WO2021018047A1 - 作为fgfr和vegfr双重抑制剂的吡啶衍生物 - Google Patents

作为fgfr和vegfr双重抑制剂的吡啶衍生物 Download PDF

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WO2021018047A1
WO2021018047A1 PCT/CN2020/104550 CN2020104550W WO2021018047A1 WO 2021018047 A1 WO2021018047 A1 WO 2021018047A1 CN 2020104550 W CN2020104550 W CN 2020104550W WO 2021018047 A1 WO2021018047 A1 WO 2021018047A1
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compound
pharmaceutically acceptable
acceptable salt
present
acid
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PCT/CN2020/104550
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English (en)
French (fr)
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陈正霞
戴美碧
张杨
陈曙辉
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南京明德新药研发有限公司
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Priority to US17/629,566 priority Critical patent/US20220267324A1/en
Priority to KR1020227006643A priority patent/KR20220052939A/ko
Priority to EP20847841.2A priority patent/EP4006027A4/en
Priority to JP2022505380A priority patent/JP7300057B2/ja
Priority to CN202080047757.XA priority patent/CN114072402B/zh
Priority to AU2020320997A priority patent/AU2020320997B2/en
Priority to CA3145680A priority patent/CA3145680C/en
Publication of WO2021018047A1 publication Critical patent/WO2021018047A1/zh

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    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a dual inhibitor of FGFR and VEGFR, in particular to a compound represented by formula (I) or a pharmaceutically acceptable salt.
  • Fibroblast growth factor receptor is a type of receptor protein that specifically binds to fibroblast growth factor (FGF).
  • the FGFRs family includes the following types: FGFR1b, FGFR1c, FGFR2b, FGFR2c, FGFR3b, FGFR3c, FGFR4 .
  • Fibroblast growth factor receptor (FGFR) is a class of biologically active substances with the functions of transmitting biological signals, regulating cell growth, and participating in tissue repair. It is clinically found that FGFR high expression, mutation or fusion and other abnormalities can cause tumor occurrence and development, such as liver cancer, bladder cancer, lung cancer, breast cancer and other diseases.
  • FGFR binds to the ligand FGF, leading to autophosphorylation of multiple tyrosine residues in the cell, and downstream signal transmission, including MEK/MAPK, PLCy/PKC, PI3K/AKT, STATS, etc. Therefore, FGFR is considered to be an important anti-tumor target.
  • VEGFR-2 is an important regulator of VEGF signal transduction that causes endothelial cell proliferation, increases vascular permeability and promotes angiogenesis, and the affinity of VEGFR-2 and VEGF is greater than 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-angiogenesis drugs.
  • VEGFR and FGFR pathways work together to complete the activation and production of endothelial cells in angiogenesis.
  • VEGF requires the presence of FGF to play its role in promoting angiogenesis.
  • the synergistic effect of FGFR and VEGFR pathways can also inhibit tumor immune escape and improve tumor suppression effect.
  • 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 each 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, the C 1-6 alkyl and C 3-5 cycloalkyl are optionally substituted with 1, 2 or 3 R b ;
  • R 5 is each independently selected from H and C 1-3 alkyl
  • Ring B is selected from 5-6 membered heteroaryl groups
  • R a and R b are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and CH 3 ;
  • the 5-6 membered heteroaryl group contains 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-mentioned R 4 is selected from H, cyclopropyl, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 and CH 2 CH 2 CH 3 , and 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 , and other variables are as described in the present 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 , and 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 aforementioned ring B is selected from imidazolyl and pyrazolyl, 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 each independently selected from H, F, Cl, Br, I, OH, NH 2 and CH 3 ;
  • R 4 is selected from H, C 1-6 alkyl, C 1-3 alkoxy, C 3-5 cycloalkyl, tetrahydropyranyl and 1,3-dioxolane, said C 1- 6 alkyl, C 1-3 alkoxy, C 3-5 cycloalkyl, tetrahydropyranyl and 1,3-dioxolanyl are optionally substituted with 1, 2 or 3 R b ;
  • R 5 is each independently selected from H and C 1-3 alkyl
  • Ring B is selected from pyrazolyl and imidazolyl, which are optionally substituted by 1 or 2 R 6 ;
  • R 6 is selected from H and C 1-3 alkyl
  • R a and R b are each 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 , 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-mentioned R 4 is selected from H, cyclopropyl, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CH 2 CH 3 , CH 2 CH (CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , tetrahydropyranyl and 1,3-dioxolanyl, the cyclopropanyl group, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , tetrahydropyranyl and 1,3-dioxolanyl are optionally selected 1, 2 or 3 R b is substituted, and other variables are as defined in the present invention.
  • R 4 is selected from H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CH 2 CH 3 , OCH 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
  • the aforementioned ring B is selected from Said Optionally substituted by 1 or 2 R 6 and 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 (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 each independently selected from H, F, Cl, Br, I, OH, NH 2 and CH 3 ;
  • R 4 is selected from H, C 1-6 alkyl, C 1-3 alkoxy, C 3-5 cycloalkyl, tetrahydropyranyl and 1,3-dioxolane, said C 1- 6 alkyl, C 1-3 alkoxy, C 3-5 cycloalkyl, tetrahydropyranyl and 1,3-dioxolanyl are optionally substituted with 1, 2 or 3 R b ;
  • R 5 is each independently selected from H and C 1-3 alkyl
  • Ring B is selected from pyrazolyl and imidazolyl, which are optionally substituted by 1 or 2 R 6 ;
  • R 6 is selected from H and C 1-3 alkyl
  • R a and R b are each 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 , 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-mentioned R 4 is selected from H, cyclopropyl, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CH 2 CH 3 , CH 2 CH (CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , tetrahydropyranyl and 1,3-dioxolanyl, the cyclopropanyl group, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , tetrahydropyranyl and 1,3-dioxolanyl are optionally selected 1, 2 or 3 R b is substituted, and other variables are as defined in the present invention.
