WO2018041263A1 - 抗流感病毒嘧啶衍生物 - Google Patents

抗流感病毒嘧啶衍生物 Download PDF

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Publication number
WO2018041263A1
WO2018041263A1 PCT/CN2017/100461 CN2017100461W WO2018041263A1 WO 2018041263 A1 WO2018041263 A1 WO 2018041263A1 CN 2017100461 W CN2017100461 W CN 2017100461W WO 2018041263 A1 WO2018041263 A1 WO 2018041263A1
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Prior art keywords
group
compound
pharmaceutically acceptable
acceptable salt
mmol
Prior art date
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PCT/CN2017/100461
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English (en)
French (fr)
Inventor
熊剑
龙超峰
王晶晶
陈小新
陈新海
谢程
李鹏
黎健
陈曙辉
Original Assignee
广东众生药业股份有限公司
南京明德新药研发股份有限公司
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Priority to CN201910800902.6A priority Critical patent/CN110623958B/zh
Priority to EP17845565.5A priority patent/EP3502112A4/en
Application filed by 广东众生药业股份有限公司, 南京明德新药研发股份有限公司 filed Critical 广东众生药业股份有限公司
Priority to BR112019004420A priority patent/BR112019004420A2/pt
Priority to SG11201901894TA priority patent/SG11201901894TA/en
Priority to JP2019512638A priority patent/JP6838773B2/ja
Priority to AU2017320088A priority patent/AU2017320088B2/en
Priority to US16/330,353 priority patent/US11136319B2/en
Priority to NZ751964A priority patent/NZ751964B2/en
Priority to CN201780054195.XA priority patent/CN109790159B/zh
Priority to CA3035680A priority patent/CA3035680C/en
Priority to KR1020197009275A priority patent/KR102312088B1/ko
Priority to RU2019109246A priority patent/RU2727772C1/ru
Priority to MX2019002541A priority patent/MX2019002541A/es
Publication of WO2018041263A1 publication Critical patent/WO2018041263A1/zh
Priority to IL265166A priority patent/IL265166B/en
Priority to ZA2019/01886A priority patent/ZA201901886B/en
Priority to US17/410,801 priority patent/US11725009B2/en
Priority to US18/337,329 priority patent/US20230339943A1/en

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Classifications

    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to a class of anti-influenza virus compounds and their use in the preparation of medicaments for the treatment of influenza viruses. Specifically, it relates to a compound of the formula (I) and a pharmaceutically acceptable salt thereof.
  • influenza virus is a segmented single-chain antisense RNA virus that causes a pandemic in humans and animals.
  • the outbreak of the flu has caused tens of thousands of deaths, causing enormous social panic and increasing social instability.
  • the flu can result in direct costs of lost productivity and related medical resources as well as indirect costs of preventive measures.
  • the flu has caused approximately $10 billion in annual losses, and it is estimated that future pandemics can cause hundreds of billions of dollars in direct and indirect costs.
  • the cost of prevention is also very high, and governments around the world have spent billions of dollars preparing and planning for possible H5N1 avian influenza pandemics, costs associated with purchasing drugs and vaccines, and strategies to develop disaster drills and improve border controls.
  • Antiviral drugs can also be used to treat influenza, in which neuraminidase inhibitors, such as oseltamivir (Duffy), are effective for influenza A virus, but have been clinically observed to inhibit this type of neuraminidase. Drug-resistant strains have emerged.
  • neuraminidase inhibitors such as oseltamivir (Duffy)
  • Duffy oseltamivir
  • Anti-influenza drugs that are in urgent need of a new mechanism of action can support the use of single-agent for the treatment of influenza A, or by using anti-influenza drugs combined with other mechanisms of action already on the market. Prevention and treatment of influenza.
  • WO2010148197 reports the following compounds:
  • the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from C 11-6 alkylthio, 5-6 heteroaryl, C 2-6 alkynyl, C 3-6 cycloalkyl optionally substituted by 1, 2 or 3 R or R';
  • T 1 is selected from N or CH;
  • T 2 is selected from N or C (R 2 );
  • R 2 is selected from the group consisting of H, F, Cl, Br, I;
  • R 3 is selected from H, halogen, CN, NH 2 , OH, or from a C 1-6 alkyl group optionally substituted by 1, 2 or 3 R or R';
  • R' is selected from the group consisting of: F, Cl, Br, I, CN, OH, NH 2 , COOH, Me, NHCH 3 , N(CH 3 ) 2 ,
  • hetero of the 5- to 6-membered heteroaryl group, the C 1-6 heteroalkyl group, the C 3-6 cycloalkyl group, and the 3 to 6-membered heterocycloalkyl group is selected from the group consisting of: N, -S-, -O- , -NH-;
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.
  • R is selected from the group consisting of: F, Cl, Br, I, OH, NH 2 , CN, COOH, Or selected from the group consisting of 1, 2 or 3 R' substitutions: Me, Et,
  • the above R is selected from the group consisting of: F, Cl, Br, I, OH, NH 2 , Me, Et, CN, COOH,
  • R 1 is selected from the group consisting of: 1, 2 or 3, R or R'; C 1-3 alkylthio, C 2-4 alkynyl, C 3-5 cycloalkyl .
  • R 1 is selected from the group consisting of: 1, 2 or 3, R or R':
  • R 1 is selected from the group consisting of
  • R 1 is selected from the group consisting of: 1, 2 or 3, R or R'; pyridinyl, pyrazolyl, imidazolyl, thienyl, oxazolyl, isoxazolyl.
  • R 1 is selected from the group consisting of: 1, 2 or 3, R or R':
  • R 1 is selected from the group consisting of
  • R 1 is selected from the group consisting of
  • the T 2 is selected from the group consisting of: N, CH or C (F).
  • said R 3 is selected from the group consisting of H, halogen, CN, NH 2 , OH, or selected from C 1-3 alkyl optionally substituted by 1, 2 or 3 R or R'.
  • said R 3 is selected from the group consisting of H, F, Cl, Br, I, CN, NH 2 , OH, or selected from the group consisting of: 1, 2 or 3, R or R': Me, Et.
  • R 3 is selected from the group consisting of H, F, Cl, Br, I, CN, NH 2 , OH, Me, Et, CF 3 .
  • R is selected from the group consisting of: F, Cl, Br, I, OH, NH 2 , CN, COOH, Or selected from the group consisting of 1, 2 or 3 R' substitutions: Me, Et, Other variables are as defined above.
  • the above R is selected from the group consisting of: F, Cl, Br, I, OH, NH 2 , Me, Et, CN, COOH, Other variables are as defined above.
  • R 1 is selected from the group consisting of: 1, 2 or 3, R or R'; C 1-3 alkylthio, C 2-4 alkynyl, C 3-5 cycloalkyl Other variables are as defined above.
  • R 1 is selected from the group consisting of: 1, 2 or 3, R or R': Other variables are as defined above.
  • R 1 is selected from the group consisting of Other variables are as defined above.
  • R 1 is selected from the group consisting of 1, 2 or 3 R or R' substituted: pyridinyl, pyrazolyl, imidazolyl, thienyl, oxazolyl, isoxazolyl, Other variables are as defined above.
  • R 1 is selected from the group consisting of: 1, 2 or 3, R or R': Other variables are as defined above.
  • R 1 is selected from the group consisting of Other variables are as defined above.
  • R 1 is selected from the group consisting of Other variables are as defined above.
  • T 2 is selected from: N, CH or C(F), and other variables are as defined above.
  • R 3 is selected from H, halogen, CN, NH 2 , OH, or selected from: C 1-3 alkyl optionally substituted by 1, 2 or 3 R or R',
  • the variables are as defined above.
  • said R 3 is selected from the group consisting of H, F, Cl, Br, I, CN, NH 2 , OH, or selected from the group consisting of: 1, 2 or 3, R or R': Me, Et, other variables are as defined above.
  • R 3 is selected from the group consisting of H, F, Cl, Br, I, CN, NH 2 , OH, Me, Et, CF 3 , and other variables are as defined above.
  • the structural unit Selected from Other variables are as defined above.
  • the above compound, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • R 1 and R 3 are as defined above.
  • the present invention also provides a compound of the formula: or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:
  • the present invention also provides a compound of the formula: or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating an anti-influenza virus.
  • the compound of the present invention is mainly used for preventing and treating influenza caused by influenza A virus and influenza caused by highly pathogenic avian influenza virus, and has high safety and oral bioavailability compared with existing clinical drugs. Influenza A strains that are resistant to existing clinical drugs still have the potential to have significant antiviral activity.
  • 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.
  • Mother of compound The bulk form 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.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • 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 group e.g., an amino group
  • an acidic functional group e.g., a carboxyl group
  • the diastereomer is removed by conventional methods well known in the art. The fractions are then recovered to give the pure enantiomer.
  • 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, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • 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.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A. 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. When the recited 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.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benziso Thiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, porphyrinyl, chromanyl, chromene, porphyrinyldecahydroquinolyl, 2H, 6H-1,5 ,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic.
  • the hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons) , C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .).
  • C 1-12 is selected from C 1
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • hydrocarbyl means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in 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 hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy). By customary expression, those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • alkenyl refers to an alkyl group having one or more carbon-carbon double bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkenyl group include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a butadienyl group, a pentadienyl group, a hexadienyl group and the like.
  • alkynyl refers to an alkyl group having one or more carbon-carbon triple bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and the like.
  • a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
  • a cycloalkenyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more unsaturated carbon-carbon double bonds at any position of the ring, and may be monosubstituted or polysubstituted, It can be one price, two price or multiple price.
  • Examples of such cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.
  • a cycloalkynyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more carbon-carbon triple bonds at any position of the ring, which may be monosubstituted or polysubstituted, and may be one Price, price or price.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents attached through an oxygen bridge
  • C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), they are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • aryl or heteroaryl groups include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isomerism Azyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, indolyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl, 1 -naphthyl, 2-naphthyl, 4-biphenylyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl
  • aryl groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • Step 1 Synthesis of Compound BB-1-2:
  • Step 5 Synthesis of Compound BB-1:
  • the organic phase was added, and the mixture was stirred at -20 ° C for 3 hours under a nitrogen atmosphere.
  • the reaction was quenched with hydrochloric acid (100 mL, 6M) and EtOAc (EtOAc).
  • the reaction was warmed to -5 °C and hydrochloric acid (60 mL, 2M) was added.
  • the mixture was stirred at about -5 ° C for 45 minutes, and then heated to about 20 ° C for 15 minutes.
  • the mixture was allowed to stand, the aqueous phase was removed, and the organic phase was added with water (35 mL) and stirred for 15 minutes and then allowed to stand for 15 minutes to remove the aqueous phase.
