WO2023222005A1 - Composé hétérocyclique aromatique et intermédiaire, composition pharmaceutique et utilisation associée - Google Patents

Composé hétérocyclique aromatique et intermédiaire, composition pharmaceutique et utilisation associée Download PDF

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Publication number
WO2023222005A1
WO2023222005A1 PCT/CN2023/094659 CN2023094659W WO2023222005A1 WO 2023222005 A1 WO2023222005 A1 WO 2023222005A1 CN 2023094659 W CN2023094659 W CN 2023094659W WO 2023222005 A1 WO2023222005 A1 WO 2023222005A1
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membered
alkyl
heterocyclyl
methyl
group
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PCT/CN2023/094659
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English (en)
Chinese (zh)
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宋云龙
刘天琪
丁祥峰
居捷
苗新园
王克柱
汪笛莎
寇红艳
卢凯
赵亮
雷响
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上海翊石医药科技有限公司
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Priority to CN202380009114.XA priority Critical patent/CN117425660A/zh
Publication of WO2023222005A1 publication Critical patent/WO2023222005A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

Definitions

  • the present invention requires an invention patent application titled "Aromatic heterocyclic compound and its preparation method” and application number 202210596201.7 submitted in China on May 18, 2022, and an invention patent application submitted in China on November 18, 2022.
  • the priority of the invention patent application titled “Aromatic heterocyclic compound and its preparation method” and application number 202211452918.0 is incorporated into this article by reference.
  • the present invention belongs to the field of medical technology. Specifically, it relates to an aromatic heterocyclic compound, an intermediate for preparing the compound, a pharmaceutical composition containing the compound, and a preparation method and use of the compound.
  • Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s disease, affecting approximately 2% of the population over the age of 60.
  • the etiology of Parkinson's disease is very complex, and is typically characterized by a decrease in dopaminergic neurons in the substantia nigra of the brain, resulting in clinical manifestations such as bradykinesia, resting tremor, myotonia, and postural gait disorder.
  • Currently available treatments for Parkinson's disease are only symptomatic, such as dopamine replacement therapy, which can relieve symptoms. There is still a lack of a cure to stop the progression of the disease or reverse it. Therefore, the need for new treatment strategies for Parkinson's disease is clear. Furthermore, this demand is clearly growing as the world's population continues to age.
  • LRRK2 has become an important player in the pathogenesis of Parkinson's disease, and LRRK2 inhibitors are promising therapeutic drugs for Parkinson's disease.
  • LRRK2 is a large protein containing 2527 amino acids and belongs to the ROCO protein kinase family. Compared with other members of the ROCO family, LRRK2 contains diverse structural domains, and its main functional domains from N-terminus to C-terminus are: ARM (Armadillo repeats), ANK (ankyrin repeats), LRR (leucine rich repeats), ROC ( Ras of complex proteins), COR (C-terminal of Roc), KIN (kinase) and WD40 (WD repeat domain). LRRK2 is widely expressed in the heart, kidneys, lungs, liver and some immune cells and the central nervous system.
  • LRRK2 in neurons is distributed in the cytoplasm and exists on various membrane structures such as mitochondria, Golgi bodies, and lysosomes. It mediates It guides the phosphorylation of downstream proteins and plays an important role in synaptic transmission, vesicle transport, mitochondrial function, regulation of autophagy, regulation of microtubule stability, and inflammatory response.
  • LRRK2 has both GTPase and kinase activities, and there is a mutual regulation mechanism between the two.
  • the kinase activity of LRRK2 depends on the formation of LRRK2 dimers, and GTPase is crucial for the formation of dimers; conversely, upon activation of the kinase, it regulates the GTPase activity of LRRK2 through autophosphorylation of the ROC domain.
  • LRRK2 inhibitors are in the clinical stage.
  • DNL151 and DNL201 have both completed Phase I clinical trials, and WXWH0226 has obtained clinical trial approval.
  • Many pharmaceutical companies have published patents on LRRK2 inhibitors.
  • the main structural types of compounds include pyrrolopyrimidines/pyridines/pyridazines (WO2015113451, WO2016130920, WO2017106771, WO2018155916, WO2015092592), aminopyrimidines (WO2017087905, WO201715649 3.WO2017218843, WO2018217946), pyrimidinyl/pyridyl isoindazoles (WO2014137719, WO2014137723, WO2014134774, WO2014137728) and macrocycles (for example, WO2013046029 containing two ring systems of benzene and pyrazolopyrimidine or imidazopyridazine in the macrocyclic structure) , WO2014140235, WO2016042089; another example, WO2019012093), which contains two ring systems of pyrazole and pyrimidine or pyridine in the macrocyclic structure, etc.
  • WO2013046029 containing two ring systems of benz
  • the object of the present invention is to provide a compound with a new structure as an LRRK2 inhibitor; at the same time, the object of the present invention is to provide intermediates for preparing the compound, and a preparation method of the compound, including the compound Pharmaceutical compositions, and uses of said compounds in preventing and/or treating diseases mediated by LRRK2.
  • the present invention provides a compound represented by formula (K), or a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof:
  • X 1 , X 2 , X 3 and X 4 are independently CH or N;
  • Y 1 , Y 2 and Y 3 are independently O, S or N R Y ; each occurrence of R Y is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne group, C 1-6 alkoxy group, C 1-6 alkylthio group, C 3-8 cycloalkyl group or 3-8 membered heterocyclyl group, the heterocyclic group contains 1 or 2 members independently selected from S , O and N heteroatoms; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl or heterocyclyl groups are optionally one or more independently selected from deuterium, halogen, The substituents of oxo, cyano, hydroxy, nitro, amino, C 1-6 alkyl, phenyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy replace;
  • R 1 and R 2 are independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 Alkylthio group, C 1-6 hydroxyalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-8 cycloalkyl group or 3-8 membered heterocyclyl group, the heterocyclyl group contains 1 or 2 heteroatoms each independently selected from S, O and N; the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl is optionally selected from one or more groups independently selected from deuterium, halogen, oxo group and cyano group Substituted with substituents of , hydroxyl, nitro,
  • R 3 The number of R 3 is 1 or 2, and each occurrence is independently halogen, cyano, hydroxyl, mercapto, nitro, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, 3-12 membered heterocyclyl, -C 1-3 alkyl Base-C 3-8 cycloalkyl, -C 1-3 alkyl-C 3-8 cycloalkenyl, -C 1-3 alkyl-3-12-membered heterocyclyl or -C(O)-3- 12-membered heterocyclyl, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N; the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-8 cycl
  • Each occurrence of R 4 is independently hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, carboxyl, cyano, nitro, oxime, C 1-6 alkenyl, C 1-6 alkynyl, C 1- 6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 haloalkyl;
  • the number of R 5 is 1, 2 or 3, and each occurrence is independently hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, carboxyl, nitro, oxime group, C 1-6 alkenyl, C 1- 6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy , C 1-6 alkylthio, C 1-6 haloalkyl, C 3-6 cycloalkyl, -NH-C 1-6 alkyl base, -N(C 1-6 alkyl) 2 , -NH-C 3-6 cycloalkyl, -N(C 3-6 cycloalkyl) 2 or cyano group;
  • n1 is 2, 3, 4 or 5;
  • n2 is 1 or 2;
  • Ring A is a 5-6 membered heteroaryl group or Ring A does not exist.
  • X 1 , X 2 , X 3 and X 4 are all N.
  • X 2 is CH, and X 1 , X 3 and X 4 are all N.
  • X 1 and X 2 are both CH, and X 3 and X 4 are both N.
  • X 1 , X 2 and X 4 are all CH, and X 3 is N.
  • Y 2 is O or S
  • Y 1 and Y 3 are each independently N R Y .
  • Y 2 is O
  • Y 1 and Y 3 are each independently NRY .
  • Y 1 is O or S
  • Y 2 and Y 3 are each independently N R Y .
  • Y 1 is O
  • Y 2 and Y 3 are each independently N R Y .
  • Y 1 is O
  • Y 2 is O
  • Y 3 is NR Y .
  • each occurrence of R Y is independently hydrogen, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 alkoxy , C 1-3 alkylthio group, C 3-8 cycloalkyl group or 3-8 membered heterocyclyl group, the heterocyclyl group contains 1 or 2 heteroatoms each independently selected from S, O and N; the The alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl or heterocyclic group is optionally selected from one or more groups independently selected from deuterium, halogen, oxo group, cyano group, hydroxyl group, Substituted with nitro and amino substituents.
  • each occurrence of R Y is independently hydrogen, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, methoxy base, ethoxy, methylthio, ethylthio, cyclopropyl, cyclohexyl, propylene oxide or butyl oxide; the methyl, ethyl, propyl, isopropyl, ethylene group, propenyl, ethynyl, propynyl, methoxy, ethoxy, methylthio, ethylthio, cyclopropyl, cyclohexyl, propylene oxide or butylene oxide, optionally Substituted with one or more substituents each independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro and amino.
  • each occurrence of R Y is independently hydrogen.
  • each occurrence of R 1 and R 2 is independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, nitro, amino, C 1-6 alkyl, C 2 -6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl or C 3-8 cycloalkyl; the alkyl, alkenyl Alkyl, alkynyl, alkoxy, alkylthio, hydroxyalkyl or cycloalkyl is optionally selected from one or more groups independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro, amino, Substituted with substituents of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy.
  • each occurrence of R 1 and R 2 is independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, nitro, amino, C 1-3 alkyl, C 1 -3 alkoxy, C 1-3 alkylthio, C 1-3 hydroxyalkyl or C 3-6 cycloalkyl; the alkyl, alkoxy, alkylthio, hydroxyalkyl or cycloalkyl optionally one or more independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro, amino, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl group and C 1-3 haloalkoxy substituents.
