WO2020135878A1 - 作为fgfr和vegfr双重抑制剂的咪唑并吡啶衍生物 - Google Patents

作为fgfr和vegfr双重抑制剂的咪唑并吡啶衍生物 Download PDF

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WO2020135878A1
WO2020135878A1 PCT/CN2019/130053 CN2019130053W WO2020135878A1 WO 2020135878 A1 WO2020135878 A1 WO 2020135878A1 CN 2019130053 W CN2019130053 W CN 2019130053W WO 2020135878 A1 WO2020135878 A1 WO 2020135878A1
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compound
added
pharmaceutically acceptable
acceptable salt
crude product
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French (fr)
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戴美碧
张杨
陈正霞
陈曙辉
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Medshine Discovery Inc
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Medshine Discovery Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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
    • A61P35/00—Antineoplastic agents
    • 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 dual inhibitor of FGFR and VEGFR, in particular to a compound represented by formula (III) or a pharmaceutically acceptable salt.
  • FGFR Fibroblast growth factor receptor
  • FGF fibroblast growth factor
  • the FGFRs family includes the following types: FGFR1b, FGFR1c, FGFR2b, FGFR2c, FGFR3b, FGFR3c, FGFR4 . Different subtypes of FGFR are different from the FGF to which they bind.
  • FGFR FGFR activation mutations or ligand/receptor overexpression lead to its continuous constitutive activation, not only with The occurrence, development, and poor prognosis of tumors are closely related, and also play an important role in tumor neovascularization, tumor invasion and metastasis. Therefore, FGFR is considered an important anti-tumor target.
  • VEGFR-2 is an important regulator of endothelial cell proliferation caused by VEGF signaling, increasing vascular permeability and promoting angiogenesis, and the affinity of VEGFR-2 and VEGF is greater than that of VEGFR-1. Studies have shown that only VEGFR-2 is expressed in endothelial cells, and activation of VEGFR-2 can effectively stimulate angiogenesis. Therefore, VEGFR-2 is the main target for the development of anti-angiogenic drugs.
  • VEGF needs the presence of FGF to play its role in promoting angiogenesis, and the VEGFR and FGFR pathways jointly complete the activation and generation of endothelial cells in angiogenesis.
  • FGFR and VEGFR can directly inhibit the growth, survival, proliferation and migration of tumor cells; they also have the inhibitory effect of tumor angiogenesis and improve the microenvironment.
  • the synergistic effect of FGFR and VEGFR pathway can also suppress tumor immune escape and improve tumor suppression effect.
  • the present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from H, —S( ⁇ O) 2 CH 3 , C 1-6 alkyl, C 1-3 alkoxy, tetrahydropyranyl, tetrahydrofuranyl and piperidinyl, said C 1-6 alkyl group, C 1-3 alkoxy, tetrahydropyranyl, tetrahydrofuranyl and piperidinyl optionally substituted with one, two or three R a;
  • R 2 and R 3 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CH 3 and OCH 3 ;
  • R 4 is selected from H, NH 2 , C 1-6 alkyl, C 1-3 alkoxy, C 3-5 cycloalkyl and The C 1-6 alkyl, C 1-3 alkoxy, C 3-5 cycloalkyl and Optionally substituted by 1, 2 or 3 R b ;
  • n 1 and 2;
  • Ring A is selected from phenyl, pyrrolyl, pyrimidinyl and pyridyl;
  • Ring B does not exist
  • ring B is selected from imidazolyl, pyrazolyl, triazolyl, piperidinyl, morpholinyl, tetrahydropyranyl and 3,6-dihydro-2H-pyranyl;
  • R 5 is independently selected from H and C 1-3 alkyl
  • R is selected from H, F, Cl, Br, I, OH and NH 2 .
  • R 1 is selected from H, —S( ⁇ O) 2 CH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , OCH 2 CH 3 , tetrahydropyranyl, tetrahydrofuranyl and piperidinyl, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , OCH 2 CH 3 , tetrahydropyridine tetrahydrothiopyranyl, tetrahydrofuranyl and piperidinyl optionally substituted with 1,2 or 3 substituents R a, the other variables are as defined in the present invention.
  • R 1 is selected from H, —S( ⁇ O) 2 CH 3 , CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 OH, OCH 2 CH 3 ,
  • Other variables are as defined in the present invention.
  • the above R 4 is selected from H, NH 2 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , cyclopropane, azetidine and pyrrolidinium, the CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CH 2 CH 3 , OCH 3.
  • OCH 2 CH 3 , cyclopropane, azetidine and pyrrolidinyl are optionally substituted with 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • R 4 is selected from H, NH 2 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 N(CH 3 ) 2 , OCH 3 ,
  • Other variables are as defined in the present invention.
  • R 5 is independently selected from H, CH 3 and CH 2 CH 3 , and other variables are as defined in the present invention.
  • Other variables are as defined in the present invention.
  • the above-LR 4 is selected from Other variables are as defined in the present invention.
  • the aforementioned ring A is selected from Other variables are as defined in the present invention.
  • the aforementioned ring B is selected from Other variables are as defined in the present invention.
  • the present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from H, C 1-6 alkyl and 4-6 membered heterocycloalkyl, the C 1-6 alkyl and 4-6 membered heterocycloalkyl are optionally substituted by 1, 2 or 3 R a replace;
  • R 2 and R 3 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CH 3 and OCH 3 ;
  • R 4 is selected from H, NH 2 , C 1-6 alkyl, C 3-5 cycloalkyl and 4-6 membered heterocycloalkyl, the C 1-6 alkyl, C 3-5 cycloalkyl and 4-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R b ;
  • Ring A is selected from phenyl and 5-6 membered heteroaryl
  • Ring B is selected from 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkenyl;
  • R 5 is independently selected from H and C 1-3 alkyl
  • R is selected from H, F, Cl, Br, I, OH, and NH 2 ;
  • the 5-6 membered heteroaryl group, 4-6 membered heterocycloalkyl group, 5-6 membered heterocycloalkyl group and 5-6 membered heterocycloalkenyl group respectively comprise 1, 2, 3 or 4 independently selected from- Heteroatoms or heteroatom groups of NH-, -O-, -S- and N.
  • the above R 1 is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , tetrahydropyranyl, tetrahydrofuranyl and piperidinyl ,
  • the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , tetrahydropyranyl, tetrahydrofuranyl and piperidinyl are optionally substituted by 1, 2 or 3 R a Instead, other variables are as defined in the present invention.
  • R 1 is selected from H, CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 OH, Other variables are as defined in the present invention.
  • the above R 4 is selected from H, NH 2 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CH 2 CH 3 , cyclopropanyl, Azetidine and pyrrolidinium, the CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CH 2 CH 3 , cyclopropane, azetidine And pyrrolidinyl is optionally substituted with 1, 2, or 3 R b , and other variables are as defined in the present invention.
  • R 4 is selected from H, NH 2 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 N(CH 3 ) 2 ,
  • Other variables are as defined in the present invention.
  • R 5 is independently selected from H, CH 3 and CH 2 CH 3 , and other variables are as defined in the present invention.
  • the above-LR 4 is selected from Other variables are as defined in the present invention.
  • the aforementioned ring A is selected from phenyl, pyrrolyl, pyrimidinyl, and pyridyl, and other variables are as defined in the present invention.
  • the above ring B is selected from imidazolyl, pyrazolyl, triazolyl, piperidinyl, morpholinyl, tetrahydropyranyl, and 3,6-dihydro-2H-pyranyl , Other variables are as defined in the present invention.
  • the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from H and optionally substituted with 1,2 or 3 substituents R a is C 1-3 alkyl;
  • R 2 and R 3 are independently selected from H, F, Cl, Br, I, OH and NH 2 ;
  • R 4 is selected from H, C 1-6 alkyl and C 3-5 cycloalkyl, and the C 1-6 alkyl and C 3-5 cycloalkyl are optionally substituted with 1, 2 or 3 R b ;
  • R 5 is independently selected from H and C 1-3 alkyl
  • Ring B is selected from 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl
  • R a and R b are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and CH 3 ;
  • the 5-6 membered heteroaryl group and 5-6 membered heterocycloalkyl group respectively contain 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N .
  • R 1 is selected from H, CH 3 and CH 2 CH 3, and the CH 3 CH 2 CH 3 optionally substituted by 1, 2 or 3 R a, according to the present invention as other variables definition.
  • R 1 is selected from H, CH 3 , CH 2 OH, CH 2 CH 2 OH, and CH 2 CH 3 , and other variables are as defined in the present invention.
  • the above R 4 is selected from H, cyclopropanyl, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 and CH 2 CH 2 CH 3 , the ring Propyl, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 and CH 2 CH 2 CH 3 are optionally substituted with 1, 2 or 3 R b , other variables are as described in this invention definition.
  • R 4 is selected from H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 and CH 2 CH 2 CH 3 , other variables are as defined in the present invention.
  • R 5 is independently selected from H, CH 3 and CH 2 CH 3 , and other variables are as defined in the present invention.
  • the above-LR 4 is selected from Other variables are as defined in the present invention.
  • the aforementioned ring B is selected from imidazolyl, pyrazolyl, piperidinyl, morpholinyl, and tetrahydropyranyl, and other variables are as defined in the present invention.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from H and optionally substituted with 1,2 or 3 substituents R a is C 1-3 alkyl;
  • R 2 and R 3 are independently selected from H, F, Cl, Br, I, OH and NH 2 ;
  • R 4 is selected from H, cyclopropanyl and C 1-3 alkyl optionally substituted with 1, 2 or 3 R b ;
  • R 5 is independently selected from H and C 1-3 alkyl
  • R a and R b are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, and CH 3 .
  • R 1 is selected from H, CH 3 and CH 2 CH 3, and the CH 3 CH 2 CH 3 optionally substituted by 1, 2 or 3 R a, according to the present invention as other variables definition.
  • R 1 is selected from H, CH 3 and CH 2 CH 3 , and other variables are as defined in the present invention.
  • R 4 is selected from H, cyclopropanyl, CH 3 and CH 2 CH 3 , the CH 3 and CH 2 CH 3 are optionally substituted with 1, 2 or 3 R b , other variables As defined in the present invention.
  • R 4 is selected from H, CH 3 and CH 2 CH 3 , other variables are as defined in the present invention.
  • R 5 is independently selected from H, CH 3 and CH 2 CH 3 , and other variables are as defined in the present invention.
  • the above-LR 4 is selected from Other variables are as defined in the present invention.
  • the above compound or a pharmaceutically acceptable salt thereof is selected from
  • R 1 , R 2 , R 3 , L, T 1 and R 4 are as defined in the present invention.
  • the above compound or a pharmaceutically acceptable salt thereof is selected from
  • R 1 , R 2 , R 3 , T 1 and R 4 are as defined in the present invention.
  • the present invention also provides a compound represented by the following formula 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 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 composition in the preparation of drugs related to dual inhibitors of FGFR and VEGFR.
  • the drug associated with the dual inhibitor of FGFR and VEGFR is a drug used for solid tumors.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, prepared from a compound having a specific substituent and a relatively non-toxic acid or base found in the present invention.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Bisulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and other similar acids; also includes salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain basic and acidic functional groups and can be converted to any
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds provided by the invention also exist in prodrug forms.
  • the prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in the in vivo environment.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated form is equivalent to the unsolvated form, and is included in the scope of the present invention.
  • optically active (R)- and (S)-isomers and 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 present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting mixture of diastereomers is separated and the auxiliary groups are cleaved to provide pure The desired enantiomer.
  • a diastereomer salt is formed with an appropriate optically active acid or base, and then by conventional methods known in the art The diastereomers are resolved and the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography that uses a chiral stationary phase and is optionally combined with chemical derivatization methods (eg, amino groups from amines) Formate).
  • the compound of the present invention may contain unnatural proportions of atomic isotopes in one or more atoms constituting the compound.
  • compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • the hydrogen can be replaced by heavy hydrogen to form a deuterated drug.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs have lower toxicity and increase drug stability. , Strengthen efficacy, prolong the biological half-life of drugs and other advantages.
  • the conversion of all isotopic compositions of the compounds of the present invention, whether radioactive or not, is included within the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include heavy hydrogen and hydrogen variants, as long as the valence state of the particular atom is normal and the compound after substitution is stable of.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical realization.
  • any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent.
  • R in each case has independent options.
  • substituents and/or variants thereof are only allowed if such combinations will produce stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means 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 connected are directly connected. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • substituents listed do not indicate through which atom they are connected to the substituted group, such substituents can be bonded through any of their atoms, for example, pyridyl as a substituent can be through any one of the pyridine rings The carbon atom is attached to the substituted group.
  • connection direction is arbitrary, for example,
  • the linking group L in the middle is -MW-, then -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the opposite direction to the reading order from left to right
  • Combinations of the linking group, substituents, and/or variants thereof are only allowed if such a combination will produce a stable compound.
  • C 1-6 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups; etc.; Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • C 1-6 alkyl examples 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 so on.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it may be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine) .
  • Example C 1- 3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n- propyl and isopropyl) and the like.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule by one oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 1-3 alkylamino refers to those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an amino group.
  • the C 1-3 alkylamino group includes C 1-2 , C 3 and C 2 alkylamino groups and the like.
  • Examples of C 1-3 alkylamino include but are not limited to -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 ,- NHCH 2 (CH 3 ) 2 etc.
  • 4-6 membered heterocycloalkyl by itself or in combination with other terms means a saturated cyclic group consisting of 4 to 6 ring atoms with 1, 2, 3 or 4 ring atoms Are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes single-ring and double-ring systems, where the double-ring system includes spiro ring, parallel ring and bridge ring.
  • the hetero atom may occupy the connection position of the heterocycloalkyl group to the rest of the molecule.
  • the 4-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered, and 6 membered heterocycloalkyl groups.
  • 4-6 membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thiatanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-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 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl,
  • C 3-5 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 5 carbon atoms, which is a monocyclic system, and the C 3-5 cycloalkyl includes C 3 -4 and C 4-5 cycloalkyl, etc.; it may be monovalent, divalent or polyvalent.
  • Examples of C 3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
  • the term "5-6 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 5 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms Are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes single-ring and double-ring systems, where the double-ring system includes spiro ring, parallel ring and bridge ring.
  • the hetero atom may occupy the connection position of the heterocyclic alkyl group to the rest of the molecule.
  • the 5-6 membered heterocycloalkyl includes 5-membered and 6-membered heterocycloalkyl.
  • 5-6 membered heterocycloalkyl examples include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-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 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydr
  • 5-6 membered heteroaryl ring and “5-6 membered heteroaryl group” of the present invention can be used interchangeably.
  • the term “5-6 membered heteroaryl group” means from 5 to 6 ring atoms
  • the monocyclic group composed of a conjugated ⁇ electron system has 1, 2, 3, or 4 ring atoms as heteroatoms independently selected from O, S, and N, and the rest are carbon atoms. Where nitrogen atoms are optionally quaternized, nitrogen and sulfur heteroatoms can be optionally oxidized (ie NO and S(O) p , p is 1 or 2).
  • the 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or carbon atom.
  • the 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyryl Oxazolyl, 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, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-iso
  • the term "5-6 membered heterocyclenyl" by itself or in combination with other terms means a partially unsaturated cyclic group consisting of 5 to 6 ring atoms containing at least one carbon-carbon double bond , 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally Oxidation (ie NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic systems, wherein the bicyclic system includes spiro ring, parallel ring and bridge ring, any ring of this system is non-aromatic.
  • the hetero atom may occupy the connection position of the heterocyclic alkenyl group with the rest of the molecule.
  • the 5-6 membered heterocyclic alkenyl group includes 5-membered and 6-membered heterocyclic alkenyl groups and the like. Examples of 5-6 membered heterocyclic alkenyl groups include, but are not limited to
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, and iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, and p-toluenesulfonate Ester, etc.; acyloxy, such as acetoxy, trifluoroacetoxy, etc.
  • protecting group includes but is not limited to "amino protecting group", “hydroxy protecting group” or “mercapto 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 (such as acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorene methoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl) methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldi
  • hydroxyl protecting group refers to a protecting group suitable for preventing side reactions of hydroxyl groups.
  • Representative hydroxy protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl, such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl groups (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (
  • 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 listed below, the embodiments formed by the combination with other chemical synthesis methods and well known to those skilled in the art Equivalently, preferred embodiments include but are not limited to the embodiments of the present invention.
  • aq stands for water
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
  • m-CPBA stands for 3-chloroperoxybenzoic acid
  • eq stands for equivalent and equivalent
  • CDI stands for Carbonyldiimidazole
  • DCM for methylene chloride
  • PE PE
  • DIAD diisopropyl azodicarboxylate
  • DMF for N,N-dimethylformamide
  • DMSO for dimethyl sulfoxide
  • EtOAc for ethyl acetate
  • EtOH stands for ethanol
  • MeOH stands for methanol
  • CBz stands for benzyloxycarbonyl, which
  • Figure 1 is the tumor growth inhibition curve
  • Figure 2 shows the body weight curve of mice during the administration period.
