WO2019001461A1 - Irak4抑制剂 - Google Patents

Irak4抑制剂 Download PDF

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Publication number
WO2019001461A1
WO2019001461A1 PCT/CN2018/093090 CN2018093090W WO2019001461A1 WO 2019001461 A1 WO2019001461 A1 WO 2019001461A1 CN 2018093090 W CN2018093090 W CN 2018093090W WO 2019001461 A1 WO2019001461 A1 WO 2019001461A1
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compound
acid
group
pharmaceutically acceptable
synthesis
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PCT/CN2018/093090
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English (en)
French (fr)
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张杨
王一恺
陈琳琳
周丽莉
方勇波
冯韬
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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Publication of WO2019001461A1 publication Critical patent/WO2019001461A1/zh

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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
    • A61K31/435—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems

Definitions

  • the present invention relates to a class of IRAK4 inhibitors and their use in the manufacture of a medicament for the treatment of diseases associated with IRAK4. Specifically, it relates to a compound of the formula (I) and a pharmaceutically acceptable salt thereof.
  • Interleukin-1 receptor kinase 4 is a serine/threonine-specific protein kinase belonging to the tyrosine-like kinase (TLK) family of interleukin-1, 18, 33 receptors and Toll-like receptors.
  • TLK tyrosine-like kinase
  • the extracellular signal molecule binds to the interleukin receptor or Toll-like receptor, it recruits to form the MyD88:IRAK4:IRAK1/2 polyprotein complex, which leads to phosphorylation of IRAK1/2, mediating a series of downstream signaling, thereby activating p38 and JNK.
  • the NF-kB signaling pathway ultimately leads to the expression of pro-inflammatory cytokines.
  • IRAK4 has become an important therapeutic target and has attracted a wide range of research and development interests.
  • the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof,
  • n is selected from: 1 or 2;
  • n is selected from: 0, 1, 2 or 3;
  • R 1 is selected from H, CN, OH, or selected from those optionally substituted by R
  • R 2 is selected from the group consisting of: H, F, Cl, Br, I;
  • R 3 is selected from OH, NH 2 , CN, halogen, or selected from C 1 1-3 alkyl, C 1-3 heteroalkyl optionally substituted by 1, 2 or 3 R;
  • L is selected from the group consisting of: a single bond, -CH 2 -, -CH 2 CH 2 -;
  • L 1 is selected from: O or NH
  • Ring A is selected from a 4-6 membered heterocycloalkyl group
  • R is selected from F, Cl, Br, I, OH, NH 2 , CN, or selected from: C 1-3 alkyl, C 1-3 heteroalkyl optionally substituted by 1, 2 or 3 R';
  • R' is selected from the group consisting of: F, Cl, Br, I, OH, NH 2 , CN, CF 3 ;
  • hetero of the C 1-3 heteroalkyl group and the 4-6 membered heterocycloalkyl group are each independently selected from: N, O, S, NH;
  • the number of the above heteroatoms or heteroatoms is independently selected from 1, 2, 3 or 4.
  • R is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, or selected from the group consisting of 1, 2 or 3 R' substitutions: Me, Et, R' The invention is defined.
  • the above R is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Et,
  • R 1 is selected from the group consisting of: H, CN, OH,
  • the structural unit Selected from: H, CN, OH, R 1 is as defined in the present invention.
  • the structural unit From:
  • the ring A is selected from the group consisting of morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl.
  • R 3 is selected from the group consisting of OH, NH 2 , CN, halogen, or selected from the group consisting of 1, 2 or 3 R: Me, Et, -NHCH 3 , R, as in the present invention definition.
  • R 3 is selected from the group consisting of OH, NH 2 , CN, F, Cl, Br, I, Me, Et, -NHCH 3 ,
  • the structural unit From: R 3 and m are as defined by the present invention.
  • the structural unit From:
  • the two R 3s are connected together, the structural unit Selected from
  • the above R is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, or selected from the group consisting of 1, 2 or 3 R' substitutions: Me, Et, other variables such as As defined above.
  • the above R is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Et, Other variables are as defined above.
  • R 1 is selected from the group consisting of: H, CN, OH, Other variables are as defined above.
  • the above ring A is selected from the group consisting of morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, and other variables are as defined above.
  • R 3 is selected from the group consisting of OH, NH 2 , CN, halogen, or selected from the group consisting of: 1, 2 or 3 R: Me, Et, -NHCH 3 , other variables as described above definition.
  • R 3 is selected from the group consisting of OH, NH 2 , CN, F, Cl, Br, I, Me, Et, -NHCH 3 , Other variables are as defined above.
  • the two R 3s are connected together, 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
  • the present invention also provides a compound of the formula: or a pharmaceutically acceptable salt thereof:
  • the above compound, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above composition for the preparation of a medicament for treating IRAK4.
  • 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 acids 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 of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of one another.
  • cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate a single bond due to a double bond or a ring-forming carbon atom.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirrored relationship.
  • wedge-shaped dashed keys Represents the absolute configuration of a solid center with straight solid keys
  • straight dashed keys Indicates the relative configuration of the stereocenter, using wavy lines Indicates a wedge solid key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid key And straight dashed keys
  • tautomer or “tautomeric form” mean that the different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. If tautomers are possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions by proton transfer, such as keto-enol isomerization and imine-enes. Amine isomerization.
  • the valence tautomer includes the mutual transformation of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms "enriched in one isomer”, “isomer enriched”, “enriched in one enantiomer” or “enantiomeric enriched” refer to one of the isomers or pairs
  • the content of the oligo is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or greater than or equal to 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomeric excess (ee value) is 80%. .
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Oxygen substitution does not occur on the aromatic group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • a substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A.
  • the substituent can be attached to more than one atom on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit. It is indicated that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene.
  • substituents When the listed substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group.
  • the medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B. It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • 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 hetero atom 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 (i.e., 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, benzofurylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl, ind
  • heteroalkyl by itself or in conjunction with another term denotes 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.
  • a heteroatom or heteroatom can be located at any internal position of a heteroalkyl group, including where the heteroalkyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thio) Alkoxy) is a conventional expression and refers to those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Examples include, but are not limited to, -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 , -CH 2 -S -CH 2 -CH 3 , -CH 2 -CH 2 , -S(O)-CH 3 , -CH 2 -CH 2 -S(O) 2 -CH 3 .
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • heterocycloalkyl a heteroatom
  • heterocycloalkyl groups include, but are not limited to, 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.
  • 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.
  • 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
  • the invention obtains a series of 4 fused ring compounds with greatly improved permeability and improved metabolic stability, and has better drug properties and higher kinase selectivity.
  • a solution of the compound A1-3 (90 g, 304.72 mmol, 1.00 eq) of formamide (395.50 g, 8.78 mol, 350.00 mL, 28.82 eq) was placed in an oil bath at 180 ° C for 24 hours. After the reaction was completed, the reaction solution was lowered. To the room temperature, slowly add water (400 mL) and ethyl acetate (200 mL), stir well, and then stand to separate the layers. After liquid separation, the aqueous phase was extracted with ethyl acetate (150 mL ⁇ 5) for 5 times, and the organic phase was combined.
  • reaction mixture was cooled to room temperature, and then added with 20 mL of brine, and the mixture was combined with ethyl acetate (20 mL ⁇ 3), and the organic phase was combined, and the organic phase was washed with saturated brine (20 mL ⁇ 2) Filtration and removal of the filtrate by rotary evaporation under reduced pressure afforded crude material.
  • Diisopropylethylamine (12.60 g, 97.47 mmol, 16.98 mL, 1.5 eq) was added sequentially to a solution of compound WX001-4 (5.8 g, crude) in N,N-dimethylformamide (300 mL) HATU (37.06 g, 97.47 mmol, 1.5 eq) and aqueous ammonia (11.39 g, 97.47 mmol, 12.51 mL, 1.5 eq). After the reaction was completed, 150 mL of water was added to the reaction solution to quench the reaction, and the quenched reaction liquid was evaporated under reduced pressure to remove the solvent to obtain a crude product.
  • HATU 54.91 mg, 144.40 umol, 2.00 eq
  • 2,2,2-trifluoroethylamine 14.30 mg, 144.40 umol, 11.35 uL, 2.00 eq
  • WX001-4 30.00 mg
  • acetonitrile 1.00mL
  • the crude product was prepared by high performance liquid chromatography column (column: Boston Green ODS 150*30) 5u; mobile phase: [water (0.1% trifluoroacetic acid)-ACN]; B%: 18%-48%, 8 min) isolated WX002.
  • the compound W1003 was synthesized from the intermediates A1 and B5.
  • the compound WX004-1 was synthesized from the intermediates A1 and B6, and subjected to preparative liquid chromatography (column: Boston Green ODS 150 mm*30 mm 5 ⁇ m; mobile phase: [water (0.1% trifluoroacetic acid)- ACN]; B%: 28%-38%, 8min) After separation, most of the products were tested as WX004, and the separated solution was concentrated under reduced pressure, then 1 drop of trifluoroacetic acid was added, stirred for 1 hour, and then decompressed again. The solvent was removed by rotary evaporation to give WX004.
  • Triethylamine (464.47 mg, 4.59 mmol, 636.26 uL, 2.00 eq), 4-dimethylaminopyridine (28.04 mg, 229.50 umol, 0.10 eq) and p-toluenesulfonyl chloride (656.32 mg, 3.44 mmol) at 0 °C , 1.50 eq) was added to a solution of WX005-1 (580.00 mg, 2.30 mmol, 1.00 eq) in dichloromethane (1 mL), and the reaction mixture was slowly warmed to room temperature. After stirring for 2 hours, the reaction solution was poured into 3 mL of 0.5 M.
  • WX008 was synthesized using the intermediates A1 and B7 as raw materials.
  • the crude product was separated by high performance liquid chromatography (column: Phenomenex Synergi C18 150mm*25mm*10 ⁇ m; mobile phase: water (0.1% trifluoroacetic acid)-ACN]; B%: 9%-39%, 13min), and WX011 was obtained.
  • Zinc powder (3.19 g, 48.72 mmol, 2.00 eq) and triethyl chlorosilane (8.00 g, 53.10 mmol, 8.99 mL, 2.18 eq) were sequentially added to 20 mL of acetonitrile at -20 ° C and stirred for 10 minutes.
  • Ethyl dibromofluoroacetate (16.07 g, 60.90 mmol, 2.50 eq) was added to the reaction mixture.
  • 2-cyclopenten-1-one (2.00 g, 24.36 mmol, 2.04 mL, 1.00 eq. ) was added to the reaction solution.
