WO2019034076A1 - Fgfr抑制剂及其医药用途 - Google Patents

Fgfr抑制剂及其医药用途 Download PDF

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Publication number
WO2019034076A1
WO2019034076A1 PCT/CN2018/100638 CN2018100638W WO2019034076A1 WO 2019034076 A1 WO2019034076 A1 WO 2019034076A1 CN 2018100638 W CN2018100638 W CN 2018100638W WO 2019034076 A1 WO2019034076 A1 WO 2019034076A1
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Prior art keywords
group
compound
synthesis
pharmaceutically acceptable
acid
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PCT/CN2018/100638
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English (en)
French (fr)
Inventor
王一恺
张杨
陈正霞
陈琳琳
冯韬
黄荣新
李秋
李德尧
孙继奎
徐洋洋
李婕
黎健
陈曙辉
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Medshine Discovery Inc
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Medshine Discovery Inc
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Priority to JP2020508589A priority Critical patent/JP7341122B2/ja
Priority to AU2018317153A priority patent/AU2018317153B2/en
Priority to KR1020207007486A priority patent/KR102707041B1/ko
Priority to RU2020110780A priority patent/RU2771311C2/ru
Priority to US16/639,442 priority patent/US11236094B2/en
Priority to EP18846045.5A priority patent/EP3670513B1/en
Priority to CA3072979A priority patent/CA3072979C/en
Priority to CN201880052899.8A priority patent/CN111247150B/zh
Publication of WO2019034076A1 publication Critical patent/WO2019034076A1/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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present invention relates to a class of FGFR inhibitors and their use in the manufacture of a medicament for the treatment of diseases associated with FGFR. Specifically, it relates to a compound of the formula (I) and a pharmaceutically acceptable salt thereof.
  • the fibroblast growth factor receptor is a receptor for fibroblast growth factor (FGF) signaling, and its family consists of four members (FGFR1, FGFR2, FGFR3, FGFR4), which are composed of extracellular immunoglobulins ( Ig) a glycoprotein consisting of a domain, a hydrophobic transmembrane region, and an intracellular portion comprising a tyrosine kinase domain.
  • FGF fibroblast growth factor
  • FGF signaling pathway abnormalities high expression, gene amplification, gene mutation, chromosome recombination, etc.
  • pathological processes such as tumor cell proliferation, migration, invasion and angiogenesis. Therefore, FGFR has become an important therapeutic target and has attracted a wide range of research and development interests.
  • a series of compounds having inhibitory activity against FGFR including reference compounds 1 and 2, are reported in WO2015008844.
  • the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof,
  • n 1 or 2;
  • L is selected from the group consisting of: a single bond, a C 2-4 alkenyl group, a C 2-4 alkynyl group;
  • R 1 is selected from H, halogen, OH, NH 2 or selected from C 1 - 3 alkyl, C 1-3 heteroalkyl optionally substituted by 1, 2 or 3 R;
  • R 2 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 ;
  • R 3 is selected from H, halogen, OH, NH 2 , CN, or selected from C 1 1-3 alkyl, C 1-3 heteroalkyl optionally substituted by 1, 2 or 3 R;
  • R 4 is selected from H, halogen, OH, NH 2 , CN, or selected from C 1 1-3 alkyl, C 1-3 heteroalkyl optionally substituted by 1, 2 or 3 R;
  • R 5 is selected from H or is selected from the group consisting of 1, 2 or 3 R substituted: C 1-3 alkyl, C 1-3 heteroalkyl, C 3-6 cycloalkyl, 4-6-membered Cycloalkyl;
  • R 6 is selected from H, halogen, OH, NH 2 or a C 1-3 alkyl group optionally substituted by 1, 2 or 3 R;
  • R is selected from the group consisting of: F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , N(CH 3 ) 2 ,
  • hetero of the C 1-3 heteroalkyl group and the 4-6 membered heterocycloalkyl group are each independently selected from: -NH-, N, -O-, -S-;
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.
  • R 1 is selected from H, halogen, OH, NH 2 or selected from the group consisting of: 1 , 2 or 3 R substituted: C 1-3 alkyl, C 1-3 alkoxy Base, R is as defined by the present invention.
  • R 1 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , Me,
  • R 3 is selected from the group consisting of H, halogen, OH, NH 2 , CN, or selected from the group consisting of: 1 , 2 or 3 R: C 1-3 alkyl, C 1-3 Alkoxy, C 1-3 alkylamino, R is as defined in the invention.
  • R 3 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 ,
  • R 4 is selected from the group consisting of H, halogen, OH, NH 2 , CN, or selected from the group consisting of: 1 , 2 or 3 R: C 1-3 alkyl, C 1-3 Alkoxy, C 1-3 alkylamino, R is as defined in the invention.
  • R 4 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 ,
  • R 5 is selected from H or is selected from the group consisting of 1, 2 or 3 R: C 1- 3 alkyl, C 1-3 alkylamino, morpholinyl, R is as defined in the invention.
  • R 5 is selected from the group consisting of: H, Me, Et,
  • R 6 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , Me.
  • the above L is selected from the group consisting of: a single bond
  • the structural unit From:
  • the structural unit From:
  • R 1 is selected from H, halogen, OH, NH 2 or selected from the group consisting of: 1 , 2 or 3 R substituted: C 1-3 alkyl, C 1-3 alkoxy Base, other variables are as defined above.
  • R 1 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , Me, Other variables are as defined above.
  • R 3 is selected from the group consisting of H, halogen, OH, NH 2 , CN, or selected from the group consisting of: 1 , 2 or 3 R: C 1-3 alkyl, C 1-3 Alkoxy, C 1-3 alkylamino, other variables are as defined above.
  • R 3 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Other variables are as defined above.
  • R 4 is selected from the group consisting of H, halogen, OH, NH 2 , CN, or selected from the group consisting of: 1 , 2 or 3 R: C 1-3 alkyl, C 1-3 Alkoxy, C 1-3 alkylamino, other variables are as defined above.
  • R 4 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, Me, CF 3 , Other variables are as defined above.
  • R 5 is selected from H or is selected from the group consisting of 1, 2 or 3 R: C 1- 3 alkyl, C 1-3 alkylamino, morpholinyl, other variables are as defined above.
  • R 5 is selected from the group consisting of: H, Me, Et, Other variables are as defined above.
  • R 6 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , Me, and other variables are as defined above.
  • the above L is selected from the group consisting of: a single bond, Other variables are as defined above.
  • the above compound, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and L are as defined above.
  • the above compound, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and L are as defined above.
  • 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 a disease associated with FGFR.
  • 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 a disease associated with FGFR.
  • the FGFR-associated disease refers to a solid tumor.
  • Some of the compounds of the present invention exhibit higher inhibitory activity against wild-type and mutant FGFR.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds 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 (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic.
  • the hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons) , C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .).
  • C 1-12 is selected from C 1
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • hydrocarbyl means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy). By customary expression, those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • alkenyl refers to an alkyl group having one or more carbon-carbon double bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkenyl group include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a butadienyl group, a pentadienyl group, a hexadienyl group and the like.
  • alkynyl refers to an alkyl group having one or more carbon-carbon triple bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and the like.
  • a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
  • 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
  • AZD4547 is synthesized by the route reported in the patent WO2009153592.
  • JNJ493 was purchased from Shanghai Qianyuan Biotechnology Co., Ltd. (CAS: 1346422-81-6).
  • Step 2-3 Synthesis of Intermediate B3 by reference to the B1 synthesis method.
  • 1 H NMR 400 MHz, deuterated methanol
  • tributyltin chloride (2.4 g, 7.37 mmol, 1.98 mL, 1.44 eq) was gradually added dropwise at -78 ° C, and the mixture was heated to -10 ° C for 1 hour. Subsequently, the reaction solution was rotary evaporated to remove tetrahydrofuran, dissolved in 1,4-dioxane and filtered to remove insolubles.
  • the intermediate B6-4 was used as a raw material, and it was synthesized by referring to the synthesis method of Example 1.
  • the retention time was determined using the following analytical column: Column: Chiralpak AS-3 150 x 4.6 mm ID, 3 ⁇ m, mobile phase: A: carbon dioxide B: methanol (0.05% diethylamine), 40% B, flow rate: 2.5 mL/min, Column temperature: 35 ° C.
  • the intermediates A1-B and B1 were used as starting materials, and were synthesized by referring to the synthesis methods of the first step and the second step in the first embodiment.
  • the intermediate WX001-2 and oleic acid were used as starting materials, and were synthesized by the method of Step 3 in Example 9.
  • chiral resolution (column: AS (250 mm * 30 mm, 10 ⁇ m); mobile phase: [0.1% ammonia ethanol]; B%: 45% - 45%) gave compound WX007A (retention time: 1.70 minutes) and WX007B ( Retention time: 2.02 minutes).
  • the retention time was determined using the following analytical column: Column: Chiralpak AS-H 150*4.6 mm ID, 5 ⁇ m, mobile phase: 40% ethanol (0.05% ethylenediamine) in carbon dioxide, flow rate: 3 mL/min, column temperature: 40 °C ).
  • Methyl lithium (1.6 M, 616.10 ⁇ L, 1.05 eq) was added dropwise to 4-amino-7-bromopyrrolo[2,1-f][1,2 in 15 min under nitrogen at -60 °C. 4]
  • a solution of triazine (0.2 g, 938.81 ⁇ mol, 1 eq) in tetrahydrofuran (15 mL).
  • the compound WX009 was synthesized by referring to the synthesis methods of Example 1 and Example 9, by SFC (column: AD (250 mm * 30 mm, 10 ⁇ m); mobile phase: [0.1% ammonia water) Propanol]; B%: 55%-55%) After isolation, compound WX009A (retention time: 5.08 min) and compound WX009B (retention time: 7.89 min) were obtained.
  • N,N-dimethylformamide 14.84 g, 203.05 mmol, 15.62 mL, 2.50 eq
  • the reaction liquid was slowly heated to 25 ° C, and the reaction was completed.
  • the reaction solution was slowly poured into 200 mL of ice water, and extracted with 200 mL of ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and then filtered through a silica gel-filled funnel. 1.
  • WX011-5 (6.40g, 24.89mmol, 1.00eq) was first dissolved in a mixed solution of 1,4-dioxane (100mL) and water (20mL), then N-Boc-2 , 5-Dihydro-1H-pyrrole-1-nonyl alcohol borate (7.35 g, 24.89 mmol, 1.00 eq), potassium phosphate (15.85 g, 74.68 mmol, 3.00 eq) and 1,1'-bis (two Phenylphosphine)ferrocene palladium chloride (1.82 g, 2.49 mmol, 0.10 eq) was added to the mixed solution.
  • Compound WX011 was resolved by chirality (column: AD (250 mm * 30 mm, 5 ⁇ m); mobile phase: [0.1% ammonia ethanol]; B%: 45% - 45%) to obtain WX011A (retention time: 0.58 minutes) and WX011B (retained Time: 0.74 minutes).
  • the retention time was determined using the following analytical column: Column: Chiralpak AD-350*4.6 mm ID, 3 ⁇ m, mobile phase: 40% isopropanol (0.05% ethylenediamine) in carbon dioxide, flow rate: 4 mL/min, column temperature: 40 °C).
  • the intermediate WX011-10 was used as an intermediate, and it was synthesized by referring to the synthesis method of Example 9.
