例134,135,136
Figure PCTCN2015079870-appb-000227
Figure PCTCN2015079870-appb-000228
第一步(134-3的合成)
将化合物134-1(700mg,1.25mmol,1.0eq),TEA(379mg,3.75mmol,3.0eq)溶于无水DCM(15mL),在28℃下缓慢加入134-2(372mg,2.5mmol,2eq)。加料完毕,反应液用氮气置换三次，搅拌30分钟。TLC显示反应完成，反应液用水(10mL)洗涤,再用DCM(20mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用柱层析纯化，洗脱剂体系为石油醚：乙酸乙酯＝50:1～3:1,得黄色固体680mg,收率81％。
LCMS(ESI)m/z:672.8[M+H+].
第二步(实施例134的合成)
将化合物134-3(680mg,1.01mmol,1.0eq)溶于乙腈(10mL),在28℃下缓慢加入碳酸钾(700mg,5.07mmol,5eq)。加料完毕,反应液用氮气置换三次，升温至90℃，搅拌16小时。TLC显示反应完成，反应液降至室温，过滤，滤液浓缩。剩余物用水(10mL)洗涤,再用DCM(20mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用柱层析纯化，洗脱剂体系为石油醚：乙酸乙酯＝30:1～4:1,得黄色固体522mg,收率81％。
实施例134的质谱数据：LCMS(ESI)m/z:659.1[M+H+].
第三步(实施例135的合成)
将化合物134(522mg,824.2umol,1.0eq)溶于无水DCM(5mL),在28℃下缓慢加入TFA(4.8g,42.1mmol,51eq)。加料完毕,反应液用氮气置换三次，在此温度下，搅拌72小时。LCMS显示反应完成，反应液降至室温，浓缩。剩余物用水(10mL)洗涤,用DCM(20mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用柱层析纯化，洗脱剂体系为石油醚：乙酸乙酯＝10:1～3:1,得黄色固体105mg,收率20％。
实施例135的核磁数据：1H NMR(400MHz,CDCl3)δ：7.90(d,J＝2.76Hz,1H),7.45(d,J＝2.51Hz,1H),7.40(d,J＝7.78Hz,1H),7.18-7.26(m,1H),7.05(d,J＝13.55Hz,2H),6.24(s,1H),5.48(dd,J＝4.27,18.32Hz, 1H),4.86(d,J＝14.31Hz,1H),4.76(dd,J＝4.39,10.67Hz,1H),4.49(dd,J＝11.17,18.20Hz,1H),4.05-4.20(m,2H),1.18(t,J＝7.03Hz,3H)
LCMS(ESI)m/z:517.0[M+H+].
第四步(136的合成)
将化合物135(170mg,329.8umol,1.0eq),碳酸钾(136.8mg,989.5umol,5eq)溶于无水DMF(10mL),在28℃下缓慢加入碘甲烷(234mg,1.65mmol,5.0eq)。加料完毕,反应液用氮气置换三次，在此温度下，搅拌30分钟。LCMS显示反应完成，反应液过滤，滤液浓缩。剩余物用水(10mL)洗涤,用DCM(20mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用柱层析纯化，洗脱剂体系为石油醚：乙酸乙酯＝10:1～3:1,得黄色固体即为实施例136120mg,收率98％。
实施例136的核磁数据：1H NMR(400MHz,CDCl3)δ：7.91(d,J＝3.26Hz,1H),7.45(d,J＝3.26Hz,1H),7.40(dd,J＝2.51,8.28Hz,1H),7.23-7.28(m,1H),7.04(dt,J＝2.51,8.16Hz,1H),6.98(d,J＝14.05Hz,1H),6.25(s,1H),5.32(d,J＝17.57Hz,1H),4.92(d,J＝14.05Hz,1H),4.76(d,J＝17.57Hz,1H),4.01-4.25(m,2H),2.97(s,3H),1.19(t,J＝7.15Hz,3H).
LCMS(ESI)m/z:531.1[M+H+].
实施例137
Figure PCTCN2015079870-appb-000229
实施例137的核磁数据：1H NMR(400MHz,CDCl3)δ:7.86(d,J＝3.2Hz,1H),7.43(d,J＝3.2Hz,1H),7.32-7.40(m,1H),6.77-6.88(m,2H),5.94(s,1H),4.63-4.70(m,1H),4.43-4.51(m,2H),4.10(q,J＝7.0Hz,2H),3.48-3.56(m,1H),3.25-3.34(m,1H),1.20(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:565.2[M+H+].
实施例138
Figure PCTCN2015079870-appb-000230
实施例138的核磁数据：1H NMR(400MHz,CDCl3)δ:8.09(br.s.,1H),7.92(br.s.,1H),7.71(br.s.,1H),6.80(d,J＝8.8Hz,2H),6.50(br.s.,1H),6.15(br.s.,1H),4.79(br.s.,1H),4.31-4.67(m,2H),4.15(d,J＝6.2 Hz,2H),3.72(d,J＝14.6Hz,1H),3.42(br.s.,1H),3.02(br.s.,3H),1.15-1.28(m,3H).
LCMS(ESI)m/z:483.1[M+H+].
实施例139
Figure PCTCN2015079870-appb-000231
实施例139的核磁数据：1H NMR(400MHz,CDCl3)δ：7.86(d,J＝3.26Hz,1H),7.42(d,J＝3.01Hz,1H),7.32(d,J＝12.00Hz,1H),7.17(dd,J＝2.51,8.53Hz,1H),6.96(dt,J＝2.64,8.22Hz,1H),6.77(d,J＝6.53Hz,1H),6.21(s,1H),5.09(d,J＝5.80Hz 2H),4.84(d,J＝5.80Hz 2H),4.71-4.82(m,1H),4.55(d,J＝5.77Hz,2H),4.09(q,J＝7.19Hz,2H),3.66(m,18.32Hz,2H),3.28(dd,J＝5.77,18.32Hz,1H),1.17(t,J＝7.15Hz,3H)
LCMS(ESI)m/z:505.2[M+H+].
实施例140
Figure PCTCN2015079870-appb-000232
实施例140的核磁数据：1H NMR(400MHz,CDCl3)δ:8.14(s,1H),8.02(s,1H),7.60(s,1H),7.13(d,J＝7.6Hz,1H),7.02(s,1H),6.31(s,1H),4.95(s,1H),4.68(s,1H),4.46(s,1H),4.15-4.06(m,2H),3.98-3.93(m,1H),3.67(s,2H),1.21(s,12H).
LCMS(ESI)m/z:525.3[M+H+].
实施例141
Figure PCTCN2015079870-appb-000233
实施例141的核磁数据：1H NMR(400MHz,CDCl3)δ:7.99(s,1H),7.77-7.70(m,2H),7.10-7.08(d,J＝8.0Hz,1H),6.95(s,1H),6.84(s,1H),6.28(s,1H),4.66-4.60(m,2H),4.35(s,1H),4.12-4.10(m,1H),3.75-3.71(m,1H),3.40(s,1H),3.02(s,3H),1.20-1.17(s,3H).
LCMS(ESI)m/z:499.2[M+H1].
实施例142
Figure PCTCN2015079870-appb-000234
实施例142的核磁数据：1H NMR(400MHz,CDCl3)δ＝8.98(s,1H),8.01(s,1H),7.73(d,1H),7.41(s,1H),7.16(d,J＝7.6,1H),7.01(s,1H),6.27(s,1H),4.86-4.79(m,2H),4.46(s,1H),4.14(m,2H),3.58(s,2H),1.20-1.14(m,3H).
LCMS m/z:517.1[M+1].
实施例143
Figure PCTCN2015079870-appb-000235
第一步(143-3)的合成
将化合物143-1(80mg,190.1umol,1.0eq),TEA(57.70mg,570.2umol,3.0eq)溶于无水DCM(3mL),在25℃下缓慢加入143-2(65.6mg,380.1umol,2.0eq)。加料完毕,反应液用氮气置换三次，在此温度下，搅拌16小时。LCMS显示反应完成，反应液浓缩。剩余物用水(10mL)洗涤,用DCM(20mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用柱层析纯化，洗脱剂体系为石油醚：乙酸乙酯＝10:1～3:1,得黄色固体25mg,收率24％。
LCMS(ESI)m/z:556.8[M+H+].
第二步(实施例143)的合成
将化合物143-3(25mg,44.9umol,1.0eq),一水氢氧化锂(18mg,448.8umol,10eq)先后溶于THF(1mL)和H2O(1mL)的混合溶液。在25℃下搅拌1小时。LCMS显示反应完成，反应液浓缩。剩余物用稀盐酸调pH＝1,水(10mL)洗涤,用DCM(20mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用机分(盐酸体系)纯化，得黄色固体19mg,收率80％。
实施例143的质谱数据：LCMS(ESI)m/z:543.1[M+H+].
实施例144
Figure PCTCN2015079870-appb-000236
实施例144的合成同实施例123的合成。
实施例144的核磁数据：1H NMR(400MHz,CDCl3-d)：7.84(d,J＝3.01Hz,1H),7.41(d,J＝3.01Hz,1H),7.21-7.25(m,1H),7.13(dd,J＝2.26,8.78Hz,1H),6.94(dt,J＝2.51,8.28Hz,1H),6.17(s,1H),5.06(d,J＝8.03Hz,1H),4.87-4.95(m,4H),4.44-4.57(m,3H),4.27-4.37(m,1H),4.05(q,J＝7.03Hz,2H),3.63(dd,J＝7.03,18.07Hz,1H),3.18(dd,J＝6.02,18.07Hz,1H),1.13(t,J＝7.03Hz,3H).
LCMS(ESI)m/z:541.3[M+H+].
实施例145
Figure PCTCN2015079870-appb-000237
实施例145的合成同实施例123的合成。
实施例145的核磁数据：1H NMR(400MHz,CDCl3)δ:7.87(d,J＝3.2Hz,1H),7.44(d,J＝3.2Hz,1H),7.37(dd,J＝5.6,8.4Hz,2H),7.02(t,J＝8.4Hz,2H),5.84(s,1H),4.65-4.46(m,3H),4.34(d,J＝5.2Hz,1H),4.17(q,J＝6.8Hz,2H),3.49-3.40(m,1H),3.36-3.27(m,1H),3.04(s,3H),1.26(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:465.2[M+H+].
实施例146
Figure PCTCN2015079870-appb-000238
第一步(146-3)的合成
将化合物146-2(1.29g,5.96mmol,1.2eq)溶于无水THF(300mL),在25℃下分批加入NaH(238.4mg,5.96mmol,1.2eq,60％含量)。加料完毕,搅拌30分钟。向反应液中加入146-1(2.50g,4.97mmol,1.0eq)，继续搅拌3小时。TLC显示反应完成。反应液用水(10mL)淬灭,乙酸乙酯(100mL)萃取三次。有机相用无水硫酸钠干燥,过滤,减压浓缩。剩余物用硅胶柱纯化,洗脱液石油醚:乙酸乙酯＝5:1,得产品2.2g,收率68％。
LCMS(ESI)m/z:640.1[M+H+].
第二步(146-4)的合成
将化合物146-3(2.2g,3.45mmol,1.0eq)溶于无水甲苯(30mL),在25℃下加入TFA(7.8g,69.0mmol,20.0eq)。加料完毕,反应液升温至120℃，搅拌5小时。TLC显示反应完成。反应液降至室温，减压浓缩，用水(50mL)洗涤,乙酸乙酯(100mL)萃取三次。有机相用无水硫酸钠干燥,过滤,减压浓缩得 粗产品2.0g。
LCMS(ESI)m/z:483.3[M+H+].