  • Phosphorus oxychloride (941.97 mg, 6.14 mmol, 570.89 ⁇ L, 3.5 eq) was added to compound WX012-3 (0.55 g, 1.76 mmol, 1 eq) and formamide (5.65 g, 125.44 mmol, 5 mL). In a mixture of 71.47 eq), the temperature was slowly raised to 25 ° C and stirred for 12 hours. After the reaction was completed, the reaction solution was poured into water (10 mL), and the pH was adjusted to 9 with a saturated sodium hydrogen carbonate solution, and extracted with ethyl acetate (10 mL ⁇ 3) three times, and the organic phase was combined, and the mixture was washed with saturated brine.
  • the aqueous phase was adjusted to pH 2 with dilute hydrochloric acid (1M), and ethyl acetate (10 mL ⁇ 4) The extraction was carried out four times, and the aqueous phase was evaporated to remove the solvent by evaporation under reduced pressure to give compound WX ⁇ /RTI> ⁇ / RTI> ⁇ / RTI> ⁇ / RTI> ⁇ RTIgt;
  • Diisopropylethylamine (49.76 mg, 385.02 ⁇ mol, 67.24 ⁇ L, 1.50 eq) was added to a solution of compound WX013-2 (110.00 mg, 256.68 ⁇ mol, 1.00 eq) in DMF (3.00 mL).
  • HATU 146.40 mg, 385.02 ⁇ mol, 1.50 eq
  • aqueous ammonia 44.98 mg, 385.02 umol, 49.43 ⁇ L, 1.50 eq
  • the quenched reaction mixture was extracted with ethyl acetate (10 mL ⁇ 8), and the organic phase was combined, and the organic phase was washed with saturated brine (50 mL) Dry over sodium sulfate, filter, and remove the solvent by rotary evaporation under reduced pressure to give a crude material.
  • Example 14 the synthesis was carried out using the intermediate A2, the compound 3,3-difluoropyrrolidine hydrochloride as a starting material.
  • the crude product was separated by preparative high performance liquid chromatography (column: Phenomenex Synergi C18 150*25*10 ⁇ m; mobile phase: [water (0.1% trifluoroacetic acid)-ACN]; B%: 9%-39%, 13 min), and WX014A was obtained. And WX014B.
  • HPLC XBridge C18UPLC column: 3.5um, 3.0 *50mm, method: 10-80CD_4min, retention time: 2.260min
  • HPLC XBridge C18UPLC column: 3.5 ⁇ m, 3.0*50 mm, method: 10-80 CD_4 min, retention time: 2.197
  • Example 14 the intermediate A2 and the compound 4,4-difluoropiperidine were synthesized as raw materials, and the crude product was separated by preparative high performance liquid chromatography (column: Phenomenex Gemini 150*25 mm*10 ⁇ m; mobile phase: [water ( 0.05% ammonia water v/v)-ACN]; B%: 30%-60%, 12min), obtained WX015, and then separated by SFC (column: AD (250mm*30mm, 10 ⁇ m); mobile phase: [0.1% ammonia water methanol ]; B%: 30%-30%, 4min; 100min), obtain WX015-P1&P2, WX015-P3, WX015-P4, and then separate by SFC (column: AS (250mm*30mm, 5 ⁇ m); mobile phase: [ 0.1% ammonia water methanol]; B%: 30%-30%, 4.4min; 60min), preparative high performance liquid chromatography separation (column: Phenomenex Gemini 150
  • Example 14 the synthesis was carried out using the intermediates A2 and B8 as raw materials, and the crude product was prepared by high performance liquid chromatography (column: Phenomenex Synergi C18 150 mm*25 mm*10 ⁇ m; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile) ]; B%: 16%-43%, 12 min) WX016 was obtained after separation.
  • Test Example 1 In vitro evaluation
  • Buffer conditions 20 mM Hepes (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 0.02% Brij 35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO.
  • Test procedure The test compound was dissolved in DMSO at room temperature to prepare a 10 mM solution for use.
  • the substrate is dissolved in a freshly prepared buffer, and the kinase to be tested is added thereto and mixed well.
  • a DMSO solution in which the test compound was dissolved was added to the above mixed reaction solution by an acoustic technique (Echo 550).
  • the concentration of the compound in the reaction mixture was 10 ⁇ M, 3.33 ⁇ M, 1.11 ⁇ M, 0.370 ⁇ M, 0.123 ⁇ M, 41.2 nM, 13.7 nM, 4.57 nM, 1.52 nM, 0.508 nM.
  • the kinase activity data was expressed as an alignment of the kinase activity of the test compound and the kinase activity of the blank group (DMSO only), and the IC50 value was obtained by curve fitting by Prism4 software (GraphPad), and the experimental results are shown in Table 2.
  • Table 1 Information on kinases, substrates and ATP in in vitro assays.
  • the compounds of the invention exhibit good inhibitory activity against IRAK4.
  • Human liver microsomes were purchased from BD and mouse liver microsomes were purchased from Xenotech. Positive controls were testosterone (3A4 substrate), propafenone (2D6 substrate) and diclofenac (2C9 substrate).
  • the test compound and the positive drug were incubated at a concentration of 1 ⁇ M, and were incubated with liver microparticles at 37 ° C, and the liver microsomal protein concentration was 0.5 mg/ml. After incubation for 0, 5, 10, 20, 30 and 60 minutes, respectively, a cold acetonitrile containing an internal standard was added to stop the reaction. The test compound and the microsomes were incubated for 60 minutes without the action of the NADPH regeneration system. Samples were analyzed by LC/MS/MS and the elimination of the compounds was evaluated by the peak area ratio of the analyte to the internal standard.
  • Test Example 3 Two-way permeability study of MDR1-MDCK cells
  • MDR1-MDCKII cells introduced from the Netherlands Cancer Institute (NKI) were used, and the cells were seeded at BD Falcon's Transwell-96 well plate at a density of 2.3 ⁇ 10 5 cells/cm 2 and placed in a carbon dioxide culture incubator. The medium was cultured for 4 to 7 days and used for experiments.
  • test compound was diluted to 2 ⁇ M with 10 mM DSMO stock solution in HBSS transport buffer and used on the apical or basal side of the monolayer.
  • the permeability of the compound from the top side to the substrate side or from the substrate side to the top side was tested using a two sample.
  • the positive drug digoxin was also tested for permeability from the apical side to the basal side or from the basal side to the apical side at an incubation concentration of 2 ⁇ M, but not from the apical side to the basal side when the incubation concentration was 2 ⁇ M for Norbert and Propranolol. Permeability.
  • the cell plates were incubated for 150 minutes in a cell incubator at 37 ⁇ 1 ° C, 5% CO 2 and saturated relative humidity. In addition, the efflux ratio of the test compound was simultaneously tested. Semi-quantitative analysis of the test substance and the reference compound was carried out by LC-MS/MS method based on the peak area ratio of the analyte and the internal standard.
  • the integrity of the MDR1-MDCK II cell membrane was measured using a Lucifer Yellow Rejection Assay.
  • the buffer at the top side and the base side was removed, then 75 ⁇ L of 100 ⁇ M fluorescent yellow buffer was added, and 250 ⁇ L of HBSS transport buffer was added to the top side and the base side, respectively.
  • the relative fluorescence unit (RFU) of the fluorescent yellow in the sample was detected at the 425/528 nm (excitation/emission) spectrum using an M2 e plate reader.
  • dC r /d t is the cumulative concentration of the compound at the receiving end per unit time ( ⁇ M/s); the volume of the solution at the receiving end of Vr (the volume of the solution at the top and the base end are 0.075 and 0.25 mL, respectively; A is the relative surface area of the cell monolayer ( 0.0804 cm 2 ); C 0 is the initial concentration (nM) of the test article at the drug delivery end or the peak area ratio of the control.
  • the efflux is calculated using the following formula:
  • the recovery rate is calculated using the following formula:
  • C 0 is the initial concentration (nM) of the test end or the peak area ratio of the control
  • V d is the volume of the drug end (0.075 mL on the top side and 0.25 mL on the basal side)
  • C d and C r The final concentration (nM) of the test sample and the peak area ratio of the reference substance for the drug delivery end and the receiving end, respectively.
  • Test Example 4 Study on pharmacokinetic parameters
  • mice Six healthy adult female Lewis rats (7-9 weeks old, purchased from pharmacokinetic parameters) were selected, 3 were intravenous injection group, and 3 were oral group.
  • the candidate compound was mixed with an appropriate amount of intravenous vehicle (5% dimethyl sulfoxide + 10% HP- ⁇ -CD + 0.5% sodium carboxymethylcellulose + 84.5% deionized water), vortexed and sonicated to prepare 0.5
  • the clear solution was mg/mL, and the microporous membrane was filtered and used; the oral medium was 0.5% methylcellulose aqueous solution, and the candidate compound was mixed with the solvent, vortexed and sonicated to prepare a 0.5 mg/mL uniform suspension for use.