  • each occurrence of R 1 and R 2 is independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, amino, C 1-3 alkyl, C 1-3 alkyl Oxygen group, C 1-3 alkylthio group, C 1-3 hydroxyalkyl group or C 3-6 cycloalkyl group; the alkyl group, alkoxy group, alkylthio group, hydroxyalkyl group or cycloalkyl group is optionally Substituted with one or more substituents each independently selected from deuterium, halogen, cyano, hydroxyl, amino and C 1-3 alkyl.
  • each occurrence of R 1 and R 2 is independently hydrogen, deuterium, cyano, hydroxyl, mercapto, amino, methyl, ethyl, n-propyl, isopropyl, Cyclopropyl, cyclobutyl, methoxy, ethoxy, -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -CH 2 CH 2 OCH 3 , fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl Fluoromethyl or trifluoromethyl.
  • each occurrence of R 1 and R 2 is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, ethoxy , -CH 2 OCH 3 , fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl or trifluoromethyl.
  • the number of R 3 is 1 or 2, and each occurrence is independently halogen, cyano, hydroxyl, mercapto, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-8 cycloalkyl, 3-12 Membered heterocyclyl, -C 1-3 alkyl-C 3-8 cycloalkyl, -C 1-3 alkyl-3-12-membered heterocyclyl or -C(O)-3-12-membered heterocyclyl , the heterocyclyl group contains 1 or 2 heteroatoms each independently selected from S, O and N; the C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 alkylthio group, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, -C 1-3 alkyl-C 3-8 cycloalkyl, -C 1-3 alkyl-3-12 membered heterocyclyl or -C
  • the number of R 3 is 1 or 2, and each occurrence is independently halogen, cyano group, hydroxyl, amino, C 1-4 alkyl, C 3-6 ring Alkyl, 3-9 membered heterocyclyl, -C 1-2 alkyl-C 3-6 cycloalkyl, -C 1-2 alkyl-3-9 membered heterocyclyl or -C(O)-3 -9-membered heterocyclyl, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N; the C 1-4 alkyl, C 3-6 cycloalkyl, 3- 9-membered heterocyclyl, -C 1-2 alkyl-C 3-6 cycloalkyl, -C 1-2 alkyl-3-9-membered heterocyclyl or -C(O)-3-9-membered heterocycle
  • the group is optionally selected from one or more groups, each independently selected from deuterium, halogen, cyano, hydroxyl,
  • the number of R 3 is 1 or 2, and each occurrence is independently halogen, cyano, hydroxyl, C 1-4 alkyl, C 3-6 cycloalkyl , 3-9 membered heterocyclyl, -C 1-2 alkyl-C 3-6 cycloalkyl, -C 1-2 alkyl-3-9 membered heterocyclyl or -C(O)-3-9
  • a membered heterocyclic group the heterocyclic group contains 1 or 2 heteroatoms each independently selected from S, O and N; the C 1-4 alkyl, C 3-6 cycloalkyl, 3-9 membered Heterocyclyl, -C 1-2 alkyl-C 3-6 cycloalkyl, -C 1-2 alkyl-3-9-membered heterocyclyl or -C(O)-3-9-membered heterocyclyl, any One or more are independently selected from deuterium, cyano, hydroxyl, methyl, ethyl, me
  • heterocyclyl containing 1 or 2 independently selected from S, O and N of heteroatoms.
  • the number of R 3 is 1 or 2, and each occurrence is independently fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-propyl, etc.
  • each occurrence of R 3 is independently Represents the R 3 connection location.
  • each occurrence of R 4 is independently hydrogen, deuterium, halogen, amino, hydroxyl, sulfhydryl, carboxyl, cyano, nitro, oxime, C 1-3 alkenyl, C 1-3 alkynyl, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio or C 1-3 haloalkyl.
  • each occurrence of R 4 is independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, etc. Fluoromethyl or trifluoromethyl.
  • each occurrence of R 4 is independently hydrogen, fluorine, or methyl.
  • the number of R 5 is 1, 2 or 3, and each occurrence is independently hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 alkoxy , C 1-3 alkylthio group, C 1-3 haloalkyl group, C 3-6 cycloalkyl group, -NH-C 1-3 alkyl group, -N(C 1-3 alkyl) 2 , -NH-C 3-6 cycloalkyl, -N(C 3-6 cycloalkyl) 2 or cyano group.
  • the number of R 5 is 1, 2 or 3, and each occurrence is independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, Isopropyl, methoxy, ethoxy, methylthio, ethylthio, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -NH-cyclopropyl, -N(cyclopropyl) 2 or cyano.
  • the number of R 5 is 1, 2 or 3, and each occurrence is independently hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, methyl sulfide. group, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -NH-cyclopropyl or cyano group.
  • the number of R 5 is 1, 2 or 3, and each occurrence is independently hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, trifluoro Methyl, cyclopropyl, -NHCH 3 , -NHCH 2 CH 3 , -NH-cyclopropyl or cyano.
  • n1 is 3.
  • n2 is 1.
  • n2 is 2.
  • Ring A is absent.
  • Ring A is a 5-6 membered heteroaromatic ring.
  • Ring A is pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or s-triazinyl.
  • Ring A is a 5-membered heteroaromatic ring.
  • Ring A is pyrrolyl, pyrazolyl or imidazolyl.
  • Ring A is ** represents the fusion site.
  • Ring A is ** represents the fusion site.
  • the present invention also provides a compound represented by any one of formulas (K1) to formula (K11), or its stereoisomers, tautomers or mixtures, or its pharmaceutically acceptable of salt:
  • R 1 , R 2 , R 3 , R 4 , R 5 , Y 1 , Y 2 , Y 3 and n1 are as defined in formula (K).
  • the present invention also provides a compound represented by formula (K1A) or formula (K1B), or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt:
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined in formula (K).
  • the present invention also provides a compound represented by formula (K2A), or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt:
  • R 1 , R 2 , R 3 , R 4 , R 5 and Y 1 are as defined in formula (K).
  • the present invention also provides a compound represented by formula (K3A) or formula (K3B), or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt:
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined in formula (K).
  • the present invention also provides a compound represented by formula (K4A), or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt:
  • R 1 , R 2 , R 3 , R 4 , R 5 and Y 1 are as defined in formula (K).
  • the present invention also provides a compound represented by formula (K5A), or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt:
  • R 1 , R 2 , R 3 , R 4 , R 5 and Y 1 are as defined in formula (K).
  • the present invention also provides a compound represented by formula (K8A) or formula (K8B), or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt:
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined in formula (K).
  • Y 1 is O or NH.
  • Y1 is NH
  • each occurrence of R 1 and R 2 is independently hydrogen, deuterium, halogen or C 1-3 alkyl; said alkyl is optionally replaced by one or more independently Substituted with substituents selected from deuterium and halogen.
  • each occurrence of R 1 and R 2 is independently hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine, bromine, monofluoromethyl base, difluoromethyl or trifluoromethyl.
  • each occurrence of R 1 and R 2 is independently hydrogen, methyl, ethyl, n-propyl, isopropyl, fluorine, chlorine or bromine.
  • the number of R 3 is 1 or 2, preferably 1.
  • each occurrence of R 3 is independently C 1-4 alkyl, C 3-6 cycloalkyl, 3-9 membered heterocyclyl or -C(O)-3 -9-membered heterocyclyl, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N; the C 1-4 alkyl, C 3-6 cycloalkyl, 3-
  • the 9-membered heterocyclyl or -C(O)-3-9-membered heterocyclyl is optionally selected from one or more groups, each independently selected from cyano, hydroxyl, methyl, ethyl, methoxy, ethoxy, Substituted with fluorine, chlorine, bromine, 3-6 membered heterocyclyl and methyl or ethyl substituted 3-6 membered heterocyclyl substituents, the heterocyclyl contains 1 or 2 each independently selected from S , O and N heteroatoms.
  • each occurrence of R 3 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-membered monoheterocyclyl, 5-membered monoheterocyclyl, 6-membered monoheterocyclyl, 7-membered bridged heterocyclyl, 8-membered bridged heterocyclyl, 7-membered spiroheterocyclyl, 8-membered spiroheterocyclyl, 9-membered spiroheterocyclyl, -C(O)-6-membered monoheterocyclyl, -C(O)-7-membered bridged heterocyclyl or -C( O)-7-membered spirohexyl, 4-membered
  • each occurrence of R 3 is independently Represents the R 3 connection location.
  • each occurrence of R 4 is independently hydrogen, deuterium, halogen, or C 1-3 alkyl.
  • each occurrence of R 4 is independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl or ethyl.
  • each occurrence of R 4 is independently hydrogen, fluorine, or methyl.
  • the number of R5 is 1, 2 or 3, preferably 1 or 2, more preferably 1 indivual.
  • each occurrence of R 5 is independently hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 haloalkyl or C 3-6 cycloalkyl.
  • each occurrence of R 5 is independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, etc. Fluoromethyl, trifluoromethyl, cyclopropyl or cyclobutyl.
  • each occurrence of R5 is independently hydrogen, fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl, trifluoromethyl or cyclopropyl.
  • R 1 and R 2 are independently hydrogen, halogen or C 1-3 alkyl each time they appear. .
  • R 1 and R 2 are independently hydrogen, methyl, ethyl, n-propyl each time they appear. base, isopropyl, fluorine, chlorine or bromine.
  • each occurrence of R 1 and R 2 is independently hydrogen, methyl or fluorine.
  • R 3 is C 3-6 cycloalkyl or 3-9 membered heterocyclyl, and the heterocyclic
  • the base contains 1 or 2 heteroatoms each independently selected from O and N; the C 3-6 cycloalkyl or 3-9 membered heterocyclic group is optionally replaced by one or more heteroatoms each independently selected from fluorine, chlorine , bromine and a 3-6 membered heterocyclyl substituent containing 1 or 2 heteroatoms each independently selected from O and N.
