WO2022206939A1 - 作为fgfr抑制剂的杂环化合物及其应用 - Google Patents

作为fgfr抑制剂的杂环化合物及其应用 Download PDF

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WO2022206939A1
WO2022206939A1 PCT/CN2022/084728 CN2022084728W WO2022206939A1 WO 2022206939 A1 WO2022206939 A1 WO 2022206939A1 CN 2022084728 W CN2022084728 W CN 2022084728W WO 2022206939 A1 WO2022206939 A1 WO 2022206939A1
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alkyl
compound
pharmaceutically acceptable
formula
stereoisomer
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PCT/CN2022/084728
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English (en)
French (fr)
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祝伟
邹昊
麦万笋
汪涛
陈祥
李正涛
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海南耀臻生物医药科技有限公司
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Priority to CN202280024337.9A priority Critical patent/CN117222640A/zh
Publication of WO2022206939A1 publication Critical patent/WO2022206939A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • Patent Application No. 202110380922.X filed with the State Intellectual Property Office of China on April 3, 2021;
  • Patent application No. 202210224490.8 submitted to the State Intellectual Property Office of China on March 7, 2022.
  • the invention belongs to the technical field of medicine, and relates to a heterocyclic compound of an FGFR inhibitor and a preparation method and application thereof.
  • FGFR Fibroblast Growth Factor Receptor, fibroblast growth factor receptor
  • FGF Fibroblast growth factor
  • FGFR signaling pathway Under normal physiological conditions, the FGFR signaling pathway is tightly regulated and is at a weakly activated level. And its excessive activation often leads to the occurrence and development of tumors.
  • the molecular mechanisms of abnormal activation of FGFR mainly include 1) gene amplification; 2) gene mutation; 3) gene fusion caused by gene translocation.
  • FGFR2 gene amplification occurs in gastric cancer (5-10%)
  • FGFR2 gene translocation occurs in intrahepatic cholangiocarcinoma (14%)
  • FGFR2 gene mutation occurs in endometrial cancer (12-14%).
  • FGFR3 genetic abnormalities are most commonly found in bladder cancer, including gene mutations (60-80% of non-muscle-invasive bladder cancers and 15-20% of muscle-invasive bladder cancers), gene translocations (3-6%), and gene Amplification (incidence not reported); followed by myeloma, with FGFR3 translocations in 15-20% of myeloma patients. Some of the above FGFR gene abnormalities have been confirmed to be associated with poor prognosis of patients.
  • the present invention provides a class of heterocyclic compounds of formula, and stereoisomers and pharmaceutically acceptable salts thereof. These compounds can inhibit the activity of FGFR, thereby affecting biological function.
  • the present invention provides a compound represented by formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof,
  • X, Z are each independently selected from CR 9 or N;
  • Ring A is selected from 5-10 membered heteroaryl or 5-10 membered heterocyclyl
  • Ring B is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl or C 3 -C 10 cyclic hydrocarbon group;
  • E is selected from C 3 -C 10 cyclic hydrocarbon group, C 6 -C 10 aryl group, 3-12 membered heterocyclic group or 5-12 membered heteroaryl group, said C 3 -C 10 cyclic hydrocarbon group C 6 -C 10 aryl group radical, 3-12 membered heterocyclyl or 5-12 membered heteroaryl optionally substituted with one or more R 1a ;
  • R 5 is independently selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 3-12 membered heterocyclyl or C 6 -C 10 aryl , the C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, C 3 -C 8 cyclic hydrocarbon group, 3-12-membered heterocyclic group or C 6 -C 10 aryl group are optionally replaced by one or more R 5a substitutions;
  • R 5a is independently selected from halogen, CN, N(R 5b ) 2 , OH, NO 2 , C 3 -C 8 cycloalkyl, or 3-12 membered heterocyclyl;
  • R 5b is independently selected from H or C 1 -C 6 alkyl
  • R 6 is selected from H, CN, halogen or C 1 -C 6 alkyl
  • R 7 is selected from C 1 -C 6 alkylene, C 3 -C 8 cycloalkylene or 3-12 membered heterocyclylene;
  • R 2 is selected from H, NH 2 , C 1 -C 6 alkyl, OH or halogen;
  • R 3 is independently selected from halogen, CN, NH 2 , OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy or C 3-8 cycloalkyl ;
  • R 4a is independently selected from halogen, CN, NH 2 , OH or C 1 -C 6 alkyl;
  • R 8a and R 8b are each independently selected from H, halogen, CN, NH 2 , OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkyl;
  • R 9 is selected from H, CN, OH, NH 2 , -NHR 10 , -NH-C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 3 -C 8 Cycloalkyl, said C1 - C6 alkyl, -NH- C1 - C6 alkyl, C1 - C6 alkoxy, or C3 - C8 cycloalkyl optionally surrounded by one or more R 10 substituted;
  • R 10 is independently selected from halogen, NH 2 , C 3 -C 8 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the NH 2 , C 3 - C8 cycloalkyl, 3-10 membered heterocyclyl, C6 - C10 membered aryl or 5-10 membered heteroaryl optionally substituted with one or more R11 ;
  • R 11 is independently selected from C 1 -C 6 alkyl, halogen, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl or 3-10 membered heterocyclyl, said C 1 -C 6 alkane group, C 3 -C 8 cycloalkyl or 3-10 membered heterocyclyl optionally by C 1 -C 6 alkyl, halogen, OH, -NH-C 1 -C 6 alkyl, -N(C 1 -C 6 alkyl) 2 substituted;
  • n and m are each independently selected from 0, 1, 2 or 3;
  • q is selected from 1, 2 or 3.
  • Ring A is selected from 5-10 membered heteroaryl.
  • Ring A is selected from 5-6 membered heteroaryl.
  • Ring A is selected from 5-6 membered heteroaryl or 5-6 membered heterocyclyl.
  • Ring A is selected from pyrimidinyl, pyridyl, or tetrahydropyrrolyl.
  • Ring A is selected from pyrimidinyl or tetrahydropyrrolyl.
  • Ring A is selected from pyridyl or pyrimidinyl.
  • Ring A is selected from pyrimidinyl.
  • Ring B is selected from C6 - C10 aryl or 5-10 membered heteroaryl.
  • Ring B is selected from C 6 -C 10 aryl or C 3 -C 10 cyclohydrocarbyl.
  • Ring B is selected from phenyl or cyclohexenyl.
  • Ring B is selected from phenyl.
  • W is selected from O.
  • Y is selected from N( CH3 ) or a bond.
  • Z is selected from CR9 .
  • E is selected from C3 - C6 cycloalkyl, C6 - C10 aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, the C3 - C6 cycloalkyl , C 6 -C 10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 1a .
  • E is selected from C 6 -C 10 aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, said C 6 -C 10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 1a .
  • E is selected from C 6 -C 10 aryl, 3-10 membered heterocyclyl, or 5-6 membered heteroaryl, said C 6 -C 10 aryl, 3-10 membered heterocyclyl or 5-6 membered heteroaryl optionally substituted with R 1a .
  • E is selected from the following groups optionally substituted with R 1a : phenyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furyl, thienyl, pyrrolyl , pyrazolyl, thiazolyl, imidazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, indolyl, quinolinyl, isoquinolinyl, Tetrahydropyrrolyl, tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2-pyridine Keto, 2-piperazinone, a
  • E is selected from the following groups optionally substituted with R 1a : phenyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furyl, thienyl, pyrrolyl , pyrazolyl, thiazolyl, imidazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, indolyl, quinolinyl, isoquinolinyl, Tetrahydropyrrolyl, tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2-pyridine Keto, 2-piperazinone, a
  • E is selected from the following groups optionally substituted with R 1a : phenyl, pyridyl, thienyl, pyrazolyl, imidazolyl, azetidinyl, tetrahydropyrrolyl, piperidine base, piperazinyl, tetrahydropyridyl, cyclohexyl, cyclohexenyl, morpholinyl, 2-piperazinone, 2-pyridone, 1,4-diazepanyl, bicyclic [1,1,1]Pentyl, 2,7-diazaspiro[4.4]nonanyl, 2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[4.5]decyl Spiro[3.5]nonanyl, 2,6-diazaspiro[3.5]nonyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diaza
  • E is selected from the following groups optionally substituted with R 1a : phenyl, pyridyl, thienyl, pyrazolyl, imidazolyl, azetidinyl, tetrahydropyrrolyl, piperidine base, piperazinyl, tetrahydropyridyl, cyclohexyl, cyclohexenyl, morpholinyl, 2-piperazinone, 2-pyridone, 1,4-diazepanyl, bicyclic [1,1,1]Pentyl, 2,7-diazaspiro[4.4]nonanyl, 2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[4.5]decyl Spiro[3.5]nonanyl, 2,6-diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diaza
  • R 1a is independently selected from halogen, CN, NH 2 , OH, -NR 8a R 8b , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-6 membered heterocyclyl , C 1 -C 6 alkoxy, the C 1 -C 6 alkyl, C 3 -C 8 cyclic hydrocarbon group, 3-6 membered heterocyclic group, C 1 -C 6 alkoxy optionally by one or Substituted with groups independently selected from halogen, OH, or C1 - C3alkoxy.
  • R 1a is independently selected from halogen, CN, NH 2 , OH, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-6 membered heterocyclyl, C 1 -C 6 Alkoxy, the C 1 -C 6 alkyl group, C 3 -C 8 cyclic hydrocarbon group, 3-6 membered heterocyclyl group, C 1 -C 6 alkoxy group are optionally selected by one or more independently selected from Group substitution with halogen, OH or C1 - C3alkoxy.
  • R 1a is independently selected from halogen, -NR 8a R 8b , C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, said C 1 -C 6 alkyl optionally being Substituted with one or more groups independently selected from halogen, OH, CN or C1 - C3alkoxy.
  • R 1a is independently selected from C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
  • R 1a is independently selected from Cl, F, CH 3 , -OCH 3 , CF 3 , -N(CH 3 ) 2 or CH 2 CN.
  • R 1a is independently selected from CH 3 or -OCH 3 .
  • R 6 is selected from H, F, Cl, CN or CH 3 .
  • R6 is selected from H, F, CN or CH3 .
  • R 5 is independently selected from H, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, said C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl being any optionally substituted with one or more R 5a .
  • R 5 is independently selected from H or C 1 -C 3 alkyl optionally substituted with one or more R 5a .
  • R 5a is independently selected from halogen, CN, N(R 5b ) 2 or 3-12 membered heterocyclyl.
  • R 5a is independently selected from halogen, CN, N(R 5b ) 2 or 3-6 membered heterocyclyl.
  • R 5a is independently selected from N(R 5b ) 2 or 3-6 membered heterocyclyl.
  • R 5a is independently selected from halogen, CN, N(CH 3 ) 2 , piperidinyl, or morpholinyl.
  • R 5a is independently selected from N(R 5b ) 2 , piperidinyl, or morpholinyl.
  • R 5b is independently selected from C 1 -C 6 alkyl.
  • R 5b is independently selected from CH 3 .
  • R 7 is selected from C 1 -C 6 alkylene, C 3 -C 6 cycloalkylene, or 3-6 membered heterocyclylene.
  • R7 is selected from the following groups: -CH2- , -CH( CH3 )-, -C( CH3 ) 2- ,
  • R7 is selected from the following groups: -CH2- , -CH( CH3 )-, -C( CH3 ) 2- ,
  • R 1 is selected from the following groups:
  • R 1 is selected from the following groups:
  • R 2 is selected from H, NH 2 , CH 3 , OH or halogen.
  • R 2 is selected from H, NH 2 , CH 3 or halogen.
  • R 2 is selected from H, NH 2 or halogen.
  • R 2 is selected from H or NH 2 .
  • R 3 is independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkyl.
  • R 3 is independently selected from halogen or C 1 -C 6 alkoxy.
  • R3 is selected from F and -OCH3 .
  • R3 is selected from halogen.
  • R3 is selected from F.
  • m is selected from 0 or 1.
  • R 4 is independently selected from halogen, CN, NH 2 , OH, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 3-10 membered heterocyclic group, the C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, C 3 -C 8 cycloalkyl group, 3-10 membered heterocyclic group are optionally replaced by one or more R 4a is substituted.
  • R 4 is independently selected from CN, halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • R 4 is independently selected from halogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
  • R 4 is independently selected from CN or C 1 -C 6 alkyl.
  • R4 is independently selected from CN or CH3 .
  • R 4 is independently selected from C 1 -C 6 alkyl.
  • R4 is independently selected from CH3 .
  • n is selected from 0 or 1.
  • R 9 is selected from H, NH 2 , -NHR 10 , -NH-C 1 -C 6 alkyl or C 1 -C 6 alkyl, said C 1 -C 6 alkyl or -NH -C 1 -C 6 alkyl is optionally substituted with one or more R 10 .
  • R 9 is selected from H, CN , OH, NH 2 , -NHR 10 or -NH - C 1 -C 6 alkyl, optionally by One or more R 10 substitutions.
  • R 10 is independently selected from halogen, NH 2 , C 3 -C 8 cycloalkyl or 3-10 membered heterocyclyl, said NH 2 , C 3 -C 8 cycloalkyl or 3-
  • the 10-membered heterocyclyl is optionally substituted with one or more R 11 .
  • R 10 is independently selected from halogen, NH 2 , C 3 -C 6 cycloalkyl, 5-6 membered heterocyclyl, C 6 -C 10 aryl, or 5-6 membered heteroaryl, Said NH2 , C3 - C6 cycloalkyl, 5-6 membered heterocyclyl, C6 - C10 aryl or 5-6 membered heteroaryl is optionally substituted with one or more R11 .
  • R 10 is independently selected from NH 2 , C 3 -C 6 cycloalkyl, 5-6 membered heterocyclyl, C 6 -C 10 aryl, or 5-6 membered heteroaryl, the NH 2 , C 3 -C 6 cycloalkyl, 5-6 membered heterocyclyl, C 6 -C 10 aryl or 5-6 membered heteroaryl are optionally substituted with one or more R 11 .
  • R 10 is independently selected from NH 2 , 3-10 membered heterocycle, C 6 -C 10 aryl, or 5-10 membered heteroaryl, said NH 2 , 3-10 membered heterocycle , C 6 -C 10 aryl or 5-10 membered heteroaryl optionally substituted with one or more R 11 .
  • R 10 is independently selected from the following groups optionally substituted with one or more R 11 : pyrazolyl, NH 2 , phenyl, pyridyl, pyrrolyl, tetrahydropyrrolyl, or Morpholine.
  • R 11 is independently selected from C 1 -C 6 alkyl, halogen, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, or 5-6 membered heterocyclyl, the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 5-6 membered heterocyclyl optionally by C 1 -C 6 alkyl, halogen, OH, -NH-C 1 -C 6 alkyl or -N(C 1 -C 6 alkyl) 2 substituted.
  • R 11 is independently selected from optionally C 1 -C 6 alkyl, halogen, OH, -NH-C 1 -C 6 alkyl, or -N(C 1 -C 6 alkyl ) 2 substituted with the following groups: methyl, ethyl, tetrahydropyrrolyl, piperidinyl, -OCH3 , F, piperazinyl, cyclopropyl or isopropyl.
  • R 11 is independently selected from the following groups optionally substituted with methyl, ethyl, OH, -N(CH 3 ) 2 or F: methyl, ethyl, tetrahydropyrrolyl , piperidinyl, -OCH3 , F, piperazinyl, cyclopropyl or isopropyl.
  • R 11 is independently selected from C 1 -C 6 alkyl.
  • R 9 is selected from the following groups: H, CN, OH, NH 2 ,
  • the compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof is selected from the compound of formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof ,
  • Rings A, X, Y, Z, E, R 1 , R 2 , R 3 , R 4 , n, m are as defined above. It is to be understood that in claim 14 relating to formula (II), when claim 14 refers to the preceding claim x, the rings A, X, Y, Z, E, R 1 , R 2 in said formula (II) , R 3 , R 4 , n, m are as defined in claim x.
  • the rings A, X, Y, Z, E, R 1 , R 2 , R 3 , R 4 , n, m in the formula (II) are as claimed in claim 1 Definition; when claim 14 refers to claim 2, the rings A, X, Y, Z, E, R 1 , R 2 , R 3 , R 4 , n, m in said formula (II) are as claimed in claim 2 definition, and so on.
  • the compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof is selected from the compound of formula (III), or a stereoisomer or pharmaceutically acceptable salt thereof ,
  • Rings B, X, Y, Z, E, R 1 , R 2 , R 3 , R 4 , n, m are as defined above. It is to be understood that in claim 15 referring to formula (III), when claim 15 refers to the preceding claim x, rings B, X, Y, Z, E, R 1 , R 2 in said formula (III) are to be understood , R 3 , R 4 , n, m are as defined in claim x.
  • the rings B, X, Y, Z, E, R 1 , R 2 , R 3 , R 4 , n, m in said formula (III) are as claimed in 1 Definition; when claim 15 refers to the preceding claim 2, the rings B, X, Y, Z, E, R 1 , R 2 , R 3 , R 4 , n, m in said formula (III) are as claimed Requirement 2 definition, and so on.
  • the compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof is selected from the compound of formula (IV), or a stereoisomer or pharmaceutically acceptable salt thereof ,
  • the compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof is selected from the compound of formula (V), or a stereoisomer or pharmaceutically acceptable salt thereof ,
  • Ring A, Ring B, Y, W, E, R 1 , R 2 , R 3 , R 4 , n, m are as defined above.
  • the ring A, ring B, Y, W, E, R 1 , R 2 , R 3 , R 4 , n, m in said formula (V) are as claimed As defined in claim 1; when claim 17 refers to the preceding claim 2, ring A, ring B, Y, W, E, R 1 , R 2 , R 3 , R 4 , n, m in said formula (V) As defined in claim 2, and so on.
  • the compound represented by formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof is selected from the following compounds, or a stereoisomer or a pharmaceutically acceptable salt thereof:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound represented by formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary material.
  • the present invention relates to the use of a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating FGFR-related diseases.
  • the present invention relates to the use of a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of FGFR-related diseases.
  • the present invention relates to a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the prevention or treatment of FGFR-related diseases.
  • the present invention also relates to a method of preventing or treating FGFR-related diseases, the method comprising administering to a subject a therapeutically effective dose of a compound of formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, according to the present invention , its pharmaceutical composition, or the pharmaceutical preparation comprising the compound of formula (I) described in the present invention, or its stereoisomer or pharmaceutically acceptable salt.
  • the FGFR-related disease is selected from cancer.
  • the cancer is, for example, a solid tumor, such as gastric cancer.
  • the present invention provides use of a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating cancer diseases.
  • the present invention provides the use of a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of cancer diseases.
  • the present invention provides a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the prevention or treatment of cancer diseases.
  • the present invention provides a method of treating a cancerous disease in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof.
  • the double arrow in the synthetic route or multiple arrows represents a multi-step reaction.
  • pharmaceutically acceptable salts refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
  • the compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • stereoisomer refers to isomers resulting from different arrangements of atoms in a molecule in space, and includes cis-trans isomers, enantiomers, diastereomers and conformers.
  • tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist as two or more interconvertible species.
  • Proton tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms.
  • Tautomers generally exist in equilibrium, and attempts to separate individual tautomers usually result in a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the ketone form predominates; in phenols, the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • composition means a mixture of one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, so long as the valence of the specified atom is normal and the compound after substitution is stable.
  • an ethyl group “optionally” substituted with halogen means that the ethyl group can be unsubstituted ( CH2CH3 ) , monosubstituted (eg CH2CH2F ) , polysubstituted (eg CHFCH2F , CH 2 CHF 2 etc.) or fully substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is sterically impossible and/or cannot be synthesized.
  • C 1 -C 6 alkyl is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbut
  • alkoxy refers to a group resulting from the loss of a hydrogen atom on the hydroxyl group of a straight or branched chain alcohol, and may be understood as “alkyloxy” or “alkyl-O-", where alkyl is as defined above .
  • C 1 -C 6 alkoxy is to be understood as “C 1 -C 6 alkyloxy” or “C 1 -C 6 alkyl-O-”.
  • the "C 1 -C 6 alkoxy group” may include a range such as "C 1 -C 3 alkoxy group”.
  • halogen refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
  • haloalkyl is intended to include monohaloalkyl and polyhaloalkyl.
  • C 1 -C 6 haloalkyl means a C 1 -C 6 alkyl group as defined above substituted with one or more halogens, including but not limited to trifluoromethyl, 2,2,2-trifluoromethyl, Fluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl and pentachloroethyl and the like.
  • haloalkoxy is intended to include monohaloalkoxy and polyhaloalkoxy wherein the halogen is substituted on the alkyl portion of the alkoxy.
  • C 1 -C 6 haloalkoxy means a C 1 -C 6 alkoxy group as defined above substituted with one or more halogens.
  • C 3 -C 10 cyclohydrocarbyl is understood to mean a saturated or partially saturated monocyclic or bicyclic hydrocarbon ring having 3 to 10 carbon atoms. It includes C 3 -C 10 cycloalkyl and C 3 -C 10 partially saturated cyclic hydrocarbon groups (eg cycloalkenyl, cycloalkynyl, etc.), the term “C 3 -C 10 cycloalkyl” means saturated monocyclic or bicyclic A hydrocarbon ring having 3 to 10 carbon atoms.
  • the C3 - C10 partially saturated cyclic hydrocarbon group represents a partially saturated monocyclic or bicyclic hydrocarbon ring having 3 to 10 carbon atoms.
  • cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecen
  • the bicyclic hydrocarbon ring includes a bridged ring, a spirocyclic ring or a paracyclic ring structure.
  • C 3 -C 8 cyclohydrocarbyl is understood to mean a saturated or partially saturated monocyclic or bicyclic hydrocarbon ring having 3 to 8 atoms, which includes C 3 -C 8 cycloalkyl and C 3 -C 8 Partially saturated cyclic hydrocarbon group, the term “C 3 -C 8 cycloalkyl” denotes a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 8 carbon atoms.
  • C 3 -C 6 cyclohydrocarbyl is understood to mean a saturated or partially saturated monocyclic or bicyclic hydrocarbon ring having 3 to 6 atoms, which includes C 3 -C 6 cycloalkyl and C 3 -C 6 Partially saturated cyclic hydrocarbon group, the term “C 3 -C 6 cycloalkyl” denotes a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms.
  • C6 - C10 aryl is to be understood as a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10 carbon atoms, in particular having 6 A ring of 1 carbon atoms (“C 6 aryl”), such as phenyl; or a ring of 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl, or a ring of 10 carbon atoms Ring (“ Cio aryl”) such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.
  • heterocyclyl is to be understood as a saturated or partially unsaturated monovalent monocyclic or bicyclic ring having 3 to 12 ring atoms.
  • the bicyclic rings include bridged rings, spiro rings, and fused rings.
  • the heterocyclyl group may be monocyclic, including but not limited to: 4-membered ring, such as azetidinyl, oxetanyl; 5-membered ring, such as tetrahydrofuranyl, dioxane Pentenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholine group, 1,1-dioxothiomorpholinyl, piperazinyl, 2-piperazinone, or trithianyl; or a 7-membered ring such as diazepanyl.
  • 4-membered ring such as azetidinyl, oxetanyl
  • 5-membered ring such as tetrahydrofuranyl, dioxane Penten
  • the heterocyclyl group may be bicyclic, such as, but not limited to, a 5,5 membered ring, such as a hexahydrocyclopento[c]pyrrol-2(1H)-yl ring, or a 5,6 membered bicyclic ring, Such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring.
  • the ring may be partially unsaturated, i.e.
  • 3-8 membered heterocyclyl is to be understood as a saturated or partially unsaturated monovalent monocyclic or bicyclic ring having 3 to 8 ring atoms.
  • 3-6 membered heterocyclyl is to be understood as a saturated or partially unsaturated monovalent monocyclic or bicyclic ring having 3 to 6 ring atoms.
  • heteroaryl is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems, in particular 5 or 6 or 9 or 10 ring atoms, and in each case may be Benzo-fused.
  • heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl Diazolyl and the like and their benzo derivatives such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinoline oxazolinyl, isoquinolinyl, etc; Naph
  • treating means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • terapéuticaally effective amount means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying
  • the amount of a compound of the present invention that constitutes a "therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art according to its own knowledge and the present disclosure.
  • mammals include mammals and non-mammals.
  • mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (eg, chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals , such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs.
  • non-human mammals include, but are not limited to, birds, fish, and the like.
  • the mammal may be a human.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • classes of the term “excipient” include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flowability and/or stickiness.
  • typical "pharmaceutically acceptable carriers” suitable for the above-mentioned preparations are: carbohydrates, starches, cellulose and their derivatives and other commonly used adjuvants in pharmaceutical preparations.
  • pharmaceutically acceptable excipients refers to those excipients which are not significantly irritating to the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • 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 enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the units of NMR shifts are 10-6 (ppm).
  • the solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
  • DMAP 4-dimethylaminopyridine; Et3N or TEA: triethylamine; THF: tetrahydrofuran; MeCN or ACN: acetonitrile; 18-crown-6 or 18-crown-6: 1,4,7,10,13,16 - Hexacyclooctadecane; Pd(dppf)Cl 2 : [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; dioxane: dioxane; Pd(PPh 4 ) 3 : Tetrakis(triphenylphosphine) palladium; DIEA or DIPEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; HATU: 2-(7-azobenzotrimine azole)-N,N,N',N'-tetramethylurea hexafluorophosphate; NMP
  • the reaction solution was evaporated under reduced pressure to remove the solvent, and water (100 mL) was added to the obtained residue.
  • the resulting mixture was extracted with ethyl acetate (100 mL ⁇ 3 times).
  • the organic phases were mixed, washed with saturated brine (100 mL ⁇ 3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column (the elution phase was a mixed solvent of petroleum ether containing 16-18% ethyl acetate) to obtain the title compound 1B (2.3 g, 8.3 mmol, yield: 36%) as a white solid.
  • the obtained organic phases were mixed, washed with saturated brine (100 mL ⁇ 3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column (the elution phase was a mixed solvent of petroleum ether containing 0-15% ethyl acetate) to obtain the title compound 1E (7.2 g, yield: 97%) as a white solid.
  • 6-Chloro-5-iodo-4-aminopyrimidine (1.7g, 6.7mmol, 1.0eq)
  • compound 1G (2.2g, 6.7mmol, 1.0eq)
  • [1,1'-bis(diphenylphosphine) [Ferrocene]palladium dichloride (0.49 g, 0.67 mmol, 0.10 eq)
  • potassium phosphate 2.8 g, 13 mmol, 2.0 eq
  • the yellow reaction solution was distilled under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column (the elution phase was a mixed solvent of petroleum ether containing 33-100% ethyl acetate) to obtain the title compound 1I as a pale yellow solid (1.10 g, yield : 50%).
