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WO2024251282A1 - Inhibiteur de dérivé pentacyclique, son procédé de préparation et son utilisation - Google Patents

Inhibiteur de dérivé pentacyclique, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2024251282A1
WO2024251282A1 PCT/CN2024/098249 CN2024098249W WO2024251282A1 WO 2024251282 A1 WO2024251282 A1 WO 2024251282A1 CN 2024098249 W CN2024098249 W CN 2024098249W WO 2024251282 A1 WO2024251282 A1 WO 2024251282A1
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Prior art keywords
alkyl
alkoxy
deuterated
cycloalkyl
aryl
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Chinese (zh)
Inventor
曾蜜
高鹏
曾明高
王永鑫
俞文胜
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems

Definitions

  • the invention belongs to the field of medicine, and specifically relates to a pentacyclic derivative inhibitor and a preparation method and application thereof.
  • TNF ⁇ is a member of the tumor necrosis factor (TNF) superfamily of proteins, a proinflammatory cytokine produced by macrophages and monocytes, involved in normal inflammatory and immune responses, and driving the expression of other cytokines such as interleukin-1 (IL-1) and interleukin-6 (IL-6). It has proinflammatory and immunomodulatory functions and is considered a pleiotropic cytokine.
  • TNF ⁇ is expressed as a membrane-bound precursor (mTNF) that requires cleavage by TNF ⁇ convertase to be released as a soluble cytokine (sTNF).
  • mTNF ⁇ and sTNF ⁇ are biologically active symmetrical trimeric proteins and signal through two separate tumor necrosis factor receptors 1 (TNFR1) and tumor necrosis factor receptor 2 (TNFR2).
  • TNFR1 is ubiquitously expressed and primarily promotes TNF-induced inflammatory responses, whereas TNFR2 expression is restricted to immune cells and maintains local immune homeostasis.
  • the TNFR1 signaling pathway uses the canonical nuclear factor- ⁇ B (NF- ⁇ B) and mitogen-activated protein kinase (MAP kinase) pathways to transmit proinflammatory signals.
  • NF- ⁇ B canonical nuclear factor- ⁇ B
  • MAP kinase mitogen-activated protein kinase
  • TNFR2 signals through the noncanonical NF- ⁇ B pathway, and activation of TNFR2 is important for the proliferation, survival, and lineage stability of Treg cells, as well as for thymic Treg cell development, and is associated with immune regulation.
  • sTNF activates TNFR1 but not TNFR2, whereas mTNF can activate both receptors.
  • TNF ⁇ has been implicated in the development of chronic inflammatory diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), psoriasis, psoriatic arthritis (PsA), ankylosing spondylitis and specific types of juvenile idiopathic arthritis (JIA).
  • RA is a common chronic inflammatory disease with a global prevalence of 0.51%. It is a complex autoimmune disease involving multiple inflammatory mediators such as TNF, IL-6 and IL-1 as well as immune cells (T cells, B cells, monocytes and macrophages) that help drive chronic inflammation in the joints.
  • RA can lead to cumulative joint damage and irreversible disability, but can also result in extra-articular manifestations such as rheumatoid nodules, lung involvement or vasculitis, as well as other systemic comorbidities.
  • Current pharmacological treatments for RA are symptomatic drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) and targeted disease-modifying drugs, known as disease-modifying antirheumatic drugs (DMARDs), which consist of small molecules and biologics.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • DMARDs disease-modifying antirheumatic drugs
  • TNF- ⁇ inhibitors such as infliximab, adalimumab, etanercept, golimumab and pecillimumab have ushered in a new era of rheumatic immunotherapy and have become one of the most powerful weapons for the treatment of rheumatic immune diseases, and have been unanimously recommended by domestic and international authoritative guidelines.
  • Anti-TNF- ⁇ biologics have been successfully used in the clinical treatment of RA, JIA, PsA, ankylosing spondylitis, psoriasis and IBD, especially Crohn's disease (CD) and ulcerative colitis (UC).
  • Anti-TNF- ⁇ biologics have revolutionized the treatment of RA.
  • RA disease remission rate
  • LDA low disease activity
  • Other limitations of anti-TNF- ⁇ biologics include the occurrence of adverse reactions, such as opportunistic infections, reactivation of latent tuberculosis, and increased risk of specific malignancies (such as lymphoma), as well as immunogenicity to the drug itself leading to the development of anti-drug antibodies (ADA), which may limit their efficacy.
  • ADA anti-drug antibodies
  • TNF ⁇ small molecule inhibitors have been reported in patents, such as: WO2016050975A1, WO2018167176, WO2018197503, WO2020084008 (Sanofi), the fastest progressing SAR-441566 is in clinical phase I, and the others are in the preclinical development stage.
  • the present invention needs to develop an orally available TNF ⁇ small molecule inhibitor.
  • the present invention provides a compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof:
  • M 1 is selected from N or CH; Ring A is selected from C 3-8 cycloalkyl;
  • the alkyl radicals are substituted with one or more of C 1-6-10- membered aryl and 5-10-membered heteroaryl; preferably, hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8-membered heterocyclyl, C 6-10 aryl, 5-10-membered heteroaryl, the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C
  • R'1-1 and R'1-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10
  • R' 1-3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocycl
  • R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membere
  • R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl , C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 member
  • R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl , -( CH2 ) m1ORa1 , -( CH2 ) m2C (O) Ra2 , -( CH2 ) m3NHC (O) Ra3 , -( CH2 ) m4C (O) NHRa4 , - ( CH2 ) m5NRa5Ra6 , -( CH2 ) m6 S(O)
  • R a10 is each independently selected from deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered hetero
  • R 4 is selected from ethyl, -CH 2 CHF 2 , -CH 2 CH 2 F,
  • the compound is as shown in formula (I-2-2), formula (I-2-3), formula (I-2-4) or formula (I-2-1-1):
  • the present invention provides a compound as shown in the general formula (IC), its stereoisomers or pharmaceutically acceptable salts thereof
  • L is selected from a bond, a C 1-6 alkyl, a C 2-6 alkenyl, a C 2-6 alkynyl, a C 1-6 deuterated alkyl, a C 1-6 haloalkyl, a C 1-6 alkoxy, a C 1-6 deuterated alkoxy, a C 1-6 haloalkoxy, a C 1-6 hydroxyalkyl, a C 3-8 cycloalkyl, a 3-8 membered heterocyclyl, a C 6-10 aryl, a 5-10 membered heteroaryl, and the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, a C 1-6 deuterated alkyl, a C 1-6 haloalkyl, a C 1-6 alkoxy, a C 1-6 deuterated alkoxy, a C 1-6 haloalkoxy, a C 1-6 hydroxyalkyl, a C 3-8 cycloalky
  • Ring A is selected from absent, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; preferably, Ring A is selected from C 3-8 cycloalkyl;
  • Ring B is selected from absent, C 3-10 cycloalkyl, 5-10 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
  • Ring B' is selected from phenyl or 6-membered heteroaryl
  • Ring C is selected from absent, C 3-10 cycloalkyl, 5-10 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
  • Ring C' is selected from phenyl or 5-6 membered heteroaryl
  • the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, the amino, C 1-6 alkyl , C 2-6 alkenyl , C 2-6 alkynyl , C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further substituted with hydrogen, deuterium, hal
  • R'1-1 and R'1-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkyl
  • R' 1-3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocycl
  • R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, -( CH2 ) m1'OR'a1 , -(CH2)m2'C( O )R'a2 , -(CH2)m3'NHC(O) R'a3 , - ( CH2 ) m4'C ( O ) NHR'a4 , - (CH2 ) m5'NR'a5R'a6 wherein the amino, C 1-6
  • the alkyl group may be substituted by one or more of C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
  • R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membere
  • R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl , C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 member
  • R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl , -( CH2 ) m1ORa1 , -( CH2 ) m2C (O) Ra2 , -( CH2 ) m3NHC (O) Ra3 , -( CH2 ) m4C (O) NHRa4 , - ( CH2 ) m5NRa5Ra6 , -( CH2 ) m6 S(O)
  • R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl , C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 member
  • R6 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membere
  • R8 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 member
  • R 9-1 and R 9-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) m1 OR a1 , -(CH 2 ) m2 C(O)R a2 , -(CH 2 ) m3 NHC(O)R a3 , -(CH 2 ) m4 C(O)NHR a4 , -(CH 2 ) m5 NR a5 R a6 , -(CH
  • R4 and R9-1 are linked to form a 5-8 membered heterocyclyl or 5-6 membered heteroaryl, wherein the 5-8 membered heterocyclyl or 5-6 membered heteroaryl may be further optionally substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl ;
  • R 10-1 and R 10-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl
  • R a1 , R a2 , R a3 , R a4 , R a5 , R a6 , R a7 , R a8 , R a9 , R a10 , R' a1 , R' a2 , R' a3 , R' a4 , R' a5 , R'a6 , R'a7 , R'a8 , R'a9 and R'a10 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membere
  • n1, m2, m3, m4, m5, m6, m8, m9, m10, m1′, m2′, m3′, m4′, m5′, m6′, m8′, m9′ and m10′ are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • n and m7' are each independently selected from 0, 1, 2 or 3.