  • a buffer solution (135 mL) (22.05 g of sodium dihydrogen phosphate, 3.6 g of disodium hydrogen phosphate dissolved in 405 mL of water) was added to the organic phase, stirred for 15 minutes, allowed to stand for 15 minutes, the aqueous phase was removed, and washed three times.
  • the organic phase was spun dry, n-heptane (50 mL) was added and the mixture was stirred at 40 <0>C for 30 min and cooled to 0-5 <0>C for 1.5 h.
  • the mixture was filtered, and the filter cake was dried and crystallised three times to give compound BB-2-3 (28.00 g, 124.86 mmol, yield 43.08%).
  • Triethylamine (27.07 g, 267.55 mmol, 37.08 mL) was added to a solution of compound BB-2-3 (25.00 g, 111.48 mmol) in toluene (300.00 mL).
  • the reaction solution was heated to 95 ° C and diphenylphosphoryl azide (30.37 g, 110.37 mmol, 23.91 mL) was added.
  • the mixture was stirred at 95 ° C for 1 hour, and benzyl alcohol (12.06 g, 111.48 mmol, 11.60 mL) was added to the reaction mixture and stirred at 95 ° C for 12 hours under nitrogen atmosphere.
  • Step 4 Synthesis of Compound BB-2:
  • Potassium iodate (17.18 g, 80.29 mmol, 17.18 mL) was added to a solution of compound BB-3-1 (18.00 g, 160.57 mmol, 1.00 eq) in sulfuric acid (100.00 mL, 2 mol), and the mixture was heated to 100 with stirring.
  • Potassium iodide 14.66 g, 88.31 mmol was dissolved in water (40.00 mL) dropwise to the mixture and stirring was continued at 100 ° C for one hour.
  • Step 1 Synthesis of Compound BB-4-2:
  • Step 1 Synthesis of Compound BB-5:
  • Step 1 Synthesis of Compound BB-6-2:
  • Potassium phosphate (117.20 mg, 552.14 umol), Pd(dtbpf)Cl, was added to a solution of the compound 1-1 (100 mg, 276 umol) and 4-bromo pyridine (41 mg, 331 umol) in tetrahydrofuran (2 mL) and water (0.5 mL). 2 (9mg, 14umol). The mixture was stirred at 25 ° C for 12 hours and then at 50 ° C for 2 hours. The reaction solution was cooled to room temperature and then filtered.
  • Potassium phosphate (31.46 mg, 148 umol) was added to a solution of compound 1-2 (30 mg, 74 umol) and compound BB-3 (37 mg, 89 umol) in 2-methyltetrahydrofuran (2.00 mL) and water (0.2 mL).
  • the mixture was stirred at 80 ° C for 12 hours under nitrogen.
  • the reaction solution was cooled to room temperature and then filtered.
  • Step 1 Synthesis of compound 5-2 to 5-1 (10.30 g, 153.58 mmol) and bispinapol borate (30 g, 118.14) at room temperature.
  • Methoxy (cyclooctadiene) ruthenium dimer (3.13 g, 4.73 mmol) and 2,9-dimethyl-1,10-phenanthroline (984.14) were added to a suspension of tetrahydrofuran (150 mL). Mg, 4.73 mmol), the reaction solution was nitrogen-protected, and the mixture was heated to 90 ° C for 12 hours. The reaction mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjj
  • Triethylsilylhydrogen (279.07 mg, 2.40 mmol) and trifluoroacetic acid (136.83 mg, 1.20 mmol) were added to a solution of compound 5-4 (880.00 mg, 1.20 mmol) in dichloromethane (10.00 mL). The reaction solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated, EtOAc EtOAc (EtOAc m.
  • EC 50 values of the compounds was evaluated antiviral activity against influenza virus (Influenza virus, IFV) measured by the EC50 compound. Cytopathic assays are widely used to determine the protective effect of a compound on a virus-infected cell to reflect the antiviral activity of the compound.
  • MDCK cells (ATCC, Cat. No. CCL-34) were seeded into black 384-well cell culture plates at a density of 2,000-3,000 cells per well, and then cultured overnight at 37 ° C in a 5% CO 2 incubator. Compounds were diluted by Echo555 non-contact nanoscale sonic pipetting system and added to the cell wells (3 fold dilution, 8 test concentration points). The influenza virus A/Weiss/43 (H1N1) strain (ATCC, Cat. No. VR-96) was then added to the cell culture well at a dose of 1-290% tissue culture infected per well (TCID90) with a final concentration of DMSO in the medium of 0.5%.
  • H1N1N1 strain ATCC, Cat. No. VR-96
  • Virus control wells (with DMSO and virus added, no compound added), and cell control wells (with DMSO added without compound and virus) were set up.
  • the cell plates were incubated for 5 days at 37 ° C in a 5% CO 2 incubator. After 5 days of culture, the cell viability was measured using the cell viability assay kit CCK8. Raw data was used for compound antiviral activity calculations.
  • the antiviral activity of the compound is represented by the inhibition rate (%) of the cellular virus effect caused by the virus by the compound. Calculated as follows:
  • mice were intranasally infected with influenza A virus H1N1 (Virapur, Inc., item number: F1003A), and treatment with the compound was started 36 hours after infection, orally, for 7 consecutive days, twice daily.
  • influenza A virus H1N1 (Virapur, Inc., item number: F1003A)
  • the anti-influenza A H1N1 effect of the compound in this model was evaluated by observing the change in body weight and survival rate of the mice.
  • the experiment used SPF grade BALB/c mice (Shanghai Lingchang Biotechnology Co., Ltd.), 6-7 weeks, female.
  • the experiment was started after the mice arrived at the BSL-2 animal house for at least 3 days.
  • the day of infection was set to day 0 of the experiment.
  • the mice were anesthetized with pentobarbital sodium (75 mg/kg, 10 ml/kg).
  • the H1N1A/WSN/33 virus was infected by intranasal injection, and the infection volume was 50 ul.
  • 10 mg/kg (administered volume 10 ml/kg) of the test compound was orally administered twice daily.
  • the first administration time was 36 hours after infection.
  • Mouse status was observed daily and mouse body weight and survival rate were recorded. On day 14, all surviving animals were euthanized.
  • the survival rate and weight loss rate of the animals were measured as shown in the following table: Compound WX-231 can achieve a protective body weight loss rate of 12.9% and a survival rate of 100% on the 9th day, and the compound WX-216 can be protected on the 9th day. The weight loss rate of animals was 4.8%, and the survival rate was 100%. On the 9th day, WX-279 could achieve a weight loss rate of 28.7%, and the survival rate was 100%. WX-290 can protect animal body weight on the 9th day. The rate of decline was 27.6% and the survival rate was 40%. On the 9th day, WX-297 could achieve a weight loss rate of 27.3%, and the survival rate was 100%. WX-351 can achieve the weight loss rate of protected animals on the 9th day. At 35.3%, the survival rate was 100%. The experimental results are shown in Table-2.

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Abstract

本发公开了一类抗流感病毒化合物，及其在制备治疗与流感病毒相关药物中的应用。具体公开了式(Ⅰ)所示化合物及其药学上可接受的盐。

Description

抗流感病毒嘧啶衍生物
相关申请的引用
本申请要求于2016年09月05日向中华人民共和国国家知识产权局提交的第201610804101.3号中国发明专利申请和2016年12月28日向中华人民共和国国家知识产权局提交的第201611238759.9号中国发明专利申请的权益，在此将其全部内容以援引的方式整体并入本文中。
技术领域
本发涉及一类抗流感病毒化合物，及其在制备治疗与流感病毒相关药物中的应用。具体涉及式(Ⅰ)所示化合物及其药学上可接受的盐。
背景技术