  • mice After 1 mg/kg of mice were administered intravenously or 2.5 mg/kg orally, whole blood was collected for a certain period of time, plasma was prepared, and the drug concentration was analyzed by LC-MS/MS method and calculated by Phoenix WinNonlin software (Pharsight, USA). Pharmacokinetic parameters. As shown in Table 5 below:

Abstract

一种IRAK4抑制剂，及其在制备治疗与IRAK4相关疾病的药物中的应用。具体公开了式(Ⅰ)所示化合物及其药学上可接受的盐。(I)

Description

IRAK4抑制剂
相关申请的引用
本申请主张如下优先权：
CN201710502669.4，申请日2017-06-27。
技术领域
本发明涉及一类IRAK4抑制剂，及其在制备治疗与IRAK4相关疾病的药物中的应用。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
白细胞介素1受体激酶4(IRAK4)是一种丝氨酸/苏氨酸特异性蛋白激酶，属于类酪氨酸激酶(TLK)家族成员，是白介素-1、18、33受体和Toll样受体参与的先天性免疫应答中的关键节点。细胞外信号分子与白介素受体或Toll样受体结合后，募集形成MyD88:IRAK4:IRAK1/2多蛋白复合体，导致IRAK1/2磷酸化，介导一系列下游信号传导，从而激活p38、JNK和NF-kB信号通路，最终导致前炎症细胞因子的表达。临床病理学研究表明，具有IRAK4突变的个体对慢性肺病、炎症性肠病有防护作用。IRAK4缺陷本身无致死性，个体能够存活至成年，且随年龄增长受感染风险降低。因此，IRAK4成为了一类重要治疗靶点，吸引了广泛的研发兴趣。
WO2013106535专利中报道了一系列对IRAK4有抑制活性的化合物，包括参考例1。
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 PCTCN2018093090-appb-000001
其中，
n选自：1或2；
m选自：0、1、2或3；
R 1选自H、CN、OH，或选自任选被R取代的
Figure PCTCN2018093090-appb-000002
R 2选自：H、F、Cl、Br、I；
R 3选自OH、NH 2、CN、卤素，或选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3杂烷基；
或者，两个R 3连接在一起，形成一个3～6元环；
L选自：单键、-CH 2-、-CH 2CH 2-；
L 1选自：O或NH；
环A选自4～6元杂环烷基；
R选自F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：C 1-3烷基、C 1-3杂烷基；
R’选自：F、Cl、Br、I、OH、NH 2、CN、CF 3；
所述C 1-3杂烷基、4～6元杂环烷基之“杂”分别独立地选自：N、O、S、NH；
上述杂原子或杂原子团的数目分别独立地选自1、2、3或4。
本发明的一些方案中，上述R选自F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：Me、Et，R'如本发明所定义。
本发明的一些方案中，上述R选自F、Cl、Br、I、OH、NH 2、CN、Me、CF 3、Et、
Figure PCTCN2018093090-appb-000003
Figure PCTCN2018093090-appb-000004
本发明的一些方案中，上述R 1选自：H、CN、OH、
Figure PCTCN2018093090-appb-000005
Figure PCTCN2018093090-appb-000006
本发明的一些方案中，上述结构单元
Figure PCTCN2018093090-appb-000007
选自：H、CN、OH、
Figure PCTCN2018093090-appb-000008
Figure PCTCN2018093090-appb-000009
R 1如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018093090-appb-000010
选自：
Figure PCTCN2018093090-appb-000011
本发明的一些方案中，上述环A选自：吗啉基、哌啶基、吖丁啶基、吡咯烷基。
本发明的一些方案中，上述R 3选自OH、NH 2、CN、卤素，或选自任选被1、2或3个R取代的：Me、Et、-NHCH 3，R如本发明所定义。
本发明的一些方案中，上述R 3选自OH、NH 2、CN、F、Cl、Br、I、Me、Et、-NHCH 3、
Figure PCTCN2018093090-appb-000012
本发明的一些方案中，上述结构单元
Figure PCTCN2018093090-appb-000013
选自：
Figure PCTCN2018093090-appb-000014
Figure PCTCN2018093090-appb-000015
R 3和m如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018093090-appb-000016
选自：
Figure PCTCN2018093090-appb-000017
Figure PCTCN2018093090-appb-000018
本发明的一些方案中，上述两个R 3连接在一起，结构单元
Figure PCTCN2018093090-appb-000019
选自
Figure PCTCN2018093090-appb-000020
本发明的一些方案中，上述R选自F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个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R选自F、Cl、Br、I、OH、NH 2、CN、Me、CF 3、Et、
Figure PCTCN2018093090-appb-000021
Figure PCTCN2018093090-appb-000022
其他变量如上述所定义。
本发明的一些方案中，上述R 1选自：H、CN、OH、
Figure PCTCN2018093090-appb-000023
Figure PCTCN2018093090-appb-000024
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 PCTCN2018093090-appb-000025
选自：H、CN、OH、
Figure PCTCN2018093090-appb-000026
Figure PCTCN2018093090-appb-000027
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 PCTCN2018093090-appb-000028
选自：
Figure PCTCN2018093090-appb-000029
其他变量如上述所定义。
本发明的一些方案中，上述环A选自：吗啉基、哌啶基、吖丁啶基、吡咯烷基，其他变量如上述所 定义。
本发明的一些方案中，上述R 3选自OH、NH 2、CN、卤素，或选自任选被1、2或3个R取代的：Me、Et、-NHCH 3，其他变量如上述所定义。
本发明的一些方案中，上述R 3选自OH、NH 2、CN、F、Cl、Br、I、Me、Et、-NHCH 3、
Figure PCTCN2018093090-appb-000030
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 PCTCN2018093090-appb-000031
选自：
Figure PCTCN2018093090-appb-000032
Figure PCTCN2018093090-appb-000033
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 PCTCN2018093090-appb-000034
选自：
Figure PCTCN2018093090-appb-000035
Figure PCTCN2018093090-appb-000036
其他变量如上述所定义。
本发明的一些方案中，上述两个R 3连接在一起，结构单元
Figure PCTCN2018093090-appb-000037
选自
Figure PCTCN2018093090-appb-000038
其他变量如上述所定义。
本发明还有一些方案是由上述变量任意组合而来。
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自：
Figure PCTCN2018093090-appb-000039
Figure PCTCN2018093090-appb-000040
其中，
m、L 1、R 3如上述所定义。
本发明还提供了下式所示化合物或其药学上可接受的盐：
Figure PCTCN2018093090-appb-000041
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 PCTCN2018093090-appb-000043
Figure PCTCN2018093090-appb-000044
Figure PCTCN2018093090-appb-000045
Figure PCTCN2018093090-appb-000046
本发明还提供了一种药物组合物，其含有治疗有效量的上述的化合物或其药学上可接受的盐和药学上可接受的载体。
本发明还提供了上述化合物或其药学上可接受的盐或上述组合物在制备治疗IRAK4相关药物中的应用。
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。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，用楔形实线键
Figure PCTCN2018093090-appb-000047
和楔形虚线键
Figure PCTCN2018093090-appb-000048
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2018093090-appb-000049
和直形虚线键
Figure PCTCN2018093090-appb-000050
表示立体中心的相对构型，用波浪线
Figure PCTCN2018093090-appb-000051
表示楔形实线键
Figure PCTCN2018093090-appb-000052
或楔形虚线键
Figure PCTCN2018093090-appb-000053
或用波浪线
Figure PCTCN2018093090-appb-000054
表示直形实线键
Figure PCTCN2018093090-appb-000055
和直形虚线键
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集” 指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是 A。当一个取代基可以连接到一个环上的一个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元
Figure PCTCN2018093090-appb-000057
表示取代基R可在环己基或者环己二烯上的任意一个位置发生取代。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2018093090-appb-000058
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2018093090-appb-000059
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2018093090-appb-000060
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，“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***基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1H-1,2,3-***基、2H-1,2,3-***基、1H-1,2,4-***基、4H-1,2,4-***基和呫吨基。还包括稠环和螺环化合物。
除非另有规定，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烷基的任何内部位置，包括该杂烷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-CH 2-CH 2-O-CH 3、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(O)-CH 3、-CH 2-CH 2-S(O) 2-CH 3。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。
除非另有规定，术语“杂环烷基”，杂原子可以占据该杂环附着于分子其余部分的位置。杂环烷基的实例包括但不限于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-CH 2F)或多取代的(如-CF 3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如， n-戊基，异戊基，新戊基)等。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C 1-C 4)烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。
“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基，除非另有规定，C 1-6烷氧基包括C 1、C 2、C 3、C 4、C 5和C 6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。
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***-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代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂。
化合物经手工或者
Figure PCTCN2018093090-appb-000061
软件命名，市售化合物采用供应商目录名称。
技术效果：
本发明得到一系列通透性大大提高、代谢稳定性有所改善的4稠环类化合物，成药性质更优，激酶选择性更高。
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：WXR1
Figure PCTCN2018093090-appb-000062
化合物WXR1参照专利WO2012/97013报道的路线合成。LCMS(ESI)m/z:417[M+H] +. 1H NMR(400MHz,氘代甲醇)δ＝8.47(s,1H),5.31-5.23(m,1H),3.82–3.80(m,1H),3.72-3.70(m,4H),3.11-3.02(m,1H),3.01-2.98(m,2H),2.79-2.68(m,1H),2.66-2.54(m,4H),2.41-2.21(m,5H),2.13-1.99(m,2H),1.72-1.42(m,4H).
中间体A1：
Figure PCTCN2018093090-appb-000063
合成路线：
Figure PCTCN2018093090-appb-000064
步骤1：化合物A1-1的合成
室温下，将溴乙酸乙酯(500g,2.99mol,331.13mL,1.00eq)加入到二甲硫醚(215.79g,3.47mol,253.87mL,1.16eq)的丙酮(1000mL)溶液中，搅拌48小时后，有大量白色固体析出，过滤，滤饼用丙酮(2000mL)洗涤，得到化合物A1-1. 1H NMR(400MHz,氘代甲醇)δ:4.58-4.51(m,2H),4.36–4.31(m,2H),3.07–3.01(m,6H),1.36–1.32(m,3H).
步骤2：化合物A1-2的合成
在15℃下，将1.8-二氮杂二环[5.4.0]十一烷-7-烯(166.10g,1.09mol,164.46mL,1.00eq)加入到化合物A1-1(250g,1.09mol,1.00eq)的二氯甲烷(2000mL)溶液中，搅拌30分钟后，再将2-环戊烯酮(89.58 g,1.09mol,91.40mL,1.00eq)加入到反应液中，搅拌反应16小时后，反应结束。反应液加水(1000mL)稀释，用稀盐酸(2M)调节PH至4，分出有机层，水层用二氯甲烷萃取(800mL×3)，合并有机相，有机相用饱和食盐水(1000L×2)洗涤两次，无水硫酸钠干燥，过滤后，滤液通过减压旋转蒸发得粗品。粗品经柱层析分离(洗脱剂：石油醚/乙酸乙酯＝50/1-8/1)得到化合物A1-2. 1H NMR(400MHz,氘代氯仿)δ＝4.19-4.07(m,2H),2.51–2.47(m,1H),2.31-2.16(m,2H),2.16-2.05(m,2H),2.04-1.96(m,2H),1.29-1.20(m,3H).
步骤3：化合物A1-3的合成
室温下，将化合物A1-2(123.5g,734.29mmol,1.00eq)，氰乙酸乙酯(99.67g,881.15mmol,94.03mL,1.20eq)，二乙胺(64.45g,881.15mmol,90.77mL,1.20eq)和升华硫(28.26g,881.15mmol,1.20eq)的乙醇(2000mL)溶液搅拌12小时。反应结束后，将反应液减压浓缩，加入乙酸乙酯(1000mL)和水(2000mL)，用分液漏斗分出有机相，水相用乙酸乙酯萃取(1000mL×2)两次，合并有机相，有机相用饱和食盐水洗涤(1000mL)，无水硫酸钠干燥，过滤，滤液通过减压旋转蒸发除去溶剂得粗品。粗品经柱层析分离(洗脱剂:石油醚/乙酸乙酯＝50/1–5/1)得化合物A1-3. 1H NMR(400MHz,氘代氯仿)δ:5.85(s,2H),4.31-4.23(m,2H),4.17–4.12(m,2H),3.09–3.05(m,1H),3.02-2.97(m,1H),2.90-2.81(m,1H),2.51–2.49(m,1H),1.40-1.34(m,1H),1.33-1.30(m,3H),1.28–1.25(t,J＝7.2Hz,3H).
