WO2022033416A1 - Fused ring compound as egfr inhibitor, and preparation method therefor and use thereof - Google Patents

Fused ring compound as egfr inhibitor, and preparation method therefor and use thereof Download PDF

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Publication number
WO2022033416A1
WO2022033416A1 PCT/CN2021/111447 CN2021111447W WO2022033416A1 WO 2022033416 A1 WO2022033416 A1 WO 2022033416A1 CN 2021111447 W CN2021111447 W CN 2021111447W WO 2022033416 A1 WO2022033416 A1 WO 2022033416A1
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alkyl
deuterium
substituted
cycloalkyl
membered
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PCT/CN2021/111447
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French (fr)
Chinese (zh)
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寻国良
喻红平
陈椎
徐耀昌
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上海和誉生物医药科技有限公司
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Priority to CN202180048447.4A priority Critical patent/CN115836070A/en
Publication of WO2022033416A1 publication Critical patent/WO2022033416A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of drug synthesis, and in particular relates to a fused-ring compound as an EGFR inhibitor, a preparation method and application thereof.
  • Lung cancer is the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) accounting for 85%.
  • Targets epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) translocation, ROS1 proto-oncogene receptor tyrosine kinase (ROS1) rearrangement and B-raf proto-oncogene, serine/threonine Kinase (BRAF) multitargeted therapy has been developed and clinically validated.
  • EGFR inhibition can significantly improve progression-free survival in adenocarcinoma NSCLC, whose acquired resistance mutations are subsequently targeted by third-generation inhibitors.
  • exon 20 mutations are heterogeneous and include in-frame insertions or duplications of 1-7 amino acids between amino acids 762-774 of the EGFR protein.
  • NSCLC the mutation frequency of EGFR exon 20 accounts for 4-10% of all mutations in EGFR.
  • EGFR exon 20 insertion mutations are also seen in a rare type of head and neck cancer, nasal squamous cell carcinoma (SNSCC).
  • SNSCC nasal squamous cell carcinoma
  • a structurally similar exon 20 insertion mutation was also found in HER2, another member of the receptor tyrosine kinase (RTK) EGFR family.
  • the object of the present invention is to provide a highly selective EGFR inhibitor.
  • the series of compounds of the present invention have a strong inhibitory effect on the cytological activity of EGFR exon 20 insertion, deletion or other mutation, and have high selectivity for EGFR wild type, and can be widely used in the preparation of treatment and/or prevention at least partially related to EGFR Drugs for cancers, tumors or metastatic diseases associated with exon 20 insertions, deletions or other mutations, especially for hyperproliferative diseases and cell death-inducing disorders, are expected to lead to the development of a new generation of EGFR inhibitors.
  • a first aspect of the present invention provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • X 1 is CR a R b , CR c or C(O);
  • X 2 is CR d Re , CR f , N or NH;
  • Y 1 , Y 2 , Y 3 and Y 4 are each independently selected from N, C(O), CR g , N(O) and NR h ;
  • Z 1 , Z 2 and Z 3 are each independently CR i or N;
  • L1 is selected from O, S , NRj , CRkRp , OCRkRp and a bond ;
  • L 2 is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl C 1-2 alkyl, 3-12 membered heterocyclyl C 1-2 alkyl, C 6-10 aryl C 1-2 alkyl and 5 -10-membered heteroaryl C 1-2 alkyl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen Substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl,
  • R a , R b , R d and R e are each independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2- 10 alkenyl and C 2-10 alkynyl, or, alternatively, one of the groups of Ra and R b , R d and Re , Ra and R d each independently together with the carbon atom to which it is directly attached forms a C 3 -8 cycloalkyl or 3-8 membered heterocyclyl, the other two groups are as previously defined;
  • R c and R f are each independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, halo-substituted C 1-10 alkyl, and deuterium substituted C 1-10 alkyl, alternatively, R c and R f are directly therewith
  • the linked moieties together form a C 3-8 cycloalkyl or 3-8 membered heterocyclyl;
  • R g is selected from hydrogen, deuterium, halogen, cyano, C 1-10 alkyl, C 1-10 alkoxy, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, halogen substituted C 1 -10 alkoxy, deuterium substituted C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl and -C 0-8 alkyl-NR 4 R 5 ;
  • R is selected from hydrogen, deuterium , hydroxyl, C 1-10 alkyl, halo-substituted C 1-10 alkyl and deuterium substituted C 1-10 alkyl;
  • R j is selected from hydrogen, deuterium, C 1-10 alkyl, halo-substituted C 1-10 alkyl and deuterium substituted C 1-10 alkyl;
  • R 2 is vinyl or ethynyl, and the above groups are independently optionally further selected from one or more groups selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium Substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -C 0-8 alkyl-C(O)OR 7 , -C 0-8 alkyl-C(O ) R 8 , -C 0-8 alkyl-C(O)-NR 9 R 10 and the substituents of -C 0-8 alkyl-NR 9 R 10 ;
  • R and L together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl ;
  • R 4 and R 5 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6- 10 -aryl, 5-10-membered heteroaryl and -NR 9 R 10 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6 -10 -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 9 R 10 substituents;
  • Each R 6 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl and -NR 9 R 10 , the above-mentioned groups independently optionally further selected by one or more groups selected from deuterium, halogen, hydroxyl, oxo, C 1-10 alkyl, C 1 -10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6- 10 -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and substituents of -NR 9 R 10 ;
  • Each R 7 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10-membered heteroaryl groups, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-10 alkyl, C 1-10 alkoxy , C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and substituents of -NR 9 R 10 ;
  • Each R 8 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 Cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10-membered heterocycle Aryl, 5-10 membered heteroaryloxy and -NR 9 R 10 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6 -10 -aryloxy, 5-10-membered heteroaryl, 5
  • R 9 and R 10 is independently selected from hydrogen, deuterium, hydroxy, C 1-10 alkoxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 -membered cycloalkyl, 3-12-membered heterocyclyl, C 6-10 -membered aryl, 5-10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl, the above groups are independently any is further selected by one or more selected from deuterium, halogen, hydroxyl, C 1-10 alkyl, C 2-10
  • R 9 and R 10 together with the nitrogen atom to which they are directly attached form a 4-10-membered heterocyclic group or a 4-10-membered heteroaryl group independently optionally further , hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-10 alkoxy base, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy , 5-10-membered heteroaryl, 5-10-membered heteroaryloxy, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl substituents;
  • n 0, 1 or 2;
  • Each r is independently 0, 1, or 2.
  • R g is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 1 -4 alkoxy, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, halogen substituted C 1-4 alkoxy, deuterium substituted C 1-4 alkoxy, C 2-4 alkene group, C 2-4 alkynyl and -C 0-4 alkyl-NR 4 R 5 ;
  • R is selected from hydrogen, deuterium , hydroxy, C 1-4 alkyl, halo-substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
  • R4 and R5 are as defined in compounds of formula (I ) .
  • R a , R b , R d and Re are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl and C 2-4 alkynyl, or, R a and R b , R One of the groups of d and Re , R a and R d each independently forms a C 3-6 cycloalkyl or 3-6 membered heterocyclic group together with the carbon atom to which it is directly attached, and the other two groups are as defined above;
  • R c and R f are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium substituted C 1-4 alkyl, alternatively, R c and R f are directly therewith
  • the linked moieties together form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl.
  • R j is selected from hydrogen, deuterium, C 1-4 alkyl, halogen-substituted C 1-4 alkyl base and deuterium substituted C 1-4 alkyl;
  • R 6 , R 7 , R 8 , R 9 , R 10 and r are as defined in compounds of formula (I).
  • L 2 is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 -alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, C 3-6 cycloalkyl, C 1-2 alkyl, 3-6 membered heterocyclyl C 1-2 alkyl, C 6-8 aryl C 1-2 alkyl and 5-8 membered heteroaryl C 1-2 alkyl, the above groups are independently optionally further One or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl,
  • R and L together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclyl ;
  • R 6 , R 7 , R 8 , R 9 , R 10 and r are as defined in compounds of formula (I).
  • the compound of formula (I) is the following compound of formula (IIa) or (IIb):
  • Y 1 , Y 2 , Y 3 and Y 4 are each independently selected from N, C(O), CR g , N(O) and NR h ;
  • Z 1 , Z 2 and Z 3 are each independently CR i or N;
  • L1 is selected from O, S , NRj , CRkRp , OCRkRp and a bond ;
  • L 2 is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl, C 3-6 cycloalkyl C 1-2 alkyl, 3-6 membered heterocyclyl C 1-2 alkyl, C 6-8 aryl C 1-2 alkyl and 5 -8-membered heteroaryl C 1-2 alkyl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen Substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl,
  • R a , R b , R d , and R e are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium-substituted C 1-4 alkyl, or, R One of a and R b , R d and Re , Ra and R d each independently forms a C 3-6 cycloalkyl together with the carbon atom to which it is directly attached, and the other two groups are as previously defined;
  • R c and R f are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium substituted C 1-4 alkyl, alternatively, R c and R f are directly therewith
  • R g is selected from hydrogen, deuterium, C 1-2 alkyl, C 1-2 alkoxy, halo-substituted C 1-2 alkyl, deuterium-substituted C 1-2 alkyl, halo-substituted C 1-2 alkoxy , deuterium substituted C 1-2 alkoxy and -C 0-2 alkyl-NR 4 R 5 ;
  • R h is each independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium substituted C 1-4 alkyl;
  • R i is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl and -C 0-2 alkyl-OR 7 ;
  • R j is selected from hydrogen, deuterium, C 1-4 alkyl, halo-substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
  • R k and R p are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl, or, R k and R p together with the carbon atom to which they are directly attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl;
  • Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl and -C 0 -2 alkyl-OR 7 ;
  • R 2 is vinyl or ethynyl, and the above groups are independently optionally further selected from one or more groups selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium Substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -C 0-2 alkyl-C(O)OR 7 , -C 0-2 alkyl-C(O ) R 8 , -C 0-2 alkyl-C(O)-NR 9 R 10 and the substituents of -C 0-2 alkyl-NR 9 R 10 ;
  • R 3 and L 2 together with the nitrogen atom to which they are directly attached form a 4-8 membered nitrogen-containing heterocyclic group
  • R 4 and R 5 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6- 8 aryl, 5-8 membered heteroaryl and -NR 9 R 10 ;
  • n 0, 1 or 2;
  • each r is independently 0, 1, or 2;
  • R 6 , R 7 , R 8 , R 9 , R 10 and r are as defined in compounds of formula (I).
  • the compound of formula (I) is the following compound of formula (IIIa 1 ) or (IIIa 2 ):
  • Y 1 is N or CH
  • each Z 1 is independently CH or N;
  • Each L 1 is independently selected from O, S , NRj , CRkRp , OCRkRp and a bond ;
  • Each L 2 is independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-4 cycloalkyl, C 1-2 alkyl and 3-4 membered heterocyclyl Heterocyclyl C 1-2 alkyl groups independently optionally further C 1 substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen -4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl and - Replaced by the substituent of OR 7 ;
  • Ra , Rb , Rd and Re is independently selected from hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, Tribromomethyl, monodeuteromethyl, dideuteromethyl and trideuteromethyl, alternatively, one of the groups of Ra and Rb , Rd and Re each independently together with the carbon atom to which it is directly attached form a C 3-6 cycloalkyl, another group is as previously defined;
  • Each R g is independently selected from hydrogen, deuterium and -NR 4 R 5 ;
  • Each Rj is independently selected from the group consisting of hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl , di-deuteromethyl and tri-deuteromethyl;
  • Each R k and R p is independently selected from hydrogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium substituted C 1-4 alkyl, alternatively, R k and R p are directly attached thereto.
  • the carbon atoms together form a C 3-6 cycloalkyl;
  • Each R 1a is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, and -OR 7 ;
  • Each R 1b is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, and -OR 7 ;
  • Each R 2 is each independently vinyl or ethynyl, independently optionally further selected by one or more groups selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, methyl, difluoromethyl, dichloro Methyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl, dideuteromethyl, trideuteromethyl, cyclopropyl and -C 0-2 alkyl- Substituents of NR 9 R 10 are substituted;
  • Each R is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 3-4 cycloalkyl, and 3-4 membered heterocyclyl, independently optionally further substituted by one or more
  • One is selected from deuterium, fluorine, chlorine, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 chain Alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, -OR 7 and -NR 9 R 10 substituents,
  • R and L together with their directly attached nitrogen atoms form the following structure:
  • Each R4 and R5 is independently selected from hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, mono deuteromethyl, di-deuteromethyl and tri-deuteromethyl;
  • n 0, 1 or 2;
  • R 7 , R 9 and R 10 are as defined in the compound of formula (IIa).
  • the compound of formula (I) is the compound of formula (IIIb) below:
  • Y 3 is N or N(O);
  • L1 is selected from O, S , NRj , CRkRp , OCRkRp and a bond ;
  • L 2 is selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-4 cycloalkyl C 1-2 alkyl and 3-4 membered heterocyclyl C 1 -2 alkyl groups, the above groups are independently optionally further substituted by one or more groups selected from the group consisting of deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl substituted with substituents of C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl and -OR 7 ;
  • Rc and Rf are each independently selected from the group consisting of hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl group, di- deuteromethyl and tri- deuteromethyl , alternatively, R and R together with the moiety to which they are directly attached form a C 3-6 cycloalkyl;
  • R g is selected from hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl, dideuteromethyl and trideuteromethyl;
  • R i is selected from hydrogen, deuterium, fluorine, chlorine and cyano;
  • R j is selected from hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl, dideuteromethyl and trideuteromethyl;
  • R k and R p are each independently selected from hydrogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium substituted C 1-4 alkyl, alternatively, the carbon atom to which R k and R p are directly attached together form a C 3-6 cycloalkyl;
  • R 1a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl and -OR 7 ;
  • R 1b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl and -OR 7 ;
  • R 2 is vinyl or ethynyl, which are independently optionally further selected from one or more groups selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, difluoromethyl, dichloromethyl, dibromo Methyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl, di-deuteromethyl, tri-deuteromethyl, cyclopropyl and -C 0-2 alkyl-NR 9 R 10 substituted by a substituent;
  • R 3 is selected from hydrogen, deuterium, C 1-4 alkyl, C 3-4 cycloalkyl and 3-4 membered heterocyclyl, the above-mentioned groups are independently optionally further substituted by one or more selected from deuterium, fluorine, Chlorine, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 Substituents of cycloalkyl, 3-6 membered heterocyclyl, phenyl, -OR 7 and -NR 9 R 10 ,
  • R and L together with their directly attached nitrogen atoms form the following structure:
  • R 7 , R 9 and R 10 are as defined in the compound of formula (IIa).
  • each R 6 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl , C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl and -NR 9 R 10 , the above groups are independent optionally further selected from deuterium, halogen, hydroxyl, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy base, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 9 R 10 substituents;
  • Each R 7 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl groups, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-4 alkyl, C 1-4 alkoxy , C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and substituents of -NR 9 R 10 ;
  • Each R 8 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 Cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heterocycle Aryl, 5-8 membered heteroaryloxy and -NR 9 R 10 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6 -8 -aryloxy, 5-8-membered heteroaryl, 5-8-member
  • R 9 and R 10 is independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl, the above groups are independently any is further selected from the group consisting of one or more deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4
  • R 9 and R 10 are taken together with the nitrogen atom to which they are directly attached to form a 4-8 membered heterocyclic group or a 4-8 membered heteroaryl group independently optionally further substituted by one or more selected from the group consisting of deuterium, halogen, Hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy , C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl substituents.
  • the compounds of formula (I), their stereoisomers or their pharmaceutically acceptable salts include but are not limited to the following compounds:
  • the second aspect of the present invention provides a preparation method of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, comprising the following steps:
  • R is R 3 or an amino protecting group, the amino protecting group is tert-butoxycarbonyl or benzyl, X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Z 1 , Z 2 , Z 3 , L 1 , L 2 , R 1 , R 2 , R 3 and m are as defined in compounds of formula (I).
  • a third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention also relates to the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of the treatment and/or prevention of cancers, tumors at least partially associated with EGFR exon 20 insertions, deletions or other mutations or the use of drugs in metastatic disease.
  • the present invention also relates to a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and/or treatment of tumors, cancers and/or metastatic diseases caused by hyperproliferative and cell death-inducing disorders use in.
  • the present invention also relates to the aforementioned compounds of formula (I), their stereoisomers or their pharmaceutically acceptable salts in the preparation of the prevention and/or treatment of lung cancer, colon cancer, pancreatic cancer, head and neck cancer caused by hyperproliferation and cell death-induced disorders , breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors , urological tumor, skin tumor, sarcoma, sinus inverted papilloma or nasal sinus squamous cell carcinoma associated with the use in the drug.
  • the present invention also relates to said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • the present invention also relates to said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of cancers associated at least in part with EGFR exon 20 insertions, deletions or other mutations , tumor or metastatic disease.
  • the present invention also relates to said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use in the prevention and/or treatment of tumors, cancers and/or metastases caused by hyperproliferative and cell death-inducing disorders use of sexually transmitted diseases.
  • the present invention also relates to the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of lung, colon, pancreatic cancer caused by hyperproliferative and cell death-induced disorders , head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndromes, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and Use in other gynecological tumors, urological tumors, skin tumors, sarcomas, naso-inverted papilloma or nasosinus-related squamous cell carcinoma of the sinuses.
  • the present invention also relates to a method of treating and/or preventing cancer, tumor or metastatic disease associated at least in part with EGFR exon 20 insertions, deletions or other mutations, comprising administering to a patient in need thereof a therapeutically effective amount of said A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a method of preventing and/or treating tumors, cancers and/or metastatic diseases caused by hyperproliferative and induced cell death disorders, comprising administering to a patient in need thereof a therapeutically effective amount of said formula (I) A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a treatment and/or prevention of lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, Myelodysplastic syndromes, malignant lymphomas, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, sinus inverted papilloma or A method of nasosinusal inverting papilloma-associated squamous cell carcinoma of the nasal cavity, comprising administering to a patient in need thereof a therapeutically effective amount of said compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof .
  • an EGFR inhibitor with the structure of the following formula (I). 20 Drugs for cancers, tumors or metastatic diseases associated with insertions, deletions or other mutations, especially for hyperproliferative and cell death-inducing disorders, are expected to be developed into next-generation EGFR inhibitors. On this basis, the present invention has been completed.
  • Alkyl refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group, preferably a straight-chain alkyl group and a branched-chain alkyl group comprising 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, Including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1, 2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl propylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- Dimethylbutyl,
  • C 1-10 alkyl refers to straight-chain alkyl groups including 1 to 10 carbon atoms and branched alkyl groups
  • C 1-4 alkyl refers to straight-chain alkyl groups including 1 to 4 carbon atoms and A branched-chain alkyl group
  • C 1-2 alkyl refers to a straight-chain alkyl group including 1 to 2 carbon atoms
  • C 0-8 alkyl refers to a straight-chain alkyl group including 0 to 8 carbon atoms and A branched-chain alkyl group
  • C 0-4 alkyl refers to a straight-chain alkyl group containing 0 to 4 carbon atoms and a branched alkyl group
  • C 0-2 alkyl refers to a group containing 0 to 4 carbon atoms straight-chain and branched-chain alkyl groups.
  • Cycloalkyl or “carbocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated ⁇ electron system, cycloalkyl is divided into monocyclic cycloalkyl, polycyclic cycloalkyl, preferably including 3 to 12 or 3 to 8 or 3 Cycloalkyl groups of up to 6 carbon atoms, for example, "C 3-12 cycloalkyl” refers to cycloalkyl groups including 3 to 12 carbon atoms, “C 3-10 cycloalkyl” refers to cycloalkyl groups including 3 to 10 carbon atoms atomic cycloalkyl, “C 3-8 cycloalkyl” refers to a cycloalkyl group comprising 3 to 8 carbon atoms, "C 3-6
  • Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl etc.
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • “Spirocycloalkyl” refers to polycyclic groups in which a single carbon atom (called a spiro atom) is shared between the monocyclic rings, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have Fully conjugated pi electron system. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into single spirocycloalkyl groups, double spirocycloalkyl groups or polyspirocycloalkyl groups, and spirocycloalkyl groups include but are not limited to:
  • fused cycloalkyl refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a fully conjugated pi electron system. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, fused cycloalkyl groups include but are not limited to:
  • “Bridged cycloalkyl” refers to an all-carbon polycyclic group in which any two rings share two non-directly attached carbon atoms, these may contain one or more (preferably 1, 2 or 3) double bonds, but none The ring has a fully conjugated pi electron system. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, including but not limited to:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl , benzocycloheptyl, etc.
  • Heterocyclyl or “heterocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a fully conjugated pi-electron system, heterocyclyl wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O ) r (where r is an integer 0, 1, 2) heteroatoms excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • Heterocyclyl groups including 3 to 12 or 3 to 8 or 3 to 6 ring atoms are preferred, for example, "3-4 membered heterocyclyl” refers to a ring group containing 3 to 4 ring atoms, "3-6 "Membered heterocyclyl” refers to a ring group containing 3 to 6 ring atoms, “3-8 membered heterocyclyl” refers to a ring group containing 3 to 8 ring atoms, and “3-10 membered heterocyclyl” refers to a ring group containing 3 A ring group of up to 10 ring atoms, “3-12 membered heterocyclyl” refers to a ring group containing 3 to 12 ring atoms, and “4-6 membered heterocyclyl” refers to a ring group containing 4 to 6 ring atoms , “4-8 membered heterocyclyl” refers to a ring group containing 4 to 8 ring atoms, and "4-10 member
  • Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, and the like.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • “Spiroheterocyclyl” refers to a polycyclic heterocyclic group in which a single atom (called a spiro atom) is shared between the monocyclic rings, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or a heteroatom of S(O) r (where r is an integer 0, 1, 2) and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2 or 3), but none of the rings have a fully conjugated pi-electron system.
  • Spiroheterocyclyls are classified into mono-, bis-, or poly-spiroheterocyclyls according to the number of spiro atoms shared between the rings.
  • Spiroheterocyclyl groups include, but are not limited to:
  • “Fused heterocyclic group” refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more (preferably 1, 2, 3 or 4) rings may be contains one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from A heteroatom of nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2) and the remaining ring atoms are carbon. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups, fused heterocyclic groups include but are not limited to:
  • Bridged heterocyclyl refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings having a fully conjugated pi-electron system in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2) Heteroatoms, the remaining ring atoms are carbon. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, bridged heterocyclic groups include but are not limited to:
  • the heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, including but not limited to:
  • Aryl or “aromatic ring” refers to an all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) groups, polycyclic rings having a conjugated pi electron system (ie, with adjacent ring) groups for carbon atoms, preferably all-carbon aryl groups containing 6-10 or 6-8 carbons, for example, “C 6-10 aryl” refers to all-carbon aryl groups containing 6-10 carbons, “C 6-8 aryl” refers to a full carbon aryl group containing 6-8 carbons, including but not limited to phenyl and naphthyl.
  • the aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:
  • Heteroaryl refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms including nitrogen, oxygen and S(O)r (where r is the integer 0 , 1, 2) heteroatoms, preferably heteroaromatic systems containing 5-10 or 5-8 or 5-6 ring atoms, for example, "4-10-membered heteroaryl” means containing 4-10 ring atoms Heteroaromatic system of ring atoms, “4-8 membered heteroaryl” refers to a heteroaromatic system containing 4-8 ring atoms, “5-6 membered heteroaryl” refers to a heteroaromatic system containing 5-6 ring atoms Aromatic system, "5-8 membered heteroaryl” refers to a heteroaromatic system containing 5-8 ring atoms, "5-10 membered heteroaryl” refers to a heteroaromatic system containing 5-10 ring atoms, Including, but not limited to, furanyl,
  • Alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight or branched chain alkenyl group containing 2-10 or 2-4 carbons
  • C 2-10 alkenyl refers to a straight-chain or branched alkenyl containing 2-10 carbons
  • C 2-4 alkenyl refers to a straight-chain or branched alkenyl containing 2-4 carbons Branched alkenyl.
  • Alkynyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight-chain or branched-chain alkynyl group containing 2-10 or 2-4 carbons,
  • C 2-10 alkynyl refers to a straight or branched chain alkynyl group containing 2-10 carbons
  • C 2-4 alkynyl refers to a straight or branched chain containing 2-4 carbons alkynyl.
  • ethynyl 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
  • Alkoxy refers to -O-alkyl, where alkyl is as defined above, eg, "C 1-10 alkoxy” refers to an alkyloxy group containing 1-10 carbons, “C 1-4 "Alkoxy” refers to an alkyloxy group containing 1-4 carbons including, but not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.
  • Cycloalkoxy and “cycloalkyloxy” refer to -O-cycloalkyl, wherein the definition of cycloalkyl is as described above, for example, “C 3-12 cycloalkoxy” refers to a group containing 3-12 Carbon cycloalkyloxy, “C 3-8 cycloalkoxy” refers to cycloalkyloxy containing 3-8 carbons, “C 3-6 cycloalkoxy” refers to 3-6 carbons Cycloalkyloxy, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Heterocyclyloxy and “heterocyclyloxy” refer to -O-heterocyclyl, wherein heterocyclyl is as defined above, including but not limited to azetidinyloxy, oxetanyloxy group, azacyclopentyloxy, nitrogen, oxanyloxy and the like.
  • C 1-10 alkanoyl refers to the monovalent atomic group left after C 1-10 alkanoic acid removes the hydroxyl group, usually also expressed as "C 0-9 -C(O)-", for example, "C 1 -C (O)-” means acetyl; “C2 - C(O)-” means propionyl; “C3 - C(O)-” means butyryl or isobutyryl.
  • C 3-10 cycloalkyl C 1-2 alkyl means that the carbon atom in “C 3-10 cycloalkyl” is attached to the C 1-2 alkyl, C 3-10 cycloalkyl and C 1- 2Alkyl is as defined above.
  • 3-12-membered heterocyclyl C 1-2 alkyl means that the carbon atom in "3-12-membered heterocyclyl” is attached to C 1-2 alkyl, 3-12-membered heterocyclyl and C 1- 2Alkyl is as defined above.
  • C 6-10 aryl C 1-2 alkyl means the carbon atom in “C 6-10 aryl” is attached to C 1-2 alkyl, C 6-10 aryl and C 1-2 alkyl is defined as above.
  • 5-10-membered heteroaryl C 1-2 alkyl means that the carbon atom in "5-10-membered heteroaryl” is attached to C 1-2 alkyl, 5-10-membered heteroaryl and C 1- 2Alkyl is as defined above.
  • Halo-substituted C 1-10 alkyl refers to 1-10 carbon alkyl groups in which the hydrogen on the alkyl group is optionally substituted by fluorine, chlorine, bromine and iodine atoms, including but not limited to difluoromethyl, dichloro Methyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
  • Halo-substituted C 1-10 alkoxy refers to a 1-10 carbon alkoxy group in which the hydrogen on the alkyl group is optionally substituted with fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.
  • Deuterium-substituted C1-10 alkyl refers to a 1-10 carbon alkyl group in which the hydrogen on the alkyl group is optionally substituted with a deuterium atom. Including but not limited to deuteromethyl, di-deuteromethyl, tri-deuteromethyl and the like.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Optional or “optionally” means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur, that is, both substituted and unsubstituted .