流行性感冒病毒，即流感病毒(influenza virus,IFV)，是一种能够导致人和动物患流行感冒的分节状单链反义RNA病毒。流感大爆发导致成千上万人死亡，引起巨大社会恐慌并增加社会不稳定因素。
流感会产生由于丧失生产力和相关医疗资源的直接成本以及预防措施的间接成本。在美国，流感累计每年大约造成100亿美元的损失，据估计未来的流感大流行可引起数千亿美元的直接和间接成本。预防成本也非常高，全球各国政府已花费数十亿美元为可能的H5N1禽流感大流行做准备和计划，成本和购买药物和疫苗，以及发展灾难演练和提高边境管制的策略相关。
目前的流感治疗选择包括接种疫苗和用抗病毒药物进行化疗和化学预防。抗病毒药物也可以用于治疗流感，其中神经氨酸酶抑制剂，如奥司他韦(达菲)，对于甲型流感病毒效果明显，但是经过临床观察发现，对于该类神经氨酸酶抑制剂已经出现了耐药的病毒株。在抗流感病毒领域，临床上亟需全新作用机制的抗流感病毒药物，能够支持单药使用治疗甲型流感，或者通过和已上市的其他作用机制的抗流感病毒药物联用，用于甲型流感的预防和治疗。
其中WO2010148197报道了如下化合物：
Figure PCTCN2017100461-appb-000001
发明内容
本发明提供了式(Ⅰ)所示化合物或其药学上可接受的盐，
Figure PCTCN2017100461-appb-000002
其中，
R1选自任选被1、2或3个R或R’取代的：C1-6烷硫基、5～6元杂芳基、C2-6炔基、C3-6环烷基；
T1选自N或CH；
T2选自N或C(R2)；
R2选自H、F、Cl、Br、I；
R3选自H、卤素、CN、NH2、OH，或选自任选被1、2或3个R或R’取代的：C1-6烷基；
R选自卤素、OH、NH2、CN、COOH、
Figure PCTCN2017100461-appb-000003
或选自任选被1、2或3个R’取代的：C1-6烷基、C1-6杂烷基、C3-6环烷基、3～6元杂环烷基、3～6元杂环烷基-C(＝O)-、3～6元杂环烷基-(CH2)1-3-；
R’选自：F、Cl、Br、I、CN、OH、NH2、COOH、Me、NHCH3、N(CH3)2、
Figure PCTCN2017100461-appb-000004
所述5～6元杂芳基、C1-6杂烷基、C3-6环烷基、3～6元杂环烷基之“杂”选自：N、-S-、-O-、-NH-；
以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
本发明的一些方案中，上述R选自：F、Cl、Br、I、OH、NH2、CN、COOH、
Figure PCTCN2017100461-appb-000005
或选自任选被1、2或3个R’取代的：C1-3烷基、C1-3杂烷基、C3-6环烷基、3～6元杂环烷基、3～6元杂环烷基-C(＝O)-、3～6元杂环烷基-CH2-。
本发明的一些方案中，上述R选自：F、Cl、Br、I、OH、NH2、CN、COOH、
Figure PCTCN2017100461-appb-000006
或选自任选被1、2或3个R’取代的：Me、Et、C1-3烷硫基、C3-6环烷基、吖丁啶基、吡咯烷基、哌嗪基、吗啉基、哌嗪基-C(＝O)-、吗啉基-C(＝O)-、吡咯烷基-C(＝O)-、哌嗪基-CH2-、吗啉基-CH2-、吡咯烷基-CH2-。
本发明的一些方案中，上述R选自：F、Cl、Br、I、OH、NH2、CN、COOH、
Figure PCTCN2017100461-appb-000007
或选自任选被1、2或3个R’取代的：Me、Et、
Figure PCTCN2017100461-appb-000008
Figure PCTCN2017100461-appb-000009
本发明的一些方案中，上述R选自：F、Cl、Br、I、OH、NH2、Me、Et、CN、COOH、
Figure PCTCN2017100461-appb-000010
Figure PCTCN2017100461-appb-000011
本发明的一些方案中，上述R1选自任选被1、2或3个R或R’取代的：C1-3烷硫基、C2-4炔基、C3-5环烷基。
本发明的一些方案中，上述R1选自任选被1、2或3个R或R’取代的：
Figure PCTCN2017100461-appb-000012
Figure PCTCN2017100461-appb-000013
本发明的一些方案中，上述R1选自：
Figure PCTCN2017100461-appb-000014
Figure PCTCN2017100461-appb-000015
本发明的一些方案中，上述R1选自任选被1、2或3个R或R’取代的：吡啶基、吡唑基、咪唑基、噻吩基、恶唑基、异恶唑基。
本发明的一些方案中，上述R1选自任选被1、2或3个R或R’取代的：
Figure PCTCN2017100461-appb-000016
Figure PCTCN2017100461-appb-000017
本发明的一些方案中，上述R1选自：
Figure PCTCN2017100461-appb-000018
Figure PCTCN2017100461-appb-000019
Figure PCTCN2017100461-appb-000020
本发明的一些方案中，上述R1选自：
Figure PCTCN2017100461-appb-000021
Figure PCTCN2017100461-appb-000022
本发明的一些方案中，上述T2选自：N、CH或C(F)。
本发明的一些方案中，上述R3选自H、卤素、CN、NH2、OH，或选自任选被1、2或3个R或R’取代的：C1-3烷基。
本发明的一些方案中，上述R3选自H、F、Cl、Br、I、CN、NH2、OH，或选自任选被1、2或3个R或R’取代的：Me、Et。
本发明的一些方案中，上述R3选自H、F、Cl、Br、I、CN、NH2、OH、Me、Et、CF3。
本发明的一些方案中，上述结构单元
Figure PCTCN2017100461-appb-000023
选自
Figure PCTCN2017100461-appb-000024
Figure PCTCN2017100461-appb-000025
本发明的一些方案中，上述R选自：F、Cl、Br、I、OH、NH2、CN、COOH、
Figure PCTCN2017100461-appb-000026
或选自任选被1、2或3个R’取代的：C1-3烷基、C1-3杂烷基、C3-6环烷基、3～6元杂环烷基、3～6元杂环烷基-C(＝O)-、3～6元杂环烷基-CH2-，其他变量如上述所定义。
本发明的一些方案中，上述R选自：F、Cl、Br、I、OH、NH2、CN、COOH、
Figure PCTCN2017100461-appb-000027
或选自任选被1、2或3个R’取代的：Me、Et、C1-3烷硫基、C3-6环烷基、吖丁啶基、吡咯烷基、哌嗪基、吗啉基、哌嗪基-C(＝O)-、吗啉基-C(＝O)-、吡咯烷基-C(＝O)-、哌嗪基-CH2-、吗啉基-CH2-、吡咯烷基-CH2-，其他变量如上述所定义。
本发明的一些方案中，上述R选自：F、Cl、Br、I、OH、NH2、CN、COOH、
Figure PCTCN2017100461-appb-000028
或选自任选被1、2或3个R’取代的：Me、Et、
Figure PCTCN2017100461-appb-000029
Figure PCTCN2017100461-appb-000030
其他变量如上述所定义。
本发明的一些方案中，上述R选自：F、Cl、Br、I、OH、NH2、Me、Et、CN、COOH、
Figure PCTCN2017100461-appb-000031
Figure PCTCN2017100461-appb-000032
Figure PCTCN2017100461-appb-000033
其他变量如上述所定义。
本发明的一些方案中，上述R1选自任选被1、2或3个R或R’取代的：C1-3烷硫基、C2-4炔基、C3-5环烷基，其他变量如上述所定义。
本发明的一些方案中，上述R1选自任选被1、2或3个R或R’取代的：
Figure PCTCN2017100461-appb-000034
Figure PCTCN2017100461-appb-000035
其他变量如上述所定义。
本发明的一些方案中，上述R1选自：
Figure PCTCN2017100461-appb-000036
Figure PCTCN2017100461-appb-000037
其他变量如上述所定义。
本发明的一些方案中，上述R1选自任选被1、2或3个R或R’取代的：吡啶基、吡唑基、咪唑基、噻吩基、恶唑基、异恶唑基，其他变量如上述所定义。
本发明的一些方案中，上述R1选自任选被1、2或3个R或R’取代的：
Figure PCTCN2017100461-appb-000038
Figure PCTCN2017100461-appb-000039
其他变量如上述所定义。
本发明的一些方案中，上述R1选自：
Figure PCTCN2017100461-appb-000040
Figure PCTCN2017100461-appb-000041
Figure PCTCN2017100461-appb-000042
其他变量如上述所定义。
本发明的一些方案中，上述R1选自：
Figure PCTCN2017100461-appb-000043
Figure PCTCN2017100461-appb-000044
Figure PCTCN2017100461-appb-000045
其他变量如上述所定义。
本发明的一些方案中，上述T2选自：N、CH或C(F)，其他变量如上述所定义。
本发明的一些方案中，上述R3选自H、卤素、CN、NH2、OH，或选自任选被1、2或3个R或R’取代的：C1-3烷基，其他变量如上述所定义。
本发明的一些方案中，上述R3选自H、F、Cl、Br、I、CN、NH2、OH，或选自任选被1、2或3个R或R’取代的：Me、Et，其他变量如上述所定义。
本发明的一些方案中，上述R3选自H、F、Cl、Br、I、CN、NH2、OH、Me、Et、CF3，其他变量如上述所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2017100461-appb-000046
选自
Figure PCTCN2017100461-appb-000047
Figure PCTCN2017100461-appb-000048
其他变量如上述所定义。
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自：
Figure PCTCN2017100461-appb-000049
其中，R1、R3如上述所定义。
本发明还有一些方案是由上述各变量任意组合而来。
本发明还提供了下式所示化合物或其药学上可接受的盐，其选自：
Figure PCTCN2017100461-appb-000050
Figure PCTCN2017100461-appb-000051
Figure PCTCN2017100461-appb-000052
本发明还提供了下式所示化合物或其药学上可接受的盐，其选自：
Figure PCTCN2017100461-appb-000053
Figure PCTCN2017100461-appb-000054
Figure PCTCN2017100461-appb-000055
本发明还提供了上述化合物或其药学上可接受的盐在制备治疗抗流感病毒药物中的应用。
技术效果：
本发明化合物主要用于预防和治疗由甲型流感病毒引起的流行性感冒、以及由高致病性禽流感病毒引起的流感，和现有临床用药相比，具有安全性高、口服生物利用度佳，并且具有对现有临床用药发生耐药的甲型流感病毒株仍然具有明显抗病毒活性的潜力。
相关定义
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。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。
除非另有说明，用楔形键和虚线键
Figure PCTCN2017100461-appb-000056
表示一个立体中心的绝对构型，用
Figure PCTCN2017100461-appb-000057
表示一个立体中心的相对构型。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常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。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。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(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。
当一个连接基团的数量为0时，比如-(CRR)0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当一个取代基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 PCTCN2017100461-appb-000058
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。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O)2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)2N(H)-或-S(＝O)N(H)-。
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的，本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是，当杂环中S及O原子的总数超过1时，这些杂原子彼此不相邻。另一个优选方案是，杂环中S及O原子的总数不超过1。如本文所用，术语“芳族杂环基团”或“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环，它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。值得注意的是，芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。
杂环化合物的实例包括但不限于：吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异 噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、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、芳基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基)，可以是单取代或多取代的，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，可以包括二价或多价原子团，具有指定数量的碳原子(如C1-C12表示1至12个碳，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。)。“烃基”包括但不限于脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烃基”表示直链的或支链的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烃基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构体。