步骤4：化合物A1-4的合成
将化合物A1-3(90g,304.72mmol,1.00eq)的甲酰胺(395.50g,8.78mol,350.00mL,28.82eq)溶液置于180℃油浴中搅拌24小时，反应结束后，将反应液降至室温，缓慢加入水(400mL)和乙酸乙酯(200mL)中，搅拌均匀后静置分层，分液后，水相用乙酸乙酯(150mL×5)萃取5次，合并有机相，用饱和食盐水洗涤(500mL×2)两次，无水硫酸钠干燥，过滤，滤液减压旋转蒸发除去溶剂，往剩余物中加入乙酸乙酯(200mL)，打浆，过滤除去固体，滤液减压旋转蒸发除去溶剂后得粗品，再经柱层析分离(洗脱剂:石油醚/乙酸乙酯＝10/1-0/1)得到A1-4. 1H NMR(400MHz,氘代氯仿)δ＝12.56(br s,1H),8.04(s,1H),4.29-4.07(m,2H),3.41-3.25(m,2H),3.21-3.05(m,1H),2.81-2.62(m,1H),1.44–1.42(m,1H),1.29(t,J＝7.2Hz,3H).
步骤5：化合物A1的合成
将化合物A1-4(49g,177.34mmol,1.00eq)和三氯氧磷(660.00g,4.30mol,400mL,24.27eq)的混合物置于100℃搅拌反应5小时。反应液通过减压旋转蒸发除去部分三氯氧磷后，加入乙酸乙酯稀释(500mL)，将稀释过的反应液缓慢倒入水中(1000mL)，用固体碳酸钠调节至pH大于7，用分液漏斗分出有机相，水相用乙酸乙酯萃取(300mL)三次,合并有机相，用饱和食盐水洗涤(2000mL)，无水硫酸钠干燥，过滤，滤液通过减压旋转蒸发除去溶剂得粗品。粗品经柱层析分离(洗脱剂:石油醚/乙酸乙酯＝50/1–20/1)得化合物A1. 1H NMR(400MHz,氘代氯仿)δ＝8.76(s,1H),4.24-4.18(m,2H),3.50-3.40 (m,1H),3.36-3.31(m,1H),3.29-3.20(m,1H),2.75(m,1H),1.49-1.44(m,1H),1.29(t,J＝7.2Hz,3H).
中间体A2
Figure PCTCN2018093090-appb-000065
合成路线：
Figure PCTCN2018093090-appb-000066
步骤1：化合物A2-1的合成
在冰水浴条件下，向1,4-环己二酮-乙二醇缩酮(10.00g,64.03mmol,1.00eq)的甲醇溶液中(60.00mL)加入硼氢化钠(3.15g,83.24mmol,1.30eq)，搅拌30分钟后，将反应液缓慢升至25℃，继续搅拌12小时。反应结束后，先将反应液减压浓缩，再加入50mL水将反应淬灭，最后，用二氯甲烷萃取(30mL×3)三次，合并有机相，有机相用饱和食盐水(30mL×2)洗涤两次，用无水硫酸钠干燥，过滤，滤液减压旋转蒸发除去溶剂得A2-1. 1H NMR(400MHz,氘代氯仿)δ＝4.00-3.89(m,4H),3.86-3.76(m,1H),1.93-1.76(m,4H),1.74-1.54(m,4H).
步骤2：化合物A2-2的合成
在冰水浴条件下，向化合物A2-1(1.00g,6.32mmol,1.00eq)和4-二甲氨基吡啶(77.21mg,632.00umol,0.10eq)的吡啶(5.00mL)溶液中加入4-甲基苯磺酰氯(1.81g,9.48mmol,1.50eq)，将反应缓慢升至25℃，搅拌12小时。反应结束后，向反应液中加入稀盐酸(2M,20mL)将反应淬灭，用乙酸乙酯(15mL×3)萃取三次，合并有机相，有机相用饱和食盐水(15mL×2)洗涤两次，用无水硫酸钠干燥，过滤，滤液通过减压旋转蒸发得化合物A2-2. 1H NMR(400MHz,氘代甲醇)δ＝7.80(d,J＝8.0Hz,2H),7.44(d,J＝8.0Hz,2H),4.63–4.58(m,1H),3.98-3.82(m,4H),2.45(s,3H),1.83-1.67(m,6H),1.59-1.46(m,2H).
步骤3：化合物A2-3的合成
室温下，向化合物A2-2(796.57mg,2.55mmol,1.50eq)和碳酸铯(1.38g,4.25mmol,2.50eq)的N,N-二甲基甲酰胺(10.00mL)溶液中加入化合物A1-4(470.00mg,1.70mmol,1.00eq)，将反应加热到90℃，搅拌12小时。反应结束后，将反应液冷却至室温，加入20mL饱和食盐水，用乙酸乙酯(20mL×3)萃取三次，合并有机相，有机相用饱和食盐水洗(20mL×2)，无水硫酸钠干燥，过滤，滤液通过减压旋转蒸发除去溶剂得粗品。粗品经柱层析分离(洗脱剂：石油醚/乙酸乙酯＝5/1-3/1)，得到化合物A2-3. 1H NMR(400MHz,氘代甲醇)δ:8.49(s,1H),5.57–5.55(m,1H),4.18-4.15(m,2H),4.03-3.95(m,4H),3.13-3.07(m,1H),2.74-2.68(m,1H),2.07-2.03(m,2H),1.95-1.59(m,8H),1.41-1.40(m,1H),1.30-1.26(m,3H).
步骤4：化合物A2的合成
室温下，向化合物A2-3(120.00mg,288.12umol,1.00eq)的四氢呋喃(5.00mL)溶液中加入稀盐酸(2M,5.00mL,34.71eq)，搅拌12小时后，向反应液中缓慢加入饱和碳酸氢钠溶液调节pH至10，用乙酸乙酯(15mL×3)萃取三次，合并有机相，有机相用饱和食盐水(15mL×2)洗涤两次，无水硫酸钠干燥，过滤，滤液通过减压旋转蒸发除去溶剂得粗品。粗品经柱层析分离(洗脱剂:石油醚/乙酸乙酯＝3/1–1/1),得到化合物A2。 1H NMR(400MHz,氘代氯仿)δ＝8.55(s,1H),5.78–5.77(m,1H),4.16-4.11(m,2H),3.37-3.36(m,1H),3.20-3.19(m,1H),3.09–3.08(m,1H),2.74-2.59(m,3H),2.42-2.37(m,4H),2.22-2.18(m,2H),1.42-1.40(m,1H),1.25-1.21(m,3H).
中间体B1：
Figure PCTCN2018093090-appb-000067
CAS:1228947-14-5
中间体B2：
Figure PCTCN2018093090-appb-000068
CAS:13482-22-9
中间体B3：
Figure PCTCN2018093090-appb-000069
CAS:111300-06-2
中间体B4：
Figure PCTCN2018093090-appb-000070
CAS:753-90-2
中间体B5：
Figure PCTCN2018093090-appb-000071
CAS:540-61-4
中间体B6：
Figure PCTCN2018093090-appb-000072
CAS:57260-73-8
中间体B7：
Figure PCTCN2018093090-appb-000073
CAS:177906-48-8
中间体B8：
Figure PCTCN2018093090-appb-000074
CAS:1037834-62-0
实施例1和2：化合物WX001A、WX001B的合成
Figure PCTCN2018093090-appb-000075
步骤1：化合物WX001-1的合成
在15℃下，向化合物B3(9.50g,44.10mmol,1.3eq)的四氢呋喃(200mL)溶液中分批加入氢化钠(2.04g,50.89mmol,纯度60％,1.5eq)，搅拌30分钟，然后向其中加入化合物A1(10g,33.93mmol,1.00eq)的四氢呋喃溶液(50mL),缓慢升温至50℃，搅拌6小时后，将反应液降至室温，向反应液中加入10mL水将反应淬灭，然后减压旋转蒸发除掉溶剂得粗品。粗品经柱层析分离(洗脱剂:石油醚/乙酸乙酯＝15/1–1/1，二氯甲烷/甲醇＝100/1-10/1)，得到化合物WX001-1. 1H NMR(400MHz,氘代氯仿)δ＝8.50(s,1H),5.35-5.09(m,1H),4.24-4.16(m,2H),4.15-4.08(m,2H),3.62–3.48(m,1H),3.39-3.29(m,1H),3.20-3.07(m,2H),2.70–2.66(m,1H),2.26-2.15(m,2H),2.13-2.05(m,2H),1.73–1.59(m,1H),1.48-1.44(m,9H),1.41-1.37(m,2H),1.28–1.26(m,3H).
步骤2：化合物WX001-2的合成
将化合物WX001-1(17.7g,37.37mmol,1eq)的盐酸/二氧六环(4M,180mL,19.26eq)溶液置于15℃搅拌反应12小时。反应结束后，将反应液减压旋转蒸发除去溶剂得化合物WX001-2的盐酸盐, 1H NMR(400MHz,氘代甲醇)δ＝8.56(s,1H),5.41-5.28(m,1H),4.21-4.12(m,2H),3.46-3.35(m,1H),3.26-3.18(m,2H),3.14-3.03(m,1H),2.72–2.68(m,1H),2.41–2.32(m,2H),2.18–2.15(m,2H),1.82-1.63(m,4H),1.44-1.42(m,1H),1.30–1.27(m,3H).
步骤3：化合物WX001-3的合成
室温下，向化合物WX001-2盐酸盐(3.2g,7.81mmol,1.00eq,)的乙腈溶液中(60mL)加入碳酸钾(6.47g,46.84mmol,6eq)，搅拌10分钟，然后向其中加入2,2-二溴***(2.17g,9.37mmol,1.17mL,1.20eq)，将反应升至70℃，搅拌18小时。反应结束后，将反应液冷却至室温，过滤，滤液减压浓缩，得到化合物WX001-3.LCMS(ESI)m/z:444[M+H] +.
步骤4：化合物WX001-4的合成
室温下，向化合物WX001-3(3.43g,粗品).的甲醇(60mL)和水(20mL)溶液中加入一水氢氧化锂(2.07g,49.42mmol,4eq)，搅拌1.5小时后，将反应液浓缩，加10mL水稀释，用稀盐酸(2M)调节pH至3，将反应减压旋转蒸发除去溶剂得到化合物WX001-4。LCMS(ESI)m/z:416[M+H] +.