  • the filter cake was transferred to a single-necked bottle via dichloromethane, and then concentrated under reduced pressure to obtain a crude product.
  • Acetic anhydride (16.02g, 156.95mmol, 14.7mL) was added to la (14.7g, 67.74mmol) at 0°C, and stirring was continued at 15°C for 30 minutes. 140 mL of crushed ice was added to the reaction solution, and a solid precipitated, which was filtered, washed twice with ice water, and the filter cake was collected and spin-dried to obtain compound 1b.
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 8.46 (s, 1H), 8.19 (s, 1H), 8.02 (s, 1H), 2.10 (s, 3H).
  • the hydrochloride salt of Compound 1 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Compound 1.
  • the crude product was purified by high-performance liquid chromatography (column column: Boston Green ODS 150*30mm*5 ⁇ m; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 25%-55%, 8min)
  • the trifluoroacetate salt of compound 2 is obtained.
  • the trifluoroacetic acid salt of compound 2 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 2.
  • the preparation of the compounds of the examples in Table 1 can be carried out by referring to the steps similar to those in the foregoing preparation example 2, except that the raw material A used in step 6 replaces ethylsulfonyl chloride to obtain the trifluoroacetate salt of the corresponding compound.
  • the trifluoroacetic acid salt of the obtained compound was added to sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the corresponding compound.
  • the trifluoroacetic acid salt of compound 4 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 4.
  • the trifluoroacetic acid salt of compound 5 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 5.
  • the crude product was purified by high performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5 ⁇ m; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 23%-53%, 10min)
  • the trifluoroacetate salt of compound 7 is obtained.
  • reaction solution was filtered with suction to obtain a filtrate, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • the crude product was purified by high-performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5 ⁇ m; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 30%-60%, 10min)
  • the trifluoroacetate salt of compound 8 is obtained.
  • the trifluoroacetic acid salt of compound 8 was added to the sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8.
  • the trifluoroacetate salt of compound 9 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 9.
  • the crude product was purified by high-performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5 ⁇ m; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 20%-50%, 12min)
  • the trifluoroacetate salt of compound 11 was obtained.
  • the trifluoroacetic acid salt of compound 11 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 11.
  • the crude product was purified by high-performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5 ⁇ m; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 20%-50%, 12min)
  • the trifluoroacetate salt of compound 12 was obtained.
  • the trifluoroacetate salt of compound 12 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 12.
  • reaction solution was concentrated to obtain a crude product, which was subjected to high-performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5 ⁇ m; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 21%- 51%, 12 min) purification to obtain the trifluoroacetate salt of compound 13.
  • the trifluoroacetic acid salt of compound 13 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 13.
  • the trifluoroacetic acid salt of compound 14 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 14.
  • the crude product was purified by high-performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5 ⁇ m; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 20%-50%, 12min)
  • the trifluoroacetate salt of compound 15 is obtained.
  • the trifluoroacetic acid salt of compound 15 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 15.
  • reaction solution was filtered, and the filtrate was subjected to high-performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5 ⁇ m; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 25%-45% , 12 min) purification to obtain the trifluoroacetate salt of compound 16.
  • the trifluoroacetic acid salt of compound 16 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 16.
  • the trifluoroacetic acid salt of compound 18 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 18.
  • the preparation of the compounds of the examples in Table 2 can be carried out by referring to the steps similar to the above route of Preparation Example 18, except that the raw material A used in step 2 replaces 2-bromopyrazine to obtain the trifluoroacetate of the corresponding compound .
  • DIEA (28.98mg, 224.22 ⁇ mol, 39.05 ⁇ L) was added to a solution of 2e (30mg, 74.74 ⁇ mol) in DCM (1mL) at 0°C, and then triphosgene (11.09mg, 37.37 ⁇ mol) was added, and the mixture was stirred at 0°C for 10 minutes while adding Add 3-methoxypyrrole (7.56 mg, 54.94 ⁇ mol, HCl) in DCM (1 mL) to DIEA (28.98 mg, 224.22 ⁇ mol, 39.05 ⁇ L) and stir for 10 minutes. Pour into the above reaction solution and stir at 0°C. 20 minutes.
  • the trifluoroacetate salt of compound 22 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 22.
  • the trifluoroacetate salt of compound 23 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 23.
  • the trifluoroacetate salt of compound 24 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 24.
  • the trifluoroacetic acid salt of compound 25 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 25.
  • the reaction solution was added with 2mL*2 of water for extraction, and the organic phase was concentrated under reduced pressure to obtain a crude product.
  • the reaction solution was added with 2mL*2 of water for extraction, and the organic phase was concentrated under reduced pressure to obtain a crude product.
  • the crude product was prepared by high performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5 ⁇ m; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 20%-60%, 7min) Purification afforded the trifluoroacetate salt of compound 26.
  • the trifluoroacetate salt of compound 26 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 26.
  • the preparation of the compounds of the examples in Table 3 can be carried out by referring to the steps similar to those of the aforementioned preparation example 26, except that the raw material A used in step 6 replaces cyclobutylamine to obtain the trifluoroacetate salt of the corresponding compound.
  • the crude product was purified by preparative HPLC (chromatographic column: Boston Green ODS 150*30mm*5 ⁇ m; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 25%-55%, 7min) to obtain the compound The trifluoroacetate of 28.
  • the trifluoroacetic acid salt of compound 28 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 28.
  • Pd(dppf)Cl 2 (13.51mg, 18.47 ⁇ mol) was added to a solution of compound 30f (100mg, 184.66 ⁇ mol), double pinacol borate (56.27mg, 221.60 ⁇ mol) in dioxane (3mL), KOAc (36.25 mg, 369.33 ⁇ mol). Stir at 90°C for 16 hours under nitrogen protection. The reaction solution was concentrated to obtain 30 g of compound.
  • reaction solution was extracted by adding 3mL of water and 5mL of ethyl acetate, and the organic phase was spin-dried to obtain a crude product, which was then purified by preparative high performance liquid chromatography (chromatographic column: Boston Green ODS 150*30mm*5 ⁇ m; mobile phase: [water (0.075% three (Fluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 20%-50%, 7 min) purification to obtain the trifluoroacetate salt of compound 32.
  • the trifluoroacetate salt of compound 32 was added to a sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 32.
  • the filtrate was separated by preparative high performance liquid chromatography (column: Phenomenex Gemini-NX 80*40mm*3 ⁇ m; mobile phase: [water (0.05% ammonia water + 10mM ammonium bicarbonate)-acetonitrile]; B (acetonitrile)%: 18%-48 %, 8 min) to obtain compound 33.
  • Buffer conditions 20mM Hepes (4- hydroxyethylpiperazine-ethanesulfonic acid) (pH 7.5), 10mM MgCl 2, 1mM EGTA ( ethylene glycol bis (2-aminoethyl ether) tetraacetic acid), 0.02% BriJ35 ( Surfactant), 0.02 mg/ml BSA (bovine serum albumin), 0.1 mM Na 3 VO 4 , 2 mM DTT, 1% DMSO.
  • Test procedure Dissolve the test compound in DMSO at room temperature to prepare a 10 mM solution for use. Dissolve the substrate in the newly prepared buffer, add the tested kinase to it and mix well. Using the acoustic technique (Echo 550), the DMSO solution in which the test compound is dissolved is added to the above mixed reaction solution.
  • the compound concentration in the reaction solution is 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 or 3 ⁇ M, 1 ⁇ M, 0.333 ⁇ M, 0.111 ⁇ M, 37.0 nM, 12.3 nM , 4.12nM, 1.37nM, 0.457nM, 0.152nM.
  • 33 P-ATP activity 0.01 ⁇ Ci/ ⁇ l, corresponding concentration listed in Table 4
  • FGFR1, FGFR4, KDR and the concentration information in the reaction solution are listed in Table 2.
  • the reaction solution was spotted on P81 ion exchange filter paper (Whatman #3698-915). After repeatedly washing the filter paper with 0.75% phosphoric acid solution, the radioactivity of the phosphorylated substrate remaining on the filter paper was measured.
  • the kinase activity data is expressed by comparing the kinase activity of the test compound with the kinase activity of the blank group (containing only DMSO), and the IC 50 value is obtained by curve fitting using Prism4 software (GraphPad). The experimental results are shown in Table 5.
  • Table 4 Information about kinases, substrates and ATP in in vitro tests.
  • the compounds of the present invention have excellent FGFR1, FGFR2, FGFR4, VEGFR2 kinase inhibitory activity.
  • the kinetic solubility samples are filtered and sampled first.
  • the final sample contains 2% DMSO.
  • K.S. shaking time 24 hours at room temperature.
  • the compound of the present invention has excellent solubility (pH 2.0) and improved medicine properties.
  • test compound inhibits the proliferation of human gastric cancer SNU-16 cells expressing FGFR2.
  • the compound used in the test was diluted at a 3-fold concentration, starting from 10 ⁇ M, 3-fold serial dilutions, 9 concentrations, 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 .
  • IR inhibition rate
  • the compound of the present invention has more excellent SNU-16 cell activity (3-5 times) than the control.
  • Tumor tissue preparation SNU-16 cells were routinely cultured in RPMI-1640 medium containing 10% fetal bovine serum under 5% CO 2 , 37°C, and saturated humidity. Passage or rehydration 1 to 2 times per week according to cell growth, with a passage ratio of 1:3 to 1:4
  • the average tumor in each group The volume is about 143mm 3 .
  • TV (mm 3 ) l ⁇ w 2 /2, where l represents the long diameter of the tumor (mm); w represents the short diameter of the tumor (mm).
  • TGI total tumor proliferation rate
  • T/C relative tumor proliferation rate
  • Relative tumor proliferation rate T/C(%) T RTV /C RTV ⁇ 100%
  • T RTV average RTV of treatment group
  • C RTV average RTV of negative control group
  • RTV relative tumor volume
  • TGI (%) [(1-(average tumor volume at the end of administration in a certain treatment group-average tumor volume at the beginning of administration in this treatment group))/(average tumor volume at the end of treatment in the solvent control group-start treatment at the solvent control group Mean tumor volume)] ⁇ 100%.
  • the compound of the present invention On the mouse gastric cancer SNU-16 model, continuous administration for 25 days, compared with the vehicle group, the compound of the present invention showed significant anti-tumor activity, tumor growth inhibition rate (%TGI): 76%, 80% 76%, the relative tumor growth rate (%T/C) is: 34%, 33%, 35%. Compared with Comparative Example 1, the compound of the present invention exhibits a better inhibitory effect.
  • Table 8 Figure 1 and Figure 2 (QD in the figure means once a day).
  • the compound of the present invention exhibits excellent tumor therapeutic effects at lower doses in preclinical animal models.

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Abstract

一种FGFR和VEGFR双重抑制剂，具体为式（III）所示化合物或药学上可接受的盐。

Description

作为FGFR和VEGFR双重抑制剂的咪唑并吡啶衍生物
相关申请的引用
本申请主张如下优先权：
CN201811640177.2，申请日：2018-12-29；
CN201910313237.8，申请日：2019-04-18；
CN201910802391.1，申请日：2019-08-28；
CN201911310776.2，申请日：2019-12-18。
技术领域
本发明涉及一种FGFR和VEGFR双重抑制剂，具体涉及式(III)所示化合物或药学上可接受的盐。
背景技术
FGFR是一类具有传导生物信号、调节细胞生长、参与组织修复等功能的生物活性物质，近年来，已有多个FGFR家族成员被发现在肿瘤发生、发展过程中起重要作用。成纤维细胞生长因子受体(FGFR)是一类可与成纤维细胞生长因子(FGF)特异性结合的受体蛋白，FGFRs家族包括以下类型：FGFR1b、FGFR1c、FGFR2b、FGFR2c、FGFR3b、FGFR3c、FGFR4。不同亚型的FGFR与之结合的FGF不一样，FGFs与FGFRs结合后导致胞内多个酪氨酸残基的自身磷酸化，磷酸化的FGFRs激活下游的信号通路包括MEK/MAPK、PLCy/PKC、PI3K/AKT、STATS等。在肿瘤中，如在肝癌，膀胱癌，肺癌，乳腺癌，子宫内膜癌，脑胶质瘤，前列腺癌等，FGFR激活突变或者配体/受体过表达导致其持续组成型激活，不仅与肿瘤的发生、发展、不良预后等密切相关，并且在肿瘤新生血管生成、肿瘤的侵袭与转移等过程中也发挥重要作用。因此，FGFR被认为是抗肿瘤重要靶点。
血管生成和淋巴管生产是肿瘤形成和转移中的重要环节，血管内皮细胞生长因子(VEGF)和VEGF受体(VEGFR)家族在上述两个环节中起着主要作用。VEGFR家族包括VEGFR-1、VEGFR-2(KDR)和VEGFR-3三种特异的酪氨酸激酶受体。VEGFR-2是VEGF信号传导引起内皮细胞增殖，增加血管通透性效应和促进血管生成的重要调节因子，而且VEGFR-2和VEGF的亲和力要大于VEGFR-1。研究表明，内皮细胞中只表达VEGFR-2，激活VEGFR-2后能高效的刺激血管生成。因此VEGFR-2是抗新生血管生成药物研发的主要靶点。
在特定的实验条件下，VEGF需要FGF的存在才能发挥其促血管生成作用，VEGFR和FGFR通路共同完成血管生成中内皮细胞的激活和生成。FGFR和VEGFR能够直接抑制肿瘤细胞的生长，存活、增殖和迁移；还具有肿瘤生血管的抑制作用，改善微环境。FGFR和VEGFR通路协同作用还可以抑制肿瘤免疫逃逸作用提高肿瘤抑制效果。
