WO2019149244A1 - Jak抑制剂及其应用 - Google Patents

Jak抑制剂及其应用 Download PDF

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WO2019149244A1
WO2019149244A1 PCT/CN2019/074145 CN2019074145W WO2019149244A1 WO 2019149244 A1 WO2019149244 A1 WO 2019149244A1 CN 2019074145 W CN2019074145 W CN 2019074145W WO 2019149244 A1 WO2019149244 A1 WO 2019149244A1
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compound
group
pharmaceutically acceptable
isomer
acceptable salt
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PCT/CN2019/074145
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English (en)
French (fr)
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毛魏魏
吴颢
郑学建
胡国平
韦昌青
黎健
陈曙辉
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南京明德新药研发股份有限公司
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Priority to CN201980006488.XA priority Critical patent/CN111479810B/zh
Priority to US16/966,112 priority patent/US11427581B2/en
Publication of WO2019149244A1 publication Critical patent/WO2019149244A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/437—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 containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • 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

Definitions

  • the present invention relates to a class of compounds as JAK inhibitors, and to the use in the manufacture of a medicament for the treatment of JAK1 and TYK2-related diseases. Specifically, it relates to a compound of the formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof.
  • JAK belongs to the family of tyrosine kinases involved in inflammation, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving cartilage turnover, congenital cartilage malformations, and/or diseases associated with excessive secretion of IL6.
  • the present invention also provides a method for producing the compound, a pharmaceutical composition containing the same, and a disease for preventing and/or treating inflammation, autoimmune diseases, proliferative diseases, transplant rejection, and diseases involving cartilage turnover by administering the compound of the present invention.
  • the present invention provides a compound of the formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,
  • n 0 or 1
  • E 1 is a single bond, -CH 2 - or -NH-;
  • T 1 is CH or N
  • T 2 is C or N
  • Ring A is a 5-membered heteroaryl group
  • R 2 and R 3 are each independently H, F, Cl, Br, I, OH, NH 2 or CN;
  • R a is F, Cl, Br, I, OH and NH 2 ;
  • the 5-membered heteroaryl contains 1, 2, 3 or 4 heteroatoms or heteroatoms independently of -NH-, -O-, -S- or N.
  • R 2 is H, F, Cl, Br, I, OH, NH 2 or CN, and other variables are as defined herein.
  • E 1 , R 1 , R 2 and R 3 are as defined in the present invention.
  • the present invention also provides a compound of the formula, an isomer thereof or a pharmaceutically acceptable salt thereof,
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, 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 pharmaceutical composition for the preparation of a medicament for treating JAK1 and TYK2-related diseases.
  • the above application is characterized in that the medicament is a medicament for the treatment of rheumatoid arthritis.
  • the series of compounds of the present invention exhibit good selective inhibition of both TYK2 and JAK1 subtypes in in vitro activity assays of four subtypes of JAK kinase (JAK1, JAK2, JAk3 and TYK2), and these compounds are in mice. Higher exposures in pharmacokinetic experiments, good oral bioavailability, are conducive to producing excellent in vivo efficacy.
  • 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 amine or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of one another.
  • cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate a single bond due to a double bond or a ring-forming carbon atom.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirrored relationship.
  • wedge-shaped dashed keys Represents the absolute configuration of a solid center with straight solid keys
  • straight dashed keys Indicates the relative configuration of the stereocenter, using wavy lines Indicates a wedge solid key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid key And straight dashed keys
  • tautomer or “tautomeric form” mean that the different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. If tautomers are possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions by proton transfer, such as keto-enol isomerization and imine-enes. Amine isomerization.
  • the valence tautomer includes the mutual transformation of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms "enriched in one isomer”, “isomer enriched”, “enriched in one enantiomer” or “enantiomeric enriched” refer to one of the isomers or pairs
  • the content of the oligo is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or greater than or equal to 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomeric excess (ee value) is 80%. .
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C).
  • hydrogen can be replaced by heavy hydrogen to form a deuterated drug.
  • the bond composed of barium and carbon is stronger than the bond composed of common hydrogen and carbon.
  • deuterated drugs have reduced side effects and increased drug stability. Enhance the efficacy and prolong the biological half-life of the drug.
  • Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • “Optional” or “optionally” means that the subsequently described event or condition may, but is not necessarily, to occur, and that the description includes instances in which the event or condition occurs and instances in which the event or condition does not occur.
  • 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 is a single bond, it means that the two groups to which it is attached are directly connected.
  • 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.
  • X when X is vacant in A-X, the structure is actually A.
  • substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group.
  • the medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B. It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl.
  • the ring includes a single ring, and also includes a bicyclic or polycyclic ring system such as a spiro ring, a ring and a bridge ring.
  • 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.
  • the "5-7 membered ring” includes, for example, phenyl, pyridyl and piperidinyl; on the other hand, the term “5-7 membered heterocycloalkyl” includes pyridyl and piperidinyl, but does not include phenyl.
  • the term “ring” also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • alkyl is used to mean a straight or branched saturated hydrocarbon group, and in some embodiments, the alkyl group is a C 1-12 alkyl group; in other embodiments The alkyl group is a C 1-6 alkyl group; in other embodiments, the alkyl group is a C 1-3 alkyl group. It may be monosubstituted (such as -CH 2 F) or polysubstituted (such as -CF 3 ), and may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). .
  • alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl) And t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl and the like.
  • alkenyl is used to indicate a straight or branched hydrocarbon group containing one or more carbon-carbon double bonds, and the carbon-carbon double bond may be located at any position of the group.
  • the alkenyl group is a C 2-8 alkenyl group; in other embodiments, the alkenyl group is a C 2-6 alkenyl group; in other embodiments, the alkenyl group is C 2-4 alkenyl. It may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl and the like.
  • alkynyl is used to indicate a straight or branched hydrocarbon group containing one or more carbon-carbon triple bonds, and the carbon-carbon triple bond may be located at any position of the group.
  • the alkynyl group is a C 2-8 alkynyl group; in other embodiments, the alkynyl group is a C 2-6 alkynyl group; in other embodiments, the alkynyl group is C 2-4 alkynyl. It may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.
  • heteroalkyl by itself or in conjunction with another term, denotes a stable straight or branched alkyl radical or a combination thereof consisting of a number of carbon atoms and at least one heteroatom or heteroatom. Things.
  • the hetero atom is B, O, N or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroalkyl group is a C1-6 heteroalkyl group; in other embodiments, the heteroalkyl group is a C1-3 heteroalkyl group.
  • a heteroatom or heteroatom can be located at any internal position of a heteroalkyl group, including the position at which the alkyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkyl) Oxyl) 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.
  • heteroalkenyl by itself or in conjunction with another term, denotes a stable straight or branched alkenyl radical or a combination thereof consisting of a number of carbon atoms and at least one heteroatom or heteroatom. Things.
  • the hetero atom is B, O, N or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroalkenyl group is a C 2-6 heteroalkenyl group; in other embodiments, the heteroalkyl group is a C 2-4 heteroalkenyl group.
  • the hetero atom or heteroatom group may be located at any internal position of the heteroalkenyl group, including the position at which the alkenyl group is attached to the rest of the molecule, but the terms "alkenyloxy”, “alkenylamino” and “alkenylthio” are customary. By expression, it is meant those alkenyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • heteroalkynyl by itself or in conjunction with another term, denotes a stable straight or branched alkynyl radical or a combination thereof consisting of a number of carbon atoms and at least one heteroatom or heteroatom. Things.
  • the hetero atom is B, O, N or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroalkynyl group is a C 2-6 heteroalkynyl group; in other embodiments, the heteroalkyl group is a C 2-4 heteroalkynyl group.
  • hetero atom or heteroatom group may be located at any internal position of the heteroalkynyl group, including the position at which the alkynyl group is attached to the rest of the molecule, but the terms "alkynyloxy", “alkynylamino” and “alkynylthio” are customary. By expression, it is meant those alkynyl groups attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • heteroalkynyl groups include, but are not limited to, Up to two heteroatoms can be continuous, for example
  • cycloalkyl includes any stable cyclic alkyl group including monocyclic, bicyclic or tricyclic systems wherein the bicyclic and tricyclic systems include spiro, co and ring.
  • the cycloalkyl group is a C 3-8 cycloalkyl group; in other embodiments, the cycloalkyl group is a C 3-6 cycloalkyl group; in other embodiments, the The cycloalkyl group is a C 5-6 cycloalkyl group. It may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0] Dicyclodecane and the like.
  • cycloalkenyl includes any stable cyclic alkenyl group containing one or more unsaturated carbon-carbon double bonds at any position of the group, including monocyclic, bicyclic or tricyclic The system wherein the bicyclic and tricyclic systems include spiro, parallel and bridged rings, but any ring of this system is non-aromatic.
  • the cycloalkenyl group is a C 3-8 cycloalkenyl group; in other embodiments, the cycloalkenyl group is a C 3-6 cycloalkenyl group; in other embodiments, the The cycloalkenyl group is a C 5-6 cycloalkenyl group.
  • cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.
  • cycloalkynyl includes any stable cyclic alkynyl group containing one or more carbon-carbon triple bonds at any position of the group, including monocyclic, bicyclic or tricyclic systems, wherein Bicyclic and tricyclic systems include spiro, parallel and bridging rings. It may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • heterocycloalkyl by itself or in conjunction with other terms, denotes a cyclized “heteroalkyl”, respectively, which includes monocyclic, bicyclic, and tricyclic systems, wherein the bicyclic and tricyclic systems include spiro rings, And ring and bridge ring. Further, in the case of the "heterocycloalkyl group", a hetero atom may occupy a position where a heterocycloalkyl group is bonded to the rest of the molecule.
  • the heterocycloalkyl group is a 4-6 membered heterocycloalkyl group; in other embodiments, the heterocycloalkyl group is a 5-6 membered heterocycloalkyl group.
  • heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophene) -2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and
  • heterocyclenyl by itself or in conjunction with other terms, denotes a cyclized “heteroalkenyl”, respectively, which includes monocyclic, bicyclic, and tricyclic systems, wherein the bicyclic and tricyclic systems include spiro rings, Rings and bridge rings, but any ring of this system is non-aromatic.
  • a heteroatom can occupy the position of attachment of the heterocyclenyl group to the rest of the molecule.