  • LCMS (ESI) m / z: 490.0 [M + H] +, 512.0 [M + Na] +, 1 H NMR (400MHz, CDCl3) ⁇ 7.90-7.80 (m, 1H), 7.22-7.18 (m, 1H ), 7.16 (s, 1H), 6.65-6.60 (m, 1H), 6.57 (brs, 2H), 4.38-4.30 (m, 2H), 4.20-3.90 (m, 6H), 3.89-3.70 (m, 1H) ), 3.68-3.38 (m, 1H), 3.28-3.18 (m, 3H), 2.80-2.65 (m, 1H), 2.44 (s, 3H), 2.18-2.08 (m, 1H), 1.98-1.85 (m , 3H).
  • the intermediate WX010-2 was used as a raw material, and it was synthesized by referring to the synthesis method of Example 1.
  • test compound The ability of the test compound to inhibit human FGFR1 and FGFR4 was evaluated by measuring the IC 50 value using a 33 P isotope-labeled kinase activity assay (Reaction Biology Corp).
  • Buffer conditions 20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 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 solution 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, or 10 ⁇ M, 2.50 ⁇ M, 0.62 ⁇ M, 0.156 ⁇ M, 39.1 nM. , 9.8 nM, 2.4 nM, 0.61 nM, 0.15 nM, 0.038 nM. After 15 minutes of incubation, 33 P-ATP (activity 0.01 ⁇ Ci/ ⁇ l, corresponding concentrations listed in Table 1) was added to initiate the reaction.
  • the supplier number, lot number, and concentration information in the reaction solution of FGFR1, FGFR4, and its substrate are listed in Table 1.
  • the reaction solution was spotted on a P81 ion exchange filter paper (Whatman #3698-915). After repeatedly washing the filter paper with a 0.75% phosphoric acid solution, the radioactivity of the phosphorylated substrate remaining on the filter paper was measured.
  • 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 wild-type kinases.
  • test compound to inhibit the FGFR mutant strain was evaluated by measuring the IC 50 value using a 33 P isotope-labeled kinase activity assay (Reaction Biology Corp).
  • Buffer conditions 20 mM Hepes (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 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 solution 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, or 10 ⁇ M, 2.50 ⁇ M, 0.62 ⁇ M, 0.156 ⁇ M, 39.1 nM. , 9.8 nM, 2.4 nM, 0.61 nM, 0.15 nM, 0.038 nM. After 15 minutes of incubation, 33 P-ATP (activity 0.01 ⁇ Ci/ ⁇ l, corresponding concentrations listed in Table 1) was added to initiate the reaction.
  • the supplier number, lot number, and concentration information in the reaction solution of FGFR1, FGFR4, and its substrate are listed in Table 3.
  • the reaction solution was spotted on a P81 ion exchange filter paper (Whatman #3698-915). After repeatedly washing the filter paper with a 0.75% phosphoric acid solution, the radioactivity of the phosphorylated substrate remaining on the filter paper was measured.
  • 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 4.
  • the rodent pharmacological characteristics of the compound after intravenous administration and oral administration were tested by a standard protocol.
  • the candidate compound was formulated into a clear solution, and the mice were administered a single intravenous injection and oral administration.
  • the vehicle was administered with 10% DMSO/10% solutol/80% water and the oral vehicle was 0.5% sodium carboxymethylcellulose + 0.2% Tween.
  • Whole blood samples were collected over a 24 hour period, and all blood samples were added to a plastic centrifuge tube labeled with 0.5 M K2-EDTA anticoagulant.
  • the supernatant plasma was aspirated at 3,000 g for 10 minutes at 4 ° C, rapidly placed in dry ice, kept at -20 ° C or lower, and the plasma concentration was quantitatively analyzed by LC-MS/MS analysis, and the pharmacokinetic parameters were calculated.
  • LC-MS/MS analysis quantitatively analyzed by LC-MS/MS analysis, and the pharmacokinetic parameters were calculated.

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Abstract

一种FGFR抑制剂，为式(Ⅰ)所示化合物或其药学上可接受的盐。以及其在制备治疗与FGFR相关的疾病例如实体瘤的药物中的应用。

Description

FGFR抑制剂及其医药用途
本申请主张如下优先权：
CN201710698086.3，申请日2017-08-15。
技术领域
本发明涉及一类FGFR抑制剂，及其在制备治疗与FGFR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
成纤维细胞生长因子受体(FGFR)是成纤维细胞生长因子(FGF)信号传导的受体，其家族由四个成员(FGFR1、FGFR2、FGFR3、FGFR4)组成，为由细胞外免疫球蛋白(Ig)样结构域、疏水性跨膜区域和包括酪氨酸激酶区域的细胞内部分所组成的糖蛋白。成纤维细胞生长因子(FGF)通过这些受体(FGFR)在细胞增殖、细胞分化、细胞迁移和血管生成等许多生理学调节过程中发挥重要作用。有许多证据将FGF信号通路异常(高表达、基因扩增、基因突变、染色体重组等)与肿瘤细胞增殖、迁移、入侵和血管形成等许多病理过程直接相关联。因此，FGFR成为了一类重要治疗靶点，吸引了广泛的研发兴趣。
WO2015008844专利中报道了一系列对FGFR有抑制活性的化合物，包括参考化合物1和2。WO2013124316、WO2013087647、US20130158000专利中报道了一系列对FGFR有抑制活性的化合物，包含本发明中使用的苯并噻吩结构，以及参考化合物3。
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 PCTCN2018100638-appb-000001
其中，
m选自1或2；
L选自：单键、C 2-4烯基、C 2-4炔基；
R 1选自H、卤素、OH、NH 2，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 2选自：H、F、Cl、Br、I、OH、NH 2；
R 3选自H、卤素、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 4选自H、卤素、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 5选自H，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、C 3-6环烷基、4～6元杂环烷基；
R 6选自H、卤素、OH、NH 2，或选自任选被1、2或3个R取代的C 1-3烷基；
R选自：F、Cl、Br、I、OH、NH 2、CN、Me、CF 3、N(CH 3) 2、
Figure PCTCN2018100638-appb-000002
所述C 1-3杂烷基、4～6元杂环烷基之“杂”分别独立地选自：-NH-、N、-O-、-S-；
以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
本发明的一些方案中，上述R 1选自H、卤素、OH、NH 2，或选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基，R如本发明所定义。
本发明的一些方案中，上述R 1选自：H、F、Cl、Br、I、OH、NH 2、Me、
Figure PCTCN2018100638-appb-000003
本发明的一些方案中，上述R 3选自H、卤素、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烷氧基、C 1-3烷氨基，R如本发明所定义。
本发明的一些方案中，上述R 3选自：H、F、Cl、Br、I、OH、NH 2、CN、Me、CF 3、
Figure PCTCN2018100638-appb-000004
Figure PCTCN2018100638-appb-000005
本发明的一些方案中，上述R 4选自H、卤素、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烷氧基、C 1-3烷氨基，R如本发明所定义。
本发明的一些方案中，上述R 4选自H、F、Cl、Br、I、OH、NH 2、CN、Me、CF 3、
Figure PCTCN2018100638-appb-000006
Figure PCTCN2018100638-appb-000007
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 5选自H，或选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氨基、吗啉基，R如本发明所定义。
本发明的一些方案中，上述R 5选自：H、Me、Et、
Figure PCTCN2018100638-appb-000008
本发明的一些方案中，上述R 6选自：H、F、Cl、Br、I、OH、NH 2、Me。
本发明的一些方案中，上述L选自：单键、
Figure PCTCN2018100638-appb-000009
本发明的一些方案中，上述结构单元
Figure PCTCN2018100638-appb-000010
选自：
Figure PCTCN2018100638-appb-000011
本发明的一些方案中，上述结构单元
Figure PCTCN2018100638-appb-000012
选自：
Figure PCTCN2018100638-appb-000013
Figure PCTCN2018100638-appb-000014
本发明的一些方案中，上述R 1选自H、卤素、OH、NH 2，或选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基，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、F、Cl、Br、I、OH、NH 2、Me、