发明内容
本发明提供了式(III)所示化合物或其药学上可接受的盐，
Figure PCTCN2019130053-appb-000001
其中，
R 1选自H、-S(＝O) 2CH 3、C 1-6烷基、C 1-3烷氧基、四氢吡喃基、四氢呋喃基和哌啶基，所述C 1-6烷基、C 1-3烷氧基、四氢吡喃基、四氢呋喃基和哌啶基任选被1、2或3个R a取代；
R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CH 3和OCH 3；
R 4选自H、NH 2、C 1-6烷基、C 1-3烷氧基、C 3-5环烷基和
Figure PCTCN2019130053-appb-000002
所述C 1-6烷基、C 1-3烷氧基、C 3-5环烷基和
Figure PCTCN2019130053-appb-000003
任选被1、2或3个R b取代；
m选自1和2；
L选自-N(R 5)C(＝O)-、-N(R 5)S(＝O) 2-、-N(R 5)C(＝O)N(R 5)-、N(R 5)S(＝O) 2N(R 5)-和-N(R 5)-；
环A选自苯基、吡咯基、嘧啶基和吡啶基；
环B不存在；
或者，环B选自咪唑基、吡唑基、三氮唑基、哌啶基、吗啉基、四氢吡喃基和3,6-二氢-2H-吡喃基；
R 5分别独立地选自H和C 1-3烷基；
R a和R b分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、-S(＝O) 2CH 3、C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基，所述-S(＝O) 2CH 3、C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基任选被1、2或3个R取代；
R选自H、F、Cl、Br、I、OH和NH 2。
本发明的一些方案中，上述R a和R b分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、-S(＝O) 2CH 3、CH 3、-OCH 3、-N(CH 3) 2和-NHCH(CH 3) 2，所述-S(＝O) 2CH 3、CH 3、-OCH 3、-N(CH 3) 2和-NHCH(CH 3) 2任选被1、2或3个R取代，其他变量如本发明所定义。
本发明的一些方案中，上述R a和R b分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2OH、-OCH 3、-S(＝O) 2CH 3、-N(CH 3) 2和-NHCH(CH 3) 2，其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自H、-S(＝O) 2CH 3、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH 2CH(CH 3) 2、OCH 2CH 3、四氢吡喃基、四氢呋喃基和哌啶基，所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH 2CH(CH 3) 2、OCH 2CH 3、四氢吡喃基、四氢呋喃基和哌啶基任选被1、2或3个R a取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自H、-S(＝O) 2CH 3、CH 3、CH 2OH、CH 2CH 3、CH 2CH 2OH、OCH 2CH 3、
Figure PCTCN2019130053-appb-000004
Figure PCTCN2019130053-appb-000005
其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自H、NH 2、CH 3、CH 2CH 3、CH(CH 3) 2、C(CH 3) 3、CH 2CH 2CH 3、OCH 3、OCH 2CH 3、环丙烷基、氮杂环丁烷和吡咯烷基，所述CH 3、CH 2CH 3、CH(CH 3) 2、C(CH 3) 3、CH 2CH 2CH 3、OCH 3、OCH 2CH 3、环丙烷基、氮杂环丁烷和吡咯烷基任选被1、2或3个R b取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自H、NH 2、CH 3、CH 2CH 3、CH(CH 3) 2、C(CH 3) 3、CH 2CH 2CH 3、CH 2CH 2N(CH 3) 2、OCH 3、
Figure PCTCN2019130053-appb-000006
Figure PCTCN2019130053-appb-000007
其他变量如本发明所定义。
本发明的一些方案中，上述R 5分别独立地选自H、CH 3和CH 2CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述L选自-NHC(＝O)-、-NHC(＝O)NH-、-NHS(＝O) 2-、-NHS(＝O) 2NH-和-NH-，其他变量如本发明所定义。
本发明的一些方案中，上述-L-R 4选自
Figure PCTCN2019130053-appb-000008
Figure PCTCN2019130053-appb-000009
Figure PCTCN2019130053-appb-000010
其他变量如本发明所定义。
本发明的一些方案中，上述环A选自
Figure PCTCN2019130053-appb-000011
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 PCTCN2019130053-appb-000012
选自
Figure PCTCN2019130053-appb-000013
Figure PCTCN2019130053-appb-000014
其他变量如本发明所定义。
本发明的一些方案中，上述环B选自
Figure PCTCN2019130053-appb-000015
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 PCTCN2019130053-appb-000016
选自
Figure PCTCN2019130053-appb-000017
Figure PCTCN2019130053-appb-000018
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 PCTCN2019130053-appb-000019
选自OCH 2CH 3、
Figure PCTCN2019130053-appb-000020
Figure PCTCN2019130053-appb-000021
Figure PCTCN2019130053-appb-000022
其他变量如本发明所定义。
本发明提供了式(III)所示化合物或其药学上可接受的盐，
Figure PCTCN2019130053-appb-000023
其中，
R 1选自H、C 1-6烷基和4-6元杂环烷基，所述C 1-6烷基和4-6元杂环烷基任选被1、2或3个R a取代；
R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CH 3和OCH 3；
R 4选自H、NH 2、C 1-6烷基、C 3-5环烷基和4-6元杂环烷基，所述C 1-6烷基、C 3-5环烷基和4-6元杂环烷基任选被1、2或3个R b取代；
L选自-N(R 5)C(＝O)-、-N(R 5)S(＝O) 2-、-N(R 5)C(＝O)N(R 5)-、和-N(R 5)-；
环A选自苯基和5-6元杂芳基；
环B选自5-6元杂芳基、5-6元杂环烷基和5-6元杂环烯基；
R 5分别独立地选自H和C 1-3烷基；
R a和R b分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、-S(＝O) 2CH 3、C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基，所述-S(＝O) 2CH 3、C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基任选被1、2或3个R取代；
R选自H、F、Cl、Br、I、OH和NH 2；
所述5-6元杂芳基、4-6元杂环烷基、5-6元杂环烷基和5-6元杂环烯基分别包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
本发明的一些方案中，上述R a和R b分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、-S(＝O) 2CH 3、CH 3、-OCH 3、-N(CH 3) 2和-NHCH(CH 3) 2，所述-S(＝O) 2CH 3、CH 3、-OCH 3、-N(CH 3) 2和-NHCH(CH 3) 2任选被1、2或3个R取代，其他变量如本发明所定义。
本发明的一些方案中，上述R a和R b分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2OH、-OCH 3、-S(＝O) 2CH 3、-N(CH 3) 2和-NHCH(CH 3) 2，其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH 2CH(CH 3) 2、四氢吡喃基、四氢呋喃基和哌啶基，所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH 2CH(CH 3) 2、四氢吡喃基、四氢呋喃基和哌啶基任选被1、2或3个R a取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自H、CH 3、CH 2OH、CH 2CH 3、CH 2CH 2OH、
Figure PCTCN2019130053-appb-000024
Figure PCTCN2019130053-appb-000025
其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自H、NH 2、CH 3、CH 2CH 3、CH(CH 3) 2、C(CH 3) 3、CH 2CH 2CH 3、环丙烷基、氮杂环丁烷和吡咯烷基，所述CH 3、CH 2CH 3、CH(CH 3) 2、C(CH 3) 3、CH 2CH 2CH 3、环丙烷基、氮杂环丁烷和吡咯烷基任选被1、2或3个R b取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自H、NH 2、CH 3、CH 2CH 3、CH(CH 3) 2、C(CH 3) 3、CH 2CH 2CH 3、CH 2CH 2N(CH 3) 2、
Figure PCTCN2019130053-appb-000026
其他变量如本发明所定义。
本发明的一些方案中，上述R 5分别独立地选自H、CH 3和CH 2CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述L选自-NHC(＝O)-、-NHC(＝O)NH-、-NHS(＝O) 2-和-NH-，其他变量如本发明所定义。
本发明的一些方案中，上述-L-R 4选自
Figure PCTCN2019130053-appb-000027
Figure PCTCN2019130053-appb-000028
Figure PCTCN2019130053-appb-000029
其他变量如本发明所定义。
本发明的一些方案中，上述环A选自苯基、吡咯基、嘧啶基和吡啶基，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 PCTCN2019130053-appb-000030
选自
Figure PCTCN2019130053-appb-000031
Figure PCTCN2019130053-appb-000032
其他变量如本发明所定义。
本发明的一些方案中，上述环B选自咪唑基、吡唑基、三氮唑基、哌啶基、吗啉基、四氢吡喃基和3,6-二氢-2H-吡喃基，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 PCTCN2019130053-appb-000033
选自
Figure PCTCN2019130053-appb-000034
Figure PCTCN2019130053-appb-000035
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 PCTCN2019130053-appb-000036
选自
Figure PCTCN2019130053-appb-000037
Figure PCTCN2019130053-appb-000038
Figure PCTCN2019130053-appb-000039
其他变量如本发明所定义。
本发明提供了式(II)所示化合物或其药学上可接受的盐，
Figure PCTCN2019130053-appb-000040
其中，
R 1选自H和任选被1、2或3个R a取代的C 1-3烷基；
R 2和R 3分别独立地选自H、F、Cl、Br、I、OH和NH 2；
R 4选自H、C 1-6烷基和C 3-5环烷基，所述C 1-6烷基和C 3-5环烷基任选被1、2或3个R b取代；
L选自-N(R 5)C(＝O)-、-N(R 5)S(＝O) 2-、-N(R 5)C(＝O)N(R 5)-和-N(R 5)-；
R 5分别独立地选自H和C 1-3烷基；
环B选自5-6元杂芳基和5-6元杂环烷基；
R a和R b分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和CH 3；
所述5-6元杂芳基和5-6元杂环烷基分别包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
本发明的一些方案中，上述R 1选自H、CH 3和CH 2CH 3，所述CH 3和CH 2CH 3任选被1、2或3个R a取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自H、CH 3、CH 2OH、CH 2CH 2OH和CH 2CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自H、环丙烷基、CH 3、CH 2CH 3、CH(CH 3) 2、C(CH 3) 3和CH 2CH 2CH 3，所述环丙烷基、CH 3、CH 2CH 3、CH(CH 3) 2、C(CH 3) 3和CH 2CH 2CH 3任选被1、2或3个R b取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自H、
Figure PCTCN2019130053-appb-000041
CH 3、CH 2CH 3、CH(CH 3) 2、C(CH 3) 3和CH 2CH 2CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 5分别独立地选自H、CH 3和CH 2CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述L选自-NHC(＝O)-、-NHC(＝O)NH-、-NHS(＝O) 2-和-NH-，其他变量如本发明所定义。
本发明的一些方案中，上述-L-R 4选自
Figure PCTCN2019130053-appb-000042
Figure PCTCN2019130053-appb-000043
其他变量如本发明所定义。
本发明的一些方案中，上述环B选自咪唑基、吡唑基、哌啶基、吗啉基和四氢吡喃基，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 PCTCN2019130053-appb-000044
选自
Figure PCTCN2019130053-appb-000045
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 PCTCN2019130053-appb-000046
选自
Figure PCTCN2019130053-appb-000047
其他变量如本发明所定义。
本发明提供了式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2019130053-appb-000048
其中，
R 1选自H和任选被1、2或3个R a取代的C 1-3烷基；
R 2和R 3分别独立地选自H、F、Cl、Br、I、OH和NH 2；
R 4选自H、环丙烷基和任选被1、2或3个R b取代的C 1-3烷基；
L选自-N(R 5)C(＝O)-、-N(R 5)S(＝O) 2-和-NH-；
R 5分别独立地选自H和C 1-3烷基；
R a和R b分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和CH 3。
本发明的一些方案中，上述R 1选自H、CH 3和CH 2CH 3，所述CH 3和CH 2CH 3任选被1、2或3个R a取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自H、CH 3和CH 2CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自H、环丙烷基、CH 3和CH 2CH 3，所述CH 3和CH 2CH 3任选被1、2或3个R b取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自H、
Figure PCTCN2019130053-appb-000049
CH 3和CH 2CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 5分别独立地选自H、CH 3和CH 2CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述L选自-NHC(＝O)-、-NHS(＝O) 2-和-NH-，其他变量如本发明所定义。
本发明的一些方案中，上述-L-R 4选自
Figure PCTCN2019130053-appb-000050
其他变量如本发明所定义。
本发明还有一些方案由上述变量任意组合而来。
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自
Figure PCTCN2019130053-appb-000051
其中，
R 1、R 2、R 3、L、T 1和R 4如本发明所定义。
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 PCTCN2019130053-appb-000052
Figure PCTCN2019130053-appb-000053
其中，
R 1、R 2、R 3、T 1和R 4如本发明所定义。
本发明还提供了下式所示化合物或其药学上可接受的盐，
Figure PCTCN2019130053-appb-000054
Figure PCTCN2019130053-appb-000055
Figure PCTCN2019130053-appb-000056
本发明还提供了一种药物组合物，包括治疗有效量的上述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
本发明还提供了上述的化合物或其药学上可接受的盐或者上述组合物在制备FGFR和VEGFR双重抑制剂相关药物上的应用。
本发明的一些方案中，上述的应用，其中所述FGFR和VEGFR双重抑制剂相关药物是用于实体瘤的药物。
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。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。
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。
术语“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 PCTCN2019130053-appb-000057
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 PCTCN2019130053-appb-000058
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 PCTCN2019130053-appb-000059
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“C 1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C 1-6烷基包括C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6和C 5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-6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，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述 C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1- 3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)等。
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定，术语“C 1-3烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氨基包括C 1-2、C 3和C 2烷氨基等。C 1-3烷氨基的实例包括但不限于-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)CH 2CH 3、-NHCH 2CH 2CH 3、-NHCH 2(CH 3) 2等。
除非另有规定，术语“4-6元杂环烷基”本身或者与其他术语联合分别表示由4至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“4-6元杂环烷基”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。所述4-6元杂环烷基包括5-6元、4元、5元和6元杂环烷基等。4-6元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、高哌嗪基或高哌啶基等。
除非另有规定，“C 3-5环烷基”表示由3至5个碳原子组成的饱和环状碳氢基团，其为单环体系，所述C 3-5环烷基包括C 3-4和C 4-5环烷基等；其可以是一价、二价或者多价。C 3-5环烷基的实例包括，但不限于，环丙基、环丁基、环戊基等。
除非另有规定，术语“5-6元杂环烷基”本身或者与其他术语联合分别表示由5至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“5-6元杂环烷基”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。所述5-6元杂环烷基包括5元和6元杂环烷基。5-6元杂环烷基的实例包括但不限于吡咯烷基、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、高哌嗪基或高哌啶基等。
除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示 由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元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)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。
除非另有规定，术语“5-6元杂环烯基”本身或者与其他术语联合分别表示包含至少一个碳-碳双键的由5至6个环原子组成的部分不饱和的环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环，此体系的任意环都是非芳香性的。此外，就该“5-6元杂环烯基”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。所述5-6元杂环烯基包括5元和6元杂环烯基等。5-6元杂环烯基的实例包括但不限于
Figure PCTCN2019130053-appb-000060
Figure PCTCN2019130053-appb-000061
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PE；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-氯代丁二酰亚胺；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；LiHMDS代表六甲基二硅基胺基锂；Xantphos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；LiAlH 4代表四氢铝锂；Pd(dba) 2代表三(二亚苄基丙酮)二钯；mCPBA代表间氯过氧苯甲酸；pd(dppf)Cl 2代表[1,1'-双(二苯基膦基)二茂铁]二氯化钯；DBU代表1,8-二氮杂双环[5.4.0]十一碳-7-烯；NIS代表N-碘代丁二酰亚胺；Pd 2(dba) 3代表三(二亚苄基丙酮)二钯；BINAP代表(±)-2,2-双(二苯膦基)-11-联萘；K 3PO 4代表磷酸钾。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2019130053-appb-000062
软件命名，市售化合物采用供应商目录名称。
技术效果
与专利WO2013053983中Example 5(本专利中对照例1)相比，本发明咪唑并吡啶母核多个化合物在FGFR1或者FGFR2激酶上提高了近4-10倍，FGFR4上提高了近3-10倍和VEGFR2激酶活性上提高了近3-20倍，细胞活性提高了近3-6倍，极有可能在临床上能够更低的剂量下展示更优异的治疗效果。在临床前动物模型中在较低的剂量下展示了优异的肿瘤治疗效果，对于FGFR异常的肿瘤抑制效果要明显优于FGFR单靶点选择性抑制剂，有望提高临床FGFR异常的患者治疗效果。
附图说明
图1为肿瘤生长抑制曲线；
图2为给药期间小鼠体重曲线。
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。
对照例1
Figure PCTCN2019130053-appb-000063
步骤一
将3,5-二硝基溴苯(10g,40.49mmol)和(2,4-二氟)苯硼酸(6.39g,40.49mmol)溶于水(2mL)和乙腈(120mL)中，加入醋酸钯(454.46mg,2.02mmol)和三乙胺(12.29g,121.46mmol,16.91mL)，85℃下搅拌反应16小时，将反应液直接旋干，得固体粗品，将粗品以PE:EA＝5:1进行过柱纯化得到化合物a。
1H NMR(400MHz,CDCl 3)δ9.06(t,J＝2.00Hz,1H),8.72(dd,J＝1.92,1.10Hz,2H),7.54(td,J＝8.74,6.32Hz,1H),7.00-7.15(m,2H).
步骤二
将化合物a(6.5g,23.20mmol)溶于EtOAc(65mL)的氢化瓶中，加入Pd/C(1g,23.20mmol,10％纯度)，于50Psi压力的氢气瓶(46.77mg,23.20mmol,1eq)中，45℃下搅拌反应16小时。反应液过滤，滤液旋干，得化合物b。
LCMS(ESI)m/z:220.9[M+1] +
1H NMR(400MHz,DMSO-d 6,):δ7.36-7.45(m,1H),7.20-7.30(m,1H),7.10(td,J＝8.52,2.44Hz,1H),5.92(d,J＝1.52Hz,2H),5.86(d,J＝1.82Hz,1H),4.84(s,4H).
步骤三
向化合物b(2.37g,10.76mmol)的DMSO(15mL)溶液中加入DIEA(417.28mg,3.23mmol,562.37μL)，乙氧基三甲基硅烷(2.29g,19.37mmol)，加入4-溴-1-氟-2-硝基-苯(2.37g,10.76mmol,1.32mL)，100℃搅拌16小时。反应液加入100mL水中搅拌，有大量固体析出，减压抽滤后收集滤饼，滤饼用20mL无水甲苯带水旋干得化合物c。
LCMS(ESI)m/z:419.9[M+3] +,421.9[M+3] +
1H NMR(400MHz,CDCl 3)δ9.40(s,1H),8.33(d,J＝2.26Hz,1H),7.33-7.46(m,2H),7.21-7.25(m,2H),7.11-7.19(m,1H),6.86-6.97(m,2H),6.76(d,J＝1.52Hz,1H),6.68(d,J＝1.76Hz,1H),6.56(t,J＝2.02Hz,1H),
步骤四
氮气保护下，向化合物c(4.5g,10.71mmol)的吡啶(30mL)混悬液中加入环丙基磺酰氯(1.66g,11.78mmol)。20℃搅拌2小时。向反应液中加入醋酸(34.6mL)，再加入水(250mL)，加入乙酸乙酯(150mL*2)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩得化合物d。
LCMS(ESI)m/z:523.8[M+1] +,525.8[M+3] +
步骤五
向化合物d(5.6g,10.68mmol)，1-甲基-4-吡唑硼酸酯(2.78g,13.35mmol)的二甲基亚砜(110mL)/水(30mL)溶液中加入三苯基膦(1.40g,5.34mmol)，醋酸钯(359.67mg,1.60mmol)，碳酸钾(3.84g,27.77mmol)。氮气保护下100℃搅拌16小时。将反应液加入含搅拌的水(200mL)，有固体析出，减压抽滤收集滤饼，滤饼经二氯甲烷转移到单口瓶中，再减压浓缩得粗品。将粗品以石油醚/乙酸乙酯＝0/1进行过柱(快速硅胶柱层析)纯化得到化合物e。
LCMS(ESI)m/z:526.4[M+3] +
1H NMR(400MHz,CDCl 3)δ9.45(s,1H),8.29(d,J＝2.02Hz,1H),7.73(s,1H),7.62(s,1H),7.53-7.58(m,1H),7.37-7.48(m,2H),7.16-7.24(m,3H),6.90-7.01(m,2H),6.71(s,1H),3.96(s,3H),2.52-2.65(m,1H),1.22-1.26(m,2H),0.98-1.11(m,2H).
