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WO2019085895A1 - 一类氨基取代含氮稠环化合物及其制备方法和用途 - Google Patents

一类氨基取代含氮稠环化合物及其制备方法和用途 Download PDF

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Publication number
WO2019085895A1
WO2019085895A1 PCT/CN2018/112661 CN2018112661W WO2019085895A1 WO 2019085895 A1 WO2019085895 A1 WO 2019085895A1 CN 2018112661 W CN2018112661 W CN 2018112661W WO 2019085895 A1 WO2019085895 A1 WO 2019085895A1
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group
compound
formula
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cancer
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English (en)
French (fr)
Inventor
王慧
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Rudong Ringene Pharmaceuticals Co Ltd
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Rudong Ringene Pharmaceuticals Co Ltd
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Priority to JP2020544089A priority Critical patent/JP7041821B2/ja
Priority to EP18874000.5A priority patent/EP3705480B1/en
Priority to KR1020207015596A priority patent/KR102421137B1/ko
Priority to US16/760,005 priority patent/US11267815B2/en
Publication of WO2019085895A1 publication Critical patent/WO2019085895A1/zh
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/4375—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 six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicinal chemistry, and particularly relates to a class of amino-substituted nitrogen-containing fused ring compounds, a preparation method thereof and use thereof.
  • FGFR fibroblast growth factor receptor
  • the technical problem to be solved by the present invention is to provide a kind of amino-substituted nitrogen-containing fused ring compound, a preparation method and use thereof for developing more FGFR small molecule inhibitors, and the amino-substituted nitrogen-containing fused ring compound of the invention belongs to a novel type.
  • the specific FGFR kinase inhibitor is excellent in FGFR-related tumor cell proliferation inhibitory activity and can be used for treating diseases such as tumors caused by abnormal FGFR kinase.
  • the present invention solves the above technical problems by the following technical solutions.
  • the present invention provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate thereof, or a plurality thereof Crystal form or prodrug,
  • R 1 is selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl, cyano; preferably from hydrogen, halogen, methyl;
  • R 2 is selected from hydrogen, C 1 -C 10 alkyl, 3-8 membered cycloalkyl or heterocycloalkyl, 5-8 membered aryl or heteroaryl; preferably substituted from hydrogen, C 1 -C 6 or Unsubstituted alkyl group;
  • R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, sulfone, sulfoxide, acyl, sulfonyl, nitro; each independently preferably selected from hydrogen, halogen, methyl ;
  • M 1 is selected from CR 6 or N;
  • R 6 is selected from the group consisting of hydrogen, halogen, C 1 -C 3 alkyl;
  • Ar is selected from a 5-6 membered aryl or heteroaryl group
  • L is selected from a chemical bond, C 1 -C 10 alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, acyl, sulfonyl, 4-8 membered cycloalkyl or heterocycloalkyl, 5 a -10 membered aryl or heteroaryl; preferably from a C 1 -C 6 alkyl group;
  • A is selected from a 4-8 membered cycloalkyl or heterocycloalkyl group, a 5-10 membered aryl group or a heteroaryl group; preferably a 5-6 membered heterocycloalkyl group, a 5-6 membered aryl group or a heteroaryl group;
  • One or more hydrogen atoms on any of the above groups may be substituted with a substituent selected from the group consisting of hydrazine, halogen, hydroxy, amino, cyano, sulfone or sulfoxide, C 1 -C 8 alkyl , C 3 -C 8 cycloalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkylamino, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 acyl Or a sulfonyl group, a 5-8 membered aryl or heteroaryl group, a 4-8 membered saturated cycloalkyl group or a heterocycloalkyl group; wherein said heteroaryl group comprises 1-3 heteroatoms selected from the group consisting of: N, O, P and S; the heterocycloalkyl group contains from 1 to 3 heteroatoms selected from the group consisting of N, O, P and S.
  • Each of the ring systems described in the above definitions may each independently be a monocyclic ring, a fused ring, a bridged ring or a spiro ring; the heteroaryl group may be partially oxidized and/or reduced.
  • the compound of the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer or solvate thereof, of the present invention polymorph or prodrug,
  • M 1 is preferably selected from CH or N;
  • R 1 is preferably selected from the group consisting of hydrogen, halogen (eg, fluorine), C 1 -C 3 alkyl (eg, methyl);
  • R 3 , R 4 and R 5 are each independently preferably selected from hydrogen, halogen (e.g., fluorine) or N(R 9 )(R 10 )-(CH 2 )p- (wherein R 9 and R 10 are both C 1 - C 6 alkyl, p is selected from 0, 1 or 2; for example, N(R 9 )(R 10 )-(CH 2 )p- is dimethylaminomethylene); more preferably R 3 is selected from hydrogen or fluorine And R 4 and R 5 are selected from hydrogen;
  • Ar is preferably selected from a 6-membered aryl group, that is, a phenyl group, and further preferably one or more (for example, one, two, three or four) hydrogen atoms on the phenyl group are selected from halogen, cyano, C 1 Substituted with a substituent of -C 8 alkyl, C 1 -C 8 alkoxy, amino, hydroxy, C 2 -C 6 acyl or sulfonyl (further preferably halogen or C 1 -C 8 alkoxy); further Preferably substituted by two halogens (for example fluorine or chlorine) and two C 1 -C 8 alkoxy groups (for example methoxy groups), for example
  • halogens for example fluorine or chlorine
  • C 1 -C 8 alkoxy groups for example methoxy groups
  • A is preferably selected from a 5-6 membered heterocycloalkyl group (the 5-6 membered heterocycloalkyl group is further preferably piperazinyl, piperidinyl or tetrahydropyrrolyl), and 5-6 membered heteroaryl-NH- (The 5-6 membered heteroaryl group is further preferably pyridyl, oxazolyl or triazolyl), -Ph-(CH 2 ) o -NH- (where o is selected from 0 or 1), 5-6 a heteroaryl-(CH 2 ) m -5-6 membered heterocycloalkyl- (wherein the 5-6 membered heterocycloalkyl group is further preferably piperazinyl, piperidinyl or tetrahydropyrrolyl,
  • the 5-6 membered heteroaryl group is further preferably a pyridyl group, an oxazolyl group or a triazozolyl group, and m is
  • A is the following structural fragment:
  • L is always attached to one end of an aryl group, a heteroaryl group or a non-fatty amine group in the A structure.
  • the compound of the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer or solvate thereof, of the present invention a polymorph or a prodrug, wherein the compound represented by the formula (I) has the following structure:
  • B ring is a 5-10 membered aromatic or aromatic heterocyclic ring; preferably a benzene ring, a pyridine ring, an oxazole ring or three Azole ring.
  • the compound of the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer or solvate thereof, of the present invention a polymorph or a prodrug, wherein the compound represented by the formula (I) has the following structure:
  • n is selected from 0, 1 or 2, and R 2 is as defined above.
  • R 2 is as defined above.
  • the present invention is a compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate thereof, or a plurality thereof a crystal form or a prodrug, wherein the compound represented by the formula (I) is any one of the following compounds:
  • the present invention provides a method for producing a compound represented by the formula (I), which comprises the steps of:
  • a compound of the formula (B) is obtained by subjecting a compound of the formula (A) to an ⁇ -halocarbonyl compound or an equivalent thereof in the presence of an acid or a base to prepare a compound of the formula (B);
  • LG represents a leaving group conventionally used in such reactions in the art, such as a halogen, a sulfone group, a sulfoxide group, a sulfonate group, and the other groups are as defined above.
  • the steps a), b), c) are each carried out in a solvent, and the solvents are each independently selected from the group consisting of water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, two Methyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and dioxane
  • the solvents are each independently selected from the group consisting of water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, two Methyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide
  • the transition metal catalyst is selected from the group consisting of tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), palladium acetate, chlorine Palladium, dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate, palladium triphenylphosphine acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, double One or more of (tri-o-phenylmethylphosphine)palladium dichloride, and 1,2-bis(diphenylphosphino)ethanepalladium dichloride;
  • the catalyst ligand is selected from the group consisting of tri-tert-butyl One or more of a phosphine, a tri-tert-butylphosphin
  • the condensation reagent is selected from one or more of DCC, DIC, CDI, EDCI, HOAt, HOBt, BOP, PyBOP, HATU, and TBTU;
  • the base comprises an organic base and/or an inorganic base; wherein the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium t-butoxide, sodium t-butoxide, potassium fluoride One or more of cesium fluoride, potassium phosphate, potassium carbonate, potassium hydrogencarbonate, sodium carbonate, and sodium hydrogencarbonate; the organic base is selected from the group consisting of pyridine, triethylamine, N,N-diisopropyl Ethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), hexamethyldisilazide, hexamethyldisilazide, and lutidine One or more of cesium fluoride, potassium phosphate, potassium carbonate, potassium hydrogencarbonate, sodium carbonate, and sodium hydrogencarbonate; the organic base is selected from the group consisting of pyridine, triethylamine, N,
  • the acid is selected from one or more of the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, and trifluoromethanesulfonic acid.
  • the compound of the above formula (A) and the respective reagents involved in the above production method are commercially available or can be prepared by a person skilled in the art with reference to a synthesis method in the prior art.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, a diastereomer Isomer, tautomer, solvate, polymorph or prodrug, and at least one pharmaceutical excipient.
  • the present invention provides a compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereomer thereof, a tautomer thereof, The use of a solvate, polymorph or prodrug, or a pharmaceutical composition as described above for the preparation of a FGFR kinase inhibitor.
  • the present invention provides a compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereomer thereof, a tautomer thereof,
  • a solvate, polymorph or prodrug, or a pharmaceutical composition as described above for the manufacture of a medicament for the prevention and/or treatment of a disease associated with the activity or expression of a protein kinase, in particular a FGFR kinase, in particular for the preparation of prophylaxis and/or Application in the treatment of anti-tumor drugs.
  • the tumor includes, but is not limited to, one or more of the following: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, epithelial cell carcinoma. , gastrointestinal stromal tumors, intestinal cancer, cholangiocarcinoma, gallbladder cancer, colorectal cancer, brain cancer, leukemia, lymphoma, nasopharyngeal cancer, bladder cancer, pancreatic cancer, etc., especially liver cancer or cholangiocarcinoma.
  • the present invention provides a method for preventing and/or treating a tumor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I), or a pharmaceutically acceptable compound thereof a salt, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof.
  • the compound represented by the formula (I) of the present invention can inhibit a variety of tumor cells, in particular, can efficiently kill hepatocellular cancer cells, and is a novel therapeutic mechanism for hepatocellular carcinoma.
  • reaction can be carried out and purified using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in the present invention.
  • the above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification.
  • group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left.
  • substituent -CH2O- is equivalent to -OCH2-.
  • C1-6 alkyl refers to an alkyl group as defined below having a total of from 1 to 6 carbon atoms.
  • the total number of carbon atoms in the simplified symbol does not include carbon that may be present in the substituents of the group.
  • halogen means fluoro, chloro, bromo or iodo.
  • Haldroxy means an -OH group.
  • Hydroalkyl means an alkyl group as defined below which is substituted by a hydroxy group (-OH).
  • Niro means -NO 2 .
  • Amino means -NH 2 .
  • Substituted amino means an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkyl Amido, aralkylamino, heteroarylalkylamino.
  • Carboxyl means -COOH.
  • alkyl group means consisting only of carbon atoms and hydrogen atoms, and is not unsaturated.
  • a bond a straight or branched hydrocarbon chain group having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and attached to the remainder of the molecule by a single bond.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2 , 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, decyl and decyl.