除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、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，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。实例包括但不限 于-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。
除非另有规定，术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外，就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言，杂原子可以占据该杂环附着于分子其余部分的位置。环烃基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH2F)或多取代的(如-CF3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等。
除非另有规定，“烯基”指在链的任何位点上具有一个或多个碳碳双键的烷基,可以是单取代或多取代的，可以是一价、二价或者多价。烯基的例子包括乙烯基，丙烯基，丁烯基，戊烯基，己烯基，丁间二烯基，戊间二烯基，己间二烯基等。
除非另有规定，“炔基”指在链的任何位点上具有一个或多个碳碳三键的烷基，可以是单取代或多取代的，可以是一价、二价或者多价。炔基的例子包括乙炔基，丙炔基，丁炔基，戊炔基等。
除非另有规定，环烷基包括任何稳定的环状或多环烃基，任何碳原子都是饱和的，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定，环烯基包括任何稳定的环状或多环烃基，该烃基在环的任何位点含有一个或多个不饱和的碳-碳双键，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烯基的实例包括，但不限于，环戊烯基、环己烯基等。
除非另有规定，环炔基包括任何稳定的环状或多环烃基，该烃基在环的任何位点含有一个或多个碳-碳三键，可以是单取代或多取代的，可以是一价、二价或者多价。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(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。除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。
“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基，除非另有规定，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。
除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代或多取代的，可以是一价、二价或者多价，它可以是单环或多环(比如1至3个环；其中至少一个环是芳族的)，它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、萘基、联苯基、吡咯基、吡唑基、咪唑基、吡嗪基、恶唑基、苯基-恶唑基、异恶唑基、噻唑基、呋喃基、噻吩基、吡啶基、嘧啶基、苯并噻唑基、嘌呤基、苯并咪唑基、吲哚基、异喹啉基、喹喔啉基、喹啉基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
除非另有规定，芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此，术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑 -1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁基羰基是一种胺保护基团；HOAc代表乙酸；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；mp代表熔点；LDA代表二异丙基胺基锂。
化合物经手工或者
Figure PCTCN2017100461-appb-000059
软件命名，市售化合物采用供应商目录名称。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
参考例1：片段BB-1
Figure PCTCN2017100461-appb-000060
合成路线：
Figure PCTCN2017100461-appb-000061
步骤1：化合物BB-1-2的合成：
在0℃，将化合物BB-1-1(100g,1mol)溶于氯仿(1L)中，滴加1,4-环己二烯(4.32g,134.7mmol)，该反应液在室温下搅拌过夜。然后将反应液减压浓缩，所得固体用甲醇(300mL)搅拌，过滤，滤饼用甲醇(100mL)洗涤，真空干燥得化合物BB-1-2(148g,0.83mol,收率83％)。
步骤2：化合物BB-1-3的合成：
在-20℃，将化合物BB-1-2(20g,112.3mmol)和奎宁(43.7g,134.7mmol)溶于甲苯(300mL)中，滴加无水甲醇(4.32g,134.7mmol)的甲苯(10mL)溶液，该混合物在-15℃下搅拌2小时，然后将反应液在室温下反应过夜，有大量白色固体析出。将水(100mL)加入反应液，用乙酸乙酯(150mL X 3)萃取，合并有机相分别用水(100mL X 2)和饱和食盐水(100mL)洗涤一次，有机相用无水硫酸钠干燥，过滤，浓缩得到粗产品BB-1-3(24g)。
步骤3：化合物BB-1-4的合成：
在-15℃下，将叔戊醇钾(20.2g,34mmol)溶于甲苯(320mL)中，滴加化合物BB-1-3(24g,159.8mmol)的甲苯(20mL)溶液，反应液在-20℃搅拌3小时。向反应液中加入硫酸水溶液(3M,80mL)，用乙酸乙酯(300mL X 3)萃取，合并有机相，分别用水(100mL X 3)，饱和食盐水(100mL)洗涤，有机相用无水硫酸钠干燥，过滤，减压浓缩，所得物经硅胶柱纯化(二氯甲烷:甲醇:乙酸＝200:10:1))得到BB-1-4(16g,76.11mmol,收率66.7％)。
步骤4：化合物BB-1-5的合成：
在室温下，向化合物BB-1-4(16g,76.11mmol)的甲苯(250.00mL)溶液中加入三乙胺(11.55g,114.17mmol，15.82mL)，叠氮磷酸二苯酯(25.13g,91.3mmol,19.8mL)。混合物在室温搅拌1小时，然后90℃反应1小时，将苄醇(16.46g,152.22mmol,15.83mL)加入反应液中,在90℃下搅拌2小时。反应液用乙酸乙酯(500mL)稀释，分别用饱和碳酸钠水溶液(100mL X 3)，饱和食盐水(100mL)洗涤，有机相用无水硫酸钠干燥，过滤，减压浓缩。所得物经硅胶柱(石油醚：乙酸乙酯10:1至5:1)纯化，所得物经制备分离得消旋化合物(15g)，经(正己烷：二氯甲烷＝15:1)重结晶2次得化合物BB-1-5(4g)。MS(ESI)m/z＝316.1[M+1]。
步骤5：化合物BB-1的合成：
在室温和下，向化合物BB-1-5(2g,6.34mmol)的甲醇(20.00mL)和四氢呋喃(20mL)溶液中加入钯碳(10％,0.2g)。混合物在氢气(50psi)下40℃搅拌12小时，反应液过滤，滤液旋干得到粗品化合物BB-1(1.1g)。1H NMR(400MHz,CHLOROFORM-d)δ3.71(s,3H),3.30-3.35(m,1H),2.75-2.77(m,1H),1.38-1.92(m,10H).
参考例2：片段BB-2
Figure PCTCN2017100461-appb-000062
合成路线：
Figure PCTCN2017100461-appb-000063
步骤1：化合物BB-2-2的合成：
在-16℃到-12℃氮气保护下，向化合物BB-2-1(92.10g,516.89mmol)和奎宁(184.46g,568.58mmol)的甲苯(3.4L)溶液中滴加无水乙醇(53mL),该混合物在-16℃到-12℃下搅拌12小时，大量白色固体析出；将反应液过滤，滤饼干燥得到化合物BB-2-2(160.00g,291.61mmol,收率56.42％)。
步骤2：化合物BB-2-3的合成：
在室温下，向化合物BB-2-2(160.00g,291.61mmol)的甲苯(900.00mL)溶液中加入盐酸(97.2mL,6M),该混合物在在室温下搅拌30分钟，将反应液静置分离，水相继续用甲苯(550.00mL)萃取一次，合并有机相。在-20℃下将叔戊醇钾(42.3g)溶于甲苯(400mL)滴加入到该有机相，耗时30分钟；第二批叔戊醇钾(9.8g)溶于甲苯(100mL)滴加入到该有机相，该混合液在氮气保护下-20℃搅拌3小时。保持温度-20下反应用盐酸(100mL,6M)淬灭并加入乙酸(8g)。反应升温至-5℃并将盐酸(60mL,2M)加入。在-5℃左右搅拌45分钟，然后升温到20℃左右搅拌15分钟。混合液静置，移除水相，有机相加水(35mL)搅拌15分钟后静置15分钟，除去水相。缓冲溶液(135mL)(22.05g磷酸二氢钠，3.6g磷酸氢二钠溶在405mL水中)加入在该有机相中，搅拌15分钟，静置15分钟，除去水相，洗涤三次。有机相旋干，加入正庚烷(50mL)并至40℃下30分钟，冷却至0-5℃下搅拌1.5小时。混合物过滤，滤饼干燥，重复三次结晶，得化合物BB-2-3(28.00g,124.86mmol,收率43.08％)。
步骤3：化合物BB-2-4的合成：
在室温下，向化合物BB-2-3(25.00g,111.48mmol)的甲苯(300.00mL)溶液中加入三乙胺(27.07g,267.55mmol,37.08mL)。反应液加热到95℃并加入叠氮磷酸二苯酯(30.37g,110.37mmol,23.91mL)。混合物在95℃搅拌1小时，苄醇(12.06g,111.48mmol,11.60mL)加入反应液中氮气保护下95℃搅拌12小时。反应液冷却至室温，减压浓缩得到粗产品，经用硅胶层析柱(石油醚：乙酸乙酯＝6:1)纯化得到化合物BB-2-4(32.00g,72.08mmol,收率64.66％)。MS(ESI)m/z＝330.0[M+1]。1H NMR(400MHz,CHLOROFORM-d)δ7.28-7.42(m,5H),6.47(t,J＝7.40Hz,1H),6.19(t,J＝7.15Hz,1H),5.01-5.17(m,2H),4.07-4.39(m,4H),2.69-2.94(m,2H),2.12(br s,1H),1.46-1.78(m,2H),0.99-1.35(m,7H)
步骤4：化合物BB-2的合成：
在室温和氮气保护下，向化合物BB-2-4(31.00g,94.11mmol)的乙醇(300.00mL)和四氢呋喃(200mL)溶液中加入钯碳(10％,5g)。氢气置换3次，随后，混合物在氢气(50psi)下搅拌12小时，反应液过滤，滤液旋干得到粗品化合物BB-2(18.30g)。
1H NMR(400MHz,DMSO-d6)δ7.28-7.34(m,1H),3.97-4.17(m,2H),3.40-3.52(m,1H),3.44(q,J＝6.86Hz,1H),2.09(br d,J＝6.27Hz,1H),1.75-1.87(m,2H),1.24-1.61(m,8H),1.18(t,J＝7.15Hz,3H),1.06(t,J＝7.03Hz,1H).
参考例3：片段BB-3
Figure PCTCN2017100461-appb-000064
合成路线：
Figure PCTCN2017100461-appb-000065
步骤1：化合物BB-3-2的合成：
向化合物BB-3-1(18.00g,160.57mmol,1.00eq)的硫酸溶液(100.00mL,2mol)中加入碘酸钾(17.18g,80.29mmol,17.18mL)，该混合物在搅拌下加热至100℃，碘化钾(14.66g,88.31mmol)溶在水(40.00mL)中滴加到该混合液中并在100℃继续搅拌一小时。反应液冷却至室温并用饱和碳酸钠溶液调至中性，用乙酸乙酯(200mL)萃取三次，有机相用无水硫酸钠干燥，过滤，浓缩得到粗产品，经用硅胶柱层析(石油醚：乙酸乙酯＝20:1至10:1)纯化得到化合物BB-3-2(18.00g,75.18mmol,收率46.82％)。MS(ESI)m/z:239.0[M+1]。
步骤2：化合物BB-3-3的合成
在室温下，向化合物BB-3-2(18.00g,75.63mmol)和三甲基硅乙炔(14.86g,151.26mmol,20.93mL)的四氢呋喃(250.00mL)溶液中加入碘化亚铜(696.18mg,3.66mmol)，二氯双(三苯基膦)钯(II)(1.59g,2.27mmol)，三乙胺(22.96g,226.89mmol,31.45mL)。反应液室温下搅拌3小时。反应液过滤，滤液旋干得粗产品，经用硅胶柱层析(石油醚：乙酸乙酯＝20:1至10:1)纯化得到粗品化合物BB-3-3(17.00g,81.20mmol)。MS(ESI)m/z:209.00[M+1]。
步骤3：化合物BB-3-4的合成：
在室温下，向化合物BB-3-3(17.00g,81.61mmol)的1-甲基-2-吡咯烷酮(200.00mL)溶液中慢慢加入钠氢(3.92g,97.93mmol,60％)。混合物在80℃下搅拌1小时。反应液冷却至室温，水(100mL)慢慢加入到该反应液中，用乙酸乙酯(100mL)萃取三次，合并有机相用饱和食盐水(100mL)洗涤三次,无水硫酸钠干燥，过滤，减压浓缩，所得粗产品经硅柱胶层析(石油醚：乙酸乙酯＝10:1至5:1)纯化得到化合物BB-3-4(9.30g,58.48mmol,收率71.66％)。MS(ESI)m/z＝136.8[M+1]。
步骤4：化合物BB-3-5的合成：
在-10℃下，向化合物BB-3-4(7.40g,54.36mmol)的DMF溶液(100.00mL)中加入N-溴代丁二酰亚胺(9.67g,54.36mmol)。混合物在-10℃下搅拌一小时。水(100mL)滴加到该反应液中，混合物经过滤，固体旋干得到化合物BB-3-5(11.50g,44.34mmol,收率81.56％)。MS(ESI)m/z＝217.0[M+1]。
步骤5：化合物BB-3-6的合成：
在0℃下，向化合物BB-3-5(9.80g,45.58mmol)的四氢呋喃(150.00mL)溶液中加入钠氢(2.19g,54.69mmol,60％)。反应液在15℃下搅拌30分钟。对甲苯磺酰氯(10.43g,54.69mmol)加入到该反应液中，反应液在15℃下搅拌12小时。将水(100mL)滴加到反应液中，用乙酸乙酯(150mL)萃取三次，合并有机相用无水硫酸钠干燥，过滤，减压浓缩，所得粗产品经用硅胶层析柱(石油醚：乙酸乙酯＝50:1至20:1)纯化得到化合物BB-3-6(15.00g,40.63mmol,收率89.13％)。MS(ESI)m/z＝370.7[M+1]。
步骤6：化合物BB-3的合成：
在室温下，向化合物BB-3-6(15.00g,40.63mmol)和双联嚬哪醇硼酸酯(12.38g,48.75mmol)的1,4-二氧六环(80.00mL)溶液中加入化合物乙酸钾(5.98g,60.94mmol)和1'-双(二叔丁基膦)二茂铁二氯化钯(1.32g,2.03mmol)，混合物在氮气保护下40℃搅拌12小时。粗品过滤，滤液用乙酸乙酯(150mL)稀释，有机相用盐水(50mL)洗涤二次,合并有机相用无水硫酸钠干燥，过滤，减压浓缩，所得粗产品经用硅胶层析柱(石油醚：乙酸乙酯＝1:0至20:1)纯化得到化合物BB-3(4.80g,6.71mmol,收率16.52％)。1H NMR(400MHz,DMSO-d6)δ8.42(d,J＝1.2Hz,1H),8.15(s,1H),7.97–8.07(m,2H),7.84–7.87(m,1H),7.43(d,J＝8.4Hz,1H),2.35(s,1H),1.32(s,1H).MS(ESI)m/z:417.0[M+1].