  • R 3 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-membered monoheterocycle base, 5-membered monoheterocyclyl or 6-membered monoheterocyclyl, the monoheterocyclyl contains 1 or 2 heteroatoms each independently selected from O and N; the cyclopropyl, cyclobutyl, cyclopropyl, Pentyl, cyclohexyl, 4-membered monoheterocyclyl, 5-membered monoheterocyclyl or 6-membered monoheterocyclyl are optionally selected from one or more fluorine, chlorine, bromine, 4-membered monoheterocyclyl , 5-membered monoheterocyclyl and 6-membered monoheterocyclyl substituents, the monoheterocyclyl contains 1 or
  • R 3 is Represents the R 3 connection location.
  • R 3 is Represents the R 3 connection location.
  • R 4 is C 1-3 alkyl.
  • R 4 is methyl or ethyl.
  • R 4 is methyl
  • R 5 is halogen, C 1-3 haloalkyl or C 3-6 cycloalkyl.
  • R 5 is fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl, trifluoromethyl , cyclopropyl or cyclobutyl.
  • R 5 is fluorine, chlorine, trifluoromethyl or cyclopropyl.
  • Y 1 is O or NH.
  • Y1 is NH
  • R 1 and R 2 each occurrence are independently hydrogen, halogen or C 1-3 alkyl.
  • R 1 and R 2 each time they appear are independently hydrogen, methyl, ethyl, n-propyl, isopropyl , fluorine, chlorine or bromine.
  • each occurrence of R 1 and R 2 is independently hydrogen, methyl or fluorine.
  • R 3 is a 3-9-membered heterocyclyl group or -C(O)-3-9-membered heterocyclyl group, and the heterocyclic group
  • the cyclic group contains 1 or 2 heteroatoms each independently selected from O and N; the 3-9-membered heterocyclyl or -C(O)-3-9-membered heterocyclyl is optionally replaced by one or more heteroatoms each independently Substitutions independently selected from hydroxyl, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine, 3-6 membered heterocyclyl and methyl or ethyl substituted 3-6 membered heterocyclyl Substituted with a heterocyclyl group, the heterocyclyl group contains 1 or 2 heteroatoms each independently selected from O and N.
  • R 3 is a 4-membered monoheterocyclyl group, a 5-membered monoheterocyclyl group, a 6-membered monoheterocyclyl group, or a 7-membered bridged heterocyclyl group.
  • Cyclic group 8-membered bridged heterocyclyl, 7-membered spiroheterocyclyl, 8-membered spiroheterocyclyl, 9-membered spiroheterocyclyl, -C(O)-6-membered monoheterocyclyl, -C(O)- 7-membered bridged heterocyclyl or -C(O)-7-membered spiroheterocyclyl, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from O and N; the 4-membered monoheterocyclyl , 5-membered monoheterocyclyl, 6-membered monoheterocyclyl, 7-membered bridged heterocyclyl, 8-membered bridged heterocyclyl, 7-membered spiroheterocyclyl, 8-membered spiroheterocyclyl, 9-membered spiroheterocyclyl,
  • R 3 is Represents the R 3 connection location.
  • each occurrence of R 4 is independently hydrogen.
  • R 5 is halogen, C 1-3 haloalkyl or C 3-6 cycloalkyl.
  • R 5 is fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl or cyclobutyl.
  • R 5 is chloro, trifluoromethyl or cyclopropyl.
  • the present invention also provides compounds represented by formula (I), or their stereoisomers, tautomers or mixtures, or their pharmaceutically acceptable salts:
  • X 1 , X 2 , X 3 and X 4 are independently CH or N;
  • Y 1 , Y 2 and Y 3 are independently O, S or N R Y ; each occurrence of R Y is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne base, C 1-6 alkoxy group, C 1-6 alkylthio group, C 3-8 cycloalkyl group or C 3-8 heterocyclyl group, the heterocyclyl group contains 1 or 2 groups each independently selected from S , O and N heteroatoms; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl or heterocyclyl groups are optionally one or more independently selected from deuterium, halogen, The substituents of oxo, cyano, hydroxy, nitro, amino, C 1-6 alkyl, phenyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy replace;
  • R 1 and R 2 are independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 Alkylthio, C 1-6 hydroxyalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl or C 3-8 heterocyclyl,
  • the heterocyclyl group contains 1 or 2 heteroatoms each independently selected from S, O and N; the alkyl group, alkenyl group, alkynyl group, alkoxy group, alkylthio group, hydroxyalkyl group, cycloalkyl group
  • the heterocyclic group is optionally composed of one or more independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro, amino, C 1-6 alkyl, phenyl, C 1-6 alkoxy Substituted with substituents of base, C 1-6 haloalky
  • R 3 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-8 cycloalkyl, C 3 -8 cycloalkenyl, C 3-12 heterocyclyl, -C 1-3 alkylene -C 3-8 cycloalkyl, -C 1-3 alkylene -C 3-8 cycloalkenyl or -C 1-3 alkylene-C 3-12 heterocyclyl, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N; the alkyl, alkenyl, alkynyl, Alkoxy, alkylthio, cycloalkyl, cycloalkenyl or heterocyclyl is optionally selected from one or more groups independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 al
  • R 4 and R 5 are independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 haloalkyl;
  • n1 is 2, 3, 4 or 5;
  • n2 is 1 or 2; when n2 is 1, ring A is a 5-6 membered heteroaryl group; when n2 is 2, ring A is a 5-6 membered heteroaryl group or ring A does not exist.
  • X 1 , X 2 , X 3 and X 4 are all N.
  • X 2 is CH, and X 1 , X 3 and X 4 are all N.
  • X 1 and X 2 are both CH, and X 3 and X 4 are both N.
  • X 1 , X 2 and X 4 are all CH, and X 3 is N.
  • Y 2 is O or S
  • Y 1 and Y 3 are each independently N R Y .
  • Y 2 is O
  • Y 1 and Y 3 are each independently NRY .
  • Y 1 is O or S
  • Y 2 and Y 3 are each independently N R Y .
  • Y 1 is O
  • Y 2 and Y 3 are each independently N R Y .
  • each occurrence of R Y is independently hydrogen, C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-3 alkoxy , C 1-3 alkylthio group, C 3-8 cycloalkyl group or C 3-8 heterocyclyl group, the heterocyclyl group contains 1 or 2 heteroatoms each independently selected from S, O and N; the The alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl or heterocyclic group is optionally selected from one or more groups independently selected from deuterium, halogen, oxo group, cyano group, hydroxyl group, Substituted with nitro and amino substituents.
  • each occurrence of R Y is independently hydrogen, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, methoxy base, ethoxy, methylthio, ethylthio, cyclopropyl, cyclohexyl, propylene oxide or butyl oxide; the methyl, ethyl, propyl, isopropyl, ethylene group, propenyl, ethynyl, propynyl, methoxy, ethoxy, methylthio, ethylthio, cyclopropyl, cyclohexyl, propylene oxide or butylene oxide, optionally Substituted with one or more substituents each independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro and amino.
  • each occurrence of R Y is independently hydrogen.
  • each occurrence of R 1 and R 2 is independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, nitro, amino, C 1-6 alkyl, C 2 -6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 hydroxyalkyl or C 3-8 cycloalkyl; the alkyl, alkenyl Alkyl, alkynyl, alkoxy, alkylthio, hydroxyalkyl or cycloalkyl is optionally selected from one or more groups independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro, amino, Substituted with substituents of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy.
  • each occurrence of R 1 and R 2 is independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, nitro, amino, C 1-3 alkyl, C 1 -3 alkoxy, C 1-3 alkylthio, C 1-3 hydroxyalkyl or C 3-6 cycloalkyl; the alkyl, alkoxy, alkylthio, hydroxyalkyl or cycloalkyl optionally one or more independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro, amino, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl group and C 1-3 haloalkoxy substituents.
  • each occurrence of R 1 and R 2 is independently hydrogen, deuterium, halogen, cyanide. group, hydroxyl, mercapto, amino, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 hydroxyalkyl or C 3-6 cycloalkyl; the alkyl group, alkoxy, alkylthio, hydroxyalkyl or cycloalkyl is optionally substituted by one or more substituents each independently selected from deuterium, halogen, cyano, hydroxyl, amino and C 1-3 alkyl. replace.
  • each occurrence of R 1 and R 2 is independently hydrogen, deuterium, cyano, hydroxyl, mercapto, amino, methyl, ethyl, n-propyl, isopropyl, Cyclopropyl, cyclobutyl, methoxy, ethoxy, -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -CH 2 CH 2 OCH 3 , fluorine, chlorine, bromine, monofluoromethyl, difluoromethyl Fluoromethyl or trifluoromethyl.
  • each occurrence of R 3 is independently C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 3-8 cycloalkyl , C 3-8 cycloalkenyl, C 3-12 heterocyclyl, -C 1-3 alkylene-C 3-8 cycloalkyl, -C 1-3 alkylene-C 3-8 cycloalkenyl Or -C 1-3 alkylene-C 3-12 heterocyclyl, the heterocyclyl contains 1 or 2 heteroatoms each independently selected from S, O and N; the alkyl, alkoxy , alkylthio, cycloalkyl, cycloalkenyl or heterocyclyl optionally be one or more independently selected from deuterium, halogen, oxo, cyano, hydroxyl, nitro, amino, C 1-6 Alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6
  • each occurrence of R 3 is independently C 1-4 alkyl, C 3-8 cycloalkyl, C 3-9 heterocyclyl, -C 1-2 alkylene -C 3-8 cycloalkyl or -C 1-2 alkylene-C 3-9 heterocyclyl, the heterocyclyl containing 1 or 2 heteroatoms each independently selected from S, O and N ;
  • the alkyl, cycloalkyl or heterocyclyl is optionally one or more independently selected from deuterium, halogen, cyano, hydroxyl, nitro, amino, C 1-3 alkyl, C 1-3 Alkoxy, C 1-3 alkylthio, C 1-3 haloalkyl, -C 1-3 alkyl-OC 1-3 alkyl and C 3-8 heterocyclyl substituents, the heterocyclic
  • the cyclic group contains 1 or 2 heteroatoms each independently selected from S, O and N.