  • alkenyl as a group or part of another group means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10) And more preferably 2 to 6) carbon atoms and a straight or branched hydrocarbon chain group attached to the remainder of the molecule by a single bond, such as, but not limited to, vinyl, propenyl, allyl, butyl- 1-Alkenyl, but-2-enyl, pent-1-enyl, pentane-1,4-dienyl and the like.
  • alkynyl as a group or part of another group means consisting solely of carbon atoms and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having for example 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and a straight or branched hydrocarbon chain group bonded to the remainder of the molecule by a single bond, such as, but not limited to, an ethynyl group , prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl and the like.
  • cycloalkyl as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, which may include condensing a ring system, a bridged ring system or a spiro ring system having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated and may be suitably employed
  • the carbon atom is connected to the rest of the molecule by a single bond.
  • a carbon atom in a cycloalkyl group may be optionally oxidized.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzene And cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl , fluorenyl, bicyclo [2.2.1] heptyl, 7,7-dimethyl-bicyclo[2.2.1]hept
  • heterocyclyl as a group or part of another group means consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur.
  • a heterocyclic group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include a fused ring system, a bridged ring system or a spiro ring system;
  • the nitrogen, carbon or sulfur atom may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated.
  • the heterocyclic group may be bonded to the remainder of the molecule via a carbon atom or a hetero atom and through a single bond.
  • one or more of the rings may be an aryl or heteroaryl group as defined hereinafter, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • the heterocyclic group is preferably a stable 4 to 11 membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heterocyclic groups include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]fluorene.
  • Alkan-7-yl 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza Cyclobutane, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, Imidazolidinyl, quinazolinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indanyl, octahydroindenyl, octahydroisodecyl, pyrrolidinyl, pyrazolidinyl , phthalimido and the like.
  • aryl as a group or part of another group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms.
  • an aryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is via The atoms on the aromatic ring are connected to the rest of the molecule by a single bond.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, anthracenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazine-3(4H)-one-7-yl and the like.
  • arylalkyl refers to an alkyl group as defined above substituted with an aryl group as defined above.
  • heteroaryl as a group or part of another group means having from 1 to 15 carbon atoms (preferably having from 1 to 10 carbon atoms) and from 1 to 6 selected from nitrogen in the ring. a 5- to 16-membered conjugated ring system of a hetero atom of oxygen and sulfur. Unless otherwise specifically indicated in the specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that The aryl group is attached to the remainder of the molecule via a single bond through an atom on the aromatic ring.
  • the nitrogen, carbon or sulfur atom in the heteroaryl group can be optionally oxidized; the nitrogen atom can optionally be quaternized.
  • the heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably from 1 to 4 selected
  • heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, fluorenyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, pyridazinyl, isodecyl, oxazolyl, isoxazolyl , mercapto, quinolyl, isoquinolyl, diazaphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, oxazolyl, porphyrin, phenanthryl, phenanthroline, acridine Base, phenazinyl,
  • heteroarylalkyl refers to an alkyl group as defined above which is substituted by a heteroaryl group as defined above.
  • optionally or “optionally” means that the subsequently described event or condition may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or condition.
  • optionally substituted aryl means that the aryl group is substituted or unsubstituted, and the description includes both the substituted aryl group and the unsubstituted aryl group.
  • a chemical moiety refers to a particular fragment or functional group in a molecule.
  • a chemical moiety is generally considered to be a chemical entity that is embedded or attached to a molecule.
  • Stepoisomer refers to a compound composed of the same atoms bonded by the same bond but having a different three-dimensional structure.
  • the invention will cover various stereoisomers and mixtures thereof.
  • the compounds of the present invention are intended to include E- and Z-geometric isomers unless otherwise stated.
  • Tautomer refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention will also be embraced within the scope of the invention.
  • the compounds of the invention may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the invention is intended to include all possible isomers, as well as racemic and optically pure forms thereof.
  • the preparation of the compounds of the invention may employ racemates, diastereomers or enantiomers as starting materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as by crystallization and chiral chromatography.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” means a salt formed with an inorganic or organic acid which retains the bioavailability of the free base without any other side effects.
  • Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate , trifluoroacetate, propionate, hexanoate, octoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, hexane Acid salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, me
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic or organic base which is capable of retaining the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines, and basic ion exchange resins.
  • ammonia isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclo Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, hydrazine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin, and the like.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • Polymorph refers to a different solid crystalline phase of certain compounds of the invention resulting from the presence of two or more different molecular arrangements in a solid state. Certain compounds of the invention may exist in more than one crystal form, and the invention is intended to include various crystal forms and mixtures thereof.
  • solvate refers to an aggregate comprising one or more molecules of the compound of the invention and one or more solvent molecules.
  • the solvent may be water, and the solvate in this case is a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms.
  • the compounds of the invention may form true solvates, but in some cases, it is also possible to retain only a variable amount of water or a mixture of water and a portion of the indefinite solvent.
  • the compound of the present invention can be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the invention are also included within the scope of the invention.
  • the invention also includes prodrugs of the above compounds.
  • prodrug means a compound which can be converted into a biologically active compound of the invention under physiological conditions or by solvolysis.
  • prodrug refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention.
  • Prodrugs may be inactive when administered to an individual in need thereof, but are converted in vivo to the active compound of the invention.
  • Prodrugs are typically rapidly converted in vivo to produce the parent compound of the invention, for example by hydrolysis in blood.
  • Prodrug compounds generally provide the advantage of solubility, tissue compatibility or sustained release in mammalian organisms.
  • Prodrugs include known amino protecting groups and carboxy protecting groups.
  • pharmaceutical composition refers to a formulation of a compound of the invention and a medium generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human.
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, thereby facilitating the absorption of the active ingredient and thereby exerting biological activity.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing undesirable organisms. The reaction or in an undesirable manner interacts with any of the components contained in the composition.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government authorities for acceptable use by humans or livestock. , diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • tumor include, but are not limited to, leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, Lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc. disease.
  • preventing include the possibility of reducing the occurrence or progression of a disease or condition by a patient.
  • treatment and other similar synonyms as used herein includes the following meanings:
  • an "effective amount,” “therapeutically effective amount,” or “pharmaceutically effective amount,” as used herein, refers to at least one agent or compound that, after administration, is sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent. The amount. The result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired change in the biological system.
  • an "effective amount” for treatment is an amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic.
  • An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.
  • administering refers to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration.
  • parenteral injections including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical administration and rectal administration.
  • the techniques of administration of the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, those discussed in Pa.
  • the compounds and compositions discussed herein are administered orally.
  • pharmaceutical combination means a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, It includes both fixed and unfixed combinations of active ingredients.
  • fixed combination refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form.
  • unfixed combination refers to the simultaneous administration, combination or sequential administration of at least one of the compounds described herein and at least one synergistic formulation to the patient in the form of separate entities. These are also applied to cocktail therapy, for example the administration of three or more active ingredients.
  • the intermediate compound functional groups may need to be protected by a suitable protecting group.
  • suitable protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, and the like.
  • Suitable protecting groups for amino, mercapto and fluorenyl include t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable mercapto protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T. W. and P. G. M. Wuts, Protective Groups in Organic Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymeric resin.
  • the present inventors prepared a novel compound having the structure shown in Formula I, and found that it has a good FGFR kinase inhibitory activity, and the compound is at a very low concentration (as low as ⁇ At 1 nmol/L, it has a specific inhibitory effect on FGFR kinase and is excellent in FGFR-related tumor cell proliferation inhibitory activity, and thus can be used for treating diseases associated with abnormal FGFR kinase mutation or expression, such as tumors. Based on the above findings, the inventors completed the present invention.
  • the second step 2,4-dichloro-1,5-dimethoxy-3-methylbenzene (31 g, 0.14 mol) was dissolved in carbon tetrachloride (600 mL) and placed in a dry round bottom flask ( In 1000 mL), azobisisobutyronitrile (3.0 g, 0.018 mol) and N-bromosuccinimide (27.6 g, 0.154 mol) were successively added at room temperature. The reaction was carried out at 80 °C for 3 h, and the reaction was quenched with aqueous sodium hydrogen carbonate, and then extracted with dichloromethane. The organic phase was dried, concentrated, and crystallized from methyl tert-butyl ether to give compound 3-bromomethyl-2,4-dichloro- 1,5-Dimethoxybenzene (30 g, white solid).
  • Step 3 Add the compound 3-bromomethyl-2,4-dichloro-1,5-dimethoxybenzene (30 g, 0.1 mol) and acetonitrile (500 mL) to a dry 1000 mL round bottom flask at room temperature Trimethylsilyl cyanide (12 g, 0.34 mmol) and tetrabutylammonium fluoride (100 mL, 1 mol/L) were added. After stirring at room temperature for 1 h, TLC showed the reaction was completed. The reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjj Base)-acetonitrile (20 g, white solid).
  • Step 4 In a dry 250 mL round bottom flask, add (2,6-dichloro-3,5-dimethoxy-phenyl)-acetonitrile (10.4 g, 0.028 mol) and N,N-dimethyl Base carboxamide (100 mL) was added 4-amino-2-methylthio-pyrimidine-5-carbaldehyde (5 g, 0.02 mol) and potassium carbonate (12.25 g, 0.06 mol), and then stirred overnight until the reaction was completed. The reaction mixture was extracted with EtOAc. EtOAc (EtOAc m.
  • Step 2 3-[4-(2,6-Dichloro-3,5-dimethoxy-phenyl)-8-methylthio-3,7,9,9b-tetraaza-cyclo Methyl amyl [a]naphthalen-2-yl]-propanoate (2.4 g) was dissolved in anhydrous methanol (20 mL). The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride, and the solvent was evaporated.
  • the third step 3-[4-(2,6-dichloro-3,5-dimethoxy-phenyl)-8-methylthio-3,7,9,9b-tetraaza-cyclo Amyl [a]naphthalen-2-yl]-propan-1-ol (1.8 g) was dissolved in ethyl acetate (20 mL), and then evaporated and evaporated. The reaction mixture was quenched by the addition of sodium thiosulfate solution, and the organic phase was separated. The organic phase was washed with saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, filtered, and evaporated.
  • Step 1 Reductive amination of N-Boc diamine
  • Step 2 Oxidation of methylthio groups to methylsulfonyl groups
  • the methylsulfonate intermediate (1 eq.) and the starting amine (2 eq.) were dissolved in anhydrous N,N-dimethylformamide and heated to 100 ° C for 2 hours. After completion of the reaction, the mixture was extracted with methylene chloride. The organic phase was washed with saturated sodium hydrogen sulfate and water, dried over anhydrous sodium sulfate, filtered,
  • the starting material (1 eq.) was dissolved in dichloromethane, and the mixture was stirred for 2 hr. After completion of the reaction, the mixture was concentrated under reduced pressure.