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more "hydrogen atoms" in a group are, independently of one another, substituted with the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, in accordance with valence bond theory in chemistry, and those skilled in the art can determine (either experimentally or theoretically) possible or impossible without undue effort replacement. For example, amino or hydroxyl groups with free hydrogen may be unstable when combined with carbon atoms with unsaturated bonds, such as alkenes.
  • Stereoisomer its English name is stereoisomer, refers to the isomers produced by the different arrangements of atoms in the molecule in space. It can be divided into cis-trans isomers and enantiomers. It can also be divided into two categories: enantiomers and diastereomers. Stereoisomers due to rotation of a single bond are called conformational stereo-isomers, and are sometimes called rotamers. Stereoisomers caused by bond length, bond angle, double bond in the molecule, ring, etc. are called configuration stereo-isomers, and configuration isomers are divided into two categories.
  • the isomers caused by the double bond or the single bond of the ring carbon atom not being able to rotate freely are called geometric isomers, also known as cis-trans isomers, which are divided into Z, E two configurations.
  • geometric isomers also known as cis-trans isomers, which are divided into Z, E two configurations.
  • cis-2-butene and trans-2-butene are a pair of geometric isomers, and the stereoisomers with different optical properties caused by the absence of anti-axial symmetry in the molecule are called optical isomers ( optical isomer), divided into R and S configurations.
  • the "stereoisomer" may be understood to include one or more of the above-mentioned enantiomers, configurational isomers and conformational isomers unless otherwise specified.
  • “Pharmaceutically acceptable salts” as used herein refers to pharmaceutically acceptable acid addition salts, including inorganic and organic acid salts, which can be prepared by methods known in the art.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). NMR was measured by Bruker AVANCE-400/500 nuclear magnetic instrument, the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), internal standard For tetramethylsilane (TMS).
  • DMSO-d 6 dimethyl sulfoxide
  • CD 3 OD deuterated methanol
  • CDCl 3 deuterated chloroform
  • TMS internal standard For tetramethylsilane
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specifications used for TLC are 0.15mm ⁇ 0.20mm, and the specifications used for TLC separation and purification products are 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or according to methods known in the art.
  • the first step the synthesis of 1-fluoro-3-isothiocyano-2-methoxybenzene
  • the second step tert-butyl 5-((3-fluoro-2-methoxyphenyl)carbamoyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H )-carboxylate synthesis
  • the third step synthesis of N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-methylthioamide
  • the first step the synthesis of 3-(2-aminoethoxy) isonicotine nitrile
  • Ethanolamine (1.40 g, 23.0 mmol) was dissolved in tetrahydrofuran (40 mL), cooled to 0 °C, sodium hydrogen (920 mg, 60%, 23.0 mmol) was added in portions, the reaction was stirred at room temperature for 0.5 h, cooled to 0 °C, A solution of 3-fluoroisonicotine nitrile (2.44 g, 20.0 mmol) in tetrahydrofuran (10 mL) was added dropwise, the dropwise addition was completed, and the reaction solution was warmed to room temperature to continue the reaction for 2 hours.
  • the second step synthesis of tert-butyl (2-((4-cyanopyridin-3-yl)oxy)ethyl)carbamate
  • the third step synthesis of tert-butyl (2-((4-(aminomethyl)pyridin-3-yl)oxy)ethyl)carbamate
  • tert-Butyl(2-((4-cyanopyridin-3-yl)oxy)ethyl)carbamate (2.80 g, 10.6 mmol) was dissolved in methanol (60 mL), 2 mL of ammonia was added, Raney nickel (3.0 g), the reaction system was replaced with hydrogen three times, stirred at room temperature for 18 hours, after the reaction, the reaction solution was filtered, washed with methanol five times, the filtrate was concentrated to dryness, and the residue was separated by flash silica gel column chromatography [ 0-10% methanol: dichloromethane] to give tert-butyl(2-((4-(aminomethyl)pyridin-3-yl)oxy)ethyl)carbamate (1.5g, yield: 53%).
  • ESI-MS 268.0[M+1] + .
  • the fourth step tert-butyl(2-((4-(((5-((3-fluoro-2-methoxyphenyl)carbamoyl)-6-oxo-1,2, Synthesis of 3,6-tetrahydropyridin-4-yl)amino)methyl)pyridin-3-yl)oxy)ethyl)carbamate
  • N-(3-Fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-methylthioamide 500 mg, 1.69 mmol
  • tert-Butyl(2-((4-(aminomethyl)pyridin-3-yl)oxy)ethyl)carbamate 632 mg, 2.36 mmol
  • N,N-dimethylacetamide 1.5 mL
  • the reaction solution was extracted with ethyl acetate (50 mL) and saturated brine (50 mL).
  • the fifth step tert-butyl (2-((4-(3-((3-fluoro-2-methoxyphenyl)amino)-4-oxo-4,5,6,7-tetrahydro Synthesis of -1H-pyrro[3,2-c]pyridin-2-yl)pyridin-3-yl)oxy)ethyl)carbamate
  • the seventh step N-(2-((4-(3-((3-fluoro-2-methoxyphenyl)amino)-4-oxo-4,5,6,7-tetrahydro-1H- Synthesis of pyrrolo[3,2-c]pyridin-2-yl)pyridin-3-yl)oxy)ethyl)acrylamide
  • Embodiments 2-33 can be prepared by selecting corresponding raw materials with reference to all or part of the synthetic methods of Example 1:
  • the first step tert-butyl(2-((4-(((5-((3-chloro-2-methoxyphenyl)aminomethylthioacyl)-6-oxo-1,2, Synthesis of 3,6-tetrahydropyridin-4-yl)amino)methyl)pyridin-3-yl)oxy)ethyl)(methyl)carbamate
  • Step 4 3-((3-Chloro-2-methoxyphenyl)amino)-2-(3-(2-(methylamino)ethoxy)pyridin-4-yl)-1,5- Synthesis of Dihydro-4H-pyrrolo[3,2-c]pyridin-4-one
  • the fifth step N-(2-((4-(3-((3-chloro-2-methoxyphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrrolo[3 Synthesis of ,2-c]pyridin-2-yl)pyridin-3-yl)oxy)ethyl)-N-methacrylamide
  • Embodiments 35-67 can be prepared by selecting corresponding raw materials with reference to all or part of the synthetic methods of Example 34:
  • the cells were placed in a 96-well plate filled with drugs at a temperature of 37°C, 5% CO 2 and 95% humidity, and cultured for 72 hours, followed by CTG analysis.
  • Cell survival rate (%) (Lum test drug-Lum culture medium control)/(Lum cell control-Lum culture medium control) ⁇ 100%.
  • the series of compounds of the present invention have a strong inhibitory effect on EGFR exon 20 insertion mutation at the cellular level, and some compounds have a strong inhibitory effect on Ba/F3 EGFR-D770-N771ins_SVD and Ba/F3
  • the activity of EGFR-V769_D770insASV cells in inhibiting proliferation relative to EGFR WT (wild-type) cells has high selectivity, and the selectivity reaches more than 10 times, even more than 20 times.
  • the selectivity of the compound of the present invention has been greatly improved.
  • the selectivity of the compounds of Examples 3, 7, and 33 has been increased by more than two times compared to the positive compound, and the selectivity of the compound of Example 45 has even been improved relative to the positive compound. to more than six times.

Abstract

Disclosed are a fused ring compound of the structure of formula (I) as an EGFR inhibitor, a preparation method therefor, a pharmaceutical composition containing same, and the use thereof in the treatment and/or prevention of cancers, tumors, or metastatic diseases which are at least partially related to the insertion or deletion mutation of EGFR exon 20, in particular to the use thereof in the treatment of hyperproliferative diseases and induced cell death disorders. Each of the substituents in formula (I) is the same as those defined in the description.

Description

作为EGFR抑制剂的稠环化合物及其制备方法和应用Condensed ring compound as EGFR inhibitor and its preparation method and application 技术领域technical field
本发明属于药物合成领域，具体涉及作为EGFR抑制剂的稠环化合物及其制备方法和应用。The invention belongs to the field of drug synthesis, and in particular relates to a fused-ring compound as an EGFR inhibitor, a preparation method and application thereof.
背景技术Background technique
肺癌是全世界癌症死亡的主要原因，其中非小细胞肺癌(NSCLC)占85％。针对表皮生长因子受体(EGFR)突变、间变性淋巴瘤激酶(ALK)易位、ROS1原癌基因受体酪氨酸激酶(ROS1)重排和B-raf原癌基因、丝氨酸/苏氨酸激酶(BRAF)的多靶点治疗已经开发出来并在临床上得到验证。EGFR抑制能显著提高腺癌NSCLC的无进展生存期，其获得性耐药突变后继而被第三代抑制剂靶向。Lung cancer is the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) accounting for 85%. Targets epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) translocation, ROS1 proto-oncogene receptor tyrosine kinase (ROS1) rearrangement and B-raf proto-oncogene, serine/threonine Kinase (BRAF) multitargeted therapy has been developed and clinically validated. EGFR inhibition can significantly improve progression-free survival in adenocarcinoma NSCLC, whose acquired resistance mutations are subsequently targeted by third-generation inhibitors.
尽管成功地抑制了经典的EGFR激活突变(外显子19和21)和耐药突变(T790M)，外显子20的框内***也导致了EGFR信号的结构性激活，并与对现有EGFR抑制剂的从头抵抗相关。外显子20突变是异质性的，包括1-7个氨基酸在EGFR蛋白的762-774个氨基酸之间的框内***或重复。在NSCLC中，EGFR外显子20的突变频率占EGFR所有突变的4-10％。这些突变与其他已知的致癌基因驱动突变相互排斥，并且在女性、非吸烟者、亚洲人群和非小细胞肺癌患者的腺癌中富集。除NSCLC外，EGFR外显子20***突变还见于一种罕见的头颈部癌，即鼻腔鳞状细胞癌(SNSCC)。此外，在受体酪氨酸激酶(RTK)EGFR家族的另一成员HER2中也发现了结构类似的外显子20***突变。Despite successful suppression of canonical EGFR activating mutations (exons 19 and 21) and resistance mutations (T790M), the in-frame insertion of exon 20 also resulted in a structural activation of EGFR signaling, which is incompatible with existing EGFR De novo resistance to inhibitors is associated. Exon 20 mutations are heterogeneous and include in-frame insertions or duplications of 1-7 amino acids between amino acids 762-774 of the EGFR protein. In NSCLC, the mutation frequency of EGFR exon 20 accounts for 4-10% of all mutations in EGFR. These mutations were mutually exclusive with other known oncogene driver mutations and were enriched in adenocarcinomas in women, non-smokers, Asian populations, and patients with non-small cell lung cancer. In addition to NSCLC, EGFR exon 20 insertion mutations are also seen in a rare type of head and neck cancer, nasal squamous cell carcinoma (SNSCC). In addition, a structurally similar exon 20 insertion mutation was also found in HER2, another member of the receptor tyrosine kinase (RTK) EGFR family.
多重回顾性分析显示，目前可用的第1代、第2代和第3代EGFR抑制剂对外显子20***突变的疗效有限，但A763-Y764insFQEA突变除外。不可逆抑制剂波齐替尼(Poziotinib)和EGFR/MET双特异性抗体amivantamab正在临床试验中。几种小分子抑制剂包括TAK-788和TAS-6417，在EGFR外显子20非小细胞肺癌患者中显示出临床上有意义的功效，但是，由于对EGFR WT的选择性有限，它们的不良反应是不可避免的，并可能导致剂量限制性毒性。因此，对于这些患者而言，迫切需要针对EGFR外显子20***突变的高选择性小分子抑制剂。Multiple retrospective analyses showed limited efficacy of currently available first-, second-, and third-generation EGFR inhibitors for exon 20 insertion mutations, with the exception of the A763-Y764insFQEA mutation. The irreversible inhibitor Poziotinib and the EGFR/MET bispecific antibody amivantamab are in clinical trials. Several small-molecule inhibitors, including TAK-788 and TAS-6417, have shown clinically meaningful efficacy in EGFR exon 20 non-small cell lung cancer patients, however, their poor selectivity against EGFR WT has Reactions are unavoidable and may lead to dose-limiting toxicity. Therefore, highly selective small-molecule inhibitors targeting EGFR exon 20 insertion mutations are urgently needed for these patients.
发明内容SUMMARY OF THE INVENTION
本发明的目的在于提供一种高选择性EGFR抑制剂。本发明系列化合物对EGFR外显子20***、缺失或其他突变细胞学活性具有很强的抑制作用，并对EGFR野生型具有高选择性，可广泛应用于制备治疗和/或预防至少部分与EGFR外显子20***、缺失或其他突变相关的癌症、肿瘤或转移性疾病的药物，特别是 治疗过度增殖性疾病和诱导细胞死亡障碍疾病的药物，从而有望开发出新一代EGFR抑制剂。The object of the present invention is to provide a highly selective EGFR inhibitor. The series of compounds of the present invention have a strong inhibitory effect on the cytological activity of EGFR exon 20 insertion, deletion or other mutation, and have high selectivity for EGFR wild type, and can be widely used in the preparation of treatment and/or prevention at least partially related to EGFR Drugs for cancers, tumors or metastatic diseases associated with exon 20 insertions, deletions or other mutations, especially for hyperproliferative diseases and cell death-inducing disorders, are expected to lead to the development of a new generation of EGFR inhibitors.
本发明第一方面提供式(I)化合物、其立体异构体或其药学上可接受盐：A first aspect of the present invention provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
Figure PCTCN2021111447-appb-000001
Figure PCTCN2021111447-appb-000001
其中，in,
Figure PCTCN2021111447-appb-000002
为单键或双键；
Figure PCTCN2021111447-appb-000002
is a single bond or a double bond;
X 1为CR aR b、CR c或C(O)； X 1 is CR a R b , CR c or C(O);
X 2为CR dR e、CR f、N或NH； X 2 is CR d Re , CR f , N or NH;
Y 1、Y 2、Y 3和Y 4各自独立地选自N、C(O)、CR g、N(O)和NR h； Y 1 , Y 2 , Y 3 and Y 4 are each independently selected from N, C(O), CR g , N(O) and NR h ;
Z 1、Z 2和Z 3各自独立地为CR i或N； Z 1 , Z 2 and Z 3 are each independently CR i or N;
L 1选自O、S、NR j、CR kR p、OCR kR p和键； L1 is selected from O, S , NRj , CRkRp , OCRkRp and a bond ;
L 2选自C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-10环烷基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、C 3-10环烷基C 1-2烷基、3-12元杂环基C 1-2烷基、C 6-10芳基C 1-2烷基和5-10元杂芳基C 1-2烷基，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 6、-C 0-8烷基-O-R 7、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基-O-C(O)R 8、-C 0-8烷基-NR 9R 10、-C 0-8烷基-C(＝NR 9)R 8、-C 0-8烷基-N(R 9)-C(＝NR 10)R 8、-C 0-8烷基-C(O)NR 9R 10和-C 0-8烷基-N(R 9)-C(O)R 8的取代基所取代； L 2 is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl C 1-2 alkyl, 3-12 membered heterocyclyl C 1-2 alkyl, C 6-10 aryl C 1-2 alkyl and 5 -10-membered heteroaryl C 1-2 alkyl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen Substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 6 , -C 0-8 alkane base-OR 7 , -C 0-8 alkyl-C(O)OR 7 , -C 0-8 alkyl-C(O)R 8 , -C 0-8 alkyl-OC(O)R 8 , -C 0-8 alkyl-NR 9 R 10 , -C 0-8 alkyl-C(=NR 9 )R 8 , -C 0-8 alkyl-N(R 9 )-C(=NR 10 ) R 8 , -C 0-8 alkyl-C(O)NR 9 R 10 and -C 0-8 alkyl-N(R 9 )-C(O)R 8 substituents;
R a、R b、R d和R e各自独立地选自氢、氘、卤素、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基和C 2-10链炔基，或者，R a和R b、R d和R e、R a和R d其中之一组各自独立地与其直接相连的碳原子一起形成一个C 3-8环烷基或3-8元杂环基，另两组如前所定义； R a , R b , R d and R e are each independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2- 10 alkenyl and C 2-10 alkynyl, or, alternatively, one of the groups of Ra and R b , R d and Re , Ra and R d each independently together with the carbon atom to which it is directly attached forms a C 3 -8 cycloalkyl or 3-8 membered heterocyclyl, the other two groups are as previously defined;
R c和R f各自独立地选自氢、氘、卤素、C 1-10烷基、卤取代C 1-10烷基和氘取代C 1-10烷基，或者，R c和R f与其直接相连的部分一起形成一个C 3-8环烷基或3-8元杂环基； R c and R f are each independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, halo-substituted C 1-10 alkyl, and deuterium substituted C 1-10 alkyl, alternatively, R c and R f are directly therewith The linked moieties together form a C 3-8 cycloalkyl or 3-8 membered heterocyclyl;
R g选自氢、氘、卤素、氰基、C 1-10烷基、C 1-10烷氧基、卤取代C 1-10烷基、氘 取代C 1-10烷基、卤取代C 1-10烷氧基、氘取代C 1-10烷氧基、C 2-10链烯基、C 2-10链炔基和-C 0-8烷基-NR 4R 5； R g is selected from hydrogen, deuterium, halogen, cyano, C 1-10 alkyl, C 1-10 alkoxy, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, halogen substituted C 1 -10 alkoxy, deuterium substituted C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl and -C 0-8 alkyl-NR 4 R 5 ;
R h选自氢、氘、羟基、C 1-10烷基、卤取代C 1-10烷基和氘取代C 1-10烷基； R is selected from hydrogen, deuterium , hydroxyl, C 1-10 alkyl, halo-substituted C 1-10 alkyl and deuterium substituted C 1-10 alkyl;
R i选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 6、-C 0-8烷基-O-R 7、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基-O-C(O)R 8、-C 0-8烷基-NR 9R 10、-C 0-8烷基-C(＝NR 9)R 8、-C 0-8烷基-N(R 9)-C(＝NR 10)R 8、-C 0-8烷基-C(O)NR 9R 10和-C 0-8烷基-N(R 9)-C(O)R 8； R i is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 chain Alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -C 0-8 Alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 6 , -C 0-8 alkyl-OR 7 , -C 0-8 alkyl-C(O)OR 7 , -C 0-8 alkyl-C(O)R 8 , -C 0-8 alkyl-OC(O)R 8 , -C 0-8 alkyl-NR 9 R 10 , -C 0-8 alkyl-C (=NR 9 )R 8 , -C 0-8 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0-8 alkyl-C(O)NR 9 R 10 and -C 0-8 alkyl-N(R 9 )-C(O)R 8 ;
R j选自氢、氘、C 1-10烷基、卤取代C 1-10烷基和氘取代C 1-10烷基； R j is selected from hydrogen, deuterium, C 1-10 alkyl, halo-substituted C 1-10 alkyl and deuterium substituted C 1-10 alkyl;
R k和R p各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 6、-C 0-8烷基-O-R 7、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基-O-C(O)R 8、-C 0-8烷基-NR 9R 10、-C 0-8烷基-C(＝NR 9)R 8、-C 0-8烷基-N(R 9)-C(＝NR 10)R 8、-C 0-8烷基-C(O)NR 9R 10和-C 0-8烷基-N(R 9)-C(O)R 8，或者，R k和R p与其直接相连的碳原子一起形成一个C 3-8环烷基或3-8元杂环基，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 6、-C 0-8烷基-O-R 7、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基-O-C(O)R 8、-C 0-8烷基-NR 9R 10、-C 0-8烷基-C(＝NR 9)R 8、-C 0-8烷基-N(R 9)-C(＝NR 10)R 8、-C 0-8烷基-C(O)NR 9R 10和-C 0-8烷基-N(R 9)-C(O)R 8的取代基所取代； R k and R p are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halo-substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl , C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 membered aryl, 5-10 membered heteroaryl, =O , -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 6 , -C 0-8 alkyl-OR 7 , -C 0-8 alkyl-C(O ) OR 7 , -C 0-8 alkyl-C(O)R 8 , -C 0-8 alkyl-OC(O)R 8 , -C 0-8 alkyl-NR 9 R 10 , -C 0 -8 alkyl-C(=NR 9 )R 8 , -C 0-8 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0-8 alkyl-C(O)NR 9 R 10 and -C 0-8 alkyl-N(R 9 )-C(O)R 8 , alternatively, R k and R p together with the carbon atom to which they are directly attached form a C 3-8 cycloalkyl or 3 -8-membered heterocyclic group, the above-mentioned groups are independently optionally further substituted by one or more C 1-10 alkyl groups selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen base, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10-membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 6 , -C 0-8 alkyl-OR 7 , - C 0-8 alkyl-C(O)OR 7 , -C 0-8 alkyl-C(O)R 8 , -C 0-8 alkyl-OC(O)R 8 , -C 0-8 alkane Base -NR 9 R 10 , -C 0-8 alkyl-C(=NR 9 )R 8 , -C 0-8 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0 -8 alkyl-C(O)NR 9 R 10 and -C 0-8 alkyl-N(R 9 )-C(O)R 8 substituents;
每个R 1各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 6、-C 0-8烷基-O-R 7、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基-O-C(O)R 8、-C 0-8烷基-NR 9R 10、-C 0-8烷基-C(＝NR 9)R 8、-C 0-8烷基-N(R 9)-C(＝NR 10)R 8、-C 0-8烷基-C(O)NR 9R 10和-C 0-8烷基-N(R 9)-C(O)R 8； Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halo-substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 6 , -C 0-8 alkyl-OR 7 , -C 0-8 alkyl-C(O) OR 7 , -C 0-8 alkyl-C(O)R 8 , -C 0-8 alkyl-OC(O)R 8 , -C 0-8 alkyl-NR 9 R 10 , -C 0- 8 alkyl-C(=NR 9 )R 8 , -C 0-8 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0-8 alkyl-C(O)NR 9 R 10 and -C 0-8 alkyl-N(R 9 )-C(O)R 8 ;
R 2为乙烯基或乙炔基，上述基团独立地任选进一步被一个或多个选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基-C(O)-NR 9R 10和-C 0-8烷基-NR 9R 10的取代基所取代； R 2 is vinyl or ethynyl, and the above groups are independently optionally further selected from one or more groups selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium Substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -C 0-8 alkyl-C(O)OR 7 , -C 0-8 alkyl-C(O ) R 8 , -C 0-8 alkyl-C(O)-NR 9 R 10 and the substituents of -C 0-8 alkyl-NR 9 R 10 ;
R 3选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基和-NR 9R 10，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、 氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 6、-C 0-8烷基-O-R 7、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基-O-C(O)R 8、-C 0-8烷基-NR 9R 10、-C 0-8烷基-C(＝NR 9)R 8、-C 0-8烷基-N(R 9)-C(＝NR 10)R 8、-C 0-8烷基-C(O)NR 9R 10和-C 0-8烷基-N(R 9)-C(O)R 8的取代基所取代， R 3 is selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl and -NR 9 R 10 , the above-mentioned groups are independently optionally further selected by one or more groups selected from deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3- 12-membered heterocyclyl, C 6-10 -membered aryl, 5-10-membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 6 , -C 0-8 alkyl-OR 7 , -C 0-8 alkyl-C(O)OR 7 , -C 0-8 alkyl-C(O)R 8 , -C 0-8 alkyl- OC(O)R 8 , -C 0-8 alkyl-NR 9 R 10 , -C 0-8 alkyl-C(=NR 9 )R 8 , -C 0-8 alkyl-N(R 9 ) Substituents for -C(=NR 10 )R 8 , -C 0-8 alkyl-C(O)NR 9 R 10 and -C 0-8 alkyl-N(R 9 )-C(O)R 8 replaced,
或者，R 3和L 2与其直接相连的氮原子一起形成一个4-10元杂环基； Alternatively, R and L together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl ;
R 4和R 5各自独立地选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基和-NR 9R 10，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 9R 10的取代基所取代； R 4 and R 5 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6- 10 -aryl, 5-10-membered heteroaryl and -NR 9 R 10 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6 -10 -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 9 R 10 substituents;
每个R 6各自独立地选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基和-NR 9R 10，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 9R 10的取代基所取代； Each R 6 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl and -NR 9 R 10 , the above-mentioned groups independently optionally further selected by one or more groups selected from deuterium, halogen, hydroxyl, oxo, C 1-10 alkyl, C 1 -10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6- 10 -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and substituents of -NR 9 R 10 ;
每个R 7各自独立地选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 6-10芳基和5-10元杂芳基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、氰基、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 9R 10的取代基所取代； Each R 7 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10-membered heteroaryl groups, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-10 alkyl, C 1-10 alkoxy , C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and substituents of -NR 9 R 10 ;
每个R 8各自独立地选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 9R 10，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 9R 10的取代基所取代； Each R 8 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 Cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10-membered heterocycle Aryl, 5-10 membered heteroaryloxy and -NR 9 R 10 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6 -10 -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 9 R 10 substituents;
每个R 9和R 10各自独立地选自氢、氘、羟基、C 1-10烷氧基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基、氨基、单C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基的取代基所取代； Each of R 9 and R 10 is independently selected from hydrogen, deuterium, hydroxy, C 1-10 alkoxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 -membered cycloalkyl, 3-12-membered heterocyclyl, C 6-10 -membered aryl, 5-10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl, the above groups are independently any is further selected by one or more selected from deuterium, halogen, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6 -10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and Substituents of C 1-10 alkanoyl groups are substituted;
或者，R 9和R 10与其直接相连的氮原子一起形成一个4-10元杂环基或4-10元杂芳基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基的取代基所取代； Alternatively, R 9 and R 10 together with the nitrogen atom to which they are directly attached form a 4-10-membered heterocyclic group or a 4-10-membered heteroaryl group independently optionally further , hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-10 alkoxy base, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy , 5-10-membered heteroaryl, 5-10-membered heteroaryloxy, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl substituents;
m为0、1或2；且m is 0, 1 or 2; and
每个r各自独立地为0、1或2。Each r is independently 0, 1, or 2.
作为优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，每个R 1各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 6、-C 0-4烷基-O-R 7、-C 0-4烷基-C(O)OR 7、-C 0-4烷基-C(O)R 8、-C 0-4烷基-O-C(O)R 8、-C 0-4烷基-NR 9R 10、-C 0-4烷基-C(＝NR 9)R 8、-C 0-4烷基-N(R 9)-C(＝NR 10)R 8、-C 0-4烷基-C(O)NR 9R 10和-C 0-4烷基-N(R 9)-C(O)R 8；其中，R 6、R 7、R 8、R 9、R 10和r如式(I)化合物中所定义。 As a preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide Nitrogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkane base, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl, =O, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O ) r R 6 , -C 0-4 alkyl-OR 7 , -C 0-4 alkyl-C(O)OR 7 , -C 0-4 alkyl-C(O)R 8 , -C 0- 4 alkyl-OC(O)R 8 , -C 0-4 alkyl-NR 9 R 10 , -C 0-4 alkyl-C(=NR 9 )R 8 , -C 0-4 alkyl-N (R 9 )-C(=NR 10 )R 8 , -C 0-4 alkyl-C(O)NR 9 R 10 and -C 0-4 alkyl-N(R 9 )-C(O)R 8 ; wherein R 6 , R 7 , R 8 , R 9 , R 10 and r are as defined in compounds of formula (I).
