WO2020064002A1 - 异吲哚啉类化合物、其制备方法、药物组合物及用途 - Google Patents

异吲哚啉类化合物、其制备方法、药物组合物及用途 Download PDF

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WO2020064002A1
WO2020064002A1 PCT/CN2019/109368 CN2019109368W WO2020064002A1 WO 2020064002 A1 WO2020064002 A1 WO 2020064002A1 CN 2019109368 W CN2019109368 W CN 2019109368W WO 2020064002 A1 WO2020064002 A1 WO 2020064002A1
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substituted
halogen
alkyl
deuterium
alkoxy
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PCT/CN2019/109368
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English (en)
French (fr)
Inventor
陈小华
李佳
程宇
周宇波
聂辉军
汪玉洁
田洪涛
阚伟娟
米田
胡小蓓
周宾山
闫克念
徐高亚
钟毓华
冯磊
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中国科学院上海药物研究所
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Priority to CA3121667A priority Critical patent/CA3121667A1/en
Priority to EP19867602.5A priority patent/EP3862348A4/en
Priority to JP2021517757A priority patent/JP7168773B2/ja
Priority to BR112021006458A priority patent/BR112021006458A2/pt
Priority to AU2019348094A priority patent/AU2019348094B2/en
Priority to KR1020217012933A priority patent/KR20210069085A/ko
Priority to US17/281,419 priority patent/US20220041576A1/en
Publication of WO2020064002A1 publication Critical patent/WO2020064002A1/zh

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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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Definitions

  • the present invention relates to a novel type of multi-substituted isoindololine compounds having a novel structure, a pharmaceutically acceptable salt, a solvate, a pharmaceutical composition thereof, and its application in the preparation of a medicament for treating or preventing various diseases.
  • Tight regulation of intracellular protein expression plays an important role in cell function, cell survival, and division. Many primary or acquired diseases often involve protein dysfunction.
  • the traditional method of regulating protein dysfunction is mainly by designing targeted inhibitors or agonists. These targeted drugs play an important role in the treatment of diseases. However, in order to obtain a satisfactory effect, these inhibitors or agonists usually need to be maintained at a higher drug concentration to achieve effective therapeutic effects, which also leads to a certain degree of adverse reactions to the drug.
  • Another method to regulate protein dysfunction is to change the dynamic balance of pathologically related proteins.
  • the dynamic balance of proteins includes protein synthesis and degradation. For example, small interfering RNA (siRNA), antisense oligonucleotides or gene editing technologies can be used.
  • nucleic acid-based technologies alter the synthesis of proteins by acting on the transcription and translation process of the target protein.
  • the biggest limitation of this type of technology lies in the low stability of the nucleic acid in vivo and its low bioavailability. To some extent, its application is limited.
  • Another strategy to regulate the dynamic balance of proteins is to regulate the degradation process of proteins. By promoting or inhibiting the degradation of proteins, the expression of target proteins in cells can be directly changed.
  • the ubiquitin-proteasome system plays an important role in the degradation of proteins. Under the action of a series of ubiquitinating enzymes, target proteins can be labeled by ubiquitination, and proteins with special ubiquitin tags can be transported. To the proteasome and degraded by it.
  • proteins can affect the process of proteins in the cell, including subcellular localization, protein storage, and protein-protein interactions, as well as protein functions, including protein functions. Activation, inhibition, or proteasome / lysosome degradation.
  • the ubiquitination process of proteins is a tandem multi-step reaction process.
  • E1 ubiquitin activating enzyme E2 ubiquitin binding enzyme
  • E3 ubiquitin ligase E3 ubiquitin ligase.
  • the ubiquitin C-terminus is activated by ATP and forms an active thioester structure with the cysteine thiol group at the active center of the E1 ubiquitin-activating enzyme.
  • This active intermediate then covalently links ubiquitin to the E2 ubiquitin-binding enzyme via a new thioester structure via a transthioester reaction.
  • E3 ubiquitin ligase recruits substrate proteins and simultaneously binds to the E2 ubiquitin-binding enzyme-ubiquitin active intermediate, transferring ubiquitin to the substrate protein to complete the ubiquitination process of the substrate protein.
  • E3 ubiquitin ligase plays an important role. It not only plays a bridge role, allowing the two reaction components (E2 ubiquitin-binding enzyme-ubiquitin conjugate and substrate protein) in the space They are close to each other and at the same time also play an enzymatic role to accelerate the rate of substrate protein being ubiquitinated.
  • E3 ubiquitin ligase requires specific substrate recognition, the mammalian genome encodes more than 600 E3 ubiquitin ligases. In contrast, only two E1 ubiquitin-activating enzymes and about 40 E2 ubiquitin-binding enzymes are currently found.
  • E3 ubiquitin ligase can be divided into three categories according to its conserved domain and mode of action. Among them, the TECT family and RBR family E3 ubiquitin ligase need to activate ubiquitin from E2 ubiquitin during substrate ubiquitination. The enzyme transfers to itself, and then transfers ubiquitin from E3 ubiquitin ligase to the substrate protein. In comparison, the RING family E3 ubiquitin ligase occupies a larger proportion of the entire E3 ubiquitin ligase.
  • This type of E3 ubiquitin ligase contains a RING domain or a RING-like domain, which can bind to E2 ubiquitin Enzyme binding promotes the direct transfer of ubiquitin from E2 ubiquitin-binding enzymes to substrate proteins.
  • CRL4 CRBN E3 ubiquitin ligase belongs to the RING family of E3 ubiquitin ligases. It is a protein complex assembled from multiple subunits. The entire complex includes a substrate protein recognition module (CRBN) and E2 ubiquitin Enzyme recognition module (RING domain) and the linker (Cullin protein) between the two. CRBN directly binds to the substrate in the entire protein complex and controls the substrate specificity of the entire ubiquitination process.
  • CRBN substrate protein recognition module
  • RING domain E2 ubiquitin Enzyme recognition module
  • Cullin protein linker
  • Small molecule modulators that act directly on CRBN can control the substrate selectivity of CRL4 CRBN E3 ubiquitin ligase.
  • Cereblon gene name: CRBN
  • Cereblon is a direct target of thalidomide and its analogues (Science, 2010, 327, 1345; Science, 2014, 343, 301; Science, 2014, 343, 305; Nature, 2015, 523, 183.).
  • doxamine immunomodulators in multiple myeloma cell lines can selectively induce the transcription factors IKZF1 and IKZF3 to undergo ubiquitination and degradation by regulating the activity of the CRBN-ubiquitin ligase complex.
  • T cells and B cells also have a toxic effect on multiple myeloma cells, thereby achieving the role of treating malignant myeloid tumors including multiple myeloma.
  • lenalidomide an analog of thalidomide
  • CRL4 CRBN E3 ubiquitin ligase can selectively induce ubiquitination and degradation of CK1 ⁇ by CRL4 CRBN E3 ubiquitin ligase, and achieve comprehensive treatment of 5q-deficient myelodysplastic Syndrome (MDS), and another structural analog of thalidomide (CC-885) is able to selectively induce and degrade GSPT1 by acting on CRL4 CRBN E3 ubiquitin ligase, showing a strong effect on a variety of tumor cells Cytotoxicity.
  • MDS myelodysplastic Syndrome
  • CC-885 another structural analog of thalidomide
  • doxamine doxamine approved by the FDA for the treatment of leprosy nodular erythema.
  • amine clinical trials it is used to treat prostate cancer, and in pomalidomide clinical trials, it is used in the treatment of myelofibrosis.
  • lenalidomide pomalidomide
  • CC-122 CC-122
  • CC-220 CC-885
  • CC-885 CC-885
  • WO2008115516A2 US8153659B2, US9181216B2, US9920027B2 disclose compounds represented by the general formula S1:
  • the main representative R1 in the general formula S1 are aryl, arylalkyl, heterocyclylalkyl, and the like.
  • WO2011100380A1 and CN102822165B disclose a class of compounds represented by the general formula S2:
  • R1 in the general formula S2 is a substituted multiple substituted aryl group, and the representative compound is CC-220:
  • WO2007027527A2 discloses a class of compounds represented by the general formula S3:
  • WO2008027542A2, US8877780B2, US9447070B2 disclose a class of compounds represented by the general formula S3:
  • the mechanism of action of lenalidomide and some of the above molecules is: compounds with different structures can bind to CRBN, causing the conformation of the CRBN binding part to change, thereby recruiting different endogenous biological macromolecules to bind to CRBN; Endogenous substrate proteins are ubiquitinated and degraded, so they can produce different pharmacological activities and are used in clinical experiments to treat different indications.
  • lenalidomide is mainly used for the treatment of multiple myeloma and myelodysplastic syndrome, and it is not ideal for other indications; other compounds mentioned above such as CC-122, CC-885 and CC -220 is still in preclinical or clinical research. Therefore, the development of compounds with novel structures as CRL4 CRBN E3 ubiquitin ligase modulators can fulfill the clinical needs of further improving the therapeutic effect of tumors and the new indications of amine drugs; amine molecules with different structures Its pharmacological activity and pharmacological properties are unknown, and its properties and effects are uncertain.
  • the inventors of the present invention obtained the following important information by analyzing the crystal structure (PDB ID: 4CI2, 5HXB) of the complex where CRBN interacts with small molecules: CRBN and small molecules have multiple binding pockets, so they can develop more complex structures. Small molecules at each binding site to achieve effective binding of CRBN to small molecules.
  • the molecular dynamics simulation method was used to analyze the structural dynamics and binding site of the model molecule and E3 ubiquitin ligase interface, combined with molecular docking and complex-based pharmacophore matching, and scoring function was used to analyze the compound in E3 ubiquitin ligase The binding mode and interaction of the active site were evaluated to obtain a new specific CRBN small molecule modulator.
  • An object of the present invention is to provide a compound represented by the following general formula (I), its enantiomer, diastereomer, racemate, isotope compound, metabolic precursor, metabolite, pharmaceutically acceptable salt, ester, Prodrugs or their hydrates.
  • Another object of the present invention is to provide important intermediates and preparation methods of such compounds.
  • Another object of the present invention is to provide a pharmaceutical composition, characterized in that it comprises a therapeutically effective dose of a compound represented by the general formula (I), its enantiomer, diastereomer, racemate, pharmaceutically acceptable Salt, ester, prodrug or hydrate thereof, and at least one pharmaceutically acceptable carrier.
  • a compound represented by the general formula (I) its enantiomer, diastereomer, racemate, pharmaceutically acceptable Salt, ester, prodrug or hydrate thereof, and at least one pharmaceutically acceptable carrier.
  • Another object of the present invention is to provide a pharmaceutical composition, characterized in that it comprises a therapeutically effective dose of a compound represented by the general formula (I), its enantiomer, diastereomer, racemate, pharmaceutically acceptable Salts, esters, prodrugs, or hydrates thereof, as well as one or more ingredients having pharmaceutical therapeutic activity.
  • the compounds represented by the general formula (I) of the present invention, the enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof may have a drug with one or more other Therapeutic active ingredients produce synergistic effects in the prevention or treatment of specific diseases or dysfunctions.
  • the compound represented by the general formula (I) of the present invention can also reduce or eliminate another One or more have toxic and side effects produced by pharmaceutical therapeutic active ingredients in preventing or treating specific diseases or dysfunctions, and vice versa.
  • Another object of the present invention is to provide another one or more ingredients having medical therapeutic activity as described above, including macromolecular compounds such as proteins, polysaccharides, and nucleic acids, etc .; and small molecule compounds such as inorganic compounds, organic metals Compounds, small organic compounds of synthetic or natural origin, etc.
  • macromolecular compounds such as proteins, polysaccharides, and nucleic acids, etc .
  • small molecule compounds such as inorganic compounds, organic metals Compounds, small organic compounds of synthetic or natural origin, etc.
  • Another object of the present invention is to provide a compound such as the general formula (I), an enantiomer, a diastereomer, a racemate, a pharmaceutically acceptable salt, an ester, a prodrug or a hydrate thereof, characterized in that:
  • the medicament is used for preparing a medicine for treating diseases related to CRL4 CRBN E3 ubiquitin ligase.
  • the diseases include, but are not limited to, cancer, pain, nervous system diseases, and immune system diseases.
  • the present invention provides compounds represented by the following general formula (I) and their tautomers, enantiomers, diastereomers, racemates, metabolic precursors, metabolites, isotopic compounds, Pharmaceutical salts, esters, prodrugs or hydrates thereof:
  • X 2 is -CH 2 -or -CO-
  • R 1 is hydrogen, deuterium, fluorine or C 1 -C 6 straight or branched chain hydrocarbon group
  • R 2 and R 4 are each independently hydrogen or deuterium
  • R 3 is hydrogen, deuterium or halogen
  • L is a substituted or unsubstituted straight-chain alkylene group containing 2 to 8 carbon atoms, the substitution means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: deuterium, halogen, Carbonyl, hydroxyl, amino, cyano, C 1 -C 6 alkyl, halogen substituted C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, -NHC (O) Ra 1 , -NHC (O) ORa 2 , -NRa 3 Ra 4 , wherein Ra 1 , Ra 2 , Ra 3 and Ra 4 are each independently selected from a hydrogen atom, a C 1-6 alkyl group substituted with halogen, hydroxyl, cyano, nitro or unsubstituted C 3-6 cycloalkyl substituted or unsubstituted by halogen, hydroxy, cyano, nitro;
  • Y does not exist or is —O–, –CO–, –CO–NH–, –NH–CO–, –NH–CO–NH–, –NH–CO–CH (NHRa 9 ) – or –CH (NHRa 9 ) –;
  • A is: 6-10 membered aryl, 5-10 membered heteroaryl, (6-10 membered aryl)-(CH 2 ) b1- , (5-10 membered heteroaryl) — (CH 2 ) b1 —, the aforementioned aryl or heteroaryl is optionally substituted by one or more of the following: deuterium, halogen, cyano, nitro, amino, hydroxyl, C 1 -C 6 alkyl , Halogen substituted C 1 -C 6 alkyl, hydroxy substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, halogen substituted C 1 -C 6 Alkoxy, hydroxy-substituted C 1 -C 6 alkoxy, cyano-substituted C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl, C 3 -C
  • b 1 is 1 or 2;
  • connection modes between Y and A, L are A–L–, A–CO–L–, A–CO–NH–L -, A is: i) a heterocyclic group selected from:
  • X 3 is C, N or O
  • n 4 is 0, 1, 2 or 3;
  • n 5 is 0, 1, 2 or 3;
  • Y 1 and Y 2 are each independently hydrogen, deuterium, halogen, cyano, carboxyl, nitro, hydroxyl, amino, aminocarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1- C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylaminocarbonyl, C 3 -C 6 cycloalkyl or heterocyclyl, C 1 -C 6 acylamino, halogen substituted C 1 -C 6 alkyl, halogen substituted C 1 -C 6 alkoxy, C 1 -C 3 alkenyl, C 1 -C 3 alkynyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, 6-10 membered aryl or 5-10 membered heteroaryl substitute
  • Y 1 and Y 2 are each independently hydrogen, deuterium, C 1 -C 6 alkoxy, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, carboxyl, C 1 -C 6 When alkylaminocarbonyl, C 1 -C 6 alkoxycarbonyl, nitro, amino, cyano, halogen substituted C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 alkylsulfonyl, and Y is absent When X 1 is not -O-;
  • Y 3 is absent or is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 alkoxycarbonyl, halogen substituted C 1 -C 6 alkyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylcarbonyl, aminocarbonyl, C 3 -C 6 heterocyclyl, C 1 -C 6 acylamino, halogen substituted C 1 -C 6 alkoxy, C 1 -C 3 alkenyl, C 1 -C 3 alkynyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, C 5 -C 10 aryl or heteroaryl substituted C 1 -C 3 straight or branched alkyl, wherein the substituted or unsubstituted 6-10 membered
  • Y 3 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 alkoxycarbonyl, halogen substituted C 1 -C 6
  • alkyl, C 1 -C 6 alkylsulfonyl or Y3 is absent, and Y is absent, X 1 is not -O-;
  • Y 4, Y 5 where for one or more heterocyclyl group substituents, Y 4, Y5 each independently deuterium, halo, oxo, C 1 -C 3 alkyl, C 1 -C 3 cycloalkyl, Halogen-substituted C 1 -C 3 alkyl or phenyl;
  • X 4 is C, N or O
  • n 6 is 0, 1, 2 or 3;
  • n 7 is 0, 1, 2 or 3;
  • n 8 is 0, 1, 2, 3, or 4;
  • the ring is selected from a benzene ring, a pyridine ring, a thiophene ring, an indole ring, a benzothiophene ring, a benzimidazole ring, a naphthalene ring, a quinoline ring, or an isoquinoline ring;
  • R 8 is each independently selected from hydrogen, deuterium, C 1 -C 3 alkoxy, halogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, carboxyl, C 1 -C 3 alkylamino Carbonyl, C 1 -C 3 alkoxycarbonyl, nitro, amino, cyano, halogen substituted C 1 -C 3 alkyl, hydroxyl, C 1 -C 3 alkylsulfonyl, C 1 -C 3 alkylamino , C 1 -C 3 acylamino, aminocarbonyl, C 3 -C 6 heterocyclyl, halogen substituted C 1 -C 3 alkoxy, phenyl or 5-6 membered heteroaryl;
  • R 8 is independently selected from any of the following substituents: hydrogen, deuterium, C 1 -C 3 alkoxy, halogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, carboxyl, C When 1- C 3 alkylaminocarbonyl, C 1 -C 3 alkoxycarbonyl, nitro, amino, cyano, halogen substituted C 1 -C 3 alkyl, hydroxy, C 1 -C 3 alkylsulfonyl, When Y does not exist, X 1 is not -O-;
  • Y 6 and Y 7 are one or more substituents on the heterocyclic ring, and each is independently selected from deuterium, halogen, C 1 -C 3 alkyl, C 1 -C 3 cycloalkyl, halogen substituted C 1 -C 3 alkyl;
  • a spiroheterocyclyl selected from:
  • n c1 is 0, 1, 2 or 3;
  • n c2 is 0, 1, 2 or 3;
  • n c3 is 1, 2 or 3;
  • n 9 is 0, 1, 2, 3, or 4;
  • R 9 is independently selected from the following substituents: deuterium, halogen, cyano, nitro, hydroxy, amino, C 1 -C 3 alkylamino, C 1 -C 3 acylamino, aminocarbonyl, linear or branched C 1 -C 6 alkyl, straight or branched C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyloxy, C 3 -C 6 cycloalkyl or heterocycloalkyl, C 1 -C 3 Alkylaminocarbonyl, C 1 -C 3 alkoxycarbonyl, C 1 -C 3 alkylsulfonyl, halogen substituted C 1 -C 3 alkyl, halogen substituted C 1 -C 3 alkoxy, phenyl, 5 -6-membered heteroaryl;
  • R 10 and R 11 are independently selected from hydrogen, substituted or unsubstituted 6-10 membered aryl groups, and substituted or unsubstituted 5-10 membered heteroaryl groups.
  • the substituents R 9 on the ring are the same;
  • Y 8 is an optionally substituted hydrogen atom in a non-aromatic moiety in a spiro ring structure, and Y 8 is optionally substituted by deuterium, halogen, C 1 -C 3 alkyl, C 1 -C 3 cycloalkyl, halogen Substituted by substituted C 1 -C 3 alkyl substituents;
  • A is selected from the group:
  • n 1 is 0, 1, 2, 3, or 4;
  • R 5 is each independently selected from deuterium, halogen, hydroxyl, amino, cyano, nitro, straight or branched C 1 -C 6 alkyl, straight or branched C 1 -C 6 alkoxy, C 1 -C 3 acylamino, aminocarbonyl, phenyl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, C 1 -C 3 alkylaminocarbonyl, C 1 -C 3 alkylsulfonyl, phenyloxy or 5-6 membered heteroaryloxy, when n 1 > 1, each R 5 may be the same or different;
  • R a9 is selected from hydrogen, substituted or unsubstituted C 1 -C 10 alkylcarbonyl, substituted or unsubstituted C 3 -C 8 cycloalkylcarbonyl, C 1 -C 8 heterocycloalkylcarbonyl, wherein the substituted It means that the carbon chain terminal is replaced by a hydroxyl group and an amino group.
  • X 2 is -CH 2 -or -CO-
  • R 1 is hydrogen, deuterium, fluorine or a C 1 -C 3 straight or branched hydrocarbon group
  • R 2 and R 4 are each independently hydrogen or deuterium
  • R 3 is hydrogen, deuterium or halogen
  • L is a substituted or unsubstituted straight-chain alkylene group containing 2 to 8 carbon atoms, the substitution means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: deuterium, halogen, Carbonyl, hydroxyl, amino, cyano, C 1 -C 3 alkyl, halogen substituted C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, -NHC (O) Ra 1 , -NHC (O) ORa 2 , -NRa 3 Ra 4 , wherein Ra 1 , Ra 2 , Ra 3 and Ra 4 are each independently selected from a hydrogen atom, a C 1-6 alkyl group substituted with halogen, hydroxyl, cyano, nitro, and halogen C 3-6 cycloalkyl substituted with hydroxy, cyano, nitro;
  • Y does not exist or is —O–, –CO–, –CO–NH–, –NH–CO–, –NH–CO–NH–, –NH–CO–CH (NHR a9 ) –, or –CH (NHR a9 ) –;
  • A is: substituted or unsubstituted 9-10 membered aryl, 9-10 membered heteroaryl, (9-10 membered aryl)-(CH2) b1- , (9-10 membered Heteroaryl) – (CH2) b1 –,
  • b 1 is 1 or 2;
  • substituted or unsubstituted 9-10 membered aryl group or 9-10 membered heteroaryl group is selected from the following groups:
  • n 2 is 0, 1, 2 or 3;
  • n 3 is 0, 1, 2 or 3;
  • R 6 and R 7 are each independently selected from the group consisting of deuterium, halogen, cyano, nitro, amino, hydroxyl, C 1 -C 6 alkyl, halogen substituted C 1 -C 6 alkyl, hydroxy substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, halogen substituted C 1 -C 6 alkoxy, hydroxy substituted C 1 -C 6 alkoxy , Cyano-substituted C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, phenyl, C 5 -C 6 heteroaryl, C 3 -C 6 heterocyclyl, -NHC (O) Ra 5 , -NHC (O) ORa 6 , -NRa 7 Ra 8 ; wherein Ra 5 , Ra 6 , Ra 7 and a 8 are each independently a hydrogen
  • Y 1 and Y 2 are each independently hydrogen, deuterium, halogen, cyano, carboxyl, nitro, hydroxyl, amino, aminocarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1- C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylaminocarbonyl, C 3 -C 6 cycloalkyl or heterocyclic Group, C 1 -C 6 acylamino, halogen substituted C 1 -C 6 alkyl, halogen substituted C 1 -C 6 alkoxy, C 1 -C 3 alkenyl, C 1 -C 3 alkynyl, substituted or Unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, 6-10 membered aryl or 5-10 membered hetero
  • Y 1 and Y 2 are each independently: hydrogen, deuterium, C 1 -C 6 alkoxy, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, carboxyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 alkoxycarbonyl, nitro, amino, cyano, halogen substituted C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 alkylsulfonyl, and Y is not When present, X 1 is not -O-;
  • Y 3 is absent or is C 1 -C 6 alkylcarbonyl, aminocarbonyl, C 3 -C 6 heterocyclyl, C 1 -C 6 acylamino, halogen substituted C 1 -C 6 alkoxy, C 1 -C 3 alkenyl, C 1 -C 3 alkynyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, C 5 -C 10 aryl or heteroaryl substituted linear or branched C 1 -C 3 alkyl, wherein said substituted or unsubstituted 6-10 membered aryl or 5-10 membered heteroaryl group refers to one or more substituents Replaced by: deuterium, halogen, cyano, nitro, hydroxyl, amino, aminocarbonyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylcarbonyl,
  • Y 3 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 alkoxycarbonyl, halogen substituted C 1 -C 6
  • alkyl, C 1 -C 6 alkylsulfonyl or Y3 is absent, and Y is absent, X 1 is not -O-;
  • Y 4, Y 5 heterocycle where one or more of its substituents, Y 4, Y5 each independently deuterium, halo, oxo, C 1 -C 3 alkyl, C 1 -C 3 cycloalkyl, or Phenyl
  • n 8 is 0, 1, 2, 3, or 4;
  • X 4 is C, N or O
  • the ring is preferably a benzene ring, a pyridine ring, a thiophene ring, an indole ring, a naphthalene ring, a benzothiophene ring, a benzimidazole ring, a quinoline ring or an isoquinoline ring;
  • R 8 is each independently selected from hydrogen, deuterium, C 1 -C 3 alkoxy, halogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, carboxyl, C 1 -C 3 alkylamino Carbonyl, C 1 -C 3 alkoxycarbonyl, nitro, amino, cyano, halogen substituted C 1 -C 3 alkyl, hydroxyl, C 1 -C 3 alkylsulfonyl, C 1 -C 3 alkylamino , C 1 -C 3 acylamino, aminocarbonyl, C 3 -C 6 heterocyclyl, halogen substituted C 1 -C 3 alkoxy, phenyl or 5-6 membered heteroaryl;
  • R 8 is independently selected from any of the following substituents: hydrogen, deuterium, C 1 -C 3 alkoxy, halogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, carboxyl, C When 1- C 3 alkylaminocarbonyl, C 1 -C 3 alkoxycarbonyl, nitro, amino, cyano, halogen substituted C 1 -C 3 alkyl, hydroxy, C 1 -C 3 alkylsulfonyl, When Y is absent, X 1 is not -O-;
  • Y 6 and Y 7 are one or more substituents on the heterocyclic ring, and each is independently selected from deuterium, halogen, C 1 -C 3 alkyl, C 1 -C 3 cycloalkyl, halogen substituted C 1 -C 3 alkyl;
  • a spiroheterocyclyl selected from:
  • n 9 is 0, 1, 2, 3, or 4;
  • R 9 is independently selected from the following substituents: deuterium, halogen, cyano, nitro, hydroxy, amino, C 1 -C 3 alkylamino, C 1 -C 3 acylamino, aminocarbonyl, linear or branched C 1- C 6 alkyl, straight or branched C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyloxy, C 3 -C 6 cycloalkyl or heterocycloalkyl, C 1 -C 3 alkylaminocarbonyl, C 1 -C 3 alkoxycarbonyl, C 1 -C 3 alkylsulfonyl, halogen substituted C 1 -C 3 alkyl, halogen substituted C 1 -C 3 alkoxy, phenyl, 5-6 membered heteroaryl, wherein when n 9 > 1, each R 9 may be the same or different;
  • Y 8 is an optionally substituted hydrogen atom in a non-aromatic moiety in a spiro ring structure, and Y 8 is optionally substituted by deuterium, halogen, C 1 -C 3 alkyl, C 1 -C 3 cycloalkyl, halogen Substituted by substituted C 1 -C 3 alkyl substituents;
  • n 1 is 0, 1, 2, 3, or 4;
  • R 5 is each independently selected from deuterium, halogen, hydroxyl, amino, cyano, nitro, straight or branched C 1 -C 6 alkyl, straight or branched C 1 -C 6 alkoxy, C 1 -C 3 acylamino, aminocarbonyl, phenyl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, C 1 -C 3 alkylaminocarbonyl, C 1 -C 3 alkylsulfonyl, phenyloxy or 5-6 membered heteroaryloxy, when n 1 > 1, each R 5 may be the same or different;
  • R a9 is independently selected from hydrogen, a substituted or unsubstituted C1-C10 alkyl carbonyl group, a substituted or unsubstituted C 3 -C 8 cycloalkylcarbonyl, C heterocycloalkyl 1 -C 8 alkylcarbonyl group, wherein said substituted It means that the carbon chain terminal is replaced by a hydroxyl group and an amino group.
  • X 2 is -CH 2 -or -CO-
  • R 1 is hydrogen, deuterium or fluorine
  • R 2 and R 4 are each independently hydrogen or deuterium
  • R 3 is hydrogen, deuterium or fluorine
  • L is a substituted or unsubstituted straight-chain alkylene group containing 2 to 8 carbon atoms, the substitution means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: deuterium, halogen, Cyano, C 1 -C 3 alkyl, halogen substituted C 1 -C 3 alkyl, -NHC (O) Ra 1 , -NHC (O) ORa 2 , -NRa 3 Ra 4 , among which Ra 1 , Ra 2 , Ra 3 and Ra 4 are each independently selected from a hydrogen atom, a C 1-6 alkyl group substituted or unsubstituted with one or more halogens, or a C 3-6 cycloalkane substituted or unsubstituted with one or more halogens base;
  • Y does not exist or is —O–, –CO–, –CO–NH–, –NH–CO–, –NH–CO–NH–, –NH–CO–CH (NHR a9 ) –, or –CH (NHR a9 ) –;
  • A is: selected from 9-10 membered aryl, 9-10 membered heteroaryl, (9-10 membered aryl)-(CH2) b1- , (9-10 membered heteroaryl) )-(CH2) b1- , the 9-10 membered aryl group or 9-10 membered heteroaryl group may be unsubstituted or substituted;
  • the substituted or unsubstituted 9-10 membered aryl group or 9-10 membered heteroaryl group is selected from the following groups:
  • b 1 is 1 or 2;
  • n 2 is 0, 1, 2 or 3;
  • n 3 is 0, 1, 2 or 3;
  • R 6 and R 7 are each independently selected from the group consisting of deuterium, halogen, cyano, nitro, amino, hydroxyl, C 1 -C 6 alkyl, halogen substituted C 1 -C 6 alkyl, hydroxyl substituted C 1- C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, halogen substituted C 1 -C 6 alkoxy, hydroxy substituted C 1 -C 6 alkoxy, Cyano-substituted C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, phenyl, C 5 -C 6 heteroaryl, C 3 -C 6 Heterocyclic group, -NHC (O) Ra 5 , -NHC (O) ORa 6 , -NRa 7 Ra 8 ; wherein Ra 5 , Ra 6 , Ra 7 and Ra 8 are each independently a hydrogen
  • Y does not exist or is -CO- or -CO-NH-.
  • connection between Y and A, L is -A–CO–L–, –A–CO–NH–L–, –A–
  • the L– and A portions contain at least one nitrogen atom and Y is connected to the nitrogen atom.
  • A is:
  • n 10 is 0, 1, 2, 3, 4 or 5;
  • Y 1 is selected from hydrogen, deuterium, halogen, cyano, carboxyl, nitro, hydroxyl, amino, aminocarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylcarbonyl , C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylaminocarbonyl, C 3 -C 6 cycloalkyl or heterocyclyl, C 1 -C 6 Acylamino, halogen-substituted C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkoxy, C 1 -C 3 alkenyl, C 1 -C 3 alkynyl, substituted or unsubstituted 6-10 member an aryl group, a substituted or unsubstituted 5-10 membered heteroaryl, 6-10 membered aryl,
  • R 10 is each independently deuterium, halogen, cyano, nitro, hydroxyl, amino, aminocarbonyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylcarbonyl, C 1- C 3 alkoxycarbonyl, C 1 -C 3 alkylsulfonyl, C 1 -C 3 alkylaminocarbonyl, C 3 -C 6 cycloalkyl or heterocyclic group, C 1 -C 3 acylamino , Halogen substituted C 1 -C 3 alkyl, halogen substituted C 1 -C 3 alkoxy, when n 10 > 1, R 10 may be the same or different;
  • Y 4 one or more of the heterocycle Y 5 where its substituent group, Y 4, Y5 each independently deuterium, halogen, methyl, ethyl, cyclopropyl or phenyl;
  • n 8 is 0, 1, 2, 3, or 4;
  • X 4 is C, N or O
  • R 8 is each independently selected from hydrogen, deuterium, C 1 -C 3 alkoxy, halogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, carboxyl, C 1 -C 3 alkylamino Carbonyl, C 1 -C 3 alkoxycarbonyl, nitro, amino, cyano, halogen substituted C 1 -C 3 alkyl, hydroxyl, C 1 -C 3 alkylsulfonyl, C 1 -C 3 alkylamino , C 1 -C 3 acylamino, aminocarbonyl, C 3 -C 6 heterocyclyl, halogen substituted C 1 -C 3 alkoxy, phenyl or 5-6 membered heteroaryl, where n 8 > 1 Each R 8 may be the same or different;
  • R 8 is independently selected from any of the following substituents: deuterium, C 1 -C 3 alkoxy, halogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, carboxyl, C 1- When C 3 alkylaminocarbonyl, C 1 -C 3 alkoxycarbonyl, nitro, amino, cyano, halogen substituted C 1 -C 3 alkyl, hydroxyl, C 1 -C 3 alkylsulfonyl, and Y When not present, X 1 is not -O-;
  • Y 6 and Y 7 are one or more substituents on the heterocyclic ring, and each is independently selected from deuterium, halogen, methyl, ethyl, cyclopropyl, and trifluoromethyl;
  • a spiroheterocyclyl selected from:
  • n 9 is 0, 1, 2, 3, or 4;
  • R 9 is each independently selected from the following substituents: deuterium, halogen, cyano, nitro, hydroxy, amino, C 1 -C 3 alkylamino, C 1 -C 3 acylamino, aminocarbonyl, linear or branched C 1 -C 6 alkyl, straight or branched C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyloxy, C 3 -C 6 cycloalkyl or heterocycloalkyl, C 1- C 3 alkylaminocarbonyl, C 1 -C 3 alkoxycarbonyl, C 1 -C 3 alkylsulfonyl, halogen substituted C 1 -C 3 alkyl, halogen substituted C 1 -C 3 alkoxy, phenyl , 5-6 membered heteroaryl, wherein when n 9 > 1, each R 9 may be the same or different;
  • Y 8 is an optionally substituted hydrogen atom in a non-aromatic moiety in a spiro ring structure, and Y 8 is optionally substituted with a deuterium, halogen, methyl, ethyl, cyclopropyl, or trifluoromethyl substituent ;
  • n 1 is 0, 1, 2, 3, or 4;
  • R 5 is each independently selected from deuterium, halogen, hydroxyl, amino, cyano, nitro, straight or branched C 1 -C 6 alkyl, straight or branched C 1 -C 6 alkoxy, C 1 -C 3 acylamino, aminocarbonyl, phenyl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, C 1 -C 3 alkylaminocarbonyl, C 1 -C 3 alkylsulfonyl, phenyloxy or 5-6 membered heteroaryloxy, when n 1 > 1, each R 5 may be the same or different;
  • R a9 is selected from hydrogen, substituted or unsubstituted C1-C10 alkylcarbonyl, substituted or unsubstituted C 3 -C 8 cycloalkylcarbonyl, C 1 -C 8 heterocycloalkylcarbonyl, wherein said substitution refers to The carbon chain terminal is replaced by a hydroxyl group and an amino group.
  • the compound represented by the general formula (I) is a compound represented by the general formulae (I-1) to (I-8):
  • X 1 is -CH 2 -or -O-;
  • X 2 is -CH 2 -or -CO-
  • R 1 is hydrogen, deuterium or fluorine
  • R 2 and R 4 are each independently selected from hydrogen or deuterium
  • R 3 is hydrogen, deuterium or fluorine
  • L is a substituted or unsubstituted straight-chain alkylene group containing 2 to 8 carbon atoms, the substitution means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: deuterium, halogen, Cyano, C 1 -C 3 alkyl, halogen substituted C 1 -C 3 alkyl, -NHC (O) Ra 1 , -NHC (O) ORa 2 , -NRa 3 Ra 4 , among which Ra 1 , Ra 2 , Ra 3 and Ra 4 are each independently selected from a hydrogen atom, a C 1-6 alkyl group substituted or unsubstituted with one or more halogens, or a C 3-6 cycloalkane substituted or unsubstituted with one or more halogens base;
  • Y does not exist, or is -CO- or -CO-NH-;
  • n 9 is 0, 1, 2, 3, or 4;
  • Y 8 is an optionally substituted hydrogen atom in a non-aromatic moiety in a spiro ring structure, and Y 8 is optionally substituted with a deuterium, halogen, methyl, ethyl, cyclopropyl, or trifluoromethyl substituent ;
  • R 9 is each independently selected from the following substituents: deuterium, halogen, cyano, nitro, hydroxy, amino, C 1 -C 3 alkylamino, C 1 -C 3 acylamino, aminocarbonyl, linear or branched C 1 -C 6 alkyl, straight or branched C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyloxy, C 3 -C 6 cycloalkyl or heterocycloalkyl, C 1- C 3 alkylaminocarbonyl, C 1 -C 3 alkoxycarbonyl, C 1 -C 3 alkylsulfonyl, halogen substituted C 1 -C 3 alkyl, halogen substituted C 1 -C 3 alkoxy, phenyl , 5-6 membered heteroaryl, wherein when n 9 > 1, each R 9 may be the same or different;
  • the compound represented by the general formula (I) is a compound represented by the general formulae (I-9) to (I-16):
  • X 1 is -CH 2 -or -O-;
  • X 2 is -CH 2 -or -CO-
  • R 1 is hydrogen, deuterium or fluorine
  • R 2 and R 4 are each independently hydrogen and deuterium
  • R 3 is hydrogen, deuterium or fluorine
  • L is a substituted or unsubstituted straight-chain alkylene group containing 2 to 8 carbon atoms, the substitution means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: deuterium, halogen, Cyano, C 1 -C 3 alkyl, halogen substituted C 1 -C 3 alkyl, -NHC (O) Ra 1 , -NHC (O) ORa 2 , -NRa 3 Ra 4 , among which Ra 1 , Ra 2 , Ra 3 and Ra 4 are each independently selected from a hydrogen atom, a C 1-6 alkyl group substituted or unsubstituted with one or more halogens, or a C 3-6 cycloalkane group substituted or unsubstituted with one or more halogens base;
  • Y does not exist, or is -CO- or -CO-NH-;
  • n 9 is 0, 1, 2, 3, or 4;
  • R 9 is each independently selected from the following substituents: deuterium, halogen, cyano, nitro, hydroxy, amino, C 1 -C 3 alkylamino, C 1 -C 3 acylamino, aminocarbonyl, linear or branched C 1 -C 6 alkyl, straight or branched C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyloxy, C 3 -C 6 cycloalkyl or heterocycloalkyl, C 1- C 3 alkylaminocarbonyl, C 1 -C 3 alkoxycarbonyl, C 1 -C 3 alkylsulfonyl, halogen substituted C 1 -C 3 alkyl, halogen substituted C 1 -C 3 alkoxy, phenyl , 5-6 membered heteroaryl, wherein when n 9 > 1, each R 9 may be the same or different;
  • Y 8 is an optionally substituted hydrogen atom in a non-aromatic moiety in a spiro ring structure, and Y 8 is optionally substituted with a deuterium, halogen, methyl, ethyl, cyclopropyl, or trifluoromethyl substituent ;
  • the compound represented by the general formula (I) is a compound represented by the general formulae (I-17) and (I-18):
  • X 1 is -CH 2 -or -O-;
  • X 2 is -CH 2 -or -CO-
  • R 1 is hydrogen, deuterium or fluorine
  • R 2 and R 4 are each independently hydrogen or deuterium
  • R 3 is selected from hydrogen, deuterium or fluorine
  • L is a substituted or unsubstituted straight-chain alkylene group containing 2 to 8 carbon atoms, the substitution means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: deuterium, halogen, Cyano, C 1 -C 3 alkyl, halogen substituted C 1 -C 3 alkyl, -NHC (O) Ra 1 , -NHC (O) ORa 2 , -NRa 3 Ra 4 , among which Ra 1 , Ra 2 , Ra 3 and Ra 4 are each independently selected from a hydrogen atom, a C 1-6 alkyl group substituted or unsubstituted with one or more halogens, or a C 3-6 cycloalkyl group substituted or unsubstituted with one or more halogens ;
  • Y does not exist, or is -CO- or -CO-NH-;
  • n 10 is 0, 1, 2, 3, 4 or 5;
  • Y 1 is each independently selected from hydrogen, deuterium, halogen, cyano, carboxyl, nitro, hydroxyl, amino, aminocarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 Alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylaminocarbonyl, C 3 -C 6 cycloalkyl or heterocyclyl, C 1 -C 6 acylamino, halogen substituted C 1 -C 6 alkyl, halogen substituted C 1 -C 6 alkoxy, C 1 -C 3 alkenyl, C 1 -C 3 alkynyl, substituted or unsubstituted 6 -10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, 6-10 membered aryl or 5-10 membered heteroaryl
  • 6-10 membered aryl substituted or unsubstituted 5-10 membered heteroaryl, preferably, 6-10 membered aryl or 5-10 membered heteroaryl is selected from thienyl, pyridine Phenyl, phenyl, benzothienyl, benzimidazolyl, indolyl, naphthyl, quinolinyl, isoquinolinyl;
  • R 10 is each independently selected from deuterium, halogen, cyano, nitro, hydroxyl, amino, aminocarbonyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylcarbonyl, C 1 -C 3 alkoxycarbonyl, C 1 -C 3 alkylsulfonyl, C 1 -C 3 alkylaminocarbonyl, C 3 -C 6 cycloalkyl or heterocyclyl, C 1 -C 3 acyl Amino, halogen-substituted C 1 -C 3 alkyl, halogen-substituted C 1 -C 3 alkoxy, when n 10 > 1, each R 10 may be the same or different;
  • the compound represented by the general formula (I) is a compound represented by the general formulae (I-19) to (I-23):
  • X 1 is -CH 2 -or -O-;
  • X 2 is -CH 2 -or -CO-
  • R 1 is hydrogen, deuterium or fluorine
  • R 2 and R 4 are each independently hydrogen or deuterium
  • R 3 is hydrogen, deuterium or fluorine
  • L is a substituted or unsubstituted straight-chain alkylene group containing 2 to 8 carbon atoms, the substitution means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: deuterium, halogen, Cyano, C 1 -C 3 alkyl, halogen substituted C 1 -C 3 alkyl, -NHC (O) Ra 1 , -NHC (O) ORa 2 , -NRa 3 Ra 4 , among which Ra 1 , Ra 2 , Ra 3 and Ra 4 are each independently selected from a hydrogen atom, a C 1-6 alkyl group substituted or unsubstituted with one or more halogens, or a C 3-6 cycloalkane group substituted or unsubstituted with one or more halogens base;
  • Y does not exist, or is -CO- or -CO-NH-;
  • n 8 is 0, 1, 2, 3, or 4;
  • X 4 is C, N or O
  • R 8 is each independently hydrogen, deuterium, C 1 -C 3 alkoxy, halogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, carboxyl, C 1 -C 3 alkylaminocarbonyl , C 1 -C 3 alkoxycarbonyl, nitro, amino, cyano, halogen substituted C 1 -C 3 alkyl, hydroxyl, C 1 -C 3 alkylsulfonyl, C 1 -C 3 alkylamino, C 1 -C 3 acylamino, aminocarbonyl, C 3 -C 6 heterocyclyl, halogen substituted C 1 -C 3 alkoxy, phenyl or 5-6 membered heteroaryl, where n 8 > 1 , Each R 8 may be the same or different;
  • R 8 is selected from any of the following substituents: deuterium, C 1 -C 3 alkoxy, halogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, carboxyl, C 1 -C 3 alkyl
  • aminocarbonyl, C 1 -C 3 alkoxycarbonyl, nitro, amino, cyano, halogen substituted C 1 -C 3 alkyl, hydroxyl, C 1 -C 3 alkylsulfonyl, and Y is absent, X 1 is not -O-;
  • Y 6 and Y 7 are one or more substituents on the heterocyclic ring, and each is independently selected from deuterium, halogen, methyl, ethyl, cyclopropyl, and trifluoromethyl;
  • the compound represented by the general formula (I) is a compound represented by the general formulae (I-24) to (I-32):
  • X 2 is -CH 2 -or -CO-;
  • R 1 is hydrogen, deuterium or fluorine
  • R 2 and R 4 are each independently hydrogen or deuterium
  • R 3 is selected from hydrogen, deuterium or fluorine
  • L is a substituted or unsubstituted straight chain alkylene group containing 2 to 8 carbon atoms, said substitution means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: deuterium, halogen, cyano , C 1 -C 3 alkyl, halogen substituted C 1 -C 3 alkyl, -NHC (O) Ra 1 , -NHC (O) ORa 2 , -NRa 3 Ra 4 , among which Ra 1 , Ra 2 , Ra 3 and Ra 4 are each independently selected from a hydrogen atom, a C 1-6 alkyl substituted or unsubstituted with one or more halogens or a C 3-6 cycloalkyl substituted or unsubstituted with one or more halogens;
  • Y does not exist, or is -CO- or -CO-NH-;
  • n 8 , n 9 , n 10 are each independently selected from 0, 1, 2, 3, or 4;
  • X 4 is C, N or O
  • R 9 is selected from the following substituents: deuterium, halogen, cyano, nitro, hydroxyl, amino, C 1 -C 3 alkylamino, C 1 -C 3 acylamino, aminocarbonyl, linear or branched C 1- C 6 alkyl, straight or branched C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyloxy, C 3 -C 6 cycloalkyl or heterocycloalkyl, C 1 -C 3 alkyl Aminoaminocarbonyl, C 1 -C 3 alkoxycarbonyl, C 1 -C 3 alkylsulfonyl, halogen substituted C 1 -C 3 alkyl, halogen substituted C 1 -C 3 alkoxy, phenyl, 5- 6-membered heteroaryl, wherein when n 9 > 1, each R 9 may be the same or different;
  • substituted or unsubstituted 6-10 membered aryl substituted or unsubstituted 5-10 membered heteroaryl, preferably 6-10 membered aryl or 5-10 membered heteroaryl selected from thienyl, pyridyl , Phenyl, benzothienyl, benzimidazolyl, indolyl, naphthyl, quinolinyl, isoquinolinyl;
  • R 10 is each independently selected from deuterium, halogen, cyano, nitro, hydroxy, amino, aminocarbonyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylcarbonyl, C 1 -C 3 alkoxycarbonyl, C 1 -C 3 alkylsulfonyl, C 1 -C 3 alkylaminocarbonyl, C 3 -C 6 cycloalkyl or heterocyclyl, C 1 -C 3 acyl Amino, halogen-substituted C 1 -C 3 alkyl, halogen-substituted C 1 -C 3 alkoxy, when n 10 > 1, each R 10 may be the same or different;
  • R 8 is each independently selected from hydrogen, deuterium, C 1 -C 3 alkoxy, halogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, carboxyl, C 1 -C 3 alkylamino Carbonyl, C 1 -C 3 alkoxycarbonyl, nitro, amino, cyano, halogen substituted C 1 -C 3 alkyl, hydroxyl, C 1 -C 3 alkylsulfonyl, C 1 -C 3 alkylamino , C 1 -C 3 acylamino, aminocarbonyl, C 3 -C 6 heterocyclyl, halogen substituted C 1 -C 3 alkoxy, phenyl or 5-6 membered heteroaryl, when n 8 > 1 , Each R 8 may be the same or different;
  • the compound represented by the general formula (I) is a compound represented by the general formulae (I-33) to (I-40):
  • X 2 is -CH 2 -or -CO-;
  • R 1 is hydrogen, deuterium or fluorine
  • R 2 and R 4 are each independently hydrogen or deuterium
  • R 3 is hydrogen, deuterium or fluorine
  • L is a substituted or unsubstituted straight-chain alkylene group containing 2 to 8 carbon atoms, the substitution means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: deuterium, halogen, Cyano, C 1 -C 3 alkyl, halogen substituted C 1 -C 3 alkyl, -NHC (O) Ra 1 , -NHC (O) ORa 2 , -NRa 3 Ra 4 , among which Ra 1 , Ra 2 , Ra 3 and Ra 4 are each independently selected from a hydrogen atom, a C 1-6 alkyl group substituted or unsubstituted with one or more halogens, or a C 3-6 cycloalkyl group substituted or unsubstituted with one or more halogens ;
  • Y does not exist or is -CO–, -CO–NH–;
  • n 8 , n 9 , and n 10 are each independently 0, 1, 2, 3, or 4;
  • X 4 is selected from C, N or O;
  • R 9 is each independently selected from the following substituents: deuterium, halogen, cyano, nitro, hydroxy, amino, C 1 -C 3 alkylamino, C 1 -C 3 acylamino, aminocarbonyl, linear or branched C 1 -C 6 alkyl, straight or branched C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyloxy, C 3 -C 6 cycloalkyl or heterocycloalkyl, C 1- C 3 alkylaminocarbonyl, C 1 -C 3 alkoxycarbonyl, C 1 -C 3 alkylsulfonyl, halogen substituted C 1 -C 3 alkyl, halogen substituted C 1 -C 3 alkoxy, phenyl , 5-6 membered heteroaryl, when n 9 > 1, each R 9 may be the same or different;
  • 6-10 membered aryl substituted or unsubstituted 5-10 membered heteroaryl, preferably, 6-10 membered aryl or 5-10 membered heteroaryl is selected from thienyl, pyridine Phenyl, phenyl, benzothienyl, benzimidazolyl, indolyl, naphthyl, quinolinyl, isoquinolinyl;
  • R 10 is each independently selected from deuterium, halogen, cyano, nitro, hydroxy, amino, aminocarbonyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylcarbonyl, C 1 -C 3 alkoxycarbonyl, C 1 -C 3 alkylsulfonyl, C 1 -C 3 alkylaminocarbonyl, C 3 -C 6 cycloalkyl or heterocyclyl, C 1 -C 3 acyl Amino, halogen-substituted C 1 -C 3 alkyl, halogen-substituted C 1 -C 3 alkoxy, when n 10 > 1, each R 10 may be the same or different;
  • R 8 is each independently selected from hydrogen, deuterium, C 1 -C 3 alkoxy, halogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, carboxyl, C 1 -C 3 alkylamino Carbonyl, C 1 -C 3 alkoxycarbonyl, nitro, amino, cyano, halogen substituted C 1 -C 3 alkyl, hydroxyl, C 1 -C 3 alkylsulfonyl, C 1 -C 3 alkylamino , C 1 -C 3 acylamino, aminocarbonyl, C 3 -C 6 heterocyclyl, halogen substituted C 1 -C 3 alkoxy, phenyl or 5-6 membered heteroaryl, where n 8 > 1 Each R 8 may be the same or different;
  • R 8 is selected from any of the following substituents: deuterium, C 1 -C 3 alkoxy, halogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, carboxyl, C 1 -C 3 alkyl
  • aminocarbonyl, C 1 -C 3 alkoxycarbonyl, nitro, amino, cyano, halogen substituted C 1 -C 3 alkyl, hydroxyl, C 1 -C 3 alkylsulfonyl, and Y is absent, X 1 is not -O-;
  • the compound represented by the general formula (I) is a compound represented by the general formulae (I-41) to (I-48):
  • X 1 is -CH 2 -or -O-;
  • X 2 is -CH 2 -or -CO-
  • R 1 is hydrogen, deuterium or fluorine
  • R 2 and R 4 are each independently hydrogen or deuterium
  • R 3 is hydrogen, deuterium or fluorine
  • L is a substituted or unsubstituted straight-chain alkylene group containing 2 to 8 carbon atoms, the substitution means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: deuterium, halogen, Cyano, C 1 -C 3 alkyl, halogen substituted C 1 -C 3 alkyl, -NHC (O) Ra 1 , -NHC (O) ORa 2 , -NRa 3 Ra 4 , among which Ra 1 , Ra 2 , Ra 3 and Ra 4 are each independently selected from a hydrogen atom, a C 1-6 alkyl group substituted or unsubstituted with one or more halogens, or a C 3-6 cycloalkane group substituted or unsubstituted with one or more halogens base;
  • n 2 is 0, 1, 2 or 3;
  • n 3 is 0, 1, 2 or 3;
  • R 6 and R 7 are each independently selected from the group consisting of deuterium, halogen, cyano, nitro, amino, hydroxyl, C 1 -C 6 alkyl, halogen substituted C 1 -C 6 alkyl, hydroxy substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, halogen substituted C 1 -C 6 alkoxy, hydroxy substituted C 1 -C 6 alkoxy , Cyano-substituted C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, phenyl, C 5 -C 6 heteroaryl, C 3 -C 6 heterocyclyl, -NHC (O) Ra 5 , -NHC (O) ORa 6 , -NRa 7 Ra 8 , wherein each of Ra 5 , Ra 6 , Ra 7 and Ra 8 is independently selected from
  • X 1 is -CH 2 -or -O-;
  • X 2 is -CH 2 -or -CO-
  • R 1 is hydrogen, deuterium or fluorine
  • R 2 and R 4 are each independently selected from hydrogen or deuterium
  • R 3 is hydrogen, deuterium or fluorine
  • L is a substituted or unsubstituted straight-chain alkylene group containing 2 to 8 carbon atoms, the substitution means that one or more hydrogen atoms in the alkylene group are optionally substituted with the following substituents: deuterium, halogen, Cyano, C 1 -C 3 alkyl, halogen substituted C 1 -C 3 alkyl, -NHC (O) Ra 1 , -NHC (O) ORa 2 , -NRa 3 Ra 4 , among which Ra 1 , Ra 2 , Ra 3 and Ra 4 are each independently selected from a hydrogen atom, a C 1-6 alkyl group substituted or unsubstituted with one or more halogens, or a C 3-6 cycloalkane group substituted or unsubstituted with one or more halogens base;
  • Y is selected from —NH–CO–, –NH–CO–NH–, –NH–CO–CH (NHR a9 ) – or –CH (NHR a9 ) –;
  • n 1 is 0, 1, 2, 3, or 4;
  • R 5 is each independently selected from deuterium, halogen, hydroxyl, amino, cyano, nitro, straight or branched C 1 -C 6 alkyl, straight or branched C 1 -C 6 alkoxy, C 1 -C 3 acylamino, aminocarbonyl, phenyl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, C 1 -C 3 alkylaminocarbonyl, C 1 -C 3 alkylsulfonyl, phenyloxy or 5-6 membered heteroaryloxy, when n 1 > 1, each R 5 may be the same or different;
  • R a9 is selected from hydrogen, substituted or unsubstituted C1-C10 alkylcarbonyl, substituted or unsubstituted C 3 -C 8 cycloalkylcarbonyl, C 1 -C 8 heterocycloalkylcarbonyl, wherein said substitution refers to The carbon chain terminal is replaced by a hydroxyl group and an amino group.
  • the compound represented by the general formula (I) is one of the following compounds:
  • the compound represented by the general formula (I) may contain one or more asymmetric or chiral centers, and thus may exist as different stereoisomers.
  • the compounds of the present invention include all stereoisomeric forms, including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof (such as racemates), are included in the present invention In the range.
  • substituted refers to the replacement of one or more hydrogen atoms on a particular group with a particular substituent.
  • the specific substituent is the substituent described in the foregoing, or the substituent appearing in each embodiment.
  • an optionally substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position.
  • a cyclic substituent, such as a heterocycloalkyl group may be connected to another ring, such as a cycloalkyl group, to form a spirobicyclic ring system, for example, two rings share one carbon atom.
  • the R substituents when the number of substituents is greater than 1, the R substituents may be the same or different substituents, which means that when the number of substituents in a certain structure is multiple, the combination of the substituents of R may be selected from multiple types. Different types of substituents.
  • substitution applies only to sites that can be replaced by substituents, and does not include substitutions that cannot be achieved with existing chemical knowledge.
  • the compounds represented by the general formula (I) may also exist in different tautomeric forms, all of which are included in the scope of the present invention.
  • tautomers refers to structural isomers with different energies that are converted via low energy barriers.
  • the reaction generally results in the movement of a hydrogen atom or a proton accompanied by the transition of a single bond and adjacent double bonds.
  • enantiomer refers to stereoisomers that are mirror images of each other and cannot overlap.
  • Diastereomer refers to a stereoisomer that has two or more chiral neutrality and is not a mirror image.
  • Racemate refers to two stereoisomers that are mirror images of each other and have opposite optical rotations and cancel each other out.
  • “Pharmaceutically acceptable salt” refers to a drug molecule that forms a corresponding salt with a corresponding organic acid, inorganic acid, or organic base, or inorganic base, such as hydrochloric acid, formic acid, trifluoroacetic acid, succinic acid, mesylate, and the like.
  • Prodrugs refer to a class of compounds that are inactive or have low activity in vitro, and release active drugs in the body through enzymatic or non-enzymatic conversion to exert their effects.
  • Hydrophilate means a compound containing water.
  • halogen includes fluorine, chlorine, bromine or iodine.
  • hydrocarbyl refers to a substituent containing only carbon and hydrogen atoms, and includes, without limitation, methyl, ethyl, isopropyl, propyl, cyclohexyl, phenyl, and the like.
  • C1-C6 alkyl refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms and includes, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl , Sec-butyl, tert-butyl, pentyl and hexyl.
  • C1-C6 alkoxy refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms and includes, without limitation, methoxy, ethoxy, propoxy, isopropoxy and Butoxy and the like.
  • C1-C6 alkoxycarbonyl includes, without limitation, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxy Carbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexanoylcarbonyl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • Monocyclic cycloalkyl includes, without limitation, cyclopropyl, cyclobutyl, cyclopentenyl, and cyclohexyl.
  • Polycyclic cycloalkyl includes spiro, fused and bridged cycloalkyl.
  • heterocyclyl refers to containing one or more saturated and / or partially saturated monocyclic or polycyclic cyclic substituents, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur, or S (O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon; for example, propylene oxide, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, A thiomorpholinyl group; a heterocyclic group may be fused to an aryl, heteroaryl, or cycloalkyl ring, and the ring connected to the parent structure is a heterocyclic group.
  • aryl refers to a 6-14 membered all-carbon monocyclic or fused polycyclic group having a conjugated p-electron system, preferably a 6 to 10 membered ring, preferably 6 to 10 membered, more preferably a phenyl group And naphthyl, most preferably phenyl.
  • the aryl ring may be fused with a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring.
  • heteroaryl refers to a 5-14 membered aryl group having 1 to 4 heteroatoms as ring atoms, and the remaining ring atoms are carbon, wherein the heteroatoms include oxygen, sulfur, and nitrogen. It is preferably 5-10 yuan. Heteroaryl is preferably 5- or 6-membered, such as thienyl, pyridyl, pyrrolyl and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring,
  • spiroheterocyclyl refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between single rings, where one or more ring atoms are selected from nitrogen, oxygen, sulfur, or S (O) m (Where m is an integer from 0 to 2) and the remaining ring atoms are carbon.
  • Spiro heterocycles can be fused to a 6-10 membered aryl or 5-10 membered heteroaryl ring, where the ring connected to the parent structure is a spiro heterocyclic ring.
  • halogen-substituted alkyl refers to a straight-chain, branched-chain, or cyclic alkyl group substituted with a single or multiple halogens, and includes without limitation 2-bromoethyl, 2-bromopropyl, and the like.
  • alkenyl refers to an alkenyl group which may be 2-10 carbons, such as vinyl, propenyl, butenyl, styryl, phenylpropenyl.
  • alkynyl refers to an alkynyl group which may be 2-10 carbons, such as ethynyl, propynyl, butynyl, phenylethynyl, phenylpropenyl.
  • C3-C8 cycloalkyl refers to a cyclic alkyl group having 3 to 8 carbon atoms on the ring, and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • 5- to 10-membered heterocyclyl refers to containing one or more saturated and / or partially saturated rings, which includes 5 to 10 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S (O) m (where m is an integer from 0 to 2) heteroatoms, the remaining ring atoms are carbon; for example, propylene oxide, tetrahydrofuryl, pyrrolidin, tetrahydropyranyl, piperidinyl, piperazinyl , Morpholinyl, thiomorpholinyl.
  • C3-C6 heterocyclyl refers to containing one or more saturated and / or partially saturated rings, which include 3 to 6 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S ( O)
  • a heteroatom of m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon; for example, propylene oxide, tetrahydrofuryl, pyrrolidin, tetrahydropyranyl, piperidinyl, piperazinyl.
  • hydroxy-substituted alkyl refers to a linear, branched, or cyclic alkyl group substituted with a single or multiple hydroxyl groups, including without limitation (S) -1-hydroxyisobut-2-yl, (R) 1-hydroxyisobut-2-yl and the like.
  • the invention also includes any of the new intermediates disclosed herein.
  • One aspect of the present invention provides a method for preparing a compound represented by the general formula (I), the method being selected from one of the following methods:
  • R 1 , R 2 , R 3 , R 4 and X 2 are the same as the foregoing definitions;
  • n 1 is an integer from 1 to 7;
  • Step 1-1 Compounds 1A and 1B are used as solvents in dipolar organic solvents such as DMF, DMA, Pd catalyst (such as Pd (PPh 3 ) 4 , Pd (PPh 3 ) 2 Cl 2, etc.), and monovalent copper catalyst (iodination Ketene) and a base (such as triethylamine or diisopropylethylamine, etc.) at room temperature or under heating conditions through a Sonogashira coupling reaction to obtain compound 1C;
  • dipolar organic solvents such as DMF, DMA, Pd catalyst (such as Pd (PPh 3 ) 4 , Pd (PPh 3 ) 2 Cl 2, etc.), and monovalent copper catalyst (iodination Ketene) and a base (such as triethylamine or diisopropylethylamine, etc.)
  • Step 1-2 Compound 1C is reduced to compound 1D by hydrogen under the catalytic conditions of Pd / C, Raney nickel or other metal catalysts (such as Wilkinson catalyst),
  • Step 1-3 Compound 1D and hydroxyquinoline 1E (or substituted or unsubstituted hydroxyquinoline and its analogs, substituted or unsubstituted naphthol and its analogs, etc.) in triphenylphosphine and azodicarboxylic acid di Reaction under isopropyl ester conditions to obtain compound 1F;
  • Step 1-4 Compound 1D is reacted in the presence of triphenylphosphine and carbon tetrabromide to obtain compound 1G;
  • Step 1-5 Compound 1G and nitrogen-containing heterocyclic compound 1H (compound 1H is various amine compounds containing A group in the foregoing definition) are reacted in the presence of sodium iodide to obtain compound 1I;
  • R 1 , R 2 , R 3 , R 4 and X 2 are the same as the foregoing definitions;
  • n 1 is an integer from 1 to 7;
  • the definition is the same as the definition of i) heterocyclyl, ii) fused heterocyclyl, and iii) spiroheterocyclyl in A;
  • G2 is a protecting group selected from TBS, Trit, and benzyl;
  • Step 2-1 Compounds 2A and 2B are reacted in aprotic solvents (such as acetonitrile, DMF, etc.), Pd catalysts (palladium (II) acetate, Pd (PPh 3 ) 4 etc.), phosphine ligands (such as triphenyl groups) Phosphine, s-Phos, etc.), organic base (triethylamine or diisopropylethylamine, etc.) in the presence of a heating reaction to generate a polysubstituted olefin derivative (Heck coupling reaction), to generate a polysubstituted olefin derivative 2C;
  • aprotic solvents such as acetonitrile, DMF, etc.
  • Pd catalysts palladium (II) acetate, Pd (PPh 3 ) 4 etc.
  • phosphine ligands such as triphenyl groups
  • organic base triethylamine or diiso
  • Step 2-2 Compound 2C is reduced to compound 2D by hydrogen under the catalytic conditions of Pd / C or other metal catalysts (such as Wilkinson catalyst);
  • Step 2-3 The dried tetrahydrofuran is used as a solvent to obtain a piperidone derivative 2E by ring closing in the presence of potassium tert-butoxide;
  • Step 2-4 Compound 2E is deprotected to obtain compound 2F under acidic conditions or in the presence of TBAF;
  • Step 2-5 Compound 2F is reacted in the presence of triphenylphosphine and carbon tetrabromide to obtain compound 2G;
  • Step 2-6 Compound 2G and nitrogen-containing heterocyclic compound 2H (compound 2H is various amine compounds containing A group in the above definition) are reacted in the presence of sodium iodide to obtain compound 2I
  • R 1 , R 2 , R 3 , R 4 , and X 2 are the same as the foregoing definitions;
  • n 2 is an integer from 1 to 7;
  • G 3 -NH 2 is various kinds of aromatic amines or fatty amine compounds used in the examples of the present invention.
  • Step 3-1 Compounds 3A and 3B are reacted in the presence of trifluoroacetic anhydride and tert-butanol to obtain compound 3C;
  • Step 3-2 Compound 3C and 3D are reacted in the presence of potassium carbonate to obtain compound 3E;
  • Step 3-3 ring closure in the presence of compound 3E potassium tert-butoxide to obtain a piperidone derivative 3F;
  • Step 3-4 Compound 3F is deprotected under hydrochloric acid to obtain compound 3G.
  • Step 3-5 Compound 3G and nitrogen-containing heterocyclic compound 3H (compound 3H is various amine compounds containing A group in the above definition) in the presence of a condensing agent (HATU, HOBt) and a base (triethylamine), Condensation to obtain compound 3I;
  • a condensing agent HATU, HOBt
  • a base triethylamine
  • Step 3-6 Compound 3G and compound 3J are condensed in the presence of a condensing agent (HATU, HOBt) and a base (triethylamine) to obtain compound 3K;
  • a condensing agent HATU, HOBt
  • a base triethylamine
  • R 1 , R 2 , R 3 , R 4 , X 2 , Ra 9 , R 11 and n 11 are the same as the foregoing definitions;
  • G 4 and G 5 are protective groups selected from tert-butoxycarbonyl or benzyl;
  • G 6 -NH 2 is various kinds of aromatic amines or fatty amine compounds
  • Step 4-1 Compounds 4A and 4B are in a Pd catalyst (such as Pd (PPh 3 ) 4 , Pd (PPh 3 ) 2 Cl 2, etc.), a monovalent copper catalyst (ketone iodide), and a base (such as triethylamine or In the presence of diisopropylethylamine, etc.), compound 4C is obtained by Sonogashira coupling reaction in the presence of room temperature or heating conditions, in the presence of a monovalent copper catalyst and a base;
  • a Pd catalyst such as Pd (PPh 3 ) 4 , Pd (PPh 3 ) 2 Cl 2, etc.
  • ketone iodide ketone iodide
  • a base such as triethylamine or In the presence of diisopropylethylamine, etc.
  • Step 4-2 Compound 4C is reduced to compound 4D by hydrogen under the catalytic conditions of Pd / C, Raney nickel or other metal catalysts (such as Wilkinson catalyst);
  • Step 4-3 Compound 4D is condensed under the conditions of amine derivative 4E and the condensing agents HATU and HOBt to obtain compound 4F;
  • Step 4-4 The protective group is removed from the compound 4F under hydrochloric acid. After the reaction, the compound 4G is spin-dried and reacted with the corresponding acid chloride or carboxylic acid to obtain the compound 4G.
  • Step 4-5 After the compound 4D and the o-phenylenediamine derivative 4H are reacted under the conditions of the condensing agents HATU and HOBt, the compound 4I is obtained under heating under acidic conditions;
  • Step 4-6 Remove the protective group of compound 4I under the condition of hydrochloric acid, and then spin-dry and react with the corresponding acid chloride or carboxylic acid to obtain compound 4J;
  • R 1 , R 2 , R 3 , R 4 , and X 2 are the same as the foregoing definitions;
  • n 3 is an integer from 1 to 7;
  • Ar is a 6-10 membered aryl group and a 5-10 membered heteroaryl group, and the aryl group or heteroaryl group is optionally substituted by one or more R 5 substituents, and R 5 has the same definition as the foregoing definition;
  • Step 5-1 Compounds 5A and 5B are reacted under the conditions of triphenylphosphine and diisopropyl azodicarboxylate to obtain compound 5C;
  • Step 5-2 Compound 5C is reacted in the presence of potassium carbonate to obtain compound 5D;
  • Step 5-3 Compound 5D is deprotected under the condition of hydrochloric acid to obtain compound 5E;
  • Step 5-4 Compound 5E and compound 5F are reacted under basic conditions (such as triethylamine or diisopropylethylamine, etc.) to obtain compound 5G;
  • Step 5-5 Compound 5E and nitrogen-containing heterocyclic compound 5H (compound 5H is various amine compounds containing A group in the above definition) under N, N'-carbonyldiimidazole and basic conditions, the compound is obtained by reaction 5I.
  • R 1 , R 2 , R 3 , R 4 , and X 2 are the same as the foregoing definitions;
  • n 4 is an integer from 1 to 7;
  • Step 6-1 Compounds 6A and 6B are reacted in the presence of potassium carbonate to obtain compound 6C;
  • Step 6-2 Compound 6C is reacted in the presence of potassium tert-butoxide to obtain compound 6D;
  • Step 6-3 Compound 6D and nitrogen-containing heterocyclic compound 6E (compound 6E is various amine compounds containing the A group in the above definition) are reacted under basic conditions to obtain compound 6F.