步骤六
向化合物e(2.8g,5.33mmol,1eq)的甲酸(30mL)溶液中加入Pd/C(1g,5.33mmol,10％纯度)，30℃置于氢气球(15psi)氛围下搅拌16小时。反应完通过硅藻土过滤，滤液减压浓缩得粗品。粗品经高效液相色谱(色谱柱:YMC-Triart Prep C18 150*40mm*7μm；流动相:[水(0.1％三氟乙酸)-乙腈]；B(乙腈)％:35％-50％,10min)得对照例1。
LCMS(ESI)m/z:506.0[M+1] +
1H NMR(400MHz,DMSO-d 6)δ10.25(br s,1H),8.65(s,1H),8.19(s,1H),7.99(s,1H),7.94(s,1H),7.71-7.81 (m,1H),7.64-7.70(m,1H),7.55-7.63(m,3H),7.40-7.51(m,2H),7.27(br t,J＝7.53Hz,1H),3.88(s,3H),2.81-2.93(m,1H),0.98-1.08(m,4H).
对照例1的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到对照例1。
实施例1
Figure PCTCN2019130053-appb-000064
步骤一
将3,5-二硝基溴苯(20g,80.97mmol)溶于冰醋酸(120mL)中，升温至90℃，将还原铁粉(11.30g,202.43mmol)在30分钟内分批缓慢加到反应液中，加完即反应结束。向反应液中加入碎冰，有固体析出，过滤，水洗3次。收集滤饼，用甲苯带水得化合物1a。
1H NMR(400MHz,DMSO-d 6)δ7.09-7.32(m,3H),6.13(br s,2H).
步骤二
0℃将下将乙酸酐(16.02g,156.95mmol,14.7mL)加入到1a(14.7g,67.74mmol)中，在15℃继续搅拌30分钟。向反应液中加入碎冰140mL，有固体析出，过滤，用冰水洗两次，收集滤饼，旋干得化合物1b。 1H NMR(400MHz,DMSO-d 6)δ8.46(s,1H),8.19(s,1H),8.02(s,1H),2.10(s,3H).
步骤三
将化合物1b(16g,61.76mmol)和2,4-二氟苯硼酸(11.70g,74.12mmol)溶于乙二醇二甲醚(160mL)和 H 2O(60mL)中，加入Pd(dppf)Cl 2(4.52g,6.18mmol)和碳酸钠(19.64g,185.29mmol)，90℃下搅拌2小时。将反应液过滤，加入水(200mL)，二氯甲烷(300mL*2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液旋干得粗品。将粗品经快速硅胶柱(石油醚/乙酸乙酯＝1:1～0:1)纯化得到化合物1c。
1H NMR(400MHz,DMSO-d 6)δ8.63(s,1H),8.09(s,1H),8.01(s,1H),7.60-7.70(m,1H),7.45-7.49(m,1H),2.12(s,3H).
步骤四
将化合物1c(4g,13.69mmol)溶于乙酸乙酯(25mL)和甲醇(50mL)中，加入干Pd/C(0.5g,13.69mmol，50％纯度)，氮气置换2次后，氢气置换2次，最后在30℃下，50psi搅拌反应8小时。反应液过滤，滤液旋干得产物1d。
1H NMR(400MHz,DMSO-d 6)δ9.75(s,1H),7.14-7.48(m,3H),6.98(s,1H),6.85(s,1H),6.38(s,1H),5.31(s,2H),2.01(s,3H).
步骤五
0℃向化合物1d(1g,3.81mmol)的乙腈(30mL)溶液中加入亚硝酸叔丁酯(786.41mg,7.63mmol)，0℃搅拌30分钟，再加入溴化亚铜(1.09g,7.63mmol)，25℃搅拌30分钟，再于60℃下搅拌1小时。向反应液中加入水(50mL)，再加入乙酸乙酯(50mL*2)萃取，收集有机相并用无水硫酸钠干燥，减压浓缩得粗品。粗品经硅胶柱层析(石油醚:乙酸乙酯＝1:1)分离得产物得化合物1e。
步骤六
向化合物1e(100mg,306.62μmol)，双联硼酸嚬哪醇酯(116.79mg,459.93μmol)的二氧六环(5mL)溶液中加入Pd(dppf)Cl 2(22.44mg,30.66μmol)，醋酸钾(60.18mg,613.24μmol)。氮气保护下100℃搅拌3小时。过滤旋干得粗品化合物1f。
LCMS(ESI)m/z:374.2[M+1] +
Figure PCTCN2019130053-appb-000065
步骤七
向4-溴-2-氨基吡啶(5g,28.90mmol)的EtOH(60mL)中滴加氯乙醛(8.51g,43.35mmol,6.97mL)，80℃搅拌16小时。反应液经减压旋干得粗品化合物1g。
1H NMR(400MHz,DMSO-d 6)δ8.89-8.96(m,1H),8.40-8.45(m,1H),8.30(d,J＝1.52Hz,1H),8.19(d,J＝2.02Hz,1H),7.70(dd,J＝1.76,7.28Hz,1H).
步骤八
将化合物1g(10g,50.75mmol)和1-甲基-4-吡唑硼酸酯(11.62g,55.83mmol)溶于二氧六环(155mL)和H 2O(75mL)中，加入Pd(dppf)Cl 2(3.71g,5.08mmol)和K 3PO 4(21.55g,101.51mmol)，100℃下搅拌反应16小时，反应液加水(150mL)，乙酸乙酯(150mL*2)进行萃取，有机相用无水硫酸钠干燥，过滤，滤液旋干得粗品。将粗品以石油醚/乙酸乙酯＝3/1进行过柱(快速硅胶柱层析)纯化得到化合物1h。LCMS(ESI)m/z:198.8[M+1] +
1H NMR(400MHz,CDCl 3)δ8.11(br d,J＝7.04Hz,1H),7.79(s,1H),7.54-7.71(m,3H),7.37(br s,1H),6.90(d,J＝6.78Hz,1H),3.96(s,3H).
步骤九
向化合物1h(0.48g,2.42mmol)的乙腈(10mL)溶液中加入溴代丁二酰亚胺(517.19mg,2.91mmol)，30℃搅拌2小时。反应液经抽滤得滤液，滤液经减压浓缩得粗品。粗品经硅胶柱层析(石油醚:乙酸乙酯＝1:1,R f＝0.59)分离得化合物1i。
LCMS(ESI)m/z:276.7[M+1] +
步骤十
向1h(2.7g,13.62mmol)的二氯甲烷(27mL)溶液中加入NIS(3.68g,16.35mmol)，30℃搅拌16小 时。向反应液加水(100mL)，再加入二氯甲烷(100mL*3)萃取，合并有机相并减压浓缩。粗品经快速硅胶柱层析分离(DCM:MeOH＝10:1,Rf＝0.13)分离得得化合物1j。
LCMS(ESI)m/z:324.9[M+1] +
步骤十一
向化合物1i(80mg,288.68μmol)，化合物1f(107.74mg,288.68μmol)的二氧六环(6mL)和H 2O(3mL)混合溶液中加入K 3PO 4(122.56mg,577.37μmol)，Pd(dppf)Cl 2(21.12mg,28.87μmol)。氮气保护下100℃反应2小时。反应液分层，有机相浓缩，经硅胶柱纯化(DCM:MeOH＝10:1)得到粗品。粗品再经高效液相色谱(色谱柱:YMC-Actus Triart C 18 100×30mm×5μm；流动相:[水(0.05％盐酸)-乙腈]；B(乙腈)％:25％-55％,10min)分离得化合物1的盐酸盐。
LCMS(ESI)m/z:444.1[M+1] +
1H NMR(400MHz,CD 3OD)δ8.72(d,J＝7.28Hz,1H),8.41(s,1H),8.11-8.17(m,3H),8.07(s,1H),7.81(d,J＝1.52Hz,1H),7.75(dd,J＝1.52,7.28Hz,1H),7.59-7.67(m,1H),7.57(d,J＝1.00Hz,1H),7.07-7.14(m,2H),4.00(s,3H),2.20(s,3H).
化合物1的盐酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物1。
实施例2
Figure PCTCN2019130053-appb-000066
步骤一
向化合物3-溴-5-硝基-苯酚(1g,4.59mmol)，2,4-二氟苯硼酸(869.21mg,5.50mmol)的THF(10mL)和H 2O(5mL)溶液中加入Pd(dppf)Cl 2(335.64mg,458.71μmol)，K 3PO 4(2.43g,11.47mmol)。氮气保护下90℃搅拌16小时。反应液中加水(50mL)，用乙酸乙酯(50mL*3)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩。粗品经硅胶柱层析分离(PE:EA＝5:1,Rf＝0.12)得化合物2a。
1H NMR(400MHz,DMSO-d 6)δ10.69(br s,1H),7.77(d,J＝1.52Hz,1H),7.68(dt,J＝6.54,8.92Hz,1H),7.59(t,J＝2.14Hz,1H),7.38-7.47(m,1H),7.35(d,J＝1.76Hz,1H),7.23(dt,J＝2.14,8.48Hz,1H).
步骤二
向化合物2a(4g,15.92mmol)的DMF(50mL)溶液中加入DIEA(6.17g,47.77mmol,8.32mL)，N-苯基双(三氟甲烷磺酰)亚胺(8.53g,23.89mmol)，15℃搅拌16小时。反应液中加水50mL，用乙酸乙酯(50mL*2)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩。粗品经硅胶柱层析分离(PE:EA＝3:1,Rf＝0.76)得化合物2b。
1H NMR(400MHz,DMSO-d 6)δ8.42-8.50(m,2H),8.25(s,1H),7.79(dt,J＝6.54,8.92Hz,1H),7.41-7.54(m,1H),7.22-7.36(m,1H).
步骤三
向化合物2b(6g,15.66mmol)的二氧六环(40mL)溶液中加入Pd(dppf)Cl 2(1.15g,1.57mmol)，双联嚬哪醇硼酸酯(4.77g,18.79mmol)，醋酸钾(3.07g,31.31mmol)。氮气保护下90℃搅拌16小时。TLC显示有新点生成。经硅藻土过滤后浓缩得化合物2c。
步骤四
向化合物2c(4.68g,12.96mmol)，1j(3.5g,10.80mmol)的二氧六环(30mL)和H 2O(10mL)溶液中加入Pd(dppf)Cl 2(790.13mg,1.08mmol)，K 3PO 4(4.58g,21.60mmol)。氮气保护下100℃搅拌3小时。反应液中加入水(200mL)，乙酸乙酯(200mL*2)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩。粗品经快速硅胶柱层析纯化(DCM:MeOH＝10:1,Rf＝0.71)得化合物2d。
LCMS(ESI)m/z:432.0[M+1] +
步骤五
向化合物2d(2.0g,4.64mmol)的MeOH(20mL)溶液中加入Pd/C(0.2g,10％纯度)，于氢气(15psi)球氛围下15℃搅拌5小时。反应液经硅藻土过滤，滤液减压浓缩。粗品经快速硅胶柱层析(DCM:MeOH＝10:1,Rf＝0.62)纯化得化合物2e。
LCMS(ESI)m/z:402.2[M+1] +
步骤六
向化合物2e(50.00mg,124.56μmol)的吡啶(2mL)溶液中加入乙基磺酰氯(38.44mg,298.95μmol, 28.26μL)，15℃搅拌2小时。反应液用醋酸(3mL)调pH至5，加入水(8mL)，加入乙酸乙酯(8mL*2)萃取，合并有机相减压浓缩。粗品经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:25％-55％,8min)纯化得到化合物2的三氟乙酸盐。
LCMS(ESI)m/z:494.0[M+1] +
1H NMR(400MHz,CD 3OD)δ8.70(d,J＝6.78Hz,1H),8.38(s,1H),8.15(s,2H),8.05(d,J＝0.76Hz,1H),7.76(dd,J＝1.76,7.28Hz,1H),7.60-7.68(m,3H),7.55-7.59(m,1H),7.09-7.18(m,2H),4.00(s,3H),3.25(q,J＝7.36Hz,2H),1.37(t,J＝7.40Hz,3H).
化合物2的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物2。
表1中实施例化合物的制备可以参照前述制备实施例2的路线类似的步骤方法进行，不同之处在于在步骤六中使用的原料A代替乙基磺酰氯得到相应化合物的三氟乙酸盐，将得到的化合物的三氟乙酸盐分别加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到相应的化合物。
表1
Figure PCTCN2019130053-appb-000067
Figure PCTCN2019130053-appb-000068
实施例4
Figure PCTCN2019130053-appb-000069
步骤一
向化合物2e(30mg,74.74μmol)，环丙基乙酸(9.65mg,112.10μmol,8.85μL)的DMF(2mL)溶液中加入HATU(42.63mg,112.10μmol)，DIEA(19.32mg,149.47μmol,26.04μL)。15℃搅拌16小时。反应液过滤。粗品经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:27％-57％,8min)纯化得到化合物4的三氟乙酸盐。
LCMS(ESI)m/z:470.1[M+1] +
1H NMR(400MHz,CD 3OD)δ8.73(d,J＝7.54Hz,1H),8.36(s,1H),8.07-8.19(m,3H),8.02(s,1H),7.78(d,J＝1.52Hz,1H),7.71(dd,J＝1.64,7.16Hz,1H),7.59-7.67(m,1H),7.57(d,J＝1.26Hz,1H),7.06-7.18(m,2H),3.99(s,3H),1.74-1.89(m,1H),0.96-1.03(m,2H),0.88-0.96(m,2H).
化合物4的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物4。
实施例5
Figure PCTCN2019130053-appb-000070
步骤一
向化合物2e(9.88mg,112.10μmol,10.40μL)，2-甲基丙酸(9.88mg,112.10μmol,10.40μL)的DMF(2mL)溶液中加入HATU(42.63mg,112.10μmol)，DIEA(19.32mg,149.47μmol,26.04μL)。15℃搅拌16小时。反应液直接过滤浓缩。粗品经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:28％-58％,8min)纯化得到化合物5的三氟乙酸盐。
LCMS(ESI)m/z:472.1[M+1] +
1H NMR(400MHz,CD 3OD)δ8.75(d,J＝7.28Hz,1H),8.38(s,1H),8.20(s,1H),8.15(d,J＝7.04Hz,2H),8.05(s,1H),7.80(s,1H),7.75(d,J＝7.28Hz,1H),7.57-7.68(m,2H),7.05-7.18(m,2H),4.00(s,3H),2.70(td,J＝6.88,13.62Hz,1H),1.24(d,J＝6.78Hz,6H).
化合物5的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物5。
实施例7
Figure PCTCN2019130053-appb-000071
步骤一
向化合物2e(30mg,74.74μmol)溶于DCM(1mL)中，加入DIEA(28.98mg,224.21μmol)，0℃下搅拌5分钟；同时环丙胺(4.27mg,74.74μmol)溶于DCM(1mL)中，加入DIEA(28.98mg,224.21μmol)和三光气(11.09mg,37.37μmol)，0℃下搅拌5分钟；然后将含环丙胺的反应液加到化合物2e的反应液中，继续0℃搅拌5分钟。反应液直接旋干。粗品经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:23％-53％,10min)纯化得到化合物7的三氟乙酸盐。
LCMS(ESI)m/z:485.2[M+1] +
1H NMR(400MHz,CD 3OD)δ8.76(d,J＝7.54Hz,1H),8.16(s,1H),8.38(s,1H),8.10(s,1H),8.02(m,2H),7.72(d,J＝7.28Hz,1H),7.60-7.68(m,2H),7.49(s,1H),7.08-7.18(m,2H),4.02(s,2H),3.98-4.05(m,1H),2.64(dt,J＝7.04,3.52Hz,1H),0.76-0.84(m,2H),0.57(br s,2H).