  • the heterocycloalkenyl is 4 to 6 membered heterocycloalkenyl; in other embodiments, the heterocycloalkenyl is 5 to 6 membered heterocycloalkenyl.
  • heterocycloalkenyl groups include, but are not limited to,
  • heterocycloalkynyl by itself or in conjunction with other terms, denotes a cyclized “heteroalkynyl” group, respectively, which includes monocyclic, bicyclic, and tricyclic systems, wherein the bicyclic and tricyclic systems include spiro rings, And ring and bridge ring.
  • a hetero atom may occupy a position where a heterocyclic alkynyl group is bonded to the rest of the molecule.
  • the heterocycloalkynyl group is a 4 to 6 membered heterocycloalkynyl group; in other embodiments, the heterocycloalkynyl group is a 5 to 6 membered heterocycloalkynyl group.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom. Further, the term “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. Unless otherwise specified, 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.
  • the alkoxy group is a C 1-3 alkoxy group.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, and S- Pentyloxy.
  • aromatic ring and “aryl” are used interchangeably and the term “aryl ring” or “aryl” means a polyunsaturated carbocyclic ring system which may be monocyclic, bicyclic or poly A ring system in which at least one ring is aromatic, and each ring in the bicyclic and polycyclic ring system is fused together. It may be mono- or poly-substituted, may be monovalent, divalent or multivalent, in some embodiments, the aryl is a C 6-12 aryl; in other embodiments, the aryl It is a C 6-10 aryl group.
  • aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, and the like).
  • the substituent of any of the above aryl ring systems is an acceptable substituent as described herein.
  • heteroaryl ring and “heteroaryl” are used interchangeably and the term “heteroaryl” means 1, 2, 3 or 4 independently B, N, O or S.
  • An aryl (or aromatic ring) of a hetero atom which may be a monocyclic, bicyclic or tricyclic ring system wherein the nitrogen atom may be substituted or unsubstituted (ie, N or NR, wherein R is H or has been defined herein)
  • the other substituents that have passed, and optionally are quaternized, the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • the heteroaryl is a 5-10 membered heteroaryl; in other embodiments, the heteroaryl is a 5-6 membered heteroaryl.
  • the heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.) , imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.) , triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4- Triazolyl
  • aralkyl is intended to include those groups in which an aryl group is attached to an alkyl group.
  • the aralkyl group is a C6-10 aryl- C1-4 alkyl group.
  • the aralkyl group is a C 6-10 aryl-C 1-2 alkyl group. Examples of aralkyl groups include, but are not limited to, benzyl, phenethyl, naphthylmethyl, and the like.
  • Aryloxy and "arylthio” mean those groups wherein the carbon atom (e.g., methyl) in the aralkyl group has been replaced by an oxygen or sulfur atom, and in some embodiments, the aryloxy group is C. 6-10 Aryl-OC 1-2 alkyl; in other embodiments, the aryloxy group is C 6-10 aryl-C 1-2 alkyl-O-. In some embodiments, the arylthio group is a C 6-10 aryl-SC 1-2 alkyl group; in other embodiments, the arylthio group is a C 6-10 aryl-C 1-2 alkyl group. -S-. Examples of aryloxy and arylthio groups include, but are not limited to, phenoxymethyl, 3-(1-naphthyloxy)propyl, phenylthiomethyl, and the like.
  • heteroarylkyl is meant to include those heteroaryl groups attached to an alkyl group, in some embodiments, the heteroaryl group is a 5-8 membered heteroaryl -C 1 -4 alkyl; in other embodiments, the heteroarylalkyl group is a 5-6 membered heteroaryl-C 1-2 alkyl group.
  • heteroarylalkyl include, but are not limited to, pyrrolylmethyl, pyrazolylmethyl, pyridylmethyl, pyrimidinylmethyl, and the like.
  • Heteroaryloxy and “heteroarylthio” mean those groups in which the carbon atom (eg, methyl) in the heteroaralkyl group has been replaced by an oxygen or sulfur atom, respectively, and in some embodiments, the heteroaryl The oxy group is a 5-8 membered heteroaryl-OC 1-2 alkyl group; in other embodiments, the heteroaryloxy group is a 5-6 membered heteroaryl-C 1-2 alkyl-O- group. In some embodiments, the heteroarylthio group is a 5-8 membered heteroaryl-SC 1-2 alkyl group; in other embodiments, the heteroarylthio group is a 5-6 membered heteroaryl-C 1 -2 alkyl-S-.
  • heteroaryloxy and heteroarylthio groups include, but are not limited to, pyrroleoxymethyl, pyrazolyloxymethyl, 2-pyridyloxymethyl, pyrrolethiomethyl, pyrazolethiomethyl, 2-pyridinethiomethyl Wait.
  • C n-n+m or C n -C n+m includes any one of n to n+m carbons, for example, C 1-12 includes 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 , also including any range of n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; similarly, n to n
  • the +m element indicates that the number of atoms on the ring is n to n+m, for example, the 3-12 element ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membere
  • a 10-membered ring, a 11-membered ring, and a 12-membered ring and includes any one of n to n+m, for example, a 3-12-membered ring including a 3-6-membered ring, a 3-9-membered ring, and a 5-6-membered ring. Ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • Figure 4 Inhibition rate of each administration group relative to the solvent control group.
  • the compound 1-6 is used as a common intermediate, and is prepared by the same amide condensation synthesis method as the compound 1-7 (adding a cyclopropyl carboxylic acid differently substituted with the compound 1-7) as the following compound 1-8, 1-9,
  • the characterization data of 1-10, 1-11, 1-12 are as follows:
  • JAK2, JAK3 and TYK2 dilution 20 mM MOPS, 1 mM EDTA, 0.01% Brij-35.5% glycerol, 0.1% ⁇ -mercaptoethanol, 1 mg/mL BSA; JAK1 dilution: 20 mM TRIS, 0.2 mM EDTA, 0.1% ⁇ -mercaptoethanol, 0.01% Brij-35.5% glycerol. All compounds were prepared in 100% DMSO solution and reached a final assay concentration of 50 fold. The test compound was subjected to a 3-fold concentration gradient dilution at a final concentration of 9 ⁇ M to 0.001 ⁇ M, and the content of DMSO in the assay reaction was 2%. The working stock of the compound was added to the assay well as the first component of the reaction and the remaining components were added according to the protocol detailed below.
  • JAK1 (h) was incubated with 20 mM Tris/HCl pH 7.5, 0.2 mM EDTA, 500 ⁇ M MGEEPLYWSFPAKKK, 10 mM magnesium acetate and [ ⁇ - 33 P]-ATP (activity and concentration as needed). The reaction was started by adding a Mg/ATP mixture, and after incubation at room temperature for 40 minutes, the reaction was terminated by the addition of 0.5% phosphoric acid. 10 [mu]L of the reaction was then spotted on a P30 filter pad and washed three times with 0.425% phosphoric acid and once with methanol for 4 minutes, dried and scintillation counted.
  • JAK3 (h) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 500 ⁇ M GGEEEEYFELVKKKK, 10 mM magnesium acetate and [ ⁇ - 33 P]-ATP (activity and concentration as needed). The reaction was started by adding a Mg/ATP mixture, and after incubation at room temperature for 40 minutes, the reaction was terminated by the addition of 0.5% phosphoric acid. 10 [mu]L of the reaction was then spotted on a P30 filter pad and washed three times with 0.425% phosphoric acid and once with methanol for 4 minutes, dried and scintillation counted.
  • TYK2 (h) was incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 ⁇ M GGMEDIYFEFMGGKKK, 10 mM magnesium acetate and [ ⁇ - 33 P]-ATP (activity and concentration as needed). The reaction was started by adding a Mg/ATP mixture, and after incubation at room temperature for 40 minutes, the reaction was terminated by the addition of 0.5% phosphoric acid. 10 [mu]L of the reaction was then spotted on a P30 filter pad and washed three times with 0.425% phosphoric acid and once with methanol for 4 minutes, dried and scintillation counted.
  • NA indicates no detection.
  • AUC 0-inf area under the plasma concentration-time curve from time 0 to extrapolation to infinity
  • Bioavailability Bioavailability.
  • the compounds of the present invention have good oral bioavailability in mice, and high exposure is beneficial to produce good in vivo efficacy.
  • Rheumatoid arthritis is a type of multiple autoimmune disease that causes inflammation, damage, and deformity of joints due to autoimmune reactions. In severe cases, it causes systemic systemic inflammatory reactions.
  • the adjuvant-induced arthritis rat model is one of the animal models commonly used in rheumatoid arthritis disease research and new drug development, and its pathogenesis and clinical symptoms are similar to human rheumatoid arthritis diseases.
  • the model induces a systemic response to immune cells and antibodies with bone and joint damage through injection of tuberculosis branches in the footpad, which is manifested in joint swelling, osteolysis, synovial damage and other symptoms similar to human rheumatoid arthritis.
  • the rats were anesthetized (isoflurane) in an anesthesia machine, and immunized after anesthesia.
  • the site was the left paw of the rat, and 0.1 ml was injected subcutaneously.
  • the normal group (5 rats) was injected with 0.1 ml of paraffin oil, and the immune site was subcutaneously placed on the left foot of the rat.
  • the first injection of the adjuvant was the 0th day.
  • Table 1 the doses for each group are shown in Table 3 below. Twice a day for a total of 14 days.
  • Weight Weighed three times from day 13 to week 27.
  • Foot volume measured once before immunization, measured three times from day 13 to week 27.
  • the experimental data were expressed as mean ⁇ standard error (Mean ⁇ SEM), and the area under the full volume curve (AUC) was analyzed by one-way ANOVA, p ⁇ 0.05 was considered significant.
  • Dexamethasone (dexamethasone, Dex.) 0.3mg/kg treatment significantly inhibited the collagen-induced arthritis clinical score, and the clinical score was maintained at around 2.0 points from the 23rd day until the end of the experiment.
  • the area under the curve AUC was calculated by analyzing the foot volume curve of each animal in each group, and the inhibition rate of each administration group relative to the solvent control group was calculated by the average value of AUC between the groups, and the results are shown in Fig. 4.