  • each occurrence of R 3 is independently Represents the R 3 connection location.
  • each occurrence of R 4 and R 5 is independently hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio group or C 1-3 haloalkyl group.
  • each occurrence of R 4 and R 5 is independently hydrogen, deuterium, halogen, C 1-3 Alkyl or C 1-3 haloalkyl.
  • each occurrence of R 4 is independently hydrogen, deuterium, or methyl.
  • each occurrence of R 5 is independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl, monofluoromethyl, difluoromethyl or trifluoromethyl.
  • Ring A is pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or s-triazinyl.
  • Ring A is pyrrolyl, pyrazolyl or imidazolyl.
  • Ring A is ** represents the fusion site.
  • Ring A is absent.
  • the present invention also provides a compound represented by formula (IA) or formula (IB), or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt:
  • each substituent is as defined in formula (I).
  • the present invention also provides a compound represented by formula (II-A) or formula (II-B), or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable of salt:
  • each substituent is as defined in formula (I).
  • the present invention also provides a compound represented by formula (III), or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt:
  • each substituent is as defined in formula (I).
  • the present invention also provides a compound represented by formula (IV), or its stereoisomer, tautomer or mixture, or its pharmaceutically acceptable salt:
  • each substituent is as defined in formula (I).
  • the compounds in the present invention are selected from:
  • the present invention provides a compound represented by formula (I) or formula (K), or a stereoisomer, tautomer or mixture thereof, or a pharmaceutically acceptable salt thereof Preparation.
  • the preparation methods include but are not limited to the following methods:
  • the intermediate (C) is obtained by substitution reaction between (A1) and (B1) or (A2) and (B2), and the intermediate (C) is obtained by intramolecular Buchwald-Hartwig coupling reaction, such as formula (I) or formula ( K) The compound shown;
  • Y 2' is -OH, -SH or -NHR Y ;
  • LG a is a leaving group, preferably Cl, Br, I or OTf, OMs;
  • LG b is a leaving group, preferably Cl, Br, I or OTf, OMs;
  • Y 3' is -OH or -SH;
  • Y 3 is O or S; other substituents are as defined above.
  • the present invention also provides a method for preparing compounds represented by formula (I) or formula (K), or their stereoisomers, tautomers or mixtures thereof, or their pharmaceutically acceptable salts Intermediate (C):
  • LG b is Cl, Br, I, OTf or OMs; Y 3' is -OH or -SH; other substituents are as defined in formula (I) or formula (K).
  • the intermediate (C') is obtained by substitution reaction between (A1) and (B1') or (A2) and (B2'), the intermediate (D) is obtained by reduction reaction of (C'), and (D) is obtained through the molecule
  • the compound represented by formula (I) or formula (K) is obtained by internal Buchwald-Hartwig coupling reaction;
  • Y 2' is -OH, -SH or -NHR Y ;
  • LG a is a leaving group, preferably Cl, Br, I or OTf, OMs;
  • LG b is a leaving group, preferably Cl, Br, I or OTf, Oms; other substituents are as defined above.
  • the present invention also provides an intermediate for preparing compounds of formula (I) or formula (K), or their stereoisomers, tautomers or mixtures thereof, or their pharmaceutically acceptable salts.
  • LG b is Cl, Br, I, OTf or OMs; other substituents are as defined in formula (I) or formula (K).
  • the present invention also provides a method for preparing the compound represented by formula (I) or formula (K), or its stereoisomers, tautomers or mixtures thereof, or its pharmaceutically acceptable salts.
  • LG b is Cl, Br, I, OTf or OMs; other substituents are as defined in formula (I) or formula (K).
  • the present invention provides a pharmaceutical composition
  • a compound of the present invention especially a compound represented by formula (K) in the first aspect, any one of formula (K1) to formula (K11)
  • the present invention also provides a pharmaceutical composition, which contains the compound of the present invention, or its stereoisomer, tautomer or mixture thereof, or its pharmaceutically acceptable salt, and a pharmaceutically acceptable salt thereof. Acceptable excipients.
  • the present invention provides compounds of the present invention (especially compounds represented by formula (K) in the first aspect, compounds represented by any one of formula (K1) to formula (K11), such as formula ( Compounds represented by I), such as compounds represented by formula (I-A), formula (I-B), formula (II-A), formula (II-B), formula (III) or formula (IV) and specific compounds), or the use of its stereoisomers, tautomers or mixtures thereof, or its pharmaceutically acceptable salts in the preparation of medicaments for the treatment or prevention of diseases mediated by LRRK2 kinase.
  • the present invention also provides the compounds of the present invention, or their stereoisomers, tautomers or mixtures thereof, or their pharmaceutically acceptable salts for the preparation of compounds for the treatment or prevention of Parkinson's disease (PD). ) in medicines.
  • PD Parkinson's disease
  • the present invention provides compounds of the present invention (especially compounds represented by formula (K) in the first aspect, compounds represented by any one of formula (K1) to formula (K11), such as formula ( Compounds represented by I), such as compounds represented by formula (I-A), formula (I-B), formula (II-A), formula (II-B), formula (III) or formula (IV) and specific compounds), or its stereoisomers, tautomers or mixtures thereof, or its pharmaceutically acceptable salts, for use as a medicament, in particular for the treatment or prevention of diseases mediated by LRRK2 kinase.
  • the present invention also provides the compounds of the present invention, or their stereoisomers, tautomers or mixtures thereof, or their pharmaceutically acceptable salts, which are used for the treatment or prevention of Parkinson's disease.
  • the present invention provides a method for treating or preventing diseases mediated by LRRK2 kinase, which includes the following steps: adding a therapeutically or preventively effective amount of a compound of the present invention (especially the formula of the first aspect)
  • a compound of the present invention especially the formula of the first aspect
  • the salt received is administered to individuals in need of it.
  • the present invention also provides a method for treating or preventing Parkinson's disease, which includes the following steps: adding a therapeutically or preventively effective amount of a compound of the present invention, or a stereoisomer or tautomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, administered to an individual in need thereof.
  • the present invention designs a class of compounds with novel structures and provides a new direction for the development of LRRK2 inhibitor drugs.
  • In vitro enzyme and cell inhibitory activity studies show that these compounds have strong inhibitory effects, so they can be used as promising compounds for the treatment of LRRK2-mediated diseases.
  • the present invention studies a specific synthesis method, which has simple process, convenient operation, and is conducive to large-scale industrial production and application.
  • oxo means that two hydrogen atoms in the same substitution position are replaced by the same oxygen atom to form a double bond.
  • alkyl refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms (i.e., C 1 to 10 Alkyl), further preferably contains 1-8 carbon atoms (C 1-8 alkyl), more preferably contains 1-6 carbon atoms (i.e. C 1-6 alkyl), such as "C 1-6 alkyl” It means that the group is an alkyl group, and the number of carbon atoms on the carbon chain is between 1 and 6 (specifically 1, 2, 3, 4, 5 or 6).
  • Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1- Dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.
  • alkenyl refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond.
  • the alkenyl group may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C 2-10 alkenyl), further preferably 2-8 carbon atoms (C 2-8 alkenyl), and more preferably 2-8 carbon atoms (C 2-8 alkenyl).
  • 2-6 carbon atoms i.e. C 2-6 alkenyl
  • 2-5 carbon atoms i.e. C 2-5 alkenyl
  • 2-4 carbon atoms i.e.
  • C 2-4 alkenyl 2- 3 carbon atoms (i.e. C 2-3 alkenyl), 2 carbon atoms (i.e. C 2 alkenyl), for example "C 2-6 alkenyl” means that the group is alkenyl, and the carbon chain The number of carbon atoms is between 2 and 6 (specifically 2, 3, 4, 5 or 6).
  • alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
  • alkynyl refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond.
  • the alkynyl group may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C 2-10 alkynyl group), further preferably 2-8 carbon atoms (C 2-8 alkynyl group), and more preferably 2-8 carbon atoms (C 2-8 alkynyl group).
  • 2-6 carbon atoms i.e. C 2-6 alkynyl
  • 2-5 carbon atoms i.e. C 2-5 alkynyl
  • 2-4 carbon atoms i.e.
  • C 2-4 alkynyl 2- 3 carbon atoms (i.e. C 2-3 alkynyl), 2 carbon atoms (i.e. C 2 alkynyl), for example "C 2-6 alkynyl” means that the group is an alkynyl group, and the carbon chain The number of carbon atoms is between 2 and 6 (specifically 2, 3, 4, 5 or 6).
  • alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and the like.
  • cycloalkyl refers to a monocyclic or polycyclic saturated aliphatic hydrocarbon group with a specific number of carbon atoms, preferably containing 3-12 carbon atoms (i.e., C 3-12 cycloalkyl), More preferably, it contains 3-10 carbon atoms (C 3-10 cycloalkyl), further preferably 3-6 carbon atoms (C 3-6 cycloalkyl), 4-6 carbon atoms (C 4-6 cycloalkyl) base), 5-6 carbon atoms (C 5-6 cycloalkyl).
  • Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.
  • alkoxy refers to -O-alkyl, which is as defined above, that is, containing 1-20 carbon atoms, preferably 1-10 carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6).
  • Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy Oxygen, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2 , 2-dimethylpropoxy, 1-ethylpropoxy, etc.
  • alkylthio means replacing -O- with -S- in the above definition of "alkoxy”.
  • halogen or “halo” means fluorine, chlorine, bromine, or iodine.
  • haloalkyl means an alkyl group as defined above in which one, two or more hydrogen atoms or all of the hydrogen atoms are replaced by halogen.