步骤5：化合物WX001-5的合成
室温下，向化合物WX001-4(5.8g,粗品)的N,N-二甲基甲酰胺(300mL)溶液中依次加入二异丙基乙胺(12.60g,97.47mmol,16.98mL,1.5eq)，HATU(37.06g,97.47mmol,1.5eq)和氨水(11.39g,97.47mmol,12.51mL,1.5eq)，搅拌12小时。反应结束后，向反应液中加入150mL水将反应淬灭，将淬灭后的反应液减压旋转蒸发除去溶剂得粗品，粗品经制备高效液相色谱柱分离(柱子:Phenomenex Gemini C18 250*50mm*10um；流动相:[水(0.05％氨水v/v)-ACN]；B％:15％-40％,26MIN；30％min)，得到化合物WX001.LCMS(ESI)m/z:415[M+H] +
步骤6：化合物WX001A和WX001B的合成
化合物WX001(3.1g,7.28mmol,1eq)经SFC(柱子:AD(250mm*30mm,10um)；流动相:[二氯甲烷-乙醇]；B％:40％-40％,4min；150min)分离，依次得到实施例1即WX001A(100％ee)。LCMS(ESI)m/z:415[M+H] +. 1H NMR(400MHz,氘代甲醇)δ＝8.47(s,1H),5.35-5.19(m,1H),3.76-3.68(m,4H),3.41-3.34(m,1H),3.20-3.16(m,1H),3.05-2.95(m,1H),2.68-2.57(m,5H),2.41-2.26(m,3H),2.10–2.06(m,2H),1.70-1.45(m,4H),1.39–1.36(m,1H).SFC(""AD-3S_3_5_40_3ML柱子:Chiralpak AD-3 100×4.6mmI.D.,3μm流动相:甲醇(0.05％DEA)-CO 2，5％～40％，流速:3mL/min；波长:220nm",RT＝3.020min)实施例2即WX001B(99.20％ee)。LCMS(ESI)m/z:415[M+H] +. 1H NMR(400MHz,氘代甲醇)δ＝8.47(s,1H),5.37-5.21(m,1H),3.77-3.65(m,4H),3.43-3.36(m,1H),3.23-3.12(m,1H),3.04–3.01(m,1H), 2.68-2.55(m,5H),2.40-2.25(m,3H),2.14-2.02(m,2H),1.70-1.45(m,4H),1.39–1.36(m,1H).SFC(""AD-3S_3_5_40_3ML柱子:Chiralpak AD-3 100×4.6mm I.D.,3μm流动相:甲醇(0.05％DEA)-CO 2,5％～40％；流速:3mL/min；检测波长:220nm",RT＝3.731min).
实施例3：化合物WX002的合成
Figure PCTCN2018093090-appb-000076
步骤1：化合物WX001-4的合成
在0℃氮气保护条件下，将氢化钠(244.27mg,6.11mmol,纯度60％,4.00eq)分批加入到B1(676.98mg,3.05mmol,2.00eq,HCl)的四氢呋喃(5.00mL)溶液中，搅拌半小时后，用注射器将A1(450.00mg,1.53mmol,1.00eq)的四氢呋喃(5.00mL)溶液加入到反应液中，将反应液缓慢升至室温，在氮气保护下，搅拌15.5小时。反应结束后，将反应液缓慢倒入饱和的氯化铵(15mL)水溶液中，用乙酸乙酯(10mL)萃取三次，有机相用无水硫酸钠干燥后，过滤，将滤液减压旋转蒸发除去溶剂得粗品。粗品用硅胶制备板分离(二氯甲烷/甲醇＝10/1)得WX001-4，LCMS(ESI)m/z:416.1[M+H] +
步骤2：化合物WX002的合成
在15℃下，将HATU(54.91mg,144.40umol,2.00eq)和2,2,2-三氟乙胺(14.30mg,144.40umol,11.35uL,2.00eq)依次加入到WX001-4(30.00mg,72.20umol,1.00eq)的乙腈(1.00mL)溶液中，搅拌半小时后，将反应液减压旋转蒸发除去溶剂得粗品，粗品经制备高效液相色谱柱(柱子:Boston Green ODS 150*30 5u；流动相:[水(0.1％三氟乙酸)-ACN]；B％:18％-48％,8min)分离得WX002。LCMS(ESI)m/z:497.1[M+H] +, 1H NMR(400MHz,氘代甲醇)δ＝8.51(s,1H),5.36-5.29(m,1H),4.14-4.03(m,2H),4.05-3.95(m,1H),3.85-3.47(m,3H),3.51-3.48(m,2H),3.43–3.35(m,2H),3.28-3.19(m,2H),3.08-3.05(m,1H),2.70-2.69(m,1H),2.57-2.43(m,2H),2.34-2.31(m,2H),1.81-1.69(m,4H),1.42-1.30(m,2H)
实施例4：化合物WX003的合成
Figure PCTCN2018093090-appb-000077
参照实施例3方法，以中间体A1和B5为原料合成化合物WX003
WX003,LCMS(ESI)m/z:454.1[M+H] +, 1H NMR(400MHz,氘代甲醇)δ＝8.51(s,1H),5.34-5.31(m,1H),4.13-4.09(m,3H),3.82-3.75(m,2H),3.54-3.50(m,2H,),3.41-3.39(m,2H),3.26-3.20(m,3H),3.19-3.08(m,1H),2.72-2.71(m,1H),2.51-2.47(m,2H),2.38-2.27(m,2H),1.80-1.67(m,4H),1.38-1.25(m,2H)
实施例5：化合物WX004的合成
Figure PCTCN2018093090-appb-000078
参照实施例3合成方法，以中间体A1，B6为原料合成化合物WX004-1，经制备液相色谱(柱子:Boston Green ODS 150mm*30mm 5μm；流动相:[水(0.1％三氟乙酸)-ACN]；B％:28％-38％,8min)分离后，经检测大部分产品为WX004，分离后的溶液减压浓缩后，再加入1滴三氟乙酸，搅拌1小时后，再次减压旋转蒸发除去溶剂得WX004。
WX004,LCMS(ESI)m/z:458.2[M+H] +, 1H NMR(400MHz,氘代甲醇)δ＝8.51(s,1H),5.36-5.29(m,1H),4.13-4.10(m,2H),3.85-3.63(m,2H),3.69-3.61(m,1H),3.54-3.51(m,2H,),3.38-3.37(m,2H),3.26-3.23(m,3H),3.09-3.07(m,3H),2.68-2.67(m,1H),2.50-2.47(m,2H),2.34-2.31(m,2H),1.78-1.73(m,4H),1.38-1.30(m,2H)
实施例6：化合物WX005的合成
Figure PCTCN2018093090-appb-000079
合成路线：
Figure PCTCN2018093090-appb-000080
步骤1：化合物WX005-1的合成
在-78℃氮气保护下，将二异丁基氢化铝(1M正己烷溶液,9.00mL,2.95eq)滴加到A1(900.00mg,3.05mmol,1.00eq)的四氢呋喃(10mL)溶液中，搅拌2小时后，将反应液缓慢滴加到5mL饱和氯化铵溶液中，再将10mL二氯甲烷加入到淬灭的反应液中，搅拌后过滤，滤液用分液漏斗分液，液相拥二氯甲烷(2mL)萃取三次，合并有机相，用无水硫酸钠干燥，过滤后，将滤液减压旋转蒸发除去溶剂得到粗品，粗品用过柱机(流动相：石油醚/乙酸乙酯＝20/1-3/1)纯化得WX005-1。LCMS(ESI)m/z:252.8[M+H] +, 1H NMR(400MHz,氘代氯仿)δ＝8.75(s,1H),3.68-3.65(m,2H),3.39-3.33(m,1H),3.20-3.16(m,1H),2.75-2.72(m,1H),2.20-2.17(m,1H),1.52-1.51(m,1H),1.09-1.04(m,1H)
步骤2：化合物WX005-2的合成
在0℃下，将三乙胺(464.47mg,4.59mmol,636.26uL,2.00eq)，4-二甲氨基吡啶(28.04mg,229.50umol,0.10eq)和对甲苯磺酰氯(656.32mg,3.44mmol,1.50eq)依次加入到WX005-1(580.00mg,2.30mmol,1.00eq)的二氯甲烷(1mL)溶液中,反应液缓慢升至室温，搅拌2小时后，将反应液倒入3mL 0.5M的稀盐酸水溶液中，用二氯甲烷(1mL)萃取3次，有机相用无水硫酸钠干燥后，过滤，将滤液减压旋转蒸发除去溶剂得到中间体。在室温下，将该中间体溶于0.5mL二甲基亚砜中，将***(168.72mg,3.44mmol,1.50eq)加入到该溶液中，搅拌2小时后，将反应液加入水(2mL)中，有固体析出，过滤收集固体，将固体真空干燥得到WX005-2。
步骤3：化合物WX005的合成
室温下，先将钠氢(122.26mg,3.06mmol,60％纯度,4.00eq)分批加入到B1(338.85mg,1.53mmol,2.00eq,HCl)的四氢呋喃(1.00mL)溶液中，再将WX005-2(200.00mg,764.15umol,1.00eq)加入到反应液中，搅拌16小时后，将反应液滴加到饱和的氯化铵(3mL)溶液中，用二氯甲烷(1mL)萃取5次，有机相用无水硫酸钠干燥，过滤后，将滤液减压旋蒸除去溶剂得粗品，粗品通过制备板(展开剂：乙酸乙酯)得到WX005，LCMS(ESI)m/z:411.1[M+H] +, 1H NMR(400MHz,氘代甲醇)δ＝8.48(s,1H),5.36-5.21(m,1H),3.81-3.63(m,4H),3.28(d,J＝6.8Hz,1H),3.19-3.08(m,1H),2.85-2.72(m,1H),2.65-2.63(m,5H),2.46-2.36(m,4H),2.20-2.090(m,3H),1.71-1.70(m,2H),1.68-1.52(m,2H),0.96-0.93(m,1H)
实施例7：化合物WX006的合成
Figure PCTCN2018093090-appb-000081
合成路线
Figure PCTCN2018093090-appb-000082
步骤1：化合物WX006的合成
室温下，化合物WX005(100.00mg,243.59umol,1.00eq)和1mL浓盐酸搅拌15分钟后，用2M的氢氧化钠水溶液调节pH至14，用二氯甲烷/甲醇(1mL)萃取3次，合并有机相，用无水硫酸钠干燥，过滤，将滤液减压旋转蒸发除去溶剂得粗品，粗品用制备板分离(展开剂：二氯甲烷/甲醇＝10/1)得到WX006，LCMS(ESI)m/z:429.1[M+H] +,451.1[M+Na] +, 1H NMR(400MHz,氘代甲醇)δ＝8.45(s,1H),5.36-5.21(m,1H),4.68-4.62(m,2H),3.79-3.70(m,4H),3.28-3.24(m,1H),3.15-3.10(m,1H),2.76-2.70(m,3H),2.55-2.50(m,2H),2.44-2.35(m,2H),2.15-2.09(m,4H),1.67-1.56(m,4H),0.93-0.90(m,1H)
实施例8：化合物WX007的合成
Figure PCTCN2018093090-appb-000083
合成路线：
Figure PCTCN2018093090-appb-000084
步骤1：化合物WX007的合成
室温下，将伯吉斯试剂(34.49mg,144.74umol,2.00eq)加入到化合物WX001(30.00mg,72.37umol,1.00eq)的甲苯溶液(2mL)中，反应液在100℃下，搅拌1小时后，冷却至室温，将反应液倒入2mL水中，用乙酸乙酯(1mL)萃取3次，有机相用无水硫酸钠干燥，过滤后，将滤液减压旋转蒸发除去溶剂的得粗品，粗品用制备板(展开剂：二氯甲烷/甲醇＝10/1)纯化得到WX007，LCMS(ESI)m/z:397.1[M+H] +, 1H NMR(400MHz,氘代甲醇)δ＝8.41(s,1H),5.30-5.15(m,1H),3.78-3.67(m,3H),3.20-3.18 (m,1H),3.16-3.09(m,1H),2.99-2.79(m,3H),2.73-2.71(m,1H),2.45-2.23(m,2H),2.17-2.06(m,2H),1.99-1.88(m,1H),1.71-1.44(m,4H),1.33-1.25(m,2H),0.83-0.72(m,2H)
实施例9：化合物WX008的合成
Figure PCTCN2018093090-appb-000085
参照实施例1方法，以中间体A1和B7为原料合成WX008。
WX008，LCMS(ESI)m/z:414[M+H] +， 1H NMR(400MHz,氘代甲醇)δ＝8.25(s,1H),4.25-4.10(m,1H),3.95-3.74(m,4H),3.38-3.36(m,1H),3.26-3.08(m,3H),3.06–2.88(m,3H),2.88-2.72(m,1H),2.66-2.62(m,1H),2.32-2.10(m,4H),1.69-1.47(m,4H),1.39-1.37(m,1H).