  • the inhibition rates of compound 4-3 (15 mg/kg) and compound 8-2 (5 mg/kg and 15 mg/kg) in the administration group were 32.3%, 38.0% and 44.5%, and the AUC of each group was compared with the solvent control group. There were significant differences (p values of 0.0011, ⁇ 0.0001 and ⁇ 0.0001, respectively) in a dose-dependent manner (p value was ⁇ 0.01 compared to the low dose group AUC compared to the low dose group).
  • the inhibition rate of Dexamethasone was 44.9%. (Figure 4).

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Abstract

本发明公开了作为JAK抑制剂的一类化合物，以及在制备治疗JAK和TYK2相关疾病的药物中的应用。具体公开了式（Ⅰ）所示化合物、其异构体或其药学上可接受的盐。

Description

JAK抑制剂及其应用
本申请主张如下优先权：
CN201810096070.X，申请日2018.01.31；
CN201810967605.6，申请日2018.08.23。
技术领域
本发明涉及作为JAK抑制剂的一类化合物，以及在制备治疗JAK1和TYK2相关疾病的药物中的应用。具体涉及式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐。
背景技术
JAK属于参与炎症、自身免疫疾病、增殖性疾病、移植排斥、涉及软骨更新(turnover)受损的疾病、先天软骨畸形和/或与IL6分泌过多相关的疾病的酪氨酸激酶家族。本发明还提供所述化合物、含有所述化合物的药物组合物的生产方法和通过施用本发明化合物预防和/或治疗炎症、自身免疫疾病、增殖性疾病、移植排斥、涉及软骨更新受损的疾病、先天软骨畸形和/或与IL6分泌过多相关的疾病的方法。
Janus激酶(JAK)是转导细胞因子信号从膜受体到STAT转录因子的细胞质酪氨酸激酶。现有技术已经描述了四种JAK家族成员：JAK1、JAK2、JAK3和TYK2。当细胞因子与其受体结合时，JAK家族成员自磷酸化和/或彼此转磷酸化，随后STATs磷酸化，然后迁移至细胞核内以调节转录。JAK-STAT细胞内信号转导适用于干扰素、大多数白细胞介素以及多种细胞因子和内分泌因子，例如EPO、TPO、GH、OSM、LIF、CNTF、GM-CSF和PRL(Vainchenker W.等人(2008))。
遗传学模型和小分子JAK抑制剂的组合研究揭示了几种JAKs的治疗潜能。通过小鼠和人遗传学确证JAK3是免疫抑制靶点(O’Shea J.等人(2004))。JAK3抑制剂成功用于临床开发，最初用于器官移植排斥，但后来也用于其它免疫炎性适应证，例如类风湿性关节炎(RA)、银屑病和克隆病(http：//clinicaltrials.gov/)。TYK2是免疫炎性疾病的潜在靶点，已经通过人遗传学和小鼠剔除研究确证(Levy D.和Loomis C.(2007))。JAK1是免疫炎性疾病领域的新靶点。将JAK1与其它JAKs杂二聚化以转导细胞因子驱动的促炎信号传导。因此，预期抑制JAK1和/或其它JAK对于一系列炎性病症和其它由JAK介导的信号转导驱动的疾病是具有治疗益处的。
发明内容
本发明提供了式(Ⅰ)化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2019074145-appb-000001
其中，
Figure PCTCN2019074145-appb-000002
为单键或双键；
m为0或1；
n为0或1；
E 1为单键、-CH 2-或-NH-；
T 1为CH或N；
T 2为C或N；
T 3为CH或N；
环A为5元杂芳基；
R 1为H、F、Cl、Br、I、OH、NH 2、CN和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R a取代；
R 2、R 3分别独立地为H、F、Cl、Br、I、OH、NH 2或CN；
R a为F、Cl、Br、I、OH和NH 2；
所述5元杂芳基包含1、2、3或4个独立为-NH-、-O-、-S-或N的杂原子或杂原子团。
本发明的一些方案中，上述R 1为H、F、Cl、Br、I、OH、NH 2、CN或和Me，其他变量如本发明所定义。
本发明的一些方案中，上述R 2为H、F、Cl、Br、I、OH、NH 2或CN，其他变量如本发明所定义。
本发明的一些方案中，上述R 3为H、F、Cl、Br、I或OH，其他变量如本发明所定义。
本发明的一些方案中，上述环A为1,2,4-三唑基或噻唑基，其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2019074145-appb-000003
为
Figure PCTCN2019074145-appb-000004
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2019074145-appb-000005
为
Figure PCTCN2019074145-appb-000006
其他变量如本发明所定义。
本发明还有一些方案，是由上述变量任意组合而来。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其化合物为
Figure PCTCN2019074145-appb-000007
其中，
E 1、R 1、R 2和R 3如本发明所定义。
本发明还提供了下式化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2019074145-appb-000008
Figure PCTCN2019074145-appb-000009
本发明的一些方案中，上述的化合物、其异构体或其药学上可接受的盐，其化合物为
Figure PCTCN2019074145-appb-000010
本发明还提供了一种药物组合物，包括治疗有效量的作为活性成分的上述的化合物、其异构体或其药学上可接受的盐以及药学上可接受的载体。
本发明还提供了上述化合物或其药学上可接受的盐或上述的药物组合物在制备治疗JAK1和TYK2相关疾病的药物中的应用。
本发明的一些方案中，上述的应用，其特征在于，所述药物是用于类风湿性关节炎治疗的药物。
技术效果
本发明的系列化合物在JAK激酶4个亚型(JAK1、JAK2、JAk3和TYK2)的体外活性实验中展现了对TYK2和JAK1两种亚型的良好选择性抑制作用，并且这些化合物在小鼠的药代动力学实验中表现出较高的暴露量,良好的口服生物利用度,有利于产生优良的体内药效。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及 其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2019074145-appb-000011
和楔形虚线键
Figure PCTCN2019074145-appb-000012
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2019074145-appb-000013
和直形虚线键
Figure PCTCN2019074145-appb-000014
表示立体中心的相对构型，用波浪线
Figure PCTCN2019074145-appb-000015
表示楔形实线键
Figure PCTCN2019074145-appb-000016
或楔形虚线键
Figure PCTCN2019074145-appb-000017
或用波浪线
Figure PCTCN2019074145-appb-000018
表示直形实线键
Figure PCTCN2019074145-appb-000019
和直形虚线键
Figure PCTCN2019074145-appb-000020
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异 构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量为单键时，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 PCTCN2019074145-appb-000021
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 PCTCN2019074145-appb-000022
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 PCTCN2019074145-appb-000023
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、、-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。所述的环包括单环，也包括螺环、并环和桥环等双环或多环体系。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、吡啶基和哌啶基；另一方面，术语“5～7元杂环烷基”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“烷基”用于表示直链或支链的饱和的碳氢基团，在一些实施方案中，所述烷基为C 1-12烷基；在另一些实施方案中，所述烷基为C 1-6烷基；在另一些实施方案中，所述烷基为C 1-3烷基。其可以是单取代(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)。烷基的实例包括但不限于甲基(Me)，乙基(Et)，丙基(包括n-丙基和异丙基)，丁基(包括n-丁基，异丁基，s-丁基和t-丁基)，戊基(包括n-戊基，异戊基和新戊基)、己基等。
除非另有规定，“烯基”用于表示直链或支链的包含一个或多个碳-碳双键的碳氢基团，碳-碳双键可以位于该基团的任何位置上。在一些实施方案中，所述烯基为C 2-8烯基；在另一些实施方案中，所述烯基为C 2-6烯基；在另一些实施方案中，所述烯基为C 2-4烯基。其可以是单取代或多取代的，可以是一价、二价或者多价。烯基的实例包括但不限于乙烯基，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”用于表示直链或支链的包含一个或多个碳-碳三键的碳氢基团，碳-碳三键可以位于该基团的任何位置上。在一些实施方案中，所述炔基为C 2-8炔基；在另一些实施方案中，所述炔基为C 2-6炔基；在另一些实施方案中，所述炔基为C 2-4炔基。其可以是单取代或多取代的，可以是一价、二价或者多价。炔基的实例包括但不限于乙炔基，丙炔基，丁炔基，戊炔基等。
