WO2021083328A1 - 多取代异吲哚啉类化合物、其制备方法、药物组合物及用途 - Google Patents

多取代异吲哚啉类化合物、其制备方法、药物组合物及用途 Download PDF

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WO2021083328A1
WO2021083328A1 PCT/CN2020/125270 CN2020125270W WO2021083328A1 WO 2021083328 A1 WO2021083328 A1 WO 2021083328A1 CN 2020125270 W CN2020125270 W CN 2020125270W WO 2021083328 A1 WO2021083328 A1 WO 2021083328A1
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substituted
halogen
alkyl
alkoxy
deuterium
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French (fr)
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陈小华
李佳
李少铜
周宇波
聂辉军
魏丹
徐高亚
周宾山
阚伟娟
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中国科学院上海药物研究所
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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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Definitions

  • the present invention relates to a class of multi-substituted isoindoline compounds with novel structures, pharmaceutically acceptable salts, solvates, pharmaceutical compositions and their use in preparing medicines for treating or preventing various diseases.
  • Tight regulation of protein expression in cells plays an important role in cell function, cell survival and division. Many primary or acquired diseases usually involve abnormal protein function.
  • the traditional method of regulating protein dysfunction is mainly to overdesign targeted inhibitors or agonists. These targeted drugs play an important role in the treatment of diseases. Nevertheless, in order to obtain a satisfactory therapeutic effect, these inhibitors or agonists usually need to be maintained at a higher drug concentration to achieve an effective therapeutic effect, which also leads to adverse drug reactions to a certain extent.
  • Another way to regulate abnormal protein function is to change the dynamic balance of pathologically related proteins.
  • the dynamic balance of protein includes protein synthesis and degradation. For example, small interfering RNA (siRNA), antisense oligonucleotides or gene editing technology can be used.
  • nucleic acid-based technologies change protein synthesis by acting on the transcription and translation process of the target protein.
  • the biggest limitation of this type of technology lies in the stability of nucleic acid in vivo and low bioavailability, and then To a certain extent, its application is limited.
  • Another strategy for regulating protein homeostasis is to regulate the degradation process of proteins. By promoting or inhibiting protein degradation, 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, the target protein can be ubiquitinated and the protein with a special ubiquitin label can be transported. To the proteasome and be degraded by it.
  • the ubiquitination process of protein is a series of multi-step reaction process, which mainly involves three types of enzymes: E1 ubiquitin activating enzyme, E2 ubiquitin conjugating enzyme, and E3 ubiquitin ligase.
  • E1 ubiquitin activating enzyme E2 ubiquitin conjugating enzyme
  • E3 ubiquitin ligase E3 ubiquitin ligase.
  • the C-terminal of ubiquitin is activated by ATP to form an active thioester structure with the cysteine sulfhydryl group in the active center of E1 ubiquitin activating enzyme.
  • the active intermediate covalently connects ubiquitin to the E2 ubiquitin conjugating enzyme through a new thioester structure through a transthioester reaction.
  • E3 ubiquitin ligase recruits the substrate protein and simultaneously binds to the E2 ubiquitin conjugating enzyme-ubiquitin active intermediate, and transfers 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 role as a bridge, but also makes the two reaction components (E2 ubiquitin conjugating enzyme-ubiquitin conjugate and substrate protein) in space. At the same time, they are close to each other, and at the same time they play an enzyme catalytic role, accelerating the rate of ubiquitination of the substrate protein.
  • E3 ubiquitin ligase needs to specifically recognize the substrate, the mammalian genome encodes more than 600 E3 ubiquitin ligases. In contrast, only two E1 ubiquitin activating enzymes and about 40 E2 ubiquitin conjugating enzymes have been discovered so far.
  • CRL4 CRBN E3 ubiquitin ligase belongs to the RING family E3 ubiquitin ligase. It is a protein complex assembled from multiple subunits. The whole complex contains the substrate protein recognition module (CRBN) and E2 ubiquitin binding. Enzyme recognition module (RING domain) and the connecting part between the two (Cullin protein). 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 Enzyme recognition module
  • Cullin protein Cullin protein
  • 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 an immunomodulator—thalidomide and its analogs (Science, 2010, 327, 1345; Science, 2014, 343, 301; Science, 2014, 343, 305; Nature, 2015, 523, 183.).
  • dosamine immunomodulators 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 produce toxic effects on multiple myeloma cells, thereby achieving the effect of treating malignant myeloid tumors including multiple myeloma.
  • lenalidomide an analogue of thalidomide
  • CRL4 CRBN E3 ubiquitin ligase can selectively induce the ubiquitination and degradation of CK1 ⁇ through CRL4 CRBN E3 ubiquitin ligase to achieve the treatment of 5q deletion myelodysplastic synthesis. (MDS), while another structural analogue of thalidomide (CC-885) can selectively induce and degrade GSPT1 by acting on CRL4 CRBN E3 ubiquitin ligase, showing a strong effect on a variety of tumor cells. The cytotoxicity.
  • the indications of the dosamine drug molecules are also expanding, such as the FDA-approved thalidomide for the treatment of leprosy erythema nodosa, lenadus Pomalidomide is used to treat prostate cancer in clinical trials, and pomalidomide is used to treat myelofibrosis in clinical trials.
  • lenalidomide lenalidomide
  • pomalidomide CC-122, CC-220, and CC-885
  • the characteristic of this class of compounds is that after structural changes and adjustments, the compounds have Different pharmacological activities and completely different therapeutic effects can be used clinically to treat different indications.
  • WO2008115516A2 US8153659B2, US9181216B2, and 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 is a variety of substituted aryl groups.
  • the representative compound is CC-220:
  • WO2007027527A2 discloses a class of compounds represented by the general formula S3:
  • WO2008027542A2, US8877780B2, and US9447070B2 disclose a class of compounds represented by the general formula S3:
  • the mechanism of action of lenalidomide and some of the above-mentioned molecules is: compounds of different structures can bind to CRBN, causing the conformational change of the CRBN binding part, thereby recruiting different endogenous biological macromolecules to bind to CRBN;
  • the endogenous substrate protein is ubiquitinated and degraded, so it can produce different pharmacological activities, which can be used to treat different indications in clinical trials.
  • lenalidomide is mainly used for the treatment of multiple myeloma and myelodysplastic syndromes, but the effect 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 novel structural compounds as modulators of CRL4 CRBN E3 ubiquitin ligase can further improve the therapeutic effect of tumors and expand the clinical needs of new indications for diamine drugs; diamine molecules with different structures The pharmacological activity and pharmacological properties of saccharin are not known, and the properties and effects of all aspects are uncertain.
  • the inventors of the present invention obtained the following important information by analyzing the crystal structure of the complex between CRBN and small molecules (PDB ID: 4CI2, 5HXB): CRBN and small molecules have multiple binding pockets, so they can develop complex structures. Small molecules with three binding sites, to realize the effective combination of CRBN and small molecules. At the same time, according to the characteristics of the crystal structure, the different structures of the chains connected to the hydrophobic fragments will determine the binding mode and binding ability of small molecules with CRBN.
  • the molecular dynamics simulation method is used to analyze the structure dynamics and binding site of the interface between the model molecule and the E3 ubiquitin ligase, combined with molecular docking and complex-based pharmacophore matching, and the compound is determined by a scoring function.
  • the binding mode and interaction of the active site of E3 ubiquitin ligase were evaluated, and a new type of small molecule regulator of CRBN specific to the linking chain was obtained.
  • the inventors designed and synthesized a series of small molecule modulators of CRBN described in this application, and tested the activity of the compounds. The test results show that the new small molecule regulator has very high cell growth inhibitory activity.
  • the designed and synthesized compound of the present invention is used in the preparation of drugs for the treatment of diseases or dysfunctions related to CRL4 CRBN E3 ubiquitin ligase.
  • the diseases or dysfunction diseases mainly include cancer, inflammation, pain, nerve System diseases and immune system diseases.
  • An object of the present invention is to provide a compound represented by the following general formula (I) or its tautomers, enantiomers, diastereomers, racemates, isotopic compounds, metabolic precursors, metabolites, and medicinal products
  • Another object of the present invention is to provide important intermediates and preparation methods of such compounds. Enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or crystal forms
  • Another object of the present invention is to provide a pharmaceutical composition, which is characterized by comprising a therapeutically effective dose of a compound selected from the general formula (I), its tautomers, enantiomers, and diastereomers , Racemates, isotopic compounds, metabolic precursors, metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates, and one or more of crystalline forms, and at least one pharmaceutically acceptable Accepted carrier.
  • a compound selected from the general formula (I) tautomers, enantiomers, and diastereomers , Racemates, isotopic compounds, metabolic precursors, metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates, and one or more of crystalline forms, and at least one pharmaceutically acceptable Accepted carrier.
  • the pharmaceutical composition may also contain another one or more ingredients with pharmacologically therapeutic activity.
  • the compound represented by the general formula (I) of the present invention its tautomers, enantiomers, diastereomers, racemates, isotopic compounds, metabolic precursors, metabolites, pharmaceutically acceptable salts, esters, Prodrugs, solvates, hydrates or crystal forms can have a synergistic effect with another one or more ingredients with pharmacologically therapeutic activity in the prevention or treatment of specific diseases or dysfunctions.
  • the compound represented by the general formula (I) of the present invention can also alleviate or eliminate the toxic and side effects of another one or more pharmacologically active ingredients in the prevention or treatment of specific diseases or dysfunctions, and vice versa The same is true.
  • ingredients with pharmacological and therapeutic activity including macromolecular compounds, such as proteins, polysaccharides and nucleic acids, etc.; and small molecular compounds, such as inorganic compounds, organometallic compounds, synthetic or natural-derived organic Small molecule compounds, etc.
  • Another object of the present invention is to provide a compound selected from the general formula (I), its tautomers, enantiomers, diastereomers, racemates, isotopic compounds, metabolic precursors, metabolites, Use of one or more of pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates and crystal forms for the preparation of drugs for the treatment of diseases or dysfunctions related to CRL4 CRBN E3 ubiquitin ligase,
  • the disease or dysfunction includes, without limitation, cancer, pain, nervous system disease and immune system disease.
  • the present invention provides a compound represented by the following general formula (I) or its tautomers, enantiomers, diastereomers, racemates, metabolic precursors, metabolites, isotopic compounds, Pharmaceutical salts, esters, prodrugs, solvates, hydrates or crystal forms:
  • n 1, 2, 3, 4 or 5;
  • X 1 is -CH 2 -, -NH-, -S- or -O-;
  • X 2 is -CH 2 -or -CO-
  • R 1 , R 2 , and R 3 are each independently hydrogen, deuterium or halogen
  • L does not exist, or is a substituted or unsubstituted linear alkylene group containing 1-5 carbon atoms, one or more of the hydrogen atoms in the alkylene group is optionally substituted by the following substituents: deuterium, halogen, Carbonyl, hydroxyl, amino, cyano;
  • A is:
  • a 1 is a 6-10 membered aryl group, a 5-10 membered heteroaryl group, (6-10 membered aryl)-(CH 2 ) b1 -, (5-10 membered heteroaryl)-(CH 2 ) b1- ,
  • the aforementioned aryl or heteroaryl group is optionally substituted by one or more of the following groups: 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,
  • b 1 is 1 or 2;
  • a 1 is selected from the following groups:
  • n 1 is 0, 1, 2, 3 or 4;
  • R 5 is each independently selected from deuterium, halogen, hydroxyl, amino, cyano, nitro, linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, C 1 -C 3 acylamino, aminocarbonyl, phenyl, 5-6 membered heteroaryl, 3-6 membered heterocyclic group, 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;
  • 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, carboxy, 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 heteroaryl substituted
  • Y 3 does not exist, 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 linear or branched alkyl, wherein the substituted or unsubstituted 6-10 membere
  • Y 4 and Y 5 are one or more substituents on the heterocyclic ring where Y 4 and Y 5 are each independently deuterium, halogen, oxygen, C 1 -C 3 alkyl, C 1 -C 3 cycloalkyl , C 1 -C 3 alkyl or phenyl substituted by halogen;
  • 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 benzene ring, pyridine ring, thiophene ring, indole ring, benzothiophene ring, benzimidazole ring, naphthalene ring, quinoline ring or 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 heterocyclic group, halogen substituted C 1 -C 3 alkoxy, phenyl or 5-6 membered heteroaryl;
  • Y 6 and Y 7 are one or more substituents on the heterocyclic ring, and are each independently selected from deuterium, halogen, C 1 -C 3 alkyl, C 1 -C 3 cycloalkyl, halogen substituted C 1 -C 3 alkyl;
  • 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, hydroxyl, amino, C 1 -C 3 alkylamino, C 1 -C 3 acylamino, aminocarbonyl, linear or branched C 1 -C 6 alkyl, linear 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, substituted or unsubstituted 5-10 membered heteroaryl, and the substitution type is the same as the above
  • the substituents R 9 on the ring are the same;
  • Y 8 is a substituent in which the hydrogen atom in the non-aromatic part of the spiro ring structure is optionally substituted, and Y 8 is optionally deuterium, halogen, C 1 -C 3 alkyl, C 1 -C 3 cycloalkyl, halogen Substituted by substituted C 1 -C 3 alkyl substituents.
  • n 1, 2, 3, 4 or 5;
  • X 1 is -CH 2 -, -NH-, -S- or -O-;
  • X 2 is -CH 2 -or -CO-
  • R 1 , R 2 , and R 3 are each independently hydrogen, deuterium or halogen
  • L does not exist, or is a substituted or unsubstituted linear alkylene group containing 1-5 carbon atoms, one or more of the hydrogen atoms in the alkylene group is optionally substituted by the following substituents: deuterium, halogen, Carbonyl, hydroxyl, amino, cyano;
  • A is:
  • a 1 is a 6-10 membered aryl group, a 5-10 membered heteroaryl group, (6-10 membered aryl)-(CH 2 ) b1 -, (5-10 membered heteroaryl)-(CH 2 ) b1- ,
  • the aforementioned aryl or heteroaryl group is optionally substituted by one or more of the following groups: 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,
  • b 1 is 1 or 2;
  • a 1 is selected from the following groups:
  • n 1 is 0, 1, 2, 3 or 4;
  • R 5 is each independently selected from deuterium, halogen, hydroxyl, amino, cyano, nitro, linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, C 1 -C 3 acylamino, aminocarbonyl, phenyl, 5-6 membered heteroaryl, 3-6 membered heterocyclic group, 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;
  • 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 heterocycle 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 3 does not exist, 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
  • Y 4 and Y 5 are one or more substituents on the heterocycle where Y 4 and Y5 are each independently deuterium, halogen, oxygen, 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
  • 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 heterocyclic group, halogen substituted C 1 -C 3 alkoxy, phenyl or 5-6 membered heteroaryl, where n 8 >1 When, each R 8 can be the same or different;
  • Y 6 and Y 7 are one or more substituents on the heterocyclic ring where they are located, and are each independently selected from deuterium, halogen, C 1 -C 3 alkyl, C 1 -C 3 cycloalkyl, halogen substituted C 1 -C 3 alkyl;
  • a spiroheterocyclic group selected from:
  • n 9 is 0, 1, 2, 3 or 4;
  • aryl ring or 5-10 heteroaryl ring preferably thiophene ring, pyrrole ring, benzene ring, pyridine ring, benzothiophene ring, benzimidazole ring, indole ring, quinoline ring and iso Quinoline ring;
  • 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 a substituent in which the hydrogen atom in the non-aromatic part of the spiro ring structure is optionally substituted, and Y 8 is optionally deuterium, halogen, C 1 -C 3 alkyl, C 1 -C 3 cycloalkyl, halogen Substituted by substituted C 1 -C 3 alkyl substituents.