参考例4：片段BB-4
Figure PCTCN2017100461-appb-000066
合成路线：
Figure PCTCN2017100461-appb-000067
步骤1：化合物BB-4-2的合成：
向化合物BB-4-1(300mg,1.97mmol)的溴仿(5mL)溶液中加入亚硝酸叔丁酯(406mg,3.94mmol)。混合物在60℃搅拌1小时，然后在90℃搅拌1小时。反应液冷却到室温后，浓缩得到粗产品，用快速硅胶层析柱(5-20％乙酸乙酯/石油醚)纯化得到化合物BB-4-2(300.00mg,收率70.50％)。1H NMR(400MHz,CHLOROFORM-d)δ:11.25(br s,1H),8.54(dd,J＝1.88,2.64Hz,1H),7.69(dd,J＝2.51,7.28Hz,1H).MS(ESI)m/z:215.9(M+H+).
步骤2：化合物BB-4-3的合成：
向化合物BB-4-2(300mg,1.39mmol)的N,N-二甲基甲酰胺(5mL)溶液中加入三苯基氯甲烷(426mg,1.53mmol)和碳酸钾(576mg,4.17mmol)，混合物在25℃搅拌12小时。反应液用乙酸乙酯(50mL)稀释，再用饱和食盐水(15mL X 3)洗涤，有机相用无水硫酸钠干燥，浓缩得到粗产品。用快速硅胶层析柱(0～10％乙酸乙酯/石油醚)纯化得到化合物BB-4-3(350mg,收率54.94％)。1H NMR(400MHz,CHLOROFORM-d)δ:8.16(dd,J＝1.25,2.76Hz,1H),7.53(dd,J＝3.01,7.53Hz,1H),7.25(s,15H).MS(ESI)m/z:458.2(M+H+).
步骤3：化合物BB-4的合成：
向化合物BB-4-3(350mg,763.66umol)和双联频哪醇硼酸酯(291mg,1.15mmol)的N,N-二甲基甲酰胺(7mL)溶液中加入醋酸钾(225mg,2.29mmol)和1'-双(二叔丁基膦)二茂铁二氯化钯(28mg,38.18umol)。混合物在100℃氮气保护下搅拌2小时。反应液冷却到室温然后过滤，滤液用乙酸乙酯(50mL)稀释，饱和食盐水(20mL X 3)洗涤。有机相用无水硫酸钠干燥，浓缩得到粗产品，用快速硅胶层析柱(0～10％乙酸乙酯/石油醚)纯化得BB-4(300mg,收率77.73％)。MS(ESI)m/z:733.2(M+Na+).
参考例5：片段BB-5
Figure PCTCN2017100461-appb-000068
合成路线：
步骤1：化合物BB-5的合成：
在-70℃下，将化合物BB-5-2(201.06mg,1.02mmol)溶于四氢呋喃溶液(3.00mL)，氮气保护下加入正丁基锂(2.5M,409.65uL)，反应液在氮气保护下搅拌15分钟。然后滴加2,4-二氯-5-氟嘧啶(100.00mg,598.91umol)的乙二醇二甲醚(1.00mL)溶液，搅拌3小时。反应液用氯化铵水溶液淬灭，用乙酸乙酯(20mL X 2)萃取，有机相减压浓缩。粗产品溶于四氢呋喃(2mL)中，加入2,3-二氯-5,6-二氰基-1,4-苯醌(149.55mg,658.80umol)的四氢呋喃(1mL)溶液，在20℃反应5小时。反应液减压浓缩，粗产品经硅胶柱(石油醚：乙酸乙酯＝10:1)纯化得到BB-5(80.00mg,收率47.11％)。1H NMR(400MHz,CHLOROFORM-d)δ7.72(dd,J＝1.38,4.14Hz,1H),6.98(d,J＝4.27Hz,1H).
参考例6：片段BB-6
Figure PCTCN2017100461-appb-000070
合成路线：
Figure PCTCN2017100461-appb-000071
步骤1：化合物BB-6-2的合成：
在室温下，将化合物2,4-二氯-5-氟嘧啶(350.00mg,2.10mml)溶于乙腈(5.00mL)和水(5.00mL)中，分别加入硝酸银(713.45mg,4.20mmol)，1-氟-环丙基甲酸(649.15mg,6.24mmol)。将反应液升温至80℃,然后滴加过硫酸铵(958.44mg,4.20mmol)的水(1mL)溶液，反应液80℃反应过夜。将反应液冷却至室温，加入乙酸乙酯(100mL)和食盐水(100mL)，将絮状物过滤，有机层分别用水(30mL X 3)和食盐水(30mL)洗涤,硫酸钠干燥，过滤，减压浓缩。粗产品用硅胶柱(石油醚：乙酸乙酯1:0至10:1)纯化得化合物BB-6-2(260mg，收率55％)。1H NMR(400MHz,CHLOROFORM-d)δ1.48-1.60(m,4H).
步骤2：化合物BB-6的合成：
在室温下，将化合物BB-6-2(100.00mg,444.40umol)溶于四氢呋喃(5mL)中，分别加入BB-2(92.05mg,466.63umol)和N,N-二异丙基乙胺(172.30mg,1.33mmol),将反应液升温至50℃过夜。将反应液减压浓缩。粗产品用硅胶柱(石油醚：乙酸乙酯10:1至3:1)纯化得化合物BB-6(149.00mg,收率79.08％)。MS(ESI)m/z:386.0(M+1+).
参照参考例6中步骤1～2的合成方法，合成下表中各参考实例。
Figure PCTCN2017100461-appb-000072
Figure PCTCN2017100461-appb-000073
实施例1
Figure PCTCN2017100461-appb-000074
合成路线：
Figure PCTCN2017100461-appb-000075
步骤1：化合物1-2的合成
向化合物1-1(100mg,276umol)和4-硼酸吡啶(41mg,331umol)的四氢呋喃(2mL)和水(0.5mL)的溶液中加入磷酸钾(117.20mg,552.14umol),Pd(dtbpf)Cl2(9mg,14umol)。混合物在25℃搅拌12小时，然后在50℃搅拌2小时。反应液冷却到室温然后过滤。向滤液中加入水(30mL)，用乙酸乙酯(10mL)萃取三次。合并有机相，用无水硫酸钠干燥，减压浓缩得到粗产品，用快速硅胶层析柱(10-30％乙酸乙酯/石油醚)纯化得到化合物1-2(30.00mg,收率26.84％)。MS(ESI)m/z:405.1(M+H+)。
步骤2：化合物1-3的合成
向化合物1-2(30mg,74umol)和化合物BB-3(37mg,89umol)的2-甲基四氢呋喃(2.00mL)和水(0.2mL)的溶液中加入磷酸钾(31.46mg,148umol)，三(二亚苄基丙酮)二钯(3mg,4umol)和2-双环己基膦-2’,4’,6’-三异丙基联苯(7mg,15umol)。混合物在80℃和氮气保护下搅拌12小时。反应液冷却到室温然后过滤。向滤液中加入水(20mL)，用乙酸乙酯(8mL X 3)萃取，合并有机相，用无水硫酸钠干燥，浓 缩得到粗产品。用快速硅胶层析柱(10-30％乙酸乙酯/石油醚)纯化得到黄色固体化合物1-3(20mg,收率40.97％)。MS(ESI)m/z:659.2(M+H+)。
步骤3：化合物WX-230的合成
向化合物1-3(20.00mg,30.36umol)的四氢呋喃(1.00mL)和水(0.25mL)的溶液中加入NaOH(6.07mg,151.80umol)。混合物在50℃搅拌12小时。浓缩除去四氢呋喃，加入1M HCl(0.5mL)，粗产品经制备纯化得到化合物WX-230(10mg,收率64.21％)。1H NMR(400MHz,METHANOL-d4)δ9.04(br d,J＝6.52Hz,2H),8.77(br d,J＝6.53Hz,3H),8.48(s,1H),8.31(br s,1H),4.81(br s,1H),2.84(br d,J＝6.53Hz,1H),2.14(br s,1H),2.06(br s,1H),1.81-2.00(m,3H),1.64-1.80(m,3H),1.56(br d,J＝12.05Hz,3H).MS(ESI)m/z:477.1(M+H+)。
参照实施例1中步骤1～3的合成方法，合成下表中各实施例。
Figure PCTCN2017100461-appb-000076
Figure PCTCN2017100461-appb-000077
Figure PCTCN2017100461-appb-000078
Figure PCTCN2017100461-appb-000079
Figure PCTCN2017100461-appb-000080
Figure PCTCN2017100461-appb-000081
实施例2
Figure PCTCN2017100461-appb-000082
合成路线：
Figure PCTCN2017100461-appb-000083
步骤1：化合物2-2的合成
在室温下，将化合物2-1(500.00mg,2.48mmol)溶于四氢呋喃(8.00mL)，在-40℃下滴加甲硫醇钠(173.82mg,2.48mmol,158.02uL)的甲醇(2mL)溶液。反应液-40℃搅拌1小时后升至室温搅拌过夜。反应液用乙酸乙酯(60mL)稀释，分别用水(15mL)，饱和食盐水(15mL)洗涤，有机相用无水硫酸钠干燥，过滤，减压浓缩得粗品化合物2-2(490.00mg,2.30mmol)。1H NMR(400MHz,CHLOFORM-d)δ2.65(s,3H).