  • the reaction solution was evaporated under reduced pressure to remove the solvent, and water (30 mL) was added to the obtained residue.
  • the resulting mixture was extracted with ethyl acetate (30 mL x 3 times).
  • the organic phases were mixed, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • the obtained residue was purified by silica gel column (the elution phase was a mixed solvent of petroleum ether containing 0-50% ethyl acetate) to obtain the title compound 2B (0.20 g, yield: 76%) as a pale yellow solid.
  • the second step 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-2-((triisopropylsilane yl)ethynyl)pyridine (3D)
  • reaction solution was evaporated under reduced pressure to remove the solvent, and the obtained residue was purified by C18 reverse-phase silica gel column (the elution phase was an aqueous solution containing 20-100% acetonitrile) and lyophilized to obtain the title compound 3D as a white solid (0.80 g, yield: 16%)
  • the third step 5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-(4-methyl-6-((triisopropylsilyl) Ethynyl)pyridin-3-yl)pyrimidin-4-amine (3E)
  • reaction solution was evaporated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column (the elution phase was a mixed solvent of petroleum ether containing 0-50% ethyl acetate) to obtain the title compound 4C (2.5 g, yield: 66%) as a white solid. ).
  • the first step 4-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)-3,6-dihydropyridine -1(2H)-Carboxylic acid tert-butyl ester (5B)
  • reaction solution was evaporated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography (the elution phase was a mixed solvent of dichloromethane containing 0-10% methanol) to obtain the title compound 5B (0.70 g, yield: 44%) as a brown solid. ).
  • the third step 1- (4-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)-3,6- Dihydropyridin-1(2H)-yl)-2-methylprop-2-en-1-one (5)
  • reaction solution was evaporated under reduced pressure to remove the solvent, and the obtained residue was purified by preparative chromatography (Waters Xbridge C18, 20-70% acetonitrile aqueous solution (containing 0.01% ammonia water)) to obtain the title compound 5 (0.070 g, yield: 39%) as a white solid ).
  • the first step 4-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)piperidine-1-carboxylic acid tertiary Butyl ester (6A)
  • the third step 1- (2-methacryloyl)-(4-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidine- 4-yl)piperidine (6)
  • reaction solution was distilled under reduced pressure to remove the solvent, and the obtained crude product was purified by preparative chromatography (Waters Xbridge C18, 20-70% acetonitrile aqueous solution (containing 0.01% ammonia water)) to obtain the title compound 7 (23 mg, yield: 10%).
  • the following compounds 8-14 can be synthesized through the similar synthetic route and procedure of Example 7, in the second step, the starting material A in the table below is used to replace the starting material 7B.
  • Example 7 Through the similar synthetic route and procedure of Example 7, in the first step, the starting material B in the following table is used to replace the starting material 1A, and the starting material C is used to replace the propynoic acid 7B in the second step to synthesize the corresponding compounds 15-26 below.
  • reaction solution was evaporated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography (the elution phase was a mixed solvent of dichloromethane containing 0-10% methanol) to obtain the title compound 31D (60 mg, yield: 12%) as a brown solid. .
  • the fourth step 1- (2-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)-2,7- Diazaspiro[3.5]nonan-7-yl)prop-2-en-1-one (31)
  • the reaction solution was distilled under reduced pressure to remove the solvent, and the obtained residue was purified by preparative chromatography (Phenomenex Luna C 18 150*25mm*10um, the elution phase was 3%-33% acetonitrile-water (containing 0.1% TFA)) to obtain a white solid
  • the title compound 31 (11 mg, yield: 30%).
  • Example 12 Through the similar synthetic route and steps of Example 12, in the first step, the different starting materials E in the following table are used to replace 31A, and the corresponding compounds 32-43 in the following table can be synthesized.
  • Compound 44 was synthesized via a synthetic route and procedure analogous to Example 12, substituting 34A for 31A in the first step and 2-chloroethylsulfonyl chloride 30A for acryloyl chloride 4B in the fourth step.
  • Example 7 Using compound 34E as a raw material, the synthesis method of the second step in Example 7 was adopted, and 7B was replaced with the raw material C in the following table to synthesize the corresponding compounds 45-48.
  • the raw material 54B of compound 54 was synthesized from 54A by the following steps.
  • the third step 4-(4-amino-6-(4-aminophenyl)pyrimidin-5-yl)cyclohex-3-ene-1-carboxylic acid ethyl ester (55E)
  • the fourth step 4-(4-amino-6-(4-(-2-butynoylamino)phenyl)pyrimidin-5-yl)cyclohex-3-ene-1-carboxylic acid ethyl ester (55G)
  • the fifth step 4-(4-amino-6-(4-(-2-butynoylamino)phenyl)pyrimidin-5-yl)cyclohex-3-ene-1-carboxylic acid (55H)
  • the first step 2,4-dichloro-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidine (60B)
  • 2,4-Dichloro-5-iodopyrimidine 60A (5.0 g, 18 mmol), compound 1G (6.0 g, 18 mmol), potassium carbonate (5.0 g, 36 mmol) and (diphenylphosphinoferrocene) dichloride Palladium (0.70 g, 0.91 mmol) was added to a mixed solvent of dioxane (50 mL) and water (5 mL), and the reaction was stirred at 100° C. for 2 hours after nitrogen replacement three times. The reaction solution was quenched with 20 mL of ammonium chloride and then extracted with 100 mL of ethyl acetate.
  • the third step 5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)-4- (3-Nitrophenyl)pyrimidin-2-amine (60F)
  • reaction solution was quenched with 20 mL of ammonium chloride, and then 50 mL of ethyl acetate was added for extraction, and the obtained organic phase was separated and concentrated to obtain a crude product.
  • the fourth step 4-(3-aminophenyl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-N-(1-methyl-1H- Pyrazol-4-yl)pyrimidin-2-amine (60G)
  • compound 61 was synthesized by a similar synthetic method as in the fifth step in Example 18-2, substituting 61A for acryloyl chloride 4B.
  • compound 62 was synthesized by a similar synthetic method as in the fifth step in Example 18-2, substituting 62A for acryloyl chloride 4B.
  • Compound 64 was synthesized using a similar synthetic procedure and method following the second step in Example 18-2, substituting 64A for 60C.
  • Compound 65 was synthesized using a similar synthetic procedure and method following the second step in Example 18-2, substituting 65A for 60C.
  • Compound 66 was synthesized using a similar synthetic procedure and method following the third step in Example 18-2, substituting 66A for 60E.
  • Compound 68 was synthesized using a similar synthetic procedure and method following the third step in Example 18-2, substituting 68A for 60E.
  • 2,4,5-Trichloropyrimidine 69A (1.8g, 10mmol), p-nitrophenylboronic acid 55C (1.7g, 10mmol), potassium carbonate (2.8g, 20mmol) and (diphenylphosphinoferrocene)di Palladium chloride (0.35 g, 0.46 mmol) was added to a mixed solvent of dioxane (20 mL) and water (2 mL), and after nitrogen replacement three times, the reaction was stirred at 70° C. for 2 hours. The reaction solution was quenched with 20 mL of ammonium chloride and then extracted with 100 mL of ethyl acetate.
  • reaction solution was quenched with 20 mL of ammonium chloride, and then 50 mL of ethyl acetate was added for extraction, and the obtained organic phase was separated and concentrated to obtain a crude product.
  • the third step 5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)-4- (4-Nitrophenyl)pyrimidin-2-amine (69D)
  • the fourth step 4-(4-aminophenyl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-N-(1-methyl-1H- Pyrazol-4-yl)pyrimidin-2-amine (69E)
  • reaction solution was distilled under reduced pressure to remove the solvent, and the obtained residue was purified by preparative chromatography (Phenomenex Luna C18 150*25mm*10um, the elution phase was 3%-55% acetonitrile-water) to obtain the title compound 69 (18 mg, yield) as a white solid. rate: 38%).
  • Compound 70 was synthesized using analogous synthetic procedures and methods following the third step in Example 27, substituting 70A for 69A.
  • Compound 71 was synthesized using analogous synthetic procedures and methods following the third step in Example 27, substituting 71A for 69A.
  • Compound 74B was synthesized using a similar route and procedure as in Example 27, substituting 74A for 60E in the second step.
  • Compound 75B can be synthesized using a similar route and procedure in Example 27, substituting 74A for 60E in the second step.
  • Compound 75 can be synthesized from compound 75B through two-step reaction.
  • the first step 4-(4-((5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-4-(4-(2-fluoroacrylamido) )Phenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate tert-butyl ester (75C)
  • Example 27 Referring to the synthetic route and method of Example 27, substituting 55A for 1G, compound 79A was synthesized. Then, compound 79A was used to replace 55G in Example 17, and compound 79 was synthesized through the synthesis steps and methods of the fifth step and the sixth step in Example 17.
  • Example 18-2 Referring to the synthetic route and method of Example 18-2, substituting 55A for 1G, compound 80A can be synthesized. Then, compound 80A was replaced by 55G in Example 17, and compound 80 was synthesized through the synthesis steps and methods of the fifth step and the sixth step in Example 17.
  • the first step (1-(2-chloro-5-bromopyrimidin-4-yl) azetidine-3-yl) tert-butyl carbamate (81C)
  • reaction solution was quenched with 20 mL of ammonium chloride, and then 50 mL of ethyl acetate was added for extraction, and the obtained organic phase was separated and concentrated to obtain a crude product.
  • the fourth step 4-(3-aminoazetidine-1-yl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-N-( 1-Methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (81F)
  • reaction solution was evaporated under reduced pressure to remove the solvent, and the obtained residue was purified by preparative chromatography (Phenomenex Luna C 18 150*25mm*10um, elution phase was 5%-75% acetonitrile-water) to obtain the title compound 81 (26 mg, 5%-75%) as a white solid. Yield: 52%).
  • the corresponding compounds 84-117 in the table can be synthesized by the similar route and procedure of Example 39, substituting the starting material I in the table below for compound 81B in the first step.
  • Example 39 Through the similar route and steps of Example 39, when the corresponding compounds 118-119 in the table are synthesized by replacing the compound 81B in the first step with 118A and 119A in the raw material I, it is necessary to replace the trifluoroacetic acid in the reaction solution in the fourth step. The concentration was increased to 50%.
  • 117A and 118A in the raw material I can be synthesized by the following steps:
  • the first step 1- (tert-butyl) 3-methyl 3-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)azetidinyl-1,3 -Dicarboxylate (117D)
  • the obtained mixture was filtered under reduced pressure, the filter cake was washed with 50 mL of ethyl acetate, the obtained filtrate was concentrated to obtain the crude product, and the crude product was purified by silica gel column (the elution phase was dichloromethane containing 3% methanol) to obtain the main product 117E (1.2 g, yield 62%).
  • 119A was synthesized via a similar synthetic method and procedure to compound 118A, using 119C in place of 117C.
  • Example 39 Through the similar method and procedure in the first to fourth step in Example 39, the compound 81B in the first step was replaced with the starting material I in the following table, and the similar method and procedure in Example 41 was adopted in the fifth step , the corresponding compounds 120-125 in the table can be synthesized.
  • Example 39 Through similar methods and steps in Example 39, using the raw material I in the following table to replace the compound 81B in the first step, and using the raw material J in the following table to replace the 60E in the third step, the corresponding compounds in the following table can be synthesized. 126-154.
  • Example 39 Through similar methods and steps in Example 39, using the raw material I in the following table to replace the compound 81B in the first step, and using the raw material K in the following table to replace the 1G in the second step, the corresponding compound 156- 159.
  • Example 17 compound 162F was used to replace 55G in Example 17, and compound 162 was synthesized through the synthesis steps and methods of the fifth step and the sixth step in Example 17.
  • the first step 4-(2-chloro-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)-3,6-dihydropyridine -1(2H)-tert-Butyl carboxylate (164B)
  • Compound 164 can be synthesized by substituting compound 164B for 81D, and using similar experimental methods and procedures in the third to fifth steps of Example 39.
  • the first step 3-(2-chloro-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)aniline (167B)
  • Step 2 4-(3-Aminophenyl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-2-amine (167C)
  • Compound 168 was synthesized using a synthetic method and procedure similar to Example 50, substituting compound 168A for compound 167A.
  • Example 39 By a similar method and procedure in the first to fourth steps in Example 39, the compound 81B in the first step was replaced with the starting material I in the following table, and then in the fifth step, a similar method and procedure in Example 41 was used , using the starting material M in the table below to replace the compound 63A, the corresponding compounds 170-174 in the table can be synthesized.
  • reaction solution was distilled to remove the solvent under reduced pressure, and the obtained crude product was purified by preparative high performance liquid chromatography (Waters Xbridge C18, 20-60% acetonitrile aqueous solution (containing 0.01% ammonia water)) to obtain compound 181 (2.4 mg, yield: 21%) ).
  • Test Example 1 FGFR enzyme inhibition experiment of the compounds of the present invention
  • the positive control compound BGJ398 used in the experiment was purchased from Selleck as S2183. Test compound samples were dissolved in DMSO, formulated as 10 mM stock solutions, and stored at -30°C.
  • the enzymatic reaction was carried out using the enzyme reaction kit (FGFR1 Kit No. V2991, FGFR2 kit No. V4060, FGFR3 kit No. VA7459, and the reaction substrate Poly E4Y1) produced by promega company, according to the method recommended by the manufacturer.
  • the reaction product was detected using the ADP detection kit (ADP-Glo TM Kinase Assay, product number V9101) produced by promega.
  • reaction system containing 0.4ng/ ⁇ L FGFR1 kinase (or 1.4ng/ ⁇ L FGFR2 (WT (wild type) or V564F mutant) kinase, or 1ng/ ⁇ L FGFR3 kinase), 0.2 ⁇ g/ ⁇ L Poly E4Y1, 5 ⁇ M ATP and serial dilution of the test compound.
  • the final concentration of DMSO in the reaction system was 1%. Reactions were performed in 384-well plates (Perkinelmer, Cat. 6007290) and all assays were performed in duplicate. In the above system, ATP was added last to initiate the reaction.
  • the above 384-well reaction plate was reacted at 25°C for 60 minutes, then 5 ⁇ L of ADP-Glo was added, the reaction was performed at 25°C for 40 minutes, and then 10 ⁇ L of detection buffer was added, and the reaction was performed at 25°C for 30 minutes. After the reaction, the Luminescence (fluorescence) value was measured with Perkinelmer Envision.
  • the Luminescence value represents the amount of ADP generated, through high signal (high signal) (Luminescence value with enzyme but no inhibitor), low signal (low signal) (Luminescence value without enzyme), sample signal (sample signal) (additional Luminescence value)
  • high signal high signal
  • low signal low signal
  • sample signal sample signal
  • additional Luminescence value The inhibitory rate of kinase activity was calculated using the Luminescence value of enzyme plus inhibitor), and the median inhibitory concentration (IC 50 ) was calculated by XLfit2.0 software (ID Business Solutions Ltd).
  • Inhibition rate % (high signal-sample signal)/(high signal-low signal) ⁇ 100%.
  • Test compound samples were dissolved in DMSO, formulated as 10 mM stock solutions, and stored at -30°C. Compounds were diluted to 10-fold the assay concentration in serum-free medium containing 5% DMSO for the assay.
  • the cell SNU-16 in the experiment was purchased from ATCC (American Type Culture Collection, USA, item number CRL-5974), RT-112 were purchased from cobioer (Nanjing Kebai Biotechnology Co., Ltd., item number CBP60316), KG-1 was purchased from ATCC (item number CCL-246), and JMSU-1 was purchased from DSMZ (item number ACC505) .
  • Medium IMDM was purchased from Gibco (Cat. No. 12440-061)
  • Medium 1640 was purchased from Gibco (Cat. No. 12634-010)
  • serum was purchased from Gibco (Cat. No. 10099-141C).
  • Cell-counting kit-8 (CK04) was purchased from Tongren Chemical Company.
  • the Luminescent Cell Viability Assay was purchased from Promega (Cat. No. G7570).
  • Cells in logarithmic growth phase were seeded in 96-well cell culture plates in a volume of 100 ⁇ L. Incubate overnight at 37°C in an incubator containing 5% carbon dioxide. The next day, 10 ⁇ L/well of the compound to be tested at gradient dilution was added, and 10 ⁇ L/well of serum-free medium containing 5% DMSO was added to the control group to replace the drug diluent, and the final concentration of DMSO was 0.5%. Incubate for 72 hours in an incubator. Add 10 ⁇ L/well Cell-counting kit-8 reagent (or 50 ⁇ L/well CTG).
  • Inhibition rate (%) [1-([ OD450 ] compound- [ OD450 ] background )/([ OD450 ] cell- [ OD450 ] background )] ⁇ 100%
  • [OD 450 ] cells represent the optical density values on day 3 of cell wells with DMSO instead of compound;
  • the compounds of the examples of the present invention were determined by the above tests in the cell proliferation test, and the measured GI 50 values are shown in Table 3.
  • the compounds of the present invention were evaluated in whole blood by liquid chromatography tandem mass spectrometry (LC/MS/MS) to determine the remaining percentages of test compounds in SD rat or human blood (containing EDTA-K2 anticoagulant) at different time points. stability.
  • LC/MS/MS liquid chromatography tandem mass spectrometry
  • the peak area ratio tmin is the peak area ratio of the tested compound (or positive compound) and the internal standard compound at the time point of t minute;
  • Peak area ratio 0 min is the peak area ratio of the tested compound (or positive compound) and the internal standard compound at the time point of 0 minutes.
  • the slope value k was determined by natural log linear regression of the remaining percent of test compound versus incubation time curve.
  • in vitro half-life (in vitro t 1/2 ) is determined by the slope value k:
  • CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 were used to assess representative substrate metabolism responses of the five major human CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4). Determination of different concentrations of test compounds for phenacetin (CYP1A2), diclofenac sodium (CYP2C9), S-mephentoin (CYP2C19), bufurolol hydrochloride by liquid chromatography tandem mass spectrometry (LC/MS/MS) Effects of salt (CYP2D6) and midazolam (CYP3A4) on metabolic responses.
  • CYP1A2A2C9, CYP2C19, CYP2D6, CYP3A4 were used to assess representative substrate metabolism responses of the five major human CYP isoforms. Determination of different concentrations of test compounds for phenace
  • test compound concentration were 0.1, 0.3, 1, 3, 10, 30 ⁇ mol/L or the reaction system of the positive compound or blank control and mixed human liver microsomes (0.2 mg/mL) 200 ⁇ L (100 mmol/L phosphate buffer) solution, pH 7.4, containing 0.3% DMSO, 0.6% acetonitrile, 0.1% methanol by volume respectively) and incubated at 37°C for 5 minutes.
  • Peak area ratio metabolite peak area/internal standard peak area
  • Residual activity ratio (%) peak area ratio of the test compound group / peak area ratio of the blank group
  • CYP median inhibitory concentration (IC 50 ) was calculated by Excel XLfit 5.3.1.3.
  • Table 5 shows the CYP median inhibitory concentration (IC 50 ) values of the compounds of the present invention.
  • the apparent permeability coefficient (P app ) of the analyzed drugs was determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) by the Caco-2 cell model.
  • Caco-2 cells were purchased from the American Type Culture Collection (ATCC), HEPES was purchased from Beijing Soleibo Technology Co., Ltd., Hank's Balanced Salt Solution (HBSS) and non-essential amino acids (NEAA) were purchased from Sai Merchant Technologies, Penicillin, Streptomycin, and Trypsin/EDTA were purchased from Solebold, Fetal Bovine Serum (FBS) and DMEM medium were purchased from Corning, HTS-96-well Transwell plates and other sterile consumables Purchased from Corning Company, Millicell resistance measurement system was purchased from Millipore, Purchased from Nexcelom Bioscience, Infinite 200 PRO microplate reader was purchased from Tecan, and MTS2/4 orbital shaker was purchased from IKA Labortechnik.
  • ATCC American Type Culture Collection
  • HEPES was purchased from Beijing Soleibo Technology Co., Ltd.
  • HBSS Hank's Balanced Salt Solution
  • NEAA non-essential amino acids
  • Caco-2 was grown in cell culture flasks.
  • the incubator was set at 37°C, 5% CO 2 , with a guaranteed relative humidity of 95%.
  • Transwells can be seeded when cells are 70-90% confluent.
  • 50 ⁇ L of cell culture medium was added to each well of the upper chamber of the Transwell, and 25 mL of cell culture medium was added to the lower plate. Plates can be used to seed cells after 1 hour of incubation in a 37°C, 5% CO 2 incubator.
  • After cell digestion transfer the cell suspension to a round bottom centrifuge tube and centrifuge at 120g for 5 minutes. Resuspend cells in medium to a final concentration of 6.86 x 10 5 cells/mL (cells/mL).
  • the cell suspension was added to the chamber of a 96-well Transwell plate at 50 ⁇ L per well at a final seeding density of 2.4 ⁇ 10 5 cells/cm 2 .
  • the medium was changed 24 hours after inoculation, and the medium was changed every other day for 14-18 days.
  • the process of replacing the medium is as follows, separate the Transwell chamber from the receiving plate, discard the medium in the receiving plate first and then discard the medium in the Transwell chamber, and finally add 75 ⁇ L of fresh medium to each chamber, and add 25 mL of fresh medium to the receiving plate.
  • the second step is to evaluate the integrity of the cell monolayer
  • a 1 mM stock solution of the test compound to be tested in DMSO was diluted with transport buffer to give a 5 [mu]M test solution.
  • the control compound digoxin or minoxidil was diluted to 2 mM with DMSO, and the control compound test solution was obtained with the above-mentioned transport buffer to 10 ⁇ M.
  • DMSO was also diluted with the above transport buffer to a receiver solution containing 0.5% DMSO.
  • the rate of compound transport from apical to basolateral was determined. Add 125 ⁇ L of test solution per well to the upper chamber (apex) and immediately transfer 50 ⁇ L of solution from the apex to 200 ⁇ L of acetonitrile (0.1 ⁇ M tolbutamide) containing internal standard as an initial tip-to-substrate sample. 235 ⁇ L of receiver solution was added to each well of the lower chamber (basal side).
  • the rate of compound transport from basolateral to apical was determined. 285 ⁇ L of receiver solution was added to each well of the upper chamber (apex) and 50 ⁇ L of solution was immediately transferred from the apex to 200 ⁇ L of acetonitrile (0.1 ⁇ M tolbutamide) containing internal standard as a base-to-apical initial sample. 75 ⁇ L of test solution was added to each well of the lower chamber (basal side).
  • Lucifer Yellow The integrity of the cell monolayer after 2 hours of incubation was assessed with the leakage of Lucifer Yellow, and the Lucifer Yellow stock solution was diluted to a final concentration of 100 ⁇ M using transport buffer (10 mM HEPES, pH 7.4). Add 100 ⁇ L of fluorescent yellow solution to each well of the upper Transwell insert, and add 300 ⁇ L of transport buffer solution (10 mM HEPES, pH 7.4) to each well of the lower receiving plate. After incubating at 37°C for 30 minutes, aspirate 80 ⁇ L of the solution from the upper and lower layers of each well into a new 96-well plate. Using a microplate reader, fluorescence measurement was performed under the conditions of excitation wavelength 485 nm and emission wavelength 530 nm.
  • Step 5 Data Analysis All calculations were performed using Microsoft Excel. Peak areas were determined from the extracted ion chromatograms.
  • the apparent permeability coefficient (P app , unit: cm/s ⁇ 10 -6 ) is calculated by the following formula:
  • VA is the volume of the receiving end solution ( Ap ⁇ Bl is 0.3mL, Bl ⁇ Ap is 0.1mL), Area (membrane area) is the membrane area of Transwell-96 well plate (0.143cm 2 ); time (time) is the incubation time (unit: s); [drug] receiver ([drug] receiving end ) is the drug concentration at the receiving end; [drug] initial, donor ([drug] initial, donor ) is the initial drug concentration at the dosing end.
  • Papp(BA) is the apparent permeability coefficient from the basal end to the apex
  • Papp(AB) is the apparent permeability coefficient from apical to basal.
  • VA is the volume of the solution at the receiving end (unit: mL);
  • V D is the volume of the solution at the giving end (unit: mL), and
  • [drug] donor [drug] donor ) is the drug concentration at the administration end.
  • the leakage rate (Percentage leakage(%) or LY(%)) is calculated using the following formula:
  • I receiver (I receiving end ) refers to the fluorescence density of the receiving hole (0.3mL)
  • I donor (I donor ) refers to the fluorescence density of the dosing hole (0.1mL).
  • LY ⁇ 1.5% indicates that the monolayer cell membrane is intact. For individual cases of LY>1.5%, if the P app value is close to other parallels, the final data can be adopted based on scientific judgment.
  • Test Example 6 In vivo pharmacokinetic test of the compound of the present invention in rats
  • LC/MS/MS method was used to determine the drug concentration in the plasma of rats at different times after intravenous injection and intragastric administration of the compounds of the present invention.
  • the pharmacokinetic behavior of the compound of the present invention in rats was studied, and its pharmacokinetic characteristics were evaluated.
  • Intravenous administration Weigh a certain amount of drug, add 10% volume of N,N-dimethylacetamide, 33% volume of triethylene glycol and 57% volume of normal saline to prepare a colorless clear transparent liquid of 1mg/mL ;
  • Oral administration weigh a certain amount of medicine, add 0.5% mass hypromellose, 0.1% volume Tween 80 and 99.6% volume normal saline to prepare a 1 mg/mL white suspension.
  • the compounds of the present invention were administered to rats by intravenous injection, and 0.2 mL of blood was collected from the jugular vein at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, and placed in a test tube containing EDTA-K2 at 4°C, 4000 Plasma was separated by centrifugation at rpm for 5 minutes and stored at -75°C.
  • mice were administered the compound of the present invention by gavage, and 0.2 mL of blood was collected from the jugular vein at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, and placed in a test tube containing EDTA-K2, 4°C, 3500 rpm Plasma was separated by centrifugation for 10 min/min and stored at -75°C.
  • Determination of the content of the test compound in rat plasma after intravenous injection or drug gavage administration of different concentrations take 30 ⁇ L of rat plasma at each time after administration, add 200 ⁇ L (50ng/mL) of acetonitrile solution of internal standard dexamethasone , vortexed for 30 seconds, centrifuged at 4700 rpm for 15 minutes at 4°C, and the supernatant of the plasma sample was diluted three times with water, and 2.0 ⁇ L was taken for LC-MS/MS analysis.