  • R 1 , R 2 , R 3 , and R 4 are the same as the foregoing definitions;
  • n 4 is an integer from 1 to 7;
  • Step 7-1 Compound 7A and 7B chloromethyl methyl ether are reacted in the presence of sodium hydride to obtain compound 7C;
  • Step 7-2 Compound 7C is reacted in the presence of 7D and azobisisobutyronitrile to obtain compound 7E;
  • Step 7-3 Compound 7E is reacted at 7F under basic conditions (such as triethylamine or diisopropylethylamine, etc.) to obtain compound 7G;
  • Step 7-4 Compound 7G is reacted under acidic conditions (hydrochloric acid, dioxane) to obtain compound 7H;
  • Step 7-5 Compounds 7I and 7F are reacted under basic (such as triethylamine or diisopropylethylamine) conditions to obtain compound 7H;
  • Step 7-6 Compound 7H and 6B are reacted in the presence of potassium carbonate to obtain compound 7J;
  • Step 7-7 Compound 7J and nitrogen-containing heterocyclic compound 7K (compound 7K is various amine compounds containing A group in the above definition) in basic (such as triethylamine or diisopropylethylamine, etc. ) Conditions, the reaction gives compound 7L.
  • basic such as triethylamine or diisopropylethylamine, etc.
  • Another object of the present invention is to provide a compound represented by the general formula (I), its tautomer, diastereomer, racemate, metabolic precursor, metabolite, isotope compound, pharmaceutically acceptable salt , Ester, prodrug or hydrate thereof, characterized in that it can regulate the activity of CRL4 CRBN E3 ubiquitin ligase.
  • Another object of the present invention is to provide a pharmaceutical composition, characterized in that it comprises a therapeutically effective dose of a compound represented by the general formula (I), its tautomer, diastereomer, racemate, Metabolic precursors, metabolites, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof, and at least one other pharmaceutically acceptable carrier.
  • a compound represented by the general formula (I) its tautomer, diastereomer, racemate, Metabolic precursors, metabolites, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof, and at least one other pharmaceutically acceptable carrier.
  • Another object of the present invention is to provide a pharmaceutical composition, characterized in that it comprises a therapeutically effective dose of a compound such as the general formula (I), its tautomers, diastereomers, racemates, pre-metabolic Body, metabolites, isotope compounds, pharmaceutically acceptable salts, esters, prodrugs, or hydrates thereof, and one or more ingredients having medicinal therapeutic activity.
  • a compound such as the general formula (I)
  • the enantiomer, diastereomer, racemate, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof may be combined with another or A variety of pharmaceutical therapeutically active ingredients produce synergistic effects in the prevention or treatment of specific diseases or dysfunctions.
  • the compound of formula (I) according to claim 1 of the present invention can also reduce or eliminate the additional One or more of the toxic and side effects of the pharmaceutical active ingredients in preventing or treating a specific disease or dysfunction, and vice versa.
  • Another object of the present invention is to provide another one or more ingredients having medicinal therapeutic activity as described above, including macromolecular compounds, such as proteins, polysaccharides, nucleic acids, and the like; and small molecule compounds such as inorganic compounds, organic metal compounds , Small organic compounds of synthetic or natural origin.
  • macromolecular compounds such as proteins, polysaccharides, nucleic acids, and the like
  • small molecule compounds such as inorganic compounds, organic metal compounds , Small organic compounds of synthetic or natural origin.
  • Another object of the present invention is to provide compounds of general formula (I), which are tautomers, diastereomers, racemates, metabolic precursors, metabolites, isotope compounds, pharmaceutically acceptable salts, esters , A prodrug or a hydrate thereof, characterized in that it is used to prepare a drug for treating diseases related to CRL4 CRBN E3 ubiquitin ligase, preferably, said diseases include, without limitation, cancer, inflammation, pain, nervous system Diseases and diseases of the immune system.
  • the compound of the present invention when it contains a basic group, it can be prepared into pharmaceutically acceptable salts, including inorganic acid salts and organic acid salts.
  • suitable acids include: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid, and acidic amino acids such as aspartic acid and glutamic acid.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by the general formula (I), a tautomer, a diastereomer, a racemate, a metabolic precursor, One or more of a metabolite, an isotope compound, a pharmaceutically acceptable salt, a prodrug, a solvate, a hydrate, and a crystalline form, and at least one excipient, diluent, or carrier.
  • a typical formulation is prepared by mixing a compound represented by the general formula (I) of the present invention and a carrier, diluent or excipient.
  • Suitable carriers, diluents or excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents , Water and other substances.
  • the particular carrier, diluent or excipient used will depend on the manner and purpose of use of the compounds of the invention. Solvents are generally selected on the basis of solvents considered by those skilled in the art to be safe and effective for administration to mammals.
  • safe solvents are non-toxic aqueous solvents such as pharmaceutical water, and other non-toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (such as PEG400, PEG300), and the like.
  • the formulation may also include one or more buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, sunscreens, glidants, processing aids,
  • the colorant, sweetener, flavoring agent, flavoring agent, or other known additive enables the compound represented by the formula (I) to be manufactured or used in an acceptable form.
  • two or more drugs may be used separately or in combination, preferably in the form of a pharmaceutical composition.
  • the compounds or pharmaceutical compositions of the invention of formula (I) can be administered separately or together in any of the known forms of oral, intravenous, rectal, vaginal, transdermal, and other topical or systemic administration. Medication to the subject.
  • compositions may also contain one or more buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, sunscreen agents, glidants, processing aids Agents, colorants, sweeteners, flavoring agents, flavoring agents, or other known additives to make the pharmaceutical composition in an acceptable form or use.
  • Solid dosage forms for oral administration may include capsules, tablets, powders or granules.
  • the compound or pharmaceutical composition of the invention is mixed with at least one inert excipient, diluent or carrier.
  • Suitable excipients, diluents or carriers include substances such as sodium citrate or dicalcium phosphate, or starch, lactose, sucrose, mannitol, silicic acid, etc .; binders such as carboxymethyl cellulose, alginic acid Salt, gelatin, polyvinylpyrrolidone, sucrose, gum arabic, etc .; wetting agents such as glycerol; disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, specific complex silicates, sodium carbonate, etc.
  • Solution blockers such as paraffin; absorption enhancers such as quaternary ammonium compounds; adsorbents such as kaolin, bentonite; etc.
  • lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate Wait.
  • the dosage form may also include buffering agents.
  • Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules using lactose and high molecular weight polyethylene glycols as excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage form may contain an inert diluent such as water or other solvents commonly used in the art; a solubilizer and an emulsifier such as ethanol, isopropyl alcohol, ethyl carbonate, acetic acid Ethyl ester, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide; oils (such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, etc. ); Glycerol; tetrahydrofurfuryl alcohol; fatty acid esters of polyethylene glycol and sorbitan; or a mixture of several of these substances, and the like.
  • an inert diluent such as water or other solvents commonly used in the art
  • composition may also include excipients such as one or more of wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents and flavoring agents.
  • excipients such as one or more of wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents and flavoring agents.
  • a carrier such as a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, microcrystalline Cellulose, aluminum hydroxide, bentonite, agar and tragacanth, or a mixture of several of these.
  • a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, microcrystalline Cellulose, aluminum hydroxide, bentonite, agar and tragacanth, or a mixture of several of these.
  • compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing a compound or combination of the invention with a suitable non-irritating excipient or vehicle such as cocoa butter, polyethylene Diol or suppository wax, which is solid at normal room temperature and liquid at body temperature, can be melted in the rectum or vagina to release the active compound.
  • a suitable non-irritating excipient or vehicle such as cocoa butter, polyethylene Diol or suppository wax, which is solid at normal room temperature and liquid at body temperature, can be melted in the rectum or vagina to release the active compound.
  • the compounds or pharmaceutical compositions of the invention can be administered in other topical dosage forms, including creams, powders, sprays and inhalants.
  • the drug can be mixed under sterile conditions with pharmaceutically acceptable excipients, diluents or carriers, and any preservatives, buffers or propellants required.
  • Ophthalmic formulations, ointments, powders and solutions are also intended to be included within the scope of the present invention.
  • Yet another object of the present invention is to provide compounds such as the general formula (I), which are tautomers, diastereomers, racemates, metabolic precursors, metabolites, isotope compounds, pharmaceutically acceptable salts, Esters, prodrugs or hydrates, or crystalline forms thereof can be used in monotherapy or in combination therapy.
  • the other one or more ingredients having medical therapeutic activity include macromolecular compounds such as proteins (antibodies or polypeptides), polysaccharides and nucleic acids (DNA or RNA), etc .; and small molecule compounds such as inorganic compounds, organic Metal compounds, organic or small-molecule compounds of synthetic or natural origin; also include radiation, surgery, cell therapy, hormone therapy, or cytokine therapy.
  • macromolecular compounds such as proteins (antibodies or polypeptides), polysaccharides and nucleic acids (DNA or RNA), etc .
  • small molecule compounds such as inorganic compounds, organic Metal compounds, organic or small-molecule compounds of synthetic or natural origin; also include radiation, surgery, cell therapy, hormone therapy, or cytokine therapy.
  • the compound of formula (I) according to claim 1 of the present invention, its prodrug, enantiomer, diastereomer, racemate and mixtures thereof, and pharmaceutically acceptable salts thereof, Crystal hydrates and solvates can work synergistically with one or more other ingredients
  • the compound of formula (I) according to claim 1 of the present invention can also reduce or eliminate the toxic and side effects of one or more pharmaceutical active ingredients in the prevention or treatment of specific diseases or dysfunctions, and vice versa.
  • Yet another object of the present invention is to provide compounds such as the general formula (I), which are tautomers, diastereomers, racemates, metabolic precursors, metabolites, isotope compounds, pharmaceutically acceptable salts, Esters, prodrugs or hydrates thereof, for use in the preparation of a medicament for the treatment or prevention of diseases in which CRL4 CRBN E3 ubiquitin ligase is involved.
  • Related diseases described by the present invention involving CRL4 CRBN E3 ubiquitin ligase include, without limitation, tumors, central system diseases, and immune diseases.
  • the diseases or dysfunctions include but are not limited to: cancer, angiogenesis-related diseases or dysfunctions, pain (including but not limited to complex local pain syndrome), macular degeneration, and related dysfunction , Skin diseases, pulmonary dysfunction, immunodeficiency diseases, central nervous system damage and dysfunction, TNF ⁇ -related diseases or dysfunction.
  • the cancer includes (but is not limited to): skin cancer (such as melanoma), lymphatic cancer, breast cancer, cervical cancer, uterine cancer, digestive tract cancer, lung cancer, ovarian cancer, prostate cancer , Colon cancer, rectal cancer, oral cancer, brain tumor, head and neck cancer, throat cancer, testicular cancer, kidney cancer, pancreatic cancer, spleen cancer, liver cancer, bladder cancer, laryngeal cancer and AIDS-related cancer.
  • the compounds provided by the present invention are also effective for hematomas and myeloma, for example, they can be used to treat multiple myeloma, lymphoma, and acute and chronic leukemia.
  • the compounds provided by the present invention can also be used to prevent or treat primary tumors and metastatic tumors.
  • deuterium (D) used in the present invention is a stable form of non-radioactive isotope of hydrogen, and its atomic weight is 2.0144. Hydrogen in nature exists as a mixture of H (hydrogen or tritium), D (2H or deuterium), and T (3H or tritium) isotopes, where the abundance of deuterium is 0.0156%. According to common technical knowledge in the art, in the structural formula of all compounds containing natural hydrogen atoms, the hydrogen atom actually represents a mixture of H, D and T. Therefore, when the deuterium abundance at any site in a compound is greater than 0.0156% of its natural abundance, these compounds should be considered unnatural or deuterium-rich.
  • isotopic compound used in the present invention refers to a compound of the general formula (I), a pharmaceutically acceptable salt, solvate, stereoisomer, metabolite, or prodrug of the present invention, which contains one or more natural compounds. Or atomic isotopes of unnatural abundance.
  • the present invention also covers isotopically-labeled compounds of the invention, except for the fact that one or more atoms have been replaced by an atom having an atomic mass or mass number different from one of the atomic masses or mass numbers common in nature. The authors are the same.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as: 2 hydrogen, 3 hydrogen, 11 carbon, 13 carbon, 14 carbon , 13 nitrogen, 15 nitrogen, 15 oxygen, 17 oxygen, 18 oxygen, 31 phosphorus, 32 phosphorus, 35 sulfur, 18 fluorine, 123 iodine, 125 iodine and 36 chlorine.
  • Certain isotopically labeled compounds of the invention are used in compound and / or substrate tissue distribution tests. Tritiated (ie 3H) and carbon-14 (ie 14C) isotopes are particularly preferred because they are easy to prepare and detect. Furthermore, substitution of heavier isotopes such as deuterium (i.e., 2H) can provide certain therapeutic advantages (e.g., increased half-life in the body or reduced dose requirements) due to greater metabolic stability, and may therefore be preferred in some cases of.
  • Positron emission isotopes such as 15O, 13N, 11C, and 18F are used in positron emission tomography (PET) studies to check substrate receptor occupancy.
  • Isotopically-labeled compounds of the invention can generally be prepared by following procedures similar to those disclosed in the protocol and / or the examples below, by replacing non-isotopically-labeled reagents with isotopically-labeled reagents. All isotopic variations of the compounds of the invention, whether or not they are radioactive, are included within the scope of the invention.
  • the raw materials in the present invention can be obtained from commercial sources, such as the main reagents purchased from Sinopharm Chemical Reagent Co., Ltd., or prepared by methods inhibited in the art, or prepared according to the methods described in the present invention.
  • Step 2 5-Amino-4- (4- (2-bromoethoxy) -1-oxoisoindolinoline-2-)-5-oxovalerate methyl ester (100 mg, 0.25 mmol, 1.0 eq) was dissolved in 20 mL of anhydrous tetrahydrofuran and stirred at -78 ° C for 15 minutes. Potassium tert-butoxide (31 mg, 0.28 mmol, 1.1 eq) was added and the reaction was continued for 90 minutes. After the reaction was completed, 1 mL of 1N hydrochloric acid was added to quench the reaction at -78 ° C.
  • Phosphine (159 mg, 0.605 mmol, 2 eq.) was dissolved in 20 mL of dry THF, and diisopropyl azodicarboxylate (120 ⁇ L, 0.605 mmol, 2 eq.) was added under the protection of nitrogen. The resulting mixed solution was stirred and reacted at room temperature for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure.
  • Step 2 Add the compound 5-amino-4- (4-hydroxy-1-oxoisoindolinoline-2-)-5-oxovalerate methyl ester (100mg, 0.34mmol, 1.0eq) to 100ml
  • 3-tert-butyldimethylsiloxy-1-propanol 174 mg, 0.85 mmol, 2.5 eq
  • triphenylphosphine 178 mg, 0.68 mmol, 2 eq
  • the reaction system was replaced with nitrogen, and 20 mL of dry tetrahydrofuran was added.
  • diisopropyl azodicarboxylate 134 ⁇ L, 0.68 mmol, 2 eq. Reaction at room temperature for 1 h. After completion of the reaction, the solvent was removed and the target product was obtained by column chromatography.
  • ESI-MS [M + H] + m / z 465.60.
  • Step 3 The product obtained in the previous step was added to a 50 mL round bottom flask, 20 mL of tetrahydrofuran was added, and tetrabutylammonium fluoride (0.64 ml, 0.64 mmol) was added to react overnight at room temperature.
  • Step 4 Add the compound 3- (4- (3-hydroxypropoxy) -1-oxoisoindoleline-2-) piperidine-2,6-dione (50 mg, 0.16 mmol, 1.0 eq) In a 100 mL round bottom flask, 4-hydroxyquinoline (68 mg, 0.47 mmol, 3 eq) and triphenylphosphine (82 mg, 0.31 mmol, 2 eq) were added. N 2 was exchanged and tetrahydrofuran (20 ml) was added. To the reaction system was added diisopropyl azodicarboxylate (62 ul, 0.31 mmol, 2 eq). Reaction at room temperature for 1 h.
  • Step 2 Add the compound 5-amino-4- (4-hydroxy-1-oxoisoindolinoline-2-)-5-oxovalerate methyl ester (100mg, 0.34mmol, 1.0eq) to 100mL
  • 4-tert-butyldimethylsiloxy-1-butanol 174 mg, 0.85 mmol, 2.5 eq
  • triphenylphosphine 178 mg, 0.68 mmol, 2 eq
  • Step 3 Add the mixture obtained in the previous step to a 50 ml round bottom flask, add 20 ml of tetrahydrofuran, add tetrabutylammonium fluoride (0.34 ml, 0.34 mmol, 1 eq) and react overnight at room temperature.
  • Step 4 Add compound- (4- (4-hydroxybutoxy) -1-oxoisoindolinline-2-) piperidine-2,6-dione (50 mg, 0.15 mmol, 1.0 eq) to In a 100 mL round bottom flask, 4-hydroxyquinoline (65 mg, 0.45 mmol, 3 eq) and triphenylphosphine (79 mg, 0.30 mmol, 2 eq) were added. N 2 was exchanged and tetrahydrofuran (20 ml) was added. Diisopropyl azodicarboxylate (59ul, 0.30mmol, 2eq) was added to the reaction system, and the reaction was performed at room temperature for 1 hour.
  • Step 3 5-Amino-4- (4- (4-((2-cyclopropylquinoline-4-) oxy) butoxy) -1-oxoisoindolin-2-)-5 -Methyl oxovalerate (40 mg, 0.075 mmol, 1 eq) was dissolved in 10 mL of dry tetrahydrofuran, potassium tert-butoxide (8.5 mg, 0.075 mmol, 1 eq) was added under ice bath conditions, and the reaction was detected after 10 minutes. After the reaction was completed, 5 ul of formic acid was added to quench the reaction, the solvent was removed, and the product was purified by HPLC to obtain 21.5 mg of the product as a white solid with a yield of 57%.
  • Step 2 2-ethylquinoline-1-phenol (100 mg, 0.57 mmol, 1 eq), 4-methoxymethoxy-1-butanol (1.16 g, 8.66 mmol, 15 eq), triphenylphosphine (2.27 g, 8.66 mmol, 15 eq) was dissolved in 40 mL of tetrahydrofuran, and diisopropyl azodicarboxylate (1.75 g, 8.66 mmol, 15 eq) was added at room temperature, and the reaction was performed at room temperature for 2 hours.
  • Step 4 Compound 5-amino-4- (4-hydroxy-1-oxoisoindolinline-2-)-5-oxovalerate methyl ester (50 mg, 0.17 mmol, 1 eq), 2-ethyl 4- (4-hydroxybutoxy) quinoline (100 mg, 0.34 mmol, 2 eq), triphenylphosphine (90 mg, 0.34 mmol, 2 eq) was added to a 50 mL round bottom flask, 20 mL of tetrahydrofuran was added, and azo was added Diisopropyl diformate (67ul, 0.34mmol, 2eq) was reacted at room temperature for 2h.
  • Step 5 5-Amino-4- (4- (4-((2-ethylquinoline-4-) oxy) butoxy) -1-oxoisoquinoline-2-)-5-oxo Methyl valproate (72 mg, 0.14 mmol, 1.0 eq) was dissolved in 10 mL of dry tetrahydrofuran, and potassium tert-butoxide (16 mg, 0.14 mmol, 1 eq) was added under ice bath conditions, and the reaction was detected after 10 minutes.
  • Step 2 Add 5- (methoxymethoxy) -1-pentanol (296mg, 2.04mmol, 3.0eq) to a 100ml round bottom flask, and add 4-hydroxyquinoline (110mg, 0.68mmol, 1eq) , Triphenylphosphine (357 mg, 1.36 mmol, 2 eq). N 2 was exchanged and tetrahydrofuran (20 ml) was added. To the reaction system was added diisopropyl azodicarboxylate (268ul, 1.36mmol, 2eq). Reaction at room temperature for 1 h.
  • Step 3 The compound 4- (5- (methoxymethoxy) pentoxy) quinoline (147 mg, 0.53 mmol) was transferred to a 100 ml round bottom flask, and 10 ml of dioxane hydrochloride and 1 ml of methanol were added. The obtained mixed system was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was swirled off, a small amount of ammonia methanol was added, and the solvent was swirled off, and purified by column chromatography to obtain 124 mg (100%) of a white solid.
  • ESI-MS [M + H] + m / z 276.57.
  • Step 4 Compound 5-amino-4- (4-hydroxy-1-oxoisoindolinoline-2-)-5-oxovalerate methyl (50 mg, 0.17 mmol, 1 eq), 5- ( Quinoline-4-oxy) -1-pentanol (100mg, 0.34mmol, 2eq), triphenylphosphine (90mg, 0.34mmol, 2eq) was added to a 50ml round bottom flask, 20ml tetrahydrofuran was added, and azodicarboxylic acid was added Diisopropyl ester (67ul, 0.34mmol, 2eq) was reacted at room temperature for 2h.
  • Step 5 5-Amino-4- (5- (4-((quinoline-4-) oxy) pentyloxy) -1-oxoisoindolinoline-2-)-5-oxovaleric acid Methyl ester (85 mg, 0.17 mmol, 1.0 eq) was dissolved in 10 mL of dry tetrahydrofuran, and potassium tert-butoxide (17 mg, 0.17 mmol, 1 eq) was added under ice-cooling, and the reaction was detected after 10 minutes.
  • Step 2 Add 6- (methoxymethoxy) -1-hexanol (180 mg, 1.24 mmol, 2.0 eq) to a 100 mL round bottom flask, and add 4-hydroxyquinoline (100 mg, 0.62 mmol, 1 eq) , Triphenylphosphine (330 mg, 1.24 mmol, 2 eq). N 2 was exchanged and tetrahydrofuran (20 ml) was added. To the reaction system was added diisopropyl azodicarboxylate (207 ul, 1.24 mmol, 2 eq). Reaction at room temperature for 1 h.
  • Step 3 The compound 4- (6- (methoxymethoxy) hexyloxy) quinoline (140 mg, 0.48 mmol) was transferred to a 100 mL round bottom flask, and 10 mL of dioxane hydrochloride and 1 mL of methanol were added. The obtained mixed system was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was swirled off, and a small amount of ammonia methanol was added.
  • Step 4 The compound 5-amino-4- (4-hydroxy-1-oxoisoindolinoline-2-)-5-oxovalerate methyl ester (50 mg, 0.17 mmol, 1 eq), 6- ( Quinoline-4-oxy) -1-hexanol (83mg, 0.34mmol, 2eq), triphenylphosphine (90mg, 0.34mmol, 2eq) was added to a 50ml round bottom flask, 20ml tetrahydrofuran was added, and azodicarboxylic acid was added Diisopropyl ester (67ul, 0.34mmol, 2eq) was reacted at room temperature for 2h.
  • Step 5 5-Amino-5-oxo-4- (1-oxo-4-((6- (quinoline-4-oxo) hexyl) oxy) isoindolinoline-2-) pentanoic acid
  • the ester 63 mg, 0.19 mmol, 1.0 eq
  • potassium tert-butoxide 22 mg, 0.19 mmol, 1 eq
  • Example 33 4- (2,3-dichlorophenyl) -N- (4-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindolinoline- 4-) oxy) butyl) piperazine-1-carboxamide (33)
  • Example 34 4- (2,3-dichlorophenyl) -N- (3-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindoleline- 4-) oxy) propyl) piperidine-1-carboxamide (34)
  • Example 36 4- (4- (4- (2- (2,6-dioxopiperidine-3-)-1-oxoisoindolline-4-) butyl) piperazine-1- Benzonitrile (36)
  • Step 1 Place 4-hydroxyquinoline (100mg, 0.69mmol, 1.0eq) in a 50ml round bottom flask, add 4-methoxymethoxy-1-butanol (278mg, 2.07mmol, 2eq), and Phenylphosphine (543 mg, 2.07 mmol, 2 eq).
  • the reaction system was replaced with nitrogen, and 15 mL of dry tetrahydrofuran was added.
  • diisopropyl azodicarboxylate (408 ⁇ L, 2.07 mmol, 2 eq). Reaction at room temperature for 1 h. The reaction was monitored by TLC and the reaction was concentrated under reduced pressure. 173 mg of the target product was obtained by column chromatography with a yield of 96%.
  • Step 2 Place 4- (4-methoxymethoxybutoxy) quinoline in a 50 mL round bottom flask, and add 10 mL of 4M dioxane hydrochloride and 1 mL of methanol. The reaction was carried out at room temperature for 1 hour. After the reaction was monitored by LC-MS, the reaction was completed, concentrated under reduced pressure, saturated sodium bicarbonate solution was added, the mixture was extracted with ethyl acetate, and the layers were separated. The organic layer was washed with saturated sodium chloride and dried. .
  • Step 3 Place 2- (2,6-dioxopiperidine-3-)-4-hydroxyisoindolin-1,3-dione (35mg, 0.128mmol) in a 50ml round bottom flask and add 4- (quinoline-4-oxo) -1-butanol (56 mg, 0.256 mmol, 2 eq), triphenylphosphine (67 mg, 0.256 mmol, 2 eq). The reaction system was replaced with nitrogen, and 5 mL of dry tetrahydrofuran was added. To the reaction system was added diisopropyl azodicarboxylate (51 ⁇ L, 0.256 mmol, 2 eq). Reaction at room temperature for 1 h.
  • Step 2 (S) -4-hydroxy-2- (3-methyl-2,6-dioxopiperidine-3-) isoindolin-1,3-dione (200 mg, 0.69 mmol, 1.0 eq) was dissolved in 20 mL of acetonitrile, and 1,3-dibromopropane (681 mg, 3.54 mmol, 3.0 eq) and anhydrous potassium carbonate (96 mg, 0.69 mmol, 1.0 eq) were added. The reaction system was reacted at 50 ° C for 24 hours. After the reaction, the solvent was swirled off.
  • Step 3 (S) -4- (3-Bromopropyl) -2- (3-methyl-2,6-dioxopiperidine-3-) isoindolin-1,3-dione (40mg, 0.098mmol, 1.0eq) dissolved in 3mL DMSO, 4- (2-chlorophenyl) piperidine-4-carbonitrile hydrochloride (38mg, 0.147mmol, 1.5eq), triethylamine (9.89mg , 0.980 mmol, 10.0 eq), reacted at 40 ° C overnight.
  • Example 51 4- (3-chlorophenyl) -1- (5- (2- (2,6-dioxopiperidine-3-)-1-oxoisoindoleline-4-) pentane Yl) piperidine-4-carbonitrile (51)
  • Example 55 4- (2-chlorophenyl) -1- (3-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindolin-4-) (Oxy) propyl) piperidine-4-carbonitrile (55)
  • Example 57 4- (3-chlorophenyl) -1- (3-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindolin-4-) (Oxy) propyl) piperidine-4-carbonitrile (57)
  • Example 61 1- (3-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindoleline-4-) oxo) propyl) -4- (2 -Fluorophenyl) piperidine-4-carbonitrile (61)
  • Example 63 1- (3-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindololine-4-) oxo) propyl) -4- (3 -Fluorophenyl) piperidine-4-carbonitrile (63)
  • Example 64 4- (2-chlorophenyl) -1- (2-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindolin-4-) (Oxy) ethyl) piperidine-4-carbonitrile (64)
  • Example 65 1- (3-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindoleline-4-) oxo) propyl) -4- (4 -Fluorophenyl) piperidine-4-carbonitrile (65)
  • Example 68 4- (2-Chloro-6-fluorophenyl) -1- (3-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindoleline -4-) oxy) propyl) piperidine-4-carbonitrile (68)
  • Example 70 4- (2,4-dichlorophenyl) -1- (3-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindoleline- 4-) oxy) propyl) piperidine-4-carbonitrile (70)
  • Example 71 1- (3-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindololine-4-) oxo) propyl) -4- (3 -Trifluoromethoxyphenyl) piperidine-4-carbonitrile (71)
  • Example 72 4- (4-chloro-2-fluorophenyl) -1- (3-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindoleline -4-) oxy) propyl) piperidine-4-carbonitrile (72)
  • Example 73 1- (3-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindololine-4-) oxo) propyl) -4- (4 -Trifluoromethoxyphenyl) piperidine-4-carbonitrile (73)
  • Example 74 4- (2-chloro-4-fluorophenyl) -1- (3-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindoleline -4-) oxy) propyl) piperidine-4-carbonitrile (74)
  • Example 75 4- (3-chlorophenyl) -1- (4-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindolin-4-) (Oxy) butyl) piperidine-4-carbonitrile (75)
  • Example 77 4- (4-chlorophenyl) -1- (4-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindoleline-4-) (Oxy) butyl) piperidine-4-carbonitrile (77)
  • Example 78 1- (3-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindoleline-4-)-oxo-) propyl) -4- (2-Trifluoromethoxyphenyl) piperidine-4-carbonitrile (78)
  • Step 2 Methyl 3-methoxymethoxy-2-methylbenzoate (25.98 g, 123.56 mmol, 1.0 eq) was dissolved in 200 ml of carbon tetrachloride, and NBS (23.09 mmol, 129.24 mmol, 1.05 mmol) was added. ), AIBN (2.03 g, 12.36 mmol, 0.1 eq), reflux at 88 ° C for 6 hours. After the reaction was completed, the solvent was swirled away under reduced pressure, and purified by column chromatography to obtain 35.73 g of a brown solid. The yield was 100%.
  • Step 3 methyl 2-bromomethyl-3-methoxymethoxybenzoate (353 mg, 1.22 mmol, 1.0 eq), (S) -3-aminoo-3-methylpiperidine-2 , 6-dione hydrochloride monohydrate (294 mg, 1.22 mmol, 1.0 eq) was dissolved in 20 ml of toluene. Triethylamine (136 mg, 1.34 mmol, 1.1 eq) was added and refluxed at 120 ° C for 24 hours. After completion of the rebate, the toluene was removed and purified by column chromatography to obtain 232 mg of a white solid with a yield of 61%.
  • Step 4 (S) -3- (4-methoxymethoxy-1-oxoisoindolin-2-)-3-methylpiperidine-2,6-dione (232 mg, 0.73 mmol, 1.0 eq) was placed in a 50 mL round bottom flask, and 20 mL of dioxane hydrochloride was added. Add 200 uL of methanol. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, the solvent was swirled off without further purification.
  • Step 5 Add (S) -3- (4-hydroxy-1-oxoisoindolinline-2-)-3-methylpiperidine-2,6-dione (200 mg, 0.73 mmol, 1.0 eq) Dissolved in 20mL of acetonitrile. 1,2-Dibromopropane (736 mg, 3.65 mmol, 5.0 eq) and anhydrous potassium carbonate (101 mg, 0.73 mmol, 1.0 eq) were added, and the mixture was reacted at 50 ° C for 24 hours. After the reaction was completed, the solvent was swirled off, diluted with ethyl acetate, washed with saturated sodium chloride, and purified by column chromatography to obtain 200 mg of a white solid with a yield of 69%.
  • Step 6 (S) -3- (4- (3-Bromopropoxy) -1-oxoisoindolinline-2-)-3-methylpiperidine-2,6-dione (40 mg, 0.10 mmol, 1.0 eq) was dissolved in 3 mL DMSO, and 4- (2-chlorophenyl) piperidine-4-carbonitrile hydrochloride (39 mg, 0.15 mmol, 1.5 eq), triethylamine (102 mg, 1.01 mmol, 10.0 eq), and reacted at 40 ° C overnight.
  • Example 81 4- (4-chlorophenyl) -1- (5-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindoleline-4-) (Oxy) pentyl) piperidine-4-carbonitrile (81)
  • Example 82 4- (2-chlorophenyl) -1- (4-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindolin-4-) (Oxy) butyryl) piperidine-4-carbonitrile (82)
  • Example 83 4- (3-chlorophenyl) -1- (4-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindolin-4-) (Oxy) butyryl) piperidine-4-carbonitrile (83)
  • Example 84 4- (4-chlorophenyl) -1- (4-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindolin-4-) (Oxy) butyryl) piperidine-4-carbonitrile (84)
  • Example 94 1- (5- (2- (2,6-dioxopiperidine-3-)-1-oxoisoindoleline-4-) pentyl) -4- (3-trifluoro (Methoxyphenyl) piperidine-4-carbonitrile (94)
  • Example 100 4- (3-chlorophenyl) -1- (6- (2- (2,6-dioxopiperidine-3-)-1-oxoisoindolline-4-) hexyl ) Piperidine-4-carbonitrile (100)
  • Example 102 4- (4-chlorophenyl) -1- (6- (2- (2,6-dioxopiperidine-3-)-1-oxoisoindolline-4-) hexyl ) Piperidine-4-carbonitrile (102)
  • Example 106 3- (4- (5- (6-Bromo-3,4-dihydroquinoline-1 (2H)-) pentyl) -1-oxoisoindololine-2-) piperidine -2,6-dione (106)
  • Example 108 2- (2,6-Dioxopiperidine-3-)-4- (4-((2-methylquinoline-4-) oxy) butoxy) isoindolin-1 , 3-dione (108)
  • Example 112 3- (4- (5- (6-Bromoindolinoline-1-) pentyl) -1-oxoisoindololine-2-) piperidine-2,6-dione (112 )
  • Example 120 3- (4- (6- (6-chloro-3H-spiro [isobenzofuran-1,4'-piperidine] -1 '-) hexyl) -1-oxoisoindoleline -2-) piperidine-2,6-dione (120)
  • Example 121 3- (1-oxo-4- (5- (2-oxospiro [indoleline-3,4'-piperidine] -1 '-) pentyl) indoleline-2- Piperidine-2,6-dione (121)
  • Example 125 3- (1-oxo-4- (5- (2-oxo-1,2-dihydrospiro [benzo [d] [1,3] oxazine-4,4'-piper Pyridyl] -1 '-) pentyl) isoindolinoline-2-) piperidine-2,6-dione (125)
  • Example 128 3- (4- (4- (6-fluoro-3H-spiro [isobenzofuran-1,4'-piperidine] -1 '-) butoxy) -1-oxoisoindole Indolin-2-) piperidine-2,6-dione (128)
  • Example 135 3- (4- (5- (5-methoxy-2-oxospiro [indoleline-3,4'-piperidine] -1 '-) pentyl) -1-oxo Isoindolin-2-) piperidine-2,6-dione (135)
  • Example 138 3- (4- (3- (6-chloro-3H-spiro [isobenzofuran-1,4'-piperidine] -1 '-) propoxy) -1-oxoisoindole Indolin-2-) piperidine-2,6-dione (138)
  • Example 140 3- (4- (3- (6-methyl-3H-spiro [isobenzofuran-1,4'-piperidine] -1 '-) propoxy) -1-oxoiso Indolin-2-) piperidine-2,6-dione (140)
  • Example 141 3- (1-oxo-4- (5- (spiro [indene-1,4'-piperidine] -1 '-) pentyl) isoindololine-2-) piperidine-2 , 6-dione (141)
  • Example 142 3- (4- (3- (6-Fluoro-3H-spiro [isobenzofuran-1,4'-piperidine] -1 '-) propoxy) -1-oxoisoindole Indolin-2-) piperidine-2,6-dione (142)
  • Example 150 3- (4-((6- (6-chloro-3H-spiro [isobenzofuran-1,4'-piperidine] -1 '-) hexyl) oxy) -1-oxoiso Indolin-2-) piperidine-2,6-dione (150)
  • Example 151 3- (4- (4- (6-chloro-3H-spiro [isobenzofuran-1,4'-piperidine] -1 '-) butyl) -1-oxoisoindole Porphyrin-2-) piperidine-2,6-dione (151)
  • Example 152 3- (4-((5- (6-chloro-3H-spiro [isobenzofuran-1,4'-piperidine] -1 '-)-5-oxopentyl) oxy) -1-oxoisoindolinoline-2-) piperidine-2,6-dione (152)
  • Example 154 6-Chloro-N- (4-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindoleline-4-)-oxo-) butyl ) -3H-spiro [isobenzofuran-1,4'-piperidine] -1'-formamide (154)
  • Example 156 3- (4- (5- (6-fluoro-3H-spiro [isobenzofuran-1,4'-piperidine] -1 '-) pentyl) -1-oxoisoindole Porphyrin-2-) piperidine-2,6-dione (156)
  • Step 2 5-Amino-4- (4-hydroxy-1-oxoisoindolinline-2-)-5-oxovalerate methyl ester (400 mg, 1.37 mmol, 1.0 eq), 4-bromo Tert-butyl butyrate (1.62 g, 6.85 mmol, 5.0 eq) was dissolved in 20 mL of DMSO, and anhydrous potassium carbonate (379 mg, 2.74 mmol, 2.0 eq) was added and reacted at 50 ° C for 24 hours.
  • Step 3 5-Amino-4- (4- (4- (tert-butoxy) -4-oxobutoxy) -1-oxoisoindololine-2-)-5-oxo Methyl valerate (530 mg, 1.18 mmol, 1.0 eq) was dissolved in 20 mg of anhydrous tetrahydrofuran and ice-baked for 15 minutes. Potassium tert-butoxide (146 mg, 1.30 mmol, 1.1 eq) was added, and the reaction was continued for 90 minutes in an ice bath. After the reaction was completed, 50 uL of formic acid was added to quench the reaction.
  • Step 4 tert-Butyl 4-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindoleline-4-) oxo) butyrate (463mg, 1.11mmol) Put in a 100 mL round bottom flask, add 20 mL of dioxane hydrochloride solution, and react at room temperature for 30 minutes.
  • Step 5 4-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindoleline-4-) oxo) butanoic acid (50 mg, 0.139 mmol, 1.0 eq) Dissolved in 3 mL of dimethyl sulfoxide, added 3-chloro-4-methylaniline (0.208 mmol, 1.5 eq), O- (7-azabenzotriazole) -N, N, N, N-tetra Methylurea hexafluorophosphate (79 mg, 0.208 mmol, 1.5 eq), 1-hydroxybenzotriazole (28 mg, 0.208 mmol, 1.5 eq), and triethylamine (141 mg, 1.39 mmol, 10 eq) were reacted at room temperature for hours.
  • Example 160 1- (3-chloro-4-methylphenyl) -3- (2-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindole Porphyrin-4-) oxy) ethyl) urea (160)
  • triphenylphosphine (672mg, 2.56mmol) was dissolved in dry tetrahydrofuran (30mL), and DIAD (504 ⁇ L, 2.56mmol) was added under stirring at room temperature. The resulting reaction solution was stirred and reacted at room temperature for 30 minutes. After the reaction was completed, the solvent was removed under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain 5-amino-4- (4- (2- (tert-butoxycarbonylamino) ethoxy) -1-oxoisoindolin-2-)-5 -468 mg of methyl oxovalerate, 63%.
  • Step 2 5-Amino-4- (4- (2- (tert-butoxycarbonylamino) ethoxy) -1-oxoisoindoleline-2-)-5-oxopentanoate
  • the ester (468mg, 1.07mmol) was dissolved in dry tetrahydrofuran (40mL), the reaction solution was cooled to 0 ° C, potassium tert-butoxide (133mg, 1.18mmol) was added under stirring, and the reaction was stirred under ice-cooling conditions for 10 hours. After the reaction was completed in minutes, the reaction solution was quenched with 60 ⁇ L of formic acid, and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 350 mg, 81% of the target product.
  • Step 3 The product obtained in Step 2 was dissolved in 20 mL of a 1,4-dioxane solution of hydrogen chloride, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure to obtain the target product as a white powder solid.
  • Step 4 3- (4- (2-Aminoethoxy) -1-oxoisoindoleline-2-) piperidine-2,6-dione hydrochloride (50 mg, 0.147 mmol) was dissolved in In 3 mL of dry DMSO, triethylamine (61 ⁇ L, 0.44 mmol) and 3-chloro-4-methylphenyl isocyanate (37 mg, 0.22 mmol) were sequentially added to the reaction solution, and the resulting reaction solution was reacted under heating at 40 ° C for 3 hours.
  • Example 161 1- (4-chloro-3-methylphenyl) -3- (3-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindole Porphyrin-4-) oxy) propyl) urea (161)
  • Example 162 1- (3-chloro-4-methylphenyl) -3- (4-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindole Porphyrin-4-) oxy) butyl) urea (162)
  • Example 163 1- (3,4-dichlorophenyl) -3- (2-((2- (2,6-dioxopiperidine-3-)-1-oxoisoindolinoline- 4-oxyethyl) urea (163)
  • Step 2 The crude reaction product obtained in Step 1 was dissolved in 10 mL of a saturated solution of 1,4-dioxane in hydrogen chloride, and the reaction solution was reacted at room temperature for 2 hours. The reaction was monitored by LC-MS, and the solvent was removed under reduced pressure. It was diluted with ethyl acetate, washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution in this order, and the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure to obtain the crude reaction product, which was directly used in the next reaction.
  • Step 3 The crude reaction product in step 2 was dissolved in 10 mL of dry dichloromethane, and triethylamine (152 ⁇ L, 1.09 mmol) and acetyl chloride (16 ⁇ L, 0.218 mmol) were sequentially added under stirring at room temperature, and the reaction solution was continued at room temperature. The reaction was stirred overnight. The reaction was monitored by LC-MS. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate and saturated sodium chloride solution in this order. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure.
  • Example 176 (2S) -N-((1S, 3S, 5S, 7S) -adamantane-2-)-2-amino-5- (2- (2,6-dioxopiperidine-3) -)-1-oxoisoindololine-4-) pentanamide (176)
  • Example 185 N-((2S) -1-((3-chloro-4-methylphenyl) amino) -5- (2- (2,6-dioxopiperidine-3-)- 1-oxoisoindoleline-4-)-1-oxopentyl-2-) cyclopropylformamide (185)
  • Triethylamine (84 ⁇ L, 0.6 mmol) and HATU (152 mg, 0.4 mmol) were added under stirring at room temperature.
  • the resulting reaction solution was stirred at room temperature for 4 hours.
  • the completion of the condensation reaction was monitored by LC-MS.
  • the solvent was removed under reduced pressure, and 5 mL of acetic acid was added to the obtained residue.
  • the temperature of the reaction solution was raised to 110 ° C. and the reaction was refluxed for 2 hours.
  • the completion of the reaction was monitored by LC-MS.
  • the solvent was removed under reduced pressure, and the residue was separated by HPLC to give the target product 3- (4-((S) -4-amino-4- (7-bromo-1H-benzo [d] imidazole-2-) butyl).
  • Example 200 (2S) -2-acetylamino-N-((1S, 3S, 5S, 7S) -adamantane-2-)-5- (2- (2,6-dioxopiperidine-3) -)-1-oxoisoindololine-4-) pentanamide (200)
  • Example 205 N-((1S) -4- (2- (2,6-dioxopiperidine-3-)-1-oxoisoindoleline-4-)-1- (3H-imidazole (4,5-c) pyridine-2-) butyl) acetamide (205)
  • Example 207 N-((2S) -5- (2- (2,6-dioxopiperidine-3-)-1-oxoisoindoleline-4-)-1-oxo-1- (3H-spiro [isobenzofuran-1,4'-piperidine] -1 '-) pentyl-2-) acetamide (207)
  • Step 2 Dissolve methyl 5-fluoro-2-methyl-3-nitrobenzoate (1.02 g, 4.8 mmol) in 20 ml of methanol, add 10% Pd / C (110 mg), and react at room temperature under normal pressure and hydrogen overnight. After the reaction was monitored by TLC, the reaction solution was filtered with suction, the solid was washed with methanol (20ml ⁇ 1), and the filtrate was concentrated to obtain 918 mg of 3-amino-5-fluoro-2-methyl-benzoic acid methyl ester as a colorless liquid, which was directly dropped step.
  • Step 3 3-amino-5-fluoro-2-methyl-benzoic acid methyl ester (918mg, crude) and 10% H 2 SO 4 (1.54ml, 28.71mmol), add sodium nitrite dropwise at 0 ° C (505mg, 7.32mmol) in aqueous solution (5ml), after reacting at the same temperature for 1h, 50% H 2 SO 4 (7.65ml, 143.555mmol) was added, and the temperature was raised to 100 ° C for 1h. After the reaction was monitored by TLC, the reaction was concentrated. 20 ml of water and 100 ml of ethyl acetate were added, and the mixture was separated by shaking.
  • the aqueous phase was extracted with ethyl acetate (50 ml ⁇ 2).
  • the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 415 mg of the product was obtained by column chromatography. Two steps The yield was 47%.
  • Step 4 Dissolve 5-fluoro-3hydroxy-2-methyl-benzoic acid methyl ester (410mg, 2.23mmol) in 20ml DMF, and add 60% sodium hydride (107mg, 2.67mmol) at 0 ° C for 1h. Then, chloromethyl methyl ether (203ul, 2.67mmol) was added dropwise at the same temperature. After the dropwise addition, the temperature was raised to room temperature and reacted for 2h. After the reaction was monitored by TLC, it was quenched with water, extracted with ethyl acetate, and the organic phase was sequentially separated. It was washed with water and saturated sodium chloride solution, dried, and subjected to column chromatography to obtain 430 mg of the product in a yield of 84%.
  • Step 5 Dissolve methyl 5-fluoro-3-methoxymethoxy-2-methylbenzoate (425 mg, 1.86 mmol) in NBS (398 mg, 2.23 mmol) in 15 ml of carbon tetrachloride, and then add 70% Benzoyl peroxide (65 mg, 0.186 mmol), heated to reflux for 3 h, concentrated under reduced pressure, and obtained 545 mg of yellow solid by flash column chromatography with a yield of 95.4%.
  • Step 6 methyl 2-bromomethyl-5-fluoro-3-methoxymethoxybenzoate (540 mg, 1.76 mmol) and methyl 4,5-diamino-5-oxopentanoate hydrochloride Salt (413mg, 2.11mmol) in acetonitrile suspension (20ml), N, N-diisopropylethylamine (873ul, 5.28mmol) was added, and the mixture was reacted at 40 ° C overnight. After the reaction was completed, it was concentrated under reduced pressure and acetic acid Ethyl acetate was diluted, washed with water and saturated sodium chloride in this order, dried, concentrated and directly used in the next step.
  • Step 7 Put the crude product from the previous step in a 50ml round-bottomed flask, add 10ml 4M dioxane hydrochloride and 1ml methanol. After reacting at room temperature for 1h, spin dry, and obtain the target product 300mg by column chromatography. The yield in two steps is 55. %.
  • Step 8 Put 5-amino-4- (6-fluoro-4-hydroxy-1-oxoisoindolinline-2-)-5-oxovalerate methyl ester (35mg, 0.11mmol) in 50ml
  • 4-((2-methylquinoline-4-) oxy) -1-butanol 51 mg, 0.22 mmol, 2 eq
  • triphenylphosphine 58 mg, 0.22 mmol, 2 eq
  • the reaction system was replaced with nitrogen, and 5 mL of dry tetrahydrofuran was added.
  • diisopropyl azodicarboxylate 43 ⁇ L, 0.22 mmol, 2 eq. Reaction at room temperature for 1 h. The reaction was monitored by TLC and the reaction was concentrated under reduced pressure. The column chromatography yielded 56.8 mg of the product with a yield of 98%.
  • Step 2 Dissolve quinoline-4-carboxylic acid (665 mg, 3.55 mmol) in 25 ml of dry THF, add triethylamine (598ul, 4.62mmol), and dropwise add isopropyl chloroformate (635ul, 4.62mmol) in an ice bath. After 0.5h, add an aqueous solution (5ml) of sodium borohydride (403mg, 10.65mmol), and react at the same temperature for 2h. After the reaction is complete, spin dry, dilute with ethyl acetate, wash with saturated sodium chloride, dry, and obtain the product by column chromatography. 390mg, yield 63%.
  • Step 3 Dissolve quinoline-4-methanol (100 mg, 0.577 mmol) in 6 ml of dry THF, cool thoroughly at 0 ° C, add 60% sodium hydride (35 mg, 0.87 mmol), react at the same temperature for 0.5 h, and add 1,4 -Dibromobutane (206ul, 0.866mmol) was heated to reflux overnight. After the reaction was completed, it was quenched with water, extracted with ethyl acetate, the organic layer was washed with saturated sodium chloride, dried, and 83 mg was obtained by column chromatography with a yield of 47%.