  • the present invention provides a compound represented by the general formula (IB), its stereoisomers or pharmaceutically acceptable salts thereof
  • L is selected from a bond, a C 1-6 alkyl, a C 2-6 alkenyl, a C 2-6 alkynyl, a C 1-6 deuterated alkyl, a C 1-6 haloalkyl, a C 1-6 alkoxy, a C 1-6 deuterated alkoxy, a C 1-6 haloalkoxy, a C 1-6 hydroxyalkyl, a C 3-8 cycloalkyl, a 3-8 membered heterocyclyl, a C 6-10 aryl, a 5-10 membered heteroaryl, and the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, a C 1-6 deuterated alkyl, a C 1-6 haloalkyl, a C 1-6 alkoxy, a C 1-6 deuterated alkoxy, a C 1-6 haloalkoxy, a C 1-6 hydroxyalkyl, a C 3-8 cycloalky
  • Ring A is selected from absent, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; preferably, Ring A is selected from C 3-8 cycloalkyl;
  • Ring B is selected from absent, C 3-10 cycloalkyl, 5-10 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
  • m1, m2, m3, m4, m5, m6, m8, m9, m10, m1’, m2’, m3’, m4’, m5’, m6’, m8’, m9’ and m10’ are each independently selected from 0, 1, 2, 3, 4, 5 or 6; m7 and m7’ are each independently selected from 0, 1, 2 or 3.
  • the ring A is selected from C 3-6 cycloalkyl or 3-8 membered heterocyclic group, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • the ring A is selected from C 3-6 cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the ring B is selected from C 3-6 cycloalkyl or 5-6 membered heterocyclic group, preferably More preferably
  • the compound represented by formula (II) is represented by formula (II-1):
  • M 2 is CH, CH 2 , N, NH, O or S;
  • M 3 is CH 2 , NH, O or S
  • v 0, 1, 2, or 3.
  • the present invention also provides a compound as shown in formula (II-2) or formula (II-2-1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • R 1-2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered
  • R 1-3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered
  • R 6-1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered
  • R 6-2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, wherein the amino, C 1-6 The alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl,
  • the present invention also provides a compound represented by general formula (III), its stereoisomers or pharmaceutically acceptable salts thereof:
  • M 1 is selected from N or CH;
  • Ring A is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
  • R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membere
  • R'1-1 and R'1-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10
  • R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl , C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 member
  • R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl , C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 member
  • R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl , -( CH2 ) m1ORa1 , -( CH2 ) m2C (O) Ra2 , -( CH2 ) m3NHC (O) Ra3 , -( CH2 ) m4C (O) NHRa4 , - ( CH2 ) m5NRa5Ra6 , -( CH2 ) m6 S(O)
  • R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6
  • Ra1 , Ra2 , Ra3 , Ra4, Ra5 , Ra6, Ra7, Ra8, Ra9 and Ra10 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C
  • n1, m2, m3, m4, m5, m6, m8, m9, m10 are each independently selected from 0, 1, 2, 3, 4, 5 or 6; m7 is selected from 0, 1, 2 or 3.
  • the present invention also provides a compound represented by the general formula (IV), its stereoisomers or pharmaceutically acceptable salts thereof:
  • Ring C is selected from C 3-8 cycloalkyl, 5-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
  • the alkyl radicals are substituted with one or more of C 1-6-10- membered aryl and 5-10-membered heteroaryl; preferably, hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8-membered heterocyclyl, C 6-10 aryl, 5-10-membered heteroaryl, the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C
  • R'1-1 and R'1-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10
  • R' 1-3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocycl
  • R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membere
  • R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl , C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 member
  • R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl , -( CH2 ) m1ORa1 , -( CH2 ) m2C (O) Ra2 , -( CH2 ) m3NHC (O) Ra3 , -( CH2 ) m4C (O) NHRa4 , - ( CH2 ) m5NRa5Ra6 , -( CH2 ) m6 S(O)
  • R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl , -( CH2 ) m1ORa1 , -( CH2 ) m2C (O) Ra2 , -( CH2 ) m3NHC (O) Ra3 , -( CH2 ) m4C (O) NHRa4 , - ( CH2 ) m5NRa5Ra6 , -( CH2 ) m6 S(O)
  • the 6-10 membered aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
  • Ra1 , Ra2 , Ra3 , Ra4, Ra5 , Ra6, Ra7, Ra8, Ra9 and Ra10 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C
  • R'1-1 and R'1-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10
  • n1, m2, m3, m4, m5, m6, m8, m9, m10 are each independently selected from 0, 1, 2, 3, 4, 5 or 6; m7 is selected from 0, 1, 2 or 3.
  • the ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thienyl, furanyl, pyrrolyl, oxadiazolyl, triazolyl,
  • the ring A is selected from C 3-6 cycloalkyl or 3-8 membered heterocyclic group, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • the present invention also provides a compound represented by the general formula (IV-1), its stereoisomers or pharmaceutically acceptable salts thereof:
  • Ring B is selected from C 3-8 cycloalkyl, 5-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
  • Ring C is selected from C 3-8 cycloalkyl, 5-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
  • R'1-1 and R'1-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10
  • R' 1-3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocycl
  • R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl , C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 member
  • R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl or 5-10 membere
  • R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl , -( CH2 ) m1ORa1 , -( CH2 ) m2C (O) Ra2 , -( CH2 ) m3NHC (O) Ra3 , -( CH2 ) m4C (O) NHRa4 , - ( CH2 ) m5NRa5Ra6 , -( CH2 ) m6 S(O)
  • R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl , C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 member
  • R6 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl , C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 member
  • Ra1 , Ra2 , Ra3 , Ra4, Ra5 , Ra6, Ra7, Ra8, Ra9 and Ra10 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C
  • n1, m2, m3, m4, m5, m6, m8, m9, m10 are each independently selected from 0, 1, 2, 3, 4, 5 or 6; m7 is selected from 0, 1, 2 or 3.
  • the present invention also provides a compound represented by the general formula (VII), its stereoisomers or pharmaceutically acceptable salts thereof:
  • M 1 is selected from N or CH; Ring A is selected from C 3-8 cycloalkyl;
  • Ring F is present or absent, and when present is selected from C 3-8 cycloalkyl, 5-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; wherein the C 3-8 cycloalkyl, 5-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl may be further optionally substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
  • the ring F is preferably a 5-6 membered heteroaryl group, and specifically preferably pyrazolyl, thiazolyl, oxazolyl, thiadiazole, imidazolyl, furyl, thienyl, pyrrolyl, isoxazole or isothiazole.
  • R'1-1 and R'1-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10
  • R' 1-3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocycl
  • R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl , C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 member
  • R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membere
  • R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl , -( CH2 ) m1ORa1 , -( CH2 ) m2C (O) Ra2 , -( CH2 ) m3NHC (O) Ra3 , -( CH2 ) m4C (O) NHRa4 , - ( CH2 ) m5NRa5Ra6 , -( CH2 ) m6 S(O)
  • R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl , C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 member
  • R 5 are linked to form a C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl may be further optionally substituted by one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
  • Ra1 , Ra2 , Ra3 , Ra4 , Ra5 , Ra6 , Ra7 , Ra8 , Ra9 and Ra10 are each independently selected from hydrogen, deuterium, halogen, ammonia C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl,
  • n1, m2, m3, m4, m5, m6, m8, m9, m10 are each independently selected from 0, 1, 2, 3, 4, 5 or 6; m7 is selected from 0, 1, 2 or 3.