第三步(146-5)的合成
将化合物146-4(2.0g,4.1mmol,1.0eq)溶于无水DCM(30mL),在28℃下加入羰基二咪唑(1.35g,8.3mmol,2.0eq)。加料完毕,反应液用氮气置换三次，在此温度下搅拌30分钟。TLC显示反应完成，将此反应液滴加到溶有硼氢化钠(1.57g,41.5mmol,10.0eq)的甲醇(30mL)溶液中，继续搅拌30分钟。TLC显示反应完成。反应液用稀HCl淬灭，用乙酸乙酯溶解，用水(100mL)洗涤,再用乙酸乙酯(50mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用柱层析纯化,洗脱剂体系为石油醚：乙酸乙酯＝5:1,得黄色油状产品1.04g。
LCMS(ESI)m/z:492.0[M+Na+].
第四步(146-6)的合成
将化合物146-5(1.04g,2.22mmol,1.0eq)溶于无水DCM(30mL),在28℃下依次加入TEA(673.9mg,6.6mmol,3.0eq),甲烷磺酰氯(780mg,6.8mmol,3.1eq)。加料完毕,反应液在此温度下搅拌3小时。TLC显示反应完成，反应液用水洗涤，DCM(50mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用柱层析纯化，洗脱剂体系为石油醚：乙酸乙酯＝5:1,得产品570mg,收率56％。
LCMS(ESI)m/z:451.0[M+Na+].
第五步(146-7)的合成
将化合物146-6(468.3mg,1.04mmol,1.0eq)溶于四氯化碳(5mL),在23℃下依次加入NBS(277.6mg,1.56mmol,1.5eq)，AIBN(8.5mg,52.umol,0.05eq)。加料完毕,反应液在此温度下搅拌2.5小时。TLC显示反应完成，反应液用水洗涤，DCM(10mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用柱层析纯化，洗脱剂体系为石油醚：乙酸乙酯＝5:1,得产品146-7140mg,收率21％和146-8150mg,收率26％。
LCMS(ESI)m/z:529.6[M+H+].
第六步(146-9)的合成
将化合物146-7(120mg,226.7umol,1.0eq)溶于DMSO(3mL),在23℃下加入叠氮化钠(10mg,153.8umol,0.68eq)。加料完毕,反应液在此温度下搅拌18小时。TLC显示反应完成，反应液用水洗涤，悬浊液过滤，棕色固体用水洗涤，干燥得粗产品110mg。
LCMS(ESI)m/z:491.2[M+H+].
第七步(146-10)的合成
将化合物146-9(110mg,223.8umol,1.0eq)溶于乙醇(3mL),在25℃下加入Pd/C(11.mg,223.8umol,1.0eq)。加料完毕,反应液在氢气(15psi)条件下搅拌16小时。TLC显示反应完成，反应液过滤，滤液浓缩得粗品100mg。
LCMS(ESI)m/z:466.9[M+H+].
第八步(实施例146)的合成
将化合物146-10(100mg,214.9umol,1.0eq)溶于DCM(3mL),在23℃下依次加入TEA(108.7mg,1.1mmol,5.0eq)和甲烷磺酰氯(73.8mg,644.7umol,3.0eq)。加料完毕,反应液在此温度下搅拌1小时。TLC显示反应完成，反应液用水洗涤，再用DCM(50mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用制备分离柱纯化得白色固体产品6.7mg,收率6％。
实施例146的核磁数据：1H NMR(400MHz,CDCl3)δ:7.84(d,J＝3.0Hz,1H),7.40(d,J＝3.0Hz,1H),7.35(dd,J＝2.4,8.4Hz,1H),7.23(dd,J＝6.4,8.8Hz,1H),6.99(dt,J＝2.4,8.4Hz,1H),6.16(s,1H),5.22(dd,J＝2.0,5.6Hz,1H),4.78(br.s.,1H),4.54(dd,J＝8.4,11.2Hz,1H),4.38(dt,J＝5.6,11.2Hz,1H),3.99-4.16(m,2H),3.19(s,3H),2.84(dd,J＝5.6,14.0Hz,1H),2.12-2.25(m,1H),1.14(t,J＝7.0Hz,3H).
LCMS(ESI)m/z:545.0[M+H+].
实施例147
Figure PCTCN2015079870-appb-000239
实施例147的核磁数据：1H NMR(400MHz,CDCl3)δ:8.13(br.s.,1H),7.93(br.s.,1H),7.83(br.s.,1H),7.35(d,J＝6.4Hz,1H),7.10(br.s.,1H),6.41(br.s.,1H),5.98(br.s.,1H),5.24(br.s.,1H),4.94(br.s.,1H),4.46(br.s.,1H),4.14(d,J＝7.0Hz,2H),3.16(s,3H),2.77(br.s.,1H),2.33(br.s.,1H),1.17(t,J＝6.8Hz,3H).
LCMS(ESI)m/z:545.0[M+H+].
实施例148
Figure PCTCN2015079870-appb-000240
实施例148的核磁数据：1H NMR(400MHz,MeOD)δ：8.20(d,J＝17.6Hz,2H),7.43-7.52(m,1H),7.28-7.38(m,2H),5.83(br.s.,1H),4.58(br.s.,1H),4.36-4.45(m,2H),4.14-4.24(m,2H),3.76(dd,J＝6.8,17.8Hz,1H),3.24(dd,J＝7.2,17.8Hz,1H),3.07(s,3H),1.24(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:483.0[M+H+].
实施例149
Figure PCTCN2015079870-appb-000241
实施例149的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.2Hz,1H),7.40(d,J＝3.2Hz,1H),7.23(dd,J＝6.4,8.4Hz,1H),7.14(dd,J＝2.4,8.4Hz,1H),6.93(dt,J＝2.4,8.0Hz,1H),6.16(s,1H),4.81(d,J＝7.2Hz,1H),4.60-4.45(m,2H),4.37-4.24(m,1H),3.67(dd,J＝7.2,18.0Hz,1H),3.61(s,3H),3.16(dd,J＝6.4,18.0Hz,1H),3.07(s,3H).
LCMS(ESI)m/z:485.2[M+H+].
实施例150
Figure PCTCN2015079870-appb-000242
实施例150的核磁数据：1H NMR(400MHz,DMSO-d6)δ:7.98(d,J＝3.0Hz,1H),7.88(d,J＝3.0Hz,1H),7.63(br.s.,1H),7.36-7.46(m,2H),7.24(d,J＝8.2Hz,1H),5.88(s,1H),4.44-4.54(m,1H),4.20(d,J＝7.2Hz,2H),3.93-4.05(m,2H),3.48(dd,J＝17.4,6.6Hz,1H),3.01(s,4H),1.09(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:499.2[M+H+].
实施例151
Figure PCTCN2015079870-appb-000243
实施例151的核磁数据：1H NMR(400MHz,DMSO-d6)δ：7.82(d,J＝3.2Hz,1H),7.40(dd,J＝2.6,5.0Hz,2H),7.13-7.25(m,2H),6.17(s,1H),4.39-4.67(m,2H),4.30(t,J＝6.6Hz,1H),4.05(q,J＝7.0Hz,2H),3.66(dd,J＝7.2,18.0Hz,1H),3.18(dd,J＝6.6,18.0Hz,1H),3.07(s,3H),1.14(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:515.1[M+H+].
实施例152
Figure PCTCN2015079870-appb-000244
实施例152的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.2Hz,1H),7.39(d,J＝3.2Hz,1H),7.29-7.26(m,1H),7.13(dd,J＝2.4,8.8Hz,1H),6.94(dt,J＝2.4,8.8Hz,1H),6.17(s,1H),4.91(quin,J＝6.4Hz,1H),4.73(d,J＝7.6Hz,1H),4.60-4.43(m,2H),4.38-4.24(m,1H),3.65(dd,J＝7.2,17.6Hz,1H),3.17(dd,J＝6.4,18.0Hz,1H),3.07(s,3H),1.20(d,J＝6.4Hz,3H),0.96(d,J＝6.0Hz,3H).
LCMS(ESI)m/z:513.1[M+H+].
实施例153
Figure PCTCN2015079870-appb-000245
实施例153的核磁数据：1H NMR(400MHz,DMSO-d6)δ：10.14(br.s.,1H),7.97(d,J＝3.0Hz,1H),7.87(d,J＝3.0Hz,1H),7.53(dd,J＝6.4,8.6Hz,1H),7.40(dd,J＝2.6,8.8Hz,1H),7.15(dt,J＝2.6,8.4Hz,1H),6.02(s,1H),4.24-4.60(m,3H),3.82-4.09(m,2H),3.54(dd,J＝7.2,17.8Hz,1H),3.15(dd,J＝5.6,17.8Hz,1H),1.05(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:553.1[M+H+].
实施例154
Figure PCTCN2015079870-appb-000246
实施例154的核磁数据：1H NMR(400MHz,CDCl3)δ:9.11(s,1H),7.22-7.26(m,1H),7.14(dd,J＝2.4,8.4Hz,1H),6.92-7.00(m,1H),6.19(s,1H),5.35(br.s.,1H),4.65(dd,J＝6.6,11.2Hz,1H),4.45(dd,J＝6.6,11.2Hz,1H),4.30-4.39(m,1H),4.06(q,J＝7.2Hz,2H),3.72(dd,J＝7.2,18.0Hz,1H),3.19(dd,J＝7.2,18.0Hz,1H),3.08(s,3H),1.14(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:500.1[M+H+].
实施例155
Figure PCTCN2015079870-appb-000247
实施例155的核磁数据：1H NMR(400MHz,CDCl3)δ：7.84(d,J＝3.0Hz,1H),7.42(d,J＝3.0Hz,1H),7.22(dd,J＝6.0,8.4Hz,1H),7.14(dd,J＝2.6,8.4Hz,1H),6.95(dt,J＝2.6,8.4Hz,1H),6.14(s,1H),4.49-4.60(m,2H),4.42(quin,J＝6.6Hz,1H),3.67(dd,J＝7.6,18.6Hz,1H),3.61(s,3H),3.30(dd,J＝6.2,18.4Hz,1H).
LCMS(ESI)m/z:539.3[M+H+].
实施例156
Figure PCTCN2015079870-appb-000248
实施例156的核磁数据：1H NMR(400MHz,CDCl3)δ:7.83(d,J＝3.2Hz,1H),7.41(d,J＝3.2Hz,1H),7.26(dd,J＝6.0,8.8Hz,1H),7.16(dd,J＝2.4,8.4Hz,1H),6.95(dt,J＝2.4,8.4Hz,1H),6.18(s,1H),4.67(d,J＝7.2Hz,1H),4.63-4.55(m,1H),4.53-4.44(m,1H),4.38-4.26(m,1H),3.70(dd,J＝7.2,18.0Hz,1H),3.63(s,3H),3.20(dd,J＝6.8,18.0Hz,1H),2.62-2.46(m,1H),1.32-1.21(m,2H),1.16-1.04(m,2H)
LCMS(ESI)m/z:511.2[M+H+].
实施例157
Figure PCTCN2015079870-appb-000249
Figure PCTCN2015079870-appb-000250
将化合物157-1(100mg,200.4umol,1.0eq),碳酸钾(83.1mg,601.2umol,,3eq)溶于无水乙腈(5mL),在28℃下缓慢加入碘甲烷(730mg,5.1mmol,25.6eq)。加料完毕,反应液用氮气置换三次，在此温度下，搅拌16小时。LCMS显示反应完成，反应液过滤，滤液浓缩。剩余物用水(10mL)洗涤,用DCM(20mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用柱层析纯化，洗脱剂体系为石油醚：乙酸乙酯＝10:1～3:1,得黄色固体50mg,收率49％。
实施例157的核磁数据：1H NMR(400MHz,CDCl3)δ：7.83(d,J＝3.6Hz,1H),7.42(d,J＝3.6Hz,1H),7.26(d,J＝6.02Hz,1H),7.15(dd,J＝2.51,8.53Hz,1H),6.96(dt,J＝2.51,8.28Hz,1H),6.18(s,1H),4.82(d,J＝6.53Hz,1H),4.54-4.59(m,1H),4.43-4.60(m,1H),4.05(q,J＝7.11Hz,2H),3.53(dd,J＝7.28,18.07Hz,1H),3.32(dd,J＝6.53,18.07Hz,1H),2.93(s,3H),2.90(s,3H)1.13(t,J＝7.03Hz,3H).