Figure PCTCN2018100638-appb-000015
其他变量如上述所定义。
本发明的一些方案中，上述R 3选自H、卤素、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烷氧基、C 1-3烷氨基，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：H、F、Cl、Br、I、OH、NH 2、CN、Me、CF 3、
Figure PCTCN2018100638-appb-000016
Figure PCTCN2018100638-appb-000017
其他变量如上述所定义。
本发明的一些方案中，上述R 4选自H、卤素、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烷氧基、C 1-3烷氨基，其他变量如上述所定义。
本发明的一些方案中，上述R 4选自H、F、Cl、Br、I、OH、NH 2、CN、Me、CF 3、
Figure PCTCN2018100638-appb-000018
Figure PCTCN2018100638-appb-000019
其他变量如上述所定义。
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 5选自H，或选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氨基、吗啉基，其他变量如上述所定义。
本发明的一些方案中，上述R 5选自：H、Me、Et、
Figure PCTCN2018100638-appb-000020
其他变量如上述所定义。
本发明的一些方案中，上述R 6选自：H、F、Cl、Br、I、OH、NH 2、Me，其他变量如上述所定义。
本发明的一些方案中，上述L选自：单键、
Figure PCTCN2018100638-appb-000021
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 PCTCN2018100638-appb-000022
选自：
Figure PCTCN2018100638-appb-000023
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 PCTCN2018100638-appb-000024
选自：
Figure PCTCN2018100638-appb-000025
Figure PCTCN2018100638-appb-000026
其他变量如上述所定义。
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自：
Figure PCTCN2018100638-appb-000027
其中，
R 1、R 2、R 3、R 4、R 5、R 6和L如上述所定义。
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自：
Figure PCTCN2018100638-appb-000028
Figure PCTCN2018100638-appb-000029
其中，
R 1、R 2、R 3、R 4、R 5、R 6和L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。
本发明还提供了下式所示化合物或其药学上可接受的盐：
Figure PCTCN2018100638-appb-000030
Figure PCTCN2018100638-appb-000031
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 PCTCN2018100638-appb-000032
Figure PCTCN2018100638-appb-000033
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FGFR相关疾病药物中的应用。
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FGFR相关疾病药物中的应用。
本发明的一些发方案中，上述FGFR相关疾病指实体瘤。
技术效果
本发明中部分化合物对野生型和突变型FGFR展现出更高的抑制活性。
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，“(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 PCTCN2018100638-appb-000034
和楔形虚线键
Figure PCTCN2018100638-appb-000035
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2018100638-appb-000036
和直形虚线键
Figure PCTCN2018100638-appb-000037
表示立体中心的相对构型，用波浪线
Figure PCTCN2018100638-appb-000038
表示楔形实线键
Figure PCTCN2018100638-appb-000039
或楔形虚线键
Figure PCTCN2018100638-appb-000040
或用波浪线
Figure PCTCN2018100638-appb-000041
表示直形实线键
Figure PCTCN2018100638-appb-000042
和直形虚线键
Figure PCTCN2018100638-appb-000043
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 PCTCN2018100638-appb-000044
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 PCTCN2018100638-appb-000045
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 PCTCN2018100638-appb-000046
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 PCTCN2018100638-appb-000047
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、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基、4H-1,2,4-三唑基和呫吨基。还包括稠环和螺环化合物。
除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、芳基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基)，可以是单取代或多取代的，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，可以包括二价或多价原子团，具有指定数量的碳原子(如C 1-C 12表示1至12个碳，C 1-12选自C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12；C 3-12选自C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12。)。“烃基”包括但不限于脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烃基”表示直链的或支链的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烃基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构体。
除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合，有一定数目的碳原子和至少一个杂原子组成。在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链 的烃原子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子或杂原子团可以位于杂烃基的任何内部位置，包括该烃基附着于分子其余部分的位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。实例包括但不限于-CH 2-CH 2-O-CH 3、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(O)-CH 3、-CH 2-CH 2-S(O) 2-CH 3、-CH＝CH-O-CH 3、-CH 2-CH＝N-OCH 3和–CH＝CH-N(CH 3)-CH 3。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。
除非另有规定，术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外，就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言，杂原子可以占据该杂环附着于分子其余部分的位置。环烃基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH 2F)或多取代的(如-CF 3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等。
除非另有规定，“烯基”指在链的任何位点上具有一个或多个碳碳双键的烷基,可以是单取代或多取代的，可以是一价、二价或者多价。烯基的例子包括乙烯基，丙烯基，丁烯基，戊烯基，己烯基，丁间二烯基，戊间二烯基，己间二烯基等。
除非另有规定，“炔基”指在链的任何位点上具有一个或多个碳碳三键的烷基，可以是单取代或多取代的，可以是一价、二价或者多价。炔基的例子包括乙炔基，丙炔基，丁炔基，戊炔基等。
除非另有规定，环烷基包括任何稳定的环状或多环烃基，任何碳原子都是饱和的，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定，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。
化合物经手工或者
Figure PCTCN2018100638-appb-000048
软件命名，市售化合物采用供应商目录名称。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
参考例1：WXR1
Figure PCTCN2018100638-appb-000049
化合物WXR1参照专利WO2015008844报道的路线合成。 1H NMR(400MHz,DMSO-d 6)δ＝8.40(d,J＝3.0Hz,1H),6.93(d,J＝2.5Hz,2H),6.74-6.52(m,2H),6.20-6.16(m,1H),5.74-5.69(m,1H),5.45-5.61(m,1H),4.12-3.90(m,2H),3.90-3.79(m,8H),2.47-2.30(m,2H).MS m/z:419.1[M+H] +
参考例2：WXR2
Figure PCTCN2018100638-appb-000050
化合物WXR1参照专利WO2015008844报道的路线合成。 1H NMR(400MHz,氘代甲醇)δ＝8.28(s,1H),6.83(br s,2H),6.60(d,J＝2.4Hz,1H),5.65-5.44(m,1H),4.12-3.98(m,1H),3.97-3.88(m,2H),3.83(s,6H),3.82-3.74(m,1H),3.74-3.63(m,1H),2.63-2.53(m,1H),2.51-2.35(m,3H),1.22-1.12(m,3H).MS m/z:421.1[M+H] +
参考例3：WXR3
Figure PCTCN2018100638-appb-000051
参考例4：AZD4547的合成
Figure PCTCN2018100638-appb-000052
AZD4547参照专利WO2009153592报道的路线合成。 1H NMR(400MHz,氘代甲醇)δ:7.93(d,J＝8.8Hz,2H),7.13(d,J＝8.8Hz,2H),6.37(s,2H),6.33(s,1H),6.31(s,1H),4.12-4.09(m,2H),3.74(s,6H),3.51-3.48(m,2H),2.99-2.93(m,4H),2.84(t,J＝12.4Hz,2H),1.42(d,J＝6.4Hz,6H).MS m/z:464.4[M+H] +
参考例5：BGJ398的合成
Figure PCTCN2018100638-appb-000053
BGJ398参照专利WO2006000420报道的路线合成。 1H NMR(400MHz,氘代甲醇)δ:8.40(s,1H),7.46 (d,J＝8.8Hz,2H),7.09(d,J＝8.8Hz,2H),6.82(s,1H),6.49(s,1H),3.96(s,6H),3.86(d,J＝12.0Hz,2H),3.69(d,J＝12.0Hz,2H),3.43(s,3H),3.33-3.20(m,4H),3.08(t,J＝12.4Hz,2H),1.42(t,J＝7.2Hz,3H).MS m/z:560.1[M+H] +
参考例6：JNJ493
Figure PCTCN2018100638-appb-000054
JNJ493从上海皓元生物科技有限公司购买得到(CAS:1346242-81-6)。 1H NMR(400MHz,氘代甲醇)δ:8.86(s,1H),8.41(s,1H),8.24(s,1H),7.77(d,J＝9.2Hz,1H),7.35(dd,J＝2.4,9.3Hz,1H),7.24(d,J＝2.4Hz,1H),6.53-6.43(m,3H),4.08-3.97(m,5H),3.80(s,6H),2.97(t,J＝7.2Hz,2H),2.90-2.78(m,1H),1.10(d,J＝6.4Hz,6H).MS m/z:447.2[M+H] +
参考例7：WXR4
Figure PCTCN2018100638-appb-000055