  • the present invention also relates to a compound represented by the general formula (VIII), its stereoisomers or pharmaceutically acceptable salts thereof:
  • Ring G is present or absent, and when present is selected from C3-8 cycloalkyl, 5-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the C3-8 cycloalkyl, 5-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl;
  • R'1-1 and R'1-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10
  • R' 1-3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocycl
  • R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl , C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 member
  • R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6
  • R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl , -( CH2 ) m1ORa1 , -( CH2 ) m2C (O) Ra2 , -( CH2 ) m3NHC (O) Ra3 , -( CH2 ) m4C (O) NHRa4 , - ( CH2 ) m5NRa5Ra6 , -( CH2 ) m6 S(O)
  • R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl , C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 member
  • Ra1 , Ra2 , Ra3 , Ra4, Ra5 , Ra6, Ra7, Ra8, Ra9 and Ra10 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 The C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C
  • n1, m2, m3, m4, m5, m6, m8, m9, m10 are each independently selected from 0, 1, 2, 3, 4, 5 or 6; m7 is selected from 0, 1, 2 or 3.
  • the compound represented by general formula (VIII), its stereoisomers or pharmaceutically acceptable salts thereof is characterized in that the ring G is selected from a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group; the 5-6 membered heterocyclic group is preferably:
  • the 5- to 6-membered heteroaryl group is preferably pyrazolyl, thiazolyl, oxazolyl, thiadiazole, imidazolyl, furyl, thienyl, pyrrolyl, isoxazole or isothiazole.
  • the present invention also relates to a compound represented by the general formula (ID), its stereoisomers or pharmaceutically acceptable salts thereof:
  • M 1 is selected from N or CH;
  • L is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl.
  • the 6-10 membered aryl or 5-10 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
  • Ring A is present or absent, and when present, is selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; preferably, Ring A is selected from C 3-8 cycloalkyl;
  • Ring B is present or absent, and when present is selected from C 3-8 cycloalkyl, 5-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
  • Ring C is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • the alkyl radicals are substituted with one or more of C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl; preferably with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C
  • R'1-1 and R'1-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl , C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10
  • R' 1-3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocycl
  • R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl , C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 member
  • R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl , C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 member
  • R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl , -( CH2 ) m1ORa1 , -( CH2 ) m2C (O) Ra2 , -( CH2 ) m3NHC (O) Ra3 , -( CH2 ) m4C (O) NHRa4 , - ( CH2 ) m5NRa5Ra6 , -( CH2 ) m6 S(O)
  • R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl , C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 member
  • R6 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl , C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 member
  • R 9-1 and R 9-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) m1 OR a1 , -(CH 2 ) m2 C(O)R a2 , -(CH 2 ) m3 NHC(O)R a3 , -(CH 2 ) m4 C(O)NHR a4 , -(CH 2 ) m5 NR a5 R a6 , -(CH
  • R4 and R9-1 are linked to form a 5-8 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 5-8 membered heterocyclic group or
  • the 5-6 membered heteroaryl may be further optionally substituted with one or more of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
  • Ra1 , Ra2 , Ra3 , Ra4, Ra5 , Ra6 , Ra7 , Ra8 , Ra9 , Ra10 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloal
  • n1, m2, m3, m4, m5, m6, m8, m9 and m10 are each independently selected from 0, 1, 2, 3, 4, 5 or 6; m7 is independently selected from 0, 1, 2 or 3.
  • L is a bond.
  • R'1-1 and R'1-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl , 5-10 membered heteroaryl, The amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy , C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered
  • R' 1-3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl substituted with cyano, C 3-12 cycloalkyl, 3-12 membered heterocycl
  • Ra1 , Ra2 , Ra3 , Ra4, Ra5 , Ra6 , Ra7 , Ra8 , Ra9 , Ra10 , Ra11 and Ra12 are each independently selected from hydrogen, deuterium , halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C
  • the H in the above CH2 may be optionally substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl , C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl ;
  • n1, m2, m3, m4, m5, m6, m8, m9, m10, m11, m12 and m13 are each independently selected from 0, 1, 2, 3, 4, 5 or 6; m7 is independently selected from 0, 1, 2 or 3.
  • Ra1 , Ra2 , Ra3 , Ra4 , Ra5 , Ra6 , Ra7 , Ra8 , Ra9 and Ra10 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl , C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6
  • n1, m2, m3, m4, m5, m6, m8, m9, m10 are each independently selected from 0, 1, 2, 3, 4, 5 or 6; m7 is selected from 0, 1, 2 or 3.
  • Ra11 , Ra21 , Ra31 , Ra41 and Ra51 are each independently selected from hydrogen, halogen, amino, cyano, hydroxyl, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, wherein the C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl
  • R 1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy , C 1-3 hydroxyalkyl, C 3-6 cycloalkyl,
  • R'1-1 and R'1-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl , 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, said amino, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl , C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycly
  • R' 1-1 and R' 1-2 are each independently selected from hydrogen or fluorine.
  • R'1-1 and R'1-2 are each independently selected from: hydrogen, fluorine, methyl or ethyl.
  • R'1-3 is independently selected from: hydrogen or methyl.
  • R1-1 and R1-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl , C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, said amino, C1-3 alkyl , C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy , C1-3 haloalkoxy , C The C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heteroaryl, said amino, C1-3
  • R 1-1 , R 1-2 and R 1-3 are each independently selected from H, D, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, ethynyl, propynyl, vinyl, propenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, NH 2 , OH, CN, CH 2 F, CHF 2 , CF 3 , CH 2 CF 3 , CD 3 , N 3 , COOCH 3 , OCOCH 3 , NHCOCH 3 , CONHCH 3 , COCH 3 , COCF 3 , SO 2 CH 3 , SO 2 NHCH 3 , NHSO 2 CH 3 , SO 2 CH 2 CH 3 , NHSO 2 CH 2 CH 3 , SO 2 NHCH 2 CH 3 , F, Cl, OCF 3 ,
  • R6-1 and R6-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl , C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, said amino, C1-3 alkyl , C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy , C1-3 haloalkoxy , C1-3 The C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 member
  • R 2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -(CH 2 ) m1' OR' a1 , -(CH 2 ) m2' C(O)R' a2 , -(CH 2 ) m3' NHC(O)R' a3 , -(CH 2 ) m4' C(O)NHR' a4 , -(CH 2 ) m1'
  • the alkyl group may be substituted by one or more of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl , C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl;
  • R'a1 , R'a2 , R'a3 , R'a4 , R'a5 , R'a6 , R'a7 , R'a8 , R'a9 and R'a10 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 deuterated alkoxy, C1-6 haloalkoxy, C1-6 hydroxyalkyl , C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein the amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6
  • m1’, m2’, m3’, m4’, m5’, m6’, m8’, m9’ and m10’ are each independently selected from 0, 1, 2, 3, 4, 5 or 6; m7’ is selected from 0, 1, 2 or 3.
  • R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, said amino, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, said amino, C1-3 alkyl
  • R'2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, -( CH2 ) OR'a11 or OR'a11, wherein said amino, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloal
  • R'a11 is independently selected from hydrogen, halogen, amino, cyano, hydroxyl, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, wherein the C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl The 6-10 membered aryl and 5-6 membered hetero
  • R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, said amino, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, said amino, C1-3 alkyl
  • R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl , -( CH2 ) m1ORa1 , -(CH2)m2C(O) Ra2 , -( CH2 ) m3NHC (O) Ra3 , -( CH2 ) m4C ( O )NHRa4, -(CH2)m5NRa5Ra6 , - ( CH2 ) m6 wherein the amino, C
  • R 4 is selected from methyl, ethyl, -CD 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, Preferably, R 4 is selected from methyl, ethyl, -CH 2 CHF 2 , -CH 2 CH 2 F, In certain embodiments of the present invention, R 4 is selected from COCH 3 .