LCMS(ESI)m/z:513.1[M+H+].
实施例169,182,183,184,186,188,192的合成同实施例157的合成相同。
实施例158
Figure PCTCN2015079870-appb-000251
实施例158的核磁数据：1H NMR(400MHz,CDCl3)δ:7.84(d,J＝3.0Hz,1H),7.41(d,J＝3.3Hz,1H),7.25(dd,J＝6.0,8.4Hz,1H),7.15(dd,J＝2.5,8.4Hz,1H),6.95(dt,J＝2.5,8.2Hz,1H),6.18(s,1H),4.66(d,J＝7.8Hz,1H),4.61-4.53(m,1H),4.52-4.43(m,1H),4.35-4.24(m,1H),3.68(dd,J＝7.4,17.9Hz,1H),3.63(s,3H),3.24-3.08(m,3H),1.43(t,J＝7.4Hz,3H).
LCMS(ESI)m/z:499.0[M+H+].
实施例159
Figure PCTCN2015079870-appb-000252
实施例159的核磁数据：1H NMR(400MHz,CDCl3)δ：7.82(d,J＝3.2Hz,1H),7.39(d,J＝3.0Hz,1H),7.24(dd,J＝6.2,8.4Hz,1H),7.14(dd,J＝2.4,8.4Hz,1H),6.93(dt,J＝2.4,8.4Hz,1H),6.16(s,1H),5.18(d,J＝6.8Hz,1H),5.06(s,2H),4.62(dd,J＝5.6,11.8Hz,1H),4.44(dd,J＝6.4,11.6Hz,1H),4.23-4.34(m,1H),3.64(d,J＝7.2Hz,1H),3.60(s,3H),3.26(dd,J＝6.0,18.2Hz,1H).
LCMS(ESI)m/z:486.1[M+H+].
实施例160
Figure PCTCN2015079870-appb-000253
实施例160的核磁数据：1H NMR(400MHz,CDCl3)δ：7.82(d,J＝3.0Hz,1H),7.40(d,J＝3.0Hz,1H),7.24(dd,J＝6.4,8.8Hz,1H),7.14(dd,J＝2.4,8.4Hz,1H),6.93(dt,J＝2.4,8.4Hz,1H),6.17(s,1H),4.67(d,J＝7.0Hz,1H),4.62(dd,J＝5.6,12.0Hz,1H),4.53(q,J＝5.0Hz,1H),4.44(dd,J＝6.0,12.0Hz,1H),4.20(sxt,J＝6.4Hz,1H),3.61(s,3H),3.57(d,J＝7.0Hz,1H),3.23(dd,J＝6.0,18.0Hz,1H),2.74(d,J＝5.0Hz,3H).
LCMS(ESI)m/z:500.2[M+H+].
实施例161,166
Figure PCTCN2015079870-appb-000254
Figure PCTCN2015079870-appb-000255
第一步(161-3)的合成
将化合物161-1(50mg,122.9umol,1.0eq),TEA(49.7mg,491.56umol,4.0eq)溶于无水DCM(1mL),在25℃下缓慢加入161-2(42.3mg,245.8umol,2.0eq)。加料完毕,反应液用氮气置换三次，在此温度下，搅拌2小时。LCMS显示反应完成，反应液浓缩。剩余物用水(10mL)洗涤,用DCM(20mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用柱层析纯化，洗脱剂体系为石油醚：乙酸乙酯＝5:1～2:1,得白色固体22mg,收率33％。
LCMS(ESI)m/z:543.1[M+H+]
第二步(161)的合成
将化合物161-3(22mg,40.5umol,1.0eq)溶于无水甲醇(2mL),在25℃下缓慢加入硼氢化钠(7.6mg,202.58umol,5..0eq)。加料完毕,反应液用氮气置换三次，在此温度下，搅拌2小时。TLC显示反应完成，反应液浓缩。剩余物用水(10mL)洗涤,用DCM(10mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用柱层析纯化，洗脱剂体系为石油醚：乙酸乙酯＝1:1～1:5,得白色固体6mg,收率29％。
实施例161的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.2Hz,1H),7.40(d,J＝3.2Hz,1H),7.23(dd,J＝6.0,8.4Hz,1H),7.14(dd,J＝2.4,8.4Hz,1H),6.94(dt,J＝2.,8.4Hz,1H),6.15(s,1H),5.07(d,J＝7.6Hz,1H),4.50(d,J＝6.0Hz,2H),4.38-4.25(m,1H),4.12(br.s.,2H),3.69-3.62(m,1H),3.61(s,3H),3.42-3.29(m,2H),3.22(dd,J＝6.4,18.0Hz,1H),2.80(br.s.,1H)
LCMS(ESI)m/z:515.2[M+H+]
第三步(166-1)的合成
将化合物161-3(30mg,58.2umol,1.0eq),TEA(17.68mg,174.75mmol,3.0eq)溶于无水DCM(2mL),在25℃下缓慢加入甲烷磺酰氯(13mg,116.5umol,2.0eq)。加料完毕,反应液用氮气置换三次，在此温度下，搅拌1小时。TLC显示反应完成，反应液用水(10mL)洗涤,用DCM(20mL)萃取三次。有 机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用薄层色谱纯化,得白色固体9mg,收率31％。
1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.6Hz,1H),7.39(d,J＝3.6Hz,1H),7.22(dd,J＝6.0,8.4Hz,1H),7.13(dd,J＝2.4,8.4Hz,1H),6.93(dt,J＝2.4,8.4Hz,1H),6.60(dd,J＝10.0,16.4Hz,1H),6.34(d,J＝16.4Hz,1H),6.15(s,1H),6.01(d,J＝10.0Hz,1H),4.96(d,J＝7.6Hz,1H),4.58-4.48(m,1H),4.47-4.36(m,1H),4.21-4.08(m,1H),3.68-3.56(m,4H),3.21-3.11(m,1H)
LCMS(ESI)m/z:497.1[M+H+]
第四步(166)的合成
将化合物二甲胺盐酸盐(8.16mg,181.10umol,10eq)溶于无水THF(2mL),在25℃下缓慢加入TEA(18.33mg,181.1umol)。加料完毕,反应液在此温度下，搅拌5分钟。之后，向反应液中加入166-1(9mg,18.1umol,1.0eq),继续搅拌15小时。TLC显示反应完成，反应液过滤，滤液浓缩，剩余物用水(10mL)洗涤,用DCM(20mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用薄层色谱纯化,得白色固体4mg,收率41％。
实施例166的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.6Hz,1H),7.38(d,J＝3.2Hz,1H),7.26-7.20(m,1H),7.13(dd,J＝2.4,8.4Hz,1H),6.93(dt,J＝2.4,8.4Hz,1H),6.16(s,1H),4.57(dd,J＝6.4,11.6Hz,1H),4.43(dd,J＝6.0,11.6Hz,1H),4.36-4.25(m,1H),3.68(dd,J＝7.2,17.6Hz,1H),3.61(s,3H),3.30(d,J＝6.0Hz,2H),3.16(dd,J＝7.2,18.2Hz,1H),3.08-2.97(m,1H),2.96-2.85(m,1H),2.41(s,6H)
LCMS(ESI)m/z:542.2[M+H+]
实施例162
Figure PCTCN2015079870-appb-000256
实施例162的核磁数据：1H NMR(400MHz,CDCl3)δ：7.82(d,J＝3.2Hz,1H),7.40(d,J＝3.2Hz,1H),7.28-7.23(m,1H),7.15(dd,J＝2.4,8.4Hz,1H),6.95(dt,J＝2.4,8.4Hz,1H),6.18(s,1H),5.92(d,J＝6.8Hz,1H),4.81-4.65(m,1H),4.46(d,J＝5.8Hz,2H),3.62(s,3H),3.62-3.53(m,1H),3.16(dd,J＝5.8,18.1Hz,1H),2.03(s,3H)
LCMS m/z:449.1[M+H+].
实施例163
Figure PCTCN2015079870-appb-000257
实施例163的核磁数据：1H NMR(400MHz,CDCl3)δ:7.81(d,J＝3.2Hz,1H),7.38(d,J＝3.2Hz,1H),7.26-7.21(m,1H),7.13(dd,J＝2.4,8.4Hz,1H),6.93(dt,J＝2.4,8.4Hz,1H),6.16(s,1H),5.01(br.s.,1H),4.54-4.43(m,2H),4.36(d,J＝5.2Hz,1H),3.70(br.s.,3H),3.64-3.56(m,4H),3.10(dd,J＝5.6,17.6Hz,1H).
LCMS m/z:465.1[M+H+].
实施例164
Figure PCTCN2015079870-appb-000258
实施例164的核磁数据：1H NMR(400MHz,MeOD-d4)δ：8.30(dd,J＝2.4,10.54Hz,2H),7.71(d,J＝6.4Hz,1H),7.54(br.s.,1H),7.32(t,J＝8.4Hz,1H),5.87(s,1H),4.61(d,J＝3.6Hz,1H),4.27-4.51(m,2H),3.74-3.87(m,1H),3.73(s,3H),3.26(dd,J＝5.6,18.2Hz,1H),3.07(s,3H)
LCMS(ESI)m/z:485.2[M+H+].
实施例165
Figure PCTCN2015079870-appb-000259
实施例165的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.2Hz,1H),7.40(d,J＝3.2Hz,1H),7.22-7.15(m,1H),7.11-7.01(m,2H),6.23(s,1H),4.80(d,J＝7.2Hz,1H),4.61-4.45(m,2H),4.38-4.25(m,1H),3.68(dd,J＝7.2,18.0Hz,1H),3.61(s,3H),3.17(dd,J＝7.2,18.0Hz,1H),3.08(s,3H).
LCMS(ESI)m/z:485.2[M+H+].
实施例167
Figure PCTCN2015079870-appb-000260
实施例167的核磁数据：1H NMR(400MHz,CDCl3)δ:7.85(d,J＝3.0Hz,1H),7.42(d,J＝3.2Hz,1H),6.98-7.06(m,1H),6.87-6.95(m,1H),5.98(s,1H),4.92(d,J＝7.6Hz,1H),4.48-4.60(m,2H),4.28(sxt,J＝6.8Hz,1H),3.64(s,3H),3.55-3.62(m,1H),3.13(dd,J＝6.8,18.0Hz,1H),3.07(s,3H).
LCMS(ESI)m/z:487.2[M+H+].
实施例168
Figure PCTCN2015079870-appb-000261
实施例168的核磁数据：1H NMR(400MHz,CDCl3)δ:8.05(br.s.,1H),7.81(br.s.,1H),7.42(br.s.,1H),6.93(q,J＝7.8Hz,1H),6.13(s,1H),6.06(br.s.,1H),4.74(d,J＝8.0Hz,1H),4.60(d,J＝12.4Hz,1H),4.40(br.s.,1H),3.71(s,3H),3.64(br.s.,1H),3.36(dd,J＝5.6,18.2Hz,1H),3.03(s,3H).
LCMS(ESI)m/z:487.2[M+H+].