  • Step 4 4-((4-bromobutoxy) methyl) -2-methylquinoline (44.7 mg, 0.145 mmol) and 5-amino-4- (4-hydroxy-1-oxoisoindole Methyl indolin-2-)-5-oxopentanoate (42 mg, 0.145 mmol) was dissolved in 6 ml of acetonitrile. Anhydrous potassium carbonate (20 mg, 0.145 mmol) was added and the temperature was raised to 80 ° C for 48 hours. Dry and purified by column chromatography to obtain the product 38.3mg, yield 51%
  • Step 5 Dissolve the product obtained in the previous step (38.3mg, 0.074mmol) in 6ml THF, add potassium tert-butoxide (9mg, 0.081mmol) at 0 ° C for 0.5h at the same temperature, quench by adding 1N HCl, ethyl acetate Diluted, washed with saturated sodium chloride, dried, spin-dried, purified by HPLC to obtain 17.7 mg of white solid, yield 49%
  • Example 220 3- (1-oxo-4- (4- (4- (3- (trifluoromethyl) phenyl) piperazin-1-yl) butyl) isoindololin-2-yl Piperidine-2,6-dione (220)

Abstract

本发明涉及如通式（I）所表示的多取代异吲哚啉类化合物，其制备方法、药物组合物及应用。具体的，本发明提供的多取代异吲哚啉类化合物作为一类结构新颖的CRL4CRBN E3泛素连接酶调节剂具有更强的抗肿瘤活性和抗肿瘤谱，可以用于制备治疗与CRL4CRBN E3泛素连接酶相关的疾病的药物。

Description

异吲哚啉类化合物、其制备方法、药物组合物及用途
优先权声明
本申请要求申请号为201811156797.9，申请日为2018年9月30日，发明名称为：“异吲哚啉类化合物、其制备方法、药物组合物及用途”的中国专利申请的优先权，在此将其全部内容并入本申请作为参考。
1.技术领域
本发明涉及一类新颖结构的多取代异吲哚啉类化合物，其药学上可接受的盐、溶剂合物、药物组合物及其在制备治疗或预防多种疾病的药物中的应用。
2.背景技术
细胞内蛋白质表达的严密调控在细胞行使功能、细胞存活以及***过程中发挥着重要作用，许多原发性或获得性疾病通常涉及蛋白质功能异常。传统的调节蛋白功能异常的方法主要是过设计靶向抑制剂或激动剂，这些靶向药物在疾病的治疗中发挥着重要作用。尽管如此，为了获得满意的疗效，这些抑制剂或激动剂通常需要维持在较高的药物浓度以达到有效治疗效果，这也在一定程度上导致了药物的不良反应。另一种调节蛋白质功能异常的方法是改变病理相关蛋白的动态平衡，蛋白质的动态平衡包括蛋白质的合成和降解，例如可以利用小干扰RNA(siRNA)、反义寡聚核苷酸或基因编辑技术来敲除或沉默靶蛋白基因，这些基于核酸的技术通过作用于靶蛋白的转录和翻译过程而改变蛋白质的合成，该类技术最大的局限在于核酸的体内稳定性以及生物利用度较低，进而在一定程度上限制了其应用。另一种调节蛋白质动态平衡的策略是调控蛋白质的降解过程，通过促进或抑制蛋白质的降解可以直接改变靶蛋白在细胞内的表达量。泛素-蛋白酶体***(UPS)在蛋白质的降解过程中发挥重要作用，在一系列泛素化酶的作用下，靶蛋白可以被泛素化标记，带有特殊泛素标签的蛋白质可以被运送至蛋白酶体并被其降解。
蛋白质泛素化存在多种模式，包括单泛素化(底物蛋白只连接一个泛素)、多-单泛素化(底物蛋白存在多个泛素化位点，每个位点被单泛素化)或多聚泛素化(形成泛素链)，此外，多聚泛素化过程也可以发生泛素自身上多个赖氨酸侧链胺基或N端胺基上。根据不同的泛素化模式，蛋白质被泛素化后既可以影响蛋白质在细胞内的过程，包括亚细胞定 位、蛋白质贮存以及蛋白-蛋白相互作用等，同时也可以影响蛋白质的功能，包括蛋白质功能激活、抑制或蛋白酶体/溶酶体降解等。
蛋白质的泛素化过程是一个串联的多步反应过程，主要有三类酶参与：E1泛素激活酶，E2泛素结合酶，E3泛素连接酶。首先，泛素C端被ATP激活而与E1泛素激活酶活性中心的半胱氨酸巯基形成活泼的硫酯结构。然后，该活泼中间体通过转硫酯反应将泛素通过新的硫酯结构共价连接到E2泛素结合酶上。最后，E3泛素连接酶招募底物蛋白并同时与E2泛素结合酶-泛素活性中间体结合，将泛素转移至底物蛋白上从而完成底物蛋白的泛素化过程。在整个泛素化过程中，E3泛素连接酶发挥着重要作用，它不仅发挥着桥梁作用，使两个反应组分(E2泛素结合酶-泛素缀合物以及底物蛋白)在空间上相互靠近，同时还发挥着酶催化作用，加速底物蛋白被泛素化的速率。由于E3泛素连接酶需要特异性识别底物，因此哺乳动物基因组编码了超过600种E3泛素连接酶。相比之下，目前只发现了两种E1泛素激活酶和约40中E2泛素结合酶。
根据E3泛素连接酶的保守结构域和作用模式可以将其分成三大类，其中TECT家族和RBR家族E3泛素连接酶在底物泛素化过程中需要先将泛素从E2泛素激活酶上转移至自身，再将泛素从E3泛素连接酶上转移至底物蛋白上。相比较而言，RING家族E3泛素连接酶在整个E3泛素连接酶中占据较大比例，这类E3泛素连接酶上含有RING结构域或RING样结构域，它们能够与E2泛素结合酶结合，促进泛素直接从E2泛素结合酶直接转移至底物蛋白上。
CRL4 CRBNE3泛素连接酶属于RING家族E3泛素连接酶，它是一种由多个亚基组装而成的蛋白复合物，整个复合物包含底物蛋白识别模块(CRBN)、E2泛素结合酶识别模块(RING结构域)以及二者之间的连接部分(Cullin蛋白)。CRBN在整个蛋白复合物中直接结合底物，控制着整个泛素化过程的底物特异性。
直接作用于CRBN的小分子调节剂可以控制CRL4 CRBNE3泛素连接酶的底物选择性。新的研究发现，Cereblon(基因名：CRBN)是免疫调节剂—沙利度胺及其类似物的直接靶点(Science,2010,327,1345；Science,2014,343,301；Science,2014,343,305；Nature,2015, 523,183.)。研究证明度胺类免疫调节剂在多发性骨髓瘤细胞系中，通过调控CRBN-泛素连接酶复合物的活性,选择性诱导转录因子IKZF1和IKZF3进行泛素化并降解，这一过程改变了T细胞和B细胞的功能，同时对多发性骨髓瘤细胞产生毒性效应，由此达到治疗多发性骨髓瘤在内的恶性髓系肿瘤的作用。最近的研究表明,来那度胺，一种沙利度胺的类似物，能够通过CRL4 CRBNE3泛素连接酶选择性诱导CK1α的泛素化并降解，实现治疗5q缺失型骨髓异常性增生综合征(MDS)，而沙利度胺的另一种结构类似物(CC-885)则能够通过作用于CRL4 CRBNE3泛素连接酶选择性诱导并降解GSPT1，对多种肿瘤细胞展现出很强的细胞毒性。
现有研究结果表明：不同度胺类药物分子与靶点CRBN相互作用后，具有不同底物蛋白降解特异性。如来那度胺在治疗多发性骨髓瘤时，其疗效主要是通过选择性降解IKZF1和IKZF3实现；而在治疗5q缺失的骨髓异常性增生综合症(del(5q)MDS)时主要通过降解CK1α达到治疗效果。由于目前发展的度胺类似物中主要是来那度胺对CK1α表现出较强的降解活性，因此是最主要的临床有效的治疗骨髓异常性增生综合征del(5q)MDS的度胺类药物。随着新的度胺类药物的研发和临床实验的开展，度胺类药物分子的适应症也在不断扩展中，如FDA批准的沙利度胺用于治疗麻风结节性红斑,来那度胺临床实验中用于治疗***癌，泊马度胺临床实验中用于治疗骨髓纤维化症。
Figure PCTCN2019109368-appb-000001
来那度胺、泊马度胺、CC-122、CC-220、CC-885这些已经报化合物的结构与沙利度相似，该类化合物的特点在于，结构上的改变和调整后，化合物具有不同的药理活性和完全不同的治疗效果，进而在临床上可用于治疗不同的适应症。
WO2008115516A2、US8153659B2、US9181216B2、US9920027B2公开了通式为S1所代表的化合物：
Figure PCTCN2019109368-appb-000002
通式S1中主要代表性R1的为芳基、芳基烷基、杂环基烷基等。
WO2011100380A1、CN102822165B，公开了一类通式为S2所代表的化合物：
Figure PCTCN2019109368-appb-000003
通式S2中R1为取代的多种取代的芳基，代表性的化合物为CC-220：
Figure PCTCN2019109368-appb-000004
WO2016065980A1、CN105566290A、US10017492B2
Figure PCTCN2019109368-appb-000005
通式S3中代表性的化合物为：
Figure PCTCN2019109368-appb-000006
WO2007027527A2、CN101291924A、US8481568B2公开了一类通式为S3所代表的化合物：
Figure PCTCN2019109368-appb-000007
通式S4、S5中代表性的化合物为：
Figure PCTCN2019109368-appb-000008
WO2008027542A2、US8877780B2、US9447070B2公开了一类通式为S3所代表的化合物：
Figure PCTCN2019109368-appb-000009
通式S6、S7中代表性的化合物为：
Figure PCTCN2019109368-appb-000010
来那度胺及上述部分分子的作用机制是：不同结构的化合物能够和CRBN结合，引起CRBN结合部分构象的改变，从而招募不同的内源性生物大分子与CRBN的结合；进而对潜在不同的内源性底物蛋白进行泛素化并降解，因而能够产生不同的药理活性，在临床实验中用于治疗不同的适应症。
综上所述，来那度胺主要用于治疗治疗多发性骨髓瘤和骨髓异常增生综合征，对其他适应症效果并不理想；其他上述提到的化合物如CC-122，CC-885和CC-220尚处于临床前或临床研究中。因此，开发结构新颖的化合物作为CRL4 CRBNE3泛素连接酶调节剂，可以实现进一步提高肿瘤的治疗效果治疗和扩展度胺类药物的新适应症的临床上的需求；结构不同的度胺类分子的药理学活性和药物学性质都不为人所知，各方面的性质和作用都具 有不确定性。基于度胺类分子的作用机制，开发新结构的度胺类分子，能够实现招募新的蛋白底物，进而实现的治疗效果的提高和新适应症的扩展。因此，继续开发新颖结构的CRL4 CRBNE3泛素连接酶调节剂以拓展新的适应症具有非常重要研究价值和现实意义。
3.发明内容
本发明的发明人通过对CRBN与小分子作用的复合物晶体结构(PDB ID：4CI2、5HXB)进行分析获得下述重要信息：CRBN与小分子存在多个结合口袋，因此可以发展结构复杂的多个结合位点的小分子，实现CRBN与小分子的有效结合。同时利用分子动力学模拟方法对模型分子和E3泛素连接酶界面进行结构动态和结合位点分析，结合分子对接和基于复合物的药效团匹配，通过打分函数对化合物在E3泛素连接酶活性位点的结合模式和相互作用进行评价，获得新型特异性的CRBN小分子调节剂。基于这些信息，我们设计并合成一系列本申请所述的CRBN的小分子调节剂，并测试了化合物的活性。测试结果表明，新型的小分子调节剂具有非常高的细胞的生长抑制活性，该分子作用于生物体后，通过调节生物体内泛素—蛋白酶体介导的蛋白降解途径，可以调控底物蛋白的降解，进而实现基于CRBN靶点的有效的疾病治疗。
本发明的一个目的是提供如下通式(I)所示的化合物、其对映体、非对映体、消旋体、同位素化合物、代谢前体、代谢产物、可药用的盐、酯、前药或其水合物。
本发明的另一个目的是提供该类化合物的重要中间体及制备方法。
本发明的另一个目的是提供一种药物组合物，其特征在于，包含治疗有效剂量的通式(I)所示的化合物，其对映体、非对映体、消旋体、可药用的盐、酯、前药或其水合物，和至少一种药学上可接受的载体。
本发明的另一个目的是提供一种药物组合物，其特征在于，包含治疗有效剂量的通式(I)所示的化合物，其对映体、非对映体、消旋体、可药用的盐、酯、前药或其水合物，以及另外一种或多种具有医药学治疗活性的成分。本发明通式(I)所示的化合物，其对映体、非对映体、消旋体、可药用的盐、酯、前药或其水合物可以和另外一种或多种具有医药学治疗活性的成分在预防或治疗特定疾病或功能紊乱过程中产生协同作用。本发明所 述的通式(I)所示的化合物，其对映体、非对映体、消旋体、可药用的盐、酯、前药或其水合物也可以减轻或消除另外一种或多种具有医药学治疗活性成分在预防或治疗特定疾病或功能紊乱过程中所产生的毒副作用，反之亦然。
本发明的另一个目的是提供如上所述的另外一种或多种具有医药学治疗活性的成分，包括大分子化合物，例如蛋白、多糖和核酸等；和小分子化合物，例如无机化合物、有机金属化合物、合成或天然来源的有机小分子化合物等。
本发明的另一个目的是提供如通式(I)的化合物，其对映体、非对映体、消旋体、可药用的盐、酯、前药或其水合物，其特征在于，用于制备治疗与CRL4 CRBNE3泛素连接酶相关的疾病的药物，优选地，所述的疾病非限制性地包括癌症、疼痛、神经***疾病和免疫***疾病。
为了实现上述目的，本发明提供了如下通式(I)表示的化合物以及它们互变异构体、对映体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物：
Figure PCTCN2019109368-appb-000011
其中X 1为-CH 2-或-O-；
X 2为-CH 2-或-CO-；
R 1为氢、氘、氟或C 1-C 6直链或支链烃基；
R 2、R 4各自独立地为氢或氘；
R 3为氢、氘或卤素；
L为含有2-8个碳原子的取代或未取代的直链亚烷基，所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代：氘、卤素、羰基、羟基、氨基、氰基、C 1-C 6烷基、卤素取代的C 1-C 6烷基、C 3-C 8环烷基、-NHC(O)Ra 1、-NHC(O)ORa 2、-NRa 3Ra 4，其 中Ra 1、Ra 2、Ra 3和Ra 4各自独立地选自氢原子、由卤素、羟基、氰基、硝基取代或未取代的C 1-6烷基、由卤素、羟基、氰基、硝基取代或未取代的C 3-6环烷基；
Y不存在，或为–O–、–CO–、–CO–NH–、–NH–CO–、–NH–CO–NH–、–NH–CO–CH(NHRa 9)–或–CH(NHRa 9)–；
Y为–O–时，A为：6-10元芳基、5-10元杂芳基，(6-10元芳基)–(CH 2) b1–、(5-10元杂芳基)–(CH 2) b1–，前述芳基或杂芳基可选地被以下一个或多个基团所取代：氘、卤素、氰基、硝基、氨基、羟基、C 1-C 6烷基、卤素取代的C 1-C 6烷基、羟基取代的C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氧基羰基、卤素取代的C 1-C 6烷氧基、羟基取代的C 1-C 6烷氧基、氰基取代的C 1-C 6烷氧基、C 3-C 6环烷基、C 3-C 6环烷基氧基、苯基、5-6元杂芳基、3-6元杂环基、-NHC(O)Ra 5、-NHC(O)ORa 6、-NRa 7Ra 8，其中Ra 5、Ra 6、Ra 7和Ra 8各自独立地为氢原子、由卤素、羟基、C 1-C 6烷氧基、氰基、硝基取代或未取代的C 1-6烷基、或由卤素、羟基、C 1-C 6烷氧基、氰基、硝基取代或未取代的C 3-6环烷基；
b 1为1或2；
Y不存在，或为–CO–或–CO–NH–时，相对应的Y与A、L形成的连接方式分别为A–L–、A–CO–L–、A–CO–NH–L–，A为：i)选自以下的杂环基：
Figure PCTCN2019109368-appb-000012
X 3为C、N或O；
n 4为0、1、2或3；
n 5为0、1、2或3；
Y 1、Y 2各自独立地为氢、氘、卤素、氰基、羧基、硝基、羟基、氨基、氨基羰基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷基羰基、C 1-C 6烷氧基羰基、C 1-C 6烷基磺酰基、C 1-C 6烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 6酰基氨基、卤素取代C 1-C 6烷基、卤素取代的C 1-C 6烷氧基、C 1-C 3烯基、C 1-C 3炔基、取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、6-10元芳基或5-10元杂芳基取代的C 1-C 3的直链或支链烷基，其中 所述取代或未取代的6-10元芳基或5-10元杂芳基是指被以下一种或多种取代基所取代：氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 3酰基氨基、卤素取代C 1-C 3烷基、卤素取代的C 1-C 3烷氧基；
当Y 1和Y 2各自独立地为氢、氘、C 1-C 6烷氧基、卤素、C 1-C 6烷基、C 3-C 6的环烷基、羧基、C 1-C 6烷基氨基羰基、C 1-C 6烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 6烷基、羟基、C 1-C 6烷基磺酰基时，并且Y不存在时，X 1不为-O-；
Y 3不存在，或为氢、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷基氨基羰基、C 1-C 6烷氧基羰基、卤素取代C 1-C 6烷基、C 1-C 6烷基磺酰基、C 1-C 6烷基羰基、氨基羰基、C 3-C 6杂环基、C 1-C 6酰基氨基、卤素取代的C 1-C 6烷氧基、C 1-C 3烯基、C 1-C 3炔基、取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、C 5-C 10的芳基或杂芳基取代的C 1-C 3的直链或支链烷基，其中所述取代或未取代的6-10元芳基或5-10元杂芳基是指被以下一种或多种取代基所取代：氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 3酰基氨基、卤素取代C 1-C 3烷基、卤素取代的C 1-C 3烷氧基；
当Y 3为氢、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷基氨基羰基、C 1-C 6烷氧基羰基、卤素取代C 1-C 6烷基、C 1-C 6烷基磺酰基或Y3不存在时，并且Y不存在时，X 1不为-O-；
Y 4、Y 5为其所在杂环上的一个或多个取代基，Y 4、Y5各自独立地为氘、卤素、氧、C 1-C 3烷基、C 1-C 3环烷基、卤素取代的C 1-C 3烷基或苯基；
ii)选自以下的稠杂环基：
Figure PCTCN2019109368-appb-000013
X 4为C、N或O；
n 6为0、1、2或3；
n 7为0、1、2或3；
n 8为0、1、2、3或4；
Figure PCTCN2019109368-appb-000014
为6-10元芳基环或5-10元杂芳基环，优选地，
Figure PCTCN2019109368-appb-000015
环选自苯环、吡啶环、噻吩环、吲哚环、苯并噻吩环、苯并咪唑环、萘环、喹啉环或异喹啉环；
R 8各自独立地选自氢、氘、C 1-C 3烷氧基、卤素、C 1-C 3烷基、C 3-C 6的环烷基、羧基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 3烷基、羟基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、C 3-C 6的杂环基、卤素取代C 1-C 3烷氧基、苯基或5-6元杂芳基；
当上述R 8各自独立地选自下列任意取代基：氢、氘、C 1-C 3烷氧基、卤素、C 1-C 3烷基、C 3-C 6的环烷基、羧基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 3烷基、羟基、C 1-C 3烷基磺酰基时，并且Y不存在时，X 1不为-O-；
Y 6、Y 7为其所在杂环上的一个或多个取代基，且各自独立地选自氘、卤素、C 1-C 3烷基、C 1-C 3环烷基、卤素取代的C 1-C 3烷基；
或者iii)选自以下的螺杂环基：
Figure PCTCN2019109368-appb-000016
n c1为0、1、2或3；
n c2为0、1、2或3；
n c3为1、2或3；
n 9为0、1、2、3或4；
Figure PCTCN2019109368-appb-000017
为6-10元芳基环或5-10杂芳基环；
R 9独立选自以下取代基：氘、卤素、氰基、硝基、羟基、氨基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、直链或支链C 1-C 6烷基、直链或支链C 1-C 6烷氧基、C 3-C 6环烷基氧基、C 3-C 6环烷基或杂环烷基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、卤素取代C 1-C 3烷基、卤素取代C 1-C 3烷氧基、苯基、5-6元杂芳基；
R 10、R 11独立选自为氢、取代或未取代6-10元芳基、取代或未取代5-10元杂芳基，所述取代类型与上述
Figure PCTCN2019109368-appb-000018
环上取代基R 9相同；
Y 8为螺环结构中非芳香结构部分中氢原子可选地被取代的取代基，Y8可选地被氘、卤素、C 1-C 3烷基、C 1-C 3环烷基、卤素取代的C 1-C 3烷基取代基所取代；
Y选自–NH–CO–、–NH–CO–NH–、–NH–CO–CH(NHR a9)–或–CH(NHR a9)–时，相对应地Y与A、L形成的连接方式为A–NH–CO––L–、A–NH–CO–NH–L–、A–NH–CO–CH(NHR a9)–L–或A–CH(NHR a9)–L–，其中A为：
6-10元芳基、5-10元杂芳基、(6-10元芳基)–CH 2–、(5-10元杂芳基)–CH 2–，所述芳基或杂芳基可选地一个或多个R 5取代基所取代，
或者A为选自以下基团：
Figure PCTCN2019109368-appb-000019
n 1为0、1、2、3或4；
R 5各自独立地选自氘、卤素、羟基、氨基、氰基、硝基、直链或支链C 1-C 6烷基、直链或支链C 1-C 6烷氧基、C 1-C 3酰基氨基、氨基羰基、苯基、5-6元杂芳基、3-6元杂环基、C 3-C 6环烷基、C 3-C 6环烷基氧基、C 1-C 3烷基氨基羰基、C 1-C 3烷基磺酰基、苯基氧基或5-6元杂芳基氧基，当n 1>1时，各个R 5可以相同或不同；
R a9选自氢、取代或未取代的C 1-C 10烷基羰基、取代或未取代C 3-C 8环烷基羰基、C 1-C 8的杂环烷基羰基，其中所述取代是指碳链末端被羟基、氨基所取代。
优选地，通式(I)所示的化合物，其中X 1为-CH 2-或-O-；
X 2为-CH 2-或-CO-；
R 1为氢、氘、氟或C 1-C 3直链或支链烃基；
R 2、R 4各自独立地为氢或氘；
R 3为氢、氘或卤素；
L为含有2-8个碳原子的取代或未取代的直链亚烷基，所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代：氘、卤素、羰基、羟基、氨基、氰基、C 1-C 3烷基、卤素取代的C 1-C 3烷基、C 3-C 6环烷基、-NHC(O)Ra 1、-NHC(O)ORa 2、-NRa 3Ra 4，其中Ra 1、Ra 2、Ra 3和Ra 4各自独立地选自氢原子、由卤素、羟基、氰基、硝基取代的C 1-6烷基、由卤素、羟基、氰基、硝基取代的C 3-6环烷基；
Y不存在，或为–O–、–CO–、–CO–NH–、–NH–CO–、–NH–CO–NH–、–NH–CO–CH(NHR a9)–或–CH(NHR a9)–；
Y为–O–时，A为：取代或未取代的9-10元芳基、9-10元杂芳基，(9-10元芳基)–(CH2) b1–、(9-10元杂芳基)–(CH2) b1–，
其中，b 1为1或2；
上述取代或未取代的9-10元芳基或9-10元杂芳基选自以下基团：
Figure PCTCN2019109368-appb-000020
n 2为0、1、2或3；
n 3为0、1、2或3；
R 6、R 7各自独立地选自以下基团：氘、卤素、氰基、硝基、氨基、羟基、C 1-C 6烷基、卤素取代的C 1-C 6烷基、羟基取代的C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氧基羰基、卤素取代的C 1-C 6烷氧基、羟基取代的C 1-C 6烷氧基、氰基取代的C 1-C 6烷氧基、C 3-C 6环烷基、 C 3-C 6环烷基氧基、苯基、C 5-C 6杂芳基、C 3-C 6杂环基，-NHC(O)Ra 5、-NHC(O)ORa 6、-NRa 7Ra 8；其中Ra 5、Ra 6、Ra 7和a 8各自独立地为氢原子、由卤素、羟基、C 1-C 6烷氧基、氰基、硝基取代基取代或未取代的C 1-6烷基、或由卤素、羟基、C 1-C 6烷氧基、氰基、硝基取代基取代或未取代的C 3-6环烷基，其中当n 2>1或者n 3>1时，R 6和R 7各自可以相同或不同；
Y不存在，或为–CO–或–CO–NH–时，相对应地Y与A、L所形成的连接方式为–A–L–、–A–CO–L–或–A–CO–NH–L–，A为：
i)选自以下的杂环基：
Figure PCTCN2019109368-appb-000021
其中，Y 1、Y 2各自独立地为氢、氘、卤素、氰基、羧基、硝基、羟基、氨基、氨基羰基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷基羰基、C 1-C 6烷氧基羰基、C 1-C 6烷基磺酰基、C 1-C 6烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 6酰基氨基、卤素取代C 1-C 6烷基、卤素取代的C 1-C 6烷氧基、C 1-C 3烯基、C 1-C 3炔基、取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、6-10元芳基或5-10元杂芳基取代的C 1-C 3的直链或支链烷基，其中所述取代或未取代的6-10元芳基或5-10元杂芳基是指被以下一种或多种取代基所取代：氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 3酰基氨基、卤素取代C 1-C 3烷基、卤素取代的C 1-C 3烷氧基；
当Y 1和Y 2各自独立地为：氢、氘、C 1-C 6烷氧基、卤素、C 1-C 6烷基、C 3-C 6的环烷基、羧基、C 1-C 6烷基氨基羰基、C 1-C 6烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 6烷基、羟基、C 1-C 6烷基磺酰基时，并且Y不存在时，X 1不为-O-；
Y 3不存在，或为C 1-C 6烷基羰基、氨基羰基、C 3-C 6杂环基、C 1-C 6酰基氨基、卤素取代的C 1-C 6烷氧基、C 1-C 3烯基、C 1-C 3炔基、取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、C 5-C 10的芳基或杂芳基取代的C 1-C 3的直链或支链烷基，其中所述取代或未取代的6-10元芳基或5-10元杂芳基是指被以下一种或多种取代基所取代：氘、卤 素、氰基、硝基、羟基、氨基、氨基羰基、C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 3酰基氨基、卤素取代C 1-C 3烷基、卤素取代的C 1-C 3烷氧基，前述6-10元芳基优选选自苯基、萘基，前述5-10元杂芳基优选选自噻吩基、吡啶基、苯并噻吩基、苯并咪唑基、吲哚基、喹啉基、异喹啉基。
当Y 3为氢、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷基氨基羰基、C 1-C 6烷氧基羰基、卤素取代C 1-C 6烷基、C 1-C 6烷基磺酰基或Y3不存在时，并且Y不存在时，X 1不为-O-；
Y 4、Y 5为其所在杂环上的一个或多个取代基，Y 4、Y5各自独立地为氘、卤素、氧、C 1-C 3烷基、C 1-C 3环烷基或苯基；
ii)选自以下的稠杂环基：
Figure PCTCN2019109368-appb-000022
n 8为0、1、2、3或4；
X 4为C、N或O；
Figure PCTCN2019109368-appb-000023
为6-10元芳基环或5-10元杂芳基环，其中
Figure PCTCN2019109368-appb-000024
环优选自苯环、吡啶环、噻吩环、吲哚环、萘环、苯并噻吩环、苯并咪唑环、喹啉环或异喹啉环；
R 8各自独立地选自氢、氘、C 1-C 3烷氧基、卤素、C 1-C 3烷基、C 3-C 6的环烷基、羧基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 3烷基、羟基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、C 3-C 6的杂环基、卤素取代C 1-C 3烷氧基、苯基或5-6元杂芳基；
当上述R 8各自独立地选自下列任意取代基：氢、氘、C 1-C 3烷氧基、卤素、C 1-C 3烷基、C 3-C 6的环烷基、羧基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 3烷基、羟基、C 1-C 3烷基磺酰基时，并且Y为不存在时，X 1不为-O-；
Y 6、Y 7为其所在杂环上的一个或多个取代基，且各自独立选自氘、卤素、C 1-C 3烷基、C 1-C 3环烷基、卤素取代的C 1-C 3烷基；
或者iii)选自以下的螺杂环基：
Figure PCTCN2019109368-appb-000025
其中，n 9为0、1、2、3或4；
Figure PCTCN2019109368-appb-000026
为6-10元芳基环或5-10杂芳基环，优选为噻吩环、吡咯环、苯环、吡啶环、苯并噻吩环、苯并咪唑环、吲哚环、喹啉环和异喹啉环；
R 9独立地选自以下取代基：氘、卤素、氰基、硝基、羟基、氨基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、直链或支链C 1-C 6烷基、直链或支链C 1-C 6烷氧基、C 3-C 6环烷基氧基、C 3-C 6环烷基或杂环烷基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、卤素取代C 1-C 3烷基、卤素取代C 1-C 3烷氧基、苯基、5-6元杂芳基，其中当n 9>1时，各个R 9可以相同或不同；
Y 8为螺环结构中非芳香结构部分中氢原子可选地被取代的取代基，Y8可选地被氘、卤素、C 1-C 3烷基、C 1-C 3环烷基、卤素取代的C 1-C 3烷基取代基所取代；
Y选自–NH–CO–、–NH–CO–NH–、–NH–CO–CH(NHR a9)–或–CH(NHR a9)–时，相对应地Y与A、L所形成的连接方式为A–NH–CO––L–、A–NH–CO–NH–L–、A–NH–CO–CH(NHR a9)–L–或A–CH(NHR a9)–L–，其中A为：
6-10元芳基、5-10元杂芳基、(6-10元芳基)–CH 2–、(5-10元杂芳基)–CH 2–，前述芳基或杂芳基可选地一个或多个R 5取代基所取代，或者A为选自以下基团：
Figure PCTCN2019109368-appb-000027
n 1为0、1、2、3或4；
R 5各自独立地选自氘、卤素、羟基、氨基、氰基、硝基、直链或支链C 1-C 6烷基、直链或支链C 1-C 6烷氧基、C 1-C 3酰基氨基、氨基羰基、苯基、5-6元杂芳基、3-6元杂环基、C 3-C 6环烷基、C 3-C 6环烷基氧基、C 1-C 3烷基氨基羰基、C 1-C 3烷基磺酰基、苯基氧基或5-6元杂芳基氧基，当n 1>1时，各个R 5可以相同或不同；
R a9独立地选自氢、取代或未取代的C1-C10烷基羰基、取代或未取代C 3-C 8环烷基羰基、C 1-C 8的杂环烷基羰基，其中所述取代是指碳链末端被羟基、氨基所取代。
进一步优选地，通式(I)所示的化合物，其中X 1为-CH 2-或-O-；
X 2为-CH 2-或-CO-；
R 1为氢、氘或氟；
R 2、R 4各自独立地为氢或氘；
R 3为氢、氘或氟；
L为含有2-8个碳原子的取代或未取代的直链亚烷基，所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代：氘、卤素、氰基、C 1-C 3烷基、卤素取代的C 1-C 3烷基、-NHC(O)Ra 1、-NHC(O)ORa 2、-NRa 3Ra 4，其中Ra 1、Ra 2、Ra 3和Ra 4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C 1-6烷基、或者由一个或多个卤素取代或未取代的C 3-6环烷基；
Y不存在，或为–O–、–CO–、–CO–NH–、–NH–CO–、–NH–CO–NH–、–NH–CO–CH(NHR a9)–或–CH(NHR a9)–；
Y为–O–时,A为：选自9-10元芳基、9-10元杂芳基，(9-10元芳基)–(CH2) b1–、(9-10元杂芳基)–(CH2) b1–，所述9-10元芳基或9-10元杂芳基可以是未取代或被取代；
所述的取代或未取代的9-10元芳基或9-10元杂芳基选自以下基团：
Figure PCTCN2019109368-appb-000028
b 1为1或2；
n 2为0、1、2或3；
n 3为0、1、2或3；
R 6、R 7各自独立选自以下基团：氘、卤素、氰基、硝基、氨基、羟基、C 1-C 6烷基、卤素取代的C 1-C 6烷基、羟基取代的C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氧基羰基、卤素取代的C 1-C 6烷氧基、羟基取代的C 1-C 6烷氧基、氰基取代的C 1-C 6烷氧基、C 3-C 6环烷基、C 3-C 6环烷基氧基、苯基、C 5-C 6杂芳基、C 3-C 6杂环基，-NHC(O)Ra 5、-NHC(O)ORa 6、-NRa 7Ra 8；其中Ra 5、Ra 6、Ra 7和Ra 8各自独立地为氢原子、由卤素、羟基、氰基取代的C 1-6烷基、或由卤素、羟基、氰基取代的C 3-6环烷基，其中当n 2>1或者n 3>1时，R 6和R 7各自可以相同或不同；
Y不存在，或为–CO–或–CO–NH–，相应地Y与A、L所形成的连接方式为–A–CO–L–、–A–CO–NH–L–、–A–L–、A部分至少含有一个氮原子且Y与氮原子连接，A为：
i)选自以下的杂环基：
Figure PCTCN2019109368-appb-000029
n 10为0、1、2、3、4或5；
Y 1选自氢、氘、卤素、氰基、羧基、硝基、羟基、氨基、氨基羰基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷基羰基、C 1-C 6烷氧基羰基、C 1-C 6烷基磺酰基、C 1-C 6烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 6酰基氨基、卤素取代C 1-C 6烷基、卤素取代的C 1-C 6烷氧基、C 1-C 3烯基、C 1-C 3炔基、取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、6-10元芳基或5-10元杂芳基取代的C 1-C 3的直链或支链烷基，其中所述取代或未取代的6-10元芳基或5-10元杂芳基是指被以下一种或多种取代基所取代：氘、卤素、氰基、 硝基、羟基、氨基、氨基羰基、C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 3酰基氨基、卤素取代C 1-C 3烷基、卤素取代的C 1-C 3烷氧基；
Figure PCTCN2019109368-appb-000030
选自取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基，优选地，6-10元芳基或5-10元杂芳基优选选自噻吩基、吡啶基、苯基、苯并噻吩基、苯并咪唑基、吲哚基、萘基、喹啉基、异喹啉基；
R 10各自独立地为氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 3酰基氨基、卤素取代C 1-C 3烷基、卤素取代的C 1-C 3烷氧基，当n 10>1时，R 10可以相同或不同；
Y 4、Y 5为其所在杂环上的一个或多个取代基，Y 4、Y5各自独立地为氘、卤素、甲基、乙基、环丙基或苯基；
ii)选自以下的稠杂环基：
Figure PCTCN2019109368-appb-000031
n 8为0、1、2、3或4；
X 4为C、N或O；
R 8各自独立地选自氢、氘、C 1-C 3烷氧基、卤素、C 1-C 3烷基、C 3-C 6的环烷基、羧基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 3烷基、羟基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、C 3-C 6的杂环基、卤素取代C 1-C 3烷氧基、苯基或5-6元杂芳基，其中当n 8>1时，各个R 8可以相同或不同；
当上述R 8各自独立地选自下列任意取代基：氘、C 1-C 3烷氧基、卤素、C 1-C 3烷基、C 3-C 6的环烷基、羧基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 3烷基、羟基、C 1-C 3烷基磺酰基时，并且Y不存在时，X 1不为-O-；
Y 6、Y 7为其所在杂环上的一个或多个取代基，且各自独立地选自氘、卤素、甲基、 乙基、环丙基、三氟甲基；
或者iii)选自以下的螺杂环基：
Figure PCTCN2019109368-appb-000032
其中，n 9为0、1、2、3或4；
R 9各自独立地选自以下取代基：氘、卤素、氰基、硝基、羟基、氨基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、直链或支链C 1-C 6烷基、直链或支链C 1-C 6烷氧基、C 3-C 6环烷基氧基、C 3-C 6环烷基或杂环烷基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、卤素取代C 1-C 3烷基、卤素取代C 1-C 3烷氧基、苯基、5-6元杂芳基，其中当n 9>1时，各个R 9可以相同或不同；
Y 8为螺环结构中非芳香结构部分中氢原子可选地被取代的取代基，Y8可选地被氘、卤素、甲基、乙基、环丙基、三氟甲基取代基所取代；
Y选自–NH–CO–、–NH–CO–NH–、–NH–CO–CH(NHR a9)–或–CH(NHR a9)–时，相应地Y与A、L所形成的连接方式为A–NH–CO––L–、A–NH–CO–NH–L–、A–NH–CO–CH(NHR a9)–L–或A–CH(NHR a9)–L–，其中A为：
Figure PCTCN2019109368-appb-000033
n 1为0、1、2、3或4；
R 5各自独立地选自氘、卤素、羟基、氨基、氰基、硝基、直链或支链C 1-C 6烷基、直链或支链C 1-C 6烷氧基、C 1-C 3酰基氨基、氨基羰基、苯基、5-6元杂芳基、3-6元杂环基、 C 3-C 6环烷基、C 3-C 6环烷基氧基、C 1-C 3烷基氨基羰基、C 1-C 3烷基磺酰基、苯基氧基或5-6元杂芳基氧基，当n 1>1时，各个R 5可以相同或不同；
R a9选自氢、取代或未取代的C1-C10烷基羰基、取代或未取代C 3-C 8环烷基羰基、C 1-C 8的杂环烷基羰基，其中所述取代是指碳链末端被羟基、氨基所取代。
在一优选实施方式中，其中通式(I)表示的化合物为通式(I-1)至(I-8)表示的化合物：
Figure PCTCN2019109368-appb-000034
其中，X 1为-CH 2-或-O-；
X 2为-CH 2-或-CO-；
R 1为氢、氘或氟；
R 2、R 4各自独立地选自为氢或氘；
R 3为氢、氘或氟；
L为含有2-8个碳原子的取代或未取代的直链亚烷基，所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代：氘、卤素、氰基、C 1-C 3烷基、卤素取代的C 1-C 3烷基、-NHC(O)Ra 1、-NHC(O)ORa 2、-NRa 3Ra 4，其中Ra 1、Ra 2、Ra 3和Ra 4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C 1-6烷基、或者由一个或多个卤素取代或未取代的C 3-6环烷基；
Y不存在，或者为–CO–或–CO–NH–；
n 9为0、1、2、3或4；
Figure PCTCN2019109368-appb-000035
为6-10元芳基环或5-10杂芳基环，
Figure PCTCN2019109368-appb-000036
与螺环母核稠合形成螺杂环基，优选地，
Figure PCTCN2019109368-appb-000037
为噻吩环、吡咯环、苯环、吡啶环、苯并噻吩环、苯并咪唑环、吲哚环、喹啉环和异喹啉环；
Y 8为螺环结构中非芳香结构部分中氢原子可选地被取代的取代基，Y8可选地被氘、卤素、甲基、乙基、环丙基、三氟甲基取代基所取代；
R 9各自独立地选自以下取代基：氘、卤素、氰基、硝基、羟基、氨基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、直链或支链C 1-C 6烷基、直链或支链C 1-C 6烷氧基、C 3-C 6环烷基氧基、C 3-C 6环烷基或杂环烷基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、卤素取代C 1-C 3烷基、卤素取代C 1-C 3烷氧基、苯基、5-6元杂芳基，其中当n 9>1时，各个R 9可以相同或不同；
在一优选实施方式中，其中通式(I)表示的化合物为通式(I-9)至(I-16)表示的化合物：
Figure PCTCN2019109368-appb-000038
其中，X 1为-CH 2-或-O-；
X 2为-CH 2-或-CO-；
R 1为氢、氘或氟；
R 2、R 4各自独立地为氢、氘；
R 3为氢、氘或氟；
L为含有2-8个碳原子的取代或未取代的直链亚烷基，所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代：氘、卤素、氰基、C 1-C 3烷基、卤素取代的C 1-C 3烷基、-NHC(O)Ra 1、-NHC(O)ORa 2、-NRa 3Ra 4，其中Ra 1、Ra 2、Ra 3和Ra 4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C 1-6烷基、或由一个或多个卤素取代或未取代的C 3-6环烷基；
Y不存在，或为–CO–或–CO–NH–；
n 9为0、1、2、3或4；
R 9各自独立地选自以下取代基：氘、卤素、氰基、硝基、羟基、氨基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、直链或支链C 1-C 6烷基、直链或支链C 1-C 6烷氧基、C 3-C 6环烷基氧基、C 3-C 6环烷基或杂环烷基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、卤素取代C 1-C 3烷基、卤素取代C 1-C 3烷氧基、苯基、5-6元杂芳基，其中当n 9>1时，各个R 9可以相同或不同；
Y 8为螺环结构中非芳香结构部分中氢原子可选地被取代的取代基，Y8可选地被氘、卤素、甲基、乙基、环丙基、三氟甲基取代基所取代；
在一优选实施方式中，其中通式(I)表示的化合物为通式(I-17)、(I-18)表示的化合物：
Figure PCTCN2019109368-appb-000039
其中，X 1为-CH 2-或-O-；
X 2为-CH 2-或-CO-；
R 1为氢、氘或氟；
R 2、R 4各自独立地为氢或氘；
R 3选自为氢、氘或氟；
L为含有2-8个碳原子的取代或未取代的直链亚烷基，所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代：氘、卤素、氰基、C 1-C 3烷基、卤素取代的C 1-C 3烷基、-NHC(O)Ra 1、-NHC(O)ORa 2、-NRa 3Ra 4，其中Ra 1、Ra 2、Ra 3和Ra 4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C 1-6烷基或由一个或多个卤素取代或未取代的C 3-6环烷基；
Y不存在，或为–CO–或–CO–NH–；
n 10为0、1、2、3、4或5；
Y 1各自独立地选自氢、氘、卤素、氰基、羧基、硝基、羟基、氨基、氨基羰基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷基羰基、C 1-C 6烷氧基羰基、C 1-C 6烷基磺酰基、C 1-C 6烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 6酰基氨基、卤素取代C 1-C 6烷基、卤素取代的C 1-C 6烷氧基、C 1-C 3烯基、C 1-C 3炔基、取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、6-10元芳基或5-10元杂芳基取代的C 1-C 3的直链或支链烷基，其中所述取代或未取代的6-10元芳基或5-10元杂芳基是指被以下一种或多种取代基所取代：氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 3酰基氨基、卤素取代C 1-C 3烷基、卤素取代的C 1-C 3烷氧基；
Figure PCTCN2019109368-appb-000040
选自取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基，优选地，6-10元芳基或5-10元杂芳基选自噻吩基、吡啶基、苯基、苯并噻吩基、苯并咪唑基、吲哚基、萘基、喹啉基、异喹啉基；
R 10各自独立地选自氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C 1-C 3烷基、 C 1-C 3烷氧基、C 1-C 3烷基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 3酰基氨基、卤素取代C 1-C 3烷基、卤素取代的C 1-C 3烷氧基，当n 10>1时，各个R 10可以相同或不同；
在一优选实施方式中，其中通式(I)表示的化合物为通式(I-19)至(I-23)表示的化合物：
Figure PCTCN2019109368-appb-000041
其中，X 1为-CH 2-或-O-；
X 2为-CH 2-或-CO-；
R 1为氢、氘或氟；
R 2、R 4各自独立地为氢或氘；
R 3为氢、氘或氟；
L为含有2-8个碳原子的取代或未取代的直链亚烷基，所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代：氘、卤素、氰基、C 1-C 3烷基、卤素取代的C 1-C 3烷基、-NHC(O)Ra 1、-NHC(O)ORa 2、-NRa 3Ra 4，其中Ra 1、Ra 2、Ra 3和Ra 4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C 1-6烷基、或由一个或多个卤素取代或未取代的C 3-6环烷基；
Y不存在，或为–CO–或–CO–NH–；
n 8为0、1、2、3或4；
X 4为C、N或O；
R 8各自独立地为氢、氘、C 1-C 3烷氧基、卤素、C 1-C 3烷基、C 3-C 6的环烷基、羧基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 3烷基、羟基、 C 1-C 3烷基磺酰基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、C 3-C 6的杂环基、卤素取代C 1-C 3烷氧基、苯基或5-6元杂芳基，其中当n 8>1时，各个R 8可以相同或不同；
当R 8选自下列任意取代基：氘、C 1-C 3烷氧基、卤素、C 1-C 3烷基、C 3-C 6的环烷基、羧基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 3烷基、羟基、C 1-C 3烷基磺酰基时，并且Y不存在时，X 1不为-O-；
Y 6、Y 7为其所在杂环上的一个或多个取代基，且各自独立地选自氘、卤素、甲基、乙基、环丙基、三氟甲基；
在一优选实施方式中，其中通式(I)表示的化合物为通式(I-24)至(I-32)表示的化合物：
Figure PCTCN2019109368-appb-000042
其中，X 2为-CH 2-或-CO-；
R 1为氢、氘或氟；
R 2、R 4各自独立地为氢或氘；
R 3选自为氢、氘或氟；
L为含有2-8个碳原子的取代或未取代的直链亚烷基，所述取代指亚烷基中一个或多个氢原子可选地被下列取代基取代：氘、卤素、氰基、C 1-C 3烷基、卤素取代的C 1-C 3烷基、-NHC(O)Ra 1、-NHC(O)ORa 2、-NRa 3Ra 4，其中Ra 1、Ra 2、Ra 3和Ra 4各自独立地选自 氢原子、由一个或多个卤素取代或未取代的C 1-6烷基或由一个或多个卤素取代或未取代的C 3-6环烷基；
Y不存在，或为–CO–或–CO–NH–；
n 8、n 9、n 10各自独立地选自0、1、2、3或4；
X 4为C、N或O；
R 9选自以下取代基：氘、卤素、氰基、硝基、羟基、氨基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、直链或支链C 1-C 6烷基、直链或支链C 1-C 6烷氧基、C 3-C 6环烷基氧基、C 3-C 6环烷基或杂环烷基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、卤素取代C 1-C 3烷基、卤素取代C 1-C 3烷氧基、苯基、5-6元杂芳基，其中当n 9>1时，各个R 9可以相同或不同；
Figure PCTCN2019109368-appb-000043
选自取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基，优选地6-10元芳基或5-10元杂芳基选自噻吩基、吡啶基、苯基、苯并噻吩基、苯并咪唑基、吲哚基、萘基、喹啉基、异喹啉基；
R 10各自独立地选自氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 3酰基氨基、卤素取代C 1-C 3烷基、卤素取代的C 1-C 3烷氧基，当n 10>1时，各个R 10可以相同或不同；
R 8各自独立地选自氢、氘、C 1-C 3烷氧基、卤素、C 1-C 3烷基、C 3-C 6的环烷基、羧基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 3烷基、羟基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、C 3-C 6的杂环基、卤素取代C 1-C 3烷氧基、苯基或5-6元杂芳基，当n 8>1时，各个R 8可以相同或不同；
在一优选实施方式中，其中通式(I)表示的化合物为通式(I-33)至(I-40)表示的化合物：
Figure PCTCN2019109368-appb-000044
其中，X 2为-CH 2-或-CO-；
R 1为氢、氘或氟；
R 2、R 4各自独立地为氢或氘；
R 3为氢、氘或氟；
L为含有2-8个碳原子的取代或未取代的直链亚烷基，所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代：氘、卤素、氰基、C 1-C 3烷基、卤素取代的C 1-C 3烷基、-NHC(O)Ra 1、-NHC(O)ORa 2、-NRa 3Ra 4，其中Ra 1、Ra 2、Ra 3和Ra 4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C 1-6烷基或由一个或多个卤素取代或未取代的C 3-6环烷基；
Y不存在，或为–CO–、–CO–NH–；
n 8、n 9、n 10各自独立地为0、1、2、3或4；
X 4选自C、N或O；
R 9各自独立地选自以下取代基：氘、卤素、氰基、硝基、羟基、氨基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、直链或支链C 1-C 6烷基、直链或支链C 1-C 6烷氧基、C 3-C 6环烷基氧基、C 3-C 6环烷基或杂环烷基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、卤素取代C 1-C 3烷基、卤素取代C 1-C 3烷氧基、苯基、5-6元杂芳基，当n 9>1时，各个R 9可以相同或不同；
Figure PCTCN2019109368-appb-000045
选自取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基，优选地，6-10元芳基或5-10元杂芳基选自噻吩基、吡啶基、苯基、苯并噻吩基、苯并咪唑基、吲哚基、萘基、喹啉基、异喹啉基；
R 10各自独立地选自氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 3酰基氨基、卤素取代C 1-C 3烷基、卤素取代的C 1-C 3烷氧基，当n 10>1时，各个R 10可以相同或不同；
R 8各自独立地选自氢、氘、C 1-C 3烷氧基、卤素、C 1-C 3烷基、C 3-C 6的环烷基、羧基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 3烷基、羟基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、C 3-C 6的杂环基、卤素取代C 1-C 3烷氧基、苯基或5-6元杂芳基，其中当n 8>1时，各个R 8可以相同或不同；
当R 8选自下列任意取代基：氘、C 1-C 3烷氧基、卤素、C 1-C 3烷基、C 3-C 6的环烷基、羧基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 3烷基、羟基、C 1-C 3烷基磺酰基时，并且Y不存在时，X 1不为-O-；
在一优选实施方式中，其中通式(I)表示的化合物为通式(I-41)至(I-48)表示的化合物：
Figure PCTCN2019109368-appb-000046
其中，X 1为-CH 2-或-O-；
X 2为-CH 2-或-CO-；
R 1为氢、氘或氟；
R 2、R 4各自独立地为氢或氘；
R 3为氢、氘或氟；
L为含有2-8个碳原子的取代或未取代的直链亚烷基，所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代：氘、卤素、氰基、C 1-C 3烷基、卤素取代的C 1-C 3烷基、-NHC(O)Ra 1、-NHC(O)ORa 2、-NRa 3Ra 4，其中Ra 1、Ra 2、Ra 3和Ra 4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C 1-6烷基、或由一个或多个卤素取代或未取代的C 3-6环烷基；
n 2为0、1、2或3；
n 3为0、1、2或3；
R 6、R 7各自独立地选自以下基团：氘、卤素、氰基、硝基、氨基、羟基、C 1-C 6烷基、卤素取代的C 1-C 6烷基、羟基取代的C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氧基羰基、卤素取代的C 1-C 6烷氧基、羟基取代的C 1-C 6烷氧基、氰基取代的C 1-C 6烷氧基、C 3-C 6环烷基、C 3-C 6环烷基氧基、苯基、C 5-C 6杂芳基、C 3-C 6杂环基，-NHC(O)Ra 5、-NHC(O)ORa 6、-NRa 7Ra 8，其中Ra 5、Ra 6、Ra 7和Ra 8各自独立地选自氢原子、由一个或多个选自卤素、羟基、氰基的取代基所取代或未取代C 1-6烷基、由一个或多个选自卤素、羟基、氰基的取代基所取代或未取代C 3-6环烷基，当n 2>1或者n 3>1时，R 6和R 7各自可以相同或不同；
在一优选实施方式中，其中通式(I)表示的化合物为通式(I-49)至(I-53)表示的化合物：
Figure PCTCN2019109368-appb-000047
其中，X 1为-CH 2-或-O-；
X 2为-CH 2-或-CO-；
R 1为氢、氘或氟；
R 2、R 4各自独立地选自氢或氘；
R 3为氢、氘或氟；
L为含有2-8个碳原子的取代或未取代的直链亚烷基，所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代：氘、卤素、氰基、C 1-C 3烷基、卤素取代的C 1-C 3烷基、-NHC(O)Ra 1、-NHC(O)ORa 2、-NRa 3Ra 4，其中Ra 1、Ra 2、Ra 3和Ra 4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C 1-6烷基、或由一个或多个卤素取代或未取代的C 3-6环烷基；
Y选自–NH–CO–、–NH–CO–NH–、–NH–CO–CH(NHR a9)–或–CH(NHR a9)–；
n 1为0、1、2、3或4；
R 5各自独立地选自氘、卤素、羟基、氨基、氰基、硝基、直链或支链C 1-C 6烷基、直链或支链C 1-C 6烷氧基、C 1-C 3酰基氨基、氨基羰基、苯基、5-6元杂芳基、3-6元杂环基、C 3-C 6环烷基、C 3-C 6环烷基氧基、C 1-C 3烷基氨基羰基、C 1-C 3烷基磺酰基、苯基氧基或5-6元杂芳基氧基，当n 1>1时，各个R 5可以相同或不同；
R a9选自氢、取代或未取代的C1-C10烷基羰基、取代或未取代C 3-C 8环烷基羰基、C 1-C 8的杂环烷基羰基，其中所述取代是指碳链末端被羟基、氨基所取代。
最优选地，通式(I)表示的化合物为下列化合物之一：
Figure PCTCN2019109368-appb-000048
Figure PCTCN2019109368-appb-000049
Figure PCTCN2019109368-appb-000050
Figure PCTCN2019109368-appb-000051
Figure PCTCN2019109368-appb-000052
Figure PCTCN2019109368-appb-000053
Figure PCTCN2019109368-appb-000054
Figure PCTCN2019109368-appb-000055
Figure PCTCN2019109368-appb-000056
Figure PCTCN2019109368-appb-000057
Figure PCTCN2019109368-appb-000058
Figure PCTCN2019109368-appb-000059
Figure PCTCN2019109368-appb-000060
Figure PCTCN2019109368-appb-000061
Figure PCTCN2019109368-appb-000062
其互变异构体、对映体、非对映体、消旋体、代谢产物、代谢前体、同位素化合物、可药用的盐、酯、前药或其水合物。
通式(I)所示的化合物可以含有一个或多个不对称或手性中心，因此可以以不同立体异构体形式存在。本发明化合物包括所有立体异构体形式，包括但不限于非对映异构体、对映异构体和阻转异构体以及它们的混合物(如外消旋体)，均包括在本发明的范围内。
术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中有相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个 任意取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。环状取代基，例如杂环烷基，可以与另一个环相连，例如环烷基，从而形成螺二环系，例如，两个环共用一个碳原子。
本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。本发明中相关结构上的取代，包括取代和未取代，如“可选地”被某种取代基取代，是指包括被某种取代基取代或者未取代的含义。
本发明中提到的当取代基数>1时，R取代基可以为相同或不同的取代基，指当某一种结构中取代基数为多个时，R的取代基组合可以为选自多种不同类型的取代基。
术语“取代”只适用于能够被取代基所取代的位点，不包括在现有的化学知识上不能实现的取代。
通式(I)所示的化合物还可以以不同互变异构体形式存在，所有这些形式均包括在本发明范围内。
术语“互变异构体”是指经由低能垒相互转化的具有不同能量的构造异构体，反应一般导致伴随单键和相邻双键转变的氢原子或质子的形式移动。
术语“对映体”是指互为镜像而不可重叠的立体异构体。
“非对映体”是指具有两个或者两个以上的手性中性，并且不成镜像的立体异构体。
“消旋体”是指两个互为镜像的立体异构体，旋光性相反，互相抵消了旋光性。
“可药用的盐”是指药物分子与对应的有机酸、无机酸或者有机碱、无机碱形成相应的盐的，例如盐酸、甲酸、三氟乙酸、琥珀酸、甲磺酸盐等。
“前药”是指在体外无活性或者活性较小，在体内经过酶或者非酶的转化释放出活性药物而发挥药效的一类化合物。
“水合物”是指含有水的化合物。
术语“卤素”包括氟、氯、溴或碘。
术语“烃基”是指只含有碳原子和氢原子的取代基，非限制性地包括甲基、乙基、异丙基、丙基、环己基、苯基等。
术语“C1-C6烷基”是指具有1至6个碳原子的直链或支链烷基，非限制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基和已基等。
术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。
术语“C1-C6烷氧基羰基”非限制性地包括甲氧基羰基、乙氧基羰基、丙氧基羰基、异丙氧基羰基、丁氧基羰基、异丁氧基羰基、仲丁氧基羰基、叔丁氧基羰基、戊氧基羰基和已氧基羰基等。
术语“环烷基”是指饱和或部分不饱和单环或者多环环状烃取代基。单环环烷基非限制性包括环丙基、环丁基、环戊烯基、环己基。多环环烷基包括螺环、稠环和桥环的环烷基。
术语“杂环基”是指含有一个或多个饱和和/或部分饱和单环或者多环环状取代基，其中一个或多个环原子选自氮、氧、硫或S(O)m(其中m是0至2的整数)的杂原子，其余环原子为碳；例如，环氧丙烷、四氢呋喃基、吡咯烷基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基；杂环基可以稠合与芳基、杂芳基、或环烷基环上，与母体结构连接在一起的环为杂环基。
术语“芳基”是指具有共轭的p电子体系的6-14元全碳单环或稠合多环基团，优选为6至10元环，优选为6至10元，更优选苯基和萘基，最优选苯基。所述芳基环可以稠合与杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环。
术语“杂芳基”是指具有1至4个杂原子作为环原子，其余的环原子为碳的5-14元芳基，其中杂原子包括氧、硫和氮。优选为5-10元。杂芳基优选为5元或6元，如噻吩基、吡啶基、吡咯基等。所述杂芳基环可以稠合与芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，
术语“螺杂环基”是指单环之间共用一个原子(称为螺原子)的多环杂环基团，其中一个或多个环原子选自氮、氧，硫或者S(O)m(其中m是0至2的整数)的杂原子，其余环原子为碳。螺杂环可以稠合与6-10元芳基或5-10元杂芳基环上，其中与母体结构连接在一起的环为螺杂环。
术语“卤素取代烷基”是指由单个或者多个卤素取代的直链、支链或者环状烷基，非限制性地包括2-溴乙基、2-溴丙基等。
术语“烯基”是指可以为2-10个碳的烯基，如乙烯基、丙烯基、丁烯基、苯乙烯基、苯丙烯基。
术语“炔基”是指可以为2-10个碳的炔基，如乙炔基、丙炔基、丁炔基、苯乙炔基、苯丙烯基。
术语“C3-C8环烷基”是指在环上具有3至8个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基、环己基等。
术语“5-10元杂环基”是指含有一个或多个饱和和/或部分饱和环，其包括5至10个环原子，其中一个或多个环原子选自氮、氧、硫或S(O)m(其中m是0至2的整数)的杂原子，其余环原子为碳；例如，环氧丙烷、四氢呋喃基、吡咯烷基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基。
术语“C3-C6杂环基”是指含有一个或多个饱和和/或部分饱和环，其包括3至6个环原子，其中一个或多个环原子选自氮、氧、硫或S(O)m(其中m是0至2的整数)的杂原子，其余环原子为碳；例如，环氧丙烷、四氢呋喃基、吡咯烷基、四氢吡喃基、哌啶基、哌嗪基。
术语“羟基取代烷基”是指由单个或者多个羟基取代的直链、支链或者环状烷基，非限制性地包括(S)-1-羟基异丁-2-基、(R)-1-羟基异丁-2-基等。
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
本发明也包含这里公布的任何一种新的中间体。
本发明有一个方面提供了通式(I)所示的化合物的制备方法，所述方法选自如下方法之一：
起始化合物，1A、2A、3D、4A、5A、6A和7A的合成参考文献WO2008115516A2、WO2011100380A1、WO2016065980A1、WO2007027527A2、WO2008027542A2。
合成方法1：
Figure PCTCN2019109368-appb-000063
其中，R 1、R 2、R 3、R 4和X 2的定义与前述定义相同；
m 1为1～7的整数；
Figure PCTCN2019109368-appb-000064
与前述A定义中的i)杂环基、ii)稠杂环基、iii)螺杂环基定义相同；
步骤1-1:化合物1A与1B在DMF、DMA等偶极有机溶剂为溶剂，Pd催化剂(如Pd(PPh 3) 4、Pd(PPh 3) 2Cl 2等)、一价铜催化剂(碘化亚酮)和碱(如三乙胺或而二异丙基乙基胺等)的存在下，在室温或加热条件通过Sonogashira偶联反应得到化合物1C；
步骤1-2:化合物1C在Pd/C、兰尼镍或其它金属催化剂(如威尔金森催化剂)催化条件下被氢气还原为化合物1D，
步骤1-3:化合物1D与羟基喹啉1E(或为取代或未取代羟基喹啉及其类似物，取代或未取代萘酚及其类似物等)在三苯基膦和偶氮二甲酸二异丙酯条件下反应得到化合物1F；
步骤1-4:化合物1D在三苯基膦和四溴化碳存在下，反应得到化合物1G；
步骤1-5:化合物1G和含氮杂环化合物1H(化合物1H为前述定义中含有A基团的各种胺类化合物)在碘化钠存在下反应得到化合物1I；
合成方法2：
Figure PCTCN2019109368-appb-000065
其中，R 1、R 2、R 3、R 4和X 2的定义与前述的定义相同；
m 1为1～7的整数；
Figure PCTCN2019109368-appb-000066
定义与前述A中的i)杂环基、ii)稠杂环基、iii)螺杂环基定义相同；
G2为保护基，选自TBS、Trit、苄基；
步骤2-1:化合物2A与2B在非质子溶剂为反应溶剂(如乙腈、DMF等)，Pd催化剂(乙酸钯(II)、Pd(PPh 3) 4等)、膦配体(如三苯基膦、s-Phos等)、有机碱(三乙胺或二异丙基乙基胺等)存在下加热反应生成多取代烯烃衍生物(Heck偶联反应)，生成多取代烯烃衍生物2C；
步骤2-2：化合物2C在在Pd/C或其它金属催化剂(如威尔金森催化剂)催化条件下被氢气还原为化合物2D；
步骤2-3：以干燥四氢呋喃为溶剂，在叔丁醇钾存在条件下关环得到哌啶酮衍生物2E；
步骤2-4：化合物2E在酸性条件下或者在TBAF存在条件下，脱除保护基得到化合物2F；
步骤2-5:化合物2F在三苯基膦和四溴化碳存在下，反应得到化合物2G；
步骤2-6:化合物2G和含氮杂环化合物2H(化合物2H为前述定义中含有A基团的 各种胺类化合物)在碘化钠存在下反应得到化合物2I；
合成方法3：
Figure PCTCN2019109368-appb-000067
其中，R 1、R 2、R 3、R 4、和X 2的定义与前述的定义相同；
m 2为1～7的整数；
Figure PCTCN2019109368-appb-000068
与前述A中i)杂环基、ii)稠杂环基、iii)螺杂环基定义相同；
G 3-NH 2为本发明实施例中使用的各类芳香胺或脂肪胺化合物；
步骤3-1:化合物3A与3B在三氟乙酸酐和叔丁醇存在下，反应得到化合物3C；
步骤3-2：化合物3C和3D在碳酸钾存在的条件下，反应得到化合物3E；
步骤3-3：化合物3E叔丁醇钾存在条件下关环得到哌啶酮衍生物3F；
步骤3-4：化合物3F在盐酸条件下，脱除保护基获得化合物3G；
步骤3-5:化合物3G和含氮杂环化合物3H(化合物3H为前述定义中含有A基团的各种胺类化合物)在缩合剂(HATU、HOBt)及碱(三乙胺)存在下，缩合获得化合物3I；
步骤3-6:化合物3G和化合物3J在缩合剂(HATU、HOBt)及碱(三乙胺)存在下，缩合获得化合物3K；
合成方法4：
Figure PCTCN2019109368-appb-000069
其中，R 1、R 2、R 3、R 4、X 2、Ra 9、R 11和n 11的定义与前述的定义相同；
G 4、G 5为保护基选自叔丁氧羰基或苄基；
G 6-NH 2为各类芳香胺或脂肪胺化合物；
步骤4-1：化合物4A与4B在Pd催化剂(如Pd(PPh 3) 4、Pd(PPh 3) 2Cl 2等)、一价铜催化剂(碘化亚酮)和碱(如三乙胺或而二异丙基乙基胺等)的存在下，在室温或加热条件、一价铜催化剂和碱的存在下，通过Sonogashira偶联反应得到化合物4C；
步骤4-2：化合物4C在Pd/C、兰尼镍或其它金属催化剂(如威尔金森催化剂)催化条件下被氢气还原为化合物4D；
步骤4-3：化合物4D在胺类衍生物4E和缩合剂HATU及HOBt条件下缩合得到化合物4F；
步骤4-4：化合物4F在盐酸条件下脱除保护基，反应后旋干与相应的酰氯或羧酸反应获得化合物4G；
步骤4-5:化合物4D和邻苯二胺衍生物4H在缩合剂HATU及HOBt条件下反应后，在酸性条件下加热条件下获得化合物4I；
步骤4-6:化合物4I在盐酸条件下脱除保护基，反应后旋干与相应的酰氯或羧酸反应 获得化合物4J；
合成方法5：
Figure PCTCN2019109368-appb-000070
其中，R 1、R 2、R 3、R 4、和X 2的定义与前述的定义相同；
m 3为1～7的整数；
Figure PCTCN2019109368-appb-000071
与前述A定义中的杂环基、稠杂环基、螺杂环基定义相同；
Ar为6-10元芳基、5-10元杂芳基，所述芳基或杂芳基可选地一个或多个R 5取代基所取代，R5定义与前述的定义相同；
步骤5-1：化合物5A与5B在三苯基膦和偶氮二甲酸二异丙酯条件下，反应得到化合物5C；
步骤5-2：化合物5C在碳酸钾存在的条件下，反应得到化合物5D；
步骤5-3：化合物5D在盐酸条件下脱除保护基，得到化合物5E；
步骤5-4：化合物5E和化合物5F在碱性条件下(如三乙胺或而二异丙基乙基胺等)反应得到化合物5G；
步骤5-5：化合物5E和含氮杂环化合物5H(化合物5H为前述定义中含有A基团的各种胺类化合物)在N,N'-羰基二咪唑和碱性条件下，反应得到化合物5I。
合成方法6：
Figure PCTCN2019109368-appb-000072
其中，R 1、R 2、R 3、R 4、和X 2的定义与前述定义相同；
m 4为1～7的整数；
Figure PCTCN2019109368-appb-000073
与前述A定义中的杂环基、稠杂环基、螺杂环基定义相同；
步骤6-1：化合物6A与6B在碳酸钾存在条件下，反应得到化合物6C；
步骤6-2：化合物6C在叔丁醇钾存在的条件下，反应得到化合物6D；
步骤6-3：化合物6D和含氮杂环化合物6E(化合物6E为前述定义中含有A基团的各种胺类化合物)在碱性条件下，反应得到化合物6F。
合成方法7
Figure PCTCN2019109368-appb-000074
其中，R 1、R 2、R 3、和R 4的定义与前述的定义相同；
m 4为1～7的整数；
Figure PCTCN2019109368-appb-000075
与前述A定义中的杂环基、稠杂环基、螺杂环基定义相同；
步骤7-1：化合物7A与7B氯甲基甲醚在氢化钠存在的条件下反应，得到化合物7C；
步骤7-2：化合物7C在7D和偶氮二异丁腈存在的条件下反应，得到化合物7E；
步骤7-3：化合物7E在7F在碱性条件下(如三乙胺或而二异丙基乙基胺等)反应，得到化合物7G；
步骤7-4：化合物7G在酸性条件下(盐酸，二氧六环)反应，得到化合物7H；
步骤7-5：化合物7I和7F在碱(如三乙胺或而二异丙基乙基胺等)性条件下反应，得到化合物7H；
步骤7-6：化合物7H与6B在碳酸钾存在条件下，反应得到化合物7J；
步骤7-7：化合物7J和含氮杂环化合物7K(化合物7K为前述定义中含有A基团的各种胺类化合物)在碱性(如三乙胺或而二异丙基乙基胺等)条件下，反应得到化合物7L。
本发明的另一个目的是提供如通式(I)所示的化合物，其互变异构体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物，其特征在于，可调控CRL4 CRBNE3泛素连接酶的活性。
本发明的另一个目的是提供一种药物组合物，其特征在于，包含治疗有效剂量的如通式(I)所示的化合物，其互变异构体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物，和至少一种其它药学上可接受的载体。
本发明的另一个目的是提供一种药物组合物，其特征在于，包含治疗有效剂量的如通式(I)的化合物，其互变异构体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物，以及另外一种或多种具有医药学治疗活性的成分。本发明权利要求1所述的如式(I)的化合物，其对映体、非对映体、消旋体、可药 用的盐、酯、前药或其水合物可以和另外一种或多种具有医药学治疗活性的成分在预防或治疗特定疾病或功能紊乱过程中产生协同作用。本发明权利要求1所述的如式(I)的化合物，其对映体、非对映体、消旋体、可药用的盐、酯、前药或其水合物也可以减轻或消除另外一种或多种具有医药学治疗活性成分在预防或治疗特定疾病或功能紊乱过程中所产生的毒副作用，反之亦然。
本发明的另一个目的是提供如上述的另外一种或多种具有医药学治疗活性的成分，包括大分子化合物，例如蛋白、多糖和核酸等；和小分子化合物，例如无机化合物、有机金属化合物、合成或天然来源的有机小分子化合物等。
本发明的另一个目的是提供如通式(I)的化合物，其互变异构体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物，其特征在于，用于制备治疗与CRL4 CRBNE3泛素连接酶相关的疾病的药物，优选地，所述的疾病非限制性地包括癌症、炎症、疼痛、神经***疾病和免疫***疾病。
本发明化合物中含有碱性基团时可以制备成药学上可接受的盐，包括无机酸盐和有机酸盐。适合形成盐的酸非限制性包括：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸等。
本发明的又一个目的是提供了一种药物组合物，其包括治疗有效量的通式(I)表示的化合物、其互变异构体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用盐、前药、溶剂化物、水合物和晶型中的一种或多种，以及至少一种赋形剂、稀释剂或载剂。
典型的配方是通过混合本发明的通式(I)表示的化合物及载体、稀释剂或赋形剂制备而成。适宜的载体、稀释剂或赋形剂是本领域技术人员所熟知的，包括诸如碳水化合物、蜡、水溶性及/或可膨胀性聚合物、亲水性或疏水性物质、明胶、油、溶剂、水等物质。所用的特定载体、稀释剂或赋形剂，将根据本发明的化合物的使用方式和目的而定。一般以本领域技术人员认为可安全有效地给药至哺乳类动物的溶剂为基础而选择溶剂。一般而言，安全的溶剂是无毒性含水溶剂诸如制药用水，以及其他可溶于水或与水混溶的无毒性溶剂。适宜的含水溶剂包括水、乙醇、丙二醇、聚乙二醇(如PEG400、PEG300)等中的一种或多种。该配方也可包括一种或多种缓冲剂、安定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、增甜剂、香料剂、调味剂或其它已知的添加剂，使式(I)表示的化合物以可被接受的形式制造或使用。
本发明如式(I)的化合物与至少一种其它药物组合使用时，两种药物或多种药物可以分开使用也可以组合使用，优选以药学组合物的形式给药。本发明的如式(I)的化合物或药物组合物能以任一已知的口服、静脉注射、直肠给药、***给药、透皮吸收、其它局部或全身给药形式，分开或一起给药至受试者。
这些药物组合物亦可含有一种或多种缓冲剂、安定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、增甜剂、香料剂、调味剂或其它已知的添加剂，使该药物组合物以可被接受的形式制造或使用。
本发明药物优选口服给药途径。用于口服给药的固态剂型可包括胶囊、片剂、粉末或颗粒制剂。在固态剂型中，本发明的化合物或药物组合物与至少一种惰性赋形剂、稀释剂或载剂混合。适宜的赋形剂、稀释剂或载剂包括诸如柠檬酸钠或磷酸二钙的物质，或淀粉、乳糖、蔗糖、甘露糖醇、硅酸等；粘合剂如羧甲基纤维素、褐藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖、***胶等；湿润剂如甘油等；崩解剂如琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、特定的络合硅酸盐、碳酸钠等；溶液阻滞剂如石蜡等；吸收促进剂如季铵化合物等；吸附剂如高岭土、膨润土等；润滑剂如滑石、硬脂酸钙、硬脂酸镁、固态 聚乙二醇、月桂基硫酸钠等。在胶囊与片剂的情况下，该剂型亦可包括缓冲剂。类似类型的固态组合物亦可作为软式与硬式填充明胶胶囊中的填料，其使用乳糖以及高分子量聚乙二醇等作为赋形剂。
用于口服给药的液态剂型包括药学上可接受的乳化液、溶液、悬浮液、糖浆液与酏剂。除了本发明的化合物或其组合物之外，该液态剂型可含有本领域中常用的惰性稀释剂，诸如水或其他溶剂；增溶剂及乳化剂诸如乙醇、异丙基醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄基酯、丙二醇、1,3-丁二醇、二甲基甲酰胺；油类(如棉籽油、落花生油、玉米胚芽油、橄榄油、蓖麻油、芝麻油等)；甘油；四氢糠基醇；聚乙二醇与脱水山梨糖醇的脂肪酸酯；或这些物质中的几种的混合物等。
除了这些惰性稀释剂之外，该组合物也可包括赋形剂，诸如润湿剂、乳化剂、悬浮剂、增甜剂、调味剂与香料剂中的一种或多种。
就悬浮液而言，除了本发明的化合物或组合之外，可进一步含有载剂诸如悬浮剂，如乙氧基化异硬脂醇、聚氧乙烯山梨醣醇、脱水山梨醣醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂及黄耆胶，或这些物质中几种的混合物等。
用于直肠或***投药之组合物优选栓剂，可通过将本发明的化合物或组合与适宜的非刺激性赋形剂或载剂混合而制备，赋形剂或载剂诸如可可豆脂、聚乙二醇或栓剂蜡，其在一般室温为固态而在体温为液态，可在直肠或***中熔化而释出活性化合物。
本发明化合物或药物组合物可采用其它局部给药剂型给药，包括膏、粉末、喷剂及吸入剂。该药物可在无菌条件下与药学上可接受的赋形剂、稀释剂或载剂以及所需要的任一防腐剂、缓冲剂或推进剂混合。眼用配方、眼用油膏、粉末与溶液，亦意欲涵盖于本发明的范围内。
本发明的又一个目的是提供了如通式(I)的化合物，其互变异构体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物，或晶型可用于单一治疗或联合治疗中。当用于联合治疗中时，包含治疗有效剂量的权利要求1所述的式(I)的化合物，其对映异构体、非对映异构体、外消旋体及其混合物，以及其 药学上可接受的盐、结晶水合物及溶剂合物，以及另外一种或多种具有医药学治疗活性的成分。所述的另外一种或多种具有医药学治疗活性的成分，包括大分子化合物，例如蛋白(抗体或多肽)、多糖和核酸(DNA或RNA)等；和小分子化合物，例如无机化合物、有机金属化合物、合成或天然来源的有机小分子化合物等；此外还包括辐射、外科手术、细胞疗法、激素疗法或细胞因子疗法等。本发明权利要求1所述的如式(I)的化合物，其前药、对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物可以和另外一种或多种具有医药学治疗活性的成分在预防或治疗特定疾病或功能紊乱过程中产生协同作用。本发明权利要求1所述的如式(I)的化合物，其前药、对映异构体、非对映异构体、外消旋体及其混合物，以及其药学上可接受的盐、结晶水合物及溶剂合物也可以减轻或消除另外一种或多种具有医药学治疗活性成分在预防或治疗特定疾病或功能紊乱过程中所产生的毒副作用，反之亦然。
本发明的又一个目的是提供了如通式(I)的化合物，其互变异构体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物，用于制备治疗或预防CRL4 CRBNE3泛素连接酶参与的疾病的药物的用途。本发明阐述的由CRL4 CRBNE3泛素连接酶参与的相关疾病非限制性包括肿瘤、中枢***疾病和免疫性疾病。
在一优选例中，所述的疾病或功能紊乱包括但不限于：癌症、与血管生成相关的疾病或功能紊乱、疼痛(包括但不限于复杂性局部疼痛综合症)、黄斑退化及相关功能紊乱、皮肤疾病、肺部功能紊乱、免疫缺陷型疾病、中枢神经***的损伤及功能紊乱、TNFα相关的疾病或功能紊乱。
在另一优选例中，所述的癌症包括(但不限于)：皮肤癌症(如黑色素瘤)、淋巴***癌症、乳腺癌、***、子宫癌、消化道癌症、肺癌、卵巢癌、***癌、结肠癌、直肠癌、口腔癌、脑瘤、头颈部癌、咽喉癌、睾丸癌、肾癌、胰腺癌、脾癌、肝癌、膀胱癌，喉癌以及与艾滋病相关的癌症。本发明所提供的化合物同样对血液瘤和骨髓瘤有效，如能用于治疗多发性骨髓瘤、淋巴瘤和急慢性白血病。本发明所提供的化合物也可用于预防或治疗原发肿瘤和转移性肿瘤。
本发明中所用术语“氘(D)”是氢的一中稳定形态的非放射性同位素，其原子量为2.0144。天然中的氢是以H(氢或氕)、D(2H或氘)和T(3H或氚)同位素混合物的形式存在的，其中氘的丰度为0.0156％。根据本领域普通技术知识，所有含有天然氢原子的化合物结构式中，氢原子实际上表示的是H、D与T的混合物。因此，化合物中任何位点处的氘丰度大于其自然丰度0.0156％时，这些化合物都应该被认为是非天然的或氘富集的。
本发明中所用术语“同位素化合物”是指本发明的通式(I)化合物、其药学上可接受的盐、溶剂化物、立体异构体、代谢物，或前药中含有一个或多个天然或非天然丰度的原子同位素。本发明也涵盖经同位素标记的本发明化合物，除了一个或多个原子是被原子质量或质量数不同于自然中常见的原子质量或质量数之一原子所置换的事实之外，其是与此述者相同。可纳入本发明的化合物中的同位素实例，包括氢、碳、氮、氧、磷、硫、氟、碘及氯之同位素，其分别诸如： 2氢、 3氢、 11碳、 13碳、 14碳、 13氮、 15氮、 15氧、 17氧、 18氧、 31磷、 32磷、 35硫、 18氟、 123碘、 125碘及 36氯。
某些同位素标记的本发明的化合物(例如用3H和14C标记的那些)用于化合物和/或底物组织分布试验。特别优选氚化(即3H)和碳-14(即14C)同位素，因为它们容易制备和检测。而且，较重的同位素如氘(即2H)进行取代可以提供由较大的代谢稳定性导致的某些治疗优点(例如体内半衰期增加或剂量需求减小)，因而在某些情况下可能是优选的。正电子发射同位素，例如15O、13N、11C和18F用于正电子发射体层摄影术(PET)研究，以检查底物受体占用率。同位素标记的本发明的化合物一般可以遵循类似于在方案和/或下文实施例中所公开的方法，通过用同位素标记的试剂替代非同位素标记的试剂来制备。本发明的化合物的所有同位素变体，无论是否具有放射性，都包括在本发明的范围内。
具体实施方法
下面结合具体实施例对本发明作进一步的阐述，但这些实施例并不限制本发明的范围。
一、制备实施例
所有实施例中， 1H NMR由Bruker Avance III-300或Avance III-400型核磁共振仪记录，化学位移以δ(ppm)表示；质谱由MS质谱UPLC-MS(ESI)测定；其中UPLC型号是Waters HPLC H-CLASS，MS(ESI)的型号是Waters SQ Detector 2；无水四氢呋喃由二苯甲酮/金属钠回流干燥除氧制得，无水甲苯和无水二氯甲烷由氯化钙回流干燥制得；石油醚、乙酸乙酯、二氯甲烷等用于柱层析流动相的溶剂均购置于国药集团化学试剂有限公司；反应检测中使用的薄层层析硅胶板(HSGF254)来自国药集团化学试剂有限公司；化合物分离选用国药集团化学试剂有限公司的200-300目硅胶。本发明中原料可以从商业途径获得，如主要试剂购买于国药集团化学试剂有限公司，或者通过本领域抑制的方法制备，或者根据本发明中所述方法制备。
1.中间体化合物的合成
参考上述合成方法1-合成方法7中的合成方法。
3-溴-2-溴甲基苯甲酸甲酯：
Figure PCTCN2019109368-appb-000076
反应完毕，减压除去溶剂，所得残余物经硅胶柱层析得到3-溴-2-溴甲基苯甲酸甲酯5.3g,无色油状物，收率98％； 1H NMR(400MHz,CDCl 3)δ7.88(dd,J＝7.8,1.3Hz,1H),7.76(dd,J＝8.0,1.3Hz,1H),7.22(t,J＝7.9Hz,1H),5.12(s,2H),3.95(s,3H).
3-(4-溴-1-氧代异吲哚啉-2-)哌啶-2,6二酮：
Figure PCTCN2019109368-appb-000077
22.88mmol)，反应混合液于80℃反应18小时。反应完毕，减压除去溶剂，出品分散于水-乙酸乙酯-石油醚(v/v/v,2:1:1)的混合溶液中，过滤所得沉淀，减压干燥得3-(4-溴-1-氧代异吲哚啉-2-)哌啶-2,6二酮(3.35g,60％). 1H NMR(400MHz,DMSO)δ11.03(s,1H),7.87(dd,J＝7.9,0.7Hz,1H),7.79–7.75(m,1H),7.51(t,J＝7.7Hz,1H),5.15(dd,J＝13.3, 5.1Hz,1H),4.42(d,J＝17.6Hz,1H),4.26(d,J＝17.6Hz,1H),2.92(ddd,J＝17.5,13.7,5.4Hz,1H),2.64–2.55(m,1H),2.55–2.39(m,1H),2.02(dtd,J＝12.5,5.2,2.0Hz,1H).
3-(4-(5-羟基戊基-1-炔-1-)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮：
Figure PCTCN2019109368-appb-000078
(118mg,0.62mmol)溶解于10mL干燥DMF.反应液用高纯氮气置换3次,再加入10mL三乙胺,反应液再用高纯氮气置换一次.反应液升温至60℃反应过夜.反应完毕,减压除去溶剂,粗品经硅胶柱层析得到产物3-(4-(5-羟基戊基-1-炔-1-)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮1.03g,白色固体，收率100％； 1H NMR(400MHz,DMSO)δ11.02(s,1H),7.71(d,J＝7.6Hz,0.8Hz,1H),7.64(dd,J＝7.6,0.8Hz,1H),7.53(t,J＝7.6Hz,1H),5.15(dd,J＝13.3,5.1Hz,1H),4.57(t,J＝5.1Hz,1H),4.46(d,J＝17.8Hz,1H),4.31(d,J＝17.8Hz,1H),3.54(dd,J＝11.4,6.1Hz,2H),2.99–2.86(m,1H),2.65–2.57(m,1H),2.56–2.39(m,3H),2.06–1.97(m,1H),1.77–1.67(m,2H).
3-(4-(6-羟己基-1-炔-1-)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮：
Figure PCTCN2019109368-appb-000079
到3-(4-(6-羟己基-1-炔-1-)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮665mg,氮黄色固体，收率84％； 1H NMR(400MHz,DMSO)δ11.00(s,1H),7.70(d,J＝7.0Hz,1H),7.63(d,J＝7.6Hz,1H),7.51(t,J＝7.6Hz,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.50–4.40(m,2H),4.30(d,J＝17.7Hz,1H),3.44(q,J＝5.9Hz,2H),2.91(ddd,J＝17.5,13.7,5.4Hz,1H),2.64–2.55(m,1H),2.50–2.40(m,3H),2.01(ddd,J＝10.2,5.0,3.2Hz,1H),1.58(ddd,J＝11.3,6.4,2.6Hz,4H).
3-(4-(5-羟戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮：
Figure PCTCN2019109368-appb-000080
(200mg)，在氢气存在条件(260psi)下加热至40℃反应7小时.反应完全后,过滤除去催化剂.滤液减压浓缩并经硅胶柱层析得到3-(4-(5-羟戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮1.02g,白色固体，收率100％； 1H NMR(400MHz,DMSO)δ10.99(s,1H),7.58–7.53(m,1H),7.48–7.43(m,2H),5.13(dd,J＝13.2,5.2Hz,1H),4.46(d,J＝17.1Hz,1H),4.35(t,J＝5.1Hz,1H),4.30(d,J＝17.1Hz,1H),3.38(dd,J＝11.6,6.4Hz,2H),2.92(ddd,J＝17.4,13.8,5.6Hz,1H),2.68–2.56(m,3H),2.48–2.37(m,1H),2.06–1.96(m,1H),1.66–1.54(m,2H),1.45(td,J＝13.4,6.5Hz,2H),1.33(dt,J＝9.4,7.5Hz,2H).
3-(4-(5-溴戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮：
Figure PCTCN2019109368-appb-000081
mg,3.036mmol)溶解于40mL干燥四氢呋喃中,向反应液中加入四溴化碳(1.506g,4.54mmol)，所得反应混合物于室温下反应1小时。T反应完毕后,减压除去溶剂,所得残余物经硅胶柱层析得到3-(4-(5-溴戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮588mg,白色固体，收率99％；1H NMR(500MHz,DMSO)δ11.01(s,1H),7.62(dd,J＝11.8,7.3Hz,1H),7.56(dd,J＝6.5,4.0Hz,1H),7.48–7.43(m,1H),5.14(dd,J＝13.4,5.2Hz,1H),4.47(d,J＝17.1Hz,1H),4.31(d,J＝17.1Hz,1H),3.54(t,J＝6.6Hz,2H),2.98–2.87(m,1H),2.63(dd,J＝22.8,14.8Hz,3H),2.43(ddd,J＝26.4,13.4,4.3Hz,1H),2.06–1.97(m,1H),1.94–1.76(m,2H),1.63(dt,J＝15.3,7.6Hz,2H),1.44(dt,J＝14.8,7.5Hz,2H).
3-(4-(4-羟丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮：
Figure PCTCN2019109368-appb-000082
兰尼镍。所得混合体系在260psi氢气压力下反应30小时。反应完毕，将反应液用硅藻土过滤，滤液减压浓缩，所得残余物经硅胶柱层析得到3-(4-(4-羟基丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮0.75g，收率100％； 1H NMR(400MHz,DMSO)δ11.01(s,1H),7.58–7.54(m,1H),7.46(d,J＝4.3Hz,2H),5.14(dd,J＝13.3,5.0Hz,1H),4.46(d,J＝17.2Hz,1H),4.41(t,J＝5.2Hz,1H),4.30(d,J＝17.1Hz,1H),3.42(dd,J＝11.7,6.3Hz,2H),3.14-3.04(m,1H),2.98-2.87(m,1H),2.69–2.60(m,3H),2.05-1.96(m,1H),1.68–1.57(m,2H),1.50–1.42(m,2H),1.17(t,J＝7.4Hz,1H).ESI-MS[M+H] +m/z＝317.24。
3-(4-(3-羟丙基-1-氧代异吲哚啉-2-)哌啶-2,6-二酮：
Figure PCTCN2019109368-appb-000083
5.13(dd,J＝13.3,5.1Hz,1H),4.46(d,J＝17.2Hz,1H),4.39(t,J＝5.2Hz,1H),4.30(d,J＝17.2Hz,1H),3.42(dd,J＝11.6,6.3Hz,2H),2.92(ddd,J＝17.5,13.7,4.7Hz,1H),2.69–2.56(m,3H),2.48–2.36(m,1H),2.01(ddd,J＝9.8,4.9,2.9Hz,1H),1.70–1.56(m,2H),1.51–1.40(m,2H).
3-(4-(2-溴乙氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮：
Figure PCTCN2019109368-appb-000084
乙烷(643mg，3.42mmol，5.0eq)和无水碳酸钾(96mg，0.68mmol，1.0eq)，50℃下剧烈搅拌24小时。反应完成后，旋走乙腈，柱层析纯化得到100mg，白色固体，产率为37％； 1H NMR(400MHz,DMSO)δ7.61(s,1H),7.47(t,J＝7.8Hz,1H),7.32(d,J＝7.3Hz,1H),7.25(d,J＝8.0Hz,1H),7.20(d,J＝9.8Hz,1H),4.74(dd,J＝10.4,5.0Hz,1H),4.55(d, J＝17.6Hz,1H),4.51–4.43(m,2H),4.39(d,J＝17.6Hz,1H),3.91–3.81(m,2H),3.53(d,J＝14.0Hz,3H),2.33–2.14(m,3H),2.12-2.03(m,1H).