  • n 1, 2, 3, 4 or 5;
  • X 1 is -CH 2 -, -NH-, -S- or -O-;
  • X 2 is -CH 2 -or -CO-
  • R 1 , R 2 , and R 3 are each independently hydrogen, deuterium or fluorine;
  • L is (CH 2 ) b3 or does not exist
  • b 3 is 1, 2, 3, 4 or 5;
  • A is:
  • a 1 is a 6-10 membered aryl group, a 5-10 membered heteroaryl group, (6-10 membered aryl)-(CH 2 ) b1 -, (5-10 membered heteroaryl)-(CH 2 ) b1- ,
  • the aforementioned 6-10 membered aryl group or 5-10 membered heteroaryl group may be unsubstituted or substituted;
  • the substituted or unsubstituted 6-10 membered aryl group or 5-10 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 following groups: 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 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 atom, composed
  • a 1 is selected from the following groups:
  • n 1 is 0, 1, 2, 3 or 4;
  • R 5 is each independently selected from deuterium, halogen, hydroxyl, amino, cyano, nitro, linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, C 1 -C 3 acylamino, aminocarbonyl, phenyl, 5-6 membered heteroaryl, 3-6 membered heterocyclic group, 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;
  • 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 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 member Aryl, substituted or unsubstituted 5-10 membered heteroaryl, 6-10 membered aryl or 5-10 membered heteroaryl substituted C 1
  • substituted or unsubstituted 6-10 membered aryl groups, substituted or unsubstituted 5-10 membered heteroaryl groups, preferably 6-10 membered aryl groups or 5-10 membered heteroaryl groups are preferably selected from thienyl groups, Pyridyl, phenyl, benzothienyl, benzimidazolyl, indolyl, naphthyl, quinolyl, isoquinolyl;
  • 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, each 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 heterocyclic group, halogen substituted C 1 -C 3 alkoxy, phenyl or 5-6 membered heteroaryl, where n 8 >1 When, each R 8 can be the same or different;
  • Y 6 and Y 7 are one or more substituents on the heterocyclic ring where they are located, and each is independently selected from deuterium, halogen, methyl, ethyl, cyclopropyl, and trifluoromethyl;
  • a spiroheterocyclic group 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, hydroxyl, amino, C 1 -C 3 alkylamino, C 1 -C 3 acylamino, aminocarbonyl, straight or branched chain C 1 -C 6 alkyl, linear 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 a substituent in which the hydrogen atom in the non-aromatic part of the spiro ring structure is optionally substituted, and Y8 is optionally substituted with deuterium, halogen, methyl, ethyl, cyclopropyl, and trifluoromethyl substituents. .
  • the compound represented by general formula (I) is a compound represented by any one of general formulas (I-1) to (I-8):
  • n 1, 2, 3, 4 or 5;
  • X 1 is -CH 2 -, -NH-, -S- or -O-;
  • X 2 is -CH 2 -or -CO-
  • R 1 , R 2 , and R 3 are each independently hydrogen, deuterium or fluorine;
  • L is (CH 2 ) b3 or does not exist
  • b 3 is 1, 2, 3, 4 or 5;
  • n 9 is 0, 1, 2, 3 or 4;
  • Is a 6-10 membered aryl ring or a 5-10 heteroaryl ring, and Condensed with the spiro ring nucleus to form a spiro heterocyclic group preferably, Be thiophene ring, pyrrole ring, benzene ring, pyridine ring, benzothiophene ring, benzimidazole ring, indole ring, quinoline ring and isoquinoline ring;
  • Y 8 is a substituent in which the hydrogen atom in the non-aromatic part of the spiro ring structure is optionally substituted, and Y8 is optionally substituted with deuterium, halogen, methyl, ethyl, cyclopropyl, and trifluoromethyl substituents. ;
  • R 9 is each independently selected from the following substituents: deuterium, halogen, cyano, nitro, hydroxyl, amino, C 1 -C 3 alkylamino, C 1 -C 3 acylamino, aminocarbonyl, straight or branched chain C 1 -C 6 alkyl, linear 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 general formula (I) is a compound represented by any one of general formulas (I-9) to (I-16):
  • n 1, 2, 3, 4 or 5;
  • X 1 is -CH 2 -, -NH-, -S- or -O-;
  • X 2 is -CH 2 -or -CO-
  • R 1 , R 2 , and R 3 are each independently hydrogen, deuterium or fluorine;
  • L is (CH 2 ) b3 or does not exist
  • b 3 is 1, 2, 3, 4 or 5;
  • n 9 is 0, 1, 2, 3 or 4;
  • R 9 is each independently selected from the following substituents: deuterium, halogen, cyano, nitro, hydroxyl, amino, C 1 -C 3 alkylamino, C 1 -C 3 acylamino, aminocarbonyl, straight or branched chain C 1 -C 6 alkyl, linear 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 a substituent in which the hydrogen atom in the non-aromatic part of the spiro ring structure is optionally substituted, and Y8 is optionally substituted with deuterium, halogen, methyl, ethyl, cyclopropyl, and trifluoromethyl substituents. .
  • the compound represented by general formula (I) is a compound represented by either general formula (I-17) or (I-18):
  • n 1, 2, 3, 4 or 5;
  • X 1 is -CH 2 -, -NH-, -S- or -O-;
  • X 2 is -CH 2 -or -CO-
  • R 1 , R 2 , and R 3 are each independently hydrogen, deuterium or fluorine;
  • L is (CH 2 ) b3 or does not exist
  • b 3 is 1, 2, 3, 4 or 5;
  • n 9 is 0, 1, 2, 3 or 4;
  • n 10 is 0, 1, 2, 3, 4 or 5;
  • Y 1 are 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 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
  • 6-10 membered aryl groups substituted or unsubstituted 5-10 membered heteroaryl groups, preferably, 6-10 membered aryl groups or 5-10 membered heteroaryl groups are selected from thienyl and pyridine Group, phenyl, benzothienyl, benzimidazolyl, indolyl, naphthyl, quinolyl, isoquinolyl;
  • 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 heterocyclic group, C 1 -C 3 acyl
  • n 10 >1 each R 10 may be the same or different.
  • the compound represented by general formula (I) is a compound represented by any one of general formulas (I-19) to (I-22):
  • n 1, 2, 3, 4 or 5;
  • X 1 is -CH 2 -, -NH-, -S- or -O-;
  • X 2 is -CH 2 -or -CO-
  • R 1 , R 2 , and R 3 are each independently hydrogen, deuterium or fluorine;
  • L is (CH 2 ) b3 or does not exist
  • b 3 is 1, 2, 3, 4 or 5;
  • 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 group, aminocarbonyl group, C 3 -C 6 heterocyclic group, halogen substituted C 1 -C 3 alkoxy group, phenyl group or 5-6 membered heteroaryl group, wherein when n 8 >1 , Each R 8 can be the same or different;
  • Y 6 and Y 7 are one or more substituents on the heterocyclic ring, and are each independently selected from deuterium, halogen, methyl, ethyl, cyclopropyl, and trifluoromethyl.
  • the compound represented by general formula (I) is a compound represented by any one of general formulas (I-23) to (I-32):
  • n 1, 2 or 3;
  • X 2 is -CH 2 -or -CO-
  • R 1 , R 2 , and R 3 are each independently hydrogen, deuterium or fluorine;
  • L is (CH 2 ) b3 or does not exist
  • b 3 is 1, 2, 3, 4 or 5;
  • n 8 , n 9 , and 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 alkane 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;
  • substituted or unsubstituted 6-10 membered aryl groups substituted or unsubstituted 5-10 membered heteroaryl groups, preferably 6-10 membered aryl groups or 5-10 membered heteroaryl groups are selected from thienyl and pyridyl groups , Phenyl, benzothienyl, benzimidazolyl, indolyl, naphthyl, quinolyl, isoquinolyl;
  • 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 heterocyclic group, 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 heterocyclic group, 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 general formula (I) is a compound represented by any one of general formulas (I-33) to (I-42):
  • n 1, 2 or 3;
  • X 2 is -CH 2 -or -CO-
  • R 1 , R 2 , and R 3 are each independently hydrogen, deuterium or fluorine;
  • L is (CH 2 ) b3 or does not exist
  • b 3 is 1, 2, 3, 4 or 5;
  • 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, hydroxyl, amino, C 1 -C 3 alkylamino, C 1 -C 3 acylamino, aminocarbonyl, straight or branched chain C 1 -C 6 alkyl, linear 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 groups substituted or unsubstituted 5-10 membered heteroaryl groups, preferably, 6-10 membered aryl groups or 5-10 membered heteroaryl groups are selected from thienyl and pyridine Group, phenyl, benzothienyl, benzimidazolyl, indolyl, naphthyl, quinolyl, isoquinolyl;
  • 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 heterocyclic group, 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 heterocyclic group, halogen substituted C 1 -C 3 alkoxy, phenyl or 5-6 membered heteroaryl, where n 8 >1 When, each R 8 may be the same or different.
  • the compound represented by general formula (I) is a compound represented by any one of general formulas (I-43) to (I-50):
  • n 1, 2 or 3;
  • X 1 is -CH 2 -or -O-;
  • X 2 is -CH 2 -or -CO-
  • R 1 , R 2 , and R 3 are each independently hydrogen, deuterium or fluorine;
  • L is (CH 2 ) b3 or does not exist
  • b 3 is 1, 2, 3, 4 or 5;
  • n 2 is 0, 1, 2 or 3;
  • n 3 is 0, 1, 2 or 3;
  • n 11 is 0, 1 or 2;
  • R 6 and R 7 are each independently selected from the following groups: deuterium, halogen, cyano, nitro, amino, hydroxy, 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 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 selected from hydrogen atoms, consisting
  • the compound represented by general formula (I) is a compound represented by any one of general formulas (I-51) to (I-58):
  • n 1, 2 or 3;
  • X 1 is -CH 2 -or -O-;
  • X 2 is -CH 2 -or -CO-
  • R 1 , R 2 , and R 3 are each independently hydrogen, deuterium or fluorine;
  • L is (CH 2 ) b3 or does not exist
  • b 3 is 1, 2, 3, 4 or 5;
  • n 1 is 0, 1, 2, 3 or 4;
  • R 5 is each independently selected from deuterium, halogen, hydroxyl, amino, cyano, nitro, linear or branched C 1 -C 6 alkyl, linear or branched C 1 -C 6 alkoxy, C 1 -C 3 acylamino, aminocarbonyl, phenyl, 5-6 membered heteroaryl, 3-6 membered heterocyclic group, 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.
  • the compound represented by 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 therefore may exist in the form of different stereoisomers.
  • the compounds of the present invention include all stereoisomeric forms, including but not limited to diastereomers, enantiomers, atropisomers and their mixtures (such as racemates), which are all included in the present invention In the range.
  • substituted refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent.
  • the specific substituents are the substituents correspondingly described in the foregoing, or the substituents appearing in each embodiment.
  • an arbitrarily substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different in each position.
  • Cyclic substituents, such as heterocycloalkyl can be attached to another ring, such as cycloalkyl, 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, can be the same or different substituents, which means that when the number of substituents in a certain structure is more than one, the combination of R substituents can be selected from multiple Different types of substituents.
  • substitution only applies to sites that can be substituted by substituents, and does not include substitutions that cannot be achieved based on existing chemical knowledge.
  • the compounds represented by the general formula (I) may also exist in different tautomeric forms, and all these forms are included in the scope of the present invention.
  • tautomers refers to structural isomers with different energies that are mutually transformed via a low energy barrier, and the reaction generally results in a shift in the form of hydrogen atoms or protons accompanying the transformation of single bonds and adjacent double bonds.
  • enantiomers refers to stereoisomers that are mirror images of each other and are not superimposable.
  • Stereomers refer to stereoisomers that have two or more chiral neutralities and are not mirror images.
  • Racemate refers to two stereoisomers that are mirror images of each other, with opposite optical rotations, which cancel each other out.
  • “Pharmaceutically acceptable salt” means that the drug molecule forms a corresponding salt with the corresponding organic acid, inorganic acid or organic base or inorganic base, such as hydrochloric acid, formic acid, trifluoroacetic acid, succinic acid, methanesulfonate and the like.
  • Prodrug refers to a class of compounds that are inactive or less active in vitro, and release active drugs through enzymatic or non-enzymatic transformation in the body to exert pharmacological effects.
  • Hydrophilate refers to a compound containing water.
  • halogen includes fluorine, chlorine, bromine or iodine.
  • hydrocarbyl refers to a substituent containing only carbon atoms 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, including, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl , Sec-butyl, tert-butyl, pentyl and hexyl etc.
  • 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 so on.
  • C1-C6 alkoxycarbonyl includes, without limitation, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxy Group carbonyl, tert-butoxycarbonyl, pentoxycarbonyl and hexoxycarbonyl, etc.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentenyl, and cyclohexyl.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyls.
  • heterocyclyl refers to a substituent 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, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, Thiomorpholinyl; heterocyclic group can be fused with aryl, heteroaryl, or cycloalkyl ring, and the ring connected with the parent structure is heterocyclic group.
  • aryl refers to a 6-14 membered all-carbon monocyclic or fused polycyclic group with a conjugated p-electron system, preferably a 6 to 10 membered ring, preferably a 6 to 10 membered ring, more preferably a phenyl group And naphthyl, phenyl is most preferred.
  • the aryl ring may be fused to 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, where the heteroatoms include oxygen, sulfur, and nitrogen. Preferably it is 5-10 yuan. Heteroaryl groups are preferably 5-membered 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,
  • spiroheterocyclic group refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between single rings, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O)m (Wherein m is an integer from 0 to 2), the remaining ring atoms are carbon.
  • the spiro heterocyclic ring can be fused to a 6-10 membered aryl or 5-10 membered heteroaryl ring, and the ring connected to the parent structure is a spiro heterocyclic ring.
  • halogen-substituted alkyl refers to a linear, branched, or cyclic alkyl group substituted with single or multiple halogens, and includes, without limitation, 2-bromoethyl, 2-bromopropyl, and the like.
  • alkenyl refers to an alkenyl group of 2-10 carbons, such as vinyl, propenyl, butenyl, styryl, and phenpropenyl.
  • alkynyl refers to an alkynyl group that can be 2-10 carbons, such as ethynyl, propynyl, butynyl, phenylethynyl, phenpropenyl.
  • C3-C8 cycloalkyl refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring, and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • 5-10 membered heterocyclic group refers to a ring containing one or more saturated and/or partially saturated rings, which includes 5 to 10 ring atoms, of which one or more ring atoms are selected from nitrogen, oxygen, sulfur or S (O) Heteroatoms of m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon; for example, propylene oxide, tetrahydrofuranyl, pyrrolidinyl, 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, of which one or more ring atoms are selected from nitrogen, oxygen, sulfur or S( O) Heteroatoms of m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon; for example, propylene oxide, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, and piperazinyl.
  • hydroxy-substituted alkyl refers to a linear, branched or cyclic alkyl group substituted with single or multiple hydroxy groups, including (S)-1-hydroxyisobut-2-yl, (R) without limitation -1-Hydroxyisobut-2-yl and the like.
  • the present invention also includes any of the new intermediates disclosed herein.
  • Another aspect of the present invention provides a method for preparing the compound represented by the general formula (I), and the method is selected from one of the following methods:
  • R 1 , R 2 , R 3 , X 2 and n are the same as those in claim 1;
  • n 1 is an integer of 1 to 4.
  • a in compound H 2 NA is the same as the definition of A in claim 1 in i) A 1 -NH-, ii) heterocyclic group, iii) fused heterocyclic group, and iv) spiro heterocyclic group;
  • Step 1-1 Compound 1A and 1B dibromo aliphatic alkane undergo nucleophilic reaction in the presence of potassium carbonate to obtain compound 1C;
  • Step 1-2 Compound 1C is reacted with carboxyl-protected amino acid 1D in the presence of potassium carbonate to obtain compound 1E;
  • Step 1-3 Compound 1E is ring closed in the presence of potassium tert-butoxide to obtain piperidone derivative 1F;
  • Steps 1-4 The protective group of compound 1F is removed under acidic conditions of dioxane hydrochloride to obtain 1G;
  • Step 1-5 Compounds 1G and 1H obtain 1I under the condition of condensing agent
  • R 1 , R 2 , R 3 , X 2 and n are the same as those in claim 1;
  • n 2 is an integer of 1 to 3;
  • a in compound H 2 NA is the same as the definition of A in claim 1 in i) A 1 -NH-, ii) heterocyclic group, iii) fused heterocyclic group, and iv) spiro heterocyclic group;
  • Step 2-1 Compounds 2A and 2B are used as solvents in dipolar organic solvents such as DMF and DMA, Pd catalysts (such as Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2, etc.), monovalent copper catalysts (iodination In the presence of ketone) and a base (such as triethylamine or diisopropylethylamine, etc.), compound 2C is obtained by Sonogashira coupling reaction at room temperature or under heating conditions;
  • Pd catalysts such as Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2, etc.
  • monovalent copper catalysts iodination In the presence of ketone
  • a base such as triethylamine or diisopropylethylamine, etc.
  • Step 2-2 Compound 2C is reduced to compound 2D by hydrogen under the catalytic conditions of Pd/C, Raney nickel or other metal catalysts (such as Wilkinson catalyst),
  • Step 2-3 Compound 2D is reacted in the presence of triphenylphosphine and carbon tetrabromide to obtain compound 2E;
  • Step 2-4 Compound 2E is reacted with carboxyl-protected amino acid 1D in the presence of potassium carbonate to obtain compound 2F;
  • Step 2-5 The protective group of compound 2F is removed under acidic conditions of dioxane hydrochloride to obtain 2G;
  • Step 2-6 Compounds 2G and 1H obtain 2I under condensing agent conditions.