实施例169
Figure PCTCN2015079870-appb-000262
实施例169的核磁数据：1H NMR(400MHz,CDCl3)δ:7.83(d,J＝3.26Hz,1H),7.40(d,J＝3.01Hz,1H),7.24(dd,J＝6.02,8.53Hz,1H),7.15(dd,J＝2.51,8.53Hz,1H),6.95(dt,J＝2.51,8.16Hz,1H),6.17(s,1H), 4.84(quin,J＝7.40Hz,1H),4.59(dd,J＝6.53,12.05Hz,1H),4.43(dd,J＝7.65,11.92Hz,1H),3.62(s,3H),3.54(dd,J＝8.28,18.32Hz,1H),3.29(dd,J＝7.28,18.32Hz,1H),2.92(d,J＝12.80Hz,6H)
LCMS(ESI)m/z:499.1[M+H+]
实施例170
Figure PCTCN2015079870-appb-000263
实施例170的核磁数据：1H NMR(400MHz,CDCl3)δ:7.84(d,J＝3.0Hz,1H),7.40(d,J＝3.0Hz,1H),7.26(dd,J＝8.4,6.40Hz,1H),7.15(dd,J＝8.4,2.26Hz,1H),6.92-6.99(m,1H),6.18(s,1H),4.64(d,J＝5.8Hz,1H),4.22-4.40(m,3H),3.70-3.79(m,1H),3.63(s,3H),3.06-3.15(m,1H),1.46(s,9H).
LCMS(ESI)m/z:527.1[M+H+].
实施例171
Figure PCTCN2015079870-appb-000264
第一步(171-3)的合成
将化合物171-1(100mg,245.7umol,1.0eq),TEA(74.6mg,737.3umol,3.0eq)溶于无水DCM(2mL),在25℃下加入171-2(100mg,368.6umol,1.5eq)。加料完毕,反应液用氮气置换三次，在此温度下，搅拌2小时。TLC显示反应完成，反应液用水(10mL)洗涤,用DCM(20mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用柱层析纯化，洗脱剂体系为石油醚：乙酸乙酯＝10:1～3:1,得白色固体44mg,收率25％。
LCMS(ESI)m/z:665.9[M+Na+]
第二步(171)的合成
将化合物171-3(20mg,31.05umol,1.0eq)溶于甲醇(2mL),在25℃下加入N2H4.H2O(15.5mg,310.5umol,10.0eq)。加料完毕,反应液在此温度下，搅拌2小时。TLC显示反应完成，反应液浓缩，剩余物用水(10mL)洗涤,用DCM(20mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用机分(氨水体系)纯化得白色固体10mg,收率58％。
实施例171的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.2Hz,1H),7.39(d,J＝3.2Hz,1H),7.25-7.20(m,1H),7.13(d,J＝6.4Hz,1H),6.99-6.88(m,1H),6.15(s,1H),4.50(br.s.,2H),4.30(t,J＝6.4Hz,1H),3.71-3.54(m,4H),3.35-3.13(m,5H)
LCMS(ESI)m/z:514.1[M+H+]
实施例172
Figure PCTCN2015079870-appb-000265
实施例172的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.0Hz,1H),7.39(d,J＝3.2Hz,1H),7.24(dd,J＝6.4,8.4Hz,1H),7.14(dd,J＝2.4,8.4Hz,1H),6.94(dt,J＝2.4,8.4Hz,1H),6.16(s,1H),5.43(d,J＝6.4Hz,1H),4.53-4.62(m,1H),4.44-4.52(m,1H),4.29-4.41(m,1H),4.13(d,J＝2.4Hz,2H),3.82(s,3H),3.68(dd,J＝7.2,18.07Hz,1H),3.61(s,3H),3.22(dd,J＝6.8,18.0Hz,1H).
LCMS(ESI)m/z:543.1[M+H+].
实施例173
Figure PCTCN2015079870-appb-000266
实施例173的核磁数据：1H NMR(400MHz,CDCl3)δ:7.81(d,J＝3.2Hz,1H),7.39(d,J＝3.2Hz,1H),7.23-7.28(m,1H),7.15(dd,J＝8.6,2.4Hz,1H),6.95(td,J＝8.2,2.4Hz,1H),6.19(s,1H),6.13(d,J＝7.2Hz,1H),4.68-4.81(m,1H),4.46(d,J＝5.6Hz,2H),3.61-3.64(m,3H),3.54-3.61(m,1H),3.19(dd,J＝18.2,6.0Hz,1H),1.30-1.43(m,1H),1.02(br.s.,2H),0.78(dd,J＝7.6,3.2Hz,2H).
LCMS(ESI)m/z:474.9[M+H+].
实施例174
Figure PCTCN2015079870-appb-000267
实施例174的核磁数据：1H NMR(400MHz,CDCl3)δ:7.81(d,J＝3.6Hz,1H),7.39(d,J＝3.0Hz,1H),7.24(dd,J＝6.2,8.8Hz,1H),7.13(dd,J＝2.4,8.6Hz,1H),6.93(dt,J＝2.4,8.4Hz,1H),6.16(s,1H),4.54(dd,J＝7.0,11.6Hz,1H),4.21(dd,J＝7.0,11.6Hz,1H),4.05-4.17(m,4H),3.96-4.05(m,1H),3.62-3.69(m,1H),3.61(s,3H),2.93-3.05(m,2H),1.36(dt,J＝2.0,7.0Hz,6H).
LCMS(ESI)m/z:543.1[M+H+].
实施例175
Figure PCTCN2015079870-appb-000268
实施例175的核磁数据：1H NMR(400MHz,MeOD-d4)δ：7.91(d,J＝3.2Hz,1H),7.69(d,J＝3.0Hz,1H),7.44(dd,J＝6.2,8.6Hz,1H),7.21(dd,J＝2.4,8.8Hz,1H),7.06(dt,J＝2.4,8.4Hz,1H),6.12(s,1H),4.50(dd,J＝6.8,11.6Hz,1H),4.28(dd,J＝6.8,11.2Hz,1H),4.14(quin,J＝7.2Hz,1H),3.62-3.72(m,1H),3.61(s,3H),3.14(dd,J＝7.2,17.8Hz,1H),
LCMS(ESI)m/z:487.1[M+H+].
实施例176
Figure PCTCN2015079870-appb-000269
实施例176的合成同实施例136的合成相同。
实施例176的核磁数据：1H NMR(400MHz,CDCl3)δ：7.92(d,J＝3.26Hz,1H),7.45-7.56(m,2H),7.17(dd,J＝2.38,8.16Hz,1H),6.96-7.09(m,2H),5.91(s,1H),5.34(s,1H),4.50(d,J＝13.30Hz,1H),4.24(tdd,J＝3.64,7.15,10.67Hz,2H),3.70-3.84(m,2H),3.59-3.68(m,1H),3.43-3.53(m,1H),3.38(s,1H),1.32(br.s.,3H).
LCMS(ESI)m/z:515.1[M+H+].
实施例177
Figure PCTCN2015079870-appb-000270
第一步(177-4的合成)
将化合物177-1(3.86g,26.36mmol,1.0eq),177-2(10.0g,26.36mmol,1.0eq),177-3(4.31g,26.36mmol,1.0eq)溶于无水DMF(100mL),在20℃下加入NaHCO3(8.86g,105.44mmol,4.00eq)。加料完毕,反应液用氮气置换三次，升温至60℃,搅拌4小时。反应液降至室温，过滤，滤液减压浓缩，剩余物用乙酸乙酯溶解，用水(100mL)洗涤,再用乙酸乙酯(100mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用柱层析纯化,洗脱剂体系为DCM/MeOH＝20/1,10/1,得黄色油状产品11g,收率66％。
LCMS(ESI)m/z:527.1[M+H+].
第二步(177-5的合成)
将化合物177-4(10.0g,18.97mmol,1.0eq)，NMM(2.49g,24.66mmol,1.30eq)溶于无水THF(50mL),在0℃下缓慢加入氯甲酸异丁酯(3.11g,22.76mmol,1.2eq)。加料完毕,反应液用氮气置换三次，在0℃下搅拌30分钟。TLC显示反应完成，反应液过滤，滤液在0℃下缓慢滴加到NaBH4(1.4g,37.94mmol,2.0eq)的水溶液(50mL)中。反应液继续搅拌1小时。TLC显示反应完成。反应液用稀HCl淬灭，用乙酸乙酯溶解，用水(100mL)洗涤,再用乙酸乙酯(100mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用柱层析纯化,洗脱剂体系为石油醚：乙酸乙酯＝10:1～3:1,得黄色固体产品6.6g,收率64％。
LCMS(ESI)m/z:513.1[M+H+].
第三步(177-6的合成)
将化合物177-5(6.60g,12.86mmol,1.0eq),TEA(2.60g,25.72mmol,2.0eq)溶于无水DCM(50mL),在0℃下缓慢加入甲烷磺酰氯(1.92g,16.76mmol,1.3eq)。加料完毕,反应液用氮气置换三次，升温至27℃，搅拌15小时。TLC显示反应完成，反应液用水(100mL)洗涤,再用DCM(100mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用柱层析纯化,洗脱剂体系为石油醚：乙酸乙酯＝10:1～3:1,得黄色固体产品5.6g,收率87％。
LCMS(ESI)m/z:495.2[M+H+].
第四步(177-7的合成)
将化合物177-6(5.60g,11.31mmol,1.0eq)溶于无水DCM(10mL),在0℃下缓慢加到HCl/EtOAc(20mL)溶液中。加料完毕,反应液搅拌1小时。TLC显示反应完成，反应液减压浓缩得黄色固体4.7g,收率92％。粗产品直接用于下一步反应。
LCMS(ESI)m/z:394.9[M+H+].
第五步(177-8的合成)
将化合物177-7(500mg,1.16mmol,1.0eq),TEA(234mg,2.32mmol,2.0eq)溶于无水DCM(5mL),在0℃下缓慢加入甲烷磺酰氯(199mg,1.7mmol,1.5eq)。加料完毕,反应液用氮气置换三次，升温至27℃,搅拌4小时。TLC显示反应完成，反应液用水(10mL)洗涤,再用DCM(10mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用柱层析纯化，洗脱剂体系为石油醚：乙酸乙酯＝10:1～3:1,得黄色固体产品300mg,收率52％。
LCMS(ESI)m/z:473.0[M+H+].
第六步(177的合成)
化合物177-8(300mg,634.26mmol)用制备分离柱(甲酸体系)得白色固体光学纯实施例17757mg,de值88％.
实施例177的核磁数据：1H NMR(400MHz,CDCl3)δ:7.85(d,J＝3.2Hz,1H),7.43(d,J＝3.2Hz,1H),7.12(d,J＝5.2Hz,1H),6.87(d,J＝5.2Hz,1H),6.14(s,1H),4.89(d,J＝7.6Hz,1H),4.66-4.56(m,1H),4.53-4.43(m,1H),4.36-4.25(m,1H),3.72-3.68(m,3H),3.63(dd,J＝7.2,17.6Hz,1H),3.16-3.09(m,1H),3.07(s,3H).
LCMS(ESI)m/z:473.0[M+H+].
实施例152,178,179,180,181,185,187,189,190,191,193,194,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220，223,224,225,226的合成同实施例177的合成相同。
实施例178
Figure PCTCN2015079870-appb-000271
实施例178的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.2Hz,1H),7.40(d,J＝3.2Hz,1H),7.23(dd,J＝6.4,8.8Hz,1H),7.14(dd,J＝2.4,8.4Hz,1H),6.93(dt,J＝245,8.4Hz,1H),6.16(s,1H),4.85(d,J＝7.6Hz,1H),4.52(dq,J＝6.4,11.6Hz,2H),4.37-4.22(m,1H),3.67(dd,J＝7.2,18.0Hz,1H),3.61(s,3H),3.17(dd,J＝7.2,18.0Hz,1H),3.10-3.04(m,3H).
LCMS(ESI)m/z:485.1[M+H+].
实施例179
Figure PCTCN2015079870-appb-000272
实施例179的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.2Hz,1H),7.39(d,J＝3.2Hz,1H),7.22-7.25(m,1H),7.14(dd,J＝8.53,2.4Hz,1H),6.95(td,J＝8.2,2.4Hz,1H),6.17(s,1H),5.83-6.08(m,1H),4.55-4.71(m,2H),4.32-4.47(m,1H),3.53-3.72(m,6H),3.20-3.32(m,1H),3.04(s,3H).