步骤2：将5-胺基-4-(4-(2-溴乙氧基)-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(100mg，0.25mmol，1.0eq)溶于20mL无水四氢呋喃中，-78℃条件下搅拌15分钟。加入叔丁醇钾(31mg，0.28mmol，1.1eq)，继续反应90分钟。反应完成后，-78℃条件下加入1mL 1N盐酸淬灭反应。反应体系逐渐升值室温，旋走溶剂，柱层析纯化得到90mg，白色固体，收率为98％； 1H NMR(400MHz,DMSO)δ10.97(s,1H),7.49(t,J＝7.8Hz,1H),7.35(d,J＝7.4Hz,1H),7.27(d,J＝8.1Hz,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.47(dt,J＝8.1,4.9Hz,2H),4.43–4.34(m,1H),4.26(d,J＝17.4Hz,1H),3.83(t,J＝5.3Hz,2H),2.90(ddd,J＝13.6,12.4,5.4Hz,1H),2.58(d,J＝18.1Hz,1H),2.49–2.40(m,1H),1.99(s,1H).
3-(4-(3-溴丙氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮：
Figure PCTCN2019109368-appb-000085
吲哚啉-2-)哌啶-2,6-二酮634mg，白色固体，收率为95％； 1H NMR(400MHz,DMSO)δ11.00(s,1H),7.49(t,J＝7.8Hz,1H),7.32(d,J＝7.4Hz,1H),7.27(d,J＝8.0Hz,1H),5.12(dd,J＝13.3,5.0Hz,1H),4.41(d,J＝17.5Hz,1H),4.23(dd,J＝14.3,8.4Hz,3H),3.71(t,J＝6.6Hz,2H),2.96–2.86(m,1H),2.58(d,J＝17.2Hz,1H),2.47–2.38(m,2H),2.32–2.22(m,2H),2.03–1.94(m,1H).
3-(4-(5-溴戊氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮：
Figure PCTCN2019109368-appb-000086
代异吲哚啉-2-)哌啶-2,6-二酮322mg，白色固体，收率为97％； 1H NMR(400MHz,CDCl 3)δ8.00(s,1H),7.48(dd,J＝7.6,0.9Hz,1H),7.43(t,J＝7.7Hz,1H),7.04–6.99(m,1H),5.23 (dd,J＝13.3,5.1Hz,1H),4.43(d,J＝16.5Hz,1H),4.30(d,J＝16.5Hz,1H),4.08(t,J＝6.2Hz,2H),3.45(t,J＝6.7Hz,2H),2.86(ddd,J＝23.2,15.9,4.1Hz,2H),2.44–2.32(m,1H),2.22(dtd,J＝10.3,5.2,2.6Hz,1H),1.99–1.90(m,2H),1.89–1.79(m,2H),1.71–1.60(m,2H).
3-(4-(6-溴己氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮：
Figure PCTCN2019109368-appb-000087
氧代异吲哚啉-2-)哌啶-2,6-二酮474mg，白色固体，收率为95％； 1H NMR(400MHz,DMSO)δ10.97(s,1H),7.47(t,J＝7.8Hz,1H),7.30(d,J＝7.4Hz,1H),7.23(d,J＝8.1Hz,1H),5.10(dd,J＝13.3,5.1Hz,1H),4.37(d,J＝17.4Hz,1H),4.22(d,J＝17.4Hz,1H),4.11(t,J＝6.3Hz,2H),3.54(t,J＝6.7Hz,2H),2.99–2.84(m,1H),2.58(d,J＝18.0Hz,1H),2.45(dd,J＝13.1,4.4Hz,1H),1.99(t,J＝5.1Hz,1H),1.89–1.68(m,4H),1.46(dd,J＝7.1,3.5Hz,4H).
(S)-2-((叔丁氧羰基)氨基)-4-戊炔酸苄酯：
Figure PCTCN2019109368-appb-000088
冷却至0℃,向反应液中逐滴加入氯甲酸苄酯(2.08mL,14.77mmol)。所得反应液在0℃反应4小时，反应完毕，反应液依次用1N硫酸氢钾水溶液洗涤，有机相用无水硫酸钠干燥，反应液过滤，减压浓缩，所得残余物经硅胶柱层析得到目标产物3.321g,无色油状物，产率78％。
(2R)-2-叔丁氧羰基胺基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-4-戊炔酸苄酯：
Figure PCTCN2019109368-appb-000089
10.47mmol)，3-(4-溴-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(2.26g,6.98mmol),双三苯基膦二氯化钯(491mg,0.70mmol)和碘化亚酮(267mg,1.40mmol)，将反应体系用氮气置换，在氮气保护下加入干燥的DMF(20mL)和干燥的三乙胺(20mL)，将反应液升温至60℃反应过夜。反应完毕，减压除去溶剂，残余物经硅胶柱层析得到(2R)-2-叔丁氧羰基胺基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-4-戊炔酸苄酯3.64g,灰白色固体，收率95％。
(2R)-2-叔丁氧羰基胺基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酸：
Figure PCTCN2019109368-appb-000090
10％Pd/C(50mg),将反应体系在氢气(8bar)条件下反应过夜，反应完毕，过滤除去催化剂，滤液减压浓缩得到化合物(2R)-2-叔丁氧羰基胺基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酸107mg,收率100％； 1H NMR(400MHz,DMSO)δ12.43(s,1H),10.99(s,1H),7.57(dd,J＝6.5,2.0Hz,1H),7.49–7.41(m,2H),7.09(d,J＝7.8Hz,1H),5.75(s,1H),5.14(ddd,J＝13.3,4.9,2.0Hz,1H),4.46(d,J＝17.1Hz,1H),4.30(dd,J＝17.2,1.3Hz,1H),3.97–3.86(m,1H),3.00–2.87(m,1H),2.71–2.57(m,3H),2.41(ddd,J＝26.4,13.3,4.2Hz,1H),2.09–1.91(m,1H),1.78–1.56(m,4H),1.37(s,9H).
2.实施例化合物的合成：
参考上述合成方法1-合成方法7中的合成方法。
实施例1:3-(1-氧代-4-(5-(喹啉-4-氧)戊基)异吲哚啉-2-)哌啶-2,6-二酮(1)
Figure PCTCN2019109368-appb-000091
膦(159mg,0.605mmol,2eq.)溶解于20mL干燥THF中，氮气保护下加入偶氮二甲酸二异丙酯(120μL,0.605mmol,2eq.)。所得混合液继续于室温下搅拌反 应2小时，反应完毕，减压除去溶剂，所得残余物先经硅胶柱层析分离，再经HPLC纯化得到3-(1-氧代-4-(5-(喹啉-4-氧)戊基)异吲哚啉-2-)哌啶-2,6-二酮52mg,白色固体，收率38％； 1H NMR(400MHz,DMSO)δ11.00(s,1H),8.71(d,J＝5.2Hz,1H),8.12–8.07(m,1H),7.93(dd,J＝8.4,0.5Hz,1H),7.73(ddd,J＝8.4,6.9,1.5Hz,1H),7.57(dd,J＝7.3,1.3Hz,1H),7.55–7.51(m,1H),7.48(dd,J＝7.5,1.4Hz,1H),7.47–7.42(m,1H),7.01(d,J＝5.3Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.47(d,J＝17.1Hz,1H),4.32(d,J＝17.1Hz,1H),4.26(t,J＝6.3Hz,2H),2.91(ddd,J＝17.6,13.8,5.3Hz,1H),2.74–2.67(m,2H),2.63–2.55(m,1H),2.39(ddd,J＝17.4,13.1,4.8Hz,1H),2.01–1.88(m,3H),1.79–1.68(m,2H),1.63–1.52(m,2H).
实施例2:3-(1-氧代-4-(3-(喹啉-4-氧)丙基)异吲哚啉-2-)哌啶-2,6-二酮(2)
Figure PCTCN2019109368-appb-000092
mg,0.32mmol)加入到100mL圆底烧瓶中，加入20mL四氢呋喃，剧烈搅拌。之后加入偶氮二甲酸二异丙酯(65mg，0.32mmol)。反应完成后，旋走溶剂，HPLC纯化得到产物17.6mg,收率26％； 1H NMR(400MHz,DMSO)δ10.96(s,1H),9.10(d,J＝6.4Hz,1H),8.26(d,J＝7.7Hz,1H),8.13(d,J＝8.4Hz,1H),8.08–8.01(m,1H),7.79(t,J＝11.3Hz,1H),7.56(t,J＝6.4Hz,2H),7.46(dd,J＝10.5,4.4Hz,2H),5.11(dd,J＝13.3,5.1Hz,1H),4.52(t,J＝5.9Hz,2H),4.47(d,J＝17.1Hz,1H),4.31(d,J＝17.1Hz,1H),3.00–2.84(m,3H),2.6(m,1H),2.36-2.14(m,3H),1.97–1.86(m,1H).
实施例3:3-(1-氧代-4-(6-(喹啉-4-氧)己基)异吲哚啉-2-)哌啶-2,6-二酮(3)
Figure PCTCN2019109368-appb-000093
3-(1-氧代-4-(5-(喹啉-4-氧)戊基)异吲哚啉-2-)哌啶-2,6-二酮，47.2mg,收率50％； 1H NMR(400MHz,DMSO)δ11.00(s,1H),8.72(d,J＝5.3Hz,1H),8.14(dd,J＝8.3,0.9Hz,1H),7.97–7.91(m,1H),7.74(ddd,J＝8.4,6.9,1.5Hz,1H),7.56(tdd,J＝4.7,3.9,1.2Hz,2H),7.48–7.40(m,2H),7.02(d,J＝5.3Hz,1H),5.13(dd,J＝13.2,5.2Hz,1H),4.46(d,J＝17.2Hz,1H),4.30(d,J＝17.1Hz,1H),4.25(t,J＝6.3Hz,2H),2.92(ddd,J＝17.5,13.5,5.5Hz,1H),2.70–2.63(m,2H),2.59(dd,J＝16.3,2.0Hz,1H),2.41(ddd,J＝26.5,13.4,4.6Hz,1H),2.05–1.95(m,1H),1.92–1.83(m,2H),1.71–1.62(m,2H),1.61–1.51(m,2H),1.44(dt,J＝15.9,8.0Hz,2H).
实施例4：3-(1-氧代-4-(3-(喹啉-4-氧)丙氧基)异吲哚啉-2-)哌啶-2,6-二酮(4)
Figure PCTCN2019109368-appb-000094
拌30分钟。后加入叔丁基二甲基氯硅烷(9.0g,5.97mmol),继续反应1h。反应完成后，加入饱和氯化铵淬灭，乙酸乙酯萃取、饱和氯化钠洗涤、干燥、浓缩、柱层析得到无色油状物(10.06g,90％) 1H NMR(400MHz,CDCl3)δ3.87-3.76(m,4H),2.65(t,J＝5.2Hz,1H),1.83–1.73(m,2H),0.89(s,9H),0.07(s,6H).
步骤2：将化合物5-胺基-4-(4-羟基-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(100mg，0.34mmol，1.0eq)加入到100ml圆底烧瓶中，加入3-叔丁基二甲基硅氧基-1-丙醇(174mg，0.85mmol，2.5eq)，三苯基膦(178mg，0.68mmol，2eq)。反应体系用氮气置换，加入20mL干燥四氢呋喃。向反应体系中加入偶氮二甲酸二异丙酯(134μL，0.68mmol，2eq)。室温反应1h。反应完成后旋走溶剂，柱层析得到目标产物。ESI-MS[M+H] +m/z＝465.60。
步骤3：将上步所得产物加入到50mL圆底烧瓶中，加入20mL四氢呋喃，加入四丁基氟化铵(0.64ml，0.64mmol)室温反应过夜。反应完成后，减压除去溶剂，柱层析纯化得到产物211mg白的固体，收率78％； 1H NMR(400MHz,DMSO)δ10.99(s,1H),7.49(t,J＝7.8Hz,1H),7.31(d,J＝7.2Hz,1H),7.25(d,J＝8.0Hz,1H),5.12(dd,J＝13.3,5.1Hz,1H), 4.59(t,J＝6.0Hz,1H),4.38(d,J＝17.4Hz,1H),4.22(d,J＝17.3Hz,1H),4.19(t,J＝6.2Hz,2H),3.58(dd,J＝11.4,6.1Hz,2H),2.97–2.85(m,1H),2.63-2.54(m,1H),2.48–2.38(m,1H),2.05–1.93(m,1H),1.89(p,J＝6.1Hz,2H)。ESI-MS[M+H] +m/z＝319.26
步骤4：将化合物3-(4-(3-羟基丙氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(50mg，0.16mmol，1.0eq)加入到100mL圆底烧瓶中，加入4-羟基喹啉(68mg，0.47mmol，3eq)，三苯基膦(82mg，0.31mmol，2eq)。抽换N 2，加入四氢呋喃(20ml)。向反应体系中加入偶氮二甲酸二异丙酯(62ul，0.31mmol，2eq)。室温反应1h。反应完成后减压除去溶剂，经HPLC纯化得到产物27.6mg，收率39％； 1H NMR(400MHz,DMSO)δ11.01(s,1H),9.13(d,J＝6.2Hz,1H),8.37(d,J＝8.4Hz,1H),8.12(d,J＝8.4Hz,1H),8.05(t,J＝7.7Hz,1H),7.81(t,J＝7.7Hz,1H),7.54(d,J＝6.3Hz,1H),7.48(t,J＝7.8Hz,1H),7.36–7.28(m,2H),5.10(dd,J＝13.3,5.0Hz,1H),4.71(t,J＝5.8Hz,2H),4.41(t,J＝5.8Hz,2H),4.32(d,J＝17.4Hz,1H),4.17(d,J＝17.4Hz,1H),2.99–2.84(m,1H),2.62-2.53(m,1H),2.48–2.39(m,2H),2.29(qd,J＝13.4,4.4Hz,1H),1.99–1.89(m,1H).ESI-MS[M+H] +m/z＝446.33。
实施例5:3-(4-(5-(异吲哚啉-5-氧)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(5)
Figure PCTCN2019109368-appb-000095
1H NMR(400MHz,DMSO)δ11.00(s,1H),9.30(s,1H),8.49(d,J＝5.9Hz,1H),7.92(d,J＝5.9Hz,1H),7.67(d,J＝8.2Hz,1H),7.63–7.54(m,2H),7.46(dt,J＝14.5,7.2Hz,2H),7.24(d,J＝7.6Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.32(d,J＝17.1Hz,1H),4.20(t,J＝6.3Hz,2H),2.92(ddd,J＝17.5,13.8,5.5Hz,1H),2.71(t,J＝7.6Hz,2H),2.64–2.55(m,1H),2.40(qd,J＝13.5,4.5Hz,1H),1.98(ddd,J＝10.5,5.0,2.4Hz,1H),1.91(dd,J＝14.5,7.0Hz,2H),1.78–1.68(m,2H),1.63–1.53(m,2H).
实施例6:3-(1-氧代-4-(4-(喹啉-4-氧)丁氧基)异吲哚啉-2-)哌啶-2,6-二酮(6)
Figure PCTCN2019109368-appb-000096
搅拌30min。后加入叔丁基二甲基氯硅烷(1.52g,10.09mmol,1eq),继续反应1h。反应完成后，加入饱和氯化铵淬灭，乙酸乙酯萃取、饱和氯化钠洗涤、干燥、浓缩、柱层析得到产物1.75g,无色油状物,收率78％； 1H NMR(400MHz,CDCl 3)δ9.71-3.60(m,4H),2.59(t,J＝5.5Hz,1H),1.70–1.58(m,4H),0.90(s,9H),0.07(s,6H).
步骤2：将化合物5-胺基-4-(4-羟基-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(100mg，0.34mmol，1.0eq)加入到100mL圆底烧瓶中，加入4-叔丁基二甲基硅氧基-1-丁醇(174mg，0.85mmol，2.5eq)，三苯基膦(178mg，0.68mmol，2eq)。反应tixi用氮气保护，加入四氢呋喃(20ml)。向反应体系中加入偶氮二甲酸二异丙酯(134ul，0.68mmol，2eq)。室温反应1小时。反应完成后旋走溶剂，柱层析纯化得到产物和三苯氧磷的混合物；ESI-MS[M+H] +m/z＝479.42。
步骤3：将上步所得混合物加入到50ml圆底烧瓶中，加入20ml四氢呋喃，加入四丁基氟化铵(0.34ml，0.34mmol，1eq)室温反应过夜。反应完成后，旋走溶剂，柱层析纯化得到产物96mg，白的固体，收率85％； 1H NMR(400MHz,DMSO)δ10.99(s,1H),7.47(t,J＝7.8Hz,1H),7.30(d,J＝7.4Hz,1H),7.23(d,J＝8.1Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.47(t,J＝5.1Hz,1H),4.37(d,J＝17.4Hz,1H),4.21(d,J＝17.4Hz,1H),4.12(t,J＝6.4Hz,2H),3.45(dd,J＝11.6,6.3Hz,2H),2.96–2.86(m,1H),2.62-2.54(m,1H),2.48–2.39(m,1H),2.03–1.94(m,1H),1.82–1.73(m,2H),1.63-1.53(m,2H)。ESI-MS[M+H] +m/z＝333.27。
步骤4：将化合物-(4-(4-羟基丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(50mg，0.15mmol，1.0eq)加入到100mL圆底烧瓶中，加入4-羟基喹啉(65mg，0.45mmol，3eq)，三苯基膦(79mg，0.30mmol，2eq)。抽换N 2，加入四氢呋喃(20ml)。向反应体系中加入偶氮二甲酸二异丙酯(59ul，0.30mmol，2eq)，室温反应1小时。反应完毕减压除去溶剂，残余物经HPLC纯化得到产物9.9mg，收率14％； 1H NMR(400MHz,DMSO)δ10.97(s, 1H),9.16(d,J＝6.4Hz,1H),8.32(d,J＝8.3Hz,1H),8.15–8.06(m,2H),7.82(t,J＝7.6Hz,1H),7.55(d,J＝6.6Hz,1H),7.46(t,J＝7.8Hz,1H),7.27(dd,J＝14.2,7.8Hz,2H),5.10(dd,J＝13.5,5.1Hz,1H),4.63(t,J＝5.9Hz,2H),4.33(d,J＝17.4Hz,1H),4.27(t,J＝5.9Hz,2H),4.19(d,J＝17.4Hz,1H),2.97–2.85(m,1H),2.63-2.54(m,1H),2.36(dt,J＝13.4,8.7Hz,1H),2.18–2.09(m,2H),2.09–1.92(m,3H)。ESI-MS[M+H] +m/z＝460.34。
实施例7:3-(4-(5-((6-甲基-2-(三氟甲基)喹啉-4-)氧)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(7)
Figure PCTCN2019109368-appb-000097
率87％； 1H NMR(400MHz,DMSO)δ10.99(s,1H),7.98(d,J＝8.6Hz,1H),7.94(s,1H),7.72(dd,J＝8.7,2.0Hz,1H),7.57(dd,J＝7.2,1.2Hz,1H),7.46(dt,J＝14.7,6.8Hz,2H),7.35(s,1H),5.12(dd,J＝13.1,5.1Hz,1H),4.47(d,J＝17.1Hz,1H),4.38(t,J＝6.4Hz,2H),4.32(d,J＝17.2Hz,1H),2.91(ddd,J＝17.8,13.6,5.2Hz,1H),2.75–2.68(m,2H),2.62–2.55(m,1H),2.52(s,3H),2.39(ddd,J＝17.4,12.9,4.0Hz,1H),1.96(ddd,J＝18.1,8.7,4.9Hz,3H),1.81–1.71(m,2H),1.64–1.54(m,2H).
实施例8:3-(4-(4-((2-环丙基喹啉-4-)氧)丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(8)
Figure PCTCN2019109368-appb-000098
9.72mmol，15eq)，三苯基膦(2.56g，9.72mmol，15eq)，加入四氢呋喃60mL剧烈搅拌。后加入偶氮二甲酸二异丙酯(1.91ml，9.72mmol，15eq)。室温反应1小时。反应完成后，减压除去溶剂，柱层析纯化除去三苯氧磷和1,4-丁二醇。所得混合物无需进一步纯化直接投下一步。ESI-MS[M+H] +m/z＝258.57。
步骤2：在氮气保护下，在100mL圆底烧瓶中加入上步所得混合物，5-胺基-4-(4- 羟基-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(50mg，0.7mmol，1eq)，三苯基膦(89mg，0.34mmol，2eq)，加入四氢呋喃20mL剧烈搅拌。后加入偶氮二甲酸二异丙酯(67ul，0.34mmol，2eq)。室温反应小时。反应完成后，旋走溶剂，柱层析纯化得到产物77mg,淡黄色油状物,收率85％；ESI-MS[M+H] +m/z＝532.31。
步骤3：5-胺基-4-(4-(4-((2-环丙基喹啉-4-)氧)丁氧基)-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(40mg，0.075mmol，1eq)溶于10mL干燥的四氢呋喃，冰浴条件下加入叔丁醇钾(8.5mg，0.075mmol，1eq)，10分钟后开始检测反应。反应完成后，加入5ul甲酸淬灭反应，旋走溶剂，HPLC纯化得到产物21.5mg,白色固体，收率57％。 1H NMR(400MHz,DMSO)δ10.97(s,1H),8.20(d,J＝8.1Hz,1H),8.08–7.97(m,2H),7.72(t,J＝6.9Hz,1H),7.47(t,J＝7.8Hz,1H),7.30(d,J＝7.4Hz,1H),7.25(d,J＝8.2Hz,1H),6.94(s,1H),5.10(dd,J＝13.3,5.1Hz,1H),4.57(t,J＝6.0Hz,2H),4.33(d,J＝17.4Hz,2H),4.26(t,J＝6.0Hz,2H),4.17(s,1H),2.99–2.84(m,1H),2.63-2.53(m,1H),2.48-2.42(m,1H),2.41–2.28(m,1H),2.15-2.07(m,2H),2.05–1.94(m,3H),1.48–1.40(m,4H).ESI-MS[M+H] +m/z＝500.47。
实施例9:3-(1-氧代-4-(5-(噻吩并[3,2-b]吡啶-7-氧)戊基)异吲哚啉-2-)哌啶-2,6-二酮(9)
Figure PCTCN2019109368-appb-000099
1H NMR(400MHz,DMSO)δ11.00(s,1H),8.52(d,J＝5.4Hz,1H),8.04(d,J＝5.4Hz,1H),7.56(dd,J＝6.9,1.7Hz,1H),7.51(d,J＝5.4Hz,1H),7.49–7.40(m,2H),7.00(d,J＝5.4Hz,1H),5.13(dd,J＝13.4,5.1Hz,1H),4.47(d,J＝17.1Hz,1H),4.30(dd,J＝15.0,8.5Hz,3H),2.92(ddd,J＝17.0,13.4,5.3Hz,1H),2.72–2.65(m,2H),2.63–2.56(m,1H),2.40(ddd,J＝26.4,13.5,4.7Hz,1H),1.98(ddd,J＝8.7,7.3,4.8Hz,1H),1.92–1.81(m,2H),1.71(dt,J＝15.5,7.9Hz,2H),1.58–1.46(m,2H).
实施例10:3-(4-(4-((2-乙基喹啉-4-)氧)丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(10)
Figure PCTCN2019109368-appb-000100
滴加入甲基甲醚(1.69ml，1.79mmol，1eq)，室温反应5h。反应完成后，加入饱和氯化铵淬灭，二氯甲烷萃取、干燥、浓缩、柱层析得到1.10g(37％)无色液体。 1H NMR(400MHz,CDCl 3)δ4.63(s,1H),3.67(s,1H),3.57(t,J＝5.9Hz,1H),3.36(s,1H),1.93(s,1H),1.70–1.64(m,2H).
步骤2：将2-乙基喹啉-1-酚(100mg，0.57mmol,1eq)，4-甲氧基甲氧基-1-丁醇(1.16g，8.66mmol，15eq)，三苯基膦(2.27g，8.66mmol，15eq)溶于40mL四氢呋喃，室温条件下加入偶氮二甲酸二异丙酯(1.75g，8.66mmol，15eq)，室温反应2小时。反应完成后旋走溶剂，TLC纯化得到产物147mg，淡黄色油状物,产率90％； 1H NMR(400MHz,CDCl 3)δ8.16(d,J＝8.3Hz,1H),7.96(d,J＝8.2Hz,1H),7.65(t,J＝6.9Hz,1H),7.45–7.40(m,1H),6.63(s,1H),4.66(s,2H),4.22(t,J＝6.3Hz,2H),3.65(t,J＝6.3Hz,2H),3.39(s,3H),2.94(q,J＝7.6Hz,2H),2.05(d,J＝27.7Hz,2H),1.92–1.86(m,2H),1.38(t,J＝7.6Hz,3H).ESI-MS[M+H] +m/z＝290.61。
步骤3：将化合物2-乙基-4-(4-(甲氧基甲氧基)丁氧基)喹啉(147mg，0.51mmol)转移到100ml圆底烧瓶中，加入10ml盐酸二氧六环和1ml甲醇。所得混合体系在室温条件下搅拌1小时。反应完成后，旋走溶剂，加入少量氨甲醇，旋走溶剂，柱层析纯化得到75mg，白色固体，收率100％；ESI-MS[M+H] +m/z＝246.65。
步骤4：将化合物5-胺基-4-(4-羟基-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(50mg，0.17mmol,1eq)，2-乙基-4-(4-羟基丁氧基)喹啉(100mg，0.34mmol,2eq)，三苯基膦(90mg，0.34mmol,2eq)加入到50mL圆底烧瓶中，加入20mL四氢呋喃，加入偶氮二甲酸二异丙酯(67ul，0.34mmol，2eq)室温反应2h。反应完成后，旋走溶剂，TLC纯化得到产物72mg，白色固体，收率81％； 1H NMR(400MHz,CDCl 3)δ8.14(d,J＝7.3Hz,1H),7.99(d,J＝8.4Hz,1H),7.68(t,J＝8.4Hz,1H),7.49–7.41(m,1H),7.06(dd,J＝6.8,2.1Hz,1H),6.68(s, 1H),6.29(s,1H),5.32(s,1H),4.92(dd,J＝8.8,6.2Hz,1H),4.44(q,J＝17.5Hz,1H),4.32(t,J＝5.5Hz,1H),4.23(d,J＝5.8Hz,1H),3.67(s,1H),2.98(q,J＝7.6Hz,1H),2.50–2.39(m,1H),2.24–2.14(m,2H),1.42(t,J＝7.6Hz,1H).ESI-MS[M+H] +m/z＝520.35。
步骤5：5-胺基-4-(4-(4-((2-乙基喹啉-4-)氧)丁氧基)-1-氧代异喹啉-2-)-5-氧代戊酸甲酯(72mg，0.14mmol，1.0eq)溶于10mL干燥的四氢呋喃，冰浴条件下加入叔丁醇钾(16mg，0.14mmol，1eq)，10分钟后开始检测反应。反应完成后，加入5ul甲酸淬灭反应，旋走溶剂，HPLC纯化得到产物54mg,白色固体，收率79％； 1H NMR(400MHz,DMSO)δ10.98(s,1H),8.27(d,J＝8.2Hz,1H),8.08(dt,J＝8.5,7.6Hz,2H),7.82–7.75(m,1H),7.52(s,1H),7.47(t,J＝7.8Hz,1H),7.28(dd,J＝17.6,7.8Hz,2H),5.11(dd,J＝13.3,5.1Hz,1H),4.62(t,J＝6.0Hz,2H),4.33(d,J＝17.4Hz,1H),4.26(t,J＝6.0Hz,2H),4.19(d,J＝17.4Hz,1H),3.11(q,J＝7.6Hz,2H),2.98–2.84(m,1H),2.62-2.53(m,1H),2.35(qd,J＝13.3,4.4Hz,1H),2.19-2.09(m,2H),2.08-1.92(m,4H),1.40(t,J＝7.6Hz,3H)。ESI-MS[M+H] +m/z＝488.43。
实施例11:3-(1-氧代-4-(5-(喹啉-3-氧代)戊基)异吲哚啉-2-)哌啶-2,6-二酮(11)
Figure PCTCN2019109368-appb-000101
NMR(400MHz,DMSO)δ11.00(s,1H),8.61(d,J＝2.9Hz,1H),7.96–7.91(m,1H),7.89–7.84(m,1H),7.76(d,J＝2.9Hz,1H),7.60–7.52(m,3H),7.51–7.43(m,2H),5.13(dd,J＝13.3,5.2Hz,1H),4.48(d,J＝17.2Hz,1H),4.33(d,J＝17.1Hz,1H),4.15(t,J＝6.5Hz,2H),2.92(ddd,J＝17.6,13.9,5.5Hz,1H),2.73–2.65(m,2H),2.58(ddd,J＝16.7,4.2,2.1Hz,1H),2.42(ddd,J＝18.3,13.1,4.4Hz,1H),2.03–1.95(m,1H),1.91–1.81(m,2H),1.76–1.66(m,2H),1.53(dt,J＝15.3,7.8Hz,2H).
实施例12:3-(1-氧代-4-((5-(喹啉-4-氧)戊基)氧)异吲哚啉-2-)哌啶-2,6-二酮(12)
Figure PCTCN2019109368-appb-000102
滴加入溴甲基甲醚(0.75ml，9.6mmol，1eq)，室温反应5h。反应完成后，加入饱和氯化铵淬灭，二氯甲烷萃取、干燥、浓缩、柱层析得到产物0.57g，无色液体，产率40％； 1H NMR(400MHz,CDCl 3)δ4.61(s,1H),3.64(t,J＝6.5Hz,1H),3.53(t,J＝6.5Hz,1H),3.35(s,1H),1.64–1.58(m,1H),1.54(s,1H),1.47–1.41(m,1H).
步骤2：将5-(甲氧基甲氧基)-1-戊醇(296mg，2.04mmol，3.0eq)加入到100ml圆底烧瓶中，加入4-羟基喹啉(110mg，0.68mmol，1eq)，三苯基膦(357mg，1.36mmol，2eq)。抽换N 2，加入四氢呋喃(20ml)。向反应体系中加入偶氮二甲酸二异丙酯(268ul，1.36mmol，2eq)。室温反应1h。反应完成后旋走溶剂，柱层析纯化得到产物147mg，无色油状物，收率79％； 1H NMR(400MHz,CDCl 3)δ8.73(d,J＝5.2Hz,1H),8.21(dd,J＝8.3,1.0Hz,1H),8.02(d,J＝8.4Hz,1H),7.69(ddd,J＝8.4,6.9,1.4Hz,1H),7.49(t,J＝8.3Hz,1H),6.71(d,J＝5.2Hz,1H),4.63(s,2H),4.20(t,J＝6.3Hz,2H),3.58(t,J＝6.2Hz,2H),3.37(s,3H),2.01–1.96(m,2H),1.76–1.63(m,4H).
步骤3：将化合物4-(5-(甲氧基甲氧基)戊氧基)喹啉(147mg，0.53mmol)转移到100ml圆底烧瓶中，加入10ml盐酸二氧六环和1ml甲醇。所得混合体系在室温条件下搅拌1小时。反应完成后，旋走溶剂，加入少量氨甲醇，旋走溶剂，柱层析纯化得到124mg(100％)白色固体。ESI-MS[M+H] +m/z＝276.57。
步骤4：将化合物5-胺基-4-(4-羟基-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(50mg，0.17mmol,1eq)，5-(喹啉-4-氧)-1-戊醇(100mg，0.34mmol,2eq)，三苯基膦(90mg，0.34mmol,2eq)加入到50ml圆底烧瓶中，加入20ml四氢呋喃，加入偶氮二甲酸二异丙酯(67ul，0.34mmol，2eq)室温反应2h。反应完成后，旋走溶剂，TLC纯化得到产物65mg,白色固体,收率76％； 1H NMR(400MHz,CDCl 3)δ8.74(d,J＝5.2Hz,1H),8.23–8.18(m,1H),8.02(d,J＝8.4Hz,1H),7.69(t,J＝8.4Hz,1H),7.49(dd,J＝11.2,4.0Hz,1H),7.44–7.39(m,2H),7.01(dq,J＝7.9,4.1Hz,1H),6.75(d,J＝5.2Hz,1H),6.40(s,1H),5.43(s,1H), 4.91(dd,J＝8.8,6.2Hz,1H),4.41(q,J＝17.6Hz,2H),4.25(t,J＝6.3Hz,2H),4.11(t,J＝10.9,2H),3.63(s,3H),2.42–1.81(m,10H).ESI-MS[M+H] +m/z＝506.83。
步骤5：5-胺基-4-(5-(4-((喹啉-4-)氧)戊氧基)-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(85mg，0.17mmol，1.0eq)溶于10mL干燥的四氢呋喃，冰浴冷却条件下加入叔丁醇钾(17mg，0.17mmol，1eq)，10分钟后开始检测反应。反应完成后，加入5ul甲酸淬灭反应，旋走溶剂，HPLC纯化得到产物29.6mg,白色固体，收率34％； 1H NMR(400MHz,DMSO)δ10.98(s,1H),9.14(d,J＝6.5Hz,1H),8.33(d,J＝8.4Hz,1H),8.14(d,J＝8.6Hz,1H),8.07(t,J＝8.6Hz,1H),7.82(t,J＝7.7Hz,1H),7.53(d,J＝6.5Hz,1H),7.46(t,J＝7.8Hz,1H),7.30(d,J＝7.3Hz,1H),7.24(d,J＝8.1Hz,1H),5.10(dd,J＝13.3,5.1Hz,1H),4.56(t,J＝6.3Hz,2H),4.35(d,J＝17.4Hz,1H),4.25–4.14(m,3H),3.00–2.84(m,1H),2.56(m,1H),2.38(qd,J＝13.1,4.3Hz,1H),2.06–1.80(m,5H),1.78-1.67(m,2H).ESI-MS[M+H] +m/z＝506.31。
实施例13:3-(1-氧代-4-(5-((2-(三氟甲基)喹啉-4-)氧)戊基)异吲哚啉-2-)哌啶-2,6-二酮(13)
Figure PCTCN2019109368-appb-000103
47％； 1H NMR(400MHz,DMSO)δ10.99(s,1H),8.19(dd,J＝8.3,0.7Hz,1H),8.08(d,J＝8.4Hz,1H),7.89(ddd,J＝8.4,6.9,1.4Hz,1H),7.75–7.69(m,1H),7.57(dd,J＝7.2,1.1Hz,1H),7.50–7.42(m,2H),7.40(s,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.47(d,J＝17.4Hz,1H),4.40(t,J＝6.3Hz,2H),4.32(d,J＝17.2Hz,1H),2.92(ddd,J＝17.4,13.9,5.9Hz,1H),2.76–2.67(m,2H),2.58(ddd,J＝6.0,3.3,1.7Hz,1H),2.39(ddd,J＝26.7,13.7,5.0Hz,1H),2.02–1.89(m,3H),1.81–1.70(m,2H),1.65–1.53(m,2H).
实施例14:3-(1-氧代-4-((6-(喹啉-4-氧)己基)氧)异吲哚啉-2-)哌啶-2,6-二酮(14)
Figure PCTCN2019109368-appb-000104
逐滴加入溴甲基甲醚(1.33ml，16.92mmol，1eq)，室温反应5h。反应完成后，加入饱和氯化铵淬灭，二氯甲烷萃取、干燥、浓缩、柱层析得到1.11g，无色液体，收率41％； 1H NMR(400MHz,CDCl 3)δ4.61(s,2H),3.63(t,J＝6.6Hz,1H),3.51(t,J＝6.6Hz,1H),3.35(s,1H),1.63-1.53(m,2H),1.51(s,1H),1.43-1.34(m,2H).
步骤2：将6-(甲氧基甲氧基)-1-己醇(180mg，1.24mmol，2.0eq)加入到100mL圆底烧瓶中，加入4-羟基喹啉(100mg，0.62mmol，1eq)，三苯基膦(330mg，1.24mmol，2eq)。抽换N 2，加入四氢呋喃(20ml)。向反应体系中加入偶氮二甲酸二异丙酯(207ul，1.24mmol，2eq)。室温反应1h。反应完成后旋走溶剂，柱层析纯化得到140mg，无色油状物，收率78％； 1H NMR(400MHz,CDCl 3)δ8.75(d,J＝5.2Hz,1H),8.23(d,J＝8.3Hz,1H),8.04(d,J＝8.5Hz,1H),7.72(d,J＝8.1Hz,1H),7.51(t,J＝8.3Hz 1H),6.73(d,J＝5.2Hz,1H),4.65(s,2H),4.21(t,J＝6.3Hz,2H),3.57(t,J＝8.1Hz 2H),3.39(s,3H),2.02–1.93(m,3H),1.71–1.49(m,6H).[M+H] +m/z＝290.39。
步骤3：将化合物4-(6-(甲氧基甲氧基)己氧基)喹啉(140mg，0.48mmol)转移到100mL圆底烧瓶中，加入10mL盐酸二氧六环和1mL甲醇。所得混合体系在室温条件下搅拌1小时。反应完成后，旋走溶剂，加入少量氨甲醇，旋走溶剂，柱层析纯化得到118mg，白色固体，收率100％； 1H NMR(400MHz,CDCl 3)δ8.72(d,J＝5.2Hz,1H),8.21(dd,J＝8.3,0.8Hz,1H),8.02(d,J＝8.4Hz,1H),7.72–7.66(m,1H),7.53–7.47(m,1H),6.71(d,J＝5.2Hz,1H),4.18(t,J＝6.4Hz,2H),3.69(t,J＝6.5Hz,2H),1.95(dd,J＝14.5,6.7Hz,2H),1.62(qd,J＝14.5,7.0Hz,4H),1.54–1.45(m,2H).[M+H] +m/z＝246.72。
步骤4：将化合物5-胺基-4-(4-羟基-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(50mg，0.17mmol,1eq)，6-(喹啉-4-氧)-1-己醇(83mg，0.34mmol,2eq)，三苯基膦(90mg，0.34mmol,2eq)加入到50ml圆底烧瓶中，加入20ml四氢呋喃，加入偶氮二甲酸二异丙酯(67ul，0.34mmol，2eq)室温反应2h。反应完成后，旋走溶剂，TLC纯化得到63mg，白 色固体，收率71％； 1H NMR(400MHz,CDCl 3)δ8.73(d,J＝5.2Hz,1H),8.20(d,J＝8.3Hz,1H),8.01(d,J＝8.4Hz,1H),7.68(t,J＝7.0Hz,1H),7.47(t,J＝7.6Hz,1H),7.39(d,J＝1.1Hz,1H),6.98(p,J＝4.0Hz,1H),6.73(d,J＝5.2Hz,1H),6.54(s,1H),5.61(s,1H),4.92(dd,J＝8.8,6.1Hz,1H),4.40(dd,J＝38.8,17.6Hz,1H),4.22(t,J＝6.3Hz,1H),4.11–4.02(m,1H),3.62(s,1H),2.46–2.27(m,1H),2.22-2.12(m,1H),2.05–1.96(m,1H),1.93–1.82(m,1H),1.70-1.66(m,2H).[M+H] +m/z＝520.35。
步骤5：5-胺基-5-氧代-4-(1-氧代-4-((6-(喹啉-4-氧)己基)氧)异吲哚啉-2-)戊酸甲酯(63mg，0.19mmol，1.0eq)溶于10ml干燥的四氢呋喃，冰浴条件下加入叔丁醇钾(22mg，0.19mmol，1eq)，10分钟后开始检测反应。反应完成后，加入5ul甲酸淬灭反应，旋走溶剂，HPLC纯化得到产物42mg,白色固体，收率45％； 1H NMR(400MHz,DMSO)δ10.98(s,1H),9.15(d,J＝6.5Hz,1H),8.34(d,J＝8.4Hz,1H),8.15(d,J＝8.6Hz,1H),8.09(t,J＝8.4Hz,1H),7.83(t,J＝8.4Hz,1H),7.54(d,J＝6.6Hz,1H),7.45(t,J＝7.8Hz,1H),7.28(d,J＝7.3Hz,1H),7.22(d,J＝8.1Hz,1H),5.10(dd,J＝13.2,5.1Hz,1H),4.55(t,J＝6.3Hz,2H),4.34(d,J＝17.4Hz,1H),4.21(d,J＝17.4Hz,1H),4.14(t,J＝6.3Hz,2H),2.97–2.84(m,1H),2.61-2.53(m,1H),2.41(qd,J＝13.3,4.5Hz,1H),2.03–1.91(m,3H),1.86–1.72(m,2H),1.67-1.52(m,4H).ESI-MS[M+H] +m/z＝488.76。
实施例15:3-(1-氧代-4-(4-(喹啉-4-氧)丁基)异吲哚啉-2-)哌啶-2,6-二酮(15)
Figure PCTCN2019109368-appb-000105
mmol)加入到100mL圆底烧瓶中，在氮气保护下加入20mL干燥四氢呋喃，搅拌至反应体系成均相，再加入偶氮二甲酸二异丙酯(65mg，0.32mmol)，继续于室温下搅拌反应30分钟。反应完成后，减压除去溶剂，残余物经HPLC分离得产物21.7mg,收率31％； 1H NMR(400MHz,DMSO)δ11.04(s,1H),9.19(d,J＝6.4Hz,1H),8.36(d,J＝8.4Hz,1H),8.21–8.06(m,2H),7.88(t,J＝7.4Hz,1H),7.60-7.44(m,,4H),5.15(dd,J＝13.3,4.9Hz, 1H),4.59(t,J＝5.8Hz,2H),4.48(d,J＝17.2Hz,1H),4.32(d,J＝17.1Hz,1H),3.00–2.87(m,1H),2.86–2.71(m,2H),2.54(s,2H),2.38–2.26(m,1H),2.05–1.82(m,5H).
实施例16:3-(4-(5-吗啉戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(16)
Figure PCTCN2019109368-appb-000106
燥DMF中，室温搅拌下加入碘化钾(50mg,0.297mmol，2eq.)，将所得反应液室温下搅拌反应过夜。反应完毕，所得反应液直接用HPLC分离得到3-(4-(5-吗啉戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮13.4mg,白色固体，收率17％； 1H NMR(400MHz,DMSO)δ11.00(s,1H),7.59–7.53(m,1H),7.45(dd,J＝6.2,2.5Hz,2H),5.13(dd,J＝13.3,5.1Hz,1H),4.46(d,J＝17.1Hz,1H),4.30(d,J＝17.1Hz,1H),3.59–3.50(m,4H),2.98–2.86(m,1H),2.67–2.56(m,3H),2.42(ddd,J＝12.6,9.7,6.9Hz,1H),2.31(s,4H),2.28–2.21(m,2H),2.06–1.96(m,1H),1.61(dt,J＝15.3,7.5Hz,2H),1.51–1.39(m,2H),1.32(dt,J＝14.9,7.3Hz,2H).
实施例17:3-(1-氧代-4-(5-(2-苯基吡咯啉-1-)戊基)吲哚啉-2-)哌啶-2,6-二酮(17)
Figure PCTCN2019109368-appb-000107
加入2-苯基吡咯啉(28mg，0.193mmol)和三乙胺(10uL,0.386mmol),室温搅拌24小时，LC-MS跟踪监测反应完毕，产物直接通过HPLC分离得到白色固体30.5mg,收率52％； 1H NMR(400MHz,DMSO)δ11.01(s,1H),7.55(d,J＝7.3Hz,1H),7.44(t,J＝7.4Hz,1H),7.38(d,J＝7.4Hz,1H),7.35–7.26(m,4H),7.22(t,J＝6.5Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.42(dd,J＝17.2,3.9Hz,1H),4.26(d,J＝17.1Hz,1H),3.31–3.19(m,2H),2.98–2.87(m,1H),2.69–2.31(m,15H),2.24–1.94(m,4H),1.79(ddd,J＝19.8,16.0,8.8Hz,2H),1.61–1.36(m,5H),1.35–1.14(m,2H).
实施例18:3-(1-氧代-4-(5-(4-苯基哌嗪-1-)戊基)吲哚啉-2-)哌啶-2,6-二酮(18)
Figure PCTCN2019109368-appb-000108
＝8.5,7.4Hz,2H),6.91(d,J＝8.0Hz,2H),6.76(t,J＝7.2Hz,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.1Hz,1H),3.15–3.05(m,4H),2.92(ddd,J＝17.6,13.7,5.4Hz,1H),2.69–2.57(m,3H),2.57–2.51(m,4H),2.43(dd,J＝13.1,4.3Hz,1H),2.38–2.30(m,2H),2.06–1.95(m,1H),1.64(dt,J＝15.2,7.6Hz,2H),1.52(dt,J＝14.8,7.6Hz,2H),1.41–1.28(m,2H).
实施例19:3-(4-(5-(4-(2-甲氧基苯基)哌嗪-1-)戊基)-1-氧代吲哚啉-2-)哌啶-2,6-二酮(19)
Figure PCTCN2019109368-appb-000109
(m,2H),6.87(d,J＝3.8Hz,2H),5.14(dd,J＝13.3,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),3.76(s,3H),3.03–2.85(m,5H),2.70–2.52(m,5H),2.48–2.24(m,4H),2.05–1.96(m,1H),1.68–1.58(m,2H),1.56–1.46(m,2H),1.40–1.18(m,3H).
实施例20:3-(1-氧代-4-(5-(4-苯基哌啶-1-)戊基)吲哚啉-2-)哌啶-2,6-二酮(20)
Figure PCTCN2019109368-appb-000110
7.33–7.16(m,5H),5.14(dd,J＝13.3,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.1Hz,1H),3.09(d,J＝11.3Hz,2H),2.99–2.86(m,1H),2.71–2.56(m,3H),2.53–2.36(m, 4H),2.22(dd,J＝11.5,9.7Hz,2H),2.01(ddd,J＝10.2,5.0,3.0Hz,1H),1.83–1.48(m,8H),1.41–1.26(m,2H).
实施例21:3-(4-(4-(4-(2,3-二氯苯基)哌嗪-1-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(21)
Figure PCTCN2019109368-appb-000111
δ11.02(s,1H),8.15(s,1H),7.61–7.55(m,1H),7.50–7.45(m,2H),7.34–7.27(m,2H),7.17–7.10(m,1H),5.15(dd,J＝13.3,5.2Hz,1H),4.48(d,J＝17.2Hz,1H),4.33(d,J＝17.2Hz,1H),3.04–2.86(m,5H),2.68(t,J＝7.6Hz,2H),2.65–2.53(m,5H),2.47–2.35(m,3H),2.07–1.98(m,1H),1.71–1.59(m,2H),1.52(dt,J＝14.2,7.1Hz,2H).
实施例22:3-(4-(5-(4-(6-氟苯并[d]异噁唑-3-)哌啶-1-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(22)
Figure PCTCN2019109368-appb-000112
DMSO)δ10.99(s,1H),8.17(s,1H),8.00(dd,J＝8.7,5.3Hz,1H),7.69(dd,J＝9.1,2.1Hz,1H),7.56(dt,J＝7.7,3.9Hz,1H),7.51–7.43(m,2H),7.28(td,J＝9.1,2.1Hz,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.1Hz,1H),3.23–3.12(m,1H),3.05(d,J＝11.6Hz,2H),2.93(ddd,J＝17.7,13.8,5.3Hz,1H),2.71–2.55(m,3H),2.47–2.35(m,3H),2.23(t,J＝11.0Hz,2H),2.09–1.97(m,3H),1.93–1.78(m,2H),1.70–1.59(m,2H),1.58–1.48(m,2H),1.41–1.30(m,2H).
实施例23：3-(1-氧代-4-(5-(4-(3-三氟甲基苯基)哌嗪-1-)戊基)异吲哚啉-2-)哌啶-2,6-二酮(23)
Figure PCTCN2019109368-appb-000113
DMSO)δ11.01(s,1H),7.57(dd,J＝5.0,2.0Hz,1H),7.49–7.44(m,2H),7.41(t,J＝8.1Hz,1H),7.21(dd,J＝8.6,2.1Hz,1H),7.15(s,1H),7.06(d,J＝7.4Hz,1H),5.14(dd,J＝13.2,5.3Hz,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.0Hz,1H),3.28(d,J＝48.8Hz,7H),2.98–2.87(m,1H),2.63(dt,J＝22.0,15.0Hz,4H),2.46–2.30(m,3H),2.05–1.95(m,1H),1.70–1.58(m,2H),1.52(dt,J＝9.8,6.2Hz,2H),1.41–1.28(m,2H).
实施例24:3-(1-氧代-4-(5-(4-(喹啉-4-)哌嗪-1-)戊基)异吲哚啉-2-)哌啶-2,6-二酮(24)
Figure PCTCN2019109368-appb-000114
8.1Hz,1H),7.95(d,J＝8.3Hz,1H),7.73–7.66(m,1H),7.60–7.52(m,2H),7.51–7.44(m,2H),6.98(d,J＝5.0Hz,1H),5.15(dd,J＝13.3,5.0Hz,1H),4.49(d,J＝17.2Hz,1H),4.32(d,J＝17.2Hz,1H),3.24–3.09(m,4H),3.00–2.88(m,1H),2.73–2.57(m,6H),2.48–2.38(m,3H),2.06–1.97(m,1H),1.66(dt,J＝15.3,7.7Hz,2H),1.60–1.49(m,2H),1.44–1.32(m,2H).
实施例25:(S)-3-(4-(3-(4-(2,3-二氯苯基)哌嗪-1-)丙氧基)-1-氧代异吲哚啉-2-)-3-甲基哌啶-2,6-二酮(25)
Figure PCTCN2019109368-appb-000115
NMR(400MHz,DMSO)δ10.87(s,1H),7.46(t,J＝7.8Hz,1H),7.34–7.11(m,5H),4.65(d,J＝17.5Hz,1H),4.54(d,J＝17.7Hz,1H),4.19(t,J＝5.9Hz,2H),3.00(s,3H),2.67(ddd,J＝ 51.9,30.3,22.3Hz,7H),2.00–1.83(m,3H),1.70(s,3H).
实施例26:3-(4-(5-(4-(2,3-二氯苯基)哌嗪-1-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(26)
Figure PCTCN2019109368-appb-000116
DMSO)δ10.99(s,1H),8.16(s,1H),7.60–7.53(m,1H),7.49–7.42(m,2H),7.33–7.26(m,2H),7.16–7.10(m,1H),5.75(s,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),3.01–2.86(m,5H),2.69–2.63(m,2H),2.58(s,1H),2.53(d,J＝6.6Hz,4H),2.47–2.38(m,1H),2.37–2.29(m,2H),2.06–1.96(m,1H),1.63(dt,J＝15.3,7.8Hz,2H),1.57–1.43(m,2H),1.40–1.29(m,2H).
实施例27:(S)-4-(3-(4-(2,3-二氯苯基)哌嗪-1-)丙氧基)-2-(3-甲基-2,6-二氧代哌啶-3-)异吲哚啉-1,3-二酮(27)
Figure PCTCN2019109368-appb-000117
NMR(400MHz,DMSO)δ11.00(s,1H),7.78(t,J＝7.9Hz,1H),7.50(d,J＝8.5Hz,1H),7.37(d,J＝7.2Hz,1H),7.33–7.27(m,2H),7.14(dd,J＝5.8,3.6Hz,1H),4.24(t,J＝6.0Hz,2H),2.98(s,4H),2.75–2.51(m,9H),2.08–1.91(m,3H),1.86(d,J＝6.1Hz,3H).
实施例28:3-(1-氧代-4-(4-氧代-4-(4-苯基哌嗪-1-)丁氧基)异吲哚啉-2-)哌啶-2,6-二酮(28)
Figure PCTCN2019109368-appb-000118
1H),7.30(d,J＝7.5Hz,1H),7.23(dd,J＝15.1,7.6Hz,3H),6.93(d,J＝8.0Hz,2H),6.80(t,J＝7.2Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.40(d,J＝17.4Hz,1H),4.24(d,J＝17.4Hz, 1H),4.16(t,J＝6.3Hz,2H),3.60(d,J＝4.6Hz,4H),3.10(dd,J＝9.7,4.7Hz,4H),2.99–2.85(m,1H),2.56(dd,J＝16.8,9.9Hz,3H),2.47–2.37(m,1H),2.06–1.93(m,3H).
实施例29:3-(4-(4-(4-(2,3-二氯苯基)哌嗪-1-)-4-氧代丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(29)
Figure PCTCN2019109368-appb-000119
收率为26％； 1H NMR(400MHz,DMSO)δ10.97(s,1H),7.48(t,J＝7.8Hz,1H),7.37–7.28(m,3H),7.25(d,J＝8.1Hz,1H),7.13–7.07(m,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.40(d,J＝17.4Hz,1H),4.25(d,J＝17.4Hz,1H),4.16(t,J＝6.3Hz,2H),3.62(d,J＝3.6Hz,4H),2.91(td,J＝14.2,7.7Hz,5H),2.64–2.53(m,3H),2.48–2.35(m,1H),2.06–1.94(m,3H).
实施例30:3-(1-氧代-4-((5-氧代-5-(4-苯基哌嗪-1-)戊氧基)异吲哚啉-2-)哌啶-2,6-二酮(30)
Figure PCTCN2019109368-appb-000120
37％； 1H NMR(400MHz,DMSO)δ10.97(s,1H),7.48(t,J＝7.8Hz,1H),7.31(d,J＝7.4Hz,1H),7.27–7.16(m,3H),6.95(d,J＝7.9Hz,2H),6.81(t,J＝7.3Hz,1H),5.10(dd,J＝13.3,5.1Hz,1H),4.38(d,J＝17.4Hz,1H),4.23(d,J＝17.4Hz,1H),4.15(t,J＝6.2Hz,2H),3.65–3.56(m,4H),3.19–3.04(m,4H),2.98–2.85(m,1H),2.57(d,J＝18.5Hz,1H),2.50–2.37(m,4H),2.04–1.93(m,1H),1.74(ddd,J＝21.7,14.2,6.9Hz,4H).
实施例31:3-(4-((5-(4-(2,3-二氯苯基)哌嗪-1-)-5-氧代戊基)氧)-1-氧代戊基-2-)哌啶-2,6-二酮(31)
Figure PCTCN2019109368-appb-000121
收率为25％； 1H NMR(400MHz,DMSO)δ10.96(s,1H),7.48(t,J＝7.8Hz,1H),7.37–7.27(m,3H),7.25(d,J＝8.1Hz,1H),7.12(dd,J＝6.3,3.3Hz,1H),5.10(dd,J＝13.3,5.1Hz,1H),4.37(d,J＝17.4Hz,1H),4.23(d,J＝17.3Hz,1H),4.15(t,J＝6.2Hz,2H),3.60(d,J＝4.6Hz,4H),3.00–2.81(m,5H),2.56(d,J＝18.6Hz,1H),2.49–2.36(m,4H),2.02–1.92(m,1H),1.74(ddd,J＝21.8,14.3,7.0Hz,4H).
实施例32:4-(2,3-二氯苯基)-N-(2-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)乙基)哌嗪-1-甲酰胺(32)
Figure PCTCN2019109368-appb-000122
0.22mmol)，反应液于40℃下搅拌反应0.5小时，待完全生成活性中间体后向反应液中加入4-(2，3-二氯苯基)哌嗪盐酸盐(59mg，0.22mmol)，所得反应液继续于40℃下搅拌反应2小时，反应完毕，反应液经HPLC分离得到目标产物39.6mg,收率48％； 1H NMR(400MHz,DMSO)δ10.97(s,1H),7.48(t,J＝7.8Hz,1H),7.35–7.26(m,3H),7.16–7.09(m,1H),6.81(t,J＝5.3Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.39(d,J＝17.4Hz,1H),4.25(d,J＝17.3Hz,1H),4.17(t,J＝5.9Hz,2H),3.58–3.37(m,6H),3.01–2.80(m,5H),2.63–2.55(m,1H),2.41(ddd,J＝26.1,13.1,4.4Hz,1H),2.04–1.94(m,1H).
实施例33:4-(2,3-二氯苯基)-N-(4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丁基)哌嗪-1-甲酰胺(33)
Figure PCTCN2019109368-appb-000123
-3-)-1-氧代异吲哚啉-4-)氧)乙基)哌嗪-1-甲酰胺，白色固体化合物，44.6mg,收率56％； 1H NMR(400MHz,DMSO)δ10.96(s,1H),7.48(t,J＝7.8Hz,1H),7.31(t,J＝5.8Hz,3H),7.24(d,J＝8.1Hz,1H),7.16–7.12(m,1H),6.60(t,J＝5.4Hz,1H),5.11(dd,J＝13.2,5.0Hz,1H),4.39(d,J＝17.4Hz,1H),4.23(d,J＝17.4Hz,1H),4.13(t,J＝6.3Hz,2H),3.46–3.39(m,4H),3.12(dd,J＝12.7,6.8Hz,2H),2.97–2.85(m,5H),2.58(d,J＝18.6Hz,1H),2.50-2.40(m,1H),2.03–1.95(m,1H),1.79-1.72(m,2H),1.64-1.54(m,2H).
实施例34：4-(2,3-二氯苯基)-N-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-1-甲酰胺(34)
Figure PCTCN2019109368-appb-000124
率29％； 1H NMR(400MHz,DMSO)δ10.97(s,1H),7.48(t,J＝8.0Hz,1H),7.34–7.29(m,3H),7.24(d,J＝8.1Hz,1H),7.15–7.11(m,1H),6.68(t,J＝5.4Hz,1H),5.11(dd,J＝13.0,5.0Hz,1H),4.39(d,J＝17.5Hz,1H),4.24(d,J＝17.5Hz,1H),4.15(t,J＝6.0Hz,2H),3.44(t,4H),3.26-3.19(m,2H),2.90(t,4H),2.63–2.55(m,1H),2.45–2.32(m,1H),2.04–1.86(m,3H).
实施例35：3-(4-(6-(4-(2,3-二氯苯基)哌嗪-1-)己基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(35)
Figure PCTCN2019109368-appb-000125
DMSO)δ10.99(s,1H),7.56(dd,J＝8.2,4.5Hz,1H),7.46(d,J＝3.5Hz,2H),7.30(dd,J＝9.1,5.3Hz,2H),7.13(dd,J＝6.3,3.1Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.46(d,J＝17.1Hz,1H),4.31(d,J＝17.2Hz,1H),3.32(s,4H),3.0-2.88(m,5H),2.68-2.56(m,3H),2.47–2.37(m,1H),2.32(s,2H),2.04–1.96(m,1H),1.66–1.56(m,2H),1.50–1.40(m,2H), 1.38-1.27(m,4H).
实施例36：4-(4-(4-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)丁基)哌嗪-1-)苯甲腈(36)
Figure PCTCN2019109368-appb-000126
DMSO)δ10.99(s,1H),7.60–7.53(m,3H),7.49–7.44(m,2H),7.00(d,J＝9.0Hz,2H),5.13(dd,J＝13.3,5.2Hz,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),3.32–3.28(m,4H),2.97–2.86(m,1H),2.67(t,J＝7.6Hz,2H),2.58(d,J＝16.3Hz,1H),2.47–2.43(m,4H),2.42–2.32(m,3H),2.05–1.96(m,1H),1.69–1.60(m,2H),1.54-1.46(m,2H).
实施例37：3-(4-(4-(4-(3-氯苯基)哌嗪-1-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(37)
Figure PCTCN2019109368-appb-000127
DMSO)δ10.99(s,1H),7.57(dt,J＝7.7,3.9Hz,1H),7.49–7.43(m,2H),7.19(t,J＝8.1Hz,1H),6.94–6.84(m,2H),6.77(dd,J＝7.8,1.4Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.32(d,J＝17.1Hz,1H),3.20–3.10(m,4H),2.98–2.86(m,1H),2.67(t,J＝7.5Hz,2H),2.59(d,J＝17.0Hz,1H),2.49-2.46(m,4H),2.45–2.35(m,3H),2.05–1.96(m,1H),1.69–1.59(m,2H),1.56–1.46(m,2H).
实施例38：2-(4-(4-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)丁基)哌嗪-1-)苯甲腈(38)
Figure PCTCN2019109368-appb-000128
DMSO)δ10.99(s,1H),7.69(dd,J＝7.7,1.5Hz,1H),7.62–7.55(m,2H),7.49–7.45(m,2H),7.14(d,J＝8.2Hz,1H),7.08(t,J＝7.6Hz,1H),5.14(dd,J＝13.2,5.1Hz,1H),4.48(d,J＝17.1Hz,1H),4.32(d,J＝17.1Hz,1H),3.17–3.10(m,4H),2.97–2.87(m,1H),2.72– 2.65(m,2H),2.60(d,J＝17.2Hz,1H),2.54(t,4H),2.47–2.36(m,3H),2.06-1.98(m,1H),1.65(dt,J＝15.6,6.3Hz,2H),1.52(dt,J＝14.8,7.5Hz,2H).
实施例39：3-(4-(4-(4-(4-氟苯基)哌嗪-1-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(39)
Figure PCTCN2019109368-appb-000129
DMSO)δ10.99(s,1H),7.57(dd,J＝5.2,3.4Hz,1H),7.49–7.44(m,2H),7.03(t,J＝8.9Hz,2H),6.96–6.89(m,2H),5.13(dd,J＝13.2,5.0Hz,1H),4.47(d,J＝17.2Hz,1H),4.32(d,J＝17.1Hz,1H),3.08–3.01(m,4H),2.97–2.86(m,1H),2.68(t,J＝7.6Hz,2H),2.58(d,J＝17.6Hz,1H),2.49-2.46(m,4H),2.44–2.34(m,3H),2.01(dt,J＝10.4,5.0Hz,1H),1.69–1.59(m,2H),1.51(dt,J＝14.2,7.1Hz,2H).
实施例40：3-(1-氧代-4-(4-(4-(3-甲基苯基)哌嗪-1-)丁基)异吲哚啉-2-)哌啶-2,6-二酮(40)
Figure PCTCN2019109368-appb-000130
MHz,DMSO)δ10.99(s,1H),7.57(dd,J＝5.4,3.2Hz,1H),7.50–7.44(m,2H),7.07(t,J＝7.8Hz,1H),6.76–6.66(m,2H),6.58(d,J＝7.3Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.32(d,J＝17.2Hz,1H),3.12–3.07(m,4H),2.97–2.86(m,1H),2.68(t,J＝7.5Hz,2H),2.58(d,J＝17.4Hz,1H),2.44–2.34(m,3H),2.23(s,3H),2.05–1.96(m,1H),1.69–1.59(m,2H),1.51(dt,J＝14.7,7.5Hz,2H).
实施例41：3-(4-(4-(4-(4-氯苯基)哌嗪-1-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(41)
Figure PCTCN2019109368-appb-000131
MHz,DMSO)δ10.99(s,1H),7.57(dd,J＝5.4,3.2Hz,1H),7.49–7.45(m,2H),7.22(d,J＝ 9.0Hz,2H),6.93(d,J＝9.0Hz,2H),5.14(dd,J＝13.2,5.1Hz,1H),4.47(d,J＝17.1Hz,1H),4.32(d,J＝17.2Hz,1H),3.14(s,4H),2.98–2.86(m,1H),2.68(t,J＝7.5Hz,2H),2.62-2.53(m,5H),2.48–2.35(m,3H),2.05–1.95(m,1H),1.65(dt,J＝15.5,6.9Hz,2H),1.53(dt,J＝15.2,7.6Hz,2H).
实施例42：3-(4-(4-(4-(4-硝基苯基)哌嗪-1-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(42)
Figure PCTCN2019109368-appb-000132
MHz,DMSO)δ10.99(s,1H),8.05(d,J＝9.4Hz,2H),7.57(dd,J＝5.4,3.2Hz,1H),7.50–7.45(m,2H),7.01(d,J＝9.5Hz,2H),5.14(dd,J＝13.3,5.0Hz,1H),4.47(d,J＝17.2Hz,1H),4.32(d,J＝17.2Hz,1H),3.45–3.41(m,4H),2.97–2.87(m,1H),2.68(t,J＝7.6Hz,2H),2.59(d,J＝17.2Hz,1H),2.49–2.44(m,4H),2.44–2.33(m,3H),2.06–1.96(m,1H),1.70–1.59(m,2H),1.51(dt,J＝15.2,7.7Hz,2H).
实施例43：3-(4-(4-(4-(2,4-二氟苯基)哌嗪-1-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(43)
Figure PCTCN2019109368-appb-000133
MHz,DMSO)δ10.99(s,1H),7.56(dt,J＝7.7,3.9Hz,1H),7.49–7.44(m,2H),7.22–7.14(m,1H),7.08–6.94(m,2H),5.14(dd,J＝13.2,4.9Hz,1H),4.47(d,J＝17.1Hz,1H),4.32(d,J＝17.2Hz,1H),2.98–2.87(m,5H),2.67(t,J＝7.6Hz,2H),2.59(d,J＝17.6Hz,1H),2.46–2.30(m,7H),2.06–1.97(m,1H),1.68–1.57(m,2H),1.55–1.45(m,2H).
实施例44：3-(4-(4-(4-(3,4-二氯苯基)哌嗪-1-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(44)
Figure PCTCN2019109368-appb-000134
-2-)哌啶-2,6-二酮，白色固体45.8mg,收率66.5％； 1H NMR(400MHz,DMSO)δ10.99(s,1H),7.56(dd,J＝8.1,4.8Hz,1H),7.49–7.45(m,2H),7.38(d,J＝9.0Hz,1H),7.10(d,J＝2.8Hz,1H),6.91(dd,J＝9.1,2.9Hz,1H),5.13(dd,J＝13.3,5.0Hz,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),3.16(m,4H),2.98–2.86(m,1H),2.67(t,J＝7.6Hz,2H),2.59(d,J＝16.4Hz,1H),2.48–2.31(m,7H),2.05–1.96(m,1H),1.64(dt,J＝15.1,7.2Hz,2H),1.56–1.45(m,2H).
实施例45：3-(1-氧代-4-(4-(4-(4-三氟甲基苯基)哌嗪-1-)丁基)异吲哚啉-2-)哌啶-2,6-二酮(45)
Figure PCTCN2019109368-appb-000135
MHz,DMSO)δ10.99(s,1H),7.58(dd,J＝5.5,3.0Hz,1H),7.55–7.46(m,4H),7.07(d,J＝7.9Hz,2H),5.14(dd,J＝13.4,5.3Hz,1H),4.48(d,J＝17.2Hz,1H),4.32(d,J＝17.1Hz,1H),3.20-3.10(m.4H),2.99–2.87(m,1H),2.72–2.65(m,2H),2.60(d,J＝16.5Hz,1H),2.46–2.30(m,7H),2.05–1.96(m,1H),1.67-1.54(m,4H).
实施例46：3-(4-(4-(4-(4-甲氧基苯基)哌嗪-1-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(46)
Figure PCTCN2019109368-appb-000136
MHz,DMSO)δ11.00(s,1H),7.58(dd,J＝5.5,3.2Hz,1H),7.51–7.46(m,2H),6.89(d,J＝9.2Hz,2H),6.82(d,J＝9.1Hz,2H),5.14(dd,J＝13.2,5.1Hz,1H),4.48(d,J＝17.2Hz,1H),4.33(d,J＝17.2Hz,1H),3.69(s,3H),3.08-2.87(m,5H),2.73–2.66(m,2H),2.60(d,J＝17.9Hz,1H),2.48–2.31(m,7H),2.06–1.97(m,1H),1.70–1.50(m,4H).
实施例47：2-(2,6-二氧代哌啶-3-)-4-(4-(喹啉-4-氧)丁氧基)异吲哚啉-1,3-二酮(47)
Figure PCTCN2019109368-appb-000137
步骤1：将4-羟基喹啉(100mg，0.69mmol，1.0eq)置于50ml圆底烧瓶中，加入4-甲氧基甲氧基-1-丁醇(278mg，2.07mmol，2eq)，三苯基膦(543mg，2.07mmol，2eq)。反应体系用氮气置换，加入15mL干燥四氢呋喃。向反应体系中加入偶氮二甲酸二异丙酯(408μL，2.07mmol，2eq)。室温反应1h。TLC监测反应完全后减压浓缩，柱层析得到目标产物173mg,收率96％。
步骤2：将4-(4-甲氧基甲氧基丁氧基)喹啉置于50mL圆底烧瓶中，加入10mL 4M盐酸二氧六环和1mL甲醇。室温反应1小时。LC-MS监测反应完全后，减压浓缩，加入饱和碳酸氢钠溶液，乙酸乙酯萃取，分液，有机层用饱和氯化钠洗涤，干燥，柱层析得到白色固体140mg,收率100％。
步骤3：将2-(2,6-二氧代哌啶-3-)-4-羟基异吲哚啉-1,3-二酮(35mg,0.128mmol)置于50ml圆底烧瓶中，加入4-(喹啉-4-氧)-1-丁醇(56mg，0.256mmol，2eq)，三苯基膦(67mg，0.256mmol，2eq)。反应体系用氮气置换，加入5mL干燥四氢呋喃。向反应体系中加入偶氮二甲酸二异丙酯(51μL，0.256mmol，2eq)。室温反应1h。TLC监测反应完全后减压浓缩，经HPLC得到白色固体20.3mg,收率33.4％； 1H NMR(400MHz,DMSO)δ11.11(s,1H),8.75(d,J＝5.3Hz,1H),8.16–8.11(m,1H),7.94(d,J＝8.4Hz,1H),7.83–7.72(m,2H),7.54(t,J＝7.7Hz,2H),7.43(d,J＝7.2Hz,1H),7.08(d,J＝5.4Hz,1H),5.08(dd,J＝12.7,5.4Hz,1H),4.41(t,J＝6.1Hz,2H),4.35(t,J＝5.8Hz,2H),2.87(dd,J＝8.5,5.3Hz,1H),2.70-2.55(m,1H),2.18–1.95(m,6H).