化合物WXR4参照专利US20140142084报道的路线合成。 1H NMR(400MHz,氘代甲醇)δ:8.41(s,2H),8.13(s,1H),7.86(s,1H),6.98(t,J＝8.3Hz,1H),5.25(s,2H),4.34(t,J＝5.0Hz,2H),3.95(t,J＝5.3Hz,2H),3.91(s,6H).MS m/z:408.1[M+H] +
中间体A1：
Figure PCTCN2018100638-appb-000056
合成路线：
Figure PCTCN2018100638-appb-000057
步骤1：化合物A1-1的合成
在室温下，先将4-氨基-7-溴吡咯并[2,1-f][1,2,4]三嗪(3.00g,14.1mmol,1.00eq)溶于1,4-二氧六环(40mL)和水(8mL)的混合溶液中，再依次将N-Boc-2,5-二氢-1H-吡咯-1嚬哪醇-硼酸酯(4.36g,14.8mmol,1.05eq)磷酸钾(8.97g,42.2mmol,3.00eq)和1,1'-双(二苯基磷)二茂铁氯化钯(1.03g,1.41mmol,0.10eq)加入到该混合溶液中。在氮气保护下，将反应液加热至80℃搅拌2小时。反应结束后，将反应液降至25℃，倒入20mL水中，有黑色固体生成，过滤收集黑色固体，然后溶于二氯甲烷/甲醇(100mL,5/1)混合溶液中，再次过滤，滤液用无水硫酸钠干燥，通过减压旋转蒸发除去有机溶剂得到粗品。粗品用乙酸乙酯(30mL)打浆，过滤得化合物A1-1。LCMS(ESI)m/z:302.1[M+H] +， 1H NMR(400MHz,氘代氯仿)δ＝8.05(s,1H),6.98-6.84(m,1H),6.72-6.54(m,2H),4.67-4.49(m,2H),4.44-4.30(m,2H).
步骤2：化合物A1-2的合成
在室温下，将氢氧化钯(615mg,438μmol)加入到A1-1(1.20g,3.98mmol,1.00eq)的甲醇(30mL)溶液中。用氢气置换3次，将反应液加热至50℃，在50psi氢气条件下，搅拌2小时后，将反应液冷却到室温，过滤除去催化剂，滤液通过减压旋转蒸发除去溶剂得A1-2。 1H NMR(400MHz,氘代甲醇)δ:7.80(s,1H),6.86(d,J＝4.4Hz,1H),6.53(d,J＝4.4Hz,1H),3.96-3.79(m,2H),3.60-3.51(m,1H),3.49-3.38(m,2H),2.39-2.36(m,1H),2.19–2.13(m,1H),1.49(d,J＝3.6Hz,9H).
步骤3：化合物A1的合成
在室温下，将碘代丁二酰亚胺(26.7g,119mmol,3.00eq)分批加入到A1-2(12.0g,39.6mmol,1.00eq)的N,N二甲基甲酰胺(150mL)溶液中。反应液在室温下搅拌1小时后，将反应液缓慢加入冰水(200mL)中，有固体生成，过滤除去溶剂，滤饼减压旋转蒸发干燥后得化合物A1。化合物A1经手性拆分(柱子：IC(250mm*50mm,10μm)；流动相：[0.1％氨水/乙醇]；B％:30％-30％)得到化合物A1-A(保留时间 2.94分钟)和化合物A1-B(保留时间3.28分钟)。
中间体A2：
Figure PCTCN2018100638-appb-000058
合成路线：
Figure PCTCN2018100638-appb-000059
步骤1：化合物A2-1的合成
在室温下，将盐酸/乙酸乙酯(4M,20.00mL,6.87eq)缓慢加入到溶有A1(5.00g,11.65mmol,1.00eq)的乙酸乙酯(30mL)溶液中，搅拌两小时后将反应液过滤，滤饼经减压旋转蒸发除去溶剂后得A2-1盐酸盐。LCMS(ESI)m/z:329.9[M+H] +, 1H NMR(400MHz,氘代甲醇)δ＝8.11(s,1H),7.20(s,1H),4.12(m,1H),3.84(m,1H),3.67-3.54(m,1H),3.51-3.37(m,2H),2.71-2.51(m,1H),2.35–2.27(m,1H)。
步骤2：化合物A2的合成
在0℃下，将三乙胺(3.60g,35.55mmol,4.93mL,5.00eq)和丙烯酰氯(707.88mg,7.82mmol,1.10eq)依次加入到A2-1(2.60g,7.11mmol,1.00eq,盐酸盐)的二氯甲烷(20.00mL)溶液中，搅拌1小时后，将反应液倒入50mL水溶液中，分液后，水相用二氯甲烷(20mL x 5)萃取，合并有机相，用无水硫酸钠干燥，过滤，减压除去溶剂得A2。LCMS(ESI)m/z:384.0[M+H] +,406.0[M+Na] +。
中间体A3：
Figure PCTCN2018100638-appb-000060
参考中间体A1合成方法。
中间体B1：
Figure PCTCN2018100638-appb-000061
合成路线：
将7-甲氧基-5-甲基苯并噻吩(2.00g,11.22mmol,1.00eq)的四氢呋喃(20.00mL)溶液冷却到-70℃。向冷却液中缓慢滴加丁基锂的正己烷溶液(2.5M,8.98mL,2.00eq)。滴完后搅拌1小时。然后加入三异丙基硼酸(2.11g,11.22mmol,1.00eq)。加完后搅拌1小时。滴加水(10mL)淬灭反应。浓缩淬灭的反应混合物除去四氢呋喃。剩余物先用石油醚(50mL)洗涤后，再用稀盐酸调pH值到5，有白色固体产生。过滤，滤饼先用水洗(50mL)，再通过真空干燥得中间体B1。 1H NMR(400MHz,氘代氯仿)δ＝7.72(s,1H),7.28(s,1H),6.67(s,1H),4.01(s,3H),2.50(s,3H)
中间体B2：
Figure PCTCN2018100638-appb-000062
由原料2-溴-5-氯苯甲醚制备4-氯-2-甲氧基苯硫酚(参照文献：J.O.Jilek et al.,Collection of Czechoslovak Chemical Communications,Vol.43,1978,p.1747-1759)，参照B1合成方法合成中间体B2。 1H NMR(400MHz,氘代甲醇)δ＝7.75(s,1H),7.46(s,1H),6.87(s,1H),4.00(s,3H)
中间体B3：
Figure PCTCN2018100638-appb-000063
合成路线：
Figure PCTCN2018100638-appb-000064
步骤1：化合物B3-1的合成
在室温下，将碳酸铯(149.24g,458.06mmol,2.00eq)加入到4-氯-2-甲氧基苯硫酚(40.00g,229.03mmol,1.00eq)和1-氯丙酮(31.78g,343.55mmol,1.50eq)的N,N-二甲基甲酰胺(500.00mL)的溶液。在氮气保护下，搅拌16小时后，将反应液加入到250mL水中，用乙酸乙酯(100mL)萃取3次。合并有机相，用饱和食盐水(250mL)洗涤三次，用无水硫酸钠干燥，过滤，滤液减压旋转蒸发除去有机溶剂得粗品。粗品通过柱层析(石油醚至石油醚/乙酸乙酯＝10/1)纯化得到化合物B3-1。 1H NMR(400MHz, 氘代氯仿)δ＝7.25(d,J＝8.0Hz,1H),7.16(d,J＝8.0Hz,1H),6.84-6.80(m,1H),3.80-3.76(m,2H),3.72(s,3H),1.35(s,3H)。
步骤2-3：参照B1合成方法合成中间体B3。 1H NMR(400MHz,氘代甲醇)δ＝7.25(d,J＝1.6Hz,1H),7.16(d,J＝2.0Hz,1H),3.87(s,2H),2.41(s,3H)。
中间体B4：
Figure PCTCN2018100638-appb-000065
参照化合物B1以及B3的合成方法合成。 1H NMR(400MHz,氘代甲醇)δ＝7.75(s,1H),7.46(s,1H),6.87(s,1H),4.00(s,3H)
中间体B5：
Figure PCTCN2018100638-appb-000066
合成路线：
Figure PCTCN2018100638-appb-000067
步骤1：化合物B5-1的合成
在室温下，先将3,5-二甲氧基苯胺(43.00g,280.72mmol,1.00eq)和硫氰酸铵(47.01g,617.58mmol,2.20eq)溶于冰乙酸(500mL)中，用冰水浴将反应液降至10℃，将液溴(43.00g,280.72mmol,1.00eq)在1小时内缓慢滴加完毕。反应在氮气保护下搅拌16小时。反应结束后，将反应液倒入1000mL水中，用2M的NaOH溶液中和调pH至9，用二氯甲烷(500mL)萃取5次，合并有机相用无水硫酸钠干燥，减压旋转蒸发除去溶剂得粗品。粗品通过柱层析(石油醚/乙酸乙酯＝10/1至乙酸乙酯)纯化得化合物B5-1。LCMS(ESI)m/z:210.8[M+H] +， 1H NMR(400MHz,氘代甲醇)δ＝6.51(d,J＝2.0Hz,1H),6.22(d,J＝2.0Hz,1H),3.77(s,3H),3.70(s,3H)。
步骤2：化合物B5-2的合成
在室温下，将化合物B5-1(5g,23.78mmol,1eq)加到二氧六环(50mL)溶液中，在室温下加入亚硝酸异戊酯(4.18g,35.67mmol,4.80mL,1.5eq)，将反应液加热至90℃，在氮气保护下，搅拌1小时后，将反应液冷却到室温，倒入100mL水中，用二氯甲烷(20mL)萃取5次，合并有机相，有机相先用无 水硫酸钠干燥，再通过减压旋转蒸发除去溶剂得粗品。粗品通过柱层析(石油醚至石油醚/乙酸乙酯＝10/1)纯化得到化合物B5-2。LCMS(ESI)m/z:195.9[M+H] +， 1H NMR(400MHz,氘代甲醇)δ＝9.16(s,1H),7.18(d,J＝1.6Hz,1H),6.66(d,J＝2.0Hz,1H),3.98(s,3H),3.90(s,3H)。
步骤3：化合物B5的合成
在一个装有搅拌子和低温温度计的100mL三口瓶中，在氮气保护的条件下，加入B5-1(1g,5.12mmol,1eq)和四氢呋喃(20mL)，待体系降温至-78℃，缓缓滴加正丁基锂的正己烷溶液(2.5M,2.46mL,1.2eq)反应体系维持-78℃搅拌1h。随后在-78℃条件下缓缓滴加三丁基氯化锡(2.4g,7.37mmol,1.98mL,1.44eq)滴加完毕后，升温至-10℃反应1小时。随后将反应液旋转蒸发除去四氢呋喃，加入1,4-二氧六环溶解并过滤除去不溶物，滤液通过减压旋转蒸发除去溶剂得中间体B5。
中间体B6
Figure PCTCN2018100638-appb-000068
合成路线：
Figure PCTCN2018100638-appb-000069
步骤1：化合物B6-1的合成
在0℃下，向3,5-二甲氧基苯甲醛(125g,752.23mmol,1eq)的乙腈(3000mL)溶液中分批加入1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(532.97g,1.50mol,2eq)，加料完毕后，将反应缓慢升至室温，搅拌48小时。反应结束后，将反应液过滤除去固体，滤液通过减压旋转蒸发除去大部分溶剂，然后用1000mL乙酸乙酯稀释，再用饱和碳酸氢钠水溶液调节pH至7-8，最后用分液漏斗分液，水相再用乙酸乙酯(1800mL)萃取三次，合并有机相，用2000mL饱和食盐水洗涤一次，在用无水硫 酸钠干燥，最后过滤，滤液通过减压旋转蒸发除去溶剂得粗品。粗品通过柱层析(100-200目硅胶，洗脱剂：石油醚/乙酸乙酯＝1/0–3/1)纯化得化合物B6-1。
步骤2：化合物B6-2的合成
在40℃下，将B6-1(10g,49.47mmol,1eq)，巯基乙酸甲酯(5.78g,54.41mmol,4.94mL,1.1eq)和碳酸钾(6.84g,49.47mmol,1eq)的N,N-二甲基甲酰胺(100mL)的反应液搅拌20小时。反应结束后，将反应液降至室温，将400mL水加入到反应液中，用200mL乙酸乙酯萃取，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粗品。粗品经过柱机(
Figure PCTCN2018100638-appb-000070
200g
Figure PCTCN2018100638-appb-000071
硅胶快速柱,流动相：0～100％乙酸乙酯/石油醚@100mL/min)纯化得化合物B6-2。
步骤3：化合物B6-3的合成
在90℃下，将B6-2(5g,18.50mmol,1eq)和一水合氢氧化锂(7.76g,185.00mmol,10eq)的二氧六环(50mL)和水(10mL)的混合溶液搅拌18小时。反应结束后，将反应液降至室温，然后通过减压旋转蒸发除去有机溶剂，再用1M的稀盐酸调节pH至6，最后用100mL乙酸乙酯萃取5次，合并有机相，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化合物B6-3。 1H NMR(400MHz,氘代氯仿)δ＝8.18(s,1H),6.68(d,J＝6.0Hz,1H),4.01(s,3H),3.99(s,3H)
步骤4：化合物B6-4的合成
在200℃下，将B6-3(2.4g,9.37mmol,1eq)，氧化亚铜(2.68g,18.73mmol,1.91mL,2eq)和喹啉(20mL)的混合物搅拌1小时。反应结束后，将反应降至室温，向反应液中加入50mL乙酸乙酯，然后用1M的稀盐酸调节pH至6，用分液漏斗分液后，有机相用无水硫酸钠干燥，过滤，滤液通过旋转蒸发除去溶剂得粗品。粗品通过过柱机(
Figure PCTCN2018100638-appb-000072
24g
Figure PCTCN2018100638-appb-000073
Silica Flash Column,流动相0～100％乙酸乙酯/石油醚@35mL/min)纯化得化合物B6-4。 1H NMR(400MHz,氘代氯仿)δ＝7.47-7.41(m,1H),7.41-7.35(m,1H),6.57(d,J＝5.6Hz,1H),3.99(s,3H),3.98(s,3H)。
步骤5：化合物B6的合成
以中间体B6-4为原料，参照实施例1的合成方法合成。 1H NMR(400MHz,氘代甲醇)δ＝7.80(s,1H),6.74(d,J＝6.0Hz,1H),3.97(s,3H),3.95(s,3H)
中间体B7
Figure PCTCN2018100638-appb-000074