除非另有规定，术语“杂烷基”本身或者与另一术语联合，表示由一定数目碳原子和至少一个杂原子或杂原子团组成的，稳定的直链或支链的烷基原子团或其组合物。在一些实施方案中，杂原子为B、O、N或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。在另一些实施方案中，杂原子团为-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-或-S(＝O)N(H)-。在一些实施方案中，所述杂烷基为C 1-6杂烷基；在另一些实施方案中，所述杂烷基为C 1-3杂烷基。杂原子或杂原子团可以位于杂烷基的任何内部位置，包括该烷基与分子其余部分的连接位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨 基或硫原子连接到分子的其余部分的那些烷基基团。杂烷基的实例包括但不限于-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH 2(CH 3) 2、-CH 2-CH 2-O-CH 3、-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)(CH 2CH 3)、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-SCH 3、-SCH 2CH 3、-SCH 2CH 2CH 3、-SCH 2(CH 3) 2、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(＝O)-CH 3、-CH 2-CH 2-S(＝O) 2-CH 3、-CH＝CH-O-CH 3、-CH 2-CH＝N-OCH 3和–CH＝CH-N(CH 3)-CH 3。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。
除非另有规定，术语“杂烯基”本身或者与另一术语联合，表示由一定数目碳原子和至少一个杂原子或杂原子团组成的，稳定的直链或支链的烯基原子团或其组合物。在一些实施方案中，杂原子为B、O、N或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。在另一些实施方案中，杂原子团为-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-或-S(＝O)N(H)-。在一些实施方案中，所述杂烯基为C 2-6杂烯基；在另一些实施方案中，所述杂烷基为C 2-4杂烯基。杂原子或杂原子团可以位于杂烯基的任何内部位置，包括该烯基与分子其余部分的连接位置，但术语“烯基氧基”、“烯基氨基”和“烯基硫基”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烯基基团。杂烯基的实例包括但不限于-O-CH＝CH 2、-O-CH＝CHCH 3、-O-CH＝C(CH 3) 2、-CH＝CH-O-CH 3、-O-CH＝CHCH 2CH 3、-CH 2-CH＝CH-OCH 3、-NH-CH＝CH 2、-N(CH＝CH 2)-CH 3、-CH＝CH-NH-CH 3、-CH＝CH-N(CH 3) 2、-S-CH＝CH 2、-S-CH＝CHCH 3、-S-CH＝C(CH 3) 2、-CH 2-S-CH＝CH 2、-S(＝O)-CH＝CH 2和-CH＝CH-S(＝O) 2-CH 3。至多两个杂原子可以是连续的，例如-CH＝CH-NH-OCH 3。
除非另有规定，术语“杂炔基”本身或者与另一术语联合，表示由一定数目碳原子和至少一个杂原子或杂原子团组成的，稳定的直链或支链的炔基原子团或其组合物。在一些实施方案中，杂原子为B、O、N或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。在另一些实施方案中，杂原子团为-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-或-S(＝O)N(H)-。在一些实施方案中，所述杂炔基为C 2-6杂炔基；在另一些实施方案中，所述杂烷基为C 2-4杂炔基。杂原子或杂原子团可以位于杂炔基的任何内部位置，包括该炔基与分子其余部分的连接位置，但术语“炔基氧基”、“炔基氨基”和“炔基硫基”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炔基基团。杂炔基的实例包括但不限于
Figure PCTCN2019074145-appb-000024
Figure PCTCN2019074145-appb-000025
Figure PCTCN2019074145-appb-000026
至多两个杂原子可以是连续的，例如
Figure PCTCN2019074145-appb-000027
除非另有规定，“环烷基”包括任何稳定的环状烷基，其包括单环、双环或者三环体系，其中双环和 三环体系包括螺环、并环和桥环。在一些实施方案中，所述环烷基为C 3-8环烷基；在另一些实施方案中，所述环烷基为C 3-6环烷基；在另一些实施方案中，所述环烷基为C 5-6环烷基。其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、环丁基、环戊基、环己基、环庚基、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烯基，在该基团的任何位点含有一个或多个不饱和的碳-碳双键，其包括单环、双环或者三环体系，其中双环和三环体系包括螺环、并环和桥环，但是此体系的任意环都是非芳香性的。在一些实施方案中，所述环烯基为C 3-8环烯基；在另一些实施方案中，所述环烯基为C 3-6环烯基；在另一些实施方案中，所述环烯基为C 5-6环烯基。其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炔基，在该基团的任何位点含有一个或多个碳-碳三键，其包含单环、双环或者三环体系，其中双环和三环体系包括螺环、并环和桥环。其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“杂环烷基”本身或者与其他术语联合分别表示环化的“杂烷基”，其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。此外，就该“杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。在一些实施方案中，所述杂环烷基为4～6元杂环烷基；在另一些实施方案中，所述杂环烷基为5～6元杂环烷基。杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或氧杂环庚烷基。
除非另有规定，术语“杂环烯基”本身或者与其他术语联合分别表示环化的“杂烯基”，其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环，但是此体系的任意环都是非芳香性的。此外，就该“杂环烯基”而言，杂原子可以占据杂环烯基与分子其余部分的连接位置。在一些实施方案中，所述杂环烯基为4～6元杂环烯基；在另一些实施方案中，所述杂环烯基为5～6元杂环烯基。杂环烯基的实例包括但不限于
Figure PCTCN2019074145-appb-000028
Figure PCTCN2019074145-appb-000029
除非另有规定，术语“杂环炔基”本身或者与其他术语联合分别表示环化的“杂炔基”，其包括单环、 双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。此外，就该“杂环炔基”而言，杂原子可以占据杂环炔基与分子其余部分的连接位置。在一些实施方案中，所述杂环炔基为4～6元杂环炔基；在另一些实施方案中，所述杂环炔基为5～6元杂环炔基。除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(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。在一些实施方案中，所述烷氧基为C 1-3烷氧基。烷氧基的实例包括但不限于：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，本发明术语“芳环”和“芳基”可以互换使用，术语“芳环”或“芳基”表示多不饱和的碳环体系，它可以是单环、双环或多环体系，其中至少一个环是芳香性的，所述双环和多环体系中的各个环稠合在一起。其可以是单取代或多取代的，可以是一价、二价或者多价，在一些实施方案中，所述芳基为C 6-12芳基；在另一些实施方案中，所述芳基为C 6-10芳基。芳基的实例包括但不限于苯基、萘基(包括1-萘基和2-萘基等)。上述任意一个芳基环系的取代基为本发明所述的可接受的取代基。
除非另有规定，本发明术语“杂芳环”和“杂芳基”可以互换使用，术语“杂芳基”是指含有1、2、3或4个独立为B、N、O或S的杂原子的芳基(或芳环)，其可以是单环、双环或三环体系，其中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)，且任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。杂芳基可通过杂原子连接到分子的其余部分。在一些实施方案中，所述杂芳基为5-10元杂芳基；在另一些实施方案中，所述杂芳基为5-6元杂芳基。所述杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基、嘧啶基(包括2-嘧啶基和4-嘧啶基等)、苯并噻唑基(包括5-苯并噻唑基等)、嘌呤基、苯并咪唑基(包括2-苯并咪唑基等)、吲哚基(包括5-吲哚基等)、异喹啉基(包括1-异喹啉基和5-异喹啉基等)、喹喔啉基(包括2-喹喔啉基和5-喹喔啉基等)、喹啉基(包括3-喹啉基和6-喹啉基等)、吡嗪基、嘌呤基、苯基并噁唑基。上述任意一个杂芳基环系的取代基为本发明所述的可接受的取代基。
除非另有规定，术语“芳烷基”意在包括芳基附着于烷基的那些基团，在一些实施方案中，所述芳烷基为C 6-10芳基-C 1-4烷基；在另一些实施方案中，所述芳烷基为C 6-10芳基-C 1-2烷基。芳烷基的实例包括但不限于苄基、苯乙基、萘甲基等。“芳氧基”和“芳硫基”分别表示芳烷基中的碳原子(如甲基)已经被氧或硫原子代替的那些基团，在一些实施方案中，所述芳氧基为C 6-10芳基-O-C 1-2烷基；在另一些实施方案中，芳氧基为C 6-10芳基-C 1-2烷基-O-。在一些实施方案中，所述芳硫基为C 6-10芳基-S-C 1-2烷基；在另一些实施方案中，芳硫基为C 6-10芳基-C 1-2烷基-S-。芳氧基和芳硫基的实例包括但不限于苯氧基甲基、3-(1-萘氧基)丙基，苯硫基甲基等。
除非另有规定，术语“杂芳烷基”意在包括杂芳基附着于烷基的那些基团，在一些实施方案中，所述杂芳烷基为5-8元杂芳基-C 1-4烷基；在另一些实施方案中，所述杂芳烷基为5-6元杂芳基-C 1-2烷基。杂芳烷基的实例包括但不限于吡咯基甲基、吡唑基甲基、吡啶基甲基、嘧啶基甲基等。“杂芳氧基”和“杂芳硫基”分别表示杂芳烷基中的碳原子(如甲基)已经被氧或硫原子代替的那些基团，在一些实施方案中，所述杂芳氧基为5-8元杂芳基-O-C 1-2烷基；在另一些实施方案中，杂芳氧基为5-6元杂芳基-C 1-2烷基-O-。在一些实施方案中，所述杂芳硫基为5-8元杂芳基-S-C 1-2烷基；在另一些实施方案中，杂芳硫基为5-6元杂芳基-C 1-2烷基-S-。杂芳氧基和杂芳硫基的实例包括但不限于吡咯氧甲基、吡唑氧甲基、2-吡啶氧甲基、吡咯硫甲基、吡唑硫甲基、2-吡啶硫甲基等。