  • IV indicates intravenous administration
  • PO indicates intragastric administration

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Abstract

提供了一类作为FGFR抑制剂的杂环化合物，具体公开了式(I)所示化合物、其立体异构体或药学上可接受的盐，

Description

作为FGFR抑制剂的杂环化合物及其应用
相关申请的交叉引用
本申请要求以下2件中国发明专利申请的权益和优先权，在此将它们的全部内容以援引的方式整体并入本文中：
2021年04月03日向中国国家知识产权局提交的第202110380922.X号专利申请；以及
2022年03月07日向中国国家知识产权局提交的第202210224490.8号专利申请。
技术领域
本发明属于医药技术领域，涉及FGFR抑制剂的杂环化合物及其制备方法和应用。
背景技术
FGFR(Fibroblast Growth Factor Receptor,成纤维细胞生长因子受体)是一种跨膜受体型酪氨酸激酶，家族主要包含四个成员FGFR1、2、3及4。FGFR与其配体FGF(成纤维细胞生长因子，Fibroblast growth factor)结合后，引起受体二聚化进而使激酶区的酪氨酸残基磷酸化而激活受体，随后活化的FGFR进一步激活下游的RAS/RAF、PI3K/AKT、JAK/STAT以及PLCγ等信号通路，参与调节细胞增殖、凋亡、迁移、损伤组织的修复以及新生血管生成等多个过程。正常生理条件下FGFR信号通路受到严格调控，处于弱活化水平。而其过度活化后往往会导致肿瘤的发生、发展。FGFR异常活化的分子机制主要包括1)基因扩增；2)基因突变；3)基因易位导致的基因融合等。例如：FGFR2基因扩增发生在胃癌(5～10％)、FGFR2基因易位发生在肝内胆管癌(14％)，FGFR2基因突变发生在子宫内膜癌(12～14％)。而FGFR3的基因异常最常见于膀胱癌，包括基因突变(60～80％的非肌肉侵袭性膀胱癌和15～20％的肌肉侵袭性膀胱癌)、基因易位(3～6％)和基因扩增(发生率未见报道)；其次是骨髓瘤，15～20％的骨髓瘤患者具有FGFR3基因易位。以上FGFR的基因异常中，部分已证实与患者的不良预后相关。
鉴于FGFR信号通路在肿瘤治疗中的重要性，针对FGFR信号通路的靶向治疗近年来已成为肿瘤治疗领域的研究热点。本专利申请发现了一类杂环化合物，可选择性抑制FGFR蛋白，例如FGFR2，对相关的肿瘤细胞有杀伤效果。
发明内容
本发明提供式一类杂环化合物、及其立体异构体和药学上可接受的盐。这些化合物可以抑制FGFR的活性，从而影响生物学功能。
具体的，本发明提供了一种式(I)所示化合物、或其立体异构体或药学上可接受的盐，
Figure PCTCN2022084728-appb-000001
X、Z各自独立地选自CR 9或N；
W选自O或C(＝O)；
Y选自C(＝O)、NHC(＝O)、C(＝O)NH、N(CH 3)或键；
环A选自5-10元杂芳基或5-10元杂环基；
环B选自C 6-C 10芳基、5-10元杂芳基或C 3-C 10环烃基；
E选自C 3-C 10环烃基、C 6-C 10芳基、3-12元杂环基或5-12元杂芳基，所述C 3-C 10环烃基C 6-C 10芳基、3-12元杂环基或5-12元杂芳基任选地被一个或多个R 1a取代；
R 1a独立地选自卤素、CN、NH 2、OH、C 1-C 6烷基、C 3-C 8环烃基、3-6元杂环基、C 1-C 6烷氧基、-S(＝O)-C 1-C 4烷基、-S(＝O) 2-C 1-C 4烷基、
Figure PCTCN2022084728-appb-000002
-S(＝O)(＝NR 8a)R 8b、-N＝S(＝O)R 8aR 8b、-NR 8aR 8b、-C(＝O)NR 8aR 8b或-NR 7C(＝O)R 8b，所述C 1-C 6烷基、C 3-C 8环烃基、3-6元杂环基、C 1-C 6烷氧基、-S(＝O)-C 1-C 4烷基或-S(＝O) 2-C 1-C 4烷基任选地被一个或多个独立地选自卤素、OH、C 1-C 3烷氧基或CN的基团取代；
R 1选自-CN、-(CH 2) qCN、-C≡CR 5、-C(＝O)C≡CR 5、-C(＝O)CR 6＝C(R 5) 2、-R 7C(＝O)CH＝C(R 5) 2、-NHC(＝O)CR 6＝C(R 5) 2、-R 7NHC(＝O)CH＝C(R 5) 2、-NHC(＝O)C≡CR 5、-S(＝O)CR 6＝C(R 5) 2、-S(＝O) 2CR 6＝C(R 5) 2、-NHS(＝O)CR 6＝C(R 5) 2、-NHS(＝O) 2CR 6＝C(R 5) 2、-NR 6C(＝O)CR 6＝C(R 5) 2或NHC(＝O)R 5；
R 5独立地选自H、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 8环烃基、3-12元杂环基或C 6-C 10芳基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 8环烃基、3-12元杂环基或C 6-C 10芳基任选地被一个或者多个R 5a取代；
R 5a独立地选自卤素、CN、N(R 5b) 2、OH、NO 2、C 3-C 8环烷基或3-12元杂环基；
R 5b独立地选自H或C 1-C 6烷基；
R 6选自H、CN、卤素或C 1-C 6烷基；
R 7选自C 1-C 6亚烷基、C 3-C 8亚环烷基或3-12元亚杂环基；
R 2选自H、NH 2、C 1-C 6烷基、OH或卤素；
R 3独立地选自卤素、CN、NH 2、OH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基或C 3- 8环烷基；
R 4独立地选自卤素、CN、NH 2、OH、NO 2、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 8环烷基、3-10元杂环基、-C(＝O)R 8a、-C(＝O)OR 8a、-NR 8aR 8b、-C(＝O)NR 8aR 8b或-NR 7C(＝O)R 8b，所述C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 8环烷基或3-10元杂环基任选地被一个或者多个R 4a取代；
R 4a独立地选自卤素、CN、NH 2、OH或C 1-C 6烷基；
R 8a、R 8b各自独立地选自H、卤素、CN、NH 2、OH、C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6卤代烷基；
R 9选自H、CN、OH、NH 2、-NHR 10、-NH-C 1-C 6烷基、C 1-C 6烷基、C 1-C 6烷氧基或C 3-C 8环烷基，所述C 1-C 6烷基、-NH-C 1-C 6烷基、C 1-C 6烷氧基或C 3-C 8环烷基任选地被一个或多个R 10取代；
R 10独立地选自卤素、NH 2、C 3-C 8环烷基、3-10元杂环基、C 6-C 10芳基或5-10元杂芳基，所述NH 2、C 3-C 8环烷基、3-10元杂环基、C 6-C 10芳基或5-10元杂芳基任选地被一个或多个R 11取代；
R 11独立地选自C 1-C 6烷基、卤素、C 1-C 6烷氧基、C 3-C 8环烷基或3-10元杂环基，所述C 1-C 6烷基、C 3-C 8环烷基或3-10元杂环基任选地被C 1-C 6烷基、卤素、OH、-NH-C 1-C 6烷基、-N(C 1-C 6烷基) 2取代；
n、m各自独立地选自0、1、2或3；
q选自1、2或3。
在一些实施方案中，环A选自5-10元杂芳基。
在一些实施方案中，环A选自5-6元杂芳基。
在一些实施方案中，环A选自5-6元杂芳基或5-6元杂环基。
在一些实施方案中，环A选自嘧啶基、吡啶基或四氢吡咯基。
在一些实施方案中，环A选自嘧啶基或四氢吡咯基。
在一些实施方案中，环A选自吡啶基或嘧啶基。
在一些实施方案中，环A选自嘧啶基。
在一些实施方案中，环B选自C 6-C 10芳基或5-10元杂芳基。
在一些实施方案中，环B选自C 6-C 10芳基或C 3-C 10环烃基。
在一些实施方案中，环B选自苯基或环己烯基。
在一些实施方案中，环B选自苯基。
在一些实施方案中，W选自O。
在一些实施方案中，Y选自C(＝O)、NHC(＝O)、C(＝O)NH或键。
在一些实施方案中，Y选自N(CH 3)或键。
在一些实施方案中，Z选自CR 9。
在一些实施方案中，E选自C 3-C 6环烃基、C 6-C 10芳基、3-10元杂环基或5-10元杂芳基，所述C 3-C 6环烃基、C 6-C 10芳基、3-10元杂环基或5-10元杂芳基任选地被R 1a取代。
在一些实施方案中，E选自C 6-C 10芳基、3-10元杂环基或5-10元杂芳基，所述C 6-C 10芳基、3-10元杂环基或5-10元杂芳基任选地被R 1a取代。
在一些实施方案中，E选自C 6-C 10芳基、3-10元杂环基或5-6元杂芳基，所述C 6-C 10芳基、3-10元杂环基或5-6元杂芳基任选地被R 1a取代。
在一些实施方案中，E选自任选地被R 1a取代的以下基团：苯基、吡喃基、吡啶基、嘧啶基、哒嗪基、吡嗪基、呋喃基、噻吩基、吡咯基、吡唑基、噻唑基、咪唑基、苯并呋喃基、苯并咪唑基、苯并噻吩基、苯并噁唑基、苯并噻唑基、吲哚基、喹啉基、异喹啉基、四氢吡咯基、四氢吡啶基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基、环丁基、环戊基、环己基、环己烯基、2-吡啶酮基、2-哌嗪酮基、氮杂环丁基、1,4-二氮杂环庚烷基、二环[1.1.1]戊烷基、2,7-二氮杂螺环[4.4]壬烷基、2,8-二氮杂螺环[4.5]癸烷基、2,7-二氮杂螺环[3.5]壬烷基、2,6-二氮杂螺环[3.5]壬烷基、2,6-二氮杂螺环[3.3]庚烷基、2,6-二氮杂螺环[3.4]辛烷基、2,5-二氮杂螺环[3.4]辛烷基、4,7-二氮杂螺环[2.5]辛烷基、2,5-二氮杂二环[2.2.1]庚烷基、5,8-二氮杂螺环[3.5]壬烷基、3,8二氮杂二环[3.2.1]辛烷基或二氢吡咯基。
在一些实施方案中，E选自任选地被R 1a取代的以下基团：苯基、吡喃基、吡啶基、嘧啶基、哒嗪基、吡嗪基、呋喃基、噻吩基、吡咯基、吡唑基、噻唑基、咪唑基、苯并呋喃基、苯并咪唑基、苯并噻吩基、苯并噁唑基、苯并噻唑基、吲哚基、喹啉基、异喹啉基、四氢吡咯基、四氢吡啶基、哌啶基、哌嗪基、吗啉基、四氢呋喃基、四氢吡喃基、环丁基、环戊基、环己基、环己烯基、2-吡啶酮基、2-哌嗪酮基、氮杂环丁基、1,4-二氮杂环庚烷基、二环[1,1,1]戊烷基、2,7-二氮杂螺环[4.4]壬烷基、2,8-二氮杂螺环[4.5]癸烷基、2,7-二氮杂螺环[3.5]壬烷基、2,6-二氮杂螺环[3.5]壬烷基、2,6-二氮杂螺环[3.3]庚烷基、2,6-二氮杂螺环[3.4]辛烷基或2,5-二氮杂螺环[3.4]辛烷基。
在一些实施方案中，E选自任选地被R 1a取代的以下基团：苯基、吡啶基、噻吩基、吡唑基、咪唑基、氮杂环丁基、四氢吡咯基、哌啶基、哌嗪基、四氢吡啶基、环己基、环己烯基、吗啉基、2-哌嗪酮基、2-吡啶酮基、1,4-二氮杂环庚烷基、二环[1,1,1]戊烷基、2,7-二氮杂螺环[4.4]壬烷基、2,8-二氮杂螺环[4.5]癸烷基、2,7-二氮杂螺环[3.5]壬烷基、2,6-二氮杂螺环[3.5] 壬烷基、2,6-二氮杂螺环[3.3]庚烷基、2,6-二氮杂螺环[3.4]辛烷基、2,5-二氮杂螺环[3.4]辛烷基、4,7-二氮杂螺环[2.5]辛烷基、2,5二氮杂二环[2,2,1]庚烷基、5,8-二氮杂螺环[3.5]壬烷基、3,8二氮杂二环[3,2,1]辛烷基或二氢吡咯基。
在一些实施方案中，E选自任选地被R 1a取代的以下基团：苯基、吡啶基、噻吩基、吡唑基、咪唑基、氮杂环丁基、四氢吡咯基、哌啶基、哌嗪基、四氢吡啶基、环己基、环己烯基、吗啉基、2-哌嗪酮基、2-吡啶酮基、1,4-二氮杂环庚烷基、二环[1,1,1]戊烷基、2,7-二氮杂螺环[4.4]壬烷基、2,8-二氮杂螺环[4.5]癸烷基、2,7-二氮杂螺环[3.5]壬烷基、2,6-二氮杂螺环[3.5]壬烷基、2,6-二氮杂螺环[3.3]庚烷基、2,6-二氮杂螺环[3.4]辛烷基或2,5-二氮杂螺环[3.4]辛烷基。
在一些实施方案中，R 1a独立地选自卤素、CN、NH 2、OH、C 1-C 6烷基、C 3-C 8环烃基、3-6元杂环基、C 1-C 6烷氧基、-S(＝O)-C 1-C 4烷基、-S(＝O) 2-C 1-C 4烷基、
Figure PCTCN2022084728-appb-000003
-S(＝O)(＝NR 8a)R 8b、-N＝S(＝O)R 8aR 8b、-NR 8aR 8b、-C(＝O)NR 8aR 8b或-NR 7C(＝O)R 8b，所述C 1-C 6烷基、C 3-C 8环烃基、3-6元杂环基、C 1-C 6烷氧基、-S(＝O)-C 1-C 4烷基或-S(＝O) 2-C 1-C 4烷基任选地被一个或多个独立地选自卤素、OH或C 1-C 3烷氧基的基团取代。
在一些实施方案中，R 1a独立地选自卤素、CN、NH 2、OH、-NR 8aR 8b、C 1-C 6烷基、C 3-C 8环烃基、3-6元杂环基、C 1-C 6烷氧基，所述C 1-C 6烷基、C 3-C 8环烃基、3-6元杂环基、C 1-C 6烷氧基任选地被一个或多个独立地选自卤素、OH或C 1-C 3烷氧基的基团取代。
在一些实施方案中，R 1a独立地选自卤素、CN、NH 2、OH、C 1-C 6烷基、C 3-C 8环烃基、3-6元杂环基、C 1-C 6烷氧基，所述C 1-C 6烷基、C 3-C 8环烃基、3-6元杂环基、C 1-C 6烷氧基任选地被一个或多个独立地选自卤素、OH或C 1-C 3烷氧基的基团取代。
在一些实施方案中，R 1a独立地选自卤素、-NR 8aR 8b、C 1-C 6烷基或C 1-C 6烷氧基，所述C 1-C 6烷基任选地被一个或多个独立地选自卤素、OH、CN或C 1-C 3烷氧基的基团取代。
在一些实施方案中，R 1a独立地选自C 1-C 6烷基或C 1-C 6烷氧基。
在一些实施方案中，R 1a独立地选自Cl、F、CH 3、-OCH 3、CF 3、-N(CH 3) 2或CH 2CN。
在一些实施方案中，R 1a独立地选自CH 3或-OCH 3。
在一些实施方案中，R 1选自-CN、-(CH 2) qCN、-C≡CH、-C(＝O)C≡CR 5、-C(＝O)CR 6＝C(R 5) 2、-R 7C(＝O)CH＝C(R 5) 2、-NHC(＝O)CR 6＝C(R 5) 2、-R 7NHC(＝O)CH＝C(R 5) 2、-NHC(＝O)C≡CR 5、-S(＝O)CR 6＝C(R 5) 2、-S(＝O) 2CR 6＝C(R 5) 2、-NHS(＝O)CR 6＝C(R 5) 2或-NHS(＝O) 2CR 6＝C(R 5) 2。
在一些实施方案中，R 1选自-C≡CR 5、-C(＝O)C≡CR 5、-C(＝O)CR 6＝C(R 5) 2、-R 7C(＝O)CH＝C(R 5) 2、-NHC(＝O)CR 6＝C(R 5) 2、-R 7NHC(＝O)CH＝C(R 5) 2、-NHC(＝O)C≡CR 5、- S(＝O)CR 6＝C(R 5) 2、-S(＝O) 2CR 6＝C(R 5) 2、-NHS(＝O)CR 6＝C(R 5) 2、-NHS(＝O) 2CR 6＝C(R 5) 2、-NR 6C(＝O)CR 6＝C(R 5) 2或NHC(＝O)R 5。
在一些实施方案中，R 1选自-CN、-(CH 2) qCN、-C≡CR 5、-C(＝O)C≡CR 5、-C(＝O)CR 6＝C(R 5) 2、-R 7C(＝O)CH＝C(R 5) 2、-NHC(＝O)CR 6＝C(R 5) 2、-R 7NHC(＝O)CH＝C(R 5) 2、-NHC(＝O)C≡CR 5、-NHS(＝O) 2CR 6＝C(R 5) 2、-NR 6C(＝O)CR 6＝C(R 5) 2或NHC(＝O)R 5。
在一些实施方案中，R 1选自-(CH 2) qCN、-C≡CH、-C(＝O)C≡CR 5、-C(＝O)CR 6＝C(R 5) 2、-R 7C(＝O)CH＝C(R 5) 2、-NHC(＝O)CR 6＝C(R 5) 2、-R 7NHC(＝O)CH＝C(R 5) 2、-NHC(＝O)C≡CR 5或-NHS(＝O) 2CR 6＝C(R 5) 2。
在一些实施方案中，R 1选自-C≡CR 5、-C(＝O)C≡CR 5、-C(＝O)CR 6＝C(R 5) 2、-R 7C(＝O)CH＝C(R 5) 2、-NHC(＝O)CR 6＝C(R 5) 2、-R 7NHC(＝O)CH＝C(R 5) 2、-NHC(＝O)C≡CR 5、-NHS(＝O) 2CR 6＝C(R 5) 2、-NR 6C(＝O)CR 6＝C(R 5) 2或NHC(＝O)R 5。
在一些实施方案中，R 6选自H、F、Cl、CN或CH 3。
在一些实施方案中，R 6选自H、F、CN或CH 3。
在一些实施方案中，R 5独立地选自H、C 1-C 3烷基或C 3-C 6环烷基，所述C 1-C 3烷基或C 3-C 6环烷基任选地被一个或者多个R 5a取代。
在一些实施方案中，R 5独立地选自H或C 1-C 3烷基，所述C 1-C 3烷基任选地被一个或者多个R 5a取代。
在一些实施方案中，R 5a独立地选自卤素、CN、N(R 5b) 2或3-12元杂环基。
在一些实施方案中，R 5a独立地选自卤素、CN、N(R 5b) 2或3-6元杂环基。
在一些实施方案中，R 5a独立地选自N(R 5b) 2或3-6元杂环基。
在一些实施方案中，R 5a独立地选自卤素、CN、N(CH 3) 2、哌啶基或吗啉基。
在一些实施方案中，R 5a独立地选自N(R 5b) 2、哌啶基或吗啉基。
在一些实施方案中，R 5b独立地选自C 1-C 6烷基。
在一些实施方案中，R 5b独立地选自CH 3。
在一些实施方案中，R 7选自C 1-C 6亚烷基、C 3-C 6亚环烷基或3-6元亚杂环基。
在一些实施方案中，R 7选自以下基团：-CH 2-、-CH(CH 3)-、-C(CH 3) 2-、
Figure PCTCN2022084728-appb-000004
Figure PCTCN2022084728-appb-000005
在一些实施方案中，R 7选自以下基团：-CH 2-、-CH(CH 3)-、-C(CH 3) 2-、
Figure PCTCN2022084728-appb-000006
在一些实施方案中，R 1选自以下基团：
Figure PCTCN2022084728-appb-000007
在一些实施方案中，R 1选自以下基团：
Figure PCTCN2022084728-appb-000008
在一些实施方案中，R 2选自H、NH 2、CH 3、OH或卤素。
在一些实施方案中，R 2选自H、NH 2、CH 3或卤素。
在一些实施方案中，R 2选自H、NH 2或卤素。
在一些实施方案中，R 2选自H或NH 2。
在一些实施方案中，R 3独立地选自卤素、C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6卤代烷基。
在一些实施方案中，R 3独立地选自卤素或C 1-C 6烷氧基。
在一些实施方案中，R 3选自F和-OCH 3。
在一些实施方案中，R 3选自卤素。
在一些实施方案中，R 3选自F。
在一些实施方案中，m选自0或1。
在一些实施方案中，R 4独立地选自卤素、CN、NH 2、OH、NO 2、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 8环烷基、3-10元杂环基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 8环烷基、3-10元杂环基任选地被一个或者多个R 4a取代。
在一些实施方案中，R 4独立地选自CN、卤素、C 1-C 6烷基或C 1-C 6烷氧基。
在一些实施方案中，R 4独立地选自卤素、C 1-C 6烷基或C 1-C 6烷氧基。
在一些实施方案中，R 4独立地选自CN或C 1-C 6烷基。
在一些实施方案中，R 4独立地选自CN或CH 3。
在一些实施方案中，R 4独立地选自C 1-C 6烷基。
在一些实施方案中，R 4独立地选自CH 3。
在一些实施方案中，n选自0或1。
在一些实施方案中，R 9选自H、NH 2、-NHR 10、-NH-C 1-C 6烷基或C 1-C 6烷基，所述C 1-C 6烷基或-NH-C 1-C 6烷基任选地被一个或多个R 10取代。
在一些实施方案中，R 9选自H、CN、OH、NH 2、-NHR 10或-NH-C 1-C 6烷基，所述-NH-C 1-C 6烷基任选地被一个或多个R 10取代。
在一些实施方案中，R 10独立地选自卤素、NH 2、C 3-C 8环烷基或3-10元杂环基，所述NH 2、C 3-C 8环烷基或3-10元杂环基任选地被一个或多个R 11取代。
在一些实施方案中，R 10独立地选自卤素、NH 2、C 3-C 6环烷基、5-6元杂环基、C 6-C 10芳基或5-6元杂芳基，所述NH 2、C 3-C 6环烷基、5-6元杂环基、C 6-C 10芳基或5-6元杂芳基任选地被一个或多个R 11取代。
在一些实施方案中，R 10独立地选自NH 2、C 3-C 6环烷基、5-6元杂环基、C 6-C 10芳基或5-6元杂芳基，所述NH 2、C 3-C 6环烷基、5-6元杂环基、C 6-C 10芳基或5-6元杂芳基任选地被一个或多个R 11取代。
在一些实施方案中，R 10独立地选自NH 2、3-10元杂环基、C 6-C 10芳基或5-10元杂芳基，所述NH 2、3-10元杂环基、C 6-C 10芳基或5-10元杂芳基任选地被一个或多个R 11取代。
在一些实施方案中，R 10独立地选自任选地被一个或多个R 11取代的下述基团：吡唑基、NH 2、苯基、吡啶基、吡咯基、四氢吡咯基或吗啉基。
在一些实施方案中，R 11独立地选自C 1-C 6烷基、卤素、C 1-C 3烷氧基、C 3-C 6环烷基或5-6元杂环基，所述C 1-C 6烷基、C 3-C 6环烷基或5-6元杂环基任选地被C 1-C 6烷基、卤素、OH、-NH-C 1-C 6烷基或-N(C 1-C 6烷基) 2取代。
在一些实施方案中，R 11独立地选自任选地被C 1-C 6烷基、卤素、OH、-NH-C 1-C 6烷基、 或-N(C 1-C 6烷基) 2取代的下述基团：甲基、乙基、四氢吡咯基、哌啶基、-OCH 3、F、哌嗪基、环丙基或异丙基。
在一些实施方案中，R 11独立地选自任选地被甲基、乙基、OH、-N(CH 3) 2或F取代的下述基团：甲基、乙基、四氢吡咯基、哌啶基、-OCH 3、F、哌嗪基、环丙基或异丙基。
在一些实施方案中，R 11独立地选自C 1-C 6烷基。
在一些实施方案中，R 9选自以下基团：H、CN、OH、NH 2、
Figure PCTCN2022084728-appb-000009
Figure PCTCN2022084728-appb-000010
在一些实施方案中，式(I)所示化合物、或其立体异构体或药学上可接受的盐选自式(II)所示化合物、或其立体异构体或药学上可接受的盐，
Figure PCTCN2022084728-appb-000011
其中，环A、X、Y、Z、E、R 1、R 2、R 3、R 4、n、m如上文的定义。应理解，在涉及式(II)的权利要求14中，当权利要求14引用前述权利要求x时，所述式(II)中的环A、X、Y、Z、E、R 1、R 2、R 3、R 4、n、m如权利要求x定义。例如，当权利要求14引用权利要求1时，所述式(II)中的环A、X、Y、Z、E、R 1、R 2、R 3、R 4、n、m如权利要求1定义；当权利要求14引用权利要求2时，所述式(II)中的环A、X、Y、Z、E、R 1、R 2、R 3、R 4、n、m如权利要求2定义，以此类推。
在一些实施方案中，式(I)所示化合物、或其立体异构体或药学上可接受的盐选自式(III)所示化合物、或其立体异构体或药学上可接受的盐，
Figure PCTCN2022084728-appb-000012
其中，环B、X、Y、Z、E、R 1、R 2、R 3、R 4、n、m如上文的定义。应理解，在涉及式(III)的权利要求15中，当权利要求15引用前述权利要求x时，所述式(III)中的环B、X、Y、Z、E、R 1、R 2、R 3、R 4、n、m如权利要求x定义。例如，当权利要求15引用前述权利要求1时，所述式(III)中的环B、X、Y、Z、E、R 1、R 2、R 3、R 4、n、m如权利要求1定义；当权利要求15引用前述权利要求2时，所述式(III)中的环B、X、Y、Z、E、R 1、R 2、R 3、R 4、n、m如权利要求2定义，以此类推。
在一些实施方案中，式(I)所示化合物、或其立体异构体或药学上可接受的盐选自式(IV)所示化合物、或其立体异构体或药学上可接受的盐，
Figure PCTCN2022084728-appb-000013
其中，X、Y、Z、E、R 1、R 2、R 3、R 4、n、m如上文的定义。
应理解，在涉及式(IV)的权利要求16中，当权利要求16引用前述权利要求x时，所述式(IV)中的X、Y、Z、E、R 1、R 2、R 3、R 4、n、m如权利要求x定义。例如，当权利要求16引用前述权利要求1时，所述式(IV)中的X、Y、Z、E、R 1、R 2、R 3、R 4、n、m如权利要求1定义；当权利要求16引用前述权利要求2时，所述式(IV)中的X、Y、Z、E、 R 1、R 2、R 3、R 4、n、m如权利要求2定义，以此类推。
在一些实施方案中，式(I)所示化合物、或其立体异构体或药学上可接受的盐选自式(V)所示化合物、或其立体异构体或药学上可接受的盐，
Figure PCTCN2022084728-appb-000014
其中，环A、环B、Y、W、E、R 1、R 2、R 3、R 4、n、m如上文的定义。
应理解，在涉及式(V)的权利要求17中，当权利要求17引用前述权利要求x时，所述式(V)中的环A、环B、Y、W、E、R 1、R 2、R 3、R 4、n、m如权利要求x定义。例如，当权利要求17引用前述权利要求1时，所述式(V)中的环A、环B、Y、W、E、R 1、R 2、R 3、R 4、n、m如权利要求1定义；当权利要求17引用前述权利要求2时，所述式(V)中的环A、环B、Y、W、E、R 1、R 2、R 3、R 4、n、m如权利要求2定义，以此类推。
在一些实施方案中，式(I)所示化合物、或其立体异构体或药学上可接受的盐选自以下化合物、或其立体异构体或药学上可接受的盐：
Figure PCTCN2022084728-appb-000015
Figure PCTCN2022084728-appb-000016
Figure PCTCN2022084728-appb-000017
Figure PCTCN2022084728-appb-000018
Figure PCTCN2022084728-appb-000019
Figure PCTCN2022084728-appb-000020
Figure PCTCN2022084728-appb-000021
Figure PCTCN2022084728-appb-000022
Figure PCTCN2022084728-appb-000023
Figure PCTCN2022084728-appb-000024
Figure PCTCN2022084728-appb-000025
进一步，本发明还提供了一种药物组合物，所述药物组合物包含式(I)所示化合物、或其立体异构体或药学上可接受的盐，以及药学上可接受的辅料。
进一步，本发明涉及式(I)化合物、或其立体异构体或药学上可接受的盐，或其药物组合物在制备预防或者治疗与FGFR相关的疾病的药物中的用途。
进一步，本发明涉及式(I)化合物、或其立体异构体或药学上可接受的盐，或其药物组合物在预防或者治疗与FGFR相关疾病中的用途。
进一步，本发明涉及用于预防或者治疗与FGFR相关的疾病的式(I)化合物、或其立体异构体或药学上可接受的盐，或其药物组合物。