实施例10：化合物WX009的合成
Figure PCTCN2018093090-appb-000086
参照中间体A1，实施例3中WX001-4及实施例1中WX001合成方法，以2-环己烯-1-酮为原料合成。WX009，LCMS(ESI)m/z:429[M+H] +， 1H NMR(400MHz,DMSO-d 6)δ＝8.55(s,1H),7.38(s,1H),6.87(br s,1H),5.28–5.16(m,1H),3.60–3.54(m,4H),2.96-2.88(m,5H),2.25–2.16(m,3H),2.09-2.07(m,1H),1.97-1.81(m,6H),1.52–1.43(m,5H).
实施例11：化合物WX010的合成
Figure PCTCN2018093090-appb-000087
参照中间体A1及实施例1合成方法，以2-环己烯-1-酮为原料合成。
WX0010，LCMS(ESI)m/z:428[M+H] +， 1H NMR(400MHz,DMSO-d 6)δ＝8.29(s,1H),7.56(br s,1H),7.07(br s,1H),5.89–5.82(m,,1H),3.99–3.90(m,1H),3.58–3.52(m,4H),2.86-2.75(m,1H),2.30-1.99(m,6H),1.92-1.69(m,6H),1.40-1.17(m,7H).
实施例12：化合物WX011的合成
Figure PCTCN2018093090-appb-000088
合成路线：
Figure PCTCN2018093090-appb-000089
步骤1：化合物WX011的合成
在25℃下，将硼烷的二甲硫醚溶液(10M,12.04uL,5.00eq)慢慢滴加到化合物WX001-4(10.00mg,24.07umol,1.00eq)的四氢呋喃(3.00mL)中，搅拌15小时后，向反应液中加入10mL饱和氯化铵溶液，将反应淬灭，用二氯甲烷萃取三次(10mL×3)，合并有机相，有机相用饱和碳酸氢钠溶液洗涤(15mL)，无水硫酸钠干燥，过滤，将滤液减压旋转蒸发除去溶剂得粗品。粗品经高效液制备相色谱分离(柱子:Phenomenex Synergi C18 150mm*25mm*10μm；流动相:水(0.1％三氟乙酸)-ACN]；B％:9％-39％,13min),得到WX011.LCMS(ESI)m/z:402[M+H] +， 1H NMR(400MHz,氘代甲醇)δ＝8.44(s,1H),5.31-5.21(m,1H),3.76-3.69(m,4H),3.60–3.56(m,1H),3.50–3.43(m,1H),3.28-3.22(m,1H),3.13-3.03(m,1H),2.67–2.63(m,4H),2.56-2.49(m,1H),2.39-2.28(m,3H),2.15-2.06(m,3H),1.69-1.48(m,4H),0.86–0.84(m,1H).
实施例13：化合物WX012的合成
Figure PCTCN2018093090-appb-000090
合成路线：
Figure PCTCN2018093090-appb-000091
步骤1：化合物WX012-1的合成
在-20℃下，将锌粉(3.19g,48.72mmol,2.00eq)和三乙基氯硅烷(8.00g,53.10mmol,8.99mL,2.18eq)依次加入到20mL乙腈中，搅拌10分钟，将二溴氟乙酸乙酯(16.07g,60.90mmol,2.50eq)加入到反应液中，继续搅拌30分钟后，将2-环戊烯-1-酮(2.00g,24.36mmol,2.04mL,1.00eq)加入到反应液中。将反应液升至25℃，在此温度下，搅拌反应16小时。反应结束后，向反应液中加稀盐酸(2M,20mL)将反应淬灭，淬灭的反应液用乙酸乙酯萃取(20mL×3)三次后，合并有机相，有机相用饱和食盐水洗涤(20mL×2)两次，用无水硫酸钠干燥，过滤，滤液减压旋转蒸发除去溶剂得粗品。粗品经柱层析分离(洗脱剂：石油醚/乙酸乙酯＝10：1-5：1)得化合物WX012-1. 1H NMR(400MHz,氘代氯仿)δ＝4.41-4.34(m,2H),3.32-3.11(m,1H),2.60-2.10(m,6H),1.40-1.35(m,3H).
步骤2：化合物WX012-2的合成
室温下，将二异丙基乙胺(4.60g,35.57mmol,6.21mL,5.00eq)加入到WX012-1(1.9g,7.11mmol,1.00eq)的N，N-二甲基甲酰胺(20mL)溶液中，搅拌12小时后，将稀盐酸(2M,10mL)加入到反应中，将反应淬灭，用乙酸乙酯(15mL×3)萃取三次，合并有机相，用饱和食盐水(15mL×2)洗涤两次，无水硫酸钠干燥，过滤，旋干。粗品经柱层析分离(洗脱剂：石油醚/乙酸乙酯＝10：1-5：1)得WX012-2. 1H NMR(400MHz,氘代氯仿)δ＝4.34-4.24(m,2H),2.78-2.69(m,1H),2.63-2.55(m,1H),2.51-2.42(m,1H),2.36-2.19(m,3H),1.37-1.32(m,3H).
步骤3：化合物WX012-3的合成
室温下，将化合物WX012-2(0.9g,4.83mmol,1eq)，氰乙酸乙酯(656.16mg,5.80mmol,619.02μL,1.2eq)，二乙胺(424.26mg,5.80mmol,597.54μL,1.2eq)和升华硫(186.00mg,5.80mmol,1.2eq)的乙醇溶液(10mL)搅拌12小时后，向反应液中加入饱和食盐水(10mL)将反应淬灭，淬灭过的反应液用乙酸乙酯萃取(15mL×3)三次,合并有机相，有机相用无水硫酸钠干燥，过滤，滤液通过减压旋转蒸发除去溶剂得粗品。粗品经柱层析分离(洗脱剂：石油醚/乙酸乙酯＝5/1)，得到化合物WX012-3.LCMS(ESI)m/z:314[M+H] +.
步骤4：化合物WX012-4的合成
在冰水浴条件下，将三氯氧磷(941.97mg,6.14mmol,570.89μL,3.5eq)加入到化合物WX012-3(0.55g,1.76mmol,1eq)和甲酰胺(5.65g,125.44mmol,5mL,71.47eq)的混合物中，缓慢升温至25℃，搅拌12小时。反应结束后，将反应液缓慢倒入水中(10mL)，用饱和碳酸氢钠溶液调节pH至9，用乙酸乙酯萃取(10mL×3)三次，合并有机相，有机箱用饱和食盐水洗涤(10mL×2)两次，用无水硫酸钠干燥，过滤，滤液通过减压旋转蒸发除去溶剂得粗品。粗品经柱层析分离(洗脱剂：石油醚/乙酸乙酯＝5/1–1/1),得到化合物WX012-4。LCMS(ESI)m/z:295[M+H] +.
步骤5：化合物WX012-5的合成
室温下，向化合物WX012-4(0.130g,441.72umol,1eq),化合物B1(98.20mg,530.07umol,1.2eq)和三苯基磷(173.79mg,662.59μmol,1.5eq)的四氢呋喃(5mL)溶液中缓慢加入偶氮二甲酸二异丙酯(133.98mg,662.59umol,128.83uL,1.5eq)，搅拌12小时后，将反应液减压浓缩得粗品，粗品经柱层析分离(洗脱剂：石油醚/乙酸乙酯＝3/1–0/1)得到化合物WX012-5. 1H NMR(400MHz,氘代甲醇)δ＝8.49(s,1H),5.36-5.16(m,1H),4.38-4.22(m,2H),3.75-3.66(m,4H),3.56-3.44(m,1H),3.41–3.38(m,1H),3.25–3.20(m,1H),2.95-2.84(m,1H),2.70-2.53(m,4H),2.43-2.24(m,3H),2.11–1.96(m,2H),1.66-1.43(m,4H),1.35-1.31(m,3H).
步骤6：化合物WX012-6的合成
室温下，向化合物WX012-5(0.05g,108.33μmol,1eq)的甲醇(1mL)和水(0.3mL)的混合溶液中加入一水和氢氧化锂(6.82mg,162.50μmol,1.5eq)，搅拌反应1小时后，向.反应液中加10mL水稀释，用乙酸乙酯萃取(10mL×1)一次，水相用稀盐酸(2M)调节pH至3，再用乙酸乙酯萃取(10mL×1)一次，水相减压旋转蒸发除去溶剂得化合物WX012-6。LCMS(ESI)m/z:434[M+H] +.