以7-甲氧基苯并呋喃为原料，参照中间体B1的合成方法合成。 1H NMR(400MHz,氘代甲醇)δ＝7.34(s,1H),7.25-7.11(m,2H),6.91(d,J＝7.6Hz,1H),4.12-3.91(m,3H)
中间体B8
Figure PCTCN2018100638-appb-000075
合成路线：
Figure PCTCN2018100638-appb-000076
步骤1：化合物B8-1的合成
在室温下，在预先干燥过的250毫升烧瓶中加入四氢呋喃(100mL)，4-溴巴豆酸乙酯(10.0g,51.80mmol,7.14mL,1.00eq)，并在在25℃下搅拌。在25℃下加入K 2CO 3(14.32g,103.61mmol,2.00eq)，和吗啉(4.74g,54.39mmol,4.79mL,1.05eq)，在25℃下搅拌12小时。反应结束后，将反应液缓慢倒入到水中(50ml)，用乙酸乙酯(50ml)萃取三次，合并有机相，无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用过柱机纯化(石油醚/乙酸乙酯＝10:1～3:1)得到化合物B8-1。 1H NMR(400MHz,氘代氯仿)δ＝7.27-6.88(m,1H),6.00-5.95(m,1H),4.15(q,J＝7.2Hz,2H),3.75-3.59(m,4H),3.12-3.10(m,2H),2.51-2.31(m,4H),1.35-1.09(m,3H)
步骤2：化合物B8的合成
准备干净的100ml三口瓶，在25℃下将化合物B8-1(1g,5.02mmol,1eq)溶于甲醇(20ml)水(10mL)中，并开始搅拌。将反应液将至0℃，将NaOH(602.27mg,15.06mmol,3eq)加入到上述反应液中，再将反应体系加热到25℃，搅拌1小时后，将反应液通过减压旋转蒸发浓缩，有固体析出，固体用二氯甲烷/甲醇(10/1)浸泡，过滤，将滤液浓缩得到化合物B8。1H NMR(400MHz,氘代甲醇)δ＝7.04-6.85(m,1H),6.43-6.23(m,1H),4.02-4.00(m,4H),3.94-3.81(m,2H),3.57-3.36(m,2H),3.27-3.17(m,2H)
中间体B9
Figure PCTCN2018100638-appb-000077
以7-甲氧基本并噻吩为原参考中间体B1的合成方法合成。 1H NMR(400MHz,DMSO-d 6)δ＝7.95-7.79(m,1H),7.61-7.39(m,1H),7.37-7.24(m,1H),6.99-6.83(m,1H),3.96-3.87(m,3H)
实施例1和2：化合物WX001(WX001A和WX001B)的合成
Figure PCTCN2018100638-appb-000078
步骤1：化合物WX001-1的合成
在室温下，将化合物B1(777.25mg,3.50mmol,2.50eq)，碳酸钠(296.77mg,2.80mmol,2.00eq)以及四三苯基磷钯(161.78mg,140.00μmol,0.10eq)依次加入到化合物A1(600.00mg,1.40mmol,1.00eq)的乙二醇二甲醚(9mL)/乙醇(3mL)/水(0.5mL)混合溶液中，用氮气置换三次以后，加热至90℃，搅拌5小时后冷却至室温，倒入30mL水中，用二氯甲烷(10mL)萃取5次，合并有机相，用无水硫酸钠干燥，过滤，减压旋转蒸发除去溶剂得粗品。粗品通过柱层析(石油醚/乙酸乙酯＝10/1至1/3)纯化得WX001-1。LCMS(ESI)m/z:480.2[M+H] +，502.2[M+Na] +, 1H NMR(400MHz,氘代甲醇)δ＝7.91(s,1H),7.27(s,2H),6.77(s,1H),6.70(s,1H),4.00(s,3H),3.96-3.90(m,2H),3.64-3.50(m,3H),2.49(s,3H),2.44-2.36(m,2H),1.50(s,9H)。
步骤2：化合物WX001-2的合成
在室温下，将盐酸乙酸乙酯溶液(4M,2.00mL,9.51eq)缓慢滴加到WX001-1(350.00mg,729.79μmol,1.00eq)的乙酸乙酯(2mL)溶液中，搅拌1小时后，过滤得固体，固体在减压条件下干燥得化合物WX001-2的盐酸盐。LCMS(ESI)m/z:380.1[M+H]+， 1H NMR(400MHz,氘代甲醇)δ＝8.17(s,1H),7.46(s,1H),7.33(s,1H),7.12-7.06(m,1H),6.84(s,1H),4.12-4.06(m,1H),4.02(s,3H),3.92-3.82(m,2H),3.67-3.58(m,2H),2.66-2.60(m,1H),2.51(s,3H),2.39-2.32(m,1H)。
步骤3：化合物WX001(WX001A和WX001B)的合成
在0℃下，依次将二异丙基乙胺(258.56mg,2.00mmol,349.41μL,4.00eq)和丙烯酰氯的二氯甲烷溶液(0.25M,1.80mL,0.90eq)加入到WX001-2盐酸盐(200.00mg,500.16μmol,1.00eq)的二氯甲烷(4.00mL)溶液中，搅拌5分钟后，将反应液倒入2mL水中，分液后，水相用二氯甲烷(1mL)萃取三次，合并有机相，有机相用无水硫酸钠干燥，过滤后，滤液通过减压旋转蒸发除去溶剂得粗品，粗品用薄层制备板(二氯甲烷/甲醇＝10/1)纯化得化合物WX001。化合物WX001经手性拆分(柱子:AS(250mm*30mm,5μm)；流动相:[0.1％氨水乙醇]；B％:40％-40％)得到WX001A(保留时间6.16分钟)和WX001B(保留时间6.98分钟)。保留时间用以下分析柱测定：柱子：Chiralpak AS-3 150×4.6mm I.D.,3μm,流动相:A:二氧化碳B:甲醇(0.05％二乙胺),40％B,流速:2.5mL/min,柱温:35℃。WX001A，LCMS(ESI)m/z:434.2[M+H] +,456.1[M+Na] +, 1H NMR(400MHz,氘代甲醇)δ＝7.75(d,J＝2.8Hz,1H),7.12-7.04(m,2H),6.61(s,1H),6.56-6.40(m,2H),6.20-6.15(m,1H),5.65-5.60(m,1H),4.11-3.94(m,1H),3.85(s,3H),3.81-3.38(m,4H),2.48-2.26(m,4H),2.22-1.93(m,1H)
WX001B，LCMS(ESI)m/z:434.2[M+H] +,456.1[M+Na] +, 1H NMR(400MHz,氘代甲醇) 1H NMR(400MHz,氘代甲醇)δ＝7.75(d,J＝2.8Hz,1H),7.08(s,2H),6.61(s,1H),6.54(d,J＝6.4Hz,1H),6.41-6.51(m,1H),6.20-6.16(m,1H),5.66-5.42(m,1H),4.09-3.96(m,1H),3.85(s,3H),3.80-3.38(m,4H),2.44-2.25(m,4H),2.21-1.99(m,1H)。
实施例3：化合物WX001C的合成
Figure PCTCN2018100638-appb-000079
由中间体A1-B和B1为原料，参照实施例1合成方法合成。与WX001A合并通过SFC(化合物WX001的SFC分析方法,保留时间：6.14分钟)鉴定为WX001A。。
实施例4：化合物WX002A的合成
Figure PCTCN2018100638-appb-000080
由中间体A1-B和B2为原料，参照实施例1合成方法合成。LCMS(ESI)m/z:454.1[M+H] +, 1H NMR(400MHz,氘代甲醇)δ＝7.81(d,J＝2.0Hz,1H),7.36(d,J＝1.6Hz,1H),7.21(s,1H),6.82(s,1H),6.64(d, J＝9.2Hz,1H),6.58-6.50(m,1H),6.22-6.17(m,1H),5.68-5.63(m 1H),4.20-3.93(m,2H),3.91(s,3H),3.77-3.44(m,3H),2.52-2.31(m,1H),2.27-2.05(m,1H)。
实施例5：化合物WX002B的合成
Figure PCTCN2018100638-appb-000081
由中间体A1-A和中间体B2为原料，参照实施例1合成方法合成。LCMS(ESI)m/z:454.1[M+H] +, 1H NMR(400MHz,氘代甲醇)δ＝7.81(d,J＝2.4Hz,1H),7.36(d,J＝1.6Hz,1H),7.20(s,1H),6.81(s,1H),6.63(d,J＝8.8Hz,1H),6.58-6.50(m,1H),6.22-6.17(m,1H),5.74-5.56(m,1H),4.18-3.92(m,2H),3.90(s,3H),3.81-3.59(m,2H),3.57-3.42(m,1H),2.50-2.30(m,1H),2.28-2.02(m,1H)。
实施例6：化合物WX003的合成
Figure PCTCN2018100638-appb-000082
由中间体A3和中间体B1为原料，参照实施例1合成方法合成。LCMS(ESI)m/z:448.1[M+H] +,470.2[M+Na] +, 1H NMR(400MHz,氘代甲醇)δ＝7.83-7.76(m,1H),7.15(s,2H),6.75-6.68(m,1H),6.66(s,1H),6.61(s,1H),6.14-6.06(m,1H),5.68-5.58(m,1H),4.42-4.27(m,1H),3.88(s,3H),3.40-3.27(m,2H),3.08-2.83(m,2H),2.37(s,3H),2.13-2.02(m,1H),1.86-1.72(m,2H),1.63-1.54(m,1H)。
实施例7和8：化合物WX004(WX004A,WX004B)的合成
Figure PCTCN2018100638-appb-000083
由中间体A2和中间体B4为原料，参照实施例1中步骤1的方法合成。合成后经手性拆分(柱子:AS(250mm*30mm,10μm)；流动相:[0.1％氨水/甲醇]；B％:40％-40％)得化合物WX004A(保留时间5.58分钟)和WX004B(保留时间6.14分钟)。保留时间用以下分析柱测定：柱子：Chiralpak AS-3 150×4.6mm  I.D.,3μm,流动相:A:二氧化碳B:甲醇(0.05％二乙胺),40％B,流速:2.5mL/min,柱温:35℃。
WX004A，LCMS(ESI)m/z:448.2[M+H] +,470.2[M+Na] +, 1H NMR(400MHz,氘代甲醇)δ＝7.90(d,J＝2.0Hz,1H),7.21(s,1H),6.81(s,1H),6.73-6.57(m,2H),6.34-6.33(m,1H),5.80-5.75(m,1H),4.32-4.12(m,1H),4.11-3.95(m,4H),3.93-3.72(m,2H),3.70-3.64(m,1H),2.64-2.42(m,4H),2.39-2.16(m,4H)WX004B，LCMS(ESI)m/z:448.2[M+H] +, 1H NMR(400MHz,氘代甲醇)δ＝7.78(d,J＝2.0Hz,1H),7.09(s,1H),6.69(s,1H),6.63-6.44(m,2H),6.22-6.17(m,1H),5.73-5.54(m,1H),4.24-4.01(m,1H),4.00-3.89(m,1H),3.87(s,3H),3.80-3.60(m,2H),3.57-3.44(m,1H),2.52-2.32(m,4H),2.30-2.10(m,4H)。
实施例9：化合物WX005的合成
Figure PCTCN2018100638-appb-000084
由中间体A1-A，B3为原料，参照实施例1合成方法合成。LCMS(ESI)m/z:490.1[M+Na] +, 1H NMR(400MHz,氘代甲醇)δ＝7.80(d,J＝2.0Hz,1H),7.32(d,J＝1.2Hz,1H),6.87(s,1H),6.67-6.49(m,2H),6.25-6.03(m,1H),5.70-5.59(m,1H),4.24-4.00(m,1H),3.99-3.85(m,3H),3.83-3.60(m,2H),3.58-3.41(m,1H),3.40-3.26(m,1H),2.50-2.34(m,1H),2.32-2.19(m,1H),2.17(s,3H)。
实施例10：化合物WX006A的合成
Figure PCTCN2018100638-appb-000085
合成路线：
Figure PCTCN2018100638-appb-000086
步骤1-2：化合物WX006A-2的合成
以中间体A1-B和B1为原料，参考实施例1中步骤1和步骤2的合成方法合成。
步骤3：化合物WX006A的合成
在0℃下，将O-(7-氮杂苯并三氮唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸酯(68.56mg,180.31μmol,1.50eq)加入到2-丁炔酸(10.11mg,120.21μmol,1.00eq)的二氯甲烷(2.00mL)溶液中，搅拌30分钟后，在在0℃下，将化合物WX006A-2(50.00mg,120.21μmol,1.00eq,HCl)和三乙胺(36.49mg,360.63μmol,49.99μL,3.00eq)加入到反应液中，缓慢升至20℃，搅拌16小时。反应结束后，将反应液用10mL二氯甲烷稀释，用15mL水洗涤三次后，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，粗品通过薄层制备板(石油醚/乙酸乙酯＝1/1)分离得化合物WX006A。LCMS(ESI)m/z:446.1[M+H] +,468.1[M+Na] +, 1H NMR(400MHz,氘代甲醇)δ＝7.78(d,J＝7.2Hz,1H),7.13(s,2H),6.64(s,1H),6.59(d,J＝6.8Hz,1H),3.98-3.74(m,5H),3.69-3.55(m,2H),3.47-3.34(m,1H),2.46-2.31(m,4H),2.22-2.07(m,1H),1.93(d,J＝9.2Hz,3H)
实施例11：化合物WX006B的合成
Figure PCTCN2018100638-appb-000087