  • R 5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, said amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy , C 1-3 hydroxyalkyl, C 3-6 cyclo
  • R 5 is independently selected from hydrogen, fluorine, chlorine, methyl, cyano, cyclopropyl, or pyrazolyl; preferably, R 5 is independently selected from hydrogen, fluorine, chlorine, methyl, cyano, cyclopropyl, or pyrazolyl; preferably, R 5 is independently selected from hydrogen, fluorine, chlorine, methyl, cyano, cyclopropyl or
  • R6 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, said amino, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, said amino, C1-3 alkyl
  • R 7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6
  • R 7 is substituted by one or more of 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl; preferably, R 7 is independently selected from hydrogen or fluorine.
  • R8 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, said amino, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl,
  • R 8 is selected from oxo, thio, C 1-3 alkyl, C 1-3 deuterated alkyl or C 1-3 haloalkyl.
  • R9-1 and R9-2 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl , C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, -( CH2 ) m1ORa1 , -(CH2) m2C (O) Ra2 , -( CH2 ) m3NHC (O) Ra3 , -( CH2 ) m4C ( O) NHRa4 , - ( CH2 ) m5NRa5Ra6 , - (CH wherein the amino , C 1-3 alkyl
  • Ra1 , Ra2 , Ra3 , Ra4, Ra5 , Ra6, Ra7, Ra8, Ra9 and Ra10 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 deuterated alkoxy, C1-3 haloalkoxy, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, and the amino, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 The C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 haloalkoxy, C 1-3 hydroxyal
  • ring B' is selected from phenyl or 5-6 membered heteroaryl, preferably, B' is selected from phenyl, pyridyl, and ring B is selected from C 5-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl.
  • B' is selected from phenyl, pyridyl, and B is selected from C 5-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
  • Further preferred are phenyl, pyridyl, naphthyl,
  • M4 is selected from C
  • M5 is selected from C; preferably Best
  • ring C" is selected from 5-membered heteroaryl and 5-membered heteroaryl, 5-membered heteroaryl and 6-membered heteroaryl, 6-membered heteroaryl and 6-membered heteroaryl, and more preferably
  • ring C' is selected from 6-membered heteroaryl, preferably pyrimidinyl or pyridinyl, preferably
  • the present invention also provides a compound represented by formula (INT), a stereoisomer thereof or a pharmaceutically acceptable salt thereof
  • R int is selected from halogen, boronic acid or boronic ester, preferably Cl, Br or
  • M 1 , M 13 , M 14 , M 15 , Ring B, R 3 , R 4 , R 5 , R 6 , R 8 , R 9-1 , R 9-2 , u, w, z and a are as defined above.
  • the present invention also provides a method for preparing a compound of formula (A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (INT-1) with a compound of formula (INT) to obtain a compound of formula (II).
  • R int is selected from halogen, boric acid or boric ester, preferably Cl, Br or
  • R int1 is selected from halogen, boronic acid or boronic ester, preferably Cl, Br or
  • the reaction is carried out in the presence of a base and a catalyst, the base is an organic base or an inorganic base, and the catalyst is a palladium catalyst;
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of the compound, its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the weight percentage of the compound, its stereoisomer or pharmaceutically acceptable salt thereof in the composition is 0.1% to 95%, preferably 0.5% to 85%, more preferably 1% to 60%, further preferably 10% to 50%, further preferably 15-40%, further preferably 20-30%, further preferably 20-25% (based on the total weight of the pharmaceutical composition).
  • the compound, its stereoisomer or its pharmaceutically acceptable salt is administered at a dosage of 1 mg-1000 mg, for example, 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg (or any integer therebetween).
  • the present invention further relates to the use of the compound, its stereoisomer or its pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of TNF ⁇ inhibitor drugs.
  • the present invention further relates to the use of the compound, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for treating an autoimmune disease, wherein the autoimmune disease is preferably selected from rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, psoriasis, Crohn's disease, ulcerative colitis, psoriasis, spondyloarthritis, plaque psoriasis, septic shock, ankylosing spondylitis, juvenile idiopathic arthritis, hidradenitis suppurativa or uveitis.
  • the autoimmune disease is preferably selected from rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, psoriasis, Crohn's disease, ulcerative colitis, psoriasis, spondyloarthritis, plaque psoriasis, septic shock, ankylosing
  • the present invention also relates to a method for preventing and/or treating autoimmune diseases, which comprises administering a therapeutically effective dose of the compound, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition to a patient.
  • the autoimmune disease is selected from rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, psoriasis, Crohn's disease, ulcerative colitis, psoriasis, spondyloarthritis, plaque psoriasis, septic shock, ankylosing spondylitis, juvenile idiopathic arthritis, hidradenitis suppurativa, uveitis, systemic lupus erythematosus (lupus), axial spondyloarthritis, polymyositis, pemphigus, multiple sclerosis, neuromyelitis optica, primary biliary cholangitis, autoimmune hepatitis, lupus nephritis, Goodpasture's syndrome, autoimmune oophoritis, or autoimmune orchitis.
  • alkyl refers to a straight or branched saturated aliphatic hydrocarbon group, which may be optionally substituted with one or more substituents.
  • the alkyl group refers to a straight chain saturated hydrocarbon group having 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 12 (C 1-12 ), 1 to 10 (C 1-10 ), 1 to 8 (C 1-8 ), 1 to 6 (C 1-6 ) or 1 to 3 (C 1-3 ) carbon atoms, or a branched saturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms.
  • C 1-6 alkyl refers to a linear saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group having 3 to 6 carbon atoms.
  • the C 1-6 alkyl contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) carbon atoms.
  • Non-limiting examples include 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-methylpropyl, 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,
  • alkylene refers to an alkyl group in which one hydrogen atom is further substituted, wherein “alkyl” is as defined above.
  • alkylene include: methylene ( -CH2- ), ethylene (-( CH2 ) 2- ), propylene (-( CH2 ) 3- ) or butylene (-( CH2 ) 4- ).
  • the alkylene is an optionally substituted alkyl group as described elsewhere herein.
  • alkenyl refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon double bond and the carbon-carbon double bond can be located at any position within the alkenyl group, and the alkenyl group can be optionally substituted with one or more substituents.
  • the alkenyl group is a straight chain unsaturated hydrocarbon group having 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2- 8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 ) carbon atoms, or having 3 to 20 (C 3-20 ), 3 to 15 (C 3-
  • alkenyl as used herein includes both straight-chain and branched alkenyl groups, unless otherwise specified.
  • a C 2-6 alkenyl group refers to a straight-chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms.
  • the C 2-6 alkenyl group contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms.
  • alkenyl groups include: One of ordinary skill in the art will appreciate that the term “alkenyl” may also include groups having "cis” and “trans” configurations, or alternatively, groups having "E” and "Z” configurations.
  • the alkenyl is an optionally substituted alkenyl described elsewhere herein.
  • alkynyl refers to a straight or branched unsaturated aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, and the carbon-carbon triple bond may be located at any position within the alkynyl group, and the alkynyl group may be optionally substituted with one or more substituents.
  • the alkynyl group is a straight chain unsaturated hydrocarbon group having 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 12 (C 2-12 ), 2 to 10 (C 2-10 ), 2 to 8 (C 2-8 ), 2 to 6 (C 2-6 ) or 2 to 4 (C 2-4 ) carbon atoms, or a branched unsaturated hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 12 (C 3-12 ), 3 to 10 (C 3-10 ) , 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms.
  • alkynyl as used herein includes both straight chain and branched chain alkynyl groups.
  • C2-6 alkynyl refers to a straight chain unsaturated hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated hydrocarbon group having 3 to 6 carbon atoms.
  • the C2-6 alkynyl contains 2 to 6 (e.g., 2, 3, 4, 5, 6) carbon atoms.
  • Non-limiting examples of alkynyl include:
  • the alkynyl group is an optionally substituted alkynyl group described elsewhere herein.
  • cycloalkyl refers to a saturated or partially unsaturated aliphatic hydrocarbon monocyclic, polycyclic (two or more) cyclic group, which may be optionally substituted by one or more substituents.
  • the cycloalkyl ring contains 3 to 20 (C 3-20 ), 3 to 12 (C 3-12 ), 3 to 8 (C 3-8 ) or 3 to 6 (C 3-6 ) carbon atoms; in one embodiment, the cycloalkyl ring contains 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) carbon atoms; it may contain one or more double bonds, but does not have a completely conjugated ⁇ electron system.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl or cyclooctyl, etc.; polycyclic cycloalkyls include spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl in one embodiment.