步骤7：化合物WX012的合成
室温下，将化合物WX012-6(0.046g,106.11μmol,1eq)，氨水(14.88mg,127.34μmol,16.35μL,1.2eq)，二异丙基乙胺(20.57mg,159.17μmol,27.72μL,1.5eq)和HATU(52.45mg,137.95μmol,1.3eq)的N,N-二甲基甲酰胺(1mL)的混合溶液搅拌2小时后，将反应液在减压旋转蒸发除去溶剂得粗品。粗品经制备高效液相色谱分离(柱子:Phenomenex Synergi C18 150mm*25mm*10μm；流动相:[水(0.1％三氟乙酸)- ACN]；B％:10％-40％,13min).得到化合物WX012的三氟乙酸盐.LCMS(ESI)m/z:433[M+H] +. 1H NMR(400MHz,氘代甲醇)δ＝8.50(s,1H),5.33–5.25(m,1H),4.18–4.05(m,2H),3.86–3.70(m,2H),3.61-3.44(m,3H),3.41-3.34(m,2H),3.30-3.17(m,3H),2.86–2.81(m,1H),2.57–2.41(m,2H),2.38–2.20(m,2H),1.88-1.61(m,4H).
实施例14：化合物WX013的合成
Figure PCTCN2018093090-appb-000092
合成路线：
Figure PCTCN2018093090-appb-000093
步骤1：化合物WX013-1的合成
室温下，向化合物A2(40.00mg,107.40μmol,1.00eq)的甲醇(2.00mL)和醋酸(200.00μL)中加入3-(二甲氨基)氮杂环丁烷二盐酸盐(22.31mg,128.88μmol,1.20eq)，搅拌10分钟后，向其中加入氰基硼氢化钠(23.62mg,375.90μmol,3.50eq)，在25℃下，继续搅拌16小时。反应结束后，向反应液中加入10mL水将反应液稀释，用乙酸乙酯(10mL×3)萃取三次，合并有机相，有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，滤液通过减压旋转蒸发除去溶剂得到化合物WX013-1.LCMS(ESI)m/z:457[M+H] +.
步骤2：化合物WX013-2的合成
在15℃下，向WX013-1(50.00mg,109.51μmol,1.00eq)的甲醇(3.00mL)和水(1.00mL)溶液中加入一水氢氧化锂(27.57mg,657.03μmol,6.00eq)，搅拌16小时。反应结束后，向反应液中加入5mL水稀释，稀释的反应液用乙酸乙酯(10mL)萃取两次后，水相用稀盐酸(1M)调节pH至2,再乙酸乙酯(10mL×4)萃取四次，水相通过减压旋转蒸发除去溶剂得化合物WX013-2.LCMS(ESI)m/z:429[M+H] +.步骤3：化合物WX013的合成
在15℃下，向化合物WX013-2(110.00mg,256.68μmol,1.00eq)的DMF(3.00mL)溶液中分别加入二异丙基乙胺(49.76mg,385.02μmol,67.24μL,1.50eq)，HATU(146.40mg,385.02μmol,1.50eq)和氨水(44.98mg,385.02umol,49.43μL,1.50eq)，继续搅拌12小时。反应结束后，向反应液加入10mL水将反应淬灭，淬灭的反应液用乙酸乙酯(10mL×8)萃取8次，合并有机相，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液通过减压旋转蒸发除去溶剂得粗品，粗品经制备高效液相色谱分离(柱子:Phenomenex Synergi C18 150mm*25mm*10μm；流动相:[水(0.1％三氟乙酸)-ACN]；B％:5％-35％,13min).得到化合物WX013.LCMS(ESI)m/z:428[M+H] +. 1H NMR(400MHz,氘代甲醇)δ:8.49(s,1H),5.40-5.29(m,1H),4.58-4.38(m,4H),4.18-4.04(m,1H),3.46-3.33(m,2H),3.23-3.14(m,1H),3.09-2.91(m,1H),2.75(s,6H),2.69-2.60(m,1H),2.43-2.3(m,2H),2.22-2.10(m,2H),1.77-1.63(m,2H),1.62-1.50(m,2H),1.41-1.36(m,1H).
实施例15和16：化合物WX014A和WX014B的合成
Figure PCTCN2018093090-appb-000094
参照实施例14合成方法，以中间体A2，化合物3,3-二氟吡咯烷盐酸盐为原料合成。粗品经制备高效液相色谱分离(柱子:Phenomenex Synergi C18 150*25*10μm；流动相:[水(0.1％三氟乙酸)-ACN]；B％:9％-39％,13min),得到WX014A和WX014B。
实施例15即WX014A，LCMS(ESI)m/z:435[M+H] +， 1H NMR(400MHz,氘代甲醇)δ＝8.48(s,1H),5.38-5.26(m,1H),3.99-3.93(m,2H),3.80-3.70(m,2H),3.41-3.32(m,2H),3.22-3.12(m,1H),2.98-3.06(m,1H),2.73-2.58(m,3H),2.47-2.37(m,2H),2.34-2.25(m,2H),1.83-1.65(m,4H),1.40-1.35(m,1H).HPLC(XBridge C18UPLC柱子:3.5um,3.0*50mm,方法：10-80CD_4min,保留时间:2.260min)
实施例15即WX014B，LCMS(ESI)m/z:435[M+H] +， 1H NMR(400MHz,氘代甲醇)δ＝8.50(s,1H),5.73-5.67(m,1H),4.11-3.62(m,4H),3.51-3.36(m,2H),3.26-3.12(m,2H),2.77-2.59(m,3H),2.42-2.19 (m,2H),2.17-2.07(m,2H),1.99-1.78(m,4H),1.45–1.40(m,1H).HPLC(XBridge C18UPLC柱子:3.5μm,3.0*50mm,方法：10-80CD_4min,保留时间:2.197)
实施例17、18、19和20：化合物WX015A，WX015B，WX015C和WX015D的合成
Figure PCTCN2018093090-appb-000095
参照实施例14合成方法，以中间体A2和化合物4,4-二氟哌啶为原料合成，粗品经制备高效液相色谱分离(柱子:Phenomenex Gemini 150*25mm*10μm；流动相:[水(0.05％氨水v/v)-ACN]；B％:30％-60％,12min),得到WX015,再经SFC分离(柱子:AD(250mm*30mm,10μm)；流动相:[0.1％氨水 甲醇]；B％:30％-30％,4min；100min),得到WX015-P1&P2,WX015-P3,WX015-P4,再依次经SFC分离(柱子:AS(250mm*30mm,5μm)；流动相:[0.1％氨水 甲醇]；B％:30％-30％,4.4min；60min),制备高效液相色谱分离(柱子:Phenomenex Gemini 150*25mm*10μm；流动相:[water(0.05％氨水v/v)-ACN]；B％:37％-50％,12min)和制备高效液相色谱分离(柱子:Phenomenex Gemini 150*25mm*10μm；流动相:[水(0.05％氨水v/v)-ACN]；B％:30％-60％,12min),得到WX015A,WX015B,WX015C和WX015D.
实施例17即WX015A，LCMS(ESI)m/z:449[M+H] +, 1H NMR(400MHz,氘代甲醇)δ＝8.46(s,1H),5.72–5.61(m,1H),3.45-3.36(m,1H),3.24–3.15(m,1H),3.13–3.06(m,1H),2.79–2.68(m,4H),2.68–2.56(m,2H),2.27–2.15(m,2H),2.11-1.97(m,4H),1.90-1.66(m,6H),1.48-1.34(m,1H).SFC(AS-3S_3_5_40_3ML柱子:Chiralpak AS-3 100×4.6mm I.D.,3μm流动相:甲醇(0.05％二乙胺)-CO 2，5％～40％；流速:3mL/min；检测波长:220nm,RT＝2.377min,99％ee).
实施例18即WX015B，LCMS(ESI)m/z:449[M+H] +, 1H NMR(400MHz,氘代甲醇)δ＝8.46(s,1H),5.70–5.62(m,1H),3.43-3.35(m,1H),3.25–3.14(m,1H),3.13–3.05(m,1H),2.78–2.68(m,4H),2.64–2.55(m,2H),2.27–2.16(m,2H),2.12-1.97(m,4H),1.87-1.69(m,6H),1.45–1.38(m,1H).SFC(AS-3S_3_5_40_3ML柱子:Chiralpak AS-3 100×4.6mm I.D.,3μm流动相:甲醇(0.05％二乙胺)-CO 2，5％～40％；流速:3mL/min；检测波长:220nm,RT＝2.562min,97％ee).
实施例19即WX015C，LCMS(ESI)m/z:449[M+H] +, 1H NMR(400MHz,氘代甲醇)δ＝8.47(s,1H),5.32-5.19(m,1H),3.42-3.34(m,1H),3.22-3.11(m,1H),3.04–3.01(m,1H),2.75–2.70(m,4H),2.67-2.52(m,2H),2.37–2.27(m,2H),2.07-1.92(m,6H),1.70-1.50(m,4H),1.38–1.36(m,1H).SFC(AD-3S_3_5_40_3ML柱子:Chiralpak AD-3 100×4.6mm I.D.,3μm流动相:甲醇(0.05％二乙胺)-CO 2，5％～40％；流速:3mL/min；检测波长:220nm,RT＝2.789min,97％ee).
实施例20即WX015D，LCMS(ESI)m/z:449[M+H] +, 1H NMR(400MHz,氘代甲醇)δ＝8.47(s,1H),5.32-5.19(m,1H),3.42-3.35(m,1H),3.22-3.14(m,1H),3.05–3.01(m,1H),2.76–2.69(m,4H),2.66-2.51(m,2H),2.36–2.28(m,2H),2.08-1.93(m,6H),1.71-1.50(m,4H),1.38–1.36(m,1H).SFC(AD-3S_3_5_40_3ML柱子:Chiralpak AD-3 100×4.6mm I.D.,3μm流动相:甲醇(0.05％二乙胺)-CO 2，5％～40％；流速:3mL/min；检测波长:220nm,RT＝3.145min,98％ee).