作为优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，R i选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 6、-C 0-4烷基-O-R 7、-C 0-4烷基-C(O)OR 7、-C 0-4烷基-C(O)R 8、-C 0-4烷基-O-C(O)R 8、-C 0-4烷基-NR 9R 10、-C 0-4烷基-C(＝NR 9)R 8、-C 0-4烷基-N(R 9)-C(＝NR 10)R 8、-C 0-4烷基-C(O)NR 9R 10和-C 0-4烷基-N(R 9)-C(O)R 8；其中，R 6、R 7、R 8、R 9、R 10和r如式(I)化合物中所定义。 As a preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R i is selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1 -4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 Membered heterocyclic group, C 6-8 aryl group, 5-8 membered heteroaryl group, =O, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O) r R 6 , -C 0-4 alkyl-OR 7 , -C 0-4 alkyl-C(O)OR 7 , -C 0-4 alkyl-C(O)R 8 , -C 0-4 alkyl-OC (O)R 8 , -C 0-4 alkyl-NR 9 R 10 , -C 0-4 alkyl-C(=NR 9 )R 8 , -C 0-4 alkyl-N(R 9 )- C(=NR 10 )R 8 , -C 0-4 alkyl-C(O)NR 9 R 10 and -C 0-4 alkyl-N(R 9 )-C(O)R 8 ; wherein R 6 , R 7 , R 8 , R 9 , R 10 and r are as defined in compounds of formula (I).
作为优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，R g选自氢、氘、卤素、氰基、C 1-4烷基、C 1-4烷氧基、卤取代C 1-4烷基、氘取代C 1-4烷基、卤取代C 1-4烷氧基、氘取代C 1-4烷氧基、C 2-4链烯基、C 2-4链炔基和-C 0-4烷基-NR 4R 5； As a preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R g is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 1 -4 alkoxy, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, halogen substituted C 1-4 alkoxy, deuterium substituted C 1-4 alkoxy, C 2-4 alkene group, C 2-4 alkynyl and -C 0-4 alkyl-NR 4 R 5 ;
R h选自氢、氘、羟基、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基； R is selected from hydrogen, deuterium , hydroxy, C 1-4 alkyl, halo-substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
其中，R 4和R 5如式(I)化合物中所定义。 wherein R4 and R5 are as defined in compounds of formula (I ) .
作为优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，R a、R b、R d和R e各自独立地选自氢、氘、卤素、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基和C 2-4链炔基，或者，R a和R b、R d和R e、R a和R d其中之一组各自独立地与其直接相连的碳原子一起形成一个C 3-6环烷基或3-6元杂环基，另二组如前所定义； As a preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R a , R b , R d and Re are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl and C 2-4 alkynyl, or, R a and R b , R One of the groups of d and Re , R a and R d each independently forms a C 3-6 cycloalkyl or 3-6 membered heterocyclic group together with the carbon atom to which it is directly attached, and the other two groups are as defined above;
R c和R f各自独立地选自氢、氘、卤素、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基，或者，R c和R f与其直接相连的部分一起形成一个C 3-6环烷基或3-6元杂环基。 R c and R f are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium substituted C 1-4 alkyl, alternatively, R c and R f are directly therewith The linked moieties together form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl.
作为优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，R j选自氢、氘、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基； As a preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, R j is selected from hydrogen, deuterium, C 1-4 alkyl, halogen-substituted C 1-4 alkyl base and deuterium substituted C 1-4 alkyl;
R k和R p各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 6、-C 0-4烷基-O-R 7、-C 0-4烷基-C(O)OR 7、-C 0-4烷基-C(O)R 8、-C 0-4烷基-O-C(O)R 8、-C 0-4烷基-NR 9R 10、-C 0-4烷基-C(＝NR 9)R 8、-C 0-4烷基-N(R 9)-C(＝NR 10)R 8、-C 0-4烷基-C(O)NR 9R 10和-C 0-4烷基-N(R 9)-C(O)R 8，或者，R k和R p与其直接相连的碳原子一起形成一个C 3-6环烷基或3-6元杂环基，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 6、-C 0-4烷基-O-R 7、-C 0-4烷基-C(O)OR 7、-C 0-4烷基-C(O)R 8、-C 0-4烷基-O-C(O)R 8、-C 0-4烷基-NR 9R 10、-C 0-4烷基-C(＝NR 9)R 8、-C 0-4烷基-N(R 9)-C(＝NR 10)R 8、-C 0-4烷基-C(O)NR 9R 10和-C 0-4烷基-N(R 9)-C(O)R 8的取代基所取代； R k and R p are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O , -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O) r R 6 , -C 0-4 alkyl-OR 7 , -C 0-4 alkyl-C(O ) OR 7 , -C 0-4 alkyl-C(O)R 8 , -C 0-4 alkyl-OC(O)R 8 , -C 0-4 alkyl-NR 9 R 10 , -C 0 -4 alkyl-C(=NR 9 )R 8 , -C 0-4 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0-4 alkyl-C(O)NR 9 R 10 and -C 0-4 alkyl-N(R 9 )-C(O)R 8 , alternatively, R k and R p together with the carbon atom to which they are directly attached form a C 3-6 cycloalkyl or 3 -6-membered heterocyclic group, the above-mentioned groups are independently optionally further substituted by one or more C 1-4 alkyl groups selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen base, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8-membered heteroaryl, =O, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O) r R 6 , -C 0-4 alkyl-OR 7 , - C 0-4 alkyl-C(O)OR 7 , -C 0-4 alkyl-C(O)R 8 , -C 0-4 alkyl-OC(O)R 8 , -C 0-4 alkane Base -NR 9 R 10 , -C 0-4 alkyl-C(=NR 9 )R 8 , -C 0-4 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0 -4 alkyl-C(O)NR 9 R 10 and -C 0-4 alkyl-N(R 9 )-C(O)R 8 substituents;
其中，R 6、R 7、R 8、R 9、R 10和r如式(I)化合物中所定义。 wherein R 6 , R 7 , R 8 , R 9 , R 10 and r are as defined in compounds of formula (I).
作为优选的方案，在所述式(I)化合物、其立体异构体或其药学上可接受盐中，L 2选自C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、C 3-6环烷基C 1-2烷基、3-6元杂环基C 1-2烷基、C 6-8芳基C 1-2烷基和5-8元杂芳基C 1-2烷基，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 6、-C 0-4烷基-O-R 7、-C 0-4烷基-C(O)OR 7、-C 0-4烷基-C(O)R 8、-C 0-4烷基-O-C(O)R 8、-C 0-4烷基-NR 9R 10、-C 0-4烷基-C(＝NR 9)R 8、-C 0-4烷基-N(R 9)-C(＝NR 10)R 8、-C 0-4烷基-C(O)NR 9R 10和-C 0-4烷基-N(R 9)-C(O)R 8的取代基所取代； As a preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, L 2 is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 -alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, C 3-6 cycloalkyl, C 1-2 alkyl, 3-6 membered heterocyclyl C 1-2 alkyl, C 6-8 aryl C 1-2 alkyl and 5-8 membered heteroaryl C 1-2 alkyl, the above groups are independently optionally further One or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -C 0-4 Alkyl-SF 5 , -C 0-4 alkyl-S(O) r R 6 , -C 0-4 alkyl-OR 7 , -C 0-4 alkyl-C(O)OR 7 , -C 0-4 alkyl-C(O)R 8 , -C 0-4 alkyl-OC(O)R 8 , -C 0-4 alkyl-NR 9 R 10 , -C 0-4 alkyl-C (=NR 9 )R 8 , -C 0-4 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0-4 alkyl-C(O)NR 9 R 10 and -C substituted by the substituent of 0-4 alkyl-N(R 9 )-C(O)R 8 ;
R 3选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基和-NR 9R 10，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 6、-C 0-4烷基-O-R 7、-C 0-4烷基-C(O)OR 7、-C 0-4烷基-C(O)R 8、-C 0-4烷基-O-C(O)R 8、-C 0-4烷基-NR 9R 10、-C 0-4烷基-C(＝NR 9)R 8、-C 0-4烷基-N(R 9)-C(＝NR 10)R 8、-C 0-4烷基-C(O)NR 9R 10和-C 0-4烷基-N(R 9)-C(O)R 8的取代基所取代， R 3 is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl and -NR 9 R 10 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- 6-membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O) r R 6 , -C 0-4 alkyl-OR 7 , -C 0-4 alkyl-C(O)OR 7 , -C 0-4 alkyl-C(O)R 8 , -C 0-4 alkyl- OC(O)R 8 , -C 0-4 alkyl-NR 9 R 10 , -C 0-4 alkyl-C(=NR 9 )R 8 , -C 0-4 alkyl-N(R 9 ) Substituents for -C(=NR 10 )R 8 , -C 0-4 alkyl-C(O)NR 9 R 10 and -C 0-4 alkyl-N(R 9 )-C(O)R 8 replaced,
或者，R 3和L 2与其直接相连的氮原子一起形成一个4-8元杂环基； Alternatively, R and L together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclyl ;
其中，R 6、R 7、R 8、R 9、R 10和r如式(I)化合物中所定义。 wherein R 6 , R 7 , R 8 , R 9 , R 10 and r are as defined in compounds of formula (I).
作为进一步优选的方案，式(I)化合物为如下式(Ⅱa)或(Ⅱb)化合物：As a further preferred solution, the compound of formula (I) is the following compound of formula (IIa) or (IIb):
Figure PCTCN2021111447-appb-000003
Figure PCTCN2021111447-appb-000003
其中，
Figure PCTCN2021111447-appb-000004
为单键或双键； in,
Figure PCTCN2021111447-appb-000004
is a single bond or a double bond;
Y 1、Y 2、Y 3和Y 4各自独立地选自N、C(O)、CR g、N(O)和NR h； Y 1 , Y 2 , Y 3 and Y 4 are each independently selected from N, C(O), CR g , N(O) and NR h ;
Z 1、Z 2和Z 3各自独立地为CR i或N； Z 1 , Z 2 and Z 3 are each independently CR i or N;
L 1选自O、S、NR j、CR kR p、OCR kR p和键； L1 is selected from O, S , NRj , CRkRp , OCRkRp and a bond ;
L 2选自C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、C 3-6环烷基C 1-2烷基、3-6元杂环基C 1-2烷基、C 6-8芳基C 1-2烷基和5-8元杂芳基C 1-2烷基，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-SF 5、-S(O) rR 6、-O-R 7、-C(O)OR 7、-C(O)R 8、-O-C(O)R 8、-NR 9R 10、-C(＝NR 9)R 8、-N(R 9)-C(＝NR 10)R 8、-C(O)NR 9R 10和-N(R 9)-C(O)R 8的取代基所取代； L 2 is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl, C 3-6 cycloalkyl C 1-2 alkyl, 3-6 membered heterocyclyl C 1-2 alkyl, C 6-8 aryl C 1-2 alkyl and 5 -8-membered heteroaryl C 1-2 alkyl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen Substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -SF 5 , -S(O) r R 6 , -OR 7 , -C(O)OR 7 , -C(O)R 8 , -OC(O)R 8 , -NR 9 R 10 , -C(=NR 9 )R 8 , -N(R 9 )-C(=NR 10 )R 8 , -C(O)NR 9 R 10 and -N(R 9 )-C(O)R 8 substituent;
R a、R b、R d和R e各自独立地选自氢、氘、卤素、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基，或者，R a和R b、R d和R e、R a和R d其中之一组各自独立地与其直接相连的碳原子一起形成一个C 3-6环烷基，另二组如前所定义； R a , R b , R d , and R e are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium-substituted C 1-4 alkyl, or, R One of a and R b , R d and Re , Ra and R d each independently forms a C 3-6 cycloalkyl together with the carbon atom to which it is directly attached, and the other two groups are as previously defined;
R c和R f各自独立地选自氢、氘、卤素、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基，或者，R c和R f与其直接相连的部分一起形成一个C 3-6环烷基； R c and R f are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium substituted C 1-4 alkyl, alternatively, R c and R f are directly therewith The linked moieties together form a C 3-6 cycloalkyl;
R g选自氢、氘、C 1-2烷基、C 1-2烷氧基、卤取代C 1-2烷基、氘取代C 1-2烷基、卤取代C 1-2烷氧基、氘取代C 1-2烷氧基和-C 0-2烷基-NR 4R 5； R g is selected from hydrogen, deuterium, C 1-2 alkyl, C 1-2 alkoxy, halo-substituted C 1-2 alkyl, deuterium-substituted C 1-2 alkyl, halo-substituted C 1-2 alkoxy , deuterium substituted C 1-2 alkoxy and -C 0-2 alkyl-NR 4 R 5 ;
R h各自独立地选自氢、氘、羟基、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基； R h is each independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium substituted C 1-4 alkyl;
R i选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基和-C 0-2烷基-O-R 7； R i is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl and -C 0-2 alkyl-OR 7 ;
R j选自氢、氘、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基； R j is selected from hydrogen, deuterium, C 1-4 alkyl, halo-substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
R k和R p各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂 环基、C 6-8芳基和5-8元杂芳基，或者，R k和R p与其直接相连的碳原子一起形成一个C 3-6环烷基或3-6元杂环基； R k and R p are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl, or, R k and R p together with the carbon atom to which they are directly attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl;
每个R 1各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基和-C 0-2烷基-O-R 7； Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl and -C 0 -2 alkyl-OR 7 ;
R 2为乙烯基或乙炔基，上述基团独立地任选进一步被一个或多个选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、-C 0-2烷基-C(O)OR 7、-C 0-2烷基-C(O)R 8、-C 0-2烷基-C(O)-NR 9R 10和-C 0-2烷基-NR 9R 10的取代基所取代； R 2 is vinyl or ethynyl, and the above groups are independently optionally further selected from one or more groups selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium Substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -C 0-2 alkyl-C(O)OR 7 , -C 0-2 alkyl-C(O ) R 8 , -C 0-2 alkyl-C(O)-NR 9 R 10 and the substituents of -C 0-2 alkyl-NR 9 R 10 ;
R 3选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基和-NR 9R 10，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-SF 5、-S(O) rR 6、-O-R 7、-C(O)OR 7、-C(O)R 8、-O-C(O)R 8、-NR 9R 10、-C(＝NR 9)R 8、-N(R 9)-C(＝NR 10)R 8、-C(O)NR 9R 10和-N(R 9)-C(O)R 8的取代基所取代， R 3 is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl and -NR 9 R 10 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- 6-membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -SF 5 , -S(O) r R 6 , -OR 7 , -C(O)OR 7 , - C(O)R 8 , -OC(O)R 8 , -NR 9 R 10 , -C(=NR 9 )R 8 , -N(R 9 )-C(=NR 10 )R 8 , -C( O) NR 9 R 10 and -N(R 9 )-C(O)R 8 substituents,
或者，R 3和L 2与其直接相连的氮原子一起形成一个4-8元含氮杂环基； Alternatively, R 3 and L 2 together with the nitrogen atom to which they are directly attached form a 4-8 membered nitrogen-containing heterocyclic group;
R 4和R 5各自独立地选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基和-NR 9R 10； R 4 and R 5 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6- 8 aryl, 5-8 membered heteroaryl and -NR 9 R 10 ;
m为0、1或2；m is 0, 1 or 2;
每个r各自独立地为0、1或2；each r is independently 0, 1, or 2;
其中，R 6、R 7、R 8、R 9、R 10和r如式(I)化合物中所定义。 wherein R 6 , R 7 , R 8 , R 9 , R 10 and r are as defined in compounds of formula (I).
作为更进一步优选的方案，式(I)化合物为如下式(Ⅲa 1)或(Ⅲa 2)化合物： As a further preferred solution, the compound of formula (I) is the following compound of formula (IIIa 1 ) or (IIIa 2 ):
Figure PCTCN2021111447-appb-000005
Figure PCTCN2021111447-appb-000005
其中，式(Ⅲa 1)化合物中，Y 1为N或CH； Wherein, in the compound of formula (IIIa 1 ), Y 1 is N or CH;
每个Z 1各自独立地为CH或N； each Z 1 is independently CH or N;
每个L 1各自独立地选自O、S、NR j、CR kR p、OCR kR p和键； Each L 1 is independently selected from O, S , NRj , CRkRp , OCRkRp and a bond ;
每个L 2各自独立地选自C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 3-4环烷基C 1-2烷基和3-4元杂环基C 1-2烷基，上述基团独立地任选进一步被一个或多个选自氘、 卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、苯基和-O-R 7的取代基所取代； Each L 2 is independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-4 cycloalkyl, C 1-2 alkyl and 3-4 membered heterocyclyl Heterocyclyl C 1-2 alkyl groups independently optionally further C 1 substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen -4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl and - Replaced by the substituent of OR 7 ;
每个R a、R b、R d和R e各自独立地选自氢、氘、甲基、二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基、一氘甲基、二氘甲基和三氘甲基，或者，R a和R b、R d和R e其中之一组各自独立地与其直接相连的碳原子一起形成一个C 3-6环烷基，另一组如前所定义； Each of Ra , Rb , Rd and Re is independently selected from hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, Tribromomethyl, monodeuteromethyl, dideuteromethyl and trideuteromethyl, alternatively, one of the groups of Ra and Rb , Rd and Re each independently together with the carbon atom to which it is directly attached form a C 3-6 cycloalkyl, another group is as previously defined;
每个R g各自独立地选自氢、氘和-NR 4R 5； Each R g is independently selected from hydrogen, deuterium and -NR 4 R 5 ;
每个R j各自独立地选自氢、氘、甲基、二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基、一氘甲基、二氘甲基和三氘甲基； Each Rj is independently selected from the group consisting of hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl , di-deuteromethyl and tri-deuteromethyl;
每个R k和R p各自独立地选自氢、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基，或者，R k和R p与其直接相连的碳原子一起形成一个C 3-6环烷基； Each R k and R p is independently selected from hydrogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium substituted C 1-4 alkyl, alternatively, R k and R p are directly attached thereto. The carbon atoms together form a C 3-6 cycloalkyl;
每个R 1a各自独立地选自氢、氘、氟、氯、溴、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基和-O-R 7； Each R 1a is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, and -OR 7 ;
每个R 1b各自独立地选自氢、氘、氟、氯、溴、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基和-O-R 7； Each R 1b is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, and -OR 7 ;
每个R 2各自独立地为乙烯基或乙炔基，上述基团独立地任选进一步被一个或多个选自氢、氘、氟、氯、氰基、甲基、二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基、一氘甲基、二氘甲基、三氘甲基、环丙基和-C 0-2烷基-NR 9R 10的取代基所取代； Each R 2 is each independently vinyl or ethynyl, independently optionally further selected by one or more groups selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, methyl, difluoromethyl, dichloro Methyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl, dideuteromethyl, trideuteromethyl, cyclopropyl and -C 0-2 alkyl- Substituents of NR 9 R 10 are substituted;
每个R 3各自独立地选自氢、氘、羟基、C 1-4烷基、C 3-4环烷基和3-4元杂环基，上述基团独立地任选进一步被一个或多个选自氘、氟、氯、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、苯基、-O-R 7和-NR 9R 10的取代基所取代， Each R is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 3-4 cycloalkyl, and 3-4 membered heterocyclyl, independently optionally further substituted by one or more One is selected from deuterium, fluorine, chlorine, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 chain Alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, -OR 7 and -NR 9 R 10 substituents,
或者，R 3和L 2与其直接相连的氮原子一起形成如下结构： Alternatively, R and L together with their directly attached nitrogen atoms form the following structure:
Figure PCTCN2021111447-appb-000006
Figure PCTCN2021111447-appb-000006
每个R 4和R 5各自独立地选自氢、氘、甲基、二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基、一氘甲基、二氘甲基和三氘甲基； Each R4 and R5 is independently selected from hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, mono deuteromethyl, di-deuteromethyl and tri-deuteromethyl;
n为0、1或2；n is 0, 1 or 2;
其中，R 7、R 9和R 10如式(Ⅱa)化合物中所定义。 wherein R 7 , R 9 and R 10 are as defined in the compound of formula (IIa).
作为进一步优选的方案，式(I)化合物为如下式(Ⅲb)化合物：As a further preferred solution, the compound of formula (I) is the compound of formula (IIIb) below:
Figure PCTCN2021111447-appb-000007
Figure PCTCN2021111447-appb-000007
其中，Y 3为N或N(O)； Wherein, Y 3 is N or N(O);
L 1选自O、S、NR j、CR kR p、OCR kR p和键； L1 is selected from O, S , NRj , CRkRp , OCRkRp and a bond ;
L 2选自C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 3-4环烷基C 1-2烷基和3-4元杂环基C 1-2烷基，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、苯基和-O-R 7的取代基所取代； L 2 is selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-4 cycloalkyl C 1-2 alkyl and 3-4 membered heterocyclyl C 1 -2 alkyl groups, the above groups are independently optionally further substituted by one or more groups selected from the group consisting of deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl substituted with substituents of C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl and -OR 7 ;
R c和R f各自独立地选自氢、氘、甲基、二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基、一氘甲基、二氘甲基和三氘甲基，或者，R c和R f与其直接相连的部分一起形成一个C 3-6环烷基； Rc and Rf are each independently selected from the group consisting of hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl group, di- deuteromethyl and tri- deuteromethyl , alternatively, R and R together with the moiety to which they are directly attached form a C 3-6 cycloalkyl;
R g选自氢、氘、甲基、二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基、一氘甲基、二氘甲基和三氘甲基； R g is selected from hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl, dideuteromethyl and trideuteromethyl;
R i选自氢、氘、氟、氯和氰基； R i is selected from hydrogen, deuterium, fluorine, chlorine and cyano;
R j选自氢、氘、甲基、二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基、一氘甲基、二氘甲基和三氘甲基； R j is selected from hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl, dideuteromethyl and trideuteromethyl;
R k和R p各自独立地选自氢、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基，或者，R k和R p与其直接相连的碳原子一起形成一个C 3-6环烷基； R k and R p are each independently selected from hydrogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium substituted C 1-4 alkyl, alternatively, the carbon atom to which R k and R p are directly attached together form a C 3-6 cycloalkyl;
R 1a选自氢、氘、氟、氯、溴、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基和-O-R 7； R 1a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl and -OR 7 ;
R 1b选自氢、氘、氟、氯、溴、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基和-O-R 7； R 1b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl and -OR 7 ;
R 2为乙烯基或乙炔基，上述基团独立地任选进一步被一个或多个选自氢、氘、氟、氯、氰基、甲基、二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基、一氘甲基、二氘甲基、三氘甲基、环丙基和-C 0-2烷基-NR 9R 10的取代基所取代； R 2 is vinyl or ethynyl, which are independently optionally further selected from one or more groups selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, difluoromethyl, dichloromethyl, dibromo Methyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl, di-deuteromethyl, tri-deuteromethyl, cyclopropyl and -C 0-2 alkyl-NR 9 R 10 substituted by a substituent;
R 3选自氢、氘、C 1-4烷基、C 3-4环烷基和3-4元杂环基，上述基团独立地任选进一步被一个或多个选自氘、氟、氯、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代 C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、苯基、-O-R 7和-NR 9R 10的取代基所取代， R 3 is selected from hydrogen, deuterium, C 1-4 alkyl, C 3-4 cycloalkyl and 3-4 membered heterocyclyl, the above-mentioned groups are independently optionally further substituted by one or more selected from deuterium, fluorine, Chlorine, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 Substituents of cycloalkyl, 3-6 membered heterocyclyl, phenyl, -OR 7 and -NR 9 R 10 ,
或者，R 3和L 2与其直接相连的氮原子一起形成如下结构： Alternatively, R and L together with their directly attached nitrogen atoms form the following structure:
Figure PCTCN2021111447-appb-000008
Figure PCTCN2021111447-appb-000008
其中，R 7、R 9和R 10如式(Ⅱa)化合物中所定义。 wherein R 7 , R 9 and R 10 are as defined in the compound of formula (IIa).
作为更进一步优选的方案，所述式(I)化合物、其立体异构体或其药学上可接受盐中，每个R 6各自独立地选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 3-8环烷基、3-8元杂环基、C 6-8芳基、5-8元杂芳基和-NR 9R 10，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 9R 10的取代基所取代； As a further preferred solution, in the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, each R 6 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl , C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl and -NR 9 R 10 , the above groups are independent optionally further selected from deuterium, halogen, hydroxyl, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy base, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 9 R 10 substituents;
每个R 7各自独立地选自氢、氘、C 1-4烷基、C 2-4链烯基、C 3-8环烷基、3-8元杂环基、C 6-8芳基和5-8元杂芳基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、氰基、C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 9R 10的取代基所取代； Each R 7 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl groups, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-4 alkyl, C 1-4 alkoxy , C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and substituents of -NR 9 R 10 ;
每个R 8各自独立地选自氢、氘、羟基、C 1-4烷基、C 1-4烷氧基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 9R 10，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氰基、C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 9R 10的取代基所取代； Each R 8 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 Cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heterocycle Aryl, 5-8 membered heteroaryloxy and -NR 9 R 10 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6 -8 -aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 9 R 10 substituents;
每个R 9和R 10各自独立地选自氢、氘、羟基、C 1-4烷氧基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 6-8芳基、5-8元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基的取代基所取代； Each of R 9 and R 10 is independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl, the above groups are independently any is further selected from the group consisting of one or more deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6 -8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and Substituted by the substituent of C 1-4 alkanoyl;
或者，R 9和R 10与其直接相连的氮原子一起形成4-8元杂环基或4-8元杂芳基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基的取代基所取代。 Alternatively, R 9 and R 10 are taken together with the nitrogen atom to which they are directly attached to form a 4-8 membered heterocyclic group or a 4-8 membered heteroaryl group independently optionally further substituted by one or more selected from the group consisting of deuterium, halogen, Hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy , C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl substituents.
作为最优选的方案，所述式(I)化合物、其立体异构体或其药学上可接受盐包括但不限于如下化合物：As the most preferred solution, the compounds of formula (I), their stereoisomers or their pharmaceutically acceptable salts include but are not limited to the following compounds:
Figure PCTCN2021111447-appb-000009
Figure PCTCN2021111447-appb-000009
Figure PCTCN2021111447-appb-000010
Figure PCTCN2021111447-appb-000010
Figure PCTCN2021111447-appb-000011
Figure PCTCN2021111447-appb-000011
Figure PCTCN2021111447-appb-000012
Figure PCTCN2021111447-appb-000012
Figure PCTCN2021111447-appb-000013
Figure PCTCN2021111447-appb-000013
本发明第二方面提供一种所述式(I)化合物、其立体异构体或其药学上可接受盐的制备方法，包括如下步骤：The second aspect of the present invention provides a preparation method of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, comprising the following steps:
Figure PCTCN2021111447-appb-000014
Figure PCTCN2021111447-appb-000014
其中，R为R 3或氨基保护基，所述氨基保护基为叔丁氧羰基或苄基，X 1、X 2、 Y 1、Y 2、Y 3、Y 4、Z 1、Z 2、Z 3、L 1、L 2、R 1、R 2、R 3和m如式(I)化合物中所定义。 Wherein, R is R 3 or an amino protecting group, the amino protecting group is tert-butoxycarbonyl or benzyl, X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Z 1 , Z 2 , Z 3 , L 1 , L 2 , R 1 , R 2 , R 3 and m are as defined in compounds of formula (I).