化合物7的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物7。
实施例8
Figure PCTCN2019130053-appb-000072
步骤一
向7-溴咪唑并[1,2-a]吡啶(10g,50.75mmol)，吗啡啉(6.63g,76.13mmol)的甲苯(100mL)溶液中加入三(二亚苄基丙酮)二钯(4.65g,5.08mmol)，(±)-2,2-双(二苯膦基)-11-联萘(6.32g,10.15mmol)，叔丁醇钠(9.76g,101.51mmol)。氮气保护下95℃搅拌3小时。LCMS表明有产物生成。反应液经抽滤得滤液，滤液经减压浓缩得粗品。粗品经硅胶柱层析分离(EA:MeOH＝10:1)纯化得到化合物8a。
LCMS(ESI)m/z:204.1[M+1] +
步骤二
向化合物8a(500mg,2.46mmol)的DCM(10mL)溶液中加入NIS(664.19mg,2.95mmol)，20℃搅拌16小时。向反应液中加水(10mL)，萃取分液，有机相用无水硫酸钠干燥减压浓缩得到化合物8b。
LCMS(ESI)m/z:329.9[M+1] +
步骤三
向化合物8b(0.9g,2.73mmol)，2c(1.19g,3.28mmol)的二氧六环(9mL)和H 2O(3mL)溶液中加入Pd(dppf)Cl 2(200.08mg,273.44μmol)，K 3PO 4(1.16g,5.47mmol)，氮气保护下90℃搅拌16小时。反应液分层后，用无水硫酸钠干燥，减压浓缩得粗品。粗品经快速硅胶柱层析(DCM:MeOH＝10:1)过柱纯化得到化合物8c。
LCMS(ESI)m/z:437.1[M+1] +
步骤四
将化合物8c(0.8g,1.83mmol)溶于MeOH(30mL)中，加入Pd/C(0.8g,10％纯度)，氮气置换2次后， 氢气置换2次，最后在30℃下，50psi搅拌反应16小时。反应液过滤，滤液旋干得化合物8d。
LCMS(ESI)m/z:407.1[M+1] +
步骤五
向化合物8d(0.16g,393.67μmol)的吡啶(2mL)溶液中加入环丙基磺酰氯(100mg,711.30μmol)。20℃搅拌3小时。反应液加入乙酸调pH至5，再加入水10mL，用乙酸乙酯(10mL*2)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩。粗品经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:30％-60％,10min)纯化得到化合物8的三氟乙酸盐。
LCMS(ESI)m/z:511.2[M+1] +
1H NMR(400MHz,CD 3OD)δ8.44(d,J＝7.78Hz,1H),7.86(s,1H),7.54-7.66(m,4H),7.28(dd,J＝2.26,8.04Hz,1H),7.07-7.17(m,2H),6.92(d,J＝2.02Hz,1H),3.80-3.91(m,4H),3.51-3.58(m,4H),2.66-2.75(m,1H),1.11(br d,J＝3.76Hz,2H),0.98-1.06(m,2H).
化合物8的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物8。
实施例9
Figure PCTCN2019130053-appb-000073
Figure PCTCN2019130053-appb-000074
步骤一
在0℃条件下，在溴乙醇中(500g,4.00mol,284.09mL)加入3,4-二氢2H-吡喃(500.00g,5.94mol,543.48mL)、浓盐酸(1.02g,10.35mmol,1.00mL)，19℃搅拌1小时。反应完成后，加入100g碳酸氢钠搅拌30分钟，过滤除去不溶物得粗品。减压蒸馏0.09MPa，收集80℃馏分，得到化合物9f。
1H NMR(400MHz,CDCl 3)δ4.66-4.60(m,1H),4.00-3.76(m,3H),3.50-3.47(m,1H),1.83-1.50(m,6H).
步骤二
将化合物9f(600.78g,2.87mol,435.35mL)、4-硼酸酯-1H-吡唑(280g,1.44mol)溶于DMF(1120mL)，加入碳酸钾(397.12g,2.87mol)，60℃搅拌48小时。过滤除去不溶物，用乙酸乙酯洗涤，合并滤液，旋除溶剂得粗品。粗品经硅胶柱层析(正庚烷：乙酸乙酯＝8:1)得化合物9g。
1H NMR(400MHz,CDCl 3)δ7.84-7.78(m,1H),4.52-4.51(m,1H),4.35-4.32(m,2H),4.05-4.04(m,1H),3.79-3.45(m,3H),1.79-1.47(m,6H),1.32(s,12H).
步骤三
向7-溴咪唑并[1,2-a]吡啶(8g,40.60mmol)，化合物9g(15.70g,48.72mmol)的二氧六环(80mL)和H 2O(40mL)溶液中加入Pd(dppf)Cl 2(2.97g,4.06mmol)，K 3PO 4(17.24g,81.21mmol)。95℃搅拌16小时。反应液分层，收集有机相并用无水硫酸钠干燥，减压浓缩。粗品经硅胶柱层析分离(DCM:MeOH＝10:1)得到化合物9a。
LCMS(ESI)m/z:313.0[M+1] +
步骤四
向化合物9a(3.7g,11.85mmol)的DCM(30mL)溶液中加入NIS(3.20g,14.21mmol)，20℃搅拌16小时。向反应液中加水(100mL)，萃取分液，有机相用无水硫酸钠干燥减压浓缩得到化合物9b。
LCMS(ESI)m/z:439.0[M+1] +
步骤五
向化合物9b(2.5g,5.70mmol)，2c(2.47g,6.85mmol)的二氧六环二氧六环(50mL)和H 2O(15mL)溶液中加入Pd(dppf)Cl 2(417.39mg,570.44μmol)，K 3PO 4(2.42g,11.41mmol)。氮气保护下90℃搅拌16小时。反应液分层后，有机相用无水硫酸钠干燥，减压浓缩。粗品经快速硅胶柱层析(DCM:MeOH＝20:1)过柱纯化得到9c。
LCMS(ESI)m/z:546.3[M+1] +
步骤六
向化合物9c(0.2g,366.61μmol)的EtOH(10mL)和H 2O(2mL)溶液中加入锌粉(239.73mg,3.67mmol)，氯化铵(196.11mg,3.67mmol)。20℃搅拌16小时。反应液直接过滤，滤液减压浓缩得到化合物9d。
LCMS(ESI)m/z:516.1[M+1] +
步骤七
向化合物9d(0.19g,368.54μmol)的吡啶(2mL)溶液中加入环丙基磺酰氯(62.17mg,442.24μmol)，20℃搅拌4小时。反应液中加入20mL冰水，再加入醋酸6mL调pH至5，加入乙酸乙酯(20mL*3)萃取，有机相减压浓缩得到化合物9e。
LCMS(ESI)m/z:620.1[M+1] +
步骤八
向化合物9e(0.19g,306.61μmol)的单口瓶中加入氯化氢/乙酸乙酯(4M,28.50mL)，20℃搅拌16小时。反应液直接减压浓缩。粗品经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:28％-58％,10min)纯化得到化合物9的三氟乙酸盐。
LCMS(ESI)m/z:536.3[M+1] +
1H NMR(400MHz,CD 3OD)δ8.67-8.74(m,1H),8.44(s,1H),8.18(d,J＝14.06Hz,2H),8.06(s,1H),7.79(dd,J＝1.64,7.16Hz,1H),7.55-7.72(m,4H),7.07-7.21(m,2H),4.33(t,J＝5.14Hz,2H),3.95(t,J＝5.14Hz,2H),2.65-2.81(m,1H),1.09-1.17(m,2H),0.98-1.07(m,2H).
化合物9的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物9。
实施例11
Figure PCTCN2019130053-appb-000075
步骤一
向4-硼酸酯-1H-吡唑(0.13g,669.97μmol)和氧杂异丁烯(633.36mg,8.78mmol,780.00μL)混悬液中加入碳酸铯(32.74mg,100.50μmol)，120℃下于微波反应器中搅16小时。直接用于下一步，无需处理。得到化合物11a。
LCMS(ESI)m/z:267.0[M+1] +
步骤二
向化合物1g(0.11g,558.29μmol)，11a(178.30mg,669.94μmol)的二氧六环(3mL)和水(1mL)溶液中加入Pd(dppf)Cl 2(40.85mg,55.83μmol)，K 3PO 4(237.01mg,1.12mmol)。氮气保护下90℃搅拌16小时。反应液分层，有机相浓缩旋干得粗品。粗品经快速硅胶柱层析(DCM:MeOH＝10:1)纯化得到化合物11b。LCMS(ESI)m/z:256.9[M+1] +
步骤三
向化合物11b(0.12g,468.20μmol)的DCM(3mL)溶液中加入NIS(126.40mg,561.84μmol)，25℃搅拌16小时。向反应液中水(20mL)，用二氯甲烷(15mL*3)萃取分液，有机相并用无水硫酸钠干燥减压浓缩得到化合物11c。
LCMS(ESI)m/z:383.0[M+1] +
步骤四
将化合物2b(17.71g,46.21mmol)溶于EtOH(150mL)和H 2O(50mL)中，加入氯化铵(24.72g,462.10mmol)混合均匀，然后缓慢加入锌粉(15.11g,231.05mmol)。80℃下搅拌反应16小时。将反应液经硅藻土过滤，滤液减压浓缩得粗品。粗品经硅胶柱层析分离(PE:EA＝10:1)得到化合物11d。
LCMS(ESI)m/z:353.9[M+1] +
1H NMR(400MHz,DMSO-d 6)δ7.58-7.54(m,1H),7.38-7.35(m,1H),7.19-7.18(m,1H),6.79(s,1H),6.79-6.62(m,2H),5.87(s,2H).
步骤五
向化合物11d(16.5g,46.71mmol)的吡啶(75mL)溶液中加入甲烷磺酰氯(8.03g,70.06mmol)，30℃搅拌3小时。反应完成后，反应液加水(100mL)，用乙酸乙酯萃取(80mL*3)萃取，合并有机相并用无水硫酸钠干燥，油泵减压浓缩得到化合物11e。
步骤六
将化合物11e，双联嚬哪醇硼酸酯(8.12g,31.99mmol)溶于二氧六环(200mL)中，加入Pd(dppf)Cl 2(1.95g,2.67mmol)，醋酸钾(5.23g,53.32mmol)100℃搅拌反应16小时。反应液经过硅藻土过滤收集滤液，滤液减压浓缩得粗品。粗品经硅胶柱层析分离(PE/EA＝5:1)得到化合物11f。
LCMS(ESI)m/z:409.13[M+1] +
1H NMR(400MHz,DMSO-d 6)δ7.93(s,1H),7.54-7.55(m,1H),7.50(s,2H),7.48-7.46(m,1H),7.33-7.42(m,1H),7.20(br d,J＝2.24Hz,1H),3.01(s,3H),1.26-1.35(m,12H).
步骤七
向化合物11c(65mg,170.07μmol)，化合物11f(153.12mg,374.15μmol)的二氧六环(3mL)和水(1mL)溶液中加入Pd(dppf)Cl 2(12.44mg,17.01μmol)，K 3PO 4(72.20mg,340.14μmol)，氮气保护下90℃搅拌16小时。反应液浓缩得粗品。粗品经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:20％-50％,12min)纯化得化合物11的三氟乙酸盐。
LCMS(ESI)m/z:538.1[M+1] +
1H NMR(400MHz,CD 3OD)δ8.71(br d,J＝7.03Hz,1H),8.40(s,1H),8.17(br d,J＝2.76Hz,2H),8.08(br s,1H),7.53-7.83(m,5H),7.13(br s,2H),4.20(s,2H),3.11(s,3H),1.23(s,6H).
化合物11的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物11。
Figure PCTCN2019130053-appb-000076
步骤一
将化合物11d(9g,25.48mmol)溶于吡啶(10mL)中，滴加乙烷磺酰氯(3.93g,30.57mmol,2.89mL)，30℃下搅拌反应4小时。反应液加水30mL和乙酸乙酯30mL萃取，有机相再用水30mL洗两次，旋干得化合物11g。
1H NMR(400MHz,CDCl 3):δ7.67(s,1H),7.27(d,J＝1.52Hz,1H),7.22(s,1H),7.11(s,1H),6.84-6.99(m,2H),3.06-3.22(m,2H),1.28-1.39(m,3H).
步骤二
将实施例11g(9g,20.21mmol)和双联嚬哪醇硼酸酯(6.16g,24.25mmol,1.2)溶于dioxane(90mL)中，加入Pd(dppf)Cl 2(1.48g,2.02mmol)和KOAc(3.97g,40.41mmol)，氮气保护下90℃搅拌反应16小时。反应液直接过滤，乙酸乙酯洗，滤液旋干得粗品,将粗品以PE/EA＝5/1进行过柱纯化得到11h。
1H NMR(400MHz,CDCl 3):δ7.68-7.71(m,1H),7.56(d,J＝2.02Hz,1H),7.49-7.55(m,1H),7.41(td,J＝8.54,6.5Hz,1H),6.84-6.96(m,2H),3.15(q,J＝7.32Hz,2H),1.32-1.35(m,12H),1.24(br s,3H).
实施例12
Figure PCTCN2019130053-appb-000077
Figure PCTCN2019130053-appb-000078
步骤一
向化合物11d(6.9g,19.53mmol)的吡啶(67.62g,854.87mmol,69.00mL)溶液中加入环丙烷磺酰氯(3.30g,23.44mmol)，20℃搅拌16小时。反应液加入醋酸(80mL)，再加入水(250mL)，乙酸乙酯(200mL*3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液旋干得到化合物12a。
步骤二
向化合物12a(8g,17.49mmol)，双联嚬哪醇硼酸酯(4.44g,17.49mmol)的二氧六环(80mL)溶液中加入Pd(dppf)Cl 2(1.28g,1.75mmol)，醋酸钾(3.43g,34.98mmol)。氮气保护下90℃搅拌16小时。反应液经硅藻土抽滤，滤液减压浓缩得粗品。粗品经快速硅胶柱(PE:EA＝3:1)过柱纯化得到化合物12b。
步骤三
向化合物11c(65mg,176.55μmol)，化合物12b(153.70mg,353.10μmol)的二氧六环(3mL)和水(1mL)溶液中加入Pd(dppf)Cl 2(12.92mg,17.65μmol)，K 3PO 4(74.95mg,353.10μmol)，氮气保护下90℃搅拌16小时。反应液浓缩得粗品。粗品经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:20％-50％,12min)纯化得化合物12的三氟乙酸盐。
LCMS(ESI)m/z:564.2[M+1] +
1H NMR(400MHz,CD 3OD)δ8.70(d,J＝7.28Hz,1H),8.40(s,1H),8.17(d,J＝6.54Hz,2H),8.07(s,1H),7.79(dd,J＝1.64,7.16Hz,1H),7.59-7.72(m,4H),7.08-7.19(m,2H),4.20(s,2H),2.66-2.80(m,1H),1.14(s,6H),1.09-1.17(m,2H),0.99-1.07(m,2H).
化合物12的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物12。
实施例13
Figure PCTCN2019130053-appb-000079
步骤一
向1g(10g,50.75mmol)，吗啡啉(6.63g,76.13mmol,6.70mL)的甲苯(100mL)溶液中加入Pd 2(dba) 3(4.65g,5.08mmol)，BINAP(6.32g,10.15mmol)，t-BuONa(9.76g,101.51mmol)。氮气保护下95℃搅拌3小时。反应液经抽滤收集滤液，滤液减压浓缩得粗品。粗品经快速硅胶柱层析(DCM:MeOH＝10:1)纯化得到化合物13b。
LCMS(ESI)m/z:204.1[M+1] +
步骤二
将化合物13b(5.8g,28.54mmol)溶DCM(110mL)中，加入NIS(7.70g,34.25mmol)，25℃搅拌反应16小时。反应液加水(100mL)，分液，收集有机相，有机相无水硫酸钠干燥，减压浓缩得到化合物13c。LCMS(ESI)m/z:329.8[M+1] +
步骤三
将化合物13c(50mg,151.91μmol)和化合物11f(93.26mg,227.87μmol)溶于THF(1.5mL)和H 2O(0.7mL)中，加入Pd(dppf)Cl 2(11.12mg,15.19μmol)和K 3PO 4(64.49mg,303.83μmol)，氮气保护下90℃搅拌反应16小时。反应液浓缩得粗品，粗品经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:21％-51％,12min)纯化得到化合物13的三氟乙酸盐。
LCMS(ESI)m/z:485.0[M+1] +
1H NMR(400MHz,CD 3OD)δppm 8.46(d,J＝8.0Hz,1H),7.86(s,1H),7.53-7.67(m,4H),7.29(dd,J＝7.78,2.52Hz,1H),7.08-7.17(m,2H),6.95(d,J＝2.26Hz,1H),3.84-3.93(m,4H),3.51-3.61(m,4H),3.11(s,3H).
化合物13的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得 到化合物13。
实施例14
Figure PCTCN2019130053-appb-000080
步骤一
将化合物9b(100mg,228.17μmol)和化合物11f(140.07mg,342.26μmol)溶于四氢呋喃(1.5mL)和水(0.7mL)中，加入Pd(dppf)Cl 2(16.70mg,22.82μmol)和K 3PO 4(96.87mg,456.35μmol)，氮气保护下微波90℃搅拌反应0.5小时。向反应液中加水(3mL)，用乙酸乙酯(3mL*2)萃取，收集有机相，有机相浓缩旋干得粗品。粗品经快速硅胶柱层析(DCM:MeOH＝20:1)纯化得到化合物14a。
LCMS(ESI)m/z:594.1[M+1] +
步骤二
将化合物14a(50mg,84.23μmol)溶于DCM(2mL)中，加入氯化氢/乙酸乙酯(4M,2mL)，25℃搅拌反应1小时。反应液直接旋干得粗品。粗品经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:15％-45％,12min)纯化得到化合物14的三氟乙酸盐。
LCMS(ESI)m/z:510.0[M+1] +
1H NMR(400MHz,CD 3OD)δppm 8.72(s,1H),8.45(s,1H),8.21(s,1H),8.17(s,1H),8.08(s,1H),7.79(dd,J＝7.32,1.6Hz,1H),7.62-7.71(m,3H),7.59(d,J＝1.60Hz,1H),7.11-7.20(m,2H),4.35(t,J＝5.20Hz,2H),3.97(t,J＝5.20Hz,2H),3.13(s,3H).