  • Example 2 1-(4-(3-(4-(2,6-Difluoro-3,5-dimethoxyaniline)-8-(methylamine)imidazole [1,2-a][1 ,6]naphthyridin-2-yl)propyl)piperazin-1-yl)prop-2-en-1-one
  • Example 4 1-(4-(3-(2-((cyclopropylmethyl)amino)-6-(2,6-dichloro-3,5-dimethoxyaniline) imidazole [1' , 2':1,6]pyridine [2,3-d]pyrimidin-8-yl)propyl)piperazin-1-yl)prop-2-en-1-one
  • Example 5 1-(4-(3-(4-(2,6-Dichloro-3,5-dimethoxyaniline)-8-(methylamine)imidazole [1,2-a][1 ,6]naphthyridin-2-yl)propyl)piperazin-1-yl)prop-2-en-1-one
  • Example 6 1-(4-(3-(6-(2,6-Dichloro-3,5-dimethoxyaniline)-2-((2-methoxyethyl)amino)imidazole [ 1',2':1,6]pyridine [2,3-d]pyrimidin-8-yl)propyl)piperazin-1-yl)prop-2-en-1-one
  • Example 7 1-(4-(3-(6-(2,6-Dichloro-3,5-dimethoxyaniline)-2-((2-(4-methylpiperazin-1-) Ethyl ethyl)amino)imidazole [1',2':1,6]pyridine [2,3-d]pyrimidin-8-yl)propyl)piperazin-1-yl)prop-2-ene 1-ketone
  • Example 8 1-(4-(3-(6-(2,6-Dichloro-3,5-dimethoxyaniline)-2-(ethylamine)imidazole [1', 2': 1, 6]pyridine [2,3-d]pyrimidin-8-yl)propyl)piperazin-1-yl)prop-2-en-1-one
  • Example 10 1-(4-(3-(6-(2,6-Dichloro-3,5-dimethoxyaniline)-2-((2,3-dihydroxypropyl)amino)imidazole [1',2':1,6]pyridine [2,3-d]pyrimidin-8-yl)propyl)piperazin-1-yl)prop-2-en-1-one
  • Example 12 1-(4-(3-(6-(2,6-Dichloro-3,5-dimethoxyaniline)-2-((2-hydroxy-2-methylpropyl)amino) Imidazole [1',2':1,6]pyridine [2,3-d]pyrimidin-8-yl)propyl)piperazin-1-yl)prop-2-en-1-one
  • Example 14 1-(4-(3-(6-(2,6-Dichloro-3,5-dimethoxyaniline)-2-(methylamine)imidazole [1', 2':1, 6]pyridine [2,3-d]pyrimidin-8-yl)propyl)-2,2-dimethylpiperazin-1-yl)prop-2-en-1-one
  • Example 15 1-(4-(3-(6-(2,6-Dichloro-3,5-dimethoxyaniline)-2-(methylamine)imidazole [1', 2':1, 6]pyridine [2,3-d]pyrimidin-8-yl)-2,2-dimethylpropyl)piperazin-1-yl)prop-2-en-1-one
  • Example 16 1-(4-((6-(2,6-Dichloro-3,5-phenyldimethoxyphenyl)-2-(methylamine)imidazole [1', 2': 1 ,6]pyridine [2,3-d]pyrimidin-8-yl)methyl)piperazin-1-yl)acrylamide
  • the second step the above intermediate (500 mg) was dissolved in anhydrous N,N-dimethylformamide (10 mL), and 1,3-dibromopropan-2-one (1.1 eq) was added at room temperature, heated at 80 degrees. The mixture was stirred until the reaction was completed. m ⁇
  • the third step the above crude product was dissolved in anhydrous N,N-dimethylformamide (10 mL), and N-Boc-piperazine (1.1 eq) was added to the mixture, and the mixture was stirred at room temperature for 2 hours, and the reaction was completed. The organic layer was extracted with EtOAc (EtOAc)EtOAc. LC-MS: 602.1/604.1.
  • Example 16 The compound of Example 16 was synthesized by the method described in General Method Three-General Method 5.
  • the intermediate 8-(4-aminophenyl)-6-(2,6-dichloro-3) is then prepared by the second step of the methylthio group oxidation reaction and the third step of the methylamine substitution reaction.
  • ,5-dimethoxyphenyl)-N-methylimidazo[1',2':1,6]pyridine [2,3-d]pyrimidin-2-amine, LC-MS: ESI [M+H ]+ 496.1/498.1.
  • the target compound N-(4-(6-(2,6-dichloro-3,5-phenyldimethoxyphenyl)-), was synthesized by the method of the fifth step of the acrylation reaction in the general method of the examples.
  • Example 18 1-(4-(3-(6-(2,6-Dichloro-3,5-dimethoxyphenyl)-2-(methylamine)imidazole [1', 2':1 ,6]pyridine [2,3-d]pyrimidin-8-yl)phenyl)piperazin-1-yl)acrylamide
  • Test Example 1 Determination of Inhibitory Activity of FGFR1 and FGFR4 Kinases by the Compounds of the Invention
  • Examples 1 to 19 provided by the present invention have better inhibitory activities against FGFR1 and FGFR4, and most of the compounds of the examples have inhibitory activity IC 50 values of less than 10 nM, and some examples (such as the examples) The inhibitory activity of 3) even an IC 50 of less than 1 nM showed a strong inhibitory activity. As shown in Table 1.
  • Test Example 2 Effect of the compound of the present invention on FGFR-mediated tumor cell proliferation ability
  • Test method Hep3B cells (ATCC) in logarithmic growth phase were inoculated into 96-well culture plates at a suitable density, 100 ⁇ L per well, and cultured overnight, and different concentrations of compounds were added for 72 hr, and set. The solvent control group (negative control) was incubated at 37 degrees under 5% CO 2 . 10 mM compound stock solution was added to the cells.
  • the effect of the compound on cell proliferation was determined by CellTiter- (Promega) assay, 30 ⁇ L of CTG reagent was added to each well, placed in a 37-degree incubator for 2-4 hours, and read with a full-wavelength microplate reader Envision at a wavelength of 450 nm.
  • Examples 1 to 19 provided by the present invention have an IC 50 value of less than 500 nM for the proliferation inhibitory activity of Hep3B cells, and most of the compounds of the examples have an inhibitory activity IC 50 value of less than 50 nM.
  • IC 50 ⁇ 20 nM is represented by "+++”
  • 20 nM ⁇ IC 50 ⁇ 200 nM is represented by "++”
  • IC 50 >200 nM is represented by "+”.
  • Test Example 3 Test of Example Compounds Not Different in Kinase Inhibitory Activity
  • the compounds of the invention also have inhibitory activities against different kinases such as EGFR, VEGFR, PDGFR, FGFR, RET, MET, Src, Lyn, Syk, MEK, CDK, RAF, ROS, etc., some of the compounds of the examples (eg
  • Example 3 shows better kinase selectivity with a selectivity greater than 100 fold.
  • Test Example 4 Proliferation inhibitory activity test of the compound of the example on different tumor cells
  • tumor cells such as HuH-7, JHH-7, DMS114, SNU-16, KG1, UM-UC-14, HCT116, NCI-H716, MCF-7, Colo-205, were tested by SRB staining or CCK8 assay.
  • Test Example 5 ADME-PK test of the compound of the example
  • Metabolic stability test 150 ⁇ L of liver microsomes (final concentration 0.5 mg/mL) were used for metabolic stability incubation.
  • the system contained NADPH (final concentration 1 mM), 1 ⁇ M test compound and positive control midazolam.
  • the lenil or negative control atenolol was stopped at 0 min, 5 min, 10 min and 30 min with tinidazole-containing acetonitrile, vortexed for 10 min, centrifuged at 15000 rpm for 10 min, and 50 ⁇ L of supernatant was injected into a 96-well plate.
  • the metabolic stability of the compound was calculated by measuring the relative reduction in the original drug.
  • Direct inhibition test direct inhibition of incubation with 100 ⁇ L of human liver microsomes (final concentration 0.2 mg/mL) containing NADPH (final concentration 1 mM), 10 ⁇ M compound, positive inhibitor cocktail (ketoconazole 10 ⁇ M, quinidine 10 ⁇ M, sulfaphenazole 100 ⁇ M, ⁇ -naphthoflavone 10 ⁇ M, tranylcypromine 1000 ⁇ M), negative control (0.1% DMSO in BPS) and mixed probe substrate (midazolam) 10 ⁇ M, testosterone 100 ⁇ M, dextromethorphan 10 ⁇ M, diclofenac 20 ⁇ M, phenacetin 100 ⁇ M, mefenexine 100 ⁇ M), and the reaction was terminated after incubation for 20 min. The relative activity of the enzyme was calculated by measuring the relative amount of production of the metabolite.
  • test animals were healthy adult male SD rats or BALB/c mice, provided by Shanghai Xipuerkekai Experimental Animal Co., Ltd.; administration mode and sample collection: respectively given to SD rats or BALB/c mice
  • Example 3 and Example 17 showed better ADME properties, and good in vivo absorption and metabolism properties of rats and mice, and indicators such as AUC/Cmax showed excellent compounds.
  • the medicinal properties were better ADME properties, and good in vivo absorption and metabolism properties of rats and mice, and indicators such as AUC/Cmax showed excellent compounds.
  • the medicinal properties were better ADME properties, and good in vivo absorption and metabolism properties of rats and mice, and indicators such as AUC/Cmax showed excellent compounds. The medicinal properties.
  • Test Example 6 Test of inhibition of growth inhibition of nude mice by the compound of the example
  • the tumor tissue in the vigorous growth period was cut into 1.5 mm 3 and inoculated subcutaneously in the right axilla of the nude mice under aseptic conditions.
  • the nude mice were transplanted subcutaneously with a vernier caliper to measure the diameter of the transplanted tumor.
  • the animals were randomly divided into tumors with an average volume of about 130 mm 3 .
  • the compound of the example administered to the desired concentration with water for injection containing 1% Tween 80
  • the diameter of the transplanted tumor was measured twice a week during the entire experiment, and the body weight of the mice was weighed.
  • Example 3 and Example 17 showed better tumor inhibition in nude mice, and at lower doses (even below 20 mg/kg), greater than 80% inhibition was achieved. rate.