以中间体A1-A和B1为原料，参考实施例1，实施例9的合成方法合成。LCMS(ESI)m/z:446.1[M+H] +, 468.0[M+Na] +, 1H NMR(400MHz,氘代甲醇)δ＝7.78(d,J＝7.2Hz,1H),7.13(s,2H),6.64(s,1H),6.59(d,J＝6.4Hz,1H),4.00-3.73(m,5H),3.70-3.51(m,2H),3.45-3.34(m,1H),2.36(s,4H),2.23-2.06(m,1H),1.93(d,J＝9.2Hz,3H)
实施例12和13：化合物WX007(WX007A,WX007B)的合成
Figure PCTCN2018100638-appb-000088
由中间体WX001-2和油酸为原料，参照实施例9中步骤3的方法合成。合成后经手性拆分(柱子:AS(250mm*30mm,10μm)；流动相:[0.1％氨水乙醇]；B％:45％-45％)得化合物WX007A(保留时间：1.70分钟)和WX007B(保留时间：2.02分钟)。保留时间用以下分析柱测定：柱子:Chiralpak AS-H 150*4.6mm I.D.,5μm,流动相:40％乙醇(0.05％乙二胺)在二氧化碳中,流速:3mL/min,柱子温度:40℃)。
WX007A，LCMS(ESI)m/z:491.2[M+H] +,513.1[M+Na] +, 1H NMR(400MHz,氘代甲醇)δ＝7.76(d,J＝3.6Hz,1H),7.09(s,2H),6.79-6.67(m,1H),6.79-6.67(m,1H),6.62(s,1H),6.55(d,J＝8.8Hz,1H),6.37-6.32(m,1H),4.12-3.92(m,1H),3.86(s,3H),3.81-3.72(m,1H),3.70-3.39(m,3H),3.07-2.99(m,2H),2.39-2.25(m,4H),2.16(s,3H),2.15(s,3H),2.12-1.99(m,1H)
WX007B，LCMS(ESI)m/z:491.2[M+H] +,513.1[M+Na] +, 1H NMR(400MHz,氘代甲醇)δ＝7.76(d,J＝3.2Hz,1H),7.10(s,2H),6.79-6.68(m,1H),6.63(s,1H),6.56(d,J＝9.2Hz,1H),6.38-6.33(m,1H),4.15-3.94(m,1H),3.86(s,3H),3.83-3.71(m,1H),3.69-3.40(m,3H),3.06-3.03(m,2H),2.40-2.32(m,4H),2.17(s,3H),2.15(s,3H),2.12-1.97(m,1H)
实施例14：化合物WX008的合成
Figure PCTCN2018100638-appb-000089
合成路线：
Figure PCTCN2018100638-appb-000090
步骤1:WX008-1的合成
在-60℃氮气保护下，15分钟内，将甲基锂(1.6M,616.10μL,1.05eq)滴加到4-氨基-7-溴吡咯并[2,1-f][1,2,4]三嗪(0.2g,938.81μmol,1eq)的四氢呋喃(15mL)的溶液中。反应30分钟后，将正丁基锂(2.5M,413.08μL,1.1eq)缓慢滴加到反应液中，反应液在-60度到-40度之间搅拌1小时后，将N-BOC-3-吡咯烷酮(347.77mg,1.88mmol,2eq)加入到反应液中，将反应液缓慢升至20℃，搅拌16小时。将反应液降温至0℃，将1mL水加入反应液中，将反应淬灭。用5mL水将反应液稀释，用乙酸乙酯(5mL)萃取三次，有机相用10mL饱和食盐水洗涤，无水硫酸钠干燥，过滤后，滤液通过减压旋转蒸发得化合物WX008-1粗品，粗品直接用于下一步反应。LCMS(ESI)m/z:319.9[M+H] +
步骤2:WX008-2的合成
由中间体WX008-1为原料，参照合成A1的方法合成。LCMS(ESI)m/z:446.0[M+H] +
步骤3-5:WX008的合成
由中间体WX008-2为原料，参照实施例1合成方法合成。LCMS(ESI)m/z:432.1[M+H] +,450.1[M+Na] +, 1H NMR(400MHz,氘代甲醇)δ＝7.81(d,J＝3.6Hz,1H),7.15(d,J＝2.4Hz,2H),6.77(d,J＝3.6Hz,1H),6.65(s,1H),6.63-6.44(m,1H),6.24-6.19(m,1H),5.72-5.57(m,1H),4.17-3.93(m,2H),3.88(s,3H),3.85-3.56(m,2H),2.86-2.61(m,1H),2.37(s,3H),2.34-2.20(m,1H)
实施例15和16：化合物WX009A和WX009B的合成
Figure PCTCN2018100638-appb-000091
以中间体A1，B1和氰基乙酸为原料，参考实施例1和实施例9的合成方法合成化合物WX009，经SFC(柱子:AD(250mm*30mm,10μm)；流动相:[0.1％氨水异丙醇]；B％:55％-55％)分离后得到化合物WX009A(保留时间：5.08分钟)和化合物WX009B(保留时间：7.89分钟)。保留时间用以下分析柱测定：柱子:Chiralpak AD-3 50*4.6mm I.D.,3μm,流动相:40％异丙醇(0.05％乙二胺)在二氧化碳中,流速:4mL/min,柱子温度:40℃)
WX009A：LCMS(ESI)m/z:447.2[M+H] +,469.1[M+H] +, 1H NMR(400MHz,氘代甲醇)δ＝7.79(d,J＝1.2Hz,1H),7.16(d,J＝1.6Hz,2H),6.75-6.54(m,2H),4.05-3.93(m,2H),3.88(s,3H),3.70-3.59(m,1H),3.56-3.39(m,2H),2.48-2.33(m,4H),2.25-2.01(m,1H)。
WX009B：LCMS(ESI)m/z:447.2[M+H] +,469.4[M+H] +, 1H NMR(400MHz,氘代甲醇)δ＝7.79(d,J＝1.6Hz,1H),7.16(d,J＝1.6Hz,2H),6.74-6.51(m,2H),4.10-3.91(m,2H),3.88(s,3H),3.71-3.59(m,1H),3.58-3.40(m,2H),2.50-2.27(m,4H),2.26-1.99(m,1H)。
实施例17：化合物WX010的合成
Figure PCTCN2018100638-appb-000092
合成路线：
Figure PCTCN2018100638-appb-000093
步骤1：化合物WX010-1的合成
在一个装有搅拌子的100mL三口瓶中，氮气保护条件下，依次加入化合物A1(1.10g,2.56mmol,1eq)，碘化亚铜(97.53mg,512.00μmol,0.2eq)，二三苯基膦二氯化钯(359.44mg,512.00μmol,0.2eq)，三乙胺(1.04g,10.24mmol,1.43mL,4eq)和1,4-二氧六环(5mL)随后加入新鲜制备的化合物B5(2.48g,5.12mmol,2eq)。用氮气置换三次后置于100℃油浴中反应12小时。反应完成后，过滤除去不溶物，滤液减压旋转蒸发得粗品，粗品通过柱层析(石油醚/乙酸乙酯＝3/1至乙酸乙酯)得到产物WX010-1。LCMS(ESI)m/z:467.1[M+H] +
步骤2和3：化合物WX010的合成
由中间体WX010-1为原料，参照实施例1步骤2和3的方法合成化合物WX010。LCMS(ESI)m/z:473.1[M+Na] +, 1H NMR(400MHz,氘代甲醇)δ＝7.86(s,1H),7.09-6.93(m,2H),6.70-6.64(m,1H),6.55(s,1H),6.37-6.31(m,1H),5.82-5.79(m,1H),4.34-4.09(m,1H),3.97(s,3H),3.89-3.83(m,5H),3.82-3.69(m,1H),3.68-3.55(m,1H),2.62-2.41(m,1H),2.38-2.12(m,1H)
实施例18和19：WX011(WX011A和WX011B)的合成
Figure PCTCN2018100638-appb-000094
合成路线：
Figure PCTCN2018100638-appb-000095
步骤1：化合物WX011-1的合成
将(1H-吡咯-1-基)氨基甲酸叔丁酯(25.00g,137.20mmol,1.00eq)的乙腈(200.00mL)溶液冷却到0℃，用注射器将氯磺酰异氰酸酯(20.39g,144.06mmol,12.51mL,1.05eq)缓慢滴加到反应液中，搅拌30分钟后有沉淀生成。在0℃继续搅拌45分钟后，用注射器将N,N-二甲基甲酰胺(14.84g,203.05mmol,15.62mL,2.50eq)滴加到反应液中，反应液中沉淀消失，在此温度下继续搅拌45分钟后，将反应液缓慢升温至25℃，反应结束。将反应液缓慢倒入200mL冰水,用200mL乙酸乙酯萃取，有机相先用无水硫酸镁干燥，然后通过填有硅胶的砂芯漏斗过滤，滤液通过减压旋转蒸发除去溶剂得到化合物WX011-1。
步骤2：化合物WX011-2的合成
在-30℃下，将二溴海因(10.69g,37.40mmol,0.50eq)分批加入到WX011-1(15.50g,74.80mmol,1.00eq)的乙腈(150mL)溶液中，将反应液缓慢升至25℃，搅拌2小时。反应结束后，将反应液加入100mL水中，水相用乙酸乙酯(100mL x 3)萃取，合并有机相，有机相用100mL饱和食盐水洗涤一次,用无水硫酸钠干燥，过滤，滤液通过减压旋转蒸发得粗品。粗品经柱层析(石油醚/乙酸乙酯＝9/1-1/1)纯化得化合物WX011-2。1H NMR(400MHz,CDCl3)δ＝7.23(brs,1H),6.85(d,J＝2.0Hz,1H),6.71(d,J＝2.0Hz,1H),1.44(s,9H)。
步骤3：化合物WX011-3的合成
在氮气保护下，将WX011-2(5.30g,18.52mmol,1.0eq)的四氢呋喃(100mL)溶液冷却到-60℃，将甲基溴化镁(3mol/L四氢呋喃溶液,6.80mL,20.38mmol,1.1eq)缓慢滴加到反应液中，搅拌30分钟后，再将正丁基锂(2.0mol/L正己烷溶液,14.80mL,37.05mmol,2.0eq)滴加到反应液中。将反应液内温保持在-40℃到-60℃之间，搅拌1小时后，将多聚甲醛(1.67g,18.52mmol,1.0eq)加入到反应液中，然后升至室温搅拌过夜。反应结束后，将反应液缓慢倒入100mL饱和食盐水中，用乙酸乙酯(100mL x3)萃取，合并有机相，有机相用100mL饱和食盐水洗涤一次，无水硫酸钠干燥，过滤后，滤液通过减压旋转蒸发得粗品。粗品经过柱机(
Figure PCTCN2018100638-appb-000096
220g
Figure PCTCN2018100638-appb-000097
Silica Flash Column,流动相0～50％乙酸乙酯/石油醚@100mL/min)纯化得化合物WX011-3。 1H NMR(400MHz,DMSO-d6):δ＝10.77(brs,1H),7.09(d,J＝1.6Hz,1H),6.86(d,J＝1.6Hz,1H),4.97(t,J＝5.6Hz,1H),4.28(d,J＝5.6Hz,2H),1.45(s,9H)。
步骤4：化合物WX011-4的合成
室温下，向化合物WX011-3(4.70g,19.81mmol,1eq)中加入氯化氢/二氧六环溶液(12mL)，搅拌5小时后，将甲醇(60mL)加入到反应液中，搅拌过夜。最后将磷酸钾(42.05g,198.10mmol,10eq)和醋酸甲脒(10.31g,99.05mmol,5eq)加入反应液,然后升温到65℃搅拌20小时。反应结束后，将反应液冷却至室温，过滤,滤液浓缩后通过过柱机纯化(
Figure PCTCN2018100638-appb-000098
220g
Figure PCTCN2018100638-appb-000099
Silica Flash Column,流动相0-3％甲醇/二氯甲烷@100mL/min)纯化得到化合物WX011-4。LCMS(ESI)m/z:178.9[M+H] +， 1H NMR(400MHz,DMSO-d6)δ＝7.78(s,1H),7.69(brs,2H),7.58(d,J＝1.2Hz,1H),6.82(d,J＝1.6Hz,1H),4.42(s,2H),3.26(s,3H)
步骤5：化合物WX011-5的合成
在-30℃下，将二溴海因(1.85g,6.46mmol,0.50eq)分批加入到WX011-4(2.30g,12.91mmol,1.00eq)的四氢呋喃(20mL)溶液中。反应液在15℃下搅拌16小时后，将反应液浓缩后通过过柱机纯化(
Figure PCTCN2018100638-appb-000100
40g
Figure PCTCN2018100638-appb-000101
Silica Flash Column,流动相0-10％二氯甲烷/甲醇@60mL/min)纯化得到白色固体WX011-5。LCMS(ESI)m/z:256.8[M+H] +，1H NMR(400MHz,DMSO-d6)δ＝7.92(s,1H),7.88(brs,1H),7.04(s,1H),4.42(s,2H),3.27(s,3H)。
步骤6：化合物WX011-6的合成
在室温下，先将WX011-5(6.40g,24.89mmol,1.00eq)溶于1,4-二氧六环(100mL)和水(20mL)的混合溶液中，再依次将N-Boc-2,5-二氢-1H-吡咯-1-嚬哪醇硼酸酯(7.35g,24.89mmol,1.00eq)，磷酸钾(15.85g,74.68mmol,3.00eq)和1,1'-双(二苯基磷)二茂铁氯化钯(1.82g,2.49mmol,0.10eq)加入到该混合溶液中。在氮气保护下，将反应液加热至80℃搅拌16小时。反应结束后，将反应液冷却到室温，缓慢倒入100mL水中，用乙酸乙酯(100mL x 3)萃取，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得化合物WX011-6。LCMS(ESI)m/z:346.0[M+H] +。
步骤7：化合物WX011-7的合成
在室温下，将氢氧化钯(65.05mg,463.24μmol,0.1eq)加入到WX011-6(1.60g,4.63mmol,1.00eq)的甲醇(30mL)溶液中。用氢气置换3次，将反应液加热至50℃，在50psi氢气条件下，搅拌16小时后，将反应液冷却到室温，过滤除去催化剂，滤液通过减压旋转蒸发除去溶剂得WX011-7。LCMS(ESI)m/z:348.1[M+H] +。
步骤8：化合物WX011-8的合成