化合物14的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物14。
实施例15
Figure PCTCN2019130053-appb-000081
步骤一
向4-硼酸酯-1H-吡唑(5g,25.77mmol)的乙腈(50mL)溶液中入1-甲烷磺酰基乙烯(4.10g,38.65mmol,3.39mL)，DBU(1.96g,12.88mmol,1.94mL)。90℃搅拌16小时。反应液减压浓缩得到化合物15a。LCMS(ESI)m/z:300.9[M+1] +
步骤二
向化合物1g(549.98mg,558.29μmol)，15a(1.0g,3.333mmol)的二氧六环(10mL)和水(5m L)溶液中加入Pd(dppf)Cl 2(203.13mg,277.61μmol)和K 3PO 4(1.18g,5.55mmol)，氮气保护下85℃搅拌反应16小时。向反应液中加水(10mL)，用乙酸乙酯(10mL*2)萃取，收集有机相，有机相浓缩得粗品。粗品经快速硅胶柱层析(DCM:MeOH＝20:1)纯化得到化合物15b。
1HNMR(400MHz,CDCl 3)δ8.08-8.15(m,1H),7.92(s,1H),7.89(s,1H),7.68(s,1H),7.56(br d,J＝13.30Hz,2H),6.93(dd,J＝1.00,7.04Hz,1H),4.66(t,J＝6.16Hz,2H),3.65-3.70(m,2H),2.62(s,3H).
步骤三
向化合物15b(100mg,344.42μmol)溶于DCM(2mL)，加入NIS(92.99mg,413.31μmol)，30℃搅拌反应16小时。反应液加水(3mL)和二氯甲烷(3mL)进行萃取分液，有机相用无水硫酸钠干燥，减压浓缩得到化合物15c。
LCMS(ESI)m/z:416.8[M+1] +
步骤四
将化合物15c(80mg,192.20μmol)和化合物11f(94.39mg,230.64μmol)溶于四氢呋喃(2mL)和水(1mL)中，加入Pd(dppf)Cl 2(14.06mg,19.22μmol)和K 3PO 4(81.59mg,384.40μmol)，氮气保护下微波90℃搅 拌反应0.5小时。反应液加水(4mL)和乙酸乙酯(4mL)萃取分液，有机相浓缩得粗品。粗品经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:20％-50％,12min)纯化得到化合物15的三氟乙酸盐。
LCMS(ESI)m/z:572.1[M+1] +
1H NMR(400MHz,CD 3OD)δ8.73(d,J＝7.28Hz,1H),8.52(s,1H),8.25(s,1H),8.18(s,1H),8.10(s,1H),7.79(dd,J＝1.60,7.28Hz,1H),7.62-7.71(m,3H),7.60(d,J＝1.76Hz,1H),7.10-7.19(m,2H),4.77(t,J＝6.40Hz,2H),3.81(t,J＝6.40Hz,2H),3.13(s,3H),2.91(s,3H).
化合物15的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物15。
实施例16
Figure PCTCN2019130053-appb-000082
步骤一
将1g(0.2g,1.02mmol)溶于DCM(4mL)中，25℃加入NIS(274.05mg,1.22mmol)，搅拌反应2小时。反应液加水(5mL)和二氯甲烷(5mL)萃取，收集有机相，浓缩得到化合物16a。
1H NMR(400MHz,DMSO-d 6)δ8.51(d,J＝7.24Hz,1H),8.18(d,J＝1.24Hz,1H),8.14(s,1H),7.51(dd,J＝1.88,7.24Hz,1H).
步骤二
将化合物16a(200mg,619.33μmol)和化合物11f(304.16mg,743.20μmol)溶于二氧六环(1mL)和水(0.25mL)中，加入碳酸钠(164.11mg,1.55mmol)和Pd(dppf)Cl 2(45.32mg,61.93μmol)，氮气保护 下110℃微波搅拌20分钟。反应液加水(3mL)和乙酸乙酯(3mL*2)萃取，有机相浓缩得粗品。粗品经快速硅胶柱层析(PE/EA＝1/1～0/1)纯化得到化合物16b。
LCMS(ESI)m/z:479.7[M+1] +
步骤三
将化合物16b(120mg,250.88μmol)和4-硼酸酯-1H-吡唑(58.42mg,301.06μmol)溶于二氧六环(2mL)和水(1mL)中，加入Pd(dppf)Cl 2(18.36mg,25.09μmol)和K 3PO 4(106.51mg,501.77μmol)，氮气保护下微波90℃搅拌反应0.5小时。反应液加水(3mL)和乙酸乙酯(4mL)萃取分液，有机相减压浓缩得到化合物16c。
LCMS(ESI)m/z:466.2[M+1] +
步骤四
将化合物16c(100mg,214.83μmol)和四氢吡喃-4-基4-甲基苯磺酸(55.07mg,214.83μmol)溶于DMF(1mL)中，加入碳酸铯(209.99mg,644.50μmol)，90℃搅拌反应16小时。反应液过滤，滤液经高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:25％-45％,12min)纯化得到化合物16的三氟乙酸盐。
LCMS(ESI)m/z:550.1[M+1] +
1H NMR(400MHz,CD 3OD)δ8.70-8.76(m,1H),8.54(s,1H),8.21(s,1H),8.17(s,1H),8.09(s,1H),7.80(dd,J＝1.52,7.28Hz,1H),7.63-7.71(m,3H),7.60(s,1H),7.11-7.21(m,2H),4.49-4.62(m,1H),4.12(br d,J＝11.04Hz,2H),3.59-3.68(m,2H),3.13(s,3H),2.15(br d,J＝3.76Hz,2H),1.26-1.42(m,2H).
化合物16的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物16。
实施例17
Figure PCTCN2019130053-appb-000083
Figure PCTCN2019130053-appb-000084
步骤一
向3-溴5-硝基-苯酚(3g,13.76mmol)，双联嚬哪醇硼酸酯(4.19g,16.51mmol)的二氧六环(50mL)溶液中加入Pd(dppf)Cl 2(1.01g,1.38mmol)，醋酸钾(2.70g,27.52mmol)。氮气保护下100℃搅拌16小时。反应液抽滤后滤液浓缩得到粗品化合物17a，未纯化直接用于下一步。
步骤二
向化合物1j(3g,9.26mmol)，17a(3.65g,13.77mmol)的二氧六环(5mL)和H 2O(1.5mL)溶液中加入Pd(dppf)Cl 2(677.25mg,925.58μmol)，K 3PO 4(3.93g,18.51mmol)。氮气保护下100℃搅拌16小时。向反应液中加水(100mL)，用乙酸乙酯(100mL*3)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩得粗品。粗品经快速硅胶柱层析(DCM:MeOH＝10:1)纯化得到化合物17b。
LCMS(ESI)m/z:335.9[M+1] +
步骤三
向化合物17b(0.8g,2.39mmol)的DMF(5mL)溶液中加入DIEA(925.05mg,7.16mmol,1.25mL)，N-苯基双(三氟甲烷磺酰)亚胺(1.28g,3.58mmol)。20℃搅拌16小时。反应液加水(50mL)，用乙酸乙酯(20mL*3)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩得粗品。粗品经快速硅胶柱层析(DCM:MeOH＝10:1)纯化得到化合物17c。
LCMS(ESI)m/z:468.0[M+1] +
步骤四
向化合物17c(320mg,684.67μmol)的EtOH(10mL)和水(2mL)溶液中加入氯化铵(366.24mg,6.85mmol)，锌粉(447.71mg,6.85mmol)。25℃搅拌16小时，升至60℃搅拌3小时。反应液直接过滤，滤液减压浓缩得到化合物17d。
LCMS(ESI)m/z:438.0[M+1] +
步骤五
0℃向17d(1.4g,3.20mmol)的吡啶(15mL)溶液中加入甲烷磺酰氯(439.98mg,3.84mmol,297.29μL)，30℃搅拌3小时。0℃下加水(10mL)淬灭，加入乙酸乙酯(20mL*3)萃取，有机相用无水硫酸钠干燥，减压浓缩得粗品，减压浓缩得粗品。粗品经快速硅胶柱层析(DCM:MeOH＝10:1)纯化得到化合物17e。LCMS(ESI)m/z:516.1[M+1] +
步骤六
向17e(0.05g,97.00μmol)，(2-氟-4-甲氧基-苯基)硼酸(19.78mg,116.40μmol)的二氧六环(3mL)和水(1mL)溶液中加Pd(dppf)Cl 2(7.10mg,9.70μmol)，K 3PO 4(41.18mg,194.00μmol)。氮气保护下于微波反应器中100℃搅拌0.5小时。反应液加入硫酸钠干燥，过滤，滤液减压浓缩得粗品。粗品经高效液相色谱(色谱柱:Welch Xtimate C18 150*25mm*5μm；流动相:[水(0.04％氨水)-乙腈]；B(乙腈)％:20％-50％,8.5min)纯化得到化合物17。
LCMS(ESI)m/z:492.1[M+1] +
1H NMR(400MHz,CD 3OD)δ8.54(d,J＝7.04Hz,1H),8.16(s,1H),7.99(s,1H),7.75(s,1H),7.69(s,1H),7.39-7.56(m,4H),7.26(d,J＝7.28Hz,1H),6.71-6.92(m,2H),3.96(s,3H),3.85(s,3H),3.02(s,3H).
实施例18
Figure PCTCN2019130053-appb-000085
步骤一
向17e(100mg,193.99μmol)，双联嚬哪醇硼酸酯(54.19mg,213.39μmol)的二氧六环(2mL)溶液中加入Pd(dppf)Cl 2(14.19mg,19.40μmol)，醋酸钾(38.08mg,387.98μmol)。氮气保护下于微波反应器中100℃搅拌1小时。反应液过滤，滤液减压浓缩得到化合物18a。
LCMS(ESI)m/z:494.2[M+1] +
步骤二
向18a(45mg,91.21μmol)，2-溴吡嗪(14.50mg,91.21μmol)的二氧六环(2mL)和水(0.5mL)溶液中加入Pd(dppf)Cl 2(6.67mg,9.12μmol)，K 3PO 4(38.72mg,182.41μmol)。氮气保护下于微波反应器中100℃搅 拌1小时。反应液抽滤得滤液，滤液减压浓缩得粗品。粗品经高效液相色谱(色谱柱:Boston Green ODS150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:10％-40％,12min)纯化得到化合物18的三氟乙酸盐。
LCMS(ESI)m/z:445.9[M+1] +
1H NMR(400MHz,DMSO-d 6)δ10.37(s,1H),9.34(s,1H),8.78(br s,1H),8.69(s,1H),8.58(s,1H),8.32(s,1H),8.21(br d,J＝12.05Hz,2H),8.14(s,1H),8.08(br s,1H),7.61-7.72(m,2H),7.10-7.27(m,1H),3.92(s,3H),3.33(br s,3H).
化合物18的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物18。
表2中实施例化合物的制备可以参照前述制备实施例18的路线类似的步骤方法进行，不同之处在于在步骤二中使用的原料A代替2-溴吡嗪得到相应化合物的三氟乙酸盐。
表2
Figure PCTCN2019130053-appb-000086
实施例21
Figure PCTCN2019130053-appb-000087
步骤一
向水(30mL)中加入化合物2-氨基-4-甲氧基吡啶(1g,7.24mmol)和盐酸(12M,60.31μL)，在25℃下搅拌2.5小时，再升温到80℃搅拌1.5小时，冷却到25℃后加入碳酸氢钠(972.85mg,11.58mmol)和溴乙醛缩二乙醇(2.85g,14.48mmol)，反应置于25℃搅拌12小时。反应液用乙酸乙酯100毫升*3萃取，有机相用无水硫酸钠干燥，过滤，旋干。经过柱纯化(二氯甲烷:甲醇＝1:0到10：1)得到化合物21a。
LCMS(ESI)m/z:163.2[M+1] +
1H NMR(399MHz,DMSO-d 6)δ8.37-8.39(d,J＝7.2Hz,1H),7.74(s,1H),7.40(s,1H),6.89–6.90(d,J＝2.8Hz,1H),6.59–6.62(m,1H),4.05–4.11(m,2H),1.34–1.37(t,J＝7.0Hz,3H).
步骤二
向无水二氯甲烷(5mL)中加入化合物21a(0.5g,3.08mmol)，N-碘代丁二酰亚胺(762.95mg,3.39mmol)，反应置于25℃反应12小时。，反应液用饱和碳酸氢钠水溶液100mL和二氯甲烷100mL*3萃取，有机相用无水硫酸钠干燥，旋干。经过柱纯化(石油醚:乙酸乙酯＝20:1到3:1)得到化合物21b。
LCMS(ESI)m/z:289.0[M+1] +
1H NMR(400MHz,DMSO-d 6)δ8.15–8.18(m,1H),7.55(s,1H),7.00(s,1H),6.73–6.75(d,J＝7.6Hz,1H),4.08–4.14(m,2H),1.35–1.38(t,J＝7.0Hz,3H).
步骤三
在反应中加入二氧六环(5mL)和水(2mL)，21b(0.01g,34.71μmol)，11f(17.05mg)，无水磷酸钾(14.74mg,69.42μmol)，1,1-双(二苯基磷)二茂铁氯化钯(2.54mg)，反应用氮气置换，在65℃下反应3小时。反应液用水20毫升和二氯甲烷(20毫升*3)萃取，有机相用无水硫酸钠干燥后，过滤，旋干。得到粗品，经制备薄层色谱硅胶板纯化得化合物21。
LCMS(ESI)m/z:444.2[M+1] +
1H NMR(400MHz,DMSO-d 6)δ10.04(s,1H),8.45–8.47(d,J＝7.6Hz,1H),7.46(s,2H),7.43–7.45(m,4H),7.04(s,1H),6.72(s,1H),4.12–4.17(m,2H),3.11(s,1H),1.38(s,3H).
实施例22
Figure PCTCN2019130053-appb-000088
步骤一
0℃将2e(30mg,74.74μmol)的DCM(1mL)溶液中加入DIEA(28.98mg,224.22μmol,39.05μL)，再加入三光气(11.09mg,37.37μmol)，0℃搅拌10分钟，同时另外将3-甲氧基吡咯(7.56mg,54.94μmol,HCl)的DCM(1mL)溶液中加入DIEA(28.98mg,224.22μmol,39.05μL)搅拌10分钟，倒入到上述反应液中，0℃搅拌20分钟。0℃加水(5mL)淬灭反应，再加入DCM(5mL*4)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩得粗品。粗品经制备高效液相色谱分离(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:23％-53％,8min)纯化得化合物22的三氟乙酸盐。
LCMS(ESI)m/z:529.1[M+1] +
1H NMR(400MHz,CD 3OD)δ8.77(d,J＝7.28Hz,1H),8.38(s,1H),8.15(s,1H),8.12(s,1H),8.05(d,J＝0.75Hz,1H),7.97(t,J＝1.76Hz,1H),7.71-7.78(m,2H),7.62(dt,J＝6.40,8.85Hz,1H),7.50(d,J＝1.51Hz,1H),7.05-7.17(m,2H),4.00(s,3H),3.49-3.68(m,5H),3.37(s,3H),1.98-2.22(m,2H).
化合物22的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物22。
实施例23
Figure PCTCN2019130053-appb-000089
Figure PCTCN2019130053-appb-000090
步骤一
将化合物2e(50.00mg,124.56μmol)溶于DCM(1mL)中，加入DIEA(48.29mg,373.68μmol,65.09μL,3eq)，加入三光气(55.44mg,186.84μmol)，0℃搅拌10min，同时将O-甲基羟胺盐酸盐(20.81mg,249.12μmol HCl)溶于DCM(1mL)中加入DIEA(48.29mg,373.68μmol,65.09μL)，0℃搅拌10分钟，再倒入到上述反应液中，0℃搅拌7-10分钟。反应液加入水2mL*2萃取，有机相减压浓缩得粗品。经制备高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:25％-55％,8min)纯化得到化合物23的三氟乙酸盐。
LCMS(ESI)m/z:475.3[M+1] +
1H NMR(400MHz,CD 3OD)δ8.75(d,J＝7.00Hz,1H),8.37(s,1H),8.13(d,J＝12.02Hz,2H),8.06(t,J＝1.74Hz,1H),8.02(s,1H),7.84(d,J＝1.64Hz,1H),7.73(dd,J＝1.70,7.32Hz,1H),7.64(dt,J＝6.50,8.82Hz,1H),7.56(d,J＝1.50Hz,1H),7.04-7.18(m,2H),3.99(s,3H),3.77(s,3H).