LCMS(ESI)m/z:549.1[M+H+].
实施例180
Figure PCTCN2015079870-appb-000273
实施例180的核磁数据：1H NMR(400MHz,CDCl3)δ:2.64(s,3H)3.08(s,3H)3.15(dd,J＝17.82,7.2Hz,1H)3.62(s,3H)3.73(dd,J＝17.8,7.28Hz,1H)4.24-4.39(m,1H)4.47-4.55(m,2H)4.83(d,J＝7.6Hz,1H)5.93(s,1H)6.77-6.84(m,1H)6.90(dd,J＝10.0,2.51Hz,1H)7.06(dd,J＝8.2,5.77Hz,1H)7.37(d,J＝3.6Hz,1H)7.79(d,J＝3.0Hz,1H)
LCMS(ESI)m/z:465.1[M+H+].
实施例181
Figure PCTCN2015079870-appb-000274
实施例181的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.6Hz,1H),7.40(d,J＝3.2Hz,1H),7.30(dd,J＝6.2,8.8Hz,1H),7.15(dd,J＝2.6,8.8Hz,1H),6.96(dt,J＝2.8,8.4Hz,1H),6.17(s,1H),4.71(d,J＝6.4Hz,1H),4.56-4.62(m,1H),4.47-4.53(m,1H),4.29-4.37(m,1H),3.63(s,3H),3.47-3.54(m,1H),3.32-3.41(m,1H),3.06(s,3H).
LCMS(ESI)m/z:485.0[M+H+].
实施例182
Figure PCTCN2015079870-appb-000275
实施例182的核磁数据：1H NMR(400MHz,CDCl3)δ:7.85(d,J＝3.01Hz,1H),7.43(d,J＝3.26Hz,1H), 7.24-7.28(m,1H),7.17(dd,J＝2.26,8.53Hz,1H),6.97(dt,J＝2.51,8.16Hz,1H),6.21(s,1H),4.67-4.81(m,2H),4.54-4.63(m,1H),4.27-4.42(m,2H),3.71(dd,J＝7.65,18.45Hz,1H),3.64(s,3H),3.46(dd,J＝6.90,18.45Hz,1H),3.17(s,3H)
LCMS(ESI)m/z:524.1[M+H+]
实施例183
Figure PCTCN2015079870-appb-000276
实施例183的核磁数据：1H NMR(400MHz,DMSO-d6)δ:7.98(d,J＝3.51Hz,1H),7.88(d,J＝3.51Hz,1H),7.51(dd,J＝8.53,6.02Hz,1H),7.43(dd,J＝8.53,2.51Hz,1H),7.18(td,J＝8.53,2.51Hz,1H),6.01(s,1H),4.62-4.72(m,1H),4.48-4.55(m,1H),4.14-4.22(m,1H),3.50-3.61(m,4H),3.30(d,J＝5.52Hz,2H),3.01-3.18(m,4H),1.15(t,J＝7.03Hz,3H)
LCMS(ESI)m/z:513.1[M+H+]
实施例184
Figure PCTCN2015079870-appb-000277
实施例184的核磁数据：1H NMR(400MHz,CDCl3)δ:7.81(d,J＝3.6Hz,1H),7.37(d,J＝3.6Hz,1H),7.29(d,J＝6.0Hz,1H),7.14(dd,J＝8.6,2.51Hz,1H),6.94(td,J＝8.2,2.51Hz,1H),6.16(s,1H),4.63(dd,J＝10.8,8.28Hz,1H),4.37-4.50(m,1H),4.21(t,J＝9..0Hz,1H),3.61(s,3H),3.93-4.02(m,1H),3.48-3.59(m,2H),2.98(s,3H),1.38(d,J＝6.4Hz,6H)
LCMS(ESI)m/z:527.2[M+H+]
实施例185
Figure PCTCN2015079870-appb-000278
实施例185的核磁数据：1H NMR(400MHz,CDCl3)δ:7.83(d,J＝3.2Hz,1H),7.40(d,J＝3.2Hz,1H),7.19-7.24(m,1H),7.14(dd,J＝3.2,8.4Hz,1H),6.94(t,J＝8.4Hz,1H),6.17(s,1H),4.64(dd,J＝5.2,11.6Hz, 1H),4.42-4.53(m,1H),4.28(d,J＝6.4Hz,1H),3.88(s,3H),3.57-3.63(m,4H),3.22-3.33(m,1H).
LCMS(ESI)m/z:501.1[M+H+].
实施例186
Figure PCTCN2015079870-appb-000279
实施例186的核磁数据：1H NMR(400MHz,CDCl3)δ:7.83(br.s.,1H),7.42(d,J＝2.76Hz,1H),7.21-7.26(m,1H),7.14(dd,J＝2.13,8.41Hz,1H),6.94(t,J＝7.15Hz,1H),6.15(s,1H),4.65-4.75(m,1H),4.46-4.52(m,1H),4.42(br.s.,1H),4.02-4.26(m,2H),3.63(d,J＝7.78Hz,1H),3.58(br.s.,3H),3.24(dd,J＝6.90,17.94Hz,1H),3.12(s,3H)
LCMS(ESI)m/z:543.0[M+H+]
实施例187
Figure PCTCN2015079870-appb-000280
实施例187的核磁数据：1H NMR(400MHz,CDCl3)δ：8.15(br.s.,1H),7.89(br.s.,1H),7.57(t,J＝6.4Hz,1H),7.17(d,J＝7.0Hz,1H),7.04(t,J＝6.8Hz,1H),6.34(br.s.,1H),5.03(br.s.,1H),4.34(br.s.,2H),3.69(s,3H),3.64(br.s.,1H),3.30-3.53(m,3H),3.24(t,J＝7.0Hz,2H),2.46(br.s.,2H).
LCMS(ESI)m/z:511.0[M+H+].
实施例188
Figure PCTCN2015079870-appb-000281
实施例188的核磁数据：1H NMR(400MHz,CDCl3)δ:7.84(d,J＝3.26Hz,1H),7.42(d,J＝3.26Hz,1H),7.26(dd,J＝6.40,8.66Hz,1H),7.16(dd,J＝2.38,8.66Hz,1H),6.97(dt,J＝2.51,8.16Hz,1H),6.18(s,1H),4.75(quin,J＝7.47Hz,1H),4.54(dd,J＝2.38,7.40Hz,2H),3.86(d,J＝4.77Hz,2H),3.67(d,J＝8.28Hz,1H),3.63(s,3H),3.39-3.51(m,2H),3.34(dd,J＝8.03,18.32Hz,1H),3.05(s,3H)
LCMS(ESI)m/z:529.1[M+H+]
实施例189
Figure PCTCN2015079870-appb-000282
实施例189的核磁数据：1H NMR(400MHz,CDCl3)δ：7.92(d,J＝7.0Hz,2H),7.76(d,J＝3.0Hz,1H),7.51-7.67(m,3H),7.37(d,J＝3.0Hz,1H),7.19(dd,J＝6.4,8.8Hz,1H),7.11(dd,J＝2.4,8.4Hz,1H),6.90(dt,J＝2.4,8.4Hz,1H),6.12(s,1H),5.12(d,J＝7.0Hz,1H),4.35-4.50(m,1H),4.22-4.34(m,1H),4.11(sxt,J＝6.8Hz,1H),3.56(s,3H),3.45(dd,J＝7.6,18.0Hz,1H),3.03(dd,J＝6.8,18.0Hz,1H).
LCMS(ESI)m/z:547.1[M+H+].
实施例190
Figure PCTCN2015079870-appb-000283
实施例190的核磁数据：1H NMR(400MHz,CDCl3)δ:7.84(d,J＝3.0Hz,1H),7.41(d,J＝3.0Hz,1H),7.25(dd,J＝8.6,6.4Hz,1H),7.15(dd,J＝8.4,2.4Hz,1H),6.94(td,J＝8.4,2.4Hz,1H),6.17(s,1H),4.54(dd,J＝11.6,6.8Hz,1H),4.25(dd,J＝11.2,7.0Hz,1H),3.96-4.12(m,1H),3.78(dd,J＝11.6,3.2Hz,6H),3.65-3.71(m,1H),3.63(s,3H),2.90-3.09(m,2H).
LCMS(ESI)m/z:515.0[M+H+].
实施例191
Figure PCTCN2015079870-appb-000284
实施例191的核磁数据：1H NMR(400MHz,CHLOROFORM-d)δ:8.34(d,J＝2.5Hz,1H),7.34(dd,J＝6.3,8.8Hz,1H),7.31-7.27(m,1H),7.12(dd,J＝2.5,8.5Hz,1H),6.97(dt,J＝2.5,8.3Hz,1H),6.22(s,1H),5.02(br.s.,1H),4.30-4.18(m,1H),3.87(dd,J＝6.3,10.8Hz,1H),3.64-3.58(m,4H),3.58-3.53(m,1H),3.25(dd,J＝5.8,18.3Hz,1H),3.02(s,3H)
LCMS(ESI)m/z:515.1[M+H+].
实施例192
Figure PCTCN2015079870-appb-000285
实施例192的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.52Hz,1H),7.40(d,J＝3.01Hz,1H),7.24(dd,J＝8.53,6.02Hz,1H),7.14(dd,J＝8.53,2.51Hz,1H),6.94(td,J＝8.28,2.51Hz,1H),6.17(s,1H),4.79(dt,J＝14.18,7.22Hz,1H),4.65(dd,J＝12.05,6.02Hz,1H),4.59(s,2H),4.41(dd,J＝12.05,7.53Hz,1H),3.62(s,3H),3.54(dd,J＝18.32,8.28Hz,1H),3.32-3.39(m,1H),2.87(s,3H)
LCMS(ESI)m/z:500.0[M+H+]
实施例193
Figure PCTCN2015079870-appb-000286
实施例193的核磁数据：1H NMR(400MHz,CDCl3)δ:7.85(d,J＝3.0Hz,1H),7.43(d,J＝3.0Hz,1H),6.98-7.06(m,1H),6.87-6.96(m,1H),5.98(s,1H),4.99(d,J＝7.0Hz,1H),4.96(s,2H),4.69(dd,J＝5.2,11.6Hz,1H),4.45(dd,J＝6.0,12.0Hz,1H),4.23-4.33(m,1H),3.64(s,3H),3.55(dd,J＝7.0,18.0Hz,1H),3.22(dd,J＝5.6,18.4Hz,1H)；
LCMS(ESI)m/z:488.2[M+H+].
实施例194
Figure PCTCN2015079870-appb-000287
实施例194的核磁数据：1H NMR(400MHz,CDCl3)δ:8.37(d,J＝2.4Hz,1H),7.84(d,J＝3.0Hz,1H),7.39-7.42(m,1H),7.31-7.38(m,1H),5.90(s,1H),4.87(d,J＝7.2Hz,1H),4.47-4.58(m,2H),4.28(qd,J＝6.8,13.6Hz,1H),3.66(s,3H),3.57-3.64(m,1H),3.08-3.16(m,1H),3.07(s,3H).
LCMS(ESI)m/z:452.0[M+H+].
实施例195
Figure PCTCN2015079870-appb-000288
第一步(195-3)的合成
将化合物195-1(100mg,245.7umol,1.0eq)溶于无水DCM(3mL),在25℃下加入195-2(76.2mg,245.8umol,1.0eq)。加料完毕,反应液在此温度下，搅拌16小时。TLC显示反应完成，反应液用水(10mL)洗涤,用DCM(20mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用柱层析纯化，洗脱剂体系为石油醚：乙酸乙酯＝30:1～10:1,得白色固体130mg,收率79％。
LCMS(ESI)m/z:649.2[M+H+]
第二步(195)的合成
将化合物195-3(130mg,200.2umol,1.0eq)溶于无水乙酸乙酯(1mL),在25℃下加入HCl/EtOAc(730mg,20.mmol,99.87eq)。加料完毕,反应液在此温度下，搅拌16小时。LCMS显示反应完成，反应液减压浓缩得黄色固体80mg,收率82％。
实施例195的核磁数据：1H NMR(400MHz,METHANOL-d4)δ：8.51-8.62(m,1H),7.92(d,J＝3.26Hz,1H),7.69(d,J＝3.26Hz,1H),7.42(dd,J＝8.53,6.27Hz,1H),7.25(dd,J＝8.78,2.51Hz,1H),7.06(td,J＝8.34,2.64Hz,1H),6.17(s,1H),4.59-4.71(m,2H),4.33-4.53(m,2H),3.55-3.69(m,4H).