  • Representative examples of haloalkyl groups include CCl 3 , CF 3 , CHCl 2 , CH 2 Cl, CH 2 Br, CH 2 I, CH 2 CF 3 , CF 2 CF 3 , and the like.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic substituent, which is a non-aromatic structure, and also includes polycyclic rings in which some of the rings are aromatic. Structure, containing 3-20 ring atoms, of which 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C, preferably containing 3-12 ring atoms, further preferably Contains 3-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms.
  • the number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e. 1, 2 or 3).
  • monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, tetrahydropyranyl, morpholinyl, and the like.
  • Polycyclic heterocyclyl groups include spirocyclic, fused cyclic and bridged cyclic heterocyclyl groups.
  • fused ring refers to a non-aromatic saturated or partially unsaturated bicyclic or polycyclic system formed by two or more cyclic structures sharing two adjacent atoms with each other, including Condensed carbocyclyl and fused heterocyclyl, the "fused heterocyclyl” optionally containing one or more heteroatoms independently selected from oxygen, nitrogen and sulfur.
  • spirocycloalkyl refers to a saturated ring system with a specified number of carbon atoms formed by carbon atoms and hydrogen atoms sharing only one ring carbon atom. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • Non-limiting examples of single spirocyclic groups are single spirocyclic rings of 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered and 5-membered/6-membered rings. base, where the count of each ring includes a spiro atom.
  • Non-limiting examples of single spirocyclyl groups include: wait.
  • heterospirocyclyl and “spiroheterocyclyl” refer to a ring with a specific number of carbon atoms and heteroatoms formed by two or more saturated rings sharing one ring carbon atom. structure.
  • the heteroatoms in the spiroheterocyclyl group are preferably 1-4, more preferably 1-3 (i.e. 1, 2 or 3), and the heteroatoms are independently selected from N, O and S. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • Non-limiting examples of spiroheterocyclyl groups are spiroheterocycles of 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered and 5-membered/6-membered rings. base, where the count of each ring includes a spiro atom.
  • Non-limiting examples of heteromonospiryl include: wait.
  • bridged cyclic group refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms that are not directly connected, and it may contain one or more double bonds, but No ring has a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • heterobridged cyclyl and “bridged heterocyclyl” refer to polycyclic heterocyclic groups with 5 to 14 members, and any two rings share two ring atoms that are not directly connected. Contains one or more double bonds, but no ring has a fully conjugated ⁇ electron system.
  • the number of heteroatoms in the bridged heterocyclyl group is one or more, preferably 1-4, more preferably 1-3 (i.e. 1, 2 or 3), and the heteroatoms are independently selected from N, O or S (O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon.
  • the bridged heterocyclic group is preferably 6 to 14 members, more preferably 7 to 10 members.
  • bridged heterocyclyl groups preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged heterocyclyl groups include:
  • aryl means a group containing 6 to 16 carbon atoms, or 6 to 14 carbon atoms, or 6 to 12 carbon atoms. or a monocyclic, bicyclic or tricyclic aromatic carbocyclic ring system of 6 to 10 carbon atoms, preferably 6 to 10 carbon atoms.
  • the term “aryl” can be used interchangeably with the term “aromatic ring group”. Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, or pyrenyl, and the like.
  • heteroaryl and “aryl hetero” represent aromatic monomers containing a 5-12-membered structure, or preferably a 5-10-membered structure, a 5-8-membered structure, and more preferably a 5-6-membered structure.
  • Ring or polycyclic ring system in which 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, the number of heteroatoms is preferably 1 1, 2 or 3.
  • heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl , tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazine, phthalazinyl, quinolyl, isoquinolinyl, pyridinyl, purinyl, indyl Indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrole Para[2,3-b]pyridyl,
  • the term “pharmaceutically acceptable salt”, “pharmaceutically acceptable salt” or “pharmaceutically acceptable salt” means salts that are suitable within the scope of reasonable medical judgment for contact with tissue of mammals, especially humans, without undue Toxicity, irritation, allergic reactions, etc. and are commensurate with a reasonable benefit/risk ratio.
  • the salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base or free acid with a suitable reagent.
  • solvate and “solvate” mean the physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain circumstances, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, solvates will be able to be separated.
  • the solvent molecules in a solvate may exist in regular and/or disordered arrangements.
  • Solvates may contain stoichiometric or non-stoichiometric amounts of solvent molecules.
  • isotope-labeled analogs refer to molecules in the compounds of the invention that are isotopically labeled, thereby providing isotopes that may have improved pharmacological activity Marked analogs.
  • the isotopes commonly used as isotope labels are: hydrogen isotopes, 2 H and 3 H; carbon isotopes: 11 C, 13 C and 14 C; chlorine isotopes: 35 Cl and 37 Cl; fluorine isotopes: 18 F; iodine isotopes: 123 I and 125 I; nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotope 35 S.
  • isotopically labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues.
  • deuterium ( 2 H) and carbon ( 13 C) are more widely used because they are easy to label and detect.
  • Isotopically labeled compounds generally start from labeled starting materials and are synthesized using known synthetic techniques as for non-isotopically labeled compounds.
  • the compounds of the present invention include isotopic derivatives (such as deuterated compounds) thereof.
  • stereoisomer refers to compounds that have the same chemical structure but different arrangements of atoms or groups in space.
  • Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography. method and/or fractional crystallization method.
  • tautomers refers to structural isomers with different energies that are interconvertible through a low energy barrier. If tautomerism is possible (eg in solution), a chemical equilibrium of tautomers can be achieved.
  • proton tautomers also known as proton transfer tautomers
  • proton migration tautomers include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization.
  • Valence tautomers involve interconversions through the reorganization of some of the bonding electrons.
  • the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, those containing asymmetric centers R, S configuration, double bond (Z), (E) isomers, and (Z), (E) conformational isomers. Therefore, individual stereochemical isomers or mixtures of enantiomers, diastereomers, or geometric isomers (or conformational isomers) of the compounds of the present invention are within the scope of the present invention.
  • cocrystal is used to describe a situation in which neutral molecular components are present in a crystalline compound in a well-defined stoichiometric ratio.
  • the preparation of pharmaceutical cocrystals enables changes to the crystalline form of the active pharmaceutical ingredient, which in turn can alter its physicochemical properties without compromising its desired biological activity (see Pharmaceutical Salts and Co-crystals, J. Wouters and L.Quere (eds., RSC Publishing, 2012).
  • the compounds described in this invention include co-crystals thereof.
  • polymorph refers to the different arrangements of chemical drug molecules, generally represented by the existence of drug raw materials in a solid state.
  • a drug can exist in multiple crystalline material states. Different crystalline forms of the same drug may have different dissolution and absorption in the body, which will affect the dissolution and release of the preparation.
  • the compounds described herein include polymorphic forms thereof.
  • the term "metabolite” refers to the product obtained by metabolism of a specific compound or its salt in the body.
  • the metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assays as described herein. Such products can be obtained by administering compounds through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, etc.
  • the invention includes metabolites of compounds, including metabolites produced by contacting a compound of the invention with a mammal for a period of time sufficient to do so.
  • the compounds described herein include metabolites thereof.
  • prodrug refers to a drug that is converted in the body to the parent drug.
  • Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, they are bioavailable via oral administration, whereas the parent body is not.
  • Prodrugs also have increased solubility in pharmaceutical compositions compared to the parent drug.
  • An example of a prodrug, but not limited thereto, may be any compound of the invention administered as an ester ("prodrug") to facilitate delivery across cell membranes, where water solubility is detrimental to mobility, but once inside Intracellular water solubility is beneficial and is subsequently metabolically hydrolyzed to carboxylic acids, the active entities.
  • Another example of a prodrug may be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to reveal the active moiety.
  • the compounds of the present invention include prodrugs thereof.
  • the term "optionally substituted” means that the hydrogen at the substitutable position of the group is unsubstituted or substituted by one or more substituents, which substituents are preferably selected from the group consisting of: Group: halogen, hydroxyl, mercapto, cyano, nitro, amino, azide, oxo, carboxyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1- 6 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C 6-14 aryl and 5-10 membered heteroaromatic ring, wherein The following C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkylsulfonyl, 3- The 10-membered heterocycloalkyl
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid mass spectrometry (LC-MS) or/and liquid chromatography (HPLC).
  • NMR nuclear magnetic resonance
  • LC-MS liquid mass spectrometry
  • HPLC liquid chromatography
  • Preparative HPLC conditions one (ammonia as additive): Instrument: Waters; Pump: 2545; Detector: 2489; Wavelength: 214nm and 254nm; Column model: Welch Xtimate C18, 21.2*250mm, 10 ⁇ m; Mobile phase: A: 0.1% ammonia ,B: acetonitrile; running time: 15min; flow rate: 25ml/min.
  • Preparative HPLC condition two (formic acid as additive): Instrument: Waters; Pump: 2545; Detector: 2489; Wavelength: 214nm and 254nm; Column model: Welch Ultimate AQ-C18, 21.2*250mm, 10 ⁇ m; Mobile phase: A: 0.1 % formic acid, B: acetonitrile; running time: 15min; flow rate: 25ml/min.
  • Preparative HPLC condition three (trifluoroacetic acid as additive): Instrument: Waters; Pump: 2545; Detector: 2489; Wavelength: 214nm and 254nm; Column model: Welch Ultimate AQ-C18, 21.2*250mm, 10 ⁇ m; Mobile phase: A :0.1% trifluoroacetic acid, B: acetonitrile; running time: 15min; flow rate: 25ml/min.
  • the starting materials in the embodiments of the present invention are known and can be purchased on the market, or can be used or in accordance with the present invention. synthesized by methods known in the art.