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1-3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
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；Pd(dppf)Cl 2代表[1,1'-双(二苯基膦基)二茂铁]二氯化钯；EDCI代表碳化二亚胺；DIEA代表N,N-二异丙基乙胺；IPA代表异丙醇；HOBt代表1-羟基苯并三唑；LiHMDS代表六甲基二硅基胺基锂；TEA代表三乙基胺；HEPES代表4-羟乙基哌嗪乙磺酸。
化合物经手工或者
Figure PCTCN2019074145-appb-000030
软件命名，市售化合物采用供应商目录名称。
附图说明：
图1：关节炎小鼠体重变化；
图2：关节炎临床评分；
图3：足体积变化曲线；
图4：各给药组相对于溶剂对照组的抑制率。
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。
实施例1
Figure PCTCN2019074145-appb-000031
步骤1：制备化合物1-2
往溶有6-溴吡啶-2-胺(30g，173.4mmol)的二氯甲烷(400mL)中慢慢滴加异硫氰酸乙酯(25.0g，190.7mmol)，加完后25℃反应16个小时。TLC监测显示反应完全后，反应液减压蒸馏，得到的残余物用200mL石油醚搅拌洗涤30分钟，过滤，收集滤饼干燥得到化合物1-2. 1H NMR(400MHz,DMSO-d 6)δ＝12.17(s,1H),11.66(br.s.,1H),8.65(d,J＝7.54Hz,1H),7.82(t,J＝7.92Hz,1H),7.49(d,J＝7.78Hz,1H),4.22(q,J＝7.18Hz,2H),1.25(t,J＝7.16Hz,3H).LCMS(ESI)m/z:304[M+H] +。
步骤2：制备化合物1-3
将盐酸羟胺(35.2g，503.1mmol)、二异丙基乙胺(54.1g，419.3mmol)溶于乙醇(500mL)和甲醇(500mL)的混合溶剂中25℃搅拌1小时后，加入化合物1-2(51.0g，167.7mmol)所得反应体系经氮气换气3次，加热到80℃反应3小时，冷却。TLC监测显示反应完全后，反应液减压蒸馏，得到的残留物用(500mL)水搅拌洗涤10分钟，过滤，收集滤饼干燥得到化合物1-3. 1H NMR(400MHz,DMSO-d 6)δ＝7.30-7.39(m,1H),7.20(dd,J＝6.78,1.76Hz,1H),6.27(s,2H).LCMS(ESI)m/z:215[M+H] +。
步骤3：制备化合物1-4
在0℃下，往溶有化合物1-3(15.0g,70.4mmol和三乙胺(21.4g，211.2mmol)的乙腈(150mL)中缓慢滴加环丙基甲酰氯(8.8g，84.5mmol)，加完后混合液升到室温反应16个小时。TLC监测显示原料反应完全后，反应液减压蒸馏，得到的残留物溶解于甲胺醇(150mL)溶液中，加热到80℃反应1小时，冷却，减压蒸馏再次得到残留物溶于水(100mL)和乙酸乙酯(200mL)的混合液中，分层萃取，合并有机相并用无水硫酸钠干燥，过滤，滤液减压蒸馏得到的粗产品用硅胶色谱柱法纯化(乙酸乙酯/石油醚＝0～70％洗脱)，得到化合物1-4. 1H NMR(400MHz,DMSO-d 6)δ＝11.20(br.s.,1H),7.68-7.73(m,1H),7.52-7.58(m,1H),7.46-7.51(m,1H),1.96-2.09(m,1H),0.82(d,J＝6.28Hz,4H).LCMS(ESI)m/z:282[M+H] +。
步骤4：制备化合物1-5
将溶有N-[4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)环己-3-烯-1-基]氨基甲酸叔丁酯(11g,34.0mmol),化合物1-4(7.6g,27.2mmol),K 2CO 3(14.11g,102.09mmol),Pd(dppf)Cl 2(2.49g,3.4mmol)的二氧六环(120mL)和水的体系(30mL)用氮气置换3次，在氮气保护下，该混合溶液在90℃下搅拌1.5小时。LCMS显示原料被消耗完，并监测到目标分子峰。将反应液减压浓缩，然后分散在100mL水中，用乙酸乙酯((150mL*3))萃取。合并有机相，并用无水硫酸钠干燥，过滤，滤液减压蒸馏得到的粗产品。用硅胶色谱柱法(乙酸乙酯/石油醚＝20～70％洗脱)纯化得到化合物1-5。LCMS(ESI)m/z:398[M+H] +。
步骤5：制备化合物1-6
将化合物1-5(12g,30.2mmol)和三氟乙酸(13.8g,120.8mmol,8.9mL)的二氯甲烷(120mL)溶液在25℃下搅拌5小时。LCMS显示原料消耗完全，并监测到目标分子离子峰。将反应液减压浓缩，残余物经饱和碳酸氢钠溶液调节pH＝8，并用二氯甲烷:甲醇(5:1,200mL*3)萃取。合并有机相，减压浓缩得到化合物1-6，未经纯化，直接用于下一步反应。LCMS(ESI)m/z:298[M+H] +。
步骤6：制备化合物1-7
向溶有2,2-二氟环丙烷羧酸(492mg,4.04mmol)的DMF(30mL)中分别加入EDCI(967mg,5.04mmol),HOBt(682mg,5.04mmol),DIEA(1.3g,10.1mmol,1.8mL)和化合物1-6(1g,3.36mmol)。该混合物在25℃下搅拌12小时。LCMS显示原料被消耗，并监测到目标分子峰。往反应混合物体系中加入60mL水，用乙酸乙酯(60mL*3)萃取。合并有机相，经饱和食盐水洗涤，硫酸钠干燥，过滤浓缩得到粗品。粗品经制备分离得到化合物1-7. 1H NMR(400MHz,METHANOL-d 4)δ0.93(dq,J＝7.43,3.63Hz,2H),1.01-1.09(m,2H),1.68-1.92(m,2H),2.02(td,J＝13.24,7.65Hz,2H),2.21-2.34(m,1H),2.50-2.87(m,4H),4.11-4.23(m,1H),4.59(s,1H),4.55-4.65(m,1H),6.58-6.67(m,1H),7.06(d,J＝7.28Hz,1H),7.52-7.57(m,1H),7.60-7.67(m,1H)。LCMS(ESI)m/z:402[M+H] +。
Figure PCTCN2019074145-appb-000032
以化合物1-6为共用中间体，运用与化合物1-7相同的酰胺缩合的合成方法制备(加入与化合物1-7不同取代的环丙基羧酸)如下化合物1-8,1-9,1-10,1-11,1-12表征数据如下：
化合物1-8： 1H NMR(400MHz,DMSO-d 6)δ0.72-0.92(m,4H),1.33-1.50(m,4H),1.68(td,J＝11.73,5.14Hz,1H),1.83-2.11(m,3H),2.27(br s,1H),2.57-2.86(m,3H),3.83-4.02(m,1H),3.83-4.02(m,1H),6.68-6.83(m,1H),7.04(dd,J＝6.15,2.13Hz,1H),7.53-7.66(m,2H),8.04(br dd,J＝7.28,5.02Hz,1H),11.01(br s,1H). LCMS(ESI)m/z:416[M+H] +。
化合物1-9： 1H NMR(400MHz,DMSO-d 6)δ0.75-0.88(m,4H),0.95-1.07(m,1H),1.44-2.28(m,7H),2.58-2.86(m,2H),3.94(br d,J＝2.51Hz,1H),4.63-5.01(m,1H),6.78(br s,1H),7.05(br d,J＝6.02Hz,1H),7.49-7.71(m,2H),8.07-8.25(m,1H),11.02(br s,1H).LCMS(ESI)m/z:384[M+H] +。
化合物1-10： 1H NMR(400MHz,DMSO-d 6)δ0.82(br s,4H),1.10(br dd,J＝12.55,6.27Hz,1H),1.27-1.45(m,1H),1.65(br d,J＝2.76Hz,1H),1.85-2.35(m,4H),2.59-2.82(m,1H),3.91(br d,J＝2.01Hz,1H),4.60-4.94(m,1H),6.78(br s,1H),7.05(br d,J＝4.52Hz,1H),7.59(br s,2H),8.34(br d,J＝7.03Hz,1H),11.03(br s,1H),10.91-11.15(m,1H).LCMS(ESI)m/z:384[M+H] +。
化合物1-11： 1H NMR(400MHz,DMSO-d 6)δ0.75-0.87(m,4H),1.47-1.60(m,4H),1.68-1.94(m,2H),1.96-2.07(m,1H),2.32-2.45(m,2H),2.57-2.82(m,2H),2.57-2.82(m,1H),3.83-4.06(m,1H),6.74(br s,1H),7.04(dd,J＝5.90,2.38Hz,1H),7.51-7.67(m,2H),8.12(br d,J＝7.78Hz,1H),11.02(br s,1H),10.95-11.11(m,1H).LCMS(ESI)m/z:391[M+H] +。
化合物1-12： 1H NMR(400MHz,DMSO-d 6)δ0.59-0.73(m,4H),0.78-0.90(m,4H),1.51-1.71(m,2H),1.86-2.25(m,3H),2.57-2.84(m,3H),3.92(br d,J＝3.26Hz,1H),6.78(br s,1H),7.06(dd,J＝6.27,2.01Hz,1H),7.49-7.70(m,2H),8.15(br d,J＝7.53Hz,1H),11.04(br s,1H).LCMS(ESI)m/z:366[M+H] +。
实施例2
Figure PCTCN2019074145-appb-000033
步骤1：制备化合物2-1
将溶有3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2,5-二氢吡咯-1-羧酸叔丁酯(0.3g,1.02mmol),化合物1-4(300mg,1.07mmol),K 2CO 3(421.39mg,3.05mmol),Pd(dppf)Cl2(74.36mg,101.63umol)的二氧六环(12mL)和水(3mL)体系用氮气置换3次，在氮气氛围内，该混合物在90℃下搅拌2小时。LCMS显示原料消耗完全，并监测到目标分子离子峰。将反应液减压浓缩干，经硅胶柱色谱分离得 到化合物2-1。LCMS(ESI)m/z:370[M+H] +。
步骤2：制备化合物2-2
将溶有化合物2-1(0.46g,1.25mmol)和三氟乙酸(3.08g,27.01mmol,2mL)的二氯甲烷(8mL)溶液在25℃下搅拌0.5小时。LCMS显示原料消耗完全，并监测到目标分子峰。将反应液减压浓缩，得到粗品化合物2-2，产品未经纯化，直接用于下一步。LCMS(ESI)m/z:270[M+H] +。
步骤3：制备化合物2-3
在氩气氛围中，向溶有化合物2-2(0.05g,185.67μmol)的甲醇(10mL)溶液中加入Pd/C(10％,0.01g)。该混合物用氢气置换3次，然后在氢气氛围(30psi)25℃下搅拌2小时。LCMS显示原料消耗完全，并监测到目标分子离子峰。将反应液过滤，浓缩得到化合物2-3，未经纯化直接用于下一步反应。LCMS(ESI)m/z:272[M+H] +。
步骤4：制备化合物2-4