实施例48：3-(4-(4-(4-(2,6-二氯苯基)哌嗪-1-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(48)
Figure PCTCN2019109368-appb-000138
MHz,DMSO)δ10.99(s,1H),7.58(dd,J＝5.8,2.7Hz,1H),7.50–7.46(m,2H),7.41(d,J＝8.1Hz,2H),7.17–7.12(m,1H),5.14(dd,J＝13.5,5.1Hz,1H),4.48(d,J＝17.1Hz,1H),4.33(d,J＝17.1Hz,1H),3.13(s,4H),2.99–2.87(m,2H),2.72–2.66(m,2H),2.61(d,J＝19.2Hz,1H),2.48-2.45(m,4H),2.42-2.33(dd,J＝14.2,6.7Hz,3H),2.07-1.99(m,1H),1.70-1.61(m,1H),1.56-1.47(m,1H).
实施例49：4-(4-氯苯基)-1-(5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊基)哌啶-4-甲腈(49)
Figure PCTCN2019109368-appb-000139
DMSO)δ11.01(s,1H),7.60–7.54(m,2H),7.54–7.49(m,2H),7.49–7.45(m,2H),5.15(dd,J＝13.3,5.4Hz,1H),4.47(d,J＝17.0Hz,1H),4.31(d,J＝17.2Hz,1H),2.99–2.88(m,1H),2.72–2.56(m,3H),2.48–2.20(m,5H),2.12(d,J＝14.0Hz,2H),2.06–1.88(m,3H),1.70–1.59(m,2H),1.52(dt,J＝13.4,6.7Hz,2H),1.36(dd,J＝14.7,5.1Hz,2H).
实施例50：(S)-4-(2-氯苯基)-1-(3-((2-(3-甲基-2,6-二氧代哌啶-3-)-1,3-二氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(50)
Figure PCTCN2019109368-appb-000140
1.22mmol，1.0eq)溶于20ml甲苯。加入三乙胺(136mg，1.34mmol，1.1eq)120℃回流24小时。反应完成后，旋走甲苯，柱层析纯化得到200mg白色固体，收率为57％。 1H NMR(400MHz,DMSO)δ11.07(s,1H),10.97(s,1H),7.62(dd,J＝8.3,7.3Hz,1H),7.22(dd,J＝ 15.6,7.7Hz,2H),2.75–2.62(m,1H),2.57–2.52(m,1H),2.06–1.97(m,1H),1.86(s,3H),1.29–1.18(m,1H).
步骤2：将(S)-4-羟基-2-(3-甲基-2,6-二氧代哌啶-3-)异吲哚啉-1,3-二酮(200mg，0.69mmol，1.0eq)溶于20mL乙腈，加入1，3-二溴丙烷(681mg，3.54mmol，3.0eq)，无水碳酸钾(96mg，0.69mmol，1.0eq)。反应体系50℃反应24小时。反应成后，旋走溶剂。乙酸乙酯稀释，饱和氯化钠洗涤，无水硫酸钠干燥，减压除溶剂，柱层析纯化得到243mg白色固体，收率为86％。 1H NMR(400MHz,DMSO)δ10.98(s,1H),7.83–7.78(m,1H),7.52(d,J＝8.5Hz,1H),7.40(d,J＝7.1Hz,1H),4.29(t,J＝5.8Hz,2H),3.72(t,J＝6.5Hz,1H),2.68(s,1H),2.31(dd,J＝13.8,7.7Hz,1H),2.03(d,J＝18.2Hz,1H),1.88(s,1H).
步骤3：将(S)-4-(3-溴丙基)-2-(3-甲基-2,6-二氧代哌啶-3-)异吲哚啉-1,3-二酮(40mg，0.098mmol，1.0eq)溶于3mL DMSO，加入4-(2-氯苯基)哌啶-4-甲腈盐酸盐(38mg，0.147mmol，1.5eq)，三乙胺(9.89mg，0.980mmol，10.0eq)，40℃反应过夜。反应完成后，用20mL乙酸乙酯稀释，饱和氯化钠洗涤，无水硫酸钠干燥，减压浓缩，薄层色谱纯化和高效液相色谱纯化得到产物23mg，白色固体，收率43％；1H NMR(400MHz,DMSO)δ10.99(d,J＝5.1Hz,1H),7.81–7.75(m,1H),7.59–7.51(m,2H),7.49(d,J＝8.6Hz,1H),7.47–7.40(m,2H),7.37(d,J＝7.2Hz,1H),4.23(t,J＝6.0Hz,2H),3.05(d,J＝9.4Hz,2H),2.76–2.62(m,1H),2.55(dd,J＝12.7,5.3Hz,3H),2.38(dd,J＝29.5,18.0Hz,5H),2.00(dd,J＝16.1,10.9Hz,5H),1.87(s,3H).
实施例51：4-(3-氯苯基)-1-(5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊基)哌啶-4-甲腈(51)
Figure PCTCN2019109368-appb-000141
δ11.01(s,1H),7.60–7.49(m,3H),7.49–7.43(m,3H),5.15(dd,J＝13.6,5.2Hz,1H),4.48(d,J＝17.1Hz,1H),4.31(d,J＝17.2Hz,1H),2.99(d,J＝12.2Hz, 2H),2.95–2.87(m,1H),2.69–2.64(m,2H),2.64–2.57(m,1H),2.49–2.41(m,1H),2.40–2.32(m,2H),2.24(td,J＝11.9,1.3Hz,2H),2.14(dd,J＝12.7,1.5Hz,2H),2.06–1.93(m,3H),1.64(dt,J＝15.3,7.7Hz,2H),1.56–1.46(m,2H),1.35(dd,J＝15.1,7.2Hz,2H).
实施例52:(S)-4-(3-氯苯基)-1-(3-((2-(3-甲基-2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(52)
Figure PCTCN2019109368-appb-000142
14mg，白色固体，收率26％； 1H NMR(400MHz,DMSO)δ10.88(s,1H),7.60(s,1H),7.50(dt,J＝17.6,7.7Hz,4H),7.24(dd,J＝12.5,7.8Hz,2H),4.66(d,J＝17.6Hz,1H),4.54(d,J＝17.6Hz,1H),4.20(t,J＝6.0Hz,2H),3.05(d,J＝10.6Hz,2H),2.80–2.52(m,5H),2.35–2.24(m,2H),2.16(d,J＝12.4Hz,2H),1.94(ddd,J＝23.3,12.4,8.2Hz,5H),1.70(s,3H).
实施例53:1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)-4-苯基哌啶-4-甲腈(53)
Figure PCTCN2019109368-appb-000143
盐酸盐(0.16mmol，1.5eq)，三乙胺(110mg，1.1mmol，10.0eq)，40℃反应过夜。反应完毕，反应液用20mL乙酸乙酯稀释，有机相用饱和氯化钠洗涤，无水硫酸钠干燥，浓缩，依次经过薄层色谱纯化、高效液相色谱纯化得到最终产物26.3mg,白色固体，收率41％； 1H NMR(400MHz,DMSO)δ10.99(s,1H),7.53(dt,J＝3.1,2.1Hz,2H),7.46(ddd,J＝13.1,11.8,7.1Hz,3H),7.36(ddd,J＝8.3,4.3,1.7Hz,1H),7.31(d,J＝7.4Hz,1H),7.25(d,J＝8.1Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.39(d,J＝17.4Hz,1H),4.24(d,J＝17.4Hz,1H),4.18(t,J＝6.2Hz,2H),3.03(d,J＝12.2Hz,2H),2.91(ddd,J＝17.4,13.7,5.4Hz,1H),2.58(dd,J＝12.2,4.8Hz,3H),2.48–2.38(m,1H),2.30(dd,J＝12.0,11.3Hz,2H),2.11(d,J＝ 13.0Hz,2H),2.05–1.89(m,5H).ESI-MS[M+H] +m/z＝487.65。
实施例54:(S)-4-(3-氯苯基)-1-(3-((2-(3-甲基-2,6-二氧代哌啶-3-)-1,3-二氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(54)
Figure PCTCN2019109368-appb-000144
18mg，白色固体，收率34％；1H NMR(400MHz,DMSO)δ11.00(s,1H),7.81–7.75(m,1H),7.58(s,1H),7.55–7.41(m,4H),7.37(d,J＝7.2Hz,1H),4.24(t,J＝6.0Hz,2H),3.02(d,J＝11.3Hz,2H),2.74–2.63(m,1H),2.62–2.51(m,4H),2.28(t,J＝11.4Hz,2H),2.14(d,J＝12.2Hz,2H),2.08–1.93(m,5H),1.87(s,3H).
实施例55：4-(2-氯苯基)-1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(55)
Figure PCTCN2019109368-appb-000145
MHz,DMSO)δ10.99(s,1H),7.61–7.52(m,2H),7.51–7.39(m,3H),7.31(d,J＝7.0Hz,1H),7.25(d,J＝8.2Hz,1H),5.12(dd,J＝13.1,6.1Hz,1H),4.39(d,J＝17.4Hz,1H),4.24(d,J＝17.2Hz,1H),4.20–4.13(m,2H),3.12–3.00(m,2H),2.97–2.85(m,1H),2.68–2.53(m,3H),2.38(ddd,J＝16.4,14.0,6.7Hz,5H),1.98(ddd,J＝21.0,12.0,4.6Hz,5H).ESI-MS[M+H] +m/z＝522.28。
实施例56：(S)-1-(3-((2-(3-甲基-2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)-4-(2-(三氟甲氧基)苯基)哌啶-4-甲腈(56)
Figure PCTCN2019109368-appb-000146
-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈，最终得到产物16mg，白色固体，收率30％；1H NMR(400MHz,DMSO)δ10.87(s,1H),7.57(dd,J＝18.0,7.6Hz,2H),7.44(dd,J＝15.4,7.6Hz,3H),7.22(dd,J＝10.7,7.9Hz,2H),4.65(d,J＝17.5Hz,1H),4.53(d,J＝17.6Hz,1H),4.18(t,J＝5.9Hz,2H),3.06(d,J＝11.1Hz,2H),2.82–2.52(m,5H),2.41–2.22(m,4H),2.11–1.84(m,5H),1.69(s,3H).
实施例57:4-(3-氯苯基)-1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(57)
Figure PCTCN2019109368-appb-000147
MHz,DMSO)δ11.00(s,1H),7.62–7.58(m,1H),7.56–7.44(m,4H),7.32(d,J＝7.2Hz,1H),7.26(d,J＝7.9Hz,1H),5.12(dd,J＝13.4,5.1Hz,1H),4.39(d,J＝17.5Hz,1H),4.24(d,J＝17.4Hz,1H),4.18(t,J＝6.2Hz,2H),3.05(dd,J＝10.8,2.7Hz,2H),2.92(ddd,J＝17.4,13.3,5.0Hz,1H),2.62–2.55(m,3H),2.49–2.40(m,1H),2.38–2.25(m,2H),2.17(d,J＝12.0Hz,2H),1.99(ddd,J＝21.0,15.7,9.3Hz,5H).
实施例58:(S)-1-(3-((2-(3-甲基-2,6-二氧代哌啶-3-)-1,3-二氧代异吲哚啉-4-)氧)丙基)-4-(2-(三氟甲氧基)苯基)哌啶-4-甲腈(58)
Figure PCTCN2019109368-appb-000148
21mg，白色固体，收率36％；1H NMR(400MHz,DMSO)δ11.00(s,1H),7.81–7.74(m,1H),7.56(dd,J＝15.7,7.6Hz,2H),7.51–7.40(m,3H),7.37(d,J＝7.2Hz,1H),4.23(t,J＝6.0Hz,2H),3.04(d,J＝11.9Hz,2H),2.68(dd,J＝12.5,6.4Hz,1H),2.60–2.51(m,4H),2.43–2.18(m,4H),2.10–1.92(m,5H),1.87(s,3H).
实施例59：4-(4-氯苯基)-1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(59)
Figure PCTCN2019109368-appb-000149
1H NMR(400MHz,DMSO)δ11.00(s,1H),7.60–7.55(m,2H),7.54–7.50(m,2H),7.48(d,J＝7.8Hz,1H),7.32(d,J＝7.5Hz,1H),7.26(d,J＝8.1Hz,1H),5.12(dd,J＝13.1,5.0Hz,1H),4.40(d,J＝17.4Hz,1H),4.25(d,J＝17.4Hz,1H),4.19(t,J＝6.0Hz,2H),3.18–3.00(m,2H),2.92(ddd,J＝18.5,13.0,4.4Hz,1H),2.59(ddd,J＝16.3,3.5,1.3Hz,3H),2.49–2.39(m,2H),2.38–2.32(m,1H),2.16(d,J＝15.1Hz,2H),2.09–1.92(m,5H).ESI-MS[M+H] +m/z＝522.28。
实施例60:(S)-1-(3-((2-(3-甲基-2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)-4-(3-(三氟甲氧基)苯基)哌啶-4-甲腈(60)
Figure PCTCN2019109368-appb-000150
18mg，白色固体，收率34％；1H NMR(400MHz,DMSO)δ10.87(s,1H),7.61(d,J＝7.0Hz,2H),7.54–7.37(m,3H),7.23(dd,J＝12.8,7.8Hz,2H),4.65(d,J＝17.6Hz,1H),4.54(d,J＝17.6Hz,1H),4.19(t,J＝5.9Hz,2H),3.05(d,J＝10.4Hz,2H),2.82–2.51(m,5H),2.37–2.24(m,2H),2.17(d,J＝12.3Hz,2H),2.11–1.85(m,5H).
实施例61：1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)-4-(2-氟苯基)哌啶-4-甲腈(61)
Figure PCTCN2019109368-appb-000151
氧)丙基)-4-苯基哌啶-4-甲腈，23.6mg,收率36％； 1H NMR(400MHz,DMSO)δ10.99(s,1H),7.50(dd,J＝15.4,7.3Hz,3H),7.37–7.22(m,4H),5.12(dd,J＝13.4,5.2Hz,1H),4.40(d,J＝17.4Hz,1H),4.24(d,J＝17.8Hz,1H),4.18(t,J＝5.8Hz,2H),3.05(ddd,J＝12.6,7.5,3.9Hz,2H),2.98–2.86(m,1H),2.65–2.55(m,3H),2.49–2.43(m,1H),2.40–2.20(m,4H),2.10–1.89(m,5H).ESI-MS[M+H] +m/z＝505.66。
实施例62:(S)-1-(3-((2-(3-甲基-2,6-二氧代哌啶-3-)-1,3-二氧代异吲哚啉-4-)氧)丙基)-4-(3-(三氟甲氧基)苯基)哌啶-4-甲腈(62)
Figure PCTCN2019109368-appb-000152
物21mg，白色固体，收率36％；1H NMR(400MHz,DMSO)δ11.00(s,1H),7.78(t,J＝7.9Hz,1H),7.65–7.56(m,2H),7.49(d,J＝8.8Hz,2H),7.38(t,J＝9.1Hz,2H),4.24(t,J＝5.8Hz,2H),3.02(d,J＝10.4Hz,2H),2.68(dd,J＝12.4,6.5Hz,1H),2.55(dd,J＝12.8,4.6Hz,4H),2.29(t,J＝11.6Hz,2H),2.16(d,J＝12.9Hz,2H),2.08–1.91(m,5H),1.87(s,3H).
实施例63:1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)-4-(3-氟苯基)哌啶-4-甲腈(63)
Figure PCTCN2019109368-appb-000153
1H NMR(400MHz,DMSO)δ11.00(s,1H),7.54–7.46(m,2H),7.44–7.37(m,2H),7.32(d,J＝7.3Hz,1H),7.28–7.19(m,2H),5.12(dd,J＝13.3,5.1Hz,1H),4.39(d,J＝17.5Hz,1H),4.24(d,J＝17.5Hz,1H),4.18(t,J＝6.2Hz,2H),3.03(d,J＝12.4Hz,2H),2.97–2.86(m,1H),2.63–2.55(m,3H),2.49–2.41(m,1H),2.30(t,J＝12.2Hz,2H),2.15(d,J＝12.4Hz,2H),2.08–1.89(m,5H).ESI-MS[M+H] +m/z＝505.66。
实施例64:4-(2-氯苯基)-1-(2-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)乙基)哌啶-4-甲腈(64)
Figure PCTCN2019109368-appb-000154
(m,5H),7.30(dd,J＝11.8,7.8Hz,2H),5.11(dd,J＝13.3,5.0Hz,1H),4.39(d,J＝17.4Hz,1H),4.26(t,J＝12.6Hz,3H),3.13(d,J＝12.2Hz,2H),3.00–2.79(m,3H),2.57(d,J＝22.0Hz,3H),2.46(d,J＝13.6Hz,3H),1.98(t,J＝9.0Hz,3H),1.23(s,3H).
实施例65:1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)-4-(4-氟苯基)哌啶-4-甲腈(65)
Figure PCTCN2019109368-appb-000155
MHz,DMSO)δ10.99(s,1H),7.58(ddd,J＝8.7,5.5,2.8Hz,2H),7.48(t,J＝7.8Hz,1H),7.33–7.22(m,4H),5.11(dd,J＝13.3,5.2Hz,1H),4.39(d,J＝17.5Hz,1H),4.23(d,J＝17.5Hz,1H),4.17(t,J＝6.2Hz,2H),3.09–2.98(m,2H),2.91(ddd,J＝17.7,13.8,5.5Hz,1H),2.64–2.54(m,3H),2.48–2.38(m,1H),2.35–2.23(m,2H),2.18–2.08(m,2H),2.05–1.89(m,5H).ESI-MS[M+H] +m/z＝505.61。
实施例66：1-(2-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)乙基)-4-(3-(三氟甲氧基)苯基)哌啶-4-甲腈(66)
Figure PCTCN2019109368-appb-000156
(m,2H),7.53–7.46(m,2H),7.40(d,J＝6.2Hz,1H),7.31(dd,J＝12.8,7.8Hz,2H),5.11(dd, J＝13.3,5.0Hz,1H),4.39(d,J＝17.5Hz,1H),4.25(t,J＝10.6Hz,3H),3.11(d,J＝11.8Hz,2H),2.98–2.80(m,3H),2.61–2.52(m,1H),2.49–2.37(m,3H),2.16(d,J＝12.6Hz,2H),2.10–1.91(m,3H).
实施例67:4-(3-氰基苯基)-1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(67)
Figure PCTCN2019109368-appb-000157
MHz,DMSO)δ10.99(s,1H),8.03(t,J＝1.5Hz,1H),7.93(ddd,J＝8.0,2.1,1.1Hz,1H),7.90–7.85(m,1H),7.67(t,J＝7.8Hz,1H),7.49(t,J＝7.9Hz,1H),7.32(d,J＝7.6Hz,1H),7.26(d,J＝7.9Hz,1H),5.16–5.08(m,1H),4.40(d,J＝17.5Hz,1H),4.24(d,J＝17.6Hz,1H),4.18(t,J＝6.6Hz,2H),3.04(dt,J＝8.5,3.7Hz,2H),2.98–2.86(m,1H),2.63–2.55(m,3H),2.48–2.40(m,1H),2.30(t,J＝11.3Hz,2H),2.19(d,J＝12.1Hz,2H),2.09–1.90(m,5H).ESI-MS[M+H] +m/z＝512.63。
实施例68：4-(2-氯-6-氟苯基)-1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(68)
Figure PCTCN2019109368-appb-000158
NMR(400MHz,DMSO)δ10.98(s,1H),7.52–7.41(m,3H),7.35–7.22(m,3H),5.11(dd,J＝13.3,5.0Hz,1H),4.39(d,J＝17.4Hz,1H),4.27–4.11(m,3H),3.03(d,J＝10.9Hz,2H),2.91(s,2H),2.57(d,J＝24.3Hz,4H),2.48–2.22(m,6H),2.03–1.89(m,3H).
实施例69:4-(4-氰基苯基)-1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(69)
Figure PCTCN2019109368-appb-000159
MHz,DMSO)δ10.99(s,1H),7.93(d,J＝8.5Hz,2H),7.76(d,J＝8.6Hz,2H),7.48(t,J＝7.8Hz,1H),7.31(d,J＝7.3Hz,1H),7.25(d,J＝8.1Hz,1H),5.11(dd,J＝13.3,5.2Hz,1H),4.39(d,J＝17.5Hz,1H),4.24(d,J＝17.4Hz,1H),4.18(t,J＝6.1Hz,2H),3.15–2.99(m,2H),2.97–2.85(m,1H),2.64–2.55(m,3H),2.48–2.39(m,1H),2.38–2.25(m,2H),2.23–2.11(m,2H),2.09–1.89(m,5H).ESI-MS[M+H] +m/z＝512.68。
实施例70：4-(2,4-二氯苯基)-1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(70)
Figure PCTCN2019109368-appb-000160
46％；1H NMR(400MHz,DMSO)δ10.98(s,1H),7.75(d,J＝1.9Hz,1H),7.58–7.44(m,3H),7.30(d,J＝7.4Hz,1H),7.24(d,J＝8.1Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.39(d,J＝17.5Hz,1H),4.23(d,J＝17.5Hz,1H),4.17(t,J＝6.1Hz,2H),3.05(d,J＝10.6Hz,2H),2.97–2.86(m,1H),2.58(d,J＝17.1Hz,3H),2.49–2.26(m,5H),2.04–1.88(m,5H).
实施例71:1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)-4-(3-三氟甲氧基苯基)哌啶-4-甲腈(71)
Figure PCTCN2019109368-appb-000161
MHz,DMSO)δ10.97(s,1H),7.63–7.56(m,2H),7.51(d,J＝2.4Hz,1H),7.47(d,J＝7.8Hz,1H),7.42–7.37(m,1H),7.31(d,J＝7.4Hz,1H),7.25(d,J＝8.1Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.39(d,J＝17.5Hz,1H),4.24(d,J＝17.4Hz,1H),4.18(t,J＝6.1Hz,2H),3.05(d,J＝9.8Hz,2H),2.91(ddd,J＝18.7,13.7,5.4Hz,1H),2.58(dd,J＝13.5,2.3Hz,3H), 2.49–2.39(m,1H),2.32(t,J＝11.7Hz,2H),2.18(d,J＝12.8Hz,2H),2.10–1.87(m,5H).ESI-MS[M+H] +m/z＝571.66。
实施例72：4-(4-氯-2-氟苯基)-1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(72)
Figure PCTCN2019109368-appb-000162
33％；1H NMR(400MHz,DMSO)δ10.98(s,1H),7.59(d,J＝11.8Hz,1H),7.56–7.45(m,2H),7.39(d,J＝8.6Hz,1H),7.31(d,J＝7.4Hz,1H),7.25(d,J＝8.1Hz,1H),5.11(dd,J＝13.2,5.0Hz,1H),4.39(d,J＝17.4Hz,1H),4.24(d,J＝17.4Hz,1H),4.17(t,J＝6.0Hz,2H),3.20–2.82(m,4H),2.58(d,J＝18.6Hz,2H),2.48–2.18(m,5H),2.09–1.89(m,5H).
实施例73:1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)-4-(4-三氟甲氧基苯基)哌啶-4-甲腈(73)
Figure PCTCN2019109368-appb-000163
(400MHz,DMSO)δ10.98(s,1H),7.68(d,J＝8.8Hz,2H),7.52–7.41(m,3H),7.31(d,J＝7.4Hz,1H),7.25(d,J＝8.2Hz,1H),5.11(dd,J＝13.5,5.0Hz,1H),4.39(d,J＝17.4Hz,1H),4.24(d,J＝17.5Hz,1H),4.18(t,J＝6.0Hz,2H),3.03(ddd,J＝7.4,4.6,1.9Hz,2H),2.98–2.85(m,1H),2.69–2.52(m,3H),2.48–2.39(m,1H),2.36–2.23(m,2H),2.14(dd,J＝13.2,5.0Hz,2H),2.08–1.86(m,5H).ESI-MS[M+H] +m/z＝571.66。
实施例74：4-(2-氯-4-氟苯基)-1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(74)
Figure PCTCN2019109368-appb-000164
NMR(400MHz,DMSO)δ10.98(s,1H),7.63–7.54(m,2H),7.48(t,J＝7.8Hz,1H),7.32(dd,J＝15.2,5.0Hz,2H),7.24(d,J＝8.1Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.39(d,J＝17.4Hz,1H),4.24(d,J＝17.4Hz,1H),4.17(t,J＝5.9Hz,2H),3.05(d,J＝11.7Hz,2H),2.97–2.85(m,1H),2.56(t,J＝13.0Hz,3H),2.45(d,J＝13.1Hz,3H),2.35(t,J＝11.6Hz,2H),2.03–1.88(m,5H).
实施例75:4-(3-氯苯基)-1-(4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丁基)哌啶-4-甲腈(75)
Figure PCTCN2019109368-appb-000165
4H),7.30(d,J＝7.5Hz,1H),7.23(d,J＝8.2Hz,1H),5.14(dd,J＝13.3,5.0Hz,1H),4.40(d,J＝17.2Hz,1H),4.24(d,J＝17.5Hz,1H),4.17(t,J＝5.7Hz,2H),3.02(d,J＝12.0Hz,2H),2.98–2.86(m,1H),2.60(dt,J＝10.3,5.1Hz,1H),2.45(t,J＝6.4Hz,3H),2.27(t,J＝12.0Hz,2H),2.12(d,J＝12.7Hz,2H),2.02–1.88(m,3H),1.80(dt,J＝13.3,6.8Hz,2H),1.70–1.59(m,2H).
实施例76：4-(2,6-二氯苯基)-1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(76)
Figure PCTCN2019109368-appb-000166
40％；1H NMR(400MHz,DMSO)δ10.98(s,1H),7.56(d,J＝8.0Hz,2H),7.48(t,J＝7.8Hz,1H),7.40(t,J＝8.0Hz,1H),7.31(d,J＝7.5Hz,1H),7.25(d,J＝8.2Hz,1H),5.11(dd,J＝ 13.3,5.1Hz,1H),4.39(d,J＝17.5Hz,1H),4.24(d,J＝17.4Hz,1H),4.17(t,J＝5.9Hz,2H),3.07(d,J＝11.3Hz,2H),2.96–2.86(m,1H),2.56(t,J＝12.2Hz,6H),2.39(d,J＝11.7Hz,4H),2.04–1.87(m,3H).
实施例77:4-(4-氯苯基)-1-(4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丁基)哌啶-4-甲腈(77)
Figure PCTCN2019109368-appb-000167
7.30(d,J＝7.5Hz,1H),7.25(d,J＝8.0Hz,1H),5.11(dd,J＝13.3,5.0Hz,1H),4.38(d,J＝17.2Hz,1H),4.22(d,J＝17.5Hz,1H),4.15(t,J＝5.7Hz,2H),3.00(d,J＝12.0Hz,2H),2.96–2.85(m,1H),2.59(dt,J＝10.3,5.1Hz,1H),2.43(t,J＝6.4Hz,3H),2.24(t,J＝12.0Hz,2H),2.10(d,J＝12.7Hz,2H),2.02–1.87(m,3H),1.78(dt,J＝13.3,6.8Hz,2H),1.69–1.57(m,2H).
实施例78：1-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-氧-)丙基)-4-(2-三氟甲氧基苯基)哌啶-4-甲腈(78)
Figure PCTCN2019109368-appb-000168
7.51–7.38(m,3H),7.30(d,J＝7.4Hz,1H),7.24(d,J＝8.1Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.39(d,J＝17.4Hz,1H),4.24(d,J＝17.4Hz,1H),4.17(t,J＝6.1Hz,2H),3.04(d,J＝12.3Hz,2H),2.96–2.85(m,1H),2.56(t,J＝12.2Hz,3H),2.48–2.41(m,1H),2.35(t,J＝11.9Hz,2H),2.26(d,J＝13.2Hz,2H),2.05–1.88(m,5H).
实施例79:4-(3-氯苯基)-1-(5-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)戊基)哌啶-4- 甲腈(79)
Figure PCTCN2019109368-appb-000169
基)-1-(5-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)戊基)哌啶-4-甲腈25mg，白色固体，收率为37％；1H NMR(400MHz,DMSO)δ10.97(s,1H),7.58(s,1H),7.54–7.41(m,4H),7.30(d,J＝7.5Hz,1H),7.24(d,J＝8.2Hz,1H),5.10(dd,J＝13.3,5.1Hz,1H),4.37(d,J＝17.4Hz,1H),4.22(d,J＝17.4Hz,1H),4.12(t,J＝6.3Hz,2H),2.99(d,J＝12.2Hz,2H),2.96–2.84(m,1H),2.56(d,J＝18.3Hz,2H),2.48–2.35(m,3H),2.25(t,J＝11.5Hz,2H),2.13(d,J＝12.4Hz,1H),1.98(t,J＝11.2Hz,3H),1.82–1.72(m,2H),1.50(dt,J＝16.5,10.5Hz,4H).
实施例80：(S)-4-(2-氯苯基)-1-(3-((2-(3-甲基l-2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)哌啶-4-甲腈(80)
Figure PCTCN2019109368-appb-000170
148.27mmol，1.2eq)，后加入MOMCl(11.94g，148.27mmol，1.2eq)，室温反应一个小时。反应返程后，加入饱和氯化铵淬灭反应，乙酸乙酯萃取3次，饱和氯化铵洗涤三次，干燥、减压浓缩，柱层析纯化得到25.98g黄色油状物，收率为100％。 1H NMR(400MHz,CDCl 3)δ7.47(dd,J＝7.5,1.4Hz,1H),7.24–7.14(m,2H),5.21(s,2H),3.89(s,3H),3.49(s,3H),2.49–2.41(m,3H).
步骤2：3-甲氧基甲氧基-2-甲基苯甲酸甲酯(25.98g，123.56mmol，1.0eq)溶于200ml四氯化碳中，加入NBS(23.09mmol，129.24mmol，1.05mmol)，AIBN(2.03g，12.36mmol，0.1eq)，88℃回流6小时。反应完成后，减压旋走溶剂，柱层析纯化得到35.73g棕色固体。收率为100％。 1H NMR(400MHz,CDCl 3)δ7.58(dd,J＝6.5,2.5Hz,1H),7.35–7.27(m,1H),5.30(s,1H),5.10–5.05(m,1H),3.94(s,1H),3.53(s,1H).
步骤3：将2-溴甲基-3-甲氧基甲氧基苯甲酸甲酯(353mg，1.22mmol，1.0eq)，(S)-3-胺基o-3-甲基哌啶-2,6-二酮盐酸盐一水合物(294mg，1.22mmol，1.0eq)溶于20ml甲苯。加入三乙胺(136mg，1.34mmol，1.1eq)120℃回流24小时。返佣完成后，旋走甲苯，柱层析纯化得到232mg白色固体，收率为61％。
步骤4：将(S)-3-(4-甲氧基甲氧基-1-氧代异吲哚啉-2-)-3-甲基哌啶-2,6-二酮(232mg，0.73mmol，1.0eq)置于50mL圆底烧瓶中，加入20mL盐酸二氧六环。加入200uL甲醇。室温反应1小时。反应完成后，旋走溶剂，无需进一步纯化，直接投下一步。
步骤5：将(S)-3-(4-羟基-1-氧代异吲哚啉-2-)-3-甲基哌啶-2,6-二酮(200mg，0.73mmol，1.0eq)溶于20mL乙腈。加入1，2-二溴丙烷(736mg，3.65mmol，5.0eq)，无水碳酸钾(101mg，0.73mmol，1.0eq)，50℃反应24小时。反应完成后，旋走溶剂，乙酸乙酯稀释，饱和氯化钠洗涤，柱层析纯化得到200mg白的固体，收率为69％。
步骤6：(S)-3-(4-(3-溴丙氧基)-1-氧代异吲哚啉-2-)-3-甲基哌啶-2,6-二酮(40mg，0.10mmol，1.0eq)溶于3mL DMSO，加入4-(2-氯苯基)哌啶-4-甲腈盐酸盐(39mg，0.15mmol，1.5eq)，三乙胺(102mg，1.01mmol，10.0eq)，40℃反应过夜。反应完成后，20mL乙酸乙酯稀释，饱和氯化钠洗涤，薄层色谱和高效液相色谱纯化得产物15mg，白色固体，收率为28％；1H NMR(400MHz,DMSO)δ10.87(s,1H),7.61–7.51(m,2H),7.45(dd,J＝12.1,6.3Hz,3H),7.22(dd,J＝11.7,7.8Hz,2H),4.65(d,J＝17.5Hz,1H),4.54(d,J＝17.6Hz,1H),4.18(t,J＝6.1Hz,2H),3.07(d,J＝11.7Hz,2H),2.80–2.51(m,7H),2.37(t,J＝12.3Hz,2H),2.08–1.84(m,5H),1.69(s,3H).
实施例81:4-(4-氯苯基)-1-(5-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)戊基)哌啶-4-甲腈(81)
Figure PCTCN2019109368-appb-000171
基)-1-(5-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)戊基)哌啶-4-甲腈21mg，白色固体， 收率为22％； 1H NMR(400MHz,DMSO)δ10.97(s,1H),7.55(d,J＝8.5Hz,2H),7.52–7.43(m,3H),7.30(d,J＝7.5Hz,1H),7.24(d,J＝8.1Hz,1H),5.11(dd,J＝13.3,5.0Hz,1H),4.37(d,J＝17.4Hz,1H),4.22(d,J＝17.4Hz,1H),4.12(t,J＝6.2Hz,2H),2.98(d,J＝11.9Hz,2H),2.94–2.84(m,1H),2.56(d,J＝17.6Hz,1H),2.48–2.34(m,3H),2.24(t,J＝11.7Hz,2H),2.09(d,J＝12.8Hz,2H),1.95(dd,J＝17.2,8.5Hz,3H),1.77(dd,J＝13.4,6.6Hz,2H),1.58–1.38(m,4H).
实施例82：4-(2-氯苯基)-1-(4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丁酰基)哌啶-4-甲腈(82)
Figure PCTCN2019109368-appb-000172
66％； 1H NMR(400MHz,DMSO)δ10.97(s,1H),7.60–7.54(m,1H),7.51–7.40(m,4H),7.30(d,J＝7.5Hz,1H),7.24(d,J＝8.2Hz,1H),5.11(dd,J＝13.2,5.0Hz,1H),4.64(d,J＝13.4Hz,1H),4.39(d,J＝17.5Hz,1H),4.25(d,J＝17.4Hz,1H),4.13(d,J＝16.2Hz,3H),3.37(d,J＝12.8Hz,1H),2.89(q,J＝13.3Hz,2H),2.64–2.53(m,3H),2.44(dd,J＝16.8,8.0Hz,4H),2.05–1.92(m,4H),1.84(d,J＝12.5Hz,1H).
实施例83:4-(3-氯苯基)-1-(4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丁酰基)哌啶-4-甲腈(83)
Figure PCTCN2019109368-appb-000173
率为49％；1H NMR(400MHz,DMSO)δ10.97(s,1H),7.61(s,1H),7.56–7.43(m,4H),7.30(d,J＝7.4Hz,1H),7.25(d,J＝8.1Hz,1H),5.11(dd,J＝13.3,5.0Hz,1H),4.62(d,J＝14.0Hz,1H),4.39(d,J＝17.4Hz,1H),4.24(d,J＝17.4Hz,1H),4.16(t,J＝6.2Hz,2H),4.09(d,J＝14.4Hz,1H),3.27(d,J＝13.2Hz,1H),2.98–2.74(m,2H),2.56 (dd,J＝13.3,6.2Hz,3H),2.43(dd,J＝13.2,4.4Hz,1H),2.24–1.79(m,7H).
实施例84:4-(4-氯苯基)-1-(4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丁酰基)哌啶-4-甲腈(84)
Figure PCTCN2019109368-appb-000174
7.43(m,5H),7.27(dd,J＝21.4,7.8Hz,2H),5.11(dd,J＝13.3,5.1Hz,1H),4.62(d,J＝13.5Hz,1H),4.39(d,J＝17.5Hz,1H),4.24(d,J＝17.4Hz,1H),4.16(t,J＝6.2Hz,2H),4.09(d,J＝13.6Hz,1H),3.27(d,J＝12.6Hz,1H),2.99–2.75(m,2H),2.56(dd,J＝13.2,7.1Hz,3H),2.43(dd,J＝13.0,4.4Hz,3H),2.13(d,J＝13.3Hz,2H),2.05–1.92(m,4H),1.86(d,J＝12.6Hz,1H).
实施例85:4-(2-氯苯基)-1-(5-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)戊酰基)哌啶-4-甲腈(85)
Figure PCTCN2019109368-appb-000175
率为33％；1H NMR(400MHz,DMSO)δ10.96(s,1H),7.57(dt,J＝7.3,3.7Hz,1H),7.54–7.41(m,4H),7.30(d,J＝7.4Hz,1H),7.24(d,J＝8.1Hz,1H),5.10(dd,J＝13.3,5.1Hz,1H),4.63(d,J＝14.1Hz,1H),4.37(d,J＝17.4Hz,1H),4.22(d,J＝17.4Hz,1H),4.13(dd,J＝14.7,8.6Hz,3H),3.37(d,J＝12.7Hz,1H),2.89(ddd,J＝25.1,15.0,8.7Hz,2H),2.59(s,1H),2.51–2.37(m,9H),1.99(dd,J＝16.4,8.8Hz,2H),1.91–1.62(m,5H).
实施例86:1-(4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-氧-)丁酰基)-4-(4-三氟甲氧基苯基哌啶-4-甲腈(86)
Figure PCTCN2019109368-appb-000176
1H NMR(400MHz,DMSO)δ10.98(s,1H),7.67(d,J＝8.5Hz,2H),7.47(dd,J＝15.0,7.9Hz,3H),7.27(dd,J＝19.9,7.8Hz,2H),5.11(dd,J＝13.4,5.0Hz,1H),4.63(d,J＝13.7Hz,1H),4.40(d,J＝17.4Hz,1H),4.25(d,J＝17.3Hz,1H),4.20–4.06(m,3H),3.28(d,J＝13.4Hz,1H),2.99–2.77(m,2H),2.65–2.54(m,3H),2.43(dd,J＝13.3,4.4Hz,1H),2.16(d,J＝13.0Hz,2H),2.01(dd,J＝13.1,6.8Hz,4H),1.92-1.80(m,1H).
实施例87：4-(3-氯苯基)-1-(5-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)戊酰基)哌啶-4-甲腈(87)
Figure PCTCN2019109368-appb-000177
收率为42％；1H NMR(400MHz,DMSO)δ10.96(s,1H),7.62(s,1H),7.56–7.43(m,4H),7.30(d,J＝7.4Hz,1H),7.24(d,J＝8.1Hz,1H),5.10(dd,J＝13.3,5.1Hz,1H),4.61(d,J＝13.6Hz,1H),4.37(d,J＝17.4Hz,1H),4.22(d,J＝17.4Hz,1H),4.15(t,J＝6.2Hz,2H),4.09(d,J＝14.2Hz,1H),3.27(t,J＝9.6Hz,1H),2.97–2.84(m,1H),2.79(t,J＝12.6Hz,1H),2.56(d,J＝17.9Hz,1H),2.50–2.34(m,6H),2.23–1.60(m,10H).
实施例88：1-(4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-氧-)丁酰基)-4-(3-三氟甲氧基苯基哌啶-4-甲腈(88)
Figure PCTCN2019109368-appb-000178
收率为56％； 1H NMR(400MHz,DMSO)δ10.98(s,1H),7.67(d,J＝8.5Hz,2H),7.47(dd,J＝15.0,7.9Hz,3H),7.27(dd,J＝19.9,7.8Hz,2H),5.11(dd,J＝13.4,5.0Hz,1H),4.63(d,J＝13.7Hz,1H),4.40(d,J＝17.4Hz,1H),4.25(d,J＝17.3Hz, 1H),4.20–4.06(m,3H),3.28(d,J＝13.4Hz,1H),2.99–2.77(m,2H),2.65–2.54(m,3H),2.43(dd,J＝13.3,4.4Hz,1H),2.16(d,J＝13.0Hz,2H),2.01(dd,J＝13.1,6.8Hz,4H),1.92-1.80(m,1H).
实施例89:4-(3-氯苯基)-1-(5-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)戊酰基)哌啶-4-甲腈(89)
Figure PCTCN2019109368-appb-000179
收率为82％；1H NMR(400MHz,DMSO)δ10.96(s,1H),7.57(d,J＝8.8Hz,2H),7.51(d,J＝8.8Hz,2H),7.47(d,J＝7.8Hz,1H),7.30(d,J＝7.5Hz,1H),7.24(d,J＝8.1Hz,1H),5.10(dd,J＝13.3,5.1Hz,1H),4.61(d,J＝12.4Hz,1H),4.37(d,J＝17.4Hz,1H),4.22(d,J＝17.4Hz,1H),4.15(t,J＝6.1Hz,2H),4.08(d,J＝14.9Hz,1H),3.28(s,1H),2.88(d,J＝12.1Hz,1H),2.79(s,1H),2.56(d,J＝18.5Hz,1H),2.45(t,J＝7.4Hz,6H),2.14(d,J＝12.5Hz,2H),2.10–1.92(m,2H),1.92–1.60(m,6H).
实施例90:1-(4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-氧-)丁酰基)-4-(2-三氟甲氧基苯基哌啶-4-甲腈(90)
Figure PCTCN2019109368-appb-000180
7.40(m,5H),7.30(d,J＝7.5Hz,1H),7.24(d,J＝8.1Hz,1H),5.11(dd,J＝13.3,5.0Hz,1H),4.63(d,J＝13.8Hz,1H),4.39(d,J＝17.4Hz,1H),4.25(d,J＝17.3Hz,1H),4.15(t,J＝6.0Hz,3H),3.35(s,1H),2.97–2.82(m,2H),2.56(t,J＝10.2Hz,3H),2.45(s,1H),2.28(d,J＝13.1Hz,2H),2.07–1.93(m,4H),1.91–1.77(m,1H).
实施例91：4-(2-氯苯基)-1-(4-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)丁基)哌啶-4-甲腈(91)
Figure PCTCN2019109368-appb-000181
MHz,DMSO)δ10.99(s,1H),7.55(ddd,J＝11.7,5.3,2.8Hz,3H),7.44(ddd,J＝7.1,5.1,2.8Hz,4H),5.13(dd,J＝13.2,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.32(d,J＝17.2Hz,1H),2.99(d,J＝12.3Hz,2H),2.96–2.85(m,1H),2.67(t,J＝7.6Hz,2H),2.58(d,J＝17.6Hz,1H),2.48–2.36(m,5H),2.30(t,J＝11.9Hz,2H),2.04–1.89(m,3H),1.63(dt,J＝15.3,7.7Hz,2H),1.56–1.45(m,2H).
实施例92：4-(2-氯苯基)-1-(5-(2-(2,6-氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊基)哌啶-4-甲腈(92)
Figure PCTCN2019109368-appb-000182
3.4Hz,4H),5.13(dd,J＝13.3,5.1Hz,1H),4.46(d,J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),3.00(d,J＝12.0Hz,2H),2.96–2.86(m,1H),2.67-2.56(m,3H),2.44(d,J＝12.9Hz,3H),2.39–2.25(m,4H),2.05–1.88(m,3H),1.63(dt,J＝15.6,7.9Hz,2H),1.55–1.44(m,2H),1.34(dt,J＝14.8,7.5Hz,2H).
实施例93：4-(3-氯苯基)-1-(4-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)丁基)哌啶-4-甲腈(93)
Figure PCTCN2019109368-appb-000183
10.99(s,1H),7.61–7.41(m,7H),5.13(dd,J＝13.3,5.1Hz,1H),4.47(d,J＝17.2Hz,1H), 4.32(d,J＝17.2Hz,1H),3.02–2.84(m,3H),2.67(t,J＝7.6Hz,2H),2.59(d,J＝16.8Hz,1H),2.46–2.35(m,3H),2.23(t,J＝11.3Hz,2H),2.13(d,J＝12.6Hz,2H),2.05–1.93(m,3H),1.65(dt,J＝16.6,6.8Hz,2H),1.51(dt,J＝15.2,7.5Hz,2H).
实施例94：1-(5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊基)-4-(3-三氟甲氧基苯基)哌啶-4-甲腈(94)
Figure PCTCN2019109368-appb-000184
11.00(s,1H),7.62–7.58(m,2H),7.56(dd,J＝5.9,2.7Hz,1H),7.50(s,1H),7.48–7.45(m,2H),7.40(d,J＝4.1Hz,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.1Hz,1H),2.98(d,J＝11.5Hz,2H),2.94–2.87(m,1H),2.67-2.56(m,3H),2.45-2.38(m,1H),2.39–2.31(m,2H),2.23(t,J＝11.4Hz,2H),2.14(d,J＝12.3Hz,2H),2.06–1.93(m,3H),1.63(dt,J＝15.1,7.6Hz,2H),1.50(dt,J＝14.8,7.6Hz,2H),1.39–1.29(m,2H).
实施例95：4-(4-氯苯基)-1-(4-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)丁基)哌啶-4-甲腈(95)
Figure PCTCN2019109368-appb-000185
11.00(s,1H),5.13(dd,J＝13.3,5.0Hz,1H),4.47(d,J＝17.2Hz,1H),4.32(d,J＝17.2Hz,1H),3.00–2.86(m,3H),2.67(t,J＝7.5Hz,2H),2.62–2.55(m,1H),2.47–2.36(m,3H),2.24(t,J＝11.9Hz,2H),2.09(d,J＝12.9Hz,2H),2.04–1.90(m,3H),1.69–1.58(m,2H),1.51(dt,J＝14.1,7.1Hz,2H),1.23–1.23(m,1H).
实施例96：1-(5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊基)-4-(4-三氟甲氧基苯基)哌 啶-4-甲腈(96)
Figure PCTCN2019109368-appb-000186
DMSO)δ11.00(s,1H),7.66(dd,J＝7.0,4.9Hz,2H),7.56(dt,J＝7.7,3.8Hz,1H),7.45(dd,J＝8.8,5.8Hz,4H),5.14(dd,J＝13.3,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.1Hz,1H),2.98(d,J＝11.3Hz,2H),2.94–2.86(m,1H),2.67-2.56(m,3H),2.43(dt,J＝13.5,9.1Hz,1H),2.38–2.33(m,2H),2.24(t,J＝11.4Hz,2H),2.12(d,J＝12.3Hz,2H),2.05–1.90(m,3H),1.63(dt,J＝15.2,7.7Hz,2H),1.55–1.45(m,2H),1.34(dt,J＝14.9,7.6Hz,2H).
实施例97：1-(4-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)丁基)-4-(3-三氟甲氧基苯基)哌啶-4-甲腈(97)
Figure PCTCN2019109368-appb-000187
δ10.99(s,1H),7.63–7.54(m,3H),7.52–7.44(m,3H),7.39(d,J＝6.6Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.32(d,J＝17.2Hz,1H),3.02–2.86(m,3H),2.67(t,J＝7.6Hz,2H),2.59(d,J＝17.1Hz,1H),2.47–2.36(m,3H),2.24(t,J＝11.6Hz,2H),2.14(d,J＝12.2Hz,2H),2.06–1.94(m,3H),1.64(dt,J＝15.7,6.5Hz,2H),1.51(dt,J＝14.5,7.2Hz,2H).
实施例98：4-(2-氯苯基)-1-(6-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)己基)哌啶-4-甲腈(98)
Figure PCTCN2019109368-appb-000188
δ10.99(s,1H),7.55(dd,J＝10.3,6.6Hz,3H),7.48–7.40(m,4H),5.13(dd,J＝13.3,5.0Hz, 1H),4.46(d,J＝17.2Hz,1H),4.30(d,J＝17.1Hz,1H),3.01(d,J＝12.2Hz,2H),2.98–2.86(m,1H),2.68-2.56(m,3H),2.47-2.41(m,3H),2.40–2.27(m,4H),2.05–1.90(m,3H),1.65-1.57(m,2H),1.50–1.40(m,2H),1.38-1.27(m,4H).
实施例99：1-(4-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)丁基)-4-(4-三氟甲氧基苯基)哌啶-4-甲腈(99)
Figure PCTCN2019109368-appb-000189
DMSO)δ11.00(s,1H),7.67(d,J＝8.9Hz,2H),7.56(dt,J＝7.6,3.8Hz,1H),7.46(dt,J＝13.1,6.3Hz,4H),5.14(dd,J＝13.3,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.32(d,J＝17.1Hz,1H),2.97(d,J＝12.0Hz,2H),2.94–2.86(m,1H),2.67(t,J＝7.6Hz,2H),2.59(d,J＝16.8Hz,1H),2.42(dd,J＝14.1,7.5Hz,3H),2.25(t,J＝11.9Hz,2H),2.12(d,J＝12.5Hz,2H),2.01-1.95(m,3H),1.63(dd,J＝14.1,6.6Hz,2H),1.52(dd,J＝13.9,7.1Hz,2H).
实施例100：4-(3-氯苯基)-1-(6-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)己基)哌啶-4-甲腈(100)
Figure PCTCN2019109368-appb-000190
DMSO)δ11.00(s,1H),7.60–7.42(m,7H),5.14(dd,J＝13.3,5.1Hz,1H),4.46(d,J＝17.2Hz,1H),4.30(d,J＝17.1Hz,1H),3.04–2.86(m,3H),2.68-2.56(m,3H),2.47–2.33(m,3H),2.26(t,J＝11.5Hz,2H),2.14(d,J＝12.3Hz,2H),2.05–1.95(m,3H),1.66–1.56(m,2H),1.51–1.41(m,2H),1.38-1.27(m,4H).
实施例101：4-(2,4-二氯苯基)-1-(4-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)丁基)哌啶-4-甲腈(101)
Figure PCTCN2019109368-appb-000191
δ10.99(s,1H),7.74(d,J＝2.0Hz,1H),7.54(qd,J＝8.7,3.7Hz,3H),7.48–7.44(m,2H),5.13(dd,J＝13.3,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.1Hz,1H),2.99(d,J＝11.9Hz,2H),2.95–2.86(m,1H),2.67(t,J＝7.6Hz,2H),2.62–2.54(m,1H),2.47-2.36(m,5H),2.30(t,J＝12.0Hz,2H),2.04-1.91(m,3H),1.69–1.57(m,2H),1.54-1.47(m,2H).
实施例102：4-(4-氯苯基)-1-(6-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)己基)哌啶-4-甲腈(102)
Figure PCTCN2019109368-appb-000192
DMSO)δ10.99(s,1H),7.58–7.53(m,3H),7.53–7.48(m,2H),7.47–7.44(m,2H),5.13(dd,J＝13.3,5.1Hz,1H),4.46(d,J＝17.2Hz,1H),4.30(d,J＝17.1Hz,1H),3.02–2.87(m,3H),2.68-2.56(m,3H),2.46–2.31(m,3H),2.24(t,J＝11.5Hz,2H),2.10(d,J＝12.0Hz,2H),2.05–1.90(m,4H),1.66–1.56(m,2H),1.50–1.40(m,2H),1.38-1.27(m,4H).
实施例103:3-(4-(5-(3,4-二氢喹啉-1(2H)-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(103)
Figure PCTCN2019109368-appb-000193
溶解于5mL干燥DMF中，室温搅拌下加入碘化钠(44mg,0.294mmol，1.5eq.)，所得反应液升至80℃反应过夜。反应完毕，所得反应液直接用HPLC分离得到3-(4-(5-(3,4-二氢喹啉-1(2H)-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮8.5mg,白色固体，收率10％； 1H NMR(400MHz,DMSO)δ11.00(s,1H),7.56(p,J＝3.9Hz,1H),7.46(dd,J＝7.6,4.0Hz,2H),6.95–6.89(m,1H),6.83(dd,J＝7.2,1.3Hz,1H),6.54–6.48(m,1H),6.42(td,J＝7.2,0.7Hz,1H),5.13(dd,J＝13.4,5.2Hz,1H),4.46(d,J＝17.1Hz,1H),4.30(d,J＝17.1Hz, 1H),3.20(dd,J＝9.8,4.9Hz,4H),2.92(ddd,J＝17.6,13.4,5.2Hz,1H),2.61(ddd,J＝8.7,6.6,4.9Hz,5H),2.45–2.31(m,1H),2.04–1.94(m,1H),1.87–1.77(m,2H),1.65(dt,J＝8.8,7.0Hz,2H),1.54(dt,J＝14.8,7.3Hz,2H),1.36(dd,J＝14.4,7.6Hz,2H).
实施例104:3-(4-(5-(6-氟-2-甲基-3,4-二氢喹啉-1(2H)-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(104)
Figure PCTCN2019109368-appb-000194
酮，17mg,收率28％； 1H NMR(400MHz,DMSO)δ11.00(s,1H),7.60–7.53(m,1H),7.45(d,J＝4.3Hz,2H),6.76(ddt,J＝12.2,5.8,3.0Hz,2H),6.42(dd,J＝8.8,4.8Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.46(dd,J＝17.2,1.9Hz,1H),4.30(dd,J＝17.2,1.7Hz,1H),3.45–3.37(m,1H),3.31–3.20(m,1H),3.12–3.02(m,1H),2.92(ddd,J＝17.1,13.6,5.4Hz,1H),2.75–2.55(m,5H),2.42(ddd,J＝26.0,13.1,4.3Hz,1H),2.04–1.94(m,1H),1.66(ddd,J＝9.5,8.0,4.6Hz,4H),1.59–1.43(m,2H),1.40–1.28(m,2H),1.03(d,J＝6.4Hz,3H).
实施例105:3-(4-(5-(2,3-二氢-4H-苯并[b][1,4]噁嗪-4-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(105)
Figure PCTCN2019109368-appb-000195
25％； 1H NMR(400MHz,DMSO)δ10.99(s,1H),7.56(dd,J＝8.2,4.5Hz,1H),7.49–7.43(m,2H),6.77–6.70(m,1H),6.68–6.61(m,2H),6.47(td,J＝7.8,1.4Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.46(d,J＝17.1Hz,1H),4.30(d,J＝17.1Hz,1H),4.15–4.07(m,2H),3.29–3.25(m,2H),3.24–3.18(m,2H),2.92(ddd,J＝17.7,13.7,5.4Hz,1H),2.63(dd,J＝22.5,14.7Hz,3H),2.42(ddd,J＝26.3,13.2,4.4Hz,1H),2.07–1.94(m,1H), 1.71–1.61(m,2H),1.60–1.49(m,2H),1.36(dt,J＝15.2,7.7Hz,2H).
实施例106:3-(4-(5-(6-溴-3,4-二氢喹啉-1(2H)-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(106)
Figure PCTCN2019109368-appb-000196
10％； 1H NMR(400MHz,DMSO)δ11.00(s,1H),7.56(p,J＝3.9Hz,1H),7.47–7.42(m,2H),7.05(dd,J＝8.8,2.5Hz,1H),6.99(d,J＝2.5Hz,1H),6.46(d,J＝8.9Hz,1H),5.13(dd,J＝13.2,5.1Hz,1H),4.46(d,J＝17.0Hz,1H),4.30(d,J＝17.3Hz,1H),3.26–3.12(m,4H),2.92(ddd,J＝17.3,13.3,5.3Hz,1H),2.64(dd,J＝9.6,5.9Hz,5H),2.47–2.31(m,2H),2.05–1.95(m,1H),1.83–1.74(m,2H),1.68–1.58(m,2H),1.52(dt,J＝14.5,7.4Hz,2H),1.40–1.28(m,2H).
实施例107:3-(4-(5-(吲哚啉-1-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(107)
Figure PCTCN2019109368-appb-000197
收率45％； 1H NMR(400MHz,DMSO)δ10.99(s,1H),7.56(dd,J＝6.1,2.4Hz,1H),7.49–7.43(m,2H),7.03–6.90(m,2H),6.53(t,J＝7.2Hz,1H),6.45(d,J＝7.8Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.46(d,J＝17.2Hz,1H),4.31(d,J＝17.1Hz,1H),3.26(t,J＝8.4Hz,2H),3.01(t,J＝7.2Hz,2H),2.97–2.89(m,1H),2.85(t,J＝8.3Hz,2H),2.69–2.64(m,2H),2.63–2.56(m,1H),2.41(ddd,J＝17.6,13.5,4.7Hz,1H),2.00(ddd,J＝10.5,6.9,3.3Hz,1H),1.73–1.53(m,4H),1.47–1.35(m,2H).
实施例108：2-(2,6-二氧代哌啶-3-)-4-(4-((2-甲基喹啉-4-)氧)丁氧基)异吲哚啉-1,3-二酮(108)
Figure PCTCN2019109368-appb-000198
DMSO)δ11.10(s,1H),8.15(d,J＝9.0Hz,1H),7.92(d,J＝8.1Hz,1H),7.88–7.78(m,2H),7.55(t,J＝11.0Hz,2H),7.44(d,J＝7.2Hz,1H),7.20(s,1H),5.07(dd,J＝12.8,5.4Hz,1H),4.49(s,2H),4.35(t,J＝5.9Hz,2H),2.88(ddd,J＝16.8,14.0,5.4Hz,1H),2.69(s,3H),2.63–2.55(m,1H),2.18–1.95(m,6H).
实施例109:3-(4-(5-(7-氯-3,4-二氢喹啉-1(2H)-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(109)
Figure PCTCN2019109368-appb-000199
率5％； 1H NMR(400MHz,DMSO)δ10.98(s,1H),7.56(dt,J＝7.7,3.9Hz,1H),7.47–7.43(m,2H),6.83(d,J＝7.9Hz,1H),6.48(d,J＝1.9Hz,1H),6.42(dd,J＝7.9,1.9Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.46(d,J＝17.2Hz,1H),4.31(d,J＝17.1Hz,1H),3.21(dd,J＝9.3,5.6Hz,4H),2.98–2.86(m,1H),2.72–2.56(m,5H),2.47–2.35(m,1H),2.01(ddd,J＝10.7,5.0,2.7Hz,1H),1.83–1.73(m,2H),1.71–1.60(m,2H),1.59–1.49(m,2H),1.35(dt,J＝15.4,7.7Hz,2H).
实施例110:3-(4-(5-(7-溴-2,3-二氢-4H-苯并[b][1,4]噁嗪-4-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(110)
Figure PCTCN2019109368-appb-000200
收率28％； 1H NMR(400MHz,DMSO)δ10.99(s,1H),7.56(t,J＝4.3Hz,1H),7.45(d,J＝4.3Hz,2H),6.87(dd,J＝8.6,2.3Hz,1H),6.80(d,J＝2.3Hz,1H),6.61(d,J＝8.7Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.46(d,J＝17.1Hz,1H),4.30(d,J＝17.1Hz,1H),4.20–4.05 (m,2H),3.30–3.25(m,2H),3.24–3.17(m,2H),2.99–2.85(m,1H),2.63(dd,J＝20.5,12.8Hz,3H),2.47–2.35(m,1H),2.07–1.93(m,1H),1.64(dt,J＝15.1,7.7Hz,2H),1.54(dt,J＝14.9,7.6Hz,2H),1.41–1.27(m,2H).
实施例111:3-(1-氧代-4-(5-(2,3,4,5-四氢-1H-苯并[b]氮杂卓-1-)戊基)异吲哚啉-2-)哌啶-2,6-二酮(111)
Figure PCTCN2019109368-appb-000201
25％； 1H NMR(400MHz,DMSO)δ10.98(d,J＝5.3Hz,1H),7.55(dd,J＝8.2,4.2Hz,1H),7.43(dd,J＝11.7,8.0Hz,2H),7.11–6.98(m,2H),6.88(t,J＝6.9Hz,1H),6.77(dd,J＝13.5,6.7Hz,1H),5.17–5.04(m,1H),4.43(dd,J＝16.7,6.2Hz,1H),4.28(dd,J＝17.0,6.2Hz,1H),3.07(dd,J＝12.5,6.2Hz,2H),2.98–2.76(m,3H),2.60(d,J＝18.9Hz,4H),2.45–2.34(m,1H),1.99(dd,J＝12.1,4.6Hz,1H),1.68–1.44(m,7H),1.43–1.32(m,2H).
实施例112:3-(4-(5-(6-溴吲哚啉-1-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(112)
Figure PCTCN2019109368-appb-000202
收率46％； 1H NMR(400MHz,DMSO)δ10.99(s,1H),7.56(dt,J＝7.7,3.8Hz,1H),7.49–7.44(m,2H),7.12(d,J＝1.7Hz,1H),7.08(dd,J＝8.3,2.0Hz,1H),6.39(d,J＝8.3Hz,1H),5.75(s,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.46(d,J＝17.1Hz,1H),4.30(d,J＝17.1Hz,1H),3.30(t,J＝8.5Hz,2H),3.01(t,J＝7.3Hz,2H),2.98–2.91(m,1H),2.87(t,J＝8.2Hz,2H),2.70–2.56(m,3H),2.42(ddd,J＝26.6,13.4,4.5Hz,1H),2.00(dtd,J＝6.8,4.9,1.8Hz,1H),1.65(dt,J＝15.5,7.8Hz,2H),1.56(dt,J＝14.8,7.5Hz,2H),1.38(dt,J＝15.0,7.7Hz,2H).
实施例113:3-(4-(5-(3,4-二氢异喹啉-2(1H)-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(113)
Figure PCTCN2019109368-appb-000203
率35％； 1H NMR(400MHz,DMSO)δ11.00(s,1H),7.50(dt,J＝20.8,6.9Hz,3H),7.23–7.03(m,4H),5.14(dd,J＝13.1,4.7Hz,1H),4.49(d,J＝17.3Hz,1H),4.32(d,J＝17.1Hz,1H),3.46–3.16(m,6H),3.07–2.76(m,5H),2.74–2.65(m,2H),2.60(dd,J＝18.5,1.8Hz,1H),2.48–2.37(m,1H),2.09–1.96(m,1H),1.79–1.58(m,4H),1.39(dd,J＝14.9,7.9Hz,2H).
实施例114:3-(4-(5-(5-溴吲哚啉-1-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(114)
Figure PCTCN2019109368-appb-000204
收率39％； 1H NMR(400MHz,DMSO)δ10.99(s,1H),7.60–7.53(m,1H),7.48–7.41(m,2H),6.90(d,J＝7.6Hz,1H),6.63(dd,J＝7.6,1.7Hz,1H),6.59(d,J＝1.6Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.46(d,J＝17.2Hz,1H),4.31(d,J＝17.1Hz,1H),3.37–3.31(m,2H),3.04(t,J＝7.2Hz,2H),2.92(ddd,J＝17.6,13.7,5.4Hz,1H),2.83(t,J＝8.4Hz,2H),2.71–2.57(m,3H),2.42(ddd,J＝26.5,13.3,4.5Hz,1H),2.01(ddd,J＝12.3,6.2,4.0Hz,1H),1.66(dt,J＝15.5,7.7Hz,2H),1.56(dt,J＝14.8,7.5Hz,2H),1.38(dt,J＝14.8,7.6Hz,2H).
实施例115:3-(4-(5-(6-氯-3,4-二氢异喹啉-1(2H)-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(115)
Figure PCTCN2019109368-appb-000205
31％； 1H NMR(400MHz,DMSO)δ11.00(s,1H),7.56(p,J＝3.8Hz,1H),7.45(d,J＝4.4Hz,2H),6.93(dd,J＝8.8,2.7Hz,1H),6.88(d,J＝2.6Hz,1H),6.50(d,J＝8.9Hz,1H),5.13 (dd,J＝13.4,5.1Hz,1H),4.46(d,J＝17.2Hz,1H),4.30(d,J＝17.2Hz,1H),3.19(dd,J＝9.8,5.4Hz,4H),2.92(ddd,J＝17.2,12.9,5.5Hz,1H),2.69–2.56(m,5H),2.48–2.32(m,1H),2.05–1.96(m,1H),1.84–1.74(m,2H),1.64(dt,J＝16.2,8.0Hz,2H),1.53(dt,J＝14.3,7.3Hz,2H),1.34(dt,J＝14.2,7.0Hz,2H).
实施例116:3-(4-(4-(吲哚啉-1-)-4-氧代丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(116)
Figure PCTCN2019109368-appb-000206
1H NMR(400MHz,DMSO)δ10.96(s,1H),8.10(d,J＝8.0Hz,1H),7.48(t,J＝7.8Hz,1H),7.34–7.16(m,3H),7.13(t,J＝7.6Hz,1H),6.96(t,J＝7.4Hz,1H),5.07(dd,J＝13.4,5.0Hz,1H),4.31(d,J＝17.3Hz,1H),4.18(dd,J＝15.4,11.7Hz,3H),4.09(t,J＝8.5Hz,2H),3.13(t,J＝8.4Hz,2H),2.95–2.82(m,1H),2.64(t,J＝6.7Hz,2H),2.55(d,J＝10.6Hz,1H),2.30–2.04(m,3H),1.97–1.87(m,1H).
实施例117:3-(4-(4-(3,4-二氢喹啉-1(2H)-)-4-氧代丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(117)
Figure PCTCN2019109368-appb-000207
1H NMR(400MHz,DMSO)δ11.00(s,1H),7.46(t,J＝7.8Hz,2H),7.29(d,J＝7.5Hz,1H),7.21(d,J＝8.1Hz,1H),7.18–7.10(m,2H),7.06(t,J＝7.3Hz,1H),5.09(dd,J＝13.3,5.1Hz,1H),4.25–4.02(m,4H),3.68(td,J＝12.6,6.2Hz,2H),3.29(s,1H),2.99–2.86(m,1H),2.77–2.55(m,5H),2.34(dd,J＝13.1,4.2Hz,1H),2.09–1.94(m,3H),1.86–1.77(m,2H).
实施例118:3-(4-((5-(吲哚啉-1-)-5-氧戊基)氧)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(118)
Figure PCTCN2019109368-appb-000208
39％； 1H NMR(400MHz,DMSO)δ10.96(s,1H),8.07(d,J＝8.0Hz,1H),7.48(t,J＝7.8Hz,1H),7.30(d,J＝7.4Hz,1H),7.25(d,J＝8.1Hz,1H),7.21(d,J＝7.3Hz,1H),7.13(t,J＝7.7Hz,1H),6.96(t,J＝7.4Hz,1H),5.10(dd,J＝13.3,5.1Hz,1H),4.37(d,J＝17.4Hz,1H),4.27–4.13(m,3H),4.08(t,J＝8.5Hz,2H),3.12(t,J＝8.4Hz,2H),2.96–2.84(m,1H),2.55(dd,J＝12.5,7.6Hz,3H),2.44–2.31(m,1H),2.02–1.92(m,1H),1.90–1.71(m,4H).
实施例119:3-(4-((5-(3,4-二氢喹啉-1(2H)-)-5-氧戊基)氧)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(119)
Figure PCTCN2019109368-appb-000209
1H NMR(400MHz,DMSO)δ10.97(s,1H),7.45(d,J＝7.7Hz,2H),7.30(d,J＝7.5Hz,1H),7.23–7.01(m,4H),5.10(dd,J＝13.3,5.1Hz,1H),4.31(s,1H),4.21(s,1H),4.08(s,2H),3.67(t,J＝6.4Hz,2H),2.96–2.84(m,1H),2.66(d,J＝6.5Hz,2H),2.55(d,J＝7.0Hz,3H),2.40(ddd,J＝35.4,17.8,9.0Hz,1H),2.05–1.93(m,1H),1.89–1.80(m,2H),1.72(s,4H).