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Abstract

本发明公开了一类氨基取代含氮稠环化合物及其制备方法和用途。本发明的氨基取代含氮稠环化合物结构如下式(I)所示，其中各基团的定义如说明书中所述。本发明的氨基取代含氮稠环化合物属于新型的特异性FGFR激酶抑制剂，对FGFR相关的肿瘤细胞增殖抑制活性相当优异，可以用于治疗与FGFR激酶突变或表达量异常引起的相关疾病如肿瘤。

Description

一类氨基取代含氮稠环化合物及其制备方法和用途
本申请要求申请日为2017年10月30日的中国专利申请CN201711039980.6的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于药物化学领域，具体涉及一类氨基取代含氮稠环化合物及其制备方法和用途。
背景技术
受体酪氨酸激酶的异常表达激活或基因突变在肿瘤的发生、发展、侵袭转移和耐药性产生等各个环节均发挥关键作用，以成为抗肿瘤药物研发的重要靶点。其中，成纤维生长因子受体(FGFR)是酪氨酸激酶家族的重要成员，主要包括FGFR1、FGFR2、FGFR3和FGFR4四种亚型。由于基因扩增、突变、融合或配体诱导等原因，FGFR各成员持续激活，诱导肿瘤细胞增殖、侵袭，促进血管生成并促进肿瘤恶化。FGFRs在多种肿瘤中高表达并异常激活，并且与肿瘤病人的不良预后密切相关。因此，FGFRs被公认为是抗肿瘤重要靶点，FGFR小分子抑制剂的研发逐步受到越来越多的关注。
临床发现多种癌症如肝细胞癌、胃癌、胰腺癌和胆管癌等恶性肿瘤的发生中均伴随着肿瘤组织的FGFR基因的过表达和过度激活。因此，特异性靶向成纤维细胞生长因子受体FGFR很可能成为多种肿瘤，特别是肝、胆细胞癌等的治疗的新策略，近年来引起各大制药公司的广泛关注。
发明内容
本发明所要解决的技术问题在于为了开发更多FGFR小分子抑制剂，因而提供了一类氨基取代含氮稠环化合物及其制备方法和用途，本发明的氨基取代含氮稠环化合物属于新型的特异性FGFR激酶抑制剂，对FGFR相关的肿瘤细胞增殖抑制活性相当优异，可以用于治疗FGFR激酶异常引起的相关疾病如肿瘤。
本发明是通过下述技术方案来解决上述技术问题的。
本发明提供了一种如式(I)所示的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，
Figure PCTCN2018112661-appb-000001
式中：
R 1选自氢、卤素、C 1-C 3烷基、氰基；优选自氢、卤素、甲基；
R 2选自氢、C 1-C 10烷基、3-8元环烷基或杂环烷基、5-8元芳基或杂芳基；优选自氢、C 1-C 6的取代或未取代的烷基；
R 3、R 4和R 5各自独立地选自氢、卤素、氰基、烷基、砜基、亚砜基、酰基、磺酰基、硝基；各自独立地优选选自氢、卤素、甲基；
M 1选自CR 6或N；R 6选自氢、卤素、C 1-C 3烷基；
Ar选自5-6元芳基或杂芳基；
L选自化学键、C 1-C 10烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、酰基、磺酰基、4-8元环烷基或杂环烷基、5-10元芳基或杂芳基；优选自C 1-C 6烷基；
A选自4-8元环烷基或杂环烷基、5-10元芳基或杂芳基；优选自5-6元杂环烷基、5-6元芳基或杂芳基；
上述的任一基团上的一个或多个氢原子或被选自下组的取代基取代：氘、卤素、羟基、氨基、氰基、砜基或亚砜基、C 1-C 8烷基、C 3-C 8环烷基、C 1-C 8烷氧基、C 1-C 8烷基氨基、C 2-C 6烯基、C 2-C 6炔基、C 2-C 6酰基或磺酰基、5-8元芳基或杂芳基、4-8元饱和环烷基或杂环烷基；其中，所述的杂芳基包含1-3个选自下组的杂原子：N、O、P和S；所述的杂环烷基包含1-3个选自下组的杂原子：N、O、P和S。
上述定义中所述的各个环系各自独立地可为单环、并环、稠环、桥环或螺环；所述的杂芳基或被部分氧化和/或还原。
进一步地，本发明所述的如式(I)所示的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，
式中，
M 1优选选自CH或N；
R 1优选选自氢、卤素(例如氟)、C 1-C 3烷基(例如甲基)；
R 2优选选自氢、C 1-C 6烷基(例如甲基)、C 1-C 6氘代烷基(例如-CD 3)、C 1-C 6卤代烷基(例如-CH 2C(CH 3) 2F)、5-8元芳基或杂芳基、4-6元环烷基或杂环烷基-(CH 2)x-、O(R 6)-(CH 2)y-、N(R 7)(R 8)-(CH 2)z-、N(CH 3) 2C(＝O)CH-、HOC(CH 3) 2CH-或CH(CH 2OH) 2-CH 2-；其中，所述的5-8元芳基或杂芳基优选为吡啶基、且优选进一步被一个6元杂环烷基(例如N-甲基哌嗪环基)取代；所述的4-6元的环烷基或杂环烷基优选为环丙基、四氢呋喃基、哌嗪基、哌啶基或四氢吡咯基，且优选进一步被C 1-C 6烷基(例如甲基)或氨基取代；R 6、R 7和R 8各自独立地选自氢或C 1-C 6烷基(例如甲基)；x、y和z各自独立地选自0、1、2、3或4；
进一步优选R 2选自H、甲基、-CD 3、-CH 2C(CH 3) 2F、N(CH 3) 2C(＝O)CH-、HOC(CH 3) 2CH-、CH(CH 2OH) 2-CH 2-、
Figure PCTCN2018112661-appb-000002
CH 3OCH 2CH 2-、
Figure PCTCN2018112661-appb-000003
Figure PCTCN2018112661-appb-000004
R 3、R 4和R 5各自独立地优选选自氢、卤素(例如氟)或N(R 9)(R 10)-(CH 2)p-(其中R 9和R 10均为C 1-C 6烷基，p选自0、1或2；例如N(R 9)(R 10)-(CH 2)p-为二甲胺基亚甲基)；更优选R 3选自氢或氟，且R 4和R 5选自氢；
Ar优选选自6元芳基即苯基，且进一步优选所述苯基上的一个或多个(例如一个、两个、三个或四个)氢原子被选自卤素、氰基、C 1-C 8烷基、C 1-C 8烷氧基、氨基、羟基、C 2-C 6酰基或磺酰基的取代基(进一步优选卤素或C 1-C 8烷氧基)所取代；更进一步优选为被两个卤素(例如氟或氯)和两个C 1-C 8烷氧基(例如甲氧基)所取代，例如
Figure PCTCN2018112661-appb-000005
Figure PCTCN2018112661-appb-000006
L优选为化学键、-(CH 2) d-(其中d为1、2或3，例如-CH 2-、-CH 2CH 2-或-CH 2CH 2CH 2-)、-(CH 2) e-CH＝CH-(其中e为1或2，例如-CH 2-CH＝CH-，并优选其中C sp3碳原子与环A相连)，或-O-(CH 2) n-(其中n为1、2、3或4，例如-O-CH 2CH 2-，且优选其中氧原子与 环A相连)；
A优选选自5-6元杂环烷基(所述5-6元杂环烷基进一步优选为哌嗪基、哌啶基或四氢吡咯基)、5-6元杂芳基-NH-(所述5-6元杂芳基进一步优选为吡啶基、噁唑基或三氮唑基)、-Ph-(CH 2) o-NH-(其中o选自0或1)、5-6元杂芳基-(CH 2) m-5-6元杂环烷基-(其中所述5-6元杂环烷基进一步优选为哌嗪基、哌啶基或四氢吡咯基，所述的5-6元杂芳基进一步优选为吡啶基、噁唑基或三氮唑基，m选自0或1)；且A优选其上两个取代基为间位或对位取代关系；
进一步优选A为下述结构片段：
Figure PCTCN2018112661-appb-000007
其中，L总是与A结构中芳基、杂芳基或者非脂肪胺基的一端连接。
进一步地，本发明所述的如式(I)所示的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其中，所述的如式(I)所示的化合物具有如下结构：
Figure PCTCN2018112661-appb-000008
进一步优选为如下结构：
Figure PCTCN2018112661-appb-000009
其中，n选自0、1或2，M 1和R 2的定义如上所述；B环为5-10元的芳香环或芳香杂环；优选为苯环、吡啶环、噁唑环或三氮唑环。
进一步地，本发明所述的如式(I)所示的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其中，所述的如式(I)所示的化合物具有如下结构：
Figure PCTCN2018112661-appb-000010
其中，n选自0、1或2，R 2的定义如上所述。
进一步优选为如下结构：
Figure PCTCN2018112661-appb-000011
其中，R 2的定义如上所述。
更进一步地，本发明如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其中，所述如式(I)所示的化合物为如下任一化合物：
Figure PCTCN2018112661-appb-000012
Figure PCTCN2018112661-appb-000013
Figure PCTCN2018112661-appb-000014
进一步地，本发明还提供了一种如式(I)所示的化合物的制备方法，其包括下述步骤：
a)在酸或碱存在的条件下，将通式(A)化合物与α-卤代羰基化合物或其等效物进行缩合反应，制备得到通式(B)化合物；和
b)在酸、碱或过渡金属催化剂存在的条件下，将通式(B)化合物与胺类化合物进行取代反应或者偶联反应，制备得到通式(C)化合物；和
c)在碱或缩合试剂存在的条件下，将通式(C)化合物与丙烯酸或丙烯酰氯类化合物进行缩合反应，制备得到通式(I)化合物；
Figure PCTCN2018112661-appb-000015
各式中，LG代表本领域此类反应中常规所用的离去基团，如卤素、砜基、亚砜基、磺酸酯基，其他各基团的定义如上所述。
优选地，所述步骤a)、b)、c)各自在溶剂中进行，且所述溶剂各自独立地选自水、甲醇、乙醇、异丙醇、乙二醇、N-甲基吡咯烷酮、二甲基亚砜，四氢呋喃、甲苯、二氯甲烷、1，2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、和二氧六环中的一种或多种；
优选地，所述过渡金属催化剂选自三(二亚苄基丙酮)二钯(Pd 2(dba) 3)、四(三苯基膦)钯(Pd(PPh 3) 4)、醋酸钯、氯化钯、二氯二(三苯基膦)钯、三氟醋酸钯、三苯基膦醋酸钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、双(三邻苯甲基膦)二氯化钯、和1,2-二(二苯基膦基)乙烷二氯化钯中的一种或多种；所述催化剂配体选自三叔丁基膦、四氟硼酸三叔丁基膦、三正丁基膦、三苯基膦、三对苯甲基膦、三环己基膦、和三邻苯甲基膦中的一种或多种；
优选地，所述缩合试剂选自DCC、DIC、CDI、EDCI、HOAt、HOBt、BOP、PyBOP、HATU、和TBTU中的一种或多种；
优选地，所述的碱包括有机碱和/或无机碱；其中，所述无机碱选自氢化钠、氢氧化钾、醋酸钠、醋酸钾、叔丁醇钾、叔丁醇钠、氟化钾、氟化铯、磷酸钾、碳酸钾、碳酸氢钾、碳酸钠、和碳酸氢钠中的一种或多种；所述有机碱选自吡啶，三乙胺，N，N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、六甲基二硅基锂、六甲基二硅基钠、和二甲基吡啶中的一种或多种；
优选地，所述酸选自盐酸、硫酸、磷酸、甲磺酸、甲苯磺酸、三氟乙酸、甲酸、乙酸、和三氟甲磺酸中的一种或多种。
本发明中，所述的通式(A)化合物以及上述制备方法中所涉及到的各个试剂均市售可得，或可由本领域技术人员参照现有技术中的合成方法制备得到。
根据本发明公开的上述制备方法，本领域技术人员可采用与之相同的原理和方法，制得本发明的通式化合物(I)中涉及的各具体化合物。
进一步地，本发明还提供了一种药物组合物，其包括治疗有效量的如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，以及至少一种药用辅料。
进一步地，本发明还提供了一种如式(I)所示的化合物、或其药学上可接受的盐、或 其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，或上述药物组合物在制备FGFR激酶抑制剂中的应用。
进一步地，本发明还提供了一种如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，或上述药物组合物在制备预防和/或治疗与蛋白激酶特别是FGFR激酶活性或表达量相关的疾病的药物中的应用，特别是制备预防和/或治疗抗肿瘤药物中的应用。其中，所述的肿瘤包括但不限于以下一种或几种：非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、前列腺癌、肝癌、皮肤癌、胃癌、上皮细胞癌、胃肠道间质瘤、肠癌、胆管癌、胆囊癌、结直肠癌、脑癌、白血病、淋巴癌、鼻咽癌、膀胱癌、胰腺癌等，特别是肝癌或胆管癌。
进一步地，本发明还提供了一种预防和/或治疗肿瘤的方法，所述的方法包括给予需要其的个体治疗有效量的如式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药。
本发明的入式(I)所示的化合物，可以抑制多种肿瘤细胞，尤其是能高效地杀死肝细胞癌细胞，是一类全新作用机制的肝细胞癌治疗药物。
术语
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4TH ED."Vols.A(2000)and B(2001),Pl烯um Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒 的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