本发明第三方面提供一种药物组合物，其包括式(I)化合物、其立体异构体或其药学上可接受盐及可药用的载体。A third aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐在制备治疗和/或预防至少部分与EGFR外显子20***、缺失或其他突变相关的癌症、肿瘤或转移性疾病的药物中的用途。The present invention also relates to the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of the treatment and/or prevention of cancers, tumors at least partially associated with EGFR exon 20 insertions, deletions or other mutations or the use of drugs in metastatic disease.
本发明还涉及式(I)化合物、其立体异构体或其药学上可接受盐在制备预防和/或治疗由过度增殖和诱导细胞死亡障碍引起的肿瘤、癌症和/或转移性疾病的药物中的用途。本发明还涉及前述式(I)化合物、其立体异构体或其药学上可接受盐在制备预防和/或治疗由过度增殖和诱导细胞死亡障碍引起的肺癌、结肠癌、胰腺癌、头颈癌、乳腺癌，卵巢癌，子宫癌、胃癌、非小细胞肺癌、白血病、骨髓增生异常综合症、恶性淋巴瘤、头颈部肿瘤、胸腔肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺和其他妇科肿瘤、泌尿科肿瘤、皮肤肿瘤、肉瘤、鼻腔鼻窦内翻性***状瘤或鼻腔鼻窦内翻性***状瘤相关的鼻腔鼻窦鳞状细胞癌药物中的用途。The present invention also relates to a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and/or treatment of tumors, cancers and/or metastatic diseases caused by hyperproliferative and cell death-inducing disorders use in. The present invention also relates to the aforementioned compounds of formula (I), their stereoisomers or their pharmaceutically acceptable salts in the preparation of the prevention and/or treatment of lung cancer, colon cancer, pancreatic cancer, head and neck cancer caused by hyperproliferation and cell death-induced disorders , breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors , urological tumor, skin tumor, sarcoma, sinus inverted papilloma or nasal sinus squamous cell carcinoma associated with the use in the drug.
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐，其用作药物。The present invention also relates to said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use as a medicament.
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐，其用于治疗和/或预防至少部分与EGFR外显子20***、缺失或其他突变相关的癌症、肿瘤或转移性疾病的用途。The present invention also relates to said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of cancers associated at least in part with EGFR exon 20 insertions, deletions or other mutations , tumor or metastatic disease.
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐，其用于预防和/或治疗由过度增殖和诱导细胞死亡障碍引起的肿瘤、癌症和/或转移性疾病的用途。The present invention also relates to said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use in the prevention and/or treatment of tumors, cancers and/or metastases caused by hyperproliferative and cell death-inducing disorders use of sexually transmitted diseases.
本发明还涉及所述式(I)化合物、其立体异构体或其药学上可接受盐，其用于治疗和/或预防由过度增殖和诱导细胞死亡障碍引起的肺癌、结肠癌、胰腺癌、头颈癌、乳腺癌，卵巢癌，子宫癌、胃癌、非小细胞肺癌、白血病、骨髓增生异常综合症、恶性淋巴瘤、头颈部肿瘤、胸腔肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺和其他妇科肿瘤、泌尿科肿瘤、皮肤肿瘤、肉瘤、鼻腔鼻窦内翻性***状瘤或鼻腔鼻窦内翻性***状瘤相关的鼻腔鼻窦鳞状细胞癌的用途。The present invention also relates to the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of lung, colon, pancreatic cancer caused by hyperproliferative and cell death-induced disorders , head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndromes, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and Use in other gynecological tumors, urological tumors, skin tumors, sarcomas, naso-inverted papilloma or nasosinus-related squamous cell carcinoma of the sinuses.
本发明还涉及一种治疗和/或预防至少部分与EGFR外显子20***、缺失或其他突变相关的癌症、肿瘤或转移性疾病的方法，其包括向所需患者施用治疗有效量的所述式(I)化合物、其立体异构体或其药学上可接受盐。The present invention also relates to a method of treating and/or preventing cancer, tumor or metastatic disease associated at least in part with EGFR exon 20 insertions, deletions or other mutations, comprising administering to a patient in need thereof a therapeutically effective amount of said A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
本发明还涉及一种预防和/或治疗由过度增殖和诱导细胞死亡障碍引起的肿瘤、癌症和/或转移性疾病的方法，其包括向所需患者施用治疗有效量的所述式(I)化合物、其立体异构体或其药学上可接受盐。The present invention also relates to a method of preventing and/or treating tumors, cancers and/or metastatic diseases caused by hyperproliferative and induced cell death disorders, comprising administering to a patient in need thereof a therapeutically effective amount of said formula (I) A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
本发明还涉及一种治疗和/或预防由过度增殖和诱导细胞死亡障碍引起的肺癌、结肠癌、胰腺癌、头颈癌、乳腺癌，卵巢癌，子宫癌、胃癌、非小细胞肺癌、白 血病、骨髓增生异常综合症、恶性淋巴瘤、头颈部肿瘤、胸腔肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺和其他妇科肿瘤、泌尿科肿瘤、皮肤肿瘤、肉瘤、鼻腔鼻窦内翻性***状瘤或鼻腔鼻窦内翻性***状瘤相关的鼻腔鼻窦鳞状细胞癌的方法，其包括向所需患者施用治疗有效量的所述式(I)化合物、其立体异构体或其药学上可接受盐。The present invention also relates to a treatment and/or prevention of lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, Myelodysplastic syndromes, malignant lymphomas, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, sinus inverted papilloma or A method of nasosinusal inverting papilloma-associated squamous cell carcinoma of the nasal cavity, comprising administering to a patient in need thereof a therapeutically effective amount of said compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof .
具体实施方式detailed description
本申请的发明人经过广泛而深入地研究，首次研发出一种具有如下式(Ⅰ)结构的EGFR抑制剂，本发明系列化合物可广泛应用于制备治疗和/或预防至少部分与EGFR外显子20***、缺失或其他突变相关的癌症、肿瘤或转移性疾病的药物，特别是治疗过度增殖性疾病和诱导细胞死亡障碍疾病的药物，有望开发成新一代EGFR抑制剂。在此基础上，完成了本发明。After extensive and in-depth research, the inventors of the present application have developed for the first time an EGFR inhibitor with the structure of the following formula (I). 20 Drugs for cancers, tumors or metastatic diseases associated with insertions, deletions or other mutations, especially for hyperproliferative and cell death-inducing disorders, are expected to be developed into next-generation EGFR inhibitors. On this basis, the present invention has been completed.
详细说明：除非有相反陈述或特别说明，下列用在说明书和权利要求书中的术语具有下述含义。DETAILED DESCRIPTION: Unless stated to the contrary or specifically stated, the following terms used in the specification and claims have the following meanings.
“烷基”指直链或含支链的饱和脂族烃基团，优选包括1至10个或1至6个碳原子或1至4个碳原子的直链烷基和含支链烷基，包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2，3-二甲基戊基、2，4-二甲基戊基、2，2-二甲基戊基、3，3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2，3-二甲基己基、2，4-二甲基己基、2，5-二甲基己基、2，2-二甲基己基、3，3-二甲基己基、4，4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基或其各种支链异构体等。“C 1-10烷基”指包括1至10个碳原子的直链烷基和含支链烷基，“C 1-4烷基”指包括1至4个碳原子的直链烷基和含支链烷基，“C 1-2烷基”指包括1至2个碳原子的直链烷基，“C 0-8烷基”指包括0至8个碳原子的直链烷基和含支链烷基，“C 0-4烷基”指包括0至4个碳原子的直链烷基和含支链烷基，“C 0-2烷基”指包括0至4个碳原子的直链烷基和含支链烷基。 "Alkyl" refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group, preferably a straight-chain alkyl group and a branched-chain alkyl group comprising 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, Including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1, 2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl propylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2- Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl , 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2, 5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof, etc. "C 1-10 alkyl" refers to straight-chain alkyl groups including 1 to 10 carbon atoms and branched alkyl groups, "C 1-4 alkyl" refers to straight-chain alkyl groups including 1 to 4 carbon atoms and A branched-chain alkyl group, "C 1-2 alkyl" refers to a straight-chain alkyl group including 1 to 2 carbon atoms, "C 0-8 alkyl" refers to a straight-chain alkyl group including 0 to 8 carbon atoms and A branched-chain alkyl group, "C 0-4 alkyl" refers to a straight-chain alkyl group containing 0 to 4 carbon atoms and a branched alkyl group, "C 0-2 alkyl" refers to a group containing 0 to 4 carbon atoms straight-chain and branched-chain alkyl groups.
烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 6、-C 0-8烷基-O-R 7、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基-O-C(O)R 8、-C 0-8烷基-NR 9R 10、-C 0-8烷基-C(＝NR 9)R 8、-C 0-8烷基-N(R 9)-C(＝NR 10)R 8、-C 0-8烷基 -C(O)NR 9R 10或-C 0-8烷基-N(R 9)-C(O)R 8的取代基所取代。 Alkyl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano group, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0-8 Alkyl-S(O) r R 6 , -C 0-8 alkyl-OR 7 , -C 0-8 alkyl-C(O)OR 7 , -C 0-8 alkyl-C(O)R 8 , -C 0-8 alkyl-OC(O)R 8 , -C 0-8 alkyl-NR 9 R 10 , -C 0-8 alkyl-C(=NR 9 )R 8 , -C 0 -8 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0-8 alkyl-C(O)NR 9 R 10 or -C 0-8 alkyl-N(R 9 ) Substituents of -C(O)R 8 are substituted.
“环烷基”或“碳环”指饱和或部分不饱和单环或多环环状烃取代基，所述部分不饱和环状烃是指环状烃可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子***，环烷基分为单环环烷基、多环环烷基，优选包括3至12个或3至8个或3至6个碳原子的环烷基，例如，“C 3-12环烷基”指包括3至12个碳原子的环烷基，“C 3-10环烷基”指包括3至10个碳原子的环烷基，“C 3-8环烷基”指包括3至8个碳原子的环烷基，“C 3-6环烷基”指包括3至6个碳原子的环烷基，“C 3-4环烷基”指包括3至4个碳原子的环烷基，其中： "Cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated π electron system, cycloalkyl is divided into monocyclic cycloalkyl, polycyclic cycloalkyl, preferably including 3 to 12 or 3 to 8 or 3 Cycloalkyl groups of up to 6 carbon atoms, for example, "C 3-12 cycloalkyl" refers to cycloalkyl groups including 3 to 12 carbon atoms, "C 3-10 cycloalkyl" refers to cycloalkyl groups including 3 to 10 carbon atoms atomic cycloalkyl, "C 3-8 cycloalkyl" refers to a cycloalkyl group comprising 3 to 8 carbon atoms, "C 3-6 cycloalkyl" refers to a cycloalkyl group comprising 3 to 6 carbon atoms, "C 3-4 cycloalkyl" refers to a cycloalkyl group comprising 3 to 4 carbon atoms, wherein:
单环环烷基包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl etc.
多环环烷基包括螺环、稠环和桥环的环烷基。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的多环基团，这些可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子***。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，螺环烷基包括但不限于：Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "Spirocycloalkyl" refers to polycyclic groups in which a single carbon atom (called a spiro atom) is shared between the monocyclic rings, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have Fully conjugated pi electron system. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into single spirocycloalkyl groups, double spirocycloalkyl groups or polyspirocycloalkyl groups, and spirocycloalkyl groups include but are not limited to:
Figure PCTCN2021111447-appb-000015
Figure PCTCN2021111447-appb-000015
“稠环烷基”指***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子***。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，稠环烷基包括但不限于："Fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a fully conjugated pi electron system. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, fused cycloalkyl groups include but are not limited to:
Figure PCTCN2021111447-appb-000016
Figure PCTCN2021111447-appb-000016
“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子***。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，桥环烷基包括但不限于："Bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two non-directly attached carbon atoms, these may contain one or more (preferably 1, 2 or 3) double bonds, but none The ring has a fully conjugated pi electron system. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, including but not limited to:
Figure PCTCN2021111447-appb-000017
Figure PCTCN2021111447-appb-000017
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，包括但不限于茚满基、四氢萘基、苯并环庚烷基等。The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl , benzocycloheptyl, etc.
环烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 6、-C 0-8烷基-O-R 7、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基-O-C(O)R 8、-C 0-8烷基-NR 9R 10、-C 0-8烷基-C(＝NR 9)R 8、-C 0-8烷基-N(R 9)-C(＝NR 10)R 8、-C 0-8烷基-C(O)NR 9R 10或-C 0-8烷基-N(R 9)-C(O)R 8的取代基所取代。 Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl , C 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 6-10 -membered aryl, 5-10-membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0- 8 alkyl-S(O) r R 6 , -C 0-8 alkyl-OR 7 , -C 0-8 alkyl-C(O)OR 7 , -C 0-8 alkyl-C(O) R 8 , -C 0-8 alkyl-OC(O)R 8 , -C 0-8 alkyl-NR 9 R 10 , -C 0-8 alkyl-C(=NR 9 )R 8 , -C 0-8 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0-8 alkyl-C(O)NR 9 R 10 or -C 0-8 alkyl-N(R 9 )-C(O)R 8 is substituted.
“杂环基”或“杂环”指饱和或部分不饱和单环或多环环状烃取代基，所述部分不饱和环状烃是指环状烃可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子***，杂环基其中一个或多个(优选1、2、3或4个)环原子选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包括3至12个或3至8个或3至6个环原子的杂环基，例如，“3-4元杂环基”指包含3至4个环原子的环基，“3-6元杂环基”指包含3至6个环原子的环基，“3-8元杂环基”指包含3至8个环原子的环基，“3-10元杂环基”指包含3至10个环原子的环基，“3-12元杂环基”指包含3至12个环原子的环基，“4-6元杂环基”指包含4至6个环原子的环基，“4-8元杂环基”指包含4至8个环原子的环基，“4-10元杂环基”指包含4至10个环原子的环基。 "Heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a fully conjugated pi-electron system, heterocyclyl wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O ) r (where r is an integer 0, 1, 2) heteroatoms excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Heterocyclyl groups including 3 to 12 or 3 to 8 or 3 to 6 ring atoms are preferred, for example, "3-4 membered heterocyclyl" refers to a ring group containing 3 to 4 ring atoms, "3-6 "Membered heterocyclyl" refers to a ring group containing 3 to 6 ring atoms, "3-8 membered heterocyclyl" refers to a ring group containing 3 to 8 ring atoms, and "3-10 membered heterocyclyl" refers to a ring group containing 3 A ring group of up to 10 ring atoms, "3-12 membered heterocyclyl" refers to a ring group containing 3 to 12 ring atoms, and "4-6 membered heterocyclyl" refers to a ring group containing 4 to 6 ring atoms , "4-8 membered heterocyclyl" refers to a ring group containing 4 to 8 ring atoms, and "4-10 membered heterocyclyl" refers to a ring group containing 4 to 10 ring atoms.
单环杂环基包括但不限于吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、氧杂环丁烷基、四氢呋喃基等。Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, and the like.
多环杂环基包括螺环、稠环和桥环的杂环基。“螺杂环基”指单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个(优选1、2、3或4个)环原子选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键(优选1、2或3个)，但没有一个环具有完全共轭的π电子***。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基。螺杂环基包括但不限于： Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls. "Spiroheterocyclyl" refers to a polycyclic heterocyclic group in which a single atom (called a spiro atom) is shared between the monocyclic rings, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or a heteroatom of S(O) r (where r is an integer 0, 1, 2) and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2 or 3), but none of the rings have a fully conjugated pi-electron system. Spiroheterocyclyls are classified into mono-, bis-, or poly-spiroheterocyclyls according to the number of spiro atoms shared between the rings. Spiroheterocyclyl groups include, but are not limited to:
Figure PCTCN2021111447-appb-000018
Figure PCTCN2021111447-appb-000018
“稠杂环基”指***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个(优选1、2、3或4个)环可以含有一个或多个(优选1、2或 3个)双键，但没有一个环具有完全共轭的π电子***，其中一个或多个(优选1、2、3或4个)环原子选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基，稠杂环基包括但不限于： "Fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more (preferably 1, 2, 3 or 4) rings may be contains one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from A heteroatom of nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2) and the remaining ring atoms are carbon. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups, fused heterocyclic groups include but are not limited to:
Figure PCTCN2021111447-appb-000019
Figure PCTCN2021111447-appb-000019
“桥杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团，这些可以含有一个或多个(优选1、2或3个)双键，但没有一个环具有完全共轭的π电子***，其中一个或多个(优选1、2、3或4个)环原子选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，桥杂环基包括但不限于： "Bridged heterocyclyl" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings having a fully conjugated pi-electron system in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2) Heteroatoms, the remaining ring atoms are carbon. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, bridged heterocyclic groups include but are not limited to:
Figure PCTCN2021111447-appb-000020
Figure PCTCN2021111447-appb-000020
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，包括但不限于：The heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, including but not limited to:
Figure PCTCN2021111447-appb-000021
Figure PCTCN2021111447-appb-000021
杂环基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 6、-C 0-8烷基-O-R 7、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基-O-C(O)R 8、-C 0-8烷基-NR 9R 10、-C 0-8烷基-C(＝NR 9)R 8、-C 0-8烷基-N(R 9)-C(＝NR 10)R 8、-C 0-8烷基-C(O)NR 9R 10或-C 0-8烷基-N(R 9)-C(O)R 8所取代。 Heterocyclyl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl , C 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 6-10 -membered aryl, 5-10-membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0- 8 alkyl-S(O) r R 6 , -C 0-8 alkyl-OR 7 , -C 0-8 alkyl-C(O)OR 7 , -C 0-8 alkyl-C(O) R 8 , -C 0-8 alkyl-OC(O)R 8 , -C 0-8 alkyl-NR 9 R 10 , -C 0-8 alkyl-C(=NR 9 )R 8 , -C 0-8 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0-8 alkyl-C(O)NR 9 R 10 or -C 0-8 alkyl-N(R 9 )-C(O)R 8 .
“芳基”或“芳环”指全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团， 具有共轭的π电子体系的多环(即其带有相邻对碳原子的环)基团，优选含有6-10个或6-8个碳的全碳芳基，例如，“C 6-10芳基”指含有6-10个碳的全碳芳基，“C 6-8芳基”指含有6-8个碳的全碳芳基，包括但不限于苯基和萘基。所述芳基环可以稠合于杂芳基、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，包括但不限于： "Aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) groups, polycyclic rings having a conjugated pi electron system (ie, with adjacent ring) groups for carbon atoms, preferably all-carbon aryl groups containing 6-10 or 6-8 carbons, for example, "C 6-10 aryl" refers to all-carbon aryl groups containing 6-10 carbons, "C 6-8 aryl" refers to a full carbon aryl group containing 6-8 carbons, including but not limited to phenyl and naphthyl. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:
Figure PCTCN2021111447-appb-000022
Figure PCTCN2021111447-appb-000022
“芳基”可以是取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 6、-C 0-8烷基-O-R 7、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基-O-C(O)R 8、-C 0-8烷基-NR 9R 10、-C 0-8烷基-C(＝NR 9)R 8、-C 0-8烷基-N(R 9)-C(＝NR 10)R 8、-C 0-8烷基-C(O)NR 9R 10或-C 0-8烷基-N(R 9)-C(O)R 8的取代基所取代。 "Aryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano group, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0-8 Alkyl-S(O) r R 6 , -C 0-8 alkyl-OR 7 , -C 0-8 alkyl-C(O)OR 7 , -C 0-8 alkyl-C(O)R 8 , -C 0-8 alkyl-OC(O)R 8 , -C 0-8 alkyl-NR 9 R 10 , -C 0-8 alkyl-C(=NR 9 )R 8 , -C 0 -8 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0-8 alkyl-C(O)NR 9 R 10 or -C 0-8 alkyl-N(R 9 ) Substituents of -C(O)R 8 are substituted.
“杂芳基”指包含一个或多个(优选1、2、3或4个)杂原子的杂芳族体系，所述杂原子包括氮、氧和S(O)r(其中r是整数0、1、2)的杂原子，优选含有5-10个或5-8个或5-6个环原子的杂芳族体系，例如，“4-10元杂芳基”指含有4-10个环原子的杂芳族体系，“4-8元杂芳基”指含有4-8个环原子的杂芳族体系，“5-6元杂芳基”指含有5-6个环原子的杂芳族体系，“5-8元杂芳基”指含有5-8个环原子的杂芳族体系，“5-10元杂芳基”指含有5-10个环原子的杂芳族体系，包括但不限于呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、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，包括但不限于："Heteroaryl" refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms including nitrogen, oxygen and S(O)r (where r is the integer 0 , 1, 2) heteroatoms, preferably heteroaromatic systems containing 5-10 or 5-8 or 5-6 ring atoms, for example, "4-10-membered heteroaryl" means containing 4-10 ring atoms Heteroaromatic system of ring atoms, "4-8 membered heteroaryl" refers to a heteroaromatic system containing 4-8 ring atoms, "5-6 membered heteroaryl" refers to a heteroaromatic system containing 5-6 ring atoms Aromatic system, "5-8 membered heteroaryl" refers to a heteroaromatic system containing 5-8 ring atoms, "5-10 membered heteroaryl" refers to a heteroaromatic system containing 5-10 ring atoms, Including, but not limited to, furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:
Figure PCTCN2021111447-appb-000023
Figure PCTCN2021111447-appb-000023
“杂芳基”可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多 个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 6、-C 0-8烷基-O-R 7、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基-O-C(O)R 8、-C 0-8烷基-NR 9R 10、-C 0-8烷基-C(＝NR 9)R 8、-C 0-8烷基-N(R 9)-C(＝NR 10)R 8、-C 0-8烷基-C(O)NR 9R 10或-C 0-8烷基-N(R 9)-C(O)R 8的取代基所取代。 "Heteroaryl" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, Halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 Alkyl, C 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 6-10 -membered aryl, 5-10-membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 6 , -C 0-8 alkyl-OR 7 , -C 0-8 alkyl-C(O)OR 7 , -C 0-8 alkyl-C( O)R 8 , -C 0-8 alkyl-OC(O)R 8 , -C 0-8 alkyl-NR 9 R 10 , -C 0-8 alkyl-C(=NR 9 )R 8 , -C 0-8 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0-8 alkyl-C(O)NR 9 R 10 or -C 0-8 alkyl-N( R 9 )-C(O)R 8 substituent.
“链烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上述定义的烷基，优选含有2-10个或2-4个碳的直链或含支链烯基，例如，“C 2-10链烯基”指含有2-10个碳的直链或含支链烯基，“C 2-4链烯基”指含有2-4个碳的直链或含支链烯基。包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-，2-或3-丁烯基等。 "Alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight or branched chain alkenyl group containing 2-10 or 2-4 carbons For example, "C 2-10 alkenyl" refers to a straight-chain or branched alkenyl containing 2-10 carbons, and "C 2-4 alkenyl" refers to a straight-chain or branched alkenyl containing 2-4 carbons Branched alkenyl. Including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.
“链烯基”可以是取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 6、-C 0-8烷基-O-R 7、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基-O-C(O)R 8、-C 0-8烷基-NR 9R 10、-C 0-8烷基-C(＝NR 9)R 8、-C 0-8烷基-N(R 9)-C(＝NR 10)R 8、-C 0-8烷基-C(O)NR 9R 10或-C 0-8烷基-N(R 9)-C(O)R 8的取代基所取代。 "Alkenyl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl , C 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 6-10 -membered aryl, 5-10-membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0- 8 alkyl-S(O) r R 6 , -C 0-8 alkyl-OR 7 , -C 0-8 alkyl-C(O)OR 7 , -C 0-8 alkyl-C(O) R 8 , -C 0-8 alkyl-OC(O)R 8 , -C 0-8 alkyl-NR 9 R 10 , -C 0-8 alkyl-C(=NR 9 )R 8 , -C 0-8 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0-8 alkyl-C(O)NR 9 R 10 or -C 0-8 alkyl-N(R 9 )-C(O)R 8 is substituted.
“链炔基”指至少两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基，优选含有2-10个或2-4个碳的直链或含支链炔基，例如，“C 2-10链炔基”指含有2-10个碳的直链或含支链炔基，“C 2-4链炔基”指含有2-4个碳的直链或含支链炔基。包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-，2-或3-丁炔基等。 "Alkynyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight-chain or branched-chain alkynyl group containing 2-10 or 2-4 carbons, For example, "C 2-10 alkynyl" refers to a straight or branched chain alkynyl group containing 2-10 carbons, and "C 2-4 alkynyl" refers to a straight or branched chain containing 2-4 carbons alkynyl. Including, but not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
“链炔基”可以是取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 6、-C 0-8烷基-O-R 7、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基-O-C(O)R 8、-C 0-8烷基-NR 9R 10、-C 0-8烷基-C(＝NR 9)R 8、-C 0-8烷基-N(R 9)-C(＝NR 10)R 8、-C 0-8烷基-C(O)NR 9R 10或-C 0-8烷基-N(R 9)-C(O)R 8的取代基所取代。 "Alkynyl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl , C 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 6-10 -membered aryl, 5-10-membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0- 8 alkyl-S(O) r R 6 , -C 0-8 alkyl-OR 7 , -C 0-8 alkyl-C(O)OR 7 , -C 0-8 alkyl-C(O) R 8 , -C 0-8 alkyl-OC(O)R 8 , -C 0-8 alkyl-NR 9 R 10 , -C 0-8 alkyl-C(=NR 9 )R 8 , -C 0-8 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0-8 alkyl-C(O)NR 9 R 10 or -C 0-8 alkyl-N(R 9 )-C(O)R 8 is substituted.
“烷氧基”指-O-烷基，其中烷基的定义如上所述，例如，“C 1-10烷氧基”指含1-10个碳的烷基氧基，“C 1-4烷氧基”指含1-4个碳的烷基氧基包括但不限于甲氧基、乙氧基、丙氧基、丁氧基等。 "Alkoxy" refers to -O-alkyl, where alkyl is as defined above, eg, "C 1-10 alkoxy" refers to an alkyloxy group containing 1-10 carbons, "C 1-4 "Alkoxy" refers to an alkyloxy group containing 1-4 carbons including, but not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.
“烷氧基”可以是任选取代的或未取代的，当被取代时，取代基，优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 6、-C 0-8烷基-O-R 7、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基 -O-C(O)R 8、-C 0-8烷基-NR 9R 10、-C 0-8烷基-C(＝NR 9)R 8、-C 0-8烷基-N(R 9)-C(＝NR 10)R 8、-C 0-8烷基-C(O)NR 9R 10或-C 0-8烷基-N(R 9)-C(O)R 8的取代基所取代。 "Alkoxy" may be optionally substituted or unsubstituted, and when substituted, the substituents, preferably one or more (preferably 1, 2, 3 or 4) of the following groups, are independently selected from deuterium , halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1- 10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , - C 0-8 alkyl-S(O) r R 6 , -C 0-8 alkyl-OR 7 , -C 0-8 alkyl-C(O)OR 7 , -C 0-8 alkyl-C (O)R 8 , -C 0-8 alkyl-OC(O)R 8 , -C 0-8 alkyl-NR 9 R 10 , -C 0-8 alkyl-C(=NR 9 )R 8 , -C 0-8 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0-8 alkyl-C(O)NR 9 R 10 or -C 0-8 alkyl-N Substituents of (R 9 )-C(O)R 8 are substituted.