  • EDTA ethylenediaminetetraacetic acid
  • HMDSLi Lithium bis(trimethylsilyl)amide (or lithium hexamethyldisilylamide)
  • NCS 1-chloropyrrolidine-2,5-dione (or N-chlorosuccinimide)
  • Xphos Dicyclohexyl (2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (or 2-dicyclohexylphosphine-2',4' ,6'-triisopropylbiphenyl)
  • DIPEA Diisopropylethylamine
  • Step 2 5-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole and 3-methyl-4-nitro-1-(tetrahydro Preparation of mixtures of -2H-pyran-3-yl)-1H-pyrazoles
  • Tetrahydro-2H-pyran-3-ylmethanesulfonate (550mg, 3.05mmol, 1.0eq) and 3-methyl-4-nitro-1H-pyrazole (1.16g, 9.15mmol, 3.0eq) Dissolve in DMF (15 mL), add potassium carbonate (640 mg, 4.63 mmol, 1.52 eq) under nitrogen protection at 90°C, and stir for 16 hours.
  • LC-MS monitored the reaction for completion. Add water to the reaction solution to quench, extract with dichloromethane (3 x 50mL), combine the organic phases, directly concentrate the organic phase and mix the sample, and separate and purify by column chromatography to obtain the target product (560 mg, yield 86.89%).
  • Tetrahydrofuran (3 mL) solution was stirred at 15°C for 2 hours under nitrogen protection.
  • LC-MS monitored the reaction for completion.
  • Saturated ammonium chloride solution was added to the reaction solution to quench, and the mixture was extracted with dichloromethane (3 x 20 mL). The organic phases were combined, concentrated, and separated and purified by column chromatography to obtain the target product (200 mg, yield 39.14%).
  • Step 6 3-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4 Preparation of -yl)amino)propan-1-ol
  • Step 7 2,5-dichloro-N-(3-((3-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-5) Preparation of -yl)oxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 8 N-(3-((4-amino-3-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-5-yl)oxy)propyl Preparation of )-2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 9 3-chloro-12-methyl-10-(tetrahydro-2H-pyran-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 5,6,7,8,10,13-hexahydro-1H-4,14-(nitrogen bridge)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[ Preparation of 4,6,10]triazacyclotridecane
  • Step 10 3-chloro-12-methyl-10-(tetrahydro-2H-pyran-3-yl)-5,6,7,8,10,13-hexahydro-1H-4,14- Preparation of (nitrogen-bridged)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane
  • Step 1 5-methyl-4-nitro-1-(oxetan-3-yl)pyrazole and 3-methyl-4-nitro-1-(oxetan-3-yl) ) Preparation of mixtures of pyrazoles
  • Step 3 2,5-Dichloro-N-(3-((3-methyl-4-nitro-1-(oxetan-3-yl)-1H-pyrazol-5-yl) Preparation of oxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 4 N-(3-((4-amino-3-methyl-1-(oxetan-3-yl)-1H-pyrazol-5-yl)oxy)propyl)-2 , Preparation of 5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 5 3-chloro-12-methyl-10-(oxetan-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-5,6 ,7,8,10,13-hexahydro-1H-4,14-(nitrogen bridge)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6 ,10]
  • Step 6 3-chloro-12-methyl-10-(oxetan-3-yl)-5,6,7,8,10,13-hexahydro-1H-4,14-(nitrogen bridge )
  • reaction solution was concentrated to obtain a crude product, tetrahydrofuran (2 mL) was added to dissolve, ammonia water (1 mL) was added, and the mixture was stirred at 25°C for 1 hour under nitrogen protection. LC-MS monitored the reaction to be complete.
  • the reaction solution was concentrated, dissolved in methanol and filtered. The filtrate was purified by preparative high-performance liquid phase separation to obtain the target product (1.44 mg, yield 9.58%).
  • Step 7 2,5-dichloro-N-(3-((5-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-3) Preparation of -yl)oxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 8 N-(3-((4-amino-5-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-3-yl)oxy)propyl Preparation of )-2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 9 3-chloro-12-methyl-11-(tetrahydro-2H-pyran-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 5,6,7,8,11,13-hexahydro-1H-4,14-(nitrogen bridge)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[ Preparation of 4,6,10]triazacyclotridecane
  • the temperature was raised to 90°C for 3 hours in a nitrogen atmosphere.
  • LC-MS monitored the reaction to be complete. Filter through diatomaceous earth, concentrate the filtrate, and separate and purify using a preparation plate to obtain the target product (80 mg, yield 45.58%).
  • Step 10 3-chloro-12-methyl-11-(tetrahydro-2H-pyran-3-yl)-5,6,7,8,11,13-hexahydro-1H-4,14- Preparation of (nitrogen-bridged)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane
  • reaction solution was concentrated, tetrahydrofuran (3 mL) was added to redissolve, and ammonia water (2 mL) was added to the reaction system. Continue the reaction for 2 hours at room temperature. LC-MS monitored the reaction to be complete.
  • the reaction solution was concentrated, 4 mL of methanol was added, and the target product (8 mg, yield 13.23%) was obtained by separation and purification by preparing high-performance liquid phase.
  • Step 1 3-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole and 5-methyl-4-nitro-1-(tetrahydro Synthesis of mixtures of -2H-pyran-2-yl)-1H-pyrazoles
  • Step 3 2,5-Dichloro-N-(3-((3-methyl-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5) Synthesis of -yl)oxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 4 N-(3-((4-amino-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)oxy)propyl Synthesis of )-2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 5 3-chloro-12-methyl-10-(tetrahydro-2H-pyran-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)- 5,6,7,8,10,13-hexahydro-1H-4,14-(nitrogen bridge)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[ Synthesis of 4,6,10]triazacyclotridecane
  • Step 6 3-chloro-12-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8,10,13-hexahydro-1H Synthesis of -4,14-(nitrogen-bridged)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane
  • Step 7 3-chloro-12-methyl-11-(tetrahydrofuran-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7, 8,11,13-hexahydro-1H-4,14-(nitrogen bridge)pyrazolo[3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10] Synthesis of Triazacyclotridecane
  • Step 8 3-chloro-12-methyl-11-(tetrahydrofuran-3-yl)-5,6,7,8,11,13-hexahydro-1H-4,14-(nitrogen-bridged)pyrazole Synthesis of [3,4-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane
  • Example 6-65 was prepared; referring to the preparation methods of Examples 194, 196 and 197, the compound of Example 66-129 was prepared
  • Step 1 Preparation of tert-butyl 2-(6-chloro-5-nitropyridin-2-yl)-2-cyanoacetate
  • Step 2 Preparation of tert-butyl 2-(6-chloro-5-nitropyridin-2-yl)-2-cyanopropionate
  • the reaction solution is concentrated under reduced pressure, water (100 mL) and ethyl acetate (125 mL) are added to the crude product and stirred for 10 minutes; after 10 minutes, let stand for liquid separation, and the aqueous phase is extracted with ethyl acetate (20 mL) 2 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and separated and purified by column chromatography to obtain the target product (4.82g, yield 90.4%).
  • Step 6 2-(5-amino-6-(3-((2,5-dichloropyrimidin-4-yl)amino)propoxy)pyridin-2-yl)-2-methylpropionitrile preparation
  • Step 7 2-(5-chloro-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge)pyrido[2,3-b][1]oxa[4,6 ,10] Preparation of triazacyclotridecane-13-yl)-2-methylpropionitrile
  • Example 130 the compounds of Examples 131-144 and 146-193 were prepared; referring to the preparation method of Example 194, the compound of Example 145 was prepared.
  • Step 3 3-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4 Preparation of -yl)amino)propan-1-ol
  • Step 4 2,5-dichloro-N-(3-((6-chloro-3-nitropyridin-2-yl)oxy)propyl)-7-((2-(trimethylsilane) Preparation of (ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 5 N-(3-((6-(2-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-nitropyridin-2-yl)oxygen methyl)propyl)-2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 5 N-(3-((6-(2-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-nitropyridin-2-yl)oxygen methyl)propyl)-2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 6 N-(3-((3-amino-6-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)pyridin-2-yl)oxy)propyl Preparation of )-2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 7 11-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-chloro-1-((2-(trimethylsilyl)ethoxy) Methyl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa Preparation of [4,6,10]triazacyclotridecane
  • Step 8 11-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-chloro-1,5,6,7,8,14-hexahydro-4, Preparation of 15-(nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane
  • 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (10g, 53.19mmol, 1.0eq) was dissolved in dichloromethane (200mL) under nitrogen, and then N was slowly added at 0°C. - Iodosuccinimide (19.15g, 85.1mmol, 1.6eq), the reaction mixture was stirred at room temperature for 16 hours. LC-MS monitored the reaction to be complete. Filter, wash the filter cake with distilled water, and dry under reduced pressure to obtain the target product (16 g, yield 96%).
  • Step 4 3-((2-chloro-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3 Preparation of -d]pyrimidin-4-yl)amino)propan-1-ol
  • Step 5 Preparation of 6-methoxy-2-azaspiro[3.3]hept-2-carboxylic acid tert-butyl ester
  • 6-Hydroxy-2-azaspiro[3.3]hept-2-carboxylic acid tert-butyl ester (6g, 28.13mmol) was dissolved in tetrahydrofuran (5mL), and sodium tert-butoxide (5.41g, 56.26mmol) was added at 0°C. ) and methyl iodide (5.99g, 42.19mmol), reacted at room temperature for 16 hours.
  • LC-MS monitored the reaction to be complete. Water (100 mL) was added to the reaction solution to quench, and the mixture was extracted with ethyl acetate (100 mL*3). The organic phases were combined and concentrated to obtain the crude target product (6 g, yield 93%).
  • Step 7 2-chloro-N-(3-((6-chloro-3-nitropyridin-2-yl)oxy)propyl)-5-(trifluoromethyl)-7-((2 Preparation of -(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • reaction solution was quenched by adding water (100 mL), extracted with ethyl acetate (100 mL*3), the organic phases were combined, concentrated, and separated and purified by column chromatography to obtain the target product (1.2 g, yield 43%).