本发明还涉及预防或者治疗与FGFR相关的疾病的方法，该方法包括给以个体治疗上有效剂量的本发明所述的式(I)化合物、或其立体异构体或药学上可接受的盐，其药物组合物，或者包含本发明所述的式(I)化合物、或其立体异构体或药学上可接受的盐的药物制剂。
进一步，所述与FGFR相关的疾病选自癌症。
本申请的一些实施方案中，所述癌症例如为实体瘤，如胃癌。
另一方面，本发明提供式(I)化合物、或其立体异构体或药学上可接受的盐、或其药物组合物在制备预防或者治疗癌症疾病的药物中的用途。
另一方面，本发明提供式(I)化合物、或其立体异构体或药学上可接受的盐、或其药物组合物在预防或者治疗癌症疾病中的用途。
另一方面，本发明提供用于预防或者治疗癌症疾病的式(I)化合物、或其立体异构体或药学上可接受的盐、或其药物组合物。
另一方面，本发明提供治疗哺乳动物癌症疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的式(I)化合物、或其立体异构体或药学上可接受的盐、或其药物组合物。
术语定义和说明
除非另有说明，本发明说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本发明说明书记载的范围内。
本文中
Figure PCTCN2022084728-appb-000026
表示连接位点。
本文中，合成路线中的双箭头
Figure PCTCN2022084728-appb-000027
或多箭头
Figure PCTCN2022084728-appb-000028
表示多步反应。
术语“药学上可接受的盐”是指药学上可接受的无毒酸或碱的盐，包括无机酸和碱、有机酸和碱的盐。
本发明的化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几 何异构体和单个的异构体都包括在本发明的范围之内。
本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对应异构体和构象异构体。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮，如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。
术语“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐或前体药物与其它化学组分的混合物，其它组分例如生理学/药学上可接受的载体和赋形剂。药物组合物的目的是促进化合物对生物体的给药。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，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。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH 2CH 3)、单取代的(如CH 2CH 2F)、多取代的(如CHFCH 2F、CH 2CHF 2等)或完全被取代的(CF 2CF 3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
术语“C 1-C 6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、 叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1，2-二甲基丙基、新戊基、1，1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3，3-二甲基丁基、2，2-二甲基丁基、1，1-二甲基丁基、2，3-二甲基丁基、1，3-二甲基丁基或1，2-二甲基丁基等。术语“C 1-C 3烷基”应理解为表示具有1、2、3个碳原子的直链或支链饱和一价烃基。
术语“烷氧基”是指直链或支链醇类失去羟基上的氢原子产生的基团，可理解为“烷基氧基”或“烷基-O-”，其中烷基如上所定义。术语“C 1-C 6烷氧基”可理解为“C 1-C 6烷基氧基”或“C 1-C 6烷基-O-”。所述“C 1-C 6烷氧基”可以包含“C 1-C 3烷氧基”等范围。
术语“卤素”指氟、氯、溴或碘，优选为氟、氯或溴。
术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“C 1-C 6卤代烷基”意指被一个或多个卤素取代的如上所定义的C 1-C 6烷基，包括但不仅限于三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基、三氯甲基、五氟乙基和五氯乙基等等。
术语“卤代烷氧基”意在包括单卤代烷氧基和多卤代烷氧基，其中卤素取代在烷氧基的烷基部分上。例如，术语“C 1-C 6卤代烷氧基”意指被一个或多个卤素取代的如上所定义的C 1-C 6烷氧基。
术语“C 3-C 10环烃基”应理解为表示饱和或部分饱和的单环或双环烃环，其具有3～10个碳原子。其包括C 3-C 10环烷基和C 3-C 10部分饱和环烃基(例如环烯基、环炔基等)，术语“C 3-C 10环烷基”表示饱和的单环或双环烃环，其具有3～10个碳原子。例如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者是双环烃基如十氢化萘环。C 3-C 10部分饱和环烃基表示部分饱和的单环或双环烃环，其具有3～10个碳原子。例如环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基、环壬烯基或环癸烯基。根据本发明，所述双环烃环包括桥环、螺环或并环结构。术语“C 3-C 8环烃基”应理解为表示饱和或部分饱和的单环或双环烃环，其具有3～8个原子，其包括C 3-C 8环烷基和C 3-C 8部分饱和环烃基，术语“C 3-C 8环烷基”表示饱和的单环或双环烃环，其具有3～8个碳原子。术语“C 3-C 6环烃基”应理解为表示饱和或部分饱和的单环或双环烃环，其具有3～6个原子，其包括C 3-C 6环烷基和C 3-C 6部分饱和环烃基，术语“C 3-C 6环烷基”表示饱和的单环或双环烃环，其具有3～6个碳原子。
术语“C 6-C 10芳基”应理解为具有6、7、8、9、10个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；或者具有9个碳原子的环(“C 9芳基”)，例如茚满基或茚基，或者具有10个碳原子的环(“C 10芳基”)，例如四氢化萘基、二氢萘基或萘基。
术语“3-12元杂环基”应理解为具有3-12个环原子的饱和的或部分不饱和的一价单环或双环。所述双环包括桥环、螺环、稠环。所述杂环基中的“杂”包括但不限于独立地选自N、O、S、C(＝O)、C(＝S)、S(＝O)、S(O) 2的原子和/或原子团，杂原子的个数可以是例如1-6个(例如1、2、3、4、5、或6个)。特别地，所述杂环基可以是单环的，包括但不限于：4元环，如氮杂环丁烷基、氧杂环丁烷基；5元环，如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基；或6元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、1,1-二氧硫代吗啉基、哌嗪基、2-哌嗪酮基或三噻烷基；或7元环，如二氮杂环庚烷基。任选地，所述杂环基可以是双环的，例如但不限于5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。所述的环可以是部分不饱和的，即它可以包含一个或多个双键，例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基，或者，它可以是苯并稠合的，例如但不限于二氢异喹啉基。术语“3-8元杂环基”应理解为具有3-8个环原子的饱和的或部分不饱和的一价单环或双环。术语“3-6元杂环基”应理解为具有3-6个环原子的饱和的或部分不饱和的一价单环或双环。
术语“5-12元杂芳基”应理解为包括一价单环、双环或三环芳香族环系，特别是5或6或9或10个环原子，另外在每一种情况下可为苯并稠合的。所述杂芳基中的“杂”表示芳香环中包括但不限于独立地选自N、O、S、C(＝O)、C(＝S)、S(＝O)、S(O) 2的原子和/或原子团，杂原子的个数可以是例如1-6个(例如1、2、3、4、5、或6个)。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、***基、噻二唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并***基、吲唑基、吲哚基、异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基或
Figure PCTCN2022084728-appb-000029
等。
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特 定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本发明化合物的用量。构成“治疗有效量”的本发明化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本发明公开内容而确定。
术语“个体”包括哺乳动物和非哺乳动物。哺乳动物的实例包括但不限于哺乳动物纲的任何成员：人，非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛、马、绵羊、山羊、猪；家养动物，例如兔、狗和猫；实验室动物，包括啮齿类动物，例如大鼠、小鼠和豚鼠等。非人哺乳动物的实例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方案中，所述哺乳动物可以为人。
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。适用于上述制剂的典型的“药学上可接受的载体”的实例为：糖类，淀粉类，纤维素及其衍生物等在药物制剂中常用到的辅料。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
词语“包括(comprise)”、“含有(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
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。
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
具体实施方式
以下实施例详细说明发明的技术方案，但本发明的保护范围包括但不限于此。
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR位移的单位为10 -6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)。
缩略词：
DMAP:4-二甲氨基吡啶；Et3N或TEA：三乙胺；THF：四氢呋喃；MeCN或ACN：乙 腈；18-冠-6或18-crown-6：1,4,7,10,13,16-六氧杂环十八烷；Pd(dppf)Cl 2：[1,1'-双(二苯基膦)二茂铁]二氯化钯；dioxane：二氧六环；Pd(PPh 4) 3:四(三苯基膦)钯；DIEA或DIPEA：N,N-二异丙基乙胺；DMF：N,N-二甲基甲酰胺；HATU：2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；NMP：N-甲基吡咯烷酮；BOP-Cl：双(2-氧代-3-噁唑烷基)次磷酰氯；Pyridine：吡啶；Pd(OAc) 2：醋酸钯；S-phos：2-二环己基膦-2',6'-二甲氧基联苯；DCM：二氯甲烷；BINAP：1,1'-联萘-2,2'-双二苯膦；TCHP：三环己基磷；TFA：三氟乙酸；LiHMDS:六甲基二硅基胺基锂；TsCl：对甲苯磺酰；MeAC：乙酸；TBAF:四丁基氟化铵；TsOH：对甲苯磺酸；LAH：氢化铝锂。
实施例1
N-(4-(6-氨基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)苯基)丙烯酰基酰胺(1)
Figure PCTCN2022084728-appb-000030
第一步 N-(4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯基)丙烯酰基酰胺(1B)
将4,4,5,5-四甲基-2-(4-氨基苯基)-1,3,2-二噁硼戊环(5.0g,23mmol,1eq),4-二甲氨基吡啶(0.70g,5.7mmol,0.25eq)和三乙胺(4.6g,46mmol,6.3mL,2eq)溶解于四氢呋喃(50 mL)中,在0摄氏度下缓慢滴加丙烯酰氯(2.5g,27mmol,2.2mL,1.2eq)的四氢呋喃(5mL)溶液。所得混合物在20摄氏度下搅拌5小时。将反应液减压蒸馏除去溶剂，所得残留物中加水(100mL)。所得混合物用乙酸乙酯萃取(100mL×3次)。将有机相混合，用饱和食盐水洗涤(100mL×3次),并用无水硫酸钠干燥后，过滤，减压蒸馏除去溶剂。所得残余物用硅胶柱纯化(洗脱相为含16～18％乙酸乙酯的石油醚混合溶剂)，得到白色固体标题化合物1B(2.3g,8.3mmol,收率:36％).
1H NMR(400MHz,DMSO-d 6):δ＝10.24(s,1H),7.73-7.66(m,2H),7.65-7.59(m,2H),6.50-6.39(m,1H),6.31-6.22(m,1H),5.77(d,J＝10.8Hz,1H),1.28(s,12H).
第二步 2-(4-溴-2-氟苯氧基)-4-甲基嘧啶(1E)
将4-溴-2氟苯酚(5.0g,26mmol,1.0eq)和2-氯-4-甲基嘧啶(3.7g,29mmol,1.1eq)溶解于乙腈(30mL)中,加入碳酸钾(7.2g,52mmol,2.0eq)和18-冠-6(0.69g,2.6mmol,0.10eq)。将所得混合物在85摄氏度下搅拌反应12小时后冷却，加入水(100mL)并用乙酸乙酯(100mL×3次)萃取。将所得有机相混合，用饱和食盐水洗涤(100mL×3次),并用无水硫酸钠干燥后，过滤，减压蒸馏除去溶剂。所得残余物用硅胶柱纯化(洗脱相为含0～15％乙酸乙酯的石油醚混合溶剂)，得到白色固体标题化合物1E(7.2g,收率:97％)。
1H NMR(400MHz,CDCl 3):δ＝8.35(d,J＝5.2Hz,1H),7.42-7.28(m,2H),7.22-7.10(m,1H),6.95(d,J＝5.2Hz,1H),2.50(s,3H).
第三步 2-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯氧基)-4-甲基嘧啶(1G)
将化合物1E(4.7g,17mmol,1.0eq),4,4,4',4',5,5,5',5'-八甲基-2,2'-联(1,3,2-二噁硼戊环)(5.1g,20mmol,1.2eq),[1,1'-双(二苯基膦)二茂铁]二氯化钯(1.2g,1.7mmol,0.1eq),乙酸钾(4.9g,50mmol,3eq)混合于二氧六环(100mL)中。将混合物在80摄氏度氮气氛围下搅拌3小时。于混合液中加入乙腈(100mL)，搅拌30分钟后过滤。将滤液浓缩得到黑色固体，为标题化合物1G(10g,粗品)。
MS(ESI+)m/z＝331.0[M+H].
第四步 6-氯-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-胺(1I)
将6-氯-5-碘-4-氨基嘧啶(1.7g,6.7mmol,1.0eq),化合物1G(2.2g,6.7mmol,1.0eq),[1,1'-双(二苯基膦)二茂铁]二氯化钯(0.49g,0.67mmol,0.10eq)和磷酸钾(2.8g,13mmol,2.0eq)混合于二氧六环(40mL)和水(4mL)中。所得混合物在85摄氏度氮气氛围下搅拌2小时。将黄色反应液减压蒸馏除去溶剂，所得残余物经硅胶柱纯化(洗脱相为含33～100％乙酸乙酯的石油醚混合溶剂)，得到浅黄色固体标题化合物1I(1.10g,收率：50％)。
1H NMR(400MHz,DMSO-d 6):δ＝8.49(d,J＝5.2Hz,1H),8.23(s,1H),7.48(t,J＝8.4Hz,1H), 7.37(d,J＝11.2Hz,1H),7.21(d,J＝5.2Hz,1H),7.17(d,J＝8.0Hz,1H),2.45(s,3H).
第五步 N-(4-(6-氨基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)苯基)丙烯酰基酰胺(1)
将化合物1I(0.24g,0.72mmol,1.0eq)，化合物1B(0.19g,0.72mmol,1.0eq)，四三苯基膦钯(84mg,0.073mmol,0.10eq)和碳酸钾(0.20g,1.5mmol,2.0eq)混合于二氧六环(10mL)和水(1mL)中。所得混合物在85摄氏度氮气氛围下搅拌18小时。于反应液中加入饱和氯化铵溶液(20mL)并用二氯甲烷(30mL×3次)萃取。将所得有机相混合，用饱和食盐水洗涤(100mL X 3次),并用无水硫酸钠干燥后，过滤，减压蒸馏除去溶剂。所得残余物经制备色谱纯化并冻干得到白色固体标题化合物1(0.15g,收率：46％)。
MS(ESI+)m/z＝443.1[M+H].
1H NMR(400MHz,DMSO-d6):δ＝10.20(s,1H),8.50(d,J＝5.2Hz,1H),8.46(s,1H),7.55(d,J＝8.4Hz,2H),7.34(t,J＝8.4Hz,1H),7.29-7.14(m,4H),7.00(dd,J 1＝8.4Hz,J 2＝1.2Hz,1H),6.74-6.29(m,3H),6.29-6.19(m,1H),5.76(dd,J 1＝10.0Hz,J 2＝2.0Hz,1H),2.43(s,3H).
实施例2
N-(4-(6-氨基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)苯基)甲基丙烯酰基酰胺(2)
Figure PCTCN2022084728-appb-000031
第一步 N-(4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯基)甲基丙烯酰基酰胺(2B)
将4,4,5,5-四甲基-2-(4-氨基苯基)-1,3,2-二噁硼戊环(0.20g,0.91mmol,1eq),甲基丙烯酸(0.16g,1.8mmol,2.0eq)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.69g,1.8mmol,2eq)和N,N-二异丙基乙胺(0.24g,0.18mmol,2.0eq)溶解于乙腈中(50mL)中，所得混合物在25摄氏度氮气氛围下搅拌2小时。将反应液减压蒸馏除去溶剂，所得残留物中加水(30mL)。所得混合物用乙酸乙酯萃取(30mL×3次)。将有机相混合，用饱和食盐水洗涤,并用无水硫酸钠干燥后，过滤，减压蒸馏除去溶剂。所得残余物用硅胶柱纯化(洗脱相为含0～50％乙酸乙酯的石油醚混合溶剂)，得到浅黄色固体标题化合物2B(0.20g，收率：76％)。
1H NMR(400MHz,CDCl 3):δ＝7.79(d,J＝8.4Hz,2H),7.59(d,J＝8.4Hz,2H),5.80(s,1H),5.48(d,J＝1.2Hz,1H),2.07(s,3H),1.35(s,12H)
第二步 N-(4-(6-氨基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)苯基)甲基丙烯酰基酰胺(2)
将化合物1I(0.030g,0.090mmol,1.0eq)，化合物2B(0.029g,0.099mmol,1.0eq)，四三苯基膦钯(0.010mg,9.4μmol,0.10eq)和碳酸钾(0.025g,0.18mmol,2.0eq)混合于二氧六环(5mL)和水(0.5mL)中。所得混合物在80摄氏度氮气氛围下搅拌2小时。于反应液中加入饱和氯化铵溶液(20mL)并用二氯甲烷(30mL×3次)萃取。将所得有机相混合，用饱和食盐水洗涤(20mL×3次),并用无水硫酸钠干燥后，过滤，减压蒸馏除去溶剂。所得残余物经制备色谱纯化并冻干得白色固体标题化合物2(3.9mg,收率：9.2％)。
MS(ESI+)m/z＝457.2[M+1].
1H NMR(400MHz,MeOD-d 4):δ＝9.50-9.40(m,2H),8.61-8.56(m,2H),8.37-8.30(m,3H),8.19-8.14(m,2H),8.12-8.08(m,1H),6.79(s,1H),6.52(s,1H),3.51(s,3H),3.02(s,3H)
实施例3
6-(6-乙炔基-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-胺(3)
Figure PCTCN2022084728-appb-000032
第一步 5-溴-4-甲基-2-((三异丙基甲硅烷基)乙炔基)吡啶(3C)
将化合物3A(10g,40mmol,1.0eq)，化合物3B(7.3g,40mmol,9.0mL,1.0eq)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(2.9g,4.0mmol,0.10eq),碘化亚铜(0.76g,4.0mmol,0.10eq)和三乙胺(8.1g,80mmol,11mL,2.0eq)混合于N,N-二甲基甲酰胺(50mL)中。所得混合物在85摄氏度氮气氛围下搅拌2小时。于反应液中加入饱和氯化铵溶液(100mL)并用二氯甲烷(100mL×3次)萃取。将所得有机相混合，用饱和食盐水洗涤(50mL×3次),并用无水硫酸钠干燥后，过滤，减压蒸馏除去溶剂。所得残余物经硅胶柱纯化(洗脱相为含5～12％乙酸乙酯的石油醚混合溶剂)，得到白色固体标题化合物3C(8.5g,收率：61％)。
1H NMR(400MHz,CDCl 3):δ＝8.56-8.47(m,1H),7.26(s,1H),2.30(s,3H),1.08-1.06(m,21H)
第二步 4-甲基-5-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-2-((三异丙基甲硅烷基)乙炔基)吡啶(3D)
将化合物3C(4.0g,11mmol,1.0eq)，化合物1F(5.8g,23mmol,2.0eq)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(0.83g,1.1mmol,0.10eq),醋酸钾(2.2g,23mmol,2.0eq)混合于1,4-二氧六环(40mL)中。所得混合物在80摄氏度氮气氛围下搅拌3小时。将反应液减压蒸馏除去溶剂，所得残余物经C18反相硅胶柱纯化(洗脱相为含20～100％乙腈的水溶液)并冻干，得到白色固体标题化合物3D(0.80g,收率：16％)
1H NMR(400MHz,DMSO-d 6):δ＝8.61(s,1H),7.38(s,1H),2.45(s,3H),1.31(s,12H),1.18-1.04(m,21H)
第三步 5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-6-(4-甲基-6-((三异丙基甲硅烷基)乙炔基)吡啶-3-基)嘧啶-4-胺(3E)
将化合物1I(0.060g,0.18mmol,1.0eq)，化合物3D(0.073g,0.18mmol,1.0eq)，四三苯基膦钯(0.021mg,18μmol,0.10eq)和碳酸钾(0.075g,0.54mmol,3.0eq)混合于二氧六环(3mL)和水(0.3mL)中。所得混合物在85摄氏度氮气氛围下搅拌12小时。将反应液减压蒸馏除去溶剂，所得残余物经制备色谱纯化并冻干得白色固体标题化合物3E(75mg,收率：73％)。
1H NMR(400MHz,CDCl 3):δ＝8.59(s,1H),8.26(d,J＝5.2Hz,1H),8.13(s,1H),7.19-7.14(m,2H),6.92-6.82(m,3H),5.29-5.07(m,2H),2.40(s,3H),2.13(s,3H),1.10-1.03(m,21H)
第四步 6-(6-乙炔基-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-胺(3)
将化合物3E(70mg,0.12mmol,1.0eq)溶解于2mL四氢呋喃中，加入三乙胺三氢氟酸盐(0.20g,1.2mmol,0.20mL,10eq)。所得混合物在40摄氏度氮气氛围下搅拌3小时。将反应液减压蒸馏除去溶剂，所得残余物经制备色谱纯化并冻干得白色固体标题化合物3(24mg,收率：47％)。
MS(ESI+)m/z＝413.1[M+H].
1H NMR(400MHz,DMSO-d 6):δ＝8.45(d,J＝5.2Hz,1H),8.48(s,1H),8.16(s,1H),7.40(s,1H),7.28-7.21(m,2H),7.16(d,J＝5.2Hz,1H),7.04-6.45(m,3H),4.29(s,1H),2.38(s,3H),2.14(s,3H)
实施例4
N-(1-(6-氨基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)哌啶-4-基)丙烯酰基酰胺(4)
Figure PCTCN2022084728-appb-000033
第一步 1-叔丁基氧羰基4-丙烯酰基酰氨基哌啶(4C)
将1-叔丁基氧羰基4-氨基哌啶(3.0g,15mmol,1.0eq)和N,N-二异丙基乙基胺(3.9g,30mmol,6.3mL,2.0eq)溶解于二氯甲烷(40mL)中,在0摄氏度下缓慢滴加丙烯酰氯(2.0g,22mmol,1.8mL,1.5eq)的二氯甲烷(5mL)溶液。所得混合物在20摄氏度下搅拌3小时。将反应液减压蒸馏除去溶剂，所得残留物硅胶柱纯化(洗脱相为含0～50％乙酸乙酯的石油醚混合溶剂)，得到白色固体标题化合物4C(2.5g,收率:66％)。
1H NMR(400MHz,CDCl 3):δ＝6.29(dd,J＝1.3,16.0Hz,1H),6.12-6.03(m,1H),5.65(dd,J＝1.3,10.4Hz,1H),5.57(br d,J＝8.0Hz,1H),4.15-3.91(m,3H),2.87(t,J＝12.0Hz,2H),2.00-1.87(m,2H),1.46(s,9H),1.39-1.30(m,2H).
第二步 4-丙烯酰基酰氨基哌啶盐酸盐(4D)
将化合物4C(2.0g,7.9mmol,1.0eq)溶解于二氯甲烷(15mL)中,在0摄氏度下缓慢滴加4M盐酸二氧六环溶液(7.86mL,4.0eq)。所得混合物在20摄氏度下搅拌2小时。将反应液减压蒸馏除去溶剂，得到固体标题化合物4D(2.5g,粗品)。
1H NMR(400MHz,DMSO-d 6):δ＝8.30(d,J＝7.2Hz,1H),6.28-6.19(m,1H),6.14-6.06(m,1H),5.60(dd,J＝2.3,10.0Hz,1H),3.30-3.19(m,2H),3.03-2.86(m,2H),1.92(dd,J＝3.0,
13.6Hz,2H),1.72-1.56(m,2H).
第三步 N-(1-(6-氨基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)哌啶-4-基)丙烯酰基酰胺(4)
将化合物4D(0.50g,3.2mmol,1eq),化合物1I(0.11mg,0.32mmol,0.1eq)和N,N-二异丙基乙基胺(0.84g,6.5mmol,1.1mL,2.0eq)溶解于N-甲基吡咯烷酮(3mL)中。所得混合物在氮气氛围中微波加热120摄氏度下搅拌反应1小时。所得反应液经制备色谱(Waters  Xbridge C18,20-70％乙腈水溶液(含0.01％氨水))纯化并冻干得白色固体标题化合物4(1.6mg,收率：1.0％)。
MS(ESI+)m/z＝450.1[M+H].