LCMS(ESI)m/z:449.1[M+H+]
实施例196
Figure PCTCN2015079870-appb-000289
Figure PCTCN2015079870-appb-000290
第一步(196-2)的合成
将化合物196-1(500mg,1.2mmol,1.0eq),BPO(327.mg,1.35mmol,1.1eq)溶于无水THF(5mL),在25℃下加入Na2HPO4(872mg,6.1mmol,5.0eq)。加料完毕,反应液升温至50℃，搅拌2小时。TLC显示反应完成，反应液减压浓缩，剩余物用水(10mL)洗涤,用DCM(20mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用柱层析纯化，洗脱剂体系为石油醚：乙酸乙酯＝1:1,得红色固体130mg,收率20％。
1H NMR(400MHz,CDCl3)δ：8.05(d,J＝7.28Hz,2H),7.84(d,J＝3.26Hz,1H),7.60-7.69(m,1H),7.51(t,J＝7.65Hz,2H),7.41(d,J＝3.26Hz,1H),7.31(s,1H),7.14(dd,J＝2.51,8.53Hz,1H),6.94(dt,J＝2.51,8.28Hz,1H),6.19(s,1H),4.79(dd,J＝3.51,12.30Hz,1H),4.44(dd,J＝6.15,12.42Hz,1H),4.12(br.s.,1H),3.61(s,3H),3.42-3.52(m,2H)
第二步(196-3)的合成
将化合物196-2(130mg,246.7umol,1.0eq),甲烷磺酰氯(141mg,1.2mmol,5.0eq)溶于吡啶(5mL),在25℃下加入DMAP(90.4mg,740.1umol,3.0eq)。加料完毕,反应液在此温度下搅拌16小时。TLC显示反应完成，反应液减压浓缩，剩余物用水(10mL)洗涤,用DCM(20mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用柱层析纯化，洗脱剂体系为石油醚：乙酸乙酯＝2:1,得淡黄色固体130mg,收率87％。
1H NMR(400MHz,CDCl3)δ：8.02(d,J＝7.53Hz,2H),7.82(d,J＝3.01Hz,1H),7.66-7.73(m,1H),7.47-7.56(m,2H),7.36(d,J＝2.51Hz,1H),7.21(dd,J＝6.53,8.53Hz,1H),7.09(dd,J＝2.51,8.53Hz,1H),6.91(dt,J＝2.51,8.03Hz,1H),5.80(br.s.,1H),5.00(quin,J＝6.27Hz,1H),4.78(br.s.,1H),4.56-4.66(m,1H),3.45-3.79(m,5H),3.14(s,3H)
第三步(196)的合成
将化合物196-3(130mg,214.85umol,1.0eq),TEA(130mg,1.29mmol,6.0eq)溶于THF(5mL),在25℃下加入盐酸羟胺(59.7mg,859.4umol,4.0eq)。加料完毕,反应液在此温度下搅拌4小时。TLC显示反应完成，反应液减压浓缩，剩余物用水(10mL)洗涤,用乙酸乙酯(10mL)萃取三次。有机相用饱和食盐水洗涤，无水硫酸钠干燥,过滤,减压浓缩。剩余物用机分(甲酸体系)纯化得白色固体14mg,收率13％。
实施例196的核磁数据：1H NMR(400MHz,CDCl3)δ7.85(d,J＝3.26Hz,1H),7.43(d,J＝3.26Hz,1H),7.24(dd,J＝6.02,8.53Hz,1H),7.16(dd,J＝2.51,8.53Hz,1H),6.95(dt,J＝2.51,8.16Hz,1H),6.18(s,1H),4.64-4.77(m,2H),4.39-4.51(m,1H),3.64(s,3H),3.56(d,J＝6.78Hz,2H),3.10(s,3H)
LCMS(ESI)m/z:501.1[M+H+]
实施例197
Figure PCTCN2015079870-appb-000291
实施例197的核磁数据：1H NMR(400MHz,MeOD-d4)δ:8.32(dd,J＝2.8,12.8Hz,2H),7.50-7.58(m,1H),7.34-7.44(m,1H),6.31(s,1H),4.59(br.s.,2H),4.38(d,J＝2.8Hz,1H),3.72-3.77(m,1H),3.71(s,3H),3.45(dd,J＝6.0,18.4Hz,1H).
LCMS(ESI)m/z:504.0[M+H+].
实施例198
Figure PCTCN2015079870-appb-000292
实施例198的核磁数据：1H NMR(400MHz,MeOD-d4)δ:8.29(dd,J＝2.64,9.66Hz,2H),7.52-7.59(m,1H),7.38(q,J＝8.8Hz,1H),6.33(s,1H),4.55-4.63(m,1H),4.46-4.53(m,1H),4.32-4.41(m,1H),3.69-3.75(m,1H),3.68(s,3H),3.36-3.43(m,1H),3.35(s,3H).
LCMS(ESI)m/z:504.0[M+H+].
实施例199
Figure PCTCN2015079870-appb-000293
实施例199的核磁数据：1H NMR(400MHz,CDCl3)δ:9.14(br.s.,1H),8.84(d,J＝4.0Hz,1H),8.20(d,J＝8.0Hz,1H),7.77(d,J＝2.4Hz,1H),7.46-7.54(m,1H),7.38(d,J＝2.4Hz,1H),7.15-7.22(m,1H),7.12(d,J＝7.0Hz,1H),6.91(t,J＝7.0Hz,1H),6.11(s,1H),5.81(br.s.,1H),4.40(d,J＝5.6Hz,2H),4.16(d,J＝5.2Hz,1H),3.57(s,3H),3.46(dd,J＝7.2,17.6Hz,1H),3.11(dd,J＝6.4,17.8Hz,1H).
LCMS(ESI)m/z:548.1[M+H+].
实施例200
Figure PCTCN2015079870-appb-000294
实施例200的核磁数据：1H NMR(400MHz,CDCl3)δ:8.71(d,J＝4.4Hz,1H),8.02-8.09(m,1H),7.96(dt,J＝1.2,7.6Hz,1H),7.75(d,J＝3.0Hz,1H),7.54(dd,J＝5.0,7.0Hz,1H),7.37(d,J＝3.0Hz,1H),7.19(dd,J＝6.0,8.4Hz,1H),7.11(dd,J＝2.4,8.4Hz,1H),6.90(dt,J＝2.4,8.4Hz,1H),6.11(s,1H),5.77(d,J＝6.4Hz,1H),4.40-4.48(m,1H),4.25-4.38(m,2H),3.57(s,3H),3.48(dd,J＝6.4,17.8Hz,1H),3.12(dd,J＝6.4,18.0Hz,1H).
LCMS(ESI)m/z:548.1[M+H+].
实施例201
Figure PCTCN2015079870-appb-000295
实施例201的核磁数据：1H NMR(400MHz,MeOD-d4)δ:8.31(d,J＝3.2Hz,2H),7.62-7.52(m,1H),7.46-7.34(m,1H),6.35(s,1H),4.67-4.55(m,1H),4.51-4.36(m,2H),3.83-3.64(m,4H),3.36(d,J＝6.0Hz,1H),3.08(s,3H).
LCMS(ESI)m/z:503.0[M+H+].
实施例202
Figure PCTCN2015079870-appb-000296
实施例202的核磁数据：1H NMR(400MHz,CDCl3)δ:7.45(s,1H),7.22(dd,J＝6.4,8.4Hz,1H),7.13(dd,J＝2.4,8.4Hz,1H),6.93(dt,J＝2.4,8.4Hz,1H),6.13(s,1H),4.88(d,J＝7.4Hz,1H),4.42-4.57(m,2H),4.21-4.35(m,1H),3.63-3.70(m,1H),3.61(s,3H),3.12-3.19(m,1H),3.07(s,3H),2.44(s,3H).
[M+1]LCMS(ESI)m/z:499.1[M+H+].
实施例203
Figure PCTCN2015079870-appb-000297
实施例203的核磁数据：1H NMR(400MHz,CDCl3)δ:7.80(d,J＝3.2Hz,1H),7.34-7.46(m,3H),7.20(td,J＝8.0,2.4Hz,1H),6.13(s,1H),4.69(d,J＝7.6Hz,1H),4.62(dd,J＝11.6,6.4Hz,1H),4.41-4.48(m,1H),4.30-4.37(m,1H),3.73(dd,J＝17.6,7.2Hz,1H),3.56(s,3H),3.19(dd,J＝18.0,7.0Hz,1H),3.08(s,3H).
LCMS(ESI)m/z:519.3[M+H+].
实施例204
Figure PCTCN2015079870-appb-000298
实施例204的核磁数据：1H NMR(400MHz,CDCl3)δ:7.95(t,J＝7.6Hz,1H),7.75(d,J＝3.0Hz,1H),7.58-7.67(m,1H),7.37(d,J＝3.0Hz,1H),7.32(t,J＝7.6Hz,1H),7.21-7.26(m,1H),7.18(dd,J＝6.0,8.4Hz,1H),7.11(dd,J＝2.4,8.4Hz,1H),6.90(dt,J＝2.4,8.4Hz,1H),6.12(s,1H),5.18(br.s.,1H),4.30-4.46(m,2H),4.20(sxt,J＝6.8Hz,1H),3.57(s,3H),3.48(dd,J＝7.0,18.0Hz,1H),3.07(dd,J＝7.0,18.0Hz,1H).
LCMS(ESI)m/z:565.3[M+H+].
实施例205
Figure PCTCN2015079870-appb-000299
实施例205的核磁数据：1H NMR(400MHz,CDCl3)δ:7.86(d,J＝3.0Hz,1H),7.44(d,J＝2.8Hz,1H),7.23-7.28(m,1H),6.76-6.89(m,2H),5.99(s,1H),4.64(d,J＝7.2Hz,1H),4.56(d,J＝6.4Hz,2H),4.27-4.36(m,1H),3.66(s,3H),3.59-3.65(m,1H),3.14(dd,J＝18.0,6.8Hz,1H),3.10(s,3H).
LCMS(ESI)m/z:469.2[M+H+].
实施例206
Figure PCTCN2015079870-appb-000300
实施例206的核磁数据：1H NMR(400MHz,CDCl3)δ:7.86(d,J＝3.0Hz,1H),7.43(d,J＝3.0Hz,1H),6.98-7.07(m,1H),6.87-6.96(m,1H),5.99(s,1H),4.62-4.71(m,1H),4.53(d,J＝6.8Hz,1H),4.40-4.50(m,2H),4.19(qd,J＝6.4,12.8Hz,1H),3.65(s,3H),3.54(dd,J＝7.0,18.0Hz,1H),3.19(dd,J＝6.4,18.0Hz,1H),2.74(d,J＝5.2Hz,3H).
LCMS(ESI)m/z:502.2[M+H+].
实施例207
Figure PCTCN2015079870-appb-000301
实施例207的核磁数据：1H NMR(400MHz,CDCl3)δ:7.85(d,J＝3.0Hz,1H),7.42(d,J＝3.0Hz,1H),6.97-7.08(m,1H),6.85-6.96(m,1H),5.99(s,1H),4.53(t,J＝6.0Hz,2H),4.35(d,J＝7.6Hz,1H),4.13-4.23(m,1H),3.64(s,3H),3.57(dd,J＝18.0,7.0Hz,1H),3.13(dd,J＝17.8,6.8Hz,1H),2.84(s,6H).