“环烷氧基”、“环烷基氧基”指-O-环烷基，其中环烷基的定义如上所述，例如，“C 3-12环烷氧基”指含3-12个碳的环烷基氧基，“C 3-8环烷氧基”指含3-8个碳的环烷基氧基，“C 3-6环烷氧基”指含3-6个碳的环烷基氧基，包括但不限于环丙氧基、环丁氧基、环戊氧基、环己氧基等。 "Cycloalkoxy" and "cycloalkyloxy" refer to -O-cycloalkyl, wherein the definition of cycloalkyl is as described above, for example, "C 3-12 cycloalkoxy" refers to a group containing 3-12 Carbon cycloalkyloxy, "C 3-8 cycloalkoxy" refers to cycloalkyloxy containing 3-8 carbons, "C 3-6 cycloalkoxy" refers to 3-6 carbons Cycloalkyloxy, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
“环烷氧基”、“环烷基氧基”可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 6、-C 0-8烷基-O-R 7、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基-O-C(O)R 8、-C 0-8烷基-NR 9R 10、-C 0-8烷基-C(＝NR 9)R 8、-C 0-8烷基-N(R 9)-C(＝NR 10)R 8、-C 0-8烷基-C(O)NR 9R 10或-C 0-8烷基-N(R 9)-C(O)R 8的取代基所取代。 "Cycloalkoxy" and "cycloalkyloxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) or less groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -C 0- 8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 6 , -C 0-8 alkyl-OR 7 , -C 0-8 alkyl-C(O)OR 7 , - C 0-8 alkyl-C(O)R 8 , -C 0-8 alkyl-OC(O)R 8 , -C 0-8 alkyl-NR 9 R 10 , -C 0-8 alkyl- C(=NR 9 )R 8 , -C 0-8 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0-8 alkyl-C(O)NR 9 R 10 or - Substituents of C 0-8 alkyl-N(R 9 )-C(O)R 8 are substituted.
“杂环氧基”、“杂环基氧基”指-O-杂环基，其中杂环基的定义如上所述，包括但不限于氮杂环丁基氧基、氧杂环丁基氧基、氮杂环戊基氧基、氮、氧杂环己基氧基等。"Heterocyclyloxy" and "heterocyclyloxy" refer to -O-heterocyclyl, wherein heterocyclyl is as defined above, including but not limited to azetidinyloxy, oxetanyloxy group, azacyclopentyloxy, nitrogen, oxanyloxy and the like.
“杂环氧基”、“杂环基氧基”可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个(优选1、2、3或4个)以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 6、-C 0-8烷基-O-R 7、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基-O-C(O)R 8、-C 0-8烷基-NR 9R 10、-C 0-8烷基-C(＝NR 9)R 8、-C 0-8烷基-N(R 9)-C(＝NR 10)R 8、-C 0-8烷基-C(O)NR 9R 10或-C 0-8烷基-N(R 9)-C(O)R 8的取代基所取代。 "Heterocyclyloxy" and "heterocyclyloxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) or less groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -C 0- 8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 6 , -C 0-8 alkyl-OR 7 , -C 0-8 alkyl-C(O)OR 7 , - C 0-8 alkyl-C(O)R 8 , -C 0-8 alkyl-OC(O)R 8 , -C 0-8 alkyl-NR 9 R 10 , -C 0-8 alkyl- C(=NR 9 )R 8 , -C 0-8 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0-8 alkyl-C(O)NR 9 R 10 or - Substituents of C 0-8 alkyl-N(R 9 )-C(O)R 8 are substituted.
“C 1-10烷酰基”指C 1-10烷基酸去掉羟基后剩下的一价原子团，通常也表示为“C 0-9-C(O)-”，例如，“C 1-C(O)-”是指乙酰基；“C 2-C(O)-”是指丙酰基；“C 3-C(O)-”是指丁酰基或异丁酰基。 "C 1-10 alkanoyl" refers to the monovalent atomic group left after C 1-10 alkanoic acid removes the hydroxyl group, usually also expressed as "C 0-9 -C(O)-", for example, "C 1 -C (O)-" means acetyl; "C2 - C(O)-" means propionyl; "C3 - C(O)-" means butyryl or isobutyryl.
“-C 0-8烷基-S(O) rR 6”指-S(O) rR 6中的硫原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-S(O) r R 6 " means that the sulfur atom in -S(O) r R 6 is attached to the C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined above said.
“-C 0-8烷基-O-R 7”指-O-R 7中的氧原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-OR 7 " means that the oxygen atom in -OR 7 is attached to a C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined above.
“-C 0-8烷基-C(O)OR 7”指-C(O)OR 7中的羰基连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-C(O)OR 7 " means that the carbonyl group in -C(O)OR 7 is attached to a C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined above.
“-C 0-8烷基-C(O)R 8”指-C(O)R 8中的羰基连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 alkyl-C(O)R 8 " means that the carbonyl group in -C(O)R 8 is attached to a C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined above.
“-C 0-8-O-C(O)R 8”指-O-C(O)R 8中的氧原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 -OC(O)R 8 " means that the oxygen atom in -OC(O)R 8 is attached to a C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined above.
“-C 0-8-NR 9R 10”指-NR 9R 10中的氮原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 -NR 9 R 10 " means that the nitrogen atom in -NR 9 R 10 is attached to a C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined above.
“-C 0-8-C(＝NR 9)R 8”指-C(＝NR 9)R 8中的氮原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 -C(=NR 9 )R 8 " means that the nitrogen atom in -C(=NR 9 )R 8 is attached to a C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined above said.
“-C 0-8-N(R 9)-C(＝NR 10)R 8”指-N(R 9)-C(＝NR 10)R 8中的氮原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 -N(R 9 )-C(=NR 10 )R 8 " means that the nitrogen atom in -N(R 9 )-C(=NR 10 )R 8 is attached to a C 0-8 alkyl group above, wherein Co- 8 alkyl is as defined above.
“-C 0-8-C(O)NR 9R 10”指-C(O)NR 9R 10中的羰基连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 -C(O)NR 9 R 10 " means that the carbonyl group in -C(O)NR 9 R 10 is attached to a C 0-8 alkyl group, wherein the C 0-8 alkyl group is as defined above described.
“-C 0-8-N(R 9)-C(O)R 8”指-N(R 9)-C(O)R 8中的氮原子连接在C 0-8烷基上，其中C 0-8烷基的定义如上所述。 "-C 0-8 -N(R 9 )-C(O)R 8 " means that the nitrogen atom in -N(R 9 )-C(O)R 8 is attached to the C 0-8 alkyl group, wherein C 0-8 Alkyl is as defined above.
“C 3-10环烷基C 1-2烷基”指“C 3-10环烷基”中的碳原子连接在C 1-2烷基上，C 3-10环烷基和C 1-2烷基的定义如上所述。 "C 3-10 cycloalkyl C 1-2 alkyl" means that the carbon atom in "C 3-10 cycloalkyl" is attached to the C 1-2 alkyl, C 3-10 cycloalkyl and C 1- 2Alkyl is as defined above.
“3-12元杂环基C 1-2烷基”指“3-12元杂环基”中的碳原子连接在C 1-2烷基上，3-12元杂环基和C 1-2烷基的定义如上所述。 "3-12-membered heterocyclyl C 1-2 alkyl" means that the carbon atom in "3-12-membered heterocyclyl" is attached to C 1-2 alkyl, 3-12-membered heterocyclyl and C 1- 2Alkyl is as defined above.
“C 6-10芳基C 1-2烷基”指“C 6-10芳基”中的碳原子连接在C 1-2烷基上，C 6-10芳基和C 1-2烷基的定义如上所述。 "C 6-10 aryl C 1-2 alkyl" means the carbon atom in "C 6-10 aryl" is attached to C 1-2 alkyl, C 6-10 aryl and C 1-2 alkyl is defined as above.
“5-10元杂芳基C 1-2烷基”指“5-10元杂芳基”中的碳原子连接在C 1-2烷基上，5-10元杂芳基和C 1-2烷基的定义如上所述。 "5-10-membered heteroaryl C 1-2 alkyl" means that the carbon atom in "5-10-membered heteroaryl" is attached to C 1-2 alkyl, 5-10-membered heteroaryl and C 1- 2Alkyl is as defined above.
“卤取代C 1-10烷基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-10个碳烷基团，包括但不限于二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基等。 "Halo-substituted C 1-10 alkyl" refers to 1-10 carbon alkyl groups in which the hydrogen on the alkyl group is optionally substituted by fluorine, chlorine, bromine and iodine atoms, including but not limited to difluoromethyl, dichloro Methyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
“卤取代C 1-10烷氧基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-10个碳烷氧基团。包括但不限于二氟甲氧基、二氯甲氧基、二溴甲氧基、三氟甲氧基、三氯甲氧基、三溴甲氧基等。 "Halo-substituted C 1-10 alkoxy" refers to a 1-10 carbon alkoxy group in which the hydrogen on the alkyl group is optionally substituted with fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.
“氘取代C 1-10烷基”指烷基上的氢任选的被氘原子取代的1-10个碳烷基团。包括但不限于一氘甲基、二氘甲基、三氘甲基等。 "Deuterium-substituted C1-10 alkyl" refers to a 1-10 carbon alkyl group in which the hydrogen on the alkyl group is optionally substituted with a deuterium atom. Including but not limited to deuteromethyl, di-deuteromethyl, tri-deuteromethyl and the like.
“卤素”指氟、氯、溴或碘。"Halogen" refers to fluorine, chlorine, bromine or iodine.
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合，也即包括取代的或未取代的两种情形。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur, that is, both substituted and unsubstituted . For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
“取代的”指基团中的一个或多个“氢原子”彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，符合化学上的价键理论，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不 可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和键的碳原子(如烯烃)结合时可能是不稳定的。"Substituted" means that one or more "hydrogen atoms" in a group are, independently of one another, substituted with the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, in accordance with valence bond theory in chemistry, and those skilled in the art can determine (either experimentally or theoretically) possible or impossible without undue effort replacement. For example, amino or hydroxyl groups with free hydrogen may be unstable when combined with carbon atoms with unsaturated bonds, such as alkenes.
“立体异构体”，其英文名称为stereoisomer，是指由分子中原子在空间上排列方式不同所产生的异构体，它可分为顺反异构体、对映异构体两种，也可分为对映异构体和非对映异构体两大类。由于单键的旋转而引起的立体异构体称为构象异构体(conformational stereo-isomer)，有时也称为旋转异构体(rotamer)。因键长、键角、分子内有双键、有环等原因引起的立体异构体称为构型异构体(configuration stereo-isomer)，构型异构体又分为两类。其中因双键或成环碳原子的单键不能自由旋转而引起的异构体成为几何异构体(geometric isomer)，也称为顺反异构体(cis-trans isomer)，分为Z、E两种构型。例如：顺-2-丁烯和反-2-丁烯是一对几何异构体，因分子中没有反轴对称性而引起的具有不同旋光性能的立体异构体称为旋光异构体(optical isomer)，分为R、S构型。在本发明中所述“立体异构体”如未特别指明，可理解为包含上述对映异构体、构型异构体和构象异构体中的一种或几种。"Stereoisomer", its English name is stereoisomer, refers to the isomers produced by the different arrangements of atoms in the molecule in space. It can be divided into cis-trans isomers and enantiomers. It can also be divided into two categories: enantiomers and diastereomers. Stereoisomers due to rotation of a single bond are called conformational stereo-isomers, and are sometimes called rotamers. Stereoisomers caused by bond length, bond angle, double bond in the molecule, ring, etc. are called configuration stereo-isomers, and configuration isomers are divided into two categories. Among them, the isomers caused by the double bond or the single bond of the ring carbon atom not being able to rotate freely are called geometric isomers, also known as cis-trans isomers, which are divided into Z, E two configurations. For example: cis-2-butene and trans-2-butene are a pair of geometric isomers, and the stereoisomers with different optical properties caused by the absence of anti-axial symmetry in the molecule are called optical isomers ( optical isomer), divided into R and S configurations. In the present invention, the "stereoisomer" may be understood to include one or more of the above-mentioned enantiomers, configurational isomers and conformational isomers unless otherwise specified.
“药学上可接受盐”在本发明中是指药学上可接受的酸加成盐，包括无机酸盐和有机酸盐，这些盐可通过本专业已知的方法制备。"Pharmaceutically acceptable salts" as used herein refers to pharmaceutically acceptable acid addition salts, including inorganic and organic acid salts, which can be prepared by methods known in the art.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
下面结合实施例对本发明做进一步详细、完整地说明，但决非限制本发明，本发明也并非仅局限于实施例的内容。The present invention will be further described in detail and completely below in conjunction with the examples, but the present invention is by no means limited, and the present invention is not limited to the contents of the examples.
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400/500核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代甲醇(CD 3OD)和氘代氯仿(CDCl 3)，内标为四甲基硅烷(TMS)。 The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). NMR was measured by Bruker AVANCE-400/500 nuclear magnetic instrument, the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), internal standard For tetramethylsilane (TMS).
液质联用色谱LC-MS的测定用Agilent 6120质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。An Agilent 6120 mass spectrometer was used for LC-MS determination. The determination of HPLC used Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6mm chromatographic column).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specifications used for TLC are 0.15mm ~ 0.20mm, and the specifications used for TLC separation and purification products are 0.4mm ~ 0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。The starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or according to methods known in the art.
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂，反应温度单位为摄氏度(℃)。Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius (°C).
一、中间体的制备1. Preparation of intermediates
中间体1:N-(3-氟-2-甲氧苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-甲硫代酰胺的制备Intermediate 1: Preparation of N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-methylthioamide
Figure PCTCN2021111447-appb-000024
Figure PCTCN2021111447-appb-000024
第一步：1-氟-3-异硫氰基-2-甲氧基苯的合成The first step: the synthesis of 1-fluoro-3-isothiocyano-2-methoxybenzene
将3-氟-2-甲氧基苯胺(5.0g，35.4mmol)溶于二氯甲烷(50mL)中，再加入饱和碳酸氢钠溶液(50mL)，冷却到0℃，慢慢滴加入硫光气(4.2g，36.1mmol)，反应在0℃下搅拌2小时，TLC或者加氨水送LCMS监测，反应结束后，有机相分离出来，依次用饱和碳酸氢钠溶液(50mL)和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩得到1-氟-3-异硫氰基-2-甲氧基苯(6.4g，粗品，收率：90％)。ESI-MS：201.0[M+NH 3+1] +(备注：用氨水送样，监测硫脲的分子量)。 Dissolve 3-fluoro-2-methoxyaniline (5.0 g, 35.4 mmol) in dichloromethane (50 mL), add saturated sodium bicarbonate solution (50 mL), cool to 0 °C, and slowly add sulfur light dropwise Gas (4.2g, 36.1mmol), the reaction was stirred at 0 ° C for 2 hours, TLC or ammonia water was added to send LCMS monitoring, after the reaction was completed, the organic phase was separated, and saturated sodium bicarbonate solution (50mL) and brine (50mL) were used successively. Washed, dried over anhydrous sodium sulfate, filtered, and concentrated to give 1-fluoro-3-isothiocyano-2-methoxybenzene (6.4 g, crude product, yield: 90%). ESI-MS: 201.0[M+NH 3 +1] + (Note: send the sample with ammonia water to monitor the molecular weight of thiourea).
第二步：叔-丁基5-((3-氟-2-甲氧苯基)氨基甲硫杂酰)-4-羟基-6-氧代-3,6-二氢吡啶-1(2H)-羧酸酯的合成The second step: tert-butyl 5-((3-fluoro-2-methoxyphenyl)carbamoyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H )-carboxylate synthesis
将粗品1-氟-3-异硫氰基-2-甲氧基苯(6.4g，31.4mmol)溶于乙腈(50mL)中，加入叔-丁基2,4-二氧代哌啶-1-羧酸酯(6.8g，32.1mmol)，将溶液冷至0℃，缓慢滴加1，8-二氮杂二环十一碳-7-烯(7.0mL，47.1mmol)，升至室温并搅拌过夜。将反应液冷却至0℃，用2N HCl酸化至pH＝2～3，搅拌半小时析出淡黄色固体，过滤并用纯水洗涤，固体干燥即得到产物叔-丁基5-((3-氟-2-甲氧苯基)氨基甲硫杂酰)-4-羟基-6-氧代-3,6-二氢吡啶-1(2H)-羧酸酯(10.1g，81％)。附注：如果固体不能析出，则用乙酸乙酯萃取，食盐水洗涤，干燥浓缩，经快速硅胶柱分离得到叔-丁基5-((3-氟-2-甲氧苯基)氨基甲硫杂酰)-4-羟基-6-氧代-3,6-二氢吡啶-1(2H)-羧酸酯。ESI-MS：342.0[M-55] +。 The crude 1-fluoro-3-isothiocyano-2-methoxybenzene (6.4 g, 31.4 mmol) was dissolved in acetonitrile (50 mL), tert-butyl 2,4-dioxopiperidine-1 was added -carboxylate (6.8 g, 32.1 mmol), the solution was cooled to 0 °C, 1,8-diazabicycloundec-7-ene (7.0 mL, 47.1 mmol) was slowly added dropwise, warmed to room temperature and Stir overnight. The reaction solution was cooled to 0°C, acidified with 2N HCl to pH=2～3, stirred for half an hour to precipitate a pale yellow solid, filtered and washed with pure water, and the solid was dried to obtain the product tert-butyl 5-((3-fluoro- 2-Methoxyphenyl)carbamoyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (10.1 g, 81%). Note: If the solid cannot be precipitated, extract with ethyl acetate, wash with brine, dry and concentrate, and separate by flash silica gel column to obtain tert-butyl 5-((3-fluoro-2-methoxyphenyl)aminomethylthiane Acyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate. ESI-MS: 342.0[M-55] + .
第三步：N-(3-氟-2-甲氧苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-甲硫代酰胺的合成The third step: synthesis of N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-methylthioamide
将叔-丁基5-((3-氟-2-甲氧苯基)氨基甲硫杂酰)-4-羟基-6-氧代-3,6-二氢吡啶-1(2H)-羧酸酯(10.1g，25.5mmol)溶于二氯甲烷(50mL)，室温下加入三氟乙酸(4.0mL，53mmol)，反应室温下搅拌2小时。LCMS显示反应结束，反应液浓缩后用乙酸乙酯溶解，再用饱和碳酸氢钠洗涤两次，有机相用无水硫酸钠干燥、过滤、浓缩，浓缩物经快速硅胶柱层析分离[洗脱剂:0～80％乙酸乙酯：二氯甲烷]得到N-(3-氟-2-甲氧苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-甲硫代酰胺(6.5g，收率：86％)。ESI-MS：297.1[M+1] +。 tert-butyl 5-((3-fluoro-2-methoxyphenyl)carbamoyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate The acid ester (10.1 g, 25.5 mmol) was dissolved in dichloromethane (50 mL), trifluoroacetic acid (4.0 mL, 53 mmol) was added at room temperature, and the reaction was stirred at room temperature for 2 hours. LCMS showed that the reaction was complete, the reaction solution was concentrated and dissolved in ethyl acetate, washed twice with saturated sodium bicarbonate, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the concentrate was separated by flash silica gel column chromatography [eluting Agent: 0～80% ethyl acetate: dichloromethane] to obtain N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine -3-Methylthioamide (6.5 g, yield: 86%). ESI-MS: 297.1[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ14.62(s,0.5H),14.27(s,0.5H),9.31(s,0.5H),8.13(s,0.5H),7.66(t,J＝8.8Hz,1H),7.26–7.09(m,2H),3.84(s,3H),3.43(td,J＝7.2,2.8Hz,1H),3.30–3.28(m,1H),2.78(t,J＝7.4Hz,1H),2.63(t,J＝7.4Hz,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ14.62(s, 0.5H), 14.27(s, 0.5H), 9.31(s, 0.5H), 8.13(s, 0.5H), 7.66(t, J = 8.8Hz, 1H), 7.26–7.09 (m, 2H), 3.84 (s, 3H), 3.43 (td, J=7.2, 2.8Hz, 1H), 3.30–3.28 (m, 1H), 2.78 (t, J=7.4Hz, 1H), 2.63 (t, J=7.4Hz, 1H).
中间体2～14可参照中间体1全部或部分合成方法选择相应的原料进行制备:Intermediates 2 to 14 can be prepared with reference to all or part of the synthesis methods of intermediate 1 and select corresponding raw materials:
Figure PCTCN2021111447-appb-000025
Figure PCTCN2021111447-appb-000025
Figure PCTCN2021111447-appb-000026
Figure PCTCN2021111447-appb-000026
二、具体实施例的制备Two, the preparation of specific embodiment
实施例1：N-(2-((4-(3-((3-氟-2-甲氧苯基)氨基)-4-氧代-4,5,6,7-四氢-1H-吡咯并[3,2-c]吡啶-2-基)吡啶-3-基)氧基)乙基)丙烯酰胺的制备Example 1: N-(2-((4-(3-((3-fluoro-2-methoxyphenyl)amino)-4-oxo-4,5,6,7-tetrahydro-1H- Preparation of pyrrolo[3,2-c]pyridin-2-yl)pyridin-3-yl)oxy)ethyl)acrylamide
Figure PCTCN2021111447-appb-000027
Figure PCTCN2021111447-appb-000027
第一步：3-(2-氨基乙氧基)异尼古丁腈的合成The first step: the synthesis of 3-(2-aminoethoxy) isonicotine nitrile
将乙醇胺(1.40g，23.0mmol)溶于四氢呋喃(40mL)中，冷却至0℃，分批加入钠氢(920mg，60％，23.0mmol)，反应在室温下搅拌0.5小时，冷却至0℃，滴加3-氟异尼古丁腈(2.44g，20.0mmol)的四氢呋喃(10mL)溶液，滴加完毕，反应液升至室温继续反应2小时。LCMS监测反应完成，加入50毫升冰水淬灭反应，所得反应液3-(2-氨基乙氧基)异尼古丁腈直接用于下一步反应。ESI-MS：164.0[M+1] +。 Ethanolamine (1.40 g, 23.0 mmol) was dissolved in tetrahydrofuran (40 mL), cooled to 0 °C, sodium hydrogen (920 mg, 60%, 23.0 mmol) was added in portions, the reaction was stirred at room temperature for 0.5 h, cooled to 0 °C, A solution of 3-fluoroisonicotine nitrile (2.44 g, 20.0 mmol) in tetrahydrofuran (10 mL) was added dropwise, the dropwise addition was completed, and the reaction solution was warmed to room temperature to continue the reaction for 2 hours. The completion of the reaction was monitored by LCMS, 50 ml of ice water was added to quench the reaction, and the obtained reaction solution 3-(2-aminoethoxy)isonicotinenitrile was directly used in the next reaction. ESI-MS: 164.0[M+1] + .
第二步：叔-丁基(2-((4-氰基吡啶-3-基)氧基)乙基)氨基甲酸酯的合成The second step: synthesis of tert-butyl (2-((4-cyanopyridin-3-yl)oxy)ethyl)carbamate
在上一步得到的3-(2-氨基乙氧基)异尼古丁腈(20.0mmol)的四氢呋喃(50mL)与水(50mL)的混合物中，加入碳酸钾(6.90g，50.0mmol)及二碳酸二叔丁酯(6.54g，30.0mmol)，室温下反应2小时。反应结束后，用乙酸乙酯稀释，有机相分离并用饱和食盐水洗涤一次。有机相干燥过滤，滤液浓缩，所得剩余物通过快速硅胶柱层析分离[0～50％乙酸乙酯：石油醚]得到叔-丁基(2-((4-氰基吡啶-3-基)氧基)乙基)氨基甲酸酯(2.80g，两步收率：53％)。ESI-MS：264.0[M+1] +。 To a mixture of 3-(2-aminoethoxy)isonicotinenitrile (20.0 mmol) obtained in the previous step in tetrahydrofuran (50 mL) and water (50 mL), potassium carbonate (6.90 g, 50.0 mmol) and dicarbonate were added tert-Butyl ester (6.54 g, 30.0 mmol) was reacted at room temperature for 2 hours. After the reaction was completed, it was diluted with ethyl acetate, and the organic phase was separated and washed once with saturated brine. The organic phase was dried and filtered, the filtrate was concentrated, and the obtained residue was separated by flash silica gel column chromatography [0-50% ethyl acetate: petroleum ether] to obtain tert-butyl (2-((4-cyanopyridin-3-yl) Oxy)ethyl)carbamate (2.80 g, two steps yield: 53%). ESI-MS: 264.0[M+1] + .
第三步：叔-丁基(2-((4-(氨基甲基)吡啶-3-基)氧基)乙基)氨基甲酸酯的合成The third step: synthesis of tert-butyl (2-((4-(aminomethyl)pyridin-3-yl)oxy)ethyl)carbamate
将叔-丁基(2-((4-氰基吡啶-3-基)氧基)乙基)氨基甲酸酯(2.80g，10.6mmol)溶于甲醇(60mL)中，加入2毫升氨水，雷尼镍(3.0g)，反应体系用氢气置换三次，室温下搅拌18小时，反应结束后，将反应液过滤，甲醇洗涤五次，滤液浓缩干，剩余物用通过快速硅胶柱层析分离[0～10％甲醇：二氯甲烷]得到叔-丁基(2-((4-(氨甲基)吡啶-3-基)氧基)乙基)氨基甲酸酯(1.5g，收率：53％)。ESI-MS：268.0[M+1] +。 tert-Butyl(2-((4-cyanopyridin-3-yl)oxy)ethyl)carbamate (2.80 g, 10.6 mmol) was dissolved in methanol (60 mL), 2 mL of ammonia was added, Raney nickel (3.0 g), the reaction system was replaced with hydrogen three times, stirred at room temperature for 18 hours, after the reaction, the reaction solution was filtered, washed with methanol five times, the filtrate was concentrated to dryness, and the residue was separated by flash silica gel column chromatography [ 0-10% methanol: dichloromethane] to give tert-butyl(2-((4-(aminomethyl)pyridin-3-yl)oxy)ethyl)carbamate (1.5g, yield: 53%). ESI-MS: 268.0[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ8.22(s,1H),8.18–8.13(m,1H),7.37(d,J＝4.7Hz,1H),7.09–6.99(m,1H),4.08(t,J＝5.5Hz,2H),3.70(s,2H),3.34–3.30(m,2H),3.17(s,2H),1.38(s,9H)。 1 H NMR (400MHz, DMSO-d 6 )δ8.22(s, 1H), 8.18-8.13(m, 1H), 7.37(d, J=4.7Hz, 1H), 7.09-6.99(m, 1H), 4.08(t, J=5.5Hz, 2H), 3.70(s, 2H), 3.34–3.30(m, 2H), 3.17(s, 2H), 1.38(s, 9H).