  • the cycloalkyl is an optionally substituted cycloalkyl or a cycloalkyl optionally fused to a heterocyclyl, aryl or heteroaryl group as described elsewhere herein, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like.
  • spirocycloalkyl refers to an aliphatic hydrocarbon polycyclic group in which a carbon atom (called a spiro atom) is shared between single rings, which may contain one or more double bonds, but none of the rings has a completely conjugated ⁇ electron system.
  • the spirocycloalkyl contains 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) (e.g., 7, 8, 9, 10) carbon atoms.
  • the spirocycloalkyl is divided into a monospirocycloalkyl, a bispirocycloalkyl or a polyspirocycloalkyl, and in one embodiment, it is a monospirocycloalkyl and a bispirocycloalkyl. In one embodiment, it is 4 yuan/4 yuan, 3 yuan/5 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan monospirocycloalkyl. In one embodiment, the spirocycloalkyl is an optionally substituted spirocycloalkyl described elsewhere herein. Non-limiting examples of spirocycloalkyl include:
  • fused cycloalkyl refers to a full carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system.
  • the fused cycloalkyl comprises 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7- 10 ) (e.g., 7, 8, 9, 10) carbon atoms.
  • the number of constituent rings it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, in one embodiment, a bicyclic or tricyclic, and further in one embodiment, a 3 yuan/5 yuan, 4 yuan/5 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan bicyclic alkyl.
  • the fused cycloalkyl is an optionally substituted fused cycloalkyl described elsewhere herein or a fused cycloalkyl optionally fused to a heterocyclic radical, an aryl or a heteroaryl.
  • fused cycloalkyl include:
  • bridged cycloalkyl refers to a full carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system.
  • the bridged cycloalkyl contains 5 to 20 (C 5-20 ), 6 to 14 (C 6-14 ) or 7 to 10 (C 7-10 ) (e.g., 7, 8, 9, 10) carbon atoms.
  • the bridged cycloalkyl is an optionally substituted bridged cycloalkyl described elsewhere herein.
  • Non-limiting examples of bridged cycloalkyl include:
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, wherein the nitrogen, phosphorus or sulfur atom may be optionally oxidized, the nitrogen atom may be optionally quaternized, the ring carbon atoms may be optionally substituted by oxygen, but does not include the ring part of -OO-, -OS-, and the remaining ring atoms are carbon, which may contain one or more double bonds, but does not have a completely conjugated ⁇ electron system.
  • the heterocyclyl contains 3 to 20, 3 to 12, 3 to 8 or 3 to 6 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heterocyclyl contains 3 to 6, 4 to 6, 3 to 8, 3 to 10, 6 to 10 or 7 to 11 ring atoms; in one embodiment, the heterocyclyl contains 3 to 6, 4 to 6, 3 to 8, 3 to 10, 6 to 10 or 7 to 11 ring atoms; In the embodiment of the present invention, heterocyclic radical comprises 3 to 8 (for example 3, 4, 5, 6, 7, 8) ring atoms.
  • monocyclic heterocyclic radical include tetrahydropyrrolyl, azetidinyl, oxetanyl, oxacyclohexane, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyr
  • spiroheterocyclyl refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between the rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon, which may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system.
  • the spiroheterocyclyl contains 5 to 20 or 6 to 14 ring atoms; in one embodiment, it contains 7 to 11 (e.g., 7, 8, 9, 10, 11) ring atoms; according to the number of spiro atoms shared between the rings, the spiroheterocyclyl is divided into a monospiroheterocyclyl, a bispiroheterocyclyl or a polyspiroheterocyclyl; preferably a monospiroheterocyclyl and a bispiroheterocyclyl; in one embodiment, the spiroheterocyclyl is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl; in one embodiment, the spiroheterocyclyl is an optionally substituted s
  • fused heterocyclic group refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon.
  • the fused heterocyclic group is a heterocyclic group containing 5 to 20 or 6 to 14 ring atoms, and in one embodiment contains 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; according to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group; preferably a bicyclic or tricyclic group; in one embodiment, it is a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group; in one embodiment, the fused heterocyclic group is a fused heterocyclic group described elsewhere herein that is optionally substituted or fused with a cycloalkyl, heterocyclic, aryl or heteroaryl group; non-limiting examples of fused heterocyclic groups include:
  • bridged heterocyclic group refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a completely conjugated ⁇ electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, boron, phosphorus or sulfur, and the remaining ring atoms are carbon.
  • the bridged heterocyclic group contains 5 to 20 or 6 to 14 ring atoms; in one embodiment, it contains 7 to 10 (e.g., 7, 8, 9, 10) ring atoms; according to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group; preferably a bicyclic, tricyclic or tetracyclic group; in one embodiment, it is a bicyclic or tricyclic group; in one embodiment, the bridged heterocyclic group is an optionally substituted bridged heterocyclic group described elsewhere herein; non-limiting examples of bridged heterocyclic groups include:
  • aryl refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group containing at least one conjugated ⁇ electron system, which may be optionally substituted by one or more substituents.
  • the aryl group contains 6 to 20, 6 to 14, or 6 to 10 ring atoms; in one embodiment, the aryl group may further refer to a bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring is an aromatic ring, and the other rings may be saturated, partially unsaturated carbon rings, or rings containing one or more heteroatoms independently selected from O, S, and N; in one embodiment, the aryl group is selected from a benzo 5-10 membered heteroaryl, a benzo 3-10 membered cycloalkyl, or a benzo 3-10 membered heterocyclyl.
  • the aryl group is selected from a benzo 5-6 membered heteroaryl, a benzo 3-6 membered cycloalkyl, or a benzo 3-6 membered heterocyclyl, wherein the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms.
  • Non-limiting examples include phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl, terphenyl, dihydronaphthyl, indenyl, tetrahydronaphthyl (tetralinyl),
  • arylene group refers to a divalent aromatic group formed by further replacing one hydrogen atom of an aromatic group, wherein the arylene group is optionally substituted or unsubstituted, and the aromatic group is as defined above.
  • heteroaryl refers to an optionally substituted monocyclic, polycyclic group or ring system containing at least one aromatic ring, wherein The aromatic ring has one or more heteroatoms independently selected from O, S and N.
  • the heteroaryl group contains 5 to 20, 5 to 15 or 5 to 10 ring atoms, of which 1 to 4 are heteroatoms; in one embodiment, the heteroaryl group contains 5 or 6 ring atoms; in a specific embodiment, the heteroaryl group may further refer to a bicyclic, tricyclic or tetracyclic ring, wherein at least one ring is an aromatic ring having one or more heteroatoms independently selected from O, S and N, and the other rings may be saturated, partially unsaturated carbocyclic rings or rings containing one or more heteroatoms independently selected from O, S and N.
  • the heteroaryl group is selected from heteroaryl and 6-10 membered aryl, heteroaryl and 3-10 membered cycloalkyl or heteroaryl and 3-10 membered heterocyclyl; further in one embodiment, the heteroaryl group is selected from 5- or 6-membered heteroaryl and 6-10 membered aryl, 5- or 6-membered heteroaryl and 3-6 membered cycloalkyl, 5- or 6-membered heteroaryl and 3-6 membered heterocyclyl, wherein the heterocyclyl group is a heterocyclyl group containing 1-3 nitrogen atoms, oxygen atoms or sulfur atoms.
  • Non-limiting examples include furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiophenyl, benzothiophenyl, benzotriazolyl, imidazopyridinyl, imidazothiazolyl , indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothiophenyl, isoindolyl, isoquinolyl, nap
  • heteroarylene refers to a divalent heteroaryl group formed by further replacing one hydrogen atom of a cycloalkyl group, wherein the heteroarylene group is optionally substituted or unsubstituted, and the heteroaryl group is as defined above.
  • heteroalkyl refers to a stable straight or branched chain, or cyclic hydrocarbon group, or a combination thereof, consisting of the indicated number of carbon atoms and one or more (in one embodiment, one to three) heteroatoms selected from O, N, Si, and S, and wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom may be optionally quaternized.
  • the heteroatoms O, N, and S may be placed at any interior position of the heteroalkyl group.
  • the heteroatom Si may be placed at any position (e.g., interior or terminal position) of the heteroalkyl group, including the position where the alkyl group is attached to the remainder of the molecule.