  • Acids suitable for salt formation include, without limitation, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, horse Organic acids such as lactic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, toluenesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, horse Organic acids such as lactic acid, lactic acid, malic acid,
  • the compound represented by the general formula (I) of the present invention can regulate the activity of CRL4 CRBN E3 ubiquitin ligase.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of a compound selected from the group consisting of general formula (I), its tautomers, diastereomers, racemates, and metabolic precursors , One or more of metabolites, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates and crystal forms, and at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention may also contain another one or more ingredients with pharmacologically therapeutic activity.
  • the compound represented by the general formula (I) of the present invention, or its tautomers, enantiomers, diastereomers, racemates, metabolic precursors, metabolites, isotopic compounds, or pharmaceutically acceptable salts thereof , Esters, prodrugs, solvates, hydrates or crystal forms can have a synergistic effect with another one or more pharmacologically active ingredients in the prevention or treatment of specific diseases or dysfunctions, or can also reduce or Eliminate the toxic and side effects of another one or more active ingredients with pharmacological treatment in the process of preventing or treating specific diseases or dysfunctions, and vice versa.
  • the other one or more ingredients with medical therapeutic activity including macromolecular compounds, such as proteins, polysaccharides and nucleic acids, etc.; and small molecule compounds, such as inorganic compounds, organometallic compounds, synthetic or natural-derived organic small molecules Compound etc.
  • macromolecular compounds such as proteins, polysaccharides and nucleic acids, etc.
  • small molecule compounds such as inorganic compounds, organometallic compounds, synthetic or natural-derived organic small molecules Compound etc.
  • the typical formulation of the pharmaceutical composition of the present invention is selected from the compound represented by the general formula (I) of the present invention, its tautomers, diastereomers, racemates, metabolic precursors, metabolites, isotopes by mixing
  • One or more of compounds, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates and crystal forms and carriers (such as diluents, excipients, etc.) are prepared.
  • Suitable carriers are well known to those skilled in the art and include substances such as carbohydrates, waxes, water-soluble and/or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water and the like.
  • 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 with 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 buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, sunscreens, glidants, processing aids, Coloring agents, sweetening agents, flavoring agents, flavoring agents or other known additives enable the compound represented by formula (I) to be manufactured or used in an acceptable form.
  • the two drugs or more drugs can be used separately or in combination, and are preferably administered in the form of a pharmaceutical composition.
  • the compound or pharmaceutical composition of formula (I) of the present invention can be administered separately or together in any known oral, intravenous, rectal, vaginal, transdermal, or other local or systemic administration form. Medicine to the subject.
  • compositions may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, sunscreens, glidants, processing aids Agents, coloring agents, sweetening agents, flavoring agents, flavoring agents or other known additives, which enable the pharmaceutical composition to be manufactured or used in an acceptable form.
  • the drug of the present invention is preferably administered by oral route.
  • Solid dosage forms for oral administration may include capsules, tablets, powder or granular formulations.
  • the compound or pharmaceutical composition of the present 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 glycerin, etc.; disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, specific complex silicates, sodium carbonate, etc.; Solution blockers such as paraffin, etc.; absorption enhancers such as quaternary ammonium compounds, etc.; adsorbents such as kaolin, bentonite, etc.; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate Wait.
  • binders such as carboxymethyl cellulose,
  • 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, which use lactose and high molecular weight polyethylene glycol as excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, acetic acid Ethyl, 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.
  • inert diluents commonly used in the art, such as water or other solvents
  • composition may also include excipients, such as one or more of wetting agents, emulsifiers, suspending agents, sweetening agents, flavoring agents, and perfumes.
  • excipients such as one or more of wetting agents, emulsifiers, suspending agents, sweetening agents, flavoring agents, and perfumes.
  • the suspension in addition to the compound or combination of the present invention, it may further contain 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 substances, etc.
  • 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 substances, etc.
  • composition for rectal or vaginal administration is preferably a suppository, which can be prepared by mixing the compound or combination of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene Glycol or suppository wax, which is solid at normal room temperature and liquid at body temperature, and can melt in the rectum or vagina to release the active compound.
  • a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene Glycol or suppository wax, which is solid at normal room temperature and liquid at body temperature, and can melt in the rectum or vagina to release the active compound.
  • the compound or pharmaceutical composition of the present invention can be administered in other topical dosage forms, including ointments, powders, sprays and inhalants.
  • the medicine can be mixed with pharmaceutically acceptable excipients, diluents or carriers and any required preservatives, buffers or propellants under aseptic conditions.
  • Ophthalmic formulations, ophthalmic ointments, powders and solutions are also intended to be included within the scope of the present invention.
  • Another object of the present invention is to provide a single treatment or combined treatment method, which comprises administering to a subject in need of the treatment a compound selected from the group consisting of general formula (I), its tautomers, diastereomers, At least one of racemates, metabolic precursors, metabolites, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates) and crystal forms.
  • a compound selected from the group consisting of general formula (I) tautomers, diastereomers, At least one of racemates, metabolic precursors, metabolites, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates) and crystal forms.
  • Said other one or more components with medical therapeutic activity including macromolecular compounds, such as proteins (antibodies or polypeptides), polysaccharides and nucleic acids (DNA or RNA), etc.; and small molecular compounds, such as inorganic compounds, organic compounds, etc.
  • the compound of general formula (I) according to the present invention, its tautomers, diastereomers, racemates, metabolic precursors, metabolites, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs , Solvates, hydrates or crystal forms can have a synergistic effect with another one or more ingredients with pharmacologically therapeutic activity in the prevention or treatment of specific diseases or dysfunctions, or can reduce or eliminate another one or A variety of pharmacologically active ingredients in the prevention or treatment of specific diseases or dysfunctions caused by toxic and side effects, and vice versa.
  • Another aspect of the present invention provides a compound selected from the group consisting of compounds represented by general formula (I), tautomers, diastereomers, racemates, metabolic precursors, metabolites, isotopic compounds, and pharmaceutically acceptable salts thereof
  • Use of one or more of, esters, prodrugs, solvates, hydrates and crystal forms to prepare drugs for treating diseases or dysfunctions related to CRL4 CRBN E3 ubiquitin ligase Use of one or more of, esters, prodrugs, solvates, hydrates and crystal forms to prepare drugs for treating diseases or dysfunctions related to CRL4 CRBN E3 ubiquitin ligase.
  • the related diseases or dysfunctions involved in CRL4 CRBN E3 ubiquitin ligase described in the present invention include, without limitation, cancer, inflammation, pain, neurological diseases and immune system diseases.
  • the disease or dysfunction includes but is not limited to: cancer, angiogenesis-related diseases or dysfunction, 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 system cancer, breast cancer, cervical cancer, uterine cancer, gastrointestinal 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 cancers related to AIDS.
  • the compounds provided by the present invention are also effective against hematoma and myeloma, such as being used for the treatment of 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 non-radioactive isotope of hydrogen with an atomic weight of 2.0144. Natural hydrogen exists in the form of a mixture of isotopes of H (hydrogen or protium), D (2H or deuterium) and T (3H or tritium), and the abundance of deuterium is 0.0156%. According to common technical knowledge in the art, in the structural formulas 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-enriched.
  • isotopic compound used in the present invention refers to the compound of general formula (I) of the present invention, its tautomers, diastereomers, racemates, metabolic precursors, metabolites, and pharmaceutically acceptable salts.
  • Ester, prodrug, solvate, hydrate or crystal form contains one or more natural or unnatural abundance of atomic isotopes.
  • the present invention also covers isotopically labeled compounds of the present invention, except for the fact that one or more atoms are replaced by an atom whose atomic mass or mass number is different from the atomic mass or mass number commonly found in nature, which is related to this Said 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 present invention are used in compound and/or substrate tissue distribution tests. Particularly preferred are tritiated (i.e. 3H) and carbon-14 (i.e. 14C) isotopes because of their ease of preparation and detection. Moreover, the substitution of heavier isotopes such as deuterium (ie 2H) can provide certain therapeutic advantages due to greater metabolic stability (such as increased in vivo half-life or reduced dosage requirements), and may therefore be preferred in some cases. of.
  • Positron emitting 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 present invention can generally be prepared by following methods similar to those disclosed in the scheme and/or the examples below, by substituting isotopically-labeled reagents for non-isotopically-labeled reagents. All isotopic variants of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • Figure 1 shows the effect of compounds 82 and 150 on the protein levels of Ikaros and Aiolos.
  • Figure 2 shows the rate and pathway of compound 82 degradation of Ikaros and Aiolos proteins.
  • the raw materials in the present invention can be obtained from commercial sources, for example, the main reagents are purchased from Sinopharm Chemical Reagent Co., Ltd., or prepared by methods inhibited in this field, or prepared according to the methods described in the present invention.
  • the solid was concentrated in vacuo to obtain a solid, which was re-dissolved in ethyl acetate solution, washed successively with saturated ammonium chloride solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated in vacuo, and then subjected to column chromatography.
  • the measured value is 560.23;
  • Example 28 1-((3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)oxy)propyl)-D -Prolyl)-4-(2-fluorophenyl)piperidine-4-carbonitrile (140)
  • Example 38 3-(4-(3-((R)-2-(4-(3,5-dichlorophenyl)piperazine-1-carbonyl)pyrrolidin-1-yl)propoxy) -1-oxoisoindol-2-yl)piperidine-2,6-dione (150)
  • Tumor cell proliferation inhibition test method The inventors of the present patent tested all the compounds of the examples on hematoma cells, multiple myeloma MM1s cell lines and some of the compounds of the examples on acute leukemia cell MV-4-11 cell lines, and their activity test methods And the result is as follows.
  • MM.1S cells were cultured and collected with 1640 plus 10% fetal bovine serum. The cell concentration was diluted according to the action time of 7 days, and 180ul of cell suspension was added to each well of the 96-well cell plate to make the cell count to 20,000. Add 20ul of DMSO with a final concentration of 0.2% to the control cell wells. The compound was diluted 5-fold from the 10mM stock solution, and 20ul was added to the compound cell wells (the final concentration of DMSO was 0.2%). The cells were placed in a 37°C, 5% CO 2 incubator and incubated for 7 days.
  • the compounds 82 and 150 with better activity were selected to conduct related biological experiments to verify whether the designed degradants have the function of down-regulating endogenous proteins.
  • Figure 1 shows the effect of compounds 82 and 150 on the protein levels of Ikaros and Aiolos.
  • the samples were prepared with the specified concentration of compound (0.1, 1.0 ⁇ M) at different times, and Western Blot experiment was performed.
  • the results are shown in the left panel of Figure 2. It can be seen from the left panel of Figure 2 that the degradation of the transcription factors Ikaros and Aiolos by compound 82 is time-dependent, and it can significantly down-regulate the protein levels of Ikaros and Aiolos starting from 3 hours. This indicates that compound 82 can quickly degrade after entering the cell.
  • the results are shown in the right panel of Figure 2. It can be seen from the right panel of Figure 2 that when MLN4924 is added, compound 82 basically does not degrade Ikaros and Aiolos, preliminarily indicating that the degradation function of such molecules depends on the E1 activating enzyme.
  • the designed and synthesized compound of the present invention can be used to prevent and treat diseases related to the regulation of CRBN (CRL4 CRBN E3 ubiquitin ligase) activity, such as multiple myeloma or non-restrictively including other potential tumor diseases, pain , Nervous system diseases and immune system diseases.
  • diseases related to the regulation of CRBN CL4 CRBN E3 ubiquitin ligase
  • diseases related to the regulation of CRBN (CRL4 CRBN E3 ubiquitin ligase) activity such as multiple myeloma or non-restrictively including other potential tumor diseases, pain , Nervous system diseases and immune system diseases.
  • the present invention provides a class of multi-substituted isoindoline compounds with novel structures, in which the representative compounds show very strong proliferation inhibitory activity on the tested hematoma cells.
  • the representative compounds provided by the present invention can effectively overcome the application limitations of existing dosamine drugs, and have a more significant effect in degrading substrates. This feature can not only effectively make up for the shortcomings of the existing Dolamine drugs, but also expand its indications to new areas, so it has very strong research potential and application prospects.