第四步：叔-丁基(2-((4-(((5-((3-氟-2-甲氧基苯基)氨基甲硫杂酰基)-6-氧代-1,2,3,6-四氢吡啶-4-基)氨基)甲基)吡啶-3-基)氧基)乙基)氨基甲酸酯的合成The fourth step: tert-butyl(2-((4-(((5-((3-fluoro-2-methoxyphenyl)carbamoyl)-6-oxo-1,2, Synthesis of 3,6-tetrahydropyridin-4-yl)amino)methyl)pyridin-3-yl)oxy)ethyl)carbamate
将N-(3-氟-2-甲氧苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-甲硫代酰胺(500mg，1.69mmol)，叔-丁基(2-((4-(氨甲基)吡啶-3-基)氧基)乙基)氨基甲酸酯(632mg，2.36mmol)溶于N,N-二甲基乙酰胺(1.5mL)中，反应在微波条件120℃下搅拌2.5小时，反应结束后，将反应液用乙酸乙酯(50mL)和饱和食盐水(50mL)分层萃取，有机相干燥过滤，滤液浓缩，剩余物通过快速硅胶柱层析分离[0～100％乙酸乙酯：二氯甲烷，之后0～12％甲醇：二氯甲烷]得到叔-丁基(2-((4-(((5-((3-氟-2-甲氧基苯基)氨基甲硫杂酰基)-6-氧代-1,2,3,6-四氢吡啶-4-基)氨基)甲基)吡啶-3-基)氧基)乙基)氨基甲酸酯(252mg，收率：27％)。ESI-MS：546.2[M+1] +。 N-(3-Fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-methylthioamide (500 mg, 1.69 mmol), tert-Butyl(2-((4-(aminomethyl)pyridin-3-yl)oxy)ethyl)carbamate (632 mg, 2.36 mmol) was dissolved in N,N-dimethylacetamide ( 1.5 mL), the reaction was stirred under microwave conditions at 120° C. for 2.5 hours. After the reaction, the reaction solution was extracted with ethyl acetate (50 mL) and saturated brine (50 mL). The organic phase was dried and filtered, the filtrate was concentrated, and the remaining The compound was separated by flash silica gel column chromatography [0-100% ethyl acetate: dichloromethane, then 0-12% methanol: dichloromethane] to give tert-butyl (2-((4-((((5-( (3-Fluoro-2-methoxyphenyl)carbamoyl)-6-oxo-1,2,3,6-tetrahydropyridin-4-yl)amino)methyl)pyridine-3- yl)oxy)ethyl)carbamate (252 mg, yield: 27%). ESI-MS: 546.2[M+1] + .
第五步：叔-丁基(2-((4-(3-((3-氟-2-甲氧基苯基)氨基)-4-氧代-4,5,6,7-四氢-1H-吡咯[3,2-c]吡啶-2-基)吡啶-3-基)氧基)乙基)氨基甲酸酯的合成The fifth step: tert-butyl (2-((4-(3-((3-fluoro-2-methoxyphenyl)amino)-4-oxo-4,5,6,7-tetrahydro Synthesis of -1H-pyrro[3,2-c]pyridin-2-yl)pyridin-3-yl)oxy)ethyl)carbamate
将叔-丁基(2-((4-(((5-((3-氟-2-甲氧基苯基)氨基甲硫杂酰基)-6-氧代-1,2,3,6-四氢吡啶-4-基)氨基)甲基)吡啶-3-基)氧基)乙基)氨基甲酸酯(252mg，0.46mmol)，溶于甲醇(6mL)中，加入三氟乙酸(74mg，0.65mmol)和过氧化氢(146mg，30％水溶液，1.29mmol)，反应在50℃搅拌18小时，反应结束后，将反应液用饱和的硫代硫酸钠(2mL)淬灭，室温搅拌1小时，然后加入三乙胺(1mL)和水(20mL)，二氯甲烷萃取两次。合并有机相，用饱和食盐水洗涤两次，无水硫酸钠干燥，过滤浓缩。浓缩物经C18反相柱分离[0～95％乙腈：0.01mM NH 4HCO 3/H 2O]得到叔-丁基 (2-((4-(3-((3-氟-2-甲氧基苯基)氨基)-4-氧代-4,5,6,7-四氢-1H-吡咯[3,2-c]吡啶-2-基)吡啶-3-基)氧基)乙基)氨基甲酸酯(160mg，收率：68％)。ESI-MS：512.3[M+1] +。 tert-butyl(2-((4-(((5-((3-fluoro-2-methoxyphenyl)carbamoyl)-6-oxo-1,2,3,6 -Tetrahydropyridin-4-yl)amino)methyl)pyridin-3-yl)oxy)ethyl)carbamate (252 mg, 0.46 mmol), dissolved in methanol (6 mL), added trifluoroacetic acid ( 74 mg, 0.65 mmol) and hydrogen peroxide (146 mg, 30% aqueous solution, 1.29 mmol), the reaction was stirred at 50 ° C for 18 hours, after the reaction was completed, the reaction solution was quenched with saturated sodium thiosulfate (2 mL), and stirred at room temperature After 1 hour, triethylamine (1 mL) and water (20 mL) were added and extracted twice with dichloromethane. The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was separated by C18 reverse phase column [0-95% acetonitrile: 0.01 mM NH 4 HCO 3 /H 2 O] to give tert-butyl (2-((4-(3-((3-fluoro-2-methyl) oxyphenyl)amino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrro[3,2-c]pyridin-2-yl)pyridin-3-yl)oxy)ethyl yl) carbamate (160 mg, yield: 68%). ESI-MS: 512.3[M+1] + .
第六步：2-(3-(2-氨基乙氧基)吡啶-4-基)-3-((3-氟-2-甲氧苯基)氨基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮的合成Step 6: 2-(3-(2-Aminoethoxy)pyridin-4-yl)-3-((3-fluoro-2-methoxyphenyl)amino)-1,5,6,7- Synthesis of Tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one
将叔-丁基(2-((4-(3-((3-氟-2-甲氧基苯基)氨基)-4-氧代-4,5,6,7-四氢-1H-吡咯[3,2-c]吡啶-2-基)吡啶-3-基)氧基)乙基)氨基甲酸酯(130mg，0.25mmol)溶于二氯甲烷(4mL)，室温下加入三氟乙酸(1mL)。反应在室温下搅拌2小时。浓缩后得到2-(3-(2-氨基乙氧基)吡啶-4-基)-3-((3-氟-2-甲氧苯基)氨基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(120mg，粗品，收率：100％)。ESI-MS：412.3[M+1] +。 tert-Butyl(2-((4-(3-((3-fluoro-2-methoxyphenyl)amino)-4-oxo-4,5,6,7-tetrahydro-1H- Pyrrolo[3,2-c]pyridin-2-yl)pyridin-3-yl)oxy)ethyl)carbamate (130 mg, 0.25 mmol) was dissolved in dichloromethane (4 mL) and trifluoro trifluorocarbon was added at room temperature Acetic acid (1 mL). The reaction was stirred at room temperature for 2 hours. After concentration, 2-(3-(2-aminoethoxy)pyridin-4-yl)-3-((3-fluoro-2-methoxyphenyl)amino)-1,5,6,7-tetrakis Hydro-4H-pyrrolo[3,2-c]pyridin-4-one (120 mg, crude, yield: 100%). ESI-MS: 412.3[M+1] + .
第七步：N-(2-((4-(3-((3-氟-2-甲氧苯基)氨基)-4-氧代-4,5,6,7-四氢-1H-吡咯并[3,2-c]吡啶-2-基)吡啶-3-基)氧基)乙基)丙烯酰胺的合成The seventh step: N-(2-((4-(3-((3-fluoro-2-methoxyphenyl)amino)-4-oxo-4,5,6,7-tetrahydro-1H- Synthesis of pyrrolo[3,2-c]pyridin-2-yl)pyridin-3-yl)oxy)ethyl)acrylamide
将2-(3-(2-氨基乙氧基)吡啶-4-基)-3-((3-氟-2-甲氧苯基)氨基)-1,5,6,7-四氢-4H-吡咯并[3,2-c]吡啶-4-酮(120mg，粗品，0.25mmol)溶于二氯甲烷(8mL)，室温下加入三乙胺(0.5mL)，搅拌均匀，冷却至0℃，慢慢滴加丙烯酰氯(24.9mg，0.28mmol)的二氯甲烷(0.5mL)溶液，反应在0℃下搅拌0.5小时左右。反应结束后，加水(10mL)稀释，用二氯甲烷萃取(2*25mL)，合并有机相，并用饱和食盐水洗涤，无水硫酸钠干燥，浓缩后反相柱层析分离[洗脱剂：0～80％乙腈：水]得到N-(2-((4-(3-((3-氟-2-甲氧苯基)氨基)-4-氧代-4,5,6,7-四氢-1H-吡咯并[3,2-c]吡啶-2-基)吡啶-3-基)氧基)乙基)丙烯酰胺(26.8mg，收率：23％)。ESI-MS：466.2[M+1] +。 2-(3-(2-Aminoethoxy)pyridin-4-yl)-3-((3-fluoro-2-methoxyphenyl)amino)-1,5,6,7-tetrahydro- 4H-pyrrolo[3,2-c]pyridin-4-one (120 mg, crude product, 0.25 mmol) was dissolved in dichloromethane (8 mL), triethylamine (0.5 mL) was added at room temperature, stirred well, and cooled to 0 At °C, a solution of acryloyl chloride (24.9 mg, 0.28 mmol) in dichloromethane (0.5 mL) was slowly added dropwise, and the reaction was stirred at 0 °C for about 0.5 hours. After the completion of the reaction, add water (10 mL) to dilute, extract with dichloromethane (2*25 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate and separate by reverse phase column chromatography [eluent: 0～80% acetonitrile: water] to give N-(2-((4-(3-((3-fluoro-2-methoxyphenyl)amino)-4-oxo-4,5,6,7- Tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)pyridin-3-yl)oxy)ethyl)acrylamide (26.8 mg, yield: 23%). ESI-MS: 466.2[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ11.10(s,1H),8.60(t,J＝6.0Hz,1H),8.38(s,1H),7.98(d,J＝4.8Hz,1H),7.56(s,1H),7.37(d,J＝5.2Hz,1H),7.14(s,1H),6.68–6.62(m,1H),6.54-6.49(m,1H),6.29(dd,J＝17.2,10.0Hz,1H),6.17(dd,J＝17.2,2.0Hz,1H),5.98(d,J＝8.4Hz,1H),5.67(dd,J＝10.0,2.0Hz,1H),4.25(t,J＝4.8Hz,2H),3.93(s,3H),3.71–3.68(m,2H),3.44–3.40(m,2H),3.01(t,J＝6.8Hz,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ 11.10(s, 1H), 8.60(t, J=6.0Hz, 1H), 8.38(s, 1H), 7.98(d, J=4.8Hz, 1H) , 7.56(s, 1H), 7.37(d, J=5.2Hz, 1H), 7.14(s, 1H), 6.68-6.62(m, 1H), 6.54-6.49(m, 1H), 6.29(dd, J =17.2,10.0Hz,1H),6.17(dd,J=17.2,2.0Hz,1H),5.98(d,J=8.4Hz,1H),5.67(dd,J=10.0,2.0Hz,1H),4.25 (t, J=4.8 Hz, 2H), 3.93 (s, 3H), 3.71-3.68 (m, 2H), 3.44-3.40 (m, 2H), 3.01 (t, J=6.8 Hz, 2H).
实施例2～33可参照实施例1全部或部分合成方法选择相应的原料进行制备:Embodiments 2-33 can be prepared by selecting corresponding raw materials with reference to all or part of the synthetic methods of Example 1:
Figure PCTCN2021111447-appb-000028
Figure PCTCN2021111447-appb-000028
Figure PCTCN2021111447-appb-000029
Figure PCTCN2021111447-appb-000029
Figure PCTCN2021111447-appb-000030
Figure PCTCN2021111447-appb-000030
Figure PCTCN2021111447-appb-000031
Figure PCTCN2021111447-appb-000031
Figure PCTCN2021111447-appb-000032
Figure PCTCN2021111447-appb-000032
Figure PCTCN2021111447-appb-000033
Figure PCTCN2021111447-appb-000033
Figure PCTCN2021111447-appb-000034
Figure PCTCN2021111447-appb-000034
Figure PCTCN2021111447-appb-000035
Figure PCTCN2021111447-appb-000035
实施例34：N-(2-((4-(3-((3-氯-2-甲氧苯基)氨基)-4-氧代-4,5-二氢-1H-吡咯并[3,2-c]吡啶-2-基)吡啶-3-基)氧基)乙基)-N-甲基丙烯酰胺的制备Example 34: N-(2-((4-(3-((3-Chloro-2-methoxyphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrrolo[3 Preparation of ,2-c]pyridin-2-yl)pyridin-3-yl)oxy)ethyl)-N-methacrylamide
Figure PCTCN2021111447-appb-000036
Figure PCTCN2021111447-appb-000036
第一步：叔-丁基(2-((4-(((5-((3-氯-2-甲氧基苯基)氨基甲硫杂酰基)-6-氧代-1,2,3,6-四氢吡啶-4-基)氨基)甲基)吡啶-3-基)氧基)乙基)(甲基)氨基甲酸酯的合成The first step: tert-butyl(2-((4-(((5-((3-chloro-2-methoxyphenyl)aminomethylthioacyl)-6-oxo-1,2, Synthesis of 3,6-tetrahydropyridin-4-yl)amino)methyl)pyridin-3-yl)oxy)ethyl)(methyl)carbamate
将N-(3-氯-2-甲氧苯基)-4-羟基-2-氧代-1,2,5,6-四氢吡啶-3-甲硫代酰胺(1.00g，3.20mmol)，叔-丁基(2-((4-(氨甲基)吡啶-3-基)氧基)乙基)(甲基)氨基甲酸酯(1.35g，4.80mmol)溶于N,N-二甲基乙酰胺(2.5mL)中，反应在微波条件120℃下搅拌2.5小时，反应结束后，将反应液用乙酸乙酯(80mL)和饱和食盐水(80mL)分层萃取，有机相干燥过滤，滤液浓缩，剩余物通过快速硅胶柱层析分离[0～100％乙酸乙酯：二氯甲烷，之后0～12％甲醇：二氯甲烷]得到叔-丁基(2-((4-(((5-((3-氯-2-甲氧基苯基)氨基甲硫杂酰基)-6-氧代-1,2,3,6-四氢吡啶-4-基)氨基)甲基)吡啶-3-基)氧基)乙基)(甲基)氨基甲酸酯(780mg,收率：42％)。ESI-MS：576.3[M+1] +。 N-(3-Chloro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-methylthioamide (1.00 g, 3.20 mmol) , tert-butyl(2-((4-(aminomethyl)pyridin-3-yl)oxy)ethyl)(methyl)carbamate (1.35 g, 4.80 mmol) in N,N- In dimethylacetamide (2.5 mL), the reaction was stirred under microwave conditions at 120°C for 2.5 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate (80 mL) and saturated brine (80 mL), and the organic phase was dried. The filtrate was filtered, the filtrate was concentrated, and the residue was separated by flash silica gel column chromatography [0-100% ethyl acetate: dichloromethane, then 0-12% methanol: dichloromethane] to give tert-butyl (2-((4- (((5-((3-Chloro-2-methoxyphenyl)carbamoyl)-6-oxo-1,2,3,6-tetrahydropyridin-4-yl)amino)methane yl)pyridin-3-yl)oxy)ethyl)(methyl)carbamate (780 mg, yield: 42%). ESI-MS: 576.3[M+1] + .
第二步：叔-丁基(2-((4-(3-((3-氯-2-甲氧基苯基)氨基)-4-氧代-4,5,6,7-四氢-1H-吡咯[3,2-c]吡啶-2-基)吡啶-3-基)氧基)乙基)(甲基)氨基甲酸酯的合成The second step: tert-butyl (2-((4-(3-((3-chloro-2-methoxyphenyl)amino)-4-oxo-4,5,6,7-tetrahydro Synthesis of -1H-pyrro[3,2-c]pyridin-2-yl)pyridin-3-yl)oxy)ethyl)(methyl)carbamate
将叔-丁基(2-((4-(((5-((3-氯-2-甲氧基苯基)氨基甲硫杂酰基)-6-氧代-1,2,3,6-四氢吡啶-4-基)氨基)甲基)吡啶-3-基)氧基)乙基)(甲基)氨基甲酸酯(780mg，1.35 mmol)，溶于甲醇(6mL)中，加入三氟乙酸(200mg，1.76mmol)和过氧化氢(398mg，30％水溶液，3.50mmol)，反应在50℃搅拌18小时，反应结束后，将反应液用饱和的硫代硫酸钠(3mL)淬灭，室温搅拌1小时，然后加入三乙胺(2mL)和水(40mL)，二氯甲烷萃取两次。合并有机相，用饱和食盐水洗涤两次，无水硫酸钠干燥，过滤浓缩。浓缩物经C18反相柱分离[0～95％乙腈：0.01mM NH 4HCO 3/H 2O]得到叔-丁基(2-((4-(3-((3-氯-2-甲氧基苯基)氨基)-4-氧代-4,5,6,7-四氢-1H-吡咯[3,2-c]吡啶-2-基)吡啶-3-基)氧基)乙基)(甲基)氨基甲酸酯(450mg，收率：61％)。ESI-MS：542.2[M+1] +。 tert-butyl(2-((4-(((5-((3-chloro-2-methoxyphenyl)carbamoyl)-6-oxo-1,2,3,6 -Tetrahydropyridin-4-yl)amino)methyl)pyridin-3-yl)oxy)ethyl)(methyl)carbamate (780 mg, 1.35 mmol), dissolved in methanol (6 mL), added Trifluoroacetic acid (200 mg, 1.76 mmol) and hydrogen peroxide (398 mg, 30% aqueous solution, 3.50 mmol), the reaction was stirred at 50 ° C for 18 hours, after the reaction was completed, the reaction solution was quenched with saturated sodium thiosulfate (3 mL). was quenched, stirred at room temperature for 1 hour, then added triethylamine (2 mL) and water (40 mL), and extracted twice with dichloromethane. The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was separated by C18 reverse phase column [0-95% acetonitrile: 0.01 mM NH 4 HCO 3 /H 2 O] to give tert-butyl (2-((4-(3-((3-chloro-2-methyl) oxyphenyl)amino)-4-oxo-4,5,6,7-tetrahydro-1H-pyrro[3,2-c]pyridin-2-yl)pyridin-3-yl)oxy)ethyl (methyl)carbamate (450 mg, yield: 61%). ESI-MS: 542.2[M+1] + .
第三步：叔-丁基(2-((4-(3-((3-氯-2-甲氧基苯基)氨基)-4-氧代-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-基)吡啶-3-基)氧基)乙基)(甲基)氨基甲酸酯的合成The third step: tert-butyl (2-((4-(3-((3-chloro-2-methoxyphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrrole Synthesis of [3,2-c]pyridin-2-yl)pyridin-3-yl)oxy)ethyl)(methyl)carbamate
将叔-丁基(2-((4-(3-((3-氯-2-甲氧基苯基)氨基)-4-氧代-4,5,6,7-四氢-1H-吡咯[3,2-c]吡啶-2-基)吡啶-3-基)氧基)乙基)(甲基)氨基甲酸酯(450mg，0.83mmol)溶于1,4-二氧六环(5mL)，室温下加入2,3-二氯-5,6-二氰基-1,4-苯醌(207mg，0.91mmol)，再滴加N,O-双(三甲基硅烷基)三氟乙酰胺(0.88mL，854mg，3.32mmol)。反应在116℃下搅拌42小时。冷却后加入乙酸乙酯稀释，再用饱和碳酸氢钠洗涤两次，食盐水洗涤一次。干燥浓缩，浓缩物经快速硅胶柱层析分离[0～10％甲醇：二氯甲烷]得到叔-丁基(2-((4-(3-((3-氯-2-甲氧基苯基)氨基)-4-氧代-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-基)吡啶-3-基)氧基)乙基)(甲基)氨基甲酸酯(120mg，收率：27％)。ESI-MS：540.3[M+1] +。 tert-Butyl(2-((4-(3-((3-chloro-2-methoxyphenyl)amino)-4-oxo-4,5,6,7-tetrahydro-1H- Pyrro[3,2-c]pyridin-2-yl)pyridin-3-yl)oxy)ethyl)(methyl)carbamate (450 mg, 0.83 mmol) in 1,4-dioxane (5 mL), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (207 mg, 0.91 mmol) was added at room temperature, and N,O-bis(trimethylsilyl) was added dropwise Trifluoroacetamide (0.88 mL, 854 mg, 3.32 mmol). The reaction was stirred at 116°C for 42 hours. After cooling, it was diluted with ethyl acetate, washed twice with saturated sodium bicarbonate and once with brine. It was dried and concentrated, and the concentrate was separated by flash silica gel column chromatography [0-10% methanol: dichloromethane] to obtain tert-butyl(2-((4-(3-((3-chloro-2-methoxybenzene yl)amino)-4-oxo-4,5-dihydro-1H-pyrro[3,2-c]pyridin-2-yl)pyridin-3-yl)oxy)ethyl)(methyl)amino Formate (120 mg, yield: 27%). ESI-MS: 540.3[M+1] + .
第四步：3-((3-氯-2-甲氧苯基)氨基)-2-(3-(2-(甲基氨基)乙氧基)吡啶-4-基)-1,5-二氢-4H-吡咯并[3,2-c]吡啶-4-酮的合成Step 4: 3-((3-Chloro-2-methoxyphenyl)amino)-2-(3-(2-(methylamino)ethoxy)pyridin-4-yl)-1,5- Synthesis of Dihydro-4H-pyrrolo[3,2-c]pyridin-4-one
将叔-丁基(2-((4-(3-((3-氯-2-甲氧基苯基)氨基)-4-氧代-4,5-二氢-1H-吡咯[3,2-c]吡啶-2-基)吡啶-3-基)氧基)乙基)(甲基)氨基甲酸酯(120mg，0.22mmol)溶于二氯甲烷(4mL)，室温下加入三氟乙酸(1mL)。反应在室温下搅拌2小时。浓缩后得到粗品3-((3-氯-2-甲氧苯基)氨基)-2-(3-(2-(甲基氨基)乙氧基)吡啶-4-基)-1,5-二氢-4H-吡咯并[3,2-c]吡啶-4-酮(150mg，收率：100％)。ESI-MS：440.2[M+1] +。 tert-butyl(2-((4-(3-((3-chloro-2-methoxyphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrrole[3, 2-c]Pyridin-2-yl)pyridin-3-yl)oxy)ethyl)(methyl)carbamate (120 mg, 0.22 mmol) was dissolved in dichloromethane (4 mL) and trifluorotrifluorocarbon was added at room temperature Acetic acid (1 mL). The reaction was stirred at room temperature for 2 hours. After concentration, crude 3-((3-chloro-2-methoxyphenyl)amino)-2-(3-(2-(methylamino)ethoxy)pyridin-4-yl)-1,5- Dihydro-4H-pyrrolo[3,2-c]pyridin-4-one (150 mg, yield: 100%). ESI-MS: 440.2[M+1] + .
第五步：N-(2-((4-(3-((3-氯-2-甲氧苯基)氨基)-4-氧代-4,5-二氢-1H-吡咯并[3,2-c]吡啶-2-基)吡啶-3-基)氧基)乙基)-N-甲基丙烯酰胺的合成The fifth step: N-(2-((4-(3-((3-chloro-2-methoxyphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrrolo[3 Synthesis of ,2-c]pyridin-2-yl)pyridin-3-yl)oxy)ethyl)-N-methacrylamide
将3-((3-氯-2-甲氧苯基)氨基)-2-(3-(2-(甲基氨基)乙氧基)吡啶-4-基)-1,5-二氢-4H-吡咯并[3,2-c]吡啶-4-酮(150mg，粗品，0.22mmol)溶于二氯甲烷(5mL)，室温下加入三乙胺(1.0mL)，搅拌均匀，冷却至0℃，慢慢滴加丙烯酰氯(20.5mg，0.23mmol)的二氯甲烷(0.5mL)溶液，反应在0℃下搅拌0.5小时左右。反应结束后，加冰水(10mL)淬灭反应，用二氯甲烷萃取(2*25mL)，合并有机相，并用饱和食盐水洗涤，无水硫酸钠干燥，浓缩后反相柱层析分离[洗脱剂：0～80％乙腈：0.01mM NH 4HCO 3/水]得到N-(2-((4-(3-((3-氯-2-甲氧苯基)氨基)-4-氧代-4,5-二氢-1H-吡咯 并[3,2-c]吡啶-2-基)吡啶-3-基)氧基)乙基)-N-甲基丙烯酰胺(23.0mg，收率：21％)。ESI-MS：494.2[M+1] +。 3-((3-Chloro-2-methoxyphenyl)amino)-2-(3-(2-(methylamino)ethoxy)pyridin-4-yl)-1,5-dihydro- 4H-pyrrolo[3,2-c]pyridin-4-one (150 mg, crude product, 0.22 mmol) was dissolved in dichloromethane (5 mL), triethylamine (1.0 mL) was added at room temperature, stirred well, and cooled to 0 At °C, a solution of acryloyl chloride (20.5 mg, 0.23 mmol) in dichloromethane (0.5 mL) was slowly added dropwise, and the reaction was stirred at 0 °C for about 0.5 hours. After the reaction, ice water (10 mL) was added to quench the reaction, extracted with dichloromethane (2*25 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and separated by reverse phase column chromatography [ Eluent: 0-80% acetonitrile: 0.01 mM NH4HCO3 /water] to give N-(2-((4-( 3 -((3-chloro-2-methoxyphenyl)amino)-4- Oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-2-yl)pyridin-3-yl)oxy)ethyl)-N-methacrylamide (23.0 mg, Yield: 21%). ESI-MS: 494.2[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ11.39(s,0.3H),11.28(s,0.7H),10.73(d,J＝5.6Hz,0.7H),10.70(d,J＝5.2Hz,0.3H),8.45(s,0.7H),8.42(s,0.3H),8.14(d,J＝4.4Hz,0.3H),8.06(d,J＝5.2Hz,0.7H),7.59(d,J＝5.2Hz,0.7H),7.48(s,0.7H),7.42(d,J＝4.8Hz,0.3H),7.33(s,0.3H),7.07-7.01(m,1H),6.85–6.41(m,4H),6.22(dd,J＝16.4,1.8Hz,0.7H),6.12–6.07(m,1H),5.93(dd,J＝16.4,1.8Hz,0.3H),5.73(dd,J＝10.4,1.8Hz,0.7H),5.32(dd,J＝10.4,1.8Hz,0.3H),4.42–4.26(m,2H),3.95–3.85(m,5H),3.14(s,2H),2.87(s,1H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.39(s, 0.3H), 11.28(s, 0.7H), 10.73(d, J=5.6Hz, 0.7H), 10.70(d, J=5.2Hz ,0.3H),8.45(s,0.7H),8.42(s,0.3H),8.14(d,J＝4.4Hz,0.3H),8.06(d,J＝5.2Hz,0.7H),7.59(d , J＝5.2Hz, 0.7H), 7.48(s, 0.7H), 7.42(d, J＝4.8Hz, 0.3H), 7.33(s, 0.3H), 7.07-7.01(m, 1H), 6.85– 6.41(m,4H),6.22(dd,J=16.4,1.8Hz,0.7H),6.12–6.07(m,1H),5.93(dd,J=16.4,1.8Hz,0.3H),5.73(dd, J=10.4, 1.8Hz, 0.7H), 5.32 (dd, J=10.4, 1.8Hz, 0.3H), 4.42–4.26 (m, 2H), 3.95–3.85 (m, 5H), 3.14 (s, 2H) , 2.87(s, 1H).