本发明中，当其中一个变量选自化学键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表化学键时表示该结构实际上是A-Z；当采用类似“R 1-R 2-R 3-”的形式对取代基的类型和范围进行定义时，其表示如“R 1-R 2-R 3-”所示的取代基整体上是以R 3与所述的化合物母体直接成键，并且其中的如R 1、R 2、R 3所示的取代基彼此之间通过化学键依次键合。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH2O-等同于-OCH2-。
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如，C1-6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。
在本申请中，术语“卤素”是指氟、氯、溴或碘。
“羟基”是指-OH基团。
“羟基烷基”是指被羟基(-OH)取代的如下文所定义的烷基。
“羰基”是指-C(＝O)-基团。
“硝基”是指-NO 2。
“氰基”是指-CN。
“氨基”是指-NH 2。
“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、芳烷基、杂芳烷基取代的氨基，例如，单烷基氨基、二烷基氨基、烷基酰氨基、芳烷基氨基、杂芳烷基氨基。
“羧基”是指-COOH。
在本申请中，作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中)，术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至12个(优选为1至8个，更优选为1至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。
在本申请中，作为基团或是其它基团的一部分，术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个(优选为2至10个，更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。
在本申请中，作为基团或是其它基团的一部分，术语“炔基”意指仅由碳原子和氢原子组成、含有至少一个三键和任选的一个或多个双键、具有例如2至14个(优选为2至10个，更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙炔基、丙-1-炔基、丁-1-炔基、戊-1-烯-4-炔基等。
在本申请中，作为基团或是其它基团的一部分，术语“环烷基”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基，其可包括稠合环体系、桥环体系或螺环体系，具有3至15个碳原子，优选具有3至10个碳原子，更优选具有3至8个碳原子，且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明，环烷基中的碳原子可以任选地被氧化。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1H-茚基和八氢-2,5-亚甲基-并环戊二烯基等。
在本申请中，作为基团或是其它基团的一部分，术语“杂环基”意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系、桥环体系或螺环体系；其杂环基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化；且杂环基可为部分或完全饱和。杂环基可以经 由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中，一个或多个环可以是下文所定义的芳基或杂芳基，条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言，杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团，更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于：吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。
在本申请中，作为基团或是其它基团的一部分，术语“芳基”意指具有6至18个碳原子(优选具有6至10个碳原子)的共轭烃环体系基团。就本发明的目的而言，芳基可以为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。
在本申请中，术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。
在本申请中，作为基团或是其它基团的一部分，术语“杂芳基”意指环内具有1至15个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明，否则杂芳基可为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化。就本发明的目的而言，杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团，更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、三唑基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、 蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁三唑基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]三唑并[4,3-b]哒嗪、[1,2,4]三唑并[4,3-a]吡嗪、[1,2,4]三唑并[4,3-c]嘧啶、[1,2,4]三唑并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。
在本申请中，术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。
在本申请中，“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。
“立体异构体”是指由相同原子组成，通过相同的键键合，但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。
当本发明的化合物中含有烯双键时，除非另有说明，否则本发明的化合物旨在包含E-和Z-几何异构体。
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。
本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子，且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体，以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald 
Figure PCTCN2018112661-appb-000016
 and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL'S烯CYCLOPEDIAOF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Sci烯tific and Technical Ltd.,Essex,1991, 809-816；Heller,Acc.Chem.Res.1990,23,128。
在本申请中，术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
“多晶型物”是指本发明的某些化合物在固体状态下由于存在两种或两种以上不同分子排列而产生的不同固体结晶相。本发明的某些化合物可以存在多于一种晶型，本发明旨在包括各种晶型及其混合物。
通常，结晶化作用会产生本发明化合物的溶剂化物。本发明中使用的术语“溶剂化物”是指包含一个或多个本发明化合物分子与一个或多个溶剂分子的聚集体。溶剂可以是水，该情况下的溶剂化物为水合物。或者，溶剂可以是有机溶剂。因此，本发明的化合物可以以水合物存在，包括单水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等，以及相应的溶剂化形式。本发明化合物可形成真实的溶剂化物，但在某些情况 下，也可以仅保留不定的水或者水加上部分不定溶剂的混合物。本发明的化合物可以在溶剂中反应或者从溶剂中沉淀析出或结晶出来。本发明化合物的溶剂化物也包含在本发明的范围之内。
本发明还包括上述化合物的前药。在本申请中，术语“前药”表示可在生理学条件下或通过溶剂分解而被转化成本发明的生物活性化合物的化合物。因此，术语“前药”是指本发明的化合物的药学上可接受的代谢前体。当被给予有需要的个体时，前药可以不具有活性，但在体内被转化成本发明的活性化合物。前药通常在体内迅速转化，而产生本发明的母体化合物，例如通过在血液中水解来实现。前药化合物通常在哺乳动物生物体内提供溶解度、组织相容性或缓释的优点。前药包括已知的氨基保护基和羧基保护基。具体的前药制备方法可参照Saulnier,M.G.,et al.,Bioorg.Med.Chem.Lett.1994,4,1985-1990；Greenwald,R.B.,et al.,J.Med.Chem.2000,43,475。
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中，“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明所述“肿瘤”，“细胞增殖异常相关疾病”等包括但不限于白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌等疾病。
本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
本文所用的术语“治疗”和其它类似的同义词包括以下含义：
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者
(iv)减轻该疾病或病症所造成的症状。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington's,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。
本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。
本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organic Synthesis, (1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，制备了一类具有式I所示结构新颖的化合物，并发现其具有较好的FGFR激酶抑制活性，且所述的化合物在极低浓度(可低至≤1nmol/L)下，即对FGFR激酶产生特异性抑制作用，并且对FGFR相关的肿瘤细胞增殖抑制活性相当优异，因而可以用于治疗与FGFR激酶突变或表达量异常引起的相关疾病如肿瘤。基于上述发现，发明人完成了本发明。
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法、通常按照常规方法和条件，或按照商品说明书选择。除非另外说明、否则百分比和份数是重量百分比和重量份数。
中间体制备
中间体1：6-(2,6-二氯-3,5-二甲氧基-苯基)-2-甲硫基-吡啶[2,3-d]嘧啶-7-基胺
Figure PCTCN2018112661-appb-000017
第一步：将1,3-二甲氧基-5-甲基苯(30g,0.20mol)和二氯甲烷(900mL)加入干燥的圆底烧瓶(1L)中，冰浴冷却下向上述溶液滴加二氯化砜(52.5g,0.40mol)，滴加完毕，室温搅拌过夜。反应结束后，滴加碳酸氢钠水溶液调节pH＝8，二氯甲烷萃取，分别用稀盐酸、蒸馏水洗涤，干燥，减压浓缩得到化合物2,4-二氯-1,5-二甲氧基-3-甲基苯(31g,白色固体)，直接用于下步反应。
第二步：将2,4-二氯-1,5-二甲氧基-3-甲基苯(31g,0.14mol)溶解于四氯化碳(600mL)后置于干燥的圆底烧瓶(1000mL)中，室温下依次加入偶氮二异丁氰(3.0g,0.018mol)及N-溴代丁二酰亚胺(27.6g,0.154mol)。80度下反应3h，加入碳酸氢钠水溶液淬灭反应，再用二氯甲烷萃取，有机相干燥，浓缩，甲基叔丁基醚结晶得到化合物3-溴甲基-2,4-二氯-1,5-二甲氧基苯(30g,白色固体)。
第三步：在干燥的1000mL圆底烧瓶中加入化合物3-溴甲基-2,4-二氯-1,5-二甲氧基苯(30g,0.1mol)和乙腈(500mL)，室温下加入三甲基硅氰(12g,0.34mmol)和四丁基氟化铵(100mL,1mol/L)。室温搅拌1h，TLC显示反应结束。反应液减压浓缩，乙酸乙酯稀释，有机相分别用水和饱和食盐水洗，干燥浓缩，浓缩物用乙酸乙酯打浆得到化合物(2,6-二氯-3,5-二甲氧基-苯基)-乙腈(20g,白色固体)。