LCMS(ESI)m/z:516.3[M+H+].
实施例208
Figure PCTCN2015079870-appb-000302
实施例208的核磁数据：1H NMR(400MHz,CDCl3)δ:7.84(d,J＝3.0Hz,1H),7.42(d,J＝3.6Hz,1H),6.97-7.06(m,1H),6.86-6.95(m,1H),5.99(s,1H),4.46-4.59(m,3H),4.13-4.25(m,1H),3.64(s,3H),3.56(dd,J＝18.0,7.0Hz,1H),3.31-3.34(m,4H),3.13(dd,J＝17.8,6.8Hz,1H),1.94(br.s.,4H).
LCMS(ESI)m/z:542.1[M+H+].
实施例209
Figure PCTCN2015079870-appb-000303
实施例209的核磁数据：1H NMR(400MHz,DMSO-d6)δ:7.97(d,J＝3.0Hz,1H),7.89(d,J＝3.2Hz,1H),7.22-7.30(m,2H),5.85-6.07(m,3H),4.50(dd,J＝11.2,6.9Hz,1H),4.19(dd,J＝11.2,6.4Hz,1H),3.92-4.07(m,1H),3.55(s,3H),3.41-3.50(m,1H),3.27-3.32(m,1H),3.06(dd,J＝17.8,6.9Hz,1H),1.12(dd,J＝6.4,3.14Hz,6H).
LCMS(ESI)m/z:530.3[M+H+].
实施例210
Figure PCTCN2015079870-appb-000304
实施例210的核磁数据：1H NMR(400MHz,CDCl3)δ:7.84(d,J＝3.6Hz,1H),7.41(d,J＝3.2Hz,1H),6.98-7.08(m,1H),6.84-6.96(m,1H),5.99(s,1H),4.55(t,J＝6.4Hz,2H),4.44-4.50(m,1H),4.24(s,1H),4.13-4.22(m,1H),3.64(s,3H),3.57(dd,J＝18.0,7.2Hz,1H),3.14(dd,J＝17.6,6.8Hz,1H),1.37(s,9H).
LCMS(ESI)m/z:544.3[M+H+].
实施例211
Figure PCTCN2015079870-appb-000305
实施例211的核磁数据：1H NMR(400MHz,DMSO-d6)δ:7.95(d,J＝3.0Hz,1H),7.86(d,J＝3.2Hz,1H),7.32-7.46(m,1H),7.11-7.24(m,2H),7.01(t,J＝7.6Hz,1H),6.74(s,2H),5.84(s,1H),4.48(dd,J＝11.0,6.8Hz,1H),4.00-4.22(m,2H),3.52(s,3H),3.04(dd,J＝17.8,7.2Hz,1H).
LCMS(ESI)m/z:470.2[M+H+].
实施例212
Figure PCTCN2015079870-appb-000306
实施例212的核磁数据：1H NMR(400MHz,CDCl3)δ:7.86(d,J＝3.0Hz,1H),7.42(d,J＝3.0Hz,1H),6.98-7.06(m,1H),6.87-6.95(m,1H),5.99(s,1H),4.48-4.62(m,2H),4.41(d,J＝7.6Hz,1H),4.22(qd,J＝6.6,13.2Hz,1H),3.91(t,J＝7.6Hz,4H),3.65(s,3H),3.56(dd,J＝7.0,18.0Hz,1H),3.16(dd,J＝6.4,18.0Hz,1H),2.22(quin,J＝7.6Hz,2H)
LCMS(ESI)m/z:528.2[M+H+].
实施例213
Figure PCTCN2015079870-appb-000307
实施例213的核磁数据：1H NMR(400MHz,CDCl3)δ:7.83(d,J＝3.0Hz,1H),7.41(d,J＝3.0Hz,1H),7.16-7.24(m,1H),7.03-7.12(m,2H),6.24(s,1H),4.80(d,J＝7.2Hz,1H),4.54-4.63(m,1H),4.41-4.51(m,1H),4.29(sxt,J＝7.0Hz,1H),3.70(dd,J＝7.2,17.8Hz,1H),3.62(s,3H),3.08-3.23(m,3H),1.43(t,J＝7.2Hz,3H)
LCMS(ESI)m/z:499.2[M+H+].
实施例214
Figure PCTCN2015079870-appb-000308
实施例214的核磁数据：1H NMR(400MHz,CDCl3)δ:7.84(d,J＝3.6Hz,1H),7.42(d,J＝3.2Hz,1H),6.97-7.08(m,1H),6.84-6.95(m,1H),5.99(s,1H),4.57-4.65(m,1H),4.46-4.54(m,1H),4.44(d,J＝7.2Hz,1H),4.33(t,J＝6.0Hz,1H),4.13-4.24(m,1H),3.64(s,3H),3.54(dd,J＝18.0,7.2Hz,1H),3.16(dd,J＝18.0,6.8Hz,1H),3.06(q,J＝6.8Hz,2H),1.53(d,J＝7.6Hz,2H),1.31-1.42(m,2H),0.93(t,J＝7.2Hz,3H).
LCMS(ESI)m/z:544.1[M+H+].
实施例215
Figure PCTCN2015079870-appb-000309
实施例215的核磁数据：1H NMR(400MHz,CDCl3)δ:7.82(d,J＝3.0Hz,1H),7.39(d,J＝3.6Hz,1H),7.15-7.23(m,1H),7.02-7.10(m,2H),6.23(s,1H),4.59(d,J＝7.0Hz,1H),4.43-4.56(m,2H),4.19(qd,J＝6.8,13.6Hz,1H),3.62-3.68(m,1H),3.61(s,3H),3.17(dd,J＝6.6,18.0Hz,1H),2.83(s,6H).
LCMS(ESI)m/z:514.0[M+H+].
实施例216
Figure PCTCN2015079870-appb-000310
实施例216的核磁数据：1H NMR(400MHz,DMSO-d6)δ:7.96(d,J＝3.0Hz,1H),7.87(d,J＝3.0Hz,1H),7.24-7.40(m,4H),6.95(d,J＝7.6Hz,1H),6.06(s,1H),4.50(dd,J＝11.2,6.8Hz,1H),4.19(dd,J＝11.2,6.4Hz,1H),4.02(q,J＝6.4Hz,1H),3.52(s,3H),3.48(d,J＝7.2Hz,1H),3.28-3.33(m,1H),3.09(dd,J＝17.8,6.8Hz,1H),1.13(t,J＝5.6Hz,6H).
LCMS(ESI)m/z:528.2[M+H+].
实施例217
Figure PCTCN2015079870-appb-000311
实施例217的核磁数据：1H NMR(400MHz,CDCl3)δ:7.87(d,J＝3.0Hz,1H),7.46(d,J＝3.0Hz,1H),7.22(dd,J＝7.8,5.2Hz,1H),7.03-7.14(m,2H),6.32(s,1H),5.24(br.s.,1H),4.50(d,J＝7.0Hz,1H),4.02(dd,J＝17.8,9.8Hz,2H),3.66(s,3H),3.13(dd,J＝17.8,7.2Hz,1H),1.46(s,9H).
LCMS(ESI)m/z:507.1[M+H+].
实施例218
Figure PCTCN2015079870-appb-000312
实施例218的核磁数据：1H NMR(400MHz,CDCl3)δ：7.89(d,J＝3.0Hz,1H),7.65(d,J＝3.0Hz,1H),7.19-7.37(m,2H),7.13(t,J＝8.4Hz,1H),6.18(s,1H),4.53(dd,J＝6.8,11.2Hz,1H),4.33(dd,J＝6.4,11.4Hz,1H),4.11-4.28(m,1H),3.66(dd,J＝7.4,17.8Hz,1H),3.59(s,3H),3.17(dd,J＝7.0,17.8Hz,1H).
LCMS(ESI)m/z:486.1[M+H+].
实施例219
Figure PCTCN2015079870-appb-000313
实施例219的核磁数据：1H NMR(400MHz,CDCl3)δ:8.35(s,1H),7.28-7.36(m,1H),7.03-7.13(m,1H),6.88-6.98(m,1H),6.01(s,1H),5.46(br.s.,1H),5.01(br.s.,2H),4.19(br.s.,1H),3.87(dd,J＝10.8,5.6Hz,1H),3.57-3.72(m,4H),3.49(dd,J＝18.0,7.2Hz,1H),3.22-3.36(m,1H).
LCMS(ESI)m/z:518.1[M+H+].
实施例220
Figure PCTCN2015079870-appb-000314
实施例220的核磁数据：1H NMR(400MHz,CDCl3)δ:7.85(d,J＝3.02Hz,1H),7.42(d,J＝2.76Hz,1H),6.93-7.17(m,3H),6.04(s,1H),5.37(d,J＝6.78Hz,1H),5.19(s,2H),4.64(dd,J＝11.68,5.66Hz,1H),4.46(dd,J＝11.80,6.27Hz,1H),4.24-4.33(m,1H),3.62(s,3H),3.52-3.60(m,1H),3.23(dd,J＝18.08,6.28Hz,1H).
LCMS(ESI)m/z:470.0[M+H+].