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Abstract

公开了通式(1)所表示的多取代异吲哚啉类化合物，其制备方法、药物组合物及用途。具体的，公开的多取代异吲哚啉类化合物作为一类结构新颖的CRL4 CRBNE3泛素连接酶调节剂具有更强大的抗肿瘤活性和抗肿瘤谱，可以用于制备治疗与CRL4 CRBNE3泛素连接酶复合物相关的疾病的药物。

Description

多取代异吲哚啉类化合物、其制备方法、药物组合物及用途 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用途。
背景技术
细胞内蛋白质表达的严密调控在细胞行使功能、细胞存活以及分裂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-蛋白酶体系统(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。
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前列腺癌，泊马度胺临床实验中用于治疗骨髓纤维化症。
Figure PCTCN2020125270-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 PCTCN2020125270-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 PCTCN2020125270-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 PCTCN2020125270-appb-000004
WO2016065980A1、CN105566290A、US10017492B2
Figure PCTCN2020125270-appb-000005
通式S3中代表性的化合物为：
Figure PCTCN2020125270-appb-000006
WO2007027527A2、CN101291924A、US8481568B2公开了一类通式为S3所代表的化合物：
Figure PCTCN2020125270-appb-000007
通式S4、S5中代表性的化合物为：
Figure PCTCN2020125270-appb-000008
WO2008027542A2、US8877780B2、US9447070B2公开了一类通式为S3所代表的化合物：
Figure PCTCN2020125270-appb-000009
通式S6、S7中代表性的化合物为：
Figure PCTCN2020125270-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。
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。同时根据晶体结构特点，与疏水性片段连接链的不同结构，将决定小分子与CRBN结合模式及结合能力。因此，本发明中利用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，获得一类连接链特异的新型CRBN小分子调节剂。基于这些信息，发明人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。本发明的设计合成的化合物用于在制备治疗与CRL4 CRBNE3泛素连接酶相关的疾病或功能紊乱的药物中的用途，所述的疾病或功能紊乱疾病主要有包括癌症、炎症、疼痛、神经系统疾病和免疫系统疾病。
本发明的一个目的是提供如下通式(I)所示的化合物或其互变异构体、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、溶剂合物、水合物或晶型。
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。对映体、非对映体、消旋体、可药用的盐、酯、前药、溶剂合物、水合物或晶型
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选自通式(I)所示的化合物，其互变异构体、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、溶剂合物、水合物和晶型中的一种或多种，和至少一种药学上可接受的载体。
所述药物组合物还可以包含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，其互变异构体、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、溶剂合物、水合物或晶型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，其互变异构体、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、溶剂合物、水合物或晶型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。
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选自如通式(I)所示的化合物，其互变异构体、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、溶剂合物、水合物和晶型中的一种或多种用于制备治疗与CRL4 CRBN E3泛素连接酶相关的疾病或功能紊乱的药物的用途，优选地，所述的疾病或功能紊乱非限制性地包括癌症、疼痛、神经系统疾病和免疫系统疾病。
为了实现上述目的，本发明提供了如下通式(I)表示的化合物或其互变异构体、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、溶剂合物、水合物或晶型：
Figure PCTCN2020125270-appb-000011
其中，n为1、2、3、4或5；
X 1为-CH 2-、-NH-、-S-或-O-；
X 2为-CH 2-或-CO-；
R 1、R 2、R 3各自独立为氢、氘或卤素；
L不存在，或为含有1-5个碳原子的取代或未取代的直链亚烷基，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；
A为：
i)A 1-NH-,
A 1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；
或者A 1为选自以下基团：
Figure PCTCN2020125270-appb-000012
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；
ii)选自以下的杂环基：
Figure PCTCN2020125270-appb-000013
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；
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；
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；
iii)选自以下的稠杂环基：
Figure PCTCN2020125270-appb-000014
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 PCTCN2020125270-appb-000015
为6-10元芳基环或5-10元杂芳基环，优选地，
Figure PCTCN2020125270-appb-000016
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；
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；
iv)选自以下的螺杂环基：
Figure PCTCN2020125270-appb-000017
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 PCTCN2020125270-appb-000018
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 PCTCN2020125270-appb-000019
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。
优选地，通式(I)所示的化合物中，n为1、2、3、4或5；
X 1为-CH 2-、-NH-、-S-或-O-；
X 2为-CH 2-或-CO-；
R 1、R 2、R 3各自独立为氢、氘或卤素；
L不存在，或为含有1-5个碳原子的取代或未取代的直链亚烷基，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；
A为：
i)A 1-NH-：
A 1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；
或者A 1为选自以下基团：
Figure PCTCN2020125270-appb-000020
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；
ii)选自以下的杂环基：
Figure PCTCN2020125270-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；
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；
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；
iii)选自以下的稠杂环基：
Figure PCTCN2020125270-appb-000022
n 8为0、1、2、3或4；
X 4为C、N或O；
Figure PCTCN2020125270-appb-000023
为6-10元芳基环或5-10元杂芳基环，其中
Figure PCTCN2020125270-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，其中当n 8>1时，各个R 8可以相同或不同；
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iv)选自以下的螺杂环基：
Figure PCTCN2020125270-appb-000025
其中，n 9为0、1、2、3或4；
Figure PCTCN2020125270-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。
进一步优选地，通式(I)所示的化合物中，n为1、2、3、4或5；
X 1为-CH 2-、-NH-、-S-或-O-；
X 2为-CH 2-或-CO-；
R 1、R 2、R 3各自独立为氢、氘或氟；
L为(CH 2) b3或不存在；
b 3为1、2、3、4或5；
A为：
i)A 1-NH-：
A 1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6-10元芳基或5-10元杂芳基可以是未取代或被取代；
所述的取代或未取代的6-10元芳基或5-10元杂芳基选自以下基团：
Figure PCTCN2020125270-appb-000027
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；
或者A 1为选自以下基团：
Figure PCTCN2020125270-appb-000028
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；
ii)选自以下的杂环基：
Figure PCTCN2020125270-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 PCTCN2020125270-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，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；
iii)选自以下的稠杂环基：
Figure PCTCN2020125270-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；
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iv)选自以下的螺杂环基：
Figure PCTCN2020125270-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。
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)中任意一个表示的化合物：
Figure PCTCN2020125270-appb-000033
其中，n为1、2、3、4或5；
X 1为-CH 2-、-NH-、-S-或-O-；
X 2为-CH 2-或-CO-；
R 1、R 2、R 3各自独立为氢、氘或氟；
L为(CH 2) b3或不存在；
b 3为1、2、3、4或5；
n 9为0、1、2、3或4；
Figure PCTCN2020125270-appb-000034
为6-10元芳基环或5-10杂芳基环，且
Figure PCTCN2020125270-appb-000035
与螺环母核稠合形成螺杂环基，优选地，
Figure PCTCN2020125270-appb-000036
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)中任意一个表示的化合物：
Figure PCTCN2020125270-appb-000037
其中，n为1、2、3、4或5；
X 1为-CH 2-、-NH-、-S-或-O-；
X 2为-CH 2-或-CO-；
R 1、R 2、R 3各自独立为氢、氘或氟；
L为(CH 2) b3或不存在；
b 3为1、2、3、4或5；
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)或(I-18)任意一个表示的化合物：
Figure PCTCN2020125270-appb-000038
其中，n为1、2、3、4或5；
X 1为-CH 2-、-NH-、-S-或-O-；
X 2为-CH 2-或-CO-；
R 1、R 2、R 3各自独立为氢、氘或氟；
L为(CH 2) b3或不存在；
b 3为1、2、3、4或5；
n 9为0、1、2、3或4；
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 PCTCN2020125270-appb-000039
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-22)中任意一个表示的 化合物：
Figure PCTCN2020125270-appb-000040
其中，n为1、2、3、4或5；
X 1为-CH 2-、-NH-、-S-或-O-；
X 2为-CH 2-或-CO-；
R 1、R 2、R 3各自独立为氢、氘或氟；
L为(CH 2) b3或不存在；
b 3为1、2、3、4或5；
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；
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-23)至(I-32)中任意一个表示的化合物：
Figure PCTCN2020125270-appb-000041
其中，n为1、2或3；
X 2为-CH 2-或-CO-；
R 1、R 2、R 3各自独立为氢、氘或氟；
L为(CH 2) b3或不存在；
b 3为1、2、3、4或5；
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 PCTCN2020125270-appb-000042
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-42)中任意一个表示的化合物：
Figure PCTCN2020125270-appb-000043
其中，n为1、2或3；
X 2为-CH 2-或-CO-；
R 1、R 2、R 3各自独立为氢、氘或氟；
L为(CH 2) b3或不存在；
b 3为1、2、3、4或5；
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 PCTCN2020125270-appb-000044
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。
在一优选实施方式中，其中通式(I)表示的化合物为通式(I-43)至(I-50)中任意一个表示的化合物：
Figure PCTCN2020125270-appb-000045
其中，n为1、2或3；
X 1为-CH 2-或-O-；
X 2为-CH 2-或-CO-；
R 1、R 2、R 3各自独立为氢、氘或氟；
L为(CH 2) b3或不存在；
b 3为1、2、3、4或5；
n 2为0、1、2或3；
n 3为0、1、2或3；
n 11为0、1或2；
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。
在一优选实施方式中，其中通式(I)表示的化合物为通式(I-51)至(I-58)中任意一个表示的 化合物：
Figure PCTCN2020125270-appb-000046
其中，n为1、2或3；
X 1为-CH 2-或-O-；
X 2为-CH 2-或-CO-；
R 1、R 2、R 3各自独立为氢、氘或氟；
L为(CH 2) b3或不存在；
b 3为1、2、3、4或5；
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。
最优选地，通式(I)表示的化合物为下列化合物之一：
Figure PCTCN2020125270-appb-000047
Figure PCTCN2020125270-appb-000048
Figure PCTCN2020125270-appb-000049
Figure PCTCN2020125270-appb-000050
Figure PCTCN2020125270-appb-000051
Figure PCTCN2020125270-appb-000052
Figure PCTCN2020125270-appb-000053
Figure PCTCN2020125270-appb-000054
Figure PCTCN2020125270-appb-000055
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。
本发明另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的合成参考文献WO2008115516A2、WO2011100380A1、WO2016065980A1、WO2007027527A2、WO2008027542A2。
合成方法一：
Figure PCTCN2020125270-appb-000056
其中，R 1、R 2、R 3、X 2和n的定义与权利要求1中的定义相同；
m 1为1～4的整数；
化合物H 2N-A中A的定义与权利要求1中A中的定义中i)A 1-NH-、ii)杂环基、iii)稠杂环基、iv)螺杂环基定义相同；
步骤1-1：化合物1A与1B二溴脂肪烷烃在碳酸钾存在下，通过亲核反应得到化合物1C；
步骤1-2：化合物1C与羧基保护的氨基酸1D在碳酸钾存在条件下，反应得到化合物1E；
步骤1-3：化合物1E在叔丁醇钾存在条件下关环得到哌啶酮衍生物1F；
步骤1-4：化合物1F在盐酸二氧六环酸性条件下脱去保护基得到1G；
步骤1-5：化合物1G和1H在缩合剂条件下得到1I；
合成方法二：
Figure PCTCN2020125270-appb-000057
其中，R 1、R 2、R 3、X 2和n的定义与权利要求1中的定义相同；
m 2为1～3的整数；
化合物H 2N-A中A的定义与权利要求1中A中的定义中i)A 1-NH-、ii)杂环基、iii)稠杂环基、iv)螺杂环基定义相同；
步骤2-1:化合物2A与2B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2C；
步骤2-2:化合物2C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2D，
步骤2-3:化合物2D在三苯基膦和四溴化碳存在下，反应得到化合物2E；
步骤2-4:化合物2E与羧基保护的氨基酸1D在碳酸钾存在条件下，反应得到化合物2F；
步骤2-5：化合物2F在盐酸二氧六环酸性条件下脱去保护基得到2G；
步骤2-6：化合物2G和1H在缩合剂条件下得到2I。
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、溶剂合物、水合物或晶型可调控CRL4 CRBN E3泛素连接酶的活性。
本发明的另一个方面提供一种药物组合物，其包含治疗有效剂量的选自通式(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、溶剂合物、水合物和晶型中的一种或多种，和至少一种药学上可接受的载体。
本发明的药物组合物还可以包含另外一种或多种具有医药学治疗活性的成分。本发明的如通式(I)所示的化合物，或其互变异构体、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、溶剂合物、水合物或晶型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，或者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。
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。
本发明的药物组合物的典型配方是通过混合选自本发明的通式(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、可药用的盐、酯、前药、溶剂合物、水合物和晶型中的一种或多种及载体(例如稀释剂、赋形剂等)制备而成。适宜的载体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、阴道给药、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、阿拉伯胶等；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。
用于直肠或阴道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，可在直肠或阴道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一种单一治疗或联合治疗方法，其包括向需要该治疗的对象给药选自通式(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、溶剂合物、水合物)和晶型中的至少一种。当用于联合治疗中时，包含治疗有效剂量的选自通式(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、溶剂合物、水合物和晶型中的至少一种，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。本发明所述的如通式(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、溶剂合物、水合物或晶型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，或者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。
本发明的另一个方面提供选自如通式(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、溶剂合物、水合物和晶型中的一种或多种用于制备治疗与CRL4 CRBNE3泛素连接酶相关的疾病或功能紊乱的药物的用途。本发明阐述的由CRL4 CRBNE3泛素连接酶参与的相关疾病或功能紊乱非限制性包括癌症、炎症、疼痛、神经系统疾病和免疫系统疾病。
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、中枢神经系统的损伤及功能紊乱、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)、淋巴系统癌症、乳腺癌、宫颈癌、子宫癌、消化道癌症、肺癌、卵巢癌、前列腺癌、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、其其互变异构体、非对映体、消旋体、代谢前体、代谢产物、可药用的盐、酯、前药、溶剂合物、水合物或晶型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。
附图说明
图1显示化合物82和150对Ikaros和Aiolos蛋白水平的影响。
图2显示化合物82降解Ikaros和Aiolos蛋白的速率与途径。
具体实施方式
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。
参考上述合成方法1-合成方法2中的合成方法。
1.中间体化合物的合成
参考上述合成方法一和合成方法二中的合成方法。
3-溴-2-溴甲基苯甲酸甲酯：
Figure PCTCN2020125270-appb-000058
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 PCTCN2020125270-appb-000059
mmol)，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 PCTCN2020125270-appb-000060
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-(5-羟戊基)-1-氧代异吲哚啉-2-)哌啶-2,6-二酮：
Figure PCTCN2020125270-appb-000061
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 PCTCN2020125270-appb-000062
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).
5-氨基-4-(4-(2-溴乙氧基)-1-氧代异吲哚-2-基)-5-氧戊酸甲酯：
Figure PCTCN2020125270-appb-000063
将化合物a(497mg，1.70mmol，1.0equiv)溶于10ml乙腈，加入1,2-二溴乙烷(1.6g，8.5mmol，5.0equiv)，加入碳酸钾(352mg，2.55mmol，1.5equiv)，60℃下过夜反应，TLC监测。反应完成后，真空浓缩得到固体，重溶于乙酸乙酯溶液后，依次用饱和氯化铵溶液和饱和氯化钠溶液洗涤，无水硫酸钠干燥后，真空浓缩后柱层析。白色固体462mg，收率68％； 1H NMR(400MHz,CDCl 3)δ7.45–7.38(m,2H),6.98(dd,J＝7.4,1.3Hz,1H),6.58(s,1H),5.63(s,1H),4.93(dd,J＝8.9,6.0Hz,1H),4.51(d,J＝17.7Hz,1H),4.39(dd,J＝14.5,8.3Hz,3H),3.66(t,J＝6.1Hz,2H),3.63(s,3H),2.47–2.30(m,3H),2.20(ddd,J＝10.5,8.1,4.7Hz,1H).ESI-MS[M+H] +m/z＝401.21,[M-H] -＝399.22.
D-脯氨酸(2-(((2-(1-(5-氨基-5-甲氧基-1,5-二氧戊环-2-基)-1-氧代异吲哚基-4-基)氧基)乙基]叔丁基：
Figure PCTCN2020125270-appb-000064
将化合物b(518mg，1.30mmol，1.0equiv)溶于10ml乙腈，加入D-脯氨酸盐酸盐(323.4mg，1.557mmol，1.2equiv)，加入碳酸钾(449.2mg，3.25mmol，2.5equiv)，130℃下过夜反应，TLC监测。反应完成后，真空浓缩得到固体，重溶于乙酸乙酯溶液后，依次用饱和氯化铵溶液和饱和氯化钠溶液洗涤，无水硫酸钠干燥后，真空浓缩后柱层析。无色油状液体242mg，收率38％； 1H NMR(400MHz,DMSO)δ7.59(s,1H),7.44(t,J＝7.8Hz,1H),7.27(d,J＝7.5Hz,1H),7.20(d,J＝7.9Hz,2H),4.73(dd,J＝10.3,4.7Hz,1H),4.50(d,J＝17.6Hz,1H),4.35(d,J＝17.6Hz,1H),4.19(t,J＝5.0Hz,2H),3.51(s,3H),3.23(dd,J＝8.8,4.5Hz,1H),3.06(dt,J＝11.5,6.1Hz,2H),2.94–2.86(m,2H),2.72(dt,J＝10.0,6.5Hz,1H),2.58–2.52(m,1H),2.30–2.23(m,2H),2.22–2.16(m,1H),2.05–1.97(m,2H),1.32(s,9H).ESI-MS[M+H] +m/z＝490.42.
D-脯氨酸叔丁基(2-((2-(2-，2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)乙基：
Figure PCTCN2020125270-appb-000065
将化合物c(242mg，0.494mmol，1.0equiv)溶于10ml无水四氢呋喃，于-78℃条件下加入叔丁醇钾(61mg，0.5434mmol，1.1equiv)，反应半小时，LC-MS监测。反应完成后，用1N盐酸溶液淬灭，用乙酸乙酯萃取后，用饱和氯化钠溶液洗涤，无水硫酸钠干燥后，真空浓缩后柱层析。白色固体163mg，收率70％； 1H NMR(400MHz,DMSO)δ7.59(s,1H),7.45(t,J＝7.8Hz,1H),7.26(d,J＝7.4Hz,1H),7.19(d,J＝7.9Hz,2H),4.72(dd,J＝10.4,4.5Hz,1H),4.49(d,J＝17.5Hz,1H),4.32(d,J＝17.6Hz,1H),4.15(ddd,J＝9.4,6.3,3.3Hz,2H),3.50(s,3H),3.04(dd,J＝8.4,4.7Hz,2H),2.92–2.86(m,1H),2.84–2.79(m,1H),2.72(dt,J＝10.0,6.5Hz,1H),2.59–2.54(m,1H),2.26(dd,J＝11.1,4.3Hz,2H),2.21–2.15(m,1H),1.92–1.87(m,2H),1.75(dd,J＝6.4,4.3Hz,2H),1.61(dd,J＝12.3,5.9Hz,2H),1.40(s,9H).ESI-MS[M+H] +m/z＝472.87.
(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚基-4-基)氧基)丙基)-D-脯氨酸：
Figure PCTCN2020125270-appb-000066
将化合物d(163mg，0.3458mmol，1.0equiv)溶于溶于二氯甲烷溶液中，加入5ml的盐酸二氧六环溶液，室温条件下过夜,LC-MS监测。反应完成后,将反应体系真空浓缩得到白色固体163mg，收率大于99％； 1H NMR(400MHz,CDCl 3)δ7.59(s,1H),7.45(t,J＝7.8Hz,1H),7.26(d,J＝7.4Hz,1H),7.19(d,J＝7.9Hz,2H),4.72(dd,J＝10.4,4.5Hz,1H),4.49(d,J＝17.5Hz,1H),4.32(d,J＝17.6Hz,1H),4.15(ddd,J＝9.4,6.3,3.3Hz,2H),3.50(s,3H),3.04(dd,J＝8.4,4.7Hz,2H),2.92–2.86(m,1H),2.84–2.79(m,1H),2.72(dt,J＝10.0,6.5Hz,1H),2.59–2.54(m,1H),2.26(dd,J＝11.1,4.3Hz,2H),2.21–2.15(m,1H),1.92–1.87(m,2H),1.75(dd,J＝6.4,4.3Hz,2H),1.61(dd,J＝12.3,5.9Hz,2H).ESI-MS[M+H] +m/z＝402.31,[M-H] -＝400.28.