第四步：在干燥的250mL圆底烧瓶中，加入(2,6-二氯-3,5-二甲氧基-苯基)-乙腈(10.4g,0.028mol)和N,N-二甲基甲酰胺(100mL),室温下依次加入4-氨基-2-甲硫基-嘧啶-5-甲醛(5g,0.02mol)和碳酸钾(12.25g,0.06mol)，反应搅拌过夜直至反应完全。反应液用乙酸乙酯萃取，有机相用蒸馏水和饱和食盐水洗，干燥过滤，减压浓缩，浓缩物用硅胶柱色谱法以洗脱剂体系(二氯甲烷:甲醇＝30:1)纯化得到化合物6-(2,6-二氯-3,5-二甲氧基-苯基)-2-甲硫基-吡啶[2,3-d]嘧啶-7-基胺(3.7g,黄色固体)。LC-MS:ESI[M+H] +＝399.0；1H-NMR(400MHz,CDCl 3)δ8.80(s,1H),7.69(s,1H),6.67(s,1H),3.97(s,,6H),2.68(s,3H)。
中间体2：7-氯-3-(2,6-二氯-3,5-二甲氧基-苯基)-[1,6]萘啶-2-基胺
Figure PCTCN2018112661-appb-000018
在干燥的250mL圆底烧瓶中，加入4-氨基-6-氯-吡啶-3-甲醛(2g,0.013mol)和N-甲基吡咯烷酮(20mL),然后依次加入化合物(2,6-二氯-3,5-二甲氧基-苯基)-乙腈(4.4g,0.018mol)，碳酸钾(5.27g,0.039mol),80度下搅拌反应。反应结束后，反应液用乙酸乙酯萃取，有机相依次用蒸馏水和饱和食盐水洗，干燥过滤，减压浓缩，浓缩物用硅胶柱色谱法以洗脱剂体系(二氯甲烷:甲醇＝30:1)纯化得到化合物7-氯-3-(2,6-二氯-3,5-二甲氧基-苯基)-[1,6]萘啶-2-基胺(0.8g,黄色固体)。LC-MS:ESI[M+H] +＝383.9；1H-NMR(400MHz,DMSO-d6)δ8.71(s,1H),7.88(s,1H),7.34(s,1H),7.00(s,1H),3.94(s,6H)。
采用上述方法制备得到以下中间体：
Figure PCTCN2018112661-appb-000019
Figure PCTCN2018112661-appb-000020
中间体5：3-[4-(2,6-二氯-3,5-二甲氧基-苯基)-8-甲硫基-3,7,9,9b-四氮杂-环戊基[a]萘-2-基]-丙醛
第一步：将6-(2,6-二氯-3,5-二甲氧基-苯基)-2-甲硫基-吡啶并[2,3-d]嘧啶-7-基胺(4g)和三乙胺(3g)溶于N,N-二甲基甲酰胺(15mL)中，搅拌下加入5-氯-4-氧代-戊酸甲酯(3.2g)。滴加完毕，加热至80度搅拌过夜。反应完毕，加入二氯甲烷(40mL)萃取，有机相依次用饱和碳酸氢钠和水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离纯化得到3-[4-(2,6-二氯-3,5-二甲氧基-苯基)-8-甲硫基-3,7,9,9b-四氮杂-环戊基[a]萘-2-基]-丙酸甲酯(2.4g)。LC-MS:ESI[M+H] +＝507.3。
第二步：将3-[4-(2,6-二氯-3,5-二甲氧基-苯基)-8-甲硫基-3,7,9,9b-四氮杂-环戊基[a]萘-2-基]-丙酸甲酯(2.4g)溶于无水甲醇(20mL)，冰浴冷却下分批加入硼氢化钠(150mg)固体，加热回流2小时。反应液中加入饱和氯化铵溶液淬灭反应，减压除去溶剂，二氯甲烷萃取，有机相依次用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤浓缩，柱层析分离纯化得到3-[4-(2,6-二氯-3,5-二甲氧基-苯基)-8-甲硫基-3,7,9,9b-四氮杂-环戊基[a]萘-2-基]-丙-1-醇(1.8g)。LC-MS:ESI[M+H] +＝480.3。
第三步：将3-[4-(2,6-二氯-3,5-二甲氧基-苯基)-8-甲硫基-3,7,9,9b-四氮杂-环戊基[a]萘-2-基]-丙-1-醇(1.8g)溶于乙酸乙酯(20mL),加入Dess-Martin氧化剂(1.3g)，加热回流3小时。反应液中加入硫代硫酸钠溶液淬灭反应，分出有机相，有机相分别用饱和碳酸氢钠溶液和水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离纯化，得到3-[4-(2,6-二氯-3,5-二甲氧基-苯基)-8-甲硫基-3,7,9,9b-四氮杂-环戊基[a]萘-2-基]-丙醛(1.1g)。LC-MS:ESI[M+H] +＝478.3。
采用中间体5相同的方法制备合成得到中间体6-9：
中间体6：3-(8-氯-4-(2,6-二氯-3,5-二甲氧基苯基)咪唑[1,2-a][1,6]萘啶-2-基)丙醛
Figure PCTCN2018112661-appb-000021
LC-MS:ESI[M+H] +＝464.3。
中间体7：3-(6-(2,6-二氟-3,5-二甲氧基苯基)-2-(甲硫基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶 -8-基)丙醛
Figure PCTCN2018112661-appb-000022
LC-MS:ESI[M+H] +＝445.3。
中间体8：
Figure PCTCN2018112661-appb-000023
LC-MS:ESI[M+H] +＝473.2。
目标产物的通用合成方法一
Figure PCTCN2018112661-appb-000024
步骤一：N-Boc二胺的还原氨化
将醛中间体(1eq.)和N-Boc二胺溶于无水甲醇中，滴加一滴冰醋酸，室温搅拌1小时后，冰浴冷却下分批加入硼氢化钠固体(2eq.),室温搅拌过夜。反应结束后，加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取，有机相分别用饱和碳酸氢钠溶液和水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离纯化等到目标中间体。
步骤二：甲硫基氧化成甲砜基
将甲硫基中间体(1eq.)溶于二氯甲烷中，冰浴冷却下分批加入间氯过氧苯甲酸(2eq.)，室温搅拌过夜。反应完毕，反应液用硫代硫酸钠溶液淬灭，分出有机相，依次用饱和碳酸氢钠溶液和水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离纯化得到甲砜基化合物中间体。
步骤三：胺取代甲砜基
将甲砜基中间体(1eq.)和原料胺(2eq.)溶于无水N,N-二甲基甲酰胺中，微波加热至100℃反应2小时。反应结束后，加入二氯甲烷萃取，有机相依次用饱和碳酸氢钠 溶液和水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离纯化得到硝基化合物中间体。
步骤四：脱Boc保护基
将原料(1eq.)溶于二氯甲烷，冰浴冷却下，加入三氟乙酸(10eq.)搅拌2小时。反应结束后，减压浓缩，剩余物未经纯化直接用于下一步反应。
步骤五：丙烯酰化
将哌嗪中间体(1eq.)和DIPEA(2eq.)溶于干燥的N,N-二甲基甲酰胺，冰浴冷却下缓慢滴加丙烯酰氯(1.2eq.)。滴加完毕，室温反应过夜。反应液用二氯甲烷和饱和碳酸氢钠溶液淬灭，分出有机相，分别用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，剩余物用制备HPLC或者Biotage Flash柱层析分离纯化，得到目标化合物。
采用中间体5-8为原料，以通用方法一所述步骤和方法制备得到以下实施例化合物：
实施例1：1-(4-(3-(6-(2,6-二氟-3,5-二甲氧基苯胺)-2-(甲胺)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-8-基)丙基)哌嗪-1-基)丙-2-烯-1-酮
Figure PCTCN2018112661-appb-000025
LC-MS:ESI[M+H]+＝552.3；H-NMR(400MHz,CD3OD)8.92(s,1H),8.30(s,1H),8.13(s,1H),7.31(s,1H),7.05(s,1H),6.59-6.65(dd,J＝10.4,16.8Hz,1H),6.10-6.15(dd,J＝2.0,16.8Hz,1H),5.65-5.69(dd,J＝2.0,10.4Hz,1H),3.92(s,6H),3.57-3.60(m,4H),3.01(s,3H),2.70-2.74(m,2H),2.59-2.62(m,6H),1.89-1.94(m,2H)。
实施例2：1-(4-(3-(4-(2,6-二氟-3,5-二甲氧基苯胺)-8-(甲胺)咪唑[1,2-a][1,6]萘啶-2-基)丙基)哌嗪-1-基)丙-2-烯-1-酮
Figure PCTCN2018112661-appb-000026
LC-MS:ESI[M+H]+＝551.3；H-NMR(400MHz,CD3OD)8.95(s,1H),8.29(s, 1H),8.11(s,1H),7.32(s,1H),7.21(s,1H),7.10(s,1H),6.61-6.65(dd,J＝10.4,16.8Hz,1H),6.12-6.15(dd,J＝2.0,16.8Hz,1H),5.63-5.68(dd,J＝2.0,10.4Hz,1H),3.93(s,6H),3.56-3.61(m,4H),3.03(s,3H),2.71-2.74(m,2H),2.60-2.63(m,6H),1.89-1.93(m,2H)。
实施例3：1-(4-(3-(6-(2,6-二氯-3,5-二甲氧基苯胺)-2-(甲胺)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-8-基)丙基)哌嗪-1-基)丙-2-烯-1-酮
Figure PCTCN2018112661-appb-000027
LC-MS:ESI[M+H]+＝583.8/585.7；H-NMR(400MHz,CD3OD)8.79(s,1H),8.25(s,1H),8.08(s,1H),7.28(s,1H),6.85(s,1H),6.61-6.68(dd,J＝10.4,16.8Hz,1H),6.10-6.14(dd,J＝2.0,16.8Hz,1H),5.65-5.68(dd,J＝2.0,10.4Hz,1H),3.87(s,6H),3.57-3.59(m,4H),3.01(s,3H),2.70-2.74(m,2H),2.59-2.62(m,6H),1.89-1.94(m,2H)。
实施例4：1-(4-(3-(2-((环丙基甲基)氨基)-6-(2,6-二氯-3,5-二甲氧基苯胺)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-8-基)丙基)哌嗪-1-基)丙-2-烯-1-酮
Figure PCTCN2018112661-appb-000028
LC-MS:ESI[M+2H]+＝312.5/313.5；H-NMR(400MHz,CD3OD)9.07(s,1H),8.18(s,1H),8.30(s,1H),7.37(s,1H),7.06(s,1H),6.74-6.81(m,1H),6.09(dd,J＝2.4,16.8Hz,1H),5.66(dd,J＝2.4,10.4Hz,1H),4.29(s,3H),3.57-3.61(m,4H),3.34-3.37(m,2H),2.65(t,J＝7.2Hz,2H),2.28-2.35(m,6H),1.75-1.82(m,2H),0.97-1.18(m,1H),0.46-0.48(m,2H),0.32-0.34(m,2H)。
实施例5：1-(4-(3-(4-(2,6-二氯-3,5-二甲氧基苯胺)-8-(甲胺)咪唑[1,2-a][1,6]萘啶-2-基)丙基)哌嗪-1-基)丙-2-烯-1-酮
Figure PCTCN2018112661-appb-000029
LC-MS:ESI[M+H]+＝583.4/585.4。H-NMR(400MHz,CD3OD)8.93(s,1H),8.32(s,1H),8.14(s,1H),7.31(s,1H),7.23(s,1H),7.08(s,1H),6.61-6.65(dd,J＝10.4,16.8Hz,1H),6.12-6.15(dd,J＝2.0,16.8Hz,1H),5.63-5.68(dd,J＝2.0,10.4Hz,1H),3.93(s,6H),3.57-3.65(m,4H),3.03(s,3H),2.71-2.74(m,2H),2.61-2.65(m,6H),1.87-1.92(m,2H)。
实施例6：1-(4-(3-(6-(2,6-二氯-3,5-二甲氧基苯胺)-2-((2-甲氧基乙基)氨基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-8-基)丙基)哌嗪-1-基)丙-2-烯-1-酮
Figure PCTCN2018112661-appb-000030
LC-MS:ESI[M+2H]+＝314.5/315.5；H-NMR(400MHz,CD3OD)8.97(s,1H),8.08(m,2H),7.39(s,1H),7.04(s,1H),6.74-6.81(m,1H),6.09(dd,J＝2.4,16.8Hz,1H),5.66(dd,J＝2.4,10.4Hz,1H),4.31(s,3H),3.58-3.64(m,4H),3.51-3.52(m,4H),3.31(s,3H),2.63-2.67(m,2H),2.31-2.35(,.6H),1.76-1.81(m,2H)。
实施例7：1-(4-(3-(6-(2,6-二氯-3,5-二甲氧基苯胺)-2-((2-(4-甲基哌嗪-1-基)乙基乙基)氨基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-8-基)丙基)哌嗪-1-基)丙-2-烯-1-酮
Figure PCTCN2018112661-appb-000031