  • heteroalkyl group is an optionally substituted heteroalkyl group described elsewhere herein. alkyl.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy.
  • the alkoxy is an optionally substituted alkoxy described elsewhere herein.
  • alkylacyl refers to a -C(O)-alkyl group wherein alkyl is as previously defined.
  • haloalkyl refers to an alkyl group substituted by one or more halogens, wherein the definition of alkyl is the same as above.
  • Non-limiting examples of the haloalkyl group include: trifluoromethyl, -CH 2 CF 3 ,
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen groups, wherein alkoxy is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • alkylthio refers to -S-(alkyl) and -S-(unsubstituted cycloalkyl), wherein alkyl or cycloalkyl are as defined above.
  • alkylthio include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio or cyclohexylthio.
  • the alkylthio is an optionally substituted alkylthio described elsewhere herein.
  • haloalkylthio refers to an alkylthio group substituted by one or more halogens, wherein alkylthio is as defined above.
  • alkenylcarbonyl refers to -C(O)-(alkenyl), wherein alkenyl is as defined above.
  • alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, or butenylcarbonyl.
  • the alkenylcarbonyl is an optionally substituted alkenylcarbonyl described elsewhere herein.
  • aminocarbonyl refers to NH2 - C(O)-.
  • alkylaminocarbonyl refers to an aminocarbonyl (NH2 - C(O)-) group in which one or both of the two hydrogen atoms are replaced by an alkyl group, wherein the alkyl group has the same definition as above.
  • alkylamino refers to an amino group in which one or both of the two hydrogen atoms are replaced by an alkyl group, wherein the alkyl group has the same definition as above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • acetyl refers to -C(O) CH3 .
  • thiol refers to -SH.
  • NaBH(OAc) 3 refers to sodium triacetoxyborohydride.
  • hydrogen includes protons ( 1H ), deuterium ( 2H ), tritium ( 3H ) and/or mixtures thereof.
  • one or more positions occupied by hydrogen in the compound may be enriched with deuterium and/or tritium.
  • isotopically enriched analogs may be prepared by appropriately isotopically labeled starting materials obtained from commercial sources or by known literature procedures.
  • alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, arylene, heteroaryl, heteroarylene, heteroalkyl, alkoxy, alkylthio, hydroxyalkyl, alkenylcarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylamino, alkylacyl may be substituted or unsubstituted.
  • the substituent is selected from one or more of the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, alkylacyl, halogen, thiol, hydroxyl, nitro, cyano, azido, oxime, phosphate, oxo, thio, carboxyl, carboxylate, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocycloalkyloxy, cycloalkylthio or heterocycloalkylthio.
  • 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.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.
  • linking substituents are described.
  • the Markush variable listed for that group should be understood as a linking group.
  • the Markush group definition for that variable lists “alkyl” or “aryl”, it should be understood that the "alkyl” or “aryl” represents an alkylene group or an arylene group, respectively, that is linked.
  • Substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable in one embodiment. In one embodiment.
  • optionally substituted means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituent may be arbitrary on the basis of chemical realization. It goes without saying that the substituent is only in their possible chemical position, and those skilled in the art can determine (by experiment or theory) possible or impossible substitution without paying too much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.
  • Steps encompass all enantiomerically/diastereomerically/stereomerically pure and enantiomerically/diastereomerically/stereomerically enriched forms of the compounds of the invention.
  • Stepomerically pure refers to a composition comprising one stereoisomer of a compound and being substantially free of another stereoisomer of the compound.
  • a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
  • a stereomerically pure composition of a compound having two chiral centers will be substantially free of the other diastereomer of the compound.
  • a typical stereomerically pure compound will contain greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomer of the compound, and greater than about 20% by weight of the other stereoisomer of the compound.
  • the invention relates to a compound having a content of one stereoisomer of the compound greater than about 90% by mass and less than about 10% by mass of another stereoisomer of the compound, a content of one stereoisomer of the compound greater than about 95% by mass and less than about 5% by mass of another stereoisomer of the compound, a content of one stereoisomer of the compound greater than about 97% by mass and less than about 3% by mass of another stereoisomer of the compound, or a content of one stereoisomer of the compound greater than about 99% by mass and less than about 1% by mass of another stereoisomer of the compound.
  • Stepoisomerically enriched refers to a composition comprising greater than about 55% by weight, greater than about 60% by weight, greater than about 70% by weight, or greater than about 80% by weight of one stereoisomer of a compound.
  • Enantiomerically pure refers to a stereomerically pure composition of a compound having one chiral center.
  • enantiomerically enriched refers to a stereomerically enriched composition of a compound having one chiral center.
  • Optically active and “enantiomeric activity” refer to a combination of molecules having an enantiomeric or diastereomeric excess of not less than about 50%, not less than about 70%, not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%.
  • the compound comprises about 95% or more of the desired enantiomer or diastereomer and about 5% or less of the less preferred enantiomer or diastereomer, based on the total weight of the racemate.
  • the prefixes R and S are used to denote the absolute configuration of the molecule with respect to its chiral center. (+) and (-) are used to denote the optical rotation of the compound, i.e., the direction of the plane of polarized light rotated by the optically active compound.
  • the prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise.
  • the prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise.
  • the signs (+) and (-) of the optical rotation have nothing to do with the absolute configuration, R and S, of the molecule.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS).
  • NMR chemical shift ( ⁇ ) is given in parts per million (ppm).
  • the NMR measurement is performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard is tetramethylsilane (TMS).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CD 3 OD deuterated methanol
  • CDCl 3 deuterated chloroform
  • TMS tetramethylsilane
  • LC-MS Liquid chromatography-mass spectrometry
  • Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
  • the specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography 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 can be purchased on the market, or can be synthesized by or according to methods known in the art.
  • Step 1 Preparation of (1s,3s)-3-(5-bromopyrimidin-2-yl)-3-hydroxy-1-methylcyclobutane-1-carbonitrile
  • reaction solution was extracted with DCM (150 mL x 3), washed with saturated sodium chloride aqueous solution (200 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography and chiral column separation to obtain the title compound (1.5 g, 10.2%).
  • Example 1 can also be synthesized according to the following steps:
  • Step 3 Preparation of N-((R)-1-(2-bromo-6-(difluoromethoxy)phenyl)but-3-en-1-yl)-2-methylpropane-2-sulfenamide
  • reaction solution was stirred at 80°C for 12 hours, and after returning to room temperature, the reaction solution was diluted with EA, and the organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by silica gel column chromatography to obtain the title compound (560g, 89%). MS m/z(ESI):447.0[M+H] + .
  • Step 6 Preparation of (R)-3-(2-bromo-6-(difluoromethoxy)phenyl)-3-((5-chloro-2-nitrophenyl)amino)propanal
  • Step 7 Preparation of (4R)-4-(2-bromo-6-(difluoromethoxy)phenyl)-4-((5-chloro-2-nitrophenyl)amino)-2-((trimethylsilyl)oxy)butyronitrile
  • Step 8 Preparation of (1R,3S)-1-(2-bromo-6-(difluoromethoxy)phenyl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol
  • Step 9 Preparation of (1R,3r)-1-(2-bromo-6-(difluoromethoxy)phenyl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-amine
  • the above liquid was dissolved in water (20 mL) and THF (100 mL), triphenylphosphine (8.70 g, 33.2 mmol) was added at room temperature, and the reaction solution was stirred at 60°C for 4 hours.
  • Step 10 Preparation of (7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazoin-5(14H)-one
  • reaction solution was replaced with dry carbon monoxide three times, the temperature was raised to 130°C and stirred for 12 hours.
  • the reaction solution was diluted with EA and washed with saturated sodium chloride.