实验例225：HBV体外测试点杂交试验
1.实验目的：
通过点杂交试验检测HepG2.2.15细胞内的HBV DNA含量，以化合物的EC50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 L-GLUTAMINE,Invitrogen-25030081；300μg/ml Geneticin，Invitrogen-10131027
2.2试剂：
胰酶(I Invitrogen-25300062)
DPBS(Hyclone-SH30028.01B)
DMSO(Sigma-D2650-100ML)
96孔细胞培养板(Corning-3599)
CO2培养箱(HERA-CELL-240)
20x SSC(水源生物)
Tris-HCl(Aldirch-154563-1KG)
氢氧化钠(国药10019718)
氯化钠(国药10019308)
杂交液(美季生物，依诺金-HYB-500)
DIG Wash and Block Buffer set(Roche-11585762001)
Anti-digoxigenin-AP,Fab fragments from sheep(Roche-11093274910)
2.3耗材与仪器：
带正电荷尼龙膜(GE-RPN2250B)
转膜装置(Bio-Rad,170-6545)
杂交炉(HL-2000hybrilinker)
3.实验步骤和方法：
3.1种HepG2.2.15细胞(4x104细胞/孔)到96孔板，在37℃，5％CO2培养过夜。
3.2第二天，稀释化合物，共6个浓度，5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％inhibition对照；1％的DMSO作为0％inhibition对照。
3.3第五天，更换含有化合物的新鲜培养液。
3.4第八天和第九天，去除培养孔中的培养液，收取细胞进行点杂交。
加入裂解液到培养孔，37℃孵育半小时以裂解细胞；离心取上清，转移至一个新的微孔板中；加入变性液，混合充分后将变性后的样品转移、印记到尼龙膜上，紫外交联将核酸固定在膜上。
预杂交：将膜在杂交液中60℃孵育1小时。
杂交：加热变性的地高辛标记的HBV DNA探针，60℃孵育过夜。
洗膜：High strigency wash两次，Low strigency wash三次。
封闭：将膜在封闭液中室温孵育30-60分钟。
杂交：将Antibody Solution用封闭液稀释，将膜放入其中室温孵育30-60分钟。
显色：将膜在Detection Buffer中洗五分钟，加上显色液压片曝光。
将照片存储成tiff格式，用quantity one软件对dot的灰度值定量。
3.5数据分析：
3.5.1计算抑制百分比：％Inh.＝【1-(样品dot灰度值–1μM GLS4dot灰度值l)/(DMSO对照dot灰度值–1μM GLS4dot灰度值l)】x100。
3.5.2计算EC50：使用GraphPad Prism软件计算化合物对HBV的50％抑制浓度(EC50)值。
4.实验结果
实验结果见表2：
表2点杂交检测EC50测试结果
Figure PCTCN2015079870-appb-000315
Figure PCTCN2015079870-appb-000316
生物活性定义：A：EC50≤100nM；B:100nM＜EC50≤500nM；C:500nM＜EC50≤1000nM；D:1000nM＜EC50≤5000nM；
结论：本发明化合物对HBV DNA的抑制作用显著。
实验例226：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EC50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 L-GLUTAMINE，Invitrogen-25030081；300μg/ml Geneticin，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)
CO2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(4x104细胞/孔)到96孔板，在37℃，5％CO2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％inhibition对照；1％的DMSO作为0％inhibition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 PCTCN2015079870-appb-000317
Figure PCTCN2015079870-appb-000318
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EC50：使用GraphPad Prism软件计算化合物对HBV的50％抑制浓度(EC50)值。
4实验结果
实验结果见表3：
表3 qPCR实验检测EC50测试结果
Figure PCTCN2015079870-appb-000319
Figure PCTCN2015079870-appb-000320
生物活性定义：A：EC50≤100nM；B:100nM＜EC50≤500nM；C:500nM＜EC50≤1000nM；D:1000nM＜EC50≤5000nM；
结论：本发明化合物对HBV DNA的抑制作用显著。

Claims (13)

  1. 式(I)所示化合物或其药学上可接受的盐，
    Figure PCTCN2015079870-appb-100001
    其中，
    D11-14中的0～2个分别独立地选自单键、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-S(＝O)N(Rd7)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-或-S(＝O)2-，其余选自-C(Rd1)(Rd2)-；
    L选自单键、-O-、-S-、-NH-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-C(＝O)N(Rd3)-、-N(Rd4)-、-[C(Rd1)(Rd2)]0～ 6；
    R2选自
    Figure PCTCN2015079870-appb-100002
    D21选自单键、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-S(＝O)N(Rd7)-、-O-、-S-、-[C(Rd1)(Rd2)]0～6；
    R3、R4分别独立地选自任选被R01取代的：C1-10烷基或杂烷基、3～6元环烷基或杂环烷基、6～10元芳环基或杂芳环基；
    R3’、R21、Rd1-d8分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、-COOH，或选自任选被R01取代的：C1-4烷基、-C0-4烷基苯基、-C0-4烷基-3～6元杂环基、3～6元杂环基酰基-、苯磺酰氨基或杂苯磺酰氨基、-D01-D02-D03-H、
    Figure PCTCN2015079870-appb-100003
    D01选自单键、-C1-4烷基-；
    D02选自O、S、NH、-C(＝O)-、-S(＝O)2-、-C(＝O)O-、-C(＝O)NH-、-C(＝S)NH-、-S(＝O)2NH-、-S(＝O)NH-、-NHC(＝O)O-、-NHC(＝O)NH-、-NHS(＝O)2NH-、-C(＝O)NHS(＝O)2-、-NHS(＝O)NH-、-C(＝O)NHS(＝O)-、-NHS(＝O)2O-、-NHS(＝O)O-、-C(＝N)-、-NH-C(＝N)-；
    D03选自单键、-C1-4烷基-、-C2-4烯基-、-C3-6环烷基-、-3～6元杂环烷基-、5～6元芳基、5～6元杂芳基；任选地，R3与R3’共同连接到同一个碳原子或杂原子上形成一个任选被取代的3～12元环；
    “杂”表示杂原子或杂原子团，选自-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-S(＝O)N(Rd7)-、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O)2-或/和-P(＝O)(ORd8)2；
    R01选自F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH、＝NH、＝O、＝S、或任选被R001取代的：C1-10烷基、C1-10烷氨基、N,N-二(C1-10烷基)氨基、C1-10烷氧基、C1-10烷酰基、C1-10烷氧羰基、-C1-5烷基-C(＝O)O-C1-5烷基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、3～10元环烷基、3～10元环烷氨基、3～10 元杂环烷氨基、3～10元环烷氧基、3～10元环烷基酰基、3～10元环烷氧羰基、3～10元环烷基磺酰基、3～10元环烷基亚磺酰基；
    R001选自F、Cl、Br、I、CN、OH、N(CH3)2、NH(CH3)、NH2、CHO、COOH、＝NH、＝O、＝S、三卤代甲基、二卤代甲基、一卤代甲基、氨甲基、羟甲基、甲基、甲氧基、甲酰基、甲氧羰基、甲磺酰基、甲基亚磺酰基；
    在上述任意一种情况下，R01、R001的数目分别独立地选自0、1、2或3，杂原子或杂原子团的数目分别独立地选自1、2或3。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其具有式(Ⅱ)所示结构：
    Figure PCTCN2015079870-appb-100004
    其中，R31-32分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、-COOH，或选自任选被1、2或3个R01取代的：C1-4烷基、-C0-4烷基苯基、-C0-4烷基-3～6元杂环基、3～6元杂环基酰基-、苯磺酰氨基或杂苯磺酰氨基、-D01-D02-D03-H、
    Figure PCTCN2015079870-appb-100005
    D01选自单键、-C1-4烷基-；
    D02选自O、S、NH、-C(＝O)-、-S(＝O)2-、-C(＝O)O-、-C(＝O)NH-、-C(＝S)NH-、-S(＝O)2NH-、-S(＝O)NH-、-NHC(＝O)O-、-NHC(＝O)NH-、-NHS(＝O)2NH-、-C(＝O)NHS(＝O)2-、-NHS(＝O)NH-、-C(＝O)NHS(＝O)-、-NHS(＝O)2O-、-NHS(＝O)O-、-C(＝N)-、-NH-C(＝N)-；
    D03选自单键、-C1-4烷基-、-C2-4烯基-、-C3-6环烷基-、-3～6元杂环烷基-、5～6元芳基、5～6元杂芳基；m、n分别独立地选自1或2；
    Figure PCTCN2015079870-appb-100006
    表示单键或双键；
    其他变量如权利要求1所定义。
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中所述R01选自卤素、CN、＝NH、＝O、＝S、COOH，或任选被1、2或3个R001取代的羟基、氨基、C1-4烷基、C1-4烷氧基、C0-4烷基-C(＝O)O-C1-4烷基；
    具体地，R01选自F、Cl、Br、I、OH、CN、NH2、＝NH、＝O、＝S、-SMe、Me、Et、
    Figure PCTCN2015079870-appb-100007
    Figure PCTCN2015079870-appb-100008
  4. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中所述R3’、R21、Rd1-d8、R31-32分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、-COOH，或选自任选被1、2或3个R01取代的CH3、
    Figure PCTCN2015079870-appb-100009
    Figure PCTCN2015079870-appb-100010
    Figure PCTCN2015079870-appb-100011
  5. 根据权利要求4所述的化合物或其药学上可接受的盐，其中所述R3’、R21、Rd1-d8、R31-32分别独立地选自：H、F、Cl、Br、I、OH、NH2、CN、-COOH、CH3、
    Figure PCTCN2015079870-appb-100012
    Figure PCTCN2015079870-appb-100013
    Figure PCTCN2015079870-appb-100014
  6. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中结构单元
    Figure PCTCN2015079870-appb-100015
    选自：
    Figure PCTCN2015079870-appb-100016
    Figure PCTCN2015079870-appb-100017
    Figure PCTCN2015079870-appb-100018
    Figure PCTCN2015079870-appb-100019
    Figure PCTCN2015079870-appb-100020
    Figure PCTCN2015079870-appb-100021
  7. 根据权利要求6所述的化合物或其药学上可接受的盐，其中所述结构单元
    Figure PCTCN2015079870-appb-100022
    选自：
    Figure PCTCN2015079870-appb-100023
    Figure PCTCN2015079870-appb-100024
    Figure PCTCN2015079870-appb-100025
    Figure PCTCN2015079870-appb-100026
    Figure PCTCN2015079870-appb-100027
    Figure PCTCN2015079870-appb-100028
    Figure PCTCN2015079870-appb-100029
    Figure PCTCN2015079870-appb-100030
    Figure PCTCN2015079870-appb-100031
  8. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中所述L、D21选自单键、-O-、-NH-；或R21选自C1-4烷基、C1-4烷氨基、N,N-二(C1-4烷基)氨基、C1-4烷氨基-C1-4烷基-、N,N-二(C1-4烷基)氨基-C1-4烷基-、C1-4烷氧基、C1-4烷氧基-C1-4烷基-、卤代C1-4烷基-、二卤代C1-4烷基-、氨氧基C1-4烷基-、羟代C1-4烷基氧基-、羟代C1-3烷基氨基-。
  9. 根据权利要求8所述的化合物或其药学上可接受的盐，其中所述R21选自甲基、乙基、正丙基、异丙基、甲氨基、乙氨基、丙氨基、二甲氨基、二乙基氨基、二丙基氨基、甲氨基乙基、乙氨基乙基、丙氨基乙基、二甲基氨基乙基、二乙基氨基甲基、二甲基氨基甲基、二乙基氨基乙基、甲氧甲基、甲氧乙基、甲氧丙基、乙氧基甲基、丙氧基甲基、乙氧基乙基、丙氧基丙基、氟甲基、氟乙基、氟丙基、二氟甲基、二氟乙基、二氟丙基、氨氧基甲基、氨氧基乙基、氨氧基丙基、羟甲基氧基、羟乙基氧基、羟丙基氧基。
  10. 根据权利要求9所述的化合物或其药学上可接受的盐，其中结构单元
    Figure PCTCN2015079870-appb-100032
    选自
    Figure PCTCN2015079870-appb-100033
    Figure PCTCN2015079870-appb-100034
    Figure PCTCN2015079870-appb-100035
    选自
    Figure PCTCN2015079870-appb-100036
  11. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中R3或R4分别独立地选自任选被1、2或3个R001取代的：苯基、吡啶基、喹啉基、异喹啉基、噻唑基、噻吩基、恶唑基、异恶唑基、吡唑基、异噻唑、呋喃基、吡咯基、吡咯烷基、1，3-氧五环基、2-吡唑啉基、吡唑烷基、咪唑基、1,2,3-唑基、1,2,3-三唑基、1,2,4-三唑基、1,3,4-噻二唑基、哌啶基、1,4-二氧六环基、吗啉基、哌嗪基、哌啶基、嘧啶基、吡嗪基、1,3,5-三噻烷基、1,3,5-三嗪基、茚基、萘基、苯并呋喃基、苯并噻吩基、吲哚基、苯并咪唑基、苯并噻唑基、苯并戊烷基、环丙基；
    或者结构单元
    Figure PCTCN2015079870-appb-100037
    选自任选被1、2或3个R001取代的苯并戊烷基、茚基；
    R001如权利要求1所定义。
  12. 根据权利要求11所述的化合物或其药学上可接受的盐，其中所述R3选自
    Figure PCTCN2015079870-appb-100038
    Figure PCTCN2015079870-appb-100039
    或所述R4选自
    Figure PCTCN2015079870-appb-100040
    Figure PCTCN2015079870-appb-100041
    或所述结构单元
    Figure PCTCN2015079870-appb-100042
    选自：
    Figure PCTCN2015079870-appb-100043
  13. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其选自：
    Figure PCTCN2015079870-appb-100044
    Figure PCTCN2015079870-appb-100045
    Figure PCTCN2015079870-appb-100046
    Figure PCTCN2015079870-appb-100047
    Figure PCTCN2015079870-appb-100048
    Figure PCTCN2015079870-appb-100049
    Figure PCTCN2015079870-appb-100050
    Figure PCTCN2015079870-appb-100051
    Figure PCTCN2015079870-appb-100052
    Figure PCTCN2015079870-appb-100053
    Figure PCTCN2015079870-appb-100054
    Figure PCTCN2015079870-appb-100055
    Figure PCTCN2015079870-appb-100056
    Figure PCTCN2015079870-appb-100057
    Figure PCTCN2015079870-appb-100058
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