1H NMR(400MHz,MEOD-d 4):δ＝8.43(d,J＝5.2Hz,1H),8.25(s,1H),7.53(t,J＝8.2Hz,1H),7.38(dd,J＝1.8,10.8Hz,1H),7.30(d,J＝7.6Hz,1H),7.18(d,J＝5.2Hz,1H),6.20(d,J＝6.4Hz,2H),5.64(t,J＝6.0Hz,1H),4.07(br d,J＝13.6Hz,2H),3.98-3.89(m,1H),3.31(s,10H),3.04(t,J＝11.6Hz,2H),2.48(s,3H),1.83(d,J＝10.8Hz,2H),1.46-1.36(m,2H)
实施例5
1-(4-(6-氨基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)-3,6-二氢吡啶-1(2H)-基)-2-甲基丙-2-烯-1-酮(5)
Figure PCTCN2022084728-appb-000034
第一步 4-(6-氨基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁基酯(5B)
将化合物1I(1.1g,3.32mmol,1.0eq)，化合物5A(1.1g,3.5mmol,1.1eq)，四三苯基膦钯(0.24g,0.33mmol,0.10eq)和碳酸钾(1.4g,10mmol,3.0eq)混合于二氧六环(30mL)和水(3mL)中。所得混合物在85摄氏度氮气氛围下搅拌12小时。将反应液减压蒸馏除去溶剂，所得残余物经硅胶柱色谱纯化(洗脱相为含0-10％甲醇的二氯甲烷混合溶剂)得棕色固体标题化合物5B(0.70g,收率：44％)。
1H NMR(400MHz,CDCl 3):δ＝8.56(s,1H),8.38(d,J＝5.2Hz,1H),7.37(t,J＝8.0Hz,1H),7.17-7.06(m,2H),6.96(d,J＝5.2Hz,1H),5.84(s,1H),5.31(s,1H),5.00(s,2H),3.90(s,2H),3.49-3.33(m,2H),2.51(s,3H),1.45(s,9H)
第二步 5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-6-(1,2,3,6-四氢吡啶-4-基)嘧啶-4-胺盐酸盐(5C)
将化合物5B(0.20g,0.42mmol,1.0eq)溶解于二氯甲烷(5mL)中,在0摄氏度下缓慢滴加4M盐酸二氧六环溶液(1.04mL,10eq)。所得混合物在25摄氏度下搅拌1小时。将反应液减压蒸馏除去溶剂，得到固体标题化合物5C(0.18g,粗品)。
MS(ESI+)m/z＝378.9[M+H].
第三步 1-(4-(6-氨基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)-3,6-二氢吡啶-1(2H)-基)-2-甲基丙-2-烯-1-酮(5)
将化合物5C(0.16g,0.39mmol,1.0eq)和三乙胺(0.12g,1.2mmol,0.16mL,3.0eq)溶解于二氯甲烷(5mL)中,在0摄氏度下缓慢滴加甲基丙烯酰氯(42mg,0.40mmol,1.0eq)。所得混合物在25摄氏度下搅拌1小时。将反应液减压蒸馏除去溶剂，所得残留物经制备色谱纯(Waters Xbridge C18,20-70％乙腈水溶液(含0.01％氨水))化得白色固体标题化合物5(0.070g,收率:39％)。
MS(ESI+)m/z＝447.2[M+H].
1H NMR(400MHz,DMSO-d 6):δ＝8.46(d,J＝4.8Hz,1H),8.37(s,1H),7.38(t,J＝8.2Hz,1H),7.24(dd,J 1＝11.2Hz,J 2＝2.0Hz,1H),7.17(d,J＝5.2Hz,1H),7.10(td,J＝8.4,0.8Hz,1H),6.17(s,2H),5.61(s,1H),5.20-5.03(m,1H),4.90(s,1H),3.89(q,J＝2.8Hz,2H),3.49(t,J＝5.6Hz,2H),2.43(s,3H),2.22(d,J＝2.0Hz,2H),1.79(s,3H).
实施例6
1-(2-甲基丙烯酰基)-(4-(6-氨基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)哌啶(6)
Figure PCTCN2022084728-appb-000035
第一步 4-(6-氨基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)哌啶-1-羧酸叔丁基酯(6A)
将化合物5B(0.40g,0.84mmol,1.0eq)溶解于甲醇(20mL)中,加入10％钯碳(0.050g)。所得混合物在氢气氛围下30摄氏度下搅拌12小时。将反应液过滤除去钯碳，减压蒸馏除去溶剂，所得残留物用含10％乙酸乙酯的石油醚溶液打浆并过滤得固体标题化合物6A(0.34g,收率:85％)。
1H NMR(400MHz,DMSO-d 6):δ＝8.51(d,J＝5.2Hz,1H),8.40-8.31(m,1H),7.52-7.43(m,1H),7.31(dd,J＝11.2Hz,1.2Hz,1H),7.22(d,J＝5.2Hz,1H),7.12(d,J＝8.0Hz,1H),6.24(s,2H),4.18-3.81(m,4H),3.17(s,1H),2.44(s,3H),1.70-1.59(m,2H),1.53(d,J＝12.8Hz,2H),1.40(s,9H)
第二步 5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-6-(哌啶-4-基)嘧啶-4-胺盐酸盐(6B)
将化合物6A(0.30g,0.62mmol,1.0eq)溶解于二氯甲烷(5mL)中,在0摄氏度下缓慢滴加4M盐酸二氧六环溶液(1mL)。所得混合物在25摄氏度下搅拌1小时。将反应液减压蒸馏除去溶剂，得到固体标题化合物6B(0.39g,粗品)。
MS(ESI+)m/z＝381.2[M+H].
第三步 1-(2-甲基丙烯酰基)-(4-(6-氨基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)哌啶(6)
将化合物6B(0.39g,0.94mmol,1.0eq)和三乙胺(0.28g,1.2mmol,0.16mL,3.0eq)溶解于二氯甲烷(5mL)中,在0摄氏度下缓慢滴加甲基丙烯酰氯(98mg,0.94mmol,1.0eq)。所得混合物在25摄氏度下搅拌1小时。将反应液减压蒸馏除去溶剂，所得残留物经制备色谱(Waters Xbridge C18,20-70％乙腈水溶液(含0.01％氨水))纯化得白色固体标题化合物6(0.075g,收率:18％)。
MS(ESI+)m/z＝449.2[M+H].
1H NMR(400MHz,DMSO-d 6):δ＝8.51(d,J＝5.2Hz,1H),8.37(s,1H),7.49(t,J＝8.4Hz,1H),7.38-7.27(m,1H),7.22(d,J＝5.2Hz,1H),7.13(d,J＝8.0Hz,1H),6.28(s,2H),5.14(s,1H),4.93(s,1H),4.37(s,1H),3.87(s,1H),2.99-2.74(m,1H),2.64-2.55(m,1H),2.45(s,3H),1.85(s,3H),1.76-1.54(m,5H)
实施例7
6-(4-丙炔酰胺基苯基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-4-氨基嘧啶(7)
Figure PCTCN2022084728-appb-000036
第一步 6-(4-氨基苯基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-4-氨基嘧啶(7A)
将化合物1I(6.0g,18.1mmol)，化合物1A(4.0g,18.1mmol)，四三苯基膦钯(2.1g,1.81mmol)和碳酸钾(5.0g,36.2mmol)混合于二氧六环(80mL)和水(8mL)中。所得混合物在100摄氏度氮气氛围下搅拌2小时。将反应液冷却减压蒸馏除去溶剂，所得残余物经硅胶柱色谱纯化(洗脱相为含0-10％甲醇的二氯甲烷混合溶剂)得棕色固体标题化合物7A(6.0g,收率：85％)。MS(ESI+)m/z＝389.2[M+H].
1H NMR(400MHz,DMSO-d 6):δ＝8.56-8.46(m,1H),8.38(s,1H),7.69-7.49(m,1H),7.35(t,J＝8.4Hz,1H),7.22-7.15(m,2H),7.01(d,J＝8.4Hz,2H),6.37(d,J＝8.4Hz,2H),5.33(s,2H),2.44(s,3H)
第二步 6-(4-丙炔酰胺基苯基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-4-氨基嘧啶(7)
将化合物7B(54mg,0.77mmol)溶解于二氯甲烷(5mL)中,在0摄氏度下缓慢滴加入双(2-氧-3-噁唑烷基)次磷酰氯(0.26g,1.0mmol)，化合物7A(0.20g,0.51mmol)和N,N-二异丙基乙基胺(0.26g,2.0mmol)。所得混合物在0摄氏度下搅拌1小时。将反应液减压蒸馏除去溶剂，所得粗品经过制备色谱(Waters Xbridge C18,20-70％乙腈水溶液(含0.01％氨水))纯化得标题化合物7(23mg,收率:10％)。
MS(ESI+)m/z＝441.1[M+H].
1H NMR(400MHz,DMSO-d 6):δ＝10.85(s,1H),8.49(d,J＝5.2Hz,1H),8.45(s,1H),7.47(d,J＝8.8Hz,2H),7.33(t,J＝8.4Hz,1H),7.27-7.14(m,4H),6.98(dd,J＝8.4,1.6Hz,1H),6.52(s,2H),4.43(s,1H),2.42(s,3H).
实施例8
经实施例7类似的合成路线和步骤，在第二步中用下表中的原料A替换原料7B可以合成如下化合物8-14。
Figure PCTCN2022084728-appb-000037
Figure PCTCN2022084728-appb-000038
Figure PCTCN2022084728-appb-000039
实施例9
经实施例7类似的合成路线和步骤，在第一步中用下表格中的原料B替换原料1A，在第二步中用原料C替换丙炔酸7B可以合成对应的如下化合物15-26。
Figure PCTCN2022084728-appb-000040
Figure PCTCN2022084728-appb-000041
Figure PCTCN2022084728-appb-000042
Figure PCTCN2022084728-appb-000043
其中化合物23A的合成路线如下：
Figure PCTCN2022084728-appb-000044
采用实施例3中第二步化合物3D类似的合成步骤，可以合成化合物23A。MS(ESI+)m/z＝263.2[M+H].
实施例10
经实施例5类似的合成路线和步骤，在第一步中用如下表格中不同原料D替换5A，并在第三步中用丙烯酰氯替换甲基丙烯酰氯，可以合成下表中对应的化合物27-29。
Figure PCTCN2022084728-appb-000045
Figure PCTCN2022084728-appb-000046
实施例11
N-(4-(6-氨基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)苯基)乙烯磺酰胺(30)
Figure PCTCN2022084728-appb-000047
将化合物7A(150mg,0.39mmol)和吡啶(122mg,1.54mmol)溶解于二氯甲烷(5mL)中,在0摄氏度下缓慢滴加入氯乙基磺酰氯30A(69mg,0.42mmol)。所得混合物在0摄氏度下搅拌3小时。将反应液减压蒸馏除去溶剂，所得粗品经过制备色谱纯化(Phenomenex Luna C 18 100*30mm*5um,5-35％乙腈水溶液流动相)得标题化合物30(13mg,收率:7.3％)。
MS(ESI+)m/z＝479.2[M+H].
1H NMR(400MHz,DMSO-d 6)δ10.17(s,1H),8.49(d,J＝5.2Hz,1H),8.43(s,1H),7.32(t,J＝8.4Hz,1H),7.23-7.17(m,4H),7.01-6.94(m,3H),6.74(dd,J＝16.4,9.6Hz,1H),6.50(s,2H),6.06(d,J＝16.4Hz,1H),5.97(d,J＝9.6Hz,1H),2.43(s,3H).
实施例12
1-(2-(6-氨基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-基)丙-2-烯-1-酮(31)
Figure PCTCN2022084728-appb-000048
第一步 2-(6-氨基-5-碘嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-羧酸叔丁基酯(31C)
将化合物31A(0.50g,2.2mmol)，化合物31B(1.1g,2.3mmol)和碳酸钾(0.61g,4.4mmol)混合于二氧六环(30mL)中。所得混合物在80摄氏度氮气氛围下搅拌4小时。将反应液减压蒸馏除去溶剂，所得残余物经硅胶柱色谱纯化(洗脱相为含25-50％乙酸乙酯的石油醚混合溶剂)得淡黄色固体标题化合物31C(1.04g,收率：97％)。
MS(ESI+)m/z＝446.3[M+H].
第二步 2-(6-氨基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷-7-羧酸叔丁基酯(31D)
将化合物31C(0.50g,0.92mmol)，化合物1G(0.36g,1.1mmol)，醋酸钯(10mg,46μmol)，2-二环己基膦-2',6'-二甲氧基联苯(38mg,92μmol)和碳酸钾(0.25g,1.84mmol)混合于二氧六环(7.5mL)和水(0.75mL)中。所得混合物在85摄氏度氮气氛围下搅拌12小时。将反应液减压蒸馏除去溶剂，所得残余物经硅胶柱色谱纯化(洗脱相为含0-10％甲醇的二氯甲烷混合溶剂)得棕色固体标题化合物31D(60mg,收率：12％)。
MS(ESI+)m/z＝522.1[M+H].
第三步 5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-6-(2,7-二氮杂螺[3.5]壬烷-2-基)-4-氨基嘧啶(31E)
将化合物31D(60mg,0.11mmol)溶解于二氯甲烷(2mL)中,在0摄氏度下缓慢滴加4M盐酸二氧六环溶液(1.0mL)。所得混合物在25摄氏度下搅拌1小时。将反应液减压蒸馏除去溶剂，得到固体标题化合物31E的盐酸盐(80mg,粗品)。
MS(ESI+)m/z＝422.1[M+H].
第四步 1-(2-(6-氨基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)-2,7-二氮杂螺[3.5]壬烷- 7-基)丙-2-烯-1-酮(31)
将化合物31E(32mg,75μmol)和三乙胺(32mg,0.32mmol)溶解于二氯甲烷(5mL)中,在0摄氏度下缓慢滴加丙烯酰氯4B的二氯甲烷溶液(5.8mg,64μmol,64uL,1.0mol/L)。所得混合物在25摄氏度下搅拌1小时。将反应液减压蒸馏除去溶剂，所得残留物经制备色谱纯化(Phenomenex Luna C 18 150*25mm*10um,洗脱相为3％-33％的乙腈-水(含0.1％TFA))得白色固体标题化合物31(11mg,收率:30％)。
MS(ESI+)m/z＝476.2[M+H].
1H NMR(400MHz,DMSO-d 6)δ8.47(d,J＝5.2Hz,1H),7.98(s,1H),7.40(t,J＝8.4Hz,1H),7.27(dd,J＝11.2,1.6Hz,1H),7.18(d,J＝5.2Hz,1H),7.12(dd,J＝8.4,1.2Hz,1H),6.76(dd,J＝16.4,10.4Hz,1H),6.05(dd,J＝16.4,2.4Hz,1H),5.79(br s,2H),5.65-5.60(m,1H),3.41-3.34(m,8H),2.37(s,3H),1.55(br s,4H).
实施例13
经实施例12类似的合成路线和步骤，在第一步中用如下表格中不同原料E替换31A，可以合成下表中对应的化合物32-43。
Figure PCTCN2022084728-appb-000049
Figure PCTCN2022084728-appb-000050
Figure PCTCN2022084728-appb-000051
Figure PCTCN2022084728-appb-000052
实施例14
N-(1-(6-氨基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)氮杂环丁基-3-基)乙烯磺酰胺(44)
Figure PCTCN2022084728-appb-000053
经实施例12类似的合成路线和步骤，在第一步中用34A替换31A，并在第四步中用2-氯乙基磺酰氯30A替换丙烯酰氯4B，合成化合物44。
MS(ESI+)m/z＝458.1[M+H].
1HNMR(400MHz,DMSO-d 6)δ8.48(d,J＝5.2Hz,1H),8.24-7.72(m,2H),7.41(t,J＝8.4Hz,1H),7.33-7.16(m,2H),7.09(d,J＝8.8Hz,1H),6.67(dd,J＝16.8,9.6Hz,1H),5.99(d,J＝16.4 Hz,1H),5.91(d,J＝9.6Hz,1H),5.85(s,2H),3.89(d,J＝4.8Hz,1H),3.71(t,J＝8.0Hz,2H),3.56-3.45(m,2H),2.41(s,3H).
实施例15
以化合物34E为原料，采用实施例7第二步的合成方法，将其中的7B替换下表中的原料C，合成对应的化合物45-48。
Figure PCTCN2022084728-appb-000054
Figure PCTCN2022084728-appb-000055
实施例16
由实施例1类似的合成方法和步骤，将第四步中的1H替换为下表格中的原料F，合成对应的化合物49-55。
Figure PCTCN2022084728-appb-000056
Figure PCTCN2022084728-appb-000057
其中化合物54的原料54B由54A经如下步骤合成。
Figure PCTCN2022084728-appb-000058
将54A(500mg,3.3mmol)溶解于10mL二氯甲烷中，在0摄氏度氮气氛围下缓慢滴加氯化碘(1.6g，10mmol)。所得反应液在室温下反应1小时后，加入5mL亚硫酸钠饱和溶液淬灭，并加入25mL二氯甲烷萃取。将有机相用无水硫酸钠干燥，减压蒸馏除去溶剂，所得粗品经硅胶柱纯化(洗脱相为0-100％的乙酸乙酯的石油醚溶液)得化合物54B(410mg,收率:45％)。
实施例17
N-(4-(6-氨基-5-(4-((S)-2-氰基吡咯烷-1-羰基)环己-1-烯-1-基)嘧啶-4-基)苯基)-2-丁炔酰胺(55)
Figure PCTCN2022084728-appb-000059
第一步 4-(4-氨基-6-氯嘧啶-5-基)环己-3-烯-1-羧酸乙酯(55B)
将4-氨基-6-氯-5-碘嘧啶1H(2.0g,7.8mmol)，化合物55A(2.6g,9.4mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(0.57g,0.78mmol)和碳酸钾(2.2g,16mmol)溶于二氧六环(20mL)和水(2mL)，氮气置换三次之后置于100℃下搅拌反应2小时。反应液冷却后加入20mL饱和氯化铵溶液并用40mL乙酸乙酯萃取。有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩所得粗品经柱层析(洗脱相为含50％乙酸乙酯的石油醚)纯化之后得到固体化合物55B(1.1g,收率:50％)。
1H NMR(400MHz,DMSO-d 6)δ8.09(s,1H),7.56-6.28(m,2H),5.67(s,1H),4.16-4.03(m,2H),2.99-2.57(m,1H),2.41-1.87(m,6H),1.20(t,J＝7.2Hz,3H)
第二步 4-(4-氨基-6-(4-硝基苯基)嘧啶-5-基)环己-3-烯-1-羧酸乙酯(55D)
将化合物55B(1.1g,3.9mmol)，4-硝基苯硼酸55C(0.78g,4.7mmol)，四(三苯基膦)钯(0.45g,0.39mmol)和碳酸钾(1.1g,7.8mmol)溶于二氧六环(15mL)和水(1.5mL)中，氮气置换三次之后置于100℃搅拌反应2小时。反应液冷却后加入20mL饱和氯化铵溶液并用40mL乙酸乙酯萃取。所得有机相经饱和食盐水洗涤，无水硫酸钠干燥之后，过滤，减压浓缩得到粗品。粗品产物经柱层析(洗脱相为含50％乙酸乙酯的石油醚)纯化得到化合物55D(0.39g,收率:27％)。
MS(ESI+)m/z＝368.2[M+H].
第三步 4-(4-氨基-6-(4-氨基苯基)嘧啶-5-基)环己-3-烯-1-羧酸乙酯(55E)
将化合物55D(0.36g,1.0mmol)溶解于10mL甲醇中，加入铁粉(0.56g,10mmol)和2mL饱和氯化铵溶液。将混合物在室温氮气氛围下搅拌16小时。所得混合物经硅藻土过滤，并用40mL乙酸乙酯洗涤滤饼。所得滤液中加入20mL饱和氯化钠溶液，并另外加入20mL乙酸乙酯萃取。所得有机相经无水硫酸钠干燥之后，过滤，减压浓缩得到粗品。粗品产物经柱层析(洗脱相为含50％-100％乙酸乙酯的石油醚)纯化得到固体55E(0.21g,收率:62％)。
MS(ESI+)m/z＝339.2[M+H].
第四步 4-(4-氨基-6-(4-(-2-丁炔酰氨基)苯基)嘧啶-5-基)环己-3-烯-1-羧酸乙酯(55G)
将化合物55E(0.21g,0.58mmol)和N,N-二异丙基乙基胺(0.23g,1.8mmol)溶解于3mL二氯甲烷中，在0摄氏度下加入2-丁炔酰氯55F(55mg,0.55mmol)。所得混合物在0摄氏度下搅拌1小时。将所得反应液减压浓缩，所得粗品经C 18反相色谱柱纯化(洗脱相为含5～80％乙腈的水溶液)，并冻干除去溶剂得到化合物55G(0.19g,收率：81％)。
MS(ESI+)m/z＝405.2[M+H].
第五步 4-(4-氨基-6-(4-(-2-丁炔酰氨基)苯基)嘧啶-5-基)环己-3-烯-1-羧酸(55H)
将化合物55G(0.19g,0.47mmol)，氢氧化锂(23mg,0.95mmol)混合于四氢呋喃(2mL)和水(0.5mL)中。所得混合物在室温下搅拌1小时后，于反应液中加入干冰(5g)。将所得混合物减压浓缩得粗品化合物55H(0.24g)。
MS(ESI+)m/z＝377.2[M+H].
第六步 N-(4-(6-氨基-5-(4-((S)-2-氰基吡咯烷-1-羰基)环己-1-烯-1-基)嘧啶-4-基)苯基)-2-丁炔酰胺(55)
将2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(57mg,0.15mmol)加入粗品55H(48mg,约为0.1mmol)的N,N-二甲基甲酰胺(1mL)溶液中，然后加入N,N-二异丙基乙胺(39mg,0.3mmol)和(S)-2-氰基吡咯烷55I(20mg,0.21mmol)。所得溶液在室温下搅拌反应2小时。混合物过滤之后经制备高效液相(Waters Xbridge C18,20-60％乙腈水溶液(含0.01％氨水))纯化得到标题化合物55(3.6mg,收率:7.9％)。
MS(ESI+)m/z＝455.2[M+H].
1H NMR(400MHz,DMSO-d6)δ10.76(s,1H),8.31(s,1H),7.62(d,J＝8.6Hz,4H),6.63(s,2H),5.76(s,1H),4.72(dt,J＝7.6,3.9Hz,1H),3.69(s,4H),2.34-2.10(m,4H),2.06(m,4H),1.71(m,2H),1.24(m,2H),0.96(m,2H).
实施例18-1
经实施例17类似的路线和步骤，用下表中的不同原料G替换第一步中的化合物55A，在第四步中用丙烯酰氯4B替代2-丁炔酰氯55F，在第六步中用下表中的原料H替换55I，合成表格中对应的化合物56-59。
Figure PCTCN2022084728-appb-000060
Figure PCTCN2022084728-appb-000061
实施例18-2
N-(3-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)苯基)丙烯酰基酰胺(60)
Figure PCTCN2022084728-appb-000062
第一步 2,4-二氯-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶(60B)
将2,4-二氯-5-碘嘧啶60A(5.0g,18mmol)，化合物1G(6.0g,18mmol)，碳酸钾(5.0g,36mmol)和(二苯基膦二茂铁)二氯化钯(0.70g,0.91mmol)加入到二氧六环(50mL)和水(5mL)的混合溶剂中，氮气置换三次之后于100℃搅拌反应2小时。反应液用20mL氯化铵淬灭之后加入100mL乙酸乙酯萃取，分离所得有机相经饱和食盐水洗涤，无水硫酸钠干燥后，过滤，减压浓缩得到粗品。粗品经柱层析(石油醚/乙酸乙酯＝4/1-2/1)纯化得到化合物60B(2.9g,收率：45％)。
MS(ESI+)m/z＝351.0[M+H].
第二步 2-氯-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-4-(3-硝基苯基)嘧啶(60D)
将化合物60B(2.1g,6.0mmol)，3-硝基苯硼酸60C(1.0g,6.0mmol)，碳酸钾(1.7g,12.0mmol)和四三苯基磷钯(0.35g,0.30mmol)加入到二氧六环(20mL)和水(2mL)的混合溶剂中，氮气置换三次之后置于100℃搅拌反应2小时。反应液用20mL氯化铵淬灭之后加入50mL乙酸乙酯萃取，分离所得有机相经浓缩得到粗品。粗品经柱层析(石油醚/乙酸乙酯＝2/1-1/1)纯化得到化合物60D(1.0g,收率：38％)。
MS(ESI+)m/z＝438.1[M+H].
1H NMR(400MHz,DMSO-d 6)δ9.05(s,1H),8.52(d,J＝5.2Hz,1H),8.39-8.31(m,2H),7.87(d,J＝8.0Hz,1H),7.79-7.71(m,1H),7.53-7.43(m,2H),7.30-7.20(m,2H),2.48-2.44(m,3H).
第三步 5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-N-(1-甲基-1H-吡唑-4-基)-4-(3-硝基苯基)嘧啶-2-胺(60F)
将化合物60D(0.40g,0.91mmol)，1-甲基-1H-吡唑-4-胺60E(0.17g,1.8mmol)，碳酸铯(0.88g,2.7mmol)，1,1'-联萘-2,2'-双二苯膦(57mg,0.091mmol)和醋酸钯(20mg,0.091mmol) 加入到二氧六环(20mL)中，氮气置换三次之后置于100℃搅拌反应2小时。反应液用20mL氯化铵淬灭之后加入50mL乙酸乙酯萃取，分离所得有机相经浓缩得到粗品。粗品经柱层析(石油醚/乙酸乙酯＝2/1-0/1)纯化得到化合物60F(0.20g,收率：44％)
MS(ESI+)m/z＝499.1[M+H].
第四步 4-(3-氨基苯基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺(60G)
将化合物60F(0.18g,0.36mmol)溶解于5mL甲醇中，加入铁粉(0.2g,3.6mmol)和1mL饱和氯化铵溶液。将混合物在室温氮气氛围下搅拌16小时。所得混合物经硅藻土过滤，并用20mL乙酸乙酯洗涤滤饼。所得滤液中加入10mL饱和氯化钠溶液，并另外加入20mL乙酸乙酯萃取。所得有机相经无水硫酸钠干燥之后，过滤，减压浓缩得到粗品。粗品产物经C 18反相柱(流动相为5-80％乙腈水溶液)纯化，并冻干除去溶剂得到固体60G(80mg,收率:47％)。MS(ESI+)m/z＝469.2[M+H].