2.实施例化合物的合成
参考上述合成方法一和合成方法二中的合成方法，合成实施例化合物
实施例1：3-(2,5-二氯苯基)-1-((2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚基-4-基)氧基)乙 基)-D-脯氨酰基)哌啶-4-腈(1)
Figure PCTCN2020125270-appb-000067
将化合物e(40mg，0.0996mmol，1.0equiv)溶于5ml DMF，加入HATU(44mg，0.1195mmol，1.1equiv)，加入DIPEA(37.2mg，0.2988mmol，3equiv)反应10min，再加入化合物f(30mg，0.1096mmol，1.2equiv)室温反应30min后，LC-MS监测。反应完成后，用乙酸乙酯稀释后，用水和饱和氯化钠溶液洗涤，无水硫酸钠干燥后，真空浓缩，所得粗品用HPLC分离得到纯的3-(2,5-二氯苯基)-1-((2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚基-4-基)氧基)乙基)-D-脯氨酰基)哌啶-4-腈(1)白色固体。 1H NMR(400MHz,DMSO)δ10.97(s,1H),7.60(d,J＝8.5Hz,1H),7.57–7.51(m,1H),7.48(d,J＝2.3Hz,1H),7.44(d,J＝7.7Hz,1H),7.28(d,J＝7.5Hz,1H),7.23(d,J＝6.2Hz,1H),5.08(dd,J＝7.1,4.6Hz,1H),4.53(dd,J＝9.2,10.7Hz,2H),4.37(d,J＝7.3Hz,2H),4.20(ddd,J＝5.7,10.4,5.1Hz,4H),3.16(s,1H),3.05–2.96(m,2H),2.93–2.83(m,2H),2.79(d,J＝6.2Hz,2H),2.66(s,1H),2.59(s,1H),2.44(s,1H),2.13–2.08(m,1H),1.98(dd,J＝12.9,6.9Hz,2H),1.84–1.71(m,4H).ESI-MS[M+H] +m/z＝638.55，实测值为638.38.
实施例2：4-(3,4-二甲氧基苯基)-1-((3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚基-4-基)氧基)丙基)-D-脯氨酰基)哌啶-4-腈(2)
Figure PCTCN2020125270-appb-000068
7.21(d,J＝12.7Hz,1H),7.07–6.92(m,3H),5.10(d,J＝8.6Hz,1H),4.52(s,2H),4.33(d,J＝17.7Hz,1H),4.18(s,2H),3.75(d,J＝6.7Hz,6H),3.63–3.48(m,1H),3.18(d,J＝5.3Hz,2H),2.99–2.86(m,2H),2.86–2.70(m,2H),2.59(s,1H),2.40(s,2H),2.16(d,J＝2.5Hz,2H),1.97(d,J＝8.9Hz,2H),1.90(s,2H),1.80(s,2H),1.37(d,J＝5.5Hz,2H),1.23(s,2H).ESI-MS[M+H] +m/z＝644.64，实测值为644.38.
实施例3：1-((3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)丙基)-D-脯氨酰基)-4-(4-(三氟甲基)苯基)哌啶-4-腈(3)
Figure PCTCN2020125270-appb-000069
哌啶-3-基)-1-氧代异吲哚-4-基)氧基)丙基)-D-脯氨酰基)-4-(4-(三氟甲基)苯基)哌啶-4-腈(3)。 1H NMR(600MHz,DMSO)δ10.98(s,1H),7.89–7.84(m,2H),7.79(d,J＝8.2Hz,2H),7.75(s,2H),7.48–7.36(m,1H),5.11(s,1H),4.57(s,2H),4.34(dd,J＝7.3,3.9Hz,1H),4.26–4.14(m,3H),3.11(s,1H),3.00(s,2H),2.95(s,2H),2.91(d,J＝7.5Hz,4H),2.83–2.78(m,1H),2.58(t,J＝7.2Hz,1H),2.45–2.38(m,2H),2.32(d,J＝5.1Hz,1H),2.27–2.22(m,2H),2.17(d,J＝4.1Hz,2H),2.00–1.97(m,1H),1.89(d,J＝5.6Hz,2H),1.77(d,J＝4.7Hz,2H).ESI-MS[M+H]+m/z＝652.69，实测值为562.65.
实施例4：4-(3,4-二甲氧基苯基)-1-((2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚基-4-基)氧基)乙基)-D-脯氨酰基)哌啶-4-腈(4)
Figure PCTCN2020125270-appb-000070
(400MHz,DMSO)δ10.98(s,1H),7.50–7.41(m,1H),7.30(d,J＝7.5Hz,1H),7.26–7.19(m,1H),7.03(s,1H),6.95(d,J＝7.6Hz,2H),5.10(dd,J＝3.1,4.5Hz,1H),4.55–4.48(m,1H),4.36(d,J＝17.5Hz,1H),4.21(s,2H),3.76(d,J＝7.3Hz,6H),3.66–3.47(m,2H),3.33(s,2H),3.23(dd,J＝5.8,2.7Hz,2H),3.01(d,J＝6.3Hz,1H),2.95–2.88(m,1H),2.78(dd,J＝m,2H),2.57(d,J＝17.5Hz,1H),2.42(d,J＝1.6Hz,1H),2.27–2.03(m,4H),1.97(s,1H),1.79(s,4H).ESI-MS[M+H]+m/z＝630.71，实测值为630.48.
实施例5：1-((4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丁基)-D-脯氨酰基)-4-(2-(三氟甲氧基)苯基)哌啶-4-腈(5)
Figure PCTCN2020125270-appb-000071
7.29–7.21(m,1H),5.18–5.10(m,1H),4.79(d,J＝51.8Hz,1H),4.56(s,1H),4.48–4.35(m,1H),4.24(dd,J＝20.3,4.7Hz,3H),4.03–3.86(m,1H),3.72(s,1H),3.16(s,1H),3.04(d,J＝10.3Hz,1H),2.99–2.87(m,2H),2.61(d,J＝12.4Hz,2H),2.43–2.32(m,3H),2.13(s,4H),2.01(d,J＝12.6Hz,2H),1.90(s,2H),1.38(s,2H).ESI-MS[M+H] +m/z＝666.41，实测值为666.44.
实施例6：(2R)-1-(2-(((2-(2,6-二氧代哌啶-3-基)1-氧代异吲哚-4-基)氧基)乙基)-N-(4-(三氟甲 基)苄基)吡咯烷-2-羧酰胺(6)
Figure PCTCN2020125270-appb-000072
MHz,DMSO)δ10.98(s,1H),8.16(d,J＝25.5Hz,1H),7.45(t,J＝7.7Hz,1H),7.30(d,J＝7.4Hz,1H),7.16(d,J＝7.8Hz,2H),7.13(d,J＝7.2Hz,2H),7.10(d,J＝8.2Hz,1H),5.10(ddd,J＝13.3,4.8,2.3Hz,1H),4.32(dd,J＝17.3,3.9Hz,1H),4.21(d,J＝4.2Hz,1H),4.19–4.17(m,1H),4.13(dd,J＝15.4,6.1Hz,2H),4.07–4.02(m,1H),3.50(d,J＝4.2Hz,4H),3.36(s,2H),3.14(s,1H),2.91(ddd,J＝14.4,11.1,5.3Hz,1H),2.73(s,1H),2.58(d,J＝17.0Hz,2H),2.44–2.38(m,1H),2.27(s,6H),2.07(s,2H),1.96(dd,J＝11.1,6.4Hz,1H),1.90–1.84(m,2H),1.73(dd,J＝23.6,5.4Hz,4H).ESI-MS[M+H] +m/z＝604.72，实测值为604.09.
实施例7：(2R)-1-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)丙基)-N-(4-(三氟甲基)苄基)吡咯烷-2-羧酰胺(7)
Figure PCTCN2020125270-appb-000073
7.78(d,J＝8.1Hz,1H),7.65–7.58(m,4H),7.46–7.40(m,1H),7.28(dd,J＝19.3,7.5Hz,1H),5.14–5.07(m,1H),4.49–4.45(m,1H),4.35(dd,J＝9.2,6.0Hz,1H),4.32(t,J＝5.3Hz,1H),4.27(dd,J＝11.5,6.3Hz,1H),4.22–4.13(m,2H),3.03–2.99(m,1H),2.74(td,J＝6.6,7.3Hz,1H),2.59–2.56(m,1H),2.42(ddd,J＝6.0,4.9,3.9Hz,1H),2.33–2.29(m,1H),2.25(dd,J＝6.4,5.4Hz,1H),2.10–2.05(m,2H),1.98(dd,J＝7.8,8.0Hz,1H),1.90(dd,J＝4.3,5.9Hz,2H),1.79–1.68(m,4H).ESI-MS[M+H] +m/z＝573.39，实测值为573.51.
实施例8：(2R)-N-(3,5-二甲氧基苯基)-1-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)丙基)吡咯烷-2-羧酰胺(8)
Figure PCTCN2020125270-appb-000074
基)吡咯烷-2-羧酰胺(28)白色固体。 1H NMR(600MHz,DMSO)δ10.94(d,J＝7.3Hz,1H),9.55(d,J＝8.6Hz,1H),7.43(td,J＝7.8,4.6Hz,1H),7.28–7.20(m,2H),6.92(d,J＝2.2Hz,1H),6.77(d,J＝2.2Hz,1H),6.13(dt,J＝4.6,2.2Hz,1H),5.06–4.98(m,1H),4.29–4.22(m,2H),4.01(q,J＝7.2Hz,2H),3.66(s,3H),3.60(s,3H),3.26–3.21(m,1H),3.09–3.04(m,1H),2.94–2.87(m,1H),2.86–2.73(m,1H),2.58(ddd,J＝6.6,5.6,4.5 Hz,2H),2.36(ddd,J＝2.5,2.5,4.9Hz,1H),2.27–2.20(m,1H),2.16–2.09(m,1H),1.97–1.88(m,3H),1.81–1.75(m,3H).ESI-MS[M+H] +m/z＝551.61，实测值为551.48.
实施例9：(2R)-N-苄基-1-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚基-4-基)氧基)丙基)吡咯烷-2-羧酰胺(9)
Figure PCTCN2020125270-appb-000075
7.60(s,1H),7.47–7.43(m,1H),7.30(d,J＝7.5Hz,1H),7.27–7.23(m,6H),5.10(dd,J＝13.3,5.2Hz,1H),4.46(dd,J＝9.9,4.3Hz,2H),4.33–4.29(m,2H),3.50(s,2H),2.99(d,J＝6.5Hz,1H),2.94–2.87(m,1H),2.74–2.71(m,1H),2.58–2.54(m,2H),2.40(dd,J＝12.0,6.8Hz,1H),2.29(s,1H),2.25(s,1H),1.98(dd,J＝4.2,6.2Hz,1H),1.90(d,J＝6.1Hz,2H),1.71(dd,J＝6.5,4.0Hz,4H).ESI-MS[M+H] +m/z＝505.51，实测值为505.29.
实施例10：N-(3,5-二甲氧基苄基)-1-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚基-4-基)氧基)丙基)吡咯烷-2-羧酰胺(10)
Figure PCTCN2020125270-appb-000076
DMSO)δ10.97(s,1H),8.18(dt,J＝7.2,6.3Hz,1H),7.44(t,J＝7.8Hz,1H),7.29(dd,J＝7.5,1.2Hz,1H),7.16–7.12(m,1H),6.34(d,J＝2.2Hz,1H),6.32(d,J＝2.2Hz,1H),6.31(dd,J＝4.3,2.1Hz,1H),5.09(dd,J＝3.4,5.1Hz,1H),4.31(dd,J＝7.3,5.1Hz,1H),4.21(dd,J＝5.0,6.4Hz,1H),4.16(ddd,J＝7.2,9.0,4.6Hz,2H),4.12–4.02(m,2H),3.67(d,J＝1.8Hz,6H),3.16–3.12(m,1H),3.01–2.97(m,1H),2.90(ddd,J＝7.4,6.7,5.4Hz,1H),2.76–2.70(m,1H),2.61–2.55(m,2H),2.44–2.35(m,1H),2.29(dd,J＝16.0,7.8Hz,1H),2.10–2.03(m,1H),1.97(ddt,J＝7.7,5.3,4.1Hz,1H),1.89(dq,J＝3.0,6.4Hz,2H),1.77–1.67(m,3H).ESI-MS[M+H] +m/z＝565.64，实测值为565.28.
实施例11：3-(4-(2-((R)-2-(4-(3,5-二氯苯基)哌嗪-1-羰基)吡咯烷-1-基)乙氧基)-1-氧代异吲哚-2-基)哌啶-2,6-二酮(11)
Figure PCTCN2020125270-appb-000077
(600MHz,DMSO)δ10.97(s,1H),7.46(t,J＝7.8Hz,1H),7.29(d,J＝7.4Hz,1H),7.24(d,J＝4.0Hz,1H),6.92(s,2H),6.87(s,1H),5.09(dd,J＝13.3,5.1Hz,1H),4.36(d,J＝17.3Hz,1H),4.27–4.19(m,3H),3.73(d,J＝40.9Hz,2H),3.55(d,J＝7.3Hz,2H),3.17(d,J＝14.3Hz,4H),3.03–2.97(m,1H),2.93–2.86(m,1H),2.79(dd,J＝12.4,6.3Hz,1H),2.57(t,J＝21.9Hz,1H),2.42(ddd,J＝19.1,13.7,7.1Hz,2H),2.09(dd,J＝19.8,8.3Hz,1H),1.96(dd,J＝15.4,7.9Hz,1H),1.78(dt,J＝15.6,7.7Hz,2H),1.76–1.69(m,1H).ESI-MS[M+H] +m/z＝615.51，实测值为615.44.
实施例12：3-(4-(2-((R)-2-(2H-螺[苯并呋喃-3,4'-哌啶]-1'-羰基)吡咯烷-1-基)乙氧基)-1-氧代异吲哚-2-(基)哌啶-2,6-二酮(12)
Figure PCTCN2020125270-appb-000078
MHz,DMSO)δ10.99(s,1H),8.24(s,1H),7.49(t,J＝7.6Hz,1H),7.33(dd,J＝6.6,3.4Hz,1H),7.25(d,J＝8.0Hz,1H),7.10(dd,J＝16.2,7.9Hz,2H),6.80(t,J＝7.3Hz,1H),6.75(d,J＝8.0Hz,1H),5.18–5.03(m,1H),4.38(dd,J＝14.4,7.5Hz,2H),4.23(s,4H),4.02(s,4H),3.14(d,J＝28.9Hz,2H),2.93–2.80(m,2H),2.71–2.60(m,1H),2.38(dd,J＝24.1,11.6Hz,1H),2.14–2.06(m,1H),1.97(s,1H),1.69(dd,J＝46.3,26.2Hz,8H).ESI-MS[M+H] +m/z＝591.55，实测值为591.37.
实施例13：(2R)-1-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)丙基)-N，N-二乙基吡咯烷-2-羧酰胺(13)
Figure PCTCN2020125270-appb-000079
Hz,1H),7.47(t,J＝7.8Hz,1H),7.30(d,J＝7.5Hz,1H),7.22(dd,J＝8.1,1.7Hz,1H),5.11(dt,J＝13.2,5.4Hz,1H),4.35(dd,J＝17.2,6.0Hz,1H),4.23–4.18(m,1H),4.16(t,J＝6.6Hz,2H),3.37(dd,J＝16.1,8.2Hz,2H),3.20(dd,J＝13.8,6.8Hz,2H),3.12(s,1H),2.96–2.88(m,1H),2.74(d,J＝21.8Hz,1H),2.59(d,J＝16.7Hz,1H),2.41(ddd,J＝26.2,13.1,4.1Hz,2H),2.05(d,J＝8.7Hz,1H),2.01–1.97(m,1H),1.85(dt,J＝13.0,6.4Hz,2H),1.77(dd,J＝13.3,6.7Hz,2H),1.63(dt,J＝9.5,8.4Hz,1H),1.26–1.22(m,2H),1.07(t,J＝6.5Hz,3H),0.95(td,J＝7.0,2.3Hz,3H).ESI-MS[M+H] +m/z＝471.55，实测值为471.92.
实施例14：1-((2-((2-(2-，2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)乙基)-D-脯氨酰基)-4-苯基哌啶-4-甲腈(14)
Figure PCTCN2020125270-appb-000080
实测值为560.23；
实施例15：4-(3,4-二甲氧基苯基)-1-((3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚基-4-基)氧基)丙基)-D-脯氨酰基)哌啶-4-腈(26)
Figure PCTCN2020125270-appb-000081
6.92(m,3H),5.10(d,J＝13.5,5.1Hz,1H),4.52(s,2H),4.33(d,J＝17.7Hz,1H),4.18(s,2H),3.75(d,J＝6.7Hz,6H),3.63–3.48(m,1H),3.21–3.16(m,2H),2.99–2.86(m,2H),2.86–2.70(m,2H),2.59(s,1H),2.40(s,2H),2.12–2.01(m,2H),1.97(d,J＝8.9Hz,2H),1.90(s,2H),1.80(s,2H),1.76–1.62(m,4H).ESI-MS[M+H] +＝644.74，实测值为644.95.