实施例35～67可参照实施例34全部或部分合成方法选择相应的原料进行制备:Embodiments 35-67 can be prepared by selecting corresponding raw materials with reference to all or part of the synthetic methods of Example 34:
Figure PCTCN2021111447-appb-000037
Figure PCTCN2021111447-appb-000037
Figure PCTCN2021111447-appb-000038
Figure PCTCN2021111447-appb-000038
Figure PCTCN2021111447-appb-000039
Figure PCTCN2021111447-appb-000039
Figure PCTCN2021111447-appb-000040
Figure PCTCN2021111447-appb-000040
Figure PCTCN2021111447-appb-000041
Figure PCTCN2021111447-appb-000041
Figure PCTCN2021111447-appb-000042
Figure PCTCN2021111447-appb-000042
Figure PCTCN2021111447-appb-000043
Figure PCTCN2021111447-appb-000043
Figure PCTCN2021111447-appb-000044
Figure PCTCN2021111447-appb-000044
Figure PCTCN2021111447-appb-000045
Figure PCTCN2021111447-appb-000045
上述实施例制备得到的化合物核磁数据如下：The NMR data of the compounds prepared in the above examples are as follows:
Figure PCTCN2021111447-appb-000046
Figure PCTCN2021111447-appb-000046
Figure PCTCN2021111447-appb-000047
Figure PCTCN2021111447-appb-000047
Figure PCTCN2021111447-appb-000048
Figure PCTCN2021111447-appb-000048
Figure PCTCN2021111447-appb-000049
Figure PCTCN2021111447-appb-000049
Figure PCTCN2021111447-appb-000050
Figure PCTCN2021111447-appb-000050
Figure PCTCN2021111447-appb-000051
Figure PCTCN2021111447-appb-000051
生物学测试评价Biological Test Evaluation
一、Ba/F3细胞系的增殖实验1. Proliferation experiment of Ba/F3 cell line
(一)试剂和耗材(1) Reagents and consumables
胎牛血清FBS(GBICO,Cat#10099-141)Fetal Bovine Serum FBS (GBICO, Cat#10099-141)
Figure PCTCN2021111447-appb-000052
发光法细胞活力检测试剂盒(Promega,Cat#G7572)
Figure PCTCN2021111447-appb-000052
Luminescence Cell Viability Assay Kit (Promega, Cat#G7572)
黑色透明平底96孔板，(
Figure PCTCN2021111447-appb-000053
Cat#3603) Black transparent flat bottom 96-well plate, (
Figure PCTCN2021111447-appb-000053
Cat#3603)
(二)仪器(2) Instruments
SpectraMax多标记微孔板检测仪MD,2104-0010A；SpectraMax Multi-label Microplate Detector MD, 2104-0010A;
二氧化碳培养箱，Thermo Scientific 3100系列；CO2 incubator, Thermo Scientific 3100 series;
生物安全柜，Thermo Scientific，1300系列A2型；Biological Safety Cabinet, Thermo Scientific, 1300 Series Type A2;
倒置显微镜，Olympus,CKX41SF；Inverted microscope, Olympus, CKX41SF;
西门子冰箱KK25E76TISiemens refrigerator KK25E76TI
(三)细胞系和培养条件(3) Cell lines and culture conditions
Figure PCTCN2021111447-appb-000054
Figure PCTCN2021111447-appb-000054
(四)实验步骤(4) Experimental steps
1、细胞培养和接种：1. Cell culture and inoculation:
(1)收获处于对数生长期的细胞，并使用血小板计数器对细胞进行计数。通过锥虫蓝排除法检测细胞活力，以确保细胞活力在90％以上。(1) Harvest cells in logarithmic growth phase and count the cells using a platelet counter. Cell viability was checked by trypan blue exclusion to ensure cell viability was above 90%.
(2)调整细胞浓度以达到最终密度；将90μL细胞悬液添加到96孔板中。(2) Adjust the cell concentration to reach the final density; add 90 μL of the cell suspension to a 96-well plate.
(3)将细胞在96孔板中于37℃，5％CO 2和95％湿度下孵育过夜。 (3) Incubate the cells in a 96-well plate overnight at 37°C, 5% CO2 and 95% humidity.
2、T0基准数据：2. T0 benchmark data:
(1)在装有细胞的T0平板的每个孔中加入10μL PBS。(1) Add 10 μL of PBS to each well of the T0 plate containing cells.
(2)解冻CTG试剂，并将细胞板平衡至室温30分钟。(2) Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes.
(3)向每个孔中添加等体积的CTG溶液。(3) Add an equal volume of CTG solution to each well.
(4)在定轨振荡器上振动5分钟以裂解细胞。(4) Shake for 5 minutes on an orbital shaker to lyse cells.
(5)将细胞板在室温下放置20分钟以稳定发光信号。(5) The cell plate was left at room temperature for 20 minutes to stabilize the luminescence signal.
(6)读取T0发光信号值。(6) Read the T0 light-emitting signal value.
3、化合物稀释和添加3. Compound dilution and addition
(1)根据化合物信息表，将相应体积的DMSO加入相应的化合物粉末中，以制备10mM储备液。(1) According to the compound information table, add the corresponding volume of DMSO to the corresponding compound powder to prepare a 10 mM stock solution.
(2)准备1000倍，3.16倍稀释的化合物溶液。(2) Prepare a 1000-fold, 3.16-fold diluted compound solution.
(3)用PBS将1000×稀释的化合物溶液稀释100倍，以制备10倍的化合物溶液，最高浓度为10μM，9种浓度，稀释3.16倍，在接种有96孔板的每个孔中加入10μL药物溶液，接种细胞。每个化合物的浓度设置三个重复孔，DMSO的最终浓度为0.1％。(3) Dilute the 1000× diluted compound solution 100 times with PBS to prepare a 10-fold compound solution with a maximum concentration of 10 μM, 9 concentrations, diluted 3.16 times, and add 10 μL to each well of the 96-well plate seeded with Drug solution, seeded cells. Three replicate wells were set up for each compound concentration and the final concentration of DMSO was 0.1%.
(4)将细胞置于装有药物的96孔板中，温度为37℃，5％CO 2和95％湿度，继续培养72小时，然后进行CTG分析。 (4) The cells were placed in a 96-well plate filled with drugs at a temperature of 37°C, 5% CO 2 and 95% humidity, and cultured for 72 hours, followed by CTG analysis.
4、发光信号读取4, luminous signal reading
(1)解冻CTG试剂，并将细胞板平衡至室温30分钟。(1) Thaw CTG reagent and equilibrate the cell plate to room temperature for 30 minutes.
(2)向每个孔中添加等体积的CTG溶液。(2) Add an equal volume of CTG solution to each well.
(3)在定轨振荡器上振动5分钟以裂解细胞。(3) Shake on an orbital shaker for 5 minutes to lyse cells.
(4)将细胞板在室温放置20分钟以稳定发光信号。(4) The cell plate was left at room temperature for 20 minutes to stabilize the luminescence signal.
(5)读取发光值。(5) Read the luminous value.
5、数据处理5. Data processing
使用GraphPad Prism 7.0软件分析数据，并使用非线性S曲线回归拟合数据以获得剂量效应曲线，并据此计算IC 50值(单位：nM)，具体实验结果见表1： Use GraphPad Prism 7.0 software to analyze the data, and use nonlinear S-curve regression to fit the data to obtain a dose-response curve, and calculate the IC 50 value (unit: nM) accordingly. The specific experimental results are shown in Table 1:
细胞存活率(％)＝(Lum试验药物-Lum培养液对照)/(Lum细胞对照-Lum培养液对照)×100％。Cell survival rate (%)=(Lum test drug-Lum culture medium control)/(Lum cell control-Lum culture medium control)×100%.
表1：生物学测试结果Table 1: Biological Test Results
Figure PCTCN2021111447-appb-000055
Figure PCTCN2021111447-appb-000055
Figure PCTCN2021111447-appb-000056
Figure PCTCN2021111447-appb-000056
从具体实施例化合物生物活性数据来看，本发明系列化合物在细胞水平上对EGFR外显子20***突变具有很强的抑制作用，且部分化合物在Ba/F3 EGFR-D770-N771ins_SVD和Ba/F3 EGFR-V769_D770insASV细胞中相对于EGFR WT(野生型)细胞抑制增殖的活性具有高选择性，选择性达到10倍以上，甚至20倍以上。相对于阳性化合物，本发明化合物选择性有了极大的提高，例如实施例3、7、33化合物相对于阳性化合物选择性提高到两倍以上，实施例45化合物相对于阳性化合物选择性甚至提高到了六倍以上。Judging from the biological activity data of the compounds in the specific examples, the series of compounds of the present invention have a strong inhibitory effect on EGFR exon 20 insertion mutation at the cellular level, and some compounds have a strong inhibitory effect on Ba/F3 EGFR-D770-N771ins_SVD and Ba/F3 The activity of EGFR-V769_D770insASV cells in inhibiting proliferation relative to EGFR WT (wild-type) cells has high selectivity, and the selectivity reaches more than 10 times, even more than 20 times. Compared with the positive compound, the selectivity of the compound of the present invention has been greatly improved. For example, the selectivity of the compounds of Examples 3, 7, and 33 has been increased by more than two times compared to the positive compound, and the selectivity of the compound of Example 45 has even been improved relative to the positive compound. to more than six times.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述公开内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above disclosure of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (16)

  1. 式(I)化合物、其立体异构体或其药学上可接受盐：A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2021111447-appb-100001
    Figure PCTCN2021111447-appb-100001
    其中，in,
    Figure PCTCN2021111447-appb-100002
    为单键或双键；
    Figure PCTCN2021111447-appb-100002
    is a single bond or a double bond;
    X 1为CR aR b、CR c或C(O)； X 1 is CR a R b , CR c or C(O);
    X 2为CR dR e、CR f、N或NH； X 2 is CR d Re , CR f , N or NH;
    Y 1、Y 2、Y 3和Y 4各自独立地选自N、C(O)、CR g、N(O)和NR h； Y 1 , Y 2 , Y 3 and Y 4 are each independently selected from N, C(O), CR g , N(O) and NR h ;
    Z 1、Z 2和Z 3各自独立地为CR i或N； Z 1 , Z 2 and Z 3 are each independently CR i or N;
    L 1选自O、S、NR j、CR kR p、OCR kR p和键； L1 is selected from O, S , NRj , CRkRp , OCRkRp and a bond ;
    L 2选自C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-10环烷基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、C 3-10环烷基C 1-2烷基、3-12元杂环基C 1-2烷基、C 6-10芳基C 1-2烷基和5-10元杂芳基C 1-2烷基，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 6、-C 0-8烷基-O-R 7、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基-O-C(O)R 8、-C 0-8烷基-NR 9R 10、-C 0-8烷基-C(＝NR 9)R 8、-C 0-8烷基-N(R 9)-C(＝NR 10)R 8、-C 0-8烷基-C(O)NR 9R 10和-C 0-8烷基-N(R 9)-C(O)R 8的取代基所取代； L 2 is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl C 1-2 alkyl, 3-12 membered heterocyclyl C 1-2 alkyl, C 6-10 aryl C 1-2 alkyl and 5 -10-membered heteroaryl C 1-2 alkyl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen Substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 6 , -C 0-8 alkane base-OR 7 , -C 0-8 alkyl-C(O)OR 7 , -C 0-8 alkyl-C(O)R 8 , -C 0-8 alkyl-OC(O)R 8 , -C 0-8 alkyl-NR 9 R 10 , -C 0-8 alkyl-C(=NR 9 )R 8 , -C 0-8 alkyl-N(R 9 )-C(=NR 10 ) R 8 , -C 0-8 alkyl-C(O)NR 9 R 10 and -C 0-8 alkyl-N(R 9 )-C(O)R 8 substituents;
    R a、R b、R d和R e各自独立地选自氢、氘、卤素、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基和C 2-10链炔基，或者，R a和R b、R d和R e、R a和R d其中之一组各自独立地与其直接相连的碳原子一起形成一个C 3-8环烷基或3-8元杂环基，另两组如前所定义； R a , R b , R d and R e are each independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2- 10 alkenyl and C 2-10 alkynyl, or, alternatively, one of the groups of Ra and R b , R d and Re , Ra and R d each independently together with the carbon atom to which it is directly attached forms a C 3 -8 cycloalkyl or 3-8 membered heterocyclyl, the other two groups are as previously defined;
    R c和R f各自独立地选自氢、氘、卤素、C 1-10烷基、卤取代C 1-10烷基和氘取代C 1-10烷基，或者，R c和R f与其直接相连的部分一起形成一个C 3-8环烷基或3-8元杂环基； R c and R f are each independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, halo-substituted C 1-10 alkyl, and deuterium substituted C 1-10 alkyl, alternatively, R c and R f are directly therewith The linked moieties together form a C 3-8 cycloalkyl or 3-8 membered heterocyclyl;
    R g选自氢、氘、卤素、氰基、C 1-10烷基、C 1-10烷氧基、卤取代C 1-10烷基、氘取代C 1-10烷基、卤取代C 1-10烷氧基、氘取代C 1-10烷氧基、C 2-10链烯基、C 2-10链炔基和-C 0-8烷基-NR 4R 5； R g is selected from hydrogen, deuterium, halogen, cyano, C 1-10 alkyl, C 1-10 alkoxy, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, halogen substituted C 1 -10 alkoxy, deuterium substituted C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl and -C 0-8 alkyl-NR 4 R 5 ;
    R h选自氢、氘、羟基、C 1-10烷基、卤取代C 1-10烷基和氘取代C 1-10烷基； R is selected from hydrogen, deuterium , hydroxyl, C 1-10 alkyl, halo-substituted C 1-10 alkyl and deuterium substituted C 1-10 alkyl;
    R i选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 6、-C 0-8烷基-O-R 7、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基-O-C(O)R 8、-C 0-8烷基-NR 9R 10、-C 0-8烷基-C(＝NR 9)R 8、-C 0-8烷基-N(R 9)-C(＝NR 10)R 8、-C 0-8烷基-C(O)NR 9R 10和-C 0-8烷基-N(R 9)-C(O)R 8； R i is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 chain Alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -C 0-8 Alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 6 , -C 0-8 alkyl-OR 7 , -C 0-8 alkyl-C(O)OR 7 , -C 0-8 alkyl-C(O)R 8 , -C 0-8 alkyl-OC(O)R 8 , -C 0-8 alkyl-NR 9 R 10 , -C 0-8 alkyl-C (=NR 9 )R 8 , -C 0-8 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0-8 alkyl-C(O)NR 9 R 10 and -C 0-8 alkyl-N(R 9 )-C(O)R 8 ;
    R j选自氢、氘、C 1-10烷基、卤取代C 1-10烷基和氘取代C 1-10烷基； R j is selected from hydrogen, deuterium, C 1-10 alkyl, halo-substituted C 1-10 alkyl and deuterium substituted C 1-10 alkyl;
    R k和R p各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 6、-C 0-8烷基-O-R 7、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基-O-C(O)R 8、-C 0-8烷基-NR 9R 10、-C 0-8烷基-C(＝NR 9)R 8、-C 0-8烷基-N(R 9)-C(＝NR 10)R 8、-C 0-8烷基-C(O)NR 9R 10和-C 0-8烷基-N(R 9)-C(O)R 8，或者，R k和R p与其直接相连的碳原子一起形成一个C 3-8环烷基或3-8元杂环基，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 6、-C 0-8烷基-O-R 7、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基-O-C(O)R 8、-C 0-8烷基-NR 9R 10、-C 0-8烷基-C(＝NR 9)R 8、-C 0-8烷基-N(R 9)-C(＝NR 10)R 8、-C 0-8烷基-C(O)NR 9R 10和-C 0-8烷基-N(R 9)-C(O)R 8的取代基所取代； R k and R p are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halo-substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl , C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 membered aryl, 5-10 membered heteroaryl, =O , -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 6 , -C 0-8 alkyl-OR 7 , -C 0-8 alkyl-C(O ) OR 7 , -C 0-8 alkyl-C(O)R 8 , -C 0-8 alkyl-OC(O)R 8 , -C 0-8 alkyl-NR 9 R 10 , -C 0 -8 alkyl-C(=NR 9 )R 8 , -C 0-8 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0-8 alkyl-C(O)NR 9 R 10 and -C 0-8 alkyl-N(R 9 )-C(O)R 8 , alternatively, R k and R p together with the carbon atom to which they are directly attached form a C 3-8 cycloalkyl or 3 -8-membered heterocyclic group, the above-mentioned groups are independently optionally further substituted by one or more C 1-10 alkyl groups selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen base, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10-membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 6 , -C 0-8 alkyl-OR 7 , - C 0-8 alkyl-C(O)OR 7 , -C 0-8 alkyl-C(O)R 8 , -C 0-8 alkyl-OC(O)R 8 , -C 0-8 alkane Base -NR 9 R 10 , -C 0-8 alkyl-C(=NR 9 )R 8 , -C 0-8 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0 -8 alkyl-C(O)NR 9 R 10 and -C 0-8 alkyl-N(R 9 )-C(O)R 8 substituents;
    每个R 1各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 6、-C 0-8烷基-O-R 7、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基-O-C(O)R 8、-C 0-8烷基-NR 9R 10、-C 0-8烷基-C(＝NR 9)R 8、-C 0-8烷基-N(R 9)-C(＝NR 10)R 8、-C 0-8烷基-C(O)NR 9R 10和-C 0-8烷基-N(R 9)-C(O)R 8； Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halo-substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 6 , -C 0-8 alkyl-OR 7 , -C 0-8 alkyl-C(O) OR 7 , -C 0-8 alkyl-C(O)R 8 , -C 0-8 alkyl-OC(O)R 8 , -C 0-8 alkyl-NR 9 R 10 , -C 0- 8 alkyl-C(=NR 9 )R 8 , -C 0-8 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0-8 alkyl-C(O)NR 9 R 10 and -C 0-8 alkyl-N(R 9 )-C(O)R 8 ;
    R 2为乙烯基或乙炔基，上述基团独立地任选进一步被一个或多个选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基-C(O)-NR 9R 10和-C 0-8烷基-NR 9R 10的取代基所取代； R 2 is vinyl or ethynyl, and the above groups are independently optionally further selected from one or more groups selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium Substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -C 0-8 alkyl-C(O)OR 7 , -C 0-8 alkyl-C(O ) R 8 , -C 0-8 alkyl-C(O)-NR 9 R 10 and the substituents of -C 0-8 alkyl-NR 9 R 10 ;
    R 3选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基和-NR 9R 10，上述基团独立地任选进一步 被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、＝O、-C 0-8烷基-SF 5、-C 0-8烷基-S(O) rR 6、-C 0-8烷基-O-R 7、-C 0-8烷基-C(O)OR 7、-C 0-8烷基-C(O)R 8、-C 0-8烷基-O-C(O)R 8、-C 0-8烷基-NR 9R 10、-C 0-8烷基-C(＝NR 9)R 8、-C 0-8烷基-N(R 9)-C(＝NR 10)R 8、-C 0-8烷基-C(O)NR 9R 10和-C 0-8烷基-N(R 9)-C(O)R 8的取代基所取代， R 3 is selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl and -NR 9 R 10 , the above-mentioned groups are independently optionally further selected by one or more groups selected from deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3- 12-membered heterocyclyl, C 6-10 -membered aryl, 5-10-membered heteroaryl, =O, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-S(O) r R 6 , -C 0-8 alkyl-OR 7 , -C 0-8 alkyl-C(O)OR 7 , -C 0-8 alkyl-C(O)R 8 , -C 0-8 alkyl- OC(O)R 8 , -C 0-8 alkyl-NR 9 R 10 , -C 0-8 alkyl-C(=NR 9 )R 8 , -C 0-8 alkyl-N(R 9 ) Substituents for -C(=NR 10 )R 8 , -C 0-8 alkyl-C(O)NR 9 R 10 and -C 0-8 alkyl-N(R 9 )-C(O)R 8 replaced,
    或者，R 3和L 2与其直接相连的氮原子一起形成一个4-10元杂环基； Alternatively, R and L together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl ;
    R 4和R 5各自独立地选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基和-NR 9R 10，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 9R 10的取代基所取代； R 4 and R 5 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6- 10 -aryl, 5-10-membered heteroaryl and -NR 9 R 10 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6 -10 -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 9 R 10 substituents;
    每个R 6各自独立地选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基和-NR 9R 10，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 9R 10的取代基所取代； Each R 6 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl and -NR 9 R 10 , the above-mentioned groups independently optionally further selected by one or more groups selected from deuterium, halogen, hydroxyl, oxo, C 1-10 alkyl, C 1 -10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6- 10 -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and substituents of -NR 9 R 10 ;
    每个R 7各自独立地选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-12环烷基、3-12元杂环基、C 6-10芳基和5-10元杂芳基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、氰基、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 9R 10的取代基所取代； Each R 7 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10-membered heteroaryl groups, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-10 alkyl, C 1-10 alkoxy , C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and substituents of -NR 9 R 10 ;
    每个R 8各自独立地选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 9R 10，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基和-NR 9R 10的取代基所取代； Each R 8 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 Cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10-membered heterocycle Aryl, 5-10 membered heteroaryloxy and -NR 9 R 10 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6 -10 -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 9 R 10 substituents;
    每个R 9和R 10各自独立地选自氢、氘、羟基、C 1-10烷氧基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-12环烷基、3-12元杂环基、C 6-10芳基、5-10元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基、氨基、单C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单C 1-10烷基氨基、二C 1-10烷基 氨基和C 1-10烷酰基的取代基所取代； Each of R 9 and R 10 is independently selected from hydrogen, deuterium, hydroxy, C 1-10 alkoxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 -membered cycloalkyl, 3-12-membered heterocyclyl, C 6-10 -membered aryl, 5-10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl, the above groups are independently any is further selected by one or more selected from deuterium, halogen, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6 -10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and Substituents of C 1-10 alkanoyl groups are substituted;
    或者，R 9和R 10与其直接相连的氮原子一起形成一个4-10元杂环基或4-10元杂芳基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、氘取代C 1-10烷基、C 1-10烷氧基、C 3-12环烷基、C 3-12环烷氧基、3-12元杂环基、3-12元杂环氧基、C 6-10芳基、C 6-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单C 1-10烷基氨基、二C 1-10烷基氨基和C 1-10烷酰基的取代基所取代； Alternatively, R 9 and R 10 together with the nitrogen atom to which they are directly attached form a 4-10-membered heterocyclic group or a 4-10-membered heteroaryl group independently optionally further , hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-10 alkoxy base, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy , 5-10-membered heteroaryl, 5-10-membered heteroaryloxy, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl substituents;
    m为0、1或2；且m is 0, 1 or 2; and
    每个r各自独立地为0、1或2。Each r is independently 0, 1, or 2.
  2. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，每个R 1各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 6、-C 0-4烷基-O-R 7、-C 0-4烷基-C(O)OR 7、-C 0-4烷基-C(O)R 8、-C 0-4烷基-O-C(O)R 8、-C 0-4烷基-NR 9R 10、-C 0-4烷基-C(＝NR 9)R 8、-C 0-4烷基-N(R 9)-C(＝NR 10)R 8、-C 0-4烷基-C(O)NR 9R 10和-C 0-4烷基-N(R 9)-C(O)R 8； The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro , azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S (O) r R 6 , -C 0-4 alkyl-OR 7 , -C 0-4 alkyl-C(O)OR 7 , -C 0-4 alkyl-C(O)R 8 , -C 0-4 alkyl-OC(O)R 8 , -C 0-4 alkyl-NR 9 R 10 , -C 0-4 alkyl-C(=NR 9 )R 8 , -C 0-4 alkyl -N(R 9 )-C(=NR 10 )R 8 , -C 0-4 alkyl-C(O)NR 9 R 10 and -C 0-4 alkyl-N(R 9 )-C(O )R 8 ;
    其中，R 6、R 7、R 8、R 9、R 10和r如权利要求1所定义。 wherein R 6 , R 7 , R 8 , R 9 , R 10 and r are as defined in claim 1 .
  3. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R i选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 6、-C 0-4烷基-O-R 7、-C 0-4烷基-C(O)OR 7、-C 0-4烷基-C(O)R 8、-C 0-4烷基-O-C(O)R 8、-C 0-4烷基-NR 9R 10、-C 0-4烷基-C(＝NR 9)R 8、-C 0-4烷基-N(R 9)-C(＝NR 10)R 8、-C 0-4烷基-C(O)NR 9R 10和-C 0-4烷基-N(R 9)-C(O)R 8； The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein R i is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3 -6-membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O) r R 6 , -C 0-4 alkyl-OR 7 , -C 0-4 alkyl-C(O)OR 7 , -C 0-4 alkyl-C(O)R 8 , -C 0-4 alkyl -OC(O)R 8 , -C 0-4 alkyl-NR 9 R 10 , -C 0-4 alkyl-C(=NR 9 )R 8 , -C 0-4 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0-4 alkyl-C(O)NR 9 R 10 and -C 0-4 alkyl-N(R 9 )-C(O)R 8 ;
    其中，R 6、R 7、R 8、R 9、R 10和r如权利要求1所定义。 wherein R 6 , R 7 , R 8 , R 9 , R 10 and r are as defined in claim 1 .
  4. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R g选自氢、氘、卤素、氰基、C 1-4烷基、C 1-4烷氧基、卤取代C 1-4烷基、氘取代C 1-4烷基、卤取代C 1-4烷氧基、氘取代C 1-4烷氧基、C 2-4链烯基、C 2-4链炔基和-C 0-4烷基-NR 4R 5； The compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein R g is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, halogen substituted C 1-4 alkoxy, deuterium substituted C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl and -C 0-4 alkyl-NR 4 R 5 ;
    R h选自氢、氘、羟基、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基； R is selected from hydrogen, deuterium , hydroxy, C 1-4 alkyl, halo-substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
    其中，R 4和R 5如权利要求1所定义。 wherein R 4 and R 5 are as defined in claim 1 .
  5. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R a、R b、R d和R e各自独立地选自氢、氘、卤素、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基和C 2-4链炔基，或者，R a和R b、R d和R e、R a和R d其中之一组各自独立地与其直接相连的碳原子一起形成一个C 3-6环烷基或3-6元杂环基，另二组如前所定义； The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein R a , R b , R d and Re are each independently selected from hydrogen, deuterium, Halogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl and C 2-4 alkynyl, or, R a and R b , R d and Re , R a and R d each independently form a C 3-6 cycloalkyl or 3-6 membered heterocyclic group together with the carbon atom to which it is directly connected, and the other two groups are as previously described definition;
    R c和R f各自独立地选自氢、氘、卤素、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基，或者，R c和R f与其直接相连的部分一起形成一个C 3-6环烷基或3-6元杂环基。 R c and R f are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium substituted C 1-4 alkyl, alternatively, R c and R f are directly therewith The linked moieties together form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl.