步骤2：化合物2-3的合成
在冰浴下，将化合物BB-1(400.00mg,2.18mmol)和化合物2-2(464.47mg,2.18mmol,1.00eq)溶于四氢呋喃(6.00mL)中，加入二异丙基乙胺(1.41g,10.90mmol,1.91mL,5.00eq)，将反应液在55℃搅拌72小时。反应液用乙酸乙酯(30mL)稀释，分别用水(10mL)和饱和食盐水(10mL)洗涤。有机相用无水硫酸钠干燥，过滤， 减压浓缩，所得物用快速硅胶柱层析(石油醚：乙酸乙酯Ethyl acetate＝100：1至5:1)得到化合物2-3(500.00mg,1.35mmol,收率61.93％)。MS(ESI)m/z:359.9(M+H+)。
步骤3：化合物2-4的合成
将化合物2-3(40.00mg,111.16umol,1.00eq),BB-3(46.27mg,111.16umol,1.00eq)溶于2-甲基四氢呋喃(3.00mL)和水(800.00uL)中，加入三(二亚苄基丙酮)二钯(10.18mg,11.12umol,0.10eq)，2-双环己基膦-2’,4’,6’-三异丙基联苯(10.60mg,22.23umol,0.20eq)和磷酸钾(47.19mg,222.32umol,2.00eq)，混合物在氮气保护中80℃搅拌10小时。反应液用乙酸乙酯(40mL)稀释,分别用水(15mL)和饱和食盐水(15mL)洗涤。有机相用无水硫酸钠干燥，过滤，减压浓缩，所得物用薄层层析板(石油醚：乙酸乙酯＝1:1)纯化得到化合物2-4(40.00mg,39.76umol,收率35.77％)
步骤4：化合物WX-139的合成
向化合物2-4(40.00mg,65.18umol)的甲醇(1没L)，四氢呋喃(1.00mL)和水(0.5mL)的溶液中加入一水合氢氧化锂(13.67mg,325.90umol)。混合物在50℃搅拌12小时。浓缩除去四氢呋喃，加入HCl(1M)调节至pH＝5，用乙酸乙酯(20mL)萃取，有机相减压浓缩，所得物经制备纯化得到化合物WX-139(16.00mg,28.17umol,收率43.22％)。1H NMR(400MHz,METHANOL-d4)δ8.59-8.68(m,1H),8.25(s,1H),8.13-8.20(m,1H),4.78-4.83(m,1H),2.71-2.75(m,1H),2.69(s,3H),2.06-2.11(m,1H),1.98–2.04(m,1H),1.79-1.97(m,3H),1.59-1.78(m,3H),1.45-1.59(m,2H).MS(ESI)m/z:446.1[M+1].
参照实施例2中步骤1～4的合成方法，合成下表中各实施例。
Figure PCTCN2017100461-appb-000084
Figure PCTCN2017100461-appb-000085
实施例3
Figure PCTCN2017100461-appb-000086
合成路线：
Figure PCTCN2017100461-appb-000087
步骤1：化合物3-2的合成
在室温下，将化合物3-1(300.00mg,828.20umol)和1-甲基-4-频哪醇硼酸酯吡唑(206.78mg,993.84umol)溶于四氢呋喃(4.00mL)和水(1.00mL)中，分别加入磷酸钾(351.61mg,1.66mmol)and 1'-双(二叔丁基膦)二茂铁二氯化钯(26.99mg,41.41umol)，反应液40℃反应过夜.将反应液冷却至室温，加入水(30mL)，然后过滤。滤液用乙酸乙酯(10mL X 3)萃取.合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，所得得粗品用快速硅胶柱(10～30％乙酸乙酯/石油醚)纯化得化合物3-2(150mg，收率44.4％)。1H NMR(400MHz,CHLOROFORM-d)δ8.05(d,J＝2.01Hz,1H),8.02(s,1H),5.23(br d,J＝5.02Hz,1H),4.51(br t,J＝5.52Hz,1H),4.23(q,J＝7.03Hz,2H),3.97(s,3H),2.39(br d,J＝6.02Hz,1H),2.02(br d,J＝2.51Hz,1H),1.90(br d,J＝2.51Hz,1H),1.77-1.87(m,1H),1.52-1.76(m,11H),1.44(br t,J＝11.29Hz,1H),1.27(t,J＝7.28Hz,4H).MS(ESI)m/z:408.1(M+H+).
步骤2：化合物3-3的合成
在室温下，将化合物3-2(150.00mg,367.76umol)和BB-4(223.03mg,441.31umol)溶于2-甲基四氢呋喃(4.00mL)和水(1.00mL)中，分别加入磷酸钾(156.13mg,735.52umol)，三(二亚苄基丙酮)二钯(16.84mg,18.39umol)和2-双环己基膦-2’,4’,6’-三异丙基联苯(35.06mg,73.55umol)，反应液80℃反应过夜.将反应液冷却至室温，加入水(30mL)，然后过滤。滤液用乙酸乙酯(10mL X 3)萃取.合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，所得得粗品用快速硅胶柱(15～30％乙酸乙酯/石油醚)纯化得化合物3-3(160.00mg,213.09umol,收率57.94％)。MS(ESI)m/z:773.4(M+H+).
步骤3：化合物3-4的合成
在室温下，将化合物3-3(160.00mg,213.09umol)溶于二氯甲烷(3.00mL)中，加入三氟乙酸(485.93mg,4.26mmol)，反应液25℃反应过夜。将反应液减压浓缩，剩余物中加入饱和碳酸氢钠水溶液(20mL)，，用乙酸乙酯(8mL X 3)萃取。合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，所得得粗品用快速硅胶柱(20～90％乙酸乙酯/石油醚)纯化得化合物3-4(60.00mg,收率55.4％)。MS(ESI)m/z:509.3(M+H+).
步骤4:化合物WX-264的合成
在室温下，将化合物3-4(60.00mg,117.99umol)溶于四氢呋喃(2.00mL)和水(500.00uL)中，加入氢氧化钠(23.60mg,589.95umol).反应液60℃反应过夜.将反应液减压浓缩，然后加入1M HCl调节至pH＝6,得化合物WX-264(50.00mg,收率88.20％)。1H NMR(400MHz,CHLOROFORM-d)δ8.65(dd,J＝2.89,8.41Hz,1H),8.54-8.58(m,1H),8.42(s,1H),8.23(s,1H),5.01(br d,J＝6.78Hz,1H),4.00(s,3H),2.85(d,J＝6.78Hz,1H),2.15(br s,1H),2.04(br s,1H),1.82-2.00(m,3H),1.63-1.80(m,3H),1.55(br d,J＝12.80Hz,2H).MS(ESI)m/z:481.2(M+H+).
参照实施例3中步骤1～3的合成方法，合成下表中各实施例。
Figure PCTCN2017100461-appb-000088
实施例4
Figure PCTCN2017100461-appb-000089
合成路线：
Figure PCTCN2017100461-appb-000090
步骤1：化合物4-2的合成
在0℃下，将化合物4-1(25.00g,149.73mmol)溶于乙二醇二甲醚(80mL)中，滴加环丙基溴化镁(0.5M,500.10mL)，反应液室温搅拌过夜。然后将反应液冷却至0℃,分别加入三乙胺(15.15g,149.73mmol,20.75mL)的四氢呋喃(30mL)溶液和碘(38.00g,149.73mmol)的四氢呋喃(30mL)溶液，反应液室温搅拌3小时。向反应液中加入乙酸乙酯(1L)，分别用水(300mL X 3)和饱和食盐水(300mL)洗涤，用无水硫酸钠干燥，过滤，减压浓缩，所得得用硅胶柱(石油醚)纯化得化合物4-2(8g，收率25.8％)。
步骤2：化合物4-3的合成
将化合物BB-2(450mg,2.28mmol)和化合物4-2(450mg,2.17mmol)溶于四氢呋喃(5.00mL)中，加入二异丙基乙胺(841.35mg,6.51mmol)，将反应液在55℃搅拌3小时。反应液减压浓缩，所得粗品用快速硅胶柱层析(石油醚：乙酸乙酯＝10：1至5:1)得到化合物4-3(460.00mg,收率57.6％)。
步骤3：化合物4-4的合成
在室温下，将化合物4-3(460.00mg,1.25mmol)和BB-4(1.05g,1.25mmol)溶于2-甲基四氢呋喃(8.00mL)和水(2.00mL)中，分别加入磷酸钾(796.34mg,3.75mmol)，三(二亚苄基丙酮)二钯(114.51mg,125.05umol)和2-双环己基膦-2’,4’,6’-三异丙基联苯(119mg,250umol)，反应液80℃反应过夜.将反应液冷却至室温，加入水(30mL)，然后过滤。滤液用乙酸乙酯(10mL X 3)萃取.合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，所得得粗品用快速硅胶柱(石油醚：乙酸乙酯＝20:1至3:1)纯化得化合物4-4(600mg,收率61％)。MS(ESI)m/z:773.4(M+H+).
步骤4：化合物4-5的合成
在室温下，将化合物4-4(600.00mg,844.11umol)溶于二氯甲烷(6.00mL)中，加入三氟乙酸(962.45mg,8.44mmol)和三乙基氢硅烷(981.53mg,8.44mmol)，反应液室温反应4小时。将反应液减压浓缩，所得得粗品用快速硅胶柱(石油醚：乙酸乙酯＝10:1至2:1)纯化得化合物4-5(350.00mg,收率87.6％)。MS(ESI)m/z:469.2(M+H+).
步骤5：化合物WX-216的合成
在室温下，将化合物4-5(160.00mg,341.52umol)溶于二氧六环(3.00mL)和水(500.00uL)中，加入氢氧化钠(136.61mg,3.42mmol).反应液80℃反应1小时。将反应液减压浓缩，然后加入1M HCl调节至pH＝5,固体析出，过滤，滤饼用水(10mL)洗涤，干燥得WX-216(55.4mg,收率36.5％)。1H NMR(400MHz,METHANOL-d4)δ8.49-8.58(m,2H),4.92(br s,1H),2.78(br d,J＝6.78Hz,1H),2.22-2.31(m,1H),2.11(br s,1H),1.80-2.02(m,4H),1.61-1.77(m,3H),1.44-1.59(m,2H),1.25-1.34(m,3H),1.03-1.11(m,2H)。MS m/z:441.1[M+1]+.