  • the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 11 Preparation of (7R,14R)-11-chloro-1-(difluoromethoxy)-6-((1-fluorocyclopropyl)methyl)-6,7-dihydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazin-5(14H)-one
  • Step 2 Preparation of (R)-N-(1-(5-bromopyrimidin-2-yl)-3-(fluoromethyl)cyclobutyl)-2-methylpropane-2-sulfenamide
  • Step 4 Preparation of (7R,14R)-1-(difluoromethoxy)-6-methyl-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacin-5(14H)-one
  • Step 5 Preparation of (R)-N-(1-(5-((7R,14R)-1-(difluoromethoxy)-6-methyl-5-carbonyl-5,6,7,14-tetrahydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacin-11-yl)pyrimidin-2-yl)-3-(fluoromethyl)cyclobutyl)-2-methylpropane-2-sulfenamide
  • Step 6 Preparation of (7R,14R)-11-(2-(1-amino-3-(fluoromethyl)cyclobutyl)pyrimidin-5-yl)-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methylenebenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diacin-5(14H)-one
  • 5-bromo-2,2-difluorobenzo[d][1,3]dioxazole (10 g, 42.2 mmol) was dissolved in a dry THF (100 mL) solution, LDA (31.6 mL, 63.3 mmol) was added dropwise and stirred for 1 hour, and dry DMF (4.9 mL, 63.3 mmol) was added dropwise and stirred for 1 hour.
  • Step 2 Preparation of (S,E)-N-((5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)methylene)-2-methylpropane-2-sulfenamide
  • Step 3 Preparation of N-((R)-1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)but-3-en-1-yl)-2-methylpropane-2-sulfenamide
  • Step 5 Preparation of (R)-N-(1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)but-3-en-1-yl)-5-chloro-2-nitroaniline
  • Step 6 Preparation of (R)-3-(5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)-3-((5-chloro-2-nitrophenyl)amino)propanal
  • Step 7 (4R)-4-(5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)-4-((5-chloro-2-nitrophenyl)amino)-2-((trimethyl Preparation of (1-(2-((1 ...-((
  • Step 8 Preparation of (1R,3S)-1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-ol
  • Step 9 Preparation of (1R,3R)-1-(5-bromo-2,2-difluorobenzo[d][1,3]dioxazol-4-yl)-7-chloro-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-amine
  • reaction solution was returned to room temperature, extracted with EtOAc (15 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue and PPh 3 (576 mg, 2.2 mmol) were dissolved in a mixed solvent of THF (10 mL) and water (10 mL), and stirred at 60°C for 1 hour.
  • the reaction solution was returned to room temperature, extracted with EtOAc (15 mL x 3), washed with saturated sodium chloride aqueous solution (20 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography The title compound (477 mg, 74.2%) was obtained after purification.
  • Step 10 Preparation of (8R,15R)-12-chloro-2,2-difluoro-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazacin-6(15H)-one
  • Step 11 Preparation of (8R,15R)-12-chloro-2,2-difluoro-7-methyl-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazacin-6(15H)-one
  • reaction solution was extracted with EtOAc (15 mL x 3), washed with saturated sodium chloride aqueous solution (20 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by silica gel column chromatography to obtain the title compound (87 mg, 84%).
  • Step 12 Preparation of N-(1-(5-((8R,15R)-2,2-difluoro-7-methyl-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacin-12-yl)pyrimidin-2-yl)cyclobutyl)-2-methylpropane-2-sulfenamide
  • reaction solution was returned to room temperature, extracted with EtOAc (30mL x 3), washed with saturated sodium chloride aqueous solution (20mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography to obtain the title compound (100mg, 74.8%).
  • Step 13 Preparation of (8R,15R)-12-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-2,2-difluoro-7-methyl-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazacin-6(15H)-one
  • Step 1 Preparation of (8R,15R)-12-chloro-2,2-difluoro-7-(methyl-d 3 )-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazin-6(15H)-one
  • Step 2 Preparation of (8R,15R)-2,2-difluoro-7-(methyl-d 3 )-12-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazacin-6(15H)-one
  • Step 3 (1S,3S)-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d 3 )-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacin-12-yl)pyrimidin-2-yl)-3-hydroxy-1-methyl
  • Step 1 Preparation of (8R,15R)-2,2-difluoro-7-methyl-12-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacin-6(15H)-one
  • Step 2 Preparation of N-((1s,3S)-1-(5-((8R,15R)-2,2-difluoro-7-methyl-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacin-12-yl)pyrimidin-2-yl)-3-(fluoromethyl)cyclobutyl)-2-methylpropane-2-sulfenamide
  • Step 3 Preparation of (8R,15R)-12-(2-((1s,3S)-1-amino-3-(fluoromethyl)cyclobutyl)pyrimidin-5-yl)-2,2-difluoro-7-methyl-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacin-6(15H)-one
  • Example 235 The preparation of Example 235 is based on Example 85, and can also be synthesized according to the following steps:
  • Step 1 Preparation of tert-butyl (1-(5-bromopyrimidin-2-yl)cyclopropyl)carbamate
  • Step 2 Preparation of tert-butyl (1-(5-((8R,15R)-2,2-difluoro-7-methyl-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacin-12-yl)pyrimidin-2-yl)cyclopropyl)carbamate
  • Step 3 Preparation of (8R,15R)-12-(2-(1-aminocyclopropyl)pyrimidin-5-yl)-2,2-difluoro-7-methyl-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazacin-6(15H)-one
  • Example 307 The preparation of Example 307 is based on Example 85, and can also be synthesized according to the following steps:
  • Step 6 Preparation of N-(1-(5-((7R,14R)-15-(difluoromethoxy)-6-methyl-5-carbonyl-5,6,7,14-tetrahydro-7,14-methylene[1,3]dioxazolo[4',5':4,5]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacin-11-yl)pyrimidin-2-yl)cyclobutyl)-2-methylpropane-2-sulfenamide
  • Step 7 Preparation of (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-15-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methylene[1,3]dioxazolo[4',5':4,5]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacin-5(14H)-one
  • Example 544 The preparation of Example 544 is based on Example 85, and can also be synthesized according to the following steps:
  • Step 1 Preparation of (8R,15R)-12-(6-acetyl-5-fluoropyridin-3-yl)-2,2-difluoro-7-methyl-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diazacin-6(15H)-one
  • reaction solution was replaced with nitrogen three times and heated to 110°C in a microwave oven for 1 hour.
  • Step 7 Preparation of N-((1s,3S)-1-(5-((8R,15R)-2,2-difluoro-7-(methyl-d 3 )-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacin-12-yl)pyrimidin-2-yl)-3-methoxy-3-methylcyclobutyl)-2-methylpropane-2-sulfenamide
  • Step 8 Preparation of (8R,15R)-12-(2-((1s,3S)-1-amino-3-methoxy-3-methylcyclobutyl)pyrimidin-5-yl)-2,2-difluoro-7-(methyl-d 3 )-7,8-dihydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacin-6(15H)-one
  • Step 1 Preparation of (1s,3s)-3-(5-bromopyrimidin-2-yl)-1-(fluoromethyl)-3-hydroxycyclobutanecarbonitrile
  • n-BuLi 2.5M, 18.9mL was added dropwise to a solution of 5-bromo-2-iodo-pyrimidine (13.45g, 47.20mmol) and 1-(fluoromethyl)-3-carbonylcyclobutanecarbonitrile (5g, 39.33mmol) in DCM (200mL), and the temperature was slowly raised to -10°C (the heating process lasted for 0.5 hours).
  • Step 2 Preparation of (1s,3s)-1-(5-bromopyrimidin-2-yl)-3-cyano-3-(fluoromethyl)cyclobutyl 4-methylbenzenesulfonate
  • Step 3 Preparation of (1r,3r)-3-azido-3-(5-bromopyrimidin-2-yl)-1-(fluoromethyl)cyclobutanecarbonitrile
  • Step 4 Preparation of (1r,3r)-3-amino-3-(5-bromopyrimidin-2-yl)-1-(fluoromethyl)cyclobutanecarbonitrile
  • Step 5 Preparation of (1R,3r)-3-amino-3-(5-((8R,15R)-2,2-difluoro-7-(methyl-d 3 )-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacin-12-yl)pyrimidin-2-yl)-1-(fluoromethyl)cyclobutane-1-carbonitrile
  • Step 2 Preparation of (S)-N-((1s,3R)-1-(5-bromopyrimidin-2-yl)-3-cyano-3-methylcyclobutyl)-2-methylpropane-2-sulfenamide
  • Step 3 Preparation of N-((1s,3S)-3-cyano-1-(5-((8R,15R)-2,2-difluoro-7-(methyl-d 3 )-6-carbonyl-6,7,8,15-tetrahydro-8,15-methylene[1,3]dioxazolo[4',5':3,4]benzo[1,2-f]benzo[4,5]imidazo[1,2-a][1,4]diacin-12-yl)pyrimidin-2-yl)-3-methylcyclobutyl)-2-methylpropane-2-sulfenamide
  • the compounds of the embodiments of the present invention showed a strong binding effect on the TNF ⁇ protein in the experiment of thermal shift effect on the TNF ⁇ protein and in the experiment of the effect on the binding of the TNF ⁇ protein to the TNFR1 receptor.