  • Step 8 2-chloro-N-(3-((6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-nitropyridin-2-yl)oxy methyl)propyl)-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4 -Preparation of amines
  • Step 9 N-(3-((3-amino-6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)pyridin-2-yl]oxy)propyl) -2-Chloro-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4- Preparation of amines
  • Step 10 11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)) Ethoxy)methyl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)pyrido[2,3-b]pyrrolo[2,3-g][ Preparation of 1]oxa[4,6,10]triazacyclotridecane
  • Step 11 11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-(trifluoromethyl)-1,5,6,7,8,14- Preparation of hexahydro-4,15-(nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane
  • Step 3 2,5-Dichloro-N-(3-((6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-nitropyridine-2- Preparation of methyl)oxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 4 N-(3-((3-amino-6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)pyridin-2-yl)oxy)propyl) Preparation of -2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 5 3-chloro-11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl base)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[ Preparation of 4,6,10]triazacyclotridecane
  • Step 6 3-Chloro-11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-1,5,6,7,8,14-hexahydro-4,15 Preparation of -(Nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane
  • Example 198 Referring to the preparation method of Example 197, the compound of Example 198 was prepared
  • Step 1 Preparation of tert-butyl 3-((6-chloro-3-nitropyridin-2-yl)oxy)propyl)carbamate
  • Step 2 3-((3-nitro-6-(2-oxa-7-azaspiro[3.5]non-7-yl)pyridin-2-yl)oxy)propyl)carbamic acid tert.
  • Step 3 3-((3-nitro-6-(2-oxa-7-azaspiro[3.5]non-7-yl)pyridin-2-yl)oxy)propan-1-amine preparation
  • Step 4 2,5-dichloro-N-(3-((3-nitro-6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-2-yl) )oxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 5 N-(3-((3-amino-6-(2-oxa-7-azaspiro[3.5]non-7-yl)pyridin-2-yl)oxy)propyl)- Preparation of 2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 6 3-chloro-11-(2-oxa-7-azaspiro[3.5]non-7-yl)-1-((2-(trimethylsilyl)ethoxy)methyl )-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4 ,6,10]
  • Step 7 3-Chloro-11-(2-oxa-7-azaspiro[3.5]non-7-yl)-1,5,6,7,8,14-hexahydro-4,15- Preparation of (nitrogen-bridged)pyrido[2,3-b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane
  • the reaction solution is spin-dried, dissolved in 20 mL of ethyl acetate, washed with saturated brine, and the organic phase is spin-dried.
  • the crude product is separated and purified by Prep-HPLC to obtain the target compound (1.36 mg, yield 3%) .
  • the first step 5-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole and 3-methyl-4-nitro-1-(tetrahydro Preparation of mixtures of -2H-pyran-3-yl)-1H-pyrazoles
  • Hexachloroethane (5.04g, 21.3mmol, 3eq) was added and the reaction was carried out at room temperature under nitrogen protection for 2 hours.
  • LC-MS monitored the reaction to be complete.
  • Step 5 2,5-dichloro-N 4 -methyl-N 6 -(3-((3-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl) Synthesis of -1H-pyrazol-5-yl)oxy)propyl)pyrimidine-4,6-diamine
  • Step 6 N 4 -(3-((4-amino-3-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-5-yl)oxy)propanyl Synthesis of -2,5-dichloro-N 6 -methylpyrimidine-4,6-diamine
  • Step 7 8-Chloro-N,3-dimethyl-1-(tetrahydro-2H-pyran-3-yl)-1,4,10,11,12,13-hexahydro-5,9 Synthesis of -(Nitrogen-bridged)pyrazolo[3,4-b][1]oxa[4,6,10]triazacyclotridecane-7-amine
  • N 4 -(3-((4-amino-3-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-5-yl)oxy)propyl)- 2,5-Dichloro-N 6 -methylpyrimidine-4,6-diamine 50 mg, 0.12 mmol, 1 eq
  • tris(dibenzylideneacetone)dipalladium(0) 10.64 mg, 0.01 mmol, 0.1 eq)
  • dicyclohexyl[2',4',6'-tris(prop-2-yl)-[1,1'-biphenyl]-2-yl]phosphine 11.08 mg, 0.02 mmol, 0.2 eq
  • cesium carbonate 151.43 mg, 0.46 mmol, 4 eq
  • Step 5 2-bromo-5-chloro-N 4 -(3-((6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-nitropyridine- Preparation of 2-yl)oxy)propyl)-N 6 -methylpyrimidine-4,6-diamine
  • Step 6 N 4 -(3-((3-amino-6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)pyridin-2-yl)oxy)propyl Preparation of )-2-bromo-5-chloro-N 6 -methylpyrimidine-4,6-diamine
  • Step 1 2,5-Dichloro-N-(3-((6-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-3-nitropyridine-2- Preparation of base)oxy)propyl)pyrimidin-4-amine
  • reaction solution was quenched with water, concentrated, extracted with ethyl acetate (100mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and separated and purified by column chromatography to obtain the target product (1.2g, yield 49.6%).
  • Step 4 13-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-5-(trifluoromethyl)-7,8,9,10-tetrahydro-1H- Preparation of 2,6-(nitrogen-bridged)pyrido[2,3-b][1]oxa[4,6,10]triazacyclotridecane
  • the first step Preparation of: (3-(5-bromo-4-fluoro-2-nitrophenoxy)propyl)carbamic acid tert-butyl ester
  • Step 2 tert-butyl (3-(4-fluoro-5-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-2-nitrophenoxy)propyl) Preparation of urethane
  • Step 4 N-(3-(2-amino-4-fluoro-5-(6-methoxy-2-azaspiro[3.3]hept-2-yl)phenoxy)propyl)-2 , Preparation of 5-dichloropyrimidin-4-amine
  • Step 5 5-chloro-14-fluoro-13-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-7,8,9,10-tetrahydro-1H-2 , Preparation of 6-(nitrogen-bridged)benzo[b][1]oxa[4,6,10]triazacyclotridecane:
  • Example 354 Referring to the preparation method of Example 354 or 427, the compounds of Examples 428-430 were prepared.
  • the first step 5-methyl-4-nitro-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole and 3-methyl-4-nitro-1-(tetrahydro Preparation of mixtures of -2H-pyran-3-yl)-1H-pyrazoles
  • LC-MS monitored the reaction to be complete. Add 50 mL of ammonia chloride aqueous solution to the reaction solution, concentrate, add ethyl acetate (200 mL*3) for extraction, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and separate and purify by column chromatography to obtain the target product (1g , yield 57.33%).
  • Step 4 N-(3-((4-amino-3-methyl-1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-5-yl)oxy)propyl )-2-Chloro-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4 -Preparation of amines
  • Step 5 12-methyl-10-(tetrahydro-2H-pyran-3-yl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl))ethoxy )methyl)-5,6,7,8,10,13-hexahydro-1H-4,14-(nitrogen bridge)pyrazolo[3,4-b]pyrrolo[2,3-g][ Preparation of 1]oxa[4,6,10]triazacyclotridecane
  • Step 1 Preparation of methyl 2-methyl-2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propionate
  • N-(3-hydroxypropyl)carbamic acid tert-butyl ester (337.32mg, 1.93mmol, 1.1eq) in N,N-dimethylformamide (10ml, 100.0%), and then batch it under ice bath Add sodium hydride (60%, 210mg, 5.25mmol, 3.0eq), react in an ice bath under nitrogen protection for half an hour, and then add 2-(5-chloro-3-methyl-4-nitro-1H-pyrazole) -1-yl)-2-methylpropionitrile (400 mg, 1.75 mmol, 1.0 eq), after replacing nitrogen, reacted at 25°C for 16 hours.
  • Step 7 2-(5-(3-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl))-7H-pyrrolo[2,3 Preparation of -d]pyrimidin-4-yl)amino)propoxy)-3-methyl-4-nitro-1H-pyrazol-1-yl)-2-methylpropionitrile
  • Step 8 2-(4-amino-5-(3-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl))-7H-pyrrolo Preparation of [2,3-d]pyrimidin-4-yl)amino)propoxy)-3-methyl-1H-pyrazol-1-yl)-2-methylpropionitrile
  • Step 10 2-(3-chloro-12-methyl-1,5,6,7,8,13-hexahydro-10H-4,14-(nitrogen bridge)pyrazolo[3,4-b Preparation of ]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane-10-yl)-2-methylpropionitrile
  • Step 1 Preparation of tert-butyl 3-fluoro-4-(3-methyl-4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate
  • the aqueous phase is extracted with ethyl acetate.
  • Step 4 4-(5-chloro-3-methyl-4-nitro-1H-pyrazol-1-yl)-3-fluoro-1-(oxetan-3-yl)piperidine preparation
  • Example 439 or 446 the compound of Example 450 was prepared.