实施例16：(2S)-N-(3-氯-4-甲基苯基)-1-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚基-4-基)氧基)丙基)吡咯烷-2-羧酰胺(34)
Figure PCTCN2020125270-appb-000082
1H),7.75(d,J＝8.4Hz,1H),7.49(t,J＝7.8Hz,1H),7.40–7.30(m,3H),7.24(dd,J＝8.1,2.7Hz,1H),5.11(dd,J＝13.0,4.6Hz,1H),4.42–4.31(m,1H),4.28–4.20(m,3H),3.74(d,J＝7.4Hz,1H),3.47(s,1H),3.34(s,3H),3.27(d,J＝7.6Hz,2H),2.92(dd,J＝8.2,3.4Hz,1H),2.62–2.52(m,2H),2.35–2.28(m,3H),2.13(s,2H),2.06–1.91(m,3H).ESI-MS[M+H] +＝539.20，实测值为539.33。
实施例17：3-(4-(3-((R)-2-(4-(苯并[b]噻吩-7-基]哌嗪-1-羰基]吡咯烷-1-基)丙氧基)-1-氧代异吲哚-2-(基)哌啶-2,6-二酮(82)
Figure PCTCN2020125270-appb-000083
1.6Hz,1H),7.63(d,J＝7.8Hz,1H),7.45(d,J＝7.5Hz,1H),7.43–7.39(m,1H),7.31–7.27(m,1H),7.27–7.21(m,2H),6.83–6.76(m,1H),5.09(dt,J＝11.8,5.7Hz,1H),4.36(d,J＝17.3Hz,1H),4.29–4.15(m,3H),3.93–3.83(m,1H),3.79(s,1H),3.71–3.61(m,2H),3.19–3.10(m,1H),2.99(s,3H),2.96–2.81(m,4H),2.58–2.52(m,1H),2.43–2.28(m,2H),2.19–2.10(m,1H),2.04–1.87(m,4H),1.85–1.72(m,3H).ESI-MS[M+H] +＝616.75，实测值为616.89。
实施例18：3-(1-氧代-4-(3-((R)-2-(4-(苯基-d5)哌嗪-1-羰基)吡咯烷-1-基)丙氧基)异吲哚-2-基)哌啶-2,6-二酮(84)
Figure PCTCN2020125270-appb-000084
5.10–5.05(m,1H),4.30(d,J＝17.2Hz,1H),4.21(d,J＝17.3Hz,1H),4.17(t,J＝5.6Hz,2H),3.92–3.81(m,1H),3.71–3.58(m,3H),3.51–3.44(m,2H),3.41–3.36(m,2H),2.99–2.92(m,2H),2.90–2.84(m,1H),2.79(dt,J＝13.7,7.4Hz,1H),2.59–2.53(m,1H),2.44–2.32(m,2H),2.30–2.20(m,1H),2.12–2.02(m,1H),1.92–1.86(m,2H),1.83–1.68(m,4H).ESI-MS[M+H] +＝565.70，实测值为565.45。
实施例19：3-(4-(2-((R)-2-(4-(3,4-二氯苯基)哌嗪-1-羰基)吡咯烷-1-基)乙氧基)-1-氧异吲哚-2-基)哌啶-2,6-二酮(131)
Figure PCTCN2020125270-appb-000085
7.48(t,J＝7.8Hz,1H),7.27(d,J＝7.4Hz,1H),7.23(d,J＝4.0Hz,2H),6.92(d,J＝1.9Hz,1H),6.62(d,J＝2.4Hz,1H),5.07(dd,J＝13.5,5.1Hz,1H),4.36(d,J＝17.3Hz,1H),4.28–4.19(m,3H),3.72(d,J＝4.9Hz,2H),3.55(d,J＝7.3Hz,2H),3.17(d,J＝14.3Hz,4H),3.05–2.99(m,1H),2.93–2.86(m,1H),2.79(dd,J＝12.4,6.3Hz,1H),2.55(t,J＝7.6Hz,1H),2.45–2.41(m,2H),2.14–2.07(m,1H),1.99–1.95(m,1H),1.82–1.76(m,2H),1.74–1.68(m,3H).ESI-MS[M+H] +＝615.52，实测值为615.89。
实施例20：叔丁基(2-((2S)-1-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)丙基)吡咯烷-2-羧酰胺基)氨基甲酸乙酯(132)
Figure PCTCN2020125270-appb-000086
氨基甲酸乙酯(132)。 1H NMR(500MHz,DMSO)δ11.00(s,1H),8.68(s,1H),7.50(t,J＝7.7Hz,1H),7.34(d,J＝7.5Hz,1H),7.24(dd,J＝8.1,3.6Hz,1H),6.87(s,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.39(d,J＝17.3Hz,1H),4.24(d,J＝19.2Hz,1H),4.20(dd,J＝11.1,7.2Hz,2H),4.04(s,1H),3.64(s,1H),3.38(s,1H),3.15(s,2H),3.04(s,2H),2.98–2.85(m,2H),2.73(s,1H),2.60(d,J＝16.9Hz,1H),2.46–2.33(m,2H),2.04(dt,J＝12.2,4.8Hz,4H),1.87(s,2H),1.35(s,9H).ESI-MS[M+H] +＝558.65，实测值为558.90。
实施例21：3-(4-(2-((S)-2-(4-(2,5-二氯苯基)哌嗪-1-羰基)吡咯烷-1-基)乙氧基)-1-氧异吲哚-2-基)哌啶-2,6-二酮(133)
Figure PCTCN2020125270-appb-000087
7.48(t,J＝7.8Hz,1H),7.44(dd,J＝8.3,1.2Hz,1H),7.31(d,J＝7.5Hz,1H),7.25(d,J＝8.1Hz,1H),7.14–7.09(m,2H),5.10(dd,J＝13.3,5.0Hz,1H),4.37(d,J＝17.3Hz,1H),4.30–4.20(m,3H),3.73–3.65(m,2H),3.54–3.48(m,2H),3.27(s,2H),3.12–3.05(m,1H),2.98–2.84(m,6H),2.63–2.53(m,2H),2.40(qd,J＝12.9,3.9Hz,1H),2.20–2.10(m,1H),2.01–1.94(m,1H),1.87–1.71(m,3H).ESI-MS[M+H] +＝614.19，实测值为614.32。
实施例22：3-(4-(3-((R)-2-(4-(4-氟苯基)哌嗪-1-羰基]吡咯烷-1-基)丙氧基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(134)
Figure PCTCN2020125270-appb-000088
6.93(s,2H),5.12(dd,J＝13.4,4.8Hz,1H),4.35(d,J＝17.2Hz,1H),4.20(dd,J＝18.8,12.3Hz,3H),3.62(d,J＝3.7Hz,3H),3.32(s,6H),3.06(dd,J＝24.3,12.9Hz,4H),2.97–2.87(m,2H),2.62–2.53(m,2H),2.41–2.33(m,1H),2.03–1.95(m,3H),1.87–1.79(m,2H).ESI-MS[M+H] +＝578.66，实测值为578.44。
实施例23：3-(4-(3-((R)-2-(4-(2-硝基苯基)哌嗪-1-羰基)吡咯烷-1-基)丙氧基)-1-氧代异吲哚啉-2-基)哌啶-2，6-二酮(135)
Figure PCTCN2020125270-appb-000089
1H),7.59–7.55(m,1H),7.46(t,J＝7.8Hz,1H),7.28(d,J＝7.5Hz,1H),7.23(d,J＝8.0Hz,1H),7.21(d,J＝8.0Hz,1H),7.16(t,J＝7.7Hz,1H),5.10(dd,J＝13.3,5.1Hz,1H),4.35(d,J＝17.3Hz,1H),4.22(d,J＝17.3Hz,1H),4.18(dt,J＝6.3,4.5Hz,2H),3.86–3.77(m,1H),3.65(dd,J＝10.9,6.9Hz,1H),3.61–3.56(m,1H),3.50–3.45(m,1H),3.24–3.17(m,1H),2.99–2.93(m,3H),2.89(dt,J＝13.6,5.2Hz,4H),2.62–2.52(m,2H),2.44–2.36(m,2H),2.11(s,1H),2.00–1.90(m,3H),1.84–1.72(m,3H).ESI-MS[M+H] +＝605.66，实测值为605.44。
实施例24：3-(4-(3-((R)-2-(4-(2,4-二氟苯基)哌嗪-1-羰基)吡咯烷-1-基)丙氧基)-1-氧代异吲哚-2-基)哌啶-2,6-二酮(136)
Figure PCTCN2020125270-appb-000090
J＝7.4Hz,1H),7.22(d,J＝8.3Hz,1H),7.20–7.16(m,1H),6.97–6.90(m,2H),5.10(dd,J＝13.3,5.2Hz,1H),4.33(d,J＝17.3Hz,1H),4.22(s,1H),4.18(t,J＝5.6Hz,2H),3.93–3.87(m,1H),3.71–3.59(m,2H),3.50–3.43(m,1H),3.39–3.34(m,2H),3.15–3.10(m,1H),2.89–2.86(m,2H),2.85–2.72(m,3H),2.59–2.53(m,1H),2.39(tt,J＝13.3,7.8Hz,2H),2.25–2.21(m,1H),2.11–2.03(m,1H),1.97–1.93(m,1H),1.93–1.85(m,2H),1.81–1.71(m,3H).ESI-MS[M+H] +＝596.65，实测值为596.86。
实施例25：1-((2-((2-(2-，2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)乙基)-L-脯氨酰基)-4-(2-氟苯基)哌啶-4-腈(137)
Figure PCTCN2020125270-appb-000091
7.42(m,3H),7.36–7.32(m,1H),7.32–7.27(m,2H),7.27–7.22(m,1H),5.11(dd,J＝13.3,5.0Hz,1H),4.94–4.84(m,1H),4.59–4.48(m,3H),4.44–4.25(m,2H),4.16(s,1H),3.94–3.79(m,2H),3.39–3.26(m,4H),3.00–2.88(m,3H),2.88–2.79(m,1H),2.64–2.56(m,1H), 2.26–2.11(m,3H),2.03–1.94(m,2H),1.88–1.80(m,2H).ESI-MS[M+H] +＝588.65，实测值为588.86。
实施例26：1-((2-((2-(2-，2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)乙基)-L-脯氨酰基)-4-苯基哌啶-4-甲腈(138)
Figure PCTCN2020125270-appb-000092
1H),7.51–7.42(m,3H),7.40(d,J＝6.7Hz,2H),7.37–7.32(m,1H),7.27(td,J＝8.2,3.6Hz,1H),5.11(dd,J＝13.3,5.0Hz,1H),4.94–4.74(m,1H),4.55–4.44(m,3H),4.41(d,J＝17.6Hz,1H),4.38(s,1H),4.32(dd,J＝11.0,6.3Hz,1H),3.94–3.79(m,2H),3.69–3.57(m,2H),3.06–2.77(m,3H),2.66–2.58(m,1H),2.45–2.31(m,1H),2.45–2.31(m,3H),,2.02(dd,J＝14.8,7.7Hz,2H),1.98–1.78(m,3H),1.63–1.54(m,1H).ESI-MS[M+H] +＝570.66，实测值为570.40。
实施例27：1-((3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)丙基)-D-脯氨酰基)-4-苯基哌啶-4-甲腈(139)
Figure PCTCN2020125270-appb-000093
7.42(m,3H),7.40(d,J＝6.7Hz,2H),7.37–7.32(m,1H),7.27(td,J＝8.2,3.6Hz,1H),5.11(dd,J＝13.3,5.0Hz,1H),4.84–4.74(m,1H),4.55–4.44(m,3H),4.41(d,J＝17.6Hz,1H),4.38(s,1H),4.32(dd,J＝11.0,6.3Hz,1H),3.94–3.79(m,2H),3.69–3.57(m,2H),3.06–2.77(m,3H),2.66–2.58(m,1H),2.45–2.31(m,1H),2.45–2.31(m,3H),2.26–2.11(m,2H),2.05–1.99(m,2H),1.98–1.78(m,4H).ESI-MS[M+H] +＝584.69，实测值为584.45。
实施例28：1-((3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)丙基)-D-脯氨酰基)-4-(2-氟苯基)哌啶-4-腈(140)
Figure PCTCN2020125270-appb-000094
7.36–7.32(m,1H),7.32–7.27(m,2H),7.27–7.22(m,1H),5.11(dd,J＝13.3,5.0Hz,1H), 4.82–4.71(m,1H),4.59–4.48(m,2H),4.44–4.25(m,4H),4.16(s,1H),3.92–3.77(m,2H),3.69–3.57(m,2H),3.39–3.26(m,2H),3.00–2.88(m,3H),2.88–2.79(m,2H),2.64–2.56(m,1H),2.26–2.11(m,1H),2.03–1.94(m,2H),1.88–1.80(m,4H).ESI-MS[M+H] +＝602.68，实测值为602.49。
实施例29：1-((3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)丙基)-L-脯氨酰基)-4-(4-氟苯基)哌啶-4-腈(141)
Figure PCTCN2020125270-appb-000095
(ddd,J＝8.9,5.1,2.3Hz,1H),7.50(m,1H),7.36–7.33(m,1H),7.33–7.31(m,1H),7.31–7.29(m,1H),7.26(t,J＝7.9Hz,1H),5.14(ddd,J＝13.3,8.1,5.5Hz,1H),4.70(ddd,J＝13.3,8.1,5.5Hz,1H),4.55(s,1H),4.43–4.35(m,1H),4.31–4.24(m,1H),4.22(d,J＝11.7Hz,2H),3.93–3.83(m,1H),3.74(s,1H),3.22(td,J＝12.4,6.1Hz,1H),3.17–3.10(m,1H),3.05–2.98(m,1H),2.92(ddd,J＝13.8,9.4,5.4Hz,1H),2.61(d,J＝7.2Hz,1H),2.58–2.52(m,1H),2.41–2.34(m,1H),2.30–2.22(m,2H),2.17–2.07(m,4H),2.06–1.83(m,6H).ESI-MS[M+H] +＝602.68，实测值为602.49。
实施例30：1-((3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)丙基)-L-脯氨酰基)-4-(3-氟苯基)哌啶-4-腈(142)
Figure PCTCN2020125270-appb-000096
7.44(m,1H),7.43–7.38(m,1H),7.34(dd,J＝8.5,7.5Hz,1H),7.26(t,J＝7.9Hz,2H),5.18–5.11(m,1H),4.70(d,J＝17.3Hz,1H),4.55(d,J＝17.5Hz,1H),4.42–4.35(m,1H),4.32–4.25(m,1H),4.22(t,J＝5.8Hz,2H),3.93–3.83(m,1H),3.72(s,1H),3.43–3.37(m,2H),3.24(m,1H),3.18–3.11(m,2H),3.05–2.98(m,1H),2.97–2.88(m,1H),2.64–2.54(m,1H),2.42–2.34(m,1H),2.29(m,2H),2.18–2.09(m,3H),2.08–1.83(m,5H).ESI-MS[M+H] +＝602.68，实测值为602.87。
实施例31：1-(2,5-二甲氧基苯基)-4-((3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚基-4-基)氧基)丙基)-L-脯氨酰基)环己烷-1-腈(143)
Figure PCTCN2020125270-appb-000097
基)-4-((3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚基-4-基)氧基)丙基)-L-脯氨酰基)环己烷-1-腈(143)。 1H NMR(400MHz,DMSO)δ10.99(s,1H),7.50–7.38(m,1H),7.29(s,1H),7.21(d,J＝8.7Hz,1H),7.07(d,J＝2.3Hz,1H),6.95(d,J＝8.1Hz,1H),6.87(d,J＝8.1,2.3Hz,1H),5.10(d,J＝13.5,5.1Hz,1H),4.52(s,2H),4.33(d,J＝17.7Hz,1H),4.18(s,2H),3.75(d,J＝6.7Hz,6H),3.63–3.48(m,1H),3.21–3.16(m,2H),2.99–2.86(m,2H),2.86–2.70(m,2H),2.59(s,1H),2.40(s,2H),2.12–2.01(m,1H),1.97(d,J＝8.9Hz,2H),1.80(s,2H),1.76–1.62(m,2H).ESI-MS[M+H] +＝643.75，实测值为643.55。
实施例32：3-(1-氧代-4-(2-((S)-2-(3-氧代-2,3-二氢螺[茚-1,4'-哌啶]-1'-羰基)]吡咯烷-1-基)乙氧基)异吲哚啉-2-基)哌啶-2,6-二酮(144)
Figure PCTCN2020125270-appb-000098
DMSO-d 6)δ10.98(s,1H),7.65(t,J＝8.0Hz,1H),7.61(d,J＝8.1Hz,1H),7.56–7.49(m,1H),7.46–7.43(m,1H),7.40–7.33(m,1H),7.30(d,J＝8.1Hz,1H),7.25(d,J＝8.0Hz,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.43–4.39(m,1H),4.36(d,J＝13.3Hz,1H),4.30(d,J＝5.8Hz,2H),4.23(d,J＝17.0Hz,1H),4.19–4.06(m,1H),3.34(s,4H),3.15–3.07(m,1H),2.95–2.86(m,1H),2.72–2.65(m,2H),2.64–2.50(m,2H),2.44–2.32(m,1H),2.25(s,2H),2.04–1.97(m,1H),1.95–1.83(m,3H),1.82–1.72(m,2H),1.57–1.43(m,2H).ESI-MS[M+H] +＝585.67，实测值为585.45。
实施例33：3-(4-(2-((S)-2-(2,3-二氢螺[茚-1,4'-哌啶]]-1'-羰基)吡咯烷-1-基)乙氧基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(145)
Figure PCTCN2020125270-appb-000099
1H),7.54–7.48(m,1H),7.35(t,J＝6.0Hz,1H),7.30–7.23(m,1H),7.18(d,J＝6.1Hz,1H),7.15–7.06(m,3H),5.12(dd,J＝13.2,5.0Hz,1H),4.39(d,J＝17.0Hz,1H),4.35–4.22(m,4H),4.04(s,1H),3.20–3.07(m,2H),2.95–2.90(m,1H),2.86(dt,J＝13.9,5.4Hz,3H),2.74–2.66(m,1H),2.65–2.52(m,2H),2.44–2.32(m,1H),2.19(s,1H),2.05–1.94(m,3H),1.94–1.72(m,4H),1.70–1.53(m,2H),1.52–1.38(m,3H).ESI-MS[M+H] +＝571.69，实测值为571.88。
实施例34：3-(1-氧代-4-(3-((R)-2-(3-氧代-2,3-二氢螺[茚-1,4'-哌啶]-1'-羰基)]吡咯烷-1-基)丙氧基)异吲哚啉-2-基)哌啶-2,6-二酮(146)
Figure PCTCN2020125270-appb-000100
–7.56(m,3H),7.52–7.40(m,2H),7.31(t,J＝6.9Hz,1H),7.24(dd,J＝6.9,8.3Hz,1H),5.10(dd,J＝13.6,5.1Hz,1H),4.43(d,J＝17.3Hz,1H),4.33(d,J＝17.3Hz,1H),4.21(t,J＝6.1Hz,2H),3.44(s,1H),3.19–3.06(m,2H),2.96–2.88(m,2H),2.87–2.73(m,2H),2.68(s,1H),2.62–2.53(m,2H),2.47–2.32(m,2H),2.31–2.24(m,1H),2.09(s,1H),2.00–1.88(m,3H),1.87–1.68(m,6H),1.51–1.43(m,2H).ESI-MS[M+H] +＝599.70，实测值为599.43。