参照实施例4中步骤3～5的合成方法，使用BB-6至BB-10合成下表中各实施例。
Figure PCTCN2017100461-appb-000091
Figure PCTCN2017100461-appb-000092
实施例5
Figure PCTCN2017100461-appb-000093
合成路线：
Figure PCTCN2017100461-appb-000094
步骤1：化合物5-2的合成室温条件下，向5-1(10.30g，153.58mmol)和双联频哪醇硼酸酯(30g，118.14 mmol)的四氢呋喃(150mL)悬浮液中加入甲氧基(环辛二烯)合铱二聚体(3.13g，4.73mmol)和2,9-二甲基-1,10-菲啰啉(984.14mg，4.73mmol)，反应液氮气保护，升温至90℃反应12小时。反应液过滤，滤液减压浓缩，所得粗产品用硅胶层析柱(石油醚：乙酸乙酯＝10:1)纯化到化合物5-2(4.8g,收率：21％)。
步骤2：化合物5-3的合成
室温条件下，向化合物1-1(1g，5.18mmol)和化合物5-1(2.06g，5.7mmol)的四氢呋喃(20.00mL)和水(1mL)中加入1,1′-双(二-叔丁基膦基)二茂铁二氯化钯(337.61mg，518.00μmol)和无水磷酸钾(3.3g，15.54mmol)。反应液氮气保护下升温至50℃搅拌12小时。反应液过滤，滤液减压浓缩，所得粗产品,经薄层层析制备板(石油醚：乙酸乙酯＝5:1)纯化，得化合物5-3(380.00mg，收率17.18％)。
步骤3：化合物5-4的合成
室温条件下，向5-3(380.00mg，967.27umol)和BB-4(977.70mg,1.16mmol)的2-甲基四氢呋喃(5mL)和水(0.5mL)的悬浮液中加入无水磷酸钾(615.97mg，2.90mmol)，2-双环己基膦-2’,4’,6’-三异丙基联苯(92.22mg，193.45μmol)，三(二亚苄基丙酮)二钯(88.57mg,96.73umol)。反应液氮气保护下升温至80℃搅拌12小时。向反应液中加水(20mL),用乙酸乙酯(30mL X 3)萃取，合并有机相并用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗产品用硅胶柱层析(石油醚：乙酸乙酯＝5:1)得到5-4(0.88g，收率60％)。
步骤4：化合物5-5的合成
室温条件下，向化合物5-4(880.00mg，1.20mmol)的二氯甲烷(10.00mL)溶液中加入三乙基硅氢(279.07mg，2.40mmol)和三氟乙酸(136.83mg，1.20mmol)，反应液室温搅拌1小时。将反应液浓缩，用饱和NaHCO3溶液调节pH至8-9，用乙酸乙酯(30mL X 3)萃取，合并的有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，粗品经硅胶柱层析(石油醚：乙酸乙酯＝3:1)得到化合物5-5(360.00mg,收率57.14％)。1H NMR(400MHz,CDOLOFORM–d1)δ8.39–8.55(m,2H),4.85–4.88(m,1H),4.10–4.20(m,2H),2.95–2.97(m,1H),1.16-2.45(m,17H).
步骤5：WX-359，WX-360的合成
室温条件下，将5-5(180.00mg，364.73μmol)溶于四氢呋喃(2.00mL)中，加入三甲基硅醇钾(233.96mg，1.82mmol)。加完后，反应液在40℃下反应12小时。将反应液浓缩，所得粗品用1N盐酸溶液调节pH至5，经制备液相色谱(column:Boston Green ODS 150*30 5u；mobile phase:[water(0.1％TFA)-ACN]；B％:42％-52％,8min)分离得到化合物WX-359(30.00mg，收率：14.19％，保留时间＝0.808min)和化合物WX-360(40.00mg，收率18.93％yield,保留时间＝0.814min)。
Figure PCTCN2017100461-appb-000095
Figure PCTCN2017100461-appb-000096
实施例6
Figure PCTCN2017100461-appb-000097
合成路线：
Figure PCTCN2017100461-appb-000098
步骤1：化合物6-2的合成
在室温下，将化合物2,4-二氯-5-氟嘧啶(1g,5.99mml)溶于乙腈(5.00mL)和水(5.00mL)中，分别加入硝酸银(2.03g,11.98mmol)，2,2-二氟环丙基羧酸(2.19g，17.93mmol)。将反应液升温至80℃,然后滴加过硫酸铵(2.73g,11.98mmol)的水(1mL)溶液，反应液80℃反应过夜，然后加热至100℃反应12小时。将反应液冷却至室温，加入乙酸乙酯(100mL)，有机层分别用水(30mL X 3)和食盐水(30mL)洗涤,硫酸钠干燥，过滤，减压浓缩。粗产品用硅胶柱(石油醚：乙酸乙酯1:0至10:1)纯化得化合物6-2(121mg，收率8.3％)。 1H NMR(400MHz,CDOLOFORM–d1)δ2.98-3.05(m,1H),2.47-2.52(m,1H),1.94-1.98(m,1H).
步骤2：化合物6-3的合成
将化合物BB-2(147mg,0.75mmol)和化合物6-2(121mg,0.49mmol)溶于四氢呋喃(3.00mL)中，加入二异丙基乙胺(193mg,1.49mmol)，将反应液在50℃搅拌1小时。将反应液冷却至室温，加入乙酸乙酯(50mL)，有机层用食盐水(20mL)洗涤,硫酸钠干燥，过滤，减压浓缩。所得粗品用快速硅胶柱层析(石油醚：乙酸乙酯＝20：1至10:1)得到化合物6-3(132.00mg,收率65.6％)。
步骤3：化合物6-4的合成
在室温下，将化合物6-3(130mg,0.32mmol)和BB-4(195g,0.39mmol)溶于2-甲基四氢呋喃(5.00mL)和水(1.00mL)中，分别加入磷酸钾(136.67mg,0.64mmol)，三(二亚苄基丙酮)二钯(14.7mg,16umol)和2-双环己基膦-2’,4’,6’-三异丙基联苯(30.69mg,64.38umol)，反应液80℃反应2小时.将反应液冷却至室温，加入水(30mL)，用乙酸乙酯(10mL X 3)萃取.合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，所得得粗品用快速硅胶柱(乙酸乙酯/石油醚＝5％-15％)纯化得化合物6-4(150mg,收率62.4％)。MS(ESI)m/z:769.4(M+23+).
步骤4：化合物6-5的合成
在室温下，将化合物6-4(150.00mg,200.86umol)溶于二氯甲烷(3.00mL)中，加入三氟乙酸(229.02mg,2.01mmol)和三乙基氢硅烷(116.78mg,0.16mmol)，反应液室温反应过夜。将反应液减压浓缩，所得得粗品用快速硅胶柱(乙酸乙酯/石油醚＝10％-30％)纯化得化合物6-5(50.00mg,收率50％)。MS(ESI)m/z:505.1(M+H+).
步骤5：化合物WX-297的合成
在室温下，将化合物6-5(50.00mg,99.11umol)溶于二氧六环(2.00mL)和水(1mL)中，加入氢氧化钠(19.82mg,0.49mmol).反应液80℃反应1小时。将反应液减压浓缩，然后加入1M HCl调节至pH＝5,用乙酸乙酯(10mL X 3)萃取.合并有机相，用无水硫酸钠干燥，减压浓缩得WX-297(30mg,收率60.4％)。1H NMR(400MHz,METHANOL-d4)δ8.57-8.67(m,1H),8.53(d,J＝1.76Hz,1H),4.94(br d,J＝6.78Hz,2H),3.04-3.15(m,1H),2.80(br d,J＝6.78Hz,1H),2.64-2.75(m,1H),2.12(br s,1H),1.78-2.06(m,7H),1.60-1.78(m,4H),1.49-1.60(m,2H).MS m/z:477.2[M+1]+.
生物部分
流感病毒细胞病变(CPE)实验
通过测定化合物的半数有效浓度(EC50)值来评价化合物对流感病毒(Influenza virus,IFV)的抗病毒活性。细胞病变实验被广泛用于测定化合物对病毒感染细胞的保护作用来反映化合物的抗病毒活性。
流感病毒CPE实验
将MDCK细胞(ATCC,货号CCL-34)以2,000-3,000细胞每孔的密度种入黑色384孔细胞培养板中，随后置于37℃，5％CO2培养箱中培养过夜。化合物由Echo555非接触式纳升级声波移液系统进行稀释并加入到细胞孔内(3倍倍比稀释，8个测试浓度点)。流感病毒A/Weiss/43(H1N1)株(ATCC,货号VR-96)随后以每孔1-290％组织培养感染剂量(TCID90)加入细胞培养孔中，培养基中DMSO终浓度为0.5％。设置病毒对照孔(加入DMSO和病毒，不加化合物)，和细胞对照孔(加入DMSO，不加化合物和病毒)。细胞板置于37℃，5％CO2培养箱中培养5天。培养5天后使用细胞活力检测试剂盒CCK8检测细胞活性。原始数据用于化合物抗病毒活性计算。
化合物的抗病毒活性由化合物对病毒引起的细胞病毒效应的抑制率(％)表示。计算公式如下：
Figure PCTCN2017100461-appb-000099
使用GraphPad Prism软件对化合物的抑制率进行非线性拟合分析，得到化合物的EC50值。实验结果见表1。
表-1
化合物 EC50(nM) 化合物 EC50(nM)
WX-139 0.02 WX-231 0.2
WX-156 0.01 WX-236 0.01
WX-160 0.5 WX-240 0.03
WX-186 0.1 WX-241 0.01
WX-234 0.1 WX-245 4
WX-230 0.1 WX-294 0.1
WX-247 56.6 WX-295 0.013
WX-249 0.009 WX-296 1
WX-254 0.2 WX-298 6.7
WX-258 0.04 WX-352 0.046
WX-260 1.1 WX-261 0.018
WX-263 1.5 WX-264 0.1
WX-275 0.009 WX-265 2.8
WX-276 3.6 WX-269 0.019
WX-278 2.7 WX-271 0.057
WX-279 0.025 WX-280 0.055
WX-281 0.026 WX-216 0.013
WX-283 0.4 WX-297 0.024
WX-284 10 WX-351 0.2
WX-285 32 WX-353 0.039
WX-286 3.7 WX-354 4.4
WX-288 2.3 WX-355 0.04
WX-289 0.1 WX-358 0.6
WX-290 0.041 WX-359 0.09
WX-293 8 WX-360 0.2
    WX-274 0.1
结果与讨论：本发明化合物，在细胞水平抑制流感病毒复制试验中展示出积极效应
实验例2：体内药效研究
评价化合物在甲型流感病毒H1N1小鼠感染模型中的药效
小鼠经滴鼻感染甲型流感病毒H1N1(Virapur公司，货号：F1003A)，感染后36小时开始用化合物处理，口服给药，连续7天，每天两次。通过观察小鼠体重变化及存活率，来评价化合物在该模型中的抗甲型流感病毒H1N1作用。
实验选用SPF级别的BALB/c小鼠(上海灵畅生物科技有限公司)，6-7周，雌性。小鼠到达BSL-2动物房后适应至少3天后开始实验。将感染当天设为实验第0天。小鼠经戊巴比妥钠腹腔注射麻醉(75mg/kg,10ml/kg)，待动物进入深麻状态后，经滴鼻感染H1N1A/WSN/33病毒，感染体积为50ul。从第1天至第7天，每天口服给予10mg/kg(给药体积10ml/kg)待测化合物，每天两次。首次给药时间为感染后36小时。每天观察小鼠状态，并记录小鼠体重及存活率。在第14天时，将所有存活动物进行安乐死。
检测动物存活率及体重下降率，如下表所示：化合物WX-231在第9天可以实现保护动物体重下降率为12.9％，存活率为100％，化合物WX-216在第9天可以实现保护动物体重下降率为4.8％，存活率为100％，WX-279在第9天可以实现保护动物体重下降率为28.7％，存活率为100％，WX-290在第9天可以实现保护动物体重下降率为27.6％，存活率为40％，WX-297在第9天可以实现保护动物体重下降率为27.3％，存活率为100％，WX-351在第9天可以实现保护动物体重下降率为35.3％，存活率为100％。实验结果见表-2。