在室温下，将溴代丁二酰亚胺(563.55mg,3.17mmol,1.10eq)分批加入到WX011-7(1.00g,2.88mmol,1.00eq)的四氢呋喃(20mL)溶液中。反应液在20℃下搅拌1小时后，将反应液加入乙酸乙酯(50mL)中，依次用30mL水和30mL饱和食盐水洗涤一次,用无水硫酸钠干燥后减压旋转蒸发得化物WX011-8。LCMS(ESI)m/z:425.9[M+H] +。
步骤9：化合物WX011-9的合成
在室温下，将化合物WX011-8(1.25g,5.63mmol,1.50eq),氟化铯(2.85g,18.77mmol,5.00eq)以及氯(2-二环己基膦基-2,4,6-三异丙基-1,1-联苯基)[2-(2-氨基-1,1-联苯)]钯(II)(295.3mg,375.32μmol,0.10eq)依次加入到化合物WX001-9(1.60mg,3.75mmol,1.00eq)的四氢呋喃(20mL)/水(2mL)混合溶液中，用氮气置换三次以后，加热至60℃，搅拌16小时后冷却至室温，倒入30mL水中，用二氯甲烷(10mL)萃取3次，合并有机相，用饱和食盐水10mL洗一次，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化合物WX011-9。LCMS(ESI)m/z:524.1[M+H] +。
步骤10：化合物WX011-10的合成
在室温下，将盐酸乙酸乙酯溶液(4M,20.00mL)加到WX011-9(1.60g,3.06mmol,1.00eq)中，搅拌1小时后，过滤得固体，固体在减压条件下干燥得化合物WX011-10的盐酸盐。LCMS(ESI)m/z:424.1[M+H] +。
步骤11：化合物WX011的合成
在0℃下，将丙烯酰氯(216.44mg,2.39mmol,1.00eq)加入到三乙胺(2.42g,23.91mmol,10.00eq)和WX011-10盐酸盐(1.10g,2.39mmol,1.00eq)的二氯甲烷(10mL)溶液中，搅拌60分钟后，反应液倒 入25mL二氯甲烷中，有机相用水(25mL)洗二次，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，粗品用薄层制备板(乙酸乙酯)纯化得化合物WX011。化合物WX011经手性拆分(柱子:AD(250mm*30mm,5μm)；流动相:[0.1％氨水乙醇]；B％:45％-45％)得到WX011A(保留时间：0.58分钟)和WX011B(保留时间：0.74分钟)。保留时间用以下分析柱测定：柱子:Chiralpak AD-350*4.6mm I.D.,3μm,流动相:40％异丙醇(0.05％乙二胺)在二氧化碳中,流速:4mL/min,柱子温度:40℃)。
WX011A，LCMS(ESI)m/z:478.1[M+H] +,500.1[M+Na] +, 1H NMR(400MHz,CDCl3)δ:7.85(d,J＝8.4Hz,1H),7.20(s,1H),7.16(s,1H),6.62(s,1H),6.51-6.30(m,2H),5.68–5.60(m,1H),5.47(2H,brs),4.34(s,2H),4.18-3.78(m,7H),3.65-3.48(m,1H),3.22(d,J＝10.0Hz,3H),2.85-2.65(m,1H),2.44(s,3H)WX011B，LCMS(ESI)m/z:478.1[M+H] +,500.0[M+Na] +, 1H NMR(400MHz,CDCl3)δ:7.84(d,J＝8.8Hz,1H),7.20(s,1H),7.16(s,1H),6.62(s,1H),6.51-6.30(m,2H),5.68–5.60(m,1H),5.42(2H,brs),4.34(s,2H),4.15-3.72(m,7H),3.62-3.48(m,1H),3.22(d,J＝10.4Hz,3H),2.90-2.65(m,1H),2.44(s,3H)。
实施例20：化合物WX012的合成
Figure PCTCN2018100638-appb-000102
合成路线：
Figure PCTCN2018100638-appb-000103
以中间体WX011-10为中间体，参照实施例9的合成方法合成。LCMS(ESI)m/z:490.0[M+H] +,512.0[M+Na] +, 1H NMR(400MHz,CDCl3)δ＝7.90-7.80(m,1H),7.22-7.18(m,1H),7.16(s,1H),6.65-6.60(m,1H),6.57(brs,2H),4.38-4.30(m,2H),4.20-3.90(m,6H),3.89-3.70(m,1H),3.68-3.38(m,1H),3.28-3.18(m,3H),2.80-2.65(m,1H),2.44(s,3H),2.18-2.08(m,1H),1.98-1.85(m,3H)。
实施例21：化合物WX013的合成
Figure PCTCN2018100638-appb-000104
以中间体A1-A和B6为原料，参照WX001的合成方法合成。LCMS(ESI)m/z:470.1[M+H] +, 1H NMR(400MHz,氘代甲醇)δ＝7.79(d,J＝3.2Hz,1H),7.20(s,1H),6.72-6.54(m,2H),4.09-3.91(m,1H),3.88(s,3H),3.87(s,3H),3.85-3.72(m,1H),3.67-3.37(m,4H),2.32-2.25(m,2H),1.05-1.00(m,3H)
实施例22：化合物WX014的合成
Figure PCTCN2018100638-appb-000105
以中间体A1-B和B6为原料，参照WX001的合成方法合成。LCMS(ESI)m/z:468.1[M+H] +, 1H NMR(400MHz,氘代甲醇)δ＝7.90(br s,1H),7.31(br d,J＝10.0Hz,1H),6.83-6.69(m,2H),6.69-6.55(m,1H),6.39-6.21(m,1H),5.83-5.70(m,1H),4.69(br d,J＝2.0Hz,1H),4.28-4.04(m,1H),3.99(d,J＝3.6Hz,3H),3.97(d,J＝2.4Hz,4H),3.89-3.70(m,2H),3.64-3.54(m,1H),2.63-2.42(m,1H),2.33-2.13(m,2H)
实施例23：化合物WX015的合成
Figure PCTCN2018100638-appb-000106
以中间体A1-A和B6为原料，参照WX001合成方法合成，LCMS(ESI)m/z:468.1[M+H] +, 1H NMR(400MHz,氘代甲醇)δ＝7.79(d,J＝1.6Hz,1H),7.18(d,J＝1.6Hz,1H),6.65-6.60(m,2H),6.56-6.47(m,1H),6.28-6.03(m,1H),5.74-5.57(m,1H),4.17-3.97(m,1H),3.88(s,3H),3.86(s,3H),3.77-3.59(m,2H),3.50-3.38(m,1H),23.07-2.96(m,1H),2.47-2.31(m,1H),2.20-2.01(m,1H)
实施例24：化合物WX016的合成
Figure PCTCN2018100638-appb-000107
以中间体A1-B和B6为原料，参照WX001合成方法合成，LCMS(ESI)m/z:470.1[M+H] +, 1H NMR(400MHz,氘代甲醇)δ＝7.79(d,J＝3.2Hz,1H),7.20(s,1H),6.71-6.49(m,2H),4.06-3.78(m,8H),3.68-3.58(m,1H),3.57-3.34(m,3H),3.15-3.05(m,1H),2.24-1.98(m,2H),1.07-1.00(m,3H)
实施例25：化合物WX017的合成
Figure PCTCN2018100638-appb-000108
以中间体A1-A和B7为原料，参照WX001合成方法合成，LCMS(ESI)m/z:404.2[M+H] +,426.1[M+Na] +, 1H NMR(400MHz,氘代甲醇)δ＝7.74(d,J＝2.4Hz,1H),7.12-7.02(m,2H),6.97-6.88(m,2H),6.79(d,J＝7.2Hz,1H),6.59-6.50(m,1H),6.24-6.10(m,1H),5.70-5.64(m,1H),4.28-3.94(m,1H),3.90(s,3H),3.84-3.45(m,3H),3.20-3.18(m,1H),2.49-2.31(m,1H),2.24-2.01(m,1H)
实施例26：化合物WX018的合成
Figure PCTCN2018100638-appb-000109
以中间体A1-B和B1为原料，参照WX001合成方法合成，LCMS(ESI)m/z:436.1[M+H] +,458.1[M+Na] +, 1H NMR(400MHz,氘代甲醇)δ＝7.76(d,J＝4.4Hz,1H),7.10(s,2H),6.67-6.61(m,1H),6.56(d,J＝13.2Hz,1H),3.97-3.89(m,1H),3.86(s,3H),3.65-3.55(m,1H),3.53-3.30(m,2H),3.20-3.18(m,1H),2.35(s,3H),2.33-2.16(m,3H),2.15-1.98(m,1H),1.07-0.97(m,3H)
实施例27：化合物WX019的合成
Figure PCTCN2018100638-appb-000110
以中间体A1-A和B1为原料，参照实施例1合成方法合成，LCMS(ESI)m/z:436.1[M+H] +,458.1[M+Na] +, 1H NMR(400MHz,氘代甲醇)δ＝7.78(d,J＝4.4Hz,1H),7.14-7.10(m,2H),6.64(s,1H),6.58(d,J＝13.2Hz,1H),4.03-3.91(m,1H),3.87(s,3H),3.66-3.57(m,1H),3.55-3.32(m,2H),3.21-3.18(m,1H),2.45-2.32(m,4H),2.28(q,J＝7.2Hz,2H),2.19-2.01(m,1H),1.05-1.01(m,3H)
实施例28：化合物WX020的合成
Figure PCTCN2018100638-appb-000111
以中间体WX010-2为原料，参照实施例1的合成方法合成。LCMS(ESI)m/z:453.1[M+H] +。
实施例29：化合物WX021的合成
Figure PCTCN2018100638-appb-000112
以中间体A1-B，B6和油酸为原料，参照实施例1和实施例9的合成方法合成，LCMS(ESI)m/z:525.1[M+H] +,547.0[M+Na] +, 1H NMR(400MHz,氘代甲醇)δ＝7.91(d,J＝2.4Hz,1H),7.30(d,J＝1.2Hz,1H),6.93-6.80(m,1H),6.79-6.65(m,2H),6.53-6.47(m,1H),4.28-4.06(m,1H),4.06-3.91(m,6H),3.90-3.70(m,2H),3.69-3.52(m,1H),3.32-3.28(m,1H),3.27-3.09(m,2H),2.59-2.40(m,1H),2.38-2.28(m,6H),2.28-2.16(m,1H)
实施例30：化合物WX022的合成
Figure PCTCN2018100638-appb-000113
以中间体A1-A，B6和油酸为原料，参照实施例1和实施例9的合成方法合成，LCMS(ESI)m/z:525.2[M+H] +, 1H NMR(400MHz,氘代甲醇)δ＝7.78(d,J＝2.4Hz,1H),7.17(s,1H),6.80-6.66(m,1H),6.65-6.53(m,2H),6.50-6.39(m,1H),4.18-3.94(m,1H),3.87(s,3H),3.86(s,3H),3.83-3.58(m,3H),3.56-3.42(m,1H),3.10(q,J＝7.2Hz,2H),2.48-2.36(m,1H),2.34(s,3H),2.33(s,3H),2.25-2.03(m,1H)
实施例31：化合物WX023A的合成
Figure PCTCN2018100638-appb-000114
以中间体A1-B，B1和B8为原料，参照实施例1和实施例9的合成方法合成。LCMS(ESI)m/z:533.5[M+H] +, 1H NMR(400MHz,氘代氯仿)δ＝7.97(d,J＝5.2Hz,1H),7.25-7.17(m,2H),7.04-6.82(m,1H),6.73-6.55(m,2H),6.37-6.31(m,1H),5.81(br s,2H),4.34-4.11(m,1H),4.10-3.94(m,4H),3.91-3.86(m,1H),3.81-3.59(m,6H),3.17(t,J＝7.2Hz,2H),2.60-2.38(m,8H),2.30-2.14(m,1H)
实施例32：化合物WX023B的合成
Figure PCTCN2018100638-appb-000115
以中间体A1-A，B1和B8为原料，参照实施例1和实施例9的合成方法合成。LCMS(ESI)m/z:533.2[M+H] +, 1H NMR(400MHz,氘代氯仿)δ＝7.96(d,J＝5.6Hz,1H),7.25-7.17(m,2H),7.00-6.84(m,1H),6.73-6.60(m,2H),6.42-6.28(m,1H),5.87(br s,2H),4.25-4.10(m,1H),4.09-3.95(m,4H),3.90-3.78(m,1H),3.77-3.59(m,6H),3.26-3.12(m,2H),2.62-2.39(m,8H),2.31-2.15(m,1H)。
实施例33：化合物WX024的合成
Figure PCTCN2018100638-appb-000116
以中间体A1-A，B9为原料，参照实施例1的合成方法合成。LCMS(ESI)m/z:420.1[M+H] +, 1H NMR(400MHz,氘代甲醇)δ＝8.12(d,J＝1.6Hz,1H),7.56-7.45(m,2H),7.43-7.31(m,1H),7.04-6.87(m,2H),6.72-6.54(m,1H),6.35-6.21(m,1H),5.80-5.68(m,1H),4.25-4.02(m,2H),4.00(s,3H),3.95-3.71(m,2H),3.68-3.56(m,1H),2.64-2.43(m,1H),2.41-2.17(m,1H)。