实施例21：化合物WX016的合成
Figure PCTCN2018093090-appb-000096
合成路线：
Figure PCTCN2018093090-appb-000097
参照实施例14合成方法，以中间体A2和B8为原料合成，粗品经高效制备液相色谱(柱子:Phenomenex Synergi C18 150mm*25mm*10μm；流动相:[水(0.1％三氟乙酸)-乙腈]；B％:16％-43％,12min)分离后得到WX016。LCMS(ESI)m/z:439.1[M+H] +
各实施例的NMR和MS数据
Figure PCTCN2018093090-appb-000098
Figure PCTCN2018093090-appb-000099
Figure PCTCN2018093090-appb-000100
Figure PCTCN2018093090-appb-000101
试验例1：体外评价
采用 33P同位素标记激酶活性测试(Reaction Biology Corp)测定IC 50值来评价受试化合物对人IRAK4的抑制能力。
缓冲液条件：20mM Hepes(pH 7.5),10mM MgCl 2,1mM EGTA,0.02％Brij35,0.02mg/ml BSA,0.1mM Na3VO4,2mM DTT,1％DMSO。
试验步骤：室温下，将受试化合物溶解在DMSO中配制成10mM溶液待用。将底物溶解在新配制的缓冲液中，向其中加入受测激酶并混合均匀。利用声学技术(Echo 550)将溶有受试化合物的DMSO溶液加入上述混匀的反应液中。反应液中化合物浓度为10μM,3.33μM,1.11μM,0.370μM,0.123μM,41.2nM,13.7nM,4.57nM,1.52nM,0.508nM。孵化15分钟后，加入 33P-ATP(活度0.01μCi/μl，相应浓度列在表1中)开始反应。IRAK4和其底物的供应商货号、批号以及在反应液中的浓度信息列在表1中。反应在室温下进行120分钟后，将反应液点在P81离子交换滤纸(Whatman#3698-915)上。用0.75％磷酸溶液反复清洗滤纸后，测定滤纸上残留的磷酸化底物的放射性。激酶活性数据用含有受试化合物的激酶活性和空白组(仅含有DMSO)的激酶活性的比对表示，通过Prism4软件(GraphPad)进行曲线拟合得到IC50值，实验结果如表2所示。
表1：体外测试中激酶、底物和ATP的相关信息。
Figure PCTCN2018093090-appb-000102
Figure PCTCN2018093090-appb-000103
表2：本发明化合物体外筛选试验结果
Figure PCTCN2018093090-appb-000104
结论：本发明化合物对IRAK4展现出较好的抑制活性。
试验例2：肝微粒体代谢稳定性
人肝微粒体购自于BD，小鼠肝微粒体购自于Xenotech。阳性对照为睾酮(3A4底物)、普罗帕酮(2D6底物)和双氯芬酸(2C9底物)。在NADPH再生体系作用下，受试化合物和阳性药的孵育浓度为1μM，在37℃与肝微粒共孵育，肝微粒体蛋白浓度为0.5mg/ml。分别孵育0、5、10、20、30和60分钟后，立即加入含内标的冷乙腈混合以终止反应。没有NADPH再生体系作用下，受试化合物和微粒体共孵育60分钟。采用LC/MS/MS分析样品，用分析物与内标的峰面积比评价化合物的消除。
表3：本发明化合物肝微粒体代谢稳定性试验结果
Figure PCTCN2018093090-appb-000105
结论：本发明中部分化合物展现出较好的肝微粒体代谢稳定性。
试验例3：MDR1-MDCK细胞双向渗透性研究
本实验采用从荷兰癌症研究所(NKI)引进的MDR1-MDCKII细胞，将细胞以2.3×10 5细胞/cm 2的密度种在BD Falcon的Transwell-96孔板里，并置于二氧化碳培培养箱中培养4～7天后用于实验。
受试化合物用HBSS转运缓冲液将10mM的DSMO储备液稀释至2μM，并用于单层细胞的顶侧或基 底侧。采用双样本测试化合物从顶侧到基底侧或从基底侧到顶侧的渗透性。阳性药地高辛同样测试孵育浓度为2μM时从顶侧到基底侧或从基底侧到顶侧的渗透性，而非诺贝特和***测试孵育浓度为2μM时从顶侧到基底侧的渗透性。将细胞板置于37±1℃，5％CO 2和饱和相对湿度的细胞培养箱中孵育150分钟。此外，同时测试受试化合物的外排比。采用LC-MS/MS法，根据分析物和内标的峰面积比对受试物和参比化合物进行半定量分析。
转运实验结束后，采用荧光黄检测实验(Lucifer Yellow Rejection Assay)检测MDR1-MDCK II细胞膜的完整性。除去顶侧端和基底侧端的缓冲液，然后加入75μL 100μM荧光黄缓冲液，再在顶侧端和基底侧端中分别加入250μL HBSS转运缓冲液。在37±1℃，5％CO 2和饱和相对湿度的细胞培养箱中孵育30分钟。孵育30分钟后，在顶侧取20μL荧光黄样品至黑色荧光板，加入60μL HBSS转运缓冲液，再从底侧80μL HBSS转运缓冲液。采用M2 e读板仪在425/528nm(激发/发射)波谱处检测样品中荧光黄的相对荧光强度(the relative fluorescence unit,RFU)。
表观渗透系数(P app,cm/s)采用如下公式计算：
Papp＝(dC r/d t)x V r/(A x C 0)
dC r/d t是化合物在单位时间内接收端的累积浓度(μM/s)；Vr接收端溶液的体积(顶端和基底端的溶液体积分别为0.075和0.25mL；A是胞单层的相对表面积(0.0804cm 2)；C 0是给药端供试品的起始浓度(nM)或对照品的峰面积比值。
外排比采用如下公式计算：
外排比＝P app(BA)/P app(AB)
回收率采用如下公式计算：
％回收率＝100x[(V r x C r)+(V d x C d)]/(V d x C 0)
C 0是给药端供试品的起始浓度(nM)或对照品的峰面积比值；V d是给药端的体积(顶侧为0.075mL，基底侧为0.25mL)；C d和C r分别为给药端和接收端供试品的终浓度(nM)或对照品的峰面积比值。
表4：本发明化合物MDR1-MDCK细胞双向渗透性研究试验结果
Figure PCTCN2018093090-appb-000106
结论：本发明化合物展现出较好的膜渗透性。
试验例4：药代参数研究
实验操作：选择健康成年雌性lewis大鼠6只(7-9周龄，购自药代参数)，3只为静注组，3只为口服组。候选化合物与适量静注组溶媒(5％二甲基亚砜+10％HP-β-CD+0.5％羧甲基纤维素钠+84.5％去离子水)混合，涡旋并超声，制备得到0.5mg/mL澄清溶液，微孔滤膜过滤后备用；口服组溶媒为0.5％甲基纤 维素水溶液，候选化合物与溶媒混合后，涡旋并超声，制备得到0.5mg/mL均一混悬液备用。小鼠1mg/kg静脉给药或2.5mg/kg口服给药后，收集一定时间的全血，制备得到血浆，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNonlin软件(美国Pharsight公司)计算药代参数。如下表5所示：
表5：本发明化合物的药代参数测定结果
药代参数 实施例2
剂量(mg/kg) 50
最大浓度(nM) 19470
最大时间(h) 1.00
半衰期(h) 1.77
暴露量 0-last(nM.h) 73082
暴露量 0-inf(nM.h) 77139
结论：本发明中化合物具有较好药代参数。

Claims (15)

  1. 式(Ⅰ)所示化合物或其药学上可接受的盐，
    Figure PCTCN2018093090-appb-100001
    其中，
    n选自：1或2；
    m选自：0、1、2或3；
    R 1选自H、CN、OH，或选自任选被R取代的
    Figure PCTCN2018093090-appb-100002
    R 2选自：H、F、Cl、Br、I；
    R 3选自OH、NH 2、CN、卤素，或选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3杂烷基；
    或者，两个R 3连接在一起，形成一个3～6元环；
    L选自：单键、-CH 2-、-CH 2CH 2-；
    L 1选自：O或NH；
    环A选自4～6元杂环烷基；
    R选自F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：C 1-3烷基、C 1-3杂烷基；R’选自：F、Cl、Br、I、OH、NH 2、CN、CF 3；
    所述C 1-3杂烷基、4～6元杂环烷基之“杂”分别独立地选自：N、O、S、NH；
    上述杂原子或杂原子团的数目分别独立地选自1、2、3或4。
  2. 根据权利要求1所述化合或其药学上可接受的盐，其中，R选自F、Cl、Br、I、OH、NH 2、CN，或选自任选被1、2或3个R’取代的：Me、Et。
  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、NH 2、CN、Me、CF 3、Et、
    Figure PCTCN2018093090-appb-100003
  4. 根据权利要求1～3任意一项所述化合物或其药学上可接受的盐，其中，R 1选自：H、CN、OH、
    Figure PCTCN2018093090-appb-100004
    Figure PCTCN2018093090-appb-100005
  5. 根据权利要求1～3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 PCTCN2018093090-appb-100006
    选自：H、
    Figure PCTCN2018093090-appb-100007
  6. 根据权利要求1～3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 PCTCN2018093090-appb-100008
    选自：
    Figure PCTCN2018093090-appb-100009
  7. 根据权利要求1所述化合物或其药学上可接受的盐，其中，环A选自：吗啉基、哌啶基、吖丁啶基、吡咯烷基。
  8. 根据权利要求1～3任意一项所述化合物或其药学上可接受的盐，其中，R 3选自OH、NH 2、CN、卤素，或选自任选被1、2或3个R取代的：Me、Et、-NHCH 3。
  9. 根据权利要求8所述化合物或其药学上可接受的盐，其中，R 3选自OH、NH 2、CN、F、Cl、Br、I、Me、Et、-NHCH 3、
    Figure PCTCN2018093090-appb-100010
  10. 根据权利要求7或9所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018093090-appb-100011
    选自：
    Figure PCTCN2018093090-appb-100012
  11. 根据权利要求10所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018093090-appb-100013
    选自：
    Figure PCTCN2018093090-appb-100014
    Figure PCTCN2018093090-appb-100015
  12. 根据权利要求1～3任意一项所述化合物或其药学上可接受的盐，其中，两个R 3连接在一起，结构单 元
    Figure PCTCN2018093090-appb-100016
    选自
    Figure PCTCN2018093090-appb-100017
  13. 根据权利要求1～5、权利要求8和权利要求9中的任意一项所述化合物或其药学上可接受的盐，其选自：
    Figure PCTCN2018093090-appb-100018
    其中，
    L 1、R 1、R 3权利要求1～5、权利要求8和权利要求9所定义。
  14. 下式所示化合物或其药学上可接受的盐：
    Figure PCTCN2018093090-appb-100019
    Figure PCTCN2018093090-appb-100020
  15. 根据权利要求14所示化合物或其药学上可接受的盐，其选自：
    Figure PCTCN2018093090-appb-100021
    Figure PCTCN2018093090-appb-100022
    Figure PCTCN2018093090-appb-100023
    Figure PCTCN2018093090-appb-100024
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