WO2022206939A1 - Composé hétérocyclique servant d'inhibiteur de fgfr et son application - Google Patents

Composé hétérocyclique servant d'inhibiteur de fgfr et son application Download PDF

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Publication number
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)
Chinese (zh)
Inventor
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/fr

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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

L'invention concerne un composé hétérocyclique servant d'inhibiteur de FGFR et spécifiquement, l'invention concerne un composé représenté par la formule (I), et un stéréoisomère ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2022/084728 2021-04-03 2022-04-01 Composé hétérocyclique servant d'inhibiteur de fgfr et son application WO2022206939A1 (fr)

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WO2024109799A1 (fr) * 2022-11-22 2024-05-30 西藏海思科制药有限公司 Dérivé de pyrimidine et son application en médecine

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CN101421262A (zh) * 2006-02-06 2009-04-29 Irm责任有限公司 作为蛋白激酶抑制剂的化合物和组合物
CN101535275A (zh) * 2006-10-25 2009-09-16 先正达参股股份有限公司 哒嗪衍生物
CN108779095A (zh) * 2015-11-04 2018-11-09 默克专利有限公司 使用具有btk抑制活性的嘧啶和吡啶化合物治疗癌症的方法
WO2020131627A1 (fr) * 2018-12-19 2020-06-25 Array Biopharma Inc. Composés pyrazolo[1,5-a]pyridine substitués servant d'inhibiteurs de tyrosine kinases fgfr
WO2020231990A1 (fr) * 2019-05-13 2020-11-19 Relay Therapeutics, Inc. Inhibiteurs de fgfr et leurs procédés d'utilisation
CN112341431A (zh) * 2019-08-09 2021-02-09 齐鲁制药有限公司 作为fgfr4抑制剂的杂环化合物

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CN101421262A (zh) * 2006-02-06 2009-04-29 Irm责任有限公司 作为蛋白激酶抑制剂的化合物和组合物
CN101535275A (zh) * 2006-10-25 2009-09-16 先正达参股股份有限公司 哒嗪衍生物
CN108779095A (zh) * 2015-11-04 2018-11-09 默克专利有限公司 使用具有btk抑制活性的嘧啶和吡啶化合物治疗癌症的方法
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WO2020231990A1 (fr) * 2019-05-13 2020-11-19 Relay Therapeutics, Inc. Inhibiteurs de fgfr et leurs procédés d'utilisation
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024109799A1 (fr) * 2022-11-22 2024-05-30 西藏海思科制药有限公司 Dérivé de pyrimidine et son application en médecine

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