实施例35：3-(4-(3-((S)-2-(6-甲基-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-羰基)吡咯烷-1-基)丙氧基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(147)
Figure PCTCN2020125270-appb-000101
7.51(dd,J＝8.5,7.6Hz,1H),7.35(dd,J＝7.4,3.3Hz,1H),7.27(dd,J＝8.5,8.2Hz,1H),7.17(d,J＝7.6Hz,1H),7.09(m,2H),5.19–5.10(m,1H),4.98(s,2H),4.39(m,2H),4.27(d,J＝3.5Hz,1H),4.23(d,J＝6.8Hz,1H),3.72(s,2H),3.42(m,2H),3.30(s,1H),3.17(d,J＝5.1Hz,1H),3.07–3.01(m,1H),2.97–2.86(m,2H),2.63–2.54(m,2H),2.29(m,4H),2.21–1.75(m,9H),1.71–1.65(m,2H).ESI-MS[M+H] +＝601.72，实测值为601.91。
实施例36：3-(4-(3-((S)-2-(6-氯-3H-螺[异苯并呋喃-1,4'-哌啶]-1'-羰基)吡咯烷-1-基)丙氧基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(148)
Figure PCTCN2020125270-appb-000102
1H),7.54–7.49(m,1H),7.41–7.32(m,4H),7.31–7.24(m,1H),5.19–5.11(m,1H),5.02(s,2H),4.40(m,2H),4.29–4.26(m,1H),4.22(dd,J＝9.9,4.2Hz,1H),3.78–3.67(m,2H),3.49–3.38(m,2H),3.32–3.22(m,2H),3.21–3.12(m,1H),3.10–2.92(m,2H),2.91–2.87(m,1H),2.67–2.53(m,1H),2.43–2.29(m,1H),2.22–1.82(m,9H),1.81–1.72(m,2H)..MW:621.13,ESI-MS[M+H] +＝621.24，实测值为621.87。
实施例37：3-(4-(3-((S)-2-(2,3-二氢螺[茚-1,4'-哌啶]]-1'-羰基)吡咯烷-1-基)丙氧基)-1-氧代异吲哚啉-2-基)哌啶-2,6-二酮(149)
Figure PCTCN2020125270-appb-000103
7.8,2.4Hz,1H),7.35(d,J＝7.4Hz,1H),7.28–7.23(m,3H),7.17–7.11(m,2H),5.17–5.10(m,1H),4.43–4.33(m,2H),4.26(d,J＝17.3Hz,1H),4.24–4.21(m,1H),3.77–3.66(m,2H),3.46–3.35(m,2H),3.32–3.23(m,2H),3.15(m,1H),2.99–2.91(m,4H),2.66–2.52(m,2H),2.41–2.27(m,1H),2.20–1.83(m,9H),1.80–1.63(m,2H),1.56(t,J＝6.5Hz,2H).ESI-MS[M+H] +＝585.72，实测值为585.90。
实施例38：3-(4-(3-((R)-2-(4-(3,5-二氯苯基)哌嗪-1-羰基)吡咯烷-1-基)丙氧基)-1-氧代异吲哚-2-基)哌啶-2,6-二酮(150)
Figure PCTCN2020125270-appb-000104
Hz,1H),7.61(dd,J＝8.3,2.0Hz,1H),7.55(d,J＝1.6Hz,1H),7.50(t,J＝7.8Hz,1H),7.35(d,J＝7.4Hz,1H),7.27(d,J＝6.9Hz,1H),7.23(d,J＝8.1Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.41–4.34(m,3H),4.28–4.22(m,1H),4.19(s,2H),3.67(dd,J＝8.9,4.9Hz,1H),3.49–3.36(m,3H),3.25–3.17(m,1H),2.97–2.88(m,2H),2.63–2.55(m,1H),2.42–2.29(m,1H),2.14–2.06(m,3H),2.04–1.98(m,1H),1.96–1.85(m,2H).ESI-MS[M+H] +＝573.16，实测值为573.30。
实施例39：(2R)-1-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)丙基)-N-(4-吗啉代苯基)吡咯烷-2-羧酰胺(151)
Figure PCTCN2020125270-appb-000105
(s,1H),7.45(dd,J＝7.8,8.0Hz,1H),7.40(d,J＝8.0Hz,1H),7.29–7.26(m,2H),7.22(t,J＝8.0Hz,1H),6.78(d,J＝8.0Hz,1H),6.67(d,J＝8.0Hz,1H),5.01(dd,J＝13.5,5.0Hz,1H),4.28–4.16(m,2H),4.06(d,J＝17.4Hz,1H),3.93(d,J＝17.3Hz,1H),3.71(s,4H),3.26–3.19(m,1H),3.01–2.94(m,4H),2.92–2.78(m,2H),2.65–2.53(m,2H),2.40–2.26(m,2H),2.25–2.16(m,1H),2.14–2.07(m,1H),1.97–1.90(m,3H),1.81–1.75(m,3H).ESI-MS [M+H] +＝576.67，实测值为576.42。
实施例40：(2S)-1-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)丙基)-N-(4-(三氟甲基)苄基)吡咯烷-2-羧酰胺(152)
Figure PCTCN2020125270-appb-000106
1H),7.71(d,J＝6.5Hz,2H),7.50(t,J＝7.9Hz,3H),7.34(d,J＝7.5Hz,1H),7.23(d,J＝8.1Hz,1H),5.13(dd,J＝13.3,5.1Hz,1H),4.50–4.44(m,2H),4.38(d,J＝17.3Hz,1H),4.28–4.23(m,1H),4.22–4.19(m,2H),3.67(d,J＝6.4Hz,1H),3.45–3.40(m,1H),3.31(dd,J＝6.9,2.4Hz,1H),3.22(dt,J＝14.5,7.6Hz,1H),2.97–2.85(m,3H),2.64–2.55(m,1H),2.38–2.30(m,1H),2.09(m,3H),2.04–1.97(m,1H),1.94–1.86(m,2H).ESI-MS[M+H] +＝573.59，实测值为573.39。
实施例41：(2S)-1-(3-((2-(2-，2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)丙基)-N-(4-(吗啉代甲基)苄基)吡咯烷-2-羧酰胺(153)
Figure PCTCN2020125270-appb-000107
J＝7.4,4.8Hz,3H),7.24(dd,J＝8.1,3.6Hz,1H),5.13(dd,J＝13.2,4.9Hz,1H),4.50–4.39(m,2H),4.37(d,J＝9.9Hz,1H),4.32(s,2H),4.26(d,J＝12.5Hz,1H),4.22–4.18(m,2H),3.95(d,J＝3.1Hz,2H),3.68(d,J＝8.2Hz,1H),3.62(d,J＝4.5Hz,2H),3.40(d,J＝5.8Hz,1H),3.32(d,J＝3.8Hz,1H),3.21(s,2H),3.09(s,2H),2.96–2.87(m,1H),2.69(s,2H),2.61–2.52(m,2H),2.34(m,1H),2.10(s,3H),2.05–1.97(m,1H),1.95–1.86(m,2H).ESI-MS[M+H] +＝604.72，实测值为604.44。
实施例42：(2S)-N-(((1r，3R，5S，7S)-3,5-二甲基金刚烷-1-基)-1-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)丙基)吡咯烷-2-羧酰胺(154)
Figure PCTCN2020125270-appb-000108
11.01(s,1H),8.19(s,1H),7.51(t,J＝7.8Hz,1H),7.35(d,J＝7.5Hz,1H),7.23(d,J＝8.1Hz, 1H),5.14(dd,J＝13.3,5.0Hz,1H),4.37(dd,J＝17.2,4.2Hz,1H),4.25(dd,J＝17.2,2.2Hz,1H),4.20(t,J＝6.1Hz,2H),4.01–3.93(m,1H),3.66(d,J＝4.3Hz,1H),3.32–3.27(m,2H),3.23–3.14(m,1H),2.99–2.89(m,1H),2.60(d,J＝2.0Hz,1H),2.44–2.31(m,2H),2.12–1.98(m,5H),1.90–1.72(m,4H),1.61–1.52(m,4H),1.27(m,6H),0.80(s,6H).ESI-MS[M+H] +＝577.74，实测值为577.96。
实施例43：L-脯氨酸叔丁基(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)氧基)丙基(155)
Figure PCTCN2020125270-appb-000109
MHz,DMSO)δ10.97(s,1H),7.47(t,J＝7.8Hz,1H),7.30(d,J＝7.5Hz,1H),7.22(d,J＝8.2Hz,1H),5.11(dd,J＝13.3,5.0Hz,1H),4.35(d,J＝17.3Hz,1H),4.24–4.14(m,3H),3.07–2.99(m,2H),2.96–2.87(m,1H),2.84–2.77(m,1H),2.62–2.52(m,2H),2.47–2.40(m,1H),2.36(m,1H),2.02–1.95(m,2H),1.88(d,J＝6.5Hz,2H),1.78–1.71(m,3H),1.35(s,9H).ESI-MS[M+H] +＝472.55，实测值为472.42。
实施例44：(2S)-N-(3,5-二氟苄基)-1-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)丙基)吡咯烷-2-羧酰胺(156)
Figure PCTCN2020125270-appb-000110
J＝7.6,5.4Hz,1H),7.50(t,J＝7.8Hz,1H),7.34(d,J＝7.4Hz,1H),7.23(d,J＝8.1Hz,1H),7.14(t,J＝8.3Hz,1H),7.01(d,J＝6.7Hz,2H),5.13(dd,J＝13.3,5.1Hz,1H),4.40(d,J＝5.4Hz,2H),4.39–4.34(m,1H),4.28–4.23(m,1H),4.22–4.18(m,2H),3.69(s,1H),3.45–3.27(m,4H),3.24–3.19(m,1H),2.97–2.88(m,1H),2.59–2.52(m,2H),2.40–2.29(m,1H),2.10(s,2H),2.04–1.97(m,1H),1.96–1.85(m,2H).ESI-MS[M+H] +＝541.57，实测值为541.83。
实施例45：叔丁基(6-((2S)-1-(3-((2-(2,6-二氧哌啶-3-基)-1-二氧哌啶-4-基)氧基-丙基)吡咯烷-2-羧酰胺)氨基甲酸己基酯(157)
Figure PCTCN2020125270-appb-000111
咯烷-2-羧酰胺)氨基甲酸己基酯(157)。 1H NMR(500MHz,DMSO)δ11.00(s,1H),8.60(s,1H),7.50(t,J＝7.8Hz,1H),7.34(d,J＝7.4Hz,1H),7.24(d,J＝8.1Hz,1H),6.76(s,1H),5.14(dd,J＝13.1,4.5Hz,1H),4.39(dd,J＝17.3,7.9Hz,1H),4.23(dt,J＝ 11.4,7.7Hz,3H),4.12–4.03(m,1H),3.66(s,1H),3.21–3.06(m,3H),3.01–2.82(m,4H),2.64–2.57(m,2H),2.41(m,2H),2.16–1.97(m,4H),1.87(m,2H),1.47–1.39(m,2H),1.36(s,9H),1.23(s,6H).ESI-MS[M+H] +＝614.76，实测值为614.51。
实施例46：(2S)-1-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)丙基)-N，N-二乙基吡咯烷-2-羧酰胺(158)
Figure PCTCN2020125270-appb-000112
1H NMR(500MHz,DMSO)δ10.99(s,1H),7.49(t,J＝7.8Hz,1H),7.32(d,J＝7.5Hz,1H),7.24(dd,J＝8.2,1.6Hz,1H),5.17–5.09(m,1H),4.36(d,J＝17.2Hz,1H),4.24(d,J＝17.2Hz,1H),4.19(dd,J＝13.1,7.6Hz,2H),3.63–3.58(m,1H),3.34(d,J＝7.1Hz,1H),3.31–3.26(m,2H),3.12(s,1H),2.99–2.88(m,2H),2.67–2.56(m,2H),2.46–2.35(m,2H),2.05–1.92(m,5H),1.86(s,2H),1.73(s,1H),1.11(t,J＝6.6Hz,3H),1.01(t,J＝6.8Hz,3H).ESI-MS[M+H] +＝471.57，实测值为471.84。
实施例47：(2S)-N-(3,5-二甲氧基苄基)-1-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚基-4-基)氧基)丙基)吡咯烷-2-羧酰胺(159)
Figure PCTCN2020125270-appb-000113
(s,1H),7.50(t,J＝7.8Hz,1H),7.34(d,J＝7.5Hz,1H),7.23(dd,J＝8.1,2.2Hz,1H),6.42(s,2H),6.39(d,J＝1.8Hz,1H),5.12(dd,J＝13.4,4.8Hz,1H),4.42–4.36(m,1H),4.34–4.31(m,1H),4.25(m,2H),4.20(d,J＝9.8Hz,2H),3.70(d,J＝2.8Hz,6H),3.39(s,2H),3.22(m,1H),2.97–2.84(m,5H),2.57(m,1H),2.40–2.26(m,1H),2.09(s,2H),2.02–1.96(m,1H),1.94–1.86(m,2H).ESI-MS[M+H] +＝565.64，实测值为565.42。
实施例48：3-((2S)-1-(3-((2-(2,6-二氧代哌啶-3-基)-1-二氧代哌啶-4-基)氧基)丙基)吡咯烷-2-羧酰胺基)苯甲酸乙酯(160)
Figure PCTCN2020125270-appb-000114
10.86(s,1H),8.25(s,1H),7.86(t,J＝8.2Hz,1H),7.73(d,J＝7.8Hz,1H),7.53(td,J＝8.0,1.9Hz,1H),7.49(td,J＝8.0,2.2Hz,1H),7.33(d,J＝7.5Hz,1H),7.25(dd,J＝8.1,4.1Hz,1H),5.13–5.09(m,1H),4.40–4.35(m,1H),4.32–4.26(m,3H),4.22(dd,J＝11.7,5.0Hz,2H),3.74(s,1H),3.53–3.45(m,1H),3.36(s,1H),3.29(s,1H),2.95–2.86(m,1H),2.63–2.55(m, 2H),2.35–2.27(m,1H),2.19–2.07(m,3H),2.10–2.04(m,2H),2.00–1.92(m,2H),1.41–1.32(m,3H).ESI-MS[M+H] +＝563.62，实测值为563.43。
实施例49：2-(3-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基氧基)丙基)-N-(4-氟-3-(三氟甲基)苯基)吡咯烷-1-羧酰胺(161)
Figure PCTCN2020125270-appb-000115
1H),8.07–8.02(m,1H),7.87–7.83(m,1H),7.59–7.53(m,1H),7.49(t,J＝7.8Hz,1H),7.34(d,J＝7.5Hz,1H),7.26–7.23(m,1H),5.12(dd,J＝13.3,5.0Hz,1H),4.41–4.34(m,1H),4.33–4.28(m,1H),4.23–4.19(m,2H),3.74(td,J＝10.8,5.2Hz,1H),3.51–3.45(m,1H),3.28(dt,J＝17.2,8.3Hz,2H),2.97–2.88(m,1H),2.62–2.53(m,2H),2.34(td,J＝13.2,4.5Hz,1H),2.17–2.11(m,3H),2.10–2.06(m,1H),2.03–1.91(m,3H).ESI-MS[M+H] +＝577.55，实测值为577.35。
参考合成方法一及合成方法二及上述实施例，可以合成以下化合物：
Figure PCTCN2020125270-appb-000116
Figure PCTCN2020125270-appb-000117
Figure PCTCN2020125270-appb-000118
Figure PCTCN2020125270-appb-000119
Figure PCTCN2020125270-appb-000120
Figure PCTCN2020125270-appb-000121
Figure PCTCN2020125270-appb-000122
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 PCTCN2020125270-appb-000123
2.化合物对MM.1S细胞中底物降解检测实验：
选择活性较好的化合物82和150进行相关生物实验，验证设计的降解剂是否具有下调内源性蛋白的功能。
通过Western Blot实验，初步验证设计的降解剂对免疫调节剂已知的降解底物Ikaros和Aiolos蛋白水平的影响。
采用不同浓度(0.01，0.1，1.0，10μM)化合物处理MM.1S细胞12h制备样品，进行Western Blot实验，结果见图1。图1显示化合物82和150对Ikaros和Aiolos蛋白水平的影响。
从图1可以看出，化合物82和150在MM.1S细胞中以剂量依赖的方式显著降低Ikaros和Aiolos的蛋白水平。与来那度胺相比，化合物82在10nM时，就能显著降解Ikaros和Aiolos；化合物150在100nM开始降解转录因子。上述实验结果发现，合成的新化合物82及150比上市药物来那度胺对相应底物的降解具有更加显著的效果。
采用指定浓度的化合物(0.1，1.0μM)处理不同时间制备样品，进行Western Blot实验，结果见图2的左图。从图2的左图可以看出，化合物82对转录因子Ikaros和Aiolos的降解具有时间依赖性，并且从3h开始能显著下调Ikaros和Aiolos蛋白水平。这表明化合物82进入细胞后能很快发挥降解作用。当用E1抑制剂MLN4924预先处理细胞，然后加入化合物，进行Western Blot实验，结果见图2的右图。从图2的右图可以看出，当加入MLN4924时，化合物82对Ikaros和Aiolos基本不降解，初步说明此类分子发挥降解功能依赖于E1激活酶。
基于以上化合物细胞生长抑制活性测试结果和底物降解实验发现，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；并且实验发现对多发性骨髓瘤MM1s细胞中底物的降解具有更佳显著的效果。另一方面，这些结构多样性化合物的开发，可以获得更高活性的药物分子和药学性质更佳的分子，为新药开发提供可选择的分子结构和分子实体的来源。因此，本发明的设计合成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、神经系统疾病和免疫系统疾病。
综上所述，本发明提供了一类结构新颖的多取代异吲哚啉类化合物，其中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，本发明提供的代表性化合物能有效克服现有度胺药物的应用局限，在降解底物方面具有更加显著的效果。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 (17)

  1. 如下通式(I)所表示的化合物或其互变异构体、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、溶剂合物、水合物或晶型：
    Figure PCTCN2020125270-appb-100001
    其中，n为1、2、3、4或5；
    X 1为-CH 2-、-NH-、-S-或-O-；
    X 2为-CH 2-或-CO-；
    R 1、R 2、R 3各自独立为氢、氘或卤素；
    L不存在，或为含有1-5个碳原子的取代或未取代的直链亚烷基，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；
    A为：
    i)A 1-NH-,