第五步 N-(3-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)苯基)丙烯酰基酰胺(60)
将化合物60G(70mg,0.15mmol)和三乙胺(45mg,0.45mmol)溶解于二氯甲烷(5mL)中,在0摄氏度下缓慢滴加丙烯酰氯4B的二氯甲烷溶液(13mg,0.15mmol,150uL,1.0mol/L)。所得混合物在0摄氏度下搅拌1小时。将反应液减压蒸馏除去溶剂，所得残留物经制备色谱纯化(Phenomenex Luna C18 150*25mm*10um,洗脱相为3％-55％的乙腈-水)得白色固体标题化合物60(20mg,收率:26％)。
MS(ESI+)m/z＝523.2[M+H].
1H NMR(400MHz,DMSO-d 6)δ10.27(s,1H),9.75(s,1H),8.53(s,1H),8.46(d,J＝4.8Hz,1H),8.43-7.80(m,2H),7.60(s,1H),7.53(s,1H),7.33-7.20(m,3H),7.18(d,J＝5.2Hz,1H),7.03(d,J＝8.0Hz,1H),6.91(d,J＝7.6Hz,1H),6.53-6.39(m,1H),6.35-6.19(m,1H),5.77(d,J＝11.2Hz,1H),3.84(s,3H),2.41(s,3H).
实施例19
N-(3-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)苯基)甲丙烯酰基酰胺(61)
Figure PCTCN2022084728-appb-000063
以化合物60G为原料，采用实施例18-2中第五步的类似合成方法，用61A替换丙烯酰氯4B，合成化合物61。
MS(ESI+)m/z＝537.1[M+H].
1H NMR(400MHz,DMSO-d 6)δ9.94(s,1H),9.76(s,1H),8.52(s,1H),8.46(d,J＝5.2Hz,1H),8.0(s,2H),7.60(s,1H),7.51(s,1H),7.32-7.16(m,4H),7.03(d,J＝8.0Hz,1H),6.86(d,J＝6.8Hz,1H),5.82(s,1H),5.54(s,1H),3.85(s,3H),2.41(s,3H),1.96(s,3H).
实施例20
N-(3-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)苯基)丙酰基酰胺(62)
Figure PCTCN2022084728-appb-000064
以化合物60G为原料，采用实施例18-2中第五步的类似合成方法，用62A替换丙烯酰氯4B，合成化合物62。
MS(ESI+)m/z＝525.1[M+H].
1H NMR(400MHz,DMSO-d 6)δ9.98(s,1H),9.73(s,1H),8.52(s,1H),8.47(d,J＝5.2Hz,1H),8.09(s,2H),7.52-7.51(m,1H),7.52(s,1H),7.36-7.13(m,4H),7.02(d,J＝8.0Hz,1H),6.84(d,J＝7.2Hz,1H),3.84(s,3H),2.42(s,3H),2.38-2.29(m,2H),1.19-1.04(m,3H).
实施例21
2-氟-N-(3-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)苯基)丙烯酰基酰胺(63)
Figure PCTCN2022084728-appb-000065
以化合物60G为原料，采用实施例7中第二步的类似合成方法，用63A替代7B，并用2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐替代双(2-氧-3-噁唑烷基)次磷酰氯，在室温下反应1小时，合成化合物63。
MS(ESI+)m/z＝541.1[M+H].
1H NMR(400MHz,DMSO-d 6)δ10.44(d,J＝4.4Hz,1H),9.77(s,1H),8.53(s,1H),8.46(d,J＝5.2Hz,1H),8.13(s,2H),7.66(d,J＝7.2Hz,1H),7.53(s,1H),7.34-7.15(m,4H),7.09-6.90(m,2H),5.83-5.63(m,1H),5.45(dd,J＝3.6,15.5Hz,1H),3.84(s,3H),2.41(s,3H).
实施例22
N-(3-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)2-甲基苯基)丙烯酰基酰胺(64)
Figure PCTCN2022084728-appb-000066
采用实施例18-2中第二步以后的类似合成步骤和方法，用64A替代60C，合成化合物64。
MS(ESI+)m/z＝537.2[M+H].
1H NMR(400MHz,DMSO-d 6)δ9.76(s,1H),9.52(s,1H),8.59(s,1H),8.44(d,J＝5.2Hz,1H),8.02-7.70(m,1H),7.64-7.43(m,2H),7.28-7.19(m,2H),7.16(d,J＝5.2Hz,1H),7.14-7.05(m,2H),6.94(d,J＝8.0Hz,1H),6.52(dd,J＝10.4,16.6Hz,1H),6.23(d,J＝17.2Hz,1H),5.73(d,J＝10.4Hz,1H),3.80(s,3H),2.39(s,3H),1.92(s,3H).
实施例23
N-(3-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)2-甲氧基苯基)丙烯酰基酰胺(65)
Figure PCTCN2022084728-appb-000067
采用实施例18-2中第二步以后的类似合成步骤和方法，用65A替代60C，合成化合物65。
MS(ESI+)m/z＝553.2[M+H].
1H NMR(400MHz,DMSO-d 6)δ9.79(s,1H),9.57(s,1H),8.59(s,1H),8.44(d,J＝5.2Hz,1H),8.18(d,J＝6.3Hz,1H),7.88(s,1H),7.53(s,1H),7.24-7.14(m,5H),6.97(dd,J＝1.6,8.4Hz,1H),6.75(dd,J＝10.0,17.0Hz,1H),6.25(dd,J＝1.8,16.8Hz,1H),5.75-5.68(m,1H),3.81(s,3H),3.44(s,3H),2.38(s,3H).
实施例24
N-(3-(2-((1-(2-(二甲氨基)乙基)-1H-吡唑-4-基)氨基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)苯基)丙烯酰基酰胺(66)
Figure PCTCN2022084728-appb-000068
采用实施例18-2中第三步以后的类似合成步骤和方法，用66A替代60E，合成化合物66。
MS(ESI+)m/z＝580.3[M+H].
实施例25
N-(3-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-(1-甲基吡咯烷-3-基)-1H-吡唑-4-基)氨基)嘧啶-4-基)苯基)丙烯酰基酰胺(67)
Figure PCTCN2022084728-appb-000069
采用实施例18-2中第三步以后的类似合成步骤和方法，用67A替代60E，合成化合物67。
MS(ESI+)m/z＝592.3[M+H].
1H NMR(400MHz,DMSO-d 6)δ10.27(t,J＝5.2Hz,1H),9.77(s,1H),8.55(s,1H),8.47(d,J＝5.2Hz,1H),8.22(s,1H),7.67-7.59(m,1H),7.57(s,1H),7.32-7.21(m,3H),7.19(d,J＝4.8Hz,1H),7.03(d,J＝6.8Hz,1H),6.94(d,J＝8.0Hz,1H),6.52-6.40(m,1H),6.33-6.24(m,1H),5.78(d,J＝11.6Hz,1H),4.91(s,1H),2.87-2.80(m,4H),2.41(s,3H),2.26(s,5H),2.05(d,J＝6.4Hz,1H).
实施例26
N-(3-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)氨基)嘧啶-4-基)苯基)丙烯酰基酰胺(68)
Figure PCTCN2022084728-appb-000070
采用实施例18-2中第三步以后的类似合成步骤和方法，用68A替代60E，合成化合物68。
MS(ESI+)m/z＝605.3[M+H].
实施例27
N-(4-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)苯基)丙烯酰基酰胺(69)
Figure PCTCN2022084728-appb-000071
第一步 2,5-二氯-4-(4-硝基苯基)嘧啶(69B)
将2,4,5-三氯嘧啶69A(1.8g,10mmol)，对硝基苯硼酸55C(1.7g,10mmol)，碳酸钾(2.8g,20mmol)和(二苯基膦二茂铁)二氯化钯(0.35g,0.46mmol)加入到二氧六环(20mL)和水(2mL)的混合溶剂中，氮气置换三次之后于70℃搅拌反应2小时。反应液用20mL氯化铵淬灭之后加入100mL乙酸乙酯萃取，分离所得有机相经饱和食盐水洗涤，无水硫酸钠干燥后，过滤，减压浓缩得到粗品。粗品经柱层析(石油醚/乙酸乙酯＝4/1-2/1)纯化得到化合物69B(1.7g,收率：63％)。
MS(ESI+)m/z＝270.0[M+H].
第二步 5-氯-N-(1-甲基-1H-吡唑-4-基)-4-(4-硝基苯基)嘧啶-2-胺(69C)
将化合物69B(0.24g,0.91mmol)，1-甲基-1H-吡唑-4-胺60E(0.17g,1.8mmol)，碳酸铯(0.88g,2.7mmol)，1,1'-联萘-2,2'-双二苯膦(57mg,0.091mmol)和醋酸钯(20mg,0.091mmol)加入到二氧六环(20mL)中，氮气置换三次之后置于100℃搅拌反应2小时。反应液用20mL氯化铵淬灭之后加入50mL乙酸乙酯萃取，分离所得有机相经浓缩得到粗品。粗品经柱层析(石油醚/乙酸乙酯＝2/1-0/1)纯化得到化合物69C(0.20g,收率：67％)
MS(ESI+)m/z＝331.0[M+H].
第三步 5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-N-(1-甲基-1H-吡唑-4-基)-4-(4-硝基苯基)嘧啶-2-胺(69D)
将化合物69C(0.20g,0.61mmol)，化合物1G(0.20g,0.61mmol)，碳酸钾(170mg,1.2mmol)，醋酸钯(13mg,0.06mmol)和三环己基磷(34mg,0.12mmol)加入到二氧六环(20mL)和水(2mL)的混合溶剂中，氮气置换三次之后置于100℃搅拌反应2小时。反应液用20mL氯化铵淬灭之后加入50mL乙酸乙酯萃取，分离所得有机相经浓缩得到粗品。粗品经柱层析(石油醚/乙酸乙酯＝2/1-0/1)纯化得到化合物69D(0.13g,收率：41％)。
MS(ESI+)m/z＝499.1[M+H].
第四步 4-(4-氨基苯基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺(69E)
将化合物69D(0.13g,0.26mmol)溶解于5mL甲醇中，加入铁粉(0.2g,3.6mmol)和1mL饱和氯化铵溶液。将混合物在室温氮气氛围下搅拌16小时。所得混合物经硅藻土过滤，并用20mL乙酸乙酯洗涤滤饼。所得滤液中加入10mL饱和氯化钠溶液，并另外加入20mL乙酸乙酯萃取。所得有机相经无水硫酸钠干燥之后，过滤，减压浓缩得到粗品。粗品产物经C18反相柱(流动相为5-80％乙腈水溶液)纯化，并冻干除去溶剂得到固体69E(42mg,收率:34％)。MS(ESI+)m/z＝469.2[M+H].
第五步 N-(4-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)苯基)丙烯酰基酰胺(69)
将化合物69E(42mg,0.09mmol)和三乙胺(18mg,0.18mmol)溶解于二氯甲烷(5mL)中,在0摄氏度下缓慢滴加丙烯酰氯4B的二氯甲烷溶液(7.6mg,0.085mmol,85uL,1.0mol/L)。所得混合物在0摄氏度下搅拌1小时。将反应液减压蒸馏除去溶剂，所得残留物经制备色谱纯化(Phenomenex Luna C18 150*25mm*10um,洗脱相为3％-55％的乙腈-水)得白色固体标题化合物69(18mg,收率:38％)。
MS(ESI+)m/z＝523.2[M+H].
1H NMR(400MHz,DMSO-d 6)δ10.30(s,1H),9.72(s,1H),8.49(s,1H),8.48(d,J＝5.0Hz,1H),7.92(s,1H),7.67(d,J＝8.4Hz,2H),7.49(d,J＝60.8Hz,3H),7.31(t,J＝8.4Hz,1H),7.26-7.21(m,1H),7.19(d,J＝5.1Hz,1H),7.05-6.98(m,1H),6.44(dd,J＝16.9,10.1Hz,1H),6.27(dd,J＝16.9,2.0Hz,1H),5.78(dd,J＝10.0,2.1Hz,1H),3.82(s,3H),2.43(s,3H).
实施例28
N-(4-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-6-甲基-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)苯基)丙烯酰基酰胺(70)
Figure PCTCN2022084728-appb-000072
采用实施例27中第三步以后的类似合成步骤和方法，用70A替代69A，合成化合物 70。
MS(ESI+)m/z＝537.2[M+H].
1H NMR(400MHz,DMSO-d 6)δ10.17(s,1H),9.54(s,1H),8.43(d,J＝5.0Hz,1H),7.57-7.50(m,2H),7.48(s,1H),7.24(t,J＝8.3Hz,1H),7.18(dd,J＝11.4,2.0Hz,1H),7.13(d,J＝5.1Hz,1H),6.95(d,J＝8.1Hz,1H),6.35(dd,J＝16.8,10.1Hz,1H),6.19(dd,J＝17.0,2.0Hz,1H),5.70(dd,J＝10.1,2.1Hz,1H),3.74(s,3H),2.35(s,3H),2.22(s,3H).
实施例29
N-(4-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-6-氨基-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)苯基)丙烯酰基酰胺(71)
Figure PCTCN2022084728-appb-000073
采用实施例27中第三步以后的类似合成步骤和方法，用71A替代69A，合成化合物71。
MS(ESI+)m/z＝538.2[M+H].
1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),8.50-8.48(m,1H),8.19-8.08(m,1H),7.74-7.51(m,4H),7.33-7.25(m,3H),7.20-7.19(m,2H),6.98-6.96(m,1H),6.69-6.66(m,2H),6.45-6.38(m,1H),6.28-6.23(m,1H),5.57-5.76(m,1H),3.80(s,3H),2.42(s,3H).
实施例30
N-(4-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)苯基)丁-2-炔酰胺(72)
Figure PCTCN2022084728-appb-000074
以化合物69E为原料，采用实施例27中第五步类似的方法，将其中的丙烯酰氯4B替代为2-丁炔酰氯55F，合成化合物72。
MS(ESI+)m/z＝535.2[M+H].
1H NMR(400MHz,DMSO-d 6)δ10.71(s,1H),9.65(s,1H),8.41(d,J＝5.0Hz,2H),7.85(s,1H),7.57-7.44(m,3H),7.32(s,2H),7.23(t,J＝8.4Hz,1H),7.19-7.08(m,2H),6.97-6.89(m,1H),3.75(s,3H),2.36(s,3H),1.98(s,3H).
实施例31
2-氟-N-(4-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)苯基)丙烯酰基酰胺(73)
Figure PCTCN2022084728-appb-000075
以化合物69E为原料，采用实施例7中第二步的类似合成方法，用63A替代7B，并用2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐替代双(2-氧-3-噁唑烷基)次磷酰氯，合成化合物73。
MS(ESI+)m/z＝541.1[M+H].
1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H),9.74(s,1H),8.51(s,1H),8.48(d,J＝5.0Hz,1H),7.92(s,1H),7.74(d,J＝8.4Hz,2H),7.57(s,1H),7.43(s,2H),7.31(t,J＝8.4Hz,1H),7.26-7.21(m,1H),7.19(d,J＝5.1Hz,1H),7.01(dd,J＝8.1,1.8Hz,1H),5.73(dd,J＝47.6,3.7Hz,1H),5.46(dd,J＝15.6,3.7Hz,1H),3.82(s,3H),2.43(s,3H).
实施例32
N-(4-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-(哌啶-4-基)-1H-吡唑-4-基)氨基)嘧啶-4-基)苯基)丙烯酰基酰胺(74)
Figure PCTCN2022084728-appb-000076
采用实施例27中类似的路线和步骤，用74A替代第二步中的60E，合成化合物74B。
将化合物74B(27mg,0.039mmol)溶解于2mL二氯甲烷中，在0摄氏度下加入1mL三氟乙酸。所得混合溶液在0摄氏度搅拌1小时。减压浓缩除去溶剂及三氟乙酸，所得粗品 经制备色谱纯化(Phenomenex Luna C 18 150*25mm*10um,洗脱相为3％-55％的乙腈-水)得化合物74(8.7mg,收率:37％)。
MS(ESI+)m/z＝592.3[M+H].
实施例33
2-氟-N-(4-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-(哌啶-4-基)-1H-吡唑-4-基)氨基)嘧啶-4-基)苯基)丙烯酰基酰胺(75)
Figure PCTCN2022084728-appb-000077
采用实施例27中类似的路线和步骤，用74A替代第二步中的60E，可以合成化合物75B。由化合物75B再经过两步反应可以合成化合物75。
第一步 4-(4-((5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-4-(4-(2-氟丙烯酰基酰氨基)苯基)嘧啶-2-基)氨基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(75C)
将化合物75B(56mg,0.088mmol),2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(38mg,0.10mmol)和2-氟丙烯酸(18mg,0.20mmol)混合于二氯甲烷溶液中，然后加入N,N-二异丙基乙胺(39mg,0.30mmol)。所得溶液在0摄氏度下搅拌反应1小时。混合物过滤之后经C 18反相色谱纯化(洗脱相为20-80％的乙腈水溶液)得到化合物75C(26mg,收率:42％)。
MS(ESI+)m/z＝710.3[M+H].
第二步 2-氟-N-(4-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-(哌啶-4-基)-1H-吡唑-4-基)氨基)嘧啶-4-基)苯基)丙烯酰基酰胺(75)
将化合物75C(26mg,0.037mmol)溶解于2mL二氯甲烷中，在0摄氏度下加入1mL三氟乙酸。所得混合溶液在0摄氏度搅拌1小时。减压浓缩除去溶剂及三氟乙酸，所得粗品经制备色谱纯化(Phenomenex Luna C 18 150*25mm*10um,洗脱相为3％-55％的乙腈-水)得化合物75(6.1mg,收率:27％)。
MS(ESI+)m/z＝610.2[M+H].
实施例34
N-(4-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3-甲基苯基)丙烯酰基酰胺(76)
Figure PCTCN2022084728-appb-000078
参照实施例27的合成路线和方法，用76A替代55C，合成化合物76。
MS(ESI+)m/z＝537.2[M+H].
1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),9.73(s,1H),8.58(s,1H),8.46(d,J＝5.0Hz,1H),7.70(m,1H),7.49(m,3H),7.23(t,J＝8.4Hz,1H),7.15(m,2H),7.12(dd,J＝11.7,1.8Hz,1H),6.89(m,1H),6.43(dd,J＝17.0,10.1Hz,1H),6.26(d,J＝18.8Hz,1H),5.76(d,J＝12.0Hz,1H),3.80(s,3H),2.40(s,3H),2.03(s,3H).
实施例35
N-(4-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3-氟苯基)丙烯酰基酰胺(77)
Figure PCTCN2022084728-appb-000079
参照实施例27的合成路线和方法，用77A替代55C，合成化合物77。
MS(ESI+)m/z＝541.2[M+H].
1H NMR(400MHz,DMSO-d 6)δ12.40(s,1H),9.20(s,1H),9.07(d,J＝6.6Hz,1H),8.49(d,J＝5.0Hz,1H),7.92(s,1H),7.83–7.55(m,2H),7.39(t,J＝8.4Hz,1H),7.32(dd,J＝11.5,2.1Hz,1H),7.24–7.13(m,2H),5.58(d,J＝3.5Hz,0.5H),5.46(d,J＝3.5Hz,0.5H),5.27(dd,J＝15.6,3.5Hz,1H),4.58–4.51(m,1H),4.12–4.00(m,2H),3.86–3.74(m,2H),2.42(s,3H).
实施例36
2-氟-N-(4-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3-甲基苯基)丙烯酰基酰胺(78)
Figure PCTCN2022084728-appb-000080
参照实施例27的合成路线和方法，用76A替代55C，同时用2-氟丙烯酰氯替换丙烯酰氯4B，合成化合物78。
MS(ESI+)m/z＝555.2[M+H].
1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),9.75(s,1H),8.59(s,1H),8.47-8.45(m,1H),7.61-7.9(m,2H),7.52(s,1H),7.25-7.11(m,5H),6.94-6.92(m,1H),5.78-5.77(m,0.5H),5.66-5.65(m,0.5H),5.47-5.42(m,1H),3.80(s,3H),2.40(s,3H).
实施例37
N-(4-(5-(4-((S)-2-氰基吡咯烷-1-羰基)环己-1-烯-1-基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)苯基)丙烯酰基酰胺(79)
Figure PCTCN2022084728-appb-000081
参照实施例27的合成路线和方法，用55A替代1G，合成化合物79A。再由化合物79A替代实施例17中的55G，经实施例17中第五步和第六步的合成步骤和方法，合成化合物79。
MS(ESI+)m/z＝523.2[M+H].
1H NMR(400MHz,DMSO-d 6)δ10.36(d,J＝3.5Hz,1H),9.49(s,1H),8.20(s,1H),7.88(d,J＝4.7Hz,1H),7.84-7.70(m,4H),7.52(s,1H),6.54-6.38(m,1H),6.35-6.20(m,1H),5.86-5.73(m,2H),4.73(ddd,J＝7.4,5.2,3.6Hz,1H),3.80(s,3H),3.74-3.61(m,1H),3.51(dt,J＝16.3,7.6Hz,1H),2.68(d,J＝9.1Hz,1H),2.41-1.63(m,10H).
实施例38
N-(3-(5-(4-((S)-2-氰基吡咯烷-1-羰基)环己-1-烯-1-基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)苯基)丙烯酰基酰胺(80)
Figure PCTCN2022084728-appb-000082
参照实施例18-2的合成路线和方法，用55A替代1G，可以合成化合物80A。再由化合物80A替代实施例17中的55G，经实施例17中第五步和第六步的合成步骤和方法，合成化合物80。
MS(ESI+)m/z＝523.2[M+H].
实施例39
N-(1-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)氮杂环丁烷-3-基)丙烯酰基酰胺(81)
Figure PCTCN2022084728-appb-000083
第一步 (1-(2-氯-5-溴嘧啶-4-基)氮杂环丁烷-3-基)氨基甲酸叔丁酯(81C)
将2,4-二氯-5-溴嘧啶81A(2.3g,10mmol)，3-叔丁氧羰基-氨基氮杂环丁烷81B(1.7g,10mmol)和N,N-二异丙基乙胺(2.6g,20mmol)混合于25mL二氧六环中。所得混合物于80℃搅拌反应1小时后减压浓缩，所得粗品81C(6.6g,约10mmol)直接用于下一步。
MS(ESI+)m/z＝363.1,365.1[M+H].
第二步 (1-(2-氯-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)氮杂环丁烷-3-基)氨基甲酸叔丁酯(81D)
将化合物81C(3.3g,粗品，约5.0mmol)，化合物1G(2.0g,6.0mmol)，碳酸钾(2.8g,20mmol)和(二苯基膦二茂铁)二氯化钯(0.38g,0.5mmol)加入到二氧六环(30mL)和水(3mL)的混合溶剂中，氮气置换三次之后于100℃搅拌反应2小时。反应液用20mL氯化铵淬灭之 后加入100mL乙酸乙酯萃取，分离所得有机相经饱和食盐水洗涤，无水硫酸钠干燥后，过滤，减压浓缩得到粗品。粗品经柱层析(石油醚/乙酸乙酯＝4/1-2/1)纯化得到化合物81D(1.7g,收率：71％)。
MS(ESI+)m/z＝487.1[M+H].
第三步 (1-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)氮杂环丁烷-3-基)氨基甲酸叔丁酯(81E)
将化合物81D(0.49g,1.0mmol)，1-甲基-1H-吡唑-4-胺60E(0.17g,1.8mmol)，碳酸铯(0.88g,2.7mmol)，1,1'-联萘-2,2'-双二苯膦(62mg,0.10mmol)和醋酸钯(22mg,0.10mmol)加入到二氧六环(20mL)中，氮气置换三次之后置于100℃搅拌反应2小时。反应液用20mL氯化铵淬灭之后加入50mL乙酸乙酯萃取，分离所得有机相经浓缩得到粗品。粗品经柱层析(石油醚/乙酸乙酯＝2/1-0/1)纯化得到化合物81E(0.37g,收率：67％)。
MS(ESI+)m/z＝548.2[M+H].
第四步 4-(3-氨基氮杂环丁烷-1-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺(81F)
将化合物81E(0.37g,0.67mmol)溶解于5mL二氯甲烷中，在0摄氏度下缓慢加入1mL三氟乙酸。所得溶液在0摄氏度下搅拌反应1小时后，减压浓缩得粗品。粗品经反相C 18色谱柱(洗脱相为5-75％乙腈水溶液(含8mmol/L NH 3))纯化得到化合物81F(0.26g,收率：87％)。MS(ESI+)m/z＝448.2[M+H].
第五步 N-(1-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)氮杂环丁烷-3-基)丙烯酰基酰胺(81)
将化合物81F(45mg,0.10mmol)和三乙胺(20mg,0.20mmol)溶解于二氯甲烷(2mL)中,在0摄氏度下缓慢滴加丙烯酰氯4B的二氯甲烷溶液(9.0mg,0.1mmol,100uL,1.0mol/L)。所得混合物在0摄氏度下搅拌1小时。将反应液减压蒸馏除去溶剂，所得残留物经制备色谱纯化(Phenomenex Luna C 18 150*25mm*10um,洗脱相为5％-75％的乙腈-水)得白色固体标题化合物81(26mg,收率:52％)。
MS(ESI+)m/z＝502.2[M+H].
1H NMR(400MHz,DMSO-d 6)δ9.21(s,1H),8.72(d,J＝6.8Hz,1H),8.49(d,J＝5.0Hz,1H),7.92(s,1H),7.83(s,1H),7.49(s,1H),7.39(t,J＝8.3Hz,1H),7.32(dd,J＝11.4,2.0Hz,1H),7.24-7.13(m,2H),6.23-6.01(m,2H),5.61(dd,J＝9.6,2.6Hz,1H),4.51(d,J＝7.4Hz,1H),4.08(s,2H),3.80(s,3H),3.66(s,2H),2.42(s,3H).
实施例40
N-(1-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)氮杂环丁烷-3-基)-2-丁炔酰胺(82)
Figure PCTCN2022084728-appb-000084
以化合物81F为原料，采用实施例27中第五步类似的方法，将其中的丙烯酰氯4B替代为2-丁炔酰氯55F，合成化合物82。
MS(ESI+)m/z＝514.2[M+H].