  • R 4 is selected from H, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , CH 2 CH 2 CH 3 , OCH 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 Said Optionally substituted by 1 or 2 R 6 and 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 above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
  • R 1 , R 2 , R 3 , L and R 4 are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
  • R 1 , R 2 , R 3 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 application of the above-mentioned compound or its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in the preparation of FGFR and VEGFR dual inhibitor related drugs.
  • the above-mentioned application wherein the FGFR and VEGFR dual inhibitor-related drugs are drugs for solid tumors.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • the base addition salt can be obtained by contacting the neutral form of the compound 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.
  • the acid addition salt can be obtained by contacting the neutral form of the compound 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, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds provided by the present invention also exist in prodrug forms.
  • the prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform into the compounds of the invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in the in vivo environment.
  • Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated form is equivalent to the unsolvated form, and both are 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 you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have reduced toxic side effects and increased drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • oxygen it means that two hydrogen atoms are replaced. Oxygen substitution will not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • any variable such as R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in 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.
  • substituents When a substituent is vacant, it means that the substituent is absent. For example, when X in AX is vacant, it means that the structure is actually A.
  • substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
  • a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
  • the middle linking group L is -MW-, at this time -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 direction opposite to the reading order from left to right Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
  • 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.; it may Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • C 1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
  • 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 can be monovalent (such as methyl), divalent (such as methylene) or multivalent (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 attached to the rest of the molecule through an 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 include but are not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy) and the like.
  • C 3-5 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 5 carbon atoms, which is a monocyclic ring system, and the C 3-5 cycloalkyl includes C 3 -4 and C 4-5 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C 3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and the like.
  • 5-6 membered heteroaryl ring and “5-6 membered heteroaryl group” can be used interchangeably in the present invention.
  • the term “5-6 membered heteroaryl group” means a ring consisting of 5 to 6 ring atoms. It is composed of a monocyclic group with a conjugated ⁇ -electron system, in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the 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, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) Azolyl, 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-
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (for example, an affinity substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes but is not limited to "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethyls
  • hydroxy protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
  • 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 groups 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 (P
  • 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 combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the compound of the present invention has excellent FGFRs and VEGFR2 kinase activity; the introduction of the aromatic ring nitrogen heteroatom in the compound of the present invention unexpectedly found that this change can significantly improve the metabolic stability of the compound in vivo, and greatly increase the oral absorption of the drug. It is possible to show a better therapeutic effect clinically; the compound of the present invention shows an excellent tumor therapeutic effect.
  • Figure 1 Tumor volume growth curve of each group during the administration period
  • Figure 2 The body weight change curve of each group during the administration period.
  • cyclopropylsulfonyl chloride (1.66 g, 11.78 mmol) was added to the suspension of compound c (4.5 g, 10.71 mmol) in pyridine (30 mL), and the mixture was stirred at 20°C for 2 hours.
  • Acetic acid (34.6 mL) was added to the reaction solution, then water (250 mL) was added, ethyl acetate (150 mL*2) was added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound d.
  • the crude product was subjected to high performance liquid chromatography (column: YMC-Triart Prep C18 150*40mm*7 ⁇ m; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 35%-50%, 10min )
  • To obtain the trifluoroacetate salt of compound A The trifluoroacetate salt of compound A 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 compound A.
  • the synthesis method is the same as that of Comparative Example 1.
  • Methanesulfonamide replaces cyclopropylsulfonamide to obtain the trifluoroacetate salt of compound B.
  • the trifluoroacetate of compound B 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 compound B.
  • the crude product was separated by preparative HPLC (chromatographic column: Welch Xtimate C18 150*25mm*5 ⁇ m; mobile phase: [water (0.225% formic acid)-acetonitrile]; B (acetonitrile)%: 15%-45%, 8.5min) to obtain The formate salt of compound C.
  • the formate of compound C 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 compound C.
  • Chloroacetaldehyde (8.51g, 43.35mmol, 6.97mL) was added dropwise to 4-bromo-2-aminopyridine (5g, 28.90mmol) in EtOH (60mL) and stirred at 80°C for 16 hours. The reaction solution was spin-dried under reduced pressure to obtain the crude compound 1a.
  • the crude product was separated by high performance liquid chromatography (column: Boston Green ODS 150mm*30mm*5 ⁇ m; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 32%-52%, 12min)
  • the compound 1 was purified to obtain the trifluoroacetate salt.
  • the trifluoroacetate salt of compound 1 is added to sodium bicarbonate solution, extracted with ethyl acetate, the organic phase is dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 1.
  • the preparation of compound 2 in Table 1 refers to the route of compound 1, except that the raw material used in step 6 replaces 2,4-difluorophenylboronic acid with the raw material B in the following table to obtain the trifluoroacetate of the corresponding compound.
  • the trifluoroacetate of the obtained compound is added to sodium bicarbonate solution, extracted with ethyl acetate, the organic phase is dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the corresponding compound.
  • the crude product was separated by preparative high performance liquid chromatography (column: Boston Green ODS 150*30mm*5 ⁇ m; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 25%-55%, 8min ) To obtain the trifluoroacetate salt of compound 3.
  • the trifluoroacetate salt of compound 3 is added to sodium bicarbonate solution, extracted with ethyl acetate, the organic phase is dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 3.
  • the preparation of compound 4 in Table 2 refers to the route of compound 3.
  • the difference is that the raw material used in step 2 replaces 2,4-difluorophenylboronic acid with raw material B in the following table to obtain the trifluoroacetate of the corresponding compound.
  • the trifluoroacetate salt of the obtained compound is added to sodium bicarbonate solution, extracted with ethyl acetate, the organic phase is dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the corresponding compound.
  • reaction solution was filtered and spin-dried to obtain a crude product, which was sent to preparative HPLC (column: Boston Green ODS 150*30mm*5 ⁇ m; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 20%- 50%, 7min) to obtain the trifluoroacetate salt of compound 6.
  • the trifluoroacetate of compound 6 is added to sodium bicarbonate solution, extracted with ethyl acetate, the organic phase is dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 6.