    A 1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；
    或者A 1为选自以下基团：
    Figure PCTCN2020125270-appb-100002
    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相同或不同；
    ii)选自以下的杂环基：
    Figure PCTCN2020125270-appb-100003
    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；
    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；
    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；
    iii)选自以下的稠杂环基：
    Figure PCTCN2020125270-appb-100004
    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 PCTCN2020125270-appb-100005
    为6-10元芳基环或5-10元杂芳基环，优选地，
    Figure PCTCN2020125270-appb-100006
    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；
    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；
    iv)选自以下的螺杂环基：
    Figure PCTCN2020125270-appb-100007
    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 PCTCN2020125270-appb-100008
    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 PCTCN2020125270-appb-100009
    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。
  2. 根据权利要求1所述的化合物或其互变异构体、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、溶剂合物、水合物或晶型，
    其中，n为1、2、3、4或5；
    X 1为-CH 2-、-NH-、-S-或-O-；
    X 2为-CH 2-或-CO-；
    R 1、R 2、R 3各自独立为氢、氘或卤素；
    L不存在，或为含有1-5个碳原子的取代或未取代的直链亚烷基，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；
    A为：
    i)A 1-NH-：
    A 1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；
    或者A 1为选自以下基团：
    Figure PCTCN2020125270-appb-100010
    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相同或不同；
    ii)选自以下的杂环基：
    Figure PCTCN2020125270-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；
    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；
    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；
    iii)选自以下的稠杂环基：
    Figure PCTCN2020125270-appb-100012
    n 8为0、1、2、3或4；
    X 4为C、N或O；
    Figure PCTCN2020125270-appb-100013
    为6-10元芳基环或5-10元杂芳基环，其中
    Figure PCTCN2020125270-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，其中当n 8>1时，各个R 8可以相同或不同；
    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iv)选自以下的螺杂环基：
    Figure PCTCN2020125270-appb-100015
    其中，n 9为0、1、2、3或4；
    Figure PCTCN2020125270-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。
  3. 根据权利要求1所述的化合物或其互变异构体、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、溶剂合物、水合物或晶型，
    其中，n为1、2、3、4或5；
    X 1为-CH 2-、-NH-、-S-或-O-；
    X 2为-CH 2-或-CO-；
    R 1、R 2、R 3各自独立为氢、氘或氟；
    L为(CH 2) b3或不存在；
    b 3为1、2、3、4或5；
    A为：
    i)A 1-NH-：
    A 1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6-10元芳基或5-10元杂芳基是未取代或被取代的；
    所述的取代或未取代的6-10元芳基或5-10元杂芳基选自以下基团：
    Figure PCTCN2020125270-appb-100017
    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各自相同或不同；
    或者A 1为选自以下基团：
    Figure PCTCN2020125270-appb-100018
    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相同或不同；
    ii)选自以下的杂环基：
    Figure PCTCN2020125270-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 PCTCN2020125270-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；
    iii)选自以下的稠杂环基：
    Figure PCTCN2020125270-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相同或不同；
    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iv)选自以下的螺杂环基：
    Figure PCTCN2020125270-appb-100022
    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。
  4. 根据权利要求1所述的化合物或其互变异构体、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、溶剂合物、水合物或晶型，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 PCTCN2020125270-appb-100023
    其中，n为1、2、3、4或5；
    X 1为-CH 2-、-NH-、-S-或-O-；
    X 2为-CH 2-或-CO-；
    R 1、R 2、R 3各自独立为氢、氘或氟；
    L为(CH 2) b3或不存在；
    b 3为1、2、3、4或5；
    n 9为0、1、2、3或4；
    Figure PCTCN2020125270-appb-100024
    为6-10元芳基环或5-10杂芳基环，
    Figure PCTCN2020125270-appb-100025
    与螺环母核稠合形成螺杂环基，优选地，
    Figure PCTCN2020125270-appb-100026
    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相同或不同。
  5. 根据权利要求1所述的化合物或其互变异构体、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、溶剂合物、水合物或晶型，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 PCTCN2020125270-appb-100027
    其中，n为1、2、3、4或5；
    X 1为-CH 2-、-NH-、-S-或-O-；
    X 2为-CH 2-或-CO-；
    R 1、R 2、R 3各自独立为氢、氘或氟；
    L为(CH 2) b3或不存在；
    b 3为1、2、3、4或5；
    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所述的化合物或其互变异构体、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、溶剂合物、水合物或晶型，
    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 PCTCN2020125270-appb-100028
    其中，n为1、2、3、4或5；
    X 1为-CH 2-、-NH-、-S-或-O-；
    X 2为-CH 2-或-CO-；
    R 1、R 2、R 3各自独立为氢、氘或氟；
    L为(CH 2) b3或不存在；
    b 3为1、2、3、4或5；
    n 9为0、1、2、3或4；
    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 PCTCN2020125270-appb-100029
    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相同或不同。
  7. 根据权利要求1所述的化合物或其互变异构体、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、溶剂合物、水合物或晶型，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 PCTCN2020125270-appb-100030
    其中，n为1、2、3、4或5；
    X 1为-CH 2-、-NH-、-S-或-O-；
    X 2为-CH 2-或-CO-；
    R 1、R 2、R 3各自独立为氢、氘或氟；
    L为(CH 2) b3或不存在；
    b 3为1、2、3、4或5；
    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相同或不同；
    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所述的化合物或其互变异构体、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、溶剂合物、水合物或晶型，其中通式(I)表示的化合物为通式(I-23)至(I-32)中任意一个表示的化合物：
    Figure PCTCN2020125270-appb-100031
    其中，n为1、2或3；
    X 2为-CH 2-或-CO-；
    R 1、R 2、R 3各自独立为氢、氘或氟；
    L为(CH 2) b3或不存在；
    b 3为1、2、3、4或5；
    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相同或不同；
    Figure PCTCN2020125270-appb-100032
    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相同或不同。
  9. 根据权利要求1所述的化合物或其互变异构体、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、溶剂合物、水合物或晶型，其中通式(I)表示的化合物为通式(I-33)至(I-42)中任意一个表示的化合物：
    Figure PCTCN2020125270-appb-100033
    其中，n为1、2或3；
    X 2为-CH 2-或-CO-；
    R 1、R 2、R 3各自独立为氢、氘或氟；
    L为(CH 2) b3或不存在；
    b 3为1、2、3、4或5；
    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相同或不同；
    Figure PCTCN2020125270-appb-100034
    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相同或不同。
  10. 根据权利要求1所述的化合物或其互变异构体、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、溶剂合物、水合物或晶型，其中通式(I)表示的化合物为通式(I-43)至(I-50)中任意一个表示的化合物：
    Figure PCTCN2020125270-appb-100035
    其中，n为1、2或3；
    X 1为-CH 2-或-O-；
    X 2为-CH 2-或-CO-；
    R 1、R 2、R 3各自独立为氢、氘或氟；
    L为(CH 2) b3或不存在；
    b 3为1、2、3、4或5；
    n 2为0、1、2或3；
    n 3为0、1、2或3；
    n 11为0、1或2；
    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各自相同或不同。
  11. 根据权利要求1所述的化合物或其互变异构体、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、溶剂合物、水合物或晶型，其中通式(I)表示的化合物为通式(I-51)至(I-58)中任意一个表示的化合物：
    Figure PCTCN2020125270-appb-100036
    其中，n为1、2或3；
    X 1为-CH 2-或-O-；
    X 2为-CH 2-或-CO-；
    R 1、R 2、R 3各自独立为氢、氘或氟；
    L为(CH 2) b3或不存在；
    b 3为1、2、3、4或5；
    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相同或不同。
  12. 根据权利要求1所述的化合物或其互变异构体、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、溶剂合物、水合物或晶型，其中通式(I)表示的化合物为下列化合物之一：
    Figure PCTCN2020125270-appb-100037
    Figure PCTCN2020125270-appb-100038
    Figure PCTCN2020125270-appb-100039
    Figure PCTCN2020125270-appb-100040
    Figure PCTCN2020125270-appb-100041
    Figure PCTCN2020125270-appb-100042
    Figure PCTCN2020125270-appb-100043
    Figure PCTCN2020125270-appb-100044
    Figure PCTCN2020125270-appb-100045
  13. 一种制备权利要求1所述通式(I)所表示的化合物的方法，所述方法选自如下方法之一：
    合成方法一：
    Figure PCTCN2020125270-appb-100046
    其中，R 1、R 2、R 3、X 2和n的定义与权利要求1中的定义相同；
    m 1为1～4的整数；
    化合物H 2N-A中A的定义与权利要求1中A中的定义中i)A 1-NH-、ii)杂环基、iii)稠杂环基、iv)螺杂环基定义相同；
    步骤1-1：化合物1A与1B二溴脂肪烷烃在碳酸钾存在下，通过亲核反应得到化合物1C；
    步骤1-2：化合物1C与羧基保护的氨基酸1D在碳酸钾存在条件下，反应得到化合物1E；
    步骤1-3：化合物1E在叔丁醇钾存在条件下关环得到哌啶酮衍生物1F；
    步骤1-4：化合物1F在盐酸二氧六环酸性条件下脱去保护基得到1G；
    步骤1-5：化合物1G和1H在缩合剂条件下得到1I；
    合成方法二：
    Figure PCTCN2020125270-appb-100047
    其中，R 1、R 2、R 3、X 2和n的定义与权利要求1中的定义相同；
    m 2为1～3的整数；
    化合物H 2N-A中A的定义与权利要求1中A中的定义中i)A 1-NH-、ii)杂环基、iii)稠杂环基、iv)螺杂环基定义相同；
    步骤2-1:化合物2A与2B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2C；
    步骤2-2:化合物2C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2D，
    步骤2-3:化合物2D在三苯基膦和四溴化碳存在下，反应得到化合物2E；
    步骤2-4:化合物2E与羧基保护的氨基酸1D在碳酸钾存在条件下，反应得到化合物2F；
    步骤2-5：化合物2F在盐酸二氧六环酸性条件下脱去保护基得到2G；
    步骤2-6：化合物2G和1H在缩合剂条件下得到2I。
  14. 一种药物组合物，其特征在于，包含治疗有效剂量的选自权利要求1至12中任意一项所述的式(I)的化合物，其互变异构体、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、溶剂合物、水合物和晶型中的一种或多种， 和至少一种其它药学上可接受的载体。
  15. 根据权利要求14所述的药物组合物，其还包括另外一种或多种具有医药学治疗活性的成分。
  16. 根据权利要求15所述的药物组合物，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)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)。
  17. 选自根据权利要求1所述的通式(I)所示的化合物，其互变异构体、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、溶剂合物、水合物和晶型中的一种或多种在制备治疗与CRL4 CRBNE3泛素连接酶相关的疾病或功能紊乱的药物中的用途，其中，优选地，所述的疾病或功能紊乱包括癌症、炎症、疼痛、神经系统疾病和免疫系统疾病。
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109415336A (zh) * 2016-04-06 2019-03-01 密执安大学评议会 Mdm2蛋白质降解剂
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CN110963994A (zh) * 2018-09-30 2020-04-07 中国科学院上海药物研究所 异吲哚啉类化合物、其制备方法、药物组合物及用途
WO2020160193A2 (en) * 2019-01-29 2020-08-06 Foghorn Therapeutics Inc. Compounds and uses thereof

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AU2019392231B2 (en) * 2018-12-06 2022-10-20 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Isoindoline compound, and preparation method, pharmaceutical composition, and application of isoindoline compound

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109415336A (zh) * 2016-04-06 2019-03-01 密执安大学评议会 Mdm2蛋白质降解剂
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WO2020160193A2 (en) * 2019-01-29 2020-08-06 Foghorn Therapeutics Inc. Compounds and uses thereof
CN110372669A (zh) * 2019-06-19 2019-10-25 浙江省医学科学院 一种基于crbn配体诱导egfr降解的化合物及其制备方法、药物组合物和应用

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