  • HepG2 cells were cultured in complete medium at 37°C, 5% CO2 until they were 70% to 90% confluent.
  • IC 50 was calculated by using Graph pad four-parameter log (inhibitor) vs. response--Variable slope (four parameters) to fit the compound concentration and the corresponding inhibition rate and reverse nonlinear fitting.
  • Test Example 2 Detection of the inhibitory effect of the compounds of the present invention on the release of IL-8 from hPBMC stimulated by TNF
  • hPBMC (Saili, XFB-HP010B), PBS (Gibco, 10010023), DMSO (Sigma: D2650), TNFa (MCE: HY-P7085), RPMI1640 medium (Gibco, 22400-105), FBS serum (Gibco, 30067-334), Pen strep double antibody (Gibco, 15140-122), cell culture plate (Corning: 3599), Human IL-8/CXCL8 DuoSet ELISA (RD, DY208-05), DuoSet ELISA Ancillary Reagent Kit 2 (RD, DY008B), 1200uL 12-channel electronic pipette (Eppendorf, J51515K)
  • IC 50 was calculated by using XLfit four-parameter log (inhibitor) vs. response--Variable slope (four parameters) to fit the compound concentration and the corresponding inhibition rate and nonlinear fitting.
  • mice were used as test animals to study the pharmacokinetic behavior of the compounds of the present invention in the plasma of mice at a dose of 30 mg/kg after oral administration.
  • Test drugs Compounds of the present invention, homemade.
  • mice Male Balb/C mice were fasted overnight and administered orally at a dose of 30 mg/kg in a volume of 10 mL/kg.
  • Mass spectrometry conditions AB Sciex API 4000 mass spectrometer
  • Liquid A is 0.1% formic acid aqueous solution
  • Liquid B is methanol Flow rate: 1mL/min
  • test compound was prepared into a 10 mM stock solution with DMSO (or other suitable solution) and stored in a -20°C refrigerator until use.
  • Cimetidine, Metoprolol, Erythromycin were prepared into 10 mM stock solutions for later use.
  • Caco-2 cells were purchased from the American Type Culture Collection (ATTC), PBS (Gibco, pH 7.4), HBSS (Thermo Fisher), DMEM medium (Gibco), Lucifer Yellow (Sigma), and HEPES (Solarbio).
  • Caco-2 cells are a type of human colon cancer cell. When cultured in vitro under specific conditions, they can form tight junctions and differentiate into cell layers similar in morphology and function to human small intestinal cells. Because they express multiple types of transporters, an in vitro model for studying drug absorption by small intestinal epithelial cells can be constructed. Using the Caco-2 cell permeability model, drugs are added to the basolateral and basolateral sides of the cell monolayer to measure the bidirectional permeability of the compound. At the same time, because the basolateral side of the cell expresses efflux transporters, the efflux ratio can be used to preliminarily evaluate whether the compound is an efflux substrate.
  • Preparation of compound working solution Preparation of compound working solution: Add 1 ⁇ L of compound stock solution to 999 ⁇ L of fluorescent yellow working solution, the final concentration is 10 ⁇ M. According to the properties of the compound, the configuration ratio can be adjusted appropriately to adjust the final concentration. Preparation of control compound working solution: Keep the same preparation process as the compound.
  • reaction stop solution dilute the internal standard with acetonitrile (or other suitable solution) to make the stop solution and store it in a refrigerator at 2-8°C.
  • Mobile phase A: 0.1% formic acid in water; B: 0.1% formic acid in acetonitrile
  • Washing gradient 0 ⁇ 0.7min 5%A to 95%A, 1.2 ⁇ 1.5min 95%A to 5%A;
  • Ion source electrospray ionization source (ESI); drying gas: N2, temperature 420°C; electrospray voltage: 5500V;
  • Detection method positive ion detection; Scanning method: reaction monitoring (MRM) method;
  • the in vivo efficacy of the compounds was evaluated in a collagen antibody-induced arthritis model in mice.
  • mice 8-10 weeks old, ⁇ , were purchased from the Experimental Animal Management Department of Shanghai Institute of Family Planning Science.
  • test drug was administered (administration method: oral administration; administration volume: 10 mL/kg; administration frequency: QD/BID; administration cycle: 7 days; solvent: 0.5% CMC-Na/1% Tween);
  • mice were weighed and their paws were scored for CAIA arthritis every day (scoring from D2 to D7); CAIA clinical scoring criteria (the total score is the sum of the four paws, with a total score of 0-16)
  • TGI (%) [1-(mean arthritis score at the end of a compound administration group/mean arthritis score at the end of a vehicle control group)] ⁇ 100%.
  • the compounds of the present invention can effectively improve arthritis symptoms, and the animals have good tolerance at the therapeutic dose.
  • Oral administration of the compounds of the present invention (30 mg/kg, BID) has a relative therapeutic rate of 55% to 95% according to the D7 score, and the relative therapeutic rate of some compounds is 70% to 90%.
  • Experimental drugs compounds of the present invention, homemade, Alamethicin (Abcam), 7-Hydroxycoumarin (Sigma), liver microsomes (XenoTech, Shanghai Quanyang Biotechnology Co., Ltd.), phosphate buffer (Gibco, Lot#SLBS7904 and Lot#SLBR3106V, pH 7.4), NADPH (reduced nicotinamide adenine dinucleotide phosphate, Shanghai BiDe Pharmaceutical Technology Co., Ltd.), UDPGA (Sigma), Alamethicin (Abcam), methanol (Merck), acetonitrile (Merck).
  • the compound of the present invention is prepared into a 10 mM stock solution with DMSO (or other suitable solution) and stored in a -20°C refrigerator until use.
  • Control compound 7-Hydroxycoumarin was prepared as a 10 mM stock solution for use.
  • buffer solution 4.01 mL of 1M K 2 HPO 4 ⁇ 3H 2 O (AR grade) and 0.99 mL of 1M KH 2 PO 4 (AR grade) were dissolved in ultrapure water and the volume was adjusted to 50 mL to prepare a phosphate buffer solution with a final concentration of 100 mM.
  • Preparation of compound working solution Add 2 ⁇ L of compound stock solution to 998 ⁇ L of phosphate buffer, with a final concentration of 20 ⁇ M. Depending on the properties of the compound, the configuration ratio can be adjusted appropriately to adjust the final concentration.
  • Preparation of working solution of control compound keep the same preparation process as that of the compound.
  • liver microsome working solution 156.3 ⁇ L 20 mg/mL microsomes, dilute to 5 mL with 100 mM phosphate buffer, mix well, the final concentration is 0.625 mg/mL.
  • NADPH and UDPGA weigh 33.3 mg of NADPH and 25.8 mg of UDPGA, add 2 mL of 100 mM phosphate buffer, and the final concentration of both is 20 mM.
  • reaction stop solution dilute the internal standard with acetonitrile (or other suitable solution) to make the stop solution and store it in a refrigerator at 2-8°C.
  • Ion source electrospray ionization source (ESI); drying gas: N2, temperature 500°C;
  • the original data is calculated according to the following formula:
  • Residual rate % peak area ratio of compound to internal standard at any time point / peak area ratio of compound to internal standard at 0 minutes ⁇ 100

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Abstract

La présente invention concerne un inhibiteur de dérivé pentacyclique, son procédé de préparation et son utilisation. En particulier, la présente invention concerne un composé, son procédé de préparation, une composition pharmaceutique le contenant, et son utilisation en tant qu'inhibiteur dans le traitement de maladies auto-immunes.
PCT/CN2024/098249 2023-06-09 2024-06-07 Inhibiteur de dérivé pentacyclique, son procédé de préparation et son utilisation Pending WO2024251282A1 (fr)

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WO2025218735A1 (fr) * 2024-04-17 2025-10-23 上海翰森生物医药科技有限公司 Inhibiteur de dérivé pentacyclique, son procédé de préparation et son utilisation

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