  • the preparation of the compounds in Table 3 refers to the route of compound 6, the difference is that the raw materials used in step 1 replace ethyl sulfonamide with raw material B in the following table to obtain the free state of the corresponding compound or trifluoroacetate, and the resulting compound
  • the trifluoroacetic acid salt was added to sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the corresponding compound.
  • the crude product was separated by preparative high performance liquid chromatography (column: Welch Xtimate C18 100*25mm*3 ⁇ m; mobile phase: [water (0.075% trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 20%-50%, 8min )
  • the trifluoroacetate salt of compound 12 is obtained.
  • the trifluoroacetate of compound 12 was added to sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 12.
  • the crude product was separated by preparative high performance liquid chromatography (column: Boston Green ODS 150*30mm*5 ⁇ m; mobile phase: [water (0.075%) (Trifluoroacetic acid)-acetonitrile]; B (acetonitrile)%: 23%-53%, 8min) to obtain the trifluoroacetate salt of compound 13.
  • the trifluoroacetate salt of compound 13 was added to sodium bicarbonate solution, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 13.
  • Buffer conditions 20mM Hepes (pH 7.5), 10mM MgCl 2 , 1mM EGTA, 0.02% Brij35, 0.02mg/mL BSA, 0.1mM Na 3 VO 4 , 2mM DTT, 1% DMSO.
  • Test procedure At room temperature, the test compound was dissolved in DMSO to prepare a 10 mM solution for later use. Dissolve the substrate in the newly prepared buffer, add the tested kinase to it and mix well. Using acoustic technology (Echo 550), the DMSO solution in which the test compound is dissolved is added to the mixed reaction solution.
  • the compound concentration in the reaction solution is 10 ⁇ M, 2.50 ⁇ M, 0.62 ⁇ M, 0.156 ⁇ M, 39.1nM, 9.8nM, 2.4nM, 0.61nM, 0.15nM, 0.038nM or 3 ⁇ M, 1 ⁇ M, 0.333 ⁇ M, 0.111 ⁇ M, 37.0nM, 12.3nM , 4.12nM, 1.37nM, 0.457nM, 0.152nM.
  • 33 P-ATP activity 0.01 ⁇ Ci/ ⁇ L, the corresponding concentration is listed in Table 4
  • FGFR1, FGFR2, KDR and the concentration information in the reaction solution are listed in Table 4.
  • Table 4 Information about kinases, substrates and ATP in in vitro tests.
  • N/A means not tested.
  • the compound of the present invention has excellent FGFRs and VEGFR2 kinase activity.
  • the imidazopyridine core compounds of the present invention have increased nearly 4-10 times on FGFR1 or FGFR2 kinase and nearly 1-13 times on the activity of VEGFR2 kinase. , It is very likely to show a better therapeutic effect at a lower dose clinically.
  • the different positions of the nitrogen atom on the aromatic ring of the compound of the present invention have a great influence on the activity. It is found that the activity of introducing heteroatom N at the 2-position of the benzene ring sulfonamide of the present invention is much higher than In 4th place, VEGFR2 activity increased 1000 times.
  • mice 0.1mg/mL 5% DMSO/10% solution 85% water clear solution of test compound was injected into female Balb/c mice (overnight fasting, 7-9 weeks old) through the tail vein, and the dosage It is 0.2mg/kg.
  • a clear solution of 0.1 mg/mL in 90% (25% HP- ⁇ -CD/10% polyoxyethylene castor oil (pH 4 to 5) test compound was administered to female Balb/c mice (overnight fasting). , 7-9 weeks of age), the dosage is 1mg/kg.
  • the two groups of animals were treated with 0.25, 0.5, 1.0, 2.0 from the jugular vein at 0.0833, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24h after administration.
  • C 0 represents the initial concentration
  • C max represents the peak concentration
  • T max represents the peak time
  • T 1/2 represents the elimination half-life
  • Vd ss represents the steady-state apparent volume of distribution
  • Cl represents the total clearance
  • T last represents the last time point at which the drug can be quantified
  • AUC 0-last represents the area under the plasma concentration-time curve from time 0 to the last quantifiable time point
  • AUC 0-inf represents from 0 The area under the plasma concentration-time curve when time is extrapolated to infinity
  • MRT 0-las represents the average residence time from time 0 to the last quantifiable time point
  • F (%) represents bioavailability.
  • the trifluoroacetate salt of the compound 1 of the present invention has nearly doubled the plasma clearance rate, doubled the intravenous drug exposure AUC, and increased the oral absorption drug exposure. To nearly twice.
  • Tumor tissue preparation SNU-16 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum under the conditions of 5% CO 2 , 37° C. and saturated humidity. According to the cell growth, passage or rehydration 1 to 2 times a week, the passage ratio is 1:3 to 1:4.
  • SNU-16 cells Collect logarithmic growth phase SNU-16 cells, count the cells and resuspend them in 50% serum-free RPMI-1640 medium and 50% Matrigel, adjust the cell concentration to 4 ⁇ 10 7 cells/mL; place the cells in In the ice box, suck the cell suspension with a 1 mL syringe, and inject it into the right armpit of the nude mouse subcutaneously.
  • Each animal is inoculated with 200 ⁇ L (8 ⁇ 10 6 cells/mouse) to establish a SNU-16 transplantation tumor model. Observe the animal status regularly, use the electronic vernier caliper to measure the tumor diameter, enter the data into an Excel spreadsheet, calculate the tumor volume, and monitor the tumor growth.
  • the average tumor in each group The volume is about 143mm 3 .
  • TGI total tumor growth rate
  • T/C relative tumor growth rate
  • Relative tumor proliferation rate T/C (%) T RTV /C RTV ⁇ 100%
  • TRTV average RTV of the treatment group
  • C RTV average RTV of the negative control group
  • RTV relative tumor volume
  • TGI (%) reflects the tumor growth inhibition rate.
  • TGI(%) [(1-(Average tumor volume at the end of a certain treatment group-average tumor volume at the start of the treatment group))/(Average tumor volume at the end of treatment in the solvent control group-start treatment in the solvent control group Average tumor volume at time)] ⁇ 100%.