实施例120：3-(4-(6-(6-氯-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)己基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(120)
Figure PCTCN2019109368-appb-000210
DMSO)δ10.99(s,1H),7.56(dd,J＝8.2,4.5Hz,1H),7.46(d,J＝3.7Hz,2H),7.36(s,1H),7.34–7.27(m,2H),5.13(dd,J＝13.3,5.1Hz,1H),4.94(s,2H),4.47(d,J＝17.1Hz,1H),4.31(d,J＝17.1Hz,1H),2.99–2.86(m,2H),2.79(d,J＝10.0Hz,2H),2.68-2.56(m,3H),2.46–2.23(m,5H),2.05–1.97(m,1H),1.92(dd,J＝12.7,9.1Hz,2H),1.61(d,J＝11.7Hz, 4H),1.46(s,2H),1.38-1.27(m,4H).
实施例121:3-(1-氧代-4-(5-(2-氧代螺[吲哚啉-3,4'-哌啶]-1'-)戊基)吲哚啉-2-)哌啶-2,6-二酮(121)
Figure PCTCN2019109368-appb-000211
7.52–7.42(m,3H),7.19(t,J＝7.5Hz,1H),6.96(t,J＝7.5Hz,1H),6.85(d,J＝7.7Hz,1H),5.15(dd,J＝13.3,5.1Hz,1H),4.49(d,J＝17.2Hz,1H),4.32(d,J＝17.2Hz,1H),2.99–2.85(m,3H),2.73–2.57(m,5H),2.48–2.37(m,1H),2.07–1.97(m,1H),1.88–1.76(m,2H),1.73–1.49(m,6H),1.37(dt,J＝14.4,7.4Hz,2H).
实施例122:3-(4-(4-(2H-螺[苯并呋喃-3,4'-哌啶]-1'-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(122)
Figure PCTCN2019109368-appb-000212
11.01(s,1H),8.17(s,1H),7.61–7.54(m,1H),7.50–7.44(m,2H),7.19(dd,J＝7.4,0.9Hz,1H),7.10(td,J＝7.9,1.3Hz,1H),6.84(dd,J＝7.8,7.0Hz,1H),6.75(d,J＝7.9Hz,1H),5.14(dd,J＝13.2,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.32(d,J＝16.4Hz,3H),2.93(ddd,J＝17.5,14.0,5.5Hz,1H),2.84(d,J＝11.8Hz,2H),2.67(t,J＝7.5Hz,2H),2.65–2.57(m,1H),2.48–2.30(m,3H),2.01(dd,J＝17.2,6.7Hz,3H),1.84(td,J＝12.8,3.7Hz,2H),1.69–1.57(m,4H),1.57–1.45(m,2H).
实施例123:3-(4-(5-(3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(123)
Figure PCTCN2019109368-appb-000213
10.99(s,1H),8.19(s,1H),7.60–7.55(m,1H),7.49–7.44(m,2H),7.30–7.20(m,3H),5.14(dd,J＝13.3,5.1Hz,1H),4.97(s,2H),4.47(d,J＝17.2Hz,1H),4.32(d,J＝17.2Hz,1H),2.92(ddd,J＝17.9,11.8,4.6Hz,3H),2.71–2.56(m,3H),2.43(dd,J＝21.2,8.6Hz,5H),1.98(dddd,J＝26.0,16.8,8.7,2.8Hz,3H),1.65(t,J＝12.0Hz,4H),1.54(dd,J＝14.6,7.7Hz,2H),1.40–1.29(m,2H).
实施例124:3-(4-(4-(6-氯-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(124)
Figure PCTCN2019109368-appb-000214
MHz,DMSO)δ10.97(s,1H),7.49(t,J＝7.8Hz,1H),7.35–7.23(m,5H),5.11(dd,J＝13.3,5.1Hz,1H),4.93(s,2H),4.38(d,J＝17.4Hz,1H),4.23(d,J＝17.4Hz,1H),4.16(t,J＝6.3Hz,2H),2.97–2.85(m,1H),2.79(d,J＝10.7Hz,2H),2.58(d,J＝18.2Hz,1H),2.48–2.36(m,3H),2.26(t,J＝10.9Hz,2H),2.03–1.94(m,1H),1.88(dd,J＝17.6,7.6Hz,2H),1.83–1.72(m,2H),1.63(dd,J＝21.1,9.9Hz,4H).
实施例125:3-(1-氧代-4-(5-(2-氧代-1,2-二氢螺[苯并[d][1,3]噁嗪-4,4'-哌啶]-1'-)戊基)异吲哚啉-2-)哌啶-2,6-二酮(125)
Figure PCTCN2019109368-appb-000215
7.43(m,2H),7.30–7.19(m,2H),7.05–6.98(m,1H),6.91–6.85(m,1H),5.13(dd,J＝13.2,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),2.98–2.86(m,1H),2.75(d, J＝10.6Hz,2H),2.70–2.56(m,3H),2.40(ddd,J＝24.4,15.6,7.6Hz,5H),1.98(ddd,J＝39.2,21.1,8.9Hz,5H),1.64(dt,J＝15.3,7.6Hz,2H),1.57–1.45(m,2H),1.35(dt,J＝14.8,7.5Hz,2H).
实施例126:3-(4-(4-(2H-螺[苯并呋喃-3,4'-哌啶]-1'-)丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(126)
Figure PCTCN2019109368-appb-000216
MHz,DMSO)δ10.97(s,1H),7.49(t,J＝7.8Hz,1H),7.31(d,J＝7.4Hz,1H),7.25(d,J＝8.1Hz,1H),7.18(d,J＝7.1Hz,1H),7.14–7.05(m,1H),6.84(t,J＝7.4Hz,1H),6.75(d,J＝7.9Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.38(d,J＝17.4Hz,1H),4.34(s,2H),4.23(d,J＝17.4Hz,1H),4.15(t,J＝6.2Hz,2H),2.92(dd,J＝22.7,8.6Hz,3H),2.60(s,1H),2.48–2.39(m,3H),2.00(ddd,J＝13.9,10.4,7.6Hz,3H),1.89–1.73(m,4H),1.65(t,J＝11.5Hz,4H).
实施例127:3-(4-(5-(6-氯-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)戊基-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(127)
Figure PCTCN2019109368-appb-000217
7.39–7.25(m,3H),5.14(dd,J＝13.3,5.1Hz,1H),4.93(s,2H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.1Hz,1H),2.99–2.86(m,1H),2.82–2.53(m,5H),2.48–2.37(m,1H),2.35–2.27(m,2H),2.26–2.15(m,2H),2.02(ddd,J＝9.9,4.9,2.9Hz,1H),1.94–1.81(m,2H),1.69–1.55(m,4H),1.54–1.43(m,2H),1.34(dt,J＝14.8,7.3Hz,2H).
实施例128:3-(4-(4-(6-氟-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(128)
Figure PCTCN2019109368-appb-000218
3H),7.14(dd,J＝8.9,2.2Hz,1H),7.12–7.05(m,1H),5.11(dd,J＝13.3,5.0Hz,1H),4.93(s,2H),4.38(d,J＝17.4Hz,1H),4.23(d,J＝17.4Hz,1H),4.15(t,J＝6.2Hz,2H),2.97–2.85(m,1H),2.81(d,J＝11.0Hz,2H),2.57(d,J＝18.0Hz,1H),2.47–2.38(m,3H),2.29(t,J＝11.5Hz,2H),2.02–1.95(m,1H),1.95–1.85(m,2H),1.83–1.73(m,2H),1.64(dd,J＝19.0,10.7Hz,4H).
实施例129:3-(4-(5-(5-氯-3-氧代-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(129)
Figure PCTCN2019109368-appb-000219
10.99(s,1H),8.15(s,1H),7.87(d,J＝1.4Hz,1H),7.82(dt,J＝13.8,5.0Hz,2H),7.57(dt,J＝7.7,3.8Hz,1H),7.51–7.41(m,2H),5.75(s,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.48(d,J＝17.2Hz,1H),4.32(d,J＝17.1Hz,1H),2.99–2.85(m,3H),2.71–2.56(m,3H),2.47–2.37(m,3H),2.36–2.27(m,2H),2.21(t,J＝12.1Hz,2H),2.07–1.95(m,1H),1.64(dd,J＝13.9,8.5Hz,4H),1.58–1.48(m,2H),1.36(dt,J＝14.8,7.5Hz,2H).
实施例130：3-(4-(4-(6-甲基-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(130)
Figure PCTCN2019109368-appb-000220
丙基)-4-苯基哌啶-4-甲腈，16.2mg,白色固体，收率29％； 1H NMR(400MHz,DMSO)δ10.97(s,1H),7.49(t,J＝7.8Hz,1H),7.31(d,J＝7.5Hz,1H),7.25(d,J＝8.1Hz,1H),7.13(d,J＝7.6Hz,1H),7.07(d,J＝7.7Hz,1H),7.00(s,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.90(s,2H),4.38(d,J＝17.4Hz,1H),4.23(d,J＝17.4Hz,1H),4.16(t,J＝6.3Hz,2H),2.98–2.85(m,1H),2.80(d,J＝11.0Hz,2H),2.57(d,J＝18.4Hz,1H),2.48–2.38(m,3H),2.35–2.23(m,5H),2.03–1.93(m,1H),1.90–1.73(m,4H),1.63(dt,J＝20.6,10.0Hz,4H).
实施例131:3-(1-氧代-4-(5-(2'-氧代-1',2'-二氢螺[哌啶-4,4'-吡啶并[2,3-d][1,3]噁嗪]-1-)戊基)异吲哚啉-2-)哌啶-2,6-二酮(131)
Figure PCTCN2019109368-appb-000221
7.72(dd,J＝7.6,1.1Hz,1H),7.59–7.54(m,1H),7.50–7.43(m,2H),7.07(dd,J＝7.6,5.0Hz,1H),5.75(s,1H),5.13(dd,J＝13.2,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.1Hz,1H),2.99–2.86(m,1H),2.78(d,J＝10.6Hz,2H),2.64(dd,J＝22.3,14.4Hz,3H),2.47–2.29(m,5H),2.09–1.88(m,5H),1.64(dt,J＝15.4,7.7Hz,2H),1.56–1.44(m,2H),1.41–1.29(m,2H).
实施例132:3-(4-((5-(6-氯-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)戊基)氧)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(132)
Figure PCTCN2019109368-appb-000222
率为48％； 1H NMR(400MHz,DMSO)δ10.97(s,1H),7.48(t,J＝7.8Hz,1H),7.36(s,1H),7.33–7.27(m,3H),7.24(d,J＝8.1Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.93(s,2H),4.37(d,J＝17.4Hz,1H),4.23(d,J＝17.4Hz,1H),4.13(t,J＝6.3Hz,2H),2.97–2.84(m,1H), 2.78(d,J＝10.5Hz,2H),2.56(d,J＝18.0Hz,1H),2.45(dd,J＝13.1,4.4Hz,1H),2.37(t,J＝7.0Hz,2H),2.27(t,J＝11.5Hz,2H),2.02–1.85(m,3H),1.82–1.71(m,2H),1.61(d,J＝12.4Hz,2H),1.48(ddd,J＝22.2,14.8,9.1Hz,4H).
实施例133:3-(4-(5-(5-氯-2-氧代螺[吲哚啉-3,4'-哌啶]-1'-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(133)
Figure PCTCN2019109368-appb-000223
DMSO)δ10.99(s,1H),10.51(s,1H),8.18(s,1H),7.57(dd,J＝6.0,2.6Hz,1H),7.53–7.43(m,3H),7.24(dd,J＝8.3,2.1Hz,1H),6.85(d,J＝8.3Hz,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.48(d,J＝17.2Hz,1H),4.32(d,J＝17.1Hz,1H),3.01–2.84(m,3H),2.63(ddd,J＝21.4,16.7,4.4Hz,5H),2.53(d,J＝6.9Hz,2H),2.48–2.36(m,1H),2.02(ddd,J＝10.2,5.0,3.1Hz,1H),1.86–1.70(m,4H),1.69–1.61(m,2H),1.60–1.50(m,2H),1.37(dt,J＝14.7,7.5Hz,2H).
实施例134：3-(4-((5-(3H-螺[异苯并呋喃-1,4'-哌啶]-1'-基)戊基)氧基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(134)
Figure PCTCN2019109368-appb-000224
异吲哚啉-2-)哌啶-2,6-二酮35mg，白色固体，收率为37％； 1H NMR(400MHz,DMSO)δ10.98(s,1H),7.49(t,J＝7.8Hz,1H),7.31(d,J＝7.5Hz,1H),7.25(d,J＝8.1Hz,1H),7.19(d,J＝7.3Hz,1H),7.11(td,J＝7.8,1.2Hz,1H),6.85(t,J＝7.4Hz,1H),6.76(d,J＝7.9Hz,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.42–4.31(m,3H),4.24(d,J＝17.4Hz,1H),4.14(t,J＝6.3Hz,2H),2.91(ddd,J＝13.4,11.9,5.7Hz,3H),2.59(s,1H),2.45(dd,J＝13.1,4.3Hz,1H), 2.38(t,J＝6.8Hz,2H),2.10–1.94(m,3H),1.91–1.72(m,4H),1.63(d,J＝13.0Hz,2H),1.59–1.39(m,4H).
实施例135：3-(4-(5-(5-甲氧基-2-氧代螺[吲哚啉-3,4'-哌啶]-1'-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(135)
Figure PCTCN2019109368-appb-000225
DMSO)δ10.99(s,1H),10.19(s,1H),8.18(s,1H),7.56(dt,J＝7.9,3.9Hz,1H),7.51–7.43(m,2H),7.02(s,1H),6.75(s,2H),5.75(s,2H),5.14(dd,J＝13.2,5.1Hz,1H),4.48(d,J＝17.2Hz,1H),4.32(d,J＝17.1Hz,1H),3.71(s,3H),2.92(ddd,J＝13.0,12.2,5.1Hz,3H),2.71–2.57(m,5H),2.54(s,2H),2.47–2.37(m,1H),2.02(ddd,J＝10.4,5.0,3.6Hz,1H),1.90–1.47(m,8H),1.44–1.28(m,2H).
实施例136:3-(4-(3-(2H-螺[异苯并呋喃-1,4'-哌啶]-1'-)丙氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(136)
Figure PCTCN2019109368-appb-000226
MHz,DMSO)δ10.98(s,1H),7.49(t,J＝7.8Hz,1H),7.32(d,J＝7.5Hz,1H),7.26(d,J＝8.1Hz,1H),7.20(d,J＝6.9Hz,1H),7.11(t,J＝7.7Hz,1H),6.86(t,J＝7.4Hz,1H),6.76(d,J＝8.0Hz,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.39(d,J＝14.5Hz,3H),4.29–4.13(m,3H),3.57–3.12(m,4H),3.07–2.83(m,3H),2.63–2.55(m,1H),2.47–2.37(m,1H),2.09–1.81(m,5H),1.69(d,J＝12.4Hz,2H).
实施例137:3-(1-氧代-4-(5-(螺[异色满-1,4'-哌啶]-1'-)戊基)异吲哚啉-2-)哌啶-2,6-二酮(137)
Figure PCTCN2019109368-appb-000227
10.99(s,1H),7.57(dt,J＝7.5,3.8Hz,1H),7.51–7.40(m,2H),7.21–7.05(m,4H),5.14(dd,J＝13.2,5.0Hz,1H),4.47(d,J＝17.2Hz,1H),4.32(d,J＝17.1Hz,1H),3.81(t,J＝5.4Hz,2H),2.99–2.86(m,1H),2.74(dd,J＝14.1,8.6Hz,4H),2.69–2.57(m,3H),2.46–2.31(m,5H),2.06–1.87(m,3H),1.78(d,J＝13.1Hz,2H),1.70–1.59(m,2H),1.53(dd,J＝12.4,6.0Hz,2H),1.36(dd,J＝13.7,7.5Hz,2H).
实施例138：3-(4-(3-(6-氯-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)丙氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(138)
Figure PCTCN2019109368-appb-000228
MHz,DMSO)δ10.99(s,1H),7.50(t,J＝7.8Hz,1H),7.40–7.30(m,3H),7.27(t,J＝7.0Hz,2H),5.12(dd,J＝13.3,5.1Hz,1H),4.99(s,2H),4.41(d,J＝17.4Hz,1H),4.24(dd,J＝17.8,11.6Hz,3H),3.47–3.16(m,6H),2.97–2.87(m,1H),2.59(dd,J＝17.2,1.0Hz,1H),2.47–2.37(m,1H),2.36–2.05(m,4H),2.04–1.97(m,1H),1.85–1.67(m,2H).
实施例139:3-(1-氧代-4-(5-(2-氧代螺[吲哚啉-3,3'-吡咯啉]-1'-)戊基)异吲哚啉-2-)哌啶-2,6-二酮(139)
Figure PCTCN2019109368-appb-000229
10.98(s,1H),10.35(s,1H),8.15(s,1H),7.56(dt,J＝7.8,3.9Hz,1H),7.49–7.40(m,2H),7.27(dd,J＝7.1,4.0Hz,1H),7.15(td,J＝7.6,0.6Hz,1H),6.94(tdd,J＝7.6,2.6,0.8Hz,1H),6.81(d,J＝7.7Hz,1H),5.75(s,2H),5.13(dd,J＝13.3,5.1Hz,1H),4.46(dd,J＝17.2,2.9Hz,1H),4.30(d,J＝17.1Hz,1H),3.09(td,J＝8.1,4.7Hz,1H),2.98– 2.85(m,1H),2.81(dd,J＝9.0,2.0Hz,1H),2.70–2.52(m,6H),2.39(ddd,J＝25.6,12.8,4.3Hz,1H),2.16(ddd,J＝12.1,7.9,4.1Hz,1H),1.99(dd,J＝11.5,5.5Hz,1H),1.88(dt,J＝12.5,7.6Hz,1H),1.64(dt,J＝14.9,7.4Hz,2H),1.57–1.46(m,2H),1.45–1.33(m,2H).
实施例140:3-(4-(3-(6-甲基-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)丙氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(140)
Figure PCTCN2019109368-appb-000230
DMSO)δ11.00(s,1H),7.50(t,J＝7.8Hz,1H),7.33(d,J＝7.5Hz,1H),7.27(d,J＝8.1Hz,1H),7.18(d,J＝7.6Hz,1H),7.12(d,J＝7.6Hz,1H),6.98(s,1H),5.13(dd,J＝13.3,5.0Hz,1H),4.96(s,2H),4.41(d,J＝17.4Hz,1H),4.31–4.17(m,3H),3.37(dd,J＝17.2,16.7Hz,6H),2.97–2.88(m,1H),2.59(d,J＝17.2Hz,1H),2.46–2.37(m,1H),2.33(s,3H),2.17(dt,J＝36.9,32.7Hz,4H),2.01(dd,J＝8.9,3.3Hz,1H),1.83–1.63(m,2H).
实施例141:3-(1-氧代-4-(5-(螺[茚-1,4'-哌啶]-1'-)戊基)异吲哚啉-2-)哌啶-2,6-二酮(141)
Figure PCTCN2019109368-appb-000231
(m,2H),7.39(d,J＝7.0Hz,1H),7.33(d,J＝7.0Hz,1H),7.26–7.15(m,2H),6.97(d,J＝5.6Hz,1H),6.80(d,J＝5.6Hz,1H),5.75(s,2H),5.14(dd,J＝13.3,5.0Hz,1H),4.47(dd,J＝17.1,8.0Hz,1H),4.31(dd,J＝17.1,7.9Hz,1H),3.06(d,J＝11.6Hz,2H),2.99–2.87(m,1H),2.72–2.53(m,5H),2.46–2.35(m,2H),2.19–2.07(m,2H),2.06–1.94(m,1H),1.63(qd,J＝14.8,8.1Hz,4H),1.43–1.31(m,2H),1.23(d,J＝12.9Hz,2H).
实施例142:3-(4-(3-(6-氟-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)丙氧基)-1-氧代异吲哚啉-2-)哌 啶-2,6-二酮(142)
Figure PCTCN2019109368-appb-000232
MHz,DMSO)δ10.99(s,1H),7.49(t,J＝7.8Hz,1H),7.34–7.22(m,3H),7.17(dd,J＝8.9,2.2Hz,1H),7.08(td,J＝9.4,2.3Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.93(s,2H),4.38(d,J＝17.4Hz,1H),4.23(d,J＝17.4Hz,1H),4.18(t,J＝6.1Hz,2H),2.97–2.86(m,1H),2.82(d,J＝10.2Hz,2H),2.63–2.52(m,3H),2.48–2.39(m,1H),2.31(t,J＝11.1Hz,2H),2.04–1.86(m,5H),1.62(d,J＝12.5Hz,2H).
实施例143:3-(4-(5-(2,3-二氢螺[茚-1,4'-哌啶]-1'-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(143)
Figure PCTCN2019109368-appb-000233
11.00(s,1H),7.57(dt,J＝7.7,3.9Hz,1H),7.50–7.43(m,2H),7.23–7.09(m,4H),5.75(s,1H),5.14(dd,J＝13.2,5.0Hz,1H),4.48(d,J＝17.2Hz,1H),4.32(d,J＝17.2Hz,1H),3.03–2.88(m,3H),2.84(t,J＝7.3Hz,2H),2.71–2.57(m,4H),2.47–2.37(m,2H),2.35–2.20(m,2H),2.06–1.92(m,3H),1.90–1.78(m,2H),1.69–1.60(m,2H),1.55(dd,J＝13.9,7.3Hz,2H),1.47(d,J＝12.6Hz,2H),1.39–1.30(m,2H).
实施例144：3-(4-((5-(6-氟-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)戊基)氧)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(144)
Figure PCTCN2019109368-appb-000234
为40％； 1H NMR(400MHz,DMSO)δ10.98(s,1H),7.48(t,J＝7.7Hz,1H),7.35–7.21(m,3H),7.19–7.13(m,1H),7.09(dd,J＝12.5,5.1Hz,1H),5.11(dd,J＝13.2,5.0Hz,1H),4.93 (s,2H),4.37(d,J＝17.4Hz,1H),4.22(d,J＝17.4Hz,1H),4.12(t,J＝6.1Hz,2H),2.98–2.85(m,1H),2.80(d,J＝9.9Hz,2H),2.58(s,1H),2.48–2.35(m,3H),2.29(t,J＝11.4Hz,2H),2.04–1.85(m,3H),1.82–1.71(m,2H),1.61(d,J＝12.7Hz,2H),1.57–1.39(m,4H).
实施例145:3-(4-(5-(2H-螺[苯并呋喃-3,4'-哌啶]-1'-)戊基-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(145)
Figure PCTCN2019109368-appb-000235
11.00(s,1H),7.63–7.53(m,1H),7.45(dd,J＝7.1,5.7Hz,2H),7.19(d,J＝7.1Hz,1H),7.11(dd,J＝11.2,4.2Hz,1H),6.85(t,J＝7.3Hz,1H),6.75(d,J＝7.9Hz,1H),5.14(dd,J＝13.2,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.36–4.28(m,3H),3.00–2.82(m,3H),2.73–2.57(m,3H),2.49–2.30(m,3H),2.12–1.96(m,3H),1.86(td,J＝12.8,3.1Hz,2H),1.63(d,J＝13.2Hz,4H),1.57–1.44(m,2H),1.41–1.28(m,2H).
实施例146:3-(4-((5-(6-甲基-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)戊基)氧)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(146)
Figure PCTCN2019109368-appb-000236
为20％； 1H NMR(400MHz,DMSO)δ10.98(s,1H),7.48(t,J＝7.8Hz,1H),7.31(d,J＝7.5Hz,1H),7.25(d,J＝8.2Hz,1H),7.14(d,J＝7.6Hz,1H),7.07(d,J＝7.8Hz,1H),7.02(s,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.91(s,2H),4.38(d,J＝17.4Hz,1H),4.23(d,J＝17.4Hz,1H),4.13(t,J＝6.2Hz,2H),2.97–2.74(m,3H),2.56(d,J＝16.4Hz,1H),2.47–2.25(m,8H),2.03–1.94(m,1H),1.93–1.83(m,2H),1.77(dd,J＝13.5,6.5Hz,2H),1.64–1.40(m,6H).
实施例147:3-(1-氧代-4-(5-(4-氧代-1-苯基-1,3,8-三氮杂螺[4.5]癸烷-8-)戊基)异吲哚啉-2-)哌啶-2,6-二酮(147)
Figure PCTCN2019109368-appb-000237
7.52–7.42(m,2H),7.22(t,J＝7.9Hz,2H),6.87(d,J＝8.2Hz,2H),6.75(t,J＝7.3Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.58(s,2H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.1Hz,1H),3.20–2.73(m,5H),2.71–2.52(m,7H),2.40(ddd,J＝26.3,13.2,4.3Hz,1H),2.07–1.95(m,1H),1.75–1.60(m,4H),1.56(dd,J＝14.2,7.6Hz,2H),1.42–1.28(m,2H).
实施例148:3-(4-((6-(2H-螺[苯并呋喃-3,4'-哌啶]-1'-)己基)氧)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(148)
Figure PCTCN2019109368-appb-000238
J＝7.8Hz,1H),7.30(d,J＝7.4Hz,1H),7.24(d,J＝8.1Hz,1H),7.18(d,J＝7.2Hz,1H),7.10(td,J＝7.9,1.2Hz,1H),6.84(t,J＝7.4Hz,1H),6.75(d,J＝7.9Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.37(d,J＝17.4Hz,1H),4.33(s,2H),4.22(d,J＝17.4Hz,1H),4.12(t,J＝6.3Hz,2H),2.97–2.87(m,1H),2.83(d,J＝11.7Hz,2H),2.57(d,J＝17.9Hz,1H),2.48–2.38(m,1H),2.36–2.25(m,2H),1.97(t,J＝10.8Hz,3H),1.83(td,J＝12.8,3.6Hz,2H),1.79–1.68(m,2H),1.61(d,J＝12.4Hz,2H),1.53–1.40(m,4H),1.39–1.30(m,2H).
实施例149：3-(4-(4-(3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(149)
Figure PCTCN2019109368-appb-000239
11.02(s,1H),7.62–7.56(m,1H),7.51–7.45(m,2H),7.31–7.21(m,4H),5.15(dd,J＝13.3,5.1Hz,1H),4.96(s,2H),4.49(d,J＝17.2Hz,1H),4.33(d,J＝17.1Hz,1H),2.94(ddd,J＝17.6,13.9,5.5Hz,1H),2.84–2.75(m,2H),2.69(t,J＝7.5Hz,2H),2.65–2.57(m,1H),2.47–2.37(m,3H),2.31(t,J＝10.9Hz,2H),2.03(dtd,J＝12.6,5.1,2.0Hz,1H),1.90(td,J＝13.1,4.3Hz,2H),1.65(ddd,J＝21.1,10.2,4.5Hz,4H),1.53(dt,J＝14.9,7.6Hz,2H).
实施例150:3-(4-((6-(6-氯-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)己基)氧)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(150)
Figure PCTCN2019109368-appb-000240
收率为26％； 1H NMR(400MHz,DMSO)δ10.98(s,1H),7.48(t,J＝7.8Hz,1H),7.35(s,1H),7.33–7.27(m,3H),7.24(d,J＝8.1Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.93(s,2H),4.37(d,J＝17.4Hz,1H),4.22(d,J＝17.4Hz,1H),4.12(t,J＝6.3Hz,2H),3.00–2.85(m,1H),2.78(d,J＝10.6Hz,2H),2.63–2.54(m,1H),2.48–2.39(m,1H),2.38–2.31(m,2H),2.27(t,J＝11.3Hz,2H),2.04–1.83(m,3H),1.80–1.68(m,2H),1.60(d,J＝12.6Hz,2H),1.47(q,J＝16.3Hz,4H),1.35(dd,J＝13.0,6.3Hz,2H).
实施例151：3-(4-(4-(6-氯-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(151)
Figure PCTCN2019109368-appb-000241
11.01(s,1H),8.18(s,1H),7.60–7.54(m,1H),7.50–7.44(m,2H),7.37(d,J＝1.4Hz,1H),7.35–7.27(m,2H),5.14(dd,J＝13.3,5.1Hz,1H),4.94(s,2H),4.48(d,J＝17.2Hz,1H), 4.32(d,J＝17.2Hz,1H),2.99–2.88(m,1H),2.82(d,J＝11.0Hz,2H),2.68(t,J＝7.5Hz,2H),2.60(dd,J＝17.0,2.8Hz,1H),2.48–2.41(m,3H),2.34(t,J＝10.8Hz,2H),2.02(ddd,J＝9.6,5.5,2.0Hz,1H),1.94(ddd,J＝14.4,10.7,3.8Hz,2H),1.70–1.59(m,4H),1.57–1.47(m,2H).
实施例152:3-(4-((5-(6-氯-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)-5-氧代戊基)氧)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(152)
Figure PCTCN2019109368-appb-000242
收率为39％；1H NMR(400MHz,DMSO)δ10.96(s,1H),7.48(t,J＝7.8Hz,1H),7.42(s,1H),7.32(q,J＝8.1Hz,3H),7.25(d,J＝8.1Hz,1H),5.10(dd,J＝13.0,4.7Hz,1H),4.47–4.34(m,2H),4.22(d,J＝17.4Hz,1H),4.15(t,J＝6.1Hz,2H),3.87(d,J＝12.3Hz,1H),3.27(s,1H),2.87(ddd,J＝31.9,19.7,9.4Hz,2H),2.62–2.53(m,1H),2.45(d,J＝6.8Hz,5H),1.94(dd,J＝23.7,11.7Hz,2H),1.87–1.57(m,7H).
实施例153:3-(4-(4-(6-氯-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)-4-氧代丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(153)
Figure PCTCN2019109368-appb-000243
Hz,1H),7.39(s,1H),7.35–7.24(m,4H),5.11(dd,J＝13.3,5.1Hz,1H),4.99(s,2H),4.48–4.36(m,2H),4.24(d,J＝17.4Hz,1H),4.17(t,J＝6.3Hz,2H),3.87(d,J＝11.9Hz,1H),3.27(s,1H),2.99–2.79(m,2H),2.65–2.52(m,3H),2.48–2.35(m,1H),2.01(dt,J＝14.6,7.3Hz,3H),1.82(ddd,J＝19.2,17.3,8.8Hz,2H),1.63(d,J＝13.0Hz,2H).
实施例154:6-氯-N-(4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-氧-)丁基)-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-甲酰胺(154)
Figure PCTCN2019109368-appb-000244
1H),7.48(t,J＝7.8Hz,1H),7.38(s,1H),7.35–7.28(m,3H),7.24(d,J＝8.1Hz,1H),6.54(t,J＝5.2Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.97(s,2H),4.39(d,J＝17.5Hz,1H),4.23(d,J＝17.4Hz,1H),4.14(t,J＝6.3Hz,2H),3.95(d,J＝11.5Hz,2H),3.12(dd,J＝12.4,6.7Hz,2H),2.99-2.85(m,3H),2.60-2.52(m,1H),2.44(dd,J＝17.5,8.9Hz,1H),2.04–1.92(m,1H),1.83-1.72(m,4H),1.62-1.55(m,4H).
实施例155:6-氯-N-(2-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)乙基)-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-甲酰胺(155)
Figure PCTCN2019109368-appb-000245
率60％； 1H NMR(400MHz,DMSO)δ10.97(s,1H),7.49(t,J＝7.8Hz,1H),7.37(s,1H),7.34–7.28(m,4H),6.76(t,J＝5.3Hz,1H),5.11(dd,J＝13.2,5.0Hz,1H),4.97(s,2H),4.39(d,J＝17.4Hz,1H),4.25(d,J＝17.4Hz,1H),4.17(t,J＝6.1Hz,2H),3.96(d,J＝12.7Hz,2H),3.43(dd,J＝11.5,5.8Hz,2H),3.02-2.95(m,2H),2.94–2.86(m,1H),2.58(d,J＝18.0Hz,1H),2.46–2.34(m,1H),2.04–1.94(m,1H),1.79(td,J＝13.0,4.5Hz,2H),1.58(d,J＝12.8Hz,2H).
实施例156：3-(4-(5-(6-氟-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(156)
Figure PCTCN2019109368-appb-000246
11.00(s,1H),7.60–7.54(m,1H),7.49–7.44(m,2H),7.29(dd,J＝8.0,4.9Hz,1H),7.18–7.06(m,2H),5.14(dd,J＝13.2,5.2Hz,1H),4.93(s,2H),4.47(d,J＝17.4Hz,1H),4.31(d,J＝17.2Hz,1H),3.00–2.79(m,3H),2.68-2.56(m,3H),2.38(dt,J＝26.6,15.4Hz,5H),2.05-1.91(m,3H),1.63(d,J＝11.3Hz,4H),1.58–1.48(m,2H),1.35(dd,J＝15.8,6.9Hz,2H).
实施例157：3-(4-(5-(6-甲基-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(157)
Figure PCTCN2019109368-appb-000247
11.00(s,1H),7.57(dd,J＝5.4,3.1Hz,1H),7.51–7.41(m,2H),7.13(d,J＝7.6Hz,1H),7.07(d,J＝7.7Hz,1H),7.02(s,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.91(s,2H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.1Hz,1H),2.98–2.87(m,1H),2.80(d,J＝10.8Hz,2H),2.70–2.56(m,3H),2.47–2.27(m,8H),2.03-1.98(m,1H),1.92–1.81(m,2H),1.69–1.47(m,6H),1.40–1.30(m,2H).
实施例158：N-(3-氯-4-甲基苯基)-4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丁酰胺(158)
Figure PCTCN2019109368-appb-000248
33.14mmol，2.0eq)，-40℃搅拌30分钟，加入叔丁醇(9.83g，132.56mmol，8.0eq)逐渐升值室温，反应过夜。反应完成后，将反应体系倒入饱和碳酸氢钠溶液中，乙酸乙酯萃取，饱和氯化钠洗涤，减压浓缩得到3.75g淡黄色油状物，收率为95％。 1H NMR(400MHz, CDCl 3)δ3.41(t,J＝6.7Hz,2H),2.25(t,J＝7.3Hz,2H),1.94–1.85(m,2H),1.79–1.68(m,2H),1.44(s,9H).
步骤2：将5-胺基-4-(4-羟基-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(400mg，1.37mmol，1.0eq)，4-溴丁酸叔丁酯(1.62g，6.85mmol，5.0eq)溶于20mL DMSO中，加入无水碳酸钾(379mg，2.74mmol，2.0eq)，50℃反应24小时。反应完成后，乙酸乙酯稀释，饱和氯化钠洗涤，干燥，减压浓缩，柱层析纯化得到530mg无色油状物，收率为86％。 1H NMR(400MHz,DMSO)δ7.61(s,1H),7.44(t,J＝7.8Hz,1H),7.27(d,J＝7.4Hz,1H),7.20(d,J＝8.3Hz,1H),4.72(dd,J＝10.4,4.8Hz,1H),4.50(d,J＝17.6Hz,1H),4.35(d,J＝17.6Hz,1H),4.11(t,J＝6.0Hz,1H),3.50(s,1H),2.31–2.14(m,2H),2.06(ddd,J＝13.7,10.3,6.5Hz,1H),1.79–1.62(m,2H),1.38(s,3H).
步骤3：将5-胺基-4-(4-(4-(叔丁氧基)-4-氧代丁氧基)-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(530mg，1.18mmol，1.0eq)溶于20mg无水四氢呋喃中，冰浴15分钟。加入叔丁醇钾(146mg，1.30mmol，1.1eq)，冰浴下继续反应90分钟。反应完成后，加入50uL甲酸淬灭反应。减压旋走溶剂，柱层析纯化得到463mg黄色固体，收率为94％； 1H NMR(400MHz,DMSO)δ10.98(s,1H),7.46(d,J＝7.8Hz,1H),7.30(d,J＝7.4Hz,1H),7.23(d,J＝8.1Hz,1H),5.11(dd,J＝13.3,5.0Hz,1H),4.37(d,J＝17.3Hz,1H),4.21(d,J＝17.2Hz,1H),4.12(t,J＝5.9Hz,2H),2.98–2.83(m,1H),2.58(d,J＝18.0Hz,1H),2.44(dd,J＝17.9,8.8Hz,2H),2.27(t,J＝7.1Hz,3H),2.03–1.92(m,1H),1.85–1.54(m,6H),1.40–1.36(m,13H).
步骤4：将4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丁酸叔丁酯(463mg，1.11mmol)置于100mL圆底烧瓶中，加入20mL盐酸二氧六环溶液，室温反应30分钟。反应完成后，旋走溶剂，无需进一步纯化直接投下一步； 1H NMR(400MHz,DMSO)δ10.99(s,1H),7.47(t,J＝7.8Hz,1H),7.30(d,J＝7.4Hz,1H),7.23(d,J＝8.1Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.41–4.32(m,1H),4.23(t,J＝12.9Hz,1H),4.12(t,J＝6.0Hz,2H),3.59–3.54(m,1H),2.90(ddd,J＝13.6,11.9,5.4Hz,1H),2.57(d,J＝17.8Hz,1H),2.47 –2.35(m,1H),2.33–2.25(m,2H),2.02–1.92(m,1H),1.71(ddd,J＝19.0,13.1,5.6Hz,4H).
步骤5：将4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丁酸(50mg，0.139mmol，1.0eq)溶于3mL二甲基亚砜中，加入3-氯-4-甲基苯胺(0.208mmol，1.5eq)，O-(7-氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(79mg，0.208mmol，1.5eq)，1-羟基苯并***(28mg，0.208mmol，1.5eq)，三乙胺(141mg，1.39mmol，10eq)室温反应小时。反应完成后，乙酸乙酯稀释，饱和氯化钠洗涤，薄层色谱和高效液相色谱纯化得到产物18mg，白色固体，收率为26％； 1H NMR(400MHz,DMSO)δ10.96(s,1H),10.03(s,1H),7.83(d,J＝1.8Hz,1H),7.48(t,J＝7.8Hz,1H),7.35–7.28(m,2H),7.24(dd,J＝8.2,3.6Hz,2H),5.07(dd,J＝13.4,5.0Hz,1H),4.27(d,J＝17.4Hz,1H),4.14(d,J＝17.1Hz,3H),2.96–2.84(m,1H),2.59–2.52(m,1H),2.25(s,3H),2.21–1.87(m,4H),1.24(s,2H).
实施例159:N-(3-氯-4-甲基苯基)-5-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)戊酰胺(159)
Figure PCTCN2019109368-appb-000249
1H NMR(400MHz,DMSO)δ10.96(s,1H),10.00(s,1H),7.80(d,J＝1.9Hz,1H),7.47(t,J＝7.8Hz,1H),7.36–7.28(m,2H),7.24(d,J＝8.4Hz,2H),5.10(dd,J＝13.3,5.1Hz,1H),4.37(d,J＝17.4Hz,1H),4.22(d,J＝17.4Hz,1H),4.14(d,J＝5.4Hz,2H),2.98–2.85(m,1H),2.56(d,J＝19.3Hz,1H),2.46–2.32(m,3H),2.25(s,3H),2.03–1.93(m,1H),1.78(d,J＝3.5Hz,4H).
实施例160:1-(3-氯-4-甲基苯基)-3-(2-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)乙基)脲(160)
Figure PCTCN2019109368-appb-000250
以及三苯基膦(672mg，2.56mmol)溶解于干燥的四氢呋喃(30mL)中，室温搅拌下加入DIAD(504μL,2.56mmol),所得反应液室温下搅拌反应30分钟，反应完毕，减压除去溶剂，所得残余物经硅胶柱层析得到5-胺基-4-(4-(2-(叔丁氧羰基胺基)乙氧基)-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯468mg,63％。
步骤2：将5-胺基-4-(4-(2-(叔丁氧羰基胺基)乙氧基)-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(468mg，1.07mmol)溶解于干燥的四氢呋喃中(40mL)，将反应液冷却至0℃,搅拌条件下加入叔丁醇钾(133mg,1.18mmol),继续于冰浴冷却条件下搅拌反应10分钟，反应完毕，反应液用60μL甲酸淬灭，减压除去溶剂，残余物经硅胶柱层析得到目标产物350mg,81％。
步骤3：将步骤2所得产物溶解于20mL氯化氢的1,4-二氧六环溶液中，室温下搅拌反应2小时，反应完毕，减压除去溶剂得到目标产物为白色粉末固体。
步骤4：3-(4-(2-胺基乙氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮盐酸盐(50mg,0.147mmol)溶解于3mL干燥DMSO中，向反应液中依次加入三乙胺(61μL,0.44mmol)和3-氯-4-甲基苯基异氰酸酯(37mg,0.22mmol)，所得反应液40℃加热条件下反应3小时，反应完毕，所得反应液经HPLC分离得到目标产物1-(3-氯-4-甲基苯基)-3-(2-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)乙基)脲48mg,收率69％； 1H NMR(400MHz,DMSO)δ10.96(s,1H),8.78(s,1H),7.66(d,J＝2.0Hz,1H),7.48(t,J＝7.8Hz,1H),7.32(d,J＝7.4Hz,1H),7.27(d,J＝8.1Hz,1H),7.21–7.00(m,4H),6.46(t,J＝5.6Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.39(d,J＝17.4Hz,1H),4.24(d,J＝17.3Hz,1H),4.17(t,J＝5.5Hz,2H),3.49(dd,J＝5.4,1.9Hz,2H),2.91(ddd,J＝17.6,13.7,5.4Hz,1H),2.58(dt,J＝6.8,3.3Hz,1H),2.33(ddd,J＝26.6,13.4,4.5Hz,1H),2.22(s,3H),2.03–1.91(m,1H).
实施例161：1-(4-氯-3-甲基苯基)-3-(3-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丙基)脲(161)
Figure PCTCN2019109368-appb-000251
收率31％； 1H NMR(400MHz,DMSO)δ10.96(s,1H),8.64–8.55(m,1H),7.64(d,J＝2.1Hz,1H),7.48(t,J＝7.8Hz,1H),7.31(d,J＝7.4Hz,1H),7.25(d,J＝8.0Hz,1H),7.15(d,J＝8.5Hz,1H),7.08(dd,J＝8.3,2.1Hz,1H),6.32(s,1H),5.09(dd,J＝13.3,5.2Hz,1H),4.39(d,J＝17.4Hz,1H),4.24(d,J＝17.4Hz,1H),4.17(t,J＝5.9Hz,2H),3.33-3.24(m,2H),2.95–2.85(m,1H),2.63–2.55(m,1H),2.45–2.32(m,1H),2.22(s,3H),2.01-1.88(m,3H).
实施例162:1-(3-氯-4-甲基苯基)-3-(4-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)氧)丁基)脲(162)
Figure PCTCN2019109368-appb-000252
收率65％； 1H NMR(400MHz,DMSO)δ10.96(s,1H),8.52(s,1H),7.63(d,J＝2.0Hz,1H),7.47(t,J＝7.8Hz,1H),7.30(d,J＝7.4Hz,1H),7.24(d,J＝8.1Hz,1H),7.16(d,J＝8.4Hz,1H),7.09(dd,J＝8.3,2.1Hz,1H),6.22(t,J＝5.8Hz,1H),5.10(dd,J＝13.3,5.0Hz,1H),4.38(d,J＝17.4Hz,1H),4.22(d,J＝17.3Hz,1H),4.15(t,J＝6.2Hz,2H),3.15(dd,J＝12.8,6.6Hz,2H),2.96–2.85(m,1H),2.56(d,J＝17.6Hz,1H),2.47–2.36(m,1H),2.22(s,3H),2.03–1.94(m,1H),1.76(dd,J＝14.3,6.4Hz,2H),1.61(dd,J＝14.4,6.9Hz,2H).
实施例163:1-(3,4-二氯苯基)-3-(2-((2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-氧乙基)脲(163)
Figure PCTCN2019109368-appb-000253
-3-)-1-氧代异吲哚啉-4-)氧)乙基)脲，白色固体化合物，50mg,收率69％； 1H NMR(400MHz,DMSO)δ10.97(s,1H),8.96(s,1H),7.85(d,J＝2.5Hz,1H),7.65-7.54(m,H),7.59–7.52(m,1H),7.52–7.42(m,2H),7.27(ddd,J＝13.5,11.3,5.0Hz,3H),6.56(t,J＝5.7Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.38(d,J＝17.4Hz,1H),4.25(d,J＝17.3Hz,1H),4.18(t,J＝5.5Hz,2H),3.55–3.47(m,1H),2.91(ddd,J＝18.6,13.6,5.2Hz,1H),2.57(d,J＝17.0Hz,2H),2.41–2.28(m,2H),2.02-1.93(m,1H).
实施例164:(2S)-2-乙酰氨基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-苯基戊酰胺(164)
Figure PCTCN2019109368-appb-000254
0.109mmol)溶解于10mL二氯甲烷中，室温搅拌条件下依次加入三乙胺(46μL,0.326mmol)、HOBt(mg,mmol)以及HATU(62mg,0.163mmol)，反应液室温下搅拌反应2小时，LC-MS监测反应完毕，将反应液用乙酸乙酯稀释，饱和氯化钠溶液洗涤，乙酸乙酯层经无水硫酸钠干燥，过滤，减压除去溶剂，所得粗品直接用于下一步。
步骤2：将步骤1得到的反应粗品溶解于10mL氯化氢的1,4-二氧六环饱和溶液，反应液在室温下反应2小时，LC-MS监测反应完毕，减压除去溶剂，残余物用乙酸乙酯稀释，依次用饱和碳酸氢钠溶液和饱和氯化钠溶液洗涤，乙酸乙酯层用无水硫酸钠干燥，过滤，减压干燥得到反应粗品直接用于下一步反应。
步骤3：将步骤2中的反应粗品溶解于10mL干燥的二氯甲烷中，室温搅拌下依次加入三乙胺(152μL,1.09mmol)和乙酰氯(16μL,0.218mmol)，反应液继续于室温下搅拌反应过夜，LC-MS监测反应完毕，减压除去溶剂，残余物溶解于乙酸乙酯中，依次用饱和碳酸氢钠和饱和氯化钠溶液洗涤。乙酸乙酯层用无水硫酸钠干燥，过滤，滤液减压干燥，所得粗品经反相HPLC分离得到(2S)-2-乙酰氨基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-苯基戊酰胺10.2mg,收率19％； 1H NMR(400MHz,DMSO)δ10.95(s,1H),10.08 (d,J＝5.3Hz,1H),8.18(d,J＝7.8Hz,1H),7.63–7.51(m,3H),7.48–7.40(m,2H),7.29(t,J＝7.8Hz,2H),7.04(t,J＝7.3Hz,1H),5.12(dd,J＝13.3,5.0Hz,1H),4.47(dd,J＝12.1,6.8Hz,1H),4.39(d,J＝17.3Hz,1H),4.26(dd,J＝17.1,6.3Hz,1H),2.99–2.85(m,1H),2.73–2.56(m,3H),2.30(dtd,J＝16.3,12.3,3.0Hz,1H),2.05–1.92(m,1H),1.86(s,3H),1.80–1.50(m,4H).
实施例165:N-((2S)-1-(苄氨基)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-1-氧代戊基-2-)环丙基甲酰胺(165)
Figure PCTCN2019109368-appb-000255
Hz,1H),7.57(d,J＝7.3Hz,1H),7.46(t,J＝7.5Hz,1H),7.40(d,J＝7.2Hz,1H),7.29(dd,J＝10.4,4.2Hz,2H),7.24–7.18(m,3H),5.75(s,2H),5.14(ddd,J＝8.5,4.9,4.1Hz,1H),4.48–4.34(m,2H),4.33–4.20(m,3H),2.99–2.86(m,1H),2.63(dd,J＝19.4,12.7Hz,3H),2.46–2.29(m,1H),2.06–1.95(m,1H),1.79–1.49(m,5H),0.73–0.57(m,4H).
实施例166:(2S)-2-乙酰氨基-N-苄基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(166)
Figure PCTCN2019109368-appb-000256
DMSO)δ11.00(s,1H),8.46(td,J＝5.7,2.6Hz,1H),8.04(d,J＝7.9Hz,1H),7.57(d,J＝7.1Hz,1H),7.49–7.37(m,2H),7.33–7.17(m,3H),5.14(ddd,J＝13.0,5.7,1.1Hz,1H),4.43(dd,J＝17.4,7.0Hz,1H),4.36–4.23(m,3H),2.99–2.87(m,1H),2.69–2.57(m,3H),2.37(ddd,J＝18.1,10.9,5.9Hz,1H),2.05–1.94(m,1H),1.85(s,3H),1.63(ddd,J＝35.4,18.8,7.9Hz,4H).
实施例167:(2S)-N-苄基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-2-异丁酰胺基戊酰胺(167)
Figure PCTCN2019109368-appb-000257
MHz,DMSO)δ11.00(s,1H),8.42(dd,J＝9.5,5.9Hz,1H),7.89(d,J＝8.2Hz,1H),7.57(d,J＝7.4Hz,1H),7.46(t,J＝7.5Hz,1H),7.40(d,J＝7.0Hz,1H),7.29(dd,J＝10.2,4.3Hz,2H),7.22(dd,J＝6.9,3.5Hz,3H),5.14(ddd,J＝13.2,5.0,3.1Hz,1H),4.43(dd,J＝17.1,6.0Hz,1H),4.38–4.31(m,1H),4.31–4.20(m,3H),2.99–2.87(m,1H),2.69–2.56(m,3H),2.49–2.43(m,1H),2.37(ddd,J＝17.8,11.3,4.4Hz,1H),2.05–1.95(m,1H),1.72(dt,J＝8.9,5.6Hz,1H),1.66–1.45(m,3H),0.98(dd,J＝6.8,3.2Hz,6H).
实施例168:(2S)-2-乙酰氨基-N-叔丁基-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(168)
Figure PCTCN2019109368-appb-000258
DMSO)δ10.99(s,1H),7.86(d,J＝8.4Hz,1H),7.59–7.51(m,2H),7.45(dt,J＝7.4,6.9Hz,2H),5.15(dd,J＝13.2,5.1Hz,1H),4.44(dd,J＝17.1,7.2Hz,1H),4.28(dd,J＝18.7,8.9Hz,2H),3.00–2.86(m,1H),2.70–2.56(m,3H),2.40(ddd,J＝28.4,14.4,5.0Hz,1H),2.02(dt,J＝12.1,4.9Hz,1H),1.82(s,3H),1.66–1.43(m,4H),1.23(d,J＝0.8Hz,9H).
实施例169:(2S)-2-乙酰氨基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-((R)-1-苯乙基)戊酰胺(169)
Figure PCTCN2019109368-appb-000259
吲哚啉-4-)-N-苯基戊酰胺，17.3mg,收率53％； 1H NMR(400MHz,DMSO)δ11.01(s,1H),8.37(dd,J＝8.0,5.0Hz,1H),7.97(d,J＝8.3Hz,1H),7.58(dd,J＝6.9,1.6Hz,1H),7.50–7.42(m,2H),7.30(d,J＝4.3Hz,4H),7.26–7.18(m,1H),5.15(dd,J＝13.3,5.1Hz,1H),4.95–4.85(m,1H),4.45(dd,J＝17.2,6.5Hz,1H),4.36(dd,J＝14.4,6.6Hz,1H),4.29(d,J＝17.0Hz,1H),2.94(ddd,J＝17.5,13.8,5.4Hz,1H),2.74–2.58(m,3H),2.41(ddd,J＝16.8,13.5,4.2Hz,1H),2.02(ddd,J＝9.6,4.7,2.2Hz,1H),1.81(s,3H),1.75–1.51(m,4H),1.32(d,J＝7.0Hz,3H).
实施例170:(2S)-2-胺基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-(2-(吡啶-2-)苯基)戊酰胺(170)
Figure PCTCN2019109368-appb-000260
(t,J＝6.1Hz,1H),8.29(dd,J＝8.2,1.3Hz,1H),7.90(tt,J＝7.8,1.9Hz,1H),7.81(d,J＝7.8Hz,1H),7.73(dt,J＝7.8,1.6Hz,1H),7.56(d,J＝7.4Hz,1H),7.48–7.40(m,2H),7.39–7.32(m,2H),7.23(td,J＝7.7,1.1Hz,1H),5.12(dd,J＝13.2,4.8Hz,1H),4.40(d,J＝17.0Hz,1H),4.25(d,J＝17.1Hz,1H),3.66(d,J＝4.6Hz,1H),2.99–2.84(m,1H),2.69–2.55(m,3H),2.39–2.22(m,1H),1.98(dd,J＝11.4,6.1Hz,1H),1.87–1.72(m,1H),1.63(s,3H).
实施例171:(2S)-2-乙酰氨基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-((S)-1-苯乙基)戊酰胺(171)
Figure PCTCN2019109368-appb-000261
49％； 1H NMR(400MHz,DMSO)δ11.00(d,J＝2.7Hz,1H),8.46(d,J＝8.0Hz,1H),7.97(d,J＝8.3Hz,1H),7.57(dd,J＝7.5,1.0Hz,1H),7.44(td,J＝7.5,1.6Hz,1H),7.33(d,J＝ 7.5Hz,1H),7.31–7.15(m,5H),5.13(ddd,J＝13.2,5.0,2.4Hz,1H),4.96–4.85(m,1H),4.44–4.33(m,2H),4.23(dd,J＝17.1,9.9Hz,1H),2.99–2.86(m,1H),2.64(ddd,J＝13.5,7.7,4.6Hz,3H),2.45–2.31(m,1H),1.99(ddd,J＝6.8,5.2,2.2Hz,1H),1.84(d,J＝1.8Hz,3H),1.69–1.41(m,4H),1.34(dd,J＝7.0,2.7Hz,3H).
实施例172:(2S)-2-胺基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-(2-(吡啶-3-)苯基)戊酰胺(172)
Figure PCTCN2019109368-appb-000262
1H),8.54(dd,J＝4.8,1.5Hz,1H),8.23(s,1H),7.85(d,J＝7.9Hz,1H),7.80(d,J＝7.8Hz,1H),7.58(dd,J＝7.0,1.2Hz,1H),7.51–7.38(m,4H),7.34(dd,J＝7.5,1.4Hz,1H),7.28(t,J＝7.4Hz,1H),5.14(dd,J＝13.2,5.1Hz,1H),4.45(d,J＝17.1Hz,1H),4.30(d,J＝17.1Hz,1H),3.41(dd,J＝6.8,5.2Hz,1H),2.99–2.85(m,1H),2.66–2.54(m,3H),2.45–2.31(m,1H),2.05–1.95(m,1H),1.73–1.62(m,1H),1.57(dt,J＝14.8,7.4Hz,2H),1.51–1.40(m,1H).
实施例173:N-((2S)-1-(苄胺)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-1-氧代戊基-2-)环丁基甲酰胺(173)
Figure PCTCN2019109368-appb-000263
Hz,1H),7.57(d,J＝7.3Hz,1H),7.45(t,J＝7.5Hz,1H),7.39(d,J＝7.3Hz,1H),7.28(dd,J＝10.3,4.3Hz,2H),7.24–7.17(m,3H),5.75(s,2H),5.18–5.10(m,1H),4.43(dd,J＝17.2,6.3Hz,1H),4.35(dd,J＝13.7,7.9Hz,1H),4.30–4.20(m,3H),3.09(p,J＝8.2Hz,1H),3.00 –2.85(m,1H),2.71–2.56(m,3H),2.39(tdd,J＝16.9,8.3,3.8Hz,1H),2.18–1.93(m,5H),1.87(dt,J＝17.6,8.7Hz,1H),1.74(ddd,J＝14.4,9.0,3.5Hz,2H),1.63–1.49(m,3H).
实施例174:(2S)-N-((3R,5R,7R)-金刚烷-1-)-2-胺基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(174)
Figure PCTCN2019109368-appb-000264
离，51mg,收率94％； 1H NMR(400MHz,DMSO)δ11.04(s,1H),8.10(d,J＝7.5Hz,1H),7.58(d,J＝7.1Hz,1H),7.50–7.40(m,2H),5.75(s,1H),5.15(dd,J＝13.2,5.0Hz,1H),4.45(d,J＝17.1Hz,1H),4.29(dd,J＝17.0,4.2Hz,1H),3.85(d,J＝6.5Hz,1H),3.71–3.64(m,1H),3.00–2.87(m,1H),2.71–2.56(m,3H),2.39(ddd,J＝26.3,13.2,4.3Hz,1H),2.06–1.90(m,2H),1.63(ddd,J＝68.6,36.4,13.9Hz,17H).
实施例175:(2S)-2-乙酰氨基-N-((S)-2,3-二氢-1H-茚-1-)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(175)
Figure PCTCN2019109368-appb-000265
DMSO)δ10.99(s,1H),8.32(d,J＝8.3Hz,1H),8.01(dd,J＝8.2,3.7Hz,1H),7.57(d,J＝6.9Hz,1H),7.44(dt,J＝7.4,6.9Hz,2H),7.26–7.09(m,3H),7.05(d,J＝6.9Hz,1H),5.27(q,J＝8.1Hz,1H),5.13(ddd,J＝13.3,4.8,3.8Hz,1H),4.36(ddd,J＝32.6,31.1,17.1Hz,3H),2.99–2.85(m,2H),2.84–2.73(m,1H),2.72–2.55(m,3H),2.45–2.29(m,2H),1.98(dddd,J＝15.4,9.8,4.8,2.6Hz,1H),1.84(s,3H),1.82–1.68(m,2H),1.63(dd,J＝18.5,6.0Hz,3H).
实施例176:(2S)-N-((1S,3S,5S,7S)-金刚烷-2-)-2-胺基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲 哚啉-4-)戊酰胺(176)
Figure PCTCN2019109368-appb-000266
离，47mg,收率87％； 1H NMR(400MHz,DMSO)δ11.01(s,1H),7.72(s,1H),7.59(d,J＝7.1Hz,1H),7.51–7.42(m,2H),5.75(s,1H),5.15(dd,J＝13.3,4.9Hz,1H),4.45(d,J＝17.1Hz,1H),4.30(dd,J＝17.1,3.2Hz,1H),3.51(s,1H),3.02–2.87(m,1H),2.70–2.57(m,3H),2.46–2.31(m,1H),2.01(s,4H),1.89(s,6H),1.73–1.48(m,10H).
实施例177:(2S)-2-乙酰氨基-N-((R)-2,3-二氢-1H-茚-1-)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(177)
Figure PCTCN2019109368-appb-000267
NMR(400MHz,DMSO)δ11.01(s,1H),8.33(d,J＝8.0Hz,1H),8.01(d,J＝7.8Hz,1H),7.58(d,J＝6.6Hz,1H),7.51–7.41(m,2H),7.29–7.12(m,4H),5.33–5.21(m,1H),5.15(dd,J＝13.0,4.4Hz,1H),4.45(dd,J＝17.4,6.7Hz,1H),4.30(t,J＝11.8Hz,2H),2.92(ddd,J＝13.1,10.9,3.5Hz,2H),2.83–2.73(m,1H),2.72–2.57(m,3H),2.46–2.29(m,2H),2.02(dd,J＝8.8,4.7Hz,1H),1.85(s,3H),1.79–1.68(m,2H),1.68–1.51(m,3H).
实施例178:(2S)-2-乙酰氨基-N-(2,4-二氟苄基)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(178)
Figure PCTCN2019109368-appb-000268
DMSO)δ11.01(s,1H),8.48(td,J＝5.7,1.8Hz,1H),8.06(dd,J＝7.9,1.4Hz,1H),7.57(d,J＝7.2Hz,1H),7.45(t,J＝7.5Hz,1H),7.39(d,J＝7.2Hz,1H),7.32(td,J＝8.6,6.8Hz,1H),7.23–7.15(m,1H),7.02(td,J＝8.6,2.5Hz,1H),5.14(dd,J＝ 13.4,5.2Hz,1H),4.43(dd,J＝17.0,4.8Hz,1H),4.34–4.23(m,4H),2.99–2.87(m,1H),2.68–2.55(m,3H),2.40(ddd,J＝16.7,13.2,5.1Hz,1H),2.06–1.96(m,1H),1.84(s,3H),1.73–1.64(m,1H),1.62–1.48(m,3H).
实施例179:(2S)-2-乙酰氨基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-((S)-1,2,3,4-四氢萘基-1-)戊酰胺(179)
Figure PCTCN2019109368-appb-000269
δ10.99(s,1H),8.26(dd,J＝8.6,1.2Hz,1H),7.97(dd,J＝8.1,2.6Hz,1H),7.57(d,J＝6.2Hz,1H),7.44(dt,J＝7.5,6.9Hz,2H),7.17–7.10(m,1H),7.06(dt,J＝12.5,5.3Hz,3H),5.13(ddd,J＝13.2,4.9,3.3Hz,1H),4.95(t,J＝7.5Hz,1H),4.36(ddd,J＝37.5,31.1,17.1Hz,3H),2.92(tdd,J＝17.3,5.1,1.6Hz,1H),2.80–2.55(m,5H),2.46–2.30(m,1H),2.04–1.94(m,1H),1.91–1.80(m,5H),1.77–1.55(m,6H).
实施例180:(2S)-2-乙酰氨基-N-(2,4-二甲氧基苄基)-5-(2-(2,6-二哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(180)
Figure PCTCN2019109368-appb-000270
DMSO)δ11.03(s,1H),8.20(td,J＝5.9,1.9Hz,1H),8.04(dd,J＝8.2,2.0Hz,1H),7.58(d,J＝7.3Hz,1H),7.46(t,J＝7.4Hz,1H),7.41(d,J＝7.5Hz,1H),7.03(d,J＝8.4Hz,1H),6.52(d,J＝2.4Hz,1H),6.42(dd,J＝8.3,2.4Hz,1H),5.15(dd,J＝12.9,4.9Hz,1H),4.44(dd,J＝17.0,6.9Hz,1H),4.38–4.32(m,1H),4.28(dd,J＝17.1,3.9Hz,1H),4.17(dd,J＝15.2,5.8Hz,1H),4.10(ddd,J＝15.4,5.7,1.6Hz,1H),3.74(s,3H),3.73(s,3H),3.01–2.87(m,1H),2.72–2.56(m,3H),2.47–2.31(m,1H),2.06–1.94(m,1H),1.84(s,3H),1.75–1.47(m,4H).
实施例181:(2S)-2-乙酰氨基-N-二苯甲基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(181)
Figure PCTCN2019109368-appb-000271
MHz,DMSO)δ11.00(d,J＝3.3Hz,1H),8.92(dd,J＝8.5,5.9Hz,1H),8.03(d,J＝8.2Hz,1H),7.57(d,J＝7.5Hz,1H),7.44(t,J＝7.5Hz,1H),7.38–7.18(m,10H),6.10(d,J＝8.7Hz,1H),5.13(dd,J＝12.9,5.2Hz,1H),4.49(dt,J＝7.8,5.2Hz,1H),4.39(dd,J＝17.1,2.3Hz,1H),4.24(dd,J＝17.1,7.2Hz,1H),3.00–2.86(m,1H),2.69–2.56(m,3H),2.45–2.29(m,1H),2.07–1.94(m,1H),1.83(d,J＝1.5Hz,3H),1.74–1.44(m,4H).
实施例182:(2S)-2-乙酰氨基-N-(3-溴苄基)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(182)
Figure PCTCN2019109368-appb-000272
MHz,DMSO)δ11.03(s,1H),8.54(td,J＝6.1,2.3Hz,1H),8.10(dd,J＝8.0,1.0Hz,1H),7.57(d,J＝7.2Hz,1H),7.49–7.38(m,4H),7.29–7.19(m,2H),5.14(ddd,J＝13.3,4.9,1.2Hz,1H),4.43(dd,J＝17.2,7.6Hz,1H),4.30(ddd,J＝17.4,11.1,4.4Hz,4H),3.00–2.87(m,1H),2.72–2.56(m,3H),2.47–2.31(m,1H),2.05–1.95(m,1H),1.85(s,3H),1.71(dt,J＝11.5,7.0Hz,1H),1.64–1.51(m,3H).
实施例183:(2S)-N-(3-氯-4-甲基苯基)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-2-异丁酰氨基戊酰胺(183)
Figure PCTCN2019109368-appb-000273
DMSO)δ11.00(d,J＝4.2Hz,1H),10.17(d,J＝2.4Hz,1H),8.03(d,J＝7.7Hz,1H),7.83–7.77(m,1H),7.57(dd,J＝6.6,1.8Hz,1H),7.50–7.40(m,2H),7.36(dd,J＝8.3,2.1Hz,1H),7.26(d,J＝8.4Hz,1H),5.13(dd,J＝13.7,5.7Hz,1H),4.42(dd,J＝17.0,11.7Hz,2H),4.28(dd,J＝17.1,5.4Hz,1H),2.99–2.87(m,1H),2.68(t,J＝7.1Hz,2H),2.65–2.55(m,2H),2.34(ddd,J＝15.4,13.2,5.0Hz,1H),2.26(s,3H),2.05–1.94(m,1H),1.82–1.53(m,4H),1.05–0.93(m,6H).
实施例184:(2S)-2-乙酰氨基-N-(3-氯苄基)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(184)
Figure PCTCN2019109368-appb-000274
DMSO)δ11.03(s,1H),8.54(td,J＝5.9,2.4Hz,1H),8.10(d,J＝8.1Hz,1H),7.57(d,J＝7.1Hz,1H),7.45(t,J＝7.4Hz,1H),7.40(d,J＝7.4Hz,1H),7.35–7.25(m,3H),7.18(d,J＝7.3Hz,1H),5.14(ddd,J＝13.5,4.8,1.0Hz,1H),4.43(dd,J＝17.2,7.3Hz,1H),4.35–4.22(m,4H),3.00–2.86(m,1H),2.72–2.56(m,3H),2.47–2.31(m,1H),2.00(dd,J＝10.4,5.7Hz,1H),1.85(s,3H),1.77–1.65(m,1H),1.65–1.49(m,3H).
实施例185:N-((2S)-1-((3-氯-4-甲基苯基)胺基)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-1-氧代戊基-2-)环丙基甲酰胺(185)
Figure PCTCN2019109368-appb-000275
8.43(d,J＝7.9Hz,1H),7.82(dd,J＝3.5,2.2Hz,1H),7.58(dd,J＝5.9,2.6Hz,1H),7.49– 7.42(m,2H),7.36(dd,J＝8.3,2.0Hz,1H),7.27(d,J＝8.3Hz,1H),5.13(dd,J＝14.0,4.9Hz,1H),4.50–4.37(m,2H),4.28(dd,J＝17.1,7.1Hz,1H),3.00–2.87(m,1H),2.69(t,J＝7.1Hz,2H),2.65–2.56(m,1H),2.44–2.29(m,1H),2.27(s,3H),2.00(tdd,J＝9.9,6.2,3.9Hz,1H),1.83–1.55(m,5H),0.65(dd,J＝6.1,2.6Hz,4H).
实施例186:(2S)-2-乙酰氨基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-(4-(吡咯烷-1-)苄基)戊酰胺(186)
Figure PCTCN2019109368-appb-000276
J＝8.3,2.0Hz,1H),7.56(d,J＝7.3Hz,1H),7.44(t,J＝7.5Hz,1H),7.38(d,J＝7.3Hz,1H),7.01(d,J＝8.3Hz,2H),6.43(dd,J＝8.7,2.4Hz,2H),5.14(dd,J＝13.5,5.2Hz,1H),4.42(dd,J＝17.1,10.4Hz,1H),4.29(ddd,J＝22.5,11.9,4.6Hz,2H),4.20–4.04(m,2H),3.16(td,J＝6.4,2.2Hz,4H),2.99–2.87(m,1H),2.60(dt,J＝5.9,4.6Hz,3H),2.46–2.31(m,1H),2.04–1.96(m,1H),1.96–1.90(m,4H),1.83(s,3H),1.73–1.64(m,1H),1.61–1.49(m,3H).
实施例187:N-((2S)-1-((3-氯-4-甲基苯基)胺基)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-1-氧代戊基-2-)环丁基甲酰胺(187)
Figure PCTCN2019109368-appb-000277
7.95(d,J＝7.9Hz,1H),7.80(dd,J＝3.2,2.3Hz,1H),7.57(dd,J＝6.6,1.7Hz,1H),7.49–7.40(m,2H),7.36(dd,J＝8.3,2.1Hz,1H),7.26(d,J＝8.3Hz,1H),5.12(ddd,J＝13.3,5.0,1.5Hz,1H),4.47–4.35(m,2H),4.27(dd,J＝17.1,5.2Hz,1H),3.11(p,J＝8.3Hz,1H),3.01 –2.87(m,1H),2.67(t,J＝7.2Hz,2H),2.64–2.56(m,1H),2.42–2.29(m,1H),2.26(s,3H),2.17–2.05(m,2H),2.04–1.95(m,3H),1.87(dt,J＝17.7,8.7Hz,1H),1.79–1.71(m,2H),1.70–1.53(m,3H).