向溶有3,3-二氟环丁烷羧酸(25.08mg,184.29μmol)的DMF(3mL)溶液中分别加入EDCI(106mg,552.7μmol)HOBt(75mg,552.9μmol),DIEA(160.50μL,921.4μmol,)和化合物2-3(50mg,184.3μmol)。该混合液在25℃下搅拌12小时。LCMS显示原料消耗完全，并检测到目标分子离子峰。往反应体系中加入10mL水淬灭反应，用乙酸乙酯(15mL*3)萃取。合并有机相，经饱和食盐水洗涤，硫酸钠干燥，过滤浓缩得到粗品。粗品经制备型HPLC分离纯化得到化合物2-4。 1H NMR(400MHz,DMSO-d 6)δ0.76-0.90(m,4H),1.24(br s,2H),1.94-2.30(m,2H),2.70-2.87(m,4H),3.07-3.28(m,1H),3.54-3.68(m,3H),3.95-4.13(m,1H),3.95-4.16(m,1H),6.96-7.13(m,1H),7.51-7.71(m,1H),7.54-7.69(m,1H),7.54-7.69(m,1H),11.06(br s,1H).LCMS(ESI)m/z:390[M+H] +。
Figure PCTCN2019074145-appb-000034
以化合物2-3为共用中间体，运用与化合物2-4相同的酰胺缩合的合成方法制备(加入与化合物2-4不同取代的环丙基羧酸)化合物2-5，表征数据如下：
化合物2-5： 1H NMR(400MHz,DMSO-d 6)δ0.75-0.90(m,4H),1.77-2.48(m,5H),2.89-3.10(m,1H),3.41-4.36(m,5H),6.93-7.19(m,1H),7.52-7.72(m,2H),11.07(br s,1H).LCMS(ESI)m/z:376[M+H] +。
实施例3
Figure PCTCN2019074145-appb-000035
步骤1：消旋化合物1-7(100mg,249.1μmol)经手性分离(SFC分离条件：柱:Chiralpak AS-H 250*30mm I.D.,5μm；流动相:[0.1％NH 3H 2O IPA]；B％:35％-35％；流速:50mL/min；柱温:38℃；波长:220nm；喷嘴压力:100Bar；嘴温度:60℃；蒸发器温度:20℃)得到4个异构体分别为化合物3-1,3-2,3-3,3-4。
化合物3-1，保留时间:4.701分钟； 1H NMR(400MHz,METHANOL-d 4)δ0.78-1.02(m,4H),1.58-2.00(m,5H),2.10-2.23(m,1H),2.41-2.77(m,4H),4.00-4.12(m,1H),6.50(br s,1H),6.94(br d,J＝6.78Hz,1H),7.40-7.47(m,1H),7.48-7.56(m,1H),LCMS(ESI)m/z:402[M+H]+。
化合物3-2，保留时间:4.842分钟； 1H NMR(400MHz,METHANOL-d 4)δ0.77-0.97(m,4H),1.59-1.99(m,5H),2.16(ddd,J＝18.38,8.09,2.64Hz,1H),2.40-2.72(m,4H),4.00-4.09(m,1H),6.53(br s,1H),6.94(br d,J＝7.28Hz,1H),7.39-7.46(m,1H),7.48-7.55(m,1H),LCMS(ESI)m/z:402[M+H] +。
化合物3-3，保留时间:5.197分钟； 1H NMR(400MHz,METHANOL-d 4)δ0.79–1.02(m,4H),1.59-1.99(m,5H),2.16(ddd,J＝18.38,8.09,2.64Hz,1H),2.41-2.72(m,4H),4.02-4.09(m,1H),6.53(br s,1H),6.94(br d,J＝7.28Hz,1H),7.40-7.46(m,1H),7.48-7.55(m,1H),LCMS(ESI)m/z:402[M+H] +。
化合物3-4，保留时间:6.016分钟； 1H NMR(400MHz,METHANOL-d 4)δ0.77-0.97(m,4H),1.59–2.01(m,5H),2.16(ddd,J＝18.38,8.09,2.64Hz,1H),2.40-2.72(m,4H),4.00-4.10(m,1H),6.53(br s,1H),6.94(br d,J＝7.28Hz,1H),7.39-7.46(m,1H),7.48-7.55(m,1H),LCMS(ESI)m/z:402[M+H] +。
实施例4
Figure PCTCN2019074145-appb-000036
步骤1：制备化合物4-1
在氩气氛围中，向溶有化合物1-6(0.14g,470.8μmol)的甲醇(15mL)溶液中加入Pd/C(14m g,含量10％)。该悬浊液用氢气置换3次，然后在氢气氛围(30psi)，25℃下搅拌2小时。LCMS显示原料消耗完全，并监测到目标分子离子峰。将反应液过滤浓缩得到化合物4-1，未经纯化，直接用于下一步反应。LCMS(ESI)m/z:300[M+H] +。
步骤2：制备化合物4-2
向溶有2,2-二氟环丙烷羧酸(62.79mg,514.41μmol)的DMF(5mL)中加入EDCI(134.5mg,701.5μmol),HOBt(94.8mg,701.5μmol),DIEA(181.3mg,1.40mmol,244.8μL)和化合物4-1(140mg,467.7μmol)。该混合物在25℃下搅拌12小时。LCMS显示原料消耗完全，并监测到目标分子离子峰。反应液减压浓缩干，经制备型HPLC分离纯化得到化合物4-2。 1H NMR(400MHz,DMSO-d 6)δ0.76-0.89(m,4H),1.38(br d,J＝11.80Hz,1H),1.56-2.17(m,11H),2.29-2.34(m,1H),2.62-2.82(m,1H),3.63-4.15(m,1H),7.00(d,J＝7.03Hz,1H),7.51-7.68(m,2H),8.30(br d,J＝7.78Hz,1H),11.02(br d,J＝9.79Hz,1H)。LCMS(ESI)m/z:404[M+H] +。
Figure PCTCN2019074145-appb-000037
以共用中间体4-1为起始原料，运用与化合物4-2相同的酰胺缩合的合成方法(加入与化合物4-2的不同取代的环丙基羧酸)制备化合物4-3，表征数据如下：
1H NMR(400MHz,DMSO-d 6)δ0.68-0.91(m,4H),1.08-1.40(m,4H),1.52-1.78(m,3H),1.80-2.18(m,6H),3.43(br s,1H),4.11(br d,J＝3.51Hz,1H),6.88-7.19(m,1H),7.45-7.75(m,2H),7.95-8.43(m,1H),11.03(br d,J＝8.03Hz,1H).LCMS(ESI)m/z:386[M+H] +。
实施例5
Figure PCTCN2019074145-appb-000038
步骤1：制备化合物5-1
将溶有1-4(1g,3.56mmol),(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,6-二氢-2H-吡啶-1-甲酸叔丁酯(1.2g,3.9mmol),Pd(dppf)Cl 2.CH 2Cl 2(291mg,355.7μmol)和K 2CO 3(1.47g,10.67mmol)的二氧六环(20mL)和水(5mL)体系用氮气置换3次。该悬浊液在氮气氛围中，90℃下搅拌12小时。LCMS显示原料消耗完全，并监测到目标分子离子峰。反应液经减压浓缩，残余物经硅胶柱色谱分离纯化得到5-1。LCMS(ESI)m/z:384[M+H] +。
步骤2：制备化合物5-2
将溶有化合物5-1(1g,2.6mmol)和TFA(7.7g,67.5mmol,5mL)的二氯甲烷(20mL)在25℃下搅拌1小时。LCMS显示原料消耗完全，并监测到目标分子离子峰。将反应液减压浓缩，得到化合物5-2。未经进一步纯化，直接用于下一步反应。LCMS(ESI)m/z:284[M+H] +。
步骤3：制备化合物5-3
向溶有1-氟环丙烷羧酸(27.55mg,264.71μmol)的DMF(5mL)和DIEA(205mg,1.6mmol,277uμL)溶液中加入EDCI(152mg,794μmol)，HOBt(107mg,794μmol)和化合物5-2(150mg,529.4μmol)。该混合物在25℃下搅拌12小时。LCMS显示原料消耗完全，并监测到目标分子离子峰。加入水10mL淬灭反应，用乙酸乙酯(20mL*3)萃取。合并有机相，经饱和食盐水洗涤，硫酸钠干燥，过滤浓缩得到粗品。粗品经制备型HPLC分离纯化得到化合物5-3. 1H NMR(400MHz,DMSO-d 6)δ0.75-0.88(m,4H),1.17-1.38(m,4H),2.05(br d,J＝17.32Hz,1H),2.78(br s,2H),3.87(br s,2H),4.27(br s,2H),7.00-7.19(m,2H),7.53-7.74(m,2H),11.07(br s,1H)。LCMS(ESI)m/z:370[M+H] +。
Figure PCTCN2019074145-appb-000039
以共用中间体5-2为起始原料运用与化合物5-3相同的酰胺缩合的合成方法(加入与化合物5-3的不同取代的环丙基羧酸)制备化合物5-4，表征数据如下：
1H NMR(400MHz,DMSO-d 6)δ0.65-0.93(m,8H),1.92-2.18(m,2H),1.92-2.18(m,1H),2.57-2.88(m,2H),3.72(br s,1H),3.93(br s,1H),4.23(br s,1H),4.51(br s,1H),6.88-7.20(m,1H),7.11(br s,1H),7.52-7.76(m,2H),11.07(br s,1H)。LCMS(ESI)m/z:352[M+H] +。
实施例6
Figure PCTCN2019074145-appb-000040
步骤1：制备化合物6-1
向溶有化合物2-2(0.1g,260.9μmol)和2,2-二氟环丙烷羧酸(31.9mg,260.9μmol)的DMF(5mL)和DIEA(101mg,782.6μmol,136uL)溶液中加入T 3P(249mg,391.3μmol,232μL)，该混合物在40℃下搅拌2小时。LCMS显示原料消耗完全，并监测到目标分子离子峰。将反应液减压浓缩，经制备型HPLC分离纯化得到化合物6-1。 1H NMR(400MHz,DMSO-d 6)δ0.73-0.98(m,4H),2.06(br s,3H),3.07(br d,J＝12.76Hz,1H),4.50(br s,1H),4.60-4.78(m,2H),4.90(br s,1H),5.13(br d,J＝13.63Hz,1H),7.16(br d,J＝7.63Hz,1H),7.64-7.76(m,2H),7.78-7.91(m,1H),11.22(br d,J＝4.25Hz,1H)。LCMS(ESI)m/z:374[M+H] +。
Figure PCTCN2019074145-appb-000041
以共用中间体2-2为起始原料，运用与化合物6-1相同的酰胺缩合的合成方法(加入与化合物6-1的不同取代的环丙基羧酸)制备化合物6-2，表征数据如下：