LC-MS:ESI[M+H]+＝696.1/698.1；H-NMR(400MHz,CD3OD)8.77(s,1H),8.01(s,1H),7.15(s,1H),6.67(s,1H),6.52-6.58(m,1H),6.26(d,J＝16.8Hz,1H),6.16(s,1H),5.67(d,J＝10.4Hz,1H),3.96(s,6H),3.67(bs,4H),3.54(s,2H),2.80-2.83(m,2H),2.69-2.71(m,2H),2.42-2.59(m,14H),2.31(s,3H),1.93-1.96(m,2H)。
实施例8：1-(4-(3-(6-(2,6-二氯-3,5-二甲氧基苯胺)-2-(乙胺)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-8-基)丙基)哌嗪-1-基)丙-2-烯-1-酮
Figure PCTCN2018112661-appb-000032
LC-MS:ESI[M+H]+＝599.7/601.6；H-NMR(400MHz,CD3OD)8.96(s,1H),1.94(bs,2H),7.37(s,1H),7.05(s,1H),6.77(dd,J＝10.4,16.8Hz,1H),6.08(dd,J＝16.8,2.0Hz,1H),5.66(dd,J＝10.8,2.0Hz,1H),3.99(s,3H),3.50(bs,6H),2.65(t,J＝7.2Hz,2H),2.31-2.35(m,6H),1.79(t,J＝7.2Hz,2H),0.85(bs,3H)。
实施例9：1-(4-(3-(6-(2,6-二氯-3,5-二甲氧基苯胺)-2-((2-(二甲胺)乙基)氨基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-8-基)丙基)哌嗪-1-基)丙-2-烯-1-酮
Figure PCTCN2018112661-appb-000033
LC-MS:ESI[M+H]+＝321.1/321.9；H-NMR(400MHz,CD3OD)8.76(s,1H),8.00(s,1H),7.15(s,1H),6.66(s,1H),6.52-6.59(m,1H),6.27(d,J＝17,2Hz,1H),6.11(s,1H),5.67(d,J＝10.4Hz,1H),3.96(s,6H),3.68(m,4H),3.54(m,4H),2.78-2.82(m,2H),2.61-2.64(m,2H),2.43(m,6H),2.33(s,6H),1.92-1.95(m,2H)。
实施例10：1-(4-(3-(6-(2,6-二氯-3,5-二甲氧基苯胺)-2-((2,3-二羟基丙基)氨基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-8-基)丙基)哌嗪-1-基)丙-2-烯-1-酮
Figure PCTCN2018112661-appb-000034
LC-MS:ESI[M+H]+＝644.2/646.2。
实施例11：1-(4-(3-(6-(2,6-二氯-3,5-二甲氧基苯胺)-2-(((四氢呋喃-3-基)甲基)氨基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-8-基)丙基)哌嗪-1-基)丙-2-烯-1-酮
Figure PCTCN2018112661-appb-000035
LC-MS:ESI[M+H]+＝654.3/656.3。
实施例12：1-(4-(3-(6-(2,6-二氯-3,5-二甲氧基苯胺)-2-((2-羟基-2-甲基丙基)氨基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-8-基)丙基)哌嗪-1-基)丙-2-烯-1-酮
Figure PCTCN2018112661-appb-000036
LC-MS:ESI[M+H]+＝642.3/644.3。
实施例13：3-((8-(3-(4-丙烯酰哌嗪-1-基)丙基)-6-(2,6-二氯-3,5-二甲氧基苯胺)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-基)氨基)丙腈
Figure PCTCN2018112661-appb-000037
LC-MS:ESI[M+H]+＝623.2/625.2。
实施例14：1-(4-(3-(6-(2,6-二氯-3,5-二甲氧基苯胺)-2-(甲胺)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-8-基)丙基)-2,2-二甲基哌嗪-1-基)丙-2-烯-1-酮
Figure PCTCN2018112661-appb-000038
LC-MS:ESI[M+H]+＝612.4/614.4。
实施例15：1-(4-(3-(6-(2,6-二氯-3,5-二甲氧基苯胺)-2-(甲胺)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-8-基)-2,2-二甲基丙基)哌嗪-1-基)丙-2-烯-1-酮
Figure PCTCN2018112661-appb-000039
LC-MS:ESI[M+H]+＝612.3/614.3。
实施例16：1-(4-((6-(2,6-二氯-3,5-苯基二甲氧基苯基)-2-(甲胺)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-8-基)甲基)哌嗪-1-基)丙烯酰胺
Figure PCTCN2018112661-appb-000040
第一步：将6-(2,6-二氯-3,5-二甲氧基-苯基)-2-甲硫基-吡啶并[2,3-d]嘧啶-7-基胺原料(3mmol)溶于无水四氢呋喃(15mL),冰浴冷却下向其中加入磺酰氯(2.54ml,30mmol)，室温反应1h。反应结束后，向反应液中缓慢加入饱和碳酸氢钠水溶液焠灭，后用二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，蒸干溶剂，硅胶柱层析纯化得到中间体2-氯-6-(2,6-二氯-3,5-二甲氧基苯基)吡啶[2,3-d]嘧啶-7-胺(640mg)。LC-MS：385.1/387.1。1H-NMR(400MHz,CDCl3)δ8.80(s,1H),7.69(s,1H),6.67(s,1H),3.97(s,6H)。
第二步：将上述中间体(500mg)溶于无水N,N-二甲基甲酰胺(10mL)，室温下加入1,3-二溴丙-2-酮(1.1eq)，80度加热搅拌至反应完成，二氯甲烷萃取，依次用饱和碳酸氢钠、水洗涤，无水硫酸钠干燥，过滤，减压浓缩，粗品未经纯化直接用于下一步反应。
第三步：将上述粗品溶于无水N,N-二甲基甲酰胺(10mL)中，冰浴下加入N-Boc-哌嗪(1.1eq)，室温搅拌2小时，反应完成。二氯甲烷萃取，依次用饱和碳酸氢钠、水洗涤，无水硫酸钠干燥，过滤，减压浓缩，剩余物柱层析纯化得到中间体4。LC-MS：602.1/604.1。
第四～第六步：采用通用方法三-通用方法五所述的方法合成得到实施例化合物16。
Figure PCTCN2018112661-appb-000041
LC-MS:ESI[M+H]+＝556.2/558.2。
实施例17：N-(4-(6-(2,6-二氯-3,5-苯基二甲氧基苯基)-2-(甲胺)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-8-基)苯基)丙烯酰胺
Figure PCTCN2018112661-appb-000042
以对硝基-2-溴苯乙酮代替5-氯-4-氧代-戊酸甲酯，采用中间体5第一步相同的方法合成制备得到关环产物6-(2,6-二氯-3,5-二甲氧基苯基)-2-(甲硫基)-8-(4-硝基苯基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶，LC-MS:ESI[M+H]+＝542.4/544.4。
然后采用实施例通用制备方法第二步甲硫基氧化反应和第三步甲胺取代反应的方法制备得到中间体8-(4-氨基苯基)-6-(2,6-二氯-3,5-二甲氧基苯基)-N-甲基咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-2-胺，LC-MS:ESI[M+H]+＝496.1/498.1。
以实施例通用方法第五步丙烯酰化反应的方法合成制备得到目标化合物，N-(4-(6-(2,6-二氯-3,5-苯基二甲氧基苯基)-2-(甲胺)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-8-基)苯基)丙烯酰胺，LC-MS:ESI[M+H]+＝549.2/551.2；H-NMR(400MHz,CD 3OD)8.79(s,1H),8.49(s,1H),7.86(d,J＝8.0Hz,1H),7.77(s,1H),7.58(d,J＝7.2Hz,1H),7.21(s,1H),6.62(s,1H),6.36-6.40(m,1H),6.18-6.20(m,1H),5.62-5.70(m,2H),3.96(s,6H),3.20(d,J＝4.8Hz,3H)。
实施例18：1-(4-(3-(6-(2,6-二氯-3,5-二甲氧基苯基)-2-(甲胺)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-8-基)苯基)哌嗪-1-基)丙烯酰胺
Figure PCTCN2018112661-appb-000043
以叔丁基-4-(3-(2-溴代乙酰基)苯基)哌嗪-1-甲酸酯代替5-氯-4-氧代-戊酸甲酯，采用 实施例17相同的方法合成，制备得到目标产物。LC-MS:ESI[M+H]+＝618.2/620.2。
实施例19：N-(3-(6-(2,6-二氯-3,5-二甲氧基苯基)-2-(甲氨基)咪唑[1',2':1,6]吡啶[2,3-d]嘧啶-8-基)苄基)丙烯酰胺
Figure PCTCN2018112661-appb-000044
以叔丁基(3-(2-溴代乙酰基)苄基)甲酸酯代替5-氯-4-氧代-戊酸甲酯，采用实施例17相同的方法合成，制备得到目标产物。LC-MS:ESI[M+H]+＝563.1/565.1。
测试例1本发明化合物对FGFR1和FGFR4激酶抑制活性的测定
(1)配制1×Kinase buffer；(2)化合物浓度梯度的配制：受试化合物测试浓度为10uM起始,3倍稀释10个浓度，复孔测试，在96孔板中梯度稀释成100倍终浓度的10个不同浓度的溶液。然后用1×Kinase buffer将各浓度的化合物进一步稀释成5倍终浓度的中间稀释溶液；(3)将配制好的化合物溶液各取5μL分别加入384孔板的化合物孔，每个浓度单孔测试；阴性对照孔和阳性对照孔中分别加5μL的5％DMSO；(4)用1×Kinase buffer配制2.5倍终浓度的激酶溶液；(5)在化合物孔和阳性对照孔分别加10μL的2.5倍终浓度的激酶溶液；在阴性对照孔中加10μL的1×Kinase buffer；(6)1000rpm离心30秒，振荡混匀后室温孵育10分钟；(7)用1×Kinase buffer配制2.5倍终浓度的ATP和Kinase substrate22的混合溶液；(8)加入10μL的2.5倍终浓度的ATP和底物的混合溶液，起始反应；(9)将384孔板1000rpm离心30秒，振荡混匀后28℃分别孵育相应的时间；(10)加入30μL终止检测液停止激酶反应，1000rpm离心30秒，振荡混匀；(11)用Caliper EZ ReaderⅡ读取转化率，以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线，从而得出各个化合物对酶活性的IC 50值。
2.结果:本发明提供的实施例1-实施例19，对FGFR1和FGFR4具有较佳的抑制活性，绝大部分实施例化合物的抑制活性IC 50值均小于10nM，部分实施例(如实施例3)的抑制活性甚至IC 50小于1nM，显示了较强的抑制活性。如表1所示。
测试例2：本发明化合物对FGFR介导的肿瘤细胞增殖能力的影响试验
1、试验方法：试验方法：取处于对数生长期的Hep3B细胞(ATCC)按合适密度接种至96孔培养板中，每孔100μL，培养过夜后，加入不同浓度的化合物作用72hr，并设定溶剂对照组(阴性对照)，37度下在5％CO 2条件下孵育。将10mM化合物储备液加入细胞中，化合物作用细胞72h后，化合物对细胞增殖的影响采用CellTiter-
Figure PCTCN2018112661-appb-000045
(Promega)法检测，每孔加入30μL CTG试剂，置于37度培养箱中放置2-4小时后，用全波长式微孔板酶标仪Envision读数，测定波长为450nm。采用以下公式计算化合物对肿瘤细胞生长的抑制率(％):抑制率(％)＝(OD阴性对照孔-OD给药孔)/OD阴性对照孔×100％。IC 50值采用Graphpad Prism 5软件以四参数法回归求得。
2.结果:本发明提供的部分实施例1-实施例19，对Hep3B细胞的增值抑制活性的IC 50值均小于500nM，绝大部分实施例化合物的抑制活性IC 50值小于50nM，部分实施例化合物(如实施例3)的抑制活性IC 50值甚至小于10nM，显示了较强的细胞增殖抑制活性。如表1所示。
表1实施例化合物1-19对FGFR1/FGFR4激酶抑制活性及Hep3B细胞增殖抑制活性
Figure PCTCN2018112661-appb-000046
Figure PCTCN2018112661-appb-000047
表1中IC 50<20nM用“+++”表示，20nM<IC 50<200nM用“++”表示，IC 50>200nM用“+”表示。
测试例3：实施例化合物不不同激酶抑制活性的测试
本发明化合物对不同激酶如EGFR、VEGFR、PDGFR、FGFR、RET，MET，Src，Lyn、Syk、MEK、CDK、RAF、ROS等的抑制活性也进行了测试，部分实施例化合物(如
实施例3、实施例17)显示了较好的激酶选择性，选择性大于100倍。