  • the compound of the present invention showed significant anti-tumor activity.
  • the tumor growth inhibition rate (%TGI) was 69%, relative to tumor
  • the value-added rate (%T/C) is 31%.
  • the specific results are shown in Table 7, Figure 1 and Figure 2 (QD in the Figure means once a day).
  • the dose on the 8th day was changed to 20 mg/kg/day, and the dose on the 17th day was changed to 40 mg/kg/day.

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Abstract

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

Description

作为FGFR和VEGFR双重抑制剂的吡啶衍生物
本申请主张如下优先权
CN201910684252.3，申请日2019-07-26；
CN201911266249.6，申请日2019-12-11；
CN 202010230493.3，申请日2020-03-27。
技术领域
本发明涉及一种FGFR和VEGFR双重抑制剂，具体涉及式(I)所示化合物或药学上可接受的盐。
背景技术
成纤维细胞生长因子受体(FGFR)是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。成纤维细胞生长因子受体(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。临床发现FGFR高表达，突变或融合等异常都会引起肿瘤发生、发展，比如在肝癌，膀胱癌，肺癌，乳腺癌等疾病中。FGFR与配体FGF结合，导致胞内多个酪氨酸残基的自身磷酸化，下游进行信号传到，包括MEK/MAPK、PLCy/PKC、PI3K/AKT、STATS等。因此，FGFR被认为是抗肿瘤重要靶点。
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。
VEGFR和FGFR通路共同完成血管生成中内皮细胞的激活和生成，有时VEGF需要FGF的存在才能发挥其促血管生成作用。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(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2020104550-appb-000001
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；
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 PCTCN2020104550-appb-000002
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 PCTCN2020104550-appb-000003
Figure PCTCN2020104550-appb-000004
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，上述环B选自咪唑基和吡唑基，其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2020104550-appb-000005
选自
Figure PCTCN2020104550-appb-000006
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 PCTCN2020104550-appb-000007
选自
Figure PCTCN2020104550-appb-000008
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 PCTCN2020104550-appb-000009
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、NH 2和CH 3；
R 4选自H、C 1-6烷基、C 1-3烷氧基、C 3-5环烷基、四氢吡喃基和1,3-二氧戊环基，所述C 1-6烷基、C 1-3烷氧基、C 3-5环烷基、四氢吡喃基和1,3-二氧戊环基任选被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)-、-N(R 5)CH 2-和-N(R 5)-；
R 5分别独立地选自H和C 1-3烷基；
环B选自吡唑基和咪唑基，所述吡唑基和咪唑基任选被1或2个R 6取代；
R 6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、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、CH 2CH 2CH 3、CH 2CH(CH 3) 2、OCH 3、OCH 2CH 3、四氢吡喃基和1,3-二氧戊环基，所述环丙烷基、CH 3、CH 2CH 3、CH(CH 3) 2、C(CH 3) 3、CH 2CH 2CH 3、CH 2CH(CH 3) 2、OCH 3、OCH 2CH 3、四氢吡喃基和1,3-二氧戊环基任选被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、
Figure PCTCN2020104550-appb-000010
CH 3、CH 2CH 3、CH(CH 3) 2、C(CH 3) 3、CH 2CH 2CH 3、OCH 2CH 3、
Figure PCTCN2020104550-appb-000011
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-、-NHCH 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 PCTCN2020104550-appb-000012
Figure PCTCN2020104550-appb-000013
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 PCTCN2020104550-appb-000014
所述
Figure PCTCN2020104550-appb-000015
任选被1或2个R 6取代，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 PCTCN2020104550-appb-000016
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 PCTCN2020104550-appb-000017
选自
Figure PCTCN2020104550-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 PCTCN2020104550-appb-000019
选自
Figure PCTCN2020104550-appb-000020
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 PCTCN2020104550-appb-000021
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、NH 2和CH 3；
R 4选自H、C 1-6烷基、C 1-3烷氧基、C 3-5环烷基、四氢吡喃基和1,3-二氧戊环基，所述C 1-6烷基、C 1-3烷氧基、C 3-5环烷基、四氢吡喃基和1,3-二氧戊环基任选被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)-、-N(R 5)CH 2-和-N(R 5)-；
R 5分别独立地选自H和C 1-3烷基；
环B选自吡唑基和咪唑基，所述吡唑基和咪唑基任选被1或2个R 6取代；
R 6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、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、CH 2CH 2CH 3、CH 2CH(CH 3) 2、OCH 3、OCH 2CH 3、四氢吡喃基和1,3-二氧戊环基，所述环丙烷基、CH 3、CH 2CH 3、CH(CH 3) 2、C(CH 3) 3、CH 2CH 2CH 3、CH 2CH(CH 3) 2、OCH 3、OCH 2CH 3、四氢吡喃基和1,3-二氧戊环基任选被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、