表-2
化合物 体重下降率(第9天) 存活率(百分比)
WX-231 12.9％ 100％
WX-216 4.8％ 100％
WX-279 28.7％ 100％
WX-290 27.6％ 40％
WX-297 27.3％ 100％
WX-351 35.3％ 20％

Claims (21)

  1. 式(Ⅰ)所示化合物或其药学上可接受的盐，
    Figure PCTCN2017100461-appb-100001
    其中，
    R1选自任选被1、2或3个R或R’取代的：C1-6烷硫基、5～6元杂芳基、C2-6炔基、C3-6环烷基；
    T1选自N或CH；
    T2选自N或C(R2)；
    R2选自H、F、Cl、Br、I；
    R3选自H、卤素、CN、NH2、OH，或选自任选被1、2或3个R或R’取代的：C1-6烷基；
    R选自卤素、OH、NH2、CN、COOH、
    Figure PCTCN2017100461-appb-100002
    或选自任选被1、2或3个R’取代的：C1-6烷基、C1-6杂烷基、C3-6环烷基、3～6元杂环烷基、3～6元杂环烷基-C(＝O)-、3～6元杂环烷基-(CH2)1-3-；
    R’选自：F、Cl、Br、I、CN、OH、NH2、COOH、Me、NHCH3、N(CH3)2、
    Figure PCTCN2017100461-appb-100003
    所述5～6元杂芳基、C1-6杂烷基、C3-6环烷基、3～6元杂环烷基之“杂”选自：N、-S-、-O-、-NH-；
    以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R选自：F、Cl、Br、I、OH、NH2、CN、COOH、
    Figure PCTCN2017100461-appb-100004
    或选自任选被1、2或3个R’取代的：C1-3烷基、C1-3杂烷基、C3-6环烷基、3～6元杂环烷基、3～6元杂环烷基-C(＝O)-、3～6元杂环烷基-CH2-。
  3. 根据权利要求2所述化合物或其药学上可接受的盐，其中，R选自：F、Cl、Br、I、OH、NH2、CN、COOH、
    Figure PCTCN2017100461-appb-100005
    或选自任选被1、2或3个R’取代的：Me、Et、C1-3烷硫基、C3-6环烷基、吖丁啶基、吡咯烷基、哌嗪基、吗啉基、哌嗪基-C(＝O)-、吗啉基-C(＝O)-、吡咯烷基-C(＝O)-、哌嗪基-CH2-、吗啉基-CH2-、吡咯烷基-CH2-。
  4. 根据权利要求3所述化合物或其药学上可接受的盐，其中，R选自：F、Cl、Br、I、OH、NH2、CN、COOH、
    Figure PCTCN2017100461-appb-100006
    或选自任选被1、2或3个R’取代的：Me、Et、
    Figure PCTCN2017100461-appb-100007
    Figure PCTCN2017100461-appb-100008
  5. 根据权利要求4所述化合物或其药学上可接受的盐，其中，R选自：F、Cl、Br、I、OH、NH2、Me、Et、CN、COOH、
    Figure PCTCN2017100461-appb-100009
    Figure PCTCN2017100461-appb-100010
  6. [根据细则91更正 22.11.2017]　
    根据权利要求1～5任意一项所述化合物或其药学上可接受的盐，其中，R1选自任选被1、2或3个R或R’取代的：C1-3烷硫基、C2-4炔基、C3-5环烷基。
  7. [根据细则91更正 22.11.2017]　
    根据权利要求7所述化合物或其药学上可接受的盐，其中，R1选自任选被1、2或3个R或R’取代的：
    Figure PCTCN2017100461-appb-100011
    Figure PCTCN2017100461-appb-100012
  8. [根据细则91更正 22.11.2017]　
    根据权利要求8所述化合物或其药学上可接受的盐，其中，R1选自：
    Figure PCTCN2017100461-appb-100013
    Figure PCTCN2017100461-appb-100014
  9. [根据细则91更正 22.11.2017]　
    根据权利要求1～5任意一项所述化合物或其药学上可接受的盐，其中，R1选自任选被1、2或3个R或R’取代的：吡啶基、吡唑基、咪唑基、噻吩基、恶唑基、异恶唑基。
  10. [根据细则91更正 22.11.2017]　
    根据权利要求10所述化合物或其药学上可接受的盐，其中，R1选自任选被1、2或3个R或R’取代的：
    Figure PCTCN2017100461-appb-100015
  11. [根据细则91更正 22.11.2017]　
    根据权利要求11所述化合物或其药学上可接受的盐，其中，R1选自：
    Figure PCTCN2017100461-appb-100016
    Figure PCTCN2017100461-appb-100017

    Figure PCTCN2017100461-appb-100018
  12. [根据细则91更正 22.11.2017]　
    根据权利要求9或12所述化合物或其药学上可接受的盐，其中，R1选自：
    Figure PCTCN2017100461-appb-100019
    Figure PCTCN2017100461-appb-100020
  13. [根据细则91更正 22.11.2017]　
    根据权利要求1～5任意一项所述化合物或其药学上可接受的盐，其中，T2选自：N、CH或C(F)。
  14. [根据细则91更正 22.11.2017]　
    根据权利要求1～5任意一项所述化合物或其药学上可接受的盐，其中，R3选自H、卤素、CN、NH2、OH，或选自任选被1、2或3个R或R’取代的：C1-3烷基。
  15. [根据细则91更正 22.11.2017]　
    根据权利要求15所述化合物或其药学上可接受的盐，其中，R3选自H、F、Cl、Br、I、CN、NH2、OH，或选自任选被1、2或3个R或R’取代的：Me、Et。
  16. [根据细则91更正 22.11.2017]　
    根据权利要求16所述化合物或其药学上可接受的盐，其中，R3选自H、F、Cl、Br、I、CN、NH2、OH、 Me、Et、CF3。
  17. [根据细则91更正 22.11.2017]　
    根据权利要求1～5任意一项所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2017100461-appb-100021
    选自
    Figure PCTCN2017100461-appb-100022
  18. [根据细则91更正 22.11.2017]　
    根据权利要求1～18任意一项所述化合物或其药学上可接受的盐，其选自：
    Figure PCTCN2017100461-appb-100023
    其中，R1、R3如权利要求1～18所定义。
  19. [根据细则91更正 22.11.2017]　
    下式所示化合物或其药学上可接受的盐，其选自：
    Figure PCTCN2017100461-appb-100024
    Figure PCTCN2017100461-appb-100025
    Figure PCTCN2017100461-appb-100026
  20. [根据细则91更正 22.11.2017]　
    根据权利要求20所述化合物或其药学上可接受的盐，其选自：
    Figure PCTCN2017100461-appb-100027
    Figure PCTCN2017100461-appb-100028
    Figure PCTCN2017100461-appb-100029
  21. [根据细则91更正 22.11.2017]　
    根据权利要求1～21任意一项所述的化合物或其药学上可接受的盐在制备治疗抗流感病毒药物中的应用。
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CN111454166A (zh) * 2019-12-30 2020-07-28 广东莱佛士制药技术有限公司 制备(2s,3s)-3-氨基-二环[2.2.2]辛烷-2-甲酸酯的方法
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US10647693B2 (en) 2016-08-30 2020-05-12 North & South Brother Pharmacy Investment Company Limited Inhibitors of influenza virus replication, application methods and uses thereof
US10987354B2 (en) 2016-12-15 2021-04-27 Sunshine Lake Pharma Co., Ltd. Inhibitors of influenza virus replication and uses thereof
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TWI794433B (zh) * 2018-03-05 2023-03-01 大陸商廣東衆生睿創生物科技有限公司 吡啶并吡唑類化合物的晶型、鹽型及其製備方法
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US11535613B2 (en) 2018-03-05 2022-12-27 Guangdong Raynovent Biotech Co., Ltd. Crystal form and salt form of pyridoimidazole compound and preparation method therefor
CN111819177B (zh) * 2018-03-05 2022-03-04 广东众生睿创生物科技有限公司 一种吡啶并咪唑类化合物的晶型、盐型及其制备方法
CN110590768A (zh) * 2018-06-13 2019-12-20 银杏树药业(苏州)有限公司 杂环化合物、其组合物及其作为抗流感病毒药物的应用
CN110590768B (zh) * 2018-06-13 2021-02-26 银杏树药业(苏州)有限公司 杂环化合物、其组合物及其作为抗流感病毒药物的应用
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CN114502150A (zh) * 2019-09-10 2022-05-13 广东众生睿创生物科技有限公司 一种用于治疗病毒性感冒的药物组合物及其制剂
CN114502150B (zh) * 2019-09-10 2023-03-24 广东众生睿创生物科技有限公司 一种用于治疗病毒性感冒的药物组合物及其制剂
CN111454166B (zh) * 2019-12-30 2021-02-26 广东莱佛士制药技术有限公司 制备(2s,3s)-3-氨基-二环[2.2.2]辛烷-2-甲酸酯的方法
CN111454166A (zh) * 2019-12-30 2020-07-28 广东莱佛士制药技术有限公司 制备(2s,3s)-3-氨基-二环[2.2.2]辛烷-2-甲酸酯的方法
WO2021175173A1 (zh) * 2020-03-06 2021-09-10 广东众生睿创生物科技有限公司 一种用于治疗流感的药物组合物及含有该药物组合物的制剂
WO2022089261A1 (zh) * 2020-10-29 2022-05-05 广东众生睿创生物科技有限公司 一种嘧啶衍生物的晶型及其制备方法
CN116323593A (zh) * 2020-10-29 2023-06-23 广东众生睿创生物科技有限公司 一种嘧啶衍生物的晶型及其制备方法

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