实施例188:(2S)-2-乙酰氨基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-(2-苯基丙基-2-)戊酰胺(188)
Figure PCTCN2019109368-appb-000278
DMSO)δ11.02(s,1H),8.16(d,J＝3.4Hz,1H),7.89(d,J＝8.1Hz,1H),7.60–7.56(m,1H),7.47(ddd,J＝13.4,9.8,4.2Hz,2H),7.29(dd,J＝5.7,4.2Hz,2H),7.23(td,J＝7.6,1.8Hz,2H),7.18–7.11(m,1H),5.15(ddd,J＝13.1,5.1,1.3Hz,1H),4.49–4.36(m,2H),4.28(dd,J＝17.3,6.2Hz,1H),3.00–2.88(m,1H),2.71–2.57(m,3H),2.45–2.31(m,1H),2.06–1.96(m,1H),1.83(s,3H),1.72–1.45(m,10H).
实施例189:6-胺基-N-((2S)-1-((3-氯-4-甲基苯基)胺基)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-1-氧代戊基-2-)己酰胺(189)
Figure PCTCN2019109368-appb-000279
DMSO)δ11.00(d,J＝3.2Hz,1H),10.29(s,1H),8.20(d,J＝6.9Hz,1H),7.83(dd,J＝8.8,6.4Hz,4H),7.57(dd,J＝6.6,1.9Hz,1H),7.42(ddd,J＝11.3,10.3,4.7Hz,3H),7.26(d,J＝8.4Hz,1H),5.13(dd,J＝13.3,5.0Hz,1H),4.43(dd,J＝17.1,11.9Hz,2H),4.28(dd,J＝17.1,4.6Hz,1H),2.93(ddd,J＝17.6,11.8,4.9Hz,1H),2.70(dt,J＝19.6,6.6Hz,4H),2.60(d,J＝17.0Hz,1H),2.43–2.30(m,1H),2.26(s,3H),2.15(t,J＝7.4Hz,2H),1.99(dd,J＝10.8,5.2Hz,1H),1.84–1.57(m,4H),1.51(tt,J＝15.6,7.7Hz,4H),1.26(dt,J＝13.7,6.9Hz,2H).
实施例190:(2S)-2-乙酰氨基-N-(4-(2-(二甲氨基)乙氧基)苄基)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(190)
Figure PCTCN2019109368-appb-000280
(400MHz,DMSO)δ11.03(s,1H),8.42(t,J＝5.2Hz,1H),8.16(s,1H),8.04(d,J＝8.4Hz,1H),7.57(d,J＝7.3Hz,1H),7.45(t,J＝7.5Hz,1H),7.39(d,J＝7.3Hz,1H),7.13(d,J＝8.4Hz,2H),6.85(d,J＝8.3Hz,2H),5.14(dd,J＝13.6,4.8Hz,1H),4.43(dd,J＝16.8,7.5Hz,1H),4.34–4.23(m,2H),4.22–4.14(m,2H),4.04(t,J＝5.5Hz,2H),3.00–2.87(m,1H),2.76(t,J＝5.4Hz,2H),2.61(dd,J＝25.9,7.7Hz,3H),2.43–2.36(m,1H),2.32(s,6H),2.05–1.95(m,1H),1.84(s,3H),1.73–1.64(m,1H),1.63–1.49(m,3H).
实施例191:N-((2S)-1-((3-氯-4-甲基苯基)胺基)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-1-氧代戊基-2-)哌啶-4-甲酰胺(191)
Figure PCTCN2019109368-appb-000281
9.3Hz,1H),8.67–8.49(m,1H),8.31(d,J＝7.8Hz,1H),7.82(t,J＝2.3Hz,1H),7.57(dd,J＝6.6,1.8Hz,1H),7.48–7.41(m,2H),7.38(dd,J＝8.3,2.0Hz,1H),7.26(d,J＝8.4Hz,1H),5.13(dd,J＝13.2,4.9Hz,1H),4.49–4.38(m,2H),4.28(dt,J＝5.9,3.5Hz,1H),3.30–3.17(m,2H),3.01–2.76(m,3H),2.68(t,J＝6.9Hz,2H),2.65–2.52(m,2H),2.37(ddd,J＝26.3,13.1,4.2Hz,1H),2.26(s,3H),2.00(td,J＝10.3,5.1Hz,1H),1.91–1.53(m,8H).
实施例192:(2S)-2-乙酰氨基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-(4-苯氧基苄基)戊酰胺(192)
Figure PCTCN2019109368-appb-000282
(dd,J＝8.0,1.2Hz,1H),7.56(dd,J＝7.0,1.5Hz,1H),7.45–7.34(m,4H),7.24(d,J＝8.6Hz,2H),7.13(td,J＝7.4,0.5Hz,1H),6.99–6.91(m,4H),5.14(dd,J＝13.2,5.0Hz,1H),4.43(dd,J＝17.2,7.4Hz,1H),4.32(ddd,J＝13.6,8.5,3.6Hz,2H),4.25(d,J＝6.1Hz,2H),2.99–2.86(m,1H),2.71–2.55(m,3H),2.40(ddd,J＝17.5,13.8,5.6Hz,1H),2.00(ddd,J＝8.4,5.8,3.2Hz,1H),1.84(s,3H),1.75–1.66(m,1H),1.65–1.47(m,3H).
实施例193:N-((2S)-1-(3-氯-4-甲基苯胺)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-1-氧代戊基-2-)-6-羟基己酰胺(193)
Figure PCTCN2019109368-appb-000283
1H NMR(400MHz,DMSO)δ10.98(s,1H),10.16(d,J＝3.4Hz,1H),8.11(d,J＝7.8Hz,1H),7.83–7.76(m,1H),7.57(dd,J＝6.4,2.0Hz,1H),7.49–7.41(m,2H),7.36(dd,J＝8.3,2.0Hz,1H),7.26(d,J＝8.3Hz,1H),5.12(dd,J＝13.3,3.5Hz,1H),4.47–4.37(m,2H),4.29(dt,J＝17.1,5.6Hz,2H),3.37–3.33(m,2H),2.93(t,J＝13.9Hz,1H),2.68(t,J＝7.0Hz,2H),2.59(d,J＝17.3Hz,1H),2.43–2.29(m,1H),2.26(s,3H),2.13(t,J＝7.2Hz,2H),1.99(dd,J＝12.0,5.2Hz,1H),1.78–1.56(m,4H),1.48(dt,J＝15.1,7.5Hz,2H),1.43–1.34(m,2H),1.30–1.19(m,2H).
实施例194:(2S)-2-乙酰氨基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-(2-(吡啶-2-)苯基)戊酰胺(194)
Figure PCTCN2019109368-appb-000284
DMSO)δ12.17(s,1H),11.01(s,1H),8.72–8.68(m,1H),8.43(dd,J＝7.2,1.9Hz,1H),8.37(dd,J＝8.2,0.6Hz,1H),7.99–7.93(m,1H),7.89(d,J＝8.3Hz,1H),7.78(dd,J＝8.0,1.3Hz,1H),7.56(dd,J＝7.2,1.2Hz,1H),7.42(ddd,J＝12.4,9.6,4.5Hz,3H),7.21(td,J＝7.9,1.3Hz,1H),5.13(dd,J＝13.3,5.2Hz,1H),4.43(d,J＝17.2Hz,1H),4.33–4.22(m,2H),3.00–2.86(m,1H),2.71–2.56(m,3H),2.44–2.27(m,1H),1.99(dtd,J＝12.5,5.1,2.4Hz,1H),1.95–1.76(m,4H),1.75–1.55(m,3H).
实施例195:3-(4-((S)-4-胺基-4-(7-溴-1H-苯并[d]咪唑-2-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(195)
Figure PCTCN2019109368-appb-000285
室温搅拌下加入三乙胺(84μL,0.6mmol)和HATU(152mg,0.4mmol),所得反应液继续于室温下搅拌反应4小时，LC-MS监测缩合反应完毕。减压除去溶剂，向所得残余物中加入乙酸5mL，将反应液温度升温至110℃回流反应2小时，LC-MS监测反应完毕。减压除去溶剂，残余物经HPLC分离得到目标产物3-(4-((S)-4-胺基-4-(7-溴-1H-苯并[d]咪唑-2-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮84mg,白色固体，收率82％； 1H NMR(400MHz,DMSO)δ7.56(dd,J＝8.2,3.0Hz,2H),7.43(q,J＝7.6Hz,3H),7.14(t,J＝7.9Hz,1H),5.12(dd,J＝13.2,4.9Hz,1H),4.50(t,J＝6.5Hz,1H),4.31(ddd,J＝24.0,19.8,12.0Hz,3H),3.00–2.86(m,1H),2.64(dd,J＝19.6,12.5Hz,3H),2.54(s,2H),2.41–2.22(m,1H),2.01(dd,J＝14.6,8.4Hz,3H),1.75–1.54(m,2H).
实施例196:(2S)-2-乙酰氨基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-(2-(吡啶-3-) 苯基)戊酰胺(196)
Figure PCTCN2019109368-appb-000286
(m,1H),8.49(dt,J＝4.8,1.6Hz,1H),8.04(dd,J＝7.7,1.7Hz,1H),7.74(ddd,J＝7.7,3.8,1.8Hz,1H),7.58(d,J＝7.4Hz,1H),7.52–7.40(m,4H),7.40–7.30(m,3H),5.14(dd,J＝12.5,5.2Hz,1H),4.43(dd,J＝17.3,9.0Hz,1H),4.30(ddd,J＝18.9,13.1,3.5Hz,2H),2.93(t,J＝14.7Hz,1H),2.60(t,J＝7.1Hz,3H),2.38(ddd,J＝20.5,14.9,4.7Hz,1H),2.05–1.93(m,1H),1.81(s,3H),1.66–1.40(m,4H).
实施例197:N-((1S)-1-(7-溴-1H-苯并[d]咪唑-2-)-4-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)丁基)乙酰胺(197)
Figure PCTCN2019109368-appb-000287
0.072mmol)，反应液继续于室温下搅拌反应2小时。反应完毕，反应液用乙酸乙酯萃取，有机相经无水硫酸钠干燥，过滤，减压干燥，所得粗品经HPLC分离得到产物15.5mg,收率46％； 1H NMR(400MHz,DMSO)δ12.63(d,J＝14.9Hz,1H),11.00(s,1H),8.51(d,J＝8.0Hz,1H),7.56(dd,J＝5.3,3.2Hz,1H),7.45(dd,J＝8.1,5.2Hz,3H),7.36(dd,J＝7.6,4.4Hz,1H),7.09(td,J＝7.5,3.0Hz,1H),5.26–5.07(m,2H),4.50–4.18(m,2H),3.00–2.87(m,1H),2.71(dd,J＝16.9,8.1Hz,2H),2.65–2.56(m,1H),2.35(ddd,J＝12.5,10.5,4.4Hz,1H),2.13–1.96(m,2H),1.95–1.82(m,4H),1.76–1.52(m,2H).
实施例198:(2S)-2-乙酰氨基-N-((3R,5R,7R)-金刚烷-1-)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(198)
Figure PCTCN2019109368-appb-000288
DMSO)δ11.01(s,1H),7.85(d,J＝8.3Hz,1H),7.57(dd,J＝7.1,1.1Hz,1H),7.44(ddd,J＝13.0,10.7,6.4Hz,3H),5.15(dd,J＝13.4,5.3Hz,1H),4.43(dd,J＝16.9,6.6Hz,1H),4.33–4.23(m,2H),3.00–2.87(m,1H),2.62(ddd,J＝19.9,7.6,3.5Hz,3H),2.46–2.32(m,1H),2.07–1.94(m,4H),1.81(d,J＝2.1Hz,9H),1.67–1.43(m,10H).
实施例199:3-(4-((S)-4-胺基-4-(1H-苯并[d]咪唑-2-)丁基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(199)
Figure PCTCN2019109368-appb-000289
DMSO)δ10.99(s,1H),8.24(s,1H),7.55(dd,J＝5.6,2.9Hz,1H),7.53–7.47(m,2H),7.46–7.40(m,2H),7.17–7.09(m,2H),5.11(dd,J＝13.3,5.1Hz,1H),4.37(dd,J＝21.6,17.2Hz,1H),4.23(dd,J＝14.5,7.8Hz,2H),2.98–2.85(m,1H),2.70–2.56(m,3H),2.30(tdd,J＝26.1,13.0,4.4Hz,2H),1.96(ddd,J＝17.0,12.2,6.0Hz,2H),1.89–1.78(m,1H),1.73–1.55(m,2H).
实施例200:(2S)-2-乙酰氨基-N-((1S,3S,5S,7S)-金刚烷-2-)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(200)
Figure PCTCN2019109368-appb-000290
DMSO)δ10.99(s,1H),7.96(d,J＝8.4Hz,1H),7.76(dd,J＝7.3,2.7Hz,1H),7.57(dd,J＝6.9,1.4Hz,1H),7.49–7.39(m,2H),5.14(dd,J＝13.2,5.1Hz,1H),4.46(ddd,J＝19.3,15.4,4.6Hz,2H),4.27(d,J＝17.1Hz,1H),3.80(d,J＝6.8Hz,1H),3.01–2.85(m,1H),2.73–2.57(m,3H),2.40(ddd,J＝22.7,13.5,4.5Hz,1H),2.11–1.92(m,2H),1.91–1.38(m,20H).
实施例201:3-(4-((S)-4-胺基-4-(3H-咪唑[4,5-c]吡啶-2-)丁基)-1-氧代吲哚啉-2-)哌啶-2,6-二酮(201)
Figure PCTCN2019109368-appb-000291
DMSO)δ11.00(s,1H),9.50(s,1H),9.04(d,J＝53.3Hz,2H),8.58(dd,J＝29.1,6.2Hz,1H),8.13(dd,J＝51.3,6.3Hz,1H),7.63–7.51(m,1H),7.43(d,J＝4.0Hz,2H),5.12(d,J＝11.0Hz,1H),4.88(s,1H),4.55–4.39(m,1H),4.34–4.21(m,1H),3.00–2.85(m,1H),2.76–2.58(m,3H),2.44–2.30(m,1H),2.18(d,J＝6.0Hz,2H),2.05–1.87(m,1H),1.78–1.61(m,2H).
实施例202:(2S)-2-乙酰氨基-N-(3-氯-4-甲基苯基)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)戊酰胺(202)
Figure PCTCN2019109368-appb-000292
DMSO)δ10.99(s,1H),10.17(d,J＝3.8Hz,1H),8.20(d,J＝7.8Hz,1H),7.81(dd,J＝3.3,2.2Hz,1H),7.57(dd,J＝5.9,2.6Hz,1H),7.49–7.41(m,2H),7.37(dd,J＝8.3,2.0Hz,1H),7.26(d,J＝8.4Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.42(dd,J＝16.9,13.3Hz,2H),4.27(dd,J＝17.1,4.5Hz,1H),3.00–2.86(m,1H),2.68(t,J＝6.8Hz,2H),2.59(ddd,J＝7.4,6.7,2.4Hz,1H),2.42–2.29(m,1H),2.26(s,3H),1.99(dd,J＝12.4,5.2Hz,1H),1.86(s,3H),1.80–1.53(m,4H).
实施例203:N-((1S)-1-(1H-苯并[d]咪唑-2-)-4-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)丁基)酰胺(203)
Figure PCTCN2019109368-appb-000293
NMR(400MHz,DMSO)δ10.99(s,1H),8.24(s,1H),7.55(dd,J＝5.6,2.9Hz,1H),7.53–7.47(m,2H),7.46–7.40(m,2H),7.17–7.09(m,2H),5.11(dd,J＝13.3,5.1Hz,1H),4.37(dd,J＝21.6,17.2Hz,1H),4.23(dd,J＝14.5,7.8Hz,2H),2.98–2.85(m,1H),2.70–2.56(m,3H),2.30(tdd,J＝26.1,13.0,4.4Hz,2H),1.96(ddd,J＝17.0,12.2,6.0Hz,2H),1.91(s,3H),1.89–1.78(m,1H),1.73–1.55(m,2H).
实施例204:(2S)-2-乙酰氨基-N-苄基-5-(2-(2,6-氧代哌啶-3-)-1-氧代异吲哚啉-4-)-N-甲基戊酰胺(204)
Figure PCTCN2019109368-appb-000294
DMSO)δ11.00(s,1H),8.20(ddd,J＝9.9,9.0,1.7Hz,1H),7.56(t,J＝6.4Hz,1H),7.49–7.40(m,2H),7.39–7.29(m,2H),7.28–7.20(m,2H),7.18(d,J＝7.2Hz,1H),5.17–5.09(m,1H),4.79(s,1H),4.64–4.18(m,4H),2.99–2.75(m,4H),2.64(ddd,J＝20.4,15.7,4.6Hz,3H),2.39(ddd,J＝22.0,16.2,7.2Hz,1H),2.01(dd,J＝10.9,5.0Hz,1H),1.80(d,J＝34.8Hz,3H),1.73–1.40(m,4H).
实施例205:N-((1S)-4-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-1-(3H-咪唑[4,5-c]吡啶-2-)丁基)乙酰胺(205)
Figure PCTCN2019109368-appb-000295
8.52(d,J＝8.0Hz,1H),8.26(d,J＝5.5Hz,1H),8.17(s,1H),7.60–7.54(m,1H),7.52–7.48(m,1H),7.47–7.42(m,2H),5.21–5.09(m,2H),4.43(t,J＝16.5Hz,1H),4.28(d,J＝17.1 Hz,1H),3.01–2.88(m,1H),2.76–2.57(m,3H),2.45–2.29(m,1H),2.13–1.96(m,2H),1.91(s,3H),1.76–1.59(m,2H).
实施例206:(2S)-N-苄基-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-2-丙酰胺基戊酰胺(206)
Figure PCTCN2019109368-appb-000296
1H),7.57(d,J＝7.2Hz,1H),7.46(t,J＝7.3Hz,1H),7.40(d,J＝7.4Hz,1H),7.32–7.25(m,2H),7.22(d,J＝7.1Hz,3H),5.75(d,J＝2.3Hz,1H),5.14(dd,J＝11.8,3.1Hz,1H),4.43(dd,J＝17.0,6.9Hz,1H),4.38–4.20(m,4H),3.01–2.85(m,1H),2.61(d,J＝19.4Hz,3H),2.39(dd,J＝27.6,13.5Hz,1H),2.14(dd,J＝14.8,7.2Hz,2H),2.05–1.94(m,1H),1.77–1.46(m,4H),0.98(t,J＝7.5Hz,3H).
实施例207:N-((2S)-5-(2-(2,6-二氧代哌啶-3-)-1-氧代异吲哚啉-4-)-1-氧-1-(3H-螺[异苯并呋喃-1,4'-哌啶]-1'-)戊基-2-)乙酰胺(207)
Figure PCTCN2019109368-appb-000297
MHz,DMSO)δ11.01(s,1H),8.17(dd,J＝18.4,7.4Hz,1H),7.64–7.54(m,1H),7.47(dd,J＝6.9,3.2Hz,2H),7.29(d,J＝8.5Hz,3H),7.24–7.06(m,1H),5.15(dd,J＝13.2,4.3Hz,1H),5.01(d,J＝3.8Hz,2H),4.81(dd,J＝7.5,4.3Hz,1H),4.55–4.23(m,3H),3.88(d,J＝9.4Hz,1H),3.32–3.24(m,1H),3.04–2.82(m,2H),2.80–2.55(m,3H),2.41(ddd,J＝22.3,15.0,9.5Hz,1H),2.02(dd,J＝14.8,5.4Hz,1H),1.85(d,J＝5.0Hz,3H),1.78–1.48(m,7H).
实施例208：3-(1-氧代-4-(4-(4-(苯基-d5)哌嗪-1-)丁基)异吲哚啉-2-)哌啶-2,6-二酮(208)
Figure PCTCN2019109368-appb-000298
10.99(s,1H),7.57(dd,J＝5.5,3.1Hz,1H),7.48–7.44(m,2H),5.13(dd,J＝13.3,5.1Hz,1H),4.47(d,J＝17.1Hz,1H),4.32(d,J＝17.1Hz,1H),3.14–3.06(m,4H),2.97–2.85(m,1H),2.68(t,J＝7.6Hz,2H),2.59-2.53(m,1H),2.49–2.38(m,5H),2.35(t,J＝7.1Hz,2H),2.05–1.96(m,1H),1.64(dt,J＝15.1,7.5Hz,2H),1.51(dt,J＝14.3,7.3Hz,2H).
实施例209：3-(1-氧-4-(6-(4-(苯基-d5)哌嗪-1-)己基)异吲哚啉-2-)哌啶-2,6-二酮(209)
Figure PCTCN2019109368-appb-000299
DMSO)δ10.99(s,1H),7.56(dd,J＝8.1,4.6Hz,1H),7.48–7.42(m,2H),5.13(dd,J＝13.3,5.1Hz,1H),4.46(d,J＝17.2Hz,1H),4.30(d,J＝17.1Hz,1H),3.32(s,4H),3.14–3.06(m,4H),2.98–2.85(m,1H),2.69–2.56(m,3H),2.46–2.37(m,1H),2.32(t,J＝7.2Hz,2H),2.05–1.98(m,1H),1.66-1.58(m,2H),1.52–1.41(m,2H),1.38-1.32(m,4H).
实施例210：3-(1-氧代-4-(5-(4-(苯基-d5)哌嗪-1-)戊基)异吲哚啉-2-)哌嗪-2,6-二酮(210)
Figure PCTCN2019109368-appb-000300
5.14(dd,J＝13.2,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.1Hz,1H),3.32(s,4H),3.10(s,4H),2.99–2.86(m,1H),2.69–2.55(m,3H),2.46–2.27(m,3H),2.05–1.95(m,1H),1.63(dd,J＝15.1,7.7Hz,2H),1.56–1.46(m,2H),1.36(dd,J＝13.8,6.9Hz,2H).
实施例211：3-(6-氟-1-氧-4-(4-(喹啉-4-氧)丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(211)
Figure PCTCN2019109368-appb-000301
率43.2％； 1H NMR(400MHz,DMSO)δ10.97(s,1H),8.73(d,J＝5.2Hz,1H),8.12(d,J＝7.2Hz,1H),7.93(d,J＝8.5Hz,1H),7.74(t,J＝7.0Hz,1H),7.53(t,J＝7.5Hz,1H),7.20(dd,J＝11.5,2.0Hz,1H),7.11–7.02(m,2H),5.08(dd,J＝13.4,5.1Hz,1H),4.35(t,J＝5.8Hz,2H),4.27(dd,J＝11.5,5.3Hz,3H),4.14(d,J＝17.4Hz,1H),2.95–2.85(m,1H),2.63–2.55(m,1H),2.45–2.32(m,1H),2.11–1.91(m,5H).
实施例212：3-(6-氟-4-(4-((2-甲基喹啉-4-)氧)丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(212)
Figure PCTCN2019109368-appb-000302
旋干，乙酸乙酯稀释，分别用饱和碳酸氢钠和饱和氯化钠洗涤，干燥，得到目标产物1.025g,收率96％。
步骤2：将5-氟-2-甲基-3-硝基苯甲酸甲酯(1.02g,4.8mmol)溶于20ml甲醇中，加入10％Pd/C(110mg),氢气常压室温反应过夜,TLC监测反应完全后，反应液抽滤，固体用甲醇洗涤(20ml×1)，滤液浓缩，得到无色液体3-氨基-5-氟-2-甲基-苯甲酸甲酯918mg,直接投下一步。
步骤3：3-氨基-5-氟-2-甲基-苯甲酸甲酯(918mg,粗品)和10％H 2SO 4(1.54ml，28.71mmol),0℃条件下逐滴加入亚硝酸钠(505mg,7.32mmol)的水溶液(5ml),相同温度反应1h后，加入50％H 2SO 4(7.65ml，143.55mmol)，升温至100℃反应1h,TLC监测反应完全后，反应液浓缩，加入水20ml和乙酸乙酯100ml,摇匀分液，水相用乙酸乙酯萃取(50ml×2)，合并有机相，无水硫酸钠干燥，减压浓缩，柱层析得到产物415mg，两步收率47％。
步骤4：将5-氟-3羟基-2-甲基-苯甲酸甲酯(410mg,2.23mmol)溶于20ml DMF，0℃条件下，加入60％氢化钠(107mg,2.67mmol),反应1h后，相同温度逐滴加入氯甲基甲醚(203ul，2.67mmol)，滴加完后升至室温反应2h,TLC监测反应完全后，加水淬灭，乙酸乙酯萃取，分液，有机相依次用水和饱和氯化钠溶液洗涤，干燥，柱层析，得到产物430mg,收率84％.
步骤5：将5-氟-3-甲氧基甲氧基-2-甲基苯甲酸甲酯(425mg,1.86mmol)NBS(398mg,2.23mmol)溶于15ml四氯化碳,然后加入70％的过氧化苯甲酰(65mg,0.186mmol)，升温回流3h,减压浓缩，经快速分离柱层析得到黄色固体545mg,收率95.4％.
步骤6：将2-溴甲基-5-氟-3-甲氧基甲氧基苯甲酸甲酯(540mg,1.76mmol)和4,5-二氨基-5-氧代戊酸甲酯盐酸盐.(413mg,2.11mmol)的乙腈悬浊液(20ml)中,加入N,N-二异丙基乙胺(873ul,5.28mmol),40℃反应过夜，反应完全后，减压浓缩，乙酸乙酯稀释，依次用水用和饱和氯化钠洗涤，干燥，浓缩直接投下一步。
步骤7：将上一步的粗品置于50ml圆底烧瓶中，加入10ml 4M的盐酸二氧六环和1ml甲醇，室温反应1h后，旋干，柱层析得到目标产物300mg,两步收率55％。
步骤8：将5-胺基-4-(6-氟-4-羟基-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(35mg,0.11mmol)置于50ml圆底烧瓶中，加入4-((2-甲基喹啉-4-)氧)-1-丁醇(51mg，0.22mmol，2eq)，三苯基膦(58mg，0.22mmol，2eq)。反应体系用氮气置换，加入5mL干燥四氢呋喃。向反应体系中加入偶氮二甲酸二异丙酯(43μL，0.22mmol，2eq)。室温反应1h。TLC监测反应完全后减压浓缩，柱层析得到产物56.8mg，收率98％。
步骤9：将上一步得到的产物(56.8mg,0.108mmol)溶于干燥的THF中,℃条件下加入叔丁醇钾(13mg,0.12mmol),相同温度反应30min,加入1N HCl淬灭,乙酯乙酯稀释，饱和氯化钠洗涤，干燥，HPLC纯化，得到白色固体20.1mg,收率37.9％； 1H NMR(400MHz,DMSO)δ10.97(s,1H),8.04(d,J＝8.3Hz,1H),7.82(d,J＝8.5Hz,1H),7.67(t,J＝7.0Hz,1H),7.43(t,J＝7.6Hz,1H),7.20(d,J＝11.6Hz,1H),7.08(dd,J＝7.4,1.8Hz,1H),6.93(s, 1H),5.08(dd,J＝13.5,4.9Hz,1H),4.36–4.23(m,5H),4.14(d,J＝17.3Hz,1H),2.95–2.85(m,1H),2.62–2.54(m,4H),2.36–2.25(m,1H),2.10–1.91(m,5H).
实施例213：3-(4-(4-((2-甲基喹啉-4-)甲氧基)丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(213)
Figure PCTCN2019109368-appb-000303
分钟后加入12ml丙酮，升温回流过夜，反应完后用1NHCl调PH至5-6之间，有固体析出，过滤得到产物666mg，收率52％。
步骤2：将喹啉-4-甲酸(665mg,3.55mmol)溶于25ml干燥的THF,加入三乙胺(598ul,4.62mmol)，冰浴下滴加氯甲酸异丙酯(635ul,4.62mmol),0.5h后，加入硼氢化钠(403mg,10.65mmol)水溶液(5ml),相同温度反应2h,反应完全后，旋干，乙酸乙酯稀释，饱和氯化钠洗涤，干燥，柱层析得到产物390mg,收率63％。
步骤3：将喹啉-4-甲醇(100mg,0.577mmol)溶于6ml干燥的THF，0℃充分冷却，加入60％氢化钠(35mg，0.87mmol),相同温度反应0.5h,加入1,4-二溴丁烷(206ul，0.866mmol)升温回流过夜，反应完全后，加水淬灭，乙酸乙酯萃取，有机层用饱和氯化钠洗涤，干燥，柱层析得到83mg,收率47％。
步骤4：4-((4-溴丁氧基)甲基)-2-甲基喹啉(44.7mg，0.145mmol)和5-胺基-4-(4-羟基-1-氧代异吲哚啉-2-)-5-氧代戊酸甲酯(42mg,0.145mmol)溶于6ml乙腈中，加入无水碳酸钾(20mg,0.145mmol)升温至80℃反应48h,反应完全后过滤旋干，柱层析纯化得到产物38.3mg，收率51％
步骤5：将上一步得到产物(38.3mg，0.074mmol)溶于6mlTHF中，0℃条件下，加入叔丁醇钾(9mg,0.081mmol)相同温度反应0.5h,加入1NHCl淬灭，乙酸乙酯稀释，饱和氯化钠洗涤，干燥，旋干，HPLC纯化得到白色固体17.7mg,收率49％
1H NMR(400MHz,DMSO)δ10.96(s,1H),8.00(d,J＝8.2Hz,1H),7.93(d,J＝8.3Hz,1H),7.70(t,J＝7.3Hz,1H),7.53(t,J＝7.4Hz,1H),7.46(t,J＝7.8Hz,1H),7.40(s,1H),7.30(d,J＝7.4Hz,1H),7.20(d,J＝8.1Hz,1H),5.09(dd,J＝13.3,5.0Hz,1H),4.96(s,2H),4.36(d,J＝17.4Hz,1H),4.21(d,J＝17.4Hz,1H),4.14(t,J＝5.9Hz,2H),3.65(t,J＝5.9Hz,2H),2.96–2.83(m,1H),2.63(s,3H),2.56(d,J＝17.5Hz,1H),2.45–2.32(m,1H),2.02–1.92(m,1H),1.89–1.74(m,4H).
实施例214：3-(4-(4-((2-乙基喹啉-4-)甲氧基)丁氧基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮(214)
Figure PCTCN2019109368-appb-000304
NMR(400MHz,DMSO)δ10.96(s,1H),8.01(d,J＝8.4Hz,1H),7.95(d,J＝8.3Hz,1H),7.70(t,J＝7.7Hz,1H),7.53(t,J＝7.6Hz,1H),7.45(dd,J＝13.6,5.7Hz,2H),7.30(d,J＝7.4Hz,1H),7.20(d,J＝8.2Hz,1H),5.09(dd,J＝13.3,5.1Hz,1H),4.97(s,2H),4.35(d,J＝17.4Hz,1H),4.21(d,J＝17.4Hz,1H),4.14(t,J＝5.9Hz,2H),3.66(t,J＝5.9Hz,2H),2.91(q,J＝7.5Hz,2H),2.56(d,J＝18.5Hz,1H),2.44–2.31(m,1H),2.01–1.91(m,1H),1.89–1.74(m,4H),1.29(t,J＝7.6Hz,3H).
实施例215：3-(4-(4-(4-(2-氯苯基)哌嗪-1-基)丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(215)
Figure PCTCN2019109368-appb-000305
8.1,1.3Hz,1H),7.03(td,J＝7.7,1.4Hz,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.48(d,J＝17.1Hz,1H),4.32(d,J＝17.1Hz,1H),3.02–2.84(m,5H),2.68(t,J＝7.6Hz,2H),2.59(d,J＝20.8Hz,5H),2.48–2.36(m,3H),2.06–1.97(m,1H).1.70–1.60(m,2H),1.57–1.47(m,2H).UPLC-MS(ESI)理论值为C 27H 31ClN 4O 3[M+H] +:495.21，实测值为495.52.
实施例216：3-(4-(4-(4-(2-硝基苯基)哌嗪-1-基)丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(216)
Figure PCTCN2019109368-appb-000306
7.4,4.3,1.6Hz,2H),7.50–7.44(m,2H),7.30(d,J＝7.7Hz,1H),7.11(t,J＝7.2Hz,1H),5.14(dd,J＝13.2,5.0Hz,1H),4.47(d,J＝17.2Hz,1H),4.32(d,J＝17.2Hz,1H),3.00–2.87(m,5H),2.67(t,J＝7.6Hz,2H),2.62–2.53(m,1H),2.48–2.43(m,4H),2.43–2.34(m,3H),2.02(ddd,J＝12.1,7.1,5.1Hz,1H),1.63(dt,J＝14.7,7.5Hz,2H),1.55–1.45(m,2H).UPLC-MS(ESI)理论值为C 27H 31N 5O 5[M+H] +:506.23，实测值为506.44.
实施例217：3-(1-氧代-4-(4-(4-(邻甲苯基)哌嗪-1-基)丁基)异吲哚啉-2-基)哌啶-2,6-二酮(217)
Figure PCTCN2019109368-appb-000307
＝7.3Hz,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.48(d,J＝17.2Hz,1H),4.32(d,J＝17.1Hz,1H),2.93(ddd,J＝17.3,13.7,5.4Hz,1H),2.83(t,4H),2.68(t,J＝7.5Hz,2H),2.64–2.53(m,5H),2.48–2.38(m,3H),2.22(s,3H),2.06–1.96(m,1H),1.70–1.59(m,2H),1.52(dt,J＝15.5,7.8Hz,2H).UPLC-MS(ESI)理论值为C 28H 34N 4O 3[M+H] +:475.26，实测值为475.49.
实施例218：3-(4-(4-(4-(2-氟苯基)哌嗪-1-基)丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(218)
Figure PCTCN2019109368-appb-000308
13.4,5.1Hz,1H),4.48(d,J＝17.2Hz,1H),4.32(d,J＝17.2Hz,1H),3.05–2.98(m,4H),2.92(ddd,J＝17.6,13.7,5.5Hz,1H),2.68(t,J＝7.5Hz,2H),2.67-2.52(m,5H),2.46–2.35(m,3H),2.06–1.97(m,1H),1.70–1.58(m,2H),1.57–1.47(m,2H).UPLC-MS(ESI)理论值为C 27H 31FN 4O 3[M+H] +:479.24，实测值为479.47.
实施例219：3-(1-氧代-4-(4-(4-(2-(三氟甲基)苯基)哌嗪-1-基)丁基)异吲哚啉-2-基)哌啶-2,6-二酮(219)
Figure PCTCN2019109368-appb-000309
13.3,5.1Hz,1H),4.48(d,J＝17.2Hz,1H),4.32(d,J＝17.2Hz,1H),3.00–2.85(m,5H),2.68(t,J＝7.6Hz,2H),2.65–2.53(m,5H),2.48–2.36(m,3H),2.07–1.98(m,1H),1.70–1.58(m,2H),1.58–1.48(m,2H).UPLC-MS(ESI)理论值为C 28H 31F 3N 4O 3[M+H] +:529.23，实测值为529.39.
实施例220：3-(1-氧代-4-(4-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丁基)异吲哚啉-2-基)哌啶-2,6-二酮(220)
Figure PCTCN2019109368-appb-000310
1H),7.15(s,1H),7.06(d,J＝7.7Hz,1H),5.14(dd,J＝13.3,4.9Hz,1H),4.47(d,J＝17.2Hz,1H),4.32(d,J＝17.2Hz,1H),3.22(t,4H),2.97–2.86(m,1H),2.68(t,J＝7.5Hz,2H),2.65–2.53(m,5H),2.45–2.35(m,3H),2.06–1.96(m,1H),1.70–1.58(m,2H),1.57–1.48(m,2H).UPLC-MS(ESI)理论值为C 28H 31F 3N 4O 3[M+H] +:529.23，实测值为529.41.
实施例221：3-(4-(4-(4-(苯并噻吩-7-基)哌嗪-1-基)丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(221)
Figure PCTCN2019109368-appb-000311
5.5Hz,1H),7.27(t,J＝7.8Hz,1H),6.88(d,J＝7.5Hz,1H),5.14(dd,J＝13.2,5.0Hz,1H),4.49(d,J＝17.2Hz,1H),4.33(d,J＝17.2Hz,1H),3.06(s,4H),2.98–2.87(m,1H),2.69(t,J＝7.5Hz,2H),2.64-2.54(m,5H),2.47–2.38(m,3H),2.06–1.98(m,1H),1.72-1.62(m,2H),1.58-1.48(m,2H).UPLC-MS(ESI)理论值为C 29H 32N 4O 3S[M+H] +:519.22，实测值为517.47.
实施例222：3-(4-(4-(4-(2,4-二氯苯基)哌嗪-1-基)丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮 (222)
Figure PCTCN2019109368-appb-000312
7.14(d,J＝8.7Hz,1H),5.14(dd,J＝13.2,5.1Hz,1H),4.47(d,J＝17.1Hz,1H),4.32(d,J＝17.1Hz,1H),2.99–2.87(m,5H),2.67(t,J＝7.5Hz,2H),2.64–2.56(m,1H),2.46–2.34(m,3H),2.08–1.95(m,1H),1.70–1.58(m,2H),1.56–1.44(m,2H).UPLC-MS(ESI)理论值为C 27H 30Cl 2N 4O 3[M+H] +:529.17，实测值为529.35.
实施例223：3-(4-(4-(4-(3,5-二氯苯基)哌嗪-1-基)丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(223)
Figure PCTCN2019109368-appb-000313
6.91(d,J＝1.6Hz,2H),6.84(t,J＝1.5Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),3.22–3.15(m,4H),2.98–2.86(m,1H),2.67(t,J＝7.5Hz,2H),2.63–2.56(m,1H),2.47–2.38(m,5H),2.33(t,J＝7.0Hz,2H),2.08–1.95(m,1H),1.69–1.57(m,2H),1.55–1.42(m,2H).UPLC-MS(ESI)理论值为C 27H 30Cl 2N 4O 3[M+H] +:529.17，实测值为529.53.
实施例224：3-(4-(4-(4-(2-甲氧基苯基)哌嗪-1-基)丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(224)
Figure PCTCN2019109368-appb-000314
＝13.3,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.32(d,J＝17.2Hz,1H),2.98-2.87(m,5H),2.68(t,J＝7.5Hz,2H),2.64–2.55(m,1H),2.48-2.42(m,2H),2.39–2.34(m,2H),2.06–1.97(m,1H),1.69–1.58(m,2H),1.55–1.44(m,2H).UPLC-MS(ESI)理论值为C 28H 34N 4O 4[M+H] +:491.26，实测值为491.53.
实施例225：3-(4-(5-(4-(苯并噻吩-7-基)哌嗪-1-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(225)
Figure PCTCN2019109368-appb-000315
5.5Hz,1H),7.27(t,J＝7.9Hz,1H),6.89(d,J＝7.6Hz,1H),5.14(dd,J＝13.3,5.0Hz,1H),4.48(d,J＝17.1Hz,1H),4.32(d,J＝17.2Hz,1H),3.10-3.01(m,4H),2.98–2.87(m,1H),2.73–2.56(m,5H),2.44(dd,J＝13.3,4.4Hz,3H),2.06–1.96(m,1H),1.72–1.59(m,2H),1.59–1.47(m,2H),1.36(dt,J＝8.6,5.6Hz,2H),1.28–1.18(m,2H).UPLC-MS(ESI)理论值为C 30H 34N 4O 3S[M+H] +:531.24，实测值为531.47.
实施例226：3-(4-(5-(4-(6-氟苯并异唑-3-基)哌啶-1-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(226)
Figure PCTCN2019109368-appb-000316
7.28(td,J＝9.2,2.0Hz,1H),5.14(dd,J＝13.2,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),3.20-3.08(m,1H),3.04–2.87(m,3H),2.70–2.64(m,2H),2.60(d,J＝17.8Hz,1H),2.47–2.30(m,3H),2.17–1.95(m,5H),1.83(dd,J＝22.7,12.1Hz,2H),1.64(dt,J＝15.2,7.6Hz,2H),1.51(dd,J＝13.1,6.9Hz,2H),1.36(dd,J＝13.4,6.3Hz,2H).UPLC-MS(ESI)理论值为C 30H 33FN 4O 4[M+H] +:533.25，实测值为533.51.
实施例227：3-(4-(4-(4-(6-氟苯并异恶唑-3-基)哌啶-1-基)丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(227)
Figure PCTCN2019109368-appb-000317
7.28(td,J＝9.2,2.2Hz,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.48(d,J＝17.2Hz,1H),4.32(d,J＝17.2Hz,1H),3.20-3.08(m,1H),3.04–2.96(m,2H),2.96–2.86(m,1H),2.68(t,J＝7.5Hz,2H),2.60(d,J＝16.8Hz,1H),2.47-2.38(m,3H),2.17(t,J＝10.2Hz,2H),2.04(dd,J＝13.4,9.5Hz,3H),1.84(dd,J＝24.4,11.9Hz,2H),1.64(dt,J＝15.3,7.8Hz,2H),1.53(dt,J＝14.7,7.5Hz,2H).UPLC-MS(ESI)理论值为C 29H 31FN 4O 4[M+H] +:519.23，实测值为519.53.
实施例228：3-(4-(4-(4-(苯并异唑-3-基)哌嗪-1-基)丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(228)
Figure PCTCN2019109368-appb-000318
＝13.3,5.1Hz,1H),4.48(d,J＝17.2Hz,1H),4.32(d,J＝17.2Hz,1H),3.46(t,J＝4.1Hz,4H),2.97–2.87(m,1H),2.68(t,J＝7.5Hz,2H),2.62–2.56(m,1H),2.54(t,J＝4.1Hz,4H),2.47–2.41(m,1H),2.38(t,J＝6.8Hz,2H),2.05–1.97(m,1H),1.68–1.61(m,2H),1.56–1.47(m,2H).UPLC-MS(ESI)理论值为C 28H 31N 5O 4[M+H] +:502.24，实测值为502.53.
实施例229：3-(4-(4-(4-(2,5-二氯苯基)哌嗪-1-基)丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(229)
Figure PCTCN2019109368-appb-000319
2.4Hz,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.32(d,J＝17.2Hz,1H),2.97(t,J＝5.6Hz,4H),2.94–2.87(m,1H),2.67(t,J＝7.5Hz,2H),2.64–2.56(m,1H),2.48(t,J＝5.6Hz,4H),2.46–2.41(m,1H),2.36(t,J＝7.5Hz,2H),2.05–1.98(m,1H),1.69–1.58(m,2H),1.46–1.53(m,2H).UPLC-MS(ESI)理论值为C 27H 30Cl 2N 4O 3[M+H] +:529.17，实测值为529.45.
实施例230：3-(4-(4-(4-(苯并异噻唑-3-基)哌嗪-1-基)丁基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(230)
Figure PCTCN2019109368-appb-000320
17.2Hz,1H),4.33(d,J＝17.1Hz,1H),3.48–3.38(m,4H),2.99–2.86(m,1H),2.69(t,J＝7.6Hz,2H),2.65–2.54(m,5H),2.47–2.35(m,3H),2.07–1.96(m,1H),1.71–1.60(m,2H),1.60–1.48(m,2H).UPLC-MS(ESI)理论值为C 28H 31N 5O 3S[M+H] +:518.21，实测值为518.45.
实施例231：3-(4-(5-(4-(苯并异唑-3-基)哌嗪-1-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二 酮(231)
Figure PCTCN2019109368-appb-000321
1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),3.53–3.39(m,4H),2.92(ddd,J＝18.4,13.6,5.2Hz,1H),2.66(t,J＝7.7Hz,2H),2.59(dd,J＝11.2,8.5Hz,1H),2.55–2.51(m,4H),2.46–2.38(m,1H),2.33(t,J＝7.0Hz,2H),2.04–1.97(m,1H),1.64(dt,J＝15.3,7.8Hz,2H),1.57–1.44(m,2H),1.41–1.30(m,2H).UPLC-MS(ESI)理论值为C 29H 33N 5O 4[M+H] +:516.25，实测值为516.51.
实施例232：3-(4-(5-(4-(苯并异噻唑-3-基)哌嗪-1-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(232)
Figure PCTCN2019109368-appb-000322
17.2Hz,1H),4.32(d,J＝17.3Hz,1H),3.47-3.37(m,4H),2.92-2.86(m,1H),2.70–2.54(m,7H),2.48–2.40(m,1H),2.34(d,J＝8.1Hz,2H),2.06-1.97(m,1H),1.70–1.60(m,2H),1.53(dt,J＝10.4,5.1Hz,2H),1.41–1.30(m,2H).UPLC-MS(ESI)理论值为C 29H 33N 5O 3S[M+H] +:532.23，实测值为532.53.
实施例233：3-(4-(5-(4-(2,5-二氯苯基)哌嗪-1-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(233)
Figure PCTCN2019109368-appb-000323
17.2Hz,1H),4.31(d,J＝17.2Hz,1H),2.99–2.95(m,4H),2.94–2.87(m,1H),2.70–2.63(m,2H),2.61–2.57(m,1H),2.49–2.47(m,4H),2.45–2.38(m,1H),2.49–2.47(m,2H),2.01–1.98(m,1H),1.67–1.59(m,2H),1.54–1.46(m,2H),1.39–1.31(m,2H).UPLC-MS(ESI)理论值为C 28H 32Cl 2N 4O 3[M+H] +:543.19，实测值为543.47.
实施例234：3-(4-(5-(4-(3,4-二氯苯基)哌嗪-1-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮 (234)
Figure PCTCN2019109368-appb-000324
2.4Hz,1H),5.13(dd,J＝13.2,5.2Hz,1H),4.47(d,J＝17.1Hz,1H),4.30(d,J＝17.1Hz,1H),3.14(t,J＝2.4Hz,4H),2.97–2.88(m,1H),2.65(t,J＝8.0Hz,2H),2.62–2.57(m,1H),2.45(t,J＝8.0Hz,4H),2.42–2.37(m,1H),2.29(t,J＝8.0Hz,2H),2.04–1.96(m,1H),1.66–1.58(m,2H),1.53–1.45(m,2H),1.37–1.29(m,2H).UPLC-MS(ESI)理论值为C 28H 32Cl 2N 4O 3[M+H] +:543.19，实测值为543.42.
实施例235：3-(4-(5-(4-(2,6-二氯苯基)哌嗪-1-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(235)
Figure PCTCN2019109368-appb-000325
＝13.3,5.2Hz,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),3.12(t,J＝3.2Hz,4H),2.98–2.88(m,1H),2.71–2.63(m,2H),2.62–2.56(m,1H),2.49–2.43(m,4H),2.42–2.37(m,1H),2.35–2.27(m,2H),2.05–1.98(m,1H),1.69–1.59(m,2H),1.54–1.45(m,2H),1.39–1.32(m,2H).UPLC-MS(ESI)理论值为C 28H 32Cl 2N 4O 3[M+H] +:543.19，实测值为543.51
实施例236：3-(4-(5-(4-(2,4-二氯苯基)哌嗪-1-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(236)
Figure PCTCN2019109368-appb-000326
8.7Hz,1H),5.14(dd,J＝13.2,5.1Hz,1H),4.47(d,J＝17.1Hz,1H),4.31(d,J＝17.1Hz,1H),2.97–2.92(m,4H),2.90–2.88(m,1H),2.65(t,J＝4.0Hz,2H),2.62–2.56(m,1H),2.48–2.47(m,4H),2.45–2.38(m,1H),2.32(t,J＝5.6Hz,2H),2.06–1.97(m,1H),1.67–1.59(m,2H),1.54–1.44(m,2H),1.38–1.30(m,2H).UPLC-MS(ESI)理论值为C 28H 32Cl 2N 4O 3[M+H] +:543.19，实测值为543.42.
实施例237：3-(4-(5-(4-(3,5-二氯苯基)哌嗪-1-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(237)
Figure PCTCN2019109368-appb-000327
5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),3.19(t,J＝4.0Hz,4H),2.97–2.88(m,1H),2.65(t,J＝8Hz,2H),2.62–2.57(m,1H),2.43(t,J＝4.0Hz,4H),2.40–2.36(m,1H),2.29(t,J＝6.6Hz,2H),2.04–1.97(m,1H),1.67–1.59(m,2H),1.53–1.46(m,2H),1.38–1.30(m,2H).UPLC-MS(ESI)理论值为C 28H 32Cl 2N 4O 3[M+H] +:543.19，实测值为543.43.
实施例238：3-(4-(3-(4-(2,3-二氯苯基)哌嗪-1-基)丙氧基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(238)
Figure PCTCN2019109368-appb-000328
(dd,J＝13.3,5.1Hz,1H),4.39(d,J＝17.5Hz,1H),4.24(d,J＝17.4Hz,1H),4.18(t,J＝6.2Hz,2H),3.02–2.86(m,5H),2.63–2.52(m,7H),2.48–2.38(m,1H),2.03–1.90(m,3H).UPLC-MS(ESI)理论值为C 26H 28Cl 2N 4O 4[M+H] +:531.15，实测值为531.35.
实施例239：3-(4-(4-(4-(苯并噻吩-7-基)哌嗪-1-基)丁氧基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(239)
Figure PCTCN2019109368-appb-000329
3H),6.89(d,J＝7.5Hz,1H),5.10(dd,J＝13.4,5.1Hz,1H),4.39(d,J＝17.4Hz,1H),4.24(d,J＝17.4Hz,1H),4.17(t,J＝6.2Hz,2H),3.11-2.99(m,4H),2.96-2.84(m,1H),2.69–2.53(m,5H),2.46-2.42(m,3H),2.03–1.95(m,1H),1.86–1.73(m,2H),1.72–1.59(m,2H).UPLC-MS(ESI)理论值为C 29H 32N 4O 4S[M+H] +:533.21，实测值为533.51.
实施例240：3-(4-(4-(4-(2,3-二氯苯基)哌嗪-1-基)丁氧基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(240)
Figure PCTCN2019109368-appb-000330
1H),4.16(t,J＝6.3Hz,2H),3.06–2.85(m,5H),2.71–2.52(m,5H),2.49–2.38(m,3H),1.99(td,J＝5.5,2.7Hz,1H),1.85–1.74(m,2H),1.69–1.59(m,2H).UPLC-MS(ESI)理论值为C 27H 30Cl 2N 4O 4[M+H] +:545.16，实测值为545.37.
实施例241：3-(4-(4-(4-(6-氟苯并异恶唑-3-基)哌啶-1-基)丁氧基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(241)
Figure PCTCN2019109368-appb-000331
(dd,J＝13.3,5.0Hz,1H),4.38(d,J＝17.4Hz,1H),4.23(d,J＝17.4Hz,1H),4.16(t,J＝6.2Hz,2H),3.23–3.12(m,2H),3.05(d,J＝11.0Hz,2H),2.95–2.86(m,1H),2.62–2.50(m,2H),2.47–2.40(m,1H),2.30–2.14(m,2H),2.10–2.01(m,2H),1.98(ddd,J＝12.3,5.4,2.1Hz,1H),1.92–1.82(m,2H),1.78(dd,J＝13.9,6.3Hz,2H),1.72–1.60(m,2H).UPLC-MS(ESI)理论值为C 29H 31FN 4O 5[M+H] +:535.23，实测值为535.49.
实施例242：3-(4-(4-(4-(苯并异唑-3-基)哌嗪-1-基)丁氧基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(242)
Figure PCTCN2019109368-appb-000332
5.1Hz,1H),4.39(d,J＝17.4Hz,1H),4.23(d,J＝17.4Hz,1H),4.16(t,J＝6.3Hz,2H),3.56–3.38(m,4H),2.96–2.84(m,1H),2.58(d,J＝13.0Hz,5H),2.47–2.34(m,3H),2.03–1.94(m,1H),1.85–1.73(m,2H),1.70–1.60(m,2H).UPLC-MS(ESI)理论值为C 28H 31N 5O 5[M+H] +:518.23，实测值为518.47.
实施例243：3-(4-(4-(4-(3,4-二氯苯基)哌嗪-1-基)丁氧基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(243)
Figure PCTCN2019109368-appb-000333
＝2.8Hz,1H),6.92(dd,J＝9.0,2.8Hz,1H),5.11(dd,J＝13.3,5.1Hz,1H),4.38(d,J＝17.4Hz,1H),4.23(d,J＝17.4Hz,1H),4.15(t,J＝6.3Hz,2H),3.15(t,J＝4.0Hz,4H),2.96–2.87(m,1H),2.61–2.55(m,1H),2.47(t,J＝4.0Hz,4H),2.40–2.44(m,1H),2.37(t,J＝6.4Hz,2H),2.03–1.95(m,1H),1.82–1.73(m,2H),1.67–1.58(m,2H).UPLC-MS(ESI)理论值为C 27H 30Cl 2N 4O 4[M+H] +:545.16，实测值为545.49.
实施例244：4-(3,5-二氯苯基)-1-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丁基)哌啶-4-甲腈(244)
Figure PCTCN2019109368-appb-000334
(d,J＝17.2Hz,1H),4.32(d,J＝17.2Hz,1H),3.14–2.86(m,3H),2.68(t,J＝7.0Hz,2H),2.60(dd,J＝17.2,1.6Hz,1H),2.47–2.36(m,3H),2.30–2.10(m,4H),2.10–1.87(m,3H),1.74–1.42(m,4H).UPLC-MS(ESI)理论值为C 29H 30Cl 2N 4O 3[M+H] +:553.17，实测值为553.49.
实施例245：4-(2-氯-4-甲氧基苯基)-1-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丁基)哌啶-4-甲腈(245)
Figure PCTCN2019109368-appb-000335
7.45(m,2H),7.42(d,J＝9.0Hz,1H),7.13(d,J＝2.7Hz,1H),6.98(dd,J＝8.9,2.7Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.47(d,J＝17.1Hz,1H),4.32(d,J＝17.1Hz,1H),3.79(s,3H),2.98(d,J＝11.1Hz,2H),2.94–2.86(m,1H),2.67(t,J＝7.7Hz,2H),2.58(d,J＝17.0Hz,1H),2.44-2.37(m,5H),2.30(t,J＝11.9Hz,2H),2.03–1.97(m,1H),1.91(t,J＝14.0Hz,2H),1.63(d,J＝7.9Hz,2H),1.56–1.46(m,2H).UPLC-MS(ESI)理论值为C 30H 33ClN 4O 4[M+H] +:549.22，实测值为549.43.
实施例246：4-(2,5-二甲氧基苯基)-1-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丁基)哌啶-4-甲腈(246)
Figure PCTCN2019109368-appb-000336
＝2.9Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.1Hz,1H),3.80(s,3H),3.72(s,3H),2.90(dd,J＝22.3,8.8Hz,3H),2.67(t,J＝7.6Hz,2H),2.58(d,J＝17.6Hz,1H),2.41(dd,J＝17.8,4.7Hz,3H),2.27(d,J＝11.5Hz,4H),2.04–1.96(m,1H),1.90(d,J＝13.3Hz,2H),1.62(dd,J＝13.9,6.7Hz,2H),1.55–1.45(m,2H).UPLC-MS(ESI)理论值为C 31H 36N 4O 5[M+H] +:545.27，实测值为545.56.
实施例247：4-(2,5-二甲氧基苯基)-1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)哌啶-4-甲腈(247)
Figure PCTCN2019109368-appb-000337
(d,J＝2.9Hz,1H),5.13(dd,J＝13.2,5.0Hz,1H),4.46(d,J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),3.80(s,3H),3.73(s,3H),3.04–2.82(m,3H),2.72–2.55(m,3H),2.45–2.40(m,1H),2.39–2.30(m,2H),2.25(t,J＝3.6Hz,4H),2.04–1.97(m,1H),1.88(t,J＝12.2,10.8Hz,2H),1.68–1.59(m,2H),1.53–1.45(m,2H),1.39–1.28(m,2H).UPLC-MS(ESI)理论值为C 32H 38N 4O 5[M+H] +:559.28，实测值为559.51.
实施例248：4-(2,5-二氯苯基)-1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)哌啶-4-甲腈(248)
Figure PCTCN2019109368-appb-000338
＝17.2Hz,1H),4.30(d,J＝17.2Hz,1H),3.00(d,J＝12.5Hz,2H),2.95–2.87(m,1H),2.69–2.62(m,2H),2.60–2.56(m,1H),2.45–2.41(m,3H),2.39–2.32(m,2H),2.32–2.20(m,2H),2.05–1.89(m,3H),1.66–1.59(m,2H),1.56–1.44(m,2H),1.41–1.28(m,2H).UPLC-MS(ESI)理论值为C 30H 32Cl 2N 4O 3[M+H] +:567.19，实测值为567.48.
实施例249：4-(3,4-二甲氧基苯基)-1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊 基)哌啶-4-甲腈(249)
Figure PCTCN2019109368-appb-000339
1H),3.78(s,3H),3.75(s,3H),3.00–2.93(m,2H),2.92–2.88(m,1H),2.65(t,J＝7.2Hz,2H),2.61–2.56(m,1H),2.45–2.41(m,1H),2.34(t,J＝7.2Hz,2H),2.22(t,J＝11.4Hz,2H),2.09(d,J＝13.4Hz,2H),2.05–1.89(m,3H),1.67–1.59(m,2H),1.53–1.46(m,2H),1.37–1.30(m,2H).UPLC-MS(ESI)理论值为C 32H 38N 4O 5[M+H] +:559.28，实测值为559.59.
实施例250：4-(2,6-二氯苯基)-1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)哌啶-4-甲腈(250)
Figure PCTCN2019109368-appb-000340
J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),3.11–3.03(m,2H),2.97–2.88(m,1H),2.70–2.63(m,2H),2.61–2.57(m,1H),2.55–2.52(m,4H),2.47–2.43(m,1H),2.42–2.31(m,4H),2.04–1.98(m,1H),1.67–1.59(m,2H),1.55–1.47(m,2H),1.37–1.30(m,2H).UPLC-MS(ESI)理论值为C 30H 32Cl 2N 4O 3[M+H] +:567.19，实测值为567.48.
实施例251：4-(3,5-二氯苯基)-1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)哌啶-4-甲腈(251)
Figure PCTCN2019109368-appb-000341
(dd,J＝13.3,5.0Hz,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),3.04–2.87(m,3H),2.70–2.63(m,2H),2.60–2.56(m,1H),2.45–2.41(m,1H),2.40–2.29(m,2H),2.29–2.09(m,4H),2.06–1.91(m,3H),1.69–1.58(m,2H),1.57–1.43(m,2H),1.37–1.29(m,2H).UPLC-MS(ESI)理论值为C 30H 32Cl 2N 4O 3[M+H] +:567.19，实测值为567.52.
实施例252：1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)-4-(4-(((S)-四氢呋喃-3-基)氧基)苯基)哌啶-4-甲腈(252)
Figure PCTCN2019109368-appb-000342
(m,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),3.92–3.71(m,4H),3.00–2.86(m,3H),2.71–2.54(m,3H),2.47–2.30(m,3H),2.27–2.16(m,3H),2.11–1.84(m,6H),1.65–1.57(m,2H),1.55–1.44(m,2H),1.38–1.29(m,2H).UPLC-MS(ESI)理论值为C 34H 40N 4O 5[M+H] +:585.30.，实测值为585.56.
实施例253：1-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丁基)-4-(2,3,4-三甲氧基苯基)哌啶-4-甲腈(253)
Figure PCTCN2019109368-appb-000343
17.2Hz,1H),4.32(d,J＝17.1Hz,1H),3.92(s,3H),3.80(s,3H),3.76(s,3H),3.03–2.84(m,3H),2.67(t,J＝7.4Hz,2H),2.62–2.53(m,1H),2.48–2.12(m,7H),2.06–1.95(m,1H),1.91–1.74(m,2H),1.70–1.56(m,2H),1.56–1.44(m,2H).UPLC-MS(ESI)理论值为C 32H 38N 4O 6[M+H] +:575.28，实测值为575.57.
实施例254：1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)-4-(2,3,4-三甲氧基苯基)哌啶-4-甲腈(254)
Figure PCTCN2019109368-appb-000344
3.76(s,3H),3.06–2.85(m,3H),2.71–2.54(m,3H),2.46–2.12(m,7H),2.05–1.96(m,1H),1.91–1.73(m,2H),1.70–1.57(m,2H),1.56–1.41(m,3H),1.38–1.27(m,2H).UPLC-MS(ESI)理论值为C 33H 40N 4O 6[M+H] +:589.30，实测值为589.58.
实施例255：4-(2,4-二甲氧基苯基)-1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)哌啶-4-甲腈(255)
Figure PCTCN2019109368-appb-000345
5.14(dd,J＝13.2,5.1Hz,1H),4.46(d,J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),3.84(s,3H),3.77(s,3H),3.05–2.82(m,3H),2.70–2.54(m,3H),2.46–2.13(m,7H),2.06–1.95(m,1H),1.92–1.76(m,2H),1.68–1.57(m,2H),1.56–1.42(m,2H),1.38–1.26(m,2H).UPLC-MS(ESI)理论值为C 32H 38N 4O 5[M+H] +:559.28，实测值为559.54.
实施例256：4-(2,4-二甲氧基苯基)-1-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丁基)哌啶-4-甲腈(256)
Figure PCTCN2019109368-appb-000346
7.19(d,J＝8.7Hz,1H),6.69–6.30(m,1H),6.57–6.51(m,1H),5.13(dd,J＝13.2,5.0Hz,1H),4.47(d,J＝17.1Hz,1H),4.31(d,J＝17.1Hz,1H),3.84(s,3H),3.77(s,3H),2.99–2.82(m,3H),2.67(t,J＝7.3Hz,2H),2.62–2.53(m,1H),2.46–2.11(m,8H),2.05–1.94(m,1H),1.89–1.77(m,2H),1.69–1.56(m,2H),2.46–2.11(m,2H).UPLC-MS(ESI)理论值为C 31H 36N 4O 5[M+H] +:545.27，实测值为545.53.
实施例257：4-(2-氯-4-(三氟甲氧基)苯基)-1-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丁基)哌啶-4-甲腈(257)
Figure PCTCN2019109368-appb-000347
17.1Hz,1H),4.31(d,J＝17.1Hz,1H),3.06–2.84(m,3H),2.73–2.54(m,3H),2.47–2.23(m,7H),2.04–1.90(m,3H),1.67–1.58(m,2H),1.56–1.44(m,2H).UPLC-MS(ESI)理论值为C 30H 30ClF 3N 4O 4[M+H] +:603.19，实测值为603.51.
实施例258：4-(2-氯-4-(三氟甲氧基)苯基)-1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)哌啶-4-甲腈(258)
Figure PCTCN2019109368-appb-000348
DMSO)δ10.99(s,1H),7.23–7.64(m,2H),7.58–7.63(m,1H),7.52–7.41(m,3H),5.14(dd,J＝13.3,5.0Hz,1H),4.46(d,J＝17.2Hz,1H),4.31(d,J＝17.1Hz,1H),3.05–2.87(m,3H),2.69–2.56(m,3H),2.47–2.22(m,7H),2.06–1.89(m,3H),1.69–1.57(m,2H),1.55–1.43(m,2H),1.41–1.29(m,2H).UPLC-MS(ESI)理论值为C 31H 32ClF 3N 4O 4[M+H] +:617.21，实测值为617.58.
实施例259：4-(2,3-二甲氧基苯基)-1-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丁基)哌啶-4-甲腈(259)
Figure PCTCN2019109368-appb-000349
(m,2H),7.13–7.04(m,2H),6.90(dd,J＝7.4,1.9Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.46(d,J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),3.87(s,3H),3.83(s,3H),2.98–2.85(m,3H),2.67(t,J＝7.6Hz,2H),2.62–2.55(m,1H),2.47–2.33(m,3H),2.33–2.16(m,4H),2.04–1.95(m,1H),1.84(t,J＝12.3Hz,2H),1.68–1.56(m,2H),1.55–1.45(m,2H).UPLC-MS(ESI)理论值为C 31H 36N 4O 5[M+H] +:545.27，实测值为545.49.
实施例260：4-(2,3-二甲氧基苯基)-1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)哌啶-4-甲腈(260)
Figure PCTCN2019109368-appb-000350
(s,3H),3.84(s,3H),3.14–3.05(m,2H),2.99–2.89(m,1H),2.68–2.57(m,3H),2.49–2.36(m,3H),2.36–2.07(m,4H),2.04–1.98(m,1H),1.88–1.84(m,2H),1.68–1.58(m,2H),1.53–1.46(m,2H),1.27–1.20(m,2H).UPLC-MS(ESI)理论值为C 32H 38N 4O 5[M+H] +:559.28，实测值为559.56.
实施例261：1-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丁基)-4-均三甲基苯基哌啶-4-甲腈(261)
Figure PCTCN2019109368-appb-000351
DMSO-d 6)δ10.99(s,1H),7.57(dd,J＝5.6,2.7Hz,1H),7.51–7.42(m,2H),6.86(s,2H),5.13(dd,J＝13.1,4.9Hz,1H),4.47(d,J＝17.0Hz,1H),4.32(d,J＝17.1Hz,1H),3.01–2.86(m,3H),2.73–2.64(m,2H),2.63–2.56(m,1H),2.51(s,6H),2.49–2.39(m,3H),2.39–2.21(m,6H),2.17(s,3H),2.09–2.03(m,1H),1.69–1.58(m,2H),1.56–1.43(m,2H).UPLC-MS(ESI)理论值为C 32H 38N 4O 3[M+H] +:527.29，实测值为527.56.
实施例262：1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)-4-均三甲基苯基哌啶-4-甲腈(262)
Figure PCTCN2019109368-appb-000352
3H),2.69–2.56(m,3H),2.51(s,6H),2.49–2.36(m,3H),2.36–2.20(m,6H),2.18(s,3H),2.05–1.97(m,1H),1.70–1.58(m,2H),1.56–1.44(m,2H),1.41–1.29(m,2H).UPLC-MS(ESI)理论值为C 33H 40N 4O 3[M+H] +:541.31，实测值为541.45.
实施例263：1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)-4-(4-(((S)-四氢呋喃-3-基)氧基)苯基)哌啶-4-甲腈(263)
Figure PCTCN2019109368-appb-000353
2H),5.14(dd,J＝13.4,5.1Hz,1H),5.08–4.97(m,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),3.89(dd,J＝10.1,4.6Hz,1H),3.86–3.80(m,1H),3.76(ddd,J＝16.5,8.7,4.9Hz,2H),3.07–2.84(m,3H),2.68–2.56(m,3H),2.43–2.36(m,3H),2.29–2.15(m,3H),2.14–1.80(m,6H),1.70–1.56(m,2H),1.56–1.42(m,2H),1.33(p,J＝8.7,8.3Hz,2H).UPLC-MS(ESI)理论值为C 34H 40N 4O 5[M+H] +:585.30，实测值为585.53.
实施例264：1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)-4-(4-(2-甲氧基乙氧基)苯基)哌啶-4-甲腈(264)
Figure PCTCN2019109368-appb-000354
5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.1Hz,1H),4.12–4.07(m,2H),3.68–3.61(m,2H),3.47-3.35(m,3H),3.30(s,3H),3.23-3.04(m,2H),2.99–2.87(m,1H),2.70-2.56(m,3H),2.46–2.35(m,2H),2.27-2.12(m,2H),2.09–1.94(m,3H),1.69–1.52(m,4H),1.41–1.29(m,2H).UPLC-MS(ESI)理论值为C 33H 40N 4O 5[M+H] +:573.30，实测值为573.53.
实施例265：1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)-4-(4-甲氧基苯基)哌啶-4-甲腈(265)
Figure PCTCN2019109368-appb-000355
17.2Hz,1H),4.32(d,J＝17.0Hz,1H),3.77(s,3H),3.44-3.23(m,6H),3.01–2.87(m,1H),2.70-2.56(m,3H),2.46–2.35(m,1H),2.29–2.14(m,2H),2.07–1.94(m,3H),1.70–1.50(m,4H),1.40-1.27(m,2H).UPLC-MS(ESI)理论值为C 31H 36N 4O 4[M+H] +:529.27，实测值为529.58.
实施例266：4-(2,6-二氯苯基)-1-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丁基)哌啶-4-甲腈(266)
Figure PCTCN2019109368-appb-000356
(d,J＝17.1Hz,1H),4.33(d,J＝17.1Hz,1H),3.52-3.17(m,4H),2.99–2.88(m,1H),2.80–2.58(m,9H),2.46–2.35(m,1H),2.08–1.98(m,1H),1.72–1.50(m,4H).UPLC-MS(ESI)理论值为C 29H 30Cl 2N 4O 3[M+H] +:553.17，实测值为553.50.