Figure PCTCN2020104550-appb-000022
CH 3、CH 2CH 3、CH(CH 3) 2、C(CH 3) 3、CH 2CH 2CH 3、OCH 2CH 3、
Figure PCTCN2020104550-appb-000023
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-、-NHCH 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 PCTCN2020104550-appb-000024
Figure PCTCN2020104550-appb-000025
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 PCTCN2020104550-appb-000026
所述
Figure PCTCN2020104550-appb-000027
任选被1或2个R 6取代，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 PCTCN2020104550-appb-000028
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 PCTCN2020104550-appb-000029
选自
Figure PCTCN2020104550-appb-000030
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 PCTCN2020104550-appb-000031
选自
Figure PCTCN2020104550-appb-000032
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 PCTCN2020104550-appb-000033
其中，
R 1、R 2、R 3、L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 PCTCN2020104550-appb-000034
其中，
R 1、R 2、R 3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 PCTCN2020104550-appb-000035
Figure PCTCN2020104550-appb-000036
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药物组合物在制备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 PCTCN2020104550-appb-000037
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 PCTCN2020104550-appb-000038
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 PCTCN2020104550-appb-000039
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，“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，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)。
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代表水溶液；eq代表当量、等量；DCM代表二氯甲烷；PE代表PE；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；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；iPrOH代表2-丙醇；mp代表熔点；Xantphos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；Pd(dppf)Cl 2代表[1,1'-双(二苯基膦基)二茂铁]二氯化钯；DIEA代表N,N'-二异丙基乙胺；NIS代表N-碘代丁二酰亚胺。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2020104550-appb-000040
软件命名，市售化合物采用供应商目录名称。
技术效果
本发明化合物具有优异的FGFRs，VEGFR2激酶活性；本发明化合物中间芳香环氮杂原子的引入，意外发现这个变化能够显著提高化合物体内的代谢稳定性，大大提高了药物口服吸收药物暴露量，极有可能在临床上展示更优治疗效果；本发明化合物展示了优异的肿瘤治疗效果。
说明书附图
图1：给药期间各组肿瘤体积增长曲线；
图2：给药期间各组动物体重变化曲线。
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 PCTCN2020104550-appb-000041
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，滤饼中加入20mL无水甲苯，旋干得到化合物c。
LCMS(ESI)m/z:419.9[M+1] +；
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:525.8[M+1] +。
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。搅拌下，向反应液加入水(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)得化合物A的三氟乙酸盐。化合物A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A。
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2
Figure PCTCN2020104550-appb-000042
合成方法同对照例1，甲磺酰胺替代环丙基磺酰胺，得到化合物B的三氟乙酸盐。化合物B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B。
LCMS(ESI)m/z:480.1[M+1] +；
1H NMR(400MHz,DMSO-d 6)δ10.35(s,1H),9.17(s,1H),8.24(s,1H),8.01(s,1H),7.97(s,1H),7.68-7.78(m,3H),7.61(br d,J＝8.53Hz,2H),7.49(s,1H),7.38-7.47(m,1H),7.27(dt,J＝2.13,8.47Hz,1H),3.88(s,3H),3.18(s,3H)。
对照例3
Figure PCTCN2020104550-appb-000043
Figure PCTCN2020104550-appb-000044
步骤一
向2,6-二氯-4-氨基吡啶(10g,61.35mmol)和(2,4-二氟苯)硼酸(11.62g,73.62mmol)的二氧六环(100mL)/水(30mL)溶液中加入Pd(dppf)Cl 2(4.49g,6.13mmol)，K 3PO 4(26.04g,122.70mmol)，氮气保护下100℃搅拌16小时。反应液完成，分液，有机相减压浓缩得粗品。将粗品以石油醚/乙酸乙酯＝5/1进行过柱(快速硅胶柱层析)纯化得到化合物k。
LCMS(ESI)m/z:240.9[M+1] +。
步骤二
向化合物k(1g,4.16mmol)的吡啶(10mL)溶液中加入甲烷磺酰氯(1.90g,16.62mmol,1.29mL)，30℃搅拌1小时。向反应液中加水(30mL)，再用乙酸乙酯(30mL*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m。LCMS(ESI)m/z:318.9[M+1] +。
步骤三
将化合物1c(0.1g,308.53umol)溶于DMF(3mL)，氮气保护下，加入六丁基二锡(268.47mg,462.79umol,231.44uL)，化合物m(157.34mg,493.64umol)，再加入Pd(dppf)Cl 2.CH 2Cl 2(125.98mg,154.26umol)，氮气保护下110℃搅拌16小时，反应完成冷至室温后，再加入反应液用氟化钾水溶液淬灭，用乙酸乙酯萃取，合并有机相减压浓缩得粗品。粗品经制备HPLC分离(色谱柱:Welch Xtimate C18 150*25mm*5μm；流动相:[水(0.225％甲酸)-乙腈]；B(乙腈)％:15％-45％,8.5min)后，得到化合物C的甲酸盐。化合物C的甲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C。