实施例34：化合物WX025的合成
Figure PCTCN2018100638-appb-000117
以中间体A1-B和B5为原料，参考实施例15和16以及实施例1合成方法合成。LCMS(ESI)m/z:451.0[M+H] +, 1H NMR(400MHz,氘代氯仿)δ＝7.94(d,J＝3.2Hz,1H),7.01(s,1H),6.90(s,1H),6.60-6.38(m,3H),5.76-5.69(m,1H),4.31-4.13(m,1H),4.11-3.86(m,7H),3.80-3.54(m,3H),2.70-2.38(m,1H),2.31-2.22(m,1H)
各实施例的NMR和MS数据
Figure PCTCN2018100638-appb-000118
Figure PCTCN2018100638-appb-000119
Figure PCTCN2018100638-appb-000120
Figure PCTCN2018100638-appb-000121
Figure PCTCN2018100638-appb-000122
实验例1：野生型激酶体外抑制活性评价
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FGFR1、FGFR4的抑制能力。
缓冲液条件：20mM Hepes(pH 7.5),10mM MgCl2,1mM 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，或为10μM,2.50μM,0.62μM,0.156μM,39.1nM,9.8nM,2.4nM,0.61nM,0.15nM,0.038nM。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。FGFR1、FGFR4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 PCTCN2018100638-appb-000123
Figure PCTCN2018100638-appb-000124
表2：本发明化合物体外筛选试验结果
Figure PCTCN2018100638-appb-000125
Figure PCTCN2018100638-appb-000126
结论：本发明化合物对野生型激酶展现出较好的抑制活性。
实验例2：突变型激酶体外抑制活性评价
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FGFR突变株的抑制能力。
缓冲液条件：20mM Hepes(pH 7.5),10mM MgCl2,1mM 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，或为10μM,2.50μM,0.62μM,0.156μM,39.1nM,9.8nM,2.4nM,0.61nM,0.15nM,0.038nM。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。FGFR1、FGFR4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3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4所示。
表3：体外测试中激酶、底物和ATP的相关信息
激酶 供应商 Cat# 反应液中激酶浓度(nM) ATP浓度(μM)
FGFR2(N549H) Millipore 14-742 0.3 50
FGFR1(V561M) Signal Chem F04-13G 15 10
FGFR2(E565G) Signal Chem F05-12CG 0.5 10
FGFR2(V564F) SignalChem F05-12FG 0.3 20
FGFR3(V555M) SignalChem F06-12GG 4 20
FGFR3(K650M) Carna Biosciences Carna 08-199 2 2.5
FGFR4(N535K) Carna Biosciences Carna 08-524 75 2.5
FGFR4(V550M) Signal Chem F07-12DG 6 2.5
激酶 底物 供应商 Cat# 反应液中底物浓度(μM)
FGFR2(N549H) pEY Sigma P7244-250MG 0.2mg/mL
FGFR1(V561M) pEY+Mn Sigma P7244-250MG 0.2mg/mL
FGFR2(E565G) pEY Sigma P7244-250MG 0.2mg/mL
FGFR2(V564F) pEY Sigma P7244-250MG 0.2mg/mL
FGFR3(V555M) pEY+Mn Sigma P7244-250MG 0.2mg/mL
FGFR3(K650M) pEY+Mn Sigma P7244-250MG 0.2mg/mL
FGFR4(N535K) pEY+Mn Sigma P7244-250MG 0.2mg/mL
FGFR4(V550M) pEY+Mn Sigma P7244-250MG 0.2mg/mL
表4：本发明化合物体外筛选试验结果
激酶 参考例4(nM) 参考例5(nM) 参考例6(nM) 参考例1(nM) 实施例2(nM)
FGFR2(N549H) 4.3 8.4 30 2.4 0.5
FGFR1(V561M) 491 2473 1313 605 38
FGFR2(E565G) 3.5 3.2 7.2 1.4 0.1
FGFR2(V564F) 1.0 1770 6520 255 33
FGFR3(V555M) 172 212 888 23 7.3
FGFR3(K650M) 28 4.4 27 2.0 0.2
FGFR4(N535K) 1431 157 1345 1812 34
FGFR4(V550M) 2407 834 3964 94 5.6
结论：本发明中部分化合物对野生型和突变型FGFR都展现出较好的抑制活性。
实验例3：化合物药代动力学评价
实验目的：测试化合物在小鼠体内药代动力学
实验材料：
Balb/c小鼠(雌性)
实验操作：
以标准方案测试化合物静脉注射及口服给药后的啮齿类动物药代特征，实验中候选化合物配成澄清溶液，给予小鼠单次静脉注射及口服给药。静注溶媒为10％DMSO/10％solutol/80％水，口服溶媒为0.5％羧甲基纤维素钠+0.2％吐温。收集24小时内的全血样品，所有血样均加入预先加好0.5M K2-EDTA抗凝剂标记好的塑料离心管。血样采集后，4℃，3000g离心10分钟吸取上清血浆，迅速置于干冰中，保持-20℃或更低温度，以LC-MS/MS分析方法定量分析血药浓度，并计算药代参数，如达峰浓度，达峰时间，清除率，半衰期，药时曲线下面积，生物利用度等。
实验结果：
表5药代动力学测试结果
Figure PCTCN2018100638-appb-000127
结论：本发明化合物小鼠药代动力学指标良好。

Claims (19)

  1. 式(Ⅰ)所示化合物或其药学上可接受的盐，
    Figure PCTCN2018100638-appb-100001
    其中，
    m选自1或2；
    L选自：单键、C 2-4烯基、C 2-4炔基；
    R 1选自H、卤素、OH、NH 2，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 2选自：H、F、Cl、Br、I、OH、NH 2；
    R 3选自H、卤素、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 4选自H、卤素、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 5选自H，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、C 3-6环烷基、4～6元杂环烷基；
    R 6选自H、卤素、OH、NH 2，或选自任选被1、2或3个R取代的C 1-3烷基；
    R选自：F、Cl、Br、I、OH、NH 2、CN、Me、CF 3、N(CH 3) 2、
    Figure PCTCN2018100638-appb-100002
    所述C 1-3杂烷基、4～6元杂环烷基之“杂”分别独立地选自：-NH-、N、-O-、-S-；
    以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 1选自H、卤素、OH、NH 2，或选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基。
  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 1选自：H、F、Cl、Br、I、OH、NH 2、Me、
    Figure PCTCN2018100638-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 3选自H、卤素、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烷氧基、C 1-3烷氨基。
  5. 根据权利要求4所述化合物或其药学上可接受的盐，其中，R 3选自：H、F、Cl、Br、I、OH、NH 2、CN、Me、CF 3、
    Figure PCTCN2018100638-appb-100004
  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，R 4选自H、卤素、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烷氧基、C 1-3烷氨基。
  7. 根据权利要求6所述化合物或其药学上可接受的盐，其中，R 4选自H、F、Cl、Br、I、OH、NH 2、CN、 Me、CF 3、
    Figure PCTCN2018100638-appb-100005
  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 5选自H，或选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氨基、吗啉基。
  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 5选自：H、Me、Et、
    Figure PCTCN2018100638-appb-100006
    Figure PCTCN2018100638-appb-100007
  10. 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 6选自：H、F、Cl、Br、I、OH、NH 2、Me。
  11. 根据权利要求1所述化合物或其药学上可接受的盐，其中，L选自：单键、
    Figure PCTCN2018100638-appb-100008
    Figure PCTCN2018100638-appb-100009
  12. 根据权利要求9或11所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018100638-appb-100010
    选自：
    Figure PCTCN2018100638-appb-100011
    Figure PCTCN2018100638-appb-100012
  13. 根据权利要求1、3或5任意一项所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018100638-appb-100013
    选自：
    Figure PCTCN2018100638-appb-100014
    Figure PCTCN2018100638-appb-100015
  14. 根据权利要求1～13任意一项所述化合物或其药学上可接受的盐，其选自：
    Figure PCTCN2018100638-appb-100016
    其中，
    R 1、R 2、R 3、R 4、R 5、R 6和L如权利要求1～12所定义。
  15. 根据权利要求14所述化合物或其药学上可接受的盐，其选自：
    Figure PCTCN2018100638-appb-100017
    其中，
    R 1、R 2、R 3、R 4、R 5、R 6和L如权利要求1～12所定义。
  16. 下式所示化合物或其药学上可接受的盐：
    Figure PCTCN2018100638-appb-100018
    Figure PCTCN2018100638-appb-100019
  17. 根据权利要求16所述化合物或其药学上可接受的盐，其选自：
    Figure PCTCN2018100638-appb-100020
    Figure PCTCN2018100638-appb-100021
    Figure PCTCN2018100638-appb-100022
  18. 根据权利要求1～17任意一项所述化合物或其药学上可接受的盐在制备治疗FGFR相关疾病药物中的应用。
  19. 根据权利要求18所述应用，其中，FGFR相关疾病是指实体瘤。
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US11236094B2 (en) 2022-02-01
KR20200041361A (ko) 2020-04-21
EP3670513A1 (en) 2020-06-24
RU2020110780A (ru) 2021-09-16
CN111247150B (zh) 2022-11-08
JP2020532500A (ja) 2020-11-12
CA3072979A1 (en) 2019-02-21
EP3670513A4 (en) 2021-04-14
AU2018317153A1 (en) 2020-03-05
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US20200207773A1 (en) 2020-07-02
KR102707041B1 (ko) 2024-09-19
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