1H NMR(400MHz,DMSO-d 6)δ0.74-0.95(m,4H),1.22-1.45(m,4H),2.00-2.13(m,1H),4.58(br d,J＝1.50Hz,1H),4.75-4.91(m,2H),5.07(br s,1H),7.07-7.23(m,1H),7.63-7.77(m,2H),7.84(br d,J＝9.51Hz,1H),11.20(br s,1H)。LCMS(ESI)m/z:356[M+H] +。
实施例8
Figure PCTCN2019074145-appb-000042
步骤1：消旋化合物4-2(100mg,247.88μmol)经手性分离(SFC分离条件：柱:DAICEL CHIRALPAK AD-H(250mm*30mm,5μm)；流动相:[0.1％NH 3H 2O EtOH]；B％:40％-40％,min；流速:50mL/min；柱温:38℃；波长:220nm；喷嘴压力:100Bar；嘴温度:60℃；蒸发器温度:20℃)得到4个异构体。
化合物8-1，保留时间5.122分钟. 1H NMR(400MHz,DMSO-d 6)δ0.65-0.94(m,1H),0.69-0.91(m,4H),1.62-1.96(m,11H),2.74(ddd,J＝14.31,10.79,8.28Hz,1H),4.00-4.19(m,1H),7.01(d,J＝7.03Hz,1H),7.44-7.76(m,2H),8.32(br d,J＝7.53Hz,1H),11.04(br s,1H)。LCMS(ESI)m/z:404[M+H] +。
化合物8-2，保留时间5.827分钟, 1H NMR(400MHz,DMSO-d 6)δ0.69-0.92(m,5H),1.63-1.97(m,11H),2.64-2.90(m,1H),3.99-4.21(m,1H),7.01(d,J＝7.28Hz,1H),7.43-7.81(m,2H),8.32(br d,J＝7.53Hz,1H),11.04(br s,1H)。LCMS(ESI)m/z:404[M+H] +。
化合物8-3,保留时间6.127分钟. 1H NMR(400MHz,DMSO-d 6)δ0.68-0.95(m,5H),1.29-1.48(m,2H),1.55-1.71(m,2H),1.75-2.18(m,7H),2.54-2.61(m,1H),3.61-3.79(m,1H),6.99(br d,J＝7.03Hz,1H),7.41-7.75(m,2H),8.34(br d,J＝7.53Hz,1H),11.02(br s,1H).LCMS(ESI)m/z:404[M+H] +。
化合物8-4,保留时间6.323分钟。 1H NMR(400MHz,DMSO-d 6)δ0.72-0.93(m,5H),1.29-1.47(m,2H),1.55-1.72(m,2H),1.74-2.00(m,5H),2.03-2.16(m,3H),3.69(br dd,J＝7.28,3.76Hz,1H),7.00(br d,J＝7.03Hz,1H),7.43-7.69(m,2H),8.33(br d,J＝7.53Hz,1H),11.02(br s,1H)。LCMS(ESI)m/z:404[M+H] +。
实施例10
Figure PCTCN2019074145-appb-000043
步骤1：制备化合物10-1
将溶有3-溴-2,4-二氯-吡啶(3.2g,14.10mmol)的氨水(38.8g,276.9mmol,42.7mL)在130℃下搅拌24小时。TLC板显示原料消耗完全，有新点生成。将反应液减压浓缩，经硅胶柱色谱分离纯化得到化合物10-1。LCMS(ESI)m/z:208[M+H] +。
步骤2：制备化合物10-2
在0℃下，向溶有化合物10-1(1.4g,6.75mmol)溶液中加入苯甲酰异硫氰酸酯(3.30g,20.25mmol,2.73mL).该混合物在25℃下搅拌12小时。LCMS显示原料消耗完全，并监测到目标分子离子峰。将反应液浓缩，残余物经硅胶柱色谱分离纯化得到化合物10-2。LCMS(ESI)m/z:371[M+H] +。
步骤3：制备化合物10-3
向溶有化合物10-2(770mg,2.08mmol)甲醇(0.75mL)滴加NaOH(2M,10.39mL)。该反应液在25℃下搅拌1小时。LCMS显示原料消耗完全，并监测到目标分子离子峰。将反应液用稀盐酸(1M)调节至pH 至6，然后抽滤得到化合物10-3。LCMS(ESI)m/z:268[M+H] +。未经进一步纯化，直接用于下一步反应。
步骤4：制备化合物10-4
在0℃下，向溶有化合物10-3(400mg,1.50mmol)的DMF(10mL)溶液中分批加入NaH(186mg,4.7mmol,含量60％)。该混合物在80℃下搅拌3小时。LCMS显示原料消耗完全，并监测到目标分子离子峰。在0℃下，用10mL饱和氯化铵溶液淬灭反应，然后用乙酸乙酯(30mL*3)萃取。合并有机相，经饱和食盐水洗涤，硫酸钠干燥，过滤浓缩得到粗品。粗品经柱色谱分离纯化得到化合物10-4。LCMS(ESI)m/z:186[M+H] +。
步骤5：制备制备化合物10-5
在0℃下，向溶有化合物10-4(70mg,377.1μmol)的乙腈(15mL)和TEA(191mg,1.89mmol,263uL)溶液中滴加环丙基甲酰氯(198mg,1.89mmol,172μL)。该混合物在25℃下搅拌1小时。LCMS显示原料消耗完全，并监测到目标分子离子峰。将反应液减压浓缩，并加入20mL水淬灭，用DCM:MeOH(20:1,30mL*3)萃取。合并有机相，经饱和食盐水洗涤，硫酸钠干燥，过滤浓缩得到化合物10-5。未经纯化，直接用于下一步反应。LCMS(ESI)m/z:254[M+H] +。
步骤6：制备化合物10-6
向溶有化合物10-5(160mg,630.7μmol)和N-[4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)环己-3-烯-1-基]氨基甲酸叔丁酯(204mg,630.6μmol)的二氧六环(12mL)和水(3mL)溶液中加入K 2CO 3(261.48mg,1.89mmol)和Pd(dppf)Cl 2.CH 2Cl 2(51.5mg,63.1μmol)。在氮气保护下，该反应液在90℃下搅拌2小时。LCMS显示原料消耗完全，并监测到目标分子离子峰。将反应液过滤，浓缩除掉溶剂。并加入15mL水，用DCM:MeOH(20:1,20mL*3)萃取。合并有机相，经饱和食盐水洗涤，硫酸钠干燥，过滤浓缩得到粗品。粗品经硅胶柱色谱分离纯化得到化合物10-6。LCMS(ESI)m/z:415[M+H] +。
步骤7：制备化合物10-7
向溶有化合物10-6(160mg,386μmol)的二氯甲烷(5mL)溶液中加入TFA(3.1g,27.0mmol,2mL)，所得混合物在25℃下搅拌1小时。LCMS显示原料消耗完全，并监测到目标分子离子峰。将反应液浓缩，得到化合物10-7。未经纯化，直接用于下一步反应。LCMS(ESI)m/z:315[M+H] +。
步骤8：制备化合物10-8
在氩气氛围内，向化合物10-7(230mg,536.85μmol,TFA)的甲醇(10mL)溶液中加入Pd/C(50mg,10％纯度)。该悬浊液用氢气置换3次。该混合物在氢气氛围(30psi)，25℃下搅拌12小时。LCMS显示原料消耗完全，并监测到目标分子峰。将反应液过滤浓缩得到化合物10-8。LCMS(ESI)m/z:317[M+H] +。
步骤9：制备化合物10-9
向溶有化合物10-8(240mg,758.5μmol)的DMF(5mL)和DIEA(294mg,2.28mmol,396.34uL)溶液中加入EDCI(218mg,1.14mmol),HOBt(153.73mg,1.14mmol)和2,2-二氟环丙烷羧酸(93mg,758.5μmol,1eq)。该混合物在25℃下搅拌12小时。LCMS显示原料被消耗完全，并监测到目标分子离子峰。加入20mL水淬灭，用DCM:MeOH(20:1,30mL*3)萃取。合并有机相，经饱和食盐水洗涤，硫酸钠干燥，过滤浓缩得到粗品。粗品经制备型HPLC分离得到化合物10-9. 1H NMR(400MHz,DMSO-d 6)δ0.92-1.07(m,4H),1.32-1.49(m,2H),1.72-2.09(m,10H),2.79-2.91(m,1H),3.59-3.72(m,1H),7.55(d,J＝5.52Hz,1H),8.32(br d,J＝7.78Hz,1H),8.46(d,J＝5.52Hz,1H)。LCMS(ESI)m/z:421[M+H] +。化合物10-10。 1H NMR(400MHz,DMSO-d 6)δ0.88-1.11(m,4H),1.62-1.93(m,8H),1.97-2.12(m,3H),2.67-2.83(m,1H),2.93(br t,J＝10.54Hz,1H),3.98(br d,J＝3.26Hz,1H),7.56(d,J＝5.52Hz,1H),8.38(br d,J＝7.03Hz,1H),8.47(d,J＝5.52Hz,1H)。LCMS(ESI)m/z:421[M+H] +。
生物活性测试
实验例1：Jak1,Jak2,Jak3,Tyk2激酶体外活性测试
实验材料
重组人源JAK1、JAK2、JAK3、Tyk2蛋白酶、主要仪器及试剂均由英国的Eurofins公司提供
实验方法
JAK2,JAK3和TYK2稀释：20mM MOPS,1mM EDTA,0.01％Brij-35.5％甘油,0.1％β-巯基乙醇,1mg/mL BSA；JAK1稀释：20mM TRIS,0.2mM EDTA,0.1％β-巯基乙醇,0.01％Brij-35.5％甘油。将所有化合物制备成100％的DMSO溶液并达到最终测定浓度50倍。测试化合物进行3倍浓度梯度稀释，终浓度为10μM到0.001μM共9个浓度，DMSO在检测反应中的含量为2％。将该化合物的工作储备液作为反应的第一组分添加到测定孔中，然后按照下面测定详述的方案加入其余组分。
JAK1(h)酶反应
JAK1(h)与20mM Tris/HCl pH7.5,0.2mM EDTA，500μM MGEEPLYWSFPAKKK，10mM乙酸镁和[γ- 33P]-ATP(根据需要制定活性和浓度)一起孵育。添加Mg/ATP混合物开始反应，在室温下孵育40分钟后，加入0.5％浓度的磷酸终止反应。然后将10μL反应物点在P30滤垫上并于4分钟内用0.425％磷酸洗涤三次和甲醇洗涤一次，干燥、闪烁计数。
JAK2(h)酶反应
JAK2(h)与8mM MOPS pH 7.0,0.2mM EDTA,
100μM KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC,10mM乙酸镁和[γ- 33P]-ATP(根据需要制定活性和浓度)一起孵育。添加Mg/ATP混合物开始反应，在室温下孵育40分钟后，加入0.5％浓度的磷酸终止反应。然后将10μL反应物点在P30滤垫上并于4分钟内用0.425％磷酸洗涤三次和甲醇洗涤一次，干燥、闪烁计数。
JAK3(h)酶反应
JAK3(h)与8mM MOPS pH 7.0,0.2mM EDTA,500μM GGEEEEYFELVKKKK,10mM乙酸镁和[γ- 33P]-ATP(根据需要制定活性和浓度)一起孵育。添加Mg/ATP混合物开始反应，在室温下孵育40分钟后，加入0.5％浓度的磷酸终止反应。然后将10μL反应物点在P30滤垫上并于4分钟内用0.425％磷酸洗涤三次和甲醇洗涤一次，干燥、闪烁计数。
TYK2(h)酶反应