LCMS(ESI)m/z:481.1[M+1] +；
1H NMR(400MHz,METHANOL-d4)δ9.97(br d,J＝7.28Hz,1H),8.37(br s,1H),8.26(s,1H),8.01-8.13(m,2H),7.69-7.84(m,1H),7.65(s,1H),7.50-7.57(m,2H),7.05-7.22(m,2H),3.98(s,3H),3.23(s,3H)。
实施例1
Figure PCTCN2020104550-appb-000045
Figure PCTCN2020104550-appb-000046
步骤一
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1a。
LCMS(ESI)m/z:197.0[M+1] +,199.0[M+3] +；
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)。
步骤二
将化合物1a(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)和磷酸钾(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1b。
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)。
步骤三
向化合物1b(24g,121.08mmol)的二氯甲烷(240mL)溶液中加入碘代丁二酰亚胺(32.69g,145.29mmol)，30℃搅拌16小时。反应液经抽滤得滤液，滤液加水(400mL)，再加入二氯甲烷(200mL*2)萃取，有机相用无水硫酸钠干燥，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1c。
LCMS(ESI)m/z:325.0[M+1] +。
步骤四
向化合物1c(1g,3.09mmol)，(2,6-二氯-4-吡啶)硼酸(650.96mg,3.39mmol)的二氧六环(10mL)和水(3mL)混合溶液中加入Pd(dppf)Cl 2(225.75mg,308.53μmol)，磷酸钾(1.31g,6.17mmol)。氮气保护下，微波反应器中120℃搅拌1小时。反应液加水(20mL)，乙酸乙酯(20mL*2)进行萃取，有机相用无水硫酸 钠干燥，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1d。LCMS(ESI)m/z:343.9[M+1] +。
步骤五
向化合物1d(150mg,435.80μmol)，环丙磺酰胺(52.80mg,435.80μmol)的二氧六环(4mL)溶液中加入醋酸钯(9.78mg,43.58μmol)，4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽(25.22mg,43.58μmol)，碳酸铯(425.97mg,1.31mmol)，微波反应器中氮气保护下120℃搅拌1小时。反应液经硅藻土抽滤，滤液减压浓缩得粗品。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1e。
LCMS(ESI)m/z:429.0[M+1] +。
步骤六
向化合物1e(150mg,349.74μmol)，2,4-二氟苯基硼酸(90.00mg,569.94μmol)的二氧六环(3mL)/水(1mL)溶液中加入Pd(dppf)Cl 2(25.59mg,34.97μmol)，磷酸钾(222.71mg,1.05mmol)，氮气保护下100℃搅拌16小时。反应液过滤，滤液减压浓缩得粗品。粗品经高效液相色谱分离(色谱柱:Boston Green ODS 150mm*30mm*5μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:32％-52％,12min)纯化得到化合物1的三氟乙酸盐。化合物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，减压下浓缩可得到化合物1。
LCMS(ESI)m/z:507.0[M+1] +；
1H NMR(400MHz,MeOD)δ8.78(d,J＝7.28Hz,1H),8.39(s,1H),8.30(s,1H),8.17-8.26(m,1H),8.16(s,1H),8.05(s,1H),7.83(s,1H),7.78(dd,J＝1.52,7.28Hz,1H),7.39(s,1H),7.10-7.20(m,2H),4.00(s,3H),3.08-3.20(m,1H),1.20-1.32(m,2H),1.04-1.14(m,2H)。
表1中化合物2的制备参照化合物1的路线，不同之处在于步骤六中使用的原料以下表中的原料B代替2,4-二氟苯硼酸，得相应化合物的三氟乙酸盐。将得到的化合物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，减压下浓缩得可到相应的化合物。
表1
Figure PCTCN2020104550-appb-000047
Figure PCTCN2020104550-appb-000048
实施例3
Figure PCTCN2020104550-appb-000049
步骤一
向化合物1d(0.5g,1.45mmol)，氨基甲酸乙酯(110.01mg,1.23mmol)的1,4-二氧六环(15mL)溶液中加入醋酸钯(32.61mg,145.27μmol)，4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽(168.11mg,290.53μmol)，碳酸铯(1.42g,4.36mmol)。氮气保护下于微波反应器中120℃搅拌20分钟。反应液直接过滤，滤液减压浓缩得粗品。粗品经硅胶柱层析(DCM:MeOH＝15:1)纯化得化合物3a。
LCMS(ESI)m/z:397.1[M+1] +。
步骤二
向化合物3a(150mg,378.00μmol)，2,4-二氟苯硼酸(71.63mg,453.60μmol)的THF(1.5mL)和H 2O(0.5mL)溶液中加入Pd(dppf)Cl 2(27.66mg,37.80μmol)，磷酸钾(160.47mg,755.99μmol)。氮气保护下于微波条件下100℃搅拌30分钟。反应液分液，有机相减压浓缩得粗品。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)％:25％-55％,8min)得化合物3的三氟乙酸盐。化合物3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，减压下浓缩可得到化合物3。
LCMS(ESI)m/z:475.1[M+1] +；
1H NMR(400MHz,CD 3OD)δ8.81(d,J＝7.28Hz,1H),8.37(s,1H),8.24-8.31(m,2H),8.12-8.21(m,2H),8.03(s,1H),7.71-7.81(m,2H),7.05-7.19(m,2H),4.27(q,J＝7.04Hz,2H),4.00(s,3H),1.35(t,J＝7.16Hz,3H)。
表2中化合物4的制备参照化合物3的路线，不同之处在于步骤二中使用的原料以下表中的原料B代替2,4-二氟苯硼酸，得相应化合物的三氟乙酸盐，将得到的化合物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，减压下浓缩可得到相应的化合物。
表2
Figure PCTCN2020104550-appb-000050
实施例6
Figure PCTCN2020104550-appb-000051
Figure PCTCN2020104550-appb-000052
步骤一
将化合物1d(200mg,581.06μmol)和乙基磺酰胺(114.16mg,1.05mmol)溶于1,4-二氧六环(5mL)中，加入醋酸钯(13.05mg,58.11μmol)，4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽(67.24mg,116.21μmol)和碳酸铯(567.96mg,1.74mmol)，氮气保护下微波120℃搅拌反应1小时。反应液直接过滤，用DCM/MeOH＝10/1洗涤滤饼，滤液旋干得粗品。粗品经快速硅胶柱纯化(DCM/MeOH＝10/1)得到化合物6a。
LCMS(ESI)m/z:417.3[M+1] +。
步骤二