1H NMR(400MHz,DMSO-d 6)δ9.13(s,1H),9.05(d,J＝6.7Hz,1H),8.42(d,J＝5.0Hz,1H),7.84(s,1H),7.75(s,1H),7.42(s,1H),7.31(t,J＝8.4Hz,1H),7.24(dd,J＝11.5,2.1Hz,1H),7.14-7.06(m,2H),4.37(s,1H),4.07-3.82(m,2H),3.73(s,3H),3.67-3.44(m,2H),2.35(s,3H),1.88(s,3H).
实施例41
2-氟-N-(1-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)氮杂环丁烷-3-基)丙烯酰基酰胺(83)
Figure PCTCN2022084728-appb-000085
将化合物81F(40mg,0.088mmol),2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(38mg,0.10mmol)和2-氟丙烯酸63A(18mg,0.20mmol)混合于二氯甲烷溶液中，然后加入N,N-二异丙基乙胺(39mg,0.30mmol)。所得溶液在0摄氏度下搅拌反应1小时。混合物过滤之后经C 18反相色谱纯化(洗脱相为20-70％的乙腈水溶液)得到化合物83(21mg,收率:46％)。MS(ESI+)m/z＝520.2[M+H].
1H NMR(400MHz,DMSO-d 6)δ9.20(s,1H),9.07(d,J＝6.9Hz,1H),8.48(d,J＝5.0Hz,1H),7.92(s,1H),7.83(s,1H),7.49(s,1H),7.39(t,J＝8.4Hz,1H),7.31(dd,J＝11.4,2.0Hz,1H),7.23-7.13(m,2H),5.52(dd,J＝47.9,3.5Hz,1H),5.27(dd,J＝15.6,3.5Hz,1H),4.58(d,J＝7.4Hz,1H),4.06(s,2H),3.94-3.46(m,5H),2.42(s,3H).
实施例42
经实施例39类似的路线和步骤，用下表中的原料I替换第一步中的化合物81B，可以合成表格中对应的化合物84-117。经实施例39类似的路线和步骤，用原料I中的118A和119A替换第一步中的化合物81B合成表格中对应的化合物118-119时，需要在第四步中将反应液中三氟乙酸浓度提高至50％。
Figure PCTCN2022084728-appb-000086
Figure PCTCN2022084728-appb-000087
Figure PCTCN2022084728-appb-000088
Figure PCTCN2022084728-appb-000089
Figure PCTCN2022084728-appb-000090
Figure PCTCN2022084728-appb-000091
Figure PCTCN2022084728-appb-000092
Figure PCTCN2022084728-appb-000093
Figure PCTCN2022084728-appb-000094
原料I中的117A，118A可以通过如下步骤合成：
Figure PCTCN2022084728-appb-000095
第一步 1-(叔丁基)3-甲基3-((S)-1-(((R)-叔丁基亚磺酰)氨基)乙基)氮杂环丁基-1,3-二羧酸酯(117D)
将化合物117B(4.4g,20mmol)和117C(1.5g,10mmol)溶解于50mL无水四氢呋喃中，所得溶液冷却至零下78摄氏度。在搅拌下缓慢滴入六甲基二硅基胺基锂溶液(1.0M四氢呋喃溶液，20mL，20mmol)，在零下78摄氏度下持续搅拌3小时。反应液中加入10mL饱和氯化氨水溶液淬灭后，缓慢升温至室温。所得混合物中加入100mL乙酸乙酯和50mL饱和氯化氨水溶液，分离所得有机相经饱和食盐水洗涤，无水硫酸钠干燥后，过滤，减压浓缩得到粗品。粗品经柱层析(石油醚/乙酸乙酯＝10/1-1/1)纯化得到化合物117D(2.1g,收率：58％)。MS(ESI+)m/z＝363.2[M+H].
第二步 3-((S)-1-(((R)-叔丁基亚磺酰)氨基)乙基)-3-(羟甲基)氮杂环丁基-1-羧酸叔丁酯(117E)
将化合物117D(2.1g,5.8mmol)溶解于40mL无水四氢呋喃中，所得溶液冷却至0摄氏度。于反应液中缓慢加入氢化铝锂(0.38g,10mmol)，并在0摄氏度下搅拌反应2小时。于所得反应液中加入10g十水合硫酸钠，0摄氏度下搅拌反应1小时缓慢升至室温，并继续搅拌16小时。所得混合物减压过滤，滤饼用50mL乙酸乙酯洗涤，所得滤液经浓缩得到粗品经硅胶柱纯化(洗脱相为含3％甲醇的二氯甲烷)，得主要产物117E(1.2g,收率62％)。
MS(ESI+)m/z＝335.2[M+H].
第三步 (S)-6-((R)-叔丁基亚磺酰)-5-甲基-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(117F)
将粗品化合物117E(1.2g,3.6mmol)和对甲苯磺酰氯(1.03g,5.4mmol)溶解于20mL无水四氢呋喃中，在0摄氏度下缓慢加入氢化钠(0.7g,60％，17.4mmol)。所得混合物在0摄氏度下搅拌反应2小时后，缓慢加入20mL水淬灭。所得反应液用30mL乙酸乙酯萃取3次，分离所得有机相经饱和食盐水洗涤，无水硫酸钠干燥后，过滤，减压浓缩得到粗品。粗品经柱层析(石油醚/乙酸乙酯＝10/1-1/1)纯化得到化合物117F(1.0g,收率：88％)。
MS(ESI+)m/z＝317.2[M+H].
第四步 (R)-5-甲基-2,6-二氮杂螺[3.3]庚烷-2-羧酸叔丁酯(117A)和(R)-2-((S)-叔丁基亚磺酰)-1-甲基-2,6-二氮杂螺[3.3]庚烷(118A)
将化合物117F(0.63g,2.0mmol)溶解于5mL二氯甲烷中，在0摄氏度下加入0.5mL三 氟乙酸。所得反应液在0摄氏度下搅拌1小时。将反应液在0摄氏度下减压浓缩，所得粗品产物经C 18反相柱(流动相为0-60％乙腈水溶液)纯化，得化合物117A(63mg,收率:15％)和118A(122mg,收率:28％)。
化合物117A MS(ESI+)m/z＝213.2[M+H].
化合物118A MS(ESI+)m/z＝217.2[M+H].
经化合物118A的类似的合成方法和步骤,使用119C替代117C，合成119A。
Figure PCTCN2022084728-appb-000096
MS(ESI+)m/z＝217.2[M+H].
实施例43
经实施例39中第一步至第四步类似的方法和步骤，用下表中的原料I替代第一步中的化合物81B，并在第五步中采用实施例41中类似的方法和步骤，可以合成表格中对应的化合物120-125。
Figure PCTCN2022084728-appb-000097
Figure PCTCN2022084728-appb-000098
Figure PCTCN2022084728-appb-000099
实施例44
经实施例39中类似的方法和步骤，用下表中的原料I替代第一步中的化合物81B，并用下表中原料J替代第三步中的60E，可以合成的下表中对应的化合物126-154。
Figure PCTCN2022084728-appb-000100
Figure PCTCN2022084728-appb-000101
Figure PCTCN2022084728-appb-000102
Figure PCTCN2022084728-appb-000103
Figure PCTCN2022084728-appb-000104
Figure PCTCN2022084728-appb-000105
Figure PCTCN2022084728-appb-000106
Figure PCTCN2022084728-appb-000107
Figure PCTCN2022084728-appb-000108
实施例45
经实施例39中类似的方法和步骤，用下表中的原料I替代第一步中的化合物81B，并用下表中原料K替代第二步中1G，合成的下表中对应的化合物156-159。
Figure PCTCN2022084728-appb-000109
Figure PCTCN2022084728-appb-000110
其中化合物158A的合成路线如下
Figure PCTCN2022084728-appb-000111
采用实施例1中化合物1G类似的合成步骤，在步骤一中用化合物158B替代化合物1C，化合物158C替代1D，反应溶剂替换为N,N-二甲基甲酰胺，并将反应温度提高至130摄氏度反应12小时，后续经历类似的步骤二可以合成化合物158A。MS(ESI+)m/z＝342.0[M+H].
1H NMR(400MHz,DMSO-d 6)δ＝7.66(t,J＝7.6Hz,1H),7.36-7.24(m,2H),7.09(d,J＝8.0Hz,1H),6.92(d,J＝7.2Hz,1H),6.69(d,J＝8.0Hz,1H),3.70(s,3H),2.26(s,3H),1.31(s,12H).
其中化合物159A的合成路线如下
Figure PCTCN2022084728-appb-000112
采用实施例1中化合物1G类似的合成步骤，在步骤一中用化合物159B代替化合物1D，可以合成化合物159A。MS(ESI+)m/z＝234.9[M+H].
1H NMR(400MHz,DMSO-d 6)δ＝8.66(d,J＝4.8Hz,2H),7.55(d,J＝8.0Hz,1H),7.51(d,J＝11.2Hz,1H),7.41(t,J＝7.2Hz,1H),7.32(t,J＝4.8Hz,1H),1.31(s,12H).
实施例46
(2S)-1-(4-(4-((2S,5R)-4-丙烯酰基-2,5-二甲基哌嗪-1-基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-5-基)环己-3-烯-1-羰基)吡咯烷-2-甲腈(162)
Figure PCTCN2022084728-appb-000113
参照实施例39的合成路线和方法，用162A替代81B，并用55A替代1G，合成化合物162F。
再由化合物162F替代实施例17中的55G，经实施例17中第五步和第六步的合成步骤和方法，合成化合物162。
MS(ESI+)m/z＝544.3[M+H].
1H NMR(400MHz,DMSO-d6)δ9.01(s,1H),7.74-7.72(m,2H),7.44-7.43(m,1H),6.89-6.76(m,1H),6.18-6.13(m,1H),5.76-5.68(m,2H),4.77-4.72(m,1H),4.60-4.41(m,3H),4.16-4.12(m,1H),3.91-3.87(m,1H),3.79(s,3H),3.74-3.70(m,2H),3.62-3.55(m,2H),2.77-2.58(m,2H),2.32-2.26(m,3H),2.21-2.15(m,2H),2.05-1.91(m,5H),1.16-1.09(m,3H),1.04-0.96(m,3H).
实施例47
(R)-4-丙烯酰-1-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-5-甲基哌嗪-2-酮(163)
Figure PCTCN2022084728-appb-000114
第一步 (R)-4-(5-溴-2-氯嘧啶-4-基)-2-甲基-5-羰基哌嗪-1-羧酸叔丁酯(163B)
将化合物163A(84mg,0.4mmol)溶解于3mL二氧六环中，在0摄氏度搅拌下加入氢化钠(32mg,60％,0.8mmol)。所得混合物在0摄氏度下搅拌30分钟后，加入2,4-二氯-5-溴嘧啶81A(123mg,0.5mmol)，在0摄氏度下继续搅拌1小时。反应液用1mL氯化铵饱和溶液淬灭后，加入20mL饱和氯化钠溶液，并用20mL乙酸乙酯萃取3次。所得有机相经饱和食盐水洗涤，无水硫酸钠干燥后，过滤，减压浓缩得到粗品。粗品经柱层析(石油醚/乙酸乙酯＝10/1-1/2)纯化得到化合物163B(89mg,收率：55％)。
MS(ESI+)m/z＝405.0,407.0[M+H].
用化合物163B替代81C，采用实施例39的第二步至第五步类似的实验方法和步骤，合成化合物163。
MS(ESI+)m/z＝544.2[M+H].
1H NMR(400MHz,DMSO-d 6)δ9.83(s,1H),8.54–8.45(m,2H),7.87(s,1H),7.54(s,1H),7.35(d,J＝11.6Hz,1H),7.28(s,1H),7.19(d,J＝5.0Hz,2H),6.72(d,J＝64.7Hz,1H),5.65(s,1H),4.73(d,J＝57.0Hz,1H),4.20(d,J＝84.4Hz,3H),3.86–3.78(m,3H),3.70(t,J＝20.6Hz,1H),2.42(s,3H),1.22(s,4H).
实施例48
1-(4-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,6-二氢吡啶-1(2H)-基)丙-2-烯-1-酮(164)
Figure PCTCN2022084728-appb-000115
第一步 4-(2-氯-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(164B)
将化合物60B(0.35g,1.0mmol)，化合物164A(0.40g,1.3mmol)，碳酸钾(0.34g,2.4mmol)和(二苯基膦二茂铁)二氯化钯(70mg,0.10mmol)加入到二氧六环(5mL)和水(0.5mL)的混合溶剂中，氮气置换三次之后置于100℃搅拌反应2小时。反应液用10mL氯化铵淬灭之后加入20mL乙酸乙酯萃取，分离所得有机相经浓缩得到粗品。粗品经柱层析(石油醚/乙酸乙酯＝2/1-1/1)纯化得到化合物164B(270mg,收率：54％)。
MS(ESI+)m/z＝498.2[M+H].
用化合物164B替代81D，采用实施例39的第三步至第五步类似的实验方法和步骤，可以合成化合物164。
MS(ESI+)m/z＝513.2[M+H].
1H NMR(400MHz,DMSO-d 6)δ9.65(s,1H),8.49(d,J＝5.0Hz,1H),8.42(s,1H),7.88(s,1H),7.53(s,1H),7.39(t,J＝8.3Hz,2H),7.30–7.14(m,2H),6.86(dd,J＝16.6,10.4Hz,1H),6.12(dd,J＝16.6,2.4Hz,1H),5.86(s,1H),5.68(d,J＝10.4Hz,1H),4.16–3.97(m,2H),3.82(s,3H),3.66(s,2H),2.48–2.29(m,5H).
实施例49
经化合物164合成中类似的方法和步骤，用下表中原料L替代第一步中164A，合成的 下表中对应的化合物165-166。
Figure PCTCN2022084728-appb-000116
实施例50
N-(3-(2-氨基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)苯基)丙烯酰基酰胺(167)
Figure PCTCN2022084728-appb-000117
第一步：3-(2-氯-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)苯胺(167B)
将化合物60B(3.0g,8.5mmol)，化合物167A(1.9g,8.5mmol)和(二苯基膦二茂铁)二氯化钯(0.38g,0.51mmol)，碳酸钾(2.4g,17mmol)溶解在二氧六环(35mL)和水(3.5mL)中。所得混合物在100℃下氮气环境中反应2小时后，减压浓缩得粗品。粗品经柱层析纯化(石油醚/乙酸乙酯＝4/1-2/1)得到化合物167B(0.40g,0.98mmol,收率：11％)。
MS(ESI+)m/z＝407.9[M+H].
第二步：4-(3-氨基苯基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-2-胺(167C)
将化合物167B(0.4g,0.98mmol)置于耐压反应管中，加入氨的甲醇溶液(7mol/L,6mL)。所得溶液在60摄氏度下密闭搅拌反应16小时。将反应液减压浓缩，粗品通过柱层析纯化(石油醚/乙酸乙酯＝3/1-1/2)，得到化合物167C(0.11g,0.28mmol,收率：29％)。
MS(ESI+)m/z＝389.2[M+H].
第三步：N-(3-(2-氨基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)苯基)丙烯酰基酰胺(167)
将化合物167C(0.10g,0.26mmol)溶解在二氯甲烷(3mL)中，加入三乙胺(78mg,0.77mmol)。在0℃下加入丙烯酰氯(19mg,0.21mmol)。反应在0℃下搅拌1小时。将反应液浓缩，粗品通过制备高效液相色谱纯化(流动相为25％-55％的乙腈水溶液(含0.1％甲酸))，得到固体化合物167(17mg,收率：15％)。
MS(ESI+)m/z＝443.0[M+H].
1H NMR(400MHz,DMSO-d 6)δ10.20(s,1H),8.45(d,J＝5.2Hz,1H),8.36(s,1H),7.83(s,1H),7.72-7.66(m,1H),7.23(dt,J＝8.2,6.4Hz,2H),7.19-7.11(m,2H),6.98-6.85(m,4H),6.47-6.38(m,1H),6.29-6.20(m,1H),5.78-5.72(m,1H),2.40(s,3H).
实施例51
N-(3-(2-氨基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)-2-甲基苯基)丙烯酰基酰胺(168)
Figure PCTCN2022084728-appb-000118
采用与实施例50类似的合成方法和步骤，用化合物168A替代化合物167A，合成化合物168。
MS(ESI+)m/z＝457.0[M+H].
1H NMR(400MHz,DMSO-d 6)δ9.49(s,1H),8.46(d,J＝5.2Hz,1H),8.33(s,1H),7.72(s,1H),7.26(t,J＝8.4Hz,1H),7.21-7.09(m,3H),6.96(d,J＝8.2Hz,1H),6.92(d,J＝8.0Hz,1H),6.87(s,2H),6.52(dd,J＝17.6,10.4Hz,1H),6.23(dd,J＝16.8,1.6Hz,1H),5.74(d,J＝9.6Hz,1H),2.41(s,3H),2.20(s,3H).
实施例52
N-(3-(2-羟基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)苯基)丙烯酰基酰胺(169)
Figure PCTCN2022084728-appb-000119
采用与实施例50第二步和第三步类似的合成方法和步骤，将7mol/L的氨的甲醇溶液替换为1.0mol/L氢氧化钠的二氧六环/水(1/1,v/v)溶液，合成化合物169。
MS(ESI+)m/z＝444.1[M+H].
实施例53
经实施例39中第一步至第四步类似的方法和步骤，用下表中的原料I替代第一步中的化合物81B，然后在第五步中采用实施例41中类似的方法和步骤，用下表中的原料M替代其中的化合物63A，可以合成表格中对应的化合物170-174。
Figure PCTCN2022084728-appb-000120
Figure PCTCN2022084728-appb-000121
实施例54
2-氟-N-(5-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)吡 啶-3-基)丙烯酰基酰胺(181)
Figure PCTCN2022084728-appb-000122
第一步 5-(2-氯-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)嘧啶-4-基)吡啶-3-胺(181B)
将化合物60B(1.5g,4.3mmol)，化合物181A(0.94g,4.3mmol)，碳酸钾(2.2g,17mmol)和(二苯基膦二茂铁)二氯化钯(0.62g,0.85mmol)混合于1,4-二氧六环(20mL)和水(2mL)中。所得混合物在氮气氛围下，于100摄氏度下搅拌反应2小时。冷却至室温，向反应液加水(50mL)，用乙酸乙酯萃取(100mL×3)，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品经制备型高效液相色谱仪(Waters Xbridge C18,20-60％乙腈水溶液(含0.01％氨水))得到化合物181B(0.67g,产率：38％)。
MS(ESI+)m/z＝409.1[M+H]
第二步 4-(5-氨基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺(181C)
将化合物118B(0.52g,1.3mmol)，化合物60E(0.24g,2.5mmol)，对甲苯磺酸(0.22g,1.3mmol)溶解于N-甲基吡咯烷酮(4mL)中。所得混合物置于微波140摄氏度下搅拌反应1小时。冷却至室温，向反应液加水(50mL)，用乙酸乙酯萃取(100mL×3)，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品。粗品经制备型高效液相色谱仪(Waters Xbridge C18,20-60％乙腈水溶液(含0.01％氨水))得到化合物181C(67mg，产率11％)。
MS(ESI+)m/z＝470.3[M+1].
第三步 2-氟-N-(5-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧)苯基)-2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)吡啶-3-基)丙烯酰基酰胺(181)
将化合物181C(10mg,0.021mmol)溶解于二氯甲烷(2mL)中,加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(16mg,0.042mmol)，化合物63A(1.9mg,0.021mmol)和N,N-二异丙基乙胺(8.1mg,0.063mmol)。所得混合物在室温下搅拌1小时。将反应液减压蒸馏除去溶剂，所得粗品经过制备型高效液相色谱仪(Waters Xbridge C18,20-60％乙腈水溶液(含0.01％氨水))纯化得化合物181(2.4mg,收率:21％)。
MS(ESI+)m/z＝542.2[M+H].
1H NMR(400MHz,DMSO-d 6)δ10.70(s,1H),9.86(s,1H),8.82(s,1H),8.80-8.61(m,1H),8.58(s,1H),8.46(d,J＝5.2Hz,1H),8.15(s,1H),8.06(s,1H),7.54(s,1H),7.38-7.26(m,2H),7.19(d,J＝5.2Hz,1H),7.06(d,J＝6.4Hz,1H),5.85-5.68(m,1H),5.51(dd,J＝15.2,3.6Hz,1H),3.84(s,3H),2.42(s,3H).