实施例267：4-(2-氯-4-甲氧基苯基)-1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)哌啶-4-甲腈(267)
Figure PCTCN2019109368-appb-000357
5.1Hz,1H),4.46(d,J＝17.2Hz,1H),4.31(d,J＝17.1Hz,1H),3.79(s,3H),3.07–2.86(m,3H),2.68-2.56(m,3H),2.46-2.36(m,3H),2.37–2.32(m,2H),2.28(t,J＝11.7Hz,2H),2.05 –1.95(m,1H),1.89(t,J＝11.1Hz,2H),1.68–1.56(m,2H),1.50(dt,J＝14.8,7.6Hz,2H),1.34(dd,J＝14.1,7.2Hz,2H).UPLC-MS(ESI)理论值为C 31H 35ClN 4O 4[M+H] +:563.23，实测值为563.52.
实施例268：4-(4-氰基苯基)-1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)哌啶-4-甲腈(268)
Figure PCTCN2019109368-appb-000358
(dd,J＝13.2,5.1Hz,1H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.1Hz,1H),3.12–2.86(m,3H),2.70-2.56(m,3H),2.46-2.38(m,3H),2.35-2.20(m,2H),2.19–2.09(m,2H),2.08–1.94(m,3H),1.63(dt,J＝15.5,7.7Hz,2H),1.53(dd,J＝12.5,7.1Hz,2H),1.40–1.29(m,2H).UPLC-MS(ESI)理论值为C 31H 33N 5O 3[M+H] +:524.26，实测值为524.55.
实施例269：4-(2,5-二氯苯基)-1-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丁基)哌啶-4-甲腈(269)
Figure PCTCN2019109368-appb-000359
Hz,1H),4.31(d,J＝17.2Hz,1H),3.08–2.86(m,3H),2.66(t,J＝7.6Hz,2H),2.59(d,J＝17.1Hz,1H),2.47–2.23(m,7H),2.05–1.93(m,3H),1.63(dd,J＝15.5,7.8Hz,2H),1.58–1.45(m,2H).UPLC-MS(ESI)理论值为C 29H 30Cl 2N 4O 3[M+H] +:553.17，实测值为553.52.
实施例270：1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)-4-(4-(氧杂环丁烷-3-基氧基)苯基)哌啶-4-甲腈(270)
Figure PCTCN2019109368-appb-000360
13.3,5.0Hz,1H),4.93(t,J＝6.7Hz,2H),4.54(dd,J＝7.4,5.1Hz,2H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),3.24–3.05(m,2H),3.04–2.83(m,3H),2.72–2.64(m,2H),2.60–2.56(m,1H),2.48–2.31(m,3H),2.23–2.09(m,2H),2.04–1.98(m,3H),1.70–1.47(m,4H),1.40–1.29(m,2H).UPLC-MS(ESI)理论值为C 33H 38N 4O 5[M+H] +:571.28， 实测值为571.53.
实施例271：1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)戊基)-4-(4-(三氟甲基)苯基)哌啶-4-甲腈(271)
Figure PCTCN2019109368-appb-000361
4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),3.03-2.95(m,2H),2.94–2.86(m,1H),2.69-2.54(m,3H),2.43(dd,J＝13.2,4.5Hz,1H),2.39–2.33(m,2H),2.24(t,J＝11.4Hz,2H),2.12(d,J＝12.3Hz,2H),2.06-1.95(m,3H),1.68–1.58(m,2H),1.55–1.46(m,2H),1.40–1.29(m,2H).UPLC-MS(ESI)理论值为C 31H 33F 3N 4O 3[M+H] +:567.25，实测值为567.53.
实施例272：4-(3,4-二氯苯基)-1-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丁基)哌啶-4-甲腈(272)
Figure PCTCN2019109368-appb-000362
13.2,5.0Hz,1H),4.47(d,J＝17.1Hz,1H),4.32(d,J＝17.1Hz,1H),3.40-3.28(m,4H),3.10-2.86(m,3H),2.68(t,J＝7.0Hz,2H),2.59(d,J＝16.6Hz,1H),2.42(dd,J＝13.2,4.3Hz,1H),2.29–2.10(m,3H),2.05-1.94(m,2H),1.69-1.40(m,4H).UPLC-MS(ESI)理论值为C 29H 30Cl 2N 4O 3[M+H] +:553.17，实测值为553.52.
实施例273：3-(4-(5-(5-氟-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(273)
Figure PCTCN2019109368-appb-000363
J＝13.3,5.0Hz,1H),5.02(s,2H),4.48(d,J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),3.50(d,J＝6.9Hz,2H),3.20-3.06(m,2H),3.00–2.88(m,1H),2.68(t,J＝7.4Hz,2H),2.64-2.56(m,1H),2.44-2.34(m,3H),2.19(t,J＝13.5Hz,2H),2.06–1.97(m,1H),1.86(d,J＝13.6Hz,2H),1.78-1.62(m,4H),1.41-1.33(m,2H).UPLC-MS(ESI)理论值 为C 30H 34FN 3O 4[M+H] +:520.25，实测值为520.53.
实施例274：3-(4-(5-(5-氯-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(274)
Figure PCTCN2019109368-appb-000364
13.3,5.1Hz,1H),5.03(s,2H),4.48(d,J＝17.1Hz,1H),4.31(d,J＝17.1Hz,1H),3.51(d,J＝12.2Hz,2H),3.20-3.08(m,2H),3.00-2.87(m,1H),2.72–2.57(m,3H),2.41(dd,J＝17.7,8.7Hz,1H),2.14(t,J＝12.0Hz,2H),2.07–1.95(m,2H),1.88(d,J＝13.2Hz,2H),1.80–1.60(m,5H),1.42-1.32(m,2H).UPLC-MS(ESI)理论值为C 30H 34ClN 3O 4[M+H] +:536.22，实测值为536.52.
实施例275：3-(4-(5-(6-氯-2-氧代螺[二氢吲哚-3,4'-哌啶]-1'-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(275)
Figure PCTCN2019109368-appb-000365
1.9Hz,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.48(d,J＝17.1Hz,1H),4.31(d,J＝17.1Hz,1H),2.99-2.85(m,3H),2.70-2.60(m,4H),2.59-2.52(m,3H),2.47–2.37(m,1H),2.06–1.97(m,1H),1.87-1.77(m,2H),1.72-1.61(m,4H),1.55(dd,J＝14.3,7.0Hz,2H),1.43–1.29(m,2H).UPLC-MS(ESI)理论值为C 30H 33ClN 4O 4[M+H] +:549.22，实测值为549.53.
实施例276：3-(4-(5-(4-氯-2-氧代螺[二氢吲哚-3,4'-哌啶]-1'-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(276)
Figure PCTCN2019109368-appb-000366
6.82(d,J＝7.6Hz,1H),5.15(dd,J＝13.3,5.1Hz,1H),4.49(d,J＝17.2Hz,1H),4.32(d,J＝17.2Hz,1H),3.15–2.88(m,5H),2.75–2.57(m,6H),2.47–2.38(m,2H),2.07–1.98(m,3H),1.76–1.58(m,6H),1.42-1.32(m,2H).UPLC-MS(ESI)理论值为C 30H 33ClN 4O 4[M+H] +:549.22，实测值为549.49.
实施例277：3-(4-(5-(6-氯-2-氧代-1,2-二氢螺[苯并[1,3]恶嗪-4,4'-哌啶]-1'-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(277)
Figure PCTCN2019109368-appb-000367
4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),2.98–2.87(m,1H),2.75(d,J＝10.3Hz,2H),2.68-2.54(m,3H),2.43(dd,J＝13.1,4.4Hz,1H),2.39–2.28(m,4H),2.07-1.98(m,3H),1.90(d,J＝13.0Hz,2H),1.68–1.58(m,2H),1.56–1.45(m,2H),1.39-1.32(m,2H).UPLC-MS(ESI)理论值为C 30H 33ClN 4O 5[M+H] +:565.21，实测值为565.53.
实施例278：3-(4-(5-(5-氟-2-氧代螺[二氢吲哚-3,4'-哌啶]-1'-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(278)
Figure PCTCN2019109368-appb-000368
5.2Hz,1H),4.48(d,J＝17.2Hz,1H),4.32(d,J＝17.2Hz,1H),2.99–2.81(m,3H),2.67(t,J＝7.8Hz,2H),2.65–2.55(m,3H),2.46–2.40(m,3H),2.06–1.98(m,1H),1.86–1.75(m,2H),1.74–1.59(m,4H),1.59–1.50(m,2H),1.42–1.32(m,2H).UPLC-MS(ESI)理论值为C 30H 33FN 4O 4[M+H] +:533.25，实测值为533.52.
实施例279：3-(4-(5-(7-氯-2-氧代螺[二氢吲哚-3,4'-哌啶]-1'-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(279)
Figure PCTCN2019109368-appb-000369
1H),7.02(t,J＝7.8Hz,1H),5.14(dd,J＝13.3,5.1Hz,1H),4.48(d,J＝17.0Hz,1H),4.32(d,J＝17.1Hz,1H),3.22–3.14(m,2H),3.05–2.88(m,3H),2.87-2.76(m,2H),2.72–2.64(m,2H),2.64–2.57(m,1H),2.46–2.36(m,1H),2.06–1.98(m,1H),1.97-1.84(m,4H),1.73-1.58(m,4H),1.44-1.33(m,2H).UPLC-MS(ESI)理论值为C 30H 33ClN 4O 4[M+H] +: 549.22，实测值为549.48.
实施例280：3-(4-(5-(4-氯-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-基)戊基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(280)
Figure PCTCN2019109368-appb-000370
＝13.4,5.1Hz,1H),5.08(s,2H),4.48(d,J＝17.2Hz,1H),4.31(d,J＝17.2Hz,1H),3.53(d,J＝11.8Hz,2H),3.23-3.10(m,4H),3.01–2.85(m,1H),2.73–2.65(m,2H),2.61(d,J＝18.7Hz,1H),2.44-2.36(m,1H),2.20–2.08(m,2H),2.07–1.99(m,2H),1.98-1.91(m,1H),1.77–1.63(m,4H),1.42-1.30(m,2H).UPLC-MS(ESI)理论值为C 30H 34ClN 3O 4[M+H] +:536.22，实测值为536.53.
二、实验实施例：
肿瘤细胞增殖抑制实验方法：本专利发明人测试了所有实施例化合物对血液瘤细胞，多发性骨髓瘤MM1s细胞系和部分实施例化合物对急性白血病细胞MV-4-11细胞系，其活性测试方法和结果如下。
1.化合物对MM.1S细胞增殖的抑制作用MTS细胞活力检测实验：
1).实验方法：
MM.1S细胞用1640加10％胎牛血清培养并收集，按7天的作用时间稀释细胞浓度，在96孔细胞板中每孔加入180ul细胞悬液，使其细胞数为20000个。对照细胞孔加入20ul终浓度为0.2％的DMSO，化合物由10mM母液5倍梯度稀释，同样加20ul到化合物细胞孔(DMSO终浓度为0.2％)。细胞放入37℃，5％CO 2培养箱孵育7天。按MTS试剂盒(Promega,G5430)配制反应液后，每孔加入20μL，37℃，5％CO 2培养箱孵育3-4小时。用酶标板读取490nm吸收光值，并以690nm吸收光值作为背景值，以OD490-OD690为最终原始数据。化合物的抑制率计算公式为：抑制率＝(OD DMSO-OD 化合物)/(OD DMSO-O 空 白)×100％。化合物的增殖抑制IC50由Graph Pad Prism 5.0拟合。实验重复三次，每次用 三个平行实验计算计算平均数和标准差。
细胞活性测试结果：****表示细胞活性IC 50>20μM，***表示细胞活性1μM<IC 50<20μM，**表示细胞活性100nM<IC 50<1μM，*表示细胞活性IC 50<100nM。
2).实验结果：
Figure PCTCN2019109368-appb-000371
Figure PCTCN2019109368-appb-000372
Figure PCTCN2019109368-appb-000373
Figure PCTCN2019109368-appb-000374
Figure PCTCN2019109368-appb-000375
基于以上化合物细胞生长抑制活性测试结果，本发明的一些实施例化合物对多发性骨髓瘤MM1s细胞生长具有很好的抑制活性，部分化合物的活性与阳性化合物相当或优于阳性化合物。另一方面，这些结构多样性化合物的开发，未获得更高活性的药物分子和药学性质更佳的分子，提供可选择的分子来源。因此，本发明的化合物可以用于预防和治疗与调节CRBN(CRL4 CRBNE3泛素连接酶)活性相关的疾病，如多发性骨髓瘤或非限制性的包括其他潜在的肿瘤疾病、疼痛、神经***疾病和免疫***疾病。
2.化合物对MV-4-11细胞增殖的抑制作用，MTS细胞活力检测实验：
1).实验方法：
MV-4-11细胞用IMDM加10％胎牛血清培养并收集，按7天的作用时间稀释细胞浓度，在96孔细胞板中每孔加入180ul细胞悬液，使其细胞数为2000个。对照细胞孔加入20ul终浓度为0.2％的DMSO，化合物由10mM母液5倍梯度稀释，同样加20ul到化合物细胞孔(DMSO终浓度为0.2％)。细胞放入37℃，5％CO 2培养箱孵育7天。按MTS试剂盒(Promega,G5430)配制反应液后，每孔加入20μL，37℃，5％CO 2培养箱孵育3-4小时。用酶标板读取490nm吸收光值，并以690nm吸收光值作为背景值，以OD490-OD690为最终原始数据。化合物的抑制率计算公式为：抑制率＝(OD DMSO-OD 化合物)/(OD DMSO-O 空 白)×100％。化合物的增殖抑制IC50由Graph Pad Prism 5.0拟合。实验重复三次，每次用三个平行实验计算计算平均数和标准差。
2).实验结果：
Figure PCTCN2019109368-appb-000376
基于以上化合物细胞生长抑制活性测试结果，本发明的一些实施例化合物对急性白血病细胞MV-4-11细胞具有非常好的抑制活性。多个化合物的IC50处于纳摩尔级别，表中测试的化合物最好的活性可以达到17nM；然而阳性化合物无论是已经上市的药物来那度胺(Lenalidomide)或泊马度胺，还是目前在临床的化合物CC-122或者CC-220在急性白血病细胞MV-4-11细胞上的细胞抑制活性(IC50)都是大于20μM。从上述表中测试结果发现，本发明的部分化合物对急性白血病细胞MV-4-11细胞增殖的抑制抑制活性强于相关阳性化合物的，最好的化合物活性是阳性化合物的1000倍以上。因此，本发明的化合物拓宽了度胺类药物在血液瘤疾病治疗中的应用范围，可以用于拓展到血液肿瘤的其他适应症，比如作为急性白血病的抑制剂，作为制备治疗该类疾病的药物。因此本发明的化合物可以作为强效新型的CRBN调节剂，用于预防和治疗与调节CRBN(CRL4CRBNE3泛素连接酶)活性相关的疾病，如多发性骨髓瘤或非限制性的包括其他潜在的肿瘤疾病、 炎症、疼痛、神经***疾病和免疫***疾病。
综上所述，本发明提供了一类结构新颖的取代异吲哚啉类化合物，其中部分代表性化合物对测试的血液瘤细胞表现出非常强的增殖抑制活性。此外，本发明提供的部分代表性化合物能有效克服现有度胺药物的应用局限，此项特征不仅可以有效弥补现有度胺药物的不足，更能将其适应症拓展到新的领域，因此具有非常强的研究潜力和应用前景。

Claims (18)

  1. 如下通式(I)表示的化合物以及它们互变异构体、对映体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物：
    Figure PCTCN2019109368-appb-100001
    其中，X 1为-CH 2-或-O-；
    X 2为-CH 2-或-CO-；
    R 1为氢、氘、氟或C 1-C 6直链或支链烃基；
    R 2、R 4各自独立地为氢或氘；
    R 3为氢、氘或卤素；
    L为含有2-8个碳原子的取代或未取代的直链亚烷基，所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代：氘、卤素、羰基、羟基、氨基、氰基、C 1-C 6烷基、卤素取代的C 1-C 6烷基、C 3-C 8环烷基、-NHC(O)Ra 1、-NHC(O)ORa 2、-NRa 3Ra 4，其中Ra 1、Ra 2、Ra 3和Ra 4各自独立地选自氢原子、由卤素、羟基、氰基、硝基取代或未取代的C 1-6烷基、由卤素、羟基、氰基、硝基取代或未取代的C 3-6环烷基；
    Y不存在，或为–O–、–CO–、–CO–NH–、–NH–CO–、–NH–CO–NH–、–NH–CO–CH(NHRa 9)–或–CH(NHRa 9)–；
    Y为–O–时，A为：6-10元芳基、5-10元杂芳基，(6-10元芳基)–(CH 2) b1–、(5-10元杂芳基)–(CH 2) b1–，前述芳基或杂芳基可选地被以下一个或多个基团所取代：氘、卤素、氰基、硝基、氨基、羟基、C 1-C 6烷基、卤素取代的C 1-C 6烷基、羟基取代的C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氧基羰基、卤素取代的C 1-C 6烷氧基、羟基取代的C 1-C 6烷氧基、氰基取代的C 1-C 6烷氧基、C 3-C 6环烷基、C 3-C 6环烷基氧基、苯基、5-6元杂芳基、3-6 元杂环基、-NHC(O)Ra 5、-NHC(O)ORa 6和-NRa 7Ra 8，其中Ra 5、Ra 6、Ra 7和Ra 8各自独立地为氢原子、由卤素、羟基、C 1-C 6烷氧基、氰基、硝基取代或未取代的C 1-6烷基、或由卤素、羟基、C 1-C 6烷氧基、氰基、硝基取代或未取代的C 3-6环烷基；
    b 1为1或2；
    条件是：当A为未取代的苯基且b 1＝1时，Y不为–O–；
    Y不存在或为–CO–或–CO–NH–时，相对应的Y与A、L形成的连接方式分别为A–L–、A–CO–L–、A–CO–NH–L–，A为：i)选自以下的杂环基：
    Figure PCTCN2019109368-appb-100002
    X 3为C、N或O；
    n 4为0、1、2或3；
    n 5为0、1、2或3，
    Y 1、Y 2各自独立地为氢、氘、卤素、氰基、羧基、硝基、羟基、氨基、氨基羰基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷基羰基、C 1-C 6烷氧基羰基、C 1-C 6烷基磺酰基、C 1-C 6烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 6酰基氨基、卤素取代C 1-C 6烷基、卤素取代的C 1-C 6烷氧基、C 1-C 3烯基、C 1-C 3炔基、取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、6-10元芳基或5-10元杂芳基取代的C 1-C 3的直链或支链烷基，其中所述取代或未取代的6-10元芳基或5-10元杂芳基是指被以下一种或多种取代基所取代：氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 3酰基氨基、卤素取代C 1-C 3烷基、卤素取代的C 1-C 3烷氧基；
    条件是：当Y 1和Y 2各自独立地为氢、氘、C 1-C 6烷氧基、卤素、C 1-C 6烷基、C 3-C 6的环烷基、羧基、C 1-C 6烷基氨基羰基、C 1-C 6烷氧基羰基、硝基、氨基、氰基、卤素取代 C 1-C 6烷基、羟基、C 1-C 6烷基磺酰基时，并且Y不存在时，X 1不为-O-；
    Y 3不存在，或为氢、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷基氨基羰基、C 1-C 6烷氧基羰基、卤素取代C 1-C 6烷基、C 1-C 6烷基磺酰基、C 1-C 6烷基羰基、氨基羰基、C 3-C 6杂环基、C 1-C 6酰基氨基、卤素取代的C 1-C 6烷氧基、C 1-C 3烯基、C 1-C 3炔基、取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、C 5-C 10的芳基或杂芳基取代的C 1-C 3的直链或支链烷基，其中所述取代或未取代的6-10元芳基或5-10元杂芳基是指被以下一种或多种取代基所取代：氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 3酰基氨基、卤素取代C 1-C 3烷基、卤素取代的C 1-C 3烷氧基；
    条件是：当Y 3为氢、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷基氨基羰基、C 1-C 6烷氧基羰基、卤素取代C 1-C 6烷基、C 1-C 6烷基磺酰基或Y3不存在时，并且Y不存在时，X 1不为-O-；
    Y 4、Y 5为其所在杂环上的一个或多个取代基，Y 4、Y 5各自独立地为氘、卤素、氧、C 1-C 3烷基、C 1-C 3环烷基、卤素取代的C 1-C 3烷基或苯基；
    ii)选自以下的稠杂环基：
    Figure PCTCN2019109368-appb-100003
    X 4为C、N或O；
    n 6为0、1、2或3；
    n 7为0、1、2或3；
    n 8为0、1、2、3或4；
    Figure PCTCN2019109368-appb-100004
    为6-10元芳基环或5-10元杂芳基环，优选地，
    Figure PCTCN2019109368-appb-100005
    环选自苯环、吡啶环、噻吩环、吲哚环、苯并噻吩环、苯并咪唑环、萘环、喹啉环或异喹啉环；
    R 8各自独立地选自氢、氘、C 1-C 3烷氧基、卤素、C 1-C 3烷基、C 3-C 6的环烷基、羧基、 C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 3烷基、羟基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、C 3-C 6的杂环基、卤素取代C 1-C 3烷氧基、苯基或5-6元杂芳基；
    条件是：当上述R 8各自独立地选自下列任意取代基：氢、氘、C 1-C 3烷氧基、卤素、C 1-C 3烷基、C 3-C 6的环烷基、羧基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 3烷基、羟基、C 1-C 3烷基磺酰基时，并且Y不存在时，X 1不为-O-；
    Y 6、Y 7为其所在杂环上的一个或多个取代基，且各自独立地选自氘、卤素、C 1-C 3烷基、C 1-C 3环烷基、卤素取代的C 1-C 3烷基；
    或者iii)选自以下的螺杂环基：
    Figure PCTCN2019109368-appb-100006
    n c1为0、1、2或3；
    n c2为0、1、2或3；
    n c3为1、2或3；
    n 9为0、1、2、3或4；
    Figure PCTCN2019109368-appb-100007
    为6-10元芳基环或5-10杂芳基环；
    R 9独立选自以下取代基：氘、卤素、氰基、硝基、羟基、氨基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、直链或支链C 1-C 6烷基、直链或支链C 1-C 6烷氧基、C 3-C 6环烷基氧基、C 3-C 6环烷基或杂环烷基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、卤素取代C 1-C 3烷基、卤素取代C 1-C 3烷氧基、苯基、5-6元杂芳基；
    R 10、R 11独立选自为氢、取代或未取代6-10元芳基、取代或未取代5-10元杂芳基，所 述取代类型与上述
    Figure PCTCN2019109368-appb-100008
    环上取代基R 9相同；
    Y 8为螺环结构中非芳香结构部分中氢原子可选地被取代的取代基，Y8可选地被氘、卤素、C 1-C 3烷基、C 1-C 3环烷基、卤素取代的C 1-C 3烷基取代基所取代；
    Y选自–NH–CO–、–NH–CO–NH–、–NH–CO–CH(NHR a9)–或–CH(NHR a9)–时，相对应地Y与A、L形成的连接方式为A–NH–CO––L–、A–NH–CO–NH–L–、A–NH–CO–CH(NHR a9)–L–或A–CH(NHR a9)–L–，其中A为：
    6-10元芳基、5-10元杂芳基、(6-10元芳基)–CH 2–、(5-10元杂芳基)–CH 2–，所述芳基或杂芳基可选地由一个或多个R 5取代基所取代，
    或者A为选自以下基团：
    Figure PCTCN2019109368-appb-100009
    n 1为0、1、2、3或4；
    R 5各自独立地选自氘、卤素、羟基、氨基、氰基、硝基、直链或支链C 1-C 6烷基、直链或支链C 1-C 6烷氧基、C 1-C 3酰基氨基、氨基羰基、苯基、5-6元杂芳基、3-6元杂环基、C 3-C 6环烷基、C 3-C 6环烷基氧基、C 1-C 3烷基氨基羰基、C 1-C 3烷基磺酰基、苯基氧基或5-6元杂芳基氧基，当n 1>1时，各个R 5可以相同或不同；
    R a9选自氢、取代或未取代的C 1-C 10烷基羰基、取代或未取代C 3-C 8环烷基羰基、C 1-C 8的杂环烷基羰基，其中所述取代是指碳链末端被羟基、氨基所取代。
  2. 根据权利要求1所述的化合物以及它们互变异构体、对映体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物，
    其中X 1为-CH 2-或-O-；
    X 2为-CH 2-或-CO-；
    R 1为氢、氘、氟或C 1-C 3直链或支链烃基；
    R 2、R 4各自独立地为氢或氘；
    R 3为氢、氘或卤素；
    L为含有2-8个碳原子的取代或未取代的直链亚烷基，所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代：氘、卤素、羰基、羟基、氨基、氰基、C 1-C 3烷基、卤素取代的C 1-C 3烷基、C 3-C 6环烷基、-NHC(O)Ra 1、-NHC(O)ORa 2、-NRa 3Ra 4，其中Ra 1、Ra 2、Ra 3和Ra 4各自独立地选自氢原子、由卤素、羟基、氰基、硝基取代的C 1-6烷基、由卤素、羟基、氰基、硝基取代的C 3-6环烷基；
    Y不存在，或为–O–、–CO–、–CO–NH–、–NH–CO–、–NH–CO–NH–、–NH–CO–CH(NHR a9)–或–CH(NHR a9)–；
    Y为–O–时，A为：取代或未取代的9-10元芳基、取代或未取代的9-10元杂芳基、(取代或未取代的9-10元芳基)–(CH 2) b1–、(取代或未取代的9-10元杂芳基)–(CH 2) b1–，
    其中，b 1为1或2；
    上述取代或未取代的9-10元芳基或取代或未取代的9-10元杂芳基选自以下基团：
    Figure PCTCN2019109368-appb-100010
    n 2为0、1、2或3；
    n 3为0、1、2或3；
    R 6、R 7各自独立地选自以下基团：氘、卤素、氰基、硝基、氨基、羟基、C 1-C 6烷基、卤素取代的C 1-C 6烷基、羟基取代的C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氧基羰基、卤素取代的C 1-C 6烷氧基、羟基取代的C 1-C 6烷氧基、氰基取代的C 1-C 6烷氧基、C 3-C 6环烷基、 C 3-C 6环烷基氧基、苯基、C 5-C 6杂芳基、C 3-C 6杂环基，-NHC(O)Ra 5、-NHC(O)ORa 6、-NRa 7Ra 8；其中Ra 5、Ra 6、Ra 7和a 8各自独立地为氢原子、由卤素、羟基、C 1-C 6烷氧基、氰基、硝基取代基取代或未取代的C 1-6烷基、或由卤素、羟基、C 1-C 6烷氧基、氰基、硝基取代基取代或未取代的C 3-6环烷基，其中当n 2>1或者n 3>1时，R 6和R 7各自可以相同或不同；
    Y不存在，或为–CO–或–CO–NH–时，相对应地Y与A、L所形成的连接方式为A–L–、A–CO–L–或A–CO–NH–L–，A为：
    i)选自以下的杂环基：
    Figure PCTCN2019109368-appb-100011
    其中，Y 1、Y 2各自独立地为氢、氘、卤素、氰基、羧基、硝基、羟基、氨基、氨基羰基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷基羰基、C 1-C 6烷氧基羰基、C 1-C 6烷基磺酰基、C 1-C 6烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 6酰基氨基、卤素取代C 1-C 6烷基、卤素取代的C 1-C 6烷氧基、C 1-C 3烯基、C 1-C 3炔基、取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、6-10元芳基或5-10元杂芳基取代的C 1-C 3的直链或支链烷基，其中所述取代或未取代的6-10元芳基或5-10元杂芳基是指被以下一种或多种取代基所取代：氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 3酰基氨基、卤素取代C 1-C 3烷基、卤素取代的C 1-C 3烷氧基；
    条件是：当Y 1和Y 2各自独立地为：氢、氘、C 1-C 6烷氧基、卤素、C 1-C 6烷基、C 3-C 6的环烷基、羧基、C 1-C 6烷基氨基羰基、C 1-C 6烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 6烷基、羟基、C 1-C 6烷基磺酰基时，并且Y不存在时，X 1不为-O-；
    Y 3不存在，或为C 1-C 6烷基羰基、氨基羰基、C 3-C 6杂环基、C 1-C 6酰基氨基、卤素取代的C 1-C 6烷氧基、C 1-C 3烯基、C 1-C 3炔基、取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、C 5-C 10的芳基或杂芳基取代的C 1-C 3的直链或支链烷基，其中所述取代或未取代的6-10元芳基或5-10元杂芳基是指被以下一种或多种取代基所取代：氘、卤 素、氰基、硝基、羟基、氨基、氨基羰基、C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 3酰基氨基、卤素取代C 1-C 3烷基、卤素取代的C 1-C 3烷氧基；前述6-10元芳基优选选自苯基、萘基，前述5-10元杂芳基优选选自噻吩基、吡啶基、苯并噻吩基、苯并咪唑基、吲哚基、喹啉基、异喹啉基；
    条件是：当Y 3为氢、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷基氨基羰基、C 1-C 6烷氧基羰基、卤素取代C 1-C 6烷基、C 1-C 6烷基磺酰基或Y3不存在时，并且Y不存在时，X 1不为-O-；
    Y 4、Y 5为其所在杂环上的一个或多个取代基，Y 4、Y5各自独立地为氘、卤素、氧、C 1-C 3烷基、C 1-C 3环烷基或苯基；
    ii)选自以下的稠杂环基：
    Figure PCTCN2019109368-appb-100012
    n 8为0、1、2、3或4；
    X 4为C、N或O；
    Figure PCTCN2019109368-appb-100013
    为6-10元芳基环或5-10元杂芳基环，其中
    Figure PCTCN2019109368-appb-100014
    环优选自苯环、吡啶环、噻吩环、吲哚环、萘环、苯并噻吩环、苯并咪唑环、喹啉环或异喹啉环；
    R 8各自独立地选自氢、氘、C 1-C 3烷氧基、卤素、C 1-C 3烷基、C 3-C 6的环烷基、羧基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 3烷基、羟基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、C 3-C 6的杂环基、卤素取代C 1-C 3烷氧基、苯基或5-6元杂芳基；
    条件是：当上述R 8各自独立地选自下列任意取代基：氢、氘、C 1-C 3烷氧基、卤素、C 1-C 3烷基、C 3-C 6的环烷基、羧基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 3烷基、羟基、C 1-C 3烷基磺酰基时，并且Y为不存在时，X 1不为-O-；
    Y 6、Y 7为其所在杂环上的一个或多个取代基，且各自独立选自氘、卤素、C 1-C 3烷基、C 1-C 3环烷基、卤素取代的C 1-C 3烷基；
    或者iii)选自以下的螺杂环基：
    Figure PCTCN2019109368-appb-100015
    其中，n 9为0、1、2、3或4；
    Figure PCTCN2019109368-appb-100016
    为6-10元芳基环或5-10杂芳基环，优选为噻吩环、吡咯环、苯环、吡啶环、苯并噻吩环、苯并咪唑环、吲哚环、喹啉环和异喹啉环；
    R 9独立地选自以下取代基：氘、卤素、氰基、硝基、羟基、氨基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、直链或支链C 1-C 6烷基、直链或支链C 1-C 6烷氧基、C 3-C 6环烷基氧基、C 3-C 6环烷基或杂环烷基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、卤素取代C 1-C 3烷基、卤素取代C 1-C 3烷氧基、苯基、5-6元杂芳基，其中当n 9>1时，各个R 9可以相同或不同；
    Y 8为螺环结构中非芳香结构部分中氢原子可选地被取代的取代基，Y8可选地被氘、卤素、C 1-C 3烷基、C 1-C 3环烷基、卤素取代的C 1-C 3烷基取代基所取代；
    Y选自–NH–CO–、–NH–CO–NH–、–NH–CO–CH(NHR a9)–或–CH(NHR a9)–时，相对应地Y与A、L所形成的连接方式为A–NH–CO––L–、A–NH–CO–NH–L–、A–NH–CO–CH(NHR a9)–L–或A–CH(NHR a9)–L–，其中A为：
    6-10元芳基、5-10元杂芳基、(6-10元芳基)–CH 2–、(5-10元杂芳基)–CH 2–，前述芳基或杂芳基可选地一个或多个R 5取代基所取代，或者A为选自以下基团：
    Figure PCTCN2019109368-appb-100017
    n 1为0、1、2、3或4；
    R 5各自独立地选自氘、卤素、羟基、氨基、氰基、硝基、直链或支链C 1-C 6烷基、直链或支链C 1-C 6烷氧基、C 1-C 3酰基氨基、氨基羰基、苯基、5-6元杂芳基、3-6元杂环基、C 3-C 6环烷基、C 3-C 6环烷基氧基、C 1-C 3烷基氨基羰基、C 1-C 3烷基磺酰基、苯基氧基或5-6元杂芳基氧基，当n 1>1时，各个R 5可以相同或不同；
    R a9独立地选自氢、取代或未取代的C1-C10烷基羰基、取代或未取代C 3-C 8环烷基羰基、C 1-C 8的杂环烷基羰基，其中所述取代是指碳链末端被羟基、氨基所取代。
  3. 根据权利要求1所述的化合物以及它们互变异构体、对映体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物，
    其中X 1为-CH 2-或-O-；
    X 2为-CH 2-或-CO-；
    R 1为氢、氘或氟；
    R 2、R 4各自独立地为氢或氘；
    R 3为氢、氘或氟；
    L为含有2-8个碳原子的取代或未取代的直链亚烷基，所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代：氘、卤素、氰基、C 1-C 3烷基、卤素取代的C 1-C 3烷基、-NHC(O)Ra 1、-NHC(O)ORa 2、-NRa 3Ra 4，其中Ra 1、Ra 2、Ra 3和Ra 4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C 1-6烷基、或者由一个或多个卤素取代或未取代的C 3-6环烷基；
    Y不存在，或为–O–、–CO–、–CO–NH–、–NH–CO–、–NH–CO–NH–、–NH–CO– CH(NHR a9)–或–CH(NHR a9)–；
    Y为–O–时,A为：选自9-10元芳基、9-10元杂芳基，(9-10元芳基)–(CH2) b1–、(9-10元杂芳基)–(CH2) b1–，所述9-10元芳基或9-10元杂芳基可以是未取代或被取代；
    所述的取代或未取代的9-10元芳基或9-10元杂芳基选自以下基团：
    Figure PCTCN2019109368-appb-100018
    b 1为1或2；
    n 2为0、1、2或3；
    n 3为0、1、2或3；
    R 6、R 7各自独立选自以下基团：氘、卤素、氰基、硝基、氨基、羟基、C 1-C 6烷基、卤素取代的C 1-C 6烷基、羟基取代的C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氧基羰基、卤素取代的C 1-C 6烷氧基、羟基取代的C 1-C 6烷氧基、氰基取代的C 1-C 6烷氧基、C 3-C 6环烷基、C 3-C 6环烷基氧基、苯基、C 5-C 6杂芳基、C 3-C 6杂环基，-NHC(O)Ra 5、-NHC(O)ORa 6、-NRa 7Ra 8；其中Ra 5、Ra 6、Ra 7和Ra 8各自独立地为氢原子、由卤素、羟基、氰基取代的C 1-6烷基、或由卤素、羟基、氰基取代的C 3-6环烷基，其中当n 2>1或者n 3>1时，R 6和R 7各自可以相同或不同；
    Y不存在，或为–CO–或–CO–NH–，相应地Y与A、L所形成的连接方式为–A–CO–L–、–A–CO–NH–L–、–A–L–、A部分至少含有一个氮原子且Y与氮原子连接，A为：
    i)选自以下的杂环基：
    Figure PCTCN2019109368-appb-100019
    n 10为0、1、2、3、4或5；
    Y 1选自氢、氘、卤素、氰基、羧基、硝基、羟基、氨基、氨基羰基、C 1-C 6烷基、C 1-C 6 烷氧基、C 1-C 6烷基羰基、C 1-C 6烷氧基羰基、C 1-C 6烷基磺酰基、C 1-C 6烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 6酰基氨基、卤素取代C 1-C 6烷基、卤素取代的C 1-C 6烷氧基、C 1-C 3烯基、C 1-C 3炔基、取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、6-10元芳基或5-10元杂芳基取代的C 1-C 3的直链或支链烷基，其中所述取代或未取代的6-10元芳基或5-10元杂芳基是指被以下一种或多种取代基所取代：氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 3酰基氨基、卤素取代C 1-C 3烷基、卤素取代的C 1-C 3烷氧基；
    Figure PCTCN2019109368-appb-100020
    选自取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基，优选地，6-10元芳基或5-10元杂芳基优选选自噻吩基、吡啶基、苯基、苯并噻吩基、苯并咪唑基、吲哚基、萘基、喹啉基、异喹啉基；
    R 10各自独立地为氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 3酰基氨基、卤素取代C 1-C 3烷基、卤素取代的C 1-C 3烷氧基，当n 10>1时，各个R 10可以相同或不同；
    Y 4、Y 5为其所在杂环上的一个或多个取代基，Y 4、Y5各自独立地为氘、卤素、甲基、乙基、环丙基或苯基；
    ii)选自以下的稠杂环基：
    Figure PCTCN2019109368-appb-100021
    n 8为0、1、2、3或4；
    X 4为C、N或O；
    R 8各自独立地选自氢、氘、C 1-C 3烷氧基、卤素、C 1-C 3烷基、C 3-C 6的环烷基、羧基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 3烷基、羟基、 C 1-C 3烷基磺酰基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、C 3-C 6的杂环基、卤素取代C 1-C 3烷氧基、苯基或5-6元杂芳基，其中当n 8>1时，各个R 8可以相同或不同；
    条件是：当上述R 8各自独立地选自下列任意取代基：氘、C 1-C 3烷氧基、卤素、C 1-C 3烷基、C 3-C 6的环烷基、羧基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 3烷基、羟基、C 1-C 3烷基磺酰基时，并且Y不存在时，X 1不为-O-；
    Y 6、Y 7为其所在杂环上的一个或多个取代基，且各自独立地选自氘、卤素、甲基、乙基、环丙基、三氟甲基；
    或者iii)选自以下的螺杂环基：
    Figure PCTCN2019109368-appb-100022
    其中，n9为0、1、2、3或4；
    R 9各自独立地选自以下取代基：氘、卤素、氰基、硝基、羟基、氨基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、直链或支链C 1-C 6烷基、直链或支链C 1-C 6烷氧基、C 3-C 6环烷基氧基、C 3-C 6环烷基或杂环烷基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、卤素取代C 1-C 3烷基、卤素取代C 1-C 3烷氧基、苯基、5-6元杂芳基，其中当n 9>1时，各个R 9可以相同或不同；
    Y 8为螺环结构中非芳香结构部分中氢原子可选地被取代的取代基，Y8可选地被氘、卤素、甲基、乙基、环丙基、三氟甲基取代基所取代；
    Y选自–NH–CO–、–NH–CO–NH–、–NH–CO–CH(NHR a9)–或–CH(NHR a9)–时，相应地Y与A、L所形成的连接方式为A–NH–CO––L–、A–NH–CO–NH–L–、A–NH–CO–CH(NHR a9)–L–或A–CH(NHR a9)–L–，其中A为：
    Figure PCTCN2019109368-appb-100023
    n 1为0、1、2、3或4；
    R 5各自独立地选自氘、卤素、羟基、氨基、氰基、硝基、直链或支链C 1-C 6烷基、直链或支链C 1-C 6烷氧基、C 1-C 3酰基氨基、氨基羰基、苯基、5-6元杂芳基、3-6元杂环基、C 3-C 6环烷基、C 3-C 6环烷基氧基、C 1-C 3烷基氨基羰基、C 1-C 3烷基磺酰基、苯基氧基或5-6元杂芳基氧基，当n 1>1时，各个R 5可以相同或不同；
    R a9选自氢、取代或未取代的C1-C10烷基羰基、取代或未取代C 3-C 8环烷基羰基、C 1-C 8的杂环烷基羰基，其中所述取代是指碳链末端被羟基、氨基所取代。
  4. 根据权利要求1所述的化合物以及它们互变异构体、对映体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物，其中通式(I)表示的化合物为通式(I-1)至(I-8)中任意一个表示的化合物：
    Figure PCTCN2019109368-appb-100024
    其中，X 1为-CH 2-或-O-；
    X 2为-CH 2-或-CO-；
    R 1为氢、氘或氟；
    R 2、R 4各自独立地选自为氢或氘；
    R 3为氢、氘或氟；
    L为含有2-8个碳原子的取代或未取代的直链亚烷基，所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代：氘、卤素、氰基、C 1-C 3烷基、卤素取代的C 1-C 3烷基、-NHC(O)Ra 1、-NHC(O)ORa 2、-NRa 3Ra 4，其中Ra 1、Ra 2、Ra 3和Ra 4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C 1-6烷基、或者由一个或多个卤素取代或未取代的C 3-6环烷基；
    Y不存在，或者为–CO–或–CO–NH–；
    n 9为0、1、2、3或4；
    Figure PCTCN2019109368-appb-100025
    为6-10元芳基环或5-10杂芳基环，
    Figure PCTCN2019109368-appb-100026
    与螺环母核稠合形成螺杂环基，优选地，
    Figure PCTCN2019109368-appb-100027
    为噻吩环、吡咯环、苯环、吡啶环、苯并噻吩环、苯并咪唑环、吲哚环、喹啉环和异喹啉环；
    Y 8为螺环结构中非芳香结构部分中氢原子可选地被取代的取代基，Y8可选地被氘、卤素、甲基、乙基、环丙基、三氟甲基取代基所取代；
    R 9各自独立地选自以下取代基：氘、卤素、氰基、硝基、羟基、氨基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、直链或支链C 1-C 6烷基、直链或支链C 1-C 6烷氧基、C 3-C 6环烷基氧基、C 3-C 6环烷基或杂环烷基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、卤素取代C 1-C 3烷基、卤素取代C 1-C 3烷氧基、苯基、5-6元杂芳基，其中当n 9>1时，各个R 9可以相同或不同；
  5. 根据权利要求1所述的化合物以及它们互变异构体、对映体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物，其中通式(I) 表示的化合物为通式(I-9)至(I-16)中任意一个表示的化合物：
    Figure PCTCN2019109368-appb-100028
    其中，X 1为-CH 2-或-O-；
    X 2为-CH 2-或-CO-；
    R 1为氢、氘或氟；
    R 2、R 4各自独立地为氢、氘；
    R 3为氢、氘或氟；
    L为含有2-8个碳原子的取代或未取代的直链亚烷基，所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代：氘、卤素、氰基、C 1-C 3烷基、卤素取代的C 1-C 3烷基、-NHC(O)Ra 1、-NHC(O)ORa 2、-NRa 3Ra 4，其中Ra 1、Ra 2、Ra 3和Ra 4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C 1-6烷基、或由一个或多个卤素取代或未取代的C 3-6环烷基；
    Y不存在，或为–CO–或–CO–NH–；
    n 9为0、1、2、3或4；
    R 9各自独立地选自以下取代基：氘、卤素、氰基、硝基、羟基、氨基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、直链或支链C 1-C 6烷基、直链或支链C 1-C 6烷氧基、C 3-C 6环烷基氧基、C 3-C 6环烷基或杂环烷基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、卤素取代C 1-C 3烷基、卤素取代C 1-C 3烷氧基、苯基、5-6元杂芳基，其中 当n 9>1时，各个R 9可以相同或不同；
    Y 8为螺环结构中非芳香结构部分中氢原子可选地被取代的取代基，Y8可选地被氘、卤素、甲基、乙基、环丙基、三氟甲基取代基所取代。
  6. 根据权利要求1所述的化合物以及它们互变异构体、对映体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物，
    其中通式(I)表示的化合物为通式(I-17)或(I-18)表示的化合物：
    Figure PCTCN2019109368-appb-100029
    其中，X 1为-CH 2-或-O-；
    X 2为-CH 2-或-CO-；
    R 1为氢、氘或氟；
    R 2、R 4各自独立地为氢或氘；
    R 3选自为氢、氘或氟；
    L为含有2-8个碳原子的取代或未取代的直链亚烷基，所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代：氘、卤素、氰基、C 1-C 3烷基、卤素取代的C 1-C 3烷基、-NHC(O)Ra 1、-NHC(O)ORa 2、-NRa 3Ra 4，其中Ra 1、Ra 2、Ra 3和Ra 4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C 1-6烷基或由一个或多个卤素取代或未取代的C 3-6环烷基；
    Y不存在，或为–CO–或–CO–NH–；
    n 10为0、1、2、3、4或5；
    Y 1各自独立地选自氢、氘、卤素、氰基、羧基、硝基、羟基、氨基、氨基羰基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷基羰基、C 1-C 6烷氧基羰基、C 1-C 6烷基磺酰基、C 1-C 6烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 6酰基氨基、卤素取代C 1-C 6烷基、卤素取代的C 1-C 6烷氧基、C 1-C 3烯基、C 1-C 3炔基、取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基、6-10元芳基或5-10元杂芳基取代的C 1-C 3的直链或支链烷基，其中所述取代或未取代的6-10元芳基或5-10元杂芳基是指被以下一种或多种取代基所取代：氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 3酰基氨基、卤素取代C 1-C 3烷基、卤素取代的C 1-C 3烷氧基；
    Figure PCTCN2019109368-appb-100030
    选自取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基，优选地，6-10元芳基或5-10元杂芳基选自噻吩基、吡啶基、苯基、苯并噻吩基、苯并咪唑基、吲哚基、萘基、喹啉基、异喹啉基；
    R 10各自独立地选自氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 3酰基氨基、卤素取代C 1-C 3烷基、卤素取代的C 1-C 3烷氧基，当n 10>1时，各个R 10可以相同或不同；
  7. 根据权利要求1所述的化合物以及它们互变异构体、对映体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物，其中通式(I)表示的化合物为通式(I-19)至(I-23)中任意一个表示的化合物：
    Figure PCTCN2019109368-appb-100031
    其中，X 1为-CH 2-或-O-；
    X 2为-CH 2-或-CO-；
    R 1为氢、氘或氟；
    R 2、R 4各自独立地为氢或氘；
    R 3为氢、氘或氟；
    L为含有2-8个碳原子的取代或未取代的直链亚烷基，所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代：氘、卤素、氰基、C 1-C 3烷基、卤素取代的C 1-C 3烷基、-NHC(O)Ra 1、-NHC(O)ORa 2、-NRa 3Ra 4，其中Ra 1、Ra 2、Ra 3和Ra 4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C 1-6烷基、或由一个或多个卤素取代或未取代的C 3-6环烷基；
    Y不存在，或为–CO–或–CO–NH–；
    n 8为0、1、2、3或4；
    X 4为C、N或O；
    R 8各自独立地为氢、氘、C 1-C 3烷氧基、卤素、C 1-C 3烷基、C 3-C 6的环烷基、羧基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 3烷基、羟基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、C 3-C 6的杂环基、卤素取代C 1-C 3烷氧基、苯基或5-6元杂芳基，其中当n 8>1时，各个R 8可以相同或不同；
    当R 8选自下列任意取代基：氘、C 1-C 3烷氧基、卤素、C 1-C 3烷基、C 3-C 6的环烷基、羧基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 3烷基、羟基、C 1-C 3烷基磺酰基时，并且Y不存在时，X 1不为-O-；
    Y 6、Y 7为其所在杂环上的一个或多个取代基，且各自独立地选自氘、卤素、甲基、乙基、环丙基、三氟甲基；
  8. 根据权利要求1所述的化合物以及它们互变异构体、对映体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物，其中通式(I)表示的化合物为通式(I-24)至(I-32)中任意一个表示的化合物：
    Figure PCTCN2019109368-appb-100032
    其中，X 2为-CH 2-或-CO-；
    R 1为氢、氘或氟；
    R 2、R 4各自独立地为氢或氘；
    R 3选自为氢、氘或氟；
    L为含有2-8个碳原子的取代或未取代的直链亚烷基，所述取代指亚烷基中一个或多个氢原子可选地被下列取代基取代：氘、卤素、氰基、C 1-C 3烷基、卤素取代的C 1-C 3烷基、-NHC(O)Ra 1、-NHC(O)ORa 2、-NRa 3Ra 4，其中Ra 1、Ra 2、Ra 3和Ra 4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C 1-6烷基或由一个或多个卤素取代或未取代的C 3-6环烷基；
    Y不存在，或为–CO–或–CO–NH–；
    n 8、n 9、n 10各自独立地选自0、1、2、3或4；
    X 4为C、N或O；
    R 9选自以下取代基：氘、卤素、氰基、硝基、羟基、氨基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、直链或支链C 1-C 6烷基、直链或支链C 1-C 6烷氧基、C 3-C 6环烷基氧基、C 3-C 6环烷基或杂环烷基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、卤素取代C 1-C 3烷基、卤素取代C 1-C 3烷氧基、苯基、5-6元杂芳基，其中当n 9>1时，各个R 9可以相同或不同；
    Figure PCTCN2019109368-appb-100033
    选自取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基，优选地6-10元芳基或5-10元杂芳基选自噻吩基、吡啶基、苯基、苯并噻吩基、苯并咪唑基、吲哚基、萘基、喹啉基、异喹啉基；
    R 10各自独立地选自氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 3酰基氨基、卤素取代C 1-C 3烷基、卤素取代的C 1-C 3烷氧基，当n 10>1时，各个R 10可以相同或不同；
    R 8各自独立地选自氢、氘、C 1-C 3烷氧基、卤素、C 1-C 3烷基、C 3-C 6的环烷基、羧基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 3烷基、羟基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、C 3-C 6的杂环基、卤素取代C 1-C 3烷氧基、苯基或5-6元杂芳基，当n 8>1时，各个R 8可以相同或不同；
  9. 根据权利要求1所述的化合物以及它们互变异构体、对映体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物，其中通式(I)表示的化合物为通式(I-33)至(I-40)中任意一个表示的化合物：
    Figure PCTCN2019109368-appb-100034
    其中，X 2为-CH 2-或-CO-；
    R 1为氢、氘或氟；
    R 2、R 4各自独立地为氢或氘；
    R 3为氢、氘或氟；
    L为含有2-8个碳原子的取代或未取代的直链亚烷基，所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代：氘、卤素、氰基、C 1-C 3烷基、卤素取代的C 1-C 3烷基、-NHC(O)Ra 1、-NHC(O)ORa 2、-NRa 3Ra 4，其中Ra 1、Ra 2、Ra 3和Ra 4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C 1-6烷基或由一个或多个卤素取代或未取代的C 3-6环烷基；
    Y不存在，或为–CO–、–CO–NH–；
    n 8、n 9、n 10各自独立地为0、1、2、3或4；
    X 4选自C、N或O；
    R 9各自独立地选自以下取代基：氘、卤素、氰基、硝基、羟基、氨基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、直链或支链C 1-C 6烷基、直链或支链C 1-C 6烷氧基、C 3-C 6环烷基氧基、C 3-C 6环烷基或杂环烷基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、卤素取代C 1-C 3烷基、卤素取代C 1-C 3烷氧基、苯基、5-6元杂芳基，当n 9>1时，各个R 9可以相同或不同；
    Figure PCTCN2019109368-appb-100035
    选自取代或未取代的6-10元芳基、取代或未取代的5-10元杂芳基，优选地，6-10元芳基或5-10元杂芳基选自噻吩基、吡啶基、苯基、苯并噻吩基、苯并咪唑基、吲哚基、萘基、喹啉基、异喹啉基；
    R 10各自独立地选自氘、卤素、氰基、硝基、羟基、氨基、氨基羰基、C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷基羰基、C 1-C 3烷氧基羰基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基羰基、C 3-C 6的环烷基或杂环基、C 1-C 3酰基氨基、卤素取代C 1-C 3烷基、卤素取代的C 1-C 3烷氧基，当n 10>1时，各个R 10可以相同或不同；
    R 8各自独立地选自氢、氘、C 1-C 3烷氧基、卤素、C 1-C 3烷基、C 3-C 6的环烷基、羧基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 3烷基、羟基、C 1-C 3烷基磺酰基、C 1-C 3烷基氨基、C 1-C 3酰基氨基、氨基羰基、C 3-C 6的杂环基、卤素取 代C 1-C 3烷氧基、苯基或5-6元杂芳基，其中当n 8>1时，各个R 8可以相同或不同；
    条件是：当R 8选自下列任意取代基：氘、C 1-C 3烷氧基、卤素、C 1-C 3烷基、C 3-C 6的环烷基、羧基、C 1-C 3烷基氨基羰基、C 1-C 3烷氧基羰基、硝基、氨基、氰基、卤素取代C 1-C 3烷基、羟基、C 1-C 3烷基磺酰基时，并且Y不存在时，X 1不为-O-。
  10. 根据权利要求1所述的化合物以及它们互变异构体、对映体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物，其中通式(I)表示的化合物为通式(I-41)至(I-48)中任意一个表示的化合物：
    Figure PCTCN2019109368-appb-100036
    其中，X 1为-CH 2-或-O-；
    X 2为-CH 2-或-CO-；
    R 1为氢、氘或氟；
    R 2、R 4各自独立地为氢或氘；
    R 3为氢、氘或氟；
    L为含有2-8个碳原子的取代或未取代的直链亚烷基，所述取代指所述亚烷基中一个或多个氢原子可选地被下列取代基取代：氘、卤素、氰基、C 1-C 3烷基、卤素取代的C 1-C 3烷基、-NHC(O)Ra 1、-NHC(O)ORa 2、-NRa 3Ra 4，其中Ra 1、Ra 2、Ra 3和Ra 4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C 1-6烷基、或由一个或多个卤素取代或未取 代的C 3-6环烷基；
    n 2为0、1、2或3；
    n 3为0、1、2或3；
    R 6和R 7各自独立地选自以下基团：氘、卤素、氰基、硝基、氨基、羟基、C 1-C 6烷基、卤素取代的C 1-C 6烷基、羟基取代的C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氧基羰基、卤素取代的C 1-C 6烷氧基、羟基取代的C 1-C 6烷氧基、氰基取代的C 1-C 6烷氧基、C 3-C 6环烷基、C 3-C 6环烷基氧基、苯基、C 5-C 6杂芳基、C 3-C 6杂环基，-NHC(O)Ra 5、-NHC(O)ORa 6、-NRa 7Ra 8，其中Ra 5、Ra 6、Ra 7和Ra 8各自独立地选自氢原子、由一个或多个选自卤素、羟基、氰基的取代基所取代或未取代C 1-6烷基、由一个或多个选自卤素、羟基、氰基的取代基所取代或未取代C 3-6环烷基，当n 2>1或者n 3>1时，R 6和R 7各自可以相同或不同。
  11. 根据权利要求1所述的化合物以及它们互变异构体、对映体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物，其中通式(I)表示的化合物为通式(I-49)至(I-53)中任意一个表示的化合物：
    Figure PCTCN2019109368-appb-100037
    其中，X 1为-CH 2-或-O-；
    X 2为-CH 2-或-CO-；
    R 1为氢、氘或氟；
    R 2、R 4各自独立地选自氢或氘；
    R 3为氢、氘或氟；
    L为含有2-8个碳原子的取代或未取代的直链亚烷基，所述取代指所述亚烷基中一个 或多个氢原子可选地被下列取代基取代：氘、卤素、氰基、C 1-C 3烷基、卤素取代的C 1-C 3烷基、-NHC(O)Ra 1、-NHC(O)ORa 2、-NRa 3Ra 4，其中Ra 1、Ra 2、Ra 3和Ra 4各自独立地选自氢原子、由一个或多个卤素取代或未取代的C 1-6烷基、或由一个或多个卤素取代或未取代的C 3-6环烷基；
    Y选自–NH–CO–、–NH–CO–NH–、–NH–CO–CH(NHR a9)–或–CH(NHR a9)–；
    n 1为0、1、2、3或4；
    R 5各自独立地选自氘、卤素、羟基、氨基、氰基、硝基、直链或支链C 1-C 6烷基、直链或支链C 1-C 6烷氧基、C 1-C 3酰基氨基、氨基羰基、苯基、5-6元杂芳基、3-6元杂环基、C 3-C 6环烷基、C 3-C 6环烷基氧基、C 1-C 3烷基氨基羰基、C 1-C 3烷基磺酰基、苯基氧基或5-6元杂芳基氧基，当n 1>1时，各个R 5可以相同或不同；
    R a9选自氢、取代或未取代的C1-C10烷基羰基、取代或未取代C 3-C 8环烷基羰基、C 1-C 8的杂环烷基羰基，其中所述取代是指碳链末端被羟基、氨基所取代。
  12. 根据权利要求1所述的化合物以及它们互变异构体、对映体、非对映体、消旋体、代谢前体、代谢产物、同位素化合物、可药用的盐、酯、前药或其水合物，通式(I)表示的化合物为下列化合物之一：
    Figure PCTCN2019109368-appb-100038
    Figure PCTCN2019109368-appb-100039
    Figure PCTCN2019109368-appb-100040
    Figure PCTCN2019109368-appb-100041
    Figure PCTCN2019109368-appb-100042
    Figure PCTCN2019109368-appb-100043
    Figure PCTCN2019109368-appb-100044
    Figure PCTCN2019109368-appb-100045
    Figure PCTCN2019109368-appb-100046
    Figure PCTCN2019109368-appb-100047
    Figure PCTCN2019109368-appb-100048
    Figure PCTCN2019109368-appb-100049
    Figure PCTCN2019109368-appb-100050
    Figure PCTCN2019109368-appb-100051
    Figure PCTCN2019109368-appb-100052
    Figure PCTCN2019109368-appb-100053
  13. 一种制备根据权利要求1所述通式(I)所示的化合物的方法，所述方法选自如下方法之一：
    合成方法1：
    Figure PCTCN2019109368-appb-100054
    其中，R 1、R 2、R 3、R 4和X 2的定义与权利要求1中定义相同；
    m 1为1～7的整数；
    Figure PCTCN2019109368-appb-100055
    与权利要求1中A定义中的i)杂环基、ii)稠杂环基、iii)螺杂环基定义相同；
    步骤1-1:化合物1A与1B在DMF、DMA等偶极有机溶剂为溶剂，Pd催化剂(如Pd(PPh 3) 4、Pd(PPh 3) 2Cl 2等)、一价铜催化剂(碘化亚酮)和碱(如三乙胺或而二异丙基乙基胺等)的存在下，在室温或加热条件通过Sonogashira偶联反应得到化合物1C；
    步骤1-2:化合物1C在Pd/C、兰尼镍或其它金属催化剂(如威尔金森催化剂)催化条件下被氢气还原为化合物1D，
    步骤1-3:化合物1D与羟基喹啉1E(或为取代或未取代羟基喹啉及其类似物，取代或未取代萘酚及其类似物等)在三苯基膦和偶氮二甲酸二异丙酯条件下反应得到化合物1F；
    步骤1-4:化合物1D在三苯基膦和四溴化碳存在下，反应得到化合物1G；
    步骤1-5:化合物1G和含氮杂环化合物1H(化合物1H为根据权利要求1中含有A基团的各种胺类化合物)在碘化钠存在下反应得到化合物1I；
    合成方法2：
    Figure PCTCN2019109368-appb-100056
    其中，R 1、R 2、R 3、R 4和X 2的定义与权利要求1中的定义相同；
    m 1为1～7的整数；
    Figure PCTCN2019109368-appb-100057
    定义与权利要求1中A中的i)杂环基、ii)稠杂环基、iii)螺杂环基定义相同；
    G2为保护基，选自TBS、Trit、苄基；
    步骤2-1:化合物2A与2B在非质子溶剂为反应溶剂(如乙腈、DMF等)，Pd催化剂(乙酸钯(II)、Pd(PPh 3) 4等)、膦配体(如三苯基膦、s-Phos等)、有机碱(三乙胺或二异丙基乙基胺等)存在下加热反应生成多取代烯烃衍生物(Heck偶联反应)，生成多取代烯烃衍生物2C；
    步骤2-2：化合物2C在在Pd/C或其它金属催化剂(如威尔金森催化剂)催化条件下被氢气还原为化合物2D；
    步骤2-3：以干燥四氢呋喃为溶剂，在叔丁醇钾存在条件下关环得到哌啶酮衍生物2E；
    步骤2-4：化合物2E在酸性条件下或者在TBAF存在条件下，脱除保护基得到化合物2F；
    步骤2-5:化合物2F在三苯基膦和四溴化碳存在下，反应得到化合物2G；
    步骤2-6:化合物2G和含氮杂环化合物2H(化合物2H为根据权利要求1中含有A 基团的各种胺类化合物)在碘化钠存在下反应得到化合物2I；
    合成方法3：
    Figure PCTCN2019109368-appb-100058
    其中，R 1、R 2、R 3、R 4、和X 2的定义与权利要求1中的定义相同；
    m 2为1～7的整数；
    Figure PCTCN2019109368-appb-100059
    与权利要求1中A中i)杂环基、ii)稠杂环基、iii)螺杂环基定义相同；
    G 3-NH 2为本发明实施例中使用的各类芳香胺或脂肪胺化合物；
    步骤3-1:化合物3A与3B在三氟乙酸酐和叔丁醇存在下，反应得到化合物3C；
    步骤3-2：化合物3C和3D在碳酸钾存在的条件下，反应得到化合物3E；
    步骤3-3：化合物3E叔丁醇钾存在条件下关环得到哌啶酮衍生物3F；
    步骤3-4：化合物3F在盐酸条件下，脱除保护基获得化合物3G；
    步骤3-5:化合物3G和含氮杂环化合物3H(化合物3H为根据权利要求1中含有A基团的各种胺类化合物)在缩合剂(HATU、HOBt)及碱(三乙胺)存在下，缩合获得化合物3I；
    步骤3-6:化合物3G和化合物3J在缩合剂(HATU、HOBt)及碱(三乙胺)存在下，缩合获得化合物3K；
    合成方法4：
    Figure PCTCN2019109368-appb-100060
    其中，R 1、R 2、R 3、R 4、X 2、Ra 9、R 11和n 11的定义与权利要求1中的定义相同；
    G 4、G 5为保护基，选自叔丁氧羰基或苄基；
    G 6-NH 2为芳香胺或脂肪胺化合物；
    步骤4-1：化合物4A与4B在Pd催化剂(如Pd(PPh 3) 4、Pd(PPh 3) 2Cl 2等)、一价铜催化剂(碘化亚酮)和碱(如三乙胺或而二异丙基乙基胺等)的存在下，在室温或加热条件、一价铜催化剂和碱的存在下，通过Sonogashira偶联反应得到化合物4C；
    步骤4-2：化合物4C在Pd/C、兰尼镍或其它金属催化剂(如威尔金森催化剂)催化条件下被氢气还原为化合物4D；
    步骤4-3：化合物4D在胺类衍生物4E和缩合剂HATU及HOBt条件下缩合得到化合物4F；
    步骤4-4：化合物4F在盐酸条件下脱除保护基，反应后旋干与相应的酰氯或羧酸反应获得化合物4G；
    步骤4-5:化合物4D和邻苯二胺衍生物4H在缩合剂HATU及HOBt条件下反应后，在酸性条件下加热条件下获得化合物4I；
    步骤4-6:化合物4I在盐酸条件下脱除保护基，反应后旋干与相应的酰氯或羧酸反应 获得化合物4J；
    合成方法5：
    Figure PCTCN2019109368-appb-100061
    其中，R 1、R 2、R 3、R 4、和X 2的定义与权利要求1中的定义相同；
    m 3为1～7的整数；
    Figure PCTCN2019109368-appb-100062
    与权利要求1中A定义中的杂环基、稠杂环基、螺杂环基定义相同；
    Ar为6-10元芳基、5-10元杂芳基，所述芳基或杂芳基可选地一个或多个R 5取代基所取代，R5定义与权利要求1中的定义相同；
    步骤5-1：化合物5A与5B在三苯基膦和偶氮二甲酸二异丙酯条件下，反应得到化合物5C；
    步骤5-2：化合物5C在碳酸钾存在的条件下，反应得到化合物5D；
    步骤5-3：化合物5D在盐酸条件下脱除保护基，得到化合物5E；
    步骤5-4：化合物5E和化合物5F在碱性条件下(如三乙胺或而二异丙基乙基胺等)反应得到化合物5G；
    步骤5-5：化合物5E和含氮杂环化合物5H(化合物5H为根据权利要求1中含有A基团的各种胺类化合物)在N,N'-羰基二咪唑和碱性条件下，反应得到化合物5I；
    合成方法6：
    Figure PCTCN2019109368-appb-100063
    其中，R 1、R 2、R 3、R 4、和X 2的定义与权利要求1中定义相同；
    m 4为1～7的整数；
    Figure PCTCN2019109368-appb-100064
    与权利要求1中A定义中的杂环基、稠杂环基、螺杂环基定义相同；
    步骤6-1：化合物6A与6B在碳酸钾存在条件下，反应得到化合物6C；
    步骤6-2：化合物6C在叔丁醇钾存在的条件下，反应得到化合物6D；
    步骤6-3：化合物6D和含氮杂环化合物6E(化合物6E为根据权利要求1中含有A基团的各种胺类化合物)在碱性条件下，反应得到化合物6F；
    合成方法7
    Figure PCTCN2019109368-appb-100065
    其中，R 1、R 2、R 3、和R 4的定义与权利要求1中的定义相同；
    m 4为1～7的整数；
    Figure PCTCN2019109368-appb-100066
    与权利要求1中A定义中的杂环基、稠杂环基、螺杂环基定义相同；
    步骤7-1：化合物7A与7B氯甲基甲醚在氢化钠存在的条件下反应，得到化合物7C；
    步骤7-2：化合物7C在7D和偶氮二异丁腈存在的条件下反应，得到化合物7E；
    步骤7-3：化合物7E在7F在碱性条件下(如三乙胺或而二异丙基乙基胺等)反应，得到化合物7G；
    步骤7-4：化合物7G在酸性条件下(盐酸，二氧六环)反应，得到化合物7H；
    步骤7-5：化合物7I和7F在碱(如三乙胺或而二异丙基乙基胺等)性条件下反应，得到化合物7H；
    步骤7-6：化合物7H与6B在碳酸钾存在条件下，反应得到化合物7J；
    步骤7-7：化合物7J和含氮杂环化合物7K(化合物7K为根据权利要求1中含有A基团的各种胺类化合物)在碱性(如三乙胺或而二异丙基乙基胺等)条件下，反应得到化合物7L。
  14. 根据权利要求1所述通式(I)所示的化合物，其对映体、非对映体、消旋体、可药用的盐、酯、前药或其水合物，其特征在于，可调控CRL4 CRBNE3泛素连接酶的活性。
  15. 一种药物组合物，其特征在于，包含治疗有效剂量的权利要求1至12中任意一项所述的式(I)的化合物，其对映体、非对映体、消旋体、可药用的盐、酯、前药或其水合物，和至少一种其它药学上可接受的载体。
  16. 一种药物组合物的联合应用，其特征在于，所述药物组合物包含治疗有效剂量的权利要求1至12中任意一项所述的通式(I)所示的化合物，其对映体、非对映体、消旋体、可药用的盐、酯、前药或其水合物，与另外一种或多种具有医药学治疗活性的成分。
  17. 根据权利要求16所述的药物组合物的联合应用，其特征在于，所述另外一种或 多种具有医药学治疗活性的成分包括大分子化合物(例如蛋白、多糖和核酸等)和小分子化合物(例如无机化合物、有机金属化合物、合成或天然来源的有机小分子化合物等)。
  18. 根据权利要求1所述的通式(I)所示的化合物，其对映体、非对映体、消旋体、可药用的盐、酯、前药或其水合物在制备治疗与CRL4 CRBNE3泛素连接酶相关的疾病的药物中的用途，其中，优选地，所述的疾病非限制性地包括癌症、炎症、疼痛、神经***疾病和免疫***疾病。
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KR20210069085A (ko) 2021-06-10
BR112021006458A2 (pt) 2021-07-06
CN110963994B (zh) 2022-02-08
EP3862348A1 (en) 2021-08-11
CA3121667A1 (en) 2020-04-02
CN114085212B (zh) 2023-05-02
US20220041576A1 (en) 2022-02-10
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CN110963994A (zh) 2020-04-07
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