将化合物6a(0.2g,479.75μmol)和2,4-二氟苯硼酸(113.64mg,719.62μmol)溶于1,4-二氧六环(6mL)和H 2O(3mL)中，加入磷酸钾(305.51mg,1.44mmol)和Pd(dppf)Cl 2(35.10mg,47.97μmol)，氮气保护下100℃搅拌反应16小时。反应液过滤，旋干得粗品，送制备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)％:20％-50％,7min)纯化得到化合物6的三氟乙酸盐。化合物6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，减压下浓缩可得到化合物6。
LCMS(ESI)m/z:495.0[M+1] +；
1H NMR(400MHz,CD 3OD)δ8.80(br d,J＝7.34Hz,1H),8.42(s,1H),8.33(s,1H),8.13-8.23(m,2H),8.10(s,1H),7.76-7.88(m,2H),7.33(s,1H),7.08-7.22(m,2H),4.02(s,3H),3.61(q,J＝7.36Hz,2H),1.43ppm(br t,J＝7.36Hz,3H)。
表3中化合物的制备参照化合物6的路线，不同之处在于步骤一中使用的原料以下表中的原料B代替乙基磺酰胺，得相应化合物的游离态或三氟乙酸盐，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，减压下浓缩可得到相应的化合物。
表3
Figure PCTCN2020104550-appb-000053
Figure PCTCN2020104550-appb-000054
Figure PCTCN2020104550-appb-000055
实施例12
Figure PCTCN2020104550-appb-000056
Figure PCTCN2020104550-appb-000057
步骤一
向化合物1a(5g,25.38mmol)，1,5-二甲基-1H-吡唑-4-硼酸嚬哪醇酯(6.20g,27.91mmol)溶液的二氧六环(45mL)/水(15mL)中加入Pd(dppf)Cl 2(1.86g,2.54mmol)，磷酸钾(10.77g,50.75mmol)。氮气保护下100℃搅拌16小时。反应液过滤，再加水(100mL)，加入二氯甲烷(100mL*3)萃取，合并有机相，用无水硫酸钠干燥，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12a。
LCMS(ESI)m/z:212.9[M+1] +。
步骤二
向化合物12a(0.12g,565.37μmol)的二氯甲烷(5mL)溶液中加入NIS(152.64mg,678.45μmol)，25℃搅拌16小时。向反应液中加水(10mL)，加入二氯甲烷(10mL*3)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩得化合物12b。
LCMS(ESI)m/z:338.9[M+1] +。
步骤三
向12b(2.72g,14.20mmol)的二氧六环(45mL)/水(15mL)溶液中加入Pd(dppf)Cl 2(865.55mg,1.18mmol)，磷酸钾(5.02g,23.66mmol)，氮气保护下100℃搅拌16小时。反应液直接过滤，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12c。
LCMS(ESI)m/z:358.1[M+1] +。
步骤四
向12c(0.15g,418.73μmol)，氨基甲酸乙酯(32mg,359.18μmol)的二氧六环(15mL)溶液中加入醋酸钯(9.40mg,41.87μmol)，碳酸铯(409.29mg,1.26mmol)，Xantphos(48.46mg,83.75μmol)。氮气保护下于微波反应器中120℃搅拌20分钟。反应液直接过滤，滤液减压浓缩得粗品。粗品经制备薄层色谱硅胶板(DCM:MeOH＝15:1)纯化得化合物12d。
LCMS(ESI)m/z:411.1[M+1] +。
步骤五
向12d(30mg,73.02μmol)，2,4-二氟苯硼酸(13.84mg,87.62μmol)的四氢呋喃(1.5mL)/水(0.5mL)溶液中加入Pd(dppf)Cl 2(5.34mg,7.30μmol)，K 3PO 4(31.00mg,146.04μmol)。氮气保护下于微波条件下100℃搅拌30分钟。反应液分层，收集有机相减压浓缩得粗品。粗品经制备高效液相色谱分离(色谱柱:Welch Xtimate C18 100*25mm*3μm；流动相:[水(0.075％三氟乙酸)-乙腈]；B(乙腈)％:20％-50％,8min)后得化合物12的三氟乙酸盐。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，减压下浓缩可得到化合物12。
LCMS(ESI)m/z:489.2[M+1] +；
1H NMR(400MHz,MeOD-d 4)δ8.85(d,J＝7.28Hz,1H),8.28(s,2H),8.11-8.22(m,1H),7.85-7.97(m,2H),7.79(s,1H),7.65(d,J＝7.54Hz,1H),7.04-7.19(m,2H),4.27(q,J＝7.04Hz,2H),3.91(s,3H),2.60(s,3H),1.35(t,J＝7.04Hz,3H)。
实施例13
Figure PCTCN2020104550-appb-000058
步骤一
向12c(0.25g,697.89μmol)，甲烷磺酰胺(132.77mg,1.40mmol)的二氧六环(5mL)溶液中加入醋酸钯(15.67mg,69.79μmol)，Xantphos(80.76mg,139.58μmol)，碳酸铯(682.16mg,2.09mmol)。氮气保护下于微波反应器中120℃搅拌1小时。反应液直接抽滤得滤液，减压浓缩后得粗品。粗品经制备TLC分离(DCM:MeOH＝10:1)分离得化合物13a。
LCMS(ESI)m/z:417.0[M+1] +。
步骤二
向13a(200mg,479.75μmol)，2,4-二氟苯硼酸(90.91mg,575.70μmol)的四氢呋喃(1.5mL)/水(0.5mL)溶液中加入Pd(dppf)Cl 2(35.10mg,47.97μmol)，磷酸钾(203.67mg,959.50μmol)，氮气保护下于微波反应器 中100℃搅拌45分钟。反应液加入水(10mL)，加入乙酸乙酯(10mL*3)萃取，合并有机相并用无水硫酸钠干燥，减压浓缩得粗品。粗品经制备薄层色谱硅胶板分离(DCM:MeOH＝10:1)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)后得化合物13的三氟乙酸盐。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，减压下浓缩可得到化合物13。
LCMS(ESI)m/z:495.0[M+1] +；
1H NMR(400MHz,CD 3OD-d 4)δ8.83(d,J＝7.28Hz,1H),8.35(s,1H),8.19(dt,J＝6.90,8.85Hz,1H),7.90-7.98(m,2H),7.84(s,1H),7.68-7.77(m,1H),7.31(d,J＝1.00Hz,1H),7.09-7.21(m,2H),3.92(s,3H),3.41(s,3H),2.61(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、FGFR2、VEGFR2的抑制能力。
缓冲液条件：20mM Hepes(pH 7.5),10mM MgCl 2,1mM EGTA,0.02％Brij35,0.02mg/mL BSA,0.1mM 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、FGFR2、KDR和在反应液中的浓度信息列在表4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 PCTCN2020104550-appb-000059
Figure PCTCN2020104550-appb-000060
表5本发明化合物激酶活性IC 50测试结果
Figure PCTCN2020104550-appb-000061
Figure PCTCN2020104550-appb-000062
注：N/A表示未测试。
结论：本发明化合物具有优异的FGFRs，VEGFR2激酶活性。与对照化合物A和B的三氟乙酸盐相比，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倍和VEGFR2激酶活性上提高了近1-13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。与对照化合物C的甲酸盐相比，本发明化合物中间芳香环上氮原子引入的位点不同对活性影响巨大，发现在本发明苯环磺酰胺的2位引入杂原子N活性要大大高于4位，VEGFR2活性提高1000倍。
实验例2：本发明化合物的药代动力学评价