  6. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，R j选自氢、氘、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基； The compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein R j is selected from hydrogen, deuterium, C 1-4 alkyl, halogen substituted C 1- 4 alkyl and deuterium substituted C 1-4 alkyl;
    R k和R p各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 6、-C 0-4烷基-O-R 7、-C 0-4烷基-C(O)OR 7、-C 0-4烷基-C(O)R 8、-C 0-4烷基-O-C(O)R 8、-C 0-4烷基-NR 9R 10、-C 0-4烷基-C(＝NR 9)R 8、-C 0-4烷基-N(R 9)-C(＝NR 10)R 8、-C 0-4烷基-C(O)NR 9R 10和-C 0-4烷基-N(R 9)-C(O)R 8，或者，R k和R p与其直接相连的碳原子一起形成一个C 3-6环烷基或3-6元杂环基，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 6、-C 0-4烷基-O-R 7、-C 0-4烷基-C(O)OR 7、-C 0-4烷基-C(O)R 8、-C 0-4烷基-O-C(O)R 8、-C 0-4烷基-NR 9R 10、-C 0-4烷基-C(＝NR 9)R 8、-C 0-4烷基-N(R 9)-C(＝NR 10)R 8、-C 0-4烷基-C(O)NR 9R 10和-C 0-4烷基-N(R 9)-C(O)R 8的取代基所取代； R k and R p are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O , -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O) r R 6 , -C 0-4 alkyl-OR 7 , -C 0-4 alkyl-C(O ) OR 7 , -C 0-4 alkyl-C(O)R 8 , -C 0-4 alkyl-OC(O)R 8 , -C 0-4 alkyl-NR 9 R 10 , -C 0 -4 alkyl-C(=NR 9 )R 8 , -C 0-4 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0-4 alkyl-C(O)NR 9 R 10 and -C 0-4 alkyl-N(R 9 )-C(O)R 8 , alternatively, R k and R p together with the carbon atom to which they are directly attached form a C 3-6 cycloalkyl or 3 -6-membered heterocyclic group, the above-mentioned groups are independently optionally further substituted by one or more C 1-4 alkyl groups selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen base, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8-membered heteroaryl, =O, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O) r R 6 , -C 0-4 alkyl-OR 7 , - C 0-4 alkyl-C(O)OR 7 , -C 0-4 alkyl-C(O)R 8 , -C 0-4 alkyl-OC(O)R 8 , -C 0-4 alkane Base -NR 9 R 10 , -C 0-4 alkyl-C(=NR 9 )R 8 , -C 0-4 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0 -4 alkyl-C(O)NR 9 R 10 and -C 0-4 alkyl-N(R 9 )-C(O)R 8 substituents;
    其中，R 6、R 7、R 8、R 9、R 10和r如权利要求1所定义。 wherein R 6 , R 7 , R 8 , R 9 , R 10 and r are as defined in claim 1 .
  7. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，L 2选自C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、C 3-6环烷基C 1-2烷基、3-6元杂环基C 1-2烷基、C 6-8芳基C 1-2烷基和5-8元杂芳基C 1-2烷基，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 6、-C 0-4烷基-O-R 7、-C 0-4烷基-C(O)OR 7、-C 0-4烷基-C(O)R 8、-C 0-4烷基-O-C(O)R 8、-C 0-4烷基-NR 9R 10、-C 0-4烷基-C(＝NR 9)R 8、-C 0-4烷基-N(R 9)-C(＝NR 10)R 8、-C 0-4烷基-C(O)NR 9R 10和-C 0-4烷基-N(R 9)-C(O)R 8的取代基所取代； The compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein L 2 is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, C 3-6 cycloalkyl, C 1-2 alkane group, 3-6 membered heterocyclyl C 1-2 alkyl, C 6-8 aryl C 1-2 alkyl and 5-8 membered heteroaryl C 1-2 alkyl, the above groups are independently optional is further selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2- 4 -alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -C 0 -4 alkyl-SF 5 , -C 0-4 alkyl-S(O) r R 6 , -C 0-4 alkyl-OR 7 , -C 0-4 alkyl-C(O)OR 7 , -C 0-4 alkyl-C(O)R 8 , -C 0-4 alkyl-OC(O)R 8 , -C 0-4 alkyl-NR 9 R 10 , -C 0-4 alkyl -C(=NR 9 )R 8 , -C 0-4 alkyl-N(R 9 )-C(=NR 10 )R 8 , -C 0-4 alkyl-C(O)NR 9 R 10 and -C 0-4 alkyl-N(R 9 )-C(O)R 8 substituent;
    R 3选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基和-NR 9R 10，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-C 0-4烷基-SF 5、-C 0-4烷基-S(O) rR 6、-C 0-4烷基-O-R 7、-C 0-4烷基-C(O)OR 7、-C 0-4烷基-C(O)R 8、-C 0-4烷基-O-C(O)R 8、-C 0-4烷基-NR 9R 10、-C 0-4烷基-C(＝NR 9)R 8、-C 0-4烷基-N(R 9)-C(＝NR 10)R 8、-C 0-4烷基-C(O)NR 9R 10和-C 0-4烷基-N(R 9)-C(O)R 8的取代基所取代， R 3 is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl and -NR 9 R 10 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- 6-membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-S(O) r R 6 , -C 0-4 alkyl-OR 7 , -C 0-4 alkyl-C(O)OR 7 , -C 0-4 alkyl-C(O)R 8 , -C 0-4 alkyl- OC(O)R 8 , -C 0-4 alkyl-NR 9 R 10 , -C 0-4 alkyl-C(=NR 9 )R 8 , -C 0-4 alkyl-N(R 9 ) Substituents for -C(=NR 10 )R 8 , -C 0-4 alkyl-C(O)NR 9 R 10 and -C 0-4 alkyl-N(R 9 )-C(O)R 8 replaced,
    或者，R 3和L 2与其直接相连的氮原子一起形成一个4-8元杂环基； Alternatively, R and L together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclyl ;
    其中，R 6、R 7、R 8、R 9、R 10和r如权利要求1所定义。 wherein R 6 , R 7 , R 8 , R 9 , R 10 and r are as defined in claim 1 .
  8. 权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，式(I)化合物为如下式(Ⅱa)或(Ⅱb)化合物：The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) is the following compound of formula (IIa) or (IIb):
    Figure PCTCN2021111447-appb-100003
    Figure PCTCN2021111447-appb-100003
    其中，
    Figure PCTCN2021111447-appb-100004
    为单键或双键；     in,
    Figure PCTCN2021111447-appb-100004
    is a single bond or a double bond;
    Y 1、Y 2、Y 3和Y 4各自独立地选自N、C(O)、CR g、N(O)和NR h； Y 1 , Y 2 , Y 3 and Y 4 are each independently selected from N, C(O), CR g , N(O) and NR h ;
    Z 1、Z 2和Z 3各自独立地为CR i或N； Z 1 , Z 2 and Z 3 are each independently CR i or N;
    L 1选自O、S、NR j、CR kR p、OCR kR p和键； L1 is selected from O, S , NRj , CRkRp , OCRkRp and a bond ;
    L 2选自C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、C 3-6环烷基C 1-2烷基、3-6元杂环基C 1-2烷基、C 6-8芳基C 1-2烷基和5-8元杂芳基C 1-2烷基，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-SF 5、-S(O) rR 6、-O-R 7、-C(O)OR 7、-C(O)R 8、-O-C(O)R 8、-NR 9R 10、-C(＝NR 9)R 8、-N(R 9)-C(＝NR 10)R 8、-C(O)NR 9R 10和-N(R 9)-C(O)R 8的取代基所取代； L 2 is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl, C 3-6 cycloalkyl C 1-2 alkyl, 3-6 membered heterocyclyl C 1-2 alkyl, C 6-8 aryl C 1-2 alkyl and 5 -8-membered heteroaryl C 1-2 alkyl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen Substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -SF 5 , -S(O) r R 6 , -OR 7 , -C(O)OR 7 , -C(O)R 8 , -OC(O)R 8 , -NR 9 R 10 , -C(=NR 9 )R 8 , -N(R 9 )-C(=NR 10 )R 8 , -C(O)NR 9 R 10 and -N(R 9 )-C(O)R 8 substituent;
    R a、R b、R d和R e各自独立地选自氢、氘、卤素、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基，或者，R a和R b、R d和R e、R a和R d其中之一组各自独立地与其直接相连的碳原子一起形成一个C 3-6环烷基，另二组如前所定义； R a , R b , R d , and R e are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium-substituted C 1-4 alkyl, or, R One of a and R b , R d and Re , Ra and R d each independently forms a C 3-6 cycloalkyl together with the carbon atom to which it is directly attached, and the other two groups are as previously defined;
    R c和R f各自独立地选自氢、氘、卤素、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基，或者，R c和R f与其直接相连的部分一起形成一个C 3-6环烷基； R c and R f are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium substituted C 1-4 alkyl, alternatively, R c and R f are directly therewith The linked moieties together form a C 3-6 cycloalkyl;
    R g选自氢、氘、C 1-2烷基、C 1-2烷氧基、卤取代C 1-2烷基、氘取代C 1-2烷基、卤取代C 1-2烷氧基、氘取代C 1-2烷氧基和-C 0-2烷基-NR 4R 5； R g is selected from hydrogen, deuterium, C 1-2 alkyl, C 1-2 alkoxy, halo-substituted C 1-2 alkyl, deuterium-substituted C 1-2 alkyl, halo-substituted C 1-2 alkoxy , deuterium substituted C 1-2 alkoxy and -C 0-2 alkyl-NR 4 R 5 ;
    R h各自独立地选自氢、氘、羟基、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基； R h is each independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium substituted C 1-4 alkyl;
    R i选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基和-C 0-2烷基-O-R 7； R i is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl and -C 0-2 alkyl-OR 7 ;
    R j选自氢、氘、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基； R j is selected from hydrogen, deuterium, C 1-4 alkyl, halo-substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
    R k和R p各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基和5-8元杂芳基，或者，R k和R p与其直接相连的碳原子一起形成一个C 3-6环烷基或3-6元杂环基； R k and R p are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl, or, R k and R p together with the carbon atom to which they are directly attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl;
    每个R 1各自独立地选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基和-C 0-2烷基-O-R 7； Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl and -C 0 -2 alkyl-OR 7 ;
    R 2为乙烯基或乙炔基，上述基团独立地任选进一步被一个或多个选自氢、氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、-C 0-2烷基-C(O)OR 7、-C 0-2烷基-C(O)R 8、-C 0-2烷基-C(O)-NR 9R 10和-C 0-2烷基-NR 9R 10的取代基所取代； R 2 is vinyl or ethynyl, and the above groups are independently optionally further selected from one or more groups selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium Substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -C 0-2 alkyl-C(O)OR 7 , -C 0-2 alkyl-C(O ) R 8 , -C 0-2 alkyl-C(O)-NR 9 R 10 and the substituents of -C 0-2 alkyl-NR 9 R 10 ;
    R 3选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基和-NR 9R 10，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基、＝O、-SF 5、-S(O) rR 6、-O-R 7、-C(O)OR 7、-C(O)R 8、-O-C(O)R 8、-NR 9R 10、-C(＝NR 9)R 8、-N(R 9)-C(＝NR 10)R 8、-C(O)NR 9R 10和-N(R 9)-C(O)R 8的取代基所取代， R 3 is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl and -NR 9 R 10 , the above-mentioned groups are independently optionally further selected by one or more groups selected from deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- 6-membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, =O, -SF 5 , -S(O) r R 6 , -OR 7 , -C(O)OR 7 , - C(O)R 8 , -OC(O)R 8 , -NR 9 R 10 , -C(=NR 9 )R 8 , -N(R 9 )-C(=NR 10 )R 8 , -C( O) NR 9 R 10 and -N(R 9 )-C(O)R 8 substituents,
    或者，R 3和L 2与其直接相连的氮原子一起形成一个4-8元含氮杂环基； Alternatively, R 3 and L 2 together with the nitrogen atom to which they are directly attached form a 4-8 membered nitrogen-containing heterocyclic group;
    R 4和R 5各自独立地选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 3-6环烷基、3-6元杂环基、C 6-8芳基、5-8元杂芳基和-NR 9R 10； R 4 and R 5 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6- 8 aryl, 5-8 membered heteroaryl and -NR 9 R 10 ;
    m为0、1或2；m is 0, 1 or 2;
    每个r各自独立地为0、1或2；each r is independently 0, 1, or 2;
    其中，R 6、R 7、R 8、R 9、R 10和r如权利要求1所定义。 wherein R 6 , R 7 , R 8 , R 9 , R 10 and r are as defined in claim 1 .
  9. 权利要求8所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，式(I)化合物为如下式(Ⅲa 1)或(Ⅲa 2)化合物： The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 8, wherein the compound of formula (I) is the following compound of formula (IIIa 1 ) or (IIIa 2 ):
    Figure PCTCN2021111447-appb-100005
    Figure PCTCN2021111447-appb-100005
    其中，式(Ⅲa 1)化合物中，Y 1为N或CH； Wherein, in the compound of formula (IIIa 1 ), Y 1 is N or CH;
    每个Z 1各自独立地为CH或N； each Z 1 is independently CH or N;
    每个L 1各自独立地选自O、S、NR j、CR kR p、OCR kR p和键； Each L 1 is independently selected from O, S , NRj , CRkRp , OCRkRp and a bond ;
    每个L 2各自独立地选自C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 3-4环烷基C 1-2烷基和3-4元杂环基C 1-2烷基，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、苯基和-O-R 7的取代基所取代； Each L 2 is independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-4 cycloalkyl C 1-2 alkyl and 3-4 membered heterocyclyl Heterocyclyl C 1-2 alkyl, the above groups are independently optionally further C 1 substituted with one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen -4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl and - Replaced by the substituent of OR 7 ;
    每个R a、R b、R d和R e各自独立地选自氢、氘、甲基、二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基、一氘甲基、二氘甲基和三氘甲基，或者，R a和R b、R d和R e其中之一组各自独立地与其直接相连的碳原子一起形成一个C 3-6环烷基，另一组如前所定义； Each of Ra , Rb , Rd and Re is independently selected from hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, Tribromomethyl, monodeuteromethyl, dideuteromethyl and trideuteromethyl, alternatively, one of the groups of Ra and Rb , Rd and Re each independently together with the carbon atom to which it is directly attached form a C 3-6 cycloalkyl, another group is as previously defined;
    每个R g各自独立地选自氢、氘和-NR 4R 5； Each R g is independently selected from hydrogen, deuterium and -NR 4 R 5 ;
    每个R j各自独立地选自氢、氘、甲基、二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基、一氘甲基、二氘甲基和三氘甲基； Each Rj is independently selected from the group consisting of hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl , di-deuteromethyl and tri-deuteromethyl;
    每个R k和R p各自独立地选自氢、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基，或者，R k和R p与其直接相连的碳原子一起形成一个C 3-6环烷基； Each R k and R p is independently selected from hydrogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium substituted C 1-4 alkyl, alternatively, R k and R p are directly attached thereto. The carbon atoms together form a C 3-6 cycloalkyl;
    每个R 1a各自独立地选自氢、氘、氟、氯、溴、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基和-O-R 7； Each R 1a is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, and -OR 7 ;
    每个R 1b各自独立地选自氢、氘、氟、氯、溴、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基和-O-R 7； Each R 1b is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, and -OR 7 ;
    每个R 2各自独立地为乙烯基或乙炔基，上述基团独立地任选进一步被一个或多个选自氢、氘、氟、氯、氰基、甲基、二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基、一氘甲基、二氘甲基、三氘甲基、环丙基和-C 0-2烷基-NR 9R 10的取代基所取代； Each R 2 is each independently vinyl or ethynyl, independently optionally further selected by one or more groups selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, methyl, difluoromethyl, dichloro Methyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl, dideuteromethyl, trideuteromethyl, cyclopropyl and -C 0-2 alkyl- Substituents of NR 9 R 10 are substituted;
    每个R 3各自独立地选自氢、氘、羟基、C 1-4烷基、C 3-4环烷基和3-4元杂环基，上述基团独立地任选进一步被一个或多个选自氘、氟、氯、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环 基、苯基、-O-R 7和-NR 9R 10的取代基所取代， Each R is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 3-4 cycloalkyl, and 3-4 membered heterocyclyl, independently optionally further substituted by one or more One is selected from deuterium, fluorine, chlorine, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 chain Alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, -OR 7 and -NR 9 R 10 substituents,
    或者，R 3和L 2与其直接相连的氮原子一起形成如下结构： Alternatively, R and L together with their directly attached nitrogen atoms form the following structure:
    Figure PCTCN2021111447-appb-100006
    Figure PCTCN2021111447-appb-100006
    每个R 4和R 5各自独立地选自氢、氘、甲基、二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基、一氘甲基、二氘甲基和三氘甲基； Each R4 and R5 is independently selected from hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, mono deuteromethyl, di-deuteromethyl and tri-deuteromethyl;
    n为0、1或2；n is 0, 1 or 2;
    其中，R 7、R 9和R 10如权利要求8所定义。 wherein R 7 , R 9 and R 10 are as defined in claim 8 .
  10. 权利要求8所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，式(I)化合物为如下式(Ⅲb)化合物：The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 8, wherein the compound of formula (I) is a compound of the following formula (IIIb):
    Figure PCTCN2021111447-appb-100007
    Figure PCTCN2021111447-appb-100007
    其中，Y 3为N或N(O)； Wherein, Y 3 is N or N(O);
    L 1选自O、S、NR j、CR kR p、OCR kR p和键； L1 is selected from O, S , NRj , CRkRp , OCRkRp and a bond ;
    L 2选自C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 3-4环烷基C 1-2烷基和3-4元杂环基C 1-2烷基，上述基团独立地任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、苯基和-O-R 7的取代基所取代； L 2 is selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-4 cycloalkyl C 1-2 alkyl and 3-4 membered heterocyclyl C 1 -2 alkyl groups, the above groups are independently optionally further substituted by one or more groups selected from the group consisting of deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl substituted with substituents of C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl and -OR 7 ;
    R c和R f各自独立地选自氢、氘、甲基、二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基、一氘甲基、二氘甲基和三氘甲基，或者，R c和R f与其直接相连的部分一起形成一个C 3-6环烷基； Rc and Rf are each independently selected from the group consisting of hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl group, di- deuteromethyl and tri- deuteromethyl , alternatively, R and R together with the moiety to which they are directly attached form a C 3-6 cycloalkyl;
    R g选自氢、氘、甲基、二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基、一氘甲基、二氘甲基和三氘甲基； R g is selected from hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl, dideuteromethyl and trideuteromethyl;
    R i选自氢、氘、氟、氯和氰基； R i is selected from hydrogen, deuterium, fluorine, chlorine and cyano;
    R j选自氢、氘、甲基、二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基、一氘甲基、二氘甲基和三氘甲基； R j is selected from hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl, dideuteromethyl and trideuteromethyl;
    R k和R p各自独立地选自氢、C 1-4烷基、卤取代C 1-4烷基和氘取代C 1-4烷基，或者，R k和R p与其直接相连的碳原子一起形成一个C 3-6环烷基； R k and R p are each independently selected from hydrogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium substituted C 1-4 alkyl, alternatively, the carbon atom to which R k and R p are directly attached together form a C 3-6 cycloalkyl;
    R 1a选自氢、氘、氟、氯、溴、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基和-O-R 7； R 1a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl and -OR 7 ;
    R 1b选自氢、氘、氟、氯、溴、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基和-O-R 7； R 1b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl and -OR 7 ;
    R 2为乙烯基或乙炔基，上述基团独立地任选进一步被一个或多个选自氢、氘、氟、氯、氰基、甲基、二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基、一氘甲基、二氘甲基、三氘甲基、环丙基和-C 0-2烷基-NR 9R 10的取代基所取代； R 2 is vinyl or ethynyl, which are independently optionally further selected from one or more groups selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, difluoromethyl, dichloromethyl, dibromo Methyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl, di-deuteromethyl, tri-deuteromethyl, cyclopropyl and -C 0-2 alkyl-NR 9 R 10 substituted by a substituent;
    R 3选自氢、氘、C 1-4烷基、C 3-4环烷基和3-4元杂环基，上述基团独立地任选进一步被一个或多个选自氘、氟、氯、氰基、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、苯基、-O-R 7和-NR 9R 10的取代基所取代， R 3 is selected from hydrogen, deuterium, C 1-4 alkyl, C 3-4 cycloalkyl and 3-4 membered heterocyclyl, the above-mentioned groups are independently optionally further substituted by one or more selected from deuterium, fluorine, Chlorine, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 Substituents of cycloalkyl, 3-6 membered heterocyclyl, phenyl, -OR 7 and -NR 9 R 10 ,
    或者，R 3和L 2与其直接相连的氮原子一起形成如下结构： Alternatively, R and L together with their directly attached nitrogen atoms form the following structure:
    Figure PCTCN2021111447-appb-100008
    Figure PCTCN2021111447-appb-100008
    其中，R 7、R 9和R 10如权利要求8所定义。 wherein R 7 , R 9 and R 10 are as defined in claim 8 .
  11. 根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，每个R 6各自独立地选自氢、氘、羟基、C 1-4烷基、C 2-4链烯基、C 3-8环烷基、3-8元杂环基、C 6-8芳基、5-8元杂芳基和-NR 9R 10，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 9R 10的取代基所取代； The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R 6 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkane group, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl and -NR 9 R 10 , the above-mentioned groups independently optionally further selected by one or more of the group consisting of deuterium, halogen, hydroxy, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkane Oxy group, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy substituted with the substituent of -NR 9 R 10 ;
    每个R 7各自独立地选自氢、氘、C 1-4烷基、C 2-4链烯基、C 3-8环烷基、3-8元杂环基、C 6-8芳基和5-8元杂芳基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氧代、氰基、C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、 3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 9R 10的取代基所取代； Each R 7 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl groups, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-4 alkyl, C 1-4 alkoxy , C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8-membered heterocyclyl, 3-8-membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and substituents of -NR 9 R 10 ;
    每个R 8各自独立地选自氢、氘、羟基、C 1-4烷基、C 1-4烷氧基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 9R 10，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、氰基、C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基和-NR 9R 10的取代基所取代； Each R 8 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 Cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heterocycle Aryl, 5-8 membered heteroaryloxy and -NR 9 R 10 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6 -8 -aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 9 R 10 substituents;
    每个R 9和R 10各自独立地选自氢、氘、羟基、C 1-4烷氧基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-8环烷基、3-8元杂环基、C 6-8芳基、5-8元杂芳基、亚磺酰基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基磺酰基、二甲氨基磺酰基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基的取代基所取代； Each of R 9 and R 10 is independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl, the above groups are independently any is further selected from the group consisting of one or more deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6 -8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and Substituted by the substituent of C 1-4 alkanoyl;
    或者，R 9和R 10与其直接相连的氮原子一起形成4-8元杂环基或4-8元杂芳基，上述基团独立地任选进一步被一个或多个选自氘、卤素、羟基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、氘取代C 1-4烷基、C 1-4烷氧基、C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 6-8芳基、C 6-8芳氧基、5-8元杂芳基、5-8元杂芳氧基、氨基、单C 1-4烷基氨基、二C 1-4烷基氨基和C 1-4烷酰基的取代基所取代。 Alternatively, R 9 and R 10 are taken together with the nitrogen atom to which they are directly attached to form a 4-8 membered heterocyclic group or a 4-8 membered heteroaryl group independently optionally further substituted by one or more selected from the group consisting of deuterium, halogen, Hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy , C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl substituents.
  12. 根据权利要求1-11任一所述的式(I)化合物、其立体异构体或其药学上可接受盐，其特征在于，选自如下化合物：The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-11, characterized in that, it is selected from the following compounds:
    Figure PCTCN2021111447-appb-100009
    Figure PCTCN2021111447-appb-100009
    Figure PCTCN2021111447-appb-100010
    Figure PCTCN2021111447-appb-100010
    Figure PCTCN2021111447-appb-100011
    Figure PCTCN2021111447-appb-100011
    Figure PCTCN2021111447-appb-100012
    Figure PCTCN2021111447-appb-100012
    Figure PCTCN2021111447-appb-100013
    Figure PCTCN2021111447-appb-100013
    Figure PCTCN2021111447-appb-100014
    Figure PCTCN2021111447-appb-100014
  13. 一种根据权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受盐的制备方法，其特征在于，包括如下步骤：A preparation method of the compound of formula (I) according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, is characterized in that, comprises the steps:
    Figure PCTCN2021111447-appb-100015
    Figure PCTCN2021111447-appb-100015
    其中，R为R 3或氨基保护基，所述氨基保护基为叔丁氧羰基或苄基，X 1、X 2、Y 1、Y 2、Y 3、Y 4、Z 1、Z 2、Z 3、L 1、L 2、R 1、R 2、R 3和m如权利要求1所定义。 Wherein, R is R 3 or an amino protecting group, the amino protecting group is tert-butoxycarbonyl or benzyl, X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Z 1 , Z 2 , Z 3 , L 1 , L 2 , R 1 , R 2 , R 3 and m are as defined in claim 1 .
  14. 一种药物组合物，其包括根据权利要求1-12中任一所述的式(I)化合物、其立体异构体或其药学上可接受盐及可药用的载体。A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-12, a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  15. 根据权利要求1-12中任一所述的式(I)化合物、其立体异构体或其药学上可接受盐在制备治疗和/或预防至少部分由与EGFR外显子20***或缺失突变相关的癌症、肿瘤或转移性性疾病的药物中的用途。A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-12, in the manufacture of therapeutic and/or prophylactic at least in part by an insertion or deletion mutation with EGFR exon 20 Use in the medicament of a related cancer, tumor or metastatic disease.
  16. 一种根据权利要求1-12中任一所述的式(I)化合物、其立体异构体或其药学上可接受盐在制备预防和/或治疗由过度增殖和诱导细胞死亡障碍引起的肿瘤、癌症和/或转移性疾病的药物中的应用，优选地，所述肿瘤、癌症和/或转移性疾病选自肺癌、结肠癌、胰腺癌、头颈癌、乳腺癌，卵巢癌，子宫癌、胃癌、非小细胞肺癌、白血病、骨髓增生异常综合症、恶性淋巴瘤、头颈部肿瘤、胸腔肿瘤、胃肠道肿瘤、内分泌肿瘤、乳腺和其他妇科肿瘤、泌尿科肿瘤、皮肤肿瘤、肉瘤、倒置***状瘤或鳞状细胞癌。A compound of formula (I) according to any one of claims 1-12, a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of preventing and/or treating tumors caused by excessive proliferation and inducing cell death disorders , application in the medicine of cancer and/or metastatic disease, preferably, described tumor, cancer and/or metastatic disease are selected from lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, Gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, Inverted papilloma or squamous cell carcinoma.
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