  • Step 1 Preparation of 2,5-dichloro-4-(3-((6-chloro-3-nitropyridin-2-yl)oxy)propoxy)pyrimidine:
  • Step 3 2-(3-((2,5-Dichloropyrimidin-4-yl)oxy)propoxy)-6-(6-methoxy-2-azaspiro[3.3]hept- Preparation of 2-yl)pyridin-3-amine:
  • Step 4 5-chloro-13-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-9,10-dihydro-1H,8H-2,6-(nitrogen bridge )
  • pyrido[2,3-b][1,10]dioxa[4,6]diazacyclotridecane
  • Step 1 Preparation of: (E)-N’-(dihydro-2H-pyran-3(4H)-ylidene)-4-methoxybenzenesulfonylhydrazide
  • Step 3 (3-(3-(2,5-dichloro-7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine Preparation of -4-yl)amino)propoxy)-4-nitrophenyl)boronic acid
  • Step 4 2,5-dichloro-N-(3-(2-nitro-5-(tetrahydro-2H-pyran-3-yl)phenoxy)propyl)-7-(2- Preparation of (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 5 N-(3-(2-amino-5-(tetrahydro-2H-pyran-3-yl)phenoxy)propyl)-2,5-dichloro-7-(2-( trimethylsilyl) Preparation of ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 6 3-chloro-11-(tetrahydro-2H-pyran-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5,6 ,7,8,14-hexahydro-4,15-(nitrogen-bridged)benzo[b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclohexane Preparation of alkanes
  • Step 7 3-Chloro-11-(tetrahydro-2H-pyran-3-yl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)benzo[ Preparation of b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotridecane
  • the reaction solution was concentrated, redissolved in tetrahydrofuran (3 mL), ammonia water (2 mL) was added, and the reaction was carried out at room temperature overnight. After the reaction was detected by LC-MS, the reaction solution was concentrated and separated and purified by Prep-HPLC to obtain the target compound (6.8 mg, yield 23%).
  • Step 2 2,5-dichloro-N-(3-(4-fluoro-5-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-2-nitrobenzene Preparation of oxy)propyl)-7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • N-(3-(5-bromo-4-fluoro-2-nitrophenoxy)propyl)-2,5-dichloro-7-(2-(trimethylsilyl)ethyl) Oxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.16 mmol, 1.0 eq), 6-methoxy-2-azaspiro[3.3]heptane Trifluoroacetate (36.63mg, 0.16mmol, 1.0eq), 1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)) (13.89 mg, 0.02mmol, 0.1eq), cesium carbonate (213.88mg, 0.66mmol, 4.0eq) was dissolved in 1,4-dioxane (4mL) and reacted at 100°C for 18 hours. After the reaction was detected by LC-MS, filter through diatomaceous
  • Step 3 N-(3-(2-amino-4-fluoro-5-(6-methoxy-2-azaspiro[3.3]hept-2-yl)phenoxy)propyl)-2 , Preparation of 5-dichloro-7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
  • Step 4 3-chloro-12-fluoro-11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-1-((2-(trimethylsilyl)ethyl)ethyl Oxy)methyl)-1,5,6,7,8,14-hexahydro-4,15-(nitrogen bridge)benzo[b]pyrrolo[2,3-g][1]oxa[ Preparation of 4,6,10]triazacyclotridecane
  • N-(3-(2-amino-4-fluoro-5-(6-methoxy-2-azaspiro[3.3]hept-2-yl)phenoxy)propyl)- 2,5-Dichloro-7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine 140mg, 0.22mmol, 1.0 eq
  • tris(dibenzylideneacetone)dipalladium (10.25mg, 0.01mmol, 0.05eq)
  • dicyclohexyl[2',4',6'-triisopropyl-[1,1'-biphenyl ]-2-yl]phosphine (16 mg, 0.03 mmol, 0.15 eq) and cesium carbonate (218.75 mg, 0.67 mmol, 3.0 eq) were dissolved in 1,4-dioxane (5 mL) and reacted at 90°C for 18 hours.
  • Step 5 3-Chloro-12-fluoro-11-(6-methoxy-2-azaspiro[3.3]hept-2-yl)-1,5,6,7,8,14-hexahydrogen Preparation of -4,15-(nitrogen-bridged)benzo[b]pyrrolo[2,3-g][1]oxa[4,6,10]triazacyclotriene
  • Step 1 Preparation of tert-butyl 2-(3-bromo-4-nitrophenyl)-2-cyanoacetate
  • Step 2 Preparation of methyl 5-(3-((2,5-dichloropyrimidin-4-yl)amino)butoxy)-2-fluoro-4-nitrobenzoate
  • Step 3 Preparation of methyl 4-amino-5-(3-((2,5-dichloropyrimidin-4-yl)amino)butoxy)-2-fluorobenzoate
  • Step 6 (5-chloro-14-fluoro-8-methyl-7,8,9,10-tetrahydro-1H-2,6-(nitrogen bridge)benzo[b][1]oxo[ Preparation of 4,6,10]triazacyclotridecane-13-yl)(morpholinyl)methanone
  • the reaction solution is poured into water, extracted with ethyl acetate, the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated, separated and purified by Prep-HPLC to obtain the target compound (27 mg , yield 12%).
  • Step 1 3-((5-bromo-2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine- Preparation of 4-yl)amino)propan-1-ol
  • Step 2 3-((2-chloro-5-cyclopropyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] Preparation of pyrimidin-4-yl)amino)propan-1-ol
  • Step 4 3-(5-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-4-fluoro-2-nitrophenoxy)propan-1-ol preparation
  • Step 5 5-(5-(3-((2,5-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl))-7H-pyrrolo[2,3 Preparation of -d]pyrimidin-4-yl)oxy)propoxy)-2-fluoro-4-nitrophenyl)-2-oxa-5-azabicyclo[2.2.1]heptane
  • Step 6 4-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-2-(3-((2,5-dichloro-7-((2-( Preparation of trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)propoxy)-5-fluoroaniline
  • Step 7 11-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-chloro-12-fluoro-1-((2-(trimethylsilyl)) Ethoxy)methyl)-1,7,8,14-tetrahydro-6H-4,15-(nitrogen bridge)benzo[b]pyrrolo[2,3-g][1,10]dioxo Preparation of hetero[4,6]diazacyclotridecane
  • Step 8 11-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-3-chloro-12-fluoro-1,7,8,14-tetrahydro-6H- Preparation of 4,15-(nitrogen-bridged)benzo[b]pyrrolo[2,3-g][1,10]dioxa[4,6]diazacyclotridecane
  • Step 1 Preparation of tert-butyl (4-hydroxybut-2-yl) carbamate
  • Step 3 Preparation of (4-((5-nitro-2-vinylpyridin-4-yl)oxy)but-2-yl)carbamic acid tert-butyl ester
  • Step 5 Preparation of tert-butyl (4-((2-(morpholine-4-carbonyl)-5-nitropyridin-4-yl)oxy)butan-2-yl)carbamate

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Abstract

La présente invention appartient au domaine technique des médicaments, et concerne une classe de composés hétérocycliques aromatiques servant d'inhibiteur de LRRK2. La présente invention concerne une classe de composés ayant une nouvelle structure, qui ont une structure représentée par la formule (K), et fournit une nouvelle direction pour le développement de médicaments inhibiteurs de LRRK2. La recherche d'activité d'inhibition d'activité cellulaire et enzymatique in vitro montrent que ces composés ont tous un effet inhibiteur relativement puissant et peuvent être des composés prometteurs pour prévenir ou traiter des maladies médiées par LRRK2.
PCT/CN2023/094659 2022-05-18 2023-05-17 Composé hétérocyclique aromatique et intermédiaire, composition pharmaceutique et utilisation associée WO2023222005A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11958865B1 (en) 2022-09-15 2024-04-16 H. Lundbeck A/S Leucine-rich repeat kinase 2 (LRRK2) inhibitors
US11993612B2 (en) 2021-10-27 2024-05-28 H. Lundbeck A/S LRRK2 inhibitors

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US20140206683A1 (en) * 2011-09-30 2014-07-24 Oncodesign S.A. Macrocyclic lrrk2 kinase inhibitors
US20160031905A1 (en) * 2013-03-15 2016-02-04 Ipsen Pharma S.A.S. Macrocyclic LRRK2 Kinase Inhibitors
CN107108641A (zh) * 2014-09-17 2017-08-29 昂科迪塞恩股份有限公司 大环lrrk2激酶抑制剂
CN110891954A (zh) * 2017-07-14 2020-03-17 葛兰素史密斯克莱知识产权发展有限公司 富含亮氨酸的重复激酶2的抑制剂
CN113164475A (zh) * 2018-11-19 2021-07-23 达纳-法伯癌症研究公司 Dyrk1a的大环抑制剂
WO2021224320A1 (fr) * 2020-05-06 2021-11-11 Les Laboratoires Servier Nouveaux inhibiteurs macrocycliques de la lrrk2 kinase
WO2022194976A1 (fr) * 2021-03-18 2022-09-22 Les Laboratoires Servier Inhibiteurs macrocycliques de la kinase lrrk2
US20230144725A1 (en) * 2021-10-27 2023-05-11 H. Lundbeck A/S Lrrk2 inhibitors

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140206683A1 (en) * 2011-09-30 2014-07-24 Oncodesign S.A. Macrocyclic lrrk2 kinase inhibitors
US20160031905A1 (en) * 2013-03-15 2016-02-04 Ipsen Pharma S.A.S. Macrocyclic LRRK2 Kinase Inhibitors
CN107108641A (zh) * 2014-09-17 2017-08-29 昂科迪塞恩股份有限公司 大环lrrk2激酶抑制剂
CN110891954A (zh) * 2017-07-14 2020-03-17 葛兰素史密斯克莱知识产权发展有限公司 富含亮氨酸的重复激酶2的抑制剂
CN113164475A (zh) * 2018-11-19 2021-07-23 达纳-法伯癌症研究公司 Dyrk1a的大环抑制剂
WO2021224320A1 (fr) * 2020-05-06 2021-11-11 Les Laboratoires Servier Nouveaux inhibiteurs macrocycliques de la lrrk2 kinase
WO2022194976A1 (fr) * 2021-03-18 2022-09-22 Les Laboratoires Servier Inhibiteurs macrocycliques de la kinase lrrk2
US20230144725A1 (en) * 2021-10-27 2023-05-11 H. Lundbeck A/S Lrrk2 inhibitors

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11993612B2 (en) 2021-10-27 2024-05-28 H. Lundbeck A/S LRRK2 inhibitors
US11958865B1 (en) 2022-09-15 2024-04-16 H. Lundbeck A/S Leucine-rich repeat kinase 2 (LRRK2) inhibitors

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