实验过程：将0.1mg/mL 5％DMSO/10％溶液85％水试验化合物的澄清溶液经尾静脉注射到雌性Balb/c小鼠体内(过夜禁食，7-9周龄)，给药剂量为0.2mg/kg。将0.1mg/mL在90％(25％HP-β-CD/10％聚氧乙烯蓖麻油(pH＝4～5)试验化合物的澄清溶液灌胃给予到雌性Balb/c小鼠(过夜禁食，7-9周龄)，给药剂量为1mg/kg。两组动物分别于给药后0.0833、0.25、0.5、1.0、2.0、4.0、8.0、24h从颈静脉和0.25、0.5、1.0、2.0、4.0、8.0、24h从尾静脉采血约30μL置于添加了EDTA-K2的抗凝管中，离心分离血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlin TM Version 6.3(Pharsight,Mountain View,CA)药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。
实验数据分析：
表6药代动力学数据汇总表
Figure PCTCN2020104550-appb-000063
Figure PCTCN2020104550-appb-000064
注：--表示该参数无法通过计算得到；C 0代表初始浓度；C max代表达峰浓度；T max代表达峰时间；T 1/2代表消除半衰期；Vd ss代表稳态表观分布容积；Cl代表总清除率；T last代表最后一个可定量测试药物的时间点；AUC 0-last代表从0时间到最后一个可定量时间点的血浆浓度-时间曲线下面积；AUC 0-inf代表从0时间到外推至无穷大时的血浆浓度-时间曲线下面积；MRT 0-las代表从0时间到最后一个可定量时间点的平均滞留时间；F(％)代表生物利用度。
本发明化合物1的三氟乙酸盐与对照化合物A的三氟乙酸盐相比，血浆清除率下降了近一倍，静脉给药药物暴露量AUC提高到两倍；口服吸收药物暴露量提高到近两倍。
实验结论：本发明化合物中间芳香环氮杂原子的引入，显著提高化合物体内的代谢稳定性，大大提高了药物口服吸收药物暴露量，将会在临床上将展示更优药代口服吸收药物暴露量，展示更优的治疗效果。
实验例3：在体内动物肿瘤模型上的抗肿瘤活性测试
实验目的：
研究本发明化合物在小鼠人胃癌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(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28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：69％，相对肿瘤增值率(％T/C)为：31％。具体结果见表7、附图1和附图2(附图中QD表示一天一次)。
表7 SNU-16肿瘤生长抑制率和相对肿瘤增殖率汇总表
Figure PCTCN2020104550-appb-000065
*所有给药组，第8天给药剂量变更为20mg/kg/天，第17天给药剂量均变更为40mg/kg/天。
实验结论：本发明化合物表现出了显著的抗肿瘤活性。

Claims (18)

  1. 式(I)所示化合物或其药学上可接受的盐，
    Figure PCTCN2020104550-appb-100001
    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、NH 2和CH 3；
    R 4选自H、C 1-6烷基、C 1-3烷氧基、C 3-5环烷基、四氢吡喃基和1,3-二氧戊环基，所述C 1-6烷基、C 1-3烷氧基、C 3-5环烷基、四氢吡喃基和1,3-二氧戊环基任选被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)-、-N(R 5)CH 2-和-N(R 5)-；
    R 5分别独立地选自H和C 1-3烷基；
    环B选自吡唑基和咪唑基，所述吡唑基和咪唑基任选被1或2个R 6取代；
    R 6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。
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 1选自H、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。
  3. 根据权利要求2所述化合物或其药学上可接受的盐，其中，R 1选自H、CH 3、CH 2OH、CH 2CH 2OH和CH 2CH 3。
  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 4选自H、环丙烷基、CH 3、CH 2CH 3、CH(CH 3) 2、C(CH 3) 3、CH 2CH 2CH 3、CH 2CH(CH 3) 2、OCH 3、OCH 2CH 3、四氢吡喃基和1,3-二氧戊环基，所述环丙烷基、CH 3、CH 2CH 3、CH(CH 3) 2、C(CH 3) 3、CH 2CH 2CH 3、CH 2CH(CH 3) 2、OCH 3、OCH 2CH 3、四氢吡喃基和1,3-二氧戊环基任选被1、2或3个R b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 4选自H、
    Figure PCTCN2020104550-appb-100002
    CH 3、CH 2CH 3、CH(CH 3) 2、C(CH 3) 3、CH 2CH 2CH 3、OCH 2CH 3、
    Figure PCTCN2020104550-appb-100003
  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 5分别独立地选自H、CH 3和CH 2CH 3。
  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，L选自-NHC(＝O)-、-NHC(＝O)NH-、-NHS(＝O) 2-、-NHCH 2-和-NH-。
  8. 根据权利要求5或7所述化合物或其药学上可接受的盐，其中，-L-R 4选自
    Figure PCTCN2020104550-appb-100004
    Figure PCTCN2020104550-appb-100005
  9. 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 PCTCN2020104550-appb-100006
    所述
    Figure PCTCN2020104550-appb-100007
    任选被1或2个R 6取代。
  10. 根据权利要求9所述化合物或其药学上可接受的盐，其中，环B选自
    Figure PCTCN2020104550-appb-100008
  11. 根据权利要求10所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2020104550-appb-100009
    选自
    Figure PCTCN2020104550-appb-100010
  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 PCTCN2020104550-appb-100011
    选自
    Figure PCTCN2020104550-appb-100012
    Figure PCTCN2020104550-appb-100013
  13. 根据权利要求1～7任意一项所述化合物或其药学上可接受的盐，其选自
    Figure PCTCN2020104550-appb-100014
    其中，
    R 1、R 2、R 3、L和R 4如权利要求1～7任意一项所定义。
  14. 根据权利要求13所述化合物或其药学上可接受的盐，其选自
    Figure PCTCN2020104550-appb-100015
    其中，
    R 1、R 2、R 3和R 4如权利要求13所定义。
  15. 下式所示化合物或其药学上可接受的盐，
    Figure PCTCN2020104550-appb-100016
    Figure PCTCN2020104550-appb-100017
  16. 一种药物组合物，包括治疗有效量的根据权利要求1～15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。
  17. 根据权利要求1～15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16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。
  18. 根据权利要求17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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