TYK2(h)与8mM MOPS pH 7.0,0.2mM EDTA,250μM GGMEDIYFEFMGGKKK,10mM乙酸镁和[γ- 33P]-ATP(根据需要制定活性和浓度)一起孵育。添加Mg/ATP混合物开始反应，在室温下孵育40分钟后，加入0.5％浓度的磷酸终止反应。然后将10μL反应物点在P30滤垫上并于4分钟内用0.425％磷酸洗涤三次和甲醇洗涤一次，干燥、闪烁计数。
数据分析
IC 50结果由IDBS公司的XLFIT5(205公式)进行分析得到，具体见表1。
表1.本发明化合物体外筛选试验结果
Figure PCTCN2019074145-appb-000044
Figure PCTCN2019074145-appb-000045
注：NA表示未做检测。
结论：本发明的化合物在激酶4个亚型JAK1、JAK2、JAk3和TYK2的体外活性测试中展现了对TYK2和JAK1的良好的选择性抑制。
实验例2：药代动力学(PK)试验
将试验化合物溶解后得到的澄清溶液分别经尾静脉注射和灌胃给予雄性小鼠(C57BL/6)或大鼠(SD)体内(过夜禁食，7～8周龄)。给予受试化合物后，静脉注射组在0.117,0.333,1,2,4,7和24小时，灌胃组在0.25,0.5,1,2,4,8和24小时，分别从下颌静脉采血并离心后获得血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlin TM Version 6.3药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。测试结果如下：
表2-1 化合物1-7在小鼠中的PK测试结果
PK参数 结果
T 1/2(hr) 2.07
C max(nM) 23867
AUC 0-inf(nM.hr) 18033
Bioavailability(％) a 75.2％
表2-2 化合物3-1在小鼠中的PK测试结果
PK参数 结果
T 1/2(hr) 3.11
C max(nM) 3800
AUC 0-inf(nM.hr) 19967
Bioavailability(％) a 30.0％
表2-3 化合物4-2在小鼠中的PK测试结果
PK参数 结果
T 1/2(h) 2.22
C max(nM) 13433
AUC 0-inf(nM.h) 11021
Bioavailability(％) a 58.6％
表2-4 化合物4-3在大鼠中的PK测试结果
PK参数 结果
T 1/2(h) 2.86
C max(nM) 24750
AUC 0-inf(nM.h) 85760
Bioavailability(％) a 89.8％
注：T 1/2：半衰期；C max：达峰浓度；
AUC 0-inf：从0时间到外推至无穷大时的血浆浓度-时间曲线下面积；
Bioavailability：生物利用度。
结论：本发明的化合物在小鼠中都有良好的口服生物利用度，较高的暴露量，有利于产生良好的体内药效。
实验例3：在佐剂诱导的关节炎模型(AIA)中的体内药效研究
实验目的：
类风湿性关节炎是一类多发的自身免疫性疾病，是由于自身免疫反应而导致关节部位发炎、损伤以及畸形，严重时会引起全身性系统性的炎症反应。佐剂诱导的关节炎大鼠模型是在类风湿性关节炎疾病研究和新药开发中常用的动物模型之一，其发病机理和临床症状均与人类风湿性关节炎疾病类似。模型通过足垫注射结核分枝杆诱导具有骨关节损伤功能的免疫细胞和抗体引起了系统性的反应，具体表现在关节肿胀，骨溶解，滑膜损伤等类似人类风湿性关节炎的症状
本次实验目的是考察化合物4-3和8-2在佐剂诱导的小鼠关节炎上的治疗效果，从而为之后的临床 研究提供临床前药效学相关信息。
一.实验方法：
1.佐剂配制：
称取结核分枝杆菌H37Ra 100mg，研磨约5分钟，石蜡油清洗研钵3次，终浓度为10mg/ml。超声破碎，冰水混合物中超声约30分钟。
2.关节炎的诱导：
①将佐剂震荡混匀，用1毫升的玻璃注射器(20G针头)抽取，再换成25G针头。免疫每只大鼠前要不停地转动注射器，以免结核分枝杆菌沉淀。
②将大鼠放入麻醉机中麻醉(异氟烷)，待麻醉后免疫，部位为大鼠左脚脚掌，皮下注射0.1ml。
③正常组(5只)注射石蜡油0.1ml，免疫部位为大鼠左脚脚掌皮下。
第一次注射佐剂当天为第0天。
3.给药和剂量设计
3.1在第13天，所有动物均显现足部红斑或红肿等关节炎症状，根据实验方案，按照体重和评分分组。使每组的这两个标准基本一致，分组情况见表1。将76只大鼠分成5组，每组10只，正常组5只。
3.2根据表1，每组的给药剂量如下表3。每天两次，共持续14天。
表3.分组及剂量设计
Figure PCTCN2019074145-appb-000046
4.关节炎发病指标测定
体重：从第13天到第27每周称重三次。
脚体积：免疫前测量一次，从第13天到第27每周测量三次。
评分：从第13到第27每周评分三次。根据病变的不同程度(红肿，关节变形)按照0-4分的标准进行评分，每个肢体的最高评分为4分，每只动物最高评分为12分(注射侧左后肢除外)。评分标准如表4。
表4.关节炎临床评分标准
Figure PCTCN2019074145-appb-000047
5.统计学处理
实验数据应用平均数±标准误差表示(Mean±SEM)，足体积曲线下面积(AUC)用单因素方差分析(One-way ANOVA)，p<0.05认为有显著性差异。
二.实验结果：
1.体重
和正常组比较，小鼠免疫造模后体重均有降低，各给药组体重均在第15天至第17天下降，随后体重又开始缓慢恢复。其中溶剂对照组体重下降幅度最大；化合物8-2在第19天开始三个剂量组之间体重开始缓慢恢复，如图1所示。
2.临床评分：
佐剂免疫后第6天大鼠开始出现关节炎症状。实验结果如图2显示，溶剂对照组的平均临床评分于第24天达到峰值约8.5分左右，标志着AIA模型的成功建立(图2)。实验终点(第27天)时，化合物4-3(15mpk)、化合物8-2(5mpk和15mpk)对关节炎大鼠临床评分的均有显著性抑制(与溶剂对照组相比，p值分别为<0.0001，<0.0001和<0.0001)，将关节炎大鼠临床评分分别降低至2.6，2.7和1.0(高剂量组和低剂量组相比，p值为0.0004)。同时，Dexamethasone(地塞米松，Dex.)0.3mg/kg治疗可显著抑制胶原诱导的关节炎临床评分，从第23天开始起临床评分维持在2.0分左右直至实验结束。
3.足体积及其曲线下面积AUC
与临床评分的结果相似，实验结果如图3所示：溶剂对照组动物的平均足体积从13天的1.6mL稳定升高至第27天实验终点时的2.8mL，标志着AIA模型的成功建立(图3)。实验终点时，各个剂量下均能显著抑制关节炎大鼠足体积的升高(与溶剂对照组比较，p值均<0.0001)，关节炎大鼠足体积均值分别减小至1.5mL，1.4mL，和1.1mL，其中化合物8-2呈剂量依赖性(高剂量组与低剂量组之间相比，p<0.0001)。Dexamethasone 0.3mg/kg很好的抑制了平均足体积的升高，该组在给药之后足体积稳步下降，至实验终点，稳定在1.1mL。
通过分析每组每只动物的足体积曲线，计算曲线下面积AUC，通过组间AUC平均值，计算各给药 组相对于溶剂对照组的抑制率，结果如图4。化合物4-3(15mg/kg)和化合物8-2(5mg/kg和15mg/kg)在给药组抑制率为32.3％，38.0％和44.5％，各组AUC与溶剂对照组相比，均存在显著性差异(p值分别为0.0011，<0.0001和<0.0001)，且呈剂量依赖性(高剂量组与低剂量组AUC相比，p值为<0.01)。Dexamethasone抑制率为44.9％。(图4)。
结论：化合物4-3(15mpk)及化合物8-2各个剂量下(5mpk、15mpk)对关节炎大鼠临床评分的均有显著性抑制，足体积在给药之后稳步下降,体重逐渐恢复，足体积曲线计算曲线下面积AUC相对于溶剂对照组的抑制率显著。

Claims (13)

  1. 式(Ⅰ)化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2019074145-appb-100001
    其中，
    Figure PCTCN2019074145-appb-100002
    为单键或双键；
    m为0或1；
    n为0或1；
    E 1为单键、-CH 2-或-NH-；
    T 1为CH或N；
    T 2为C或N；
    T 3为CH或N；
    环A为5元杂芳基；
    R 1为H、F、Cl、Br、I、OH、NH 2、CN或C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R a取代；
    R 2、R 3分别独立地为H、F、Cl、Br、I、OH、NH 2或CN；
    R a为F、Cl、Br、I、OH或NH 2；
    所述5元杂芳基包含1、2、3或4个独立为-NH-、-O-、-S-或N的杂原子或杂原子团。
  2. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，R 1为H、F、Cl、Br、I、OH、NH 2、CN或Me。
  3. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，R 2为H、F、Cl、Br、I、OH、NH 2或CN。
  4. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，R 3为H、F、Cl、Br、I或OH。
  5. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，环A为1,2,4-三唑基或噻 唑基。
  6. 根据权利要求1或5所述的化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019074145-appb-100003
    为
    Figure PCTCN2019074145-appb-100004
  7. 根据权利要求1所述的化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019074145-appb-100005
    为
    Figure PCTCN2019074145-appb-100006
  8. 根据权利要求1～4任意一项所述的化合物、其异构体或其药学上可接受的盐，其化合物为
    Figure PCTCN2019074145-appb-100007
    其中，
    E 1如权利要求1所定义；
    R 1如权利要求1或2所定义；
    R 2如权利要求1或3所定义；
    R 3如权利要求1或4所定义。
  9. 下式化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2019074145-appb-100008
  10. 根据权利要求9所述的化合物、其异构体或其药学上可接受的盐，其化合物为
    Figure PCTCN2019074145-appb-100009
    Figure PCTCN2019074145-appb-100010
  11. 一种药物组合物，包括治疗有效量的作为活性成分的根据权利要求1～10任意一项所述的化合物、其异构体或其药学上可接受的盐以及药学上可接受的载体。
  12. 根据权利要求1～10任意一项所述化合物或其药学上可接受的盐或根据权利要求11所述的药物组合物在制备治疗JAK1和TYK2相关疾病的药物中的应用。
  13. 根据权利要求12所述的应用，其特征在于，所述药物是用于类风湿性关节炎治疗的药物。
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