生物学评价
以下结合测试例进一步描述解释本申请中，但这些实施例并非意味着限制本申请中的范围。
测试例1、本发明化合物的FGFR酶抑制实验
实验中所用对照阳性化合物BGJ398购自Selleck货号为S2183。受试化合物样品溶解在DMSO中，配制成10mM贮存溶液，于-30℃保存。
酶反应使用promega公司生产的酶反应试剂盒(FGFR1 Kit货号V2991，FGFR2 kit货号V4060,FGFR3 kit货号VA7459,反应底物为Poly E4Y1)，根据生产商推荐的方法进行。反应产物检测使用的是promega公司生产的ADP检测试剂盒(ADP-Glo TM Kinase Assay，货号V9101)。
5μL反应***中含有0.4ng/μLFGFR1激酶(或1.4ng/μL FGFR2(WT(野生型)或V564F突变型)激酶，或1ng/μL FGFR3激酶)、0.2μg/μL Poly E4Y1、5μM ATP以及梯度稀释的受试化合物。反应***中DMSO的终浓度为1％。反应在384孔板中进行(Perkinelmer，Cat.6007290)，所有检测均为双复孔。在以上***中，最后加入ATP启动反应。将上述384孔反应板在25℃反应60分钟，然后加入5μL ADP-Glo，25℃反应40分钟，再加入10μL检测buffer(缓冲液)，25℃反应30分钟。反应结束后用Perkinelmer Envision测定Luminescence(荧光)值。Luminescence值代表ADP的生成量，通过high signal(高信号)(加酶不加抑制剂的Luminescence值)，low signal(低信号)(不加酶的Luminescence值)，sample signal(样品信号)(加酶加抑制剂的Luminescence值)来计算激酶活性的抑制率，通过XLfit2.0软件(ID Business Solutions Ltd)计算半数抑制浓度(IC 50)。
抑制率％＝(high signal-sample signal)/(high signal-low signal)×100％。
本发明实施例化合物对野生型FGFR2酶体外活性通过以上的试验进行测定，测得的IC 50值见表1。
表1
化合物编号 IC 50(nM) 化合物编号 IC 50(nM) 化合物编号 IC 50(nM)
1 62.6 79 63.9 134 32.3
8 69.3 80 5.1 135 8.3
12 85.5 81 9.5 136 59.6
18 92.6 82 124.0 137 130.6
20 124.7 83 164.1 138 27.4
45 175.4 84 8.1 139 80.1
47 94.8 89 80.2 140 44.4
50 179.5 90 40.4 141 154.8
57 194.8 93 88.7 142 63.3
60 27.5 96 135.9 143 47.3
64 9.9 97 137.2 145 17.7
65 13.2 98 26.1 146 12.6
66 30.2 99 152.0 147 8.6
67 16.6 105 123.5 148 42.7
68 18.0 109 8.7 149 48.9
69 23.2 114 69.8 150 179.7
70 175.2 115 104.1 156 72.9
71 37.8 118 140.4 159 52.5
72 25.8 119 94.6 164 8.7
74 43.1 120 127.1 167 178.3
75 189.6 130 17.2 170 120.7
76 11.5 132 34.4 174 56.6
77 11.5 133 151.8 181 149.0
本发明实施例化合物对V564F突变型FGFR2酶体外活性通过以上的试验进行测定，测得的IC 50值见表2。
表2
化合物编号 IC 50(nM) 化合物编号 IC 50(nM) 化合物编号 IC 50(nM)
1 104.2 8 105.2 43 200.4
50 125.9 60 11.6 65 13.4
67 15.6 69 22 71 55.7
72 12.5 76 14.6 77 14.8
78 22 79 105.2 80 11.9
81 19.8 84 43.8 89 151.6
90 19.6 93 61.3 96 131.6
98 23 99 35.2 105 21.1
109 11.1 114 41.4 115 43.6
118 142.1 119 62.2 130 15.8
132 25 133 82.4 134 22.8
135 9.1 136 35.9 138 16.6
139 75.4 140 37.4 141 161.5
142 146.2 143 101 144 136.4
145 11.9 146 16.7 147 16.3
148 24 149 28.1 154 29.4
156 47.5 159 34 162 181.2
163 201.2 163 56.1 164 16.6
170 125 174 20.4 BGJ398 >1000
测试例2、本发明化合物的细胞增殖实验
受试化合物样品溶解在DMSO中，配制成10mM贮存溶液，于-30℃保存。测定时将化合物在含有5％DMSO的无血清培养基中稀释至10倍于测定浓度。
实验中细胞SNU-16购自ATCC(American Type Culture Collection，USA，货号
Figure PCTCN2022084728-appb-000123
CRL-5974)、RT-112购自cobioer(南京科佰生物科技有限公司，货号为CBP60316)、KG-1购自ATCC(货号为CCL-246)、JMSU-1购自DSMZ(货号是ACC505)。培养基IMDM购自Gibco(货号为12440-061)，培养基1640购自Gibco(货号为12634-010)，血清购自Gibco(货号为10099-141C)。Cell-counting kit-8(CK04)购自同仁化学公司。
Figure PCTCN2022084728-appb-000124
Luminescent Cell Viability Assay购自Promega(货号为G7570)。
将对数生长期的细胞接种在96孔细胞培养板中，体积为100μL。在含有5％二氧化碳的培养箱中于37℃培养过夜。次日，加入10μL/孔梯度稀释的待测化合物，对照组加入10μL/孔含有5％DMSO的无血清培养基代替药物稀释液，DMSO的终浓度为0.5％。在培养箱中保温72小时。加入10μL/孔Cell-counting kit-8试剂(或50μL/孔CTG)。在二氧化碳培养箱中 于37℃孵育40分钟，在Perkinelmer Envision上读取450nm处(CTG读取Luminescence)的光吸收值。化合物对细胞生长的抑制率根据以下公式进行计算，用XLFit2.0软件计算药物的半数增殖抑制浓度(GI 50)。
抑制率(％)＝[1-([OD 450] 化合物-[OD 450] 背景)/([OD 450] 细胞-[OD 450] 背景)]×100％
其中：
[OD 450] 化合物代表化合物处理孔的光密度值；
[OD 450] 细胞代表以DMSO代替化合物的细胞孔第3天的光密度值；
[OD 450] 背景代表以DMSO代替化合物的细胞孔第0天的光密度值；
本发明实施例化合物在细胞增殖实验通过以上的试验进行测定，测得的GI 50值见表3。
表3
Figure PCTCN2022084728-appb-000125
Figure PCTCN2022084728-appb-000126
“-”表示未测试
测试例3、本发明化合物的血液稳定性测试
通过液相色谱串联质谱(LC/MS/MS)测定不同时间点被测化合物在SD大鼠或者人血液(含EDTA-K2抗凝剂)中的剩余百分比来评估本发明化合物在全血中的稳定性。
将398μL血液加入培养板孔中，在37摄氏度下预处理15分钟。将2μL被测化合物(1mmol/L DMSO溶液)或者阳性化合物(1mmol/L DMSO溶液)加入预处理后的398μL血液并混合，使被测化合物(或者阳性化合物)的最终浓度为5μM，有机溶剂的最终浓度为0.5％。每个待测化合物或者阳性化合物都进行两次测试。所得混合物样本在37摄氏度下孵育。在反应的0、15、30、60、120、240分钟时，各取50uL样本，并加入50μL超纯水和400μL含内标化合物(0.5μM甲苯磺丁脲)的冷乙腈终止反应。所有样品涡旋10分钟，并在3220g离心30分钟沉淀蛋白质。取200μL上清液进行LC-MS/MS分析。
所有计算都使用Microsoft Excel进行。从提取的离子色谱图中确定峰面积比。每个时间点的剩余化合物百分比由以下公式计算:
剩余百分比 t min(％)＝峰面积比 t min/峰面积比 0 min x 100％
其中峰面积比 t min为在t分钟时间点被测化合物(或者阳性化合物)和内标化合物的峰面积比；
峰面积比 0 min为0分钟时间点被测化合物(或者阳性化合物)和内标化合物的峰面积比。
斜率值k是通过被测化合物剩余百分比与孵育时间曲线的自然对数线性回归确定的。
体外半衰期(in vitro t 1/2)由斜率值k确定:
in vitro t 1/2＝-(0.693/k)
本发明化合物所测得的在SD大鼠或者人血液中的半衰期见表4。
表4.本发明化合物在SD大鼠和人血液中的稳定性
Figure PCTCN2022084728-appb-000127
“-”表示未测试
测试例4、本发明化合物的CYP酶抑制测试
使用150个供体混合人肝微粒体(购自Corning,货号452117)评估人主要5个CYP亚型 (CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP3A4)的代表性底物代谢反应。通过液相色谱串联质谱(LC/MS/MS)测定不同浓度待测化合物对非那西丁(CYP1A2)、双氯芬酸钠(CYP2C9)、S-美芬妥英(CYP2C19)、丁呋洛尔盐酸盐(CYP2D6)、咪达***(CYP3A4)代谢反应的影响。
将30μM非那西丁、10μM双氯芬酸钠、35μM S-美芬妥英、5μM丁呋洛尔盐酸盐、3μM咪达***、1mM还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)、待测化合物(浓度分别为0.1、0.3、1、3、10、30μmol/L)或阳性化合物或空白对照与混合人肝微粒体(0.2mg/mL)的反应体系200μL(100mmol/L磷酸盐缓冲液，pH 7.4，含体积比分别为0.3％的DMSO、0.6％的乙腈、0.1％的甲醇)在37℃孵育5分钟。然后加入200μL含3％甲酸及40nM内标维拉帕米的乙腈溶液，4000rpm离心50分钟。置于冰上冷却20分钟，再4000rpm离心20分钟析出蛋白。取200μL上清液进行LC-MS/MS分析。
峰面积根据色谱图计算。残余活性比例(％)用如下公式进行计算：
峰面积比例＝代谢产物峰面积/内标峰面积
残余活性比例(％)＝待测化合物组的峰面积比例/空白组的峰面积比例
CYP半数抑制浓度(IC 50)通过Excel XLfit 5.3.1.3计算得到。
测得本发明化合物的CYP半数抑制浓度(IC 50)数值见表5。
表5.本发明化合物对CYP的半数抑制浓度(IC 50)
Figure PCTCN2022084728-appb-000128
测试例5、Caco-2渗透性实验
通过Caco-2细胞模型利用液相色谱串联质谱(LC-MS/MS)测定分析药物的表观渗透系数(P app)。
该测试例中，Caco-2细胞购自美国典型菌种保藏中心(ATCC)，HEPES购自北京索莱宝科技有限公司，汉克平衡盐溶液(HBSS)和非必需氨基酸(NEAA)购自赛默飞世尔科技公司，青霉素、链霉素和胰蛋白酶/EDTA购自索莱宝公司，胎牛血清(FBS)和DMEM培养基购自Corning公司，HTS-96孔Transwell板和其他无菌耗材购自Corning公司，Millicell电阻测定***购自Millipore，
Figure PCTCN2022084728-appb-000129
购自Nexcelom Bioscience，Infinite 200 PRO酶标 仪购自Tecan，MTS2/4 orbital摇床购自IKA Labortechnik。
第一步 细胞培养和种板
将Caco-2培养于细胞培养瓶。培养箱设置为37℃、5％CO 2、保证相对湿度95％。细胞汇合度达到70-90％时可用于接种Transwell。细胞接种前，向Transwell上室每孔中加入50μL细胞培养基，下层培养板内加入25mL细胞培养基。将培养板置于37℃,5％CO 2培养箱内孵育1小时后可用于接种细胞。细胞消化后，吸取细胞混悬液转移至圆底离心管120g离心5分钟。使用培养基重悬细胞，终浓度为6.86×10 5cells/mL(个细胞/mL)。将细胞悬液以50μL每孔加入到96孔Transwell培养板上室中，最终接种密度为2.4×10 5cells/cm 2。接种后24小时开始换液，培养14-18天，隔一天换一次培养基。更换培养基过程如下，将Transwell小室与接收板分开，先弃掉接收板中培养基然后再弃掉Transwell小室培养基，最后每个小室加入75μL新鲜培养基，接收板加入25mL新鲜培养基。
第二步 细胞单层膜完整性的评价
Caco-2经过大约14天培养后，达到汇合并完成分化。此时，可应用于穿透试验。用电阻仪(Millipore，USA)测量单层膜电阻，记录每孔电阻。测定结束后，将Transwell培养板放回培养箱。电阻值的计算：测定电阻值(ohms)×膜面积(cm 2)＝TEER值(ohm·cm 2)，若TEER值<230ohms·cm 2，则该孔不能用于穿透试验。
第三步 溶液配制
分别称取2.38g HEPES，0.35g碳酸氢钠，加900mL纯水让其溶解，然后加100mL 10×HBSS搅拌均匀，调PH至7.4，最后过滤得1L转运缓冲液(HBSS，10mM HEPES，pH 7.4)。
将1mM的待测受试化合物的DMSO溶液物储备液用转运缓冲液稀释得到5μM测试溶液。对照化合物地高辛或者米诺地尔用DMSO稀释到2mM，并用上述转运缓冲液至10μM得对照化合物测试溶液。另外DMSO也用上述转运缓冲液稀释至含0.5％DMSO的接收端溶液。
第四步 药物穿透试验
从培养箱中取出Transwell培养板。使用转运缓冲溶液(10mM HEPES,pH 7.4)缓冲液润洗细胞单层膜两次，37℃条件下孵育30分钟。
测定化合物由顶端到基底端的转运速率。向上层小室(顶端)每孔加入125μL测试溶液，并立即从顶端转移50μL溶液至200μL含内标的乙腈(0.1μM甲苯磺丁脲)中作为顶端到基底的初始样本。下层小室(基底端)每孔加入235μL接收端溶液。
测定化合物由基底端到顶端的转运速率。向上层小室(顶端)每孔加入285μL接收端溶 液，并立即从顶端转移50μL溶液至200μL含内标的乙腈(0.1μM甲苯磺丁脲)中作为基底到顶端的初始样本。下层小室(基底端)每孔加入75μL测试溶液。
将上下的转运装置合并后，37℃条件下孵育2小时。
孵育完成后，分别从Transwell培养板上室和下室每孔取样50μL加入到新的样品管中。向样品管内加入200μL含内标的乙腈(0.1μM甲苯磺丁脲)，涡旋10分钟后，于3220g离心40分钟。吸取上清液150μL，与150μL水稀释之后进行LC-MS/MS分析。所有样品进行三次平行制备。
用荧光黄的渗漏评价孵育2小时后细胞单层膜的完整性，使用转运缓冲溶液(10mM HEPES，pH 7.4)稀释荧光黄储备液至最终浓度100μM。在上侧的Transwell插板的每个孔中加入荧光黄溶液100μL，下侧接收板的每个孔中加300μL转运缓冲溶液(10mM HEPES,pH 7.4)。37℃下孵育30分钟后，分别从每孔上下层吸出80μL溶液至一个新的96孔板中。使用酶标仪，激发波长485nm和发射波长530nm条件下进行荧光测定。
第五步 数据分析所有的计算都是使用微软Excel进行。用提取的离子色谱图测定峰面积。
表观渗透系数(P app，单位：cm/s×10 -6)用以下公式计算得出：
Figure PCTCN2022084728-appb-000130
公式中：V A为接收端溶液的体积(Ap→Bl是0.3mL，Bl→Ap是0.1mL)，Area(膜面积)为Transwell-96孔板膜面积(0.143cm 2)；time(时间)为孵育时间(单位：s)；[drug] receiver([药物] 接收端)为接收端药物浓度；[drug] initial，donor([药物] 初始，供体)为给药端初始药物浓度。
外排率(Efflux ratio)使用以下的公式计算得出：
Figure PCTCN2022084728-appb-000131
公式中：P app(B-A)为由基底端到顶端的表观渗透系数；
P app(A-B)为由顶端到基底端的表观渗透系数。
回收率("Percentage recovery"(％))使用以下的公式计算得出：
Figure PCTCN2022084728-appb-000132
公式中：V A为接收端的溶液体积(单位：mL)；V D为给予端的溶液体积(单位：mL)，[drug] donor([药物] 供体)为给药端药物浓度。
渗漏率(Percentage leakage(％)或LY(％))使用以下的公式计算得出：
Figure PCTCN2022084728-appb-000133
公式中：I receiver(I 接收端)是指接收孔(0.3mL)的荧光密度，I donor(I 供体)是指加药孔(0.1mL)的荧光密度。LY<1.5％表示单层细胞膜完好。对于个别LY>1.5％的情况，如果P app值和其它平行接近，基于科学的判断，最终数据可以采纳。
本发明化合物经测试所得的Caco2渗透性数据如下表6。
表6.本发明化合物的Caco2渗透性数据
化合物编号 Papp (A-B)(10 -6,cm/s) Papp (B-A)(10 -6,cm/s) Efflux Ratio
8 0.90 15.4 17.2
34 0.50 27.1 54.7
78 0.71 5.0 7.0
83 1.45 19.5 13.5
84 0.59 32.0 54.4
89 0.53 30.6 58.3
90 0.85 14.6 17.3
93 1.20 20.2 16.9
98 3.10 12.4 4.0
99 3.75 19.9 5.4
105 1.47 23.7 16.1
109 0.89 17.8 20.2
114 1.27 6.5 5.1
115 1.76 21.2 12.1
118 0.55 24.1 44.2
119 1.62 23.9 14.9
120 1.75 18.8 10.8
142 0.39 23.6 60.2
143 0.40 28.7 71.2
144 0.70 13.0 18.8
154 2.08 6.2 3.0
164 1.99 18.0 9.2
测试例6、本发明化合物的大鼠体内药代动力学测试
以SD大鼠为受试动物，应用LC/MS/MS法测定了大鼠静脉注射以及灌胃给予本发明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体内的药代动力学行为，评价其药动学特征。
每组健康6-8周雄性SD大鼠3只。
静脉注射给药：称取一定量药物，加10％体积的N,N-二甲基乙酰胺、33％体积的三甘醇和57％体积的生理盐水配制成1mg/mL的无色澄清透明液体；
灌胃给药：称取一定量药物，加0.5％质量的羟丙甲纤维素、0.1％体积的吐温80和99.6％体积的生理盐水配制成1mg/mL的白色悬浊液。
SD大鼠禁食过夜后，静脉注射或者灌胃给药。
大鼠静脉注射给药本发明化合物，给药后0.083、0.25、0.5、1、2、4、8、24小时由颈静脉采血0.2mL，置于含EDTA-K2的试管中，4℃，4000转/分钟离心5分钟分离血浆，于-75℃保存。
或者大鼠灌胃给药本发明化合物，给药后0.25、0.5、1、2、4、8、24小时由颈静脉采血0.2mL，置于含EDTA-K2的试管中，4℃，3500转/分钟离心10分钟分离血浆，于-75℃保存。
测定不同浓度的静脉注射或者药物灌胃给药后大鼠血浆中的待测化合物含量：取给药后各时刻的大鼠血浆30μL，加入内标***的乙腈溶液200μL(50ng/mL)，涡旋混合30秒，4℃，4700转/分钟离心15分钟，血浆样品取上清液加水稀释三倍，取2.0μL进行LC-MS/MS分析。
本发明化合物的大鼠体内药代动力学参数如下表7：
表7.本发明化合物的SD大鼠体内药代动力学结果
Figure PCTCN2022084728-appb-000134
Figure PCTCN2022084728-appb-000135
IV表示静脉注射给药；PO表示灌胃给药。

Claims (21)

  1. 一种式(I)所示化合物、或其立体异构体或药学上可接受的盐，
    Figure PCTCN2022084728-appb-100001
    X、Z各自独立地选自CR 9或N；
    W选自O或C(＝O)；
    Y选自C(＝O)、NHC(＝O)、C(＝O)NH、N(CH 3)或键；
    环A选自5-10元杂芳基或5-10元杂环基；
    环B选自C 6-C 10芳基、5-10元杂芳基或C 3-C 10环烃基；
    E选自C 3-C 10环烃基、C 6-C 10芳基、3-12元杂环基或5-12元杂芳基，所述C 3-C 10环烃基C 6-C 10芳基、3-12元杂环基或5-12元杂芳基任选地被一个或多个R 1a取代；
    R 1a独立地选自卤素、CN、NH 2、OH、C 1-C 6烷基、C 3-C 8环烃基、3-6元杂环基、C 1-C 6烷氧基、-S(＝O)-C 1-C 4烷基、-S(＝O) 2-C 1-C 4烷基、
    Figure PCTCN2022084728-appb-100002
    -S(＝O)(＝NR 8a)R 8b、-N＝S(＝O)R 8aR 8b、-NR 8aR 8b、-C(＝O)NR 8aR 8b或-NR 7C(＝O)R 8b，所述C 1-C 6烷基、C 3-C 8环烃基、3-6元杂环基、C 1-C 6烷氧基、-S(＝O)-C 1-C 4烷基或-S(＝O) 2-C 1-C 4烷基任选地被一个或多个独立地选自卤素、OH、C 1-C 3烷氧基或CN的基团取代；
    R 1选自-CN、-(CH 2) qCN、-C≡CR 5、-C(＝O)C≡CR 5、-C(＝O)CR 6＝C(R 5) 2、-R 7C(＝O)CH＝C(R 5) 2、-NHC(＝O)CR 6＝C(R 5) 2、-R 7NHC(＝O)CH＝C(R 5) 2、-NHC(＝O)C≡CR 5、-S(＝O)CR 6＝C(R 5) 2、-S(＝O) 2CR 6＝C(R 5) 2、-NHS(＝O)CR 6＝C(R 5) 2、-NHS(＝O) 2CR 6＝C(R 5) 2、-NR 6C(＝O)CR 6＝C(R 5) 2或NHC(＝O)R 5；
    R 5独立地选自H、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 8环烃基、3-12元杂环基或C 6-C 10芳基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 8环烃基、3-12元杂环基或C 6-C 10芳基任选地被一个或者多个R 5a取代；
    R 5a独立地选自卤素、CN、N(R 5b) 2、OH、NO 2、C 3-C 8环烷基或3-12元杂环基；
    R 5b独立地选自H或C 1-C 6烷基；
    R 6选自H、CN、卤素或C 1-C 6烷基；
    R 7选自C 1-C 6亚烷基、C 3-C 8亚环烷基或3-12元亚杂环基；
    R 2选自H、NH 2、C 1-C 6烷基、OH或卤素；
    R 3独立地选自卤素、CN、NH 2、OH、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基或C 3- 8环烷基；
    R 4独立地选自卤素、CN、NH 2、OH、NO 2、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 8环烷基、3-10元杂环基、-C(＝O)R 8a、-C(＝O)O R 8a、-NR 8aR 8b、-C(＝O)N R 8aR 8b或-NR 7C(＝O)R 8b，所述C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 8环烷基或3-10元杂环基任选地被一个或者多个R 4a取代；
    R 4a独立地选自卤素、CN、NH 2、OH或C 1-C 6烷基；
    R 8a、R 8b各自独立地选自H、卤素、CN、NH 2、OH、C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6卤代烷基；
    R 9选自H、CN、OH、NH 2、-NHR 10、-NH-C 1-C 6烷基、C 1-C 6烷基、C 1-C 6烷氧基或C 3-C 8环烷基，所述C 1-C 6烷基、-NH-C 1-C 6烷基、C 1-C 6烷氧基或C 3-C 8环烷基任选地被一个或多个R 10取代；
    R 10独立地选自卤素、NH 2、C 3-C 8环烷基、3-10元杂环基、C 6-C 10芳基或5-10元杂芳基，所述NH 2、C 3-C 8环烷基、3-10元杂环基、C 6-C 10芳基或5-10元杂芳基任选地被一个或多个R 11取代；
    R 11独立地选自C 1-C 6烷基、卤素、C 1-C 6烷氧基、C 3-C 8环烷基或3-10元杂环基，所述C 1-C 6烷基、C 3-C 8环烷基或3-10元杂环基任选地被C 1-C 6烷基、卤素、OH、-NH-C 1-C 6烷基、-N(C 1-C 6烷基) 2取代；
    n、m各自独立地选自0、1、2或3；
    q选自1、2或3。
  2. 根据权利要求1所述式(I)所示化合物、或其立体异构体或药学上可接受的盐，其特征在于：环A选自5-6元杂芳基或5-6元杂环基；或者
    环A选自5-6元杂芳基；或者
    环A选自嘧啶基、吡啶基或者四氢吡咯基。
  3. 根据权利要求1或2任一项所述式(I)所示化合物、或其立体异构体或药学上可接受的盐，其特征在于：环B选自C 6-C 10芳基或C 3-C 10环烃基；或者
    环B选自苯基或环己烯基；或者
    环B选自苯基。
  4. 根据权利要求1-3中任一项所述式(I)所示化合物、或其立体异构体或药学上可接受的盐，其特征在于：E选自C 3-C 6环烃基、C 6-C 10芳基、3-10元杂环基或5-10元杂芳基，所述C 3-C 6环烃基、C 6-C 10芳基、3-10元杂环基或5-10元杂芳基任选地被R 1a取代。
  5. 根据权利要求1-4中任一项所述式(I)所示化合物、或其立体异构体或药学上可接受的盐，其特征在于：R 1a独立地选自卤素、CN、NH 2、OH、-NR 8aR 8b、C 1-C 6烷基、C 3-C 8环烃基、3-6元杂环基、C 1-C 6烷氧基，所述C 1-C 6烷基、C 3-C 8环烃基、3-6元杂环基、C 1-C 6烷氧基任选地被一个或多个独立地选自卤素、OH或C 1-C 3烷氧基的基团取代；或者
    R 1a独立地选自卤素、CN、NH 2、OH、C 1-C 6烷基、C 3-C 8环烃基、3-6元杂环基、C 1-C 6烷氧基，所述C 1-C 6烷基、C 3-C 8环烃基、3-6元杂环基、C 1-C 6烷氧基任选地被一个或多个独立地选自卤素、OH或C 1-C 3烷氧基的基团取代；或者
    R 1a独立地选自卤素、-NR 8aR 8b、C 1-C 6烷基或C 1-C 6烷氧基，所述C 1-C 6烷基任选地被一个或多个独立地选自卤素、OH、CN或C 1-C 3烷氧基的基团取代。
  6. 根据权利要求1-5中任一项所述式(I)所示化合物、或其立体异构体或药学上可接受的盐，其特征在于：R 1选自-C≡CR 5、-C(＝O)C≡CR 5、-C(＝O)CR 6＝C(R 5) 2、-R 7C(＝O)CH＝C(R 5) 2、-NHC(＝O)CR 6＝C(R 5) 2、-R 7NHC(＝O)CH＝C(R 5) 2、-NHC(＝O)C≡CR 5、-S(＝O)CR 6＝C(R 5) 2、-S(＝O) 2CR 6＝C(R 5) 2、-NHS(＝O)CR 6＝C(R 5) 2、-NHS(＝O) 2CR 6＝C(R 5) 2、-NR 6C(＝O)CR 6＝C(R 5) 2或NHC(＝O)R 5；或者
    R 1选自-CN、-(CH 2) qCN、-C≡CR 5、-C(＝O)C≡CR 5、-C(＝O)CR 6＝C(R 5) 2、-R 7C(＝O)CH＝C(R 5) 2、-NHC(＝O)CR 6＝C(R 5) 2、-R 7NHC(＝O)CH＝C(R 5) 2、-NHC(＝O)C≡CR 5、-NHS(＝O) 2CR 6＝C(R 5) 2、-NR 6C(＝O)CR 6＝C(R 5) 2或NHC(＝O)R 5；或者
    R 1选自-C≡CR 5、-C(＝O)C≡CR 5、-C(＝O)CR 6＝C(R 5) 2、-R 7C(＝O)CH＝C(R 5) 2、-NHC(＝O)CR 6＝C(R 5) 2、-R 7NHC(＝O)CH＝C(R 5) 2、-NHC(＝O)C≡CR 5、-NHS(＝O) 2CR 6＝C(R 5) 2、-NR 6C(＝O)CR 6＝C(R 5) 2或NHC(＝O)R 5。
  7. 根据权利要求6所述式(I)所示化合物、或其立体异构体或药学上可接受的盐，其特征在于：R 1选自以下基团：
    Figure PCTCN2022084728-appb-100003
    Figure PCTCN2022084728-appb-100004
  8. 根据权利要求1-7中任一项所述式(I)所示化合物、或其立体异构体或药学上可接受的盐，其特征在于：R 2选自H、NH 2、CH 3、OH或卤素；或者R 2选自H、NH 2、CH 3或卤素。
  9. 根据权利要求1-8中任一项所述式(I)所示化合物、或其立体异构体或药学上可接受的盐，其特征在于：R 3独立地选自卤素、C 1-C 6烷基、C 1-C 6烷氧基或C 1-C 6卤代烷基；或者R 3独立地选自卤素或C 1-C 6烷氧基；或者R 3选自卤素。
  10. 根据权利要求1-9中任一项所述式(I)所示化合物、或其立体异构体或药学上可接受的盐，其特征在于：m选自0或1。
  11. 根据权利要求1-10中任一项所述式(I)所示化合物、或其立体异构体或药学上可接受的盐，其特征在于：R 4独立地选自卤素、CN、NH 2、OH、NO 2、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 8环烷基、3-10元杂环基，所述C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 8环烷基、3-10元杂环基任选地被一个或者多个R 4a取代；或者
    R 4独立地选自CN、卤素、C 1-C 6烷基或C 1-C 6烷氧基；或者
    R 4独立地选自CN或C 1-C 6烷基。
  12. 根据权利要求1-11中任一项所述式(I)所示化合物、或其立体异构体或药学上可接受的盐，其特征在于：n选自0或1。
  13. 根据权利要求1-12中任一项所述式(I)所示化合物、或其立体异构体或药学上可接受的盐，其特征在于：R 9选自H、CN、OH、NH 2、-NHR 10或-NH-C 1-C 6烷基，所述-NH-C 1-C 6烷基任选地被一个或多个R 10取代；或者
    R 9选自H、NH 2、-NHR 10、-NH-C 1-C 6烷基或C 1-C 6烷基，所述C 1-C 6烷基或-NH-C 1-C 6烷基任选地被一个或多个R 10取代。
  14. 根据权利要求1-2或4-13中任一项所述式(I)所示化合物、或其立体异构体或药学上可接受的盐，其特征在于：所述式(I)所示化合物、或其立体异构体或药学上可接受的盐选自式(II)所示化合物、或其立体异构体或药学上可接受的盐，
    Figure PCTCN2022084728-appb-100005
  15. 根据权利要求1或3-13中任一项所述式(I)所示化合物、或其立体异构体或药学上可接受的盐，其特征在于：所述式(I)所示化合物、或其立体异构体或药学上可接受的盐选自式(III)所示化合物、或其立体异构体或药学上可接受的盐，
    Figure PCTCN2022084728-appb-100006
  16. 根据权利要求14或15所述式(I)所示化合物、或其立体异构体或药学上可接受的盐，其特征在于：所述式(I)所示化合物、或其立体异构体或药学上可接受的盐选自式(IV)所示化合物、或其立体异构体或药学上可接受的盐，
    Figure PCTCN2022084728-appb-100007
  17. 权利要求1-13中任一项所述式(I)所示化合物、或其立体异构体或药学上可接受的盐，其特征在于：式(I)所示化合物、或其立体异构体或药学上可接受的盐选自式(V)所示化合物、或其立体异构体或药学上可接受的盐，
    Figure PCTCN2022084728-appb-100008
  18. 根据权利要求1所述的式(I)所示化合物、或其立体异构体或药学上可接受的盐，其特征在于：式(I)所示化合物、或其立体异构体或药学上可接受的盐选自以下化合物、或其立体异构体或药学上可接受的盐，
    Figure PCTCN2022084728-appb-100009
    Figure PCTCN2022084728-appb-100010
    Figure PCTCN2022084728-appb-100011
    Figure PCTCN2022084728-appb-100012
    Figure PCTCN2022084728-appb-100013
    Figure PCTCN2022084728-appb-100014
    Figure PCTCN2022084728-appb-100015
    Figure PCTCN2022084728-appb-100016
    Figure PCTCN2022084728-appb-100017
    Figure PCTCN2022084728-appb-100018
  19. 一种药物组合物，所述药物组合物包含权利要求1-18中任一项所述式(I)所示化合物、或其立体异构体或药学上可接受的盐，以及药学上可接受的辅料。
  20. 权利要求1-18中任一项所述式(I)所示化合物、或其立体异构体或药学上可接受的盐，或权利要求19所述药物组合物在制备预防或者治疗与FGFR相关的疾病的药物中的用途。
  21. 根据权利要求20所述的用途，其特征在于：所述与FGFR相关的疾病选自癌症。
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