化合物23的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物23。
实施例24
Figure PCTCN2019130053-appb-000091
步骤一
将化合物2e(0.03g,74.74μmol)溶于DCM(1mL)中，加入DIEA(28.98mg,224.21μmol,39.05μL)加入三光气(33.27mg,112.10μmol)，0℃搅拌10分钟，同时另外将2-(二甲氨基)乙醇(13.32mg,149.47μmol,15.00μL)溶于DCM(1mL)加入DIEA(28.98mg,224.21μmol,39.05μL)，0℃搅拌10分钟，倒入到上述反应液中，0℃搅拌7-10分钟。反应液加入水2mL*2萃取，有机相减压浓缩得粗品。经制备高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:25％-55％,8min)纯化得到化合物24的三氟乙酸盐。
LCMS(ESI)m/z:517.3[M+1] +
1H NMR(400MHz,CD 3OD)δ8.69(d,J＝7.54Hz,1H),8.34(s,1H),8.12(s,1H),8.05(d,J＝9.80Hz,2H),7.96(s,1H),7.79(s,1H),7.67(br d,J＝7.54Hz,1H),7.55(s,1H),7.35(d,J＝8.28Hz,1H),7.06-7.20(m,2H),4.50-4.61(m,2H),4.00(s,3H),3.50-3.59(m,2H),3.01(s,6H).
化合物24的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物24。
实施例25
Figure PCTCN2019130053-appb-000092
步骤一
将化合物2e(0.04g,99.65μmol)溶于吡啶(3mL)中，缓慢加入用吡啶(3mL)稀释的2-甲氧基-1-乙基磺酰氯(79.02mg,498.24μmol)，25℃下搅拌反应2小时。反应液加水淬灭，加乙酸乙酯10mL*3萃取有机相，有机相减压旋蒸得粗品。粗品经制备高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.1％三氟乙酸)-乙腈]；B(乙腈)％:26％-％,7min)纯化得到化合物25的三氟乙酸盐。
LCMS(ESI)m/z:524.1[M+1] +
1H NMR(400MHz,CD 3OD)δ8.72(d,J＝7.28Hz,1H),8.39(s,1H),8.16(d,J＝2.52Hz,2H),8.07(s,1H),7.77(dd,J＝1.76,7.28Hz,1H),7.73-7.81(m,1H),7.58-7.71(m,4H),7.14(br d,J＝4.02Hz,2H),4.01(s,3H),3.78-3.90(m,2H),3.47(s,2H),3.31(br s,3H).
化合物25的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物25。
实施例26
Figure PCTCN2019130053-appb-000093
步骤一
将化合物2e(0.03g,74.74μmol)溶于DCM(1mL)中，加入DIEA(28.98mg,224.21μmol,39.05μL)，三光气(11.09mg,37.37μmol)，0℃搅拌10分钟；同时另外将氮杂环丁烷(6.99mg,74.74μmol,8.26μL,HCl)溶 于DCM(1mL)中，加入DIEA(28.98mg,224.21μmol,39.05μL,3eq)，0℃搅拌10分钟；倒入到上述反应液中，0℃搅拌7-10分钟。反应液加入水2mL*2萃取，有机相减压浓缩得粗品。反应液加入水2mL*2萃取，有机相减压浓缩得粗品。粗品经制备高效液相色谱(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.1％三氟乙酸)-乙腈]；B(乙腈)％:20％-60％,7min)纯化得到化合物26的三氟乙酸盐。
LCMS(ESI)m/z:485.3[M+1] +
1H NMR(400MHz,CD 3OD)δ8.74(d,J＝7.04Hz,1H),8.36(s,1H),8.14(s,1H),8.08(s,1H),7.95-8.04(m,2H),7.68-7.78(m,2H),7.61(d,J＝6.54Hz,1H),7.47(d,J＝1.24Hz,1H),7.02-7.19(m,2H),4.14(t,J＝7.64Hz,4H),4.00(s,3H),2.34(s,2H).
化合物26的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物26。
表3中实施例化合物的制备可以参照前述制备实施例26的路线类似的步骤方法进行，不同之处在于在步骤六中使用的原料A代替环丁胺得到相应化合物的三氟乙酸盐。
表3
Figure PCTCN2019130053-appb-000094
实施例28
Figure PCTCN2019130053-appb-000095
Figure PCTCN2019130053-appb-000096
步骤一
向1g(6g,30.45mmol)，4-吡唑硼酸嚬哪醇酯(8.86g,45.68mmol)的四氢呋喃(60mL)和水(30mL)溶液中加入Pd(dppf)Cl 2(2.23g,3.05mmol)，磷酸钾(12.93g,60.90mmol)。氮气保护下80℃搅拌16小时。反应液分液，收集有机相，减压浓缩得粗品。将粗品以二氯甲烷/甲醇＝10/1进行过柱(快速硅胶柱层析)纯化得化合物28a。
LCMS(ESI)m/z:184.9[M+1] +
步骤二
向化合物28a(2.5g,13.57mmol)的二氯甲烷(25mL)和DMF(25mL)溶液中加入NIS(3.66g,16.29mmol)，30℃搅拌16小时。向反应液中加入水(50mL)，再加入二氯甲烷(50mL*3)萃取，合并有机相并用油泵减压旋干得化合物28b。
LCMS(ESI)m/z:310.7[M+1] +
步骤三
0℃向化合物28b(2g,6.45mmol)的二氯甲烷(25mL)溶液中加入三乙胺(1.96g,19.35mmol,2.69mL)，MsCl(1.48g,12.90mmol,998.40μL)，30℃搅拌3小时。反应液加水(25mL)，二氯甲烷(25mL*3)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩得粗品，粗品经DCM:MeOH＝25:25打浆处理，抽滤得化合物28c。
LCMS(ESI)m/z:388.8[M+1] +
步骤四
向化合物28c(0.1g,257.61μmol)，11f(137.06mg,334.89μmol)的四氢呋喃(5mL)和水(2.5mL)溶液中加入Pd(dppf)Cl 2(18.85mg,25.76μmol)，硫酸钾(109.36mg,515.22μmol)。氮气保护下90℃搅拌16小时。反应液分层后有机相浓缩得粗品。粗品经制备HPLC(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:25％-55％,7min)纯化得化合物28的三氟乙酸盐。
LCMS(ESI)m/z:544.1[M+1] +
1H NMR(400MHz,CD 3OD)δ9.00(s,1H),8.77(d,J＝7.28Hz,1H),8.54(s,1H),8.26(s,1H),8.23(s,1H),7.86(dd,J＝1.25,7.28Hz,1H),7.56-7.70(m,4H),7.07-7.18(m,2H),3.47-3.59(m,3H),3.05-3.16(m,3H).
化合物28的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物28。
实施例29
Figure PCTCN2019130053-appb-000097
步骤一
将化合物2e(0.15g,373.68μmol)溶于二氯甲烷(10mL)中，降温到0℃加入吡啶(88.67mg,1.12mmol,90.48μL)和甲胺磺酰氯(58.10mg,448.42μmol)，反应在0℃搅拌1小时。向反应液中加入水(100mL)和二氯甲烷(200mL)萃取分液，有机相干燥，过滤浓缩得到粗品。粗品经高效液相色谱纯化(色谱柱:Welch Xtimate C18 100*25mm*3μm；流动相:[水(10mM碳酸氢铵)-乙腈]；B(乙腈)％:27％-57％,10.5min)得到化合物29。
LCMS(ESI)m/z:495.1[M+1] +
1H NMR(399MHz,DMSO-d 6)δ8.53-8.56(m,1H)8.35(s,1H)8.08(s,1H)7.87(s,1H)7.79(s,1H)7.71-7.73(m,2H)7.51-7.56(m,2H)7.49(s,1H)7.41(s,1H)7.33(s,1H)7.23-7.28(m,2H)3.86-3.91(m,3H)3.28-3.32(m,3H).
实施例30
Figure PCTCN2019130053-appb-000098
Figure PCTCN2019130053-appb-000099
步骤一
将3-溴-5-硝基-苯酚(20g,91.74mmol)和双联嚬哪醇硼酸酯(25.63g,100.92mmol)溶于二氧六环(200mL)中，加入KOAc(18.01g,183.48mmol)和Pd(dppf)Cl 2(3.36g,4.59mmol)，氮气保护下90℃搅拌16小时。反应液直接垫硅藻土过滤，用乙酸乙酯洗两次，收集滤液旋干得粗品,将粗品以PE/EA＝5/1进行过柱纯化得到化合物30a。
1H NMR(400MHz,CDCl 3)δ8.17(d,J＝1.52Hz,1H),7.76(t,J＝2.26Hz,1H),7.57(d,J＝2.02Hz,1H),7.00(br s,1H),1.35(s,12H).
步骤二
向化合物30a(3g,11.32mmol)和二甲基叔丁基氯硅烷(2.05g,13.58mmol,1.66mL)溶于DMF(30mL)中，加入咪唑(1.93g,28.29mmol)和DMAP(138.27mg,1.13mmol)，室温下30℃搅拌反应16小时。反应液加水3mL萃取，收集有机相，无水硫酸钠干燥，旋干得粗品。不做纯化直接得到化合物30b。
1H NMR(400MHz,DMSO-d 6)δ8.01(d,J＝1.24Hz,1H),7.69(t,J＝2.12Hz,1H),7.45(d,J＝1.52Hz,1H),1.32(s,12H),0.98(s,9H),0.24(s,6H).
步骤三
将化合物30b(2.8g,7.38mmol)溶于乙醇(120mL)和水(20mL)中，加入氯化铵(3.95g,73.81mmol)和锌粉(4.83g,73.81mmol)，室温30℃下搅拌反应16小时。反应液直接过滤，用无水乙醇洗两次，滤液旋干得粗品。将粗品以PE/EA＝5/1进行过柱纯化得到化合物30c。
LCMS(ESI)m/z:350.0[M+1] +
步骤四
将化合物30c(1.9g,5.44mmol)溶于吡啶(5mL)中，加入环丙磺酰氯(917.55mg,6.53mmol)，30℃下搅拌反应16小时。反应液加水10mL和乙酸乙酯15mL萃取，有机相再用水10mL洗两次，无水硫酸钠干燥，旋干得粗品。将粗品以PE/EA＝5/1～1/1进行过柱纯化得到化合物30d。
LCMS(ESI)m/z:454.1[M+1] +
步骤五
向化合物30d(2.85g,6.28mmol)，化合物1j(1.36g,4.19mmol)的二氧六环(30mL)和H 2O(10mL)的溶液中加入Pd(dppf)Cl 2(306.58mg,418.99μmol)，硫酸钾(1.78g,8.38mmol)。氮气保护下100℃搅拌16小时。反应液加水(80mL)，加入乙酸乙酯(50mL*3)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩得粗品。将粗品以DCM/MeOH＝20/1进行过柱纯化得到化合物30e。
LCMS(ESI)m/z:410.1[M+1] +
步骤六
向化合物30e(870mg,2.12mmol)的DMF(9mL)溶液中加入DIEA(823.83mg,6.37mmol)，N-苯基双(三氟甲烷磺酰)亚胺(1.14g,3.19mmol)，20℃搅拌16小时。反应液中加入水(20mL)，加入乙酸乙酯(20mL*3)萃取，合并有机相并用水洗(50mL*3)，有机相再用无水硫酸钠干燥，减压浓缩得粗品。将粗品以DCM/MeOH＝20/1进行过柱纯化得到化合物30f。
LCMS(ESI)m/z:542.1[M+1] +
步骤七
向化合物30f(100mg,184.66μmol)，双联频哪醇硼酸酯(56.27mg,221.60μmol)的二氧六环(3mL)溶液中加入Pd(dppf)Cl 2(13.51mg,18.47μmol)，KOAc(36.25mg,369.33μmol)。氮气保护下90℃搅拌16小时。反应液浓缩得化合物30g。
LCMS(ESI)m/z:520.1[M+1] +
步骤八
向化合物30g(95mg,182.90μmol)，2-溴3,5-二氟吡啶(40mg,206.21μmol)的二氧六环(3mL)和H 2O(1mL)溶液中加入Pd(dppf)Cl 2(15.09mg,20.62μmol)，磷酸钾(87.54mg,412.42μmol,2eq)。氮气保护下100℃搅拌3小时。反应液直接干燥，滤液减压浓缩得粗品。粗品经制备薄层色谱硅胶板分离(DCM:MeOH＝10:1)得粗品，粗品再经制备高效液相色谱纯化(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:20％-50％,7min)得化合物30的三氟乙酸盐。
LCMS(ESI)m/z:507.1[M+1] +
1H NMR(400MHz,CD 3OD)δ8.73(d,J＝7.03Hz,1H),8.56(d,J＝2.26Hz,1H),8.39(s,1H),8.17(d,J＝5.52Hz,2H),7.99-8.09(m,3H),7.74-7.82(m,3H),4.00(s,3H),2.68-2.80(m,1H),1.09-1.19(m,2H),0.99-1.07(m,2H).化合物30的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得 到化合物30。
实施例31
Figure PCTCN2019130053-appb-000100
步骤一
将化合物33c(20g,57.25mmol,1eq)和乙磺酰氯(8.83g,68.70mmol)溶于吡啶(80mL)中，室温25℃搅拌反应16小时，反应液加水100mL和乙酸乙酯100mL*3萃取3次，有机相用无水硫酸钠干燥，旋干得粗品，将粗品以PE/EA＝5/1进行过柱纯化，所得粗品旋干后用石油醚25℃打浆2小时，得到化合31a。
LCMS(ESI)m/z:442.2[M+1] +
1H NMR(400MHz,DMSO-d 6):δ9.68-9.78(m,1H),7.14(d,J＝1.52Hz,1H),6.94(t,J＝2.12Hz,1H),6.82(d,J＝1.86Hz,1H),3.05(q,J＝7.32Hz,2H),1.29(s,12H),1.17(t,J＝7.40Hz,3H),0.95(s,9H),0.16-0.20(m,6H).步骤二
将化合物31a(11g,24.92mmol)和化合物1j(6.73g,20.76mmol)溶于二氧六环(100mL)和H 2O(50mL)中，加入Pd(dppf)Cl 2(1.52g,2.08mmol)和硫酸钾(8.82g,41.53mmol)，氮气保护下90℃搅拌反应16小时，反应液加水100mL和乙酸乙酯100mL*2萃取，有机相用无水硫酸钠干燥，旋干得粗品，将粗品以DCM/MeOH＝20/1进行过柱纯化得到化合物31b。
LCMS(ESI)m/z:398.0[M+1] +
步骤三
将化合物31b(2.6g,6.54mmol)和N-苯基双(三氟甲烷磺酰)亚胺(3.51g,9.81mmol)溶于DMF(20mL)中，加入DIEA(3.38g,26.17mmol,4.56mL)，室温25℃下搅拌16小时。反应液中加入水(20mL)，加入乙酸乙酯(50mL*3)萃取，合并有机相并用水洗(50mL*3)，有机相用无水硫酸钠干燥，旋干得粗品。将粗品以DCM/MeOH＝20/1进行过柱纯化得到化合物31c。
LCMS(ESI)m/z:530.3[M+1] +
步骤四
将化合物31c(2.6g,4.91mmol)和双联嚬哪醇硼酸酯(1.50g,5.89mmol)溶于二氧六环(1.5mL)中，加入Pd(dppf)Cl 2(359.28mg,491.02μmol)和KOAc(963.79mg,9.82mmol)，氮气保护下90℃搅拌反应16小时。反应液直接用于下一步反应。最终得到化合物31d。
LCMS(ESI)m/z:508.2[M+1] +
步骤五
将化合物31d(2.2g,4.34mmol)和2-溴3,5-二氟吡啶(1.68g,8.67mmol)溶于二氧六环(1.5mL)和H 2O(0.5mL)中，加入Pd(dppf)Cl 2(317.25mg,433.57μmol)和硫酸钾(1.84g,8.67mmol)，氮气保护下100℃搅拌反应3小时。反应液加入无水硫酸钠干燥，过滤，滤液旋干得粗品。粗品以DCM/MeOH＝20/1进行过柱纯化得粗产物，再经制备高效液相色谱(色谱柱:Welch Xtimate C18 100*40mm*3μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:15％-45％,7min)纯化得化合物31的三氟乙酸盐。
LCMS(ESI)m/z:495.0[M+1] +
1H NMR(400MHz,CD 3OD):δ8.72(d,J＝7.34Hz,1H),8.52-8.59(m,1H),8.34-8.44(m,1H),8.17(d,J＝7.56Hz,2H),8.08(s,1H),7.98(s,2H),7.69-7.84(m,3H),4.01(s,3H),3.27(q,J＝7.38Hz,2H),1.39(t,J＝7.44Hz,3H).化合物31的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物31。
实施例32
Figure PCTCN2019130053-appb-000101
Figure PCTCN2019130053-appb-000102
步骤一
向2-溴-3,5-二氟-吡啶(4g,20.62mmol)，30a(6.01g,22.68mmol)的二氧六环(40mL)和水(10mL)溶液中加入Pd(dppf)Cl 2(1.51g,2.06mmol,0.1eq)，磷酸钾(8.75g,41.24mmol,2eq)。氮气保护下100℃搅拌16小时。反应液加水(100mL)，加乙酸乙酯(100mL*3)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩得粗品。将粗品以PE/EA＝10/1进行过柱纯化得到化合物32a。
LCMS(ESI)m/z:252.9[M+1] +
步骤二
向化合物32a(3.85g,15.27mmol)的DMF(50mL)溶液中加入DIEA(5.92g,45.80mmol,7.98mL)，再加入N-苯基双(三氟甲烷磺酰)亚胺(8.18g,22.90mmol)，20℃搅拌16小时。反应液加水(200mL)，加入乙酸乙酯(200mL*3)萃取，合并有机相加水反洗(300mL*3)，饱和氯化钠水溶液洗(300mL)，收集有机相并用无水硫酸钠干燥，减压浓缩得粗品32b。
LCMS(ESI)m/z:384.8[M+1] +
步骤三
将化合物32b(13g,33.83mmol)溶于乙醇(130mL)和水(13mL)中，加入氯化铵(18.10g,338.33mmol)和锌粉(22.12g,338.33mmol)，室温20℃搅拌反应16小时。反应液直接过滤，滤液旋干得粗品，不做纯化得到化合物32c。
LCMS(ESI)m/z:354.8[M+1] +
步骤四
将化合物32c(5g,14.11mmol)溶于吡啶(25mL)中，滴加甲烷磺酰氯(2.43g,21.17mmol,1.64mL)，室温20℃搅拌反应16小时。反应液加水50mL淬灭，加乙酸乙酯50mL*2萃取，再用水50mL*3洗涤，有机相用无水硫酸钠干燥，旋干得粗品,将粗品以PE/EA＝5/1进行过柱纯化,得到化合物32d。
LCMS(ESI)m/z:432.9[M+1] +
步骤五
将化合物32d(2.3g,5.32mmol)和双联嚬哪醇硼酸酯(2.03g,7.98mmol)溶于二氧六环(20mL)中，加入Pd(dppf)Cl 2(389.26mg,531.99μmol)和KOAc(1.04g,10.64mmol)，氮气保护下90℃搅拌反应16小时。反应液直接过滤，滤液浓缩得粗品,粗品以PE/EA＝5/1进行过柱纯化得到化合物32e。
LCMS(ESI)m/z:411.0[M+1] +
步骤六
将1g(50mg,154.26μmol)和化合物32e(94.93mg,231.39μmol)溶于二氧六环(2mL)和H 2O(0.5mL)中，加入Pd(dppf)Cl 2(11.29mg,15.43μmol)和硫酸钾(65.49mg,308.52μmol)，氮气保护下90℃搅拌反应16小时。反应液加入水3mL和乙酸乙酯5mL萃取，有机相旋干得粗品，粗品再经制备高效液相色谱纯化(色谱柱:Boston Green ODS 150*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:20％-50％,7min)纯化得到化合物32的三氟乙酸盐。
LCMS(ESI)m/z:480.9[M+1] +
1H NMR(400MHz,CD 3OD):δ8.71-8.76(m,1H),8.54-8.57(m,1H),8.38-8.41(m,1H),8.17-8.21(m,1H),8.16(s,1H),8.08(s,1H),7.97-8.03(m,2H),7.70-7.81(m,3H),4.01(s,3H),3.13(s,3H).