测试例4：实施例化合物对不同肿瘤细胞的增殖抑制活性测试
采用SRB染色法或CCK8法，测试多种肿瘤细胞，如HuH-7、JHH-7、DMS114、SNU-16、KG1、UM-UC-14、HCT116、NCI-H716、MCF-7、Colo-205、KMS11、RT-112、OPM-2、NCI-H460、SNU-869、CNE、NCI-H2122、NCI-H1299、A549、MG63、Kappars-299、SK-OV-3、U87MG、BT474、LNCAP、A498、KYSE140、HUCC-T1、PANC-1等的增殖抑制活性，部分实施例化合物(如实施例3，实施例17)对不同细胞的增值抑制显示了较强的抑制活性，显示了较好的抗肿瘤活性，对多种肿瘤细胞的增殖抑制活性小于100nM。
测试例5：实施例化合物的ADME-PK测试
(1)代谢稳定性试验：用体系为150μL的肝微粒体(终浓度0.5mg/mL)进行代谢稳定性温孵，体系含NADPH(终浓度1mM)、1μM受试化合物和阳性对照咪达唑仑或阴性对照阿替洛尔，分别在0min、5min、10min和30min用含替硝唑的乙腈终止反应，涡旋10min，15000rmp离心10min，取50μL上清于96孔板中进样。通过测定原药的相对减少量计算化合物代谢稳定性。
(2)直接抑制试验(DI试验)：用体系为100μL的人肝微粒体(终浓度0.2mg/mL)进行直接抑制温孵，体系含NADPH(终浓度1mM)、10μM化合物、阳性抑制剂cocktail(酮康唑10μM，奎尼丁10μM，磺胺苯吡唑100μM，α-萘黄酮10μM，反苯环丙胺1000μM)、阴性对照(0.1％DMSO的BPS)和混合探针底物(咪达唑仑10μM、睾酮100μM、右美沙芬10μM、双氯芬酸20μM、非那西丁100μM，美芬妥英100μM)，温孵20min后终止反应。通过测定代谢物的相对生成量计算酶相对活性。
(3)应用LC/MS/MS法测定大鼠或小鼠分别灌胃和静注给予实施例化合物后不同时 刻血浆中的药物浓度，研究本发明化合物在大鼠或小鼠体内的药代动力学行为，评价其药动学特征。实验方案：试验动物为健康成年雄性SD大鼠或BALB/c小鼠，由上海西普尔必凯实验动物有限公司提供；给药方式及样品采集：分别给于SD大鼠或BALB/c小鼠静脉注射(3mg/kg，1mg/mL受试化合物的混悬液)和灌胃给药(10mg/kg，1mg/mL受试化合物的混悬液)，分别于给药前和给药后2、5、15、30、60、90、120、240、360、480、1440min于大鼠或小鼠眼底静脉丛取血0.4mL；取血浆样品50μL，分别加入200μL含内标的乙腈溶液沉淀蛋白，涡旋10min，6000转/分离心10min；取200μL上清6000转/分再次离心10min；再取75μL上清液，加梯度初始流动相稀释，6000转/分离心10min；最终取上清液70μL于96孔板中进样，进样量5μL，进行LC-MS-MS分析。
2、部分实施例化合物(如实施例3、实施例17)显示了较好的ADME性质，和良好的大鼠、小鼠的体内吸收和代谢性质，并且AUC/Cmax等指标均显示了化合物优良的成药性。
测试例6：实施例化合物对裸小鼠移植瘤生长抑制的测试
1、取生长旺盛期的瘤组织剪切成1.5mm 3左右，在无菌条件下，接种于裸小鼠右侧腋窝皮下。裸小鼠皮下移植瘤用游标卡尺测量移植瘤直径，待肿瘤平均体积至130mm 3左右将动物随机分组。实施例化合物(用含1％Tween 80的注射用水配置到所需浓度后待用)以给定剂量每天口服给药，连续给药三周，溶剂对照组给等量溶剂。整个实验过程中，每周2次测量移植瘤直径，同时称量小鼠体重。肿瘤体积(tumor volume,TV)的计算公式为：TV＝1/2×a×b 2，其中a、b分别表示长、宽。根据测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为：RTV＝Vt/V0。其中V0为分笼给药时(即d0)测量所得肿瘤体积，Vt为每一次测量时的肿瘤体积。抗肿瘤活性的评价指标为1)相对肿瘤增殖率T/C(％)，计算公式如下：T/C(％)＝(TRTV/CRTV)×100％，TRTV：治疗组RTV；CRTV：阴性对照组RTV；2)肿瘤体积增长抑制率GI％，计算公式如下：GI％＝[1-(TVt-TV0)/(CVt-CT0)]×100％，TVt为治疗组每次测量的瘤体积；TV0为治疗组分笼给药时所得瘤体积；CVt为对照组每次测量的瘤体积；CV0为对照组分笼给药时所得瘤体积；3)瘤重抑制率，计算公式如下：瘤重抑制率％＝(Wc-WT)/Wc×100％，Wc：对照组瘤重，WT：治疗组瘤重。
2、部分实施例化合物(如实施例3、实施例17)显示了较好的裸鼠体内抑瘤效果，在较低剂量下(甚至低于20mg/kg剂量)就能达到大于80％抑瘤率。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅 是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (10)

  1. 一种如式(I)所示的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，
    Figure PCTCN2018112661-appb-100001
    式中：
    R 1选自氢、卤素、C 1-C 3烷基、氰基；
    R 2选自氢、C 1-C 10烷基、3-8元环烷基或杂环烷基、5-8元芳基或杂芳基；
    R 3、R 4和R 5各自独立地选自氢、卤素、氰基、烷基、砜基、亚砜基、酰基、磺酰基、硝基；
    M 1选自CR 6或N；R 6选自氢、卤素、C 1-C 3烷基；
    Ar选自5-6元芳基或杂芳基；
    L选自化学键、C 1-C 10烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、酰基、磺酰基、4-8元环烷基或杂环烷基、5-10元芳基或杂芳基；
    A选自4-8元环烷基或杂环烷基、5-10元芳基或杂芳基；
    上述的任一基团上的一个或多个氢原子或被选自下组的取代基取代：氘、卤素、羟基、氨基、氰基、砜基或亚砜基、C 1-C 8烷基、C 3-C 8环烷基、C 1-C 8烷氧基、C 1-C 8烷基氨基、C 2-C 6烯基、C 2-C 6炔基、C 2-C 6酰基或磺酰基、5-8元芳基或杂芳基、4-8元饱和环烷基或杂环烷基；其中，所述的杂芳基包含1-3个选自下组的杂原子：N、O、P和S；所述的杂环烷基包含1-3个选自下组的杂原子：N、O、P和S。
  2. 如权利要求1所述的如式(I)所示的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其特征在于，
    式中，
    M 1选自CH或N；
    和/或，R 1选自氢、卤素、C 1-C 3烷基；
    和/或，R 2选自氢、C 1-C 6烷基、C 1-C 6氘代烷基、C 1-C 6卤代烷基、5-8元芳基或杂芳基、4-6元环烷基或杂环烷基-(CH 2)x-、O(R 6)-(CH 2)y-、N(R 7)(R 8)-(CH 2)z-、N(CH 3) 2C(＝O)CH-、HOC(CH 3) 2CH-或CH(CH 2OH) 2-CH 2-；其中，所述的5-8元芳基或杂芳基优选为吡啶基、且优选进一步被一个6元杂环烷基取代；所述的4-6元的环烷基或杂环烷基优选为环丙基、四氢呋喃基、哌嗪基、哌啶基或四氢吡咯基，且优选进一步被C 1-C 6烷基或氨基取代；R 6、R 7和R 8各自独立地选自氢或C 1-C 6烷基；x、y和z各自独立地选自0、1、2、3或4；
    和/或，R 3、R 4和R 5各自独立地选自氢、卤素或N(R 9)(R 10)-(CH 2)p-；其中R 9和R 10均为C 1-C 6烷基，p选自0、1或2；更优选R 3选自氢或氟，且R 4和R 5选自氢；
    和/或，Ar选自苯基，且进一步优选所述苯基上的一个或多个氢原子被选自卤素、氰基、C 1-C 8烷基、C 1-C 8烷氧基、氨基、羟基、C 2-C 6酰基或磺酰基的取代基所取代；更进一步优选为被两个卤素和两个C 1-C 8烷氧基所取代；
    和/或，L选自化学键、-(CH 2) d-、-(CH 2) e-CH＝CH-，或-O-(CH 2) n-；其中d为1、2或3，e为1或2，n为1、2、3或4；
    和/或，A选自5-6元杂环烷基、5-6元杂芳基-NH-、-Ph-(CH 2) o-NH-、5-6元杂芳基-(CH 2) m-5-6元杂环烷基-；其中，o选自0或1；所述5-6元杂环烷基进一步优选为哌嗪基、哌啶基或四氢吡咯基，所述的5-6元杂芳基进一步优选为吡啶基、噁唑基或三氮唑基，m选自0或1；且A优选其上两个取代基为间位或对位取代关系；
    其中，L总是与A结构中芳基、杂芳基或者非脂肪胺基的一端连接。
  3. 如权利要求2所述的如式(I)所示的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其特征在于，
    式中，
    R 2选自H、甲基、-CD 3、-CH 2C(CH 3) 2F、N(CH 3) 2C(＝O)CH-、HOC(CH 3) 2CH-、CH(CH 2OH) 2-CH 2-、
    Figure PCTCN2018112661-appb-100002
    CH 3OCH 2CH 2-、
    Figure PCTCN2018112661-appb-100003
    Figure PCTCN2018112661-appb-100004
    和/或，L选自化学键、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-CH 2-CH＝CH-、或-O-CH 2CH 2-；
    和/或，A选自下述结构片段：
    Figure PCTCN2018112661-appb-100005
  4. 如权利要求1-3任一项所述的如式(I)所示的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其特征在于，
    其中，所述的如式(I)所示的化合物具有如下结构：
    Figure PCTCN2018112661-appb-100006
    进一步优选为如下结构：
    Figure PCTCN2018112661-appb-100007
    其中，n选自0、1或2，M 1和R 2的定义均如权利要求1-3任一项所述；B环为5-10元的芳香环或芳香杂环；优选为苯环、吡啶环、噁唑环或三氮唑环。
  5. 如权利要求1-3任一项所述的如式(I)所示的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其特征在于，
    其中，所述的如式(I)所示的化合物具有如下结构：
    Figure PCTCN2018112661-appb-100008
    其中，n选自0、1或2，R 2的定义如权利要求1-3任一项所述；
    进一步优选为如下结构：
    Figure PCTCN2018112661-appb-100009
    其中，R 2的定义如权利要求1-3任一项所述。
  6. 如权利要求1所述的如式(I)所示的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，其特征在于，
    其中，所述如式(I)所示的化合物为如下任一化合物：
    Figure PCTCN2018112661-appb-100010
    Figure PCTCN2018112661-appb-100011
    Figure PCTCN2018112661-appb-100012
  7. 一种如权利要求1-6任一项所述的如式(I)所示的化合物的制备方法，其包括下述步骤：
    a)在酸或碱存在的条件下，将通式(A)化合物与α-卤代羰基化合物或其等效物进行缩合反应，制备得到通式(B)化合物；和
    b)在酸、碱或过渡金属催化剂存在的条件下，将通式(B)化合物与胺类化合物进行取代反应或者偶联反应，制备得到通式(C)化合物；和
    c)在碱或缩合试剂存在的条件下，将通式(C)化合物与丙烯酸或丙烯酰氯类化合物进行缩合反应，制备得到通式(I)化合物；
    Figure PCTCN2018112661-appb-100013
    各式中，LG为卤素、砜基、亚砜基、或磺酸酯基，其他各基团的定义如权利要求1-6任一项所述。
  8. 一种药物组合物，其包括治疗有效量的如权利要求1-6任一项所述的式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，以及至少一种药用辅料。
  9. 一种如权利要求1-6任一项所述的式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，或如权利要求8所述的药物组合物在制备FGFR激酶抑制剂中的应用。
  10. 一种如权利要求1-6任一项所述的式(I)所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，或如权利要求8所述的药物组合物在制备预防和/或治疗与蛋白激酶特别是FGFR激酶活性或表达量相关的疾病的药物中的应用，特别是制备预防和/或治疗抗肿瘤药物中的应用；其中，所述的肿瘤选自非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、前列腺癌、肝癌、皮肤癌、胃癌、上皮细胞癌、胃肠道间质瘤、肠癌、胆管癌、胆囊癌、结直肠癌、脑癌、白血病、淋巴癌、鼻咽癌、膀胱癌、胰腺癌，特别是肝癌或胆管癌。
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