化合物32的三氟乙酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物32。
实施例33
Figure PCTCN2019130053-appb-000103
步骤一
向化合物16c(50mg,107.42μmol)的DMF(2mL)溶液中加入3-溴丙烷-1,2-二醇(83.24mg,537.09μmol,47.03μL)，碳酸铯(105.00mg,322.25μmol)。80℃搅拌16小时。补加3-溴丙烷-1,2-二醇(83.24mg,537.09μmol,47.03μL)，碳酸铯(50mg)，升温至100℃搅拌16小时。反应液直接过滤，收集滤液。滤液 经制备高效液相色谱分离(column:Phenomenex Gemini-NX 80*40mm*3μm；mobile phase:[水(0.05％氨水+10mM碳酸氢铵)-乙腈]；B(乙腈)％:18％-48％,8min)后得到化合物33。
LCMS(ESI)m/z:540.1[M+1] +
1H NMR(400MHz,CD 3OD)δ8.54(d,J＝7.28Hz,1H),8.21(s,1H),8.02(s,1H),7.77(s,1H),7.72(s,1H),7.58-7.68(m,1H),7.54(dd,J＝1.64,4.90Hz,2H),7.47(d,J＝1.52Hz,1H),7.29(dd,J＝1.76,7.28Hz,1H),7.05-7.18(m,2H),4.37(dd,J＝4.02,14.06Hz,1H),4.16-4.24(m,1H),3.98-4.10(m,1H),3.52-3.58(m,2H),3.08(s,3H)
生物测试数据：
实验例1：本发明化合物的体外酶活性测试
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、VEGFR2的抑制能力。
缓冲液条件：20mM Hepes(4-羟乙基哌嗪乙磺酸)(pH 7.5),10mM MgCl 2,1mM EGTA(乙二醇双(2-氨基乙基醚)四乙酸),0.02％BriJ35(表面活性剂),0.02mg/ml BSA(牛血清白蛋白),0.1mM Na 3VO 4,2mM 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,2.50μM,0.62μM,0.156μM,39.1nM,9.8nM,2.4nM,0.61nM,0.15nM,0.038nM或3μM,1μM,0.333μM,0.111μM,37.0nM,12.3nM,4.12nM,1.37nM,0.457nM,0.152nM。孵化15分钟后，加入 33P-ATP(活度0.01μCi/μl，相应浓度列在表4中)开始反应。FGFR1、FGFR4、KDR和在反应液中的浓度信息列在表2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IC 50值，实验结果如表5所示。
表4：体外测试中激酶、底物和ATP的相关信息。
Figure PCTCN2019130053-appb-000104
Figure PCTCN2019130053-appb-000105
表5 本发明化合物激酶活性IC 50测试结果
Figure PCTCN2019130053-appb-000106
Figure PCTCN2019130053-appb-000107
Figure PCTCN2019130053-appb-000108
N/A：未检测。
结论：本发明的化合物具有优异的FGFR1,FGFR2,FGFR4,VEGFR2激酶抑制活性。
实验例2：本发明化合物的动力学溶解度数据测试
动力学溶解度样品先过滤采样。最终样品中含2％DMSO。通过紫外测定，并通过3条标准曲线(1、20、200μM)进行校准。K.S.摇动时间：室温下24小时。
表6 本发明化合物动力学溶解度数据
Figure PCTCN2019130053-appb-000109
Figure PCTCN2019130053-appb-000110
结论：本发明的化合物具有优异的溶解度(pH 2.0)，成药性质提高。
实验例3：本发明化合物的胃癌细胞系SNU-16细胞活性测试
实验目的
测试化合物对FGFR2表达的人胃癌SNU-16细胞的增殖抑制作用。
实验方法
测试所用化合物进行3倍浓度稀释，浓度为从10μM，3倍系列稀释液开始，9个浓度，10μM,2.50μM,0.62μM,0.156μM,39.1nM,9.8nM,2.4nM,0.61nM,0.15nM。
仪器
(1)Promega CellTiter-Glo发光细胞活力测定试剂盒(Promega-G7573)。
(2)2104EnVision多标签阅读器，PerkinElmer。
结果分析：被测化合物的抑制率(IR)由下式确定：IR(％)＝(1–(RLU化合物–RLU空白)/(RLU对照–RLU空白))*100％。将在Excel文件中计算不同剂量化合物的抑制率，参数曲线拟合(GraphPad Software)得到化合物IC 50数据。
表7 本发明化合物激酶活性IC 50测试结果
  SNU-16IC 50(nM)
对照例1的三氟乙酸盐 66
化合物2的三氟乙酸盐 11
化合物6 11
化合物10 23
化合物30的三氟乙酸盐 18
化合物31的三氟乙酸盐 10
结论：本发明化合物相比对照例具有更优异SNU-16细胞活性(3-5倍)。
实验例4：在体内动物肿瘤模型上的抗肿瘤活性测试
实验目的
在小鼠人胃癌SNU-16皮下异种移植肿瘤模型该发明化合物的抑瘤效果
实验方法：
1)肿瘤组织准备
肿瘤组织准备：在5％CO 2、37℃、饱和湿度条件下，SNU-16细胞在含10％胎牛血清的RPMI-1640培养基中进行常规细胞培养。根据细胞生长情况，每周传代或补液1到2次，传代比例1:3到1:4
2)组织接种及分组
收取对数生长期SNU-16细胞，细胞计数后重悬于于50％不含血清的RPMI-1640培养基及50％Matrigel中，调整细胞浓度至4×10 7细胞/mL；将细胞置于冰盒中，用1mL注射器吸取细胞悬液，注射到裸鼠前右侧腋窝皮下，每只动物接种200μL(8×10 6细胞/只)，建立SNU-16移植瘤模型。定期观察动物状态，使用电子游标卡尺测量瘤径，数据输入Excel电子表格，计算肿瘤体积，监测肿瘤生长情况。待瘤体积达到100～300mm 3，挑选健康状况良好、肿瘤体积相近的荷瘤鼠60只(肿瘤体积104～179mm 3)，采用随机区组法分为10(n＝6)，每组平均肿瘤体积约143mm 3。
3)每周测量2次瘤径，计算肿瘤体积，同时称量动物体重并记录。
肿瘤体积(TV)计算公式如下：TV(mm 3)＝l×w 2/2其中，l表示肿瘤长径(mm)；w表示肿瘤短径(mm)。
化合物的抑瘤疗效用TGI(％)或相对肿瘤增殖率T/C(％)评价。相对肿瘤增殖率T/C(％)＝T RTV/C RTV×100％(T RTV：治疗组平均RTV；C RTV：阴性对照组平均RTV)。根据肿瘤测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为RTV＝V t/V 0，其中V 0是分组给药时(即D0)测量所得肿瘤体积，V t为对应小鼠某一次测量时的肿瘤体积，T RTV与C RTV取同一天数据。
TGI(％)，反映肿瘤生长抑制率。TGI(％)＝[(1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积))/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。
实验结果：
在小鼠胃癌SNU-16模型上，连续给药25天，与溶媒组相比，本发明化合物表现出了显著的抗肿瘤活性，肿瘤生长抑制率(％TGI)分别为：76％,80％,76％，相对肿瘤增值率(％T/C)为：34％，33％，35％，相比对照例1，本发明化合物展示了更优的抑制效果。具体结果见表8、附图1和附图2(附图中QD表示一天一次)。
表8 SNU-16肿瘤生长抑制率和相对肿瘤增殖率汇总表
Figure PCTCN2019130053-appb-000111
*所有给药组，第9天给药剂量变更为30mg/kg/天，第12天给药剂量均变更为20mg/kg/天。
实验结论：本发明化合物在临床前动物模型中在较低的剂量下展示了优异的肿瘤治疗效果。

Claims (21)

  1. 式(III)所示化合物或其药学上可接受的盐，
    Figure PCTCN2019130053-appb-100001
    其中，
    R 1选自H、-S(＝O) 2CH 3、C 1-6烷基、C 1-3烷氧基、四氢吡喃基、四氢呋喃基和哌啶基，所述C 1-6烷基、C 1-3烷氧基、四氢吡喃基、四氢呋喃基和哌啶基任选被1、2或3个R a取代；
    R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CH 3和OCH 3；
    R 4选自H、NH 2、C 1-6烷基、C 1-3烷氧基、C 3-5环烷基和
    Figure PCTCN2019130053-appb-100002
    所述C 1-6烷基、C 1-3烷氧基、C 3-5环烷基和
    Figure PCTCN2019130053-appb-100003
    任选被1、2或3个R b取代；
    m选自1和2；
    L选自-N(R 5)C(＝O)-、-N(R 5)S(＝O) 2-、-N(R 5)C(＝O)N(R 5)-、N(R 5)S(＝O) 2N(R 5)-和-N(R 5)-；
    环A选自苯基、吡咯基、嘧啶基和吡啶基；
    环B不存在；
    或者，环B选自咪唑基、吡唑基、三氮唑基、哌啶基、吗啉基、四氢吡喃基和3,6-二氢-2H-吡喃基；
    R 5分别独立地选自H和C 1-3烷基；
    R a和R b分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、-S(＝O) 2CH 3、C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基，所述-S(＝O) 2CH 3、C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基任选被1、2或3个R取代；
    R选自H、F、Cl、Br、I、OH和NH 2。
  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 a和R b分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、-S(＝O) 2CH 3、CH 3、-OCH 3、-N(CH 3) 2和-NHCH(CH 3) 2，所述-S(＝O) 2CH 3、CH 3、-OCH 3、-N(CH 3) 2和-NHCH(CH 3) 2任选被1、2或3个R取代。
  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 a和R b分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2OH、-OCH 3、-S(＝O) 2CH 3、-N(CH 3) 2和-NHCH(CH 3) 2。
  4. 根据权利要求1～3任意一项所述化合物或其药学上可接受的盐，其中，R 1选自H、-S(＝O) 2CH 3、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH 2CH(CH 3) 2、OCH 2CH 3、四氢吡喃基、四氢呋喃基和哌啶基，所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH 2CH(CH 3) 2、OCH 2CH 3、四氢吡喃基、四氢呋喃基和哌啶基任选被1、2或3个R a取代。
  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 1选自H、-S(＝O) 2CH 3、CH 3、CH 2OH、CH 2CH 3、CH 2CH 2OH、OCH 2CH 3、
    Figure PCTCN2019130053-appb-100004
    Figure PCTCN2019130053-appb-100005
  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、NH 2、CH 3、CH 2CH 3、CH(CH 3) 2、C(CH 3) 3、CH 2CH 2CH 3、OCH 3、OCH 2CH 3、环丙烷基、氮杂环丁烷和吡咯烷基，所述CH 3、CH 2CH 3、CH(CH 3) 2、C(CH 3) 3、CH 2CH 2CH 3、OCH 3、OCH 2CH 3、环丙烷基、氮杂环丁烷和吡咯烷基任选被1、2或3个R b取代。
  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、NH 2、CH 3、CH 2CH 3、CH(CH 3) 2、C(CH 3) 3、CH 2CH 2CH 3、CH 2CH 2N(CH 3) 2、OCH 3、
    Figure PCTCN2019130053-appb-100006
    Figure PCTCN2019130053-appb-100007
  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分别独立地选自H、CH 3和CH 2CH 3。
  9. 根据权利要求7所述化合物或其药学上可接受的盐，其中，L选自-NHC(＝O)-、-NHC(＝O)NH-、-NHS(＝O) 2-、-NHS(＝O) 2NH-和-NH-。
  10. 根据权利要求7或9所述化合物或其药学上可接受的盐，其中，-L-R 4选自
    Figure PCTCN2019130053-appb-100008
    Figure PCTCN2019130053-appb-100009
  11. 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，环A选自
    Figure PCTCN2019130053-appb-100010
    Figure PCTCN2019130053-appb-100011
  12. 根据权利要求11所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019130053-appb-100012
    选自
    Figure PCTCN2019130053-appb-100013
    Figure PCTCN2019130053-appb-100014
  13. 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，环B选自
    Figure PCTCN2019130053-appb-100015
    Figure PCTCN2019130053-appb-100016
  14. 根据权利要求13所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019130053-appb-100017
    选自
    Figure PCTCN2019130053-appb-100018
    Figure PCTCN2019130053-appb-100019
  15. 根据权利要求5或13所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2019130053-appb-100020
    选自OCH 2CH 3、
    Figure PCTCN2019130053-appb-100021
  16. 根据权利要求1～6任意一项所述化合物或其药学上可接受的盐，其选自
    Figure PCTCN2019130053-appb-100022
    其中，
    T 1选自CH和N；
    R 2和R 3如权利要求1所定义；
    R 1如权利要求1、4或5所定义；
    R 4如权利要求1、6或7所定义；
    L如权利要求1或9所定义。
  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 PCTCN2019130053-appb-100023
    Figure PCTCN2019130053-appb-100024
    其中，
    T 1选自CH和N；
    R 1、R 2、R 3和R 4如权利要求16所定义。
  18. 下式所示化合物或其药学上可接受的盐，
    Figure PCTCN2019130053-appb-100025
    Figure PCTCN2019130053-appb-100026
    Figure PCTCN2019130053-appb-100027
  19. 一种药物组合物，包括治疗有效量的根据权利要求1～18任意一项所述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
  20. 根据权利要求1～18任意一项所述的化合物或其药学上可接受的盐或者权利要求19所述的组合物在制备FGFR和VEGFR双重抑制剂相关药物上的应用。
  21. 根据权利要求20所述的应用，其特征在于，所述FGFR和VEGFR双重抑制剂相关药物是用于实体瘤的药物。
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CN116783192B (zh) * 2021-01-26 2025-10-31 盛世泰科生物医药技术(苏州)股份有限公司 甲基吡唑取代的吡啶并咪唑类化合